Introduction

Depression is, of course, widely recognised as a major public health problem around the world. The mainstay of treatment is the prescription of antidepressants although, of late, psychological treatments have found a place as an alternative to antidepressants in milder forms of depression.¹ Other methods of treating depression (vagal nerve stimulation [VNS],² transcranial magnetic stimulation [TMS],³ etc.) have also emerged but remain somewhat experimental and are not widely available. The basic principles of prescribing are described below along with a summary of National Institute of Health and Care Excellence (NICE) guidance.

Basic principles of prescribing in depression

• Discuss with the patient choice of drug and utility/availability of other, nonpharmacological treatments.
• Discuss with the patient likely outcomes, such as gradual relief from depressive symptoms over several weeks.
• Prescribe a dose of antidepressant (after titration, if necessary) that is likely to be effective.
• For a single episode, continue treatment for at least 6–9 months after resolution of symptoms (multiple episodes may require longer).
• Withdraw antidepressants gradually; always inform patients of the risk and nature of discontinuation symptoms.

Official guidance on the treatment of depression

NICE guidelines:¹ a summary

• Antidepressants are not recommended as a first-line treatment in recent-onset, mild depression—active monitoring, individual guided self-help, cognitive behavioural therapy (CBT) or exercise are preferred.
• Antidepressants are recommended for the treatment of moderate to severe depression and for dysthymia.
• When an antidepressant is prescribed, a generic selective serotonin reuptake inhibitor (SSRI) is recommended.
• All patients should be informed about the withdrawal (discontinuation) effects of antidepressants.
• For treatment-resistant depression, recommended strategies include augmentation with lithium or an antipsychotic or the addition of a second antidepressant (see section on 'Refractory depression' in this chapter).
• Patients with two prior episodes and functional impairment should be treated for at least 2 years.
• The use of electroconvulsive therapy (ECT) is supported in severe and treatmentresistant depression.

This chapter concentrates on the use of antidepressants and offers advice on drug choice, dosing, switching strategies and sequencing of treatments. The near exclusion of other treatment modalities does not imply any lack of confidence in their efficacy but simply reflects the need (in a prescribing guideline) to concentrate on medicines-related subjects.

References

1. National Institute for Health and Clinical Excellence. Depression: the treatment and management of depression in adults (update). Clinical Guideline 90, 2009. http://www.nice.org.uk/
2. George MS et al. Vagus nerve stimulation for the treatment of depression and other neuropsychiatric disorders. Expert Rev Neurother 2007; 7:63–74.
3. Loo CK et al. A review of the efficacy of transcranial magnetic stimulation (TMS) treatment for depression, and current and future strategies to optimize efficacy. J Affect Disord 2005; 88:255–267.

Antidepressants: general overview

Effectiveness

The severity of depression at which antidepressants show consistent benefits over placebo is poorly defined. Although it is generally accepted that the more severe the symptoms, the greater the benefit from antidepressant treatment^1–3, there is some evidence to support the view that response may be independent of symptom severity.⁴ Antidepressants are normally recommended as first-line treatment in patients whose depression is of at least moderate severity. Of this patient group, approximately 20% will recover with no treatment at all, 30% will respond to placebo and 50% will respond to antidepressant drug treatment.⁵ This gives a number needed to treat (NNT) of 3 for antidepressant over true no-treatment control and an NNT of 5 for antidepressant over placebo. Note though that response in clinical trials is generally defined as a 50% reduction in depression rating scale scores, a somewhat arbitrary dichotomy, and that change measured using continuous scales tends to show a relatively small mean difference between active treatment and placebo (which itself is an effective treatment for depression). Drug–placebo differences have diminished over time largely because of methodological changes.⁶

In patients with sub-syndromal depression, it is difficult to separate the response rate to antidepressants from that to placebo; antidepressant treatment is not indicated unless the patient has a history of severe depression (where less severe symptoms may indicate the onset of another episode), or if symptoms persist. Patients with dysthymia (symptom duration of at least 2 years) benefit from antidepressant treatment; the minimum duration of symptoms associated with benefit is unknown. In other patients, the sideeffects associated with antidepressant treatment may outweigh any small benefit seen.

Onset of action

It is widely held that antidepressants do not exert their effects for 2–4 weeks. This is a myth. All antidepressants show a pattern of response where the rate of improvement is highest during weeks 1–2 and lowest during weeks 4–6. Statistical separation from placebo is seen at 2–4 weeks in single trials (hence the idea of a lag effect) but after only 1–2 weeks in (statistically more powerful) meta-analyses^7,8. Thus, where large numbers of patients are treated and detailed rating scales are used, an antidepressant effect is statistically evident at 1 week. In clinical practice using simple observations, an antidepressant effect in an individual is usually seen by 2 weeks.⁹ It follows that in individuals where no antidepressant effect is evident after 3–4 weeks' treatment, a change in dose or drug may be indicated. It is important, however, to be clear about what constitutes 'no effect'. Different patterns of response have been identified¹⁰ and, in some, response is slow to emerge. However, in those ultimately responsive to treatment, all will have begun to show at least minor improvement at 3 weeks. Thus, those showing no discernible improvement at this time will very probably never respond to the prescribed drug at that dose. In contrast, those showing small improvements at 3 weeks (that is, improvement not meeting criteria for 'response') may well go on to respond fully.¹¹

Choice of antidepressant and relative side-effects

Selective serotonin reuptake inhibitors (SSRIs) (Table 4.1) are well tolerated compared with the older tricyclic antidepressants (TCAs) (Table 4.2) and monoamine oxidase inhibitors (MAOIs) (Table 4.3), and are generally recommended as first-line pharmacological treatment for depression.¹ There is a suggestion from a network meta-analysis¹² that some antidepressants may be more effective overall than others but this has not been consistently demonstrated in head to head studies, and should therefore be treated with caution. Side-effect profiles of antidepressants do differ. For example, paroxetine has been associated with more weight gain and a higher incidence of sexual dysfunction, and sertraline with a higher incidence of diarrhoea than other SSRIs.¹³ Dual reuptake inhibitors such as venlafaxine and duloxetine tend to be tolerated less well than SSRIs but better than TCAs (Table 4.4). With all drugs there is marked interindividual variation in tolerability which is not easily predicted by knowledge of a drug's likely adverse effects. A flexible approach is usually required to find the right drug for a particular patient.

As well as headache and GI symptoms, SSRIs as a class are associated with a range of other side-effects including sexual dysfunction (see section on 'Antidepressants and sexual dysfunction' in this chapter), hyponatraemia (see section on 'Antidepressantinduced hyponatraemia' in this chapter) and GI bleeds (see section on 'SSRIs and bleeding' in this chapter). TCAs have a number of adverse cardiovascular effects (hypotension, tachycardia and QTc prolongation), and are particularly toxic in overdose¹⁴ (see section on 'Overdose' in Chapter 8). The now rarely used MAOIs have the potential to interact with tyramine-containing foods to cause hypertensive crisis. All antidepressant drugs can cause discontinuation symptoms with short half-life drugs being most problematic in this respect (see section on 'Antidepressant discontinuation symptoms' in this chapter).

Drug interactions

Some SSRIs are potent inhibitors of individual or multiple hepatic cytochrome P450 (CYP) pathways and the magnitude of these effects is dose related. A number of clinically significant drug interactions can therefore be predicted. For example, fluvoxamine is a potent inhibitor of CYP1A2 which can result in increased theophylline serum levels, fluoxetine is a potent inhibitor of CYP2D6 which can result in increased seizure risk with clozapine, and paroxetine is a potent inhibitor of CYP2D6 which can result in treatment failure with tamoxifen (a pro-drug) leading to increased mortality.¹⁵

Antidepressants can also cause pharmacodynamic interactions. For example, the cardiotoxicity of TCAs may be exacerbated by drugs such as diuretics that can cause electrolyte disturbances. A summary of clinically relevant drug interactions with antidepressants can be found in Table 4.16.

Potential pharmacokinetic and pharmacodynamic interactions between antidepressants have to be considered when switching from one antidepressant to another (see section on 'Swapping and stopping' in this chapter).

Table 4.1 Antidepressant drugs: SSRIs*

Table 4.2 Antidepressant drugs: tricyclics*

Table 4.3 Antidepressant drugs: monoamine oxidase inhibitors*

Table 4.4 Antidepressant drugs: others*

Suicidality

Antidepressant treatment has been associated with an increased risk of suicidal thoughts and acts, particularly in adolescents and young adults,^16,17 leading to the recommendation that patients should be warned of this potential adverse effect during the early weeks of treatment and know how to seek help if required. All antidepressants have been implicated,¹⁸ including those that are marketed for an indication other than depression (e.g. atomoxetine). It should be noted that:

• although the relative risk may be elevated above placebo rates in some patient groups, the absolute risk remains very small
• the most effective way to prevent suicidal thoughts and acts is to treat depression^19–21
• antidepressant drugs are the most effective treatment currently available.^5,22

For the most part, suicidality is greatly reduced by the use of antidepressants.^23–25 Note, however, that those who experience treatment-emergent or worsening suicidal ideation with one antidepressant may be more likely to have a similar experience with subsequent treatments.²⁶

Toxicity in overdose varies both between and within groups of antidepressants.²⁷ See section on 'Psychotropics in overdose' in Chapter 8.

Duration of treatment

Antidepressants relieve the symptoms of depression but do not treat the underlying cause. They should therefore be taken for 6–9 months after recovery from a single episode (to cover the assumed duration of most single untreated episodes). In those patients who have had multiple episodes, there is evidence of benefit from maintenance treatment for at least 2 years; no upper duration of treatment has been identified (see section on 'Antidepressant prophylaxis' in this chapter). There are few data on which to base recommendations about the duration of treatment of augmentation regimens.

Next step treatments

Approximately a third of patients do not respond to the first antidepressant that is prescribed. Options in this group include dose escalation, switching to a different drug and a number of augmentation strategies. The lessons from STAR*D (Sequenced Treatment Alternatives to Relieve Depression) are that a small proportion of nonresponders will respond with each treatment change, but that effect sizes are modest and there is no clear difference in effectiveness between strategies. See section on 'Treatment of refractory depression' in this chapter.

Use of antidepressants in anxiety spectrum disorders

Antidepressants are first-line treatments in a number of anxiety spectrum disorders. See section on 'Anxiety spectrum disorders' in this chapter.

References

1. National Institute for Health and Clinical Excellence. Depression in adults: the treatment and management of depression in adults. Clinical Guideline 90, 2009. http://www.nice.org.uk/Guidance/cg90
2. Kirsch I et al. Initial severity and antidepressant benefits: a meta-analysis of data submitted to the Food and Drug Administration. PLoS Med 2008; 5:e45.
3. Fournier JC et al. Antidepressant drug effects and depression severity: a patient-level meta-analysis. JAMA 2010; 303:47–53.
4. Gibbons RD et al. Benefits from antidepressants: synthesis of 6-week patient-level outcomes from double-blind placebo-controlled randomized trials of fluoxetine and venlafaxine. Arch Gen Psychiatry 2012; 69:572–579.
5. Anderson IM et al. Evidence-based guidelines for treating depressive disorders with antidepressants: a revision of the 2000 British Association for Psychopharmacology guidelines. J Psychopharmacol 2008; 22:343–396.
6. Khan A et al. Why has the antidepressant-placebo difference in antidepressant clinical trials diminished over the past three decades? CNS Neurosci Ther 2010; 16:217–226.
7. Taylor MJ et al. Early onset of selective serotonin reuptake inhibitor antidepressant action: systematic review and meta-analysis. Arch Gen Psychiatry 2006; 63:1217–1223.
8. Papakostas GI et al. A meta-analysis of early sustained response rates between antidepressants and placebo for the treatment of major depressive disorder. J Clin Psychopharmacol 2006; 26:56–60.
9. Szegedi A et al. Early improvement in the first 2 weeks as a predictor of treatment outcome in patients with major depressive disorder: a meta-analysis including 6562 patients. J Clin Psychiatry 2009; 70:344–353.
10. Uher R et al. Early and delayed onset of response to antidepressants in individual trajectories of change during treatment of major depression: a secondary analysis of data from the Genome-Based Therapeutic Drugs for Depression (GENDEP) study. J Clin Psychiatry 2011; 72: 1478–1484.
11. Posternak MA et al. Response rates to fluoxetine in subjects who initially show no improvement. J Clin Psychiatry 2011; 72:949–954.
12. Cipriani A et al. Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis. Lancet 2009; 373:746–758.
13. Gartlehner G et al. Comparative benefits and harms of second-generation antidepressants: background paper for the American College of Physicians. Ann Intern Med 2008; 149:734–750.
14. Flanagan RJ. Fatal toxicity of drugs used in psychiatry. Hum Psychopharmacol 2008; 23 Suppl 1:43–51.
15. Kelly CM et al. Selective serotonin reuptake inhibitors and breast cancer mortality in women receiving tamoxifen: a population based cohort study. BMJ 2010; 340:c693.
16. Stone M et al. Risk of suicidality in clinical trials of antidepressants in adults: analysis of proprietary data submitted to US Food and Drug Administration. BMJ 2009; 339:b2880.
17. Carpenter DJ et al. Meta-analysis of efficacy and treatment-emergent suicidality in adults by psychiatric indication and age subgroup following initiation of paroxetine therapy: a complete set of randomized placebo-controlled trials. J Clin Psychiatry 2011; 72:1503–1514.
18. Schneeweiss S et al. Variation in the risk of suicide attempts and completed suicides by antidepressant agent in adults: a propensity scoreadjusted analysis of 9 years' data. Arch Gen Psychiatry 2010; 67:497–506.
19. Isacsson G et al. The increased use of antidepressants has contributed to the worldwide reduction in suicide rates. Br J Psychiatry 2010; 196:429–433.
20. Gibbons RD et al. Suicidal thoughts and behavior with antidepressant treatment: reanalysis of the randomized placebo-controlled studies of fluoxetine and venlafaxine. Arch Gen Psychiatry 2012; 69:580–587.
21. Lu CY et al. Changes in antidepressant use by young people and suicidal behavior after FDA warnings and media coverage: quasi-experimental study. BMJ 2014; 348:g3596.
22. Isacsson G et al. Antidepressant medication prevents suicide in depression. Acta Psychiatr Scand 2010; 122:454–460.
23. Simon GE et al. Suicide risk during antidepressant treatment. Am J Psychiatry 2006; 163:41–47.
24. Mulder RT et al. Antidepressant treatment is associated with a reduction in suicidal ideation and suicide attempts. Acta Psychiatr Scand 2008; 118:116–122.
25. Tondo L et al. Suicidal status during antidepressant treatment in 789 Sardinian patients with major affective disorder. Acta Psychiatr Scand 2008; 118:106–115.
26. Perlis RH et al. Do suicidal thoughts or behaviors recur during a second antidepressant treatment trial? J Clin Psychiatry 2012; 73:1439–1442.
27. Hawton K et al. Toxicity of antidepressants: rates of suicide relative to prescribing and non-fatal overdose. Br J Psychiatry 2010; 196:354–358.

St John's wort

St John's wort (SJW) is the popular name for the plant Hypericum perforatum. It contains a combination of at least 10 different components, including hypericins, flavonoids and xanthons.¹ Preparations of SJW are often unstandardised and this has complicated the interpretation of clinical trials.

The active ingredient(s) and mechanism(s) of action of SJW are unclear. Constituents of SJW may inhibit MAO,² inhibit the reuptake of noradrenaline and serotonin,³ upregulate serotonin receptors³ and decrease serotonin receptor expression.⁴

Some preparations of SJW have been granted a traditional herbal registration certificate; note that this is based on traditional use rather than proven efficacy and tolerability. SJW is licensed in Germany for the treatment of depression.

Evidence for SJW in the treatment of depression

A number of trials have examined the efficacy of SJW in the treatment of depression. They have been extensively reviewed^1,5,6 and most authors conclude that SJW is likely to be effective in the treatment of dysthymia⁷ and mild to moderate depression,^4,5,8 e.g. Cochrane concludes that SJW is more effective than placebo in the treatment of mild to moderate depression, and is as effective as, and better tolerated than, standard antidepressants.⁶ Studies in German-speaking countries showed more favourable results than studies elsewhere. Efficacy in severe depression remains uncertain.⁶ A reanalysis of data from a large negative randomised controlled trial (RCT) of SJW found that subjects who guessed that they had been randomised to active treatment fared better than those who guessed that they had received placebo: patient guess regarding receiving active treatment was associated with improvement while actual treatment allocation was not.⁹

It should be noted that:

• the active component of SJW for treating depression has not yet been determined. Trials used different preparations of SJW which were standardised according to their total content of hypericins. However, evidence suggests that hypericins alone do not treat depression¹⁰
• published studies are generally acute treatment studies. There are fewer data to support the effectiveness of SJW in the medium term¹¹ or for prophylaxis.⁸

On balance, SJW should not be prescribed: we lack understanding of what the active ingredient is or what constitutes a therapeutic dose. Most preparations of SJW are unlicensed.

Adverse effects

St John's wort appears to be well tolerated.¹² Pooled data from 35 RCTS show that drop-out rates and adverse effects were less than with older antidepressants, slightly less than SSRIs and similar to placebo.¹³ The most common, if infrequent, side-effects are dry mouth, nausea, constipation, fatigue, dizziness, headache and restlessness.^14–17 In addition, SJW contains a red pigment that can cause photosensitivity reactions.¹⁸ It has been suggested that hypericin may be phototoxic to the retina, and contribute to the early development of macular degeneration.¹⁹ SJW may also share the propensity of SSRIs to increase the risk of bleeding; a case report describes prolonged epistaxis after nasal insertion of SJW.²⁰ In common with other antidepressant drugs, SJW has been known to precipitate hypomania in people with bipolar affective disorder.²¹

Drug interactions

St John's wort is a potent inducer of intestinal and hepatic CYP3A4, CYP2C9, CYP2C19, CYP2E1 and intestinal p-glycoprotein.^22–24 Hyperforin is responsible for this effect.²⁵ The hyperforin content of SJW preparations varies 50-fold, which will result in a different propensity for drug interactions between brands. Preparations with < 1 mg/dose hyperforin do not induce CYP enzymes.²² CYP3A4 activity is induced over 1–2 weeks and returns to normal approximately 7 days after SJW is discontinued.²⁶

Studies have shown that SJW significantly reduces plasma concentrations of digoxin and indinavir^27,28 (a drug used in the treatment of HIV). According to case reports, SJW has lowered the plasma concentrations of clozapine,²⁹ theophylline, ciclosporin, warfarin, gliclazide, atorvastatin and the combined oral contraceptive pill and has led to treatment failure.^23,24,30,31 There is a theoretical risk that SJW may interact with some anticonvulsant drugs³². It has also been reported that SJW can increase the effects of clopidogrel (a pro-drug).³³ Serotonin syndrome has been reported when SJW was taken together with sertraline, paroxetine, nefazodone and the triptans^32,34 (a group of serotonin agonists used to treat migraine). SJW should not be taken with any drugs that have a predominantly serotonergic action.

