Chapter 7

Use of psychotropic drugs in special patient groups

The elderly

General principles of prescribing in the elderly

The pharmacokinetics and pharmacodynamics of most drugs are altered to an important extent in the elderly. These changes in drug handling and action must be taken into account if treatment is to be effective and adverse effects minimised. The elderly often have a number of concurrent illnesses and may require treatment with several drugs. This leads to a greater chance of problems arising because of drug interactions and to a higher rate of drug-induced problems in general.1 It is reasonable to assume that all drugs are more likely to cause adverse effects in the elderly than in younger patients.

How drugs affect the ageing body (altered pharmacodynamics)

As we age, control over reflex actions such as blood pressure and temperature regulation is reduced. Receptors may become more sensitive. This results in an increased incidence and severity of side-effects. For example, drugs that decrease gut motility are more likely to cause constipation (e.g. anticholinergics and opioids) and drugs that affect blood pressure are more likely to cause falls (e.g. tricyclic antidepressants [TCAs] and diuretics). The elderly are more sensitive to the effects of benzodiazepines than younger adults. Therapeutic response can also be delayed; the elderly may take longer to respond to antidepressants than younger adults.2

The elderly may be more prone to develop serious side-effects from some drugs such as agranulocytosis3 and neutropenia4 with clozapine, stroke with antipsychotic drugs5 and bleeding with selective serotonin reuptake inhibitors (SSRIs).

How ageing affects drug therapy (altered pharmacokinetics)6

Absorption

Gut motility decreases with age, as does secretion of gastric acid. This leads to drugs being absorbed more slowly, resulting in a slower onset of action. The same amount of drug is absorbed as in a younger adult, but rate of absorption is slower.

Distribution

The elderly have more body fat, less body water and less albumin than younger adults. This leads to an increased volume of distribution and a longer duration of action for some fat-soluble drugs (e.g. diazepam), higher concentrations of some drugs at the site of action (e.g. digoxin) and a reduction in the amount of drug bound to albumin (increased amounts of active 'free drug', e.g. warfarin, phenytoin).

Metabolism

The majority of drugs are hepatically metabolised. Liver size is reduced in the elderly, but in the absence of hepatic disease or significantly reduced hepatic blood flow, there is no significant reduction in metabolic capacity. The magnitude of pharmacokinetic interactions is unlikely to be altered but the pharmacodynamic consequences of these interactions may be amplified.

Excretion

Renal function declines with age: 35% of function is lost by the age of 65 years and 50% by the age of 80.

More function is lost if there are concurrent medical problems such as heart disease, diabetes or hypertension. Measurement of serum creatinine or urea can be misleading in the elderly because muscle mass is reduced, so less creatinine is produced. It is particularly important that estimated glomerular filtration rate (eGFR)7 is used as a measure of renal function in this age group. It is best to assume that all elderly patients have at most two-thirds of normal renal function.

Most drugs are eventually (after metabolism) excreted by the kidney. A few do not undergo biotransformation first. Lithium and sulpiride are important examples. Drugs primarily excreted via the kidney will accumulate in the elderly, leading to toxicity and side-effects. Dosage reduction is likely to be required (see section on 'Renal impairment' in this chapter).

Drug interactions

Some drugs have a narrow therapeutic index (a small increase in dose can cause toxicity and a small reduction in dose can cause a loss of therapeutic action). The most commonly prescribed ones are: digoxin, warfarin, theophylline, phenytoin and lithium. Changes in the way these drugs are handled in the elderly and the greater chance of interaction with other drugs mean that toxicity and therapeutic failure are more likely. These drugs can be used safely but extra care must be taken and blood concentrations should be measured where possible. See Box 7.1.

Some drugs inhibit or induce hepatic metabolising enzymes. Important examples include some SSRIs, erythromycin and carbamazepine. This may lead to the metabolism of another drug being altered. Many drug interactions occur through this mechanism.

Box 7.1 Reducing drug-related risk in the elderly

Adherence to the following principles will reduce drug-related morbidity and mortality.

  • Use drugs only when absolutely necessary.
  • Avoid, if possible, drugs that block α1-adrenoceptors, have anticholinergic side-effects, are very sedative, have a long half-life or are potent inhibitors of hepatic metabolising enzymes.
  • Start with a low dose and increase slowly but do not undertreat. Some drugs still require the full adult dose.
  • Try not to treat the side-effects of one drug with another drug. Find a better-tolerated alternative.
  • Keep therapy simple; that is, once daily administration whenever possible.

Details of individual interactions and their consequences can be found in Appendix 1 of the BNF.8 Most can be predicted by a sound knowledge of pharmacology.

Administering medicines in foodstuffs9–11

Sometimes patients may refuse treatment with medicines, even when such treatment is thought to be in their best interests. Where the patient has a mental illness or has capacity, the Mental Health Act should be used, but if the patient lacks capacity, this option may not be desirable. Medicines should never be administered covertly to elderly patients with dementia without a full discussion with the multi-disciplinary team (MDT) and the patient's relatives. The outcome of this discussion should be clearly documented in the patient's clinical notes. Medicine should be administered covertly only if the clear and express purpose is to reduce suffering for the patient. For further information, see section on 'Covert administration of medicines within food and drink' in Chapter 8.

For advice on dosing of psychotropics in the elderly, see Table 7.1.

References

  1. Royal College of Physicians. Medication for older people. Summary and recommendations of a report of a working party. J R Coll Physicians Lond 1997; 31:254–257.
  2. Baldwin R et al. Management of depression in later life. Adv Psychiatr Treat 2004; 10:131–139.
  3. Munro J et al. Active monitoring of 12,760 clozapine recipients in the UK and Ireland. Beyond pharmacovigilance. Br J Psychiatry 1999; 175:576–580.
  4. O'Connor DW et al. The safety and tolerability of clozapine in aged patients: a retrospective clinical file review. World J Biol Psychiatry 2010; 11:788–791.
  5. Douglas IJ et al. Exposure to antipsychotics and risk of stroke: self controlled case series study. BMJ 2008; 337:a1227.
  6. Mayersohn M. Special pharmacokinetic considerations in the elderly. In: Evans WE, Schentag JJ, Jusko WJ, eds. Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring. Spokane, WA: Applied Therapeutics Inc; 1986. pp. 229–293.
  7. Morriss R et al. Lithium and eGFR: a new routinely available tool for the prevention of chronic kidney disease. Br J Psychiatry 2008; 193:93–95.
  8. Joint Formulary Committee. BNF 67 March-September 2014 (online). London: Pharmaceutical Press; 2014. http://www.medicinescomplete. com/mc/bnf/current/
  9. Royal College of Psychiatrists. College Statement on Covert Administration of Medicines. Psychiatr Bull 2004; 28:385–386.
  10. Haw C et al. Administration of medicines in food and drink: a study of older inpatients with severe mental illness. Int Psychogeriatr 2010; 22:409–416.
  11. Haw C et al. Covert administration of medication to older adults: a review of the literature and published studies. J Psychiatr Ment Health Nurs 2010; 17:761–768.

Further reading

National Service Framework for Older People. London: Department of Health; 2001.

Table 7.1 A guide to medication doses of commonly used psychotropics in older adults

Drug

Specific indication/additional notes

Starting dose

Usual maintenance dose

Maximum dose in elderly

Antidepressants

Agomelatine

Depression
Monitor LFTs
Data suggest agomelatine is not effective in patients > 75 years

25 mg nocte

25-50 mg daily

50 mg nocte

Citalopram

Depression/anxiety disorder

10 mg mane

10-20 mg mane

20 mg mane

Clomipramine

Depression/phobic and obsessional states

10 mg nocte
(dose increases should be cautious)

30-75 mg daily1 should be reached after about 10 days

75 mg daily*

Desvenlafaxine

No formal recommendations are available for dosing in older adults2

Duloxetine

Depression/anxiety disorder

30 mg daily*

60 mg daily

120 mg daily*
(caution as limited data in elderly for this dose)

Escitalopram

Depression/anxiety disorder

5 mg mane

5-10 mg mane

10 mg mane

Fluoxetine

Depression/anxiety disorder
Caution as long half-life and inhibitor of several CYP enzymes

20 mg mane

20 mg mane

40 mg mane usually
(but 60 mg can be used)

Lofepramine

Depression

35 mg nocte*

70 mg nocte*

140 mg nocte or in divided doses*
(occasionally 210 mg nocte required)

Mirtazapine

Depression

7.5 mg nocte or usually 15 mg nocte*

1 5-30mg nocte

45 mg nocte

Sertraline

Depression/anxiety disorder

25-50 mg mane
(25 mg can be increased to 50 mg mane after 1 week)

50-100 mg mane*

100 mg
(occasionally up to 150 mg mane)*

Trazodone

Depression

50 mg bd

100-200 mg daily*

300 mg daily4

Agitation in dementia
Avoid single doses > 100 mg

25 mg bd*

25-100 mg daily*

200 mg daily*
(in divided doses)

Venlafaxine

Depression/anxiety disorder
Monitor BP on initiation

37.5 mg mane (increased to 75 mg [ER] mane after 1 week)*

75-150 mg (ER) mane*

150 mg daily
(occasionally 225 mg daily necessary)*

Vortioxetine

Major depressive disorder

5-10 mg daily5

5-20 mg daily5

20 mg daily5

Antipsychotics

Amisulpride

Chronic schizophrenia

50 mg daily*

100-200 mg daily*

400 mg daily6
(caution > 200 mg daily)*

Late life psychosis

25-50mg daily*

50-100 mg daily*
(increase in 25 mg steps)

200 mg daily7
(caution > 100 mg daily)*

Agitation/psychosis in dementia
Caution QTc prolongation

25 mg nocte8

25-50mg daily8

50 mg daily8

Aripiprazole

Schizophrenia, mania (oral)

5 mg mane*

5-1 5 mg daily*

20 mg mane*

Control of agitation
(IM injection)

5.25 mg*

5.25-9.75 mg*

15 mg daily*
(combined oral + IM)

Clozapine

Schizophrenia

6.25-12.5 mg daily9,10
increased by no more than 6.25-12.5 mg once or twice a week9

50-100 mg daily9,10

100 mg daily9,10

Parkinson's related psychosis

6.25 mg daily11

25-37.5 mg daily11

50 mg daily11

lloperidone

No formal recommendations are available for dosing in older adults

Lurasidone

No formal recommendations are available for dosing in older adults

In elderly patients (55 to 85 years) lurasidone concentrations were similar to those in young subjects. It is unknown whether dose adjustment is necessary on the basis of age alone (but dose reduction required in moderate and severe renal impairment—see product information)12

Olanzapine

Schizophrenia

2.5 mg nocte*

5-10 mg daily*

15 mg nocte10

Agitation/psychosis in dementia

2.5 mg nocte*

2.5-10 mg daily*

10 mg nocte*
(optimal dose is 5 mg daily)10

Quetiapine

Schizophrenia

12.5-25 mg daily10

75-125 mg daily9

200-300 mg daily10

Agitation/psychosis in dementia

12.5-25 mg daily*

50-100 mg daily*

100-300 mg daily10

Risperidone

Psychosis

0.5 mg bd
(0.25-0.5 mg daily in some cases)10

1.0-2.5 mg daily9

4 mg daily

Late onset psychosis

0.5 mg daily*

1 mg daily*

2 mg daily*
(optimal dose is 1 mg daily)

Agitation/psychosis in dementia

0.25 mg daily* or bd

0.5 mg bd

2 mg daily
(optimal dose is 1 mg daily)10

Haloperidol

Psychosis

0.25-0.5 mg daily9

1.0-3.5 mg daily9

Caution > 3.5 mg - assess tolerability and ECG
Max 10 mg/day (oral)
Max 5 mg/day (IM)

Agitation
Avoid in older adults (except in delirium) owing to risk of QTc prolongation

0.25-0.5mg daily*

0.5-1.5 mg daily or bd

Long-acting conventional antipsychotic drugs

Flupentixol decanoate (Depixol)

 

Test dose: 5-10 mg

After at least 7 days of test dose:
10-20mg every 2-4 weeks*
Dose increased gradually according to response and tolerability in steps of 5-10 mg every 2 weeks*

40 mg every 2 weeks*
(extend frequency to every 3-4 weeks if EPS develop)
(occasionally up to 50 or 60 mg every 2 weeks* may be used if tolerated)

Fluphenazine

decanoate

Caution - high risk of EPS

Test dose 6.25 mg

After 4-7 days of test dose:
12.5-25mg every 2-4 weeks
Dose increased gradually according to response and tolerability in steps of 12.5 mg every 2-4 weeks*

50 mg every 4 weeks*

Haloperidol decanoate

Risk of EPS and QTc prolongation

(No test dose)
12.5-25 mg every 4 weeks

12.5-25 mg every 4 weeks

50 mg every 4 weeks*

Pipotiazine palmitate

 

Test dose:
5-10 mg
(or 12.5 mg*)

After 4-7 days of test dose:
12.5-25 mg every 2-4 weeks (initially can be every 2 weeks to achieve steady state quickly) then 25-50 mg every 4 weeks*

50 mg every 4 weeks*

Zuclopenthixol decanoate (Clopixol)

 

Test dose:
25-50 mg

After at least 7 days of test dose:
50-200 mg every 2-4 weeks*

200 mg every 2 weeks*

Long-acting atypical antipsychotic drugs

Aripiprazole Long-acting injection

No formal recommendations are available for dosing in older adults

However, no detectable effect of age on pharmacokinetics13

Paliperidone palmitate

Dose based on renal function-
Because elderly patients may have diminished renal function, they are dosed as in mild renal impairment even if tests show normal renal function*

Loading doses:
Day 1: 100 mg
Day 8: 75 mg
(lower loading doses may be appropriate in some)*

25-100 mg monthly*

100 mg monthly*

Risperidone
Long-acting
injection

Monitor renal function

25 mg every 2 weeks

25 mg every 2 weeks

25 mg every 2 weeks
Consider 37.5mg every 2 weeks in patients treated with oral risperidone doses > 4 mg/day14

Mood stabilisers

Carbamazepine

Bipolar disorder
Caution - drug interactions
Check LFTs, FBC and U&Es
Consider checking plasma levels

50 mg bd or 100 mg bd*

200-400 mg/day*

600-800 mg/day*

Lamotrigine

Bipolar disorder
(titration as in young adults)
Check for interactions and make appropriate dose alterations (see BNF)

25 mg daily
(monotherapy)

Increase by 25 mg steps every 14 days

200 mg/day*

25 mg on alternate days
(if with valproate)

Increase by 25 mg steps every 14 days

100 mg/day*

50 mg daily
(if with carbamazepine)

Increase by 50 mg steps every 14 days

100 mg bd*

Lithium carbonate M/R

Bipolar disorder
Mania/depression
Caution - drug interactions
Check renal and thyroid function and regularly monitor plasma levels

100-200 mg nocte*

200-600 mg daily*

600-1200 mg daily
(aim for plasma levels 0.4-0.8 mmol/L in elderly)15

Sodium valproate

Bipolar disorder
Check LFTs and consider checking plasma levels

Sodium valproate:
100 mg-200 mg bd*
Semi-sodium valproate: 250 mg daily or bd*

Sodium valproate:
200-400 mg bd*
Semi-sodium valproate: 500 mg -1 g daily*

Sodium valproate:
400 mg bd*
Semi-sodium valproate: 1 g daily*

Agitation in dementia (not licensed and not recommended)
Check response, tolerability and plasma levels for guide

Sodium valproate:
50 mg bd (liquid) or 100 mg bd*

Sodium valproate:
100-200 mg bd*

Sodium valproate:
200 mg bd*

Anxiolytics/hypnotics

Clonazepam

Agitation

0.5 mg daily

1-2 mg/day*

4 mg/day*

Diazepam

Agitation

1 mg tds

 

6 mg/day*

Lorazepam

PRN only - avoid regular use due to short half-life and risk of dependence

0.5 mg daily

0.5-2 mg daily*

2 mg/day

Melatonin

Insomnia - short term use (up to 13 weeks)

2 mg (modified release) once daily
(1-2 hours before bedtime)

Pregabalin

Generalised anxiety disorder
Dose adjustment based on renal function (see product information)16

Usually 25 mg bd
(increase by 25 mg bd weekly)
Up to 75 mg bd (if healthy and normal renal function)

Usually 150 mg daily*
Up to 150 mg bd
(if healthy and normal renal function)

150-300 mg/day*

Zolpidem

Insomnia (short term use - up to 4 weeks)

5 mg nocte

5 mg nocte

5 mg nocte

Zopiclone

Insomnia (short term use - up to 4 weeks)

3.75 mg nocte

3.75-7.5 mg nocte

7.5 mg nocte

*There is no information available in the literature for these drug doses in elderly patients—the doses stated are a guide only. Where there are no data, the maximum doses are conservative and may be exceeded if the drug is well tolerated and following clinician's assessment.

All doses are from the British National Formulary (66th edition 2013) unless otherwise indicated.

bd, bis die (twice a day); BP, blood pressure; CYP, cytochrome P450; EPS, extrapyramidal side-effects; ER, extended release; FBC, full blood count; IM, intramuscular; LFTs, liver function tests; mane, morning; nocte, at night; prn, pro re nata (as required); tds, ter die sumendum (three times a day); U&Es, urea and electrolytes.

References

  1. Novartis Pharmaceuticals UK Ltd. Summary of Product Characteristics. Anafranil 75mg SR Tablets. 2014. http://www.medicines.org.uk/emc/ medicine/1267
  2. Physicians' Desk Reference. Drug Summary - Desvenlafaxine. 2014. http://www.pdr.net/drug-summary/pristiq?druglabelid=625
  3. Eli Lilly and Company Limited. Summary of Product Characteristics. Cymbalta 30mg hard gastro-resistant capsules, Cymbalta 60mg hard gastro-resistant capsules. 2013. http://www.medicines.org.uk/
  4. Zentiva. Summary of Product Characteristics. Molipaxin 100mg Capsules. 2013. http://www.medicines.org.uk/
  5. Physicians' Desk Reference. Drug Summary - Vortioxetine. 2014. http://www.pdr.net/drug-summary/brintellix?druglabelid=3348
  6. Muller MJ et al. Amisulpride doses and plasma levels in different age groups of patients with schizophrenia or schizoaffective disorder. J Psychopharmacol 2009; 23:278–286.
  7. Psarros C et al. Amisulpride for the treatment of very-late-onset schizophrenia-like psychosis. Int J Geriatr Psychiatry 2009; 24:518–522.
  8. Clark-Papasavas C et al. Towards a therapeutic window of D2/3 occupancy for treatment of psychosis in Alzheimer's disease, with [F]fallypride positron emission tomography. Int J Geriatr Psychiatry 2014; Epub ahead of print.
  9. Jeste DV et al. Conventional vs. newer antipsychotics in elderly patients. Am J Geriatr Psychiatry 1999; 7:70–76.
  10. Karim S et al. Treatment of psychosis in elderly people. Adv Psychiatr Treat 2005; 11:286–296.
  11. The Parkinson Study Group. Low-dose clozapine for the treatment of drug-induced psychosis in Parkinson's Disease. N Engl J Med 1999; 340:757–763.
  12. Physicians' Desk Reference. Drug Summary - Lurasidone Hydrochloride. 2014. http://www.pdr.net/drug-summary/latuda?druglabelid=553
  13. Otsuka Pharmaceuticals (UK) Ltd. Summary of Product Characteristics. ABILIFY MAINTENA 400 mg powder and solvent for prolongedrelease suspension for injection. 2014. https://www.medicines.org.uk/
  14. Janssen-Cilag Ltd. Risperdal Consta 25, 37.5 and 50 mg powder and solvent for prolonged-release suspension for intramuscular injection. 2013. http://www.medicines.org.uk/
  15. Sanofi. Summary of Product Characteristics. Priadel 200mg prolonged release tablets. 2013. http://www.medicines.org.uk
  16. Pfizer Limited. Summary of Product Characteristics. Lyrica Capsules. 2014. http://www.medicines.org.uk/

Dementia

Dementia is a progressive, degenerative, neurological syndrome affecting around 5% of those aged over 65 years, rising to 20% in the over 80s. This age-related disorder is characterised by cognitive decline, impaired memory and thinking, and a gradual loss of skills needed to carry out activities of daily living. Often, other mental functions may also be affected, including changes in mood, personality and social behaviour.1

The various types of dementia are classified according to the different disease processes affecting the brain. The most common cause of dementia is Alzheimer's disease, accounting for around 60% of all cases. Vascular dementia and dementia with Lewy bodies (DLB) are responsible for most other cases. Alzheimer's disease and vascular dementia may co-exist and are often difficult to separate clinically. Dementia is also encountered in about 30% to 70% of patients with Parkinson's disease1 (see section on 'Parkinson's disease' in this chapter).

Alzheimer's disease

Mechanism of action of cognitive enhancers used in Alzheimer's disease

Acetylcholinesterase (AChE) inhibitors

The cholinergic hypothesis of Alzheimer's disease is predicated on the observation that the cognitive deterioration associated with the disease results from progressive loss of cholinergic neurones and decreasing levels of acetylcholine (ACh) in the brain.2 Both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) have been found to play an important role in the degradation of ACh.3

Three inhibitors of AChE are currently licensed in the UK for the treatment of mild to moderate dementia in Alzheimer's disease: donepezil, rivastigmine and galantamine. In addition, rivastigmine is licensed in the treatment of mild-to-moderate dementia associated with Parkinson's disease. Cholinesterase inhibitors differ in pharmacological action: donepezil selectively inhibits AChE, rivastigmine affects both AChE and BuChE and galantamine selectively inhibits AChE and also has nicotinic receptor agonist properties.4 To date, these differences have not been shown to result in differences in efficacy or tolerability. See Table 7.2 for comparison of AChE inhibitors.

Memantine

Memantine is licensed in the UK for the treatment of moderate-to-severe dementia in Alzheimer's disease. It acts as an antagonist at N-methyl-D-aspartate (NMDA) glutamate receptors. See Table 7.2.

Efficacy of drugs used in dementia

All three AChE-inhibitors seem to have broadly similar clinical effects, as measured with the Mini Mental State Examination (MMSE), a 30-point basic evaluation of cognitive function, and the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog), a 70-point evaluation largely of cognitive dysfunction. Estimates of the number needed to treat (NNT) (improvement of > 4 points ADAS-cog) range from 4 to 12.14

Cochrane reviews for all three AChE-Is have been carried out, both collectively as a group and individually for each drug. In the review for all AChE-Is, which included 10 randomised controlled trials (RCTs), results demonstrated that treatment over 6 months produced improvements in cognitive function, of, on average,–2.7 points (95% CI–3.0 to–2.3, p< 0.00001) on the ADAS-cog scale. Benefits were also noted on measures of Activities of Daily Living (ADL) and behaviour, although none of these treatment effects was large. Despite the slight variations in the mode of action of the three drugs, there is no evidence of any differences between them with respect to efficacy.15

Table 7.2 Characteristics of cognitive enhancers5–13

Characteristic

Donepezil (Aricept®) (Pfizer, Eisai)

Rivastigmine
(Exelon®)
(Novartis)

Galantamine
(Reminyl®)
(Shire/Janssen-Cilag)

Memantine
(Exiba®)
(Lundbeck)

Primary mechanism

AChE-I
(selective + reversible)

AChE-I
(pseudo-irreversible)

AChE-I
(selective + reversible)

NMDA receptor antagonist

Other mechanism

None

BuChE-I

Nicotine modulator

5-HT3 receptor antagonist

Starting dose

5 mg daily

1.5 mg bd (oral)
(or 4.6 mg/24 hours patch)

4 mg bd
(or 8 mg ER daily)

5 mg daily

Usual treatment dose
(max. dose)

10 mg daily

6 mg bd (oral) or 9.5 mg /24 hours patch

12 mg bd
(or 24 mg ER daily)

20 mg daily or (10 mg bd)

Recommended minimum interval between dose increases

4 weeks
(increase by 5 mg daily)

2 weeks for oral (increase by 1.5 mg twice a day)

4 weeks for patch (increase to 9.5 mg/24 hours)
(can consider increase to 13.3 mg/24 hours after 6 months if tolerated and meaningful cognitive/functional decline occurs on 9.5 mg/24 hours)

4 weeks
(increase by 4 mg twice a day or 8 mg ER daily)

1 week
(increase by 5 mg daily)

Adverse effects5-12

Diarrhoea*
Nausea*
Headache*
Common cold Anorexia Hallucinations Agitation
Aggressive behaviour
Abnormal dreams
and nightmares
Syncope
Dizziness
Insomnia
Vomiting
Abdominal
disturbance
Rash
Pruritis
Muscle cramps Urinary incontinence Fatigue Pain

Anorexia*
Dizziness*
Nausea*
Vomiting*
Diarrhoea*
Agitation
Confusion
Anxiety
Headache
Somnolence
Tremor
Abdominal pain and
dyspepsia
Sweating
Fatigue and asthenia,
Malaise
Weight loss

Nausea*
Vomiting*
Decreased appetite
Anorexia
Hallucinations
Depression
Syncope
Dizziness
Tremor
Headache
Somnolence
Lethargy
Bradycardia
Hypertension
Abdominal pain and
discomfort
Diarrhoea
Dyspepsia
Sweating
Muscle spasms
Fatigue and asthenia
Malaise
Weight loss
Fall

Drug hypersensitivity
Somnolence
Dizziness
Balance disorders
Hypertension
Dyspnoea
Constipation
Elevated liver
function test
Headache

Half life (hours)

~70

~1 (oral) 3.4 (patch)

7-8 (tablets/oral solution)

8-10 (ER capsules)

60-100

Metabolism

CYP 3A4 CYP 2D6 (minor)

Non-hepatic

CYP 3A4 CYP 2D6

Primarily

non-hepatic

Drug-drug

interactions

Yes

(see Table 7.3)

Interactions unlikely

Yes

(see Table 7.3)

Yes

(see Table 7.3)

Effect of food on absorption

None

Delays rate and extent of absorption

Delays rate but not extent of absorption

None

Cost of preparations13 (for 1-month treatment at usual i.e. max. dose)

Tablets: £1.60 Orodispersible tablets: £12.00

Capsules:£33.24 Oral solution (2 mg/mL): £126.71 Patches (Exelon®) 4.6 mg, 9.5 mg and 13.3 mg: £77.97

Tablets: £74.10 Capsules MR: £79.80 Oral solution (Reminyl®) (4 mg/mL): £201.60

Tablets: £28.85 Oral solution (10 mg/mL): £67.12 NB: Bottles supplied with a dosing pump dispensing 5 mg in 0.5 mL per actuation

Relative cost

$

$$

$$$

$$

Patent status

Generic available

Generic available (but not patches)

Generic available (branded oral solution cheaper than generic)

Generic available

* very common: ≥ 1/10 and common: ≥ 1/100.

AChE-I, acetylcholinesterase inhibitor; bd, bis die (twice a day); BuChE-I, butyrylcholinesterase inhibitor; CYP, cytochrome P450; ER, extended release; 5-HT3, 5-hydroxytryptamine (serotonin); MR, modified release; NMDA, N-methyl-D-aspartate.

A review of the Technology Appraisal for AChE-Is and memantine concluded that the evidence of additional clinical effectiveness continues to suggest clinical benefit from AChE-Is in alleviating the symptoms of Alzheimer's disease, although there is considerable debate about the magnitude of effect. There is also some evidence that AChE-Is have an impact on controlling disease progression. Although there is also new evidence for the effectiveness of memantine, it remains less robust than the evidence supporting AChE-Is.16

Donepezil

Pivotal trials of donepezil17–19 suggest an advantage over placebo of 2.5–3.1 points on the ADAS-cog scale. Results from the donepezil Cochrane review suggested statistically significant improvements for both 5 mg and 10 mg/day at 24 weeks compared with placebo on the ADAS-cog scale with a 2.01 point and a 2.80 point reduction, respectively.20 A long-term placebo-controlled trial of donepezil in 565 patients with mild-to-moderate Alzheimer's disease found a small but significant benefit on cognition compared with placebo. This was reflected in a 0.8 point difference in the MMSE score (95% CI 0.5–1.2; p< 0.0001).21 The size of the effect is similar to other trials.

Rivastigmine

Studies for rivastigmine22,23 suggest an advantage of 2.6–4.9 points on the ADAS-cog scale over placebo. In the Cochrane review, high dose rivastigmine (6–12 mg daily) was associated with a 2 point improvement in cognitive function on the ADAS-cog score compared with placebo and a 2.2 point improvement in ADL at 26 weeks. At lower doses (4 mg daily or lower) differences were in the same direction but were only statistically significant for cognitive function.15 Rivastigmine transdermal patch (9.5 mg/24 hours) has been shown to be as effective as the highest doses of capsules but with a superior tolerability profile in a 6-month double-blind, placebo-controlled RCT.24

Galantamine

Studies with galantamine25–27 suggest an advantage over placebo of 2.9–3.9 on the ADAS-cog scale. The galantamine Cochrane review reported that treatment with the drug led to a significantly greater proportion of subjects with improved or unchanged global scale rating at all doses except for 8 mg/day. Point estimate of effect was lower for 8 mg/day but similar for 16–36 mg/day. Treatment effect for 24 mg/day over 6 months was 3.1 point reduction in ADAS-cog.28 Data from two trials of galantamine in mild cognitive impairment suggest marginal clinical benefit but a yet unexplained excess in death rate.28 Galantamine has been shown to be effective (albeit marginally so) in severe Alzheimer's disease in subjects with MMSE scores of 5–12 points.29

Memantine

A number needed to treat analysis of memantine found it to have an NNT (improvement) of 3–8.30 The efficacy of memantine is evaluated using the ADAS-cog subscale to evaluate cognitive abilities in mild to moderate Alzheimer's disease and the Severe Impairment Battery (SIB) to evaluate cognitive functions in moderate to severe Alzheimer's disease. The SIB is a 40-item test with scores ranging from 0 to 100, higher scores reflecting higher levels of cognitive ability.31 Trials in moderate-to-severe dementia found that memantine showed significant benefits on both scales.32 A Cochrane review of memantine concluded that it had a small beneficial effect at 6 months in moderate-tosevere Alzheimer's disease. Statistically significant effects were detected on cognition, ADL and behaviour.33

Early data suggested memantine was effective in mild-to-moderate Alzheimer's disease with an advantage over placebo of 1.9 points on ADAS-cog.34 Pooled data from unpublished studies in the Cochrane review in mild-to-moderate Alzheimer's disease indicated a marginal benefit at 6 months on cognition which was barely detectable clinically (0.99 points on ADAS-cog) but no effect on behaviour, ADL or observed case analysis of cognition.33 A meta-analysis however found no significant differences between memantine and placebo on any outcome for patients with mild Alzheimer's disease either within any individual trial or when data were combined (ADAS-cog–0.17; p = 0.82). For patients with moderate Alzheimer's disease, there were no significant differences between memantine and placebo on the ADAS-cog in any individual trial, although there was a significant effect when the three trials were statistically combined (–1.33; p = 0.006).35

Since these systematic reviews, a large multicentre study36 of community-dwelling patients with moderate or severe Alzheimer's disease investigated the long-term effects of donepezil over 12 months compared with stopping donepezil after 3 months, switching to memantine or combining donepezil with memantine. Continued treatment with donepezil was associated with continued cognitive benefits and patients with a MMSE score as low as 3 were still benefiting from treatment. This suggests that patients should continue treatment with AChE-Is for as long as possible and there should not be a cut-off MMSE score where treatment is stopped automatically.

A meta-analysis evaluating the efficacy of the three AChE-Is and memantine in relation to the severity of Alzheimer's disease found that the efficacy of all drugs except memantine was independent of dementia severity in all domains. The effect of memantine on functional impairment was better in patients with more severe Alzheimer's disease. Results demonstrated that patients in differing stages of Alzheimer's disease retain the ability to respond to treatment with AChE-Is and memantine. Medication effects are therefore substantially independent from disease severity and patients with a wide range of severities can benefit from drug therapy. This suggests that the severity of a patient's illness should not preclude treatment with these drugs.37

Quantifying the effects of drugs in dementia

All the above results need to be interpreted with caution because of differences in the populations included in the different studies, especially as so few head-to-head studies have been published. Alzheimer's disease is usually characterised by inexorable cognitive decline, which is generally well quantified by tests such as ADAS-cog and MMSE. The average annual rate of decline in untreated patients ranges between 6 to12 points on the ADAS-cog (and the annual increase in ADAS-cog in patients with untreated moderate Alzheimer's disease has been estimated to be as much as 9 to11 points per year). A 4-point change in the ADAS-cog score is considered clinically meaningful.38 It is, however, difficult to accurately predict treatment effect in individual patients. Acetylcholinesterase inhibitors, on average, have a modest symptomatic effect on cognition.

Switching between drugs used in dementia

The benefits of treatment with AChE-Is are rapidly lost when drug administration is interrupted39 and may not be fully regained when drug treatment is reinitiated.40 Poor tolerability with one agent does not rule out good tolerability with another.41 Two cases of discontinuation syndrome upon stopping donepezil have been published42 suggesting that a gradual withdrawal should be carried out where possible. However, a study comparing abrupt versus stepwise switching from donepezil to memantine found no clinically relevant differences in adverse effects despite patients in the abrupt group experiencing more frequent adverse effects than the stepwise discontinuation group (46% versus 32% respectively).43 See section on 'Tolerability', below, for switching to a rivastigmine patch.

Following a systematic review of the literature,44 a practical approach to switching between AChE-Is has been proposed: in the case of intolerance, switching to another agent should be done only after complete resolution of side-effects following discontinuation of the initial agent. In the case of lack of efficacy, switching can be done overnight, with a quicker titration scheme thereafter. Switching to another AChE-I is not recommended in individuals who show loss of benefit several years after initiation of therapy.

Other effects

AChE inhibitors may also affect non-cognitive aspects of Alzheimer's disease and other dementias. Several studies have investigated their safety and efficacy in managing the non-cognitive symptoms of dementia. For more information about the management of these symptoms, see section on 'Management of non-cognitive symptoms of dementia' in this chapter.

Dosing

Different titration schedules do, to some extent, differentiate AChE-Is (see Table 7.2 for dosing information). Donepezil has been perhaps the easiest to use and is given once daily. Both rivastigmine and galantamine have prolonged titration schedules and used to be given twice a day. These factors may be important to prescribers, patients and carers. This was demonstrated in a retrospective analysis of the patterns of use of AChE-Is, where it was shown that donepezil was significantly more likely to be prescribed at an effective dose than either rivastigmine or galantamine.45 Galantamine, however, is now usually given once daily as the controlled-release formulation and rivastigmine is now available as a patch. Memantine once-daily dosing has been found to be similar in safety and tolerability as twice-daily dosing and may be more practical.46

Tolerability

Drug tolerability may differ between AChE-Is, but, again, in the absence of sufficient direct comparisons, it is difficult to draw definitive conclusions. Overall tolerability can be broadly evaluated by reference to the numbers withdrawing from clinical trials. Withdrawal rates in trials of donepezil17,18 ranged from 4% to 16% (placebo 1–7%). With rivastigmine22,23, rates ranged from 7% to 29% (placebo 7%) and with galantamine25–27 from 7% to 23% (placebo 7–9%). These figures relate to withdrawals specifically associated with adverse effects. The number needed to harm (NNH) has been reported to be 12.14 A study of the French pharmacovigilance database identified age, the use of antipsychotic drugs, antihypertensives, and drugs targeting the alimentary tract and metabolism, as factors associated with serious reactions to AChE-Is.47

Tolerability seems to be affected by speed of titration and, perhaps less clearly, by dose. Most adverse effects occurred in trials during titration, and slower titration schedules are recommended in clinical use. This may mean that these drugs are equally well tolerated in practice.

Rivastigmine patch may offer convenience and a superior tolerability profile to rivastigmine capsules.24 Data from three trials found that rivastigmine patch was better tolerated than the capsules with fewer gastrointestinal adverse effects and discontinuations due to these adverse effects.48 Data support recommendations for patients on high doses of rivastigmine capsules (> 6 mg/day) to switch directly to the 9.5 mg/24-hours patch, while those on lower doses (≤ 6 mg/day) should start on 4.6 mg/hour patch for 4 weeks before increasing to the 9.5 mg/hour patch. This latter switch is also recommended for patients switching from other oral cholinesterase inhibitors to the rivastigmine patch (with a 1 week washout period in patients sensitive to adverse effects or who have very low body weight or a history of bradycardia).49 A new strength for rivastigmine patches (13.3 mg/24 hours) has recently been approved. It is possible to consider increasing the dose to 13.3 mg/24 hours after 6 months on 9.5 mg/24 hours if tolerated and meaningful cognitive or functional decline occurs. A 48-week RCT found the higher strength patch to significantly reduce deterioration in instrumental activities of daily living (IADL) compared with the 9.5 mg/24-hours patch and was well tolerated.50

Memantine appears to be well tolerated51,52 and the only conditions associated with warnings include hepatic impairment and epilepsy/seizures.53

Adverse effects

When adverse effects occur with AChE-Is, they are largely predictable: excess cholinergic stimulation can lead to nausea, vomiting, dizziness, insomnia and diarrhoea.54 Such effects are most likely to occur at the start of therapy or when the dose is increased. They are dose-related and tend to be transient. Urinary incontinence has also been reported.55 There appear to be no important differences between drugs in respect to type or frequency of adverse events, although clinical trials do suggest a relatively lower frequency of adverse events for donepezil. This may simply be a reflection of the aggressive titration schedules used in trials of other drugs. Gastrointestinal effects appeared to be more common with oral rivastigmine in clinical trials than with other cholinesterase inhibitors, however slower titration, ensuring oral rivastigmine is taken with food or using the patch, reduces the risk of gastrointestinal effects.

In view of their pharmacological action, AChE-Is may have vagotonic effects on heart rate (i.e. bradycardia). The potential for this action may be of particular importance in patients with 'sick sinus syndrome' or other supraventricular cardiac conduction disturbances, such as sinoatrial or atrioventricular block.5–11

Concerns over the potential cardiac adverse effects associated with AChE-Is were raised following findings from controlled trials of galantamine in mild cognitive impairment (MCI) in which increased mortality was associated with galantamine compared with placebo (1.5% versus 0.5% respectively).56 Although no specific cause of death was predominant, half the deaths reported were due to cardiovascular disorders. As a result, the FDA issued a warning restricting galantamine in patients with MCI. The relevance in Alzheimer's disease remains unclear.57 A Cochrane review of pooled data from RCTs of the AChE-Is revealed that there was a significantly higher incidence of syncope amongst the AChE-I groups compared with the placebo groups (3.43 versus 1.87%, p= 0.02). A population-based study using a case-time-control design examined health records for 1.4 million older adults in Ontario and found that treatment with AChE-Is was associated with doubling the risk of hospitalisation for bradycardia. (The drugs were resumed at discharge in over half the cases suggesting that cardiovascular toxicity of AChE-Is is underappreciated by clinicians.)58 It seems that patients with DLB are more susceptible to the bradyarrhythmic adverse effects of these drugs owing to the autonomic insufficiency associated with the disease.59 A similar study found hospital visits for syncope were also more frequent in people receiving AChE-Is than in controls: 31.5 versus 18.6 events per 1000 person-years (adjusted HR 1.76; 95% CI, 1.57–1.98).60

The manufacturers of all three agents therefore advise that the drugs should be used with caution in patients with cardiovascular disease or in those taking concurrent medicines that reduce heart rate, e.g. digoxin or beta-blockers. Although a pre-treatment mandatory electrocardiogram (ECG) has been suggested,57 a review of published evidence showed that the incidence of cardiovascular side-effects is low and that serious adverse effects are rare. In addition, the value of pre-treatment screening and routine ECGs is questionable and is not currently routinely recommended by the National Institute of Health and Care Excellence (NICE). However, in patients with a history of cardiovascular disease, or who are prescribed concomitant negative chronotropic drugs with AChE-Is, an ECG may be advised.

A study of 204 elderly patients with Alzheimer's disease had their ECG and blood pressure assessed before and after starting AChE-I therapy. It was noted that none of the AChE-Is was associated with increased negative chronotropic, arrythmogenic or hypotensive effects and therefore a preferred drug could not be established with regards to vagotonic effects.61 Similarly, a Danish retrospective cohort study62 found no substantial differences in the risk of myocardial infarction (MI) or heart failure between participants on donepezil and those using the other AChE-Is. Memantine was in fact associated with greatest risk of all-cause mortality, although sicker individuals were selected for memantine therapy. A Swedish cohort study63 found that AChE-Is were associated with a 35% reduced risk of MI or death in patients with Alzheimer's disese. These associations were stronger with increasing doses of AChE-Is. RCTs are required in order to confirm findings from this observational study.

An analysis of pooled data for memantine revealed that the most frequently reported adverse effects in placebo-controlled trials included agitation (7.5% memantine versus 12% placebo), falls (6.8% versus 7.1%), dizziness (6.3% versus 5.7%), accidental injury (6.0% versus 7.2%), influenza-like symptoms (6.0% versus 5.8%), headache (5.2% versus 3.7%) and diarrhoea (5.0% versus 5.6%).64

An analysis of the French pharmacovigilance database compared adverse effects reported with donepezil with memantine. The most frequent adverse drug reactions with donepezil alone and memantine alone were respectively: bradycardia (10% versus 7%), weakness (5% versus 6%) and convulsions (4% versus 3%). Although it is well known that donepezil is often associated with bradycardia, and memantine associated with seizures, this analysis suggests that memantine can also induce bradycardia and donepezil can also induce seizures; thus highlighting the care required when treating patients with dementia who have a history of bradycardia or epilepsy.65

Interactions

Potential for interaction may also differentiate currently available cholinesterase inhibitors. Donepezil66 and galantamine67 are metabolised by cytochromes 2D6 and 3A4 and so drug levels may be altered by other drugs affecting the function of these enzymes. Cholinesterase inhibitors themselves may also interfere with the metabolism of other drugs, although this is perhaps a theoretical consideration. Rivastigmine has almost no potential for interaction since it is metabolised at the site of action and does not affect hepatic cytochromes. A prospective pharmacodynamic analysis of potential drug interactions between rivastigmine and other medications (22 different therapeutic classes) commonly prescribed in the elderly population compared adverse effects odds ratios between rivastigmine and placebo. Rivastigmine did not reveal any significant pattern of increase in adverse effects that would indicate a drug interaction compared with placebo.68

Rivastigmine appears to be least likely to cause problematic drug interactions, a factor that may be important in an elderly population subject to polypharmacy (see Table 7.3).

Analysis of the French pharmacovigilance database found that the majority of reported drug interactions concerning AChE-Is were found to be pharmacodynamic in nature and most frequently involved the combination of AChE-I and bradycardic drugs (beta-blockers, digoxin, amiodarone, calcium channel antagonists). Almost a third of these interactions resulted in cardiovascular adverse drug reactions (ADRs) such as bradycardia, atrioventricular block and arterial hypotension. The second most frequent drug interaction reported was the combination of AChE-I with anticholinergic drugs leading to pharmacological antagonism.69

The pharmacodynamics, pharmacokinetic and pharmacogenetic aspects of drugs used in dementia have recently been summarised in a comprehensive review.70

Combination treatment

The benefits of adding memantine to AChE-Is are not clear but the combination appears to be well tolerated71,72 and may even result in a decreased incidence of gastrointestinal adverse effects compared with monotherapy with an AChE-I.73 Studies investigating the benefits of combining AChE-Is with memantine have found conflicting results. Long-term observational controlled studies have shown that combination therapy is associated with better cognitive outcomes and greater delays in time to nursing home admission compared with monotherapy or no treatment.74. Whilst a recent review75 found that combination treatment in moderate-to-severe Alzheimer's disease produces consistent benefits that appear to increase over time and that are beyond AChE-Is therapy alone, a metaanalysis76 concluded that despite significant changes found in favour of the combination, it was unclear if these were clinically significant. Similarly, a large multicentre study36 concluded that the efficacy of donepezil and of memantine did not differ significantly in the presence or absence of the other and that there were no significant benefits for the combination over donepezil alone. Studies have confirmed that there are no pharmacokinetic or pharmacodynamic interactions between AChE-Is and memantine.77,78

NICE recommendations

NICE guidance on dementia1, which has been amended to incorporate the updated NICE technology appraisal of drugs for Alzheimer's disease, was published in March 201181 and is due to be reviewed in 2015. See Box 7.2.

Table 7.3 Drug–drug interactions6–11,79,80

Drug

Metabolism

Plasma levels increased by

Plasma levels decreased by

Pharmacodynamic interactions

Donepezil
(Aricept®)

Substrate at 3A4 and 2D6

Ketoconazole
Itraconazole
Erythromycin
Quinidine
Fluoxetine

Rifampicin
Phenytoin
Carbamazepine
Alcohol

Antagonistic with anticholinergic drugs
Potential for synergistic activity with cholinomimetics such as neuro-muscular blocking agents (e.g. succinylcholine), cholinergic agonists and peripherally acting cholinesterase inhibitors, e.g. neostigmine
Beta-blockers, amiodarone or calcium channel blockers may have additive effects on cardiac conduction

Rivastigmine
(Exelon®)

Non-hepatic
metabolism

Metabolic interactions appear unlikely
Rivastigmine may inhibit the butyryl-cholinesterase-mediated metabolism of other substances, e.g. cocaine

Antagonistic effects with anticholinergic drugs and additive effects with cholinomimetic drugs, succinylcholine-type muscle relaxants, cholinergic agonists, e.g. bethanecol, or peripherally acting cholinesterase inhibitors, e.g. neostigmine
Synergistic effects on cardiac conduction with beta-blockers, amiodarone and calcium channel blockers

Galantamine
(Reminyl®)

Substrate at 3A4 and 2D6

Ketoconazole
Erythromycin
Ritonavir
Quinidine
Paroxetine
Fluoxetine
Fluvoxamine
Amitriptyline

None known

Antagonistic effects with anticholinergic drugs and additive effects with cholinomimetics, succinylcholine-type muscle relaxants, cholinergic agonists and peripherally acting cholinesterase inhibitors, e.g. neostigmine
Possible interaction with agents that significantly reduce heart rate, e.g. digoxin, beta-blockers, certain calcium-channel blockers and amiodarone
Caution with agents that can cause torsades de pointes (manufacturers recommend ECG in such cases)

Memantine
(Exiba®)

Primarily
non-hepatic
metabolism

Renally
eliminated

Cimetidine
Ranitidine
Procainamide
Quinidine
Quinine
Nicotine

Isolated cases of INR increases reported with concomitant warfarin (close monitoring of prothrombin time or INR advisable).

Drugs that alkalinize urine (pH ~8) may reduce renal elimination of memantine, eg. carbonic anhydrase inhibitors, sodium bicarbonate

None known
Possibility of reduced serum level of hydrochlorothiazide when co administered with memantine

Effects of L-dopa, dopaminergic agonists and anticholinergics may be enhanced
Effects of barbiturates and neuroleptics may be reduced
Avoid concomitant use with amantadine, ketamine and dextromethorphan -risk of pharmacotoxic psychosis.
One published case report on possible risk for phenytoin and memantine combination
Dosage adjustment may be necessary for antispasmodic agents, dantrolene or baclofen when administered with memantine

Note: this list is not exhaustive - caution with other drugs that are also inhibitors or enhancers of CYP 3A4 and 2D6 enzymes.

ECG, electrocardiogram; INR, international normalised ratio.

Box 7.2 Summary of NICE guidance for the treatment of Alzheimer's disease1,81

  • The three acetylcholinesterase inhibitors (AChE-Is) donepezil, galantamine and rivastigmine are recommended for managing mild-to-moderate Alzheimer's disease.
  • Memantine is recommended for managing moderate Alzheimer's disease for people who are intolerant of, or have a contraindication to, AChE-Is, or for managing severe Alzheimer's disease.
  • Carers' view on the patient's condition should be sought at baseline and follow-up.
  • Patients who continue on the drug should be reviewed regularly using cognitive, global, functional and behavioural assessment. Treatment should be reviewed by an appropriate specialist team, unless there are locally agreed protocols for shared care.
  • Therapy with AChE-I should be initiated with a drug with the lowest acquisition cost (taking into account required daily dose and the price per dose once shared care has started). An alternative may be considered on the basis of adverse effects profile, expectations about adherence, medical co-morbidity, possibility of drug interactions and dosing profiles.
  • When assessing the severity of Alzheimer's disease and the need for treatment, healthcare professionals should not rely solely on cognition scores in circumstances in which it would be inappropriate to do so, and should take into account any physical, sensory or learning disabilities, or communication difficulties that could affect the results. Any adjustments considered appropriate should be made.

