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.

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 foodstuffs^9–11

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

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 enhancers^5–13

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 donepezil^17–19 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 rivastigmine^22,23 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 galantamine^25–27 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 donepezil^17,18 ranged from 4% to 16% (placebo 1–7%). With rivastigmine^22,23, rates ranged from 7% to 29% (placebo 7%) and with galantamine^25–27 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 tolerated^51,52 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 tolerated^71,72 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 interactions^6–11,79,80

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 galantamine^119–121 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

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101. Akhondzadeh S et al. A 22-week, multicenter, randomized, double-blind controlled trial of Crocus sativus in the treatment of mild-tomoderate Alzheimer's disease. Psychopharmacology (Berl) 2010; 207:637–643.
102. Plosker GL et al. Spotlight on cerebrolysin in dementia. CNS Drugs 2010; 24:263–266.
103. McGuinness B et al. Cochrane review on 'Statins for the treatment of dementia'. Int J Geriatr Psychiatry 2013; 28:119–126.
104. Sorond FA et al. Neurovascular coupling, cerebral white matter integrity, and response to cocoa in older people. Neurology 2013; 81:904–909.
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108. Doody RS et al. A phase 3 trial of semagacestat for treatment of Alzheimer's disease. N Engl J Med 2013; 369:341–350.
109. Doody RS et al. Phase 3 trials of solanezumab for mild-to-moderate Alzheimer's disease. N Engl J Med 2014; 370:311–321.
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118. Moretti R et al. Rivastigmine in subcortical vascular dementia: a randomized, controlled, open 12-month study in 208 patients. Am J Alzheimers Dis Other Demen 2003; 18:265–272.
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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

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

• Loperamide: although loperamide may have some anticholinergic activity, there are no data to suggest that it can worsen cognitive function in patients with dementia. It may add to the anticholinergic cognitive burden if used in conjunction with other anticholinergic drugs, however.
• Laxatives: there is no evidence to suggest that laxatives have any negative impact on cognitive function. In fact since constipation can lead to behavioural and psychological symptoms of dementia (BPSD), treating it can improve these symptoms in many cases.
• Antiemetics
• Cyclizine is a first-generation histamine antagonist and can impair cognitive and psychomotor performance (see section on 'Antihistamines' in this section).²²
• Metoclopramide has little anticholinergic action, but the D₂ receptor antagonism of both metoclopramide and prochlorperazine can produce movement disorders and so these drugs must be used with great caution in people with dementia.
• Domperidone is a dopamine D₂ receptor antagonist that does not usually cross the blood–brain barrier. However, since blood–brain barrier alterations can occur in dementia, CNS penetration of domperidone and resulting adverse effects can occur.²³ Recent reports have highlighted a small increased risk of serious cardiac adverse effects with domperidone, especially in older people. The maximum dose has been reduced to 30 mg/day and the maximum treatment duration should not exceed one week. Domperidone is now contraindicated in those with underlying cardiac conditions or severe hepatic impairment and in patients receiving other medications known to prolong QT interval or potent CYP3A4 inhibitors.²⁴
• Serotonin 5HT₃ receptor antagonists, used for treating chemotherapy-induced nausea and vomiting do not have adverse effects on cognition, and may have some cognitive enhancing action.²⁵ These drugs carry cardiovascular warnings and should be used cautiously in patients with cardiac co-morbidities or taking concomitant arrhythmogenic drugs or drugs known to prolong QT interval. Granisetron allows for once daily administration, which is preferable in elderly patients with memory problems or swallowing difficulties. Granisetron is metabolised exclusively via a single CYP family (CYP3A4) and thus has lower propensity for drug interactions.²⁶ All 5HT₃ antagonists cause constipation.

Table 7.6 Physiochemical properties of anticholinergic drugs in urinary incontinence^15,19

• Antispasmodics
• Hyoscine hydrobromide (scopolamine) is a centrally acting anticholinergic which is lipophilic and penetrates the blood–brain barrier easily. It impairs memory, speed of processing and attention. Older patients suffer these symptoms at lower doses and are more vulnerable to confusion and hallucinations.²⁷ People with Alzheimer's disease have experienced clinically significant cognitive impairment at lower doses compared with healthy, aged-matched controls.⁵ The effect that hyoscine has on cognition is so significant that it is used in trials to produce memory deficits similar to those seen in dementia (the scopolamine challenge test).²⁸
• Hyoscine butylbromide (Buscopan) exerts topical spasmolytic action on smooth muscle of the GI tract. Hyoscine butylbromide does not enter the CNS, therefore anticholinergic adverse effects at the CNS are extremely rare.²⁹
• Alverine, mebeverine and peppermint oil are relaxants of intestinal smooth muscle and do not appear to have an effect on cognition.

Bronchodilators

• Beta-agonists: in patients with co-existing Parkinson's disease or essential tremor, tremor induced by beta-agonists may result in misdiagnosis and over-treatment of Parkinson's disease.³⁰ Tremor is a common adverse effect of cholinesterase inhibitors so caution should be exercised when used with beta-agonists.
• Anticholinergic bronchodilators: inhaled anticholinergic drugs have few systemic side effects compared with oral medication.³⁰ A randomised, double blind placebo controlled comparison of ipratropium and theophylline treatment was unable to detect a negative effect with either drug on the psychometric test performance of elderly patients. This suggests that treatment with inhaled ipratropium is not associated with significant cognitive impairment in older people.³¹
• Theophylline: as with cholinesterase inhibitors, nausea and vomiting are common adverse effects of theophylline. Neurological effects such as headaches, anxiety, behavioural disturbances, depression and seizures can occur in 50% of patients on theophylline. Although seizures are rare, they are significantly more likely in older people than younger people. Theophylline does not cause significant cognitive impairment.³¹

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

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. Aromatherapy^14,15 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 tolerated^20,21 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 poor^32–34 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 aripiprazole^45–47 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 antipsychotics^57,58 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 similar^62–64 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.