Key points that patients should know

• Evidence suggests that SJW may be effective in the treatment of mild to moderate depression, but we do not know enough about how much should be taken or what the side-effects are. There is less evidence of benefit in severe depression.
• SJW is not a licensed medicine.
• SJW can interact with other medicines, resulting in serious side-effects. Some important drugs may be metabolised more rapidly and therefore become ineffective with serious consequences (e.g. increased viral load in HIV, failure of oral contraceptives leading to unwanted pregnancy, reduced anticoagulant effect with warfarin leading to thrombosis).
• The symptoms of depression can sometimes be caused by other physical or mental illness. It is important that these possible causes are investigated.
• It is always best to consult the doctor if any herbal or natural remedy is being taken or the patient is thinking of taking one.

Many people regard herbal remedies as 'natural' and therefore harmless.³⁵ Many are not aware of the potential of such remedies for causing side-effects or interacting with other drugs. A large study from Germany (n = 588), where SJW is a licensed antidepressant, found that for every prescription written for SJW, one person purchased SJW without seeking the advice of a doctor.³⁶ Many of these people had severe or persistent depression but few told their doctor that they took SJW. A small US study (n = 22) found that people tend to take SJW because it is easy to obtain alternative medicines and also because they perceive herbal medicines as being purer and safer than prescription medicines. Few would discuss this medication with their conventional healthcare provider.¹⁷ Clinicians need to be proactive in asking patients if they use such treatments and try to dispel the myth that natural is the same as safe.

References

1. Linde K et al. St John's Wort for depression: meta-analysis of randomised controlled trials. Br J Psychiatry 2005; 186:99–107.
2. Cott JM. In vitro receptor binding and enzyme inhibition by Hypericum perforatum extract. Pharmacopsychiatry 1997; 30 Suppl 2:108–112.
3. Muller WE et al. Effects of Hypericum extract (LI 160) in biochemical models of antidepressant activity. Pharmacopsychiatry 1997; 30 Suppl 2:102–107.
4. Kasper S et al. Superior efficacy of St John's wort extract WS 5570 compared to placebo in patients with major depression: a randomized, double-blind, placebo-controlled, multi-center trial [ISRCTN77277298]. BMC Med 2006; 4:14.
5. National Institute for Health and Clinical Excellence. Depression: the treatment and management of depression in adults (update). Clinical Guideline 90, 2009. http://www.nice.org.uk/
6. Linde K et al. St John's Wort for major depression. Cochrane Database Syst Rev 2008: 4:CD000448.
7. Randlov C et al. The efficacy of St. John's Wort in patients with minor depressive symptoms or dysthymia—a double-blind placebo-controlled study. Phytomedicine 2006; 13:215–221.
8. Kasper S et al. Continuation and long-term maintenance treatment with Hypericum extract WS 5570 after recovery from an acute episode of moderate depression—a double-blind, randomized, placebo controlled long-term trial. Eur Neuropsychopharmacol 2008; 18:803–813.
9. Chen JA et al. Association between patient beliefs regarding assigned treatment and clinical response: reanalysis of data from the Hypericum Depression Trial Study Group. J Clin Psychiatry 2011; 72:1669–1676.
10. Teufel-Mayer R et al. Effects of long-term administration of Hypericum extracts on the affinity and density of the central serotonergic 5-HT1 A and 5-HT2 A receptors. Pharmacopsychiatry 1997; 30 Suppl 2:113–116.
11. Anghelescu IG et al. Comparison of Hypericum extract WS 5570 and paroxetine in ongoing treatment after recovery from an episode of moderate to severe depression: results from a randomized multicenter study. Pharmacopsychiatry 2006; 39:213–219.
12. Kasper S et al. Better tolerability of St. John's wort extract WS 5570 compared to treatment with SSRIs: a reanalysis of data from controlled clinical trials in acute major depression. Int Clin Psychopharmacol 2010; 25:204–213.
13. Knuppel L et al. Adverse effects of St. John's Wort: a systematic review. J Clin Psychiatry 2004; 65:1470–1479.
14. Volz HP. Controlled clinical trials of Hypericum extracts in depressed patients—an overview. Pharmacopsychiatry 1997; 30 Suppl 2:72–76.
15. Gaster B et al. St John's Wort for depression: a systematic review. Arch Intern Med 2000; 160:152–156.
16. Woelk H. Comparison of St John's Wort and imipramine for treating depression: randomised controlled trial. BMJ 2000; 321:536–539.
17. Wagner PJ et al. Taking the edge off: why patients choose St. John's Wort. J Fam Pract 1999; 48:615–619.
18. Bove GM. Acute neuropathy after exposure to sun in a patient treated with St John's Wort. Lancet 1998; 352:1121–1122.
19. Wielgus AR et al. Phototoxicity in human retinal pigment epithelial cells promoted by hypericin, a component of St. John's wort. Photochem Photobiol 2007; 83:706–713.
20. Crampsey DP et al. Nasal insertion of St John's wort: an unusual cause of epistaxis. J Laryngol Otol 2007; 121:279–280.
21. Nierenberg AA et al. Mania associated with St. John's wort. Biol Psychiatry 1999; 46:1707–1708.
22. Rahimi R et al. An update on the ability of St. John's wort to affect the metabolism of other drugs. Expert Opin Drug Metab Toxicol 2012; 8:691–708.
23. Xu H et al. Effects of St John's wort and CYP2C9 genotype on the pharmacokinetics and pharmacodynamics of gliclazide. Br J Pharmacol 2008; 153:1579–1586.
24. Russo E et al. Hypericum perforatum: pharmacokinetic, mechanism of action, tolerability, and clinical drug-drug interactions. Phytother Res 2014; 28:643–655.
25. Madabushi R et al. Hyperforin in St. John's wort drug interactions. Eur J Clin Pharmacol 2006; 62:225–233.
26. Imai H et al. The recovery time-course of CYP3A after induction by St John's wort administration. Br J Clin Pharmacol 2008; 65:701–707.
27. Johne A et al. Pharmacokinetic interaction of digoxin with an herbal extract from St John's Wort (Hypericum perforatum). Clin Pharmacol Ther 1999; 66:338–345.
28. Piscitelli SC et al. Indinavir concentrations and St John's Wort. Lancet 2000; 355:547–548.
29. Van Strater AC et al. Interaction of St John's wort (Hypericum perforatum) with clozapine. Int Clin Psychopharmacol 2012; 27:121–124.
30. Ernst E. Second thoughts about safety of St John's Wort. Lancet 1999; 354:2014–2016.
31. Andren L et al. Interaction between a commercially available St. John's wort product (Movina) and atorvastatin in patients with hypercholesterolemia. Eur J Clin Pharmacol 2007; 63:913–916.
32. Anon. Reminder: St John's Wort (Hypericum perforatum) interactions. Curr Probl Pharmacovigilance 2000; 26:6–7.
33. Lau WC et al. The effect of St. John's wort on the pharmacodynamic response of clopidogrel in hyporesponsive volunteers and patients: increased platelet inhibition by enhancement of CYP 3A4 metabolic activity. J Cardiovasc Pharmacol 2011; 57:86–93.
34. Lantz MS et al. St. John's wort and antidepressant drug interactions in the elderly. J Geriatr Psychiatry Neurol 1999; 12:7–10.
35. Barnes J et al. Different standards for reporting ADRs to herbal remedies and conventional OTC medicines: face-to-face interviews with 515 users of herbal remedies. Br J Clin Pharmacol 1998; 45:496–500.
36. Linden M et al. Self medication with St. John's wort in depressive disorders: an observational study in community pharmacies. J Affect Disord 2008; 107:205–210.

Recognised minimum effective doses of antidepressants

The recommended minimum effective doses of antidepressants are summarised in Table 4.5.

Table 4.5 The recommended minimum effective doses of antidepressants

References

1. Furukawa TA et al. Meta-analysis of effects and side effects of low dosage tricyclic antidepressants in depression: systematic review. BMJ 2002; 325:991.
2. Donoghue J et al. Suboptimal use of antidepressants in the treatment of depression. CNS Drugs 2000; 13:365–368.
3. Lancaster SG et al. Lofepramine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in depressive illness. Drugs 1989; 37:123–140.
4. Montgomery SA et al. The optimal dosing regimen for citalopram—a meta-analysis of nine placebo-controlled studies. Int Clin Psychopharmacol 1994; 9 Suppl 1:35–40.
5. Burke WJ et al. Fixed-dose trial of the single isomer SSRI escitalopram in depressed outpatients. J Clin Psychiatry 2002; 63:331–336.
6. Altamura AC et al. The evidence for 20mg a day of fluoxetine as the optimal dose in the treatment of depression. Br J Psychiatry 1988; 3 Suppl: 109–112.
7. Walczak DD et al. The oral dose-effect relationship for fluvoxamine: a fixed-dose comparison against placebo in depressed outpatients. Ann Clin Psychiatry 1996; 8:139–151.
8. Dunner DL et al. Optimal dose regimen for paroxetine. J Clin Psychiatry 1992; 53 Suppl:21–26.
9. Moon CAL et al. A double-blind comparison of sertraline and clomipramine in the treatment of major depressive disorder and associative anxiety in general practice. J Psychopharmacol 1994; 8:171–176.
10. Loo H et al. Determination of the dose of agomelatine, a melatoninergic agonist and selective 5-HT(2C) antagonist, in the treatment of major depressive disorder: a placebo-controlled dose range study. Int Clin Psychopharmacol 2002; 17:239–247.
11. Goldstein DJ et al. Duloxetine in the treatment of depression: a double-blind placebo-controlled comparison with paroxetine. J Clin Psychopharmacol 2004; 24:389–399.
12. Detke MJ et al. Duloxetine, 60 mg once daily, for major depressive disorder: a randomized double-blind placebo-controlled trial. J Clin Psychiatry 2002; 63:308–315.
13. van Moffaert M et al. Mirtazapine is more effective than trazodone: a double-blind controlled study in hospitalized patients with major depression. Int Clin Psychopharmacol 1995; 10:3–9.
14. Priest RG et al. Moclobemide in the treatment of depression. Rev Contemp Pharmacother 1994; 5:35–43.
15. Schatzberg AF. Clinical efficacy of reboxetine in major depression. J Clin Psychiatry 2000; 61 Suppl 10:31–38.
16. Brogden RN et al. Trazodone: a review of its pharmacological properties and therapeutic use in depression and anxiety. Drugs 1981; 21:401–429.
17. Feighner JP et al. Efficacy of once-daily venlafaxine extended release (XR) for symptoms of anxiety in depressed outpatients. J Affect Disord 1998; 47:55–62.
18. Mahableshwarkar AR et al. A randomized, double-blind, fixed-dose study comparing the efficacy and tolerability of vortioxetine 2.5 and 10 mg in acute treatment of adults with generalized anxiety disorder. Hum Psychopharmacol 2014; 29:64–72.
19. Takeda Pharmaceuticals America Inc. Highlights of Prescribing Information. Brintellix (vortioxetine) tablets. http://www.us.brintellix.com/

Drug treatment of depression

The drug treatment of depression is summarised in Figure 4.1.

Figure 4.1 Drug treatment of depression. SSRI, selective serotonin reuptake inhibitor.

Notes to Figure 4.1

• Tools such as the Montgomery–Asberg Depression Rating Scale (MADRS)¹² and the Hamilton Depression Rating Scale (HAM-D)¹³ are used in trials to assess drug effect. The HAM-D is now somewhat anachronistic and few clinicians are familiar with the MADRS (although it is probably the best scale to measure severity and change). The PHQ-9¹⁴ is simple to use and is recommended for assessing symptom change in depression (although it better measures frequency rather than severity of symptoms).
• Switching between drug classes in cases of poor tolerability is not clearly supported by published studies but has a strong theoretical basis. Having said that, in practice, many patients who cannot tolerate one SSRI will readily tolerate another
• In cases of non-response, there is some evidence that switching within a drug class is effective,^8,15–18 but switching between classes is, in practice, the most common option and is supported by some analyses.¹⁹ NICE and the American Psychological Association (APA) recommend both options.^2,9
• There is minimal evidence to support increasing the dose of most SSRIs in depression.²⁰ Slightly better evidence suggests that increasing the dose of venlafaxine, escitalopram and tricyclics may be helpful.³
• Switch treatments early (e.g. after a week or two) if adverse effects intolerable or if no improvement at all is seen by 3–4 weeks. Opinions on when to switch vary somewhat but it is clear that antidepressants have a fairly prompt onset of action^21–23 and that non-response at 2–6 weeks is a good predictor of overall non-response.^24–26 The absence of any improvement at all at 3–4 weeks should normally provoke a change in treatment (British Association for Psychopharmacology [BAP] guidelines suggest 4 weeks³). If there is some improvement at this time, continue and assess for a further 2–3 weeks (see section on 'Antidepressants: general overview' in this chapter).

References

1. Leuchter AF et al. Role of pill-taking, expectation and therapeutic alliance in the placebo response in clinical trials for major depression. Br J Psychiatry 2014; 205:443–449.
2. American Psychiatric Association. Practice Guideline for the Treatment of Patients with Major Depressive Disorder, 3rd edn. Washington, DC: American Psychiatric Association.doi: 10.1176/appi.books.9780890423387.654001, 2010
3. Anderson IM et al. Evidence-based guidelines for treating depressive disorders with antidepressants: a revision of the 2000 British Association for Psychopharmacology guidelines. J Psychopharmacol 2008; 22:343–396.
4. Crismon ML et al. The Texas Medication Algorithm Project: report of the Texas Consensus Conference Panel on Medication Treatment of Major Depressive Disorder. J Clin Psychiatry 1999; 60:142–156.
5. Kocsis JH et al. Maintenance therapy for chronic depression. A controlled clinical trial of desipramine. Arch Gen Psychiatry 1996; 53:769–774.
6. Dekker J et al. The use of antidepressants after recovery from depression. Eur J Psychiatry 2000; 14:207–212.
7. Nelson JC. Treatment of antidepressant nonresponders: augmentation or switch? J Clin Psychiatry 1998; 59 Suppl 15:35–41.
8. Joffe RT. Substitution therapy in patients with major depression. CNS Drugs 1999; 11:175–180.
9. National Institute for Health and Clinical Excellence. Depression in adults: the treatment and management of depression in adults. Clinical Guideline 90, 2009. http://www.nice.org.uk/Guidance/cg90
10. Montgomery SA et al. A randomised, double-blind study in adults with major depressive disorder with an inadequate response to a single course of selective serotonin reuptake inhibitor or serotonin-noradrenaline reuptake inhibitor treatment switched to vortioxetine or agomelatine. Hum Psychopharmacol 2014; 29:470–482.
11. Sparshatt A et al. A naturalistic evaluation and audit database of agomelatine: clinical outcome at 12 weeks. Acta Psychiatr Scand 2013; 128:203–211.
12. Montgomery SA et al. A new depression scale designed to be sensitive to change. Br J Psychiatry 1979; 134:382–389.
13. Hamilton M. Development of a rating scale for primary depressive illness. Br J Soc Clin Psychol 1967; 6:278–296.
14. Kroenke K et al. The PHQ-9: validity of a brief depression severity measure. J Gen Intern Med 2001; 16:606–613.
15. Thase ME et al. Citalopram treatment of fluoxetine nonresponders. J Clin Psychiatry 2001; 62:683–687.
16. Rush AJ et al. Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression. N Engl J Med 2006; 354:1231–1242.
17. Ruhe HG et al. Switching antidepressants after a first selective serotonin reuptake inhibitor in major depressive disorder: a systematic review. J Clin Psychiatry 2006; 67:1836–1855.
18. Brent D et al. Switching to another SSRI or to venlafaxine with or without cognitive behavioral therapy for adolescents with SSRI-resistant depression: the TORDIA Randomized Controlled Trial. JAMA 2008; 299:901–913.
19. Papakostas GI et al. Treatment of SSRI-resistant depression: a meta-analysis comparing withinversus across-class switches. Biol Psychiatry 2008; 63:699–704.
20. Adli M et al. Is dose escalation of antidepressants a rational strategy after a medium-dose treatment has failed? A systematic review. Eur Arch Psychiatry Clin Neurosci 2005; 255:387–400.
21. Papakostas GI et al. A meta-analysis of early sustained response rates between antidepressants and placebo for the treatment of major depressive disorder. J Clin Psychopharmacol 2006; 26:56–60.
22. Taylor MJ et al. Early onset of selective serotonin reuptake inhibitor antidepressant action: systematic review and meta-analysis. Arch Gen Psychiatry 2006; 63:1217–1223.
23. Posternak MA et al. Is there a delay in the antidepressant effect? A meta-analysis. J Clin Psychiatry 2005; 66:148–158.
24. Szegedi A et al. Early improvement in the first 2 weeks as a predictor of treatment outcome in patients with major depressive disorder: a meta-analysis including 6562 patients. J Clin Psychiatry 2009; 70:344–353.
25. Baldwin DS et al. How long should a trial of escitalopram treatment be in patients with major depressive disorder, generalised anxiety disorder or social anxiety disorder? An exploration of the randomised controlled trial database. Hum Psychopharmacol 2009; 24:269–275.
26. Nierenberg AA et al. Early nonresponse to fluoxetine as a predictor of poor 8-week outcome. Am J Psychiatry 1995; 152:1500–1503.

Further reading

Barbui C et al. Amitriptyline v. the rest: still the leading antidepressant after 40 years of randomised controlled trials. Br J Psychiatry 2001;178:129–144.

Preskorn SH. The use of biomarkers in psychiatric research: how serotonin transporter occupancy explains the dose-response curves of SSRIs. J Psychiatr Pract 2012; 18:38–45.

Rubinow DR. Treatment strategies after SSRI failure—good news and bad news. N Engl J Med 2006;354:1305–1307.

Smith D et al. Efficacy and tolerability of venlafaxine compared with selective serotonin reuptake inhibitors and other antidepressants: a meta-analysis. Br J Psychiatry 2002;180:396–404.

Treatment of refractory depression

Refractory depression is difficult to treat successfully and outcomes are poor,^1–3 especially if evidence-based protocols are not followed.⁴ Refractory depression is not a uniform entity but a complex spectrum of severity which can be graded⁵ and in which outcome is closely linked to grading.⁶ A significant minority of apparently resistant unipolar depression may in fact be bipolar-type depression^7,8 which is often unresponsive to antidepressants^9,10 (see section on 'Bipolar depression' in Chapter 3).

Treatment of refractory depression is to some extent informed by results of the STAR*D programme (Sequenced Treatment Alternatives to Relieve Depression). This was a pragmatic effectiveness study which used remission of symptoms as its main outcome. At stage 1,¹¹2786 subjects received citalopram (mean dose 41.8 mg/day) for 14 weeks; remission was seen in 28% (response [50% reduction in symptoms score] 47%). Subjects who failed to remit were entered into the continued study of sequential treatments.^12–16 Remission rates are given in Figure 4.2. Very few statistically significant differences were noted from this point on. At stage 3,¹⁵ T₃ was found to be significantly better tolerated than lithium. At stage 4,¹⁶ tranylcypromine was less effective and less well tolerated than the mirtazapine/venlafaxine combination. Overall, remission rates, as can be seen, were worryingly low for individual treatments, although it should be noted that the trial consisted of subjects with long histories of recurrent depression, and the majority ultimately responded.

Figure 4.2 Remission rates in STAR*D.