Other treatments

Ginkgo biloba

A Cochrane review found that although Ginkgo biloba appears to be safe with no excess side-effects compared with placebo, there was no convincing evidence that it is efficacious for dementia and cognitive impairment. Many of the trials were too small and used unsatisfactory methods and publication bias could not be excluded. The review concluded that ginkgo's clinical benefit in dementia or cognitive impairment is somewhat inconsistent and unconvincing.82 A randomised, double-blind trial, which compared Ginkgo biloba, donepezil, or both combined, found no statistically significant or clinically relevant differences between the three groups with respect to efficacy. In addition, they noted that combined treatment adverse effects were less frequent than with donepezil alone.83 Several reports have noted that ginkgo may increase the risk of bleeding.84 The drug is widely used in Germany but less so elsewhere.

Vitamin E

A Cochrane review of vitamin E for Alzheimer's disease and mild cognitive impairment (MCI) examined two studies meeting the inclusion criteria. The authors' conclusions were that there is no evidence of efficacy of vitamin E in prevention or treatment of people with Alzheimer's disease or MCI and that further research is required in order to identify its role in this area.85 A more recent RCT86 compared the effects of vitamin E (alpha tocopherol) 2000 IU/day, memantine 20 mg/day, the combination or placebo in 613 patients with mildto-moderate Alzheimer's disease. Findings showed that alpha tocopherol resulted in slower functional decline than placebo. However, there were no significant differences between memantine alone or memantine plus alpha tocopherol groups. Due to limitations of this trial, further evidence is needed to support these findings.

Folic acid

A placebo-controlled pilot RCT of 1 mg folic acid supplementation of AChE-Is over 6 months in 57 patients with Alzheimer's disease showed significant benefit in combined IADL and social behaviour scores (folate + 1.50 (SD 5.32) versus placebo–2.29 (SD 6.16) (p = 0.03) but no change in MMSE scores.87 Another RCT examining the efficacy of multivitamins and folic acid as an adjunctive to AChE-Is over 26 weeks in 89 patients with Alzheimer's disease found no statistically significant benefits between the two groups on cognition or ADL function.88 A Cochrane review found no evidence that folic acid with or without vitamin B12 improves cognitive function of unselected elderly people with or without dementia. However, long term supplementation may benefit cognitive function of healthy older people with high homocysteine levels.89 Elevated homocysteine, decreased folate and low vitamin B12 serum levels are associated with poor cognitive function, cognitive decline and dementia. A systematic and critical review of the literature did not provide any clear evidence that supplementation with vitamin B12 and/or folate improves cognition or dementia even though it might normalise homocysteine levels.90 A small RCT found that vitamin B, which lowers homocysteine levels, appeared to slow cognitive and clinical decline in people with MCI, in particular those with elevated homocysteine levels, however further trials are needed to establish whether reducing homocysteine levels will slow or prevent conversion from MCI to dementia.91

Omega-3

Omega-3 supplementation in mild-to-moderate Alzheimer's disease has been evaluated in 174 patients in a placebo-controlled RCT but there were no significant overall effects on neuropsychiatric symptoms, on activities of daily living or on caregiver's burden, although some possible positive effects were seen on depressive symptoms (assessed by Montgomery-Asberg Depression Rating Scale [MADRS]) and agitation symptoms (assessed by neuropsychiatric inventory [NPI]).92

Ginseng

A prospective open-label study of ginseng in Alzheimer's disease measured cognitive performance in 97 patients randomly assigned ginseng or placebo for 12 weeks and then 12 weeks after the ginseng had been discontinued. After ginseng treatment, the cognitive subscales of ADAS and MMSE score began to show improvement continued up to 12 weeks (p = 0.029 and p = 0.009 versus baseline respectively) but scores declined to levels of the control group following discontinuation of ginseng.93

Dimebon

Dimebon, a non-selective antihistamine previously approved in Russia but later discontinued for commercial reasons, has been assessed for safety, tolerability and efficacy in the treatment of patients with mild-to-moderate Alzheimer's disease. It acts as a weak inhibitor of butyrylcholinesterase and acetylcholinesterase, weakly blocks the NMDA-receptor signalling pathway and inhibits the mitochondrial permeability transition pore opening.94 A meta-analysis found that dimebon generally presented a good safety profile and was well tolerated. Heterogeneous results were noted between trials, however, and it failed to exert a significant beneficial effect (although it tended to improve cognitive scores).95

Hirudin

Natural hirudin, isolated from salivary gland of medicinal leech, is a direct thrombin inhibitor and has been used for many years in China. It does not share the usual limitations of other anticoagulant drugs like heparin, such as the potential to cause bleeding and variable anticoagulant effects. Since thrombosis and ischaemia are the primary vascular risk factors, improvement of cerebral blood flow may be helpful in the treatment and rehabilitation of patients with Alzheimer's disease. A 20-week open label RCT of 84 patients receiving donepezil or donepezil plus hirudin (3 g/day) found that patients on the combination showed significant decrease in ADAS-cog scores and significant increase in ADL scores compared with donepezil alone. However, haemorrhage and hypersensitivity reactions were more common in the combination group compared with donepezil group (11.9% and 7.1% versus 2.4% and 2.4% respectively).96

Huperzine A

Huperzine A, a novel alkaloid isolated from the Chinese herb Huperzia serrata, is a potent, highly selective, reversible AChE-I used for treating Alzheimer's disease since 1994 in China and available as a nutraceutical in the US. A recent meta-analysis found that huperzine A 300–500μg daily for 8–24 weeks in Alzheimer's disease led to significant improvements in MMSE (mean change 3.5157; p< 0.05) and ADL with effect size shown to increase over treatment time. Most adverse effects were cholinergic in nature and no serious adverse effects occurred.97 A Cochrane review of huperzine A in vascular dementia, however, found no convincing evidence for its value in vascular dementia.98 Similarly, a Cochrane review of huperzine A for mild cognitive impairment concluded that the current evidence is insufficient for this indication as no eligible trials were identified.99

Saffron

There is increasing evidence to suggest possible efficacy of Crocus sativus(saffron) in the management of Alzheimer's disease. In a 16-week placebo-controlled RCT, saffron produced a significantly better outcome on cognitive function than placebo and there were no significant differences between the two groups in terms of observed adverse events.100 A 22-week double-blind study included 55 patients randomly assigned to saffron capsules 15 mg bd or donepezil 5 mg bd. Results found no significant differences between the two groups in terms of efficacy or adverse effects, although vomiting occurred significantly more frequently in the donepezil group.101

Cerebrolysin

Cerebrolysin is a parenterally administered, porcine brain-derived peptide preparation that has pharmacodynamic properties similar to those of endogenous neurotrophic factors. Cerebrolysin was superior to placebo in improving global outcome measures and cognitive ability in several RCTs of up to 28 weeks in patients with Alzheimer's disease. In addition, a large RCT comparing cerebrolysin, donepezil or combination therapy showed beneficial effects on global measures and cognition for all three treatment groups compared with baseline. Although not as extensively studied in vascular dementia, cerebrolysin has also showed beneficial effects on global measures and cognition in this patient group. Cerebrolysin was generally well tolerated in trials with dizziness being the most frequently reported adverse event.102

Statins

In Alzheimer's disease, amyloid protein is deposited in the form of extracellular plaques and studies have determined that amyloid protein generation is cholesterol-dependent. Hypercholesterolaemia has also been implicated in the pathogenesis of vascular dementia. Due to the role of statins in cholesterol reduction, they have been explored as a means to treat dementia. A Cochrane review, however, found that there is still insufficient evidence to recommend statins for the treatment of dementia. Analysis from the studies available, indicate that they have no benefit on the outcome measures ADAS-Cog or MMSE.103

Cocoa

Sixty older people were studied in a clinical trial of neurovascular coupling and cognition in response to 30 days of cocoa consumption. Two cups of cocoa daily for 30 days resulted in higher neurovascular coupling (NVC) and individuals with higher NVC had better cognitive function and greater cerebral white matter structural integrity.104

Souvenaid

Souvenaid is a medical food for the dietary management of early Alzheimer's disease. The mix of nutrients in this drink is suggested to have a beneficial effect on cognitive function; however health claims for medical foods are not checked by government agencies. Souvenaid has been investigated in three clinical trials. The first trial showed that Souvenaid produced a significant improvement in delayed verbal recall, but not in other psychological tests.105 The second and largest trial showed no effect on any outcome.106 A third trial showed no significant effect at 12 or 24 weeks, but a significant difference in the 24-week time course of the composite memory score.107 However, none of these outcomes was clearly specified as a primary outcome at trial registration. There is currently therefore no convincing proof that Souvenaid benefits cognitive function. Further regulated and robust efficacy data are required.

Three new drugs have failed to improve clinical outcomes in phase III trials for Alzheimer's disease. These include: Semagacestat, a γ-secretase inhibitor,108 solanezumab, a humanised monoclonal antibody that binds soluble forms of amyloid and promotes its clearance from the brain109 and bapineuzumab, a humanised anti-amyloid-β monoclonal antibody.110

Vascular dementia (VaD)

Vascular dementia has been reported to comprise 10–50% of dementia cases and is the second most common type of dementia after Alzheimer's disease. It is caused by ischaemic damage to the brain and is associated with cognitive impairment and behavioural disturbances. The management options are currently very limited and focus on controlling the underlying risk factors for cerebrovascular disease.111

None of the currently available drugs is formally licensed in the UK for vascular dementia. The management of vascular dementia has been summarised.112,113 Unlike the situation with stroke, there is no conclusive evidence that treatment of hyperlipidemia with statins, or treatment of blood clotting abnormalities with acetylsalicylic acid, do have an effect on vascular dementia incidence or disease progression.114 Similarly, a Cochrane review found that there were no studies supporting the role of statins in the treatment of VaD.103 There is however growing evidence for donepezil,115,116 rivastigmine,117,118 galantamine119–121 and memantine.122,123 The largest clinical trial of donepezil in vascular dementia found small but significant improvement on the vascular ADAS-cog subscale but no difference was seen on the Clinician's InterviewBased Impression of Change (CIBIC-Plus)124. These results are consistent with prior trials suggesting that donepezil may have a greater impact on cognitive rather than global outcomes in vascular dementia. The Cochrane review for donepezil in vascular cognitive impairment however found evidence to support its benefit in improving cognition function, clinical global impression and activities of daily living after 6 months treatment.116 In the Cochrane review for galantamine for vascular cognitive impairment,15,125 there were limited data suggesting some advantage over placebo in areas of cognition and global clinical state. However, authors thought more studies were needed to confirm these results. Trials of galantamine reported high rates of gastrointestinal side effects. The Cochrane review for rivastigmine in vascular cognitive impairment found some evidence of benefit, however the conclusion was based on one large study and side effects with rivastigmine lead to withdrawal in a significant proportion of patient.103,126 Furthermore, a meta-analysis of RCTs found that cholinesterase inhibitors and memantine produce small benefits in cognition of uncertain clinical significance and concluded that data were insufficient to support widespread use of these agents in vascular dementia.111

Note that it is impossible to diagnose with certainty vascular or Alzheimer's dementia and much dementia has mixed causation. This might explain why certain AChE-Is do not always provide consistent results in probable vascular dementia and the data indicating efficacy in cognitive outcomes was derived from older patients, who were therefore likely to have concomitant Alzheimer's disease pathology.127

Dementia with Lewy bodies

It has been suggested that dementia with Lewy bodies (DLB) may account for 15–25% of cases of dementia (although autopsy suggests much lower rates). Characteristic symptoms are dementia with fluctuation of cognitive ability, early and persistent visual hallucinations and spontaneous motor features of parkinsonism. Falls, syncope, transient disturbances of consciousness, neuroleptic sensitivity and hallucinations in other modalities are also common.128

A Cochrane review for AChE-Is in DLB and Parkinson's disease dementia and cognitive impairment found evidence supporting their use in Parkinson's disease but no statistically significant improvement was observed in patients with DLB and that further trials were necessary to clarify their effects in this patient group.129 A comparative analysis of cholinesterase inhibitors in DLB, which included open label trials as well as the placebo-controlled randomized trial of rivastigmine, found that, so far, there is no compelling evidence that one AChE-I is better that the other in DLB.130 Despite certain reports of patients with DLB worsening or responding adversely when exposed to memantine,131 a recent RCT of memantine (funded by the manufacturer) found it to be mildly beneficial in terms of global clinical status and behavioural symptoms in patients with DLB.132

Mild cognitive impairment (MCI)

Mild cognitive impairment is hypothesised to represent a pre-clinical stage of dementia but forms a heterogeneous group with variable prognosis. A Cochrane review assessing the safety and efficacy of AChE-Is in MCI found there was very little evidence that they affect progression to dementia or cognitive test scores. This weak evidence was countered by the increased risk of adverse effects, particularly gastrointestinal effects, meaning that AChE-Is could not be recommended in MCI.133 A recent systematic review134 found that there was no replicated evidence that any intervention was effective for MCI including AChE-Is and the non-steroidal anti-inflammatory drug (NSAID) rofecoxib.

Summary of clinical practice guidance with anti-dementia drugs from BAP

A revised consensus statement from the British Association of Psychopharmacology (BAP)135 states that: AChE-Is are effective in mild-to-moderate Alzheimer's disease and memantine in moderate-to-severe Alzheimer's disease. Other drugs including statins, antiinflammatory drugs, vitamin E and ginkgo cannot be recommended either for the treatment or prevention of Alzheimer's disease. Neither AChE-Is nor memantine are effective in MCI. AChE-Is are not effective in frontotemporal dementia and may cause agitation. AChE-Is may be used for people with DLB (can produce cognitive improvements) and Parkinson's disease dementia, especially for neuropsychiatric symptoms. There is no clear evidence that any intervention can prevent or delay the onset of dementia. See Table 7.4.

Table 7.4 Summary of recommendations

 

First choice

Second choice

Alzheimer's disease

AChE-Is

Memantine

Vascular dementia

None

None

Mixed dementia

AChE-Is

Memantine

Dementia with Lewy bodies

AChE-Is

Memantine

Mild cognitive impairment

None

None

Dementia with Parkinson's disease

AChE-Is

None

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Safer prescribing of physical health medicines in dementia

People with dementia are more susceptible to cognitive side-effects of drugs. Drugs may affect cognition through their action on cholinergic, histaminergic or opioid neurotransmitter pathways or through more complex actions. Medications prescribed for physical disorders may also interact with cognitive-enhancing medication.

Anticholinergic drugs

Anticholinergic drugs reduce the efficacy of acetylcholinesterase inhibitors and so concomitant use should be avoided.1,2 Anticholinergic drugs also cause sedation, cognitive impairment, delirium3 and falls.4 These effects may be worse in older patients with dementia.5 Table 7.5 summarises the anticholinergic potency of drugs commonly used in physical health conditions.6 Combining several drugs with anticholinergic activity increases the anticholinergic cognitive burden (ACB) for an individual. One study showed that a high ACB total score was associated with a greater decline in MMSE score and a higher mortality.7 It is good practice to keep the ACB to a minimum in older people, especially if they have cognitive impairment.

Where possible, drugs with an equivalent therapeutic effect, but a mode of action which does not affect the cholinergic system, should be used. If this is not possible, the prescription of a drug with low anticholinergic activity or high specificity to the site of action (and thus minimal central activity) should be encouraged. Anticholinergic drugs that do not cross the blood–brain barrier have less profound effects on cognitive function.8

Anticholinergic drugs used in urinary incontinence

Oxybutynin easily penetrates the central nervous system (CNS) and has consistently been associated with deterioration in cognitive function. Although studies of tolterodine found no adverse CNS effects,9 case reports have described adverse effects including memory loss, hallucinations and delirium.10–12 In contrast, darifenacin, an M3 selective receptor antagonist, has been investigated in healthy elderly subjects for its effects on cognitive function and was noted to have no significant effects on cognitive tests compared with placebo;13,14 although studies in dementia are lacking. Solifenacin has been shown to cause impairment of working memory15 although it was investigated in stroke patients and was found not to affect their short term cognitive performance.16 A study looking at the use of trospium with galantamine in patients with Alzheimer's disease found no significant change in cognitive function.17 There are no in vivo studies investigating whether or not fesoterodine causes cognitive impairment but in vitro evaluation found that its active metabolite 5-hydroxy-methyl-tolterodine (5-HMT) had one of the highest detectable serum anticholinergic activities and therefore it has potential to induce central anticholinergic adverse effects. However, anticholinergic activity measured in serum does not necessarily reflect brain concentrations18 and theoretically, fesoterodine has a very low ability to cross the blood–brain barrier.15

Table 7.5 Anticholinergic potency for some physical health drugs commonly used in elderly patients

Drugs with unknown anticholinergic effect

Drugs with improbable or no anticholinergic action

Low effect anticholinergic drugs *Caution*

High effect anticholinergic drugs *Avoid*

A to K

L to Z

Colchicine
Digoxin
Furosemide
Metoclopramide

Allopurinol
Amlodipine
Amoxicillin
Ampicillin
Aspirin
Atenolol
Atorvastatin
Azathioprine
Benazapril
Betaxolol
Bisacodyl
Captopril
Carbidopa
Cefalexin (+other cephalosporins)
Celecoxib
Ciclosporin
Clindamycin
Clopidogrel
Cortisone
Cycloserine
Dexamethasone
Dextromethorphan
Dicycloverine
Diltiazem
Dipyridamole
Duloxetine
Enalapril
Famotidine
Fluticasone
Gemfibrozil
Glipizide
Glyceryl trinitrate (GTN)
Gentamicin
Guaifenesin
Hydralazine
Hydrochlorothiazide
Hydrocortisone
Ibuprofen
Insulin
Isosorbide mononitrate
Ketoprofen

Lansoprazole
Levodopa
Lisinopril
Losartan
Metformin
Methotrexate
Metoprolol
Naratriptan
Nifedipine
Omeprazole
Pantoprazole
Paracetamol
Phenobarbital
Phenytoin
Pioglitazone
Piperacillin
Piroxicam
Prednisolone
Propranolol
Pseudoephedrine
Rabeprazole
Ropinirole
Rosiglitazone
Salmeterol
Selegiline
Senna
Simvastatin
Spironolactone
Sumatriptan
Tamoxifen
Terbutaline
Timolol
Topiramate
Trandolapril
Triamcinolone
Triamterene
Trimethoprim
Valproate
Verapamil
Vancomycin
Warfarin
Zolmitriptan

Amantadine
Baclofen
Bromocriptine
Carbamazepine
Cetirizine
Cimetidine
Codeine
Disopyramide
Domperidone
Entacapone
Fentanyl
Fexofenadine
Hydrocodone
Ketorolac
Loperamide
Loratadine
Meperidine
Methadone
Methocarbamol
Morphine
Oxcarbazepine
Oxycodone
Prochlorperazine
Ranitidine
Theophylline
Tramadol

Atropine
Benzatropine
Chlorphenamine
Clemastine
Cyproheptadine
Flavoxate
Hydroxyzine
Hyoscine
Ipratropium
Orphenadrine
Oxybutynin
Procyclidine
Promethazine
Propantheline
Tolterodine
Tizanidine
Trihexyphenidyl (benzhexol)

Note: This list is not exhaustive and includes drugs used for physical health conditions only (i.e. not psychotropic drugs).

Adapted from Bishara D et al.20 with permission.

All tertiary amine drugs, i.e. oxybutynin, tolterodine, fesoterodine and darifenacin are metabolised by cytochrome P450 (CYP450) enzymes. Increasing age or co-administration of drugs that inhibit these enzymes (e.g. erythromycin, fluoxetine) can lead to higher serum levels and therefore increased adverse effects. The metabolism of trospium is unknown, although metabolism via CYP450 system does not occur, meaning that pharmacokinetic drug interactions are unlikely with this drug.9

See Table 7.6 for a summary of the physiochemical properties of anticholinergic drugs used in urinary incontinence.

Alpha-blockers for urinary retention

Alpha-blockers such as tamsulosin, alfuzosin and prazosin are reported to cause drowsiness, dizziness and depression.21 There is no published literature reporting their effects on cognition and alpha-blockers do not feature on any anticholinergic cognitive burden list.

Drugs used in gastrointestinal disorders

Table 7.6 Physiochemical properties of anticholinergic drugs in urinary incontinence15,19

Drug

Muscarinic receptor (M3:M1 affinity ratio)

Polarity

Lipophilicity

Molecular weight (kDa)

P-gp substrate

Theoretical ability to cross blood-brain barrier

Effect on cognition

Darifenacin

Mainly M3, (9.3:1)

Neutral

High

507.5 (relatively large)

Yes

High (but bladder selective and P-gp substrate)

-

Fesoterodine

Non-selective

Neutral

Very low

411.6

Yes

Very low

No data yet

Oxybutynin

Non-selective

Neutral

Moderate

357 (relatively small)

No

Moderate/high

+++

Solifenacin

Mainly M3, (2.5:1)

Neutral

Moderate

480.6

No

Moderate

-/+

Tolterodine

Non-selective

Neutral

Low

475.6

No

Low

+

Trospium chloride

Non-selective

Positively charged

Not lipophilic

428

Yes

Almost none

-

P-gp, P-glycoprotein.

-, no reports of adverse effects on cognition; +, some adverse effects on cognition reported; +++, consistent reports of adverse effects on cognition.

Adapted from Bishara D et al.20 with permission.

Bronchodilators

Hypersalivation

Oral anticholinergic agents used for hypersalivation (e.g. hyoscine hydrobromide) should be avoided in the elderly because of the risk of cognitive impairment, delirium and constipation (see section on 'Anticholinergic drugs' in this section). Pirenzepine is a relatively selective M1 and M4 muscarinic receptor antagonist which does not cross the blood–brain barrier and therefore has little CNS penetration.32

Atropine solution given sublingually or used as a mouthwash is sometimes used to manage hypersalivation. There are no data available for the extent of penetration through the blood–brain barrier when atropine is administered by this route.

Myasthenia gravis

Unlike acetylcholinesterase inhibitors used in Alzheimer's disease (donepezil, rivastigmine and galantamine), those used in myasthenia gravis (pyridostigmine, neostigmine) act peripherally and do not cross the blood–brain barrier (so as to minimise unwanted central effects).33 It is possible that combining peripheral and central acetylcholinesterase inhibitors may add to the cholinomimetic adverse effect burden (e.g. nausea, vomiting diarrhoea, abdominal cramps and increased salivation). Memantine may be an alternative to cholinesterase inhibitors in cases where the combined cholinomimetic effects of drugs used for myasthenia gravis and Alzheimer's disease are not tolerated.

Analgesics

NSAIDs and paracetamol

Paracetamol is a safe drug and there is no evidence that it causes cognitive impairment other than in overdose when it may cause delirium.34 There is some evidence that chronic use of aspirin can cause confusional states.35 Case reports implicate non-steroidal anti-inflammatory drugs (NSAIDs) in causing delirium and psychosis36 although clinical trials have not demonstrated significant adverse effects on cognition with naproxen37 or indomethacin.38 NSAIDs are difficult to use in older people due to their cardiovascular risk and risk of gastrointestinal bleeding.39 It is good practice to prescribe gastroprotection with these drugs. Although there is little evidence for their efficacy and safety in dementia, consideration should be given to the use of topical NSAIDs (if clinically appropriate), to reduce GI risk.

Opiates

Sedation is a potential problem with all opiates.40 Delirium induced by opioids may be associated with agitation, hallucinations or delusions.40 Pethidine is associated with a high risk of cognitive impairment, as its metabolites have anticholinergic properties, and accumulate rapidly if renal function is impaired.41 Codeine may increase the risk of falls, and both tramadol and codeine have a high risk of drug–drug interactions, as well as considerable variation in response and adverse effects.42 Fentanyl patches, useful as they can be in chronic pain and palliative care, should not be used to initiate opioid analgesia in frail older people43 because of their long duration of action even after the patch is removed, making the treatment of side-effects more difficult.42 Morphine is a very effective analgesic but is likely to cause cognitive problems and other adverse effects in elderly patients.44 Oxycodone has a short half-life, few drug–drug interactions, and more predictable dose–response relationships than other opiates. It is therefore, theoretically at least, a good candidate for oral analgesia in dementia.42 Buprenorphine transdermal patches probably have fewer side effects than many other opiates.

Antihistamines

First-generation H1 antihistamines include chlorphenamine, hydroxyzine, cyclizine and promethazine. They are non-selective, have anticholinergic activity and readily penetrate the blood–brain barrier, which can lead to unwanted cognitive side-effects. They can impair cognitive and psychomotor performance and can trigger seizures, dyskinesia, dystonia and hallucinations. The second-generation H1 antihistamines (such as loratadine, cetirizine and fexofenadine) penetrate poorly into the CNS and are considerably less likely to cause these adverse effects. Moreover, they lack any anticholinergic effects.22

Statins

A recent Cochrane systematic review assessed the clinical efficacy and tolerability of statins in the treatment of dementia45 and showed that there was no significant benefit from statins in terms of cognitive function, but equally no evidence that statins were detrimental to cognition. Earlier case reports had highlighted subjective complaints of memory loss associated with the use of statins.46 This tended to occur in the first two months after starting the drug, and was most commonly associated with simvastatin. In the event of a patient experiencing cognitive problems on simvastatin it may be worth first stopping the drug, and if the complaint resolves, try atorvastatin or pravastatin instead, as these drugs are less likely to cross the blood–brain barrier.

Antihypertensives

Mid-life hypertension has negative effects on cognition and increases the risk of a person developing dementia.47 A recent systematic review found that treatment reduced the risk of all-cause dementia by 9% in comparison with the control group.48 Antihypertensive treatment, regardless of drug class, had a positive effect on global cognition and on all cognitive functions except language. Angiotensin II receptor blockers (ARBs) were more effective than beta-blockers, diuretics, and angiotensin-converting enzyme inhibitors in improving scores of cognition.

Other cardiac drugs

Digoxin has been associated with acute confusional states at therapeutic drug concentrations.49 It has also been reported to cause nightmares.50 However, one study showed the treatment of cardiac failure with digoxin improved cognitive performance in 25% of patients treated (and in 23% of the patients treated who did not have cardiac failure).51 There are some case reports of amiodarone being associated with delirium.52,53

Table 7.7 Recommended drugs and drugs to avoid in dementia

Condition

Drug class or drug name

Drugs to avoid in dementia

Recommended drugs in dementia

Allergic conditions

Antihistamines

Chlorphenamine
Promethazine
Hydroxyzine
Cyproheptadine
Cyclizine
(and other first-generation antihistamines)

Cetirizine
Loratadine
Fexofenadine
(and other second-generation antihistamines)

Asthma/COPD

Bronchodilators

 

Beta-agonists

Inhaled anticholinergics (have not been reported to affect cognition)

Theophylline

Constipation

Laxatives

No evidence to suggest that laxatives have any negative impact on cognitive function

Constipation itself may worsen cognition

Diarrhoea

Loperamide

Low-potency anticholinergic

Not known to have effects on cognitive function, however may add to the anticholinergic cognitive burden if used in combination with other anticholinergics

Hyperlipidaemia

Statins

 

All are safe but atorvastatin and pravastatin less likely to cross blood-brain barrier

Hypersalivation

Anticholinergics

Hyoscine hydrobromide

Pirenzepine
Atropine (sublingually)

Hypertension

Antihypertensives

Beta-blockers (avoidance may not always be possible)

Calcium channel blockers, angiotensin converting enzyme inhibitors, and angiotensin receptor blockers may all improve cognitive function

Infections

Antibiotics

Delirium reported most commonly with quinolone and macrolide antibiotics

But given the importance of treating infections, the most appropriate antibiotic for the infections should be used

Myasthenia gravis

Peripheral acetylcholinesterase inhibitors, e.g. neostigmine and pyridostigmine

May add to the cholinergic adverse effects of central acetylcholinesterase inhibitors (e.g. donepezil, etc.) in patients with dementia, i.e. increased risk of nausea, vomiting, etc.

Nausea/vomiting

Antiemetics

Cyclizine
Metoclopramide
Prochlorperazine

Domperidone (see text for restrictions) Serotonin 5HT3 receptor antagonists

Other gastrointestinal conditions

Antispasmodics

Atropine sulphate

Dicycloverine
hydrochloride

Alverine
Mebeverine
Peppermint oil
Hyoscine-n-butylbromide
Propantheline bromide

Pain

Analgesics

Pethidine
Pentazocine
Dextropropoxyphene
Codeine
Tramadol
Methadone

Paracetamol
Oxycodone
Buprenorphine
Topical NSAIDs (where appropriate)

Fentanyl patches (caution in opioid naive patients)

Morphine (may be indicated in treatment resistant pain or palliative care; use cautiously due to associated cognitive and other adverse effects)

Urinary frequency

Anticholinergic drugs used in overactive bladder

Oxybutynin
Tolterodine

Darifenacin
Trospium
Solifenacin (use if others not available; some reports of cognitive adverse effects)

Data for fesoterodine are still lacking; it is non-selective, has high central anticholinergic activity but theoretically has very low ability to cross the blood-brain barrier

Urinary retention

Alpha-blockers

Not known to have effects on cognitive function

COPD, chronic obstructive pulmonary disease; NSAIDs, non-steroidal anti-inflammatory drugs.

Adapted from Bishara D et al.20 with permission.

H2 antagonists and proton pump inhibitors

Although histamine-2 (H2) receptor antagonists (e.g. cimetidine, ranitidine) are not used widely now, it is not uncommon to see patients with dementia who have been prescribed these drugs for several years. Central nervous system reactions to these drugs have been reviewed.54 Neurotoxicity in the form of delirium, sometimes with agitation and hallucinations, generally occurred in the first two weeks of therapy and resolved within three days of stopping the drug. The estimated incidence of these reactions was 0.2% or less in outpatients, but much higher in hospitalised patients, particularly in patients with hepatic and liver failure.55 So if someone with dementia is stable on a H2 antagonist, there is no reason to stop it. Proton pump inhibitors appear less likely to cause cognitive problems.

Antibiotics

Many antibiotics have been associated rarely with delirium but there is no consistent pattern of them causing cognitive impairment. Given the importance of treating infection in dementia the most appropriate antibiotic for the infection being treated should be used. The evidence might suggest that if there is a choice between either a quinolone or macrolide antibiotic with another class of antibiotic, the other class might be the preferred for someone with dementia given the possible risk of these two classes of drugs triggering cognitive disorders. Antituberculous therapy, particularly isoniazid, has attracted some case reports of adverse psychiatric reactions.56

Table 7.7 summarises those drugs that are recommended for use in dementia and the drugs to avoid.

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Management of non-cognitive symptoms of dementia

The non-cognitive or neuropsychiatric symptoms of dementia can include: psychosis, agitation and mood disorder1 and can affect more than 90% of patients to varying degrees.2 More specifically, they often present as delusions, hallucinations, agitation, aggression, wandering, abnormal vocalisations and disinhibition (often of a sexual nature). The number, type and severity of these symptoms vary amongst patients and the fact that several types occur simultaneously in individuals, makes it difficult to target specific ones therapeutically. The safe and effective management of these symptoms is the subject of a longstanding debate because treatment is not well informed by properly conducted studies3 and many available agents have been linked to serious adverse effects.

Analgesics

It has been suggested that pain in patients with impaired language and abstract thinking may manifest as agitation and therefore treatment of undiagnosed pain may contribute to the overall prevention and management of agitation.4 An RCT investigating the effects of a stepwise protocol of treatment with analgesics in patients with moderate-to-severe dementia and agitation noted significant improvement in agitation, overall neuropsychiatric symptoms and pain. The majority of patients in the study received only paracetamol (acetaminophen).

 

Recommendation: the assessment and effective treatment of pain is important. Even in people without overt pain, a trial of paracetamol is worthwhile.

Non-drug measures

A variety of non-pharmacological methods5 have been developed and some are reasonably well supported by cogent research.6–8 Behavioural management techniques, and caregiver psycho-education, centred on individual patient's behaviour are generally successful and the effects can last for months.7 Music therapy9 and some types of sensory stimulation are useful during the sessions but have no longer-term effects.7,10 Snoezelen (specially designed rooms with soothing and stimulating environment) have shown some short term benefits in the past,11 however, a recent Cochrane Summary found that two new trials did not show any significant effects on behaviour, interactions, and mood of people with dementia.12 A number of different complementary therapies13 have been used in dementia including massage, reflexology, administration of herbal medicines and aromatherapy. Aromatherapy14,15 is the fastest growing of these therapies, with extracts from lavender and Melissa officinalis (lemon balm) most commonly used.5 While some positive results from controlled trials have shown significant reduction in agitation,16 when assessed using a rigorous blinded RCT, there was no evidence that Melissa aromatherapy is superior to placebo or donepezil.17 Overall, the evidence base remains sparse and the side effect profile relatively unexplored.18 A systematic review of aromatherapy use in non-cognitive symptoms of dementia identified adverse effects including vomiting, dizziness, abdominal pain and wheezing when essential oils were taken orally and diarrhoea, allergic skin reactions, drowsiness and serious unspecified adverse events when administered topically or by inhalation.15 Given concerns over almost all drug therapies, non-pharmacological measures should always be considered first.

 

Recommendation: evidence-based, non-drug measures are first-line treatments.

Antipsychotics in non-cognitive symptoms of dementia

First-generation antipsychotics (FGAs) have been widely used for decades in behavioural disturbance associated with dementia. They are probably effective19 but, because of extrapyramidal and other adverse effects, are less well tolerated20,21 than secondgeneration antipsychotics (SGAs). SGAs have been shown to be comparable in efficacy to FGAs for behavioural symptoms of dementia,22–24 with one study finding risperidone to be superior to haloperidol.25 SGAs were once widely recommended in dementiarelated behaviour disturbance26 but their use is now highly controversial.27,28 There are three reasons for this: effect size is small,29–32 tolerability is poor32–34 and there is a tentative association with increased mortality.35

Various reviews and trials support the efficacy of olanzapine,22,36 risperidone,37–41 quetiapine,24,42–44 aripiprazole45–47 and amisulpride.48,49 One study comparing olanzapine with risperidone31 and one comparing quetiapine with risperidone50 found no significant differences between treatment groups. However, more recent data outlined below have led to risperidone (licensed) followed by olanzapine (unlicensed) being the treatments of choice in managing psychosis or aggression in dementia. One study found clozapine to be beneficial in treatment resistant agitation associated with dementia.51

The most compelling data come from the CATIE-AD trial. This study52 showed very minor effectiveness advantages for olanzapine and risperidone (but not for quetiapine) over placebo in terms of time to discontinuation, but all drugs were poorly tolerated because of sedation, confusion and extrapyramidal side-effects (the last of these not a problem with quetiapine). Similarly, in a second report53 greater improvement was noted with olanzapine or risperidone on certain neuropsychiatric rating scales compared with placebo (but not with quetiapine). A Cochrane review54 of atypical antipsychotics for aggression and psychosis in Alzheimer's disease found that evidence suggests that risperidone and olanzapine are useful in reducing aggression and risperidone reduces psychosis. However, the authors concluded that because of modest efficacy and significant increase in adverse effects, neither risperidone nor olanzapine should be routinely used to treat patients with dementia unless there is severe distress or a serious risk of physical harm to those living or working with the patient.

Increased mortality with antipsychotics in dementia

Following analysis of published and unpublished data in 2004, initial warnings were issued in the UK and USA regarding increased mortality in patients with dementia using certain SGAs (mainly risperidone and olanzapine).55–57 These warnings have been extended to include all SGAs as well as conventional antipsychotics57,58 in view of more recent data. The inclusion of a warning about a possible risk of cerebrovascular accidents (CVAs) has now been added to product labelling for all FGAs and SGAs.

Several published analyses support these warnings,35,59 confirming an association between SGAs and stroke.60,61 The magnitude of increased mortality with FGAs has been shown to be similar62–64 to that with SGAs and possibly even greater.65–69 Some studies suggested that the risk of CVAs in elderly users of antipsychotics may not be cumulative.70,71 The risk was found to be elevated especially during the first weeks of treatment but then decreased over time, returning to base level after 3 months. In contrast, a long-term study (24–54 months) deduced that mortality was progressively increased over time for antipsychotic-treated (risperidone and FGAs) patients compared with those receiving placebo.72 At present this is not a widely held view.

Whether the risk of mortality differs from one antipsychotic to another has recently been investigated in two separate studies. The first study73 found that among nursing home residents prescribed antipsychotics, when compared with risperidone, haloperidol users had an increased risk of mortality whereas quetiapine users had a decreased risk. No clinically meaningful differences were observed for the other drugs investigated: olanzapine, aripiprazole and ziprasidone. The effects were strongest shortly after the start of treatment and remained after adjustment for dose. There was a dose–response relation for all drugs except quetiapine.73 The second study74 confirmed these findings. This study included elderly patients with dementia and also assessed risk of mortality with valproic acid. Haloperidol was associated with the highest rates of mortality, followed by risperidone, olanzapine, valproic acid and then quetiapine. One study70 suggests affinity for M1 and α2-receptors predicts effects on stroke.

Several mechanisms have been postulated for the underlying causes of CVAs with antipsychotics.75 Orthostatic hypotension may aggravate the deficit in cerebral perfusion in an individual with cerebrovascular insufficiency or atherosclerosis thus causing a CVA. Tachycardia may similarly decrease cerebral perfusion or dislodge a thrombus in a patient with atrial fibrillation (see section on 'Atrial fibrillation' in this chapter). Following an episode of orthostatic hypotension, there could be a rebound excess of catecholamines with vasoconstriction thus aggravating cerebral insufficiency. In addition, hyperprolactinaemia could in theory accelerate atherosclerosis and sedation might cause dehydration and haemoconcentration, each of which are possible mechanisms for increased risk of cerebrovascular events.75

A review of the literature on the safety of antipsychotics in elderly patients with dementia found that overall, atypical and typical antipsychotics were associated with similar increased risk for all-cause mortality and cerebrovascular events. Patients being treated with typical agents have an increased risk of cardiac arrhythmias and extrapyramidal symptoms relative to atypical users. Conversely, users of atypical antipsychotics are exposed to an increased risk of venous thromboembolism and aspiration pneumonia. Despite metabolic effects having consistently been documented in studies with atypical antipsychotics, this effect tends to be attenuated with advancing age and in elderly patients with dementia.76

Both typical77 and atypical antipsychotics78 may also hasten cognitive decline in dementia, although there is some evidence to refute this.50,79,80

 

Recommendation: use of risperidone (licensed for persistent aggression in Alzheimer's disease) and olanzapine may be justified in some cases. Effect is modest at best.

Clinical information for antipsychotic use in dementia

Risperidone is the only drug licensed in the UK for the management of non-cognitive symptoms associated with dementia and is therefore the agent of choice. It is specifically indicated for short term treatment (up to 6 weeks) of persistent aggression in patients with moderate-to-severe Alzheimer's disease unresponsive to non-pharmacological approaches and when there is a risk of harm to self or others.81 Risperidone is licensed up to 1 mg twice a day82, although optimal dose in dementia has been found to be 500 μg twice a day (1 mg daily).83

Monitoring recommendations are as follows.

Alternative antipsychotic drugs may be used (off-licence) if risperidone is contraindicated or not tolerated. Olanzapine has some positive efficacy data for reducing aggression in dementia,54 work is underway investigating the efficacy and tolerability of amisulpride in dementia,84 and quetiapine (although not as effective as risperidone and olanzapine) may be considered in patients with Parkinson's disease, or Lewy body dementia (at very small doses) because of its low propensity for causing movement disorders.

Other pharmacological agents in non-cognitive symptoms of dementia

Cognitive enhancers

Donepezil,85,86 rivastigmine87–90 and galantamine91–93 may afford some benefit in reducing behavioural disturbance in dementia. Their effect seems apparent only after several weeks of treatment.94 However, the evidence is somewhat inconsistent and a study of donepezil in agitation associated with dementia found no apparent benefit compared with placebo.95 Rivastigmine has shown positive results for neuropsychiatric symptoms associated with vascular87 and Lewy body dementia.87,96 A meta-analysis investigating the impact of acetylcholinesterase inhibitors (AChE-Is) on non-cognitive symptoms of dementia found a statistically significant reduction in symptoms among patients with Alzheimer's disease, however the clinical relevance of this effect remained unclear.97 A systematic review of RCTs concluded that cholinesterase inhibitors have, at best, a modest impact on non-cognitive symptoms of dementia. However, in the absence of alternative safe and effective pharmacological options, a trial of a cholinesterase inhibitor is an appropriate pharmacological strategy for the management of behavioural disturbances in Alzheimer's disease.98

NICE guidance suggests considering a cholinesterase inhibitor only for:99,100

Growing evidence for memantine also suggests benefits for neuropsychiatric symptoms associated with Alzheimer's disease.101–103 A Cochrane review104 of memantine found that slightly fewer patients with moderate-to-severe Alzheimer's disease taking memantine develop agitation, but one study105 found no effect for memantine in established agitation. The review also suggested that memantine may have a small beneficial effect on behaviour in mild-to-moderate vascular dementia but this was not supported by clinical global measures.104 Despite apparently positive findings in studies (often manufacturer-sponsored) the use of cognitive enhancing agents for behavioural disturbance remains controversial.

 

Recommendation: use of AChE-Is or memantine can be justified in situations described above. Effect is modest at best.

Benzodiazepines

Benzodiazepines106,107 are widely used but their use is poorly supported. Benzodiazepines have been associated with cognitive decline106 and may contribute to increased frequency of falls and hip fractures107,108 in the elderly population.

 

Recommendation: avoid.

Antidepressants

Substantial evidence suggests that depression can be considered both a cause and consequence of Alzheimer's disease. Depression is considered causative because it is a risk factor for Alzheimer's disease. In fact, the prevalence rate of depression and Alzheimer's disease co-morbidity is estimated to be 30–50%.109 Two potential mechanisms by which antidepressants affect cognition in depression have been postulated: a direct effect caused by the pharmacological action of the drugs on specific neurotransmitters and a secondary effect caused by improvement of depression.110

Despite reports of a possible modest advantage over placebo, SSRIs have shown doubtful efficacy in non-cognitive symptoms of dementia in the past.111,112 One review however, contradicted previous findings and indicated that antidepressants (mainly SSRIs) not only showed efficacy in treating non-cognitive symptoms, but were also well tolerated.113 The authors noted that the most common antidepressants used in dementia were sertraline followed by citalopram and trazodone. Some of the clinical evidence demonstrating the beneficial effects of SSRIs in patients with Alzheimer's disease either alone or in combination with cholinesterase inhibitors have been summarised in recent papers.109,114 The Citalopram for Agitation in AD Study (CitAD) found that the addition of citalopram titrated up to 30 mg/day significantly reduced agitation and caregivers' distress compared with placebo in 186 patients who were receiving psychosocial intervention. This is perhaps of academic interest only, as the maximum dose of citalopram in this group of patients is 20 mg a day because of the drug's effect on cardiac QT interval.115

Findings suggest that in patients with Alzheimer's disease treated with cholinesterase inhibitors, SSRIs may exert some degree of protection against the negative effects of depression on cognition. To date, literature analysis does not clarify if the combined effect of SSRIs and AChE-Is is synergistic, additive or independent.110 In addition, it is still unclear whether SSRIs have beneficial effects on cognition in patients with Alzheimer's disease who are not actively manifesting mood or behavioural problems.114 Trazodone116,117 is sometimes used for non-cognitive symptoms although evidence is limited. It has been found to reduce irritability and cause a slight reduction in agitation, most probably by means of its sedative effects.116,117 A Cochrane review of trazodone for agitation in dementia116 however found insufficient evidence from RCTs to support its use in dementia.

A second, more recent Cochrane review investigating the efficacy and safety of antidepressants for agitation and psychosis in dementia has also been published.118 The authors concluded that there are currently relatively few studies available but there is some evidence to support the use of certain antidepressants for agitation and psychosis in dementia. The SSRIs sertraline and citalopram were associated with a reduction in symptoms of agitation when compared with placebo in two studies. Both SSRIs and trazodone appear to be tolerated reasonably well when compared with placebo, typical antipsychotics and atypical antipsychotics. Future studies involving more subjects are required however to determine the effectiveness and safety of SSRIs, trazodone, or other antidepressants in managing these symptoms.

A Cochrane review investigating whether antidepressants are clinically effective and acceptable for the treatment of patients with depression in the context of dementia concluded that antidepressants are not necessarily ineffective in dementia but rather there is not much evidence to support their efficacy and therefore they should be used with caution.119 Furthermore, a large, independent, parallel group RCT found no difference in depression scores when comparing placebo, sertraline or mirtazapine in patients with dementia suggesting that first line treatment for depression in Alzheimer's disease should be reconsidered.120

Tricyclic antidepressants are best avoided in patients with dementia. They can cause falls, possibly via orthostatic hypotension, and increase confusion because of their anticholinergic adverse effects.121

 

Recommendation: use of SSRIs may be justified in some cases. Effect is modest at best. Supporting evidence is weak.

Mood stabilisers/anticonvulsants

Randomised controlled trials of mood stabilisers in non-cognitive symptoms of dementia have been completed for oxcarbazepine122 carbamazepine123 and valproate.124 Gabapentin, lamotrigine and topiramate have also been used.125 Of the mood stabilisers, carbamazepine has the most robust evidence of efficacy in non-cognitive symptoms.126 However, its serious adverse effects (especially Stevens-Johnson syndrome) and its potential for drug interactions somewhat limit its use. One RCT of valproate, which included an open-label extension, found valproate to be ineffective in controlling symptoms. Seven of the thirty-nine patients enrolled died during the 12-week extension phase study period, although the deaths could not be attributed to the drug.127 A study investigating the optimal dose of valproic acid in dementia found that whilst serum levels between 40 and 60 μg/L and relatively low doses (7–12 mg/kg per day) are associated with improvements in agitation in some patients, similar levels produced no significant improvements in others and led to substantial side-effects.128 A Cochrane review of valproate for the treatment of agitation in dementia found no evidence of efficacy but advocated the need for further research into its use in dementia.129 Valproate does not delay emergence of agitation in dementia.130 Literature reviews of anticonvulsants in non-cognitive symptoms of dementia found that valproate, oxcarbazepine and lithium showed low or no evidence of efficacy and that more RCTs are needed to strengthen the evidence for gabapentin, topiramate and lamotrigine.126 Although clearly beneficial in some patients, anticonvulsant mood stabilisers cannot be recommended for routine use in the treatment of the neuropsychiatric symptoms in dementia at present.125

 

Recommendation: limited evidence to support use. Use may be justified where other treatments are contraindicated or ineffective. Valproate best avoided.

Miscellaneous agents

There is growing evidence for the effects of Ginkgo biloba on neuropsychiatric symptoms of dementia especially for apathy, anxiety, depression and irritability.131 A once daily dose of 240 mg was safe and effective in patients with mild-to-moderate dementia.132

Summary

The evidence base available to guide treatment in this area is insufficient to allow specific recommendations on appropriate management and drug choice. The basic approach is to try non-drug measures and analgesia before resorting to the use of psychotropics. Whichever drug is chosen, the following approach should be noted.