• Baseline ECG, weight, pulse and BP, fasting blood glucose, HbA1c, blood lipid profile and prolactin levels. Routine bloods also include U&Es, LFTs and FBC.
• Pulse, BP and above tests should be repeated at 3 months, at 1 year and then annually (more frequently for in-patients).
• The ECG should be repeated at between 4 weeks and 3 months and then annually (or when clinically indicated)
• Weights should be recorded monthly for the first 3 months, then at 1 year and then annually provided weight is stable.
• Very ill or physically frail patients may need more frequent physical health monitoring than this.
• Review of the antipsychotic drug needs to be done at 4–6 weeks (may be earlier for in-patients), then at 3 months and then every 6 months if physically stable and there are no adverse effects.

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 rivastigmine^87–90 and galantamine^91–93 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

• people with Lewy body dementia who have non-cognitive symptoms causing significant distress or leading to behaviour that challenges
• people with mild, moderate or severe Alzheimer's disease who have non-cognitive symptoms and/or behaviour that challenges causing significant distress or potential harm to the individual if:
• a non-pharmacological approach is inappropriate or has been ineffective, and
• antipsychotic drugs are inappropriate or have been ineffective.

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

Benzodiazepines^106,107 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 fractures^107,108 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 Trazodone^116,117 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.

• Exclude physical illness potentially precipitating non-cognitive symptoms of dementia, e.g. constipation, infection, pain.
• Target the symptoms requiring treatment.
• Consider non-pharmacological methods.
• Carry out a risk–benefit analysis tailored to individual patient needs when selecting a drug.
• Make evidence-based decisions when choosing a drug.
• Discuss treatment options and explain the risks to patient (if they have capacity) and family/carers.
• Titrate drug from a low starting dose and maintain the lowest dose possible for the shortest period necessary.
• Review appropriateness of treatment regularly so that the ineffective drug is not continued unnecessarily.
• Monitor for adverse effects.
• Document clearly treatment choices and discussions with patient, family or carers.

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91. Cummings JL et al. Reduction of behavioral disturbances and caregiver distress by galantamine in patients with Alzheimer's disease. Am J Psychiatry 2004; 161:532–538.
92. Herrmann N et al. Galantamine treatment of problematic behavior in Alzheimer disease: post-hoc analysis of pooled data from three large trials. Am J Geriatr Psychiatry 2005; 13:527–534.
93. Tangwongchai S et al. Galantamine for the treatment of BPSD in Thai patients with possible Alzheimer's disease with or without cerebrovascular disease. Am J Alzheimers Dis Other Demen 2008; 23:593–601.
94. Barak Y et al. Donepezil for the treatment of behavioral disturbances in Alzheimer's disease: a 6-month open trial. Arch Gerontol Geriatr 2001; 33:237–241.
95. Howard RJ et al. Donepezil for the treatment of agitation in Alzheimer's disease. N Engl J Med 2007; 357:1382–1392.
96. 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.
97. Campbell N et al. Impact of cholinesterase inhibitors on behavioral and psychological symptoms of Alzheimer's disease: a meta-analysis. Clin Interv Aging 2008; 3:719–728.
98. Rodda J et al. Are cholinesterase inhibitors effective in the management of the behavioral and psychological symptoms of dementia in Alzheimer's disease? A systematic review of randomized, placebo-controlled trials of donepezil, rivastigmine and galantamine. Int Psychogeriatr 2009; 21:813–824.
99. National Institute for Health and Clinical Excellence. Donepezil, galantamine, rivastigmine and memantine for the treatment of Alzheimer's disease. TA 217, 2011. http://www.nice.org.uk/guidance/index.jsp?action=byID&o=13419
100. National Institute for Health and Clinical Excellence. Dementia. Supporting people with dementia and their carers in health and social care. Clincial Guideline 42, 2011. Updated March 2011. http://www.nice.org.uk/nicemedia/live/10998/30318/30318.pdf
101. Cummings JL et al. Behavioral effects of memantine in Alzheimer disease patients receiving donepezil treatment. Neurology 2006; 67:57–63.
102. Wilcock GK et al. Memantine for agitation/aggression and psychosis in moderately severe to severe Alzheimer's disease: a pooled analysis of 3 studies. J Clin Psychiatry 2008; 69:341–348.
103. Gauthier S et al. Improvement in behavioural symptoms in patients with moderate to severe Alzheimer's disease by memantine: a pooled data analysis. Int J Geriatr Psychiatry 2007; 23:537–545.
104. McShane R et al. Memantine for dementia. Cochrane Database Syst Rev 2006;CD003154.
105. Fox C et al. Efficacy of memantine for agitation in Alzheimer's dementia: a randomised double-blind placebo controlled trial. PLoS One 2012; 7:e35185.
106. Verdoux H et al. Is benzodiazepine use a risk factor for cognitive decline and dementia? A literature review of epidemiological studies. Psychol Med 2005; 35:307–315.
107. Lagnaoui R et al. Benzodiazepine utilization patterns in Alzheimer's disease patients. Pharmacoepidemiol Drug Saf 2003; 12:511–515.
108. Chang CM et al. Benzodiazepine and risk of hip fractures in older people: a nested case-control study in Taiwan. Am J Geriatr Psychiatry 2008; 16:686–692.
109. Aboukhatwa M et al. Antidepressants are a rational complementary therapy for the treatment of Alzheimer's disease. Mol Neurodegener 2010; 5:10.
110. Rozzini L et al. Efficacy of SSRIs on cognition of Alzheimer's disease patients treated with cholinesterase inhibitors. Int Psychogeriatr 2010; 22:114–119.
111. Deakin JB et al. Paroxetine does not improve symptoms and impairs cognition in frontotemporal dementia: a double-blind randomized controlled trial. Psychopharmacology 2004; 172:400–408.
112. Finkel SI et al. A randomized, placebo-controlled study of the efficacy and safety of sertraline in the treatment of the behavioral manifestations of Alzheimer's disease in outpatients treated with donepezil. Int J Geriatr Psychiatry 2004; 19:9–18.
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.