STAR*D demonstrated that the treatment of refractory depression requires a flexible approach and that response to a particular treatment option is not readily predicted by pharmacology or previous treatments. The programme established bupropion and buspirone augmentation as worthwhile options and resurrected from some obscurity the use of T₃ augmentation and of nortriptyline. It also, to some extent, confirmed the safety and (to a lesser extent) efficacy of the combination of mirtazapine and venlafaxine.

Treatment of refractory depression: first choice

The treatments commonly used in the treatment of refractory depression, with generally good evidence from the literature, are shown in Table 4.6.

Table 4.6 First choice: commonly used treatments generally well supported by published literature (no preference implied by order)

References

1. Dunner DL et al. Prospective, long-term, multicenter study of the naturalistic outcomes of patients with treatment-resistant depression. J Clin Psychiatry 2006; 67:688–695.
2. Wooderson SC et al. Prospective evaluation of specialist inpatient treatment for refractory affective disorders. J Affect Disord 2011; 131:92–103.
3. Fekadu A et al. What happens to patients with treatment-resistant depression? A systematic review of medium to long term outcome studies. J Affect Disord 2009; 116:4–11.
4. Trivedi MH et al. Clinical results for patients with major depressive disorder in the Texas Medication Algorithm Project. Arch Gen Psychiatry 2004; 61:669–680.
5. Fekadu A et al. A multidimensional tool to quantify treatment resistance in depression: the Maudsley staging method. J Clin Psychiatry 2009; 70:177–184.
6. Fekadu A et al. The Maudsley Staging Method for treatment-resistant depression: prediction of longer-term outcome and persistence of symptoms. J Clin Psychiatry 2009; 70:952–957.
7. Angst J et al. Toward a re-definition of subthreshold bipolarity: epidemiology and proposed criteria for bipolar-II, minor bipolar disorders and hypomania. J Affect Disord 2003; 73:133–146.
8. Smith DJ et al. Unrecognised bipolar disorder in primary care patients with depression. Br J Psychiatry 2011; 199:49–56.
9. Sidor MM et al. Antidepressants for the acute treatment of bipolar depression: a systematic review and meta-analysis. J Clin Psychiatry 2011; 72:156–167.
10. Taylor DM et al. Comparative efficacy and acceptability of drug treatments for bipolar depression: a multiple-treatments meta-analysis. Acta Psychiatr Scand 2014; 130:452–469.
11. Trivedi MH et al. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry 2006; 163:28–40.
12. Rush AJ et al. Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression. N Engl J Med 2006; 354:1231–1242.
13. Trivedi MH et al. Medication augmentation after the failure of SSRIs for depression. N Engl J Med 2006; 354:1243–1252.
14. Fava M et al. A comparison of mirtazapine and nortriptyline following two consecutive failed medication treatments for depressed outpatients: a STAR*D report. Am J Psychiatry 2006; 163:1161–1172.
15. Nierenberg AA et al. A comparison of lithium and T(3) augmentation following two failed medication treatments for depression: a STAR*D report. Am J Psychiatry 2006; 163:1519–1530.
16. McGrath PJ et al. Tranylcypromine versus venlafaxine plus mirtazapine following three failed antidepressant medication trials for depression: a STAR*D report. Am J Psychiatry 2006; 163:1531–1541.
17. National Institute for Health and Clinical Excellence. Depression: the treatment and management of depression in adults (update). Clinical Guideline 90, 2009. http://www.nice.org.uk/
18. Fava M et al. Lithium and tricyclic augmentation of fluoxetine treatment for resistant major depression: a double-blind, controlled study. Am J Psychiatry 1994; 151:1372–1374.
19. Bauer M et al. Lithium augmentation in treatment-resistant depression: meta-analysis of placebo-controlled studies. J Clin Psychopharmacol 1999; 19:427–434.
20. Crossley NA et al. Acceleration and augmentation of antidepressants with lithium for depressive disorders: two meta-analyses of randomized, placebo-controlled trials. J Clin Psychiatry 2007; 68:935–940.
21. Nierenberg AA et al. Lithium augmentation of nortriptyline for subjects resistant to multiple antidepressants. J Clin Psychopharmacol 2003; 23:92–95.
22. Folkerts HW et al. Electroconvulsive therapy vs. paroxetine in treatment-resistant depression—a randomized study. Acta Psychiatr Scand 1997; 96:334–342.
23. Gonzalez-Pinto A et al. Efficacy and safety of venlafaxine-ECT combination in treatment-resistant depression. J Neuropsychiatry Clin Neurosci 2002; 14:206–209.
24. Eranti S et al. A randomized, controlled trial with 6-month follow-up of repetitive transcranial magnetic stimulation and electroconvulsive therapy for severe depression. Am J Psychiatry 2007; 164:73–81.
25. Garlow SJ et al. The combination of triiodothyronine (T3) and sertraline is not superior to sertraline monotherapy in the treatment of major depressive disorder. J Psychiatr Res 2012; 46:1406–1413.
26. Joffe RT et al. A comparison of triiodothyronine and thyroxine in the potentiation of tricyclic antidepressants. Psychiatry Res 1990; 32:241–251.
27. Anderson IM. Drug treatment of depression: reflections on the evidence. Adv Psychiatr Treat 2003; 9:11–20.
28. Iosifescu DV et al. An open study of triiodothyronine augmentation of selective serotonin reuptake inhibitors in treatment-resistant major depressive disorder. J Clin Psychiatry 2005; 66:1038–1042.
29. Abraham G et al. T3 augmentation of SSRI resistant depression. J Affect Disord 2006; 91:211–215.
30. Kelly TF et al. Long term augmentation with T3 in refractory major depression. J Affect Disord 2009; 115:230–233.
31. Shelton RC et al. Olanzapine/fluoxetine combination for treatment-resistant depression: a controlled study of SSRI and nortriptyline resistance. J Clin Psychiatry 2005; 66:1289–1297.
32. Corya SA et al. A randomized, double-blind comparison of olanzapine/fluoxetine combination, olanzapine, fluoxetine, and venlafaxine in treatment-resistant depression. Depress Anxiety 2006; 23:364–372.
33. Takahashi H et al. Augmentation with olanzapine in TCA-refractory depression with melancholic features: a consecutive case series. Hum Psychopharmacol 2008; 23:217–220.
34. Thase ME et al. A randomized, double-blind comparison of olanzapine/fluoxetine combination, olanzapine, and fluoxetine in treatmentresistant major depressive disorder. J Clin Psychiatry 2007; 68:224–236.
35. Trivedi MH et al. An integrated analysis of olanzapine/fluoxetine combination in clinical trials of treatment-resistant depression. J Clin Psychiatry 2009; 70:387–396.
36. Jensen NH et al. N-desalkylquetiapine, a potent norepinephrine reuptake inhibitor and partial 5-HT1A agonist, as a putative mediator of quetiapine's antidepressant activity. Neuropsychopharmacology 2008; 33:2303–2312.
37. El-Khalili N et al. Extended-release quetiapine fumarate (quetiapine XR) as adjunctive therapy in major depressive disorder (MDD) in patients with an inadequate response to ongoing antidepressant treatment: a multicentre, randomized, double-blind, placebo-controlled study. Int J Neuropsychopharmacol 2010; 13:917–932.
38. Bauer M et al. Extended-release quetiapine as adjunct to an antidepressant in patients with major depressive disorder: results of a randomized, placebo-controlled, double-blind study. J Clin Psychiatry 2009; 70:540–549.
39. Bauer M et al. A pooled analysis of two randomised, placebo-controlled studies of extended release quetiapine fumarate adjunctive to antidepressant therapy in patients with major depressive disorder. J Affect Disord 2010; 127:19–30.
40. Montgomery S et al. P01-75—Quetiapine XR or lithium combination with antidepressants in treatment resistant depression. Eur Psychiatry 2010; 25:296–296.
41. Doree JP et al. Quetiapine augmentation of treatment-resistant depression: a comparison with lithium. Curr Med Res Opin 2007; 23:333–341.
42. Yoshimura R et al. Addition of risperidone to sertraline improves sertraline-resistant refractory depression without influencing plasma concentrations of sertraline and desmethylsertraline. Hum Psychopharmacol 2008; 23:707–713.
43. Mahmoud RA et al. Risperidone for treatment-refractory major depressive disorder: a randomized trial. Ann Intern Med 2007; 147:593–602.
44. Ostroff RB et al. Risperidone augmentation of selective serotonin reuptake inhibitors in major depression. J Clin Psychiatry 1999; 60:256–259.
45. Rapaport MH et al. Effects of risperidone augmentation in patients with treatment-resistant depression: results of open-label treatment followed by double-blind continuation. Neuropsychopharmacology 2006; 31:2505–2513.
46. Stoll AL et al. Tranylcypromine plus risperidone for treatment-refractory major depression. J Clin Psychopharmacol 2000; 20:495–496.
47. Keitner GI et al. A randomized, placebo-controlled trial of risperidone augmentation for patients with difficult-to-treat unipolar, nonpsychotic major depression. J Psychiatr Res 2009; 43:205–214.
48. Marcus RN et al. The efficacy and safety of aripiprazole as adjunctive therapy in major depressive disorder: a second multicenter, randomized, double-blind, placebo-controlled study. J Clin Psychopharmacol 2008; 28:156–165.
49. Hellerstein DJ et al. Aripiprazole as an adjunctive treatment for refractory unipolar depression. Prog Neuropsychopharmacol Biol Psychiatry 2008; 32:744–750.
50. Simon JS et al. Aripiprazole augmentation of antidepressants for the treatment of partially responding and nonresponding patients with major depressive disorder. J Clin Psychiatry 2005; 66:1216–1220.
51. Papakostas GI et al. Aripiprazole augmentation of selective serotonin reuptake inhibitors for treatment-resistant major depressive disorder. J Clin Psychiatry 2005; 66:1326–1330.
52. Berman RM et al. Aripiprazole augmentation in major depressive disorder: a double-blind, placebo-controlled study in patients with inadequate response to antidepressants. CNS Spectr 2009; 14:197–206.
53. Fava M et al. A double-blind, placebo-controlled study of aripiprazole adjunctive to antidepressant therapy among depressed outpatients with inadequate response to prior antidepressant therapy (ADAPT-A Study). Psychother Psychosom 2012; 81:87–97.
54. Jon DI et al. Augmentation of aripiprazole for depressed patients with an inadequate response to antidepressant treatment: a 6-week prospective, open-label, multicenter study. Clin Neuropharmacol 2013; 36:157–161.
55. Yoshimura R et al. Comparison of the efficacy between paroxetine and sertraline augmented with aripiprazole in patients with refractory major depressive disorder. Prog Neuropsychopharmacol Biol Psychiatry 2012; 39:355–357.
56. Zisook S et al. Use of bupropion in combination with serotonin reuptake inhibitors. Biol Psychiatry 2006; 59:203–210.
57. Fatemi SH et al. Venlafaxine and bupropion combination therapy in a case of treatment-resistant depression. Ann Pharmacother 1999; 33:701–703.
58. Pierre JM et al. Bupropion-tranylcypromine combination for treatment-refractory depression. J Clin Psychiatry 2000; 61:450–451.
59. Lam RW et al. Citalopram and bupropion-SR: combining versus switching in patients with treatment-resistant depression. J Clin Psychiatry 2004; 65:337–340.
60. Papakostas GI et al. The combination of duloxetine and bupropion for treatment-resistant major depressive disorder. Depress Anxiety 2006; 23:178–181.
61. Carpenter LL et al. A double-blind, placebo-controlled study of antidepressant augmentation with mirtazapine. Biol Psychiatry 2002; 51:183–188.
62. Carpenter LL et al. Mirtazapine augmentation in the treatment of refractory depression. J Clin Psychiatry 1999; 60:45–49.
63. Ferreri M et al. Benefits from mianserin augmentation of fluoxetine in patients with major depression non-responders to fluoxetine alone. Acta Psychiatr Scand 2001; 103:66–72.

Treatment of refractory depression: second choice

Treatments that may be used in the treatment of refractory depression, although less commonly and with less support from published evaluations, are shown in Table 4.7.

Table 4.7 Second choice: less commonly used, variably supported by published evaluations (no preference implied by order)

References

1. aan het Rot M et al. Safety and efficacy of repeated-dose intravenous ketamine for treatment-resistant depression. Biol Psychiatry 2010; 67:139–145.
2. Ibrahim L et al. Course of improvement in depressive symptoms to a single intravenous infusion of ketamine vs add-on riluzole: results from a 4-week, double-blind, placebo-controlled study. Neuropsychopharmacology 2012; 37:1526–1533.
3. Murrough JW et al. Rapid and longer-term antidepressant effects of repeated ketamine infusions in treatment-resistant major depression. Biol Psychiatry 2013; 74:250–256.
4. Murrough JW et al. Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial. Am J Psychiatry 2013; 170:1134–1142.
5. Segmiller F et al. Repeated S-ketamine infusions in therapy resistant depression: a case series. J Clin Pharmacol 2013; 53:996–998.
6. Diamond PR et al. Ketamine infusions for treatment resistant depression: a series of 28 patients treated weekly or twice weekly in an ECT clinic. J Psychopharmacol 2014; 28:536–544.
7. Normann C et al. Lamotrigine as adjunct to paroxetine in acute depression: a placebo-controlled, double-blind study. J Clin Psychiatry 2002; 63:337–344.
8. Barbosa L et al. A double-blind, randomized, placebo-controlled trial of augmentation with lamotrigine or placebo in patients concomitantly treated with fluoxetine for resistant major depressive episodes. J Clin Psychiatry 2003; 64:403–407.
9. Santos MA et al. Efficacy and safety of antidepressant augmentation with lamotrigine in patients with treatment-resistant depression: a randomized, placebo-controlled, double-blind study. Prim Care Companion J Clin Psychiatry 2008; 10:187–190.
10. Barbee JG et al. Lamotrigine as an augmentation agent in treatment-resistant depression. J Clin Psychiatry 2002; 63:737–741.
11. Barbee JG et al. A double-blind placebo-controlled trial of lamotrigine as an antidepressant augmentation agent in treatment-refractory unipolar depression. J Clin Psychiatry 2011; 72:1405–1412.
12. Trivedi MH et al. Medication augmentation after the failure of SSRIs for depression. N Engl J Med 2006; 354:1243–1252.
13. Appelberg BG et al. Patients with severe depression may benefit from buspirone augmentation of selective serotonin reuptake inhibitors: results from a placebo-controlled, randomized, double-blind, placebo wash-in study. J Clin Psychiatry 2001; 62:448–452.
14. National Institute for Health and Clinical Excellence. Depression: the treatment and management of depression in adults (update). Clinical Guideline 90, 2009. http://www.nice.org.uk/
15. Poirier MF et al. Venlafaxine and paroxetine in treatment-resistant depression. Double-blind, randomised comparison. Br J Psychiatry 1999; 175:12–16.
16. Nierenberg AA et al. Venlafaxine for treatment-resistant unipolar depression. J Clin Psychopharmacol 1994; 14:419–423.
17. Smith D et al. Efficacy and tolerability of venlafaxine compared with selective serotonin reuptake inhibitors and other antidepressants: a meta-analysis. Br J Psychiatry 2002; 180:396–404.
18. Rush AJ et al. Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression. N Engl J Med 2006; 354:1231–1242.

Treatment of refractory depression: other reported treatments

Other pharmacological treatments have been reported in the literature, but the evidence is sparse (Table 4.8). Prescribers must familiarise themselves with the primary literature before using these strategies.

Table 4.8 Other reported treatments (no preference implied by order)