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  113. Henry G et al. Efficacy and tolerability of antidepressants in the treatment of behavioral and psychological symptoms of dementia, a literature review of evidence. Am J Alzheimers Dis Other Demen 2011; 26:169–183.
  114. Chow TW et al. Potential cognitive enhancing and disease modification effects of SSRIs for Alzheimer's disease. Neuropsychiatr Dis Treat 2007; 3:627–636.
  115. Porsteinsson AP et al. Effect of citalopram on agitation in Alzheimer disease: the CitAD randomized clinical trial. JAMA 2014; 311:682–691.
  116. Martinon-Torres G et al. Trazodone for agitation in dementia. Cochrane Database Syst Rev 2004; CD004990.
  117. Lopez-Pousa S et al. Trazodone for Alzheimer's disease: a naturalistic follow-up study. Arch Gerontol Geriatr 2008; 47:207–215.
  118. Seitz DP et al. Antidepressants for agitation and psychosis in dementia. Cochrane Database Syst Rev 2011; 2: CD008191.
  119. Bains J et al. The efficacy of antidepressants in the treatment of depression in dementia. Cochrane Database Syst Rev 2002; CD003944.
  120. Banerjee S et al. Sertraline or mirtazapine for depression in dementia (HTA-SADD): a randomised, multicentre, double-blind, placebocontrolled trial. Lancet 2011; 378:403–411.
  121. Ballard C et al. Management of neuropsychiatric symptoms in people with dementia. CNS Drugs 2010; 24:729–739.
  122. Sommer OH et al. Effect of oxcarbazepine in the treatment of agitation and aggression in severe dementia. Dement Geriatr Cogn Disord 2009; 27:155–163.
  123. Tariot PN et al. Efficacy and tolerability of carbamazepine for agitation and aggression in dementia. Am J Psychiatry 1998; 155:54–61.
  124. Lonergan E et al. Valproate preparations for agitation in dementia. Cochrane Database Syst Rev 2009; CD003945.
  125. Konovalov S et al. Anticonvulsants for the treatment of behavioral and psychological symptoms of dementia: a literature review. Int Psychogeriatr 2008; 20:293–308.
  126. Yeh YC et al. Mood stabilizers for the treatment of behavioral and psychological symptoms of dementia: an update review. Kaohsiung J Med Sci 2012; 28:185–193.
  127. Sival RC et al. Sodium valproate in aggressive behaviour in dementia: a twelve-week open label follow-up study. Int J Geriatr Psychiatry 2004; 19:305–312.
  128. Dolder CR et al. Valproic acid in dementia: does an optimal dose exist? J Pharm Pract 2012; 25:142–150.
  129. Lonergan E et al. Valproate preparations for agitation in dementia. Cochrane Database Syst Rev 2009; CD003945.
  130. Tariot PN et al. Chronic divalproex sodium to attenuate agitation and clinical progression of Alzheimer disease. Arch Gen Psychiatry 2011; 68:853–861.
  131. Scripnikov A et al. Effects of Ginkgo biloba extract EGb 761 on neuropsychiatric symptoms of dementia: findings from a randomised controlled trial. Wien Med Wochenschr 2007; 157:295–300.
  132. Bachinskaya N et al. Alleviating neuropsychiatric symptoms in dementia: the effects of Ginkgo biloba extract EGb 761. Findings from a randomized controlled trial. Neuropsychiatr Dis Treat 2011; 7:209–215.

Parkinson's disease

Parkinson's disease is a progressive, degenerative neurological disorder characterised by resting tremor, cogwheel rigidity, bradykinesia and postural instability. The prevalence of co-morbid psychiatric disorders is high. Approximately 25% will suffer from major depression at some point during the course of their illness, a further 25% from milder forms of depression, 25% from anxiety spectrum disorders, 25% from psychosis and up to 80% will develop dementia.1–3 While depression and anxiety can occur at any time, psychosis, dementia and delirium are more prevalent in the later stages of the illness. Close co-operation between the psychiatrist and neurologist is required to optimise treatment for this group of patients.

Depression in Parkinson's disease

Depression in Parkinson's disease predicts greater cognitive decline, deterioration in functioning and progression of motor symptoms;4 possibly reflecting more advanced and widespread neurodegeneration involving multiple neurotransmitter pathways.5 Depression may also occur after the withdrawal of dopamine agonists.6 Pre-existing dementia is an established risk factor for the development of depression.Recommendations for the treatment of depression in Parkinson's disease are shown in Box 7.3.

Box 7.3 Recommendations for the treatment of depression in Parkinson's disease

Step

Intervention

1

Exclude/treat organic causes such as hypothyroidism (the prevalence of which is relatively high in Parkinson's disease4).

2

SSRIs are considered to be first-line treatment although the effect size is modest.7-9 Some patients may experience a worsening of motor symptoms although the absolute risk is low.10,11 Care must be taken when combining SSRIs with selegiline, as the risk of serotonin syndrome is increased.4 The SNRIs venlafaxine12 and duloxetine13 also appear to have some effect although venlafaxine may modestly worsen motor symptoms.12 TCAs are generally poorly tolerated because of their anticholinergic (can worsen cognitive problems; constipation) and alpha-blocking effects (can worsen symptoms of autonomic dysfunction). Note though that several meta-analyses8,9 have reported that low dose TCAs to be more effective than SSRIs,14-16 although low dose amitriptyline and sertraline seem to be equally effective.17 Atomoxetine is not effective.18 CBT should always be considered.19

3

Consider augmentation with dopamine agonists/releasers such as pramiprexole.20 Note though that these drugs increase the risk of impulse control disorders.21,22 They have also been associated with the development of psychosis.23

4

Consider ECT. Depression and motor symptoms generally respond well4 but the risk of inducing delirium is high,24 particularly in patients with pre-existing cognitive impairment.

5

Follow the algorithm for treatment-resistant depression (see section on 'Treatment of refractory depression' in Chapter 4) from this point. Be aware of the increased propensity for adverse effects and drug interactions in this patient group.

CBT, cognitive behavioural therapy; ECT, electroconvulsive therapy; SNRI, selective noradrenaline reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressants.

Psychosis in Parkinson's disease

Psychosis in Parkinson's disease is often characterised by visual hallucinations.25 Auditory hallucinations and delusions occur far less frequently,26 and usually in younger patients.27 Psychosis and dementia frequently co-exist. Having one predicts the development of the other.28 Sleep disorders are also an established risk factor for the development of psychosis.29

Abnormalities in dopamine, serotonin and acetylcholine neurotransmission have all been implicated, but the exact aetiology of Parkinson's disease psychosis is poorly understood. In the majority of patients, psychotic symptoms are thought to be secondary to dopaminergic medication rather than part of Parkinson's disease itself; psychosis secondary to medication may be determined at least in part through polymorphisms of the angiotensin-converting enzyme (ACE) gene.30 From the limited data available, anticholinergics and dopamine agonists seem to be associated with a higher risk of inducing psychosis than levodopa or catechol-O-methyltransferase (COMT) inhibitors.26,31 Psychosis is a major contributor to caregiver distress and a risk factor for institutionalisation and early death.28

Box 7.4 Recommendations for the treatment of psychosis in Parkinson's disease

Step

Intervention

1

Exclude organic causes (delirium).

2

Optimise the environment to maximise orientation and minimise problems due to poor caregiver-patient interactions.

3

If the patient has insight and hallucinations are infrequent and not troubling, do not treat.

4

Consider reducing or stopping anticholinergics and dopamine agonists. Monitor for signs of motor deterioration. Be prepared to restart/increase the dose of these drugs again to achieve the best balance between psychosis and mobility.

5

Try an atypical antipsychotic. The efficacy of clozapine (see point 7) is supported by placebo-controlled randomised controlled trials.25 In contrast, there are several negative placebo-controlled trials each for quetiapine and olanzapine.25 Low dose quetiapine is the best tolerated, although extrapyramidal side-effects and stereotypical movements can occur. It is probably reasonable to try quetiapine before clozapine but the success rate may be low. Olanzapine, ziprasidone and aripiprazole are likely to all have greater adverse effects on motor function than quetiapine, although one small trial32 supports the safe use of ziprasidone. Risperidone and typical antipsychotics should be avoided completely. Severe rebound psychosis has been described when antipsychotic drugs (quetiapine or clozapine) are discontinued.

Note that all antipsychotics may be even less effective in managing psychotic symptoms in patients with dementia, and such patients may be more prone to developing motor and cognitive side effects.33 Antipsychotics have been associated with an increased risk of vascular events in the elderly. See section on 'Antipsychotics and non-cognitive symptoms of dementia' in this chapter.

6

Consider a cholinesterase inhibitor, particularly if the patient has co-morbid dementia.25,34 Cholinesterase inhibitors may also reduce the risk of falls.35

7

Try clozapine. Start at 6.25 mg - usual dose 25 mg-35 mg/day.25,32 Usually safe but neuroleptic malignant syndrome has been reported.36

Monitor as for clozapine in schizophrenia. The elderly are more prone to develop serious blood dyscrasia. A case of aplastic anaemia has been reported.37

8

Consider ECT.38 Psychotic and motor symptoms usually respond well39 but the risk of inducing delirium is high,24 particularly in patients with pre-existing cognitive impairment.

ECT, electroconvulsive therapy.

Recommendations for the treatment of psychosis in Parkinson's disease are shown in Box 7.4. In addition to the studies described, there is one failed RCT of pimavanserin, a 5HT2a inverse agonist40 and one demonstrating useful activity.41 Pimavanserin remains unlicensed.

Dementia in Parkinson's disease

Cholinesterase inhibitors have been shown to improve cognition, delusions and hallucinations in patients with Lewy body dementia (which has some similarities to Parkinson's disease). Motor function may deteriorate.42,43 Improvements in cognitive functioning are modest.44,45 A Cochrane review and recent large RCTs45–47 conclude that there is evidence that cholinesterase inhibitors lead to improvements in global functioning, cognition, behavioural disturbance and activities of daily living in Parkinson's disease. Again, motor function may deteriorate.47,48 Evidence for memantine is mixed.49,50 Most patients with Parkinson's disease use complementary therapies, some of which may be modestly beneficial. See Zesiewicz et al.40 Caffeine may offer a protective effect against the development of Parkinson's disease and also modestly improve motor function in established disease.51

References

  1. Hely MA et al. The Sydney multicenter study of Parkinson's disease: the inevitability of dementia at 20 years. Mov Disord 2008; 23:837–844.
  2. Riedel O et al. Frequency of dementia, depression, and other neuropsychiatric symptoms in 1,449 outpatients with Parkinson's disease. J Neurol 2010; 257:1073–1082.
  3. Reijnders JS et al. A systematic review of prevalence studies of depression in Parkinson's disease. Mov Disord 2008; 23:183–189.
  4. McDonald WM et al. Prevalence, etiology, and treatment of depression in Parkinson's disease. Biol Psychiatry 2003; 54:363–375.
  5. Palhagen SE et al. Depressive illness in Parkinson's disease—indication of a more advanced and widespread neurodegenerative process? Acta Neurol Scand 2008; 117:295–304.
  6. Rabinak CA et al. Dopamine agonist withdrawal syndrome in Parkinson disease. Arch Neurol 2010; 67:58–63.
  7. Rocha FL et al. Antidepressants for depression in Parkinson's disease: systematic review and meta-analysis. J Psychopharmacol 2013; 27:417–423.
  8. Liu J et al. Comparative efficacy and acceptability of antidepressants in Parkinson's disease: a network meta-analysis. PLoS One 2013; 8:e76651.
  9. Troeung L et al. A meta-analysis of randomised placebo-controlled treatment trials for depression and anxiety in Parkinson's disease. PLoS One 2013; 8:e79510.
  10. Gony M et al. Risk of serious extrapyramidal symptoms in patients with Parkinson's disease receiving antidepressant drugs: a pharmacoepidemiologic study comparing serotonin reuptake inhibitors and other antidepressant drugs. Clin Neuropharmacol 2003; 26:142–145.
  11. Kulisevsky J et al. Motor changes during sertraline treatment in depressed patients with Parkinson's disease. Eur J Neurol 2008; 15:953–959.
  12. Richard IH et al. A randomized, double-blind, placebo-controlled trial of antidepressants in Parkinson disease. Neurology 2012; 78:1229–1236.
  13. Bonuccelli U et al. A non-comparative assessment of tolerability and efficacy of duloxetine in the treatment of depressed patients with Parkinson's disease. Expert Opin Pharmacother 2012; 13:2269–2280.
  14. Serrano-Duenas M. A comparison between low doses of amitriptyline and low doses of fluoxetine used in the control of depression in patients suffering from Parkinson's disease (Spanish). Rev Neurol 2002; 35:1010–1014.
  15. Menza M et al. A controlled trial of antidepressants in patients with Parkinson disease and depression. Neurology 2009; 72:886–892.
  16. Devos D et al. Comparison of desipramine and citalopram treatments for depression in Parkinson's disease: a double-blind, randomized, placebo-controlled study. Mov Disord 2008; 23:850–857.
  17. Antonini A et al. Randomized study of sertraline and low-dose amitriptyline in patients with Parkinson's disease and depression: effect on quality of life. Mov Disord 2006; 21:1119–1122.
  18. Weintraub D et al. Atomoxetine for depression and other neuropsychiatric symptoms in Parkinson disease. Neurology 2010; 75:448–455.
  19. Dobkin RD et al. Cognitive-behavioral therapy for depression in Parkinson's disease: a randomized, controlled trial. Am J Psychiatry 2011; 168:1066–1074.
  20. Barone P et al. Pramipexole versus sertraline in the treatment of depression in Parkinson's disease: a national multicenter parallel-group randomized study. J Neurol 2006; 253:601–607.
  21. Antonini A et al. A reassessment of risks and benefits of dopamine agonists in Parkinson's disease. Lancet Neurol 2009; 8:929–937.
  22. Weintraub D et al. Impulse control disorders in Parkinson disease: a cross-sectional study of 3090 patients. Arch Neurol 2010; 67:589–595.
  23. Li CT et al. Pramipexole-induced psychosis in Parkinson's disease. Psychiatry Clin Neurosci 2008; 62:245.
  24. Figiel GS et al. ECT-induced delirium in depressed patients with Parkinson's disease. J Neuropsychiatry Clin Neurosci 1991; 3:405–411.
  25. Friedman JH. Parkinson's disease psychosis 2010: a review article. Parkinsonism Relat Disord 2010; 16:553–560.
  26. Ismail MS et al. A reality test: How well do we understand psychosis in Parkinson's disease? J Neuropsychiatry Clin Neurosci 2004; 16:8–18.
  27. Kiziltan G et al. Relationship between age and subtypes of psychotic symptoms in Parkinson's disease. J Neurol 2007; 254:448–452.
  28. Factor SA et al. Longitudinal outcome of Parkinson's disease patients with psychosis. Neurology 2003; 60:1756–1761.
  29. Reich SG et al. Ten most commonly asked questions about the psychiatric aspects of Parkinson's disease. Neurologist 2003; 9:50–56.
  30. Lin JJ et al. Genetic polymorphism of the angiotensin converting enzyme and L-dopa-induced adverse effects in Parkinson's disease. J Neurol Sci 2007; 252:130–134.
  31. Ives NJ et al. Dopamine agonist therapy in early Parkinson's disease: a systematic review of randomised controlled trials. Mov Disord 2004; 19 Suppl 9.
  32. Pintor L et al. Ziprasidone versus clozapine in the treatment of psychotic symptoms in Parkinson disease: a randomized open clinical trial. Clin Neuropharmacol 2012; 35:61–66.
  33. Prohorov T et al. The effect of quetiapine in psychotic Parkinsonian patients with and without dementia. An open-labeled study utilizing a structured interview. J Neurol 2006; 253:171–175.
  34. Marti M et al. Dementia in Parkinson's disease. J Neurol 2007; 254 Suppl 1:41–48.
  35. Chung KA et al. Effects of a central cholinesterase inhibitor on reducing falls in Parkinson disease. Neurology 2010; 75:1263–1269.
  36. Mesquita J et al. Fatal neuroleptic malignant syndrome induced by clozapine in Parkinson's psychosis. J Neuropsychiatry Clin Neurosci 2014; 26:E34.
  37. Ziegenbein M et al. Clozapine-induced aplastic anemia in a patient with Parkinson's disease. Can J Psychiatry 2003; 48:352.
  38. Factor SA et al. Combined clozapine and electroconvulsive therapy for the treatment of drug-induced psychosis in Parkinson's disease. J Neuropsychiatry Clin Neurosci 1995; 7:304–307.
  39. Martin BA. ECT for Parkinson's? CMAJ 2003; 168:1391–1392.
  40. Zesiewicz TA et al. Potential influences of complementary therapy on motor and non-motor complications in Parkinson's disease. CNS Drugs 2009; 23:817–835.
  41. Cummings J et al. Pimavanserin for patients with Parkinson's disease psychosis: a randomised, placebo-controlled phase 3 trial. Lancet 2014; 383:533–540.
  42. Richard IH et al. Rivastigmine-induced worsening of motor function and mood in a patient with Parkinson's disease. Mov Disord 2001; 16:33–34.
  43. McKeith I et al. Efficacy of rivastigmine in dementia with Lewy bodies: a randomised, double-blind, placebo-controlled international study. Lancet 2000; 356:2031–2036.
  44. Emre M et al. Rivastigmine for dementia associated with Parkinson's disease. N Engl J Med 2004; 351:2509–2518.
  45. Aarsland D et al. Donepezil for cognitive impairment in Parkinson's disease: a randomised controlled study. J Neurol Neurosurg Psychiatry 2002; 72:708–712.
  46. Rolinski M et al. Cholinesterase inhibitors for dementia with Lewy bodies, Parkinson's disease dementia and cognitive impairment in Parkinson's disease. Cochrane Database Syst Rev 2012; 3: CD006504.
  47. Dubois B et al. Donepezil in Parkinson's disease dementia: a randomized, double-blind efficacy and safety study. Mov Disord 2012; 27:1230–1238.
  48. Connolly BS et al. Pharmacological treatment of Parkinson disease: a review. JAMA 2014; 311:1670–1683.
  49. Emre M et al. Memantine for patients with Parkinson's disease dementia or dementia with Lewy bodies: a randomised, double-blind, placebocontrolled trial. Lancet Neurol 2010; 9:969–977.
  50. Seppi K et al. The Movement Disorder Society Evidence-Based Medicine Review Update: Treatments for the non-motor symptoms of Parkinson's disease. Mov Disord 2011; 26 Suppl 3:S42–S80.
  51. Postuma RB et al. Caffeine for treatment of Parkinson disease: a randomized controlled trial. Neurology 2012; 79:651–658.

Further reading

Goldman JG et al. Treatment of psychosis and dementia in Parkinson's disease. Curr Treat Options Neurol 2014; 16:281.

Multiple sclerosis

Multiple sclerosis (MS) is a common cause of neurological disability affecting approximately 85,000 people in the UK with the onset usually between 20–50 years of age. Individuals with MS experience a variety of psychiatric/neurological disorders such as depression, anxiety, pathological laughter and crying (PLC) (pseudobulbar affect, PBA), mania and euphoria, psychosis/bipolar disorder, fatigue and cognitive impairment. Psychiatric disorders result from the psychological impact of MS diagnosis and prognosis, perceived lack of social support or unhelpful coping styles,1 increased stress,2 iatrogenic effects of treatments commonly used with MS,3 or damage to neuronal pathways.3 According to some studies, shorter duration of illness confers a greater risk of depression.

Depression

In people with MS, depression is common with a point prevalence of 14–27%4,5 and lifetime prevalence of up to 50%.5 Suicide rates are 2–7.5 times higher than the general population.6 Depression is often associated with fatigue and pain, though the relationship direction is unclear. Overlapping symptoms of depression, PBA and MS can complicate diagnosis and so co-operation between neurologists and psychiatrists is essential to ensure optimal treatment for individuals with MS.

The role of interferon-beta in the aetiology of MS depression is unclear, but it is now thought that depression occurs no more frequently in people treated with interferonbeta.7,8 Standard care for initiation of interferon-beta should include assessment for depression and, for those with a past history of depressive illness, prophylactic treatment with an antidepressant.3 Recommendations for the treatment of depression in MS are shown in Box 7.5.

Anxiety

Anxiety affects many people with MS, with a point prevalence of up to 50%25 and lifetime incidence of 35–37%26. Elevated rates in comparison with the general population are seen for generalized anxiety disorder, panic disorder, obsessive compulsive disorder26 and social anxiety. Anxiety appears linked to perceived lack of support, increased pain, fatigue, sleep disturbance, depression, alcohol misuse, and suicidal ideas. There are no published trials for the treatment of anxiety in MS, but SSRIs can be used and, in non-responsive cases, venlafaxine might be an option.

Benzodiazepines may be used for acute and severe anxiety of less than 4 weeks duration but should not be prescribed in the long term. Buspirone and beta-blockers could also be considered although there is unproven efficacy in MS. Pregabalin is also licensed for anxiety and may be useful in this population group. People with MS may also respond to CBT. Generally treatment is as for non-MS anxiety disorders (see section on 'Anxiety spectrum disorders' in Chapter 4)

Pseudobulbar affect (PBA)

Up to 10% of individuals with MS experience PLC. It is more common in the advanced stages of the disease and is associated with cognitive impairment.26 There have been a few open label trials recommending the use of small doses of TCAs, e.g. amitriptyline, or SSRIs, e.g. fluoxetine27,28 in MS. Citalopram29 or sertraline30 have been investigated in people with post-stroke PLC and shown reasonable efficacy and rapid response. The combination of dextromethorphan and quinidine (Nuedexta) is effective.31

Box 7.5 Recommendations for the treatment of depression in MS

Step

Intervention

1

Screen for depression with PHQ-9 HADS/BDI9/CES-D.10 Exclude and treat any organic causes. Consider iatrogenic effects of medications as potential cause of depression. Ensure there is no past history of mania or bipolar disorder. People with mild depression could be considered for CBT11 or self-help.12

2

SSRIs should be first line treatment3,10,13 because of their relatively benign side-effect profile.

Sertraline was as effective as CBT in one trial,14 but paroxetine was found to be no more effective than placebo in another study.15 Because of reduced tolerability of side-effects in this patient group, medications should be titrated from an initial half dose. Many MS patients are prescribed low dose TCAs for pain/bladder disturbance and so SSRIs should be used with caution and patients should be observed for serotonin syndrome. For those with co-morbid pain, consideration should be given to treating with an SNRI such as duloxetine or venlafaxine.16 One RCT of desipramine showed it was more effective than placebo but tricyclics are often poorly tolerated.17 Cochrane is not convinced by the studies cited here,18 but there is no reason to suppose that antidepressants are any less effective in depression associated with physical illness.19 CBT is the most appropriate psychological intervention with best efficacy in comparison to supportive therapy or usual care, and should be used in conjunction with medication for those who are moderately-severely depressed.13,14,20 Mindfulness training may also help.21

3

If SSRIs are not tolerated, or there is no response, there are limited data that moclobemide is effective and well tolerated.23,23 There are no published trials on venlafaxine, duloxetine and mirtazapine but these are used widely.

4

ECT could be considered for people who are actively suicidal or severely depressed and at high risk, but it may trigger an exacerbation of MS symptoms, although some studies suggest that no neurological disturbance occurs.24

BDI, Beck Depression Inventory; CBT, cognitive behavioural therapy; HADS, Hospital Anxiety and Depression Scale; CES-D, Centre for Epidemiological Studies Depression Scale; MS, multiple sclerosis; PHQ-9, Patient Health Questionnaire-9; RCT, randomised controlled trial; SNRI, serotonin noradrenaline reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant.

Mania/euphoria/bipolar disorder

Incidence of bipolar disorder can be as high as 13% in the MS population2 compared with 1–6% in the general population. Mania can be induced by drugs such as steroids or baclofen.32

Anecdotal evidence suggests that patients presenting with mania/bipolar disorder should be treated with mood stabilisers such as sodium valproate as these are better tolerated than lithium.33

Lithium can cause diuresis and thus lead to increased difficulties with tolerance. Mania accompanied by psychosis could be treated with low dose atypical antipsychotics such as risperidone, olanzapine,2 ziprasidone.34 Patients requiring psychiatric treatment for steroid-induced mania with psychosis have been known to respond well to olanzapine;35 further case reports suggest risperidone is also useful. There have been no trials in this area.

Psychosis

Psychosis occurs in 1.1% of the MS population and compared with other psychiatric disorders is relatively uncommon.34 There have been few published trials, but risperidone or clozapine have been recommended because of their low risk of extra pyramidal symptoms.32 On this basis, olanzapine, aripiprazole and quetiapine might also, in theory at least, be possible options.

Psychosis may rarely be the presentation of an MS relapse in which case steroids may be beneficial but would need to be given under close supervision. Note also the small risk of psychotic reactions in patients receiving cannabinnoids for MS.36

Cognitive impairment

Cognitive impairment occurs in at least 40–65% of people with MS. Some of the effects of medications commonly prescribed can worsen cognition, e.g. tizanidine, diazepam, gabapentin.37 Although there are no published trials, evidence from clinical case studies suggests that the treatment of sleep difficulties, depression and fatigue can enhance cognitive function.37 There have been two small, underpowered trials with donepezil for people with mild-to-moderate cognitive impairment showing moderate efficacy.442,443 A larger study found no effect.40 Similarly, data supporting the use of memantine are weak.41 Overall, no symptomatic treatment has proven efficacy and disease modifying agents offer greater promise.42

Fatigue

Fatigue is a common symptom in MS with up to 80% of people with MS affected.43 The aetiology of fatigue is unclear but there have been suggestions that disruption of neuronal networks,44 depression or psychological reactions,32 sleep disturbances or medication may play a role in its development. Pharmacological and non-pharmacological strategies43 should be used in a treatment strategy.

Non-pharmacological strategies include reviewing history for any possible contributing factors, assessment and treatment of underlying depression if present, medication, pacing activities and appropriate exercise. One trial suggests that CBT reduces fatigue scores.45

Pharmacological strategies include the use of amantadine46 or modafinil. NICE guidelines suggest no medicine should be used routinely but that amantadine could have a small benefit.47 A Cochrane review of amantadine in people with MS suggests that the quality and outcomes of the amantadine trials are inconsistent and therefore efficacy remains unclear.46 In the only study published since then,48 amantadine outperformed placebo on some measures of fatigue. Modafinil has mixed results in clinical trials. Early studies49,50 showed statistically significant improvements in fatigue, but these studies were subject to some bias. A later randomized placebo-controlled double blind study51 found no improvement in fatigue compared with placebo. The most recent study52 showed distinct advantages for modafinil over placebo. Despite doubts over its efficacy modafanil is widely used in MS.53

Other pharmacological agents recommended for use in MS fatigue include: pemoline or aspirin. A double blind crossover study of aspirin compared with placebo favoured aspirin but further studies are required.54 Data relating to ginseng are mixed.55,56

References

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  9. Moran PJ et al. The validity of Beck Depression Inventory and Hamilton Rating Scale for Depression items in the assessment of depression among patients with multiple sclerosis. J Behav Med 2005; 28:35–41.
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  14. Mohr DC et al. Comparative outcomes for individual cognitive-behavior therapy, supportive-expressive group psychotherapy, and sertraline for the treatment of depression in multiple sclerosis. J Consult Clin Psychol 2001; 69:942–949.
  15. Ehde DM et al. Efficacy of paroxetine in treating major depressive disorder in persons with multiple sclerosis. Gen Hosp Psychiatry 2008; 30:40–48.
  16. Hilty DM et al. Psychopharmacology for neurologists: principles, algorithms, and other resources. Continuum 2006; 12:33–46.
  17. Barak Y et al. Treatment of depression in patients with multiple sclerosis. Neurologist 1998; 4:99–104.
  18. Koch MW et al. Pharmacologic treatment of depression in multiple sclerosis. Cochrane Database Syst Rev 2011; 2: CD007295.
  19. Taylor D et al. Pharmacological interventions for people with depression and chronic physical health problems: systematic review and metaanalyses of safety and efficacy. The British Journal of Psychiatry 2011; 198:179–188.
  20. Larcombe NA et al. An evaluation of cognitive-behaviour therapy for depression in patients with multiple sclerosis. Br J Psychiatry 1984; 145:366–371.
  21. man P et al. MS quality of life, depression, and fatigue improve after mindfulness training: a randomized trial. Neurology 2010; 75:1141–1149.
  22. Schiffer RB et al. Antidepressant pharmacotherapy of depression associated with multiple sclerosis. Am J Psychiatry 1990; 147:1493–1497.
  23. Barak Y et al. Moclobemide treatment in multiple sclerosis patients with comorbid depression: an open-label safety trial. J Neuropsychiatry Clin Neurosci 1999; 11:271–273.
  24. Rasmussen KG et al. Electroconvulsive therapy in patients with multiple sclerosis. J ECT 2007; 23:179–180.
  25. Jones KH et al. A large-scale study of anxiety and depression in people with Multiple Sclerosis: a survey via the web portal of the UK MS Register. PLoS One 2012; 7:e41910.
  26. Korostil M et al. Anxiety disorders and their clinical correlates in multiple sclerosis patients. Mult Scler 2007; 13:67–72.
  27. Feinstein A et al. The effects of anxiety on psychiatric morbidity in patients with multiple sclerosis. Mult Scler 1999; 5:323–326.
  28. Feinstein A et al. Prevalence and neurobehavioral correlates of pathological laughing and crying in multiple sclerosis. Arch Neurol 1997; 54:1116–1121.
  29. Andersen G et al. Citalopram for post-stroke pathological crying. Lancet 1993; 342:837–839.
  30. Burns A et al. Sertraline in stroke-associated lability of mood. Int J Geriatr Psychiatry 1999; 14:681–685.
  31. Pioro EP et al. Dextromethorphan plus ultra low-dose quinidine reduces pseudobulbar affect. Ann Neurol 2010; 68:693–702.
  32. Jefferies K. The neuropsychiatry of multiple sclerosis. Adv Psychiatr Treat 2006; 12:214–220.
  33. Stip E et al. Valproate in the treatment of mood disorder due to multiple sclerosis. Can J Psychiatry 1995; 40:219–220.
  34. Davids E et al. Antipsychotic treatment of psychosis associated with multiple sclerosis. Prog Neuropsychopharmacol Biol Psychiatry 2004; 28:743–744.
  35. Budur K et al. Olanzapine for corticosteroid-induced mood disorders. Psychosomatics 2003; 44:353.
  36. Aragona M et al. Psychopathological and cognitive effects of therapeutic cannabinoids in multiple sclerosis: a double-blind, placebo controlled, crossover study. Clin Neuropharmacol 2009; 32:41–47.
  37. Pierson SH et al. Treatment of cognitive impairment in multiple sclerosis. Behav Neurol 2006; 17:53–67.
  38. Krupp LB et al. Donepezil improved memory in multiple sclerosis in a randomized clinical trial. Neurology 2004; 63:1579–1585.
  39. Greene YM et al. A 12-week, open trial of donepezil hydrochloride in patients with multiple sclerosis and associated cognitive impairments. J Clin Psychopharmacol 2000; 20:350–356.
  40. Krupp LB et al. Multicenter randomized clinical trial of donepezil for memory impairment in multiple sclerosis. Neurology 2011; 76:1500–1507.
  41. Lovera JF et al. Memantine for cognitive impairment in multiple sclerosis: a randomized placebo-controlled trial. Mult Scler 2010; 16:715–723.
  42. Patti F. Treatment of cognitive impairment in patients with multiple sclerosis. Expert Opin Investig Drugs 2012; 21:1679–1699.
  43. Bakshi R. Fatigue associated with multiple sclerosis: diagnosis, impact and management. Mult Scler 2003; 9:219–227.
  44. Sepulcre J et al. Fatigue in multiple sclerosis is associated with the disruption of frontal and parietal pathways. Mult Scler 2009; 15:337–344.
  45. van KK et al. A randomized controlled trial of cognitive behavior therapy for multiple sclerosis fatigue. Psychosom Med 2008; 70:205–213.
  46. Pucci E et al. Amantadine for fatigue in multiple sclerosis. Cochrane Database Syst Rev 2007; CD002818.
  47. National Institute for Health and Clinical Excellence. Management of multiple sclerosis in primary and secondary care. Clinical Guideline 8, 2003. http://www.nice.org.uk/
  48. Ashtari F et al. Does amantadine have favourable effects on fatigue in Persian patients suffering from multiple sclerosis? Neurol Neurochir Pol 2009; 43:428–432.
  49. Rammohan KW et al. Efficacy and safety of modafinil (Provigil) for the treatment of fatigue in multiple sclerosis: a two centre phase 2 study. J Neurol Neurosurg Psychiatry 2002; 72:179–183.
  50. Zifko UA et al. Modafinil in treatment of fatigue in multiple sclerosis. Results of an open-label study. J Neurol 2002; 249:983–987.
  51. Stankoff B et al. Modafinil for fatigue in MS: A randomized placebo-controlled double-blind study. Neurology 2005; 64:1139–1143.
  52. Lange R et al. Modafinil effects in multiple sclerosis patients with fatigue. J Neurol 2009; 256:645–650.
  53. Davies M et al. Safety profile of modafinil across a range of prescribing indications, including off-label use, in a primary care setting in England: results of a modified prescription-event monitoring study. Drug Saf 2013; 36:237–246.
  54. Wingerchuk DM et al. A randomized controlled crossover trial of aspirin for fatigue in multiple sclerosis. Neurology 2005; 64:1267–1269.
  55. Kim E et al. American ginseng does not improve fatigue in multiple sclerosis: a single center randomized double-blind placebo-controlled crossover pilot study. Mult Scler 2011; 17:1523–1526.
  56. Etemadifar M et al. Ginseng in the treatment of fatigue in multiple sclerosis: a randomized, placebo-controlled, double-blind pilot study. Int J Neurosci 2013; 123:480–486.

Huntington's disease

Huntington's disease is a genetic condition involving slow progressive degeneration of neurones in the basal ganglia and cerebral cortex. Prevalence is estimated to be 12.4/100,000 population in Western societies.1 Neurones are damaged when the mutated Huntingtin protein gradually aggregates and interferes with normal metabolism and functioning. The mechanism is poorly understood2 making it difficult to develop drugs that slow or stop progression. Therefore, only symptomatic treatment is used in an attempt to improve quality of life. Choreiform movements occur in approximately 90% of patients and between 23% and 73% develop depression or psychosis during the course of their illness.3 Anxiety, apathy, obsessions, compulsions, impulsivity, irritability and aggression can all be problematic.4 Dementia is inevitable.

There is very little primary literature to guide practice in this area. A summary can be found in Table 7.8. Clinicians who treat patients with Huntington's disease are encouraged to publish reports of both positive and negative outcomes to increase the primary literature base.

Table 7.8 Recommendations for the treatment of symptoms in Huntington's disease

Symptoms

Treatment

Choreiform movements

Note that these are often more distressing for carers and healthcare professionals than they are for the patient and it should not be assumed that intervention is always in the patient's best interests

  • Discontinue dopaminergic drugs such as piracetam and cabergoline.5 Consider the contribution of psychotropic drugs with dopaminergic effects such as aripiprazole and venlafaxine or bupropion
  • The use of tetrabenazine is supported by RCTs.6-8 Up to 80% of patients experience dose-limiting symptoms9 such as depression, anxiety and insomnia, but a pre-existing diagnosis of depression is not an absolute contraindication to treatment.9 Studies suggest that clinical benefits can be observed rapidly and a multiple daily dosing regimen (e.g. tds) may be needed10
  • A small dose of a conventional antipsychotic such as haloperidol, fluphenazine,11 or sulpiride9 is established clinical practice12
  • Findings with second-generation antipsychotics are mixed. Two open studies of olanzapine 5 mg were negative13,14 but a third using 30 mg showed improved motor function.15 Case reports support the use of risperidone both at low16 and higher dose.17,18 Quetiapine19 and aripiprazole20 may also be effective. There is a small positive RCT of pridopidine (a dopamine partial agonist)21
  • A small, open-label study suggested levetiracetam may be effective in reducing chorea. Side-effects included somnolence and dyskinesias22
  • A large, double-blind trial found no benefit with riluzole in symptomatic effects or neuroprotection23
  • The results of several small studies suggest that amantadine may help chorea at a dose of > 400 mg/day. Improvements are modest and transient and unlikely to be clinically useful.24 Possible side-effects include agitation, confusion and sleep disturbances9
  • Valproic acid does not seem to be effective in treating chorea.9 However, cortical myoclonus, a rare, but potentially disabling feature of adult Huntington's disease, was shown in several case reports to improve with valproic acid925
  • Positive and negative data also exists for lamotrigine in the treatment of motor and mood symptoms in Huntington's disease926
  • A small RCT found nabilone to be more effective than placebo in the treatment of motor symptoms, cognition and behaviour27

Hypokinetic rigidity

  • Treatment is similar to that of Parkinson's disease although response is often suboptimal. Anticholinergics and dopamine agonists are sometimes used. Note the potential for such drugs to exacerbate choreiform movements and precipitate psychosis
  • Muscle relaxants, such as diazepam can also be effective in treating rigidity and are usually well tolerated,5 although aspiration secondary to sedation is a potential risk

Psychosis

There are no RCTs to guide choice. Treatment is empirical. Note that antipsychotic drugs may exacerbate any underlying movement disorder

  • Some evidence supports the efficacy of conventional antipsychotics, particularly haloperidol, when the Huntington's disease is mild to moderate.12 As Huntington's disease progresses, typicals tend to be poorly tolerated because of dystonia and parkinsonism12
  • Case reports support the efficacy of risperidone,17,18,28 quetiapine29 and amisulpride30 although extrapyramidal side-effects can be problematic with all of these drugs. A positive case report also exists for aripiprazole31

Depression

There are no RCTs to guide choice. Note that the suicide rate in patients with Huntington's disease is 4-6 times higher than in the background population12

  • An open study supports the efficacy of venlafaxine, although adverse effects can be problematic32
  • Case reports support the efficacy of a wide range of antidepressants but TCAs are poorly tolerated (sedation, falls and anticholinergic-induced cognitive impairment) and MAOIs can worsen choreiform movements. SSRIs are preferred33,34
  • Reviews state that lithium is best avoided; clinical experience suggests that response is likely to be poor and that toxic effects may be particularly problematic.12 There is no primary literature
  • ECT seems to be relatively well tolerated in patients with Huntington's disease 12

Dementia

Positive and negative case reports exist for the use of cholinesterase inhibitors in patients with Huntington's disease

  • Based on available evidence, the treatment of Huntington's disease with acetylcholinesterase inhibitors does not significantly alter cognitive decline, and has little impact on daily functionality of patients with Huntington's disease. Therefore these drugs have no specific indication in the treatment of this disease9
  • One small sample study concluded that donepezil was not an effective treatment for Huntington's disease35
  • However, a two year follow-up of rivastigmine treatment showed positive results in slowing motor deterioration and possibly reducing cognitive impairment36
  • Positive case reports also exist for memantine in preventing the progression of cognitive symptoms37
  • A large (n = 403) RCT found no benefit for latrepirdine (an experimental drug that stabilises mitochondrial membranes and function) with respect to improving cognition or global function38

ECT, electroconvulsive therapy; MAOI, monoamine oxidase inhibitor; RCT, randomised controlled trial; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant; tds, ter die sumendus (three times a day).

Table 7.8 represents a review of the literature rather than a guide to treatment. Readers are directed to the reports cited here for details of dosage regimens and further information about tolerability.

References

  1. Spinney L. Uncovering the true prevalence of Huntington's disease. Lancet Neurol 2010; 9:760–761.
  2. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 5th edn (DSM-5). Arlington, VA: American Psychiatric Association; 2013.
  3. Petrikis P et al. Treatment of Huntington's disease with galantamine. Int Clin Psychopharmacol 2004; 19:49–50.
  4. Scher LM et al. How to target psychiatric symptoms of Huntington's disease. Current Psychiatry 2012; 11:34–38.
  5. Bonelli RM et al. Huntington's disease: present treatments and future therapeutic modalities. Int Clin Psychopharmacol 2004; 19:51–62.
  6. McLellan DL et al. A double-blind trial of tetrabenazine, thiopropazate, and placebo in patients with chorea. Lancet 1974; 1:104–107.
  7. Jankovic J. Treatment of hyperkinetic movement disorders with tetrabenazine: a double-blind crossover study. Ann Neurol 1982; 11:41–47.
  8. Mestre T et al. Therapeutic interventions for symptomatic treatment in Huntington's disease. Cochrane Database Syst Rev 2009; CD006456.
  9. Adam OR et al. Symptomatic treatment of Huntington disease. Neurotherapeutics 2008; 5:181–197.
  10. Kenney C et al. Short-term effects of tetrabenazine on chorea associated with Huntington's disease. Mov Disord 2007; 22:10–13.
  11. Bonelli RM et al. Pharmacological management of Huntington's disease: an evidence-based review. Curr Pharm Des 2006; 12:2701–2720.
  12. Rosenblatt A et al. Neuropsychiatry of Huntington's disease and other basal ganglia disorders. Psychosomatics 2000; 41:24–30.
  13. Squitieri F et al. Short-term effects of olanzapine in Huntington disease. Neuropsychiatry Neuropsychol Behav Neurol 2001; 14:69–72.
  14. Paleacu D et al. Olanzapine in Huntington's disease. Acta Neurol Scand 2002; 105:441–444.
  15. Bonelli RM et al. High-dose olanzapine in Huntington's disease. Int Clin Psychopharmacol 2002; 17:91–93.
  16. Erdemoglu AK et al. Risperidone in chorea and psychosis of Huntington's disease. Eur J Neurol 2002; 9:182–183.
  17. Dallocchio C et al. Effectiveness of risperidone in Huntington chorea patients. J Clin Psychopharmacol 1999; 19:101–103.
  18. Duff K et al. Risperidone and the treatment of psychiatric, motor, and cognitive symptoms in Huntington's disease. Ann Clin Psychiatry 2008; 20:1–3.
  19. Bonelli RM et al. Quetiapine in Huntington's disease: a first case report. J Neurol 2002; 249:1114–1115.
  20. Brusa L et al. Treatment of the symptoms of Huntington's disease: preliminary results comparing aripiprazole and tetrabenazine. Mov Disord 2009; 24:126–129.
  21. Lundin A et al. Efficacy and safety of the dopaminergic stabilizer Pridopidine (ACR16) in patients with Huntington's disease. Clin Neuropharmacol 2010; 33:260–264.
  22. Zesiewicz TA et al. Open-label pilot study of levetiracetam (Keppra) for the treatment of chorea in Huntington's disease. Mov Disord 2006; 21:1998–2001.
  23. Landwehrmeyer GB et al. Riluzole in Huntington's disease: a 3-year, randomized controlled study. Ann Neurol 2007; 62:262–272.
  24. Reilmann R. Pharmacological treatment of chorea in Huntington's disease-good clinical practice versus evidence-based guideline. Mov Disord 2013; 28:1030–1033.
  25. Saft C et al. Dose-dependent improvement of myoclonic hyperkinesia due to Valproic acid in eight Huntington's Disease patients: a case series. BMC Neurol 2006; 6:11.
  26. Shen YC. Lamotrigine in motor and mood symptoms of Huntington's disease. World J Biol Psychiatry 2008; 9:147–149.
  27. Curtis A et al. A pilot study using nabilone for symptomatic treatment in Huntington's disease. Mov Disord 2009; 24:2254–2259.
  28. Madhusoodanan S et al. Use of risperidone in psychosis associated with Huntington's disease. Am J Geriatr Psychiatry 1998; 6:347–349.
  29. Seitz DP et al. Quetiapine in the management of psychosis secondary to huntington's disease: a case report. Can J Psychiatry 2004; 49:413.
  30. Saft C et al. Amisulpride in Huntington's disease. Psychiatr Prax 2005; 32:363–366.
  31. Lin WC et al. Aripiprazole effects on psychosis and chorea in a patient with Huntington's disease. Am J Psychiatry 2008; 165:1207–1208.
  32. Holl AK et al. Combating depression in Huntington's disease: effective antidepressive treatment with venlafaxine XR. Int Clin Psychopharmacol 2010; 25:46–50.
  33. De Marchi N et al. Fluoxetine in the treatment of Huntington's disease. Psychopharmacology 2001; 153:264–266.
  34. Rosenblatt A et al. A Physician's Guide to the Management of Huntington's Disease, 2nd edn. New York: Huntington's Disease Society of America; 1999.
  35. Cubo E et al. Effect of donepezil on motor and cognitive function in Huntington disease. Neurology 2006; 67:1268–1271.
  36. de TM et al. Two years' follow-up of rivastigmine treatment in Huntington disease. Clin Neuropharmacol 2007; 30:43–46.
  37. Cankurtaran ES et al. Clinical experience with risperidone and memantine in the treatment of Huntington's disease. J Natl Med Assoc 2006; 98:1353–1355.
  38. HORIZON Investigators of the Huntington Study Group and European Huntington's Disease Network. A randomized, double-blind, placebo-controlled study of latrepirdine in patients with mild to moderate Huntington disease. JAMA Neurol 2013; 70:25–33.

Further reading

Armstrong MJ et al. Evidence-based guideline: pharmacologic treatment of chorea in Huntington disease: report of the guideline development subcommittee of the American Academy of Neurology. Neurology 2012; 79:597–603.

Tyagi SN et al. Symptomatic Treatment and Management of Huntington's Disease: An Overview. Global J Pharmacol 2010; 4:6–12.

Pregnancy

A 'normal' outcome to pregnancy can never be guaranteed. The spontaneous abortion rate in confirmed early pregnancy is 10–20% and the risk of spontaneous major malformation is 2–3% (approximately 1 in 40 pregnancies).1

Lifestyle factors have an important influence on pregnancy outcome. It is well established that smoking cigarettes, eating a poor diet and drinking alcohol during pregnancy can have adverse consequences for the foetus. Moderate maternal caffeine consumption has been associated with low birth weight,2 and pre-pregnancy obesity increases the risk of neural tube defects; (obese women seem to require higher doses of folate supplementation than women who have a BMI in the healthy range3).

In addition, psychiatric illness during pregnancy is an independent risk factor for congenital malformations and perinatal mortality.4 Affective illness increases the risk of pre-term delivery.5,6 Note that pre-term delivery is associated with an increased risk of depression, bipolar disorder and schizophrenia spectrum disorders in adult life.7

Drugs account for a very small proportion of abnormalities (approximately 5% of the total). Potential risks of drugs include major malformation (first-trimester exposure), neonatal toxicity (third-trimester exposure), longer-term neurobehavioural effects and increased risk of physical health problems in adult life.

The safety of psychotropics in pregnancy cannot be clearly established because robust, prospective trials are obviously unethical. Individual decisions on psychotropic use in pregnancy are therefore based on database studies that have many limitations (e.g. failure to control for the effects of illness and other medication, multiple statistical tests increasing the risk of Type 2 error and exposure status based on pharmacy data), limited prospective data from teratology information centres, and published case reports which are known to be biased towards adverse outcomes. At worst there may be no human data at all, only animal data from early preclinical studies. With new drugs early reports of adverse outcomes may or may not be replicated and a 'best guess' assessment must be made of the risks and benefits associated with withdrawal or continuation of drug treatment. Even with established drugs, data related to long-term outcomes are rare. Pregnancy does not protect against mental illness and may even elevate overall risk. The patient's view of risks and benefits will have paramount importance. This section provides a brief summary of the relevant issues and evidence to date.

General principles of prescribing in pregnancy

Box 7.6 outlines the general principles of prescribing in pregnancy.

What to include in discussions with pregnant women13

Discussions should include the following.

Box 7.6 General principles of prescribing in pregnancy

In all women of child bearing potential

  • Always discuss the possibility of pregnancy; half of all pregnancies are unplanned.8
  • Avoid using drugs that are contraindicated during pregnancy in women of reproductive age, (especially valproate and carbamazepine). If these drugs are prescribed, women should be made fully aware of their teratogenic properties even if not planning pregnancy. Consider prescribing folate. Valproate should be reserved for post-menopausal women only. Its use in younger women should be treatment of last resort.

If mental illness is newly diagnosed in a pregnant woman

  • Try to avoid all drugs in the first trimester (when major organs are being formed) unless benefits outweigh risks.
  • If non-drug treatments are not effective/appropriate, use an established drug at the lowest effective dose.

If a woman taking psychotopic drugs is planning a pregnancy

  • Consideration should be given to discontinuing treatment if the woman is well and at low risk of relapse.
  • Discontinuation of treatment for women with severe mental illness and at a high risk of relapse is unwise, but consideration should be given to switching to a low risk drug. Be aware that switching drugs may increase the risk of relapse.

If a woman taking psychotropic medication discovers that she is pregnant

  • Abrupt discontinuation of treatment post-conception for women with severe mental illness and at a high risk of relapse is unwise; relapse may ultimately be more harmful to the mother and child than continued, effective drug therapy.
  • Consider remaining with current (effective) medication rather than switching, to minimise the number of drugs to which the foetus is exposed.

If the patient smokes (smoking is more common in pregnant women with psychiatric illness)9

  • Always encourage switching to nicotine replacement therapy; smoking has numerous adverse outcomes, nicotine replacement therapy (NRT) does not.10 Referral to smoking cessation services is very desirable.

In all pregnant women

  • Ensure that the parents are as involved as possible in all decisions.
  • Use the lowest effective dose.
  • Use the drug with the lowest known risk to mother and foetus.
  • Prescribe as few drugs as possible both simultaneously and in sequence.
  • Be prepared to adjust doses as pregnancy progresses and drug handling is altered. Dose increases are frequently required in the third trimester11 when blood volume expands by around 30%. Plasma level monitoring is helpful, where available. Note that hepatic enzyme activity changes markedly during pregnancy; CYP2D6 activity is increased by almost 50% by the end of pregnancy while the activity of CYP1A2 is reduced by up to 70%.12
  • Consider referral to specialist perinatal services.
  • Ensure adequate foetal screening.
  • Be aware of potential problems with individual drugs around the time of delivery.
  • Inform the obstetric team of psychotropic use and possible complications.
  • Monitor the neonate for withdrawal effects after birth.
  • Document all decisions.