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

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 5HT_2a 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 RCTs^45–47 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

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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. fluoxetine^27,28 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

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 studies^49,50 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

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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

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.

• The woman's ability to cope with untreated illness/sub-threshold symptoms.
• The potential impact of an untreated mental disorder on the foetus or infant.
• The risks from stopping medication abruptly.
• Severity of previous episodes, response to treatment and the woman's preference.

• The background risk of foetal malformations for pregnant women without a mental disorder.
• The increased risk of harm associated with drug treatments during pregnancy, and the post-natal period, including the risk in overdose (and acknowledge uncertainty surrounding risks).
• The possibility that stopping a drug with known teratogenic risk after pregnancy is confirmed may not remove the risk of malformations.

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

• Pregnancy does not protect against relapse.
• Psychiatric illness during pregnancy predicts post-partum psychosis.¹⁴
• The risk of perinatal psychosis is 0.1–0.25% in the general population, but is about 50% in women with a history of bipolar disorder.
• During the month after childbirth there is a 20-fold increase (to 30–50%) in the relative risk of psychosis.
• The risk of recurrent post-partum psychosis is 50–90%.
• The mental health of the mother in the perinatal period influences foetal well-being, obstetric outcome and child development.

The risks of not treating psychosis include:

• harm to the mother through poor self-care or judgement, lack of obstetric care or impulsive acts
• harm to the foetus or neonate (ranging from neglect to infanticide).

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.

• Most data originate from studies that included primarily women with hyperemesis gravidarum (a condition associated with an increased risk of congenital malformations) treated with low doses of phenothiazines. The modest increase in risk identified in some of these studies, along with no clear clustering of congenital abnormalities suggest that the condition being treated may be responsible rather than drug treatment.
• There may be an association between haloperidol and limb defects, but if real, the risk is likely to be extremely low.
• A recent prospective study that included 284 women who took an FGA (mostly haloperidol, promethazine or flupentixol) during pregnancy concluded that pre-term birth and low birth weight were more common with FGAs than SGAs (or no antipsychotic exposure).¹⁷ In total, 20% of neonates exposed to an FGA in the last week of gestation experienced early somnolence and jitteriness. The rate of major malformations, at 5%, was double that of controls (no antipsychotic exposure) but there was no clustering of abnormalities.
• Neonatal dyskinesia has been reported with FGAs.¹⁸
• Neonatal jaundice has been reported with phenothiazines.¹⁵

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.

• There are most data for olanzapine which has been associated with both lower birth weight and increased risk of intensive care admission,²⁰ a large head circumference²¹ and with macrosomia;²² the last of these is consistent with the reported increase in the risk of gestational diabetes.^15,21,23,24 Olanzapine seems to be relatively safe with respect to congenital malformations; the prevalence being consistent with population norms in a study that reported on 610 prospectively followed pregnancies.²⁵ Olanzapine has however been associated with a range of problems including hip dysplasia,²⁶ meningocele, ankyloblepharon,²⁷ and neural tube defects;¹⁵ (an effect that could be related to pre-pregnancy obesity rather than drug exposure²). Importantly there is no clustering of congenital malformations. Further, a recent prospective study that included 561 women who took an SGA (mostly olanzapine, quetiapine, clozapine, risperidone or aripiprazole) during pregnancy concluded that SGA exposure was associated with increased birth weight, a modestly increased risk of cardiac septal defects (possibly due to screening bias or co-exposure to SSRIs), and, as with FGAs, withdrawal effects in 15% neonates.¹⁷
• The risk of gestational diabetes may be increased with all SGAs.²¹
• The use of clozapine appears to present no increased risk of malformation, although gestational diabetes and neonatal seizures may be more likely to occur.²³ There is a single case report of maternal overdose resulting in foetal death¹⁵ and there are theoretical concerns about the risk of agranulocytosis in the foetus/neonate.¹⁵ NICE has, in the past, recommended that pregnant women should be switched from clozapine to another antipsychotic.¹³ However, for almost all women who are prescribed clozapine, a switch to a different antipsychotic will result in relapse. On the balance of evidence available, clozapine should usually be continued.
• A small prospective case control study reported that babies who were exposed to antipsychotics in utero, had delayed cognitive, motor and social-emotional development at 2 and 6 months old but not at 12 months.²⁸ The clinical significance of this finding, if any, is unclear.

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.

Depression during pregnancy and post-partum^30–32

• Approximately 10% of pregnant women develop a depressive illness and a further 16% a self-limiting depressive reaction. Much post-partum depression begins before birth.
• Risk may be at least partially genetically determined.
• There is a significant increase in new psychiatric episodes in the first 3 months after delivery. At least 80% are mood disorders, primarily depression.
• Women who have had a previous episode of depressive illness (post-partum or not) are at higher risk of further episodes during pregnancy and post-partum. The risk is highest in women with bipolar illness.
• It is unclear if depression increases the risk of spontaneous abortion, having a low birth weight or small for gestational age baby, or of pre-term delivery.^33,34 The mental health of the mother influences foetal well-being, obstetric outcome and child development.