References

1. Stryjer R et al. Amantadine as augmentation therapy in the management of treatment-resistant depression. Int Clin Psychopharmacol 2003; 18:93–96.
2. Takahashi H et al. Addition of a dopamine agonist, cabergoline, to a serotonin-noradrenalin reuptake inhibitor, milnacipran as a therapeutic option in the treatment of refractory depression: two case reports. Clin Neuropharmacol 2003; 26:230–232.
3. Heresco-Levy U et al. A randomized add-on trial of high-dose d-cycloserine for treatment-resistant depression. Int J Neuropsychopharmacol 2013; 16:501–506.
4. George TP et al. Nicotinic antagonist augmentation of selective serotonin reuptake inhibitor-refractory major depressive disorder: a preliminary study. J Clin Psychopharmacol 2008; 28:340–344.
5. Bacher I et al. Mecamylamine—a nicotinic acetylcholine receptor antagonist with potential for the treatment of neuropsychiatric disorders. Expert Opin Pharmacother 2009; 10:2709–2721.
6. McAskill R et al. Pindolol augmentation of antidepressant therapy. Br J Psychiatry 1998; 173:203–208.
7. Rasanen P et al. Mitchell B. Balter Award—1998. Pindolol and major affective disorders: a three-year follow-up study of 30,485 patients. J Clin Psychopharmacol 1999; 19:297–302.
8. Perry EB et al. Pindolol augmentation in depressed patients resistant to selective serotonin reuptake inhibitors: a double-blind, randomized, controlled trial. J Clin Psychiatry 2004; 65:238–243.
9. Sokolski KN et al. Once-daily high-dose pindolol for SSRI-refractory depression. Psychiatry Res 2004; 125:81–86.
10. Whale R et al. Pindolol augmentation of serotonin reuptake inhibitors for the treatment of depressive disorder: a systematic review. J Psychopharmacol 2010; 24:513–520.
11. Tobe EH et al. Possible usefulness of tianeptine in treatment-resistant depression. Int J Psychiatry Clin Pract 2013; 17:313–316.
12. Woo YS et al. Tianeptine combination for partial or non-response to selective serotonin re-uptake inhibitor monotherapy. Psychiatry Clin Neurosci 2013; 67:219–227.
13. Angst J et al. The treatment of depression with L-5-hydroxytryptophan versus imipramine. Results of two open and one double-blind study. Arch Psychiatr Nervenkr 1977; 224:175–186.
14. Alino JJ et al. 5-Hydroxytryptophan (5-HTP) and a MAOI (nialamide) in the treatment of depressions. A double-blind controlled study. Int Pharmacopsychiatry 1976; 11:8–15.
15. Hale AS et al. Clomipramine, tryptophan and lithium in combination for resistant endogenous depression: seven case studies. Br J Psychiatry 1987; 151:213–217.
16. Young SN. Use of tryptophan in combination with other antidepressant treatments: a review. J Psychiatry Neurosci 1991; 16:241–246.
17. Siwek M et al. Zinc supplementation augments efficacy of imipramine in treatment resistant patients: a double blind, placebo-controlled study. J Affect Disord 2009; 118:187–195.
18. Papakostas GI et al. Ziprasidone augmentation of selective serotonin reuptake inhibitors (SSRIs) for SSRI-resistant major depressive disorder. J Clin Psychiatry 2004; 65:217–221.
19. Dunner DL et al. Efficacy and tolerability of adjunctive ziprasidone in treatment-resistant depression: a randomized, open-label, pilot study. J Clin Psychiatry 2007; 68:1071–1077.
20. Papakostas GI et al. A 12-week, randomized, double-blind, placebo-controlled, sequential parallel comparison trial of ziprasidone as monotherapy for major depressive disorder. J Clin Psychiatry 2012; 73:1541–1547.
21. White K et al. The combined use of MAOIs and tricyclics. J Clin Psychiatry 1984; 45:67–69.
22. Kennedy N et al. Treatment and response in refractory depression: results from a specialist affective disorders service. J Affect Disord 2004; 81:49–53.
23. Connolly KR et al. If at first you don't succeed: a review of the evidence for antidepressant augmentation, combination and switching strategies. Drugs 2011; 71:43–64.
24. Dinan TG et al. Dexamethasone augmentation in treatment-resistant depression. Acta Psychiatr Scand 1997; 95:58–61.
25. Bodani M et al. The use of dexamethasone in elderly patients with antidepressant-resistant depressive illness. J Psychopharmacol 1999; 13:196–197.
26. Drevets WC et al. Antidepressant effects of the muscarinic cholinergic receptor antagonist scopolamine: a review. Biol Psychiatry 2013; 73:1156–1163.
27. Wolkowitz OM et al. Antiglucocorticoid treatment of depression: double-blind ketoconazole. Biol Psychiatry 1999; 45:1070–1074.
28. DeBattista C et al. A prospective trial of modafinil as an adjunctive treatment of major depression. J Clin Psychopharmacol 2004; 24:87–90.
29. Ninan PT et al. Adjunctive modafinil at initiation of treatment with a selective serotonin reuptake inhibitor enhances the degree and onset of therapeutic effects in patients with major depressive disorder and fatigue. J Clin Psychiatry 2004; 65:414–420.
30. Menza MA et al. Modafinil augmentation of antidepressant treatment in depression. J Clin Psychiatry 2000; 61:378–381.
31. Taneja I et al. A randomized, double-blind, crossover trial of modafinil on mood. J Clin Psychopharmacol 2007; 27:76–78.
32. Feighner JP et al. Clinical effect of nemifitide, a novel pentapeptide antidepressant, in the treatment of severely depressed refractory patients. Int Clin Psychopharmacol 2008; 23:29–35.
33. Nierenberg AA et al. Nortriptyline for treatment-resistant depression. J Clin Psychiatry 2003; 64:35–39.
34. Nierenberg AA et al. Lithium augmentation of nortriptyline for subjects resistant to multiple antidepressants. J Clin Psychopharmacol 2003; 23:92–95.
35. Fava M et al. A comparison of mirtazapine and nortriptyline following two consecutive failed medication treatments for depressed outpatients: a STAR*D report. Am J Psychiatry 2006; 163:1161–1172.
36. Shelton RC et al. Olanzapine/fluoxetine combination for treatment-resistant depression: a controlled study of SSRI and nortriptyline resistance. J Clin Psychiatry 2005; 66:1289–1297.
37. Stahl SM. Basic psychopharmacology of antidepressants, part 2: Oestrogen as an adjunct to antidepressant treatment. J Clin Psychiatry 1998; 59 Suppl 4:15–24.
38. Nemets B et al. Addition of omega-3 fatty acid to maintenance medication treatment for recurrent unipolar depressive disorder. Am J Psychiatry 2002; 159:477–479.
39. Appleton KM et al. Updated systematic review and meta-analysis of the effects of n-3 long-chain polyunsaturated fatty acids on depressed mood. Am J Clin Nutr 2010; 91:757–770.
40. Whiskey E et al. Pramipexole in unipolar and bipolar depression. Psychiatr Bull 2004; 28:438–440.
41. Cusin C et al. A randomized, double-blind, placebo-controlled trial of pramipexole augmentation in treatment-resistant major depressive disorder. J Clin Psychiatry 2013; 74:e636–641.
42. Zarate CA Jr et al. An open-label trial of riluzole in patients with treatment-resistant major depression. Am J Psychiatry 2004; 161:171–174.
43. Pancheri P et al. A double-blind, randomized parallel-group, efficacy and safety study of intramuscular S-adenosyl-L-methionine 1,4-butanedisulphonate (SAMe) versus imipramine in patients with major depressive disorder. Int J Neuropsychopharmacol 2002; 5:287–294.
44. Alpert JE et al. S-adenosyl-L-methionine (SAMe) as an adjunct for resistant major depressive disorder: an open trial following partial or nonresponse to selective serotonin reuptake inhibitors or venlafaxine. J Clin Psychopharmacol 2004; 24:661–664.
45. Taylor D. Selective serotonin reuptake inhibitors and tricyclic antidepressants in combination—interactions and therapeutic uses. Br J Psychiatry 1995; 167:575–580.
46. Malhi GS et al. Management of resistant depression. Int J Psychiatry Clin Pract 1997; 1:269–276.
47. Pope HG Jr et al. Testosterone gel supplementation for men with refractory depression: a randomized, placebo-controlled trial. Am J Psychiatry 2003; 160:105–111.
48. Harrison CL et al. Tolerability of high-dose venlafaxine in depressed patients. J Psychopharmacol 2004; 18:200–204.
49. Fountoulakis KN et al. Combined oral venlafaxine and intravenous clomipramine-A: successful temporary response in a patient with extremely refractory depression. Can J Psychiatry 2004; 49:73–74.

Treatment of refractory depression: sequence of treatments—summary

Figure 4.3 outlines the sequence of treatment options for refractory depression.

Figure 4.3 Treatment sequence options for refractory depression.

*Some may consider the closely supervised use of older antidepressants—TCAs (e.g. amitriptyline or nortriptyline) or MAOIs (e.g. phenelzine) at this point. MAOI, monoamine oxidase inhibitor; SNRI, selective noradrenaline reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant.

Psychotic depression

Although psychotic symptoms can occur across the whole spectrum of depression severity,¹ those patients who have psychotic symptoms are generally more severely unwell than those who do not have psychotic symptoms.² Combined treatment with an antidepressant and antipsychotic is often the recommended first line³ but until recently the data underpinning this practice have been weak.^4,5

When given in adequate doses, TCAs are probably more effective than newer antidepressants in the treatment of psychotic depression.^4,6,7 Prior failure to respond to previous adequate treatment predicts reduced chance of response to subsequent treatment.⁸

There are few studies of newer antidepressants and atypical antipsychotics, either alone or in combination, specifically for psychotic depression. One large RCT showed response rates of 64% for combined olanzapine and fluoxetine compared to 35% for olanzapine alone and 28% for placebo.⁹ Another showed a remission rate of 42% with olanzapine plus sertraline compared with 24% with olanzapine alone.¹⁰ There was no antidepressant-alone group in either study. Small open studies have found quetiapine,¹¹ aripiprazole¹² and amisulpride¹³ augmentation of an antidepressant to be effective and relatively well tolerated, but again there were no data available for antidepressant treatment alone. One RCT (n = 122)⁷ found venlafaxine plus quetiapine to be more effective than venlafaxine alone but not more effective than imipramine alone. These findings could be interpreted as either supporting the increased efficacy of a TCA over venlafaxine, and/or supporting combined antidepressant and antipsychotic treatment over an antidepressant drug alone. A review of all combination studies concluded that an antipsychotic+antidepressant was superior to either alone (four of nine studies showed some advantage for combination¹⁴). A recent meta-analysis concluded that a combination of an antipsychotic and an antidepressant is more effective than either an antipsychotic alone (NNT 5) or an antidepressant alone (NNT 7).¹⁵ NICE¹⁶ recommends that consideration should be given to augmenting an antidepressant with an antipsychotic in the treatment of an acute episode of psychotic depression. Cochrane is in agreement but with reservations.¹⁷ Note that these data relate to acute treatment.

Virtually nothing is known of the optimum duration of treatment with a combination of an antidepressant and antipsychotic. NICE recommends augmentation of an antidepressant with an antipsychotic in non-psychotic depression that does not respond adequately to an antidepressant alone and states that if one agent is to be stopped during the maintenance phase, it should usually be the augmenting agent. It would seem reasonable to use the same approach in psychotic depression.

In clinical practice, at least until recent years, only a small proportion of patients with psychotic depression received an antipsychotic drug,¹⁸ perhaps reflecting clinicians' uncertainty regarding the risk–benefit ratio of this treatment strategy and the lack of consensus across published guidelines.¹⁹ Under-diagnosis (and hence inadequacy of treatment) of psychotic symptoms in depression is also a significant problem.²⁰ Nonetheless, some antipsychotic drugs such as quetiapine and olanzapine have useful antidepressant effects (as well as being antipsychotic) and so there is an empirical basis (in addition to the trial outcomes above) for their use as additive agents to antidepressant treatment.

Long-term outcome is generally poorer for psychotic than non-psychotic depression.^21,22 Patients with psychotic depression may also have a poorer response to combined pharmacological and psychological treatment than those with non-psychotic depression.²³

Psychotic depression is one of the indications for ECT. Not only is ECT effective, it may also be more protective against relapse in psychotic depression than in non-psychotic depression.²⁴ One small RCT demonstrated superiority of maintenance ECT plus nortriptyline over nortriptyline alone at 2 years.²⁵

Novel approaches being developed include those based on antiglucocorticoid strategies, since hypothalamic-pituitary-adrenal (HPA) axis hyperactivity is more common in psychotic depression; one small open study found rapid effects of the glucocorticoid receptor antagonist mifepristone,²⁶ although these findings have been criticised.²⁷ Response may be related to mifepristone plasma levels (> 1800 ng/mL).²⁸ There is an anecdotal report of the successful use of methylphenidate in a patient who did not respond to robust doses of an antidepressant and antipsychotic combined.²⁹ Minocycline has also shown good effect in an open study.³⁰

There is no specific indication for other therapies or augmentation strategies in psychotic depression over and above that for resistant depression or psychosis described elsewhere.

Summary

• TCAs are probably the drugs of first choice in psychotic depression.
• SSRIs/SNRIs are a second-line alternative when TCAs are poorly tolerated.
• Augmentation of an antidepressant with olanzapine or quetiapine is recommended.
• The optimum dose and duration of antipsychotic augmentation are unknown. If one treatment is to be stopped during the maintenance phase, this should usually be the antipsychotic.
• ECT should always be considered where a rapid response is required or where other treatments have failed.

References

1. Forty L et al. Is depression severity the sole cause of psychotic symptoms during an episode of unipolar major depression? A study both between and within subjects. J Affect Disord 2009; 114:103–109.
2. Gaudiano BA et al. Depressive symptom profiles and severity patterns in outpatients with psychotic vs nonpsychotic major depression. Compr Psychiatry 2008; 49:421–429.
3. Anderson IM et al. Evidence-based guidelines for treating depressive disorders with antidepressants: a revision of the 2000 British Association for Psychopharmacology guidelines. J Psychopharmacol 2008; 22:343–396.
4. Wijkstra W et al. Pharmacological treatment for unipolar psychotic depression: systematic review and meta-analysis. Br J Psychiatry 2006; 188:410–415.
5. Mulsant BH et al. A double-blind randomized comparison of nortriptyline plus perphenazine versus nortriptyline plus placebo in the treatment of psychotic depression in late life. J Clin Psychiatry 2001; 62:597–604.
6. Birkenhager TK et al. Efficacy of imipramine in psychotic versus nonpsychotic depression. J Clin Psychopharmacol 2008; 28:166–170.
7. Wijkstra J et al. Treatment of unipolar psychotic depression: a randomized, double-blind study comparing imipramine, venlafaxine, and venlafaxine plus quetiapine. Acta Psychiatr Scand 2010; 121:190–200.
8. Blumberger DM et al. Impact of prior pharmacotherapy on remission of psychotic depression in a randomized controlled trial. J Psychiatr Res 2011; 45:896–901.
9. Rothschild AJ et al. A double-blind, randomized study of olanzapine and olanzapine/fluoxetine combination for major depression with psychotic features. J Clin Psychopharmacol 2004; 24:365–373.
10. Meyers BS et al. A double-blind randomized controlled trial of olanzapine plus sertraline vs olanzapine plus placebo for psychotic depression: the study of pharmacotherapy of psychotic depression (STOP-PD). Arch Gen Psychiatry 2009; 66:838–847.
11. Konstantinidis A et al. Quetiapine in combination with citalopram in patients with unipolar psychotic depression. Prog Neuropsychopharmacol Biol Psychiatry 2007; 31:242–247.
12. Matthews JD et al. An open study of aripiprazole and escitalopram for psychotic major depressive disorder. J Clin Psychopharmacol 2009; 29:73–76.
13. Politis AM et al. Combination therapy with amisulpride and antidepressants: clinical observations in case series of elderly patients with psychotic depression. Prog Neuropsychopharmacol Biol Psychiatry 2008; 32:1227–1230.
14. Rothschild AJ. Challenges in the treatment of major depressive disorder with psychotic features. Schizophr Bull 2013; 39:787–796.
15. Farahani A et al. Are antipsychotics or antidepressants needed for psychotic depression? A systematic review and meta-analysis of trials comparing antidepressant or antipsychotic monotherapy with combination treatment. J Clin Psychiatry 2012; 73:486–496.
16. National Institute for Health and Care Excellence. Depression in adults: the treatment and management of depression in adults. Clinical Guideline 90, 2009. http://www.nice.org.uk/Guidance/cg90
17. Wijkstra J et al. Pharmacological treatment for psychotic depression. Cochrane Database Syst Rev 2013; 11:CD004044.
18. Andreescu C et al. Persisting low use of antipsychotics in the treatment of major depressive disorder with psychotic features. J Clin Psychiatry 2007; 68:194–200.
19. Leadholm AK et al. The treatment of psychotic depression: is there consensus among guidelines and psychiatrists? J Affect Disord 2013; 145:214–220.
20. Rothschild AJ et al. Missed diagnosis of psychotic depression at 4 academic medical centers. J Clin Psychiatry 2008; 69:1293–1296.
21. Flint AJ et al. Two-year outcome of psychotic depression in late life. Am J Psychiatry 1998; 155:178–183.
22. Maj M et al. Phenomenology and prognostic significance of delusions in major depressive disorder: a 10-year prospective follow-up study. J Clin Psychiatry 2007; 68:1411–1417.
23. Gaudiano BA et al. Differential response to combined treatment in patients with psychotic versus nonpsychotic major depression. J Nerv Ment Dis 2005; 193:625–628.
24. Birkenhager TK et al. One-year outcome of psychotic depression after successful electroconvulsive therapy. J ECT 2005; 21:221–226.
25. Navarro V et al. Continuation/maintenance treatment with nortriptyline versus combined nortriptyline and ECT in late-life psychotic depression: a two-year randomized study. Am J Geriatr Psychiatry 2008; 16:498–505.
26. Belanoff JK et al. An open label trial of C-1073 (mifepristone) for psychotic major depression. Biol Psychiatry 2002; 52:386–392.
27. Rubin RT. Dr. Rubin replies (letter). Am J Psychiatry 2004; 161:1722.
28. Blasey CM et al. A multisite trial of mifepristone for the treatment of psychotic depression: a site-by-treatment interaction. Contemp Clin Trials 2009; 30:284–288.
29. Huang CC et al. Adjunctive use of methylphenidate in the treatment of psychotic unipolar depression. Clin Neuropharmacol 2008; 31:245–247.
30. Miyaoka T et al. Minocycline as adjunctive therapy for patients with unipolar psychotic depression: an open-label study. Prog Neuropsychopharmacol Biol Psychiatry 2012; 37:222–226.

Electroconvulsive therapy and psychotropic drugs

Psychotropics are often continued during ECT and some agents (particularly antidepressants^1,2) enhance its efficacy.

Table 4.9 summarises the effect of various psychotropics on seizure duration during ECT. Note that there are few well-controlled studies in this area and so recommendations should be viewed with this in mind. Note also that choice of anaesthetic agent profoundly affects seizure duration,^3–8 post-ictal confusion and ECT efficacy.⁹ Besides concurrent medication, there are many factors that influence seizure threshold and duration.¹⁰

Table 4.9 Effect of psychotropic drugs on seizure duration in ECT

For drugs known to lower seizure threshold, treatment is best begun with a low-energy stimulus (50 mC). Staff should be alerted to the possibility of prolonged seizures and intravenous (IV) diazepam should be available. With drugs known to elevate seizure threshold, higher stimuli may, of course, be required. Methods are available to lower seizure threshold or prolong seizures,⁴⁰ but discussion of these is beyond the scope of this book.

Electroconvulsive therapy frequently causes confusion and disorientation; more rarely, it causes delirium. Close observation is essential. Very limited data support the use of thiamine (200 mg daily) in reducing post-ECT confusion.⁴¹ Nortriptyline seems to enhance ECT efficacy and reduce cognitive adverse effects.¹ Donepezil has been shown to improve recovery time post ECT (and appears to be safe).⁴² Ibuprofen may be used to prevent headache,⁴³ and intranasal sumatriptan⁴⁴ can be used to treat it.