Where possible, written material should be provided to explain the risks (preferably individualised). Absolute and relative risks should be discussed. Risks should be described using natural frequencies rather than percentages (for example, 1 in 10 rather than 10%) and common denominators (for example, 1 in 100 and 25 in 100, rather than 1 in 100 and 1 in 4).

Psychosis during pregnancy and post-partum

The risks of not treating psychosis include:

It has long been established that people with schizophrenia are more likely to have minor physical anomalies than the general population. Some of these anomalies may be apparent at birth, while others are more subtle and may not be obvious until later in life. This background risk complicates assessment of the effects of antipsychotic drugs. (Psychiatric illness itself during pregnancy is an independent risk factor for congenital malformations and perinatal mortality.)

Treatment with antipsychotics

Older, first-generation antipsychotics are generally considered to have minimal risk of teratogenicity,15,16 although data are less than convincing, as might be expected.

It remains uncertain whether FGAs are entirely without risk to the foetus or to later development.15,16 However, this continued uncertainty and the wide use of these drugs over several decades suggest that any risk is small—an assumption borne out by most studies.19

Second-generation antipsychotics are unlikely to be major teratogens but are associated with some problems.

Overall, these data do not allow an assessment of relative risks associated with different agents and certainly do not confirm absolutely the safety of any particular drug. At least two studies have suggested a small increased risk of malformation,17,20 and one study a higher risk of caesarean section in people receiving antipsychotics.20 As with other drugs, decisions must be based on the latest available information and an individualised assessment of probable risks and benefits. If possible, specialist advice should be sought, and primary reference sources consulted. Box 7.7 summarises the recommendations for the treatment of psychosis in pregnancy.

Box 7.7 Recommendations for the treatment of psychosis in pregnancy

  • Patients with a history of psychosis who are maintained on antipsychotic medication should be advised to discuss a planned pregnancy as early as possible.
  • Be aware that drug-induced hyperprolactinaemia may prevent pregnancy. Consider switching to alternative drug.
  • Such patients, particularly if they have suffered repeated relapses, are best maintained on antipsychotics during and after pregnancy. This may minimise foetal exposure by avoiding the need for higher doses, and/or multiple drugs should relapse occur.
  • There is most experience with chlorpromazine (constipation and sedation can be a problem), trifluoperazine, haloperidol, olanzapine, quetiapine and clozapine (gestational diabetes may be a problem with all SGAs). If the patient is established on another antipsychotic, the most up-to-date advice should always be obtained; a change in treatment may not be necessary or wise.
  • NICE recommends avoiding depot preparations and anticholinergic drugs in pregnancy.
  • A few authorities recommend discontinuation of antipsychotics 5–10 days before anticipated delivery to minimise the chances of neonatal effects. This may, however, put mother and infant at risk and needs to be considered carefully. Antipsychotic discontinuation symptoms can occur in the neonate (e.g. crying, agitation, increased suckling). This is thought to be a class effect.29 When antipsychotics are taken in pregnancy it is recommended that the woman gives birth in a unit that has access to paediatric intensive care facilities.17 Some centres used mixed (breast/ bottle) feeding to minimise withdrawal symptoms.

Depression during pregnancy and post-partum30–32

The risks of not treating depression include:

Treatment with antidepressants

The use of antidepressants during pregnancy is common; in the Netherlands, up to 2% of women are prescribed antidepressants during the first trimester,35 and in the US around 10% of women are prescribed antidepressants at some point during their pregnancy,33,36 and this rate is increasing.37 The majority of prescriptions are for SSRIs. In the UK, the large majority of women who are prescribed antidepressants, stop taking them in very early pregnancy (< 6 weeks gestation),38 most likely because of concerns about teratogenicity. A large Danish study has also noted that pregnant women are considerably less likely to be prescribed antidepressants than women who are not pregnant.39 Relapse rates are high in those with a history of depression who discontinue medication. One study found that 68% of women who were well on antidepressant treatment and stopped during pregnancy relapsed, compared with 26% who continued antidepressants.30 Some data suggest that antidepressants may increase the risk of spontaneous abortion (but note that confounding factors were not controlled for).33,40 SSRIs do not increase the risk of stillbirth or neonatal mortality.41,42 Antidepressants may increase the risk of pre-term delivery, respiratory distress in the neonate, a low Apgar score at birth and admission to a special care baby unit.33,43–48 Note though that most studies are observational and do not control for maternal depression. Limited data suggest that when this is done, antidepressants pose no additional risk, at least with respect to pre-term birth.49 While it is reasonably certain that commonly used antidepressants are not major teratogens,50 some antidepressants have been associated with specific congenital malformations, many of which are rare. Most of these potential associations remain unreplicated.33 There are conflicting data on the issue of the influence of duration of antidepressant use.51,52 The effects on early growth and neuro-development are poorly studied; the limited data that do exist are reassuring.47,53,54 One small study reported abnormal general movements in neonates exposed to SSRIs in utero.55 A small increase in the risk of childhood autism has also been suggested.56,57

Women who take antidepressants during pregnancy may be at increased risk of developing hypertension (NNH 83),58 pre-eclampsia (NNH 40)59 and post-partum haemorrhage (NNH 80). It has been suggested that SSRIs may cause the last of these by reducing serotonin-mediated uterine contraction as well as interfering with hemostasis.60 A subsequent smaller study did not confirm this association; possibly because it was underpowered to do so.61

Tricyclic antidepressants
SSRIs
Other antidepressants

Box 7.8 summarises the recommendations for the treatment of depression in pregnancy.

Bipolar illness during pregnancy and post-partum

Box 7.8 Recommendations for the treatment of depression in pregnancy

  • Patients who are already receiving antidepressants and are at high risk of relapse are best maintained on antidepressants during and after pregnancy.
  • Those who develop a moderate or severe depressive illness during pregnancy should be treated with antidepressant drugs.
  • There is most experience with amitriptyline, imipramine (constipation and sedation can be a problem with both; withdrawal symptoms may occur) sertraline (low infant exposure) and fluoxetine (increased chance of earlier delivery and reduced birth weight). If the patient is established on another antidepressant, always obtain the most up-to-date advice. Experience with other drugs is growing and a change in treatment may not be necessary or wise. Paroxetine may be less safe than other SSRIs.
  • Screen for alcohol use and be vigilant for the development of hypertension and pre-eclampsia. Women who take SSRIs may be at increased risk of post-partum haemorrhage.
  • When taken in late pregnancy, SSRIs may increase the risk of persistent pulmonary hypertension of the newborn.
  • The neonate may experience discontinuation symptoms such as agitation and irritability, or even respiratory distress and convulsions (with SSRIs). The risk is assumed to be particularly high with short half-life drugs such as paroxetine and venlafaxine. Continuing to breast feed and then 'weaning' by switching to mixed (breast/bottle) feeding may help reduce the severity of reactions.

The risks of not stabilising mood include:

Treatment with mood stabilisers

Most data relating to carbamazepine, valproate and lamotrigine come from studies in epilepsy, a condition associated with increased neonatal malformation. These data may not be precisely relevant to use in mental illness.

Box 7.9 summarises the recommendations for the treatment of bipolar disorder in pregnancy.

Box 7.9 Recommendations for the treatment of bipolar disorder in pregnancy

  • For women who have had a long period without relapse, the possibility of switching to a safer drug (antipsychotic) or withdrawing treatment completely before conception and for at least the first trimester should be considered.
  • The risk of relapse both preand post-partum is very high if medication is discontinued abruptly.
  • Women with severe illness or who are known to relapse quickly after discontinuation of a mood stabiliser should be advised to continue their medication following discussion of the risks.
  • No mood stabiliser is clearly safe. Women prescribed lithium should undergo level two ultrasound of the foetus at 6 and 18 weeks' gestation to screen for Ebstein's anomaly. Those prescribed valproate or carbamazepine (both teratogenic) should receive prophylactic folic acid to reduce the incidence of neural tube defects, and receive appropriate antenatal screening tests.
  • If carbamazepine is used, prophylactic vitamin K should be administered to the mother and neonate after delivery.
  • Valproate (the most teratogenic) and combinations of mood stabilisers should be avoided.
  • NICE recommends the use of mood-stabilising antipsychotics as a preferable alternative to continuation with a mood stabiliser.
  • In acute mania in pregnancy use an antipsychotic and if ineffective consider ECT.
  • In bipolar depression during pregnancy use CBT for moderate depression and an SSRI for more severe depression. Olanzapine plus fluoxetine may also be used.

Epilepsy during pregnancy and post-partum

The risks of not treating epilepsy include:

Treatment with anticonvulsant drugs

It is established that treatment with anticonvulsant drugs increases the risk of having a child with major congenital malformation to twoto three-fold that seen in the general population. Congenital heart defects (1.8%) and facial clefts (1.7%) are the most common congenital malformations.

Both carbamazepine and valproate are associated with a hugely increased incidence of spina bifida at 0.5–1% and 1–2%, respectively. The risk of other neural tube defects is also increased. In women with epilepsy, the risk of foetal malformations with carbamazepine is 2.6%;128 with lamotrigine 2.3%;128 and with valproate 7.2%,137 possibly even higher.123,127–129 Higher doses (particularly doses of valproate exceeding 1000 mg/day) and anticonvulsant polypharmacy are particularly problematic.127–129,138 The risks of malformation with carbamazepine and lamotrigine are also probably dose related with risk increasing sharply above daily doses of 1000 mg and 400 mg respectively.128 It should be noted that these data are derived from databases (they are essentially observational) and it is therefore possible that women prescribed higher doses had more difficult to control seizures which may independently affect outcomes.

Box 7.10 Recommendations for the treatment of epilepsy in pregnancy

  • For women who have been seizure free for a long period, the possibility of withdrawing treatment before conception, and for at least the first trimester, should be considered.
  • No anticonvulsant is clearly safer. Valproate should be avoided if possible. Women prescribed valproate or carbamazepine should receive prophylactic folic acid, ideally starting prior to conception. Prophylactic vitamin K should be administered to the mother and neonate after delivery.
  • Valproate and combinations of anticonvulsants should be avoided if possible
  • All women with epilepsy should have a full discussion with their neurologist to quantify the risks and benefits of continuing anticonvulsant drugs during pregnancy.

It is of note that women prescribed anticonvulsant medication who have given birth to a child with congenital abnormalities, have a 10-fold increased risk of their subsequent child also having abnormalities if they continue to take the same treatment (particularly if this treatment is valproate), suggesting a genetically determined vulnerability.139 Interestingly, the nature of abnormalities is not consistent across pregnancies.

Cognitive deficits have been reported in older children who have been exposed to valproate in utero,109,125 as have both childhood autism and autistic spectrum disorder.140 Those exposed to carbamazepine may not be similarly disadvantaged.141

Barbiturates (rarely used in the management of epilepsy) are major teratogens, being particularly associated with cardiac malformations.125 Growing, but still limited, data do not raise any particular concerns over the teratogenic potential of oxcarbazepine, topiramate, gabapentin or levetiracetam.134

Pharmacokinetics change during pregnancy, and there is marked inter-individual variation.142 Dosage adjustment may be required to keep the patient seizure-free.143 Serum levels usually return to pre-pregnancy levels within a month of delivery often much more rapidly. Doses may need to be reduced at this point.

Best practice guidelines recommend that a woman should receive the lowest possible dose of a single anticonvulsant. Box 7.10 summarises the recommendations for the treatment of epilepsy in pregnancy.

Anxiety disorders and insomnia: sedatives

Anxiety disorders and insomnia are commonly seen in pregnancy.144 Preferred treatments are CBT and sleep-hygiene measures respectively.

Rapid tranquillisation

There is almost no published information on the use of rapid tranquillisation in pregnant women. The acute use of short-acting benzodiazepines such as lorazepam and of the sedative antihistamine promethazine is unlikely to be harmful. Presumably, the use of either drug will be problematic immediately before birth. NICE also recommends the use of an antipsychotic but do not specify a particular drug.13 Note that antipsychotics are not generally recommended as a first line treatment for managing acute behavioural disturbance (see section on 'Acutely disturbed and violent behaviour' in this chapter)

Table 7.9 Recommendations* for the use of psychotropic drugs in pregnancy
Minimise the number of drugs the foetus is exposed to.

Psychotropic group

Recommendations

Antidepressants

Nortriptyline

Amitriptyline

Imipramine

Sertraline

Antipsychotics

No clear evidence that any antipsychotic is a major teratogen

Consider using/continuing drug mother has previously responded to rather than switching prior to/during pregnancy

Most experience with chlorpromazine, trifluoperazine, haloperidol, olanzapine

Experience growing with risperidone, quetiapine and aripiprazole

Screen for adverse metabolic effects

Arrange for the woman to give birth in a unit with access to neonatal intensive care facilities

Mood stabilisers

Consider using an antipsychotic as a mood stabiliser rather than an anticonvulsant drug

Lamotrigine is also an option (bipolar depression only)

Avoid other anticonvulsants unless risks and consequences of relapse outweigh the known risk of teratogenesis

Women of childbearing potential taking carbamazepine or valproate should receive prophylactic folic acid

Avoid valproate and combinations where possible

Sedatives

Non drug measures are preferred

Benzodiazepines are probably not teratogenic but are best avoided in late pregnancy

Promethazine is widely used but supporting safety data are scarce

*It cannot be overstated that treatment needs to be individualised for each patient. This summary box is not intended to suggest that all patients should be switched to a recommended drug. For each patient, take into account their current prescription, response to treatment, history of response to other treatments and the risks known to apply in pregnancy (both for current treatment and for switching).

Attention deficit hyperactivity disorder

Limited data suggest that methylphenidate is not a major teratogen.149

 

Table 7.9 summarises the recommendations for the use of psychotropic drugs in pregnancy.

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Further reading

National Institute for Health and Care Excellence. Antenatal and postnatal mental health: clinical management and service guidance. Clinical Guideline 192, 2014. https://www.nice.org.uk/guidance/cg192

Paton C. Prescribing in pregnancy. Br J Psychiatry 2008; 192:321–322.

Ruchkin V et al. SSRIs and the developing brain. Lancet 2005; 365:451–453.

Sanz EJ et al. Selective serotonin reuptake inhibitors in pregnant women and neonatal withdrawal syndrome: a database analysis. Lancet 2005; 365:482–487.

Other sources of information

National Teratology Information Service. http://www.hpa.org.uk/

Breastfeeding

Data on the safety of psychotropic medication in breastfeeding are largely derived from small studies or case reports and case series. Reported infant and neonatal outcomes in most cases are limited to short term acute adverse effects. Long-term safety cannot therefore be guaranteed for the psychotropics reviewed here. The information presented must be interpreted with caution with respect to the limited data from which it is derived and the need for such information to be regularly updated.

Infant exposure

All psychotropics are excreted in breast milk, to varying degrees. The most direct measure of infant exposure is, of course, infant plasma levels, but these data are often not available. Instead, many cases report drug concentrations in breast milk and maternal plasma. These data can be used to estimate the daily infant dose (by assuming a milk intake of 150 mL/kg/day). The infant weight-adjusted dose when expressed as a proportion of the maternal weight-adjusted dose is known as the relative infant dose (RID). Drugs with a RID below 10% are widely regarded as safe in breastfeeding.

RID = infant dose (mg/kg/day)/maternal dose (mg/kg/day)

Where measured, infant plasma levels below 10% of average maternal plasma levels have been proposed as safe in breastfeeding.1

The RIDs, where available from the literature, are given in Tables 7.11–7.14. The RID should be used as a guide only, as values are estimates and vary widely in the literature for individual drugs.

General principles of prescribing psychotropics in breastfeeding

Wherever possible:

Table 7.10 summarises the recommendations for drug use in breastfeeding. Further information is provided in Tables 7.11–7.14.

Table 7.10 Summary of recommendations

Drug group

Recommended drugs

Antidepressants

Sertraline (others may be used, e.g. paroxetine, nortriptyline, imipramine, see Table 7.11)

Antipsychotics

Olanzapine (others may be used, see Table 7.12)

Mood stabilisers

Often best to switch to mood-stabilising antipsychotic (see Table 7.13)

Valproate can be used but only where there is adequate protection against pregnancy (breastfeeding itself is not adequate protection). Beware risk of hepatotoxicity in breastfed infants

Sedatives

Lorazepam for anxiety and sleep (see Table 7.14)

Antidepressants in breast-feeding

Manufacturers' advice on drugs in breastfeeding is available in the Summary of Product Characteristics or European Public Assessment Report for individual drugs. Table 7.11 does not include or repeat this advice, but instead uses primary reference sources.

Table 7.11 Antidepressants in breastfeeding

Drug

Comment

Estimated daily infant dose as proportion of maternal dose (RID)

Agomelatine11,91

Peak breast milk levels were seen 1-2 hours post dose in a mother taking 25 mg agomelatine. The drug was undetectable 4 hours post dose.

Effects in the neonate were not reported.

Not available

Bupropion11,21,82-87

Reported infant serum levels range from low to undetectable. Bupropion has been detected in the urine of 1 infant.

No adverse effects were noted in four infants (in three separate case reports) exposed to bupropion in breast milk. Infant effects were not assessed in the other cases.

There is one report of a seizure in a 6-month-old infant exposed to bupropion in breast milk. Neither breast milk nor infant serum levels were determined in this case.

0.2-2%

Citalopram1,2,11,13-22

Reported infant serum levels are variable, ranging from undetectable or low to > 10% of maternal serum levels. Recorded levels are higher than those for fluvoxamine-sertraline, paroxetine and escitalopram, but lower than for fluoxetine.

Breast milk peak levels have been observed 3-9 hours after maternal dose.

There is one case report of uneasy sleep in an infant exposed to citalopram while breastfeeding which resolved on halving the mother's dose. Irregular breathing, sleep disorder, hypo, and hypertonia were observed up to 3 weeks after delivery in another breastfeeding infant exposed to citalopram in utero. The symptoms were attributed to withdrawal syndrome from citalopram despite the mother continuing citalopram post-partum.

In a study of 31 exposed infants, one case each of colic, decreased feeding, and irritability/restlessness was reported. Normal growth and development were noted in a 6-month old infant whose mother took a combination of ziprasidone and citalopram whilst breastfeeding (and during pregnancy).

In a study of 78 breastfeeding infants of mothers taking an SSRI or venlafaxine no difference in weight was noted at 6 months when compared with the 'normative' weight. In one study, normal neurodevelopment was observed, up to the age of 1-year, in all 11 infants exposed to citalopram in utero and through breast milk. One of the children, at 1-year, was unable to walk. However, the neurological status of this child was deemed normal 6 months later.

3-10.9%

Duloxetine11,21,88-90

In a study of six nursing women breast-milk concentrations of duloxetine were found to be low. Neither infant serum levels nor infant effects were assessed.

In two separate case reports infant serum levels of duloxetine were found to be low. In addition, no short-term adverse effects were noted in the infants.

< 1%

Escitalopram11,21,23-28

Reported infant serum levels are low or undetectable. Adverse effects were not seen in two separate case reports. In a study of eight women breast milk peak levels of escitalopram were observed 2-11 hours post maternal dose. No adverse effects were noted in the infants.

There is one case of necrotising enterocolitis (necessitating intensive care admission and intravenous antibiotic treatment) in a 5-day old infant exposed to escitalopram in utero and through breast milk. The infant's symptoms on admission were lethargy, decreased oral intake and blood in the stools.

3-8.3%

Fluoxetine1, 2, 11, 21,22,36-46

Reported infant serum levels are variable and higher than those for paroxetine, fluvoxamine, sertraline, citalopram and escitalopram. In a pooled analysis of antidepressant levels fluoxetine produced the highest proportion of infant levels above 10% of the average maternal levels.

Peak breast milk levels have been observed approximately 8 hours post maternal dose.

Adverse effects have not been reported for the majority of fluoxetine-exposed infants. Reported adverse effects include colic, excessive crying, decreased sleep, diarrhoea and vomiting, somnolence, decreased feeding, hypotonia, moaning, grunting, hyperactivity.

Seizure activity at 3 weeks, 4 months and then 5 months was reported in an infant whose mother was taking a combination of fluoxetine and carbamazepine.

A retrospective study found the growth curves of breastfed infants of mothers taking fluoxetine to be significantly below those of infants receiving breast milk free of fluoxetine. However, in another study of 78 breastfeeding infants of mothers taking an SSRI or venlafaxine no difference in weight was noted at 6 months when compared with the 'normative' weight. Neurological developments and weight gain were found to be normal in 11 infants exposed to fluoxetine during pregnancy and lactation. No developmental abnormalities were noted in another four infants exposed to fluoxetine during breastfeeding. In a study of eleven infants exposed to fluoxetine whilst breastfeeding, a drop in platelet serotonin was noted in one of the infants.

1.6-14.6%

Fluvoxamine1, 2, 11, 21,22,36-46

Reported infant serum levels vary from undetectable to up to half the maternal serum level. No infant adverse effects have been reported. Peak drug levels in breast milk have been observed 4 hours after maternal dose.

1-2%

Monoamine oxidase inhibitors (MAOIs)

No published data could found.

 

Mianserin11,76

Adverse effects were not seen in two infants studied.

 

Mirtazapine1, 2, 11, 21,22,36-46

Reported infant serum levels range from undetectable to low. Psychomotor development in one infant after 6 weeks of exposure was found to be normal.

No adverse effects were noted in any of the eight infants in a study of exposure to mirtazapine in breast milk. In addition, developmental milestones were being achieved by all infants at the time of the study. However, the weights for three of the infants were observed to be between the 10th to 25th percentiles. All three were noted to also have a low birth weight.

There is one case of higher mirtazapine serum levels in a breastfeeding infant than have been previously reported. The authors explain this by suggesting that there may be a large difference in mirtazapine elimination rates between individual infants. In this same infant the mother reported a greater weight gain and uninterrupted night-time sleep compared with her other children.

0.5-4.4%

Moclobemide1, 2, 11, 21,22,36-46

Reported infant serum levels appear to be low.

No adverse effects were detected in these infants. Peak drug levels in breast milk were seen at 3 hours.

The manufacturers of moclobemide advise that its use in breastfeeding can be considered if the benefits outweigh the risk to the child.

3.4%

Paroxetine1, 2, 11, 21,22,36-46

Reported infant serum levels vary from low to undetectable. Adverse effects have not been reported for the majority of paroxetine-exposed infants. However, vomiting and irritability were reported in a breastfeeding baby of 18 months. The symptoms were attributed to severe hyponatraemia in the infant. The maternal paroxetine dose was 40 mg. Paroxetine levels were not determined in the breast milk or infant serum.

In a study of 78 breastfeeding infants of mothers taking an SSRI or venlafaxine no difference in weight was noted at 6 months when compared with the 'normative' weight. Breastfed infants of 27 women taking paroxetine reached the usual developmental milestones at 3, 6 and 12 months-similar to a control group.

The manufacturers of paroxetine advise that its use in breastfeeding can be considered.

0.5-2.8%

Reboxetine11,21,65

Reported infant serum levels range from low to undetectable and no adverse effects were noted in four infants. In addition, normal developmental milestones were reached by three of the infants. The fourth had developmental problems thought not to be related to maternal reboxetine therapy. Breast milk peak levels were observed 1-9 hours after maternal dose.

The manufacturers of reboxetine advise that its use in breastfeeding can be considered if the benefits outweigh the risk to the child.

1-3%

Sertraline11, 21, 22,40,51,56-64

Reported infant serum levels appear to be low and in some cases undetectable. Peak drug levels in breast milk have been observed 7-10 hours after the maternal dose. There is one report of an unusually high infant serum level (half maternal serum level). The infant was reported to be 'clinically thriving'.

Adverse effects have not been observed in the majority of nursing infants.

A drop in platelet serotonin levels was not seen in a study of 14 breastfeeding infants of mothers taking sertraline. Serotonergic overstimulation, associated with exposure through breast milk, has been reported in one pre-term infant. Reported symptoms included hyperthermia, shivering, myoclonus and tremor, irritability, decreased suckling reflex and reactivity, tremor and high pitched crying. The symptoms ceased on discontinuation of breastfeeding. The neonate was exposed to sertraline in utero.

In a study of 78 breastfeeding infants of mothers taking an SSRI or venlafaxine no difference in weight was noted at 6 months when compared with the 'normative' weight. Withdrawal symptoms (agitation, restlessness, insomnia and an enhanced startle reaction) developed in a breastfed neonate, after abrupt withdrawal of maternal sertraline. The neonate was exposed to sertraline in utero.

The manufacturers of sertraline advise against its use in breastfeeding, but NICE state that breast milk levels of sertraline are relatively lower (than what, it is not clear) and so tacitly recommends the use of sertraline.12

0.5-3%

Trazodone11,81

Trazodone is excreted into breast milk in small quantities-based on assessments after a single maternal dose.

2.8%

Tricyclic

antidepressants

(TCAs)1-11

Reported infant serum levels range from undetectable to low. Adverse effects have not been reported in infants exposed to amitriptyline, nortriptyline, clomipramine, imipramine-dothiepin (dosulepin) and desipramine. There are two case reports of doxepin exposure during breastfeeding leading to adverse effects in the infant. In one, an 8-week-old infant experienced respiratory depression, which resolved 24 hours after stopping nursing. In the other, poor suckling, muscle hypotonia and drowsiness were observed in a newborn, again resolving 24 hours after removing doxepin exposure.

A study of 15 children did not show a negative outcome on cognitive development in children 3 to 5 years post-partum, following breast milk exposure to dothiepin. NICE states that imipramine, nortriptyline are present in breast milk 'at relatively low levels'.12 Thus these drugs are at least tacitly recommended by NICE. However-nortriptyline is formally contraindicated in breastfeeding mothers.

Data on TCAs not mentioned in this section were not available and their use can therefore not be recommended unless used during pregnancy.

Nortriptyline,
Amitriptyline,
Clomipramine
=1-3%

Venlafaxine11, 21, 22,40,51,66-73

Reported infant serum levels appear to be higher than those seen with fluvoxamine, sertraline and paroxetine. No adverse effects have been reported.

Symptoms of lethargy, jitteriness, rapid breathing, poor suckling and dehydration seen two days after delivery of an infant exposed to venlafaxine in utero, subsided over a week on exposure to venlafaxine via breast milk. It was suggested in this case that breastfeeding may have helped manage the withdrawal symptoms experienced post-partum.

In a study of 13 infants the highest levels of venlafaxine (and desvenlafaxine) were noted 8 hours after maternal dose. Concentrations in breast milk were found to be higher for desvenlafaxine than venlafaxine.

An infant exposed to a combination of venlafaxine and amisulpride from the age of 2 months was found to be healthy during a clinical assessment at 5 months. No health issues were observed and the infant was found to have a Denver developmental age consistent with its chronological age.

In a study of 78 breastfeeding infants of mothers taking an SSRI or venlafaxine no difference in weight was noted at 6 months when compared with the 'normative' weight. 'Typical' development (measured using the Bayley Scale of Infant Development) was observed in two infants exposed to a combination of venlafaxine and quetaipine whilst breastfeeding. In one of the cases the mother was also taking trazodone.

6-9%

Vortioxetine

No data available.

Not available

Table 7.12 Antipsychotics in breastfeeding

Drug

Comment

Estimated daily infant dose as proportion of maternal dose (RID)

Amisulpride11,69,103

In two separate cases, amisulpride concentrations in breast milk were found to be high. Infant serum levels were not directly measured in either case. However-the estimated relative infant dose was calculated in one case to be above the accepted safe level and in the other within the safe limit. The doses of amisulpride in the above cases were 400 mg and 250 mg, respectively. No acute adverse effects or health issues were observed in either infant. The Denver developmental age was consistent, for both infants, with the chronological age. In one of the cases the mother was also taking venlafaxine. Breastfeeding is contraindicated by the manufacturers of amisulpride.

10.7%

Aripiprazole11,104-107

A 3-month old infant was found to be growing 'normally' after exposure to aripiprazole in breast milk and in utero. No further infant data were available. Aripiprazole was undetectable in the three breast milk specimens analysed in this case.

A plasma level of 7.6 ng/ml (approximately 4% of maternal plasma concentration) was recorded 6 days after delivery in a breastfed infant exposed to aripiprazole in utero. The authors proposed that a proportion of the drug detected may be due to placental transfer of aripiprazole. Adverse effects were not noted in the neonate.

There is one case of a woman's failure to lactate after being treated with aripiprazole during pregnancy.

0.9%

Asenapine

No data available.

Not available

Butyrophenones2,3,11,40,92-94

Reported breast milk concentrations are variable. Normal development was noted in one infant. However, delayed development was noted in three infants exposed to a combination of haloperidol and chlorpromazine in breast milk.

Data on butyrophenones not mentioned in this section were not available.

Haloperidol = 0.2-12%

Clozapine2,3,11,40,93,108,109

In a study of four infants exposed to clozapine in breast milk, sedation was noted in one and another developed agranulocytosis, which resolved on stopping clozapine. No adverse effects were noted in the other two. Decreased sucking reflex, irritability, seizures and cardiovascular instability have also been reported in nursing infants exposed to clozapine.

A high breast milk clozapine level (2-3 times maternal plasma level) was reported in one case. The infant was not breastfed.

There is one case report of delayed speech acquisition in an infant who was exposed to clozapine during breastfeeding. The infant was also exposed to clozapine in utero.

Because of the risk of neutropenia and seizures, it is advisable to avoid breastfeeding while on clozapine until more data become available.

1.4%

Lurasidone

No data available.

Not available

Olanzapine2,11,40,110-117

Reported infant serum levels range from undetectable to low.

There is one case of an infant developing jaundice and sedation on exposure to olanzapine during breasfeeding. This continued on cessation of breastfeeding. This infant was exposed to olanzapine in utero and had cardiomegaly. In another, no adverse effects were noted.

No adverse effects were reported in four of seven breastfed infants of mothers taking olanzapine. Of the rest, one was not assessed, one had a lower developmental age than chronological age (but the mother had also been taking additional psychotropic medication)- and drowsiness was noted in another, which resolved on halving the maternal dose. The median maximum concentration in the milk was found at around 5 hours after maternal ingestion.

In one breastfeeding infant, olanzapine serum levels decreased over the course of 5 months. The authors' explanation for this is that the infant's capacity to metabolise olanzapine 'developed rapidly' around the age of 4 months.

No increase in the rate of adverse outcomes (at the age of 1-2 years) was noted in a study comparing 37 infants exposed to olanzapine whilst breastfeeding with non-exposed infants. However, speech delay was noted in one olanzapine-exposed infant and motor developmental delay in another. 'Failure to gain weight' was reported in the case of two infants.

Other reported adverse effects include somnolence, irritability, tremor and insomnia in infants exposed to olanzapine whilst breastfeeding.

1.0–1.6%

Paliperidone

No specific data available. See data for risperidone.

Not available

Phenothiazines2,3,11,92-94

Most of the data relate to chlorpromazine. There is a wide variation in the breast milk concentrations quoted. Similarly, infant serum levels vary greatly. Lethargy was reported in one infant whose mother was taking chlorpromazine while breastfeeding. In another case, however, an infant exposed to much higher levels showed no signs of lethargy. There is a report of delayed development in three infants exposed to a combination of chlorpromazine and haloperidol while breastfeeding.

In the one case of perphenazine exposure and two cases of trifluoperazine exposure, no adverse effects were noted in the infants.

Data on phenothiazines not mentioned in this section were not available.

Chlorpromazine=0.3%

Quetiapine11,70,118-126

Peak breast milk concentrations have been reported one hour after maternal dose (using IR dosage form). Adverse effects were not noted in infants in three separate case reports. One of these infants was exposed to a combination of quetiapine and paroxetine.

In addition, no adverse effects were noted in an infant exposed to a combination of quetiapine and fluvoxamine whilst breastfeeding. The baby reached developmental milestones.

In a separate small study of quetiapine augmentation of maternal antidepressant therapy, two out of six babies showed mild developmental delays not thought to be related to quetiapine treatment. The doses in this study ranged from 25-400 mg/day. Quetiapine was undetected in milk samples from four of mothers, all of whom were taking a dose below 100 mg. There is one reported case of an infant 'sleeping more than expected' whilst exposed to quetiapine, mirtazapine and a benzodiazepine in breast milk. The drowsiness is thought to be a result of exposure to the benzodiazepine.

0.09-0.1%

Risperidone11,127-131

Reported breast milk concentrations of risperidone are higher than for olanzapine and quetiapine. No adverse effects were noted in the reported cases. In two cases where development was assessed, no abnormalities were observed.

Risperidone=2.8-9.1%
9-hydoxyrisperidone= 3.46-4.7%
(based on breast milk concentrations of lactating women taking risperidone)

Sertindole

No published data could be found.

 

Sulpiride11,98-102

There are a number of small studies in which sulpiride has been shown to improve lactation in nursing mothers. Relative infant dose estimations are high.

No adverse effects were noted in the nursing infants.

2.7-20.7%

Thioxanthenes2,11,94-97

There are two cases of infant exposure to flupentixol and seven to zuclopentixol.

No adverse effects or developmental abnormalities were noted in the infant exposed infant exposed to flupentixol. The clinical status of the other infant was not reported.

No adverse effects were reported in the cases of zuclopentixol exposure.

Zuclopentixol = 0.4-0.9%

Ziprasidone11,20,94-132

In one case, where breast-milk concentrations were measured, levels were found to be undetectable or low. Infant effects were not determined in this case. In another case, normal growth and development were noted in a 6-month old infant whose mother took a combination of ziprasidone and citalopram whilst breastfeeding (and during pregnancy). Ziprasidone plasma levels in breast milk were not determined in this case.

0.07-1.2%

Iloperidone

No data available.

Not available

Carbamazepine2,11,133-142

Reported infant serum levels are generally low although higher levels of up 4.8 μg/mL have been reported. Adverse effects have been reported in a number of infants exposed to carbamazepine during breastfeeding. These include one case of cholestatic hepatitis, and one of transient hepatic dysfunction with hyperbilirubinaemia and elevated gamma-glutamyl transferase (GGT). The adverse effects in the first case resolved after discontinuation of breastfeeding and the second resolved despite continued feeding. Other adverse effects reported include seizure-like activity, drowsiness, irritability and high-pitched crying in one infant whose mother was on multiple agents, hyperexcitability in two infants, poor suckling in one and poor feeding in another three. In contrast, in a number of infants, no adverse effects were noted.

A prospective study of children of women with epilepsy found that breastfeeding whilst taking an anticonvulsant was not associated with adverse development of infants at ages 6 to 36 months. The study assessed outcomes in children exposed to anticonvulsants in utero who were subsequently breastfed compared with those who were not.

A study of 199 infants exposed to anticonvulsant medications (carbamazepine, valproate, phenytoin, lamotrigine) during breastfeeding failed to show a difference in IQ between breastfed and non-breastfed infants at the age of 3 years.

The infants were exposed to anticonvulsant medications in utero.

The manufacturers of carbamazepine advise that breastfeeding can be considered if the benefits outweigh the risk to the child. The infant must be observed for possible adverse reactions.

1.1–7.3%

Lamotrigine11,136,141,143-152

Lamotrigine is excreted in breast milk. Infant serum levels range between 18% and 50% of maternal serum levels.

No adverse effects were noted in 30 nursing infants exposed to lamotrigine. In particular none of the infants developed a rash. In addition, no change in the hepatic and electrolyte profiles was noted in 10 of the infants for whom clinical laboratory data were available. However, thrombocytosis was noted in seven infants.

A case of a severe cyanotic episode (preceded by mild episodes of apnoea) requiring resuscitation has been reported in a 16-day old infant exposed to lamotrigine in utero and through breast milk. Neonatal serum concentration was in the upper therapeutic range. The mother was taking a high dose (850 mg/day).

A prospective study of children of women with epilepsy found that breastfeeding whilst taking an anticonvulsant was not associated with adverse development of infants at ages 6 to 36 months. The study assessed outcomes in children exposed to anticonvulsants in utero who were subsequently breastfed compared with those who were not.

Three infants exposed to lamotrigine in utero and through breast milk were reported to be showing 'normal growth and development' at 15 to 18 months of age. All three developed a rash 3 and 4 months post, partum. In one case the rash was attributed to eczema, and to soy allergy in another. The third case resolved spontaneously.

9.2-18.3%

 

Because of the theoretical risk of life-threatening rashes, it is 12-30.1% advisable to avoid lamotrigine while breastfeeding until more data on its effects become available.

A study of 199 infants exposed to anticonvulsant medications (carbamazepine, valproate, phenytoin, lamotrigine) during breastfeeding failed to show a difference in IQ between breastfed and non-breastfed infants at the age of 3 years.

The infants were exposed to anticonvulsant medications in utero.

12-30.1%

Lithium11,133,135,153-156

Infant serum levels range from 10% to 50% of maternal serum concentrations.

In a study of 10 infants, growth and developmental delays were not reported by any of the mothers. In the same study an elevated thyroid stimulating hormone (TSH) was seen in one case (following exposure in utero), an increased urea in a further two and a raised creatinine in another.

Adverse effects have been reported in infants exposed to lithium while breastfeeding. One infant developed cyanosis, lethargy, hypothermia, hypotonia and a heart murmur, all of which resolved within 3 days of stopping breastfeeding. The infant was exposed to lithium in utero. Non-specific signs of toxicity have been reported in others. Early feeding problems have been reported in two infants exposed to lithium in utero and through breast milk. There are also reports of no adverse effects in some infants exposed to lithium while breastfeeding. Opinions on the use of lithium while breastfeeding vary from absolute contraindication to mother's informed choice. Conditions which may alter the infant's electrolyte balance and state of hydration must be borne in mind. If it is used, the infant must be carefully monitored for signs of toxicity. Breastfeeding is contraindicated by the manufacturers of lithium. NICE recommends that lithium should not routinely be prescribed for women who are breastfeeding.

 

Valproate2,11,133-136,141,157,158

Valproate is excreted into breast milk. Reported infant serum 1.4—1.7% levels are low.

Thrombocytopenia and anaemia were reported in a 3-month-old infant exposed to valproate in utero and while breastfeeding. This reversed on stopping breastfeeding.

A study of 199 infants exposed to anticonvulsant medications (carbamazepine, valproate, phenytoin, lamotrigine) during breastfeeding failed to show a difference in IQ between breastfed and non-breastfed infants at the age of 3 years.

The infants were exposed to anticonvulsant medications in utero.

A prospective study of children of women with epilepsy found that breastfeeding whilst taking an anticonvulsant was not associated with adverse development of infants at ages 6 to 36 months. The study assessed outcomes in children exposed to anticonvulsants in utero who were subsequently breastfed compared with those who were not.

The manufacturers of valproate state that there appears to be no contraindication to its use in breastfeeding. However, hepatotoxicity due to valproate is much more likely in the young so there is a theoretical and important risk in breastfed infants.

1.4-1.7%

Benzodiazepines2,11,40,159-166

Diazepam can accumulate in breast milk and in infant serum. Reported adverse effects include sedation, lethargy, weight loss and mild jaundice. No adverse effects have been reported in others.

Lorazepam, temazepam and clonazepam are excreted in breast milk in small amounts. Apart from one case report of persistent apnoea in one infant exposed to clonazepam in utero and during breastfeeding, no adverse effects were reported.

Restlessness has been reported in one infant and mild drowsiness in another whose mothers were taking alprazolam during breastfeeding.

In a telephone survey of 124 women taking benzodiazepines two mothers reported central nervous system (CNS) depression in their breastfeeding neonates. One of the children was exposed to benzodiazepines in utero.

Benzodiazepines with a long half-life, such as diazepam should be avoided in breastfeeding. Any infant exposed to benzodiazepines in breast milk should be monitored for CNS depression and apnoea.

Not available

Promethazine

No published data could be found. The manufacturers of promethazine issue no specific advice on its use in breastfeeding.

Not available

Zopiclone, zolpidem and

zaleplon11,167-169

All three are excreted into breast milk in small amounts. No adverse effects were noted in exposed infants. Zolpidem was detected in the breast milk of five lactating women for up to 4 hours after a 20 mg dose. Zaleplon peak breast milk levels were found 1 hour after the dose and breast milk concentrations were approximately 50% of plasma concentrations.

Zaleplon = 1.5%
Zopiclone = 1.5%
Zolpidem = 4.7-19.1%

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Further reading

Field T. Breastfeeding and antidepressants. Infant Behav Dev 2008; 31:481–487.

Gentile S et al. SSRIs during breastfeeding: spotlight on milk-to-plasma ratio. Arch Womens Ment Health 2007; 10:39–51.

Gentile S. Infant safety with antipsychotic therapy in breast-feeding: a systematic review. J Clin Psychiatry 2008; 69:666–673.

National Institute for Health and Care Excellence. Antenatal and postnatal mental health: clinical management and service guidance. Clinical Guideline 192, 2014. https://www.nice.org.uk/guidance/cg192

Renal impairment

Using drugs in patients with renal impairment needs careful consideration. This is because some drugs are nephrotoxic and also because pharmacokinetics (absorption, distribution, metabolism, excretion) of drugs are altered in renal impairment. Essentially, patients with renal impairment have a reduced capacity to excrete drugs and their metabolites.

General principles of prescribing in renal impairment

Cockroft and Gault equation*

CrCl (mL/ min)=F(140-age (in years)) x ideal body weight(kg))

Serum creatinine(mol/L)

F= 1.23 (men) and 1.04 (women)

Ideal body weight should be used for patients at extremes of body weight or else the calculation is inaccurate

For men, ideal body weight (kg) = 50 kg + 2.3 kg per inch over 5 feet

For women, ideal body weight (kg) = 45.5 kg + 2.3 kg per inch over 5 feet

* This equation is not accurate if plasma creatinine is unstable, in pregnant women, children or in diseases causing production of abnormal amounts of creatinine and has only been validated in Caucasian patients. Creatinine clearance is less representative of GFR in severe renal failure.

When calculating drug doses use estimated CrCl from the Cockroft and Gault equation. Do not use MDRD formula for dose calculation because most current dose recommendations are based on the creatinine clearance estimations from Cockroft and Gault.

Modification of diet in renal disease (MDRD) formula

This gives an estimated GFR (eGFR) for a 1.73 m2 body surface area. If the body surface area is > or < than 1.73 m2 then eGFR becomes less accurate and representative (use correction below). Adjustments are made for female gender and Black ethnicity. Many pathology departments report eGFR.

Actual GFR can be calculated as follows:

Actual GFR (eGFR BSA/1.73)

BSA = body surface area =

Height(cm) x Weight(kg)

3600

Use Cockroft and Gault for drug dose calculation.

Classify the stage of renal impairment as below:

Stage

Description

1

GFR > 90 mL/min/1.73 m2 with other evidence of chronic kidney damage*

2

Mild impairment; GFR 60-89 mL/min/1.73 m2 with other evidence of kidney damage*

3

Moderate impairment, GFR 30-59 mL/min/1.73 m2

4

Severe impairment, GFR 15-29 mL/min/1.73 m2

5

Established renal failure, GFR < 15 mL/min/1.73 m2 or on dialysis

* Other evidence of chronic kidney damage is one or more of the following; persistent microalbuminuria; persistent proteinuria; persistent haematuria; structural kidney abnormalities; biopsy-proven chronic glomerulonephritis.

Table 7.15 summarises the recommendations for psychotropic drug use in renal impairment. Further information is given in Tables 7.16–7.20.

Table 7.15 Recommendations for the use of psychotropics in renal impairment

Drug group

Recommended drugs

Antipsychotics

No agent clearly preferred to another, however:

  • avoid sulpiride and amisulpride
  • avoid highly anticholinergic agents because they may cause urinary retention
  • first-generation antipsychotic - suggest haloperidol 2-6 mg a day
  • second-generation antipsychotic - suggest olanzapine 5 mg a day

Antidepressants

No agent clearly preferred to another, however:

  • citalopram (care QTc prolonging effects) and sertraline are suggested as reasonable choices

Mood stabilisers

No agent clearly preferred to another, however:

  • avoid lithium if possible
  • suggest start one the following at a low dose and increase slowly, monitor for adverse effects: valproate, carbamazepine or lamotrigine

Anxiolytics and hypnotics

No agent clearly preferred to another, however:

  • excessive sedation is more likely to occur in patients with renal impairment, so monitor all patients carefully
  • lorazepam and zopiclone are suggested as reasonable choices

Anti-dementia drugs

No agent clearly preferred to another, however: rivastigmine is a reasonable choice

Table 7.16 Antipsychotics in renal impairment

Drug

Comments

Amisulpride7-10

Primarily renally excreted. 50% excreted unchanged in urine. Limited experience in renal disease. Manufacturer states no data with doses of > 50 mg but recommends following dosing: 50% of dose if GFR 30-60 mL/min; 33% of dose if GFR is 10-30 mL/min; no recommendations for GFR < 10 mL/min so best avoided in established renal failure

Aripiprazole7,8,10-13

Less than 1% of unchanged aripiprazole renally excreted. Manufacturer states no dose adjustment required in renal failure as pharmacokinetics are similar in healthy and severely renally diseased patients. There is one case report of safe use of oral aripiprazole 5 mg in an 83-year-old man having haemodialysis. Avoid depot formulation - no current experience

Asenapine8,14

Manufacturer states no dose adjustment required for patients with renal impairment but no experience with use if GFR < 15 mL/min. A 5 mg single dose study in renal impairment suggests that no dose adjustment is needed

Chlorpromazine7,8,10,15,16

Less than 1% excreted unchanged in urine. Manufacturer advises avoiding in renal dysfunction. Dosing: GFR 10-50 mL/min, dose as in normal renal function; GFR < 10 mL/min, start with a small dose because of an increased risk of anticholinergic, sedative and hypotensive side effects. Monitor carefully

Clozapine8,10,17-20

Only trace amounts of unchanged clozapine excreted in urine; however there are rare case reports of interstitial nephritis and acute renal failure. Nocturnal enuresis and urinary retention are common side-effects. Contraindicated by manufacturer in severe renal disease. Anticholinergic, sedative and hypotensive side effects occur more frequently in patients with renal disease. Dosing: GFR 10-50 mL/min as in normal renal function but with caution; GFR < 10 mL/min start with a low dose and titrate slowly (based on renal expert opinion). Levels are useful to guide dosing. May cause and aggravate diabetes, a common cause of renal disease

Flupentixol7,8,10

Negligible renal excretion of unchanged flupentixol. Dosing: GFR 10-50 mL/min dose as in normal renal function; GFR < 10 mL/min start with one-quarter to one-half of normal dose and titrate slowly. May cause hypotension and sedation in renal impairment and can accumulate. Manufacturer recommends caution in renal failure. Avoid depot preparations in renal impairment

Fluphenazine8,10

Little information available; manufacturer cautions in renal impairment and contraindicates in renal failure. Dosing: GFR 10-50 mL/min dose as in normal renal function; GFR < 10 mL/min start with a low dose and titrate slowly. Avoid depot preparations in renal impairment

Haloperidol4,7,8,10,21,22

Less than 1% excreted unchanged in the urine. Manufacturer advises caution in renal failure. Dosing: GFR 10-50 mL/min, dose as in normal renal function;

GFR < 10 mL/min start with a lower dose as can accumulate with repeated dosing. A case report of haloperidol use in renal failure suggests starting at a low dose and increasing slowly. Has been used to treat uraemia associated nausea in renal failure. Avoid depot preparations in renal impairment

Lurasidone23

9% excreted unchanged in the urine. Manufacturer recommends dose adjustment if GFR < 30 mL/min to 50 mL/min patients (starting dose is 20 mg/day, maximum 80 mg/day). Renal failure has been reported rarely

Olanzapine3,7,8,10,22,24

57% of olanzapine is excreted mainly as metabolites (7% excreted unchanged) in urine. Dosing: GFR < 50 mL/min initially 5 mg daily and titrate as necessary. Avoid long acting preparations in renal impairment unless the oral dose is well tolerated and effective. Manufacturer recommends a lower long acting injection starting dose of 150 mg 4-weekly in patients with renal impairment. May cause and aggravate diabetes, a common cause of renal disease. Hypothermia has been reported when used in renal failure

Paliperidone7,8,10

Paliperidone is also a metabolite of risperidone. 59% excreted unchanged in urine. Dosing: GFR 30-80 mL/min, 3 mg daily and increase according to response to maximum of 6 mg daily; GFR 10-30 mL/min, 3 mg alternate days increasing to 3 mg daily according to response. Use with caution as clearance is reduced by 71% in severe kidney disease. Manufacturer contraindicates oral if GFR < 10 mL/min due to lack of experience and depot preparation if GFR < 50 mL/min (reduced loading doses if GFR ≥ 50 to < 80 mL/min)

Pimozide7,8,10

Less than 1% of pimozide is excreted unchanged in the urine; dose reductions not usually needed in renal impairment. Dosing: GFR 10-50 mL/min, dose as in normal renal function; GFR < 10 mL/min start at a low dose and increase according to response. Manufacturer cautions in renal failure

Pipotiazine8

Little information available; contraindicated in renal failure by manufacturer. Avoid depot preparations in renal impairment

Quetiapine7,8,10,25,26

Less than 5% of quetiapine excreted unchanged in the urine. Plasma clearance reduced by an average of 25% in patients with a GFR < 30 mL/min. In patients with GFR of < 10 to 50 mL/min start at 25 mg/day and increase in daily increments of 25-50 mg to an effective dose. Two separate case reports one of thrombotic thrombocytopenic purpura and another of non-NMS rhabdomyolyisis both resulting in acute renal failure with quetiapine have been published

Risperidone7,8,10,22,27-29

Clearance of risperidone and the active metabolite of risperidone is reduced by 60% in patients with moderate to severe renal disease. Dosing : GFR < 50 mL/min 0.5 mg twice daily for at least 1 week then increasing by 0.5 mg twice daily to 1-2 mg bd. The manufacturer advises caution when using risperidone in renal impairment. The long-acting injection should only be used after titration with oral risperidone as described above. If 2 mg orally is tolerated, 25 mg intramuscularly every 2 weeks can be administered. However there is a case report of successful use of risperidone long-acting injection at a dose of 50 mg 2- weekly in a patient on haemodialysis. Another describes the successful use of risperidone in a child with steroid-induced psychosis and nephrotic syndrome

Sulpiride2,7,8,10,30

Almost totally renally excreted, with 95% excreted in urine and faeces as unchanged sulpiride. Dosing regimen: GFR 30-60 mL/min, give 70% of normal dose; GFR 10-30 mL/min give 50% of normal dose; GFR < 10 mL/min give 34% of normal dose. There is a case report of renal failure with sulpiride due to diabetic coma and rhabdomyolyisis. Probably best avoided in renal impairment

Trifluoperazine10

Less than 1% excreted unchanged in the urine. Dose GFR < 10-50 mL/min as for normal renal function - start with a low dose. Very limited data

Ziprasidone7,22,31,32

< 1% is renally excreted unchanged. No dose adjustment needed for GFR > 10 mL/min but care needed with using the injection as it contains a renally eliminated excipient (cyclodextrin sodium)

Zuclopentixol7,8,10

10-20% of unchanged drug and metabolites excreted unchanged in urine.