The risks of not treating depression include:

• harm to the mother through poor self-care, lack of obstetric care or self-harm
• harm to the foetus or neonate (ranging from neglect to infanticide).

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

• Foetal exposure to TCAs (via umbilicus and amniotic fluid) is high.^62,63
• TCAs have been widely used throughout pregnancy without apparent detriment to the foetus^50,64,65 and have for many years been agents of choice in pregnancy.
• A weak association between clomipramine use and cardiovascular defects cannot be excluded⁶⁶ and the European SPC for Anafranil states: 'Neonates whose mothers had taken tricyclic antidepressants until delivery have developed dyspnoea, lethargy, colic, irritability, hypotension or hypertension, tremor or spasms, during the first few hours or days. Studies in animals have shown reproductive toxicity. Anafranil is not recommended during pregnancy and in women of childbearing potential not using contraception.'
• Limited data suggest in utero exposure to TCAs has no effects on later development.^67,68
• Some authorities recommend the use of nortriptyline and desipramine (not available in the UK) because these drugs are less anticholinergic and hypotensive than amitriptyline and imipramine (respectively, their tertiary amine parent molecules).
• TCA use during pregnancy increases the risk of pre-term delivery.^64,65,69
• Use of TCAs in the third trimester is well known to produce neonatal withdrawal effects; agitation, irritability, seizures, respiratory distress and endocrine and metabolic disturbances.⁶⁴ These are usually mild and self-limiting.
• Little is known of the developmental effects of prenatal exposure to TCAs, although one small study detected no adverse consequences.⁶⁷

SSRIs

• Sertraline appears to result in the least placental exposure.⁷⁰
• SSRIs appear not to be major teratogens,^50,52,64,71 with most data supporting the safety of fluoxetine.^67,72–75 Note though that one study revealed a slight overall increase in rate of malformation with SSRIs.⁷⁶ Database and case control studies have reported an association between SSRIs and anencephaly, craniosynostosis, omphalocele, and persistent pulmonary hypertension of the newborn.^77,78 These associations have not been replicated.
• Paroxetine has been specifically associated with cardiac malformations^79,80 particularly after high dose (> 25 mg/day), first trimester exposure.⁸¹ However, some studies have failed to replicate this finding for paroxetine,^64,82 and have implicated other SSRIs.^83,84 Other studies have found no association between any SSRI and an increased risk of cardiac septal defects.^78,85,86 Note that one database study reported that foetal alcohol disorders were 10 times more common in those exposed to SSRIs in utero than controls,⁸⁷ and that alcohol use during pregnancy is associated with an increased risk of cardiac defects in the foetus.⁶⁶
• SSRIs have also been associated with decreased gestational age⁸⁸ (usually a few days which is of questionable clinical significance⁴⁹), spontaneous abortion⁸⁹ and decreased birth weight (mean 175 g).^72,73,90 It is possible that these effects are primarily associated with maternal depression rather than specifically with antidepressant treatment.⁴⁹ The longer the duration of in utero exposure, the greater the chance of low birth weight and respiratory distress.⁵¹ Three groups of symptoms are seen in neonates exposed to antidepressants in late pregnancy; those associated with serotonergic toxicity, those associated with antidepressant discontinuation symptoms and those related to early birth.⁹¹ Third-trimester exposure to sertraline has been associated with reduced early APGAR scores.⁷² Third-trimester use of paroxetine may give rise to neonatal complications, presumably related to abrupt withdrawal.^92,93 Other SSRIs have similar, possibly less severe effects.^93,94 Body temperature instability, poor feeding, respiratory distress, cardiac rhythm disturbance, lethargy, muscle tone anomalies, jitteriness, jerky movements and seizures have been reported.⁶⁶
• Data relating to neurodevelopmental outcome of foetal exposure to SSRIs suggest that these drugs are safe, although data are less than conclusive.^67,68,95,96 Depression itself may have more obvious adverse effects on development.⁶⁷
• When taken in late pregnancy, SSRIs may increase the risk of persistent pulmonary hypertension of the newborn (NNH 300). Note this increased risk is compared with population norms, not women with depression, in whom the risk is unquantified.⁹⁷

Other antidepressants

• No specific risks were identified with duloxetine in a study that prospectively followed 233 women through pregnancy and delivery.⁹⁸
• Rather more scarce data suggest the absence of teratogenic potential with moclobemide⁹⁹ and reboxetine.¹⁰⁰ Venlafaxine may be associated with cardiac defects, anencephaly and cleft palate¹⁰¹ and neonatal withdrawal may occur.^73,102,103 Second trimester exposure to venlafaxine has been associated with babies being born small for gestational age.⁴⁵ None of these drugs can be specifically recommended. Similarly, trazodone, bupropion (amfebutamone) and mirtazapine cannot be recommended because there are few data supporting their safety.^73,104,105 Data suggest that both bupropion and mirtazapine are not associated with malformations but, like SSRIs, may be linked to an increased rate of spontaneous abortion.^106,107 Bupropion exposure in utero has been associated with an increased risk of attention deficit hyperactivity disorder (ADHD) in young children.^108,109
• Monoamine oxidase inhibitors (MAOIs) should be avoided in pregnancy because of a suspected increased risk of congenital malformation and because of the risk of hypertensive crisis.¹¹⁰
• There is no evidence to suggest that ECT causes harm to either the mother or foetus during pregnancy¹¹¹ although general anaesthesia is, of course, not without risks. In resistant depression, NICE recommend that ECT is used before/instead of drug combinations.
• Omega-3 fatty acids may also be a treatment option¹¹² although efficacy and safety data are scant.