References

1. Sackeim HA et al. Effect of concomitant pharmacotherapy on electroconvulsive therapy outcomes: short-term efficacy and adverse effects. Arch Gen Psychiatry 2009; 66:729–737.
2. Baghai TC et al. The influence of concomitant antidepressant medication on safety, tolerability and clinical effectiveness of electroconvulsive therapy. World J Biol Psychiatry 2006; 7:82–90.
3. Avramov MN et al. The comparative effects of methohexital, propofol, and etomidate for electroconvulsive therapy. Anesth Analg 1995; 81:596–602.
4. Stadtland C et al. A switch from propofol to etomidate during an ECT course increases EEG and motor seizure duration. J ECT 2002; 18:22–25.
5. Gazdag G et al. Etomidate versus propofol for electroconvulsive therapy in patients with schizophrenia. J ECT 2004; 20:225–229.
6. Conca A et al. Etomidate vs. thiopentone in electroconvulsive therapy. An interdisciplinary challenge for anesthesiology and psychiatry. Pharmacopsychiatry 2003; 36:94–97.
7. Rasmussen KG et al. Seizure length with sevoflurane and thiopental for induction of general anesthesia in electroconvulsive therapy: a randomized double-blind trial. J ECT 2006; 22:240–242.
8. Bundy BD et al. Influence of anesthetic drugs and concurrent psychiatric medication on seizure adequacy during electroconvulsive therapy. J Clin Psychiatry 2010; 71:775–777.
9. Eser D et al. The influence of anaesthetic medication on safety, tolerability and clinical effectiveness of electroconvulsive therapy. World J Biol Psychiatry 2010; 11:447–456.
10. van Waarde JA et al. Clinical predictors of seizure threshold in electroconvulsive therapy: a prospective study. Eur Arch Psychiatry Clin Neurosci 2013; 263:167–175.
11. Royal College of Psychiatrists. The ECT Handbook—Council Report 176, 3rd edn. London: RCPsych Publications, 2013.
12. Kellner CH et al. ECT–drug interactions: a review. Psychopharmacol Bull 1991; 27:595–609.
13. Creelman W et al. Electroconvulsive Therapy. In: Ciraulo DA, Shader RI, Greenblatt DJ et al., eds. Drug Interactions in Psychiatry, 3rd edn. Philadelphia: Lippincott Williams and Wilkins; 2005, 337–389.
14. Naguib M et al. Interactions between psychotropics, anaesthetics and electroconvulsive therapy: implications for drug choice and patient management. CNS Drugs 2002; 16:229–247.
15. Maidment I. The interaction between psychiatric medicines and ECT. Hosp Pharm 1997; 4:102–105.
16. Masdrakis VG et al. The safety of the electroconvulsive therapy-escitalopram combination. J ECT 2008; 24:289–291.
17. Dursun SM et al. Effects of antidepressant treatments on first-ECT seizure duration in depression. Prog Neuropsychopharmacol Biol Psychiatry 2001; 25:437–443.
18. Jarvis MR et al. Novel antidepressants and maintenance electroconvulsive therapy: a review. Ann Clin Psychiatry 1992; 4:275–284.
19. Papakostas YG et al. Administration of citalopram before ECT: seizure duration and hormone responses. J ECT 2000; 16:356–360.
20. Gonzalez-Pinto A et al. Efficacy and safety of venlafaxine-ECT combination in treatment-resistant depression. J Neuropsychiatry Clin Neurosci 2002; 14:206–209.
21. Li TC et al. Mirtazapine relieves post-electroconvulsive therapy headaches and nausea: a case series and review of the literature. J ECT 2011; 27:165–167.
22. Hanretta AT et al. Combined use of ECT with duloxetine and olanzapine: a case report. J ECT 2006; 22:139–141.
23. Heinz B et al. Postictal ventricular tachycardia after electroconvulsive therapy treatment associated with a lithium-duloxetine combination. J ECT 2013; 29:e33–35.
24. Dolenc TJ et al. Electroconvulsive therapy in patients taking monoamine oxidase inhibitors. J ECT 2004; 20:258–261.
25. Jha AK et al. Negative interaction between lithium and electroconvulsive therapy—a case-control study. Br J Psychiatry 1996; 168:241–243.
26. Rucker J et al. A case of prolonged seizure after ECT in a patient treated with clomipramine, lithium, L-tryptophan, quetiapine, and thyroxine for major depression. J ECT 2008; 24:272–274.
27. Dolenc TJ et al. The safety of electroconvulsive therapy and lithium in combination: a case series and review of the literature. J ECT 2005; 21:165–170.
28. Havaki-Kontaxaki BJ et al. Concurrent administration of clozapine and electroconvulsive therapy in clozapine-resistant schizophrenia. Clin Neuropharmacol 2006; 29:52–56.
29. Nothdurfter C et al. The influence of concomitant neuroleptic medication on safety, tolerability and clinical effectiveness of electroconvulsive therapy. World J Biol Psychiatry 2006; 7:162–170.
30. Gazdag G et al. The impact of neuroleptic medication on seizure threshold and duration in electroconvulsive therapy. Ideggyogy Sz 2004; 57:385–390.
31. Masdrakis VG et al. The safety of the electroconvulsive therapy-aripiprazole combination: four case reports. J ECT 2008; 24:236–238.
32. Oulis P et al. Corrected QT interval changes during electroconvulsive therapy-antidepressants-atypical antipsychotics coadministration: safety issues. J ECT 2011; 27:e4–e6.
33. Biedermann F et al. Combined clozapine and electroconvulsive therapy in clozapine-resistant schizophrenia: clinical and cognitive outcomes. J ECT 2011; 27:e61–62.
34. Flamarique I et al. Electroconvulsive therapy and clozapine in adolescents with schizophrenia spectrum disorders: is it a safe and effective combination? J Clin Psychopharmacol 2012; 32:756–766.
35. van Waarde JA et al. Patient, treatment, and anatomical predictors of outcome in electroconvulsive therapy: a prospective study. J ECT 2013; 29:113–121.
36. Penland HR et al. Combined use of lamotrigine and electroconvulsive therapy in bipolar depression: a case series. J ECT 2006; 22:142–147.
37. Zarate CA Jr et al. Combined valproate or carbamazepine and electroconvulsive therapy. Ann Clin Psychiatry 1997; 9:19–25.
38. Sienaert P et al. Concurrent use of lamotrigine and electroconvulsive therapy. J ECT 2011; 27:148–152.
39. Jahangard L et al. Comparing efficacy of ECT with and without concurrent sodium valproate therapy in manic patients. J ECT 2012; 28:118–123.
40. Datto C et al. Augmentation of seizure induction in electroconvulsive therapy: a clinical reappraisal. J ECT 2002; 18:118–125.
41. Linton CR et al. Using thiamine to reduce post-ECT confusion. Int J Geriatr Psychiatry 2002; 17:189–192.
42. Prakash J et al. Therapeutic and prophylactic utility of the memory-enhancing drug donepezil hydrochloride on cognition of patients undergoing electroconvulsive therapy: a randomized controlled trial. J ECT 2006; 22:163–168.
43. Leung M et al. Pretreatment with ibuprofen to prevent electroconvulsive therapy-induced headache. J Clin Psychiatry 2003; 64:551–553.
44. Markowitz JS et al. Intranasal sumatriptan in post-ECT headache: results of an open-label trial. J ECT 2001; 17:280–283.

Psychostimulants in depression

Psychostimulants reduce fatigue, promote wakefulness and are mood elevating (as distinct from antidepressant). Amfetamines have been used as treatments for depression since the 1930s¹ and more recently, modafinil has been evaluated as an adjunct to standard antidepressants.² Amfetamines are now rarely used in depression because of their propensity for the development of tolerance and dependence. Prolonged use of high doses is associated with paranoid psychosis.³ Methylphenidate is now more widely used but may have similar shortcomings. Modafinil seems not to induce tolerance, dependence or psychosis but lacks the euphoric effects of amfetamines. Armodafinil, the longer acting isomer of modafinil, is available in some countries.

Psychostimulants differ importantly from standard antidepressants in that their effects are usually seen within a few hours. Amfetamines and methylphenidate may thus be useful where a prompt effect is required and where dependence would not be problematic (e.g. in depression associated with terminal illness) although ketamine might also be considered. Their use might also be justified in severe, prolonged depression unresponsive to standard treatments (e.g. in those considered for psychosurgery). Modafinil might justifiably be used as an adjunct to antidepressants in a wider range of patients and as a specific treatment for hypersomnia and fatigue.⁴

Table 4.10 outlines support (or the absence of it) for the use of psychostimulants in various clinical situations. Generally speaking, data relating to stimulants in depression are poor and inconclusive.^5,6 Careful consideration should be given to any use of any psychostimulant in depression since their shortand long-term safety have not been clearly established. Inclusion of individual drugs in Table 4.10 should not in itself be considered a recommendation for their use.

Table 4.10 Psychostimulants in depression

References

1. Satel SL et al. Stimulants in the treatment of depression: a critical overview. J Clin Psychiatry 1989; 50:241–249.
2. Menza MA et al. Modafinil augmentation of antidepressant treatment in depression. J Clin Psychiatry 2000; 61:378–381.
3. Warneke L. Psychostimulants in psychiatry. Can J Psychiatry 1990; 35:3–10.
4. Goss AJ et al. Modafinil augmentation therapy in unipolar and bipolar depression: a systematic review and meta-analysis of randomized controlled trials. J Clin Psychiatry 2013; 74:1101–1107.
5. Candy M et al. Psychostimulants for depression. Cochrane Database Syst Rev 2008: 2:CD006722.
6. Hardy SE. Methylphenidate for the treatment of depressive symptoms, including fatigue and apathy, in medically ill older adults and terminally ill adults. Am J Geriatr Pharmacother 2009; 7:34–59.
7. Lundt L. Modafinil treatment in patients with seasonal affective disorder/winter depression: an open-label pilot study. J Affect Disord 2004; 81:173–178.
8. Kaufman KR et al. Modafinil monotherapy in depression. Eur Psychiatry 2002; 17:167–169.
9. Little KY. d-Amphetamine versus methylphenidate effects in depressed inpatients. J Clin Psychiatry 1993; 54:349–355.
10. Robin AA et al. A controlled trial of methylphenidate (ritalin) in the treatment of depressive states. J Neurol Neurosurg Psychiatry 1958; 21:55–57.
11. Lavretsky H et al. Combined treatment with methylphenidate and citalopram for accelerated response in the elderly: an open trial. J Clin Psychiatry 2003; 64:1410–1414.
12. Postolache TT et al. Early augmentation of sertraline with methylphenidate. J Clin Psychiatry 1999; 60:123–124.
13. Abolfazli R et al. Double-blind randomized parallel-group clinical trial of efficacy of the combination fluoxetine plus modafinil versus fluoxetine plus placebo in the treatment of major depression. Depress Anxiety 2011; 28:297–302.
14. Gwirtsman HE et al. The antidepressant response to tricyclics in major depressives is accelerated with adjunctive use of methylphenidate. Psychopharmacol Bull 1994; 30:157–164.
15. Dunlop BW et al. Coadministration of modafinil and a selective serotonin reuptake inhibitor from the initiation of treatment of major depressive disorder with fatigue and sleepiness: a double-blind, placebo-controlled study. J Clin Psychopharmacol 2007; 27:614–619.
16. Fava M et al. Modafinil augmentation of selective serotonin reuptake inhibitor therapy in MDD partial responders with persistent fatigue and sleepiness. Ann Clin Psychiatry 2007; 19:153–159.
17. Kerr CW et al. Effects of methylphenidate on fatigue and depression: a randomized, double-blind, placebo-controlled trial. J Pain Symptom Manage 2012; 43:68–77.
18. DeBattista C et al. Adjunct modafinil for the short-term treatment of fatigue and sleepiness in patients with major depressive disorder: a preliminary double-blind, placebo-controlled study. J Clin Psychiatry 2003; 64:1057–1064.
19. Fava M et al. A multicenter, placebo-controlled study of modafinil augmentation in partial responders to selective serotonin reuptake inhibitors with persistent fatigue and sleepiness. J Clin Psychiatry 2005; 66:85–93.
20. Rasmussen NA et al. Modafinil augmentation in depressed patients with partial response to antidepressants: a pilot study on self-reported symptoms covered by the major depression inventory (MDI) and the symptom checklist (SCL-92). Nordic J Psychiatry 2005; 59:173–178.
21. DeBattista C et al. A prospective trial of modafinil as an adjunctive treatment of major depression. J Clin Psychopharmacol 2004; 24:87–90.
22. Markovitz PJ et al. An open-label trial of modafinil augmentation in patients with partial response to antidepressant therapy. J Clin Psychopharmacol 2003; 23:207–209.
23. Ravindran AV et al. Osmotic-release oral system methylphenidate augmentation of antidepressant monotherapy in major depressive disorder: results of a double-blind, randomized, placebo-controlled trial. J Clin Psychiatry 2008; 69:87–94.
24. Fawcett J et al. CNS stimulant potentiation of monoamine oxidase inhibitors in treatment refractory depression. J Clin Psychopharmacol 1991; 11:127–132.
25. Parker G et al. Do the old psychostimulant drugs have a role in managing treatment-resistant depression? Acta Psychiatr Scand 2010; 121:308–314.
26. Trivedi MH et al. A randomized controlled trial of the efficacy and safety of lisdexamfetamine dimesylate as augmentation therapy in adults with residual symptoms of major depressive disorder after treatment with escitalopram. J Clin Psychiatry 2013; 74:802–809.
27. Madhoo M et al. Lisdexamfetamine dimesylate augmentation in adults with persistent executive dysfunction after partial or full remission of major depressive disorder. Neuropsychopharmacology 2014; 39:1388–1398.
28. Frye MA et al. A placebo-controlled evaluation of adjunctive modafinil in the treatment of bipolar depression. Am J Psychiatry 2007; 164:1242–1249.
29. Calabrese JR et al. Adjunctive armodafinil for major depressive episodes associated with bipolar I disorder: a randomized, multicenter, double-blind, placebo-controlled, proof-of-concept study. J Clin Psychiatry 2010; 71:1363–1370.
30. Dell'Osso B et al. Assessing the roles of stimulants/stimulant-like drugs and dopamine-agonists in the treatment of bipolar depression. Curr Psychiatr Rep 2013; 15:378.
31. Fernandez F et al. Methylphenidate for depressive disorders in cancer patients. Psychosomatics 1987; 28:455–461.
32. Macleod AD. Methylphenidate in terminal depression. J Pain Symptom Manage 1998; 16:193–198.
33. Homsi J et al. Methylphenidate for depression in hospice practice. Am J Hosp Palliat Care 2000; 17:393–398.
34. Sarhill N et al. Methylphenidate for fatigue in advanced cancer: a prospective open-label pilot study. Am J Hosp Palliat Care 2001; 18:187–192.
35. Homsi J et al. A phase II study of methylphenidate for depression in advanced cancer. Am J Hosp Palliat Care 2001; 18:403–407.
36. Burns MM et al. Dextroamphetamine treatment for depression in terminally ill patients. Psychosomatics 1994; 35:80–83.
37. Olin J et al. Psychostimulants for depression in hospitalized cancer patients. Psychosomatics 1996; 37:57–62.
38. Ng CG et al. Rapid response to methylphenidate as an add-on therapy to mirtazapine in the treatment of major depressive disorder in terminally ill cancer patients: a four-week, randomized, double-blinded, placebo-controlled study. Eur Neuropsychopharmacol 2014; 24:491–498.
39. Kaplitz SE. Withdrawn, apathetic geriatric patients responsive to methylphenidate. J Am Geriatr Soc 1975; 23:271–276.
40. Wallace AE et al. Double-blind, placebo-controlled trial of methylphenidate in older, depressed, medically ill patients. Am J Psychiatry 1995; 152:929–931.
41. Grade C et al. Methylphenidate in early poststroke recovery: a double-blind, placebo-controlled study. Arch Phys Med Rehabil 1998; 79:1047–1050.
42. Lazarus LW et al. Efficacy and side effects of methylphenidate for poststroke depression. J Clin Psychiatry 1992; 53:447–449.
43. Lingam VR et al. Methylphenidate in treating poststroke depression. J Clin Psychiatry 1988; 49:151–153.
44. Delbari A et al. Effect of methylphenidate and/or levodopa combined with physiotherapy on mood and cognition after stroke: a randomized, double-blind, placebo-controlled trial. Eur Neurol 2011; 66:7–13.
45. Sugden SG et al. Modafinil monotherapy in poststroke depression. Psychosomatics 2004; 45:80–81.
46. Rosenberg PB et al. Methylphenidate in depressed medically ill patients. J Clin Psychiatry 1991; 52:263–267.
47. Woods SW et al. Psychostimulant treatment of depressive disorders secondary to medical illness. J Clin Psychiatry 1986; 47:12–15.
48. Kaufmann MW et al. The use of d-amphetamine in medically ill depressed patients. J Clin Psychiatry 1982; 43:463–464.
49. Wagner GJ et al. Dexamphetamine as a treatment for depression and low energy in AIDS patients: a pilot study. J Psychosom Res 1997; 42:407–411.
50. Wagner GJ et al. Effects of dextroamphetamine on depression and fatigue in men with HIV: a double-blind, placebo-controlled trial. J Clin Psychiatry 2000; 61:436–440.

Post-stroke depression

Depression itself is a well-established risk factor for stroke.^1–3 In addition, depression is seen in at least 30–40% of survivors of stroke^4,5 and post-stroke depression is known to slow functional rehabilitation.⁶ Antidepressants may reduce depressive symptoms and thereby facilitate faster rehabilitation.⁷ They may also improve global cognitive functioning⁸ and enhance motor recovery.⁹ Despite these benefits, most post-stroke depression goes untreated.¹⁰

Prophylaxis

The high incidence of depression after stroke makes prophylaxis worthy of consideration. Pooled data suggest a robust prophylactic effect for antidepressants.¹¹ Nortriptyline, fluoxetine, escitalopram, duloxetine and sertraline appear to prevent post-stroke depression.^12–16 Mirtazapine may both protect against depressive episodes and treat them.¹⁷ Note, though, that a large cohort study that examined adverse outcomes in elderly patients treated with antidepressants reported that mirtazapine (and venlafaxine) may be associated with an increased risk of a new stroke compared with SSRIs or TCAs.¹⁸ Mianserin seems ineffective in the treatment of post-stroke depression.¹⁹ Amitriptyline is effective in treating central post-stroke pain.²⁰

Treatment

Treatment is complicated by medical co-morbidity and by the potential for interaction with other co-prescribed drugs (especially warfarin—see below). Contraindication to antidepressant treatment is more likely with tricyclics than with SSRIs.²¹ Fluoxetine,^9,22,23 citalopram^8,24 and nortriptyline^25,26 are probably the most studied²⁷ and seem to be effective and safe.²⁸ SSRIs and nortriptyline are widely recommended for post-stroke depression. Reboxetine (which does not affect platelet activity) may also be effective and well tolerated²⁹ although its effects overall are doubtful.³⁰

Despite fears, SSRIs seem not to increase risk of stroke³¹ (post-stroke), although some doubt remains.^32,33 (Stroke can be embolic or haemorrhagic—SSRIs may protect against the former and provoke the latter^34,35–see section on 'SSRIs and bleeding' in this chapter). Antidepressants are clearly effective in post-stroke depression^28,36 and treatment should not usually be withheld (although Cochrane is rather lukewarm about the benefits of antidepressants³⁷).

Post-stroke depression—recommended drugs

• SSRIs*
• Nortriptyline

*Caution is clearly required if the index stroke was known to be haemorrhagic because SSRIs increase the risk of de novo haemorrhagic stroke (absolute risk is low) when combined with warfarin or other antiplatelet drugs.³⁸ If the patient is also taking warfarin, suggest citalopram or escitalopram (probably lowest interaction potential³⁹). Where SSRIs are given in any anticoagulated or aspirin-treated patient, consideration should be given to the prescription of a proton pump inhibitor for gastric protection.