Manufacturer cautions use in renal disease as can accumulate. Dosing: 10-50 mL/min dose as in normal renal function; GFR < 10 mL/min start with 50% of the dose and titrate slowly. Avoid both depot preparations (acetate and decanoate) in renal impairment

GFR, glomerular filtration rate.

Table 7.17 Antidepressants in renal impairment6

Drug

Comments

Agomelatine8

Negligible renal excretion of unchanged agomelatine. No data on use in renal disease. Manufacturer says pharmacokinetics unchanged in small study of 25 mg dose in severe renal impairment but cautions use in moderate or severe renal disease

Amitriptyline7,8,10,16,22,33-35

< 2% excreted unchanged in urine; no dose adjustment needed in renal failure. Dose as in normal renal function but start at a low dose and increase slowly. Monitor patient for urinary retention, confusion, sedation and postural hypotension. Has been used to treat pain in those with renal disease.

Plasma level and ECG monitoring may be useful

Bupropion7,8,10,16,22,36,37

(amfebutamone)

0.5% excreted unchanged in the urine. Dosing: GFR < 50 mL/min 150 mg once daily. A single dose study in haemodialysis patients (stage 5 disease) recommended a dose of 150 mg every 3 days. Metabolites may accumulate in renal impairment and clearance is reduced. Elevated levels increase risk of seizures

Citalopram7,8,10,22,38-43

< 13% of citalopram is excreted unchanged in the urine. Single-dose studies in mild and moderate renal impairment show no change in the pharmacokinetics of citalopram. Dosing is as for normal renal function; however' use with caution if GFR < 10 mL/min due to reduced clearance.The manufacturer does not advise use if GFR < 20 mL/min. Renal failure has been reported with citalopram overdose. Citalopram can treat depression in chronic renal failure and improve quality of life. A case report of hyponatraemia has been reported in a renal transplant patient on citalopram

Clomipramine7,8,10,16,44

2% of unchanged clomipramine is excreted in the urine. Dosing: GFR 20-50 mL/min' dose as for normal renal function; GFR < 20 mL/min' effects unknown' start at a low dose and monitor patient for urinary retention' confusion' sedation and postural hypotension as accumulation can occur. There is a case report of clomipramine-induced interstitial nephritis and reversible acute renal failure

Desvenlafaxine6,7,45,46

45% of desvenlafaxine is excreted unchanged in the urine. Dosing advice is conflicting. Manufacturer recommends: GFR 30 to 50 mL/min' 50 mg per day; GFR < 30 mL/min' 50 mg every other day. However other authors6 recommend 25 mg per day in all stages of renal impairment. Half-life is prolonged and desvenlafaxine accumulates as GFR decreases. Urinary retention' delay when starting to pass urine and proteinuria have been reported as adverse effects

Dosulepin7,10,47

(dothiepin)

56% of mainly active metabolites renally excreted. They have a long half-life and may accumulate' resulting in excessive sedation. Dosing: GFR 20-50 mL/min' dose as for normal renal function; GFR < 20 mL/min' start with a small dose and titrate to response. Monitor patient for urinary retention' confusion' sedation and postural hypotension

Doxepin7,8,10,16

< 1% excreted unchanged in urine. Dose as in normal renal function but monitor patient for urinary retention' confusion' sedation and postural hypotension. Manufacturer advises using with caution. Haemolytic anaemia with renal failure has been reported with doxepin

Duloxetine7,10,48,49

< 1% excreted unchanged in urine. Manufacturer states no dose adjustment is necessary for GFR > 30 mL/min; however starting at a low dose and increasing slowly is advised. Duloxetine is contraindicated in patients with a GFR < 30 mL/min as it can accumulate in chronic kidney disease. Licensed to treat diabetic neuropathic pain and stress incontinence in women. Diabetes is a common cause of renal impairment. A case report of acute renal failure with duloxetine has been reported

Escitalopram7,10,50-52

8% excreted unchanged in urine. The manufacturer states dosage adjustment is not necessary in patients with mild or moderate renal impairment but caution is advised if GFR < 30 mL/min so start with a low dose and increase slowly. A case report of reversible renal tubular defects and another of renal failure have been reported with escitalopram. One study says effective versus placebo in end stage renal disease

Fluvoxamine7,10,16,22

2% is excreted unchanged in urine. Little information on its use in renal impairment. Manufacturer cautions in renal impairment. Dosing: GFR 10-50 mL/min dose as for normal renal function; GFR < 10 mL/min dose as for normal renal function but start on a low dose and titrate slowly

Fluoxetine7,8,10,16,22,53-56

2.5-5% of fluoxetine and 10% of the active metabolite norfluoxetine are excreted unchanged in the urine. Dosing: GFR 20-50 mL/min dose as normal renal function; GFR < 20 mL/min use a low dose or on alternate days and increase according to response. Plasma levels after 2 months treatment with 20 mg (in patients on dialysis with GFR < 10 mL/min) are similar to those with normal renal function. Efficacy studies of fluoxetine in depression and renal disease are conflicting. One small placebo controlled study of fluoxetine in patients on chronic dialysis found no significant differences in depression scores between the two groups after 8 weeks of treatment. Another found fluoxetine effective

Imipramine7,8,10,16,33

< 5% excreted unchanged in the urine. No specific dose adjustment necessary in renal impairment (GFR < 10-50 mL/min). Monitor patient for urinary retention, confusion, sedation and postural hypotension. Renal impairment with imipramine has been reported and manufacturer advises caution in severe renal impairment. Renal damage reported rarely

Lofepramine7,8,10,57

There is little information about the use of lofepramine in renal impairment. Less than 5% is excreted unchanged in the urine. Dosing: GFR 10-50 mL/min dose as in normal renal function; GFR < 10 mL/min start with a small dose and titrate slowly. Manufacturer contraindicates in severe renal impairment

Mirtazapine7,8,10,58

75% excreted unchanged or as metabolites in the urine. Clearance is reduced by 30% in patients with a GFR of 11-39 mL/min and by 50% in patients with a GFR < 10 mL/min. Dosing advice: GFR 10-50 mL/min dose as for normal renal function; GFR < 10 mL/min start at a low dose and monitor closely. Mirtazapine has been used to treat puritis caused by renal failure and is associated with kidney calculus formation

Moclobemide7,8,10,59,60

< 1% of parent drug excreted unchanged in the urine. However, an active metabolite was found to be raised in patients with renal impairment but was not thought to affect dosing. The manufacturer advises that dose adjustments are not required in renal impairment. Dosing: GFR < 10-50 mL/min dose as in normal renal function

Nortriptyline7,10,16,22,33,61

< 5% excreted unchanged in urine. If GFR 10-50 mL/min, dose as in normal renal function; if GFR < 10 mL/min start at a low dose. Plasma level monitoring recommended at doses of > 100 mg/day as plasma concentrations of active metabolites are raised in renal impairment. Worsening of GFR in elderly patients has also been reported. Plasma level monitoring can be useful

Paroxetine7,8,10,16,62-65

Less than 2% of oral dose is excreted unchanged in the urine. Single-dose studies show increased plasma concentrations of paroxetine when GFR < 30 mL/min. Dosing advice differs: GFR 30-50 mL/min dose as normal renal function; GFR < 10-30 mL/min start at 10 mg/day (other source says start at 20 mg) and increase dose according to response. Paroxetine 10 mg daily and psychotherapy have been used sucessfully to treat depression in patients on chronic haemodialysis. Rarely associated with Fanconi syndrome and acute renal failure

Phenelzine7,10

Approximately 1% excreted unchanged in the urine. No dose adjustment required in renal failure

Reboxetine7,8,10,66,67

Approximately 10% of unchanged drug is excreted unchanged in the urine. Dosing: GFR < 20 mL/min, 2 mg twice daily, adjusting dose according to response. Half-life is prolonged as renal function decreases

Vortioxetine68

Negligible amounts are excreted unchanged in urine. Manufacturer advises that no dose adjustment is needed in renal impairment and end stage disease

Sertraline7,8,10,16,69-72

< 0.2% of unchanged sertraline excreted in urine. Pharmacokinetics in renal impairment are unchanged in single dose studies but no published data on multiple dosing. Dosing is as for normal renal function. Sertraline has been used to treat dialysis-associated hypotension and uraemic pruritis; however acute renal failure has been reported so it should be used with caution. An RCT of sertraline in kidney disease is ongoing. Has been associated with serotonin syndrome when used in patents on haemodialysis

Trazodone7,8,10,73

< 5% excreted unchanged in urine but care needed as approximately 70% of active metabolite also excreted. Dosing: GFR 20-50 mL/min, dose as normal renal function; GFR 10-20 mL/min, dose as normal renal function but start with small dose and increase gradually; GFR < 10 mL/min, start with small doses and increase gradually

Trimipramine7,10,16,33,74,75

No dose reduction required in renal impairment; however, elevated urea, acute renal failure and interstitial nephritis have been reported. As with all tricyclic antidepressants, monitor patient for urinary retention, confusion, sedation and postural hypotension as patients with renal impairment are at increased risk of having these side-effects

Venlafaxine7,8,16,76-78

1-10% is excreted unchanged in the urine (30% as the active metabolite). Clearance is decreased and half-life prolonged in renal impairment. Dosing advice differs: GFR 30-50 mL/min, dose as in normal renal function or reduce by 50%; GFR 10-30 mL/min reduce dose by 50% and give tablets once daily; GFR < 10 mL/min, reduce dose by 50% and give once daily however manufacturer advises avoiding use in these patients. Avoid using the ER preparation if GFR < 30 mL/min. Rhabdomyolyisis and renal failure have been reported rarely with venlafaxine.

Has been used to treat peripheral diabetic neuropathy in haemodialysis patients. High doses may cause hypertension

ECG, electrocardiogram; ER, extended release; GFR, glomerular filtration rate; RCT, randomised controlled trial.

Table 7.18 Mood stabilisers in renal impairment

Drug

Comments

Carbamazepine7,8,10,79-86

2-3% of the dose is excreted unchanged in urine. Dose reduction not necessary in renal disease, although cases of renal failure, tubular necrosis and tubulointerstitial nephritis have been reported rarely and metabolites may accumulate. Can cause Stevens-Johnson syndrome and toxic epidermal necrolysis which may result in acute renal failure

Lamotrigine7,8,10,87-90

< 10% of lamotrigine is excreted unchanged in the urine. Single-dose studies in renal failure show pharmacokinetics are little affected: however, inactive metabolites can accumulate (effects unknown) and half-life can be prolonged. Renal failure and interstitial nephritis have also been reported. Dosing: GFR < 10-50 mL/min, use cautiously, start with a low dose, increase slowly and monitor closely. One source suggests in GFR < 10 mL/min use 100 mg every other day

Lithium7,8,10,16,91,92

Lithium is nephrotoxic and contraindicated in severe renal impairment; 95% is excreted unchanged in the urine. Long-term treatment may result in impaired renal function ('creatinine creep'), permanent changes in kidney histology, nephrogenic diabetes insipidus, nephrotic syndrome and both reversible and irreversible kidney damage.

If lithium is used in renal impairment, toxicity is more likely. The manufacturer contraindicates lithium in renal impairment. Dosing: GFR 10-50 mL/min, avoid or reduce dose (50-75% of normal dose) and monitor levels; GFR < 10 mL/min, avoid if possible, however if used it is essential to reduce dose (25-50% of normal dose). Renal damage is more likely with chronic toxicity than acute

Valproate7,8,10,93-99

Approximately 2% excreted unchanged. Dose adjustment usually not required in renal impairment; however, free valproate levels may be increased. Renal impairment, interstitial nephritis, Fanconi syndrome, renal tubular acidosis and renal failure have been reported. Dose as in normal renal function, however, in severe impairment (GFR < 10 mL/min) it may be necessary to alter doses according to free (unbound) valproate levels

GFR, glomerular filtration rate.

Table 7.19 Anxiolytics and hypnotics in renal impairment

Drug

Comments

Buspirone7,8,10,16

Less than 1% is excreted unchanged; however, active metabolite is renally excreted. Dosing advice contradictory, suggest: GFR 10-50 mL/min dose as normal; GFR < 10 mL/min avoid if possible due to accumulation of active metabolites;if essential, reduce dose by 25-50% if patient is anuric. Manufacturer contraindicates in severe renal impairment

Clomethiazole7,8,10,100

(chlormethiazole)

0.1-5% of unchanged drug excreted unchanged in urine. Dose as in normal renal function but monitor for excessive sedation. Manufacturer recommends caution in renal disease

Chlordiazepoxide8, 10, 16

1-2%% excreted unchanged but chlordiazepoxide has a long-acting active metabolite that can accumulate. Dosing: GFR 10-50 mL/min, dose as normal renal function; GFR < 10 mL/min, reduce dose by 50%. Monitor for excessive sedation. Manufacturer cautions in chronic renal disease

Clonazepam7, 8, 10, 101

< 0.5% of clonazepam excreted unchanged in urine. Dose adjustment not required in impaired renal function; however with long-term administration, active metabolites may accumulate so start at a low doses and increase according to response. Monitor for excessive sedation. Has been used for insomnia in patients on haemodialysis

Diazepam7, 10, 16, 102

Less than 0.5% is excreted unchanged. Dosing: GFR 20-50 mL/min, dose as in normal renal function; GFR < 20 mL/min, use small doses and titrate to response. Long-acting, active metabolites accumulate in renal impairment; monitor patients for excessive sedation and encephalopathy. One case of interstitial nephritis with diazepam has been reported in a patient with chronic renal failure

Eszopiclone103

Less than 10% excreted unchanged in the urine. No dose adjustment is needed in renal impairment

Lorazepam7,8,10,16,104-109

< 1% excreted unchanged in urine. Dose as in normal renal function but carefully according to response as some may need lower doses. Monitor for excessive sedation. Impaired elimination reported in two patients with severe renal impairment and also reports of propylene glycol in lorazepam injection causing renal impairment and acute tubular necrosis. However, lorazepam injection has been successfully used to treat catatonia in two patients with renal failure

Nitrazepam8, 10

Less than 5% excreted unchanged in the urine. Dosing GFR 10-50 mL/min as per normal renal function; GFR < 10 mL/min start with small dose and increase slowly. Manufacturer advises reducing dose in renal impairment. Monitor patient for sedation

Oxazepam7, 10, 16, 110

Less than 1% excreted unchanged in the urine. Dose adjustment needed in severe renal impairment. Oxazepam may take longer to reach steady state in patients with renal impairment. Dosing: GFR 10-50 mL/min, dose as in normal renal function; GFR < 10 mL/min, start at a low dose and increase according to response. Monitor for excessive sedation

Promethazine7, 8, 10, 16, 111

Dose reduction usually not necessary; however, promethazine has a long half-life so monitor for excessive sedative effects in patients with renal impairment. Manufacturer advises caution in renal impairment. There is a case report of interstitial nephritis in a patient who was a poor metaboliser of promethazine

Temazepam7,8,10,16

< 2% excreted unchanged in urine. In renal impairment the inactive metabolite can accumulate. Monitor for excessive sedative effects. Dosing: GFR 20-50 mL/min, dose as normal renal function; GFR < 20 mL/min, dose as in normal renal function but start with 5 mg

Zaleplon7,8,112,113

In renal impairment inactive metabolites accumulate. No dose adjustment appears to be necessary in patients with a GFR > 20 mL/min. Zaleplon is not recommended if GFR < 20 mL/min, however, it has been used in patients on haemodialysis

Zolpidem7, 8, 10, 101, 112

Clearance moderately reduced in renal impairment. No dose adjustment required in renal impairment. Zolpidem 1 mg has been used to treat insomnia in patients on haemodialysis

Zopiclone7, 8, 10, 114, 115

Less than 5% excreted unchanged in urine. Manufacturer states no accumulation of zopiclone in renal impairment but suggests starting at 3.75 mg. Dosing: GFR < 10 mL/min, start with lower dose. Interstitial nephritis reported rarely

GFR, glomerular filtration rate.

Table 7.20 Anti-dementia drugs in renal impairment

Drug

Comments

Donepezil8, 10, 116-118

17% excreted unchanged in urine. Dosing is as in normal renal function for GFR < 10-50 mL/min. Manufacturer states that clearance not affected by renal impairment. Single dose studies find similar pharmacokinetics in moderate and severe renal impairment compared with healthy controls. Has been used at a dose of 3 mg/day in an elderly patient with Alzheimer's dementia on dialysis

Galantamine8, 10

18-22% is excreted unchanged in urine. Dose as in normal renal function for GFR 10-50 mL/min and at GFR < 10 mL/min start at a low dose and increase slowly. Manufacturer contraindicates use in GFR < 10 mL/min. Plasma levels may be increased in patients with moderate and severe renal impairment

Memantine7, 8, 119

Manufacturers recommend a 10 mg dose if GFR 5-29 mL/min; 10 mg daily for 7 days then increased to 20 mg daily if tolerated for GFR > 30-49 mL/min. Renal tubular acidosis, severe urinary tract infections and alkalisation of urine (e.g. by drastic dietary changes) can increase plasma levels of memantine. Acute renal failure has been reported

Rivastigmine8, 10

0% excreted unchanged in urine. Dosing advice for GFR < 50 mL/min start at a low dose and gradually increase

GFR, glomerular filtration rate.

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Hepatic impairment

Patients with hepatic impairment may have the following characteristics.

General principles of prescribing in hepatic impairment

Liver function tests (LFTs) are a poor marker of hepatic metabolising capacity, as the hepatic reserve is large. Note that many patients with chronic liver disease are asymptomatic or have fluctuating clinical symptoms. Always consider the clinical presentation rather than adhere to rigid rules involving LFTs.

There are few clinical studies relating to the use of psychotropic drugs in people with hepatic disease. The following principles should be adhered to:

These rules should always be observed in severe liver disease (low albumin, increased clotting time, ascites, jaundice, encephalopathy, etc.). The information above, and on the following pages, should be interpreted in the context of the patient's clinical presentation. Table 7.21 summarises the recommendations for psychotropic drug use in hepatic impairment. Further information is given in Tables 7.22–7.25.

Antipsychotics in hepatic impairment

One third of patients who are prescribed antipsychotic medication have at least one abnormal LFT and in 4% at least one LFT is elevated three times above the upper limit of normal. Transaminases are most often affected and this generally occurs within 1–6 weeks of treatment initiation. Only rarely does clinically significant hepatic damage result.1

Antidepressants in hepatic impairment

Of those treated with antidepressants, 0.5–3% develop asymptomatic mild elevation of hepatic transaminases. Onset is normally between several days and six months of treatment initiation and the elderly are more vulnerable. Frank clinically significant liver damage, however, is rare, mostly idiosyncratic (unpredictable and not related to dose). Cross toxicity within class has been described.23

Drug-induced hepatic damage

Hy's rule, defined as the occurrence of ALT> 3 times the upper limit of normal combined with serum bilirubin > 2 times the upper limit of normal is recommended by the FDA to assess the hepatotoxicity of new drugs.55

Table 7.21 Recommendations for the use of psychotropics in hepatic impairment

Drug group

Recommended drugs

Antipsychotics

Haloperidol: low dose

or

Sulpiride/amisulpride: no dosage reduction required if renal function is normal

Paliperidone: if depot required

Antidepressants

Imipramine: start with 25 mg/day and titrate slowly (weekly at most) if required

or

Paroxetine or citalopram: start at 10 mg if severe hepatic impairment. Titrate slowly (if required) as above

Mood stabilisers

Lithium: use plasma levels to guide dosage. Care needed if ascites status changes

Sedatives

Lorazepam, oxazepam, temazepam: as short half-life with no active metabolites. Use low doses with caution, as sedative drugs can precipitate hepatic encephalopathy

Zopiclone: 3.75 mg with care in moderate hepatic impairment

Table 7.22 Antipsychotics in hepatic impairment

Drug

Comments

Amisulpride2,3

Predominantly renally excreted, so dosage reduction should not be necessary as long as renal function is normal but there are no clinical studies in people with hepatic impairment and little clinical experience. Caution required

Aripiprazole2

Extensively hepatically metabolised. Limited data that hepatic impairment has minimal effect on pharmacokinetics. SPC states no dosage reduction required in mild-moderate hepatic impairment, but caution required in severe impairment. Limited clinical experience. Caution required. Small number of reports of hepatotoxicity; increased LFTs, hepatitis and jaundice

Asenapine2

Hepatically metabolised. SPC recommends avoid in severe hepatic disease

Clozapine2-6

Very sedative and constipating. Contraindicated in active liver disease associated with nausea, anorexia or jaundice, progressive liver disease or hepatic failure. In less severe disease, start with 12.5 mg and increase slowly, using plasma levels to gauge metabolising capacity and guide dosage adjustment. Transient elevations in AST, ALT and GGT to over twice the normal range occur in over 10% of physically healthy people. Clozapine-induced hepatitis, jaundice, cholestasis and liver failure have been reported. If jaundice develops, clozapine should be discontinued

Flupentixol/

zuclopenthixol2,3,7,8

Both are extensively hepatically metabolised. Small, transient elevations in transaminases have been reported in some patients treated with zuclopenthixol. No other literature reports of use or harm. Both drugs have been in use for many years. Depot preparations are best avoided, as altered pharmacokinetics will make dosage adjustment difficult and side-effects from dosage accumulation more likely

Haloperidol2,9

Drug of choice in clinical practice and no problems reported although UK SPC states 'caution in liver disease'. Isolated reports of cholestatic hepatitis

Iloperidone10

Hepatically metabolised. Reduce dose in moderate hepatic impairment and avoid completely in severe hepatic impairment

Lurasidone11

Hepatically metabolised. SPC recommends starting dose of 20 mg in hepatic impairment and maximum dose of 40 mg/day in severe hepatic impairment

Olanzapine2-4,12

Although extensively hepatically metabolised, the pharmacokinetics of olanzapine seem to change little in severe hepatic impairment. It is sedative and anticholinergic (can cause constipation) so caution is advised. Start with 5 mg/day and consider using plasma levels to guide dosage (aim for 20-40 μg/L). Dose-related, transient, asymptomatic elevations in ALT and AST reported in physically healthy adults. People with liver disease may be at increased risk. Rare cases of hepatitis in the literature

Paliperidone13

Mainly excreted unchanged by the kidneys so no dosage adjustment required. However, no data are available with respect to severe hepatic impairment and clinical experience is limited. Caution required

Phenothiazines2,3,14-16

All cause sedation and constipation. Associated with cholestasis and some reports of fulminant hepatic cirrhosis. Best avoided completely in hepatic impairment. Chlorpromazine is particularly hepatotoxic

Quetiapine2,17-20

Extensively hepatically metabolised but short half-life. Clearance reduced by a mean of 30% in hepatic impairment so small dosage adjustments may be required. Can cause sedation and constipation. Little clinical experience in hepatic impairment so caution recommended. One case of fatal hepatic failure and another of hepatocellular damage reported in the literature

Risperidone2-4

Extensively hepatically metabolised and highly protein bound. Manufacturers recommend a reduced starting dose, slower dose titration and a maximum dose of 4 mg in hepatic impairment. Transient, asymptomatic elevations in LFTs, cholestatic hepatitis and rare cases of hepatic failure have been reported. Steatohepatitis may arise as a result of weight gain. Clinical experience limited in hepatic impairment so caution recommended

Sulpiride2,3,21,22

Almost completely renally excreted with a low potential to cause sedation or constipation. Dosage reduction should not be required. Some clinical experience in hepatic impairment with few problems. Fairly old established drug. Isolated case reports of cholestatic jaundice and primary biliary cirrhosis. SPC states contraindicated in severe hepatic disease

ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma-glutamyl transferase; LFT, liver function test; SPC, summary of product characteristics.

Table 7.23 Antidepressants in hepatic impairment

Drug

Comments

Agomelatine23-25

Liver injury including hepatic failure reported. Best avoided in established liver disease. SPC recommends LFTs at baseline, 3, 6, 12, 24 weeks and thereafter where clinically indicated

Duloxetine2, 3, 26, 27

Hepatically metabolised. Clearance markedly reduced even in mild impairment. Reports of hepatocellular injury and, less commonly, jaundice. Isolated case report of fulminant hepatic failure. Limited experience. Best avoided

Fluoxetine2, 3, 28-32

Extensively hepatically metabolised with a long half-life. Kinetic studies demonstrate accumulation in compensated cirrhosis. Although dosage reduction (of at least 50%) or alternate day dosing could be used, it would take many weeks to reach steady-state serum levels, making fluoxetine complex to use. Asymptomatic increases in LFTs found in 0.5% of healthy adults. Rare cases of hepatitis reported

MAOIs2,3,33,34

People with hepatic impairment reported to be more sensitive to the side-effects of MAOIs. MAOIs are also more hepatotoxic than other antidepressants, so best avoided completely

Mirtazapine2,3,35

Hepatically metabolised and sedative. 50% dose reduction recommended based on kinetic data, but clinical experience limited. Mild, asymptomatic increases in LFTs seen in healthy adults (ALT > 3 times the upper limit of normal in 2%). Few cases of cholestatic and hepatocellular damage reported. Best avoided

Moclobemide2, 3, 36, 37

Clinical experience limited but probably safer than the irreversible MAOIs. 50% reduction in dose advised by manufacturers. Rare cases of hepatotoxicity reported. Caution advised

Other SSRIs2, 3, 32, 38-49

All are hepatically metabolised and accumulate on chronic dosing. Dosage reduction may be required. Sertraline has been found to be both safe and effective in a placebo controlled RCT of the management of cholestatic pruritus. Raised LFTs and rare cases of hepatitis, including chronic active hepatitis, have been reported with paroxetine. Sertraline and fluvoxamine have also been associated with hepatitis. Citalopram and escitalopram have minimal effects on hepatic enzymes and may be the SSRI of choice although clinical experience is limited and occasional hepatotoxicity has been reported. Paroxetine is used by some specialised liver units with few apparent problems

Reboxetine2, 3, 50

50% reduction in starting dose recommended. Clinical experience limited. Does not seem to be associated with hepatotoxicity. Caution advised

Tricyclics2,3,51

All are hepatically metabolised, highly protein bound and will accumulate. They vary in their propensity to cause sedation and constipation. All are associated with raised LFTs and rare cases of hepatitis. There is most clinical experience with imipramine. Sedative TCAs such as trimipramine, dothiepin (dosulepin) and amitriptyline are best avoided. Lofepramine is possibly the most hepatotoxic and should be avoided completely

Venlafaxine/desvenlafaxine2, 3, 52-54

Dosage reduction of 50% advised in moderate hepatic impairment. Little clinical experience. Rare cases of cholestatic hepatitis reported. Caution advised

ALT, alanine aminotransferase; LFT, liver function test; MAOI, monoamine oxidase inhibitor; RCT, randomised controlled trial; SPC, summary of product characteristics; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressants.

Table 7.24 Mood stabilisers in hepatic impairment945,946,998

Drug

Comments

Carbamazepine55

Extensively hepatically metabolised and potent inducer of CYP450 enzymes. Contraindicated in acute liver disease. In chronic stable disease, caution advised.

Reduce starting dose by 50%, and titrate up slowly, using plasma levels to guide dosage. Stop if LFTs deteriorate. Associated with hepatitis, cholangitis, cholestatic and hepatocellular jaundice, and hepatic failure (rare). Adverse hepatic effects are most common in the first month of treatment. Hepatocellular damage is often associated with a poor outcome. Vulnerability to carbamazepine-induced hepatic damage may be genetically determined

Lamotrigine

Manufacturers recommend 50% reduction in initial dose, dose escalation and maintenance dose in moderate hepatic impairment and 75% in severe hepatic impairment. Discontinue if lamotrigine-induced rash (which can be serious). Extreme caution advised, particularly if co-prescribed with valproate. Elevated LFTs and hepatitis reported

Lithium56,57

Not metabolised so dosage reduction not required as long as renal function is normal. Use serum levels to guide dosage and monitor more frequently if ascites status changes (volume of distribution will change). One case of ascites and one of hyperbilirubinaemia reported over many decades of lithium use worldwide

Valproate58

Highly protein bound and hepatically metabolised. Dosage reduction with close monitoring of LFTs in moderate hepatic impairment. Use plasma levels (free levels if possible) to guide dosage. Caution advised. Contraindicated in severe and/or active hepatic impairment; impairment of usual metabolic pathway can lead to generation of hepatotoxic metabolites via alternative pathway. Associated with elevated LFTs and serious hepatotoxicity including fulminant hepatic failure. Mitochondrial disease, learning disability, polypharmacy, metabolic disorders and underlying hepatic disease may be risk factors. Particularly hepatotoxic in very young children. The greatest risk is in the first 3 months of treatment.

LFT, liver function test.

Table 7.25 Stimulants in hepatic impairment59

Drug

Comments

Atomoxetine

Rare reports of liver toxicity, manifested by elevated hepatic enzymes, and raised bilirubin with jaundice. SPC states 'discontinue in patients with jaundice or laboratory evidence of liver injury, and do not restart'

Methylphenidate

Rare reports of liver dysfunction and hypersensitivity reactions. Limited clinical experience. Caution advised

SPC, summary of product characteristics.

Hepatic toxicity

Drug induced hepatic damage can be due to:

Almost any type of liver damage can occur, ranging from mild transient asymptomatic increases in LFTs to fulminant hepatic failure. See Tables 7.22–7.25 for details of the hepatotoxic potential of individual drugs.

Risk factors for drug-induced hepatotoxicity include:60

When interpreting LFTs, remember that:61

When monitoring LFTs:

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HIV infection

General principles of prescribing in HIV

Individuals with HIV/AIDs may experience symptoms of mental illness either as a direct consequence of (organic origin), a reaction to, or in addition to their underlying infection. In the first scenario, the focus of treatment should be the underlying infection. Where this is not feasible, or the presentation is not of organic origin, psychotropic medication will be the primary treatment.

When prescribing psychotropics, the following principles should be adhered to:

Although most psychotropic agents are thought to be safe in HIV-infected individuals, definitive data are lacking in many cases, and it has been suggested that this group may be more sensitive to higher doses, adverse side-effects and interactions.1 Patients with low CD4 counts and high viral loads are more likely to have exaggerated adverse reactions to psychotropic medications.

Psychosis

Atypicals are usually used as a first-line. Risperidone is the most widely studied2 and generally appears to be safe, although idiosyncratic interactions with ritonavir have been reported.3,4 Quetiapine, aripiprazole and olanzapine may also be used.5–7 The use of clozapine is not routinely recommended, although it may be useful in low doses in patients with higher CD4 counts who are otherwise medically stable. Clozapine may also be helpful in the treatment of individuals with HIV-associated psychosis with drug-induced parkinsonism.8 Although it is not known whether patients with HIV have a greater risk of agranulocytosis, extremely close monitoring of the white cell count is recommended. Patients with HIV may be more susceptible to extrapyramidal side-effects,9 neuroleptic malignant syndrome10 and tardive dyskinesia.11

Delirium

Organic causes should be identified and treated. Short-term symptomatic treatment may include low-dose atypicals such as risperidone,12 olanzapine,13 quetiapine14 or ziprasidone.15 The concomitant use of short courses of low dose, short-acting benzodiazepines such as lorazepam may also be helpful, although use as a sole agent may worsen delirium.6 Chlorpromazine and haloperidol have been successfully used.16

Depression

Depression is common in individuals with HIV, and a recent study estimated the prevalence in this population to be as high as 84%.17 Of note, depression may be a risk factor for HIV,18 and it has been further suggested that much of this depression is either unrecognised or insufficiently managed.19 First-line agents include SSRIs, especially escitalopram/citalopram5,20 (because it does not inhibit CYP2D6 or CYP3A4), with further treatment as per standard protocols. Oddly, the most recent study of escitalopram found no difference from placebo.21 There is limited evidence that SSRIs enhance HIVrelated immunity.22 The risk of serotonin syndrome may be increased.23 The use of TCAs may be appropriate in some cases, although side-effects may limit efficacy and compliance.24 MAOIs are not recommended in this population. Other agents (bupropion,25 mirtazapine,26 reboxetine27 and trazodone28) have been investigated, and although these agents were shown to reduce depressive symptoms, the high prevalence of side-effects limited their utility. Their routine use is therefore not recommended. Testosterone and stimulants have also been successfully used.29

Bipolar affective disorder

Mania is a recognised presentation in HIV30 and individuals with HIV may be more sensitive to the side-effects of mood stabilisers such as lithium,31 especially if they have neurocognitive dysfunction.30 Conventional agents such as valproate, lamotrigine and gabapentin may be used cautiously, but carbamazepine should be avoided because of important interactions with antiretroviral agents such as ritonavir,32 as well as the risk of neutropenia. In one case series lithium was shown to be poorly tolerated33 and it may be advisable to limit its use to asymptomatic individuals with higher CD4 counts and to monitor closely these individuals. The use of antimanic antipsychotics such as risperidone, quetiapine and olanzapine is also an option.5

Anxiety disorders

Benzodiazepines may have some utility in the acute treatment of anxiety in individuals with HIV, but caution should be exercised because of the potential for both misuse and multiple, and in rare cases, potentially serious interactions. Some authorities suggest benzodiazepines are drugs of choice for anxiety in HIV.5 SSRIs (remember interactions) and other antidepressants may be efficacious, and there is evidence that buspirone may be especially useful.34

HIV neurocognitive disorders

Individuals with HIV may present with cognitive impairment at any time in the course of their illness; this may range from mild forgetfulness ('minor cognitive and motor disorder') to severe and debilitating dementia. The mainstay of treatment is combination antiretroviral therapy,35 with judicious, short-term use of an antipsychotic such as risperidone36 if necessary. Treatment of these individuals is carried out primarily by HIV physicians, with liaison psychiatric input as required.

References

  1. Ayuso JL. Use of psychotropic drugs in patients with HIV infection. Drugs 1994; 47:599–610.
  2. Singh AN et al. Risperidone in HIV-related manic psychosis. Lancet 1994; 344:1029–1030.
  3. Jover F et al. Reversible coma caused by risperidone-ritonavir interaction. Clin Neuropharmacol 2002; 25:251–253.
  4. Kelly DV et al. Extrapyramidal symptoms with ritonavir/indinavir plus risperidone. Ann Pharmacother 2002; 36:827–830.
  5. Freudenreich O et al. Psychiatric treatment of persons with HIV/AIDS: an HIV-Psychiatry Consensus Survey of Current Practices. Psychosomatics 2010; 51:480–488.
  6. Brogan K et al. Management of common psychiatric conditions in the HIV-positive population. Curr HIV/AIDS Rep 2009; 6:108–115.
  7. Singh D et al. Choice of antipsychotic in HIV-infected patients. J Clin Psychiatry 2007; 68:479–480.
  8. Lera G et al. Pilot study with clozapine in patients with HIV-associated psychosis and drug-induced parkinsonism. Mov Disord 1999; 14:128–131.
  9. Hriso E et al. Extrapyramidal symptoms due to dopamine-blocking agents in patients with AIDS encephalopathy. Am J Psychiatry 1991; 148:1558–1561.
  10. Horwath E et al. NMS and HIV. Psychiatr Serv 1999; 50:564.
  11. Shedlack KJ et al. Rapidly progressive tardive dyskinesia in AIDS. Biol Psychiatry 1994; 35:147–148.
  12. Sipahimalani A et al. Treatment of delirium with risperidone. Int J Geriatr Psychopharmacol 1997; 1:24–26.
  13. Sipahimalani A et al. Olanzapine in the treatment of delirium. Psychosomatics 1998; 39:422–430.
  14. Schwartz TL et al. Treatment of delirium with quetiapine. Prim Care Companion J Clin Psychiatry 2000; 2:10–12.
  15. Leso L et al. Ziprasidone treatment of delirium. Psychosomatics 2002; 43:61–62.
  16. Breitbart W et al. A double-blind trial of haloperidol, chlorpromazine, and lorazepam in the treatment of delirium in hospitalized AIDS patients. Am J Psychiatry 1996; 153:231–237.
  17. Anon. Depression is common among AIDS patients. Psych consult often is necessary. AIDS Alert 2002; 17:153–154.
  18. McDermott BE et al. Diagnosis, health beliefs, and risk of HIV infection in psychiatric patients. Hosp Community Psychiatry 1994; 45:580–585.
  19. Katz MH et al. Depression and use of mental health services among HIV-infected men. AIDS Care 1996; 8:433–442.
  20. Currier MB et al. Citalopram treatment of major depressive disorder in Hispanic HIV and AIDS patients: a prospective study. Psychosomatics 2004; 45:210–216.
  21. Hoare J et al. Escitalopram treatment of depression in human immunodeficiency virus/acquired immunodeficiency syndrome: a randomized, double-blind, placebo-controlled study. J Nerv Ment Dis 2014; 202:133–137.
  22. Benton T et al. Selective serotonin reuptake inhibitor suppression of HIV infectivity and replication. Psychosom Med 2010; 72:925–932.
  23. DeSilva KE et al. Serotonin syndrome in HIV-infected individuals receiving antiretroviral therapy and fluoxetine. AIDS 2001; 15:1281–1285.
  24. Elliott AJ et al. Randomized, placebo-controlled trial of paroxetine versus imipramine in depressed HIV-positive outpatients. Am J Psychiatry 1998; 155:367–372.
  25. Currier MB et al. A prospective trial of sustained-release bupropion for depression in HIV-seropositive and AIDS patients. Psychosomatics 2003; 44:120–125.
  26. Elliott AJ et al. Mirtazapine for depression in patients with human immunodeficiency virus. J Clin Psychopharmacol 2000; 20:265–267.
  27. Carvalhal AS et al. An open trial of reboxetine in HIV-seropositive outpatients with major depressive disorder. J Clin Psychiatry 2003; 64:421–424.
  28. De WS et al. Efficacy and safety of trazodone versus clorazepate in the treatment of HIV-positive subjects with adjustment disorders: a pilot study. J Int Med Res 1999; 27:223–232.
  29. Hill L et al. Pharmacotherapy considerations in patients with HIV and psychiatric disorders: focus on antidepressants and antipsychotics. Ann Pharmacother 2013; 47:75–89.
  30. El-Mallakh RS. Mania in AIDS: clinical significance and theoretical considerations. Int J Psychiatry Med 1991; 21:383–391.
  31. Tanquary J. Lithium neurotoxicity at therapeutic levels in an AIDS patient. J Nerv Ment Dis 1993; 181:518–519.
  32. Berbel GA et al. Protease inhibitor-induced carbamazepine toxicity. Clin Neuropharmacol 2000; 23:216–218.
  33. Parenti DM et al. Effect of lithium carbonate in HIV-infected patients with immune dysfunction. J Acquir Immune Defic Syndr 1988; 1:119–124.
  34. Batki SL. Buspirone in drug users with AIDS or AIDS-related complex. J Clin Psychopharmacol 1990; 10:111S–115S.
  35. Portegies P et al. Guidelines for the diagnosis and management of neurological complications of HIV infection. Eur J Neurol 2004; 11:297–304.
  36. Belzie LR. Risperidone for AIDS-associated dementia: a case series. AIDS Patient Care STDS 1996; 10:246–249.

Drugs for HIV

Interactions

Table 7.26 lists drug–drug interactions that are included in the summary of product characteristics (SPCs: accessed May 2014) for antiretroviral agents. The concomitant prescribing of drugs that are highlighted in bold is contraindicated.

Table 7.26 Pharmacokinetic interaction with HIV drugs

Antiretroviral drug

Effect on CYP enzyme(s)

Anticipated clinical effect on psychotropic drug(s)

Anticipated clinical effect of psychotropic drug(s) on antiretroviral drug

Protease inhibitors - (mostly potent 3A4 inhibition)

Atazanavir plus ritonavir (as pharmacokinetic booster)
CYP3A4 substrates

Potent CYP3A4 inhibition
Modest CYP3A4 induction
Modest CYP2D6 inhibition

Psychotropic drug levels increased:

pimozide, oral midazolam, quetiapine, buprenorphine, carbamazepine, parenteral midazolam, lurasidone

Psychotropic drug levels decreased:

Phenobarbital, phenytoin, lamotrigine

St John's wort (SJW, Hypericum perforatum), carbamazepine, phenytoin, phenobarbital:

decreased atazanavir and ritonavir levels

Darunavir plus ritonavir (as pharmacokinetic booster)

CYP3A4 substrates

Potent CYP3A4 inhibition
Modest CYP3A4 induction
Modest CYP2D6 inhibition
CYP2C19 induction
CYP2C9 induction

Psychotropic drug levels increased:

pimozide, oral midazolam, sertindole, quetiapine, buprenorphine, carbamazepine, parenteral midazolam, lurasidone

Psychotropic drug levels decreased:

methadone, paroxetine, sertraline

SJW, phenytoin, phenobarbital:

decreased darunavir and ritonavir levels

Fosamprenavir (active metabolite = amprenavir) plus ritonavir (as pharmacokinetic booster)

CYP3A4 substrates

Potent CYP3A4 inhibition
Modest CYP3A4 induction
Modest CYP2D6 inhibition
CYP2C9 induction
CYP1A2 induction

Psychotropic drug levels increased:

pimozide, oral midazolam, quetiapine, parenteral midazolam, tricyclic antidepressants (TCAs), lurasidone

Psychotropic drug levels decreased:

methadone and paroxetine, phenytoin

SJW, carbamazepine, phenobarbital:

decreased fosamprenavir and ritonavir levels

Indinavir plus ritonavir (as pharmacokinetic booster)

CYP3A4 substrates

Potent CYP3A4 inhibition
Modest CYP3A4 induction
Modest CYP2D6 inhibition
CYP2C9 induction

Psychotropic drug levels increased:

alprazolam, buspirone, diazepam, oral midazolam, quetiapine, carbamazepine, flurazepam, pimozide, parenteral midazolam, trazodone, phenytoin, phenobarbital, clozapine, lurasidone

Psychotropic drug levels decreased:

lamotrigine, valproic acid, methadone

SJW, carbamazepine, phenobarbital, phenytoin: decreased indinavir and ritonavir levels

Lopinavir plus ritonavir (as pharmacokinetic booster)

CYP3A4 substrates

Potent CYP3A4 inhibition
Modest CYP3A4 induction
Modest CYP2D6 inhibition
CYP2B6 induction
CYP2C9 induction
CYP2C19 induction

Psychotropic drug levels increased:

carbamazepine, phenobarbital, pimozide, oral midazolam, quetiapine, parenteral midazolam, trazodone, lurasidone

Psychotropic drug levels decreased:

bupropion, lamotrigine, valproate, methadone, phenytoin

SJW, carbamazepine, phenobarbital, phenytoin: decreased lopinavir and ritonavir levels

Ritonavir

CYP3A4 substrate

Potent CYP3A4 inhibitor
Modest CYP3A4 inducer
Modest CYP2D6 inhibitor
CYP2C9 inhibitor
CYP2C9 inducer
CYP2C19 inhibitor
CYP2B6 inhibitor

Psychotropic drug levels increased:

alprazolam, buprenorphine, buspirone, diazepam, oral midazolam, quetiapine, carbamazepine, flurazepam, pimozide, parenteral midazolam, trazodone, zolpidem, amitriptyline, amfetamine, clozapine, fluoxetine, haloperidol, imipramine, nortriptyline, paroxetine, risperidone, sertraline, lurasidone

Psychotropic drug levels decreased:

lamotrigine, phenytoin, valproic acid, bupropion, methadone

SJW:

decreased ritonavir levels

Saquinavir plus ritonavir (as pharmacokinetic booster)

CYP3A4 substrates

Potent CYP3A4 inhibition
Modest CYP3A4 induction
Modest CYP2D6 inhibition

Psychotropic drug levels increased:

alprazolam, clozapine, diazepam, flurazepam, haloperidol, parenteral midazolam, phenothiazines, pimozide, oral midazolam, trazodone, TCAs, lurasidone

Psychotropic drug levels decreased:

methadone

SJW, carbamazepine, phenobarbital, phenytoin: decreased saquinavir levels

Tipranavir plus ritonavir (as pharmacokinetic booster)

CYP3A4 substrates

Potent CYP3A4 inhibition
Modest CYP3A4 induction
Modest CYP2D6 inhibition
CYP 1A2, CYP2C9 and CYP2C19, inhibition CYP1A2 and to a much lesser extent, CYP2C9 induction

Psychotropic drug levels increased:

carbamazepine, pimozide, oral midazolam, quetiapine, sertindole, parenteral midazolam, trazodone, lurasidone

Psychotropic drug levels decreased:

methadone, buprenorphine, bupropion

SJW, carbamazepine, phenobarbital, phenytoin: decreased tipranavir and ritonavir levels

Non-nucleoside reverse transcriptase inhibitors

Efavirenz

CYP3A4 substrate

CYP3A4 inducer and to a much lesser extent, CYP3A4 inhibitor CYP2C19 inhibitor CYP2B6 inhibitor

Psychotropic drug levels increased:

lorazepam, midazolam, pimozide, lurasidone

Psychotropic drug levels decreased:

buprenorphine, carbamazepine, methadone, bupropion, sertraline

SJW, carbamazepine: decreased efavirenz levels

Etravirine

CYP3A4 substrate
CYP2C9 substrate
CYP2C19 substrate

Weak CYP3A4 inducer

Weak CYP2C9 inhibitor

Weak CYP2C19 inhibitor

Psychotropic drug levels increased:

diazepam

Carbamazepine, phenobarbital, phenytoin,

SJW:

decreased etravirine levels

Nevirapine

CYP3A4 substrate

CYP3A4 inducer

?CYP2B6 inducer

Psychotropic drug levels decreased:

methadone

SJW:

decreased nevirapine levels

Rilpivirine

CYP3A4 substrate

Nil activity of clinical relevance

Psychotropic drug levels decreased:

methadone

SJW, carbamazepine, oxcarbazepine, phenobarbital, phenytoin: decreased rilpivirine levels

Nucleoside and nucleotide reverse transcriptase inhibitors

Abacavir

Nil activity of clinical relevance

Levels decreased:

methadone

Phenobarbital, phenytoin:

decreased abacavir levels

Zidovudine

 

 

Methadone, valproic acid:

increased zidovudine levels.