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

Bipolar illness during pregnancy and post-partum

• The risk of relapse during pregnancy if mood stabilising medication is discontinued is high; one study found that bipolar women who were euthymic at conception and discontinued mood stabilisers were twice as likely to relapse and spent five times as long in relapse ill than women who continued mood stabilisers.¹¹³
• The risk of relapse after delivery is hugely increased: up to eight-fold in the first month post-partum.
• The mental health of the mother influences foetal well-being, obstetric outcome and child development.
• Women with bipolar illness are 50% more likely than controls to have their labour induced or a caesarean delivery, a pre-term delivery, and a neonate that is small for gestational age; the neonate is also more likely to have hypoglycaemia and microcephaly.⁶ These associations hold true in both treated and untreated women.

• Bipolar illness itself does not seem to significantly increase the malformation rate; any such association is with mood stabilising drugs.⁶

The risks of not stabilising mood include:

• harm to the mother through poor self-care, lack of obstetric care or self-harm
• harm to the foetus or neonate (ranging from neglect to infanticide).

Treatment with mood stabilisers

• Lithium completely equilibrates across the placenta.¹¹⁴
• Although the overall risk of major malformations in infants exposed in utero has probably been overestimated, lithium should be avoided in pregnancy if possible. Slow discontinuation before conception is the preferred course of action^23,115 because abrupt discontinuation is suspected of worsening the risk of relapse. The relapse rate post-partum may be as high as 70% in women who discontinued lithium before conception.¹¹⁶ If discontinuation is unsuccessful during pregnancy—restart and continue.
• Lithium use during pregnancy has a well-known association with the cardiac malformation Ebstein's anomaly (relative risk is 10–20 times more than control, but the absolute risk is low at 1:1000).¹¹⁷ The period of maximum risk to the foetus is 2–6 weeks after conception,¹¹⁸ before many women know that they are pregnant. The risk of atrial and ventricular septal defects may also be increased.²⁰ A recent review suggests the exact nature and incidence of congenital malformation is 'uncertain'.¹¹⁹
• If lithium is continued during pregnancy, high-resolution ultrasound and echocardiography should be performed at 6 and 18 weeks of gestation.
• In the third trimester, the use of lithium may be problematic because of changing pharmacokinetics: an increasing dose of lithium is required to maintain the lithium level during pregnancy as total body water increases, but the requirements return abruptly to pre-pregnancy levels immediately after delivery.¹²⁰ Lithium plasma levels should be monitored every month during pregnancy and immediately after birth. Women taking lithium should deliver in hospital where fluid balance can be monitored and maintained.
• Neonatal goitre, hypotonia, lethargy and cardiac arrhythmia can occur.

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.

• Both carbamazepine and valproate have a clear causal link with increased risk of a variety of foetal abnormalities, particularly spina bifida.¹²¹ Both drugs should be avoided, if possible, and an antipsychotic prescribed instead. Valproate confers a higher risk than carbamazapine^122,123 and should not be used in women of child-bearing age except where all other treatment has failed. Although 1 in 20 women of child-bearing age who are in long term contact with mental health services are prescribed mood stabilising drugs, awareness of the teratogenic potential of these drugs amongst psychiatrists is low.¹²¹
• Valproate monotherapy has also been associated with an increased relative risk of atrial septal defects, cleft palate, hypospadias, polydactyly and craniosynostosis, although absolute risks are low.¹²⁴ Valproate is also associated with a reduced head circumference in the neonate.¹²⁵
• Where continued use of valproate or carbamazepine is deemed essential, low-dose monotherapy is strongly recommended, as the teratogenic effect is probably doserelated.^126,127 NICE recommends that the dose of valproate should be limited to 1000 mg a day. The dose of carbamazepine is also best limited to 1000 mg a day.^128,129
• Vulnerability to valproate-induced neural tube defects may be genetically determined via genes that code for folate metabolism/handling.¹³⁰
• Ideally, all patients should take folic acid (5 mg daily) for at least a month before conception (this may reduce the risk of neonatal neural tube defects). Note, however, that some authorities recommend a lower dose,¹³¹ presumably because of a risk of twin births.¹³² Note that there is no evidence that folate protects against anticonvulsantinduced neural tube defects if given during pregnancy,¹²⁸ but may do so if given prior to conception (the neural tube is essentially formed by the eighth week of pregnancy¹³³ before many women realise they are pregnant). However, folate supplementation may be beneficial with regard to early neurodevelopment and so should always be offered.¹²⁸
• Use of carbamazepine in the third trimester may necessitate maternal vitamin K.
• There is growing evidence that lamotrigine is safer in pregnancy than carbamazepine or valproate across a range of outcomes.^128,129,134 Clearance of lamotrigine seems to increase radically during pregnancy¹³⁵ and then reduces post-partum.¹³⁶ NICE suggest that lamotrigine should not be routinely prescribed in pregnancy.

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

Epilepsy during pregnancy and post-partum

• In pregnant women with epilepsy, there is an increased risk of maternal complications such as severe morning sickness, eclampsia, vaginal bleeding and premature labour. Women should get as much sleep and rest as possible and comply with medication (if prescribed) in order to minimise the risk of seizures.
• The risk of having a child with minor malformations may be increased regardless of treatment with anticonvulsants.

The risks of not treating epilepsy include:

• the increased risk of accidents resulting in foetal injury if seizures are inadequately controlled. Post-partum, the mother may be less able to look after herself and her child
• tonic-clonic seizures during pregnancy can lead to foetal lactic acidosis and hypoxia,¹²⁵ the long term consequences of which include neurodevelopmental delay and poor school performance¹²⁹
• the risk of seizures during delivery is 1–2%, potentially worsening maternal and neonatal mortality. Overall, 5% maternal deaths are in women with epilepsy.¹²⁵

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.