References

1. Pan A et al. Depression and risk of stroke morbidity and mortality: a meta-analysis and systematic review. JAMA 2011; 306:1241–1249.
2. Pequignot R et al. Depressive symptoms, antidepressants and disability and future coronary heart disease and stroke events in older adults: the Three City Study. Eur J Epidemiol 2013; 28:249–256.
3. Li CT et al. Major depressive disorder and stroke risks: a 9-year follow-up population-based, matched cohort study. PLoS One 2012; 7:e46818.
4. Gainotti G et al. Relation between depression after stroke, antidepressant therapy, and functional recovery. J Neurol Neurosurg Psychiatry 2001; 71:258–261.
5. Hayee MA et al. Depression after stroke-analysis of 297 stroke patients. Bangladesh Med Res Counc Bull 2001; 27:96–102.
6. Paolucci S et al. Post-stroke depression, antidepressant treatment and rehabilitation results. A case-control study. Cerebrovasc Dis 2001; 12:264–271.
7. Gainotti G et al. Determinants and consequences of post-stroke depression. Curr Opin Neurol 2002; 15:85–89.
8. Jorge RE et al. Escitalopram and enhancement of cognitive recovery following stroke. Arch Gen Psychiatry 2010; 67:187–196.
9. Chollet F et al. Fluoxetine for motor recovery after acute ischaemic stroke (FLAME): a randomised placebo-controlled trial. Lancet Neurol 2011; 10:123–130.
10. El Husseini N et al. Depression and antidepressant use after stroke and transient ischemic attack. Stroke 2012; 43:1609–1616.
11. Chen Y et al. Antidepressant prophylaxis for poststroke depression: a meta-analysis. Int Clin Psychopharmacol 2007; 22:159–166.
12. Narushima K et al. Preventing poststroke depression: a 12-week double-blind randomized treatment trial and 21-month follow-up. J Nerv Ment Dis 2002; 190:296–303.
13. Rasmussen A et al. A double-blind, placebo-controlled study of sertraline in the prevention of depression in stroke patients. Psychosomatics 2003; 44:216–221.
14. Robinson RG et al. Escitalopram and problem-solving therapy for prevention of poststroke depression: a randomized controlled trial. JAMA 2008; 299:2391–2400.
15. Almeida OP et al. Preventing depression after stroke: results from a randomized placebo-controlled trial. J Clin Psychiatry 2006; 67:1104–1109.
16. Zhang LS et al. Prophylactic effects of duloxetine on post-stroke depression symptoms: an open single-blind trial. Eur Neurol 2013; 69:336–343.
17. Niedermaier N et al. Prevention and treatment of poststroke depression with mirtazapine in patients with acute stroke. J Clin Psychiatry 2004; 65:1619–1623.
18. Coupland C et al. Antidepressant use and risk of adverse outcomes in older people: population based cohort study. BMJ 2011; 343:d4551.
19. Palomaki H et al. Prevention of poststroke depression: 1 year randomised placebo controlled double blind trial of mianserin with 6 month follow up after therapy. J Neurol Neurosurg Psychiatry 1999; 66:490–494.
20. Lampl C et al. Amitriptyline in the prophylaxis of central poststroke pain. Preliminary results of 39 patients in a placebo-controlled, long-term study. Stroke 2002; 33:3030–3032.
21. Cole MG et al. Feasibility and effectiveness of treatments for post-stroke depression in elderly inpatients: systematic review. J Geriatr Psychiatry Neurol 2001; 14:37–41.
22. Wiart L et al. Fluoxetine in early poststroke depression: a double-blind placebo-controlled study. Stroke 2000; 31:1829–1832.
23. Choi-Kwon S et al. Fluoxetine improves the quality of life in patients with poststroke emotional disturbances. Cerebrovasc Dis 2008; 26:266–271.
24. Andersen G et al. Effective treatment of poststroke depression with the selective serotonin reuptake inhibitor citalopram. Stroke 1994; 25:1099–1104.
25. Robinson RG et al. Nortriptyline versus fluoxetine in the treatment of depression and in short-term recovery after stroke: a placebocontrolled, double-blind study. Am J Psychiatry 2000; 157:351–359.
26. Zhang W et al. Nortriptyline protects mitochondria and reduces cerebral ischemia/hypoxia injury. Stroke 2008; 39:455–462.
27. Starkstein SE et al. Antidepressant therapy in post-stroke depression. Expert Opin Pharmacother 2008; 9:1291–1298.
28. Mead GE et al. Selective serotonin reuptake inhibitors for stroke recovery. JAMA 2013; 310:1066–1067.
29. Rampello L et al. An evaluation of efficacy and safety of reboxetine in elderly patients affected by 'retarded' post-stroke depression. A random, placebo-controlled study. Arch Gerontol Geriatr 2005; 40:275–285.
30. Eyding D et al. Reboxetine for acute treatment of major depression: systematic review and meta-analysis of published and unpublished placebo and selective serotonin reuptake inhibitor controlled trials. BMJ 2010; 341:c4737.
31. Douglas I et al. The use of antidepressants and the risk of haemorrhagic stroke: a nested case control study. Br J Clin Pharmacol 2011; 71:116–120.
32. Ramasubbu R. SSRI treatment-associated stroke: causality assessment in two cases. Ann Pharmacother 2004; 38:1197–1201.
33. Hackam DG et al. Selective serotonin reuptake inhibitors and brain hemorrhage: a meta-analysis. Neurology 2012; 79:1862–1865.
34. Trifiro G et al. Risk of ischemic stroke associated with antidepressant drug use in elderly persons. J Clin Psychopharmacol 2010; 30:252–258.
35. Wu CS et al. Association of cerebrovascular events with antidepressant use: a case-crossover study. Am J Psychiatry 2011; 168:511–521.
36. Chen Y et al. Treatment effects of antidepressants in patients with post-stroke depression: a meta-analysis. Ann Pharmacother 2006; 40:2115–2122.
37. Hackett ML et al. Interventions for treating depression after stroke. Cochrane Database Syst Rev 2008: 4:CD003437.
38. Quinn GR et al. Effect of selective serotonin reuptake inhibitors on bleeding risk in patients with atrial fibrillation taking warfarin. Am J Cardiol 2014; 114:583–586.
39. Sayal KS et al. Psychotropic interactions with warfarin. Acta Psychiatr Scand 2000; 102:250–255.

Further reading

Robinson RG et al. Poststroke depression: a review. Can J Psychiatry 2010; 55:341–349.

Treatment of depression in the elderly

The prevalence of most physical illnesses increases with age. Many physical problems such as cardiovascular disease, chronic pain, diabetes and Parkinson's disease are associated with a high risk of depressive illness.^1,2 The morbidity and mortality associated with depression are increased in the elderly³ as they are more likely to be physically frail and therefore vulnerable to serious consequences from self-neglect (e.g. life-threatening dehydration or hypothermia) and immobility (e.g. venous stasis). Almost 20% of completed suicides occur in the elderly.⁴ Mortality is reduced by effective treatment of depression.

In common with placebo-controlled studies in younger adults, at least some adequately powered studies in elderly patients have failed to find 'active' antidepressants to be more effective than placebo,^5–8 although it is commonly perceived that the elderly may take longer to respond to antidepressants than younger adults.⁹ Even in the elderly, it may still be possible to identify non-responders as early as 4 weeks into treatment.¹⁰ Two studies have found that in elderly people who had recovered from an episode of depression and had received antidepressants for 2 years, 60% relapsed within 2 years if antidepressant treatment was withdrawn.^11,12 This finding held true for first-episode patients. Lower doses of antidepressants may be effective as prophylaxis. Dothiepin (dosulepin) 75 mg/day has been shown to be effective in this regard.¹³ Note that NICE recommends that dosulepin should not be used as it is particularly cardiotoxic in overdose.¹⁴ There is no evidence to suggest that the response to antidepressants is reduced in the physically ill,¹⁵ although outcome in the elderly in general is often suboptimal.^16,17

There is no ideal antidepressant in the elderly. All are associated with problems (Table 4.11). SSRIs are generally better tolerated than TCAs;¹⁸ they do, however, increase the risk of gastrointestinal (GI) bleeds, particularly in the very elderly and those with established risk factors such as a history of bleeds or treatment with a nonsteroidal anti-inflammatory drug (NSAID), steroid or warfarin. The risk of other types of bleed such as haemorrhagic stroke may also be increased¹⁹ (see section on 'SSRIs and bleeding' in this chapter). The elderly are also particularly prone to develop hyponatraemia²⁰ with SSRIs (see section on 'Antidepressant-induced hyponatraemia' in this chapter), as well as postural hypotension and falls (the clinical consequences of which may be increased by SSRI-induced osteopenia²¹). Agomelatine is effective in older patients, is well tolerated and has not been linked to hyponatraemia.^22,23 Its use is limited by the need for frequent blood sampling to check liver function tests (LFTs). Vortioxetine and duloxetine have also been shown to be effective and reasonably well tolerated in the elderly²⁴ but caveats related to SSRIs, above, are relevant here. A general practice database study found that, compared with SSRIs, 'other antidepressants' (venlafaxine, mirtazapine, etc.) were associated with a greater risk of a number of potentially serious side-effects in the elderly (stroke/transient ischaemic attack (TIA), fracture, seizures, attempted suicide/self-harm) as well as increased all-cause mortality;²⁰ the study was observational and so could not separate the effect of antidepressants from any increased risk inherent in the group of patients treated with these antidepressants. Polyunsaturated fatty acids (fish oils) are probably not effective.²⁵

Ultimately, choice is determined by the individual clinical circumstances of each patient, particularly physical co-morbidity and concomitant medication (both prescribed and 'over the counter') (see section on 'Drug interactions with antidepressants' in this chapter).

Table 4.11 Antidepressants and the elderly

References

1. Katona C et al. Impact of screening old people with physical illness for depression? Lancet 2000; 356:91–92.
2. Lyketsos CG. Depression and diabetes: more on what the relationship might be. Am J Psychiatry 2010; 167:496–497.
3. Gallo JJ et al. Long term effect of depression care management on mortality in older adults: follow-up of cluster randomized clinical trial in primary care. BMJ 2013; 346:f2570.
4. Cattell H et al. One hundred cases of suicide in elderly people. Br J Psychiatry 1995; 166:451–457.
5. Schatzberg A et al. A double-blind, placebo-controlled study of venlafaxine and fluoxetine in geriatric outpatients with major depression. Am J Geriatr Psychiatry 2006; 14:361–370.
6. Wilson K et al. Antidepressant versus placebo for depressed elderly. Cochrane Database Syst Rev 2001; 2:CD000561.
7. O'Connor CM et al. Safety and efficacy of sertraline for depression in patients with heart failure: results of the SADHART-CHF (Sertraline Against Depression and Heart Disease in Chronic Heart Failure) trial. J Am Coll Cardiol 2010; 56:692–699.
8. Seitz DP et al. Citalopram versus other antidepressants for late-life depression: a systematic review and meta-analysis. Int J Geriatr Psychiatry 2010; 25:1296–1305.
9. Paykel ES et al. Residual symptoms after partial remission: an important outcome in depression. Psychol Med 1995; 25:1171–1180.
10. Mulsant BH et al. What is the optimal duration of a short-term antidepressant trial when treating geriatric depression? J Clin Psychopharmacol 2006; 26:113–120.
11. Flint AJ et al. Recurrence of first-episode geriatric depression after discontinuation of maintenance antidepressants. Am J Psychiatry 1999; 156:943–945.
12. Reynolds CF III et al. Maintenance treatment of major depression in old age. N Engl J Med 2006; 354:1130–1138.
13. Old Age Depression Interest Group. How long should the elderly take antidepressants? A double-blind placebo-controlled study of continuation/prophylaxis therapy with dothiepin. Br J Psychiatry 1993; 162:175–182.
14. National Institute for Health and Care Excellence. Depression in adults: the treatment and management of depression in adults. Clinical Guideline 90, 2009. http://www.nice.org.uk/Guidance/cg90
15. Evans M et al. Placebo-controlled treatment trial of depression in elderly physically ill patients. Int J Geriatr Psychiatry 1997; 12:817–824.
16. Calati R et al. Antidepressants in elderly: metaregression of double-blind, randomized clinical trials. J Affect Disord 2013; 147:1–8.
17. Tedeschini E et al. Efficacy of antidepressants for late-life depression: a meta-analysis and meta-regression of placebo-controlled randomized trials. J Clin Psychiatry 2011; 72:1660–1668.
18. Mottram P et al. Antidepressants for depressed elderly. Cochrane Database Syst Rev 2006; 1:CD003491.
19. Smoller JW et al. Antidepressant use and risk of incident cardiovascular morbidity and mortality among postmenopausal women in the Women's Health Initiative study. Arch Intern Med 2009; 169:2128–2139.
20. Coupland C et al. Antidepressant use and risk of adverse outcomes in older people: population based cohort study. BMJ 2011; 343:d4551.
21. Williams LJ et al. Selective serotonin reuptake inhibitor use and bone mineral density in women with a history of depression. Int Clin Psychopharmacol 2008; 23:84–87.
22. Heun R et al. The efficacy of agomelatine in elderly patients with recurrent Major Depressive Disorder: a placebo-controlled study. J Clin Psychiatry 2013; 74:587–594.
23. Laux G. The antidepressant efficacy of agomelatine in daily practice: results of the non-interventional study VIVALDI. Eur Psychiatry 2011; 26 Suppl 1:647.
24. Katona C et al. A randomized, double-blind, placebo-controlled, duloxetine-referenced, fixed-dose study comparing the efficacy and safety of Lu AA21004 in elderly patients with major depressive disorder. Int Clin Psychopharmacol 2012; 27:215–223.
25. Sinn N et al. Effects of n-3 fatty acids, EPA v. DHA, on depressive symptoms, quality of life, memory and executive function in older adults with mild cognitive impairment: a 6-month randomised controlled trial. Br J Nutr 2012; 107:1682–1693.
26. Draper B et al. Tolerability of selective serotonin reuptake inhibitors: issues relevant to the elderly. Drugs Aging 2008; 25:501–519.
27. Bose A et al. Escitalopram in the acute treatment of depressed patients aged 60 years or older. Am J Geriatr Psychiatry 2008; 16:14–20.
28. Raskin J et al. Safety and tolerability of duloxetine at 60 mg once daily in elderly patients with major depressive disorder. J Clin Psychopharmacol 2008; 28:32–38.
29. Johnson EM et al. Cardiovascular changes associated with venlafaxine in the treatment of late-life depression. Am J Geriatr Psychiatry 2006; 14:796–802.

Further reading

National Institute for Health and Clinical Excellence. Depression with a chronic physical health problem. Clinical Guideline 91, 2009. http://www.nice.org.uk/CG91

Pinquart M et al. Treatments for later-life depressive conditions: a meta-analytic comparison of pharmacotherapy and psychotherapy. Am J Psychiatry 2006; 163:1493–1501.

Van der Wurff FB et al. Electroconvulsive therapy for the depressed elderly. Cochrane Database Syst Rev 2003; 2:CD003593.

Antidepressant discontinuation symptoms

What are discontinuation symptoms?

The term 'discontinuation symptoms' is used to describe symptoms experienced on stopping prescribed drugs that are not drugs of dependence. There is an important semantic difference between 'discontinuation' and 'withdrawal' symptoms—the latter implies addiction; the former does not. While this distinction is important for precise medical terminology, it may be irrelevant to patient experience. Discontinuation symptoms may occur after stopping many drugs, including antidepressants, and can sometimes be explained in the context of 'receptor rebound'^1,2–e.g. an antidepressant with potent anticholinergic side-effects may be associated with diarrhoea on discontinuation.

Discontinuation symptoms may be entirely new or similar to some of the original symptoms of the illness, and so cannot be attributed to other causes. They can be broadly divided into six categories; affective (e.g. irritability); gastrointestinal (e.g. nausea); neuromotor (e.g. ataxia); vasomotor (e.g. diaphoresis); neurosensory (e.g. paraesthesia); and other neurological (e.g. increased dreaming).² Rarely, mania may occur.⁴ Discontinuation symptoms are experienced by at least a third of patients^5–8 and are seen to some extent with all antidepressants,⁹ with the possible exceptions of agomelatine¹⁰ and vortioxetine.¹¹

The onset of symptoms is usually within 5 days of stopping treatment (depending on the half-life of the antidepressant) or occasionally during taper or after missed doses^12,13 (short half-life drugs only). Symptoms can vary in form and intensity and occur in any combination. They are usually mild and self-limiting, but can occasionally be severe and prolonged. The perception of symptom severity is probably made worse by the absence of forewarnings. Some symptoms are more likely with individual drugs (Table 4.12). Symptoms can be quantified using the Discontinuation–Emergent Signs and Symptoms (DESS) scale.⁶

Agomelatine seems to be associated with a very low, if any, risk of discontinuation symptoms.¹⁰ Mirtazapine withdrawal seems to be characterised by anxiety, insomnia and nausea.^15–17 Bupropion withdrawal syndrome is similar to that seen with SSRIs. Limited data suggest vortioxetine has a low potential for withdrawal symtpoms¹¹ and its Summary of Product Characteristics (SPC) suggests abrupt withdrawal is possible.¹⁸

Clinical relevance¹⁹

The symptoms of a discontinuation reaction may be mistaken for a relapse of illness or the emergence of a new physical illness,²⁰ leading to unnecessary investigations or reintroduction of the antidepressant. Symptoms may be severe enough to interfere with daily functioning and those who have experienced discontinuation symptoms may reason (perhaps appropriately) that antidepressants are 'addictive' and not wish to accept treatment. There is also evidence of emergent suicidal thoughts on discontinuation with paroxetine.⁸

Table 4.12 Antidepressant discontinuation symptoms

Who is most at risk?^19,20

Although anyone can experience discontinuation symptoms, the risk is increased in those prescribed short half-life drugs^6,12,21–24 (e.g. paroxetine, venlafaxine), particularly if they do not take them regularly. Two-thirds of patients prescribed antidepressants skip a few doses from time to time,²⁵ and many patients stop their antidepressant abruptly.⁵ The risk is also increased in those who have been taking antidepressants for 8 weeks or longer,²⁶ those who have developed anxiety symptoms at the start of antidepressant therapy (particularly with SSRIs), those receiving other centrally acting medication (e.g. antihypertensives, antihistamines, antipsychotics), children and adolescents, and those who have experienced discontinuation symptoms before.

Antidepressant discontinuation symptoms are common in neonates born to women taking antidepressants (see section on 'Pregnancy' in Chapter 7).

How to avoid discontinuation symptoms^19–21

Generally, antidepressant therapy should be discontinued over at least a 4-week period (this is not required with fluoxetine).¹² The shorter the half-life of the drug, the more important that this rule is followed. The end of the taper may need to be slower, as symptoms may not appear until the reduction in the total daily dosage of the antidepressant is (proportionately) substantial. Patients receiving MAOIs may need to be tapered over a longer period. Tranylcypromine may be particularly difficult to stop.¹⁴ At-risk patients (see above) may need a slower taper. Agomelatine and vortioxetine can probably be stopped abruptly.

Many people suffer symptoms despite slow withdrawal and even if they have received adequate education regarding discontinuation symptoms.^8,23 For these patients, the option of abrupt withdrawal should be discussed. Some may prefer to face a week or two of intense symptoms rather than months of less severe discontinuation effects.

How to treat discontinuation symptoms^19,20

There are few systematic studies in this area. Treatment is pragmatic. If symptoms are mild, reassure the patient that these symptoms are common after discontinuing an antidepressant and will pass in a few days. If symptoms are severe, reintroduce the original antidepressant (or another with a longer half-life from the same class) and taper gradually while monitoring for symptoms.

Some evidence supports the use of anticholinergic agents in tricyclic withdrawal²⁷ and fluoxetine for symptoms associated with stopping clomipramine²⁸ or venlafaxine²⁹–fluoxetine, having a longer plasma half-life, seems to be associated with a lower incidence of discontinuation symptoms than other similar drugs.³⁰

Key points that patients should know

• Antidepressants are not addictive (a survey of 1946 people across the UK conducted in 1997 found that 74% thought that antidepressants were addictive³). Note, however, that the semantic and categorical distinctions between addiction and the withdrawal symptoms seen with antidepressants may be unimportant to patients.
• Patients should be informed that they may experience discontinuation symptoms (and the most likely symptoms associated with the drug that they are taking) when they stop their antidepressant.
• Short half-life antidepressants should not generally be stopped abruptly, although some patients may prefer to risk a short period of intense symptoms rather than a prolonged period of milder symptoms.
• Discontinuation symptoms can occur after missed doses if the antidepressant prescribed has a short half-life. A very few patients experience pre-dose discontinuation symptoms which provoke the taking of the antidepressant at an earlier time each day.