Didanosine

Nil activity of clinical relevance

 

 

Emtricitabine

Nil activity of clinical relevance

 

 

Stavudine

Nil activity of clinical relevance

 

 

Tenofovir

Nil activity of clinical relevance

 

 

Lamivudine

Nil activity of clinical relevance

 

 

Fusion inhibitor

 

 

 

Enfuvirtide

Nil activity of clinical relevance

 

 

Entry/integrase inhibitors

Maraviroc

CYP3A4 substrate

?CYP2D6 inhibitor

 

SJW:

decreased maraviroc levels

Raltegravir

Nil activity of clinical relevance

 

 

Elvitegravir

CYP3A4 substrate

Modest CYP2C9, CYP1A2, CYP2C19, CYP3A, CYP2B6 and CYP2C8 induction

Psychotropic drug levels increased:

buprenorphine

SJW, carbamazepine, phenobarbital, phenytoin:

decreased elvitegravir levels

Dolutegravir

CYP3A4 substrate

 

 

SJW, carbamazepine, oxcarbazepine, phenobarbital, phenytoin:

decreased dolutegravir levels

Refer to the section on 'Cytochrome P450 (CYP) substrates, inhibitors and/or inducers' in this chapter to determine other potential drug–drug interactions.

Table 7.27 summarises the adverse psychiatric effects of antiretroviral drugs. Notes:

Table 7.27 Adverse psychiatric effects of antiretroviral drugs

Adverse psychiatric effect

Implicated antiretroviral drug(s)

Abnormal dreams

Atazanavir, efavirenz, emtricitabine, etravirine, lopinavir, raltegravir, ritonavir, stavudine, darunavir, rilpivirine, dolutegravir

Agitation

Efavirenz

Amnesia

Raltegravir

Anxiety

Atazanavir, efavirenz, enfurvirtide, etravirine, lopinavir, raltegravir, ritonavir, stavudine, zidovudine, darunavir

Delusions/'psychosis-like behaviour'

Efavirenz

Depression

Atazanavir, maraviroc, raltegravir, stavudine, zidovudine, darunavir, efavirenz, rilpivirine, elvitegravir

Disorientation

Atazanavir, darunavir, etravirine

Fatal suicide

Efavirenz

Hypersomnia

Etravirine, raltegravir

Insomnia

Atazanavir, efavirenz, emtricitabine, etravirine, indinavir, lamivudine, maraviroc, lopinavir, raltegravir, ritonavir, stavudine, tipranavir, zidovudine, darunavir, rilpivirine, dolutegravir, elvitegravir

Irritability

Enfurvirtide

Mania

Efavirenz

Nightmare

Enfurvirtide, etravirine, raltegravir, darunavir

Panic attack

Raltegravir

Reduced libido

Lopinavir, saquinavir, darunavir

Severe/major depression

Efavirenz, raltegravir

Somnolence

Efavirenz, etravirine, raltegravir, ritonavir, stavudine, zidovudine darunavir, saquinavir, tipranivir, rilpivirine, elvitegravir

Suicidal ideation

Efavirenz, raltegravir, elvitegravir29

Suicide attempt

Efavirenz, raltegravir, elvitegravir29

'Abnormal thinking'

Stavudine, efavirenz

'Cognitive disorder'

Raltegravir

'Confusional state'

Raltegravir, darunavir, etravirine

'Disturbance in concentration'/'disturbance in attention'

Enfurvirtide, etravirine, raltegravir, ritonavir

'Emotional lability'

Stavudine, efavirenz

'Impaired concentration'

Efavirenz

'Memory impairment'

Raltegravir

'Sleep disorder'

Atazanavir, etravirine, raltegravir, saquinavir, tipranavir, darunavir, rilpivirine

*In patients with a pre-existing history of psychiatric illness. All data derived from SPCs, accessed May 2014.

Table 7.28 Potential pharmacodynamic interactions with HIV drugs

Potential adverse effect

Implicated antiretroviral drug(s)

Implications for psychotropic prescribing

Seizure(s)

Efavirenz, etravirine, lopinavir, darunavir, maraviroc, ritonavir, zidovudine, saquinavir

May increase seizure risk associated with certain psychotropic drugs

Metabolic abnormalities such as hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hyperglycaemia and hyperlactataemia

All combination antiretroviral therapy

May compound risk of metabolic adverse effects associated with certain psychotropic drugs

ECG changes

Atazanavir, lopinavir, ritonavir, saquinavir, darunavir

May increase risk of arrhythmias associated with certain psychotropic drugs

Raised creatine kinase (CK)

Emtricitabine, raltegravir

May be important to acknowledge associated link if diagnosis of NMS is being considered

ECG, electrocardiogram; NMS, neuroleptic malignant syndrome.

Reference

http://www.medicines.org.uk/emc/

Eating disorders

Eating disorders are increasingly common, especially in children and adolescents. Lifetime prevalence is 0.6% for anorexia nervosa, 1% for bulimia and 3% for binge eating disorder (rates for women are about three times higher than men).1 There are many similarities between the different types of eating disorders and patients often traverse diagnoses, which can complicate treatment.2 Other psychiatric conditions (particularly anxiety, depression and obsessive compulsive disorder) often coexist with eating disorders and this may in part explain the benefit seen with medication.

Anorexia nervosa carries considerable risk of mortality or serious physical morbidity. Patients may present with multiple physical conditions including amenorrhoea, muscle wasting, electrolyte abnormalities, cardiovascular complications and osteoporosis. Patients who purge through vomiting are at high risk of loss of tooth enamel, gastro-oesophageal erosion and dehydration.2 Other modes of purging include laxative and diuretic misuse.

Any medicine prescribed should be accompanied by close monitoring to check for possible adverse reactions.

Anorexia nervosa

General guidance

There are few controlled trials to guide treatment with medicines for anorexia nervosa. Prompt weight restoration to a safe weight, family therapy and structured psychotherapy are the main interventions.3,4 The aim of (physical) treatment is to improve nutritional health through re-feeding, with very limited evidence for the use of any pharmacological interventions other than those prescribed to correct metabolic deficiencies. Medicines may be used to treat co-morbid conditions,3 but have a very limited role in weight restoration.5 Olanzapine is the only one shown conclusively to have any effect on weight restoration in anorexia nervosa,6–8 while early data for quetiapine were encouraging9 but were not replicated in a more recent RCT.10

Dronabinol, a synthetic cannabinoid agonist, may induce slight weight gain11 but remains an experimental treatment. The use of medicines to restore weight in anorexia nervosa is controversial, Behavioural interventions which have been shown to have a more long lasting effect are preferred.

Healthcare professionals should be aware of the risk of medicines that prolong the QT interval. All patients with a diagnosis of anorexia nervosa should have an alert placed in their prescribing record noting that they are at increased risk of arrhythmias secondary to electrolyte disturbances and potential cardiac complications associated with inadequate nutrition. ECG monitoring should be undertaken if the prescription of any medicine that may compromise cardiac functioning is essential.3

Physical aspects

Vitamins and minerals

Treatment with a multivitamin/multimineral supplement in oral form is recommended during both inpatient and outpatient weight restoration3 (in the UK, Forceval or Sanatogen Gold one capsule daily may be used).

Electrolytes

Electrolyte disturbances (e.g. hypokalaemia) may develop slowly over time and may be asymptomatic and resolve with re-feeding. Hypophosphataemia may also be precipitated by re-feeding. Rapid correction may be hazardous. Oral supplementation is therefore used to prevent serious sequelae rather than simply to restore normal levels. If supplements are used, urea and electrolytes, HCO3, Ca, P and Mg need to be monitored and an ECG needs to be performed.12

Osteoporosis

Bone loss is a serious complication of anorexia with serious consequences. Hormonal treatment using oestrogen or dehydroepiandrosterone (DHEA) does not have a positive impact on bone density and oestrogen is not recommended in children and adolescents due to the risk of premature fusion of the bones.3 Antipsychotics that raise prolactin levels can further increase the risk of bone loss and osteoporosis. Bisphosphonates are not generally recommended for women with anorexia nervosa due to the lack of data about both the benefits and also safety; they are not licensed for use in pre-menopausal girls.

Psychiatric aspects

Acute illness: antidepressants

A Cochrane review found no evidence from four placebo-controlled trials that antidepressants improved weight gain, eating disorder or associated psychopathology.13 It has been suggested that neurochemical abnormalities in starvation may partially explain this non-response.13 Co-prescribing nutritional supplementation (including tryptophan) with fluoxetine has not been shown to increase efficacy.14

Other psychotropic medicines

Antipsychotics (e.g. olanzapine), minor tranquilisers or antihistamines (e.g. promethazine) are often used to reduce the high levels of anxiety associated with anorexia nervosa but they are not usually recommended for the promotion of weight gain.3 Case reports and retrospective studies have suggested that olanzapine may reduce agitation (and possibly improve weight gain).15,16 One RCT7 showed that 87.5% of patients given olanzapine achieved weight restoration (55.6% placebo). Quetiapine may improve psychological symptoms but there are few data.9 Only prolactin-sparing antipsychotics should be considered. Many other medications5 have been investigated in small placebo-controlled trials of varying quality and success, these include zinc,17 naltrexone18 and cyproheptadine.19

Relapse prevention

There is evidence from one small trial that fluoxetine may be useful in improving outcome and preventing relapse of patients with anorexia nervosa after weight restoration.20 Other studies have found no benefit.13,21 SSRIs can, albeit very rarely, elevate prolactin, so caution is required.

Co-morbid disorders

Antidepressants are often used to treat co-morbid major depressive disorder and obsessive compulsive disorder. However, caution should be used as these conditions may resolve with weight gain alone.3

Bulimia nervosa and binge eating disorder

Psychological interventions should be considered first-line for bulimia.22 Adults with bulimia nervosa and binge eating disorder (BED) may be offered a trial of an antidepressant. SSRIs (specifically fluoxetine23–24) are the antidepressant of first choice. The effective dose of fluoxetine is 60 mg daily.26 Patients should be informed that this can reduce the frequency of binge eating and purging but long-term effects are unknown.3 Early response (at 3 weeks) is a strong predictor of response overall.27

Antidepressants may be used for the treatment of bulimia nervosa in adolescents but they are not licensed for this age group and there is little evidence for this practice. They should not be considered as a first-line treatment in adolescent bulimia nervosa.3

There is some reasonable evidence that topiramate reduces frequency of binge-eating28 and limited evidence for the usefulness of bupropion29, duloxetine,30 lamotrigine,31 zonisamide,32,33 acamprosate34 and sodium oxybate.35

Other atypical eating disorders

There have been no studies of the use of medicines to treat atypical eating disorders other than anorexia nervosa, bulimia nervosa and BED.3,36 In the absence of evidence to guide the management of other atypical eating disorders (also known as 'eating disorders not otherwise specified'), it is recommended that the clinician considers following the guidance of the eating disorder that mostly resembles the individual patient's eating disorder.3 See Box 7.11.

Box 7.11 Summary of NICE guidance on eating disorders3

Anorexia nervosa

  • Psychological interventions are the treatments of choice and should be accompanied by monitoring of the patient's physical state.
  • No pharmacological intervention is recommended. A range of medicines may be used in the treatment of co-morbid conditions.

Bulimia nervosa

  1. An evidence-based self-help programme or cognitive behaviour therapy for bulimia nervosa should be the first choice of treatment.
  2. A trial of fluoxetine may be offered as an alternative or additional first step.

Binge eating disorder

  1. An evidence based self-help programme of cognitive behavioural therapy for binge eating disorder should be the first choice of treatment.
  2. A trial of an SSRI can be considered as an alternative or additional first step.

Although this guidance is 10 years old, updates of literature reviews have not yet given NICE cause to change its advice.37

References

  1. Treasure J et al. Eating disorders. Lancet 2010; 375:583–593.
  2. Steffen KJ et al. Emerging drugs for eating disorder treatment. Expert Opin Emerg Drugs 2006; 11:315–336.
  3. National Institute for Health and Clinical Excellence. Eating disorders: Core interventions in the treatment and management of anorexia nervosa, bulimia nervosa and related eating disorders. Clinical Guideline 9, 2004. http://www.nice.org.uk
  4. American Psychiatric Association. Treatment of patients with eating disorders, third edition. Am J Psychiatry 2006; 163:4–54.
  5. Crow SJ et al. What potential role is there for medication treatment in anorexia nervosa? Int J Eat Disord 2009; 42:1–8.
  6. Dunican KC et al. The role of olanzapine in the treatment of anorexia nervosa. Annal Pharmacother 2007; 41:111–115.
  7. Bissada H et al. Olanzapine in the treatment of low body weight and obsessive thinking in women with anorexia nervosa: a randomized, double-blind, placebo-controlled trial. Am J Psychiatry 2008; 165:1281–1288.
  8. Leggero C et al. Low-dose olanzapine monotherapy in girls with anorexia nervosa, restricting subtype: focus on hyperactivity. J Child Adolesc Psychopharmacol 2010; 20:127–133.
  9. Court A et al. Investigating the effectiveness, safety and tolerability of quetiapine in the treatment of anorexia nervosa in young people: a pilot study. J Psychiatr Res 2010; 44:1027–1034.
  10. Powers PS et al. Double-blind placebo-controlled trial of quetiapine in anorexia nervosa. Eur Eat Disord Rev 2012; 20:331–334.
  11. Andries A et al. Dronabinol in severe, enduring anorexia nervosa: a randomized controlled trial. Int J Eat Disord 2014; 47:18–23.
  12. Connan F et al. Biochemical and endocrine complications. Eur Eat Disord Rev 2007; 8:144–157.
  13. Claudino AM et al. Antidepressants for anorexia nervosa. Cochrane Database Syst Rev 2006; CD004365.
  14. Barbarich NC et al. Use of nutritional supplements to increase the efficacy of fluoxetine in the treatment of anorexia nervosa. Int J Eat Disord 2004; 35:10–15.
  15. Malina A et al. Olanzapine treatment of anorexia nervosa: a retrospective study. Int J Eat Disord 2003; 33:234–237.
  16. La Via MC et al. Case reports of olanzapine treatment of anorexia nervosa. Int J Eat Disord 2000; 27:363–366.
  17. Su JC et al. Zinc supplementation in the treatment of anorexia nervosa. Eat Weight Disord 2002; 7:20–22.
  18. Marrazzi MA et al. Naltrexone use in the treatment of anorexia nervosa and bulimia nervosa. Int Clin Psychopharmacol 1995; 10:163–172.
  19. Halmi KA et al. Anorexia nervosa. Treatment efficacy of cyproheptadine and amitriptyline. Arch Gen Psychiatry 1986; 43:177–181.
  20. Kaye WH et al. Double-blind placebo-controlled administration of fluoxetine in restrictingand restricting-purging-type anorexia nervosa. Biol Psychiatry 2001; 49:644–652.
  21. Walsh BT et al. Fluoxetine after weight restoration in anorexia nervosa: a randomized controlled trial. JAMA 2006; 295:2605–2612.
  22. Vocks S et al. Meta-analysis of the effectiveness of psychological and pharmacological treatments for binge eating disorder. Int J Eat Disord 2010; 43:205–217.
  23. Fluoxetine Bulimia Nervosa Collaborative Study Group. Fluoxetine in the treatment of bulimia nervosa. A multicenter, placebo-controlled, double-blind trial. Arch Gen Psychiatry 1992; 49:139–147.
  24. Goldstein DJ et al. Long-term fluoxetine treatment of bulimia nervosa. Fluoxetine Bulimia Nervosa Research Group. Br J Psychiatry 1995; 166:660–666.
  25. Romano SJ et al. A placebo-controlled study of fluoxetine in continued treatment of bulimia nervosa after successful acute fluoxetine treatment. Am J Psychiatry 2002; 159:96–102.
  26. Bacaltchuk J et al. Antidepressants versus placebo for people with bulimia nervosa. Cochrane Database Syst Rev 2003; CD003391.
  27. Sysko R et al. Early response to antidepressant treatment in bulimia nervosa. Psychol Med 2010; 40:999–1005.
  28. Arbaizar B et al. Efficacy of topiramate in bulimia nervosa and binge-eating disorder: a systematic review. Gen Hosp Psychiatry 2008; 30:471–475.
  29. White MA et al. Bupropion for overweight women with binge-eating disorder: a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry 2013; 74:400–406.
  30. Leombruni P et al. Duloxetine in obese binge eater outpatients: preliminary results from a 12-week open trial. Hum Psychopharmacol 2009; 24:483–488.
  31. Guerdjikova AI et al. Lamotrigine in the treatment of binge-eating disorder with obesity: a randomized, placebo-controlled monotherapy trial. Int Clin Psychopharmacol 2009; 24:150–158.
  32. Ricca V et al. Zonisamide Combined with Cognitive Behavioral Therapy in Binge Eating Disorder: A One-year Follow-up Study. Psychiatry (Edgmont) 2009; 6:23–28.
  33. Guerdjikova AI et al. Zonisamide in the treatment of bulimia nervosa: an open-label, pilot, prospective study. Int J Eat Disord 2013; 46:747–750.
  34. McElroy SL et al. Acamprosate in the treatment of binge eating disorder: a placebo-controlled trial. Int J Eat Disord 2011; 44:81–90.
  35. McElroy SL et al. Sodium oxybate in the treatment of binge eating disorder: An open-label, prospective study. Int J Eat Disord 2011; 44:262–268.
  36. Leombruni P et al. A 12 to 24 weeks pilot study of sertraline treatment in obese women binge eaters. Hum Psychopharmacol 2006; 21:181–188.
  37. National Institute for Health and Care Excellence. Eating disorders: surveillance review decision December 2013. 2013. http://www.nice.org. uk/nicemedia/live/10932/66224/66224.pdf.

Further reading

Jackson CW et al. Pharmacotherapy of eating disorders. Nutr Clin Pract 2010; 25:143–159.

Reas DL et al. Review and meta-analysis of pharmacotherapy for binge-eating disorder. Obesity (Silver Spring) 2008; 16:2024–2038.

Acutely disturbed or violent behaviour

Acute behavioural disturbance can occur in the context of psychiatric illness, physical illness, substance abuse or personality disorder. Psychotic symptoms are common and the patient may be aggressive towards others secondary to persecutory delusions or auditory, visual or tactile hallucinations.

The clinical practice of rapid tranquillisation (RT) is used when appropriate psychological and behavioural approaches have failed to de-escalate acutely disturbed behaviour. It is, essentially, a treatment of last resort. Patients who require RT are often too disturbed to give informed consent and therefore participate in RCTs, but, with the use of a number of creative methodologies, the evidence base with respect to the efficacy and tolerability of pharmacological strategies is growing. Recommendations, however, remain based partly on research data, partly on theoretical considerations and partly on clinical experience.

Several studies supporting the efficacy of oral SGAs have been published.1–4 The level of behavioural disturbance exhibited by the patients in these studies was moderate at most, and all subjects accepted oral treatment (this degree of compliance would be unusual in clinical practice). Note too that patients recruited to these studies received the SGA as antipsychotic monotherapy. The efficacy and safety of adding a second antipsychotic as 'prn' has not been explicitly tested in formal RCTs.

The efficacy of inhaled loxapine (in behavioural disturbance that is moderate in severity) is also supported by RCTs;5,6 note that use of this preparation requires the cooperation of the patient, and that bronchospasm is an established side-effect.

Larger, placebo-controlled RCTs support the efficacy of IM preparations of olanzapine, ziprasidone and aripiprazole. When considered together these trials suggested that IM olanzapine is more effective than IM haloperidol which in turn is more effective than IM aripiprazole.7 Again, the level of behavioural disturbance in these studies was moderate at most.

Five large RCTs have investigated the effectiveness of parenteral medication in 'reallife' acutely disturbed patients.

Note that TREC 311 found IM haloperidol alone to be poorly tolerated; 6% of patients had an acute dystonic reaction. Cochrane concludes that haloperidol alone is effective in the management of acute behavioural disturbance but poorly tolerated, and that coadministration of promethazine but not lorazepam improves tolerability.13 However NICE considers the evidence relating to the use of promethazine for this purpose to be inconclusive.14

In a meta-analysis that examined the tolerability of IM antipsychotics when used for the treatment of agitation, the incidence of acute dystonia with haloperidol was reported to be 5%, with SGAs faring considerably better.15 Acute extrapyramidal symptoms may adversely affect longer-term compliance.16 In addition, the SPC for haloperidol requires a pre-treatment ECG17,18 and recommends that concomitant antipsychotics are not prescribed. The mean increase in QTc after 10 mg IM haloperidol has been administered has been reported to be 15 ms but the range is wide.19 Note that promethazine may inhibit the metabolism of haloperidol;20 a pharmacokinetic interaction that is potentially clinically significant given the potential of haloperidol to prolong QTc. While this is unlikely to be problematic if a single dose is administered, repeat dosing may confer risk.

A large observational study supports the efficacy and tolerability of IM olanzapine in clinical emergencies (where disturbance was severe).21

In an acute psychiatric setting, high dose sedation (defined as a dose of more than 10 mg of haloperidol, droperidol or midazolam in routine clinical practice) was not more effective than lower doses but was associated with more adverse effects (hypotension and oxygen desaturation).22 Consistent with this, a small RCT supports the efficacy of low dose haloperidol, although both efficacy and tolerability were superior when midazolam was co-prescribed.23 These data support the use of standard doses in clinical emergencies.

A small observational study supports the effectiveness of buccal midazolam in a psychiatric intensive care unit (PICU) setting.24 Parenteral administration of midazolam, particularly in higher doses, may cause over-sedation accompanied by respiratory depression.25 Lorazepam IM is an established treatment and TREC 212 supports its efficacy, although combining all results from the TREC studies suggests midazolam 7.5–15 mg is probably more effective. Cochrane supports the efficacy of benzodiazepines when used alone and concludes that there is no advantage of benzodiazepineantipsychotic combinations over benzodiazepines alone.26

With respect to those who are behaviourally disturbed secondary to acute intoxication with alcohol or illicit drugs, there are fewer data to guide practice. A large observational study of IV sedation in patients intoxicated with alcohol found that combination treatment (most commonly haloperidol 5 mg and lorazepam 2mg) was more effective and reduced the need for subsequent sedation than either drug given alone.27 A case series (n =59) of patients who received modest doses of oral, IM or IV haloperidol to manage behavioural disturbance in the context of phencyclidine (PCP) consumption, reported that haloperidol was effective and well tolerated (one case each of mild hypotension and mild hypoxia).28

Plans for the management of individual patients should ideally be made in advance. The aim is to prevent disturbed behaviour and reduce risk of violence. Nursing interventions (de-escalation, time out, seclusion29), increased nursing levels, transfer of the patient to a PICU and pharmacological management are options that may be employed. Care should be taken to avoid combinations and high cumulative doses of antipsychotic drugs. The monitoring of routine physical observations after RT is essential. Note that RT is often viewed as punitive by patients. There is little research into the patient experience of RT.

The aims of RT are threefold.

Note: Despite the need for rapid and effective treatment, concomitant use of two or more antipsychotics (antipsychotic polypharmacy) should be avoided on the basis of risk associated with QT prolongation (common to almost all antipsychotics). This is a particularly important consideration in RT where the patient's physical state predisposes to cardiac arrhythmia.

Table 7.29 outlines the interventions to use in an emergency situation. Remedial measures are shown in Table 7.30. Box 7.12 describes physical monitoring requirements in RT; Box 7.13 the use of flumazenil; and Box 7.14 shows guidelines for the use of zuclopenthixol acetate.

Table 7.29 Recommended interventions for patients showing acutely disturbed or violent behaviour

Step

Intervention

Comment

1

De-escalation, time out, placement, etc., as appropriate

 

2

Offer oral treatment

If the patient is prescribed a regular antipsychotic, lorazepam 1-2 mg alone avoids the risks associated with combining antipsychotics

Repeat after 45-60 minutes

Monotherapy with buccal midazolam, 10-20 mg may avoid the need for IM treatment

Note that this preparation is unlicensed

An oral antipsychotic is an option in patients not already taking a regular oral or depot antipsychotic

  • Quetiapine 50-100 mg
  • Olanzapine 10 mg or
  • Risperidone 1-2 mg or
  • Haloperidol 5 mg (best with promethazine 25 mg)
 

Go to step 3 if two doses fail or sooner if the patient is placing themselves or others at significant risk

Note that the SPC for haloperidol recommends:

  • Avoid concomitant antipsychotics
  • A pre-treatment ECG

3

Consider IM treatment

Lorazepam 2 mga,b

Promethazine 50 mgc

Olanzapine 10 mgd

Aripiprazole 9.75 mg

Haloperidol 5 mg

Repeat after 30-60 minutes if insufficient effect

Have flumazenil to hand in case of benzodiazepine-induced respiratory depression

IM promethazine is a useful option in a benzodiazepine-tolerant patient

IM olanzapine should NOT be combined with an IM benzodiazepine, particularly if alcohol has been consumed30

Less hypotension than olanzapine, but possibly less effective3,7,31

Haloperidol should be the last drug considered

  • The incidence of acute dystonia is high; combine with IM promethazine and ensure IM procyclidine is available
  • The SPC recommends a pre-treatment ECG

4

Consider IV treatment Diazepam 10 mg over at least 5 minutesb,e Repeat after 5-10 minutes if insufficient effect (up to 3 times)

Have flumazenil to hand

 

5

Seek advice from a senior psychiatrist or senior clinical pharmacistf

 

a Carefully check administration instructions, which differ between manufacturers. With respect to Ativan (the most commonly used preparation), mix lorazepam 1:1 with water for injections before injecting. Some centres use 2–4 mg. An alternative is midazolam 7.5–15 mg. The risk of respiratory depression is dose-related with both but generally greater with midazolam.

b Caution in the very young and elderly and those with pre-existing brain damage or impulse control problems, as disinhibition reactions are more likely.32

c Promethazine has a slow onset of action but is often an effective sedative. Dilution is not required before IM injection. May be repeated up to a maximum of 100 mg/day. Wait 1–2 hours after injection to assess response. Note that promethazine alone has been reported, albeit very rarely, to cause NMS33 although it is an extremely weak dopamine antagonist. Note the potential pharmacokinetic interaction between promethazine and haloperidol (reduced metabolism of haloperidol) which may confer risk if repeated doses of both are administered.

d Recommended by NICE only for moderate behavioural disturbance, but data from a large observational study also support efficacy in clinical emergencies.

e Use Diazemuls to avoid injection site reactions. IV therapy may be used instead of IM when a very rapid effect is required. IV therapy also ensures near immediate delivery of the drug to its site of action and effectively avoids the danger of inadvertent accumulation of slowly absorbed IM doses. Note also that IV doses can be repeated after only 5–10 minutes if no effect is observed.

f Options at this point are limited. IM amylobarbitone and paraldehyde have been used in the past but are used now only extremely rarely. ECT is probably a better option. Behavioural disturbance secondary to the use of illicit drugs can be very difficult to manage. Time and supportive care may be safer than administering more sedative medication.

Box 7.12 Rapid tranquillisation: physical monitoring

After any parenteral drug administration, monitor as follows:

  • temperature
  • pulse
  • blood pressure
  • respiratory rate

every 10 minutes for 1 hour, and then half-hourly until the patient is ambulatory. Patients who refuse to have their vital signs monitored, or who remain too behaviourally disturbed to be approached, should be observed for signs/symptoms of pyrexia, hypotension, over-sedation and general physical wellbeing.

If the patient is asleep or unconscious, the continuous use of pulse oximetry to measure oxygen saturation is desirable. A nurse should remain with the patient until ambulatory.

ECG and haematological monitoring are also strongly recommended when parenteral antipsychotics are given, especially when higher doses are used.34,35 Hypokalaemia, stress and agitation place the patient at risk of cardiac arrhythmia36 (see section on 'QT prolongation' in Chapter 2). ECG monitoring is formally recommended for all patients who receive haloperidol.

Table 7.30 Remedial measures in rapid tranquillisation

Problem

Remedial measures

Acute dystonia (including oculogyric crises)

Give procyclidine 5-10 mg IM or IV

Reduced respiratory rate (< 10/min) or oxygen saturation (< 90%)

Give oxygen, raise legs, ensure patient is not lying face down

 

Give flumazenil if benzodiazepine-induced respiratory depression suspected

 

If induced by any other sedative agent: transfer to a medical bed and ventilate mechanically

Irregular or slow (< 50/min) pulse

Refer to specialist medical care immediately

Fall in blood pressure (> 30 mmHg orthostatic drop or < 50 mmHg diastolic)

Have patient lie flat, tilt bed towards head. Monitor closely

Increased temperature

Withold antipsychotics (risk of NMS and perhaps arrhythmia). Check creatinine kinase urgently

IM, intramuscular; IV, intravenous; NMS, neuroleptic malignant syndrome.

Box 7.13 Guidelines for the use of flumazenil

Indication for use

If, after the administration of lorazepam, midazolam or diazepam, respiratory rate falls below 10/minute.

Contraindications

Patients with epilepsy who have been receiving long-term benzodiazepines.

Caution

Dose should be carefully titrated in hepatic impairment.

Dose and route of administration

Initial: 200 μg intravenously over 15 seconds - if required level of consciousness not achieved after 60 seconds, then, subsequent dose: 100 μg over 10 seconds.

Time before dose can be repeated

60 seconds.

Maximum dose

1 mg in 24 hours (one initial dose and eight subsequent doses).

Side-effects

Patients may become agitated, anxious or fearful on awakening. Seizures may occur in regular benzodiazepine users.

Management

Side-effects usually subside.

Monitoring

 

What to monitor?

Respiratory rate

How often?

Continuously until respiratory rate returns to baseline level. Flumazenil has a short half-life (much shorter than diazepam) and respiratory function may recover and then deteriorate again.

Note: If respiratory rate does not return to normal or patient is not alert after initial doses given, assume that sedation is due to some other cause.

Box 7.14 Guidelines for the use of Clopixol Acuphase (zuclopenthixol acetate)

Acuphase should be used only after an acutely psychotic patient has required repeated injections of short-acting antipsychotic drugs such as haloperidol or olanzapine, or sedative drugs such as lorazepam. It is perhaps best reserved for those few patients who have a prior history of good response to Acuphase.

Acuphase should be given only when enough time has elapsed to assess the full response to previously injected drugs: allow 15 minutes after IV injections; 60 minutes after IM.

Acuphase should never be administered:

  • in an attempt to 'hasten' the antipsychotic effect of other antipsychotic therapy
  • for rapid tranquillisation (onset of effect is too slow)
  • at the same time as other parenteral antipsychotics or benzodiazepines (may lead to oversedation which is difficult to reverse)
  • as a 'test dose' for zuclopenthixol decanoate depot
  • to a patient who is physically resistant (risk of intravasation and oil embolus).

Acuphase should never be used for, or in, the following:

  • patients who accept oral medication
  • patients who are neuroleptic-naïve
  • patients who are sensitive to EPS
  • patients who are unconscious
  • patients who are pregnant
  • those with hepatic or renal impairment
  • those with cardiac disease.

Onset and duration of action

Sedative effects usually begin to be seen 2 hours after injection and peak after 12 hours. The effects may last for up to 72 hours. Note: Acuphase has no place in rapid tranquillisation: its action is not rapid. Cochrane concludes that Acuphase has no advantages over other options in the immediate management of an episode of behavioural disturbance but that patients who receive this preparation may need fewer subsequent injections in the medium term (7 days).37

Dose

Acuphase should be given in a dose of 50–150 mg (note there is no evidence to support any advantage of higher over lower doses),37 up to a maximum of 400 mg over a 2-week period. This maximum duration ensures that a treatment plan is put in place. It does not indicate that there are known harmful effects from more prolonged administration, although such use should be very exceptional. There is no such thing as a 'course of Acuphase'. The patient should be assessed before each administration.

Injections should be spaced at least 24 hours apart.

Note: zuclopenthixol acetate was formerly widely misused as a sort of 'chemical straitjacket'. In reality it is a potentially toxic preparation with very little published information to support its use.37

References

  1. Currier GW et al. Acute treatment of psychotic agitation: a randomized comparison of oral treatment with risperidone and lorazepam versus intramuscular treatment with haloperidol and lorazepam. J Clin Psychiatry 2004; 65:386–394.
  2. Ganesan S et al. Effectiveness of quetiapine for the management of aggressive psychosis in the emergency psychiatric setting: a naturalistic uncontrolled trial. Int J Psychiatry Clin Pract 2005; 9:199–203.
  3. Simpson JR, Jr. et al. Impact of orally disintegrating olanzapine on use of intramuscular antipsychotics, seclusion, and restraint in an acute inpatient psychiatric setting. J Clin Psychopharmacol 2006; 26:333–335.
  4. Hsu WY et al. Comparison of intramuscular olanzapine, orally disintegrating olanzapine tablets, oral risperidone solution, and intramuscular haloperidol in the management of acute agitation in an acute care psychiatric ward in Taiwan. J Clin Psychopharmacol 2010; 30:230–234.
  5. Lesem MD et al. Rapid acute treatment of agitation in individuals with schizophrenia: multicentre, randomised, placebo-controlled study of inhaled loxapine. Br J Psychiatry 2011; 198:51–58.
  6. Kwentus J et al. Rapid acute treatment of agitation in patients with bipolar I disorder: a multicenter, randomized, placebo-controlled clinical trial with inhaled loxapine. Bipolar Disord 2012; 14:31–40.
  7. Citrome L. Comparison of intramuscular ziprasidone, olanzapine, or aripiprazole for agitation: a quantitative review of efficacy and safety. J Clin Psychiatry 2007; 68:1876–1885.
  8. Chan EW et al. Intravenous droperidol or olanzapine as an adjunct to midazolam for the acutely agitated patient: a multicenter, randomized, double-blind, placebo-controlled clinical trial. Ann Emerg Med 2013; 61:72–81.
  9. TREC Collaborative Group. Rapid tranquillisation for agitated patients in emergency psychiatric rooms: a randomised trial of midazolam versus haloperidol plus promethazine. BMJ 2003; 327:708–713.
  10. Raveendran NS et al. Rapid tranquillisation in psychiatric emergency settings in India: pragmatic randomised controlled trial of intramuscular olanzapine versus intramuscular haloperidol plus promethazine. BMJ 2007; 335:865.
  11. Huf G et al. Rapid tranquillisation in psychiatric emergency settings in Brazil: pragmatic randomised controlled trial of intramuscular haloperidol versus intramuscular haloperidol plus promethazine. BMJ 2007; 335:869.
  12. Alexander J et al. Rapid tranquillisation of violent or agitated patients in a psychiatric emergency setting. Pragmatic randomised trial of intramuscular lorazepam v. haloperidol plus promethazine. Br J Psychiatry 2004; 185:63–69.
  13. Powney MJ et al. Haloperidol for psychosis-induced aggression or agitation (rapid tranquillisation). Cochrane Database Syst Rev 2012; 11: CD009377.
  14. National Institute for Health and Care Excellence. Evidence Summaries: Unlicensed/Off-Label Medicines: Rapid tranquillisation in mental health settings: promethazine hydrochloride (ESUOM 28), 2014. http://www.nice.org.uk/
  15. Satterthwaite TD et al. A meta-analysis of the risk of acute extrapyramidal symptoms with intramuscular antipsychotics for the treatment of agitation. J Clin Psychiatry 2008; 69:1869–1879.
  16. van Harten PN et al. Acute dystonia induced by drug treatment. Br Med J 1999; 319:623–626.
  17. Pharmacovigilance Working Party. Public Assessment Report on Neuroleptics and Cardiac safety, in particular QT prolongation, cardiac arrhythmias, ventricular tachycardia and torsades de pointes, 2006. http://www.mhra.gov.uk
  18. Janssen-Cilag Ltd. Summary of Product Characteristics. Haldol Injection, 2014. https://www.medicines.org.uk/
  19. Miceli JJ et al. Effects of high-dose ziprasidone and haloperidol on the QTc interval after intramuscular administration: a randomized, singleblind, parallel-group study in patients with schizophrenia or schizoaffective disorder. Clin Ther 2010; 32:472–491.
  20. Suzuki A et al. Histamine H1-receptor antagonists, promethazine and homochlorcyclizine, increase the steady-state plasma concentrations of haloperidol and reduced haloperidol. Ther Drug Monit 2003; 25:192–196.
  21. Perrin E et al. A prospective, observational study of the safety and effectiveness of intramuscular psychotropic treatment in acutely agitated patients with schizophrenia and bipolar mania. Eur Psychiatry 2012; 27:234–239.
  22. Calver L et al. A prospective study of high dose sedation for rapid tranquilisation of acute behavioural disturbance in an acute mental health unit. BMC Psychiatry 2013; 13:225.
  23. Mantovani C et al. Are low doses of antipsychotics effective in the management of psychomotor agitation? A randomized, rated-blind trial of 4 intramuscular interventions. J Clin Psychopharmacol 2013; 33:306–312.
  24. Taylor D et al. Buccal midazolam for rapid tranquillisation. Int J Psychiatry Clin Pract 2008; 12:309–311.
  25. Spain D et al. Safety and effectiveness of high-dose midazolam for severe behavioural disturbance in an emergency department with suspected psychostimulant-affected patients. Emerg Med Australas 2008; 20:112–120.
  26. Gillies D et al. Benzodiazepines for psychosis-induced aggression or agitation. Cochrane Database Syst Rev 2013; 9: CD003079.
  27. Li SF et al. Safety and efficacy of intravenous combination sedatives in the ED. Am J Emerg Med 2013; 31:1402–1404.
  28. MacNeal JJ et al. Use of haloperidol in PCP-intoxicated individuals. Clin Toxicol (Phila) 2012; 50:851–853.
  29. Huf G et al. Physical restraints versus seclusion room for management of people with acute aggression or agitation due to psychotic illness (TREC-SAVE): a randomized trial. Psychol Med 2012; 42:2265–2273.
  30. Wilson MP et al. Potential complications of combining intramuscular olanzapine with benzodiazepines in emergency department patients. J Emerg Med 2012; 43:889–896.
  31. Villari V et al. Oral risperidone, olanzapine and quetiapine versus haloperidol in psychotic agitation. Prog Neuropsychopharmacol Biol Psychiatry 2008; 32:405–413.
  32. Paton C. Benzodiazepines and disinhibition: a review. Psychiatr Bull 2002; 26:460–462.
  33. Chan-Tack KM. Neuroleptic malignant syndrome due to promethazine. South Med J 1999; 92:1017–1018.
  34. Appleby L et al. Sudden unexplained death in psychiatric in-patients. Br J Psychiatry 2000; 176:405–406.
  35. Yap YG et al. Risk of torsades de pointes with non-cardiac drugs. Doctors need to be aware that many drugs can cause QT prolongation. BMJ 2000; 320:1158–1159.
  36. Taylor DM. Antipsychotics and QT prolongation. Acta Psychiatr Scand 2003; 107:85–95.
  37. Jayakody K et al. Zuclopenthixol acetate for acute schizophrenia and similar serious mental illnesses. Cochrane Database Syst Rev 2012; 4: CD000525.

Further reading

National Institute for Health and Clinical Excellence. Violence—The short-term management of disturbed/violent behaviour in in-patient psychiatric settings and emergency departments. Clinical Guideline 25, 2005. www.nice.org.uk

Borderline personality disorder

Borderline personality disorder (BPD) is common in psychiatric settings with a reported prevalence of up to 20%.2 In BPD, co-morbid depression, anxiety spectrum disorders and bipolar illness occur more frequently than would be expected by chance association alone, and the lifetime risk of having at least one co-morbid mental disorder approaches 100%.3 The suicide rate in BPD is similar to that seen in affective disorders and schizophrenia.4,5

Although it is classified as a personality disorder, several 'symptoms' of BPD may intuitively be expected to respond to drug treatment. These include affective instability, transient stress-related psychotic symptoms, suicidal and self-harming behaviours, and impulsivity.5 A high proportion of people with BPD are prescribed psychotropic drugs.3,6,7 The prevalence of prescribing of antipsychotics, antidepressants and mood stabilisers in those with borderline personality disorder as a sole psychiatric diagnosis is not notably different than in those with borderline personality disorder and a comorbid diagnosis of schizophrenia, depression or bipolar disorder respectively7. No drug is specifically licensed for the treatment of BPD.

NICE1 recommend that:

Since the publication of the NICE guideline for BPD, two further independent systematic reviews have been published.8,9 Essentially the same studies were considered in all three reviews and where numerical data were combined in meta-analyses the results of these analyses were similar across all three systematic reviews. In addition, all noted that the majority of studies of drug treatment in BPD last for only 6 weeks and that the large number of different outcome measures that were used made it difficult to evaluate and compare studies.

NICE considered that the data were not robust enough to be the basis for recommendations to the NHS while the other two reviews concluded that some of the analyses showed promising results and that these were sufficiently cogent to inform clinical practice.

Antipsychotics

Open studies have found benefit for a number of first and second-generation antipsychotics over a wide range of symptoms. In contrast, placebo-controlled RCTs generally show more modest benefits for active drug over placebo. The symptoms/symptom clusters that may respond are affect dysregulation, impulsivity and cognitive-perceptual symptoms.8–10 Open studies report reductions in aggression and self-harming behaviour with clozapine11–13 and clozapine has been shown to have an anti-aggressive effect in people with schizophrenia.14 A recent RCT showed clinically significant efficacy for quetiapine 150 mg/day.15 Antipsychotic medications are associated with a wide range of adverse effects (see Chapter 2).

Antidepressants

Several open studies have found that SSRIs reduce impulsivity and aggression in BPD, but these findings have not been replicated in RCTs. It can be concluded with reasonable certainty that there is no robust evidence to support the use of antidepressants in treating depressed mood or impulsivity in people with BPD.8,9

Mood stabilisers

Up to a half of people with BPD may also have a bipolar spectrum disorder16 and mood stabilisers are commonly prescribed.3 There is some evidence that mood stabilisers reduce impulsivity, anger, and affect dysregulation in people with BPD.8,9 Lithium is licensed for the control of aggressive behaviour or intentional self-harm.17 A large RCT of lamotrigine is currently recruiting in the UK.18

Management of crisis

Drug treatments are often used during periods of crisis when 'symptoms' can be severe, distressing and potentially life-threatening. By their very nature, these symptoms can be expected to wax and wane.4 Drug therapy may then be required intermittently. It is generally easy to see when treatment is required, but much more difficult to decide when modest gains are worthwhile and whether or not continuation is likely to be necessary.

NICE1 recommend that during periods of crisis, time-limited treatment with a sedative drug may be helpful. Anticipated side-effect profile and potential toxicity in overdose should guide choice. For example, benzodiazepines (particularly short-acting drugs) can cause disinhibition in this group of patients,19 potentially compounding problems; sedative antipsychotics can cause EPS and/or considerable weight gain (see section on 'Antipsychotics and weight gain' in Chapter 2), and tricyclic antidepressants are particularly toxic in overdose (see section on 'Psychotropics in overdose' in Chapter 8). A sedative antihistamine such as promethazine is quite well tolerated and may be a helpful short-term treatment when used as part of a co-ordinated care plan. Its adverse effects (dry mouth, constipation) and lack of clear anxiolytic effects may militate against longer term use.

References

  1. National Institute for Health and Clinical Excellence. Borderline personality disorder: treatment and management. Clinical Guideline 78, 2009. http://www.nice.org.uk
  2. Kernberg OF et al. Borderline personality disorder. Am J Psychiatry 2009; 166:505–508.
  3. Pascual JC et al. A naturalistic study of changes in pharmacological prescription for borderline personality disorder in clinical practice: from APA to NICE guidelines. Int Clin Psychopharmacol 2010; 25:349–355.
  4. Links PS et al. Prospective follow-up study of borderline personality disorder: prognosis, prediction of outcome, and Axis II comorbidity. Can J Psychiatry 1998; 43:265–270.
  5. Oldham JM. Guideline watch: practice guideline for the treatment of patients with borderline personality disorder. Focus 2005; 3:396–400.
  6. Baker-Glenn E et al. Use of psychotropic medication among psychiatric out-patients with personality disorder. Psychiatrist 2010; 34:83–86.
  7. Paton C. Prescribing for people with emotionally unstable personality disorder under the care of UK mental health services. J Clin Psychiatry 2014; submitted.
  8. Lieb K et al. Pharmacotherapy for borderline personality disorder: Cochrane systematic review of randomised trials. Br J Psychiatry 2010; 196:4–12.
  9. Ingenhoven T et al. Effectiveness of pharmacotherapy for severe personality disorders: meta-analyses of randomized controlled trials. J Clin Psychiatry 2010; 71:14–25.
  10. Zanarini MC et al. A dose comparison of olanzapine for the treatment of borderline personality disorder: a 12-week randomized, doubleblind, placebo-controlled study. J Clin Psychiatry 2011; 72:1353–1362.
  11. Benedetti F et al. Low-dose clozapine in acute and continuation treatment of severe borderline personality disorder. J Clin Psychiatry 1998; 59:103–107.
  12. Frogley C et al. A case series of clozapine for borderline personality disorder. Ann Clin Psychiatry 2013; 25:125–134.
  13. Chengappa KN et al. Clozapine reduces severe self-mutilation and aggression in psychotic patients with borderline personality disorder. J Clin Psychiatry 1999; 60:477–484.
  14. Volavka J et al. Heterogeneity of violence in schizophrenia and implications for long-term treatment. Int J Clin Pract 2008; 62:1237–1245.
  15. Black DW et al. Comparison of low and moderate doses of extended-release quetiapine in borderline personality disorder: a randomized, double-blind, placebo-controlled trial. Am J Psych 2014; 171:1174–1182.
  16. Deltito J et al. Do patients with borderline personality disorder belong to the bipolar spectrum? J Affect Disord 2001; 67:221–228.
  17. Sanofi. Summary of product characteristics. Priadel 400 mg prolonged release tablets, 2014. https://www.medicines.org.uk/
  18. NHS National Institute for Health Research, Imperial College London. LABILE Clinical Trial - Lamotrigine and borderline personality disorder: investigating long-term effectiveness, 2013. http://www.labile.org/
  19. Gardner DL et al. Alprazolam-induced dyscontrol in borderline personality disorder. Am J Psychiatry 1985; 142:98–100.

Further reading

National Health and Medical Research Council. Clinical practice guideline for the management of borderline personality disorder. MH25, 2012. https://www.nhmrc.gov.au/guidelines/publications/mh25

Ripoll LH et al. Evidence-based pharmacotherapy for personality disorders. Int J Neuropsychopharmacol 2011; 14:1257–1288.

Learning disabilities

General considerations1

Prescribing psychotropic medications for people with learning disabilities (LD) is a challenging and controversial area of psychiatric practice.2,3 There are concerns that psychotropic drugs of all kinds (antipsychotics, antidepressants, benzodiazepines, both regular and as required, and anticonvulsants as mood stabilisers) are overprescribed with poor review and assessment of their benefit.

Although prescribing for individuals with mild or borderline intellectual impairment may be undertaken by mainstream mental health services, the assessment and treatment of behavioural and emotional disorders in people with more marked (or, as in the case of autism, atypical patterns of significant cognitive impairment) should be undertaken in the first instance by, or at least in consultation with, specialist clinicians.

The term 'dual diagnosis' in this context refers to the co-occurrence of an identifiable psychiatric disorder (mental illness, personality disorder) and LD. 'Diagnostic overshadowing' is the misattribution of emotional or behavioural problems to LD itself rather than a co-morbid condition. LD is an important risk factor for all psychiatric disorders (including dementia, particularly for individuals with Down's syndrome).4 Where it is possible to diagnose a mental illness using conventional or modified criteria then drug treatment in the first instance should, in general, be similar to that in the population at large. Most treatment guidelines are increasingly stating their intended applicability to people with LD in this regard.

Mental illness may initially present in unusual ways, e.g. depression as self-injurious behaviour, persecutory ideation as complaints of being 'picked on'. Conversely, behaviours such as self-talk may be normal in some individuals but mistakenly identified as psychosis. In general, diagnosis becomes increasingly complex with severity of disability and associated communication impairment.