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.

• First-trimester exposure to benzodiazepines has been associated with an increased risk of oral clefts in newborns,¹⁴⁵ although two subsequent studies have failed to confirm this association.^146,147
• Benzodiazepines have been associated with pylorostenosis and alimentary tract atresia.¹⁴⁶ A large Swedish cohort study (n = 1,406 women who took a benzodiazepine during pregnancy) did not confirm these associations, nor suggest others.¹⁴⁷ Note that data on elective terminations were not available.
• There is an association between benzodiazepine use in pregnancy, low birth weight and pre-term delivery.^43,46
• Third-trimester use is commonly associated with neonatal difficulties (floppy baby syndrome).¹⁴⁸
• Promethazine has been used in hyperemesis gravidarum and appears not to be teratogenic, although data are limited.
• NICE recommends the use of low dose chlorpromazine or amitriptyline.

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.

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

• In each case, the benefits of breastfeeding to the mother and infant must be weighed against the risk of drug exposure in the infant.
• The infants should be monitored for any specific adverse effects of the drugs as well as for feeding patterns and growth and development.
• Neonates and infants do not have the same capacity for drug clearance as adults. In addition, premature infants and infants with renal, hepatic, cardiac or neurological impairment are at a greater risk from exposure to drugs.
• It is usually inappropriate to withhold treatment to allow breastfeeding where there is a high risk of relapse. Treatment of maternal illness is the highest priority.
• Where a mother has taken a particular psychotropic drug during pregnancy and until delivery, continuation with the drug while breastfeeding may be appropriate as this may minimise withdrawal symptoms in the infant. However, it is important to note that certain drugs may persist in infant plasma after delivery, leading to high levels in the early post-natal stage during breastfeeding.
• Half-lives of the drugs should be considered: drugs with a long half-life can accumulate in breast milk and infant serum.
• Infant plasma levels should be monitored if toxicity is suspected.
• Women receiving sedating medication should be strongly advised not to sleep with the baby in bed with them.

Wherever possible:

• use the lowest effective dose
• avoid polypharmacy
• time dosing to avoid feeding at peak plasma/milk levels or express milk to give later (this may be impractical in small infants feeding every 2–3 hours).

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

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

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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

• Estimate the excretory capacity of the kidney by calculating the glomerular filtration rate (GFR). GFR can be directly measured by collection of urine over 24 hours, isotope determination or estimated in adults in one of two ways;¹ that is creatinine clearance (CrCl) using the Cockroft and Gault equation or estimated GFR (eGFR) using the modification of diet in renal disease (MDRD) below.

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)

Use Cockroft and Gault for drug dose calculation.

Classify the stage of renal impairment as below:

• Elderly patients (> 65 years) are assumed to have mild renal impairment. Their serum creatinine may not be raised because they have a smaller muscle mass.
• Avoid drugs that are nephrotoxic (e.g. lithium) in moderate or severe renal failure.
• Chose a drug that is safer to use in renal impairment (see Tables 7.16–7.20 below).
• Be cautious when using drugs that are extensively renally cleared (e.g. sulpiride, amisulpride, lithium).
• Start at a low dose and increase slowly because, in renal impairment, the half-life of a drug and the time for it to reach steady state are often prolonged. Plasma level monitoring may be useful for some drugs.
• Avoid long acting drugs (e.g. depot preparations). Their dose and frequency cannot be easily adjusted should renal function change.
• Prescribe as few drugs as possible. Patients with renal failure take many medications requiring regular review. Interactions and side effects can be avoided if fewer drugs are used.
• Monitor patient for adverse effects. Patients with renal impairment are more likely to experience side effects and they may take longer to develop than in healthy patients. Adverse effects such as sedation, confusion and postural hypotension can be more common.
• Be cautious when using drugs with anticholinergic effects, since they may cause urinary retention.
• There are few clinical studies of the use of psychotropic drugs in people with renal impairment. Advice about drug use in renal impairment is often based on knowledge of the drug's pharmacokinetics in healthy patients.
• The effect of renal replacement therapies (e.g. dialysis) on drugs is difficult to predict. Dosing advice is available from tables and data on each drug's volume of distribution and protein binding affinity. Seek specialist advice.
• Avoid drugs known to prolong QTc interval. In established renal failure electrolyte changes are common so probably best to avoid antipsychotics with the greatest risk of QTc prolongation (see section on 'QT prolongation' in Chapter 2).
• Monitor weight carefully. Weight gain predisposes to diabetes which can cause rhabdomyolysis² and renal failure. Psychotropic medications commonly cause weight gain.
• Be vigilant for serotonin syndrome with antidepressants, dystonias and neuroleptic malignant syndrome (NMS) with antipsychotics. The resulting rhabdomyolysis can cause renal failure and there are case reports of rhabdomyolysis occurring with antipsychotics without other symptoms of NMS.^3–5
• Depression is common in chronic kidney disease but evidence on effectiveness of antidepressants in this condition is lacking.⁶

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

Table 7.16 Antipsychotics in renal impairment

Table 7.17 Antidepressants in renal impairment⁶

Table 7.18 Mood stabilisers in renal impairment

Table 7.19 Anxiolytics and hypnotics in renal impairment

Table 7.20 Anti-dementia drugs in renal impairment

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113. Sabbatini M et al. Zaleplon improves sleep quality in maintenance hemodialysis patients. Nephron Clin Pract 2003; 94:c99–103.
114. Goa KL et al. Zopiclone. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy as an hypnotic. Drugs 1986; 32:48–65.
115. Hussain N et al. Zopiclone-induced acute interstitial nephritis. Am J Kidney Dis 2003; 41:E17.
116. Suwata J et al. New acetylcholinesterase inhibitor (donepezil) treatment for Alzheimer's disease in a chronic dialysis patient. Nephron 2002; 91:330–332.
117. Nagy CF et al. Steady-state pharmacokinetics and safety of donepezil HCl in subjects with moderately impaired renal function. Br J Clin Pharmacol 2004; 58 Suppl 1:18–24.
118. Tiseo PJ et al. An evaluation of the pharmacokinetics of donepezil HCl in patients with moderately to severely impaired renal function. Br J Clin Pharmacol 1998; 46 Suppl 1:56–60.
119. Periclou A et al. Pharmacokinetic study of memantine in healthy and renally impaired subjects. Clin Pharmacol Ther 2006; 79:134–143.