References

1. Blier P et al. Physiologic mechanisms underlying the antidepressant discontinuation syndrome. J Clin Psychiatry 2006; 67 Suppl 4:8–13.
2. Delgado PL. Monoamine depletion studies: implications for antidepressant discontinuation syndrome. J Clin Psychiatry 2006; 67 Suppl 4: 22–26.
3. Paykel ES et al. Changes in public attitudes to depression during the Defeat Depression Campaign. Br J Psychiatry 1998; 173:519–522.
4. Narayan V et al. Antidepressant discontinuation manic states: a critical review of the literature and suggested diagnostic criteria. J Psychopharmacol 2011; 25:306–313.
5. van Geffen, EC et al. Discontinuation symptoms in users of selective serotonin reuptake inhibitors in clinical practice: tapering versus abrupt discontinuation. Eur J Clin Pharmacol 2005; 61:303–307.
6. Fava M. Prospective studies of adverse events related to antidepressant discontinuation. J Clin Psychiatry 2006; 67 Suppl 4:14–21.
7. Perahia DG et al. Symptoms following abrupt discontinuation of duloxetine treatment in patients with major depressive disorder. J Affect Disord 2005; 89:207–212.
8. Tint A et al. The effect of rate of antidepressant tapering on the incidence of discontinuation symptoms: a randomised study. J Psychopharmacol 2008; 22:330–332.
9. Taylor D et al. Antidepressant withdrawal symptoms—telephone calls to a national medication helpline. J Affect Disord 2006; 95:129–133.
10. Goodwin GM et al. Agomelatine prevents relapse in patients with major depressive disorder without evidence of a discontinuation syndrome: a 24-week randomized, double-blind, placebo-controlled trial. J Clin Psychiatry 2009; 70:1128–1137.
11. Jain R et al. A randomized, double-blind, placebo-controlled 6-wk trial of the efficacy and tolerability of 5 mg vortioxetine in adults with major depressive disorder. Int J Neuropsychopharmacol 2013; 16:313–321.
12. Rosenbaum JF et al. Selective serotonin reuptake inhibitor discontinuation syndrome: a randomized clinical trial. Biol Psychiatry 1998; 44:77–87.
13. Michelson D et al. Interruption of selective serotonin reuptake inhibitor treatment. Double-blind, placebo-controlled trial. Br J Psychiatry 2000; 176:363–368.
14. Gahr M et al. Withdrawal and discontinuation phenomena associated with tranylcypromine: a systematic review. Pharmacopsychiatry 2013; 46:123–129.
15. Berigan TR. Mirtazapine-associated withdrawal symptoms: a case report. Prim Care Companion J Clin Psychiatry 2001; 3:143.
16. Benazzi F. Mirtazapine withdrawal symptoms. Can J Psychiatry 1998; 43:525.
17. Berigan TR et al. Bupropion-associated withdrawal symptoms: a case report. Prim Care Companion J Clin Psychiatry 1999; 1:50–51.
18. Takeda Pharmaceuticals America Inc. Highlights of Prescribing Information. Brintellix (vortioxetine) tablets. http://www.us.brintellix.com/
19. Lejoyeux M et al. Antidepressant withdrawal syndrome: recognition, prevention and management. CNS Drugs 1996; 5:278–292.
20. Haddad PM. Antidepressant discontinuation syndromes. Drug Saf 2001; 24:183–197.
21. Sir A et al. Randomized trial of sertraline versus venlafaxine XR in major depression: efficacy and discontinuation symptoms. J Clin Psychiatry 2005; 66:1312–1320.
22. Baldwin DS et al. A double-blind, randomized, parallel-group, flexible-dose study to evaluate the tolerability, efficacy and effects of treatment discontinuation with escitalopram and paroxetine in patients with major depressive disorder. Int Clin Psychopharmacol 2006; 21:159–169.
23. Fava GA et al. Effects of gradual discontinuation of selective serotonin reuptake inhibitors in panic disorder with agoraphobia. Int J Neuropsychopharmacol 2007; 10:835–838.
24. Montgomery SA et al. Discontinuation symptoms and taper/poststudy-emergent adverse events with desvenlafaxine treatment for major depressive disorder. Int Clin Psychopharmacol 2009; 24:296–305.
25. Meijer WE et al. Spontaneous lapses in dosing during chronic treatment with selective serotonin reuptake inhibitors. Br J Psychiatry 2001; 179:519–522.
26. Kramer JC et al. Withdrawal symptoms following discontinuation of imipramine therapy. Am J Psychiatry 1961; 118:549–550.
27. Dilsaver, SC et al. Antidepressant withdrawal symptoms treated with anticholinergic agents. Am J Psychiatry 1983; 140:249–251
28. Benazzi F. Fluoxetine for clomipramine withdrawal symptoms. Am J Psychiatry 1999; 156:661–662.
29. Giakas WJ et al. Intractable withdrawal from venlafaxine treated with fluoxetine. Psychiatr Ann 1997; 27:85–93.
30. Coupland NJ et al. Serotonin reuptake inhibitor withdrawal. J Clin Psychopharmacol 1996; 16:356–362.

Further reading

Blier P et al. Physiologic mechanisms underlying the antidepressant discontinuation syndrome. J Clin Psychiatry 2006; 67 Suppl 4:8–13.

Haddad PM et al. Recognising and managing antidepressant discontinuation symptoms. Adv Psychiatr Treat 2007; 13:447–457.

Schatzberg AF et al. Antidepressant discontinuation syndrome: consensus panel recommendations for clinical management and additional research. J Clin Psychiatry 2006; 67 Suppl 4:27–30.

Shelton RC. The nature of the discontinuation syndrome associated with antidepressant drugs. J Clin Psychiatry 2006; 67 Suppl 4:3–7.

Antidepressant prophylaxis

First episode

A single episode of depression should be treated for at least 6–9 months after full remission.¹ If antidepressant therapy is stopped immediately on recovery, 50% of patients experience a return of their depressive symptoms within 3–6 months.^1,2 Even non-continuous use of antidepressants during the first 6 months of treatment predicts higher rates of relapse.³

Recurrent depression

Of those patients who have one episode of major depression, 50–85% will go on to have a second episode, and 80–90% of those who have a second episode will have a third.⁴ Many factors are known to increase the risk of recurrence, including a family history of depression, recurrent dysthymia, concurrent non-affective psychiatric illness, female gender, long episode duration, degree of treatment resistance,⁵ chronic medical illness and social factors (e.g. lack of confiding relationships and psychosocial stressors). Some prescription drugs may precipitate depression.^5,6

Figure 4.4 outlines the risk of recurrence for multiple-episode patients: those recruited to the study had already experienced at least three episodes of depression, with 3 years or less between episodes.^7,8 People with depression are at increased risk of cardiovascular disease.⁹ Suicide mortality is significantly increased over population norms.

A meta-analysis of antidepressant continuation studies¹⁰ concluded that continuing treatment with antidepressants reduces the odds of depressive relapse by around two-thirds, which is approximately equal to halving the absolute risk. A later meta-analysis of 54 studies produced almost exactly the same results: odds of relapse were reduced by 65%.¹¹ The risk of relapse is greatest in the first few months after discontinuation; this holds true irrespective of the duration of prior treatment.¹² Benefits persist at 36 months and beyond and seem to be similar across heterogeneous patient groups (first episode, multiple episode and chronic), although none of the studies included first-episode patients only. Specific studies in first-episode patients are required to confirm that treatment beyond 6–9 months confers additional benefit in this patient group. Most data are for adults.

Figure 4.4 The risk of recurrence of depression in multi-episode patients. Patients had experienced at least three episodes of depression with 3 years or less between episodes.

An RCT of maintenance treatment in elderly patients, many of whom were first episode, found continuation treatment with antidepressants beneficial over 2 years with a similar effect size to that seen in adults.¹³ One small RCT (n = 22) demonstrated benefit from prophylactic antidepressants in adolescents.¹⁴

Many patients who might benefit from maintenance treatment with antidepressants do not receive them.¹⁵ Assuring optimal management of long-term depression vastly reduces mortality associated with the condition.¹⁶

Potential disadvantages of long-term antidepressants include an increased risk of GI and cerebral haemorrhage (see section on 'SSRIs and bleeding' in this chapter) and an additional risk of interaction with co-prescribed drugs likely to increase risk of bleeding or hyponatraemia.

NICE recommends that:¹⁷

• patients who have had two or more episodes of depression in the recent past, and who have experienced significant functional impairment during these episodes, should be advised to continue antidepressants for at least 2 years
• patients on maintenance treatment should be re-evaluated, taking into account age, co-morbid conditions and other risk factors in the decision to continue maintenance treatment beyond 2 years.

Dose for prophylaxis

Adults should receive the same dose as used for acute treatment.¹ There is some evidence to support the use of lower doses in elderly patients: dosulepin 75 mg/day offers effective prophylaxis¹⁸ but is now rarely used. There is no evidence to support the use of lower than standard doses of SSRIs.¹⁹

Relapse rates after ECT are similar to those after stopping antidepressants.²⁰ Antidepressant prophylaxis will be required, ideally with a different drug from the one that failed to get the patient well in the first instance, although good data in this area are lacking.

Lithium also has some efficacy in the prophylaxis of unipolar depression; efficacy relative to antidepressants is unknown.²¹ NICE recommends that lithium should not be used as the sole prophylactic drug in unipolar depression.¹⁷ There is some support for the use of a combination of lithium and nortriptyline.²²

Maintenance treatment with lithium protects against suicide.¹

Key points that patients should know

• A single episode of depression should be treated for at least 6–9 months after remission.
• The risk of recurrence of depressive illness is high and increases with each episode.
• Those who have had multiple episodes may require treatment for many years.
• The chances of staying well are greatly increased by taking antidepressants.
• Antidepressants are:
• effective
• not addictive
• not known to lose their efficacy over time
• not known to cause new long-term side-effects.
• Medication needs to be continued at the treatment dose. If side-effects are intolerable, it may be possible to find a more suitable alternative.
• If patients decide to stop their medication, this must not be done abruptly, as this may lead to unpleasant discontinuation effects (see section on 'Antidepressant discontinuation symptoms' in this chapter) and confers a higher risk of relapse.²³ The medication needs to be reduced slowly under the supervision of a doctor.

References

1. Anderson IM et al. Evidence-based guidelines for treating depressive disorders with antidepressants: a revision of the 2000 British Association for Psychopharmacology guidelines. J Psychopharmacol 2008; 22:343–396.
2. Reimherr FW et al. Optimal length of continuation therapy in depression: a prospective assessment during long-term fluoxetine treatment. Am J Psychiatry 1998; 155:1247–1253.
3. Kim KH et al. The effects of continuous antidepressant treatment during the first 6 months on relapse or recurrence of depression. J Affect Disord 2011; 132:121–129.
4. Forshall S et al. Maintenance pharmacotherapy of unipolar depression. Psychiatr Bull 1999; 23:370–373.
5. National Institute for Health and Clinical Excellence. Depression in adults with a chronic physical health problem: treatment and management. Clinical Guideline 91, 2009. http://www.nice.org.uk/CG91
6. Patten SB et al. Drug-induced depression. Psychother Psychosom 1997; 66:63–73.
7. Frank E et al. Three-year outcomes for maintenance therapies in recurrent depression. Arch Gen Psychiatry 1990; 47:1093–1099.
8. Kupfer DJ et al. Five-year outcome for maintenance therapies in recurrent depression. Arch Gen Psychiatry 1992; 49:769–773.
9. Taylor D. Antidepressant drugs and cardiovascular pathology: a clinical overview of effectiveness and safety. Acta Psychiatr Scand 2008; 118:434–442.
10. Geddes JR et al. Relapse prevention with antidepressant drug treatment in depressive disorders: a systematic review. Lancet 2003; 361:653–661.
11. Glue P et al. Meta-analysis of relapse prevention antidepressant trials in depressive disorders. Aust NZ J Psychiatry 2010; 44:697–705.
12. Keller MB et al. The Prevention of Recurrent Episodes of Depression with Venlafaxine for Two Years (PREVENT) Study: outcomes from the 2-year and combined maintenance phases. J Clin Psychiatry 2007; 68:1246–1256.
13. Reynolds CF III et al. Maintenance treatment of major depression in old age. N Engl J Med 2006; 354:1130–1138.
14. Cheung A et al. Maintenance study for adolescent depression. J Child Adolesc Psychopharmacol 2008; 18:389–394.
15. Holma IA et al. Maintenance pharmacotherapy for recurrent major depressive disorder: 5-year follow-up study. Br J Psychiatry 2008; 193:163–164.
16. Gallo JJ et al. Long term effect of depression care management on mortality in older adults: follow-up of cluster randomized clinical trial in primary care. BMJ 2013; 346:f2570.
17. National Institute for Health and Clinical Excellence. Depression: the treatment and management of depression in adults (update). Clinical Guideline 90, 2009. http://www.nice.org.uk/
18. Old Age Depression Interest Group. How long should the elderly take antidepressants? A double-blind placebo-controlled study of continuation/prophylaxis therapy with dothiepin. Br J Psychiatry 1993; 162:175–182.
19. Franchini L et al. Dose-response efficacy of paroxetine in preventing depressive recurrences: a randomized, double-blind study. J Clin Psychiatry 1998; 59:229–232.
20. Nobler MS et al. Refractory depression and electroconvulsive therapy. In: Nolen WA, Zohar J, Roose SP, eds. Refractory Depression: Current Strategies and Future Directions. Chichester: John Wiley & Sons Ltd; 1994, p.69–81.
21. Cipriani A et al. Lithium versus antidepressants in the long-term treatment of unipolar affective disorder. Cochrane Database Syst Rev 2006; 4:CD003492.
22. Sackeim HA et al. Continuation pharmacotherapy in the prevention of relapse following electroconvulsive therapy: a randomized controlled trial. JAMA 2001; 285:1299–1307.
23. Baldessarini RJ et al. Illness risk following rapid versus gradual discontinuation of antidepressants. Am J Psychiatry 2010; 167:934–941.

Antidepressants: alternative routes of administration

In rare cases, patients may be unable or unwilling to take antidepressants orally, and alternative treatments including psychological interventions and ECT are either impractical or contraindicated.

One such scenario is depression in the medically ill,¹ particularly in those who have undergone surgical resection procedures affecting the GI tract. Where the intra-gastric (IG) route is used, antidepressants can usually be crushed and administered. If an intrajejunal (IJ) tube is used then more care is required because of changes in pharmacokinetics; there are few data on the exact site of absorption for the majority of antidepressants. In clinical practice it is often assumed (perhaps wrongly) that administration via the IJ route is likely to result in the same absorption characteristics as via the oral or IG route.

Very few non-oral formulations are available as commercial products. Most formulations do not have UK licences and may be very difficult to obtain, being available only through pharmaceutical importers or from Specials manufacturers. In addition, the use of these preparations beyond their licence or in the absence of a licence usually means that accountability for adverse effects lies with the prescriber. As a consequence, non-oral administration of antidepressants should be undertaken only when absolutely necessary. Table 4.13 shows possible alternative formulations and routes of administration.

Alternative antidepressant delivery methods

Sublingual

There are a small number of case reports supporting the effectiveness of fluoxetine liquid used sublingually in depressed, medically compromised patients.² In these reports doses of up to 60 mg a day produced plasma fluoxetine and norfluoxetine levels towards the lower end of the proposed therapeutic range.² There are no published data supporting the use of other (low-volume) liquid antidepressant formulations sublingually. If other antidepressants were to be used then it would be advisable to carry out plasma level monitoring of the antidepressant to assess the extent of sublingual absorption.

Intravenous and intramuscular injections

Intravenous citalopram followed by maintenance oral citalopram is a clinically useful treatment strategy for severely depressed, hospitalised patients.³ The IV preparation appears to be well tolerated with the most common adverse events being nausea, headache, tremor and somnolence, similar to oral administration.^4,5 A case report of a 65-year-old man describes acute hyperkinetic delirium associated with IV citalopram.⁶ Intravenous escitalopram also exists although studies reported to date are pharmacokinetic studies.⁷ Note that oral citalopram is associated with a higher risk of QTc prolongation than other SSRIs; if used IV in a medically compromised patient, electrocardiogram (ECG) monitoring is recommended.

Table 4.13 Alternative formulations and routes of administration of antidepressants

Mirtazapine is also available as an intravenous preparation. It has been administered by slow infusion at a dose of 15 mg a day for 14 days in two studies and was well tolerated in depressed patients.^8,9 There are reports of IV mirtazapine 6–30 mg/day being used to treat hyperemesis gravidarum.^10,11

Amitriptyline is available as both an IV and IM injection (IM injection has been given IV) and both routes have been used in the treatment of post-operative pain and depression.¹² The concentration of the IM preparation (10 mg/mL) necessitates a high-volume injection to achieve antidepressant doses; this clearly discourages its use intramuscularly.¹³ Clomipramine is the most widely studied IV antidepressant. Pulse loading doses of intravenous clomipramine have been shown to produce a larger, more rapid decrease in obsessive compulsive disorder symptoms compared with oral doses.^14,15 The potential for serious cardiac side-effects when using any tricyclic antidepressant intravenously necessitates monitoring of pulse, blood pressure and ECG.

The primary rationale for IV administration of antidepressants is the more rapid onset of antidepressant action. However, most trials have generally not supported this assumption.¹⁶ Intravenous formulations also avoid the first-pass effect, leading to higher drug plasma levels^14,17 and perhaps greater response.^17,18 However, negative reports also exist.^3,18,19 The placebo effect associated with IV administration is known to be large.²⁰ Note that calculating the correct parenteral dose of antidepressants is difficult given the variable first-pass effect to which oral drugs are usually subjected. Parenteral doses can be expected to be much lower than oral doses and give the same effect.

Extensive studies of IV ketamine, a glutamate N-methyl-D-aspartate (NMDA) receptor antagonist, have demonstrated rapid, albeit short-lived antidepressant effects; however, more information is required on safety, dosing and duration of response before implementation into clinical practice.²¹ Intravenous scopolamine (hyoscine) as an antidepressant has also been investigated and has produced rapid antidepressant effects within 72 hours in both unipolar and bipolar depression.^22–24 Again, further investigation is needed before use in clinical practice.

Transdermal

Amitriptyline usually in the form of a gel preparation is used in pain clinics as an adjuvant in the treatment of a variety of chronic pain conditions.^25,26 It is usually prepared as a 50 mmol/L or 100 mmol/L gel with or without lidocaine and although it has proven analgesic activity, there are no published data on the plasma levels attained via this route. Nortriptyline hydrochloride has been formulated as a transdermal patch for the use in smoking cessation.²⁷ Nanoemulsion formulations of imipramine and of doxepin have also been formulated for transdermal delivery for use as an analgesic.²⁸ At the time of writing, there are no published studies on nortriptyline patches or imipramine or doxepin nanoemulsions in depression.