Co-morbid autistic spectrum disorder has special assessment considerations and in its own right is an important risk factor for psychiatric disorder, in particular anxiety and depression, bipolar spectrum disorder, severe obsessional behaviour, anger disorders and psychosis-like episodes that may not meet criteria for schizophrenia but nonetheless require treatment. Autistic traits are common amongst patients using LD services.

Key practice areas

Capacity and consent: it is uncommon for patients in LD services (who often represent a sub-population of those identified with special educational needs in childhood) to have sufficient understanding of their treatment in order to be able to make truly informed decisions, and there is inevitably an increased onus on the clinician to bear the weight of decision-making. Decision-making capacity, depending on the severity of intellectual impairment, may be improved through appropriate verbal and written communication. The involvement of carers in this process is generally essential.

Physical co-morbidity, especially epilepsy: epilepsy is over-represented in LD populations, becoming more prevalent as severity increases with approximately one third of affected individuals developing a seizure disorder by early adulthood. Special consideration is needed when considering the use of medications that may lower seizure threshold.

Table 7.31 Current and historically-used medications for behaviour disorder

Drug class

Clinical applications

Notes

Antipsychotics5

Used across a broad range of behavioural disturbances. Most consistently useful for aggression and irritability

The most widely used yet most controversial medication for behavioural problems.6,7 Although a recent RCT8 cast doubt on their efficacy the study was not without its problems and there is a significant body of other evidence supporting their use including a number of small RCTs in children with LD

Discontinuation studies in long-term treatment commonly show re-emergence of problem behaviours

Before the advent of atypicals the best evidence was for haloperidol9 in the context of autism and for zuclopenthixol for behavioural disturbance10

The best evidence is for risperidone11,12 at low dose (0.5-2 mg) for aggression and mood instability (now licensed for short-term use), particularly with associated autism though in non-autistic cases also. Aripiprazole has a FDA licence for behavioural disturbance in young people with autism13,14

Some evidence to support olanzapine15 and case reports of clozapine16 for very severe cases of aggression though not widely used and unlikely to emerge outside highly specialist (inpatient) settings

Results for quetiapine are modest at best17

SSRIs

Helpful for severe anxiety and obsessionality in autistic spectrum disorder. Use here is off-licence unless an additional diagnosis of anxiety disorder or OCD is made. Also used as a first-line alternative to antipsychotics for aggression and impulsivity

Commonly used in combination with antipsychotics though limited evidence base for combination treatment. Effectiveness in absence of mood or anxiety-spectrum disorder is unclear, however, and recent Cochrane Review pessimistic18 about the evidence for their effectiveness for behaviour disorder in autistic children (who may be at heightened risk of adverse effects), though a little more encouraging in adults.

Note quality of trials poor and effects may be exaggerated by use in less severe cases.19 Caution needed because of the risk of precipitation of hypomania in this population.20 Also major concerns about overprescribing

Anticonvulsants21

Aggression and self-injury

Some uncontrolled studies supporting sodium valproate22 in LD populations though evidence not strong and research findings contradictory in this population. However, remains best supported of the anticonvulsants for mood lability and aggression partly because of positive studies in the non-LD groups23

Limited studies of lamotrigine, mostly in children, suggest no effect, at least in autism and in the absence of affective instability17

Data for carbamazepine also unconvincing, but it is still widely

used24

Lithium25

Licensed for the treatment of self-injurious behaviour and aggression

Some RCT evidence26 for LD but no studies in this population for many years, although there has been one more recent positive RCT for aggression in adolescents without developmental impairment.27 Experience suggests lithium can be very helpful in individual cases where other treatments have failed and is possibly underused though side-effects can be problematic. Perhaps best considered where there is a sub-syndromal or nonspecific 'affective component'. Some authorities suggest that, on close examination, challenging behaviour may occur in the context of very rapid cycling bipolar disorder in some individuals with severe and profound learning disability and that the diagnosis is easily missed

Naltrexone28

Has been used for severe self-injurious behaviour29

Evidence not strong and results are inconsistent. Use may still be an option in severe and intractable cases

FDA, Food and Drug Administration; LD, learning disability; OCD, obsessive compulsive disorder; RCT, randomised controlled trial; SSRI, selective serotonin reuptake inhibitor.

Assessment of care environments: behavioural and emotional disturbance may sometimes be a reflection of problems or failings in the care environment. Different staff in a care home may have different thresholds of tolerance (or make different attributions) for these difficulties which can lead to varied reports of their significance and impact. Allowing for a period of prospective assessment and using simple assessment tools, (for example, simple ABC or sleep charts) can be very helpful to the clinician in making judgements about recommending medication. If medication is used in a care home, staff may need special education in its use and anticipated side-effects and, for 'as required' medications, clear guidelines for its use. This may make it difficult to initiate certain treatments in the community.

Side-effect sensitivity: it is widely thought that people with LD are especially sensitive to side-effects of psychotropics and more at risk of long-term effects such as the metabolic syndrome, however this is not supported by study evidence. It is good practice to start at lower doses and increase more slowly than might be usual in general psychiatric practice. Notable side effects include worsening of seizures, sedation, extrapyramidal reactions (including with risperidone at normal doses, especially in individuals who already have mobility problems), problems with swallowing (with clozapine and other antipsychotics) and worsening of cognitive function with anticholinergic medications (see section on 'Prescribing in dementia' in this chapter).

Psychological interventions: in the absence of an identifiable mental illness (including atypical presentations) with clear treatment implications, psychological interventions such as functional behavioural analysis should be considered as first-line intervention for all but the most serious or intractable presentations of behavioural disturbance. In studies where it has been possible to infer severity of challenging behaviour treatment, response is generally associated with more severe problems at baseline.

Table 7.31 shows current and historically-used medications for behaviour disorder in people with learning disabilities.

References

  1. Deb S. The use of medications for the management of problem behaviours in adults who has Intellectual [Learning] Disabilities, 2012. http://www. intellectualdisability.info/mental-health/the-use-of-drugs-for-the-treatment-of-behaviour-disorders-in-adults-who-have-learningintellectual-disabilities
  2. Tyrer P et al. Drug treatments in people with intellectual disability and challenging behaviour. BMJ 2014; 349:g4323.
  3. Glover G et al. Use of medication for challenging behaviour in people with intellectual disability. Br J Psychiatry 2014; 205:6–7.
  4. Cooper SA et al. Mental ill-health in adults with intellectual disabilities: prevalence and associated factors. Br J Psychiatry 2007; 190:27–35.
  5. Antochi R et al. Psychopharmacological treatments in persons with dual diagnosis of psychiatric disorders and developmental disabilities. Postgrad Med J 2003; 79:139–146.
  6. Deb S et al. The effectiveness of antipsychotic medication in the management of behaviour problems in adults with intellectual disabilities. J Intellect Disabil Res 2007; 51:766–777.
  7. Roy D et al. Pharmacologic Management of Aggression in Adults with Intellectual Disability. J Intellect Disabil Res 2013; 1:28–43.
  8. Tyrer P et al. Risperidone, haloperidol, and placebo in the treatment of aggressive challenging behaviour in patients with intellectual disability: a randomised controlled trial. Lancet 2008; 371:57–63.
  9. Malone RP et al. The role of antipsychotics in the management of behavioural symptoms in children and adolescents with autism. Drugs 2009; 69:535–548.
  10. Malt UF et al. Effectiveness of zuclopenthixol compared with haloperidol in the treatment of behavioural disturbances in learning disabled patients. Br J Psychiatry 1995; 166:374–377.
  11. Nagaraj R et al. Risperidone in children with autism: randomized, placebo-controlled, double-blind study. J Child Neurol 2006; 21:450–455.
  12. Pandina GJ et al. Risperidone improves behavioral symptoms in children with autism in a randomized, double-blind, placebo-controlled trial. J Autism Dev Disord 2007; 37:367–373.
  13. Owen R et al. Aripiprazole in the treatment of irritability in children and adolescents with autistic disorder. Pediatrics 2009; 124:1533–1540.
  14. Marcus RN et al. A placebo-controlled, fixed-dose study of aripiprazole in children and adolescents with irritability associated with autistic disorder. J Am Acad Child Adolesc Psychiatry 2009; 48:1110–1119.
  15. Fido A et al. Olanzapine in the treatment of behavioral problems associated with autism: an open-label trial in Kuwait. Med Princ Pract 2008; 17:415–418.
  16. Zuddas A et al. Clinical effects of clozapine on autistic disorder. Am J Psychiatry 1996; 153:738.
  17. Stigler KA et al. Pharmacotherapy of irritability in pervasive developmental disorders. Child Adolesc Psychiatr Clin N Am 2008; 17:739–752.
  18. Williams K et al. Selective serotonin reuptake inhibitors (SSRIs) for autism spectrum disorders (ASD). Cochrane Database Syst Rev 2013; 8: CD004677.
  19. Myers SM. Citalopram not effective for repetitive behaviour in autistic spectrum disorders. Evid Based Ment Health 2010; 13:22.
  20. Cook EH, Jr. et al. Fluoxetine treatment of children and adults with autistic disorder and mental retardation. J Am Acad Child Adolesc Psychiatry 1992; 31:739–745.
  21. Deb S et al. The effectiveness of mood stabilizers and antiepileptic medication for the management of behaviour problems in adults with intellectual disability: a systematic review. J Intellect Disabil Res 2008; 52:107–113.
  22. Ruedrich S et al. Effect of divalproex sodium on aggression and self-injurious behaviour in adults with intellectual disability: a retrospective review. J Intellect Disabil Res 1999; 43 (Pt 2):105–111.
  23. Donovan SJ et al. Divalproex treatment for youth with explosive temper and mood lability: a double-blind, placebo-controlled crossover design. Am J Psychiatry 2000; 157:818–820.
  24. Unwin GL et al. Use of medication for the management of behavior problems among adults with intellectual disabilities: a clinicians' consensus survey. Am J Ment Retard 2008; 113:19–31.
  25. Pary RJ. Towards defining adequate lithium trials for individuals with mental retardation and mental illness. Am J Ment Retard 1991; 95:681–691.
  26. Craft M et al. Lithium in the treatment of aggression in mentally handicapped patients. A double-blind trial. Br J Psychiatry 1987; 150:685–689.
  27. Malone RP et al. A double-blind placebo-controlled study of lithium in hospitalized aggressive children and adolescents with conduct disorder. Arch Gen Psychiatry 2000; 57:649–654.
  28. Campbell M et al. Naltrexone in autistic children: an acute open dose range tolerance trial. J Am Acad Child Adolesc Psychiatry 1989; 28:200–206.
  29. Barrett RP et al. Effects of naloxone and naltrexone on self-injury: a double-blind, placebo-controlled analysis. Am J Ment Retard 1989; 93:644–651.

Delirium

Delirium is a common neuropsychiatric condition that presents in medical and surgical settings and is known by various names including organic brain syndrome, intensive care psychosis and acute confusional state.1

Diagnostic criteria for delirium2

Tools for evaluation3

A brief cognitive assessment should be included in the examination of patients at risk of delirium. A standardised tool, the Confusion Assessment Method (CAM) is a brief, validated algorithm currently used to diagnose delirium. CAM relies on the presence of acute onset of symptoms, fluctuating course, inattention and either disorganised thinking or an altered level of consciousness.

Clinical subtypes of delirium4–6

Prevalence

Delirium is present in 10% of hospitalised medical patients and a further 10–30% develop delirium after admission.4 Postoperative delirium occurs in 15–53% of patients and in 70–87% of those in intensive care.7

Risk factors

Delirium is almost invariably multifactorial and it is often inappropriate to isolate a single precipitant as the cause.4 The most important risk factors have consistently emerged as:4,5,8,9

Outcome

Patients with delirium have an increased length of hospital stay, increased mortality and increased risk of long-term institutional placement.1,5 Hospital mortality rates of patients with delirium range from 6% to 18% and are twice that of matched controls.5 The one-year mortality rate associated with cases of delirium is 35–40%.7 Up to 60% of individuals suffer persistent cognitive impairment following delirium and these patients are also three times more likely to develop dementia.1,5

Management

Preventing delirium is the most effective strategy for reducing its frequency and complications.7 Delirium is a medical emergency and the identification and treatment of the underlying cause should be the first aim of management.10

Non-pharmacological or environmental support strategies should be instituted wherever possible. These include, co-ordinating nursing care, preventing sensory deprivation and disorientation, and maintaining competence.5,11 Pharmacological treatment should be directed first at the underlying cause (if known) and then at the relief of specific symptoms of delirium.

The common errors in the pharmacological management of delirium are to use antipsychotic medications in excessive doses, give them too late or to overuse benzodiazepines.4

General principles4,5,12–14

Pharmacological prophylaxis15,16

Data are sparse and conflicting around the use of medication to prevent delirium. Most studies use low dose haloperidol in patients deemed at high risk of developing delirium (elderly, post-surgical or ICU patients). Prophylactic low dose haloperidol (around 3 mg/day) may reduce the severity and duration of delirium episodes and shorten the length of hospital stay in patients at high risk of developing the condition, but further research is needed before routinely recommending this strategy. Some evidence exists to support non-drug measures to minimise the risk of delirium.17 Even low dose antipsychotics have serious adverse effects in elderly patients.

Table 7.31 Drugs used to treat delirium

Drug

Dose

Adverse effects

Notes

First-generation antipsychotics

Haloperidol1,5,7,11,18-20

Oral 0.5-1 mg bd

with additional doses every 4 hourly as needed

(peak effect: 4-6 hours)

IM 0.5-1 mg, observe for 30-60 minutes and repeat if necessary

(peak effect: 20-40 minutes)

EPS can occur especially at doses above 3 mg

Prolonged QT interval

Increased risk of stroke in patients with dementia

Considered first-line agent. No trial data have demonstrated superiority of other antipsychotics over haloperidol, however care must be taken to monitor for EPS and cardiac side-effects

Baseline ECG is recommended for all patients, and especially for the elderly or those with a family or personal history of cardiac disease

Regular monitoring of the ECG and potassium levels should be carried out if there are other conditions present that may prolong the QT interval

Avoid in Lewy body dementia and Parkinson's disease

Avoid IV use where possible. However, in the medical ICU setting, IV is often used with close continuous ECG monitoring

Second-generation antipsychotics

Amisulpride11,12,21,22

Oral 50-300mg od, up to a maximum of 800 mg od

Doses higher than 300mg should be given in two divided doses

Prolonged QT interval

Increased risk of stroke in patients with dementia

Very limited evidence

As amisulpride is almost entirely excreted via the kidneys it is imperative to monitor renal function when used in medically ill or elderly patients

Aripiprazole11,12,21-23

Oral 5-15 mg/day, up to a maximum of 30mg/day

Akathisia or worsening sleep cycle may be problematic

Increased risk of stroke in patients with dementia

Very limited evidence

The rapid-acting intramuscular preparation has not been assessed for the treatment of delirium

Olanzapine1191-1195

Oral 2.5-5mg od, up to a maximum of 20 mg/day

EPS less likely than with haloperidol

Sedation is the most commonly reported side effect

Increased risk of stroke in patients with dementia

A trial comparing olanzapine, risperidone, haloperidol and quetiapine showed that all were equally efficacious and safe in the treatment of delirium, but the response rate to olanzapine was poorer in the older age group (> 75 years)29

The rapid-acting intramuscular preparations has not been assessed for the treatment of delirium

Risperidone26,27,30-35

Oral 0.5 mg bd with additional doses every 4 hourly as needed.

Usual maximum 4mg/day

The most common reported side effects are hypotension and EPS

Increased risk of stroke in patients with dementia

A trial comparing risperidone with olanzapine showed that both were equally effective in reducing delirium symptoms but the response to risperidone was poorer in the older age group (> 70 years)27

Quetiapine36-40

Oral 12.5-50mg bd

This may be increased every 12 hours to 200 mg daily if it is well tolerated

Sedation and postural hypotension are the most common reported side effects

Increased risk of stroke in patients with dementia

There is an increasing number of trials demonstrating safety and efficacy of low dose quetiapine compared with haloperidol both in and outside the medical ICU

Ziprasidone41

IM 10 mg every 2 hourly

Usual maximum 40mg/day

QT prolongation

Increased risk of stroke in patients with dementia

Very limited evidence

Not available in the UK

Benzodiazepines

Lorazepam1,5,7

Oral/IM

0.25-1 mg every 2 to 4 hourly as needed

Usual maximum 3 mg in 24 hours

IV use is usually reserved for emergencies

More likely than antipsychotics to cause respiratory depression, over sedation and paradoxical excitement

Associated with prolongation and worsening of delirium symptoms

Used in alcohol or sedative hypnotic withdrawal, Parkinson's disease and NMS

Otherwise - avoid

Diazepam42

Starting oral dose of 5-10mg

In the elderly a starting dose of 2 mg is recommended

Much longer half life in comparison with lorazepam

Associated with prolongation and worsening of delirium symptoms

Used in alcohol or sedative hypnotic withdrawal, Parkinson's disease and NMS

Otherwise - avoid

Cholinesterase inhibitors

Donepezil43,44

Oral 5 mg od

Reasonably well tolerated compared with placebo. Nausea, vomiting and diarrhoea are the most common adverse effects reported

Very limited evidence. In the small studies where it has been used, clinical benefits have not been convincing.

Not recommended

Rivastigmine45,44

Oral 1.5-6 mg bd

A study which added rivastigmine to usual care (haloperidol), showed that rivastigmine did not decrease the duration of delirium but in fact was associated with a more severe type of delirium, a longer stay in intensive care and higher mortality compared with placebo

Use of rivastigmine to treat delirium in critically ill patients is not recommended

Other drugs

Melatonin47,48

Oral 2 mg od

Sedation is the most commonly reported adverse effect

Very limited experience, used mainly to correct altered sleep-wake cycle. Not recommended

Trazodone4,7

25-150mg nocte

Over sedation is problematic

Limited experience - used only in uncontrolled studies.

Not recommended

Sodium valproate49

Oral/IM/IV

250mg bd increased to plasma level of 50-100mg/L

Contraindicated in active liver disease

Some case reports of its use where antipsychotics and/or benzodiazepines are ineffective, otherwise not recommended

bd, bis die (twice a day); ECG, electrocardiogram; EPS, extrapyramidal side-effects; ICU, intensive care unit; IM, intramuscular; IV, intravenous; NMS, neuroleptic malignant syndrome; nocte, at night; od, omne in die (once a day).

Table 7.32 gives a summary of the drugs used to treat delirium.

References

  1. van Zyl LT et al. Delirium concisely: condition is associated with increased morbidity, mortality, and length of hospitalization. Geriatrics 2006; 61:18–21.
  2. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). Arlington, VA: American Psychiatric Association; 2013.
  3. Inouye SK et al. Clarifying confusion: the confusion assessment method. A new method for detection of delirium. Ann Intern Med 1990; 113:941–948.
  4. Nayeem K et al. Delirium. Clin Med 2003; 3:412–415.
  5. Potter J et al. The prevention, diagnosis and management of delirium in older people: concise guidelines. Clin Med 2006; 6:303–308.
  6. Fong TG et al. Delirium in elderly adults: diagnosis, prevention and treatment. Nat Rev Neurol 2009; 5:210–220.
  7. Inouye SK. Delirium in older persons. N Engl J Med 2006; 354:1157–1165.
  8. Saxena S et al. Delirium in the elderly: a clinical review. Postgrad Med J 2009; 85:405–413.
  9. Naja M et al. Delirium in geriatric medicine is related to anticholinergic burden. Eur Geriatr Med 2013; 4 Suppl 1:S208.
  10. Burns A et al. Delirium. J Neurol Neurosurg Psychiatry 2004; 75:362–367.
  11. Schwartz TL et al. The role of atypical antipsychotics in the treatment of delirium. Psychosomatics 2002; 43:171–174.
  12. Seitz DP et al. Antipsychotics in the treatment of delirium: a systematic review. J Clin Psychiatry 2007; 68:11–21.
  13. National Institute for Health and Clinical Excellence. Delirium: diagnosis, prevention and management. Clinical Guideline 103, 2010. http://www.nice.org.uk/
  14. Donders E et al. Effect of haloperidol dosing frequencies on the duration and severity of delirium in elderly hip fracture patients. A prospective randomized trial. Eur Geriatr Med 2012; 3 Suppl 1:S118–S119.
  15. Siddiqi N et al. Interventions for preventing delirium in hospitalised patients. Cochrane Database Syst Rev 2007; CD005563.
  16. van den Boogaard M et al. Haloperidol prophylaxis in critically ill patients with a high risk for delirium. Crit Care 2013; 17:R9.
  17. Clegg A et al. Interventions for preventing delirium in older people in institutional long-term care. Cochrane Database Syst Rev 2014; 1: CD009537.
  18. Fricchione GL et al. Postoperative delirium. Am J Psychiatry 2008; 165:803–812.
  19. Lonergan E et al. Antipsychotics for delirium (review). Cochrane Database Syst Rev 2007; CD005594.
  20. Page VJ et al. Effect of intravenous haloperidol on the duration of delirium and coma in critically ill patients (Hope-ICU): a randomised, double-blind, placebo-controlled trial. Lancet Respir Med 2013; 1:515–523.
  21. Boettger S et al. Atypical antipsychotics in the management of delirium: a review of the empirical literature. Palliat Support Care 2005; 3:227–237.
  22. Leentjens AF et al. Delirium in elderly people: an update. Curr Opin Psychiatry 2005; 18:325–330.
  23. Boettger S et al. Aripiprazole and haloperidol in the treatment of delirium. Aust N Z J Psychiatry 2011; 45:477–482.
  24. Skrobik YK et al. Olanzapine vs haloperidol: treating delirium in a critical care setting. Intensive Care Med 2004; 30:444–449.
  25. Sipahimalani A et al. Olanzapine in the treatment of delirium. Psychosomatics 1998; 39:422–430.
  26. Duff G. Atypical antipsychotic drugs and stroke, 2004. http://www.mhra.gov.uk
  27. Kim SW et al. Risperidone versus olanzapine for the treatment of delirium. Hum Psychopharmacol 2010; 25:298–302.
  28. Grover S et al. Comparative efficacy study of haloperidol, olanzapine and risperidone in delirium. J Psychosom Res 2011; 71:277–281.
  29. Yoon HJ et al. Efficacy and safety of haloperidol versus atypical antipsychotic medications in the treatment of delirium. BMC Psychiatry 2013; 13:240.
  30. Bourgeois JA et al. Prolonged delirium managed with risperidone. Psychosomatics 2005; 46:90–91.
  31. Gupta N et al. Effectiveness of risperidone in delirium. Can J Psychiatry 2005; 50:75.
  32. Liu CY et al. Efficacy of risperidone in treating the hyperactive symptoms of delirium. Int Clin Psychopharmacol 2004; 19:165–168.
  33. Horikawa N et al. Treatment for delirium with risperidone: results of a prospective open trial with 10 patients. Gen Hosp Psychiatry 2003; 25:289–292.
  34. Han CS et al. A double-blind trial of risperidone and haloperidol for the treatment of delirium. Psychosomatics 2004; 45:297–301.
  35. Hakim SM et al. Early treatment with risperidone for subsyndromal delirium after on-pump cardiac surgery in the elderly: a randomized trial. Anesthesiology 2012; 116:987–997.
  36. Torres R et al. Use of quetiapine in delirium: case reports. Psychosomatics 2001; 42:347–349.
  37. Sasaki Y et al. A prospective, open-label, flexible-dose study of quetiapine in the treatment of delirium. J Clin Psychiatry 2003; 64:1316–1321.
  38. Devlin JW et al. Efficacy and safety of quetiapine in critically ill patients with delirium: a prospective, multicenter, randomized, double-blind, placebo-controlled pilot study. Crit Care Med 2010; 38:419–427.
  39. Hawkins SB et al. Quetiapine for the treatment of delirium. J Hosp Med 2013; 8:215–220.
  40. Tahir TA et al. A randomized controlled trial of quetiapine versus placebo in the treatment of delirium. J Psychosom Res 2010; 69:485–490.
  41. Young CC et al. Intravenous ziprasidone for treatment of delirium in the intensive care unit. Anesthesiology 2004; 101:794–795.
  42. Chan D et al. Delirium: making the diagnosis, improving the prognosis. Geriatrics 1999; 54:28–42.
  43. Overshott R et al. Cholinesterase inhibitors for delirium. Cochrane Database Syst Rev 2008; CD005317.
  44. Sampson EL et al. A randomized, double-blind, placebo-controlled trial of donepezil hydrochloride (Aricept) for reducing the incidence of postoperative delirium after elective total hip replacement. Int J Geriatr Psychiatry 2007; 22:343–349.
  45. Dautzenberg PL et al. Adding rivastigmine to antipsychotics in the treatment of a chronic delirium. Age Ageing 2004; 33:516–517.
  46. van Eijk MM et al. Effect of rivastigmine as an adjunct to usual care with haloperidol on duration of delirium and mortality in critically ill patients: a multicentre, double-blind, placebo-controlled randomised trial. Lancet 2010; 376:1829–1837.
  47. Hanania M et al. Melatonin for treatment and prevention of postoperative delirium. Anesth Analg 2002; 94:338–9, table.
  48. Cronin AJ et al. Melatonin secretion after surgery. Lancet 2000; 356:1244–1245.
  49. Bourgeois JA et al. Adjunctive valproic acid for delirium and/or agitation on a consultation-liaison service: a report of six cases. J Neuropsychiatry Clin Neurosci 2005; 17:232–238.

Further reading

Donders E et al. Effect of haloperidol dosing frequencies on the duration and severity of delirium in elderly hip fracture patients. Eur Geriatr Med 2012; 3(S118-119), 1878–7649.

Boettger S et al. Aripiprazole and haloperidol in the treatment of delirium. Aust NZ J Psychiat 2011; 45(6):477–482.

Yoon H-J et al. Efficacy and safety of typical and atypical antipsychotic medications in the treatment of delirium. Int Psychogeriatrics 2013; 25(S133):1041–6102.

Hakim SM, Othman AI, Naoum DO. Early treatment with risperidone for subsyndromal delirium after on-pump cardiac surgery in the elderly: a randomized trial. Anaesthesiology 2012; 116(5):987–997

Hawkins SB et al. Quetiapine for the treatment of delirium. J Hosp Med 2013; 8(4):215–220.

Page VJ et al. Effect of intravenous haloperidol on the duration of delirium and coma in critically ill patients (Hope-ICU): a randomised, doubleblind, placebo-controlled trial. Lancet Resp Med 2013; 1(7):515–523.

Tahir TA et al. A randomised controlled trial of quetiapine versus placebo in the treatment of delirium. J Psychosom Res 2010; 69(5):485–490.

Naja M et al. Delirium in geriatric medicine is related to anticholinergic burden. Eur Geriatr Med 2013; 4(S208).

Van Den Boogaard M et al. Haloperidol prophylaxis in critically ill patients with a high risk for delirium. Crit Care 2013; 17:1–11.

Siddiqi H et al. Interventions for preventing delirium in hospitalised patients. Cochrane Database Syst Rev 2007; CD005563.

Epilepsy

Depression and psychosis in epilepsy

The prevalence of depression in people with epilepsy is reported to range from 9% to 22%,1,2 with higher rates in those with poor seizure control.3 Depressive symptoms may occur in up to 60% of people with intractable epilepsy.4 This association may be explained in part by serotonin; depletion of serotonin increases the risk of both depression and epilepsy.5 Suicide rates in epilepsy have been estimated to be 4–5 times that of the general population.1,2,6 The prevalence of psychotic illness in people with epilepsy is at least 4%.4 A diagnosis of temporal lobe epilepsy does not seem to confer additional risk.7

Peri-ictal depression or psychosis (that is, symptoms temporally related to seizure activity) should initially be treated by optimising anticonvulsant therapy.8 Interictal depression or psychosis (symptoms occurring independently of seizures) are likely to require treatment with antidepressants or antipsychotics.2,8

Use of antidepressants and antipsychotics in epilepsy

The prevalence of active epilepsy in adults under the age of 65 is 0.6% and the annual incidence 0.03%.9 It is notable that the incidence of unprovoked seizures in the placebo arms of randomised controlled trials of antidepressants and antipsychotics is approximately 15-fold higher, suggesting that both depression and psychosis are risk factors for seizures.10 Reports of seizures associated with drug treatment should be interpreted in the context of this background risk and single case reports treated with caution. Note also that almost all antidepressants and antipsychotics have been associated with hyponatraemia (see section on 'Hyponatraemia' in Chapter 4) and seizures may occur if this is severe.11 Some antipsychotics and antidepressants can reduce the seizure threshold1,2,12,13 and the risk is dose-related (see Table 7.33).

There are few systematic studies of antipsychotics or antidepressants in people with epilepsy. Data are mainly derived from animal studies, clinical trials, case reports and spontaneous reporting to regulatory bodies. Table 7.33 gives some general guidance. Treatment should be commenced at the lowest dose and this should be gradually increased until a therapeutic dose is achieved.2,13,14 As a very general rule, the more sedating a drug is, the more likely it is to induce seizures,13 although mirtazapine is a notable exception.15

Electroconvulsive therapy (ECT) has anticonvulsive properties and is worth considering in the treatment of depression in patients with unstable epilepsy.1,2 ECT does not appear to cause epilepsy.16

Depression and psychosis associated with anticonvulsant drugs

Anticonvulsant drugs have been associated with new-onset depression and psychosis.1 If anticonvulsants have recently been changed, this should always be considered as a potential cause of a new/worsening depressive or psychotic illness (for example a newly started or discontinued drug may have antidepressant effects, may worsen depression or may induce or inhibit hepatic CYP enzymes thus interfering with existing treatments for depression). Lowering of folate levels by some anticonvulsants may also influence the expression of depression.1 Folate levels should be checked and remedied where necessary.

Table 7.33 Psychotropics in epilepsy

 

Safety in epilepsy

Special considerations

Antidepressant

Moclobemide30

Good choice

Not known to be pro-convulsive

SSRIs31 (not citalopram)

Mirtazapine15,32

Good choice

SSRIs may be anticonvulsant at therapeutic doses10,33 and protect against hypoxic damage;34 no clear difference between drugs,9 except citalopram35

Citalopram35,36/venlafaxine37,38

Care required

Venlafaxine and citalopram pro-convulsive in overdose

Use with care

Duloxetine,11,17 vortioxetine, agomelatine, reboxetine

Care required

Very limited data and clinical experience

Amoxapine39 (not available in the UK)

Amitriptyline

Dosulepin (dothiepin)40

Clomipramine41

Bupropion10

Avoid

Most TCAs are epileptogenic,42 particularly at higher doses, as is bupropion (amfebutamone)

Ideally, should be avoided completely

Lithium2

Care required

Low pro-convulsive effect at therapeutic doses

Marked pro-convulsive activity in overdose

Antipsychotic

Trifluoperazine/haloperidol2,13,43

Good choice

Low pro-convulsive effect

Carbamazepine increases the metabolism of some antipsychotics and larger doses of an antipsychotic may be required

Sulpiride44/amisulpride45,46

Good choice

Low pro-convulsive effect, very few reports of suspected drug-related seizures47

No known interactions with anticonvulsants

Risperidone10

Olanzapine10

Quetiapine10

Care required

Doubts about safety in epilepsy

Olanzapine may affect EEG48 and myoclonic seizures have been reported49,50

Seizures rarely reported with quetiapine51 but also shown to have anticonvulsant activity in ECT44

Both olanzapine and quetiapine may increase the seizure threshold up to two-fold10 and are linked to higher rates of drug-related seizure47

Aripiprazole

Care required

Very limited data and clinical experience

Seizures have been reported rarely52,53

Clozapine8,12,54

Avoid if possible

Very epileptogenic

Approximately 5% who receive more than 600 mg/day develop seizures

Sodium valproate or lamotrigine are the anticonvulsant of choice as they have a lower incidence of leucopenia than carbamazepine

Lurasidone, asenapine

Avoid if possible

Not thought to affect seizure threshold but experience is limited

Chlorpromazine8

Loxapine (not available in the UK)

Avoid

Most epileptogenic of the older drugs

Ideally best avoided completely

Zotepine

(now withdrawn in the UK)

Avoid

Has established dose-related pro-convulsive effect

Best avoided completely

Depot antipsychotics

Avoid

None of the depot preparations currently available are thought to be epileptogenic, however:

  • the kinetics of depots are complex (seizures may be delayed)
  • if seizures do occur, the offending drug may not be easily withdrawn. Depots should be used with extreme care

This table contains information about the pro-convulsive effects of antidepressants and antipsychotics when used in therapeutic doses. See section on ‘Psychotropics in overdose’ in Chapter 8 for information about supra-therapeutic doses.

ECT, electroconvulsive therapy; EEG, electroencephalogram; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant.

Psychosis17

Summary of product characteristics and/or case reports associate the following anticonvulsants with the onset of psychotic symptoms: carbamazepine, ethosuximide, gabapentin, lamotrigine,18 levetiracetam,19,20 piracetam, pregabalin,21 primidone, tiagabine, topiramate,22 valproate, vigabatrin and zonisamide.23 Some of these reports may relate to the process of 'forced normalisation' in which a diminished frequency of seizures allows psychotic symptoms to emerge (a kind of 'reverse ECT').

Depression17,24,25

Summary of product characteristics and case reports associate the following anticonvulsants with the onset of depressive symptoms: acetazolamide, barbiturates, carbamazepine, ethosuximide, felbamate, gabapentin, levitiracetam*, phenytoin, piracetam, tiagabine*, topiramate*, vigabatrin* and zonisamide. Iatrogenic depression is more likely in patients with a history of depression. Risk may be increased by more rapid dosage titration; this has been shown for topiramate.26 There is limited evidence that these anti-epileptic drugs that are associated with a higher incidence of depression in clinical trials (marked*) may increase the risk of self-harm and suicidal behaviour.27 Lamotrigine has also been implicated.28 Note also that carbamazepine and lamotrigine have antidepressant properties and gabapentin is anxiolytic.

Interactions

Pharmacokinetic interactions between anticonvulsants and antidepressants/antipsychotics are common. These interactions are primarily mediated through cytochrome P450 enzymes.1,2 Fluoxetine and paroxetine are potent inhibitors of several hepatic CYP enzyme systems (CYP2D6, CYP3A4). Sertraline is a less potent inhibitor, but this effect is dose-related and higher doses of sertraline are commonly used. Citalopram is a weak inhibitor. Carbamazepine and phenytoin have a narrow therapeutic index and plasma levels can be increased by enzyme inhibitors. This is particularly important with phenytoin. Plasma levels should be monitored and dosage adjustment may be required. Carbamazepine is an enzyme inducer (mainly CYP3A4) and can lower plasma levels of some antipsychotic drugs.29 Many other medicines can cause problems in people with epilepsy by raising or reducing the seizure threshold or interacting with anticonvulsant drugs.

Epilepsy and driving

In the UK, people with epilepsy may not drive a car if they have had a seizure while awake in the previous year or, if seizures occur only during sleep, this has been an established nocturnal pattern for at least 3 years. The consequences of inducing seizure with antidepressants or antipsychotics can therefore be significant. For further information see www.dvla.gov.uk.

References

  1. Harden CL et al. Mood disorders in patients with epilepsy: epidemiology and management. CNS Drugs 2002; 16:291–302.
  2. Curran S et al. Selecting an antidepressant for use in a patient with epilepsy. Safety considerations. Drug Saf 1998; 18:125–133.
  3. Dias R et al. Depression in epilepsy is associated with lack of seizure control. Epilepsy Behav 2010; 19:445–447.
  4. Lambert MV et al. Depression in epilepsy: etiology, phenomenology, and treatment. Epilepsia 1999; 40 Suppl 10:S21–S47.
  5. Bagdy G et al. Serotonin and epilepsy. J Neurochem 2007; 100:857–873.
  6. Mula M et al. Suicidality in epilepsy and possible effects of antiepileptic drugs. Curr Neurol Neurosci Rep 2010; 10:327–332.
  7. Adams SJ et al. Neuropsychiatric morbidity in focal epilepsy. Br J Psychiatry 2008; 192:464–469.
  8. Blumer D et al. Treatment of the interictal psychoses. J Clin Psychiatry 2000; 61:110–122.
  9. Montgomery SA. Antidepressants and seizures: emphasis on newer agents and clinical implications. Int J Clin Pract 2005; 59:1435–1440.
  10. Alper K et al. Seizure incidence in psychopharmacological clinical trials: an analysis of Food and Drug Administration (FDA) summary basis of approval reports. Biol Psychiatry 2007; 62:345–354.
  11. Maramattom BV. Duloxetine-induced syndrome of inappropriate antidiuretic hormone secretion and seizures. Neurology 2006; 66:773–774.
  12. Pisani F et al. Effects of psychotropic drugs on seizure threshold. Drug Saf 2002; 25:91–110.
  13. Marks RC et al. Antipsychotic medications and seizures. Psychiatr Med 1991; 9:37–52.
  14. Rosenstein DL et al. Seizures associated with antidepressants: a review. J Clin Psychiatry 1993; 54:289–299.
  15. Berling I et al. Mirtazapine overdose is unlikely to cause major toxicity. Clin Toxicol (Phila) 2014; 52:20–24.
  16. Ray AK. Does electroconvulsive therapy cause epilepsy? J ECT 2013; 29:201–205.
  17. Datapharm Communications Ltd. Electronic Medicines Compendium. 2014. https://www.medicines.org.uk/emc/
  18. Brandt C et al. Development of psychosis in patients with epilepsy treated with lamotrigine: report of six cases and review of the literature. Epilepsy Behav 2007; 11:133–139.
  19. Youroukos S et al. Acute psychosis associated with levetiracetam. Epileptic Disord 2003; 5:117–119.
  20. Bhardwaj R et al. Levetiracetam-induced psychosis. Epilepsy Behav 2010; 17:614.
  21. Olaizola I et al. Pregabalin-associated acute psychosis and epileptiform EEG-changes. Seizure 2006; 15:208–210.
  22. Karslioaylu EH et al. Topiramate-induced psychotic exacerbation: case report and review of literature. Int J Psychiatry Clin Pract 2007; 11:285–290.
  23. Michael CT et al. Psychosis following initiation of zonisamide. Am J Psychiatry 2007; 164:682.
  24. Besag FM. Behavioural effects of the newer antiepileptic drugs: an update. Expert Opin Drug Saf 2004; 3:1–8.
  25. Barry JJ et al. Consensus statement: the evaluation and treatment of people with epilepsy and affective disorders. Epilepsy Behav 2008; 13 Suppl 1:S1–29.
  26. Mula M et al. The role of titration schedule of topiramate for the development of depression in patients with epilepsy. Epilepsia 2009; 50:1072–1076.
  27. Andersohn F et al. Use of antiepileptic drugs in epilepsy and the risk of self-harm or suicidal behavior. Neurology 2010; 75:335–340.
  28. Patorno E et al. Anticonvulsant medications and the risk of suicide, attempted suicide, or violent death. JAMA 2010; 303:1401–1409.
  29. Tiihonen J et al. Carbamazepine-induced changes in plasma levels of neuroleptics. Pharmacopsychiatry 1995; 28:26–28.
  30. Schiwy W et al. Therapeutic and side-effect profile of a selective and reversible MAO-A inhibitor, brofaromine. Results of dose-finding trials in depressed patients. J Neural Transm Suppl 1989; 28:33–44.
  31. Wedin GP et al. Relative toxicity of cyclic antidepressants. Ann Emerg Med 1986; 15:797–804.
  32. Zia Ul HM et al. Mirtazapine precipitated seizures: a case report. Prog Neuropsychopharmacol Biol Psychiatry 2008; 32:1076–1078.
  33. Hamid H et al. Should antidepressant drugs of the selective serotonin reuptake inhibitor family be tested as antiepileptic drugs? Epilepsy Behav 2013; 26:261–265.
  34. Bateman LM et al. Serotonin reuptake inhibitors are associated with reduced severity of ictal hypoxemia in medically refractory partial epilepsy. Epilepsia 2010; 51:2211–2214.
  35. Judge BS et al. Antidepressant overdose-induced seizures. Psychiatr Clin North Am 2013; 36:245–260.
  36. Reichert C et al. Seizures after single-agent overdose with pharmaceutical drugs: Analysis of cases reported to a poison center. Clin Toxicol (Phila) 2014; 52:629–634.
  37. Juckel G et al. Epileptiform EEG patterns induced by mirtazapine in both psychiatric patients and healthy volunteers. J Clin Psychopharmacol 2003; 23:421–422.
  38. Alldredge BK. Seizure risk associated with psychotropic drugs: clinical and pharmacokinetic considerations. Neurology 1999; 53:S68–S75.
  39. Barry JJ et al. Consensus statement: the evaluation and treatment of people with epilepsy and affective disorders. Epilepsy Behav 2008; 13 Suppl 1:S1–29.
  40. Buckley NA et al. Greater toxicity in overdose of dothiepin than of other tricyclic antidepressants. Lancet 1994; 343:159–162.
  41. Stimmel GL et al. Psychotrophic drug-induced reductions in seizure threshold: incidence and consequences. CNS Drugs 1996; 5:3750.
  42. Koster M et al. Seizures during antidepressant treatment in psychiatric inpatients—results from the transnational pharmacovigilance project "Arzneimittelsicherheit in der Psychiatrie" (AMSP) 1993-2008. Psychopharmacology (Berl) 2013; 230:191–201.
  43. Darby JK et al. Haloperidol dose and blood level variability: toxicity and interindividual and intraindividual variability in the nonresponder patient in the clinical practice setting. J Clin Psychopharmacol 1995; 15:334–340.
  44. Gazdag G et al. The impact of neuroleptic medication on seizure threshold and duration in electroconvulsive therapy. Ideggyogy Sz 2004; 57:385–390.
  45. Patat A et al. Effects of 50 mg amisulpride on EEG, psychomotor and cognitive functions in healthy sleep-deprived subjects. Fundam Clin Pharmacol 1999; 13:582–594.
  46. Tracqui A et al. Amisulpride poisoning: a report on two cases. Hum Exp Toxicol 1995; 14:294–298.
  47. Lertxundi U et al. Antipsychotics and seizures: higher risk with atypicals? Seizure 2013; 22:141–143.
  48. Amann BL et al. EEG abnormalities associated with antipsychotics: a comparison of quetiapine, olanzapine, haloperidol and healthy subjects. Hum Psychopharmacol 2003; 18:641–646.
  49. Camacho A et al. Olanzapine-induced myoclonic status. Clin Neuropharmacol 2005; 28:145–147.
  50. Rosen JB et al. Olanzapine-associated myoclonus. Epilepsy Res 2012; 98:247–250.
  51. Dogu O et al. Seizures associated with quetiapine treatment. Ann Pharmacother 2003; 37:1224–1227.
  52. Tsai JF. Aripiprazole-associated seizure. J Clin Psychiatry 2006; 67:995–996.
  53. Thabet FI et al. Aripiprazole-induced seizure in a 3-year-old child: a case report and literature review. Clin Neuropharmacol 2013; 36:29–30.
  54. Toth P et al. Clozapine and seizures: a review. Can J Psychiatry 1994; 39:236–238.

Further reading

Arana A et al. Suicide-related events in patients treated with antiepileptic drugs. N Engl J Med 2010; 363:542–551.

Farooq S et al. Interventions for psychotic symptoms concomitant with epilepsy. Cochrane Database Syst Rev 2008; CD006118.

Trimble M et al. Postictal psychosis. Epilepsy Behav 2010; 19:159–161.

Surgery

There are few worthwhile studies of the effects of non-anaesthetic drugs on surgery and the anaesthetic process.1,2 Practice is therefore largely based on theoretical considerations, case reports, clinical experience and personal opinion. Any guidance given in this area is therefore somewhat speculative.

The decision as to whether or not to continue a drug during surgery and the perioperative period should take into account a number of interacting factors. Some general considerations include:

For the most part, psychotropic drugs should be continued during the perioperative period, assuming agreement of the anaesthetist concerned. Table 7.34 provides some discussion of the merits or otherwise of continuing individual psychotropics during surgery. Note, however, that psychotropic and other drugs are frequently (accidentally and/or unthinkingly) withheld from preoperative patients simply because they are 'nil by mouth'.1 Patients may be labelled 'nil by mouth' for several reasons, including unconsciousness, to rest the gut postoperatively or as a result of the surgery itself. Patients may also develop an intolerance of oral medicines at any time during a stay in hospital, often because of nausea and vomiting. When it is decided to continue a psychotropic, this needs to be explicitly outlined to appropriate medical and nursing staff. For many patients undergoing surgery and recovery in a hospital there will be little or no opportunity to smoke. Abrupt cessation is likely to affect mental state and may also result in drug toxicity if psychotropics are continued (see section on 'Psychotropics and smoking' in Chapter 8).

Alternative routes and formulations may be sought. When changing the route or formulation, care should be taken to ensure the appropriate dose and frequency is prescribed as these may not be the same as for the oral route or previous formulation. Oral preparations may sometimes be administered via a nasogastric (NG), percutaneous endoscopic gastrostomy (PEG) or jejunostomy tube.

Table 7.34 Psychotropic drugs and surgery

Drug or drug group

Considerations

Safe in surgery?

Alternative formulations

Anticonvulsants4,15

  • CNS depressant activity may reduce anaesthetic requirements
  • Drug level monitoring may be required

Probably, usually continued for people with epilepsy

Carbamazepine liquid or suppositories are available: 100mg tablet=125mg suppository.

Maximum by rectum 1 g daily in four divided doses

Phenytoin is available IV or liquid: IV dose = oral dose

Sodium valproate is available IV or liquid: IV dose = oral dose

Before crushing tablets and mixing with water, confirm with either local guidelines or the drug company for stability information

Antidepressants

- MAOIs3,4,16-20

  • Dangerous, potentially fatal interaction with pethidine and dextromethorphan (serotonin syndrome or coma/respiratory depression may occur)
  • Action of inhaled anaesthetics and neuromuscular blockers is reduced
  • Sympathomimetic agents may result in hypertensive crisis
  • Phenylephrine only agent safe for hypotension
  • MAO inhibition lasts for up to 2 weeks: early withdrawal is required
  • Switching to moclobemide 2 weeks before surgery allows continued treatment up until day of surgery (do not give moclobemide on the day of surgery)

Probably not, but careful selection of anaesthetic agents may reduce risks if continuation is essential

None

Antidepressants — SSRIs4,5,7,19,21-24

  • Danger of serotonin syndrome if administered with pethidine, fentanyl, pentazocine or tramadol
  • Occasional seizures reported
  • Cessation may result in withdrawal syndrome
  • Various interactions with drugs used in surgery
  • Venlafaxine may provoke opioid-induced rigidity
  • Increases risk of perioperative bleeding

Probably, but avoid other serotonergic agents

Liquid escitalopram, fluoxetine and paroxetine are available

Oral disintegrating tablets of mirtazapine have been used perioperatively (for nausea)25

Antidepressants

— TCAs4,6,14,19,21,22,24

  • a, blockade may lead to hypotension and interfere with effects of epinephrine/norepinephrine
  • Danger of serotonin syndrome (clomipramine; amitriptyline) if administered with pethidine, pentazocine or tramadol
  • Many drugs prolong QT interval so arrhythmia more likely
  • Most drugs lower seizure threshold
  • May decrease core hypothermia
  • Sympathomimetic agents may give exaggerated response
  • Effects persist for several days after cessation so will need to be stopped some time before surgery
  • Clomipramine, amitriptyline may increase bleeding risk

Unclear, but anaesthetic agents need to be carefully chosen

Some authorities recommend slow discontinuation before surgery

Liquid amitriptyline is available. It is acidic and may interact with enteral feeds

Dosulepin (dothiepin) capsules can be opened and mixed with water before flushing well. This is preferred over crushing tablets

Most tricyclics have potent local anaesthetic effects - oral delivery in liquid form is likely to cause local anaesthesia

Antipsychotics4,13,19,26-29

  • Some antipsychotics widely used in anaesthetic practice
  • Increased risk of arrhythmia with most drugs
  • α1 blockade may lead to hypotension and interfere with effects of epinephrine/norepinephrine
  • Most drugs lower seizure threshold
  • May enhance interoperative core hypothermia
  • Clozapine may delay recovery from anaesthesia
  • Gaseous anaesthetics may affect dopamine metabolism
  • Preoperative olanzapine reduces risk of delirium30

Probably, usually continued to avoid relapse

Liquid preparations of some antipsychotics are available

Some 'specials' liquids can be made for nasogastric delivery

Before crushing tablets and mixing with water, confirm with either local guidelines or the drug company for stability information

Benzodiazepines4,15

  • Reduced requirements for induction and maintenance anaesthetics
  • Many have prolonged action (days or weeks), so early withdrawal is necessary
  • Withdrawal symptoms possible

Probably; usually continued

Liquid, IM, IV and rectal diazepam are available (do not use IM route)

Buccal liquid available for midazolam

Sublingual (use normal tablets), IM, IV and lorazepam are available

Lithium3,4,19,31

  • Prolongs the action of both depolarising and non-depolarising muscle relaxants
  • Surgery-related electrolyte disturbance and reduced renal function may precipitate lithium toxicity. Avoid dehydration and NSAIDs
  • Possible increased risk of arrhythmia

Probably safe in minor surgery but usually discontinued before major procedures and re-started once electrolytes normalise

Slow discontinuation is essential -anaesthetists may not appreciate this32

The bioavailability of lithium varies between brands. Care is needed with equivalent doses of salts: lithium carbonate 200mg = lithium citrate 509mg.