Hepatic impairment

Patients with hepatic impairment may have the following characteristics.

• Reduced capacity to metabolise biological waste products, dietary proteins and foreign substances such as drugs. Clinical consequences include hepatic encephalopathy and increased dose-related side-effects from drugs.
• Reduced ability to synthesise plasma proteins and vitamin K-dependent clotting factors. Clinical consequences include hypoalbuminaemia, leading in extreme cases to ascites. Increased toxicity from highly protein-bound drugs should be anticipated. There is also an increased risk of bleeding from GI irritant drugs and perhaps with SSRIs.
• Reduced hepatic blood flow. Clinical consequences include oesophageal varices and elevated plasma levels of drugs subject to first pass metabolism.

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:

• Prescribe as few drugs as possible.
• Use lower starting doses, particularly of drugs that are highly protein bound. TCAs, SSRIs (except citalopram), trazodone and antipsychotics may have increased free plasma levels, at least initially. This will not be reflected in measured (total) plasma levels. Use lower doses of drugs known to be subject to extensive first pass metabolism. Examples include TCAs and haloperidol.
• Be cautious with drugs that are extensively hepatically metabolised(most psychotropic drugs). Lower doses may be required. Exceptions are sulpiride, amisulpride, lithium and gabapentin, which all undergo no or minimal hepatic metabolism.
• Leave longer intervals between dosage increases. Remember that the half-life of most drugs is prolonged in hepatic impairment, so it will take longer for plasma levels to reach steady state.
• If albumin is reduced, consider the implications for drugs that are highly protein bound, and if ascites is present consider the increased volume of distribution for water soluble drugs.
• Avoid medicines with a long-half life or those that need to be metabolised to render them active (pro-drugs).
• Always monitor carefully for side-effects, which may be delayed.
• Avoid drugs that are very sedative because of the risk of precipitating hepatic encephalopathy.
• Avoid drugs that are very constipating because of the risk of precipitating hepatic encephalopathy.
• Avoid drugs that are known to be hepatotoxic in their own right (e.g. MAOIs, chlorpromazine).
• Choose a low-risk drug (see Tables 7.22–7.25) and monitor LFTs weekly, at least initially. If LFTs deteriorate after a new drug is introduced, consider switching to another drug.

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

Table 7.22 Antipsychotics in hepatic impairment

Table 7.23 Antidepressants in hepatic impairment

Table 7.24 Mood stabilisers in hepatic impairment^945,946,998

Table 7.25 Stimulants in hepatic impairment⁵⁹

Hepatic toxicity

Drug induced hepatic damage can be due to:

• direct dose-related hepatotoxicity (Type 1 ADR). A small number of drugs fall into this category e.g. paracetamol, alcohol
• hypersensitivity reactions (Type 2 ADR). These can present with rash, fever and eosinophilia. Almost all drugs have been associated with cases of heptatoxicity; frequency varies.

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

• increasing age
• female gender
• alcohol consumption
• co-prescription of enzyme inducing drugs
• genetic predisposition
• obesity
• pre-existing liver disease (small effect).

When interpreting LFTs, remember that:⁶¹

• 12% of the healthy adult population have one LFT outside (above or below) the normal reference range
• up to 10% of patients with clinically significant hepatic disease have normal LFTs
• individual LFTs lack specificity for the liver, but > 1 abnormal test greatly increases the likelihood of liver pathology
• the absolute values of LFTs are a poor indicator of disease severity.

When monitoring LFTs:

• ideally LFTs should be measured before treatment starts so that 'baseline' values are available
• LFT elevations of < 2 times the upper limit of the normal reference range are rarely clinically significant
• most drug related LFT elevations occur early in treatment (first month) and are transient. They may indicate adaptation of the liver to the drug rather than damage per se. Transient LFT elevations may also occur during periods of weight gain⁶²
• if LFTs are persistently elevated > 3 fold, continuing to rise or accompanied by clinical symptoms, the suspected drugs should be withdrawn
• when tracking change, > 20% change in liver enzymes is required to exclude biological or analytical variation.

References

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5. Brown CA et al. Clozapine toxicity and hepatitis. J Clin Psychopharmacol 2013; 33:570–571.
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7. Amdisen A et al. Zuclopenthixol acetate in viscoleo - a new drug formulation. An open Nordic multicentre study of zuclopenthixol acetate in Viscoleo in patients with acute psychoses including mania and exacerbation of chronic psychoses. Acta Psychiatr Scand 1987; 75:99–107.
8. Wistedt B et al. Zuclopenthixol decanoate and haloperidol decanoate in chronic schizophrenia: a double-blind multicentre study. Acta Psychiatr Scand 1991; 84:14–21.
9. Ozcanli T et al. Severe liver enzyme elevations after three years of olanzapine treatment: a case report and review of olanzapine associated hepatotoxicity. Prog Neuropsychopharmacol Biol Psychiatry 2006; 30:1163–1166.
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12. Dominguez-Jimenez JL et al. Liver toxicity due to olanzapine. Rev Esp Enferm Dig 2012; 104:617–618.
13. Vermeir M et al. Absorption, metabolism, and excretion of paliperidone, a new monoaminergic antagonist, in humans. Drug Metab Dispos 2008; 36:769–779.
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15. Zimmerman HJ et al. Drug-induced cholestasis. Med Toxicol 1987; 2:112–160.
16. de Abajo FJ et al. Acute and clinically relevant drug-induced liver injury: a population based case-control study. Br J Clin Pharmacol 2004; 58:71–80.
17. Thyrum PT et al. Single-dose pharmacokinetics of quetiapine in subjects with renal or hepatic impairment. Prog Neuropsychopharmacol Biol Psychiatry 2000; 24:521–533.
18. Nemeroff CB et al. Quetiapine: preclinical studies, pharmacokinetics, drug interactions, and dosing. J Clin Psychiatry 2002; 63 Suppl 13:5–11.
19. El Hajj I et al. Subfulminant liver failure associated with quetiapine. Eur J Gastroenterol Hepatol 2004; 16:1415–1418.
20. Lin CH et al. Quetiapine-induced hepatocellular damage. Psychosomatics 2012; 53:601–602.
21. Melzer E et al. Severe cholestatic jaundice due to sulpiride. Isr J Med Sci 1987; 23:1259–1260.
22. Ohmoto K et al. Symptomatic primary biliary cirrhosis triggered by administration of sulpiride. Am J Gastroenterol 1999; 94:3660–3661.
23. Voican CS et al. Antidepressant-induced liver injury: a review for clinicians. Am J Psychiatry 2014; 171:404–415.
24. Dolder CR et al. Agomelatine treatment of major depressive disorder. The Annals of Pharmacotherapy 2008; 42:1822–1831.
25. Stuhec M. Agomelatine-induced hepatotoxicity. Wien Klin Wochenschr 2013; 125:225–226.
26. Hanje AJ et al. Case report: fulminant hepatic failure involving duloxetine hydrochloride. Clin Gastroenterol Hepatol 2006; 4:912–917.
27. Vuppalanchi R et al. Duloxetine hepatotoxicity: a case-series from the drug-induced liver injury network. Aliment Pharmacol Ther 2010; 32:1174–1183.
28. Schenker S et al. Fluoxetine disposition and elimination in cirrhosis. Clin Pharmacol Ther 1988; 44:353–359.
29. Cai Q et al. Acute hepatitis due to fluoxetine therapy. Mayo Clin Proc 1999; 74:692–694.
30. Friedenberg FK et al. Hepatitis secondary to fluoxetine treatment. Am J Psychiatry 1996; 153:580.
31. Johnston DE et al. Chronic hepatitis related to use of fluoxetine. Am J Gastroenterol 1997; 92:1225–1226.
32. Hale AS. New antidepressants: use in high-risk patients. J Clin Psychiatry 1993; 54 Suppl:61–70.
33. Gomez-Gil E et al. Phenelzine-induced fulminant hepatic failure. Ann Intern Med 1996; 124:692–693.
34. Bonkovsky HL et al. Severe liver injury due to phenelzine with unique hepatic deposition of extracellular material. Am J Med 1986; 80:689–692.
35. Kang SG et al. Mirtazapine-induced hepatocellular-type liver injury. Ann Pharmacother 2011; 45:825–826.
36. Stoeckel K et al. Absorption and disposition of moclobemide in patients with advanced age or reduced liver or kidney function. Acta Psychiatr Scand Suppl 1990; 360:94–97.
37. Timmings P et al. Intrahepatic cholestasis associated with moclobemide leading to death. Lancet 1996; 347:762–763.
38. Benbow SJ et al. Paroxetine and hepatotoxicity. BMJ 1997; 314:1387.
39. Odeh M et al. Severe hepatotoxicity with jaundice associated with paroxetine. Am J Gastroenterol 2001; 96:2494–2496.
40. Dunbar GC. An interim overview of the safety and tolerability of paroxetine. Acta Psychiatr Scand Suppl 1989; 350:135–137.
41. Kuhs H et al. A double-blind study of the comparative antidepressant effect of paroxetine and amitriptyline. Acta Psychiatr Scand Suppl 1989; 350:145–146.
42. De Bree H et al. Fluvoxamine maleate: disposition in men. Eur J Drug Metab Pharmacokinet 1983; 8:175–179.
43. Green BH. Fluvoxamine and hepatic function. Br J Psychiatry 1988; 153:130–131.
44. Milne RJ et al. Citalopram. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in depressive illness. Drugs 1991; 41:450–477.
45. Lopez-Torres E et al. Hepatotoxicity related to citalopram (Letter). Am J Psychiatry 2004; 161:923–924.
46. Colakoglu O et al. Toxic hepatitis associated with paroxetine. Int J Clin Pract 2005; 59:861–862.
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48. Suen CF et al. Acute liver injury secondary to sertraline. BMJ Case Rep 2013; 2013.
49. Mayo MJ et al. Sertraline as a first-line treatment for cholestatic pruritus. Hepatology 2007; 45:666–674.
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58. Krahenbuhl S et al. Mitochondrial diseases represent a risk factor for valproate-induced fulminant liver failure. Liver 2000; 20:346–348.
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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:

• Start with a low dose and titrate according to tolerability and response.
• Select the simplest dosing regime possible. (Remember that the patient's drug regime is likely to be complex already.)
• Select an agent with the fewest side-effects/interactions. Medical co-morbidity and potential drug interactions must be considered.
• Ensure that management is conducted in close cooperation with the HIV physicians and the rest of the multi-disciplinary team.

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/citalopram^5,20 (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.
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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