Liquid lithium citrate is available and is usually administered twice daily

Methadone 3,15

  • May reduce opiate requirements
  • Naloxone may induce withdrawal
  • Methadone prolongs QT interval
  • When using opiates, use only full agonists (avoid buprenorphine)

Probably, usually continued

IM dose = oral dose

Modafinil33,34

  • Limited data suggest no interference with anaesthesia
  • Improves recovery after anaesthesia

Probably, data limited

None

CNS, central nervous system; IM, intramuscular; IV, intravenous; MAOI, monoamine oxidase inhibitor; NSAID, non-steroidal anti-inflammatory drug; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant.

Risks associated with discontinuing psychotropics

Risks associated with continuing psychotropics

References

  1. Noble DW et al. Interrupting drug therapy in the perioperative period. Drug Saf 2002; 25:489–495.
  2. Noble DW et al. Risks of interrupting drug treatment before surgery. BMJ 2000; 321:719–720.
  3. Anon. Drugs in the peri-operative period: 1—Stopping or continuing drugs around surgery. Drug Ther Bull 1999; 37:62–64.
  4. Smith MS et al. Perioperative management of drug therapy, clinical considerations. Drugs 1996; 51:238–259.
  5. Chui PT et al. Medications to withhold or continue in the preoperative consultation. Curr Anaesth Crit Care 1998; 9:302–306.
  6. Kudoh A et al. Antidepressant treatment for chronic depressed patients should not be discontinued prior to anesthesia. Can J Anaesth 2002; 49:132–136.
  7. Spivey KM et al. Perioperative seizures and fluvoxamine. Br J Anaesth 1993; 71:321.
  8. De Baerdemaeker L et al. Anaesthesia for patients with mood disorders. Curr Opin Anaesthesiol 2005; 18:333–338.
  9. Faedda GL et al. Outcome after rapid vs gradual discontinuation of lithium treatment in bipolar disorders. Arch Gen Psychiatry 1993; 50:448–455.
  10. Yerevanian BI et al. Antidepressants and suicidal behaviour in unipolar depression. Acta Psychiatr Scand 2004; 110:452–458.
  11. Copeland LA et al. Postoperative complications in the seriously mentally ill: a systematic review of the literature. Ann Surg 2008; 248:31–38.
  12. Paton C et al. SSRIs and gastrointestinal bleeding. BMJ 2005; 331:529–530.
  13. Kudoh A et al. Chronic treatment with antipsychotics enhances intraoperative core hypothermia. Anesth Analg 2004; 98:111–115.
  14. Kudoh A et al. Chronic treatment with antidepressants decreases intraoperative core hypothermia. Anesth Analg 2003; 97:275–279.
  15. Morrow JI et al. Essential drugs in the perioperative period. Curr Pract Surg 1990; 90:106–109.
  16. Rahman MH et al. Medication in the peri-operative period. Pharm J 2004; 272:287–289.
  17. Blom-Peters L et al. Monoamine oxidase inhibitors and anesthesia: an updated literature review. Acta Anaesthesiol Belg 1993; 44:57–60.
  18. Hill S et al. MAOIs to RIMAs in anaesthesia: a literature review. Psychopharmacology 1992; 106 Suppl:S43–S45.
  19. Huyse FJ et al. Psychotropic drugs and the perioperative period: a proposal for a guideline in elective surgery. Psychosomatics 2006; 47:8–22.
  20. Bajwa SJ et al. Psychiatric diseases: need for an increased awareness among the anesthesiologists. J Anaesthesiol Clin Pharmacol 2011; 27:440–446.
  21. Chui PT et al. Medications to withhold or continue in the preoperative consultation. Curr Anaesth Crit Care 1998; 9:302–306.
  22. Takakura K et al. Refractory hypotension during combined general and epidural anaesthesia in a patient on tricyclic antidepressants. Anaesth Intensive Care 2008; 34:111–114.
  23. Roy S et al. Fentanyl-induced rigidity during emergence from general anesthesia potentiated by venlafexine. Can J Anaesth 2003; 50:32–35.
  24. Mahdanian AA et al. Serotonergic antidepressants and perioperative bleeding risk: a systematic review. Expert Opin Drug Saf 2014; 13:695–704.
  25. Chang FL et al. Efficacy of mirtazapine in preventing intrathecal morphine-induced nausea and vomiting after orthopaedic surgery. Anaesthesia 2010; 65:1206–1211.
  26. Doherty J et al. Implications for anaesthesia in a patient established on clozapine treatment. Int J Obstet Anesth 2006; 15:59–62.
  27. Geeraerts T et al. Delayed recovery after short-duration, general anesthesia in a patient chronically treated with clozapine. Anesth Analg 2006; 103:1618.
  28. Adachi YU et al. Isoflurane anesthesia inhibits clozapineand risperidone-induced dopamine release and anesthesia-induced changes in dopamine metabolism was modified by fluoxetine in the rat striatum: an in vivo microdialysis study. Neurochem Internat 2008; 52:384–391.
  29. Parlow JL et al. Single-dose haloperidol for the prophylaxis of postoperative nausea and vomiting after intrathecal morphine. Anesth Analg 2004; 98:1072–6.
  30. Larsen KA et al. Administration of olanzapine to prevent postoperative delirium in elderly joint-replacement patients: a randomized, controlled trial. Psychosomatics 2010; 51:409–418.
  31. Rahman MH et al. Medication in the peri-operative period. Pharm J 2004; 272:287–289.
  32. Attri JP et al. Psychiatric patient and anaesthesia. Indian J Anaesth 2012; 56:8–13.
  33. Larijani GE et al. Modafinil improves recovery after general anesthesia. Anesth Analg 2004; 98:976–81.
  34. Doyle A et al. Day case general anaesthesia in a patient with narcolepsy. Anaesthesia 2008; 63:880–882.

Velo-cardio-facial syndrome

Description

Velo-cardio-facial syndrome (VCFS), also known as DiGeorge or Shprintzen syndrome, and 22q11.2 syndrome, is a congenital disorder caused by a microdeletion of chromosome 22 at band q11.2. It has an estimated incidence of 1 in 5000 births.1 Although considerable phenotypic variability occurs, with over 180 clinical features described, it is characterized by:

These abnormalities have been collectively named CATCH 22(22 refers to chromosome 22),2 a somewhat inappropriate name for a syndrome that can often be treated very effectively.3 The typical facial features of patients with VCFS include a long face, prominent nose with bulbous tip and narrow orbital features.4 Cardiac defects usually involve major structural abnormalities (tetralogy of Fallot). Hypocalcaemia is caused by parathyroid dysfunction.

Mental retardation and learning disabilities (including impairment in the development of language, reading, spelling and numeracy skills) are common. A high rate of psychiatric morbidity has also been identified in VCFS patients, with schizophrenia and bipolar disorder being most commonly reported.4 This is probably related to partial deletion of the gene coding for catechol-o-methyltransferase (COMT) which effectively results in increased concentrations of dopamine and noradrenaline.3

There are currently limited data on the treatment of psychiatric disorders in VCFS, with most of the evidence coming from a small number of anecdotal reports. The majority of patients do not require medication to treat the behavioural symptoms associated with the syndrome.3 However, the range of psychiatric disorders seen in VCFS has been observed to respond to standard treatment protocols in both children and adults.1

Adults

Neuropsychiatric symptoms

A large study evaluating rates of psychiatric disorders in adult patients with VCFS reported that about 30% had a psychotic disorder; with 24% fulfilling DSM-IV criteria for schizophrenia and 12% had major depression without psychotic features.5 The most recent study found that 41% of VCFS patients over the age of 25 years had a diagnosable psychotic disorder.6 Individuals with schizophrenia associated with VCFS often have fewer negative symptoms and a relatively later age of onset (mean = 26 years) compared with control patients who did not have VCFS.7 Psychotic symptoms are transient in some.8 Results from genetic studies have estimated the prevalence of schizophrenia in VCFS patients as 22%, a much higher figure than the 0.5% prevalence of schizophrenia in the general population.9,10 In fact, VCFS has been found to be the highest known risk factor for the development of schizophrenia.11

Management of psychiatric symptoms

It has been suggested that neuropsychiatric symptoms of VCFS only partially respond to typical antipsychotics.4 While the early introduction of clozapine is favoured,4 experience suggests newer atypical antipsychotics are also effective in the treatment of VCFS-related schizophrenia.1 Quetiapine12 and aripiprazole13 have been successfully used. Caution is required with most antipsychotics in VCFS because of the potential for cardiac toxicity (see section on 'QT changes' in Chapter 2).

Drugs which act directly against catecholamine excess may also be effective. There are case studies of successful use of methyldopa14 and the catecholamine depleter, metyrosine.15

The use of atypical antipsychotics in VCFS patients with general developmental disabilities has been investigated and studies have found them to be broadly effective against challenging behaviours such as self-injury and aggression.16,17 In addition, they have been found to be better tolerated than typical antipsychotics in this population.18 Most evidence supports the use of risperidone.16 The frequency of use of clozapine in learning disabilities still lags behind its use in the general population, despite the higher prevalence of psychiatric disorders in these patients. Clozapine has been associated with marked improvements in psychosis and aggressive behaviours in learning disabled patients. However, although it showed no worsening of seizure control or provocation of seizures in one study, a reduction in seizure threshold is a well-established and potentially serious adverse effect of clozapine. Unlike the other antipsychotics that do not precipitate seizures in patients with intellectual disability who have no history of seizures, this is not the case with clozapine. Therefore special caution should be observed in this population.19

Depression and anxiety symptoms are also common in VCFS.1328,1338 Studies of treatment are few and far between but S-adenosyl-L-methionine has been shown to be effective.21 SSRIs are commonly used.20

Children

Neuropsychiatric symptoms

Children with VCFS have been reported to have high rates of bipolar II disorder (47%), attention deficit hyperactivity disorder (ADHD) (27%) and attention deficit disorder without hyperactivity (ADD) (13%). The most recent (and largest) study suggest ADHD, with a prevalence of 37%, is the most common psychiatric disorder in VCFS children.6 Data suggests that the inattentive subtype is the most common subtype of ADHD in children with VCFS. These children are less likely to be hyperactive or impulsive than children with idiopathic ADHD.22 Some studies have also shown high rates of autism spectrum disorder, anxiety disorders and emotional instability in children with VCFS.1

Management of psychiatric symptoms

Concern has been raised over the theoretical risk of inducing psychosis in children with VCFS and co-morbid ADHD by using the psychostimulant methylphenidate. This is of particular concern in older adolescents or young adults. However, standard treatment for ADHD is recommended following experience suggesting psychosis is not a significant clinical risk.1 Low doses of methylphenidate (0.3 mg/kg) have been shown to be effective in controlling VCFS-related ADHD and were generally well tolerated.23 Note that there is also evidence that ADHD is under treated in VCFS.20

References

  1. Murphy KC. Annotation: velo-cardio-facial syndrome. J Child Psychol Psychiatry 2005; 46:563–571.
  2. Buchanan LM et al. Velocardiofacial syndrome or DiGeorge's anomaly. Lancet 2001; 358:420.
  3. Shprintzen RJ. Velo-cardio-facial syndrome: 30 years of study. Dev Disabil Res Rev 2008; 14:3–10.
  4. Gothelf D et al. Clinical characteristics of schizophrenia associated with velo-cardio-facial syndrome. Schizophr Res 1999; 35:105–112.
  5. Murphy KC et al. High rates of schizophrenia in adults with velo-cardio-facial syndrome. Arch Gen Psychiatry 1999; 56:940–945.
  6. Schneider M et al. Psychiatric disorders from childhood to adulthood in 22q11.2 deletion syndrome: results from the International Consortium on Brain and Behavior in 22q11.2 Deletion Syndrome. Am J Psychiatry 2014.
  7. Murphy KC et al. Velo-cardio-facial syndrome: a model for understanding the genetics and pathogenesis of schizophrenia. Br J Psychiatry 2001; 179:397–402.
  8. Schneider M et al. Clinical and cognitive risk factors for psychotic symptoms in 22q11.2 deletion syndrome: a transversal and longitudinal approach. Eur Child Adolesc Psychiatry 2014; 23:425–436.
  9. Karayiorgou M et al. Schizophrenia susceptibility associated with interstitial deletions of chromosome 22q11. Proc Natl Acad Sci U S A 1995; 92:7612–7616.
  10. Monks S et al. Further evidence for high rates of schizophrenia in 22q11.2 deletion syndrome. Schizophr Res 2014; 153:231–236.
  11. Eliez S et al. Parental origin of the deletion 22q11.2 and brain development in velocardiofacial syndrome: a preliminary study. Arch Gen Psychiatry 2001; 58:64–68.
  12. Muller UJ et al. Successful treatment of long-lasting psychosis in a case of 22q11.2 deletion syndrome. Pharmacopsychiatry 2008; 41:158–159.
  13. Lin CE et al. Treatment of schizophreniform disorder by aripiprazole in a female adolescent with 22q11.2 deletion syndrome. Prog Neuropsychopharmacol Biol Psychiatry 2010; 34:1141–1143.
  14. O'Hanlon JF et al. Replacement of antipsychotic and antiepileptic medication by L-alpha-methyldopa in a woman with velocardiofacial syndrome. Int Clin Psychopharmacol 2003; 18:117–119.
  15. Carandang CG et al. Metyrosine in psychosis associated with 22q11.2 deletion syndrome: case report. J Child Adolesc Psychopharmacol 2007; 17:115–120.
  16. Aman MG et al. Atypical antipsychotics in persons with developmental disabilities. Ment Retard Dev Disabil Res Rev 1999; 5:253–263.
  17. Williams H et al. Use of the atypical antipsychotics olanzapine and risperidone in adults with intellectual disability. J Intellect Disabil Res 2000; 44 ( Pt 2):164–169.
  18. Connor DF et al. A brief review of atypical antipsychotics in individuals with developmental disability. Ment Health Aspects Dev Disabil 1998; 1:93–101.
  19. Gladston S et al. Clozapine treatment of psychosis associated with velo-cardio-facial syndrome: benefits and risks. J Intellect Disabil Res 2005; 49:567–570.
  20. Tang SX et al. Psychiatric disorders in 22q11.2 deletion syndrome are prevalent but undertreated. Psychol Med 2014; 44:1267–1277.
  21. Green T et al. The feasibility and safety of S-adenosyl-L-methionine (SAMe) for the treatment of neuropsychiatric symptoms in 22q11.2 deletion syndrome: a double-blind placebo-controlled trial. J Neural Transm 2012; 119:1417–1423.
  22. Antshel KM et al. Comparing ADHD in velocardiofacial syndrome to idiopathic ADHD: a preliminary study. J Atten Disord 2007; 11:64–73.
  23. Gothelf D et al. Methylphenidate treatment for attention-deficit/hyperactivity disorder in children and adolescents with velocardiofacial syndrome: an open-label study. J Clin Psychiatry 2003; 64:1163–1169.

Cytochrome (CYP) function

Information on the effect of drugs on cytochrome function helps predict or confirm suspected interactions which may not have been uncovered in regulatory trials or in clinical use (sometimes called prediction from 'first principles'). Using 'first principles' essentially means understanding and interpreting pharmacokinetic information and anticipating the net effect of combining two or more drugs in vivo.

Apart from the effect of co-administered drugs on CYP function, genetic polymorphism associated with some enzyme pathways (e.g. 2D6, 2C9, 2C19 enzymes) may also account for inter-individual variations in metabolism of certain drugs.

The effects of polymorphism and pharmacokinetic interaction are difficult to predict because some drugs are metabolised by more than one enzyme and an alternative pathway(s) may compensate if other enzyme pathways are inhibited.

Also note that the function of CYPs is not the only consideration. P-glycoprotein (P-gp) is a drug transporter protein found in the gut wall. P-gp can eject (active process) drugs that diffuse (passive process) across the gut wall. P-gp is also found in testes and in the blood–brain barrier. Drugs that inhibit P-gp are anticipated to increase the uptake of other drugs (that are substrates for P-gp) and drugs that induce P-gp are anticipated to reduce the uptake of drugs (that are substrates for P-gp). Many drugs that are substrates for CYP3A4 have also been found to be substrates for P-gp.

UDP-glucuronosyl transferase (UGT) has been identified as an enzyme that is responsible for phase II (conjugation) reactions. The increasing importance of drug–drug interactions associated with UGT is emerging.

Table 7.35 summarises the interactions of psychotropic drugs with cytochromes. It does not include details of the effects of non-psychotropics on CYP function.

Table 7.35 Interactions of psychotropic drugs with cytochromes

Substrates

Inhibitors

Inducers

CPY1A2

Agomelatine

Amitriptyline*

Asenapine

Bupropion*

Chlorpromazine

Clomipramine*

Clozapine

Duloxetine

Fluphenazine

Fluvoxamine

Imipramine*

Melatonin

Mirtazapine*

Olanzapine

Perphenazine

?Pimozide*

Zolpidem*

Fluvoxamine

Moclobemide

Perphenazine

'Barbiturates'

Carbamazepine

Modafinil*

Phenobarbital

Phenytoin

Smoking

CYP2A6

Bupropion*

Nicotine

Tranylcypromine

Phenobarbital

CPY2B6

Bupropion

Methadone*

Nicotine

Sertraline*

Fluoxetine*

Fluvoxamine

Memantine

Paroxetine*

Sertraline*

Carbamazepine*

Modafinil*

Phenobarbital

Phenytoin

CYP2B7

Buprenorphine*

Not known

Not known

CPY2C8

Zopiclone*

Not known

Not known

CPY2C9

Agomelatine*

Amitriptyline

Bupropion*

Fluoxetine*

Lamotrigine

Phenobarbital

Phenytoin

Sertraline*

Valproic acid

Fluoxetine*

Fluvoxamine

Modafinil

Valproic acid

Carbamazepine

SJW

CPY2C19

Agomelatine*

Amitriptyline

Carbamazepine*

Citalopram

Clomipramine*

Diazepam

Escitalopram

Fluoxetine*

Imipramine*

?Melatonin

?Methadone

Moclobemide

Phenytoin

Sertraline*

Trimipramine*

Escitalopram*

Fluvoxamine

Moclobemide

Modafinil

Topiramate

Carbamazepine

SJW

CPY2D6

Amitriptyline

'Amfetamines'

Atomoxetine

Aripiprazole

Chlorpromazine

Citalopram

Clomipramine

Clozapine*

Donepezil*

Duloxetine

Escitalopram

Fluoxetine

Fluvoxamine

Fluphenazine

Galantamine

Haloperidol

Iloperidone

Imipramine

Methadone*

Mianserin

Mirtazapine*

Moclobemide

Nortriptyline

Olanzapine

Paroxetine

Perphenazine

Pimozide*

Quetiapine*

Risperidone

Sertraline

Trazodone*

Trimipramine

Venlafaxine

Vortioxetine

Zuclopenthixol

Amitriptyline

Asenapine

Bupropion

Chlorpromazine

Citalopram*

Clomipramine

Clozapine

Duloxetine

Escitalopram

Fluoxetine

Fluphenazine

Fluvoxamine*

Haloperidol

Levomepromazine

Methadone*

Moclobemide

Paroxetine

Perphenazine

Reboxetine*

Risperidone

Sertraline

Venlafaxine*

Not known

CYP2E1

Bupropion

Ethanol

Disulfiram

Paracetamol

Ethanol

CYP3A4

Alfentanyl

Alprazolam

Amitriptyline

Aripiprazole

Buprenorphine

Bupropion*

Buspirone

Carbamazepine

Chlorpromazine

Citalopram

Clomipramine*

Clonazepam

Clozapine*

Diazepam

Donepezil

Dosulepin

Escitalopram*

Fentanyl

Fluoxetine*

?Flurazepam

Galantamine

Haloperidol

Imipramine

Lurasidone

Methadone

Midazolam

Mirtazapine

Modafinil

Nitrazepam

Perphenazine

Pimozide

Quetiapine

Reboxetine

Risperidone*

Sertindole

Sertraline*

Trazodone

Trimipramine*

Venlafaxine

Zaleplon

Ziprasidone

Zolpidem

Zopiclone

Fluoxetine

Fluvoxamine

Paroxetine

Perphenazine

Reboxetine*

Asenapine?

Carbamazepine

Modafinil

Phenobarbital

'and probably other barbiturates'

Phenytoin

SJW

Topiramate

Drugs highlighted in bold indicate:

  • predominant metabolic enzyme pathway or
  • predominant enzyme activity (inhibition or induction).

Drugs annotated with * indicate:

  • known to be a minor metabolic enzyme pathway or activity (i.e. not demonstrated to be clinically significant).

Drugs in normal font (not bold and without *) indicate:

  • metabolic enzyme pathway(s) or activity where significance is unclear or unknown.

Information on CYP function derived from individual SPCs and US

Labelling (accessed June 2014).

SJW, St John’s wort.

Psychiatric side-effects of non-psychotropic drugs

It is increasingly recognised that non-psychotropic medications can induce a wide range of psychiatric symptoms, with one report estimating that up to two thirds of all available medications may be implicated.1 Additionally, individuals with psychiatric problems in general have increased rates of physical illness,2 especially those with schizophrenia3,4 which will necessitate additional medication treatment. These patients are thus more likely to be exposed to polypharmacy, both of psychotropics5 as well as non-psychotropics.6,7

Table 7.36 summarises the main behavioural, cognitive and psychiatric, side-effects of commonly prescribed non-psychotropics, with information compiled from various sources.8–15 The information presented below is inevitably incomplete, and is intended as a general guide only. For details of agents not listed below, additional sources of information should be consulted (especially references 14 and 15). In the majority of cases the evidence for these various psychiatric and behavioural side-effects is limited, with details obtained mainly from case reports and manufacturers' information sheets. Although cessation of the implicated agent in question may be indicated, such decisions should always be made with caution as many of these presentations are idiosyncratic and many may be unrelated to the suspected causative agent. It should be further noted that medical co-morbidity, psychiatric and non-psychiatric polypharmacy, and the effects of non-prescribed agents may all influence the clinical presentation and outcome. Note that neuropsychiatric effects of anti-HIV medications and psychiatric sideeffects of psychotropics are summarised elsewhere in the Guidelines.

Table 7.36 Summary of psychiatric side-effects of commonly prescribed non-psychotropic drugs

Event

Implicated agent

Agitation

Amantadine, aminophylline, apomorphine, aspirin, atropine, baclofen, benazapril, benzhexol, captopril, cimetidine, clonidine, corticosteroids, co-trimoxazole, cyclizine, cyproheptadine, dantrolene, doxazosin, enalapril, ethionamide, ethotoin, famotidine, fentanyl, flumazenil, fosinopril, fosphenytoin, gabapentin, ganciclovir, glucocorticoids, hydralazine, ibuprofen, indomethacin, isoniazid, isosorbide dinitrate, isosorbide mononitrate, L-dopa, levothyroxine, mefenamic acid, mefloquine, methoxamine, mephenytoin, methyltestosterone, misoprostol, morphine, naltrexone, naproxen, neostigmine, nitroglycerin, octreotide, omeprazole, orphenadrine, pentazocine, phenobarbital, piperazine, piroxicam, prednisone, procyclidine, promethazine, pseudoephedrine, ranitidine, salbutamol, selegiline, sibutramine, streptokinase, theophylline, tizanidine, trimeprazine, vigabatrin, yohimbine

Abnormal dreams

Atenolol, baclofen, chloroquine, dantrolene, L-dopa, mefloquine, metoprolol, oxprenolol, propranolol, sotalol, stanozolol, tizanidine

Aggression

Amantadine, apomorphine, bromocriptine, carbamazepine, corticosteroids, dapsone, diazepam, flunitrazepam, lamotrigine, lisuride, odafinil, naloxone, nandrolone, omeprazole, oxandrolone, pergolide, selegeline, stanozolol, testosterone, vigabatrin

Anxiety

Acetazolamide, amantadine, apomorphine, aspirin, atropine, baclofen, bendroflumethiazide, benzhexol, benzthiazide, benzatropine, biperiden, bromocriptine, cabergoline, chloroquine, chlorthalidone, cimetidine, clonidine, corticosteroids, co-trimoxazole, ciclosporin, dantrolene, dichlorphenamide, doxazosin, famotidine, fentanyl, flumazenil, ganciclovir, glucocorticoids, hydralazine, ibuprofen, indomethacin, isoniazid, isosorbide dinitrate, isosorbide mononitrate, L-dopa, levothyroxine, lisuride, mefenamic acid, mefloquine, methoxamine, methyltestosterone, misoprostol, morphine, naltrexone, nandrolone, naproxen, neostigmine, nitroglycerin, octreotide, omeprazole, orphenadrine, penicillins, pentazocine, pergolide, phentolamine, piperazine, piroxicam, pramipexole, prazosin, prednisone, procyclidine, pseudoephedrine, quinidine, quinine, ranitidine, ropinirole, salbutamol, sibutramine, stanozolol, streptokinase, tacrolimus, terazosin, testosterone, theophylline, tizanidine, yohimbine

Asthenia/ lethargy

Aciclovir, corticosteroids, digitoxin, digoxin, lidocaine, magnesium, mexilitine, moricizine, procainamide, vigabatrin

Change of behaviour

Anabolic steroids, barbiturates, benzodiazepines, clonazepam, L-dopa

Cognitive impairment

Acebutolol, apomorphine, atenolol, bromocriptine, clonidine, ciclosporin, ethotoin, foscarnet sodium, fosphenytoin, interferons, isoniazid, L-dopa, lidocaine, lisuride, mephenytoin, mexilitine, moricizine, nadolol, pergolide, phenobarbital, pindolol, procainamide, propranolol, quinidine, selegiline, topiramate, vigabatrin

Decreased concentration

Amantadine, tetracyclines, topiramate

Delirium

Acetazolamide, acebutolol, aciclovir, adrenocorticotrophin, amantadine, a-methyldopa, a-methyl-p-tyrosine, amiloride, aminophylline, amiodarone, amphotericin B, anaesthetics, apomorphine, aspirin, atenolol, atropine, baclofen, barbiturates, benazapril, benzhexol, benzatropine, biperiden, bromocriptine, cabergoline, captopril, carbamazepine, cephalosporins, chloramphenicol, chloroquine, ciclosporin A, cimetidine, ciprofloxacin, clarithromycin, clonidine, corticosteroids, cycloserine, dantrolene, dichlorphenamide, digitoxin, digoxin, disopyramide, doxapram, doxazosin, enalapril, entacapone, ethosuximide, ethotoin, famotidine, fenoprofen, fosinopril, fosphenytoin, ganciclovir,

 

hydralazine, hydroxychloroquine, hypoglycaemics, ibuprofen, indomethacin, interferons, isoniazid, isosorbide dinitrate, isosorbide mononitrate, L-dopa, lidocaine, lisuride, magnesium, mefenamic acid, mefloquine, mentholatum, mephenytoin, methotrexate, methylprednisolone, metoprolol, methixene, methyldopa, mexilitine, misoprostol, moricizine, nabilone, nadolol, naproxen, nitroglycerin, oxprenolol, papaveretum, penicillin, pergolide, phenobarbital, phentolamine, phenytoin, pindolol, piperazine, piroxicam, pramipexole, prazosin, primidone, procainamide, propranolol, quinidine, quinine, ranitidine, rifampicin, ropinirole, scopolamine, selegiline, sotalol, spironolactone, streptomycin, sulfasalazine, sulindac, sulphadiazine, sulphonamides, tacrolimus, terazosin, theophylline, tramadol, triamcinolone

Depression

Acetazolamide, acebutolol, alimenazine, allopurinol, amantadine, a-methyldopa, a-methyl-p-tyrosine, amiodarone, aminophylline, anaesthetics, atenolol, baclofen, benazapril, calcium-channel blockers, captopril, cephradine, chloramphenicol, chloroquine, cimetidine, cinnarizine, clofazimine, clomifene, clonidine, clotrimazole, codeine, corticosteroids, co-trimoxazole, cycloserine, ciclosporin, danazol, dapsone, dexamethasone, dichlorphenamide, digitoxin, digoxin, diltiazem, diphenoxylate, enalapril, ephedrine, ethionamide, ethotoin, etretinate, felodipine, fentanyl, finasteride, lunisolide, flurbiprofen, fosinopril, fosphenytoin, ganciclovir, griseofulvin, guanethidine, hydralazine, hydroxyzine, imidapril, indomethacin, inositol, interferons, ketoconazole, L-dopa, lignocaine, mefloquine, mephenytoin, mesna, metoclopramide, methyldopa, metoprolol, metronidazole, mexilitine, mitramycin, nabilone, nadolol, nandrolone, nicardipine, nifedipine, oestrogens, omega 3 fatty acids, ondansetron, opioids, oral contraceptives, organophosphates, oxprenolol, pentazocine, phenobarbital, phenylpropanolamine, picamycin, pindolol, piperazine, pravastatin, prednisolone, prednisone, primaquine, procainamide, progestogens, propranolol, quinapril, quinidine, ramipril, ranitidine, reserpine, ribavirin, isotretinoin, simvastatin, sotalol, stanozolol, streptokinase, sulphazalazine, sulindac, sulphonamides, tacrolimus, tamoxifen, testosterone, theophylline, tiagabine, timolol, topiramate, tramadol, triamcinolone, trimeprazine, trimethoprim, vigabatrin, xylometazoline

Disorientation/ confusion

Amiloride, baclofen, dantrolene, enalapril, imidapril, quinapril, quinine, ramipril, spironolactone, tizanidine

Fatigue/ lethargy

Acebutolol, a-methyldopa, a-methyl-p-tyrosine, amlodipine, amantadine, amiloride, anticholinergics, aspirin, atenolol, benazapril, bepridil, captopril, chlorphenamine, cimetidine, clemastine, cyproheptadine, diphenhydramine, doxazosin, enalapril, famotidine, felodipine, flunarizine, foscarnet sodium, fosinopril, gabapentin, hydroxyzine, ibuprofen, indomethacin, L-dopa, lignocaine, mefenamic acid, mexilitine, nadolol, naproxen, nicardipine, phentolamine, pindolol, piroxicam, prazosin, procainamide, propranolol, ranitidine, spironolactone, terazosin, verapamil

Hallucinations

Acebutolol, amantadine, amoxicillin, anticholinergics, apomorphine, aspirin, atenolol, baclofen, benazapril, beta-blockers, bromocriptine, buprenorphine, cabergoline, captopril, celecoxib, cephalosporins, chloroquine, cimetidine, ciprofloxacin, clonidine, corticosteroids, dantrolene, dextromethorphan, digoxin, diltiazem, disopyramide, enalapril, entacapone, erythropoetin, famotidine, fenbufen, flucytosine, fosinopril, gentamicin, hydroxyurea, ibuprofen, indomethacin, itraconazole, L-dopa, lisuride, mefenamic acid, mefloquine, nadolol, naproxen, penicillins, pentazocine, pergolide, phenylephrine, phenylpropanolamine, pindolol, piroxicam, procainamide, promethazine, propranolol, pseudoephedrine, ranitidine, ropinirole, pramipexole, salbutamol, salicylates, selegeline, streptokinase, sulphasalazine, timolol, tizanidine, tolterodine, tramadol

Insomnia

Baclofen, benzhexol, dantrolene, doxazosin, orphenadrine, phentolamine, prazosin, procyclidine, terazosin, tizanidine

Irritability

Amantadine, cycloserine, ethionamide, ethosuximide, levetiracetam, methotrexate, penicillins, vigabatrin

Mood changes/lability

Amiodarone, amlodipine, aspirin, baclofen, bepridil, bromocriptine, dantrolene, diltiazem, disopyramide, ethosuximide, felopidine, flunarizine, foscarnet sodium, ganciclovir, ibuprofen, indomethacin, isoniazid, ketoconazole, L-dopa, lidocaine, mefenamic acid, mexilitine, moricizine, naproxen, nicardipine, opioids, piroxicam, primidone, procainamide, procyclidine, quinolones, tetracyclines, topiramate, verapamil

Mania, euphoria, hypomania

ACTH, aminophylline, amlodipine, amantadine, baclofen, beclomethasone, benazapril, bepridil, bromocriptine, buprenorphine, captopril, chloroquine, ciclosporin, cimetidine, clarithromycin, clonidine, corticosteroids, cortisone, cyclizine, cyproheptadine, dantrolene, dapsone, dexamethasone, dextromethorphan, digoxin, dihydroepiandrosterone, diltiazem, enalapril, felodipine, flunarizine, fosinopril, frovatriptan, hydralazine, hydrocortisone, indomethacin, interferon alpha, isoniazid, isosorbide dinitrate, isosorbide mononitrate, L-dopa, mepacrine, metoclopramide, nandrolone, nefopam, nicardipine, nitrofurans, nitroglycerin, omega 3 fatty acids, pentazocine, procainamide, procarbazine, procyclidine, propranolol, ranitidine, salbutamol, sildenafil, stanozolol, steroids, testosterone, tizanidine, tramadol, triptorelin, triamcinolone, tri-iodothyronine, verapamil

Misuse potential

Anabolic steroids, benzhexol, benzatropine, corticosteroids, orphenadrine, oxymetazoline, procyclidine

Nervousness

Amantadine, atropine, baclofen, co-trimoxazole, doxazosin, enalapril, fentanyl, flumazenil, ganciclovir, glucocorticoids, hydralazine, imidapril, isoniazid, L-dopa, levothyroxine, mefloquine, methoxamine, methyltestosterone, misoprostol, morphine, naltrexone, neostigmine, octreotide, omeprazole, pentazocine, piperazine, prednisone, pseudoephedrine, quinapril, ramipril, salbutamol, sibutramine, streptokinase, theophylline

Obsessive-compulsive symptoms

Cabergoline, colchicine, topiramate

Panic attacks/disorder

Calcium lactate, carvedilol, chloroquine, co-trimoxazole, mefloquine, oxymetazoline, phenylephrine, sibutramine, steroids, sumatriptan, yohimbine

Personality change

Corticosteroids, methotrexate

Psychomotor restlessness

Apomorphine, bromocriptine, cabergoline, lisuride, pergolide, ropinirole, pramipexole

Psychosis

Acebutolol, aciclovir, adrenocorticotrophin, amantadine, a-methyldopa, a-methyl-p-tyrosine, amiloride, amiodarone, amlodipine, amphotericin B, amyl nitrate, apomorphine, aspirin, atenolol, atropine, baclofen, benzhexol, benzatropine, bepridil, beta-blockers, biperiden, bromocriptine, cabergoline, calcium lactate, carbaryl, carbimazole, cefuroxime, cephalexin, cephalothin, chloroquine, chlorphenamine, cimetidine, ciprofloxacin, clarithromycin, clomifene, clonidine, colistin, corticosteroids, cortisone, cycloserine, cyclizine, ciclosporin, cyproheptadine, dapsone, desmopressin, dextromethorphan, dicyclomine, digitoxin, digoxin, diphenhydramine, diltiazem, disopyramide, disulfiram, doxazosin, enalapril, erythromycin, ethosuximide, ethionamide, ethotoin, felodipine, flunarizine, foscarnet sodium, fosphenytoin, ganciclovir, griseofulvin, hydralazine, hyoscine, ibuprofen, indomethacin, interferon alpha,

 

isoniazid, isosorbide dinitrate, isosorbide mononitrate, isotretoin, ketoconazole, L-dopa, levetiracetam, levofloxacin, lidocaine, lisuride, melatonin, mefenamic acid, mefloquine, mephenytoin, methixene, methyldopa, methylprednisolone, methyltestosterone, metronidazole, mexilitine, moricizine, nabilone, nadolol, nalidixic acid, nandrolone, naproxen, nicardipine, nifedipine, nitrofurans, nitroglycerin, opioids, orphenadrine, oxymetazoline, penicillin G, pentazocine, pergolide, phenobarbital, phenylephrine, phenylpropanolamine, pindolol, piroxicam, prednisone, procainamide, procaine, procyclidine, promethazine, propranolol, quinolones, ropinirole, pramipexole, primaquine, primidone, procaine, pyridostigmine, quinine, quinidine, reserpine, salbutamol, scopolamine, selegiline, sibutramine, stanozolol, sulindac, sulphonamides, tacrolimus, testosterone, tiagabine, tobramycin, tocainide, topiramate, tramadol, trimeprazine, trimethoprim, verapamil, vigabatrin

Sedation

Acetazolamide, acebutolol, amiodarone, apomorphine, atenolol, bendroflumethiazide, benzthiazide, benzatropine, biperiden, bromocriptine, cabergoline, chlorphenamine, chlorthalidone, clemastine, cyclizine, cyproheptadine, dichlorphenamide, digitoxin, digoxin, diphenhydramine, disopyramide, doxazosin, ethionamide, ethotoin, flucytosine, fosphenytoin, gabapentin, guanethidine, hydroxyzine, levetiracetam, lisuride, mephenytoin, nadolol, penicillins, pergolide, phenobarbital, phentolamine, pindolol, pramipexole, prazosin, primidone, promethazine, propranolol, reserpine, rifampicin, ropinirole, terazosin, tiagabine, trimeprazine

Sleep disturbance

Acebutolol, amantadine, a-methyldopa, a-methyl-p-tyrosine, aminophylline, amiodarone, apomorphine, aspirin, atenolol, baclofen, bendroflumethiazide, benzthiazide, bromocriptine, bromopheniramine, cabergoline, carvedilol, cephalosporins, chlorthalidone, cinoxacin, ciprofloxacin, clomifene, clonidine, corticosteroids, dantrolene, dexamethasone, diclofenac, diflunisal, digoxin, diltiazem, entacapone, ethosuximide, ethotoin, fenoprofen, fosphenytoin, ganciclovir, griseofulvin, ibuprofen, indomethacin, interferons, isradipine, L-dopa, lisuride, lovastatin, mefenamic acid, mephenytoin, methyldopa, nadolol, naproxen, nitrofurans, pergolide, phenobarbital, pindolol, piroxicam, pramipexole, propranolol, propantheline, pseudoephedrine, quinolones, ranitidine, ropinirole, selegiline, sibutramine, simvastatin, sulfasalazine, sulindac, tetracyclines, theophylline, tolzamide, triamcinolone

Suicidal ideation

Chloroquine, clofazimine, interferons, mefloquine, reserpine

Visual hallucinations

Amantadine, benzhexol, benzatropine, biperiden, L-dopa, orphenadrine, procyclidine

References

  1. Smith DA. Psychiatric side effects of non-psychiatric drugs. S D J Med 1991; 44:291–292.
  2. Goldman LS. Comorbid medical illness in psychiatric patients. Curr Psychiatry Rep 2000; 2:256–263.
  3. Jones DR et al. Prevalence, severity, and co-occurrence of chronic physical health problems of persons with serious mental illness. Psychiatr Serv 2004; 55:1250–1257.
  4. Leucht S et al. Physical illness and schizophrenia: a review of the literature. Acta Psychiatr Scand 2007; 116:317–333.
  5. Taylor D. Antipsychotic polypharmacy - confusion reigns. Psychiatrist 2010; 34:41–43.
  6. Davies SJ et al. PRN prescribing in psychiatric inpatients: potential for pharmacokinetic drug interactions. J Psychopharmacol 2007; 21:153–160.
  7. Bingefors K et al. Antidepressant-treated patients in ambulatory care long-term use of non-psychotropic and psychotropic drugs. Br J Psychiatry 1996; 168:292–298.
  8. Datapharm Communications Ltd. Electronic Medicines Compendium. 2014. https://www.medicines.org.uk/emc/
  9. Joint Formulary Committee. BNF 67 March-September 2014 (online). London: Pharmaceutical Press; 2014. http://www.medicinescomplete. com/mc/bnf/current/
  10. Sidhu KS et al. Watch for nonpsychotropics causing psychiatric side effects. Curr Psychiatry 2008; 7:61–74.
  11. Turjanski N et al. Psychiatric side-effects of medications: recent developments. Adv Psychiatr Treat 2005; 11:58–70.
  12. Ashton HC. Psychiatric effects of drugs for other disorders. Medicine 2008; 36:501–504.
  13. Bazire S. Psychotropic Drug Directory. UK: Lloyd-Reinhold Communcations LLP; 2014.
  14. American Pharmacists Association. Drug Information Handbook 2014-2015, 23rd edn. United States: Lexi-Comp; 2014.
  15. Brown TM et al. Psychiatric side-effects of prescription and over the counter medications: recognition and management. Washington, DC: American Psychiatric Press; 1998.

Atrial fibrillation

Atrial fibrillation (AF) is the most common cardiac arrhythmia. It particularly affects older people but may occur in an important proportion of people under the age of 40. Risk factors include anxiety, obesity, diabetes, hypertension, long-standing aerobic exercise and high alcohol consumption.1–3 AF itself is not usually life-threatening, but stasis of blood in the atria during fibrillation predisposes to clot formation and substantially increases the risk of stroke.4 The use of warfarin or novel oral anticoagulants is therefore essential.3

AF can be defined as 'lone' or paroxysmal (occurring infrequently and spontaneously reverting to sinus rhythm), persistent (repeated and prolonged [> one week] episodes, which are usually, if temporarily, responsive to treatment) or permanent (unresponsive). Risk of stroke is increased in all three conditions.3

Treatment may involve DC conversion, rhythm control (usually flecainide, propafenone or amiodarone) or rate control (with diltiazem, verapamil or sotalol). With rhythm control the aim is to maintain sinus rhythm, although this is not always achieved. With rate control, atrial fibrillation is allowed to continue but ventricular response is controlled and ventricles are filled passively. Many people with paroxysmal or persistent AF can now be effectively cured of the condition by catheter or cryo-ablation of aberrant electrical pathways.5,6

Atrial fibrillation is commonly encountered in psychiatry not least because of the high rates of obesity, diabetes and alcohol misuse seen in mental health patients. When considering the use of psychotropics several factors need to be taken into account.

Recommendations for using psychotropic drugs in AF are shown in Table 7.37.

Table 7.37 Recommendations for using psychotropic drugs in AF

Condition

Suggested drugs

Drugs to avoid

Schizophrenia/schizoaffective disorder

(The condition itself may be associated with an increased risk of AF)9

In paroxysmal or persistent AF, aripiprazole or lurasidone may be appropriate choices.

In permanent AF with rate control, drug choice is less crucial but probably best to avoid drugs with potent effects on the ECG (ziprasidone, pimozide, sertindole, etc.) and those which increase heart rate.

AF reported with clozapine,10 olanzapine11,12 and paliperidone.13 Causation not established but avoid use in paroxysmal or persistent AF.

Avoid QT-prolonging drugs in ischaemic heart disease (see section on QT prolongation in Chapter 2).

Bipolar disorder

Valproate

Lithium

Mood stabilisers appear not to affect risk of AF.

Depression

(note - untreated depression predicts recurrence of AF)14

SSRIs (may be beneficial in paroxysmal AF)15 but beware interaction with warfarin and other anticoagulants.16

Animal studies suggest an antiarrhythmic effect for SSRIs.17,18

Venlafaxine does not directly affect atrial conduction19 and may cardiovert paroxysmal AF.20

No evidence that agomelatine affects cardiac conduction or clotting.

Avoid tricyclics in coronary disease.21 Tricyclics may also provoke AF22,23 but do not increase risk of haemorrhage when combined with warfarin.16

Anxiety disorders

(anxiety symptoms increase risk of AF)24

Benzodiazepines

SSRIs (see above)

Tricyclics (see above).

Alzheimer's disease

Acetylcholinesterase inhibitors (but beware bradycardic effects in patients with paroxysmal 'vagal' AF [paroxysmal AF provoked by low heart rate])

Rivastigmine has least interaction potential.

Memantine

Avoid cholinesterase inhibitors in paroxysmal 'vagal' AF.

AF, atrial fibrillation; ECG, electrocardiogram; SSRI, selective serotonin reuptake inhibitor.

References

  1. Chen LY et al. Epidemiology of atrial fibrillation: a current perspective. Heart Rhythm 2007; 4:S1–S6.
  2. Tully PJ et al. Anxiety, depression, and stress as risk factors for atrial fibrillation after cardiac surgery. Heart Lung 2011; 40:4–11.
  3. National Institute for Health and Care Excellence. Atrial fibrillation: the management of atrial fibrillation. Clinical Guideline 180, 2014. http://www.nice.org.uk/guidance/cg180
  4. Lakshminarayan K et al. Clinical epidemiology of atrial fibrillation and related cerebrovascular events in the United States. Neurologist 2008; 14:143–150.
  5. Rodgers M et al. Curative catheter ablation in atrial fibrillation and typical atrial flutter: systematic review and economic evaluation. Health Technol Assess 2008; 12:iii–xiii, 1.
  6. Latchamsetty R et al. Catheter ablation of atrial fibrillation. Cardiol Clin 2014; 32:551–561.
  7. Investigators, TCASTI. Effect of the antiarrhythmic agent moricizine on survival after myocardial infarction. N Engl J Med 1992; 327:227–233.
  8. Epstein AE et al. Mortality following ventricular arrhythmia suppression by encainide, flecainide, and moricizine after myocardial infarction. The original design concept of the Cardiac Arrhythmia Suppression Trial (CAST). JAMA 1993; 270:2451–2455.
  9. Emul M et al. P wave and QT changes among inpatients with schizophrenia after parenteral ziprasidone administration. Pharmacol Res 2009; 60:369–372.
  10. Low RA Jr. et al. Clozapine induced atrial fibrillation. J Clin Psychopharmacol 1998; 18:170.
  11. Waters BM et al. Olanzapine-associated new-onset atrial fibrillation. J Clin Psychopharmacol 2008; 28:354–355.
  12. Yaylaci S et al. Atrial fibrillation due to olanzapine overdose. Clin Toxicol (Phila) 2011; 49:440.
  13. Schneider RA et al. Apparent seizure and atrial fibrillation associated with paliperidone. Am J Health Syst Pharm 2008; 65:2122–2125.
  14. Lange HW et al. Depressive symptoms predict recurrence of atrial fibrillation after cardioversion. J Psychosom Res 2007; 63:509–513.
  15. Shirayama T et al. Usefulness of paroxetine in depressed men with paroxysmal atrial fibrillation. Am J Cardiol 2006; 97:1749–1751.
  16. Quinn GR et al. Effect of selective serotonin reuptake inhibitors on bleeding risk in patients with atrial fibrillation taking warfarin. Am J Cardiol 2014; 114:583–586.
  17. Pousti A et al. Effect of sertraline on ouabain-induced arrhythmia in isolated guinea-pig atria. Depress Anxiety 2009; 26:E106–E110.
  18. Pousti A et al. Effect of citalopram on ouabain-induced arrhythmia in isolated guinea-pig atria. Human Psychopharmacol 2003; 18:121–124.
  19. Emul M et al. The influences of depression and venlafaxine use at therapeutic doses on atrial conduction. J Psychopharmacol (Oxford, England) 2009; 23:163–167.
  20. Finch SJ et al. Cardioversion of persistent atrial arrhythmia after treatment with venlafaxine in successful management of major depression and posttraumatic stress disorder. Psychosomatics 2006; 47:533–536.
  21. Taylor D. Antidepressant drugs and cardiovascular pathology: a clinical overview of effectiveness and safety. Acta Psychiatr Scand 2008; 118:434–442.
  22. Moorhead CN et al. Imipramine-induced auricular fibrillation. Am J Psychiatry 1965; 122:216–217.
  23. Rosen BH. Case report of auricular fibrillation following the use of imipramine (Tofranil). J Mt Sinai Hosp NY 1960; 27:609–611.
  24. Eaker ED et al. Tension and anxiety and the prediction of the 10-year incidence of coronary heart disease, atrial fibrillation, and total mortality: the Framingham Offspring Study. Psychosom Med 2005; 67:692–696.