Oral selegiline at doses greater than 20 mg/day may be an effective antidepressant, but enzyme selectivity is lost at these doses, necessitating a tyramine-restricted diet.^29,30 Selegiline can be administered transdermally; it is efficacious and tolerable and delivers 25–30% of the selegiline content over 24 hours and steady-state plasma concentrations are achieved within 5 days of daily dosing.³¹ This route bypasses first-pass metabolism, thereby providing a higher, more sustained plasma concentration of selegiline while being relatively sparing of the gastrointestinal MAO-A system;^32,33 there seems to be no need for tyramine restriction when the lower dose patch (6 mg/24 hour) is used and there have been no reports of hypertensive reactions even with the higher dose patch. However, because safety experience with the higher selegiline transdermal system (STS) doses (9 mg/24 hour and 12 mg/24 hour) is more limited, it is recommended that patients using these patches should avoid very high tyramine content food substances.³⁴ Age and gender do not affect the pharmacokinetics of the STS.^35,36 When administered transdermally, application site reactions and insomnia are the two most commonly reported adverse effects; both are dose related, usually mild or moderate in intensity and do not lead to dropout from treatment.^34,35,37,38 There appear to be no clinically significant effects of the STS on sexual function or weight gain.^35,38 Advantages of the STS include once-daily dosing, visual indicator of adherence and its potential in dysphagic patients.³⁶

Rectal

The rectal mucosa lacks the extensive villi and microvilli of other parts of the gastrointestinal tract, limiting its surface area. Therefore rectal agents need to be in a formulation that maximises the extent of contact the active ingredient will have with the mucosa. There are no readily available antidepressant suppositories, but extemporaneous preparation is possible. For example, amitriptyline (in cocoa butter) suppositories have been manufactured by a hospital pharmacy and administered in a dose of 50 mg twice daily with some subjective success.^39,40 Doxepin capsules have been administered via the rectal route directly in the treatment of cancer-related pain (without a special formulation) and produced plasma concentrations within the supposed therapeutic range.⁴¹ Similarly, it has been reported that extemporaneously manufactured imipramine and clomipramine suppositories produced plasma levels comparable with the oral route of administration.⁴² Trazodone has also been successfully administered in a suppository formulation post-operatively for a patient who was stable on the oral formulation prior to surgery.^40,41

References

1. Cipriani A et al. Metareview on short-term effectiveness and safety of antidepressants for depression: an evidence-based approach to inform clinical practice. Can J Psychiatry 2007; 52:553–562.
2. Pakyurek M et al. Sublingually administered fluoxetine for major depression in medically compromised patients. Am J Psychiatry 1999; 156:1833–1834.
3. Baumann P et al. A double-blind double-dummy study of citalopram comparing infusion versus oral administration. J Affect Disord 1998; 49:203–210.
4. Guelfi JD et al. Efficacy of intravenous citalopram compared with oral citalopram for severe depression. Safety and efficacy data from a double-blind, double-dummy trial. J Affect Disord 2000; 58:201–209.
5. Kasper S et al. Intravenous antidepressant treatment: focus on citalopram. Eur Arch Psychiatry Clin Neurosci 2002; 252:105–109.
6. Delic M et al. Delirium during i. v. citalopram treatment: a case report. Pharmacopsychiatry 2013; 46:37–38.
7. Sogaard B et al. The pharmacokinetics of escitalopram after oral and intravenous administration of single and multiple doses to healthy subjects. J Clin Pharmacol 2005; 45:1400–1406.
8. Konstantinidis A et al. Intravenous mirtazapine in the treatment of depressed inpatients. Eur Neuropsychopharmacol 2002; 12:57–60.
9. Muhlbacher M et al. Intravenous mirtazapine is safe and effective in the treatment of depressed inpatients. Neuropsychobiology 2006; 53:83–87.
10. Guclu S et al. Mirtazapine use in resistant hyperemesis gravidarum: report of three cases and review of the literature. Arch Gynecol Obstet 2005; 272:298–300.
11. Schwarzer V et al. Treatment resistant hyperemesis gravidarum in a patient with type 1 diabetes mellitus: neonatal withdrawal symptoms after successful antiemetic therapy with mirtazapine. Arch Gynecol Obstet 2008; 277:67–69.
12. Collins JJ et al. Intravenous amitriptyline in pediatrics. J Pain Symptom Manage 1995; 10:471–475.
13. Elavil. http://www.rxlist.com
14. Deisenhammer EA et al. Intravenous versus oral administration of amitriptyline in patients with major depression. J Clin Psychopharmacol 2000; 20:417–422.
15. Koran LMet al. Pulse loading versus gradual dosing of intravenous clomipramine in obsessive-compulsive disorder. Eur Neuropsychopharmacol 1998; 8:121–126.
16. Moukaddam NJ et al. Intravenous antidepressants: a review. Depress Anxiety 2004; 19:1–9.
17. Koran LM et al. Rapid benefit of intravenous pulse loading of clomipramine in obsessive-compulsive disorder. Am J Psychiatry 1997; 154:396–401.
18. Svestka J et al. [Citalopram (Seropram) in tablet and infusion forms in the treatment of major depression]. Cesk Psychiatr 1993; 89:331–339.
19. Pollock BG et al. Acute antidepressant effect following pulse loading with intravenous and oral clomipramine. Arch Gen Psychiatry 1989; 46:29–35.
20. Sallee FR et al. Pulse intravenous clomipramine for depressed adolescents: double-blind, controlled trial. Am J Psychiatry 1997; 154:668–673.
21. Murrough JW et al. Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial. Am J Psychiatry 2013; 170:1134–1142.
22. Jaffe RJ et al. Scopolamine as an antidepressant: a systematic review. Clin Neuropharmacol 2013; 36:24–26.
23. Furey ML et al. Pulsed intravenous administration of scopolamine produces rapid antidepressant effects and modest side effects. J Clin Psychiatry 2013; 74:850–851.
24. Drevets WC et al. Replication of scopolamine's antidepressant efficacy in major depressive disorder: a randomized, placebo-controlled clinical trial. Biol Psychiatry 2010; 67:432–438.
25. Gerner P et al. Topical amitriptyline in healthy volunteers. Reg Anesth Pain Med 2003; 28:289–293.
26. Ho KY et al. Topical amitriptyline versus lidocaine in the treatment of neuropathic pain. Clin J Pain 2008; 24:51–55.
27. Melero A et al. Nortriptyline for smoking cessation: release and human skin diffusion from patches. Int J Pharmacol 2009; 378:101–107.
28. Sandig AG et al. Transdermal delivery of imipramine and doxepin from newly oil-in-water nanoemulsions for an analgesic and anti-allodynic activity: development, characterization and in vivo evaluation. Colloids Surf B Biointerfaces 2013; 103:558–565.
29. Sunderland T et al. High-dose selegiline in treatment-resistant older depressive patients. Arch Gen Psychiatry 1994; 51:607–615.
30. Mann JJ et al. A controlled study of the antidepressant efficacy and side effects of (-)-deprenyl. A selective monoamine oxidase inhibitor. Arch Gen Psychiatry 1989; 46:45–50.
31. Mylan Specialty LP. Highlights of Prescribing Information: EMSAM^®(Selegiline Transdermal System) Continous Delivery for Once-Daily Application. http://www.emsam.com/
32. Wecker L et al. Transdermal selegiline: targeted effects on monoamine oxidases in the brain. Biol Psychiatry 2003; 54:1099–1104.
33. Azzaro AJ et al. Pharmacokinetics and absolute bioavailability of selegiline following treatment of healthy subjects with the selegiline transdermal system (6 mg/24 h): a comparison with oral selegiline capsules. J Clin Pharmacol 2007; 47:1256–1267.
34. Amsterdam JD et al. Selegiline transdermal system in the prevention of relapse of major depressive disorder: a 52-week, double-blind, placebo-substitution, parallel-group clinical trial. J Clin Psychopharmacol 2006; 26:579–586.
35. Nandagopal JJ et al. Selegiline transdermal system: a novel treatment option for major depressive disorder. Expert Opin Pharmacother 2009; 10:1665–1673.
36. VanDenBerg CM. The transdermal delivery system of monoamine oxidase inhibitors. J Clin Psychiatry 2012; 73 Suppl 1:25–30.
37. Robinson DS et al. The selegiline transdermal system in major depressive disorder: a systematic review of safety and tolerability. J Affect Disord 2008; 105:15–23.
38. Citrome L et al. Placing transdermal selegiline for major depressive disorder into clinical context: number needed to treat, number needed to harm, and likelihood to be helped or harmed. J Affect Disord 2013; 151:409–417.
39. Adams S. Amitriptyline suppositories. N Engl J Med 1982; 306:996.
40. Mirassou MM. Rectal antidepressant medication in the treatment of depression. J Clin Psychiatry 1998; 59:29.
41. Storey P et al. Rectal doxepin and carbamazepine therapy in patients with cancer. N Engl J Med 1992; 327:1318–1319.
42. Chaumeil JC et al. Formulation of suppositories containing imipramine and clomipramine chlorhydrates. Drug Dev Ind Pharm 1988; 15-17:2225–2239.
43. Lopes R et al. The utility of intravenous clomipramine in a case of Cotard's syndrome. Rev Bras Psiquiatr 2013; 35:212–213.
44. Fallon BA et al. Intravenous clomipramine for obsessive-compulsive disorder refractory to oral clomipramine: a placebo-controlled study. Arch Gen Psychiatry 1998; 55:918–924.

Antidepressants: swapping and stopping

General guidelines

• All antidepressants have the potential to cause withdrawal phenomena.¹ When taken continuously for 6 weeks or longer, antidepressants should not be stopped abruptly unless a serious adverse event has occurred (e.g. cardiac arrhythmia with a tricyclic). (see section on 'Antidepressant discontinuation symptoms' in this chapter.)
• Although abrupt cessation is generally not recommended, slow tapering may not reduce the incidence or severity of discontinuation reactions.² Some patients may therefore prefer abrupt cessation and a shorter discontinuation syndrome.
• When changing from one antidepressant to another, abrupt withdrawal should usually be avoided. Cross-tapering is preferred, in which the dose of the ineffective or poorly tolerated drug is slowly reduced while the new drug is slowly introduced. See Table 4.14 for an example.
• The speed of cross-tapering is best judged by monitoring patient tolerability. Few studies have been done, so caution is required.
• Note that the co-administration of some antidepressants, even when cross-tapering, is absolutely contraindicated. In other cases, theoretical risks or lack of experience preclude recommending cross-tapering.
• In some cases cross-tapering may not be considered necessary. An example is when switching from one SSRI to another: their effects are so similar that administration of the second drug is likely to ameliorate withdrawal effects of the first. In fact, the use of fluoxetine has been advocated as an abrupt switch treatment for SSRI discontinuation symptoms.³ Abrupt cessation may also be acceptable when switching to a drug with a similar, but not identicial, mode of action.⁴ Thus, in some cases, abruptly stopping one antidepressant and starting another antidepressant at the usual dose may not only be well tolerated, but may also reduce the risk of discontinuation symptoms.
• Potential dangers of simultaneously administering two antidepressants include pharmacodynamic interactions (serotonin syndrome,^5–8 hypotension, drowsiness) and pharmacokinetic interactions (e.g. elevation of tricyclic plasma levels by some SSRIs). See Figure 4.5.
• The advice given in Table 4.15 should be treated with caution and patients should be very carefully monitored when switching.

Table 4.14 Changing from citalopram to mirtazapine

Figure 4.5 Serotonin syndrome: symptoms.^5,6

• Agomelatine can be started immediately while tapering the dosage of a SSRI/SNRI. Early discontinuation symptoms that arise upon cessation of SSRI/SNRI can alter the patient's perception of the clinical benefit of the new antidepressant. Agomelatine should also be stopped completely before beginning another antidepressant. It does not seem to be associated with a discontinuation syndrome.¹⁰ Given agomelatine's mode of action (melatonin agonism; 5HT_2c antagonism), it is not expected to mitigate discontinuation reactions of other antidepressants. Agomelatine can be co­administrated with other antidepressants (except co­administration with fluvoxamine which is contraindicated)
• Similarly, little information is available for switching to or from vortioxetine. See following table for suggestions on switching.

Table 4.15 Changing from citalopram to mirtazapine

Table 4.15 (Continued)

References

1. Taylor D et al. Antidepressant withdrawal symptoms—telephone calls to a national medication helpline. J Affect Disord 2006; 95:129–133.
2. Tint A et al. The effect of rate of antidepressant tapering on the incidence of discontinuation symptoms: a randomised study. J Psychopharmacol 2008; 22:330–332.
3. Benazzi F. Fluoxetine for the treatment of SSRI discontinuation syndrome. Int J Neuropsychopharmacol 2008; 11:725–726.
4. Perahia DG et al. Switching to duloxetine from selective serotonin reuptake inhibitor antidepressants: a multicenter trial comparing 2 switching techniques. J Clin Psychiatry 2008; 69:95–105.
5. Sternbach H. The serotonin syndrome. Am J Psychiatry 1991; 148:705–713.
6. Mir S et al. Serotonin syndrome. Psychiatr Bull 1999; 23:742–747.
7. Pan JJ et al. Serotonin syndrome induced by low-dose venlafaxine. Ann Pharmacother 2003; 37:209–211.
8. Houlihan DJ. Serotonin syndrome resulting from coadministration of tramadol, venlafaxine, and mirtazapine. Ann Pharmacother 2004; 38:411–413.
9. Dolder CR et al. Agomelatine treatment of major depressive disorder. Ann Pharmacother 2008; 42:1822–1831.
10. Goodwin GM et al. Agomelatine prevents relapse in patients with major depressive disorder without evidence of a discontinuation syndrome: a 24-week randomized, double-blind, placebo-controlled trial. J Clin Psychiatry 2009; 70:1128–1137.
11. Chen G et al. Pharmacokinetic drug interactions involving vortioxetine (Lu AA21004), a multimodal antidepressant. Clin Drug Invest 2013; 33:727–736.
12. Citrome L. Vortioxetine for major depressive disorder: a systematic review of the efficacy and safety profile for this newly approved antidepressant—what is the number needed to treat, number needed to harm and likelihood to be helped or harmed? Int J Clin Pract 2014; 68:60–82.

Drug interactions with antidepressants

Drugs can interact with each other in two different ways.

• Pharmacokinetic interactions where one drug interferes with the absorption, distribution, metabolism or elimination of another drug. This may result in a subtherapeutic effect or toxicity. The largest group of pharmacokinetic interactions involves drugs that inhibit or induce hepatic CYP450 enzymes (see Table 4.16 and Table 7.35). Other enzyme systems include FMO¹ and UGT.² While both of these latter enzyme systems are involved in the metabolism of psychotropic drugs, the potential for drugs to inhibit or induce these enzyme systems has been poorly studied. The clinical consequences of pharmacokinetic interactions in an individual patient can be difficult to predict. Some are highly clinically significant; for example when paroxetine is taken with tamoxifen, up to one extra woman in 20 will die within 5 years of stopping tamoxifen.³ The following factors affect outcome of interactions: the degree of enzyme inhibition or induction, the pharmacokinetic properties of the affected drug and other co-administered drugs, the relationship between plasma level and pharmacodynamic effect for the affected drug, and patient-specific factors such as variability in the role of primary and secondary metabolic pathways and the presence of co-morbid physical illness.⁴
• Pharmacodynamic interactions where the effects of one drug are altered by another drug via physiological mechanisms such as direct competition at receptor sites (e.g. dopamine agonists with dopamine blockers negate any therapeutic effect), augmentation of the same neurotransmitter pathway (e.g. fluoxetine with tramadol or a triptan can lead to serotonin syndrome) or an effect on the physiological functioning of an organ/organ system in different ways (e.g. SSRIs impair clotting and NSAIDs irritate the gastric mucosa; when these drugs are used together, the risk of GI bleeds is increased). Most of these interactions can be easily predicted by a sound knowledge of pharmacology. An up-to-date list of important interactions can be found at the back of the BNF.

Pharmacodynamic interactions

Tricyclic antidepressants:^5,6

• are H₁ blockers (sedative). This effect can be exacerbated by other sedative drugs or alcohol. Beware respiratory depression
• are anticholinergic (dry mouth, blurred vision, constipation). This effect can be exacerbated by other anticholinergic drugs such as antihistamines or antipsychotics. Beware cognitive impairment and GI obstruction
• are adrenergic α₁ blockers (postural hypotension). This effect can be exacerbated by other drugs that block α₁-receptors and by antihypertensive drugs in general. Beware falls. Adrenaline in combination with α₁-blockers can lead to hypertension
• are arrhythmogenic. Caution is required with other drugs that can alter cardiac conduction directly (e.g. antiarrhythmics or phenothiazines) or indirectly through a potential to cause electrolyte disturbance (e.g. diuretics)

Table 4.16 Pharmacokinetic interactions of antidepressants with cytochromes^3,7,20

• lower the seizure threshold. Caution is required with other proconvulsive drugs (e.g. antipsychotics) and particularly if the patient is being treated for epilepsy (higher doses of anticonvulsants may be required)
• may be serotonergic (e.g. amitriptyline, clomipramine). There is the potential for these drugs to interact with other serotonergic drugs (e.g. tramadol, SSRIs, selegiline, triptans) to cause serotonin syndrome.

SSRIs/SNRIs:^7,8–12

• increase serotonergic neurotransmission. The main concern when co-prescribed with other serotonergic drugs is serotonin syndrome
• inhibit platelet aggregation and increase the risk of bleeding, particularly of the upper GI tract. This effect is exacerbated by aspirin and NSAIDs (see section on 'SSRIs and bleeding' in this chapter)
• may be more likely than other antidepressants to cause hyponatraemia (see section on 'Antidepressant-induced hyponatraemia' in this chapter). This may exacerbate electrolyte disturbances caused by other drugs such as diuretics
• may cause osteopenia. This adds to the negative effects prolactin elevating drugs have on bone mineral density and increases the risks of clinical harm should the patient have a fall.

MAOIs:^13,14

• prevent the destruction of monoamine neurotransmitters. Sympathomimetic and dopaminergic drugs can lead to monoamine overload and hypertensive crisis. Pethidine and fermented foods can have the same effect
• can interact with serotonergic drugs to cause serotonin syndrome.

Avoid/minimise problems by:

• where antidepressant polypharmacy is used, select drugs that are safer to use together and monitor carefully for side-effects when the second antidepressant is initiated (see section on 'Treatment of refractory depression' in this chapter)
• avoiding the co-prescription of other drugs with a similar pharmacology but not marketed as antidepressants (e.g. atomoxetine, bupropion)
• knowing your pharmacology (most interactions can be easily predicted).

References

1. Cashman JR. Human flavin-containing monooxygenase: substrate specificity and role in drug metabolism. Curr Drug Metab 2000; 1:181–191.
2. Anderson GD. A mechanistic approach to antiepileptic drug interactions. Ann Pharmacother 1998; 32:554–563.
3. Kelly CM et al. Selective serotonin reuptake inhibitors and breast cancer mortality in women receiving tamoxifen: a population based cohort study. BMJ 2010; 340:c693.
4. Devane CL. Antidepressant-drug interactions are potentially but rarely clinically significant. Neuropsychopharmacology 2006; 31: 1594–1604.
5. Watsky EJ et al. Psychotropic drug interactions. Hosp Community Psychiatry 1991; 42:247–256.
6. Joint Formulary Committee. BNF 67 March-September 2014 (online). London: Pharmaceutical Press; 2014. http://www.medicinescomplete. com/mc/bnf/current/
7. Mitchell PB. Drug interactions of clinical significance with selective serotonin reuptake inhibitors. Drug Saf 1997; 17:390–406.
8. Edwards JG et al. Systematic review and guide to selection of selective serotonin reuptake inhibitors. Drugs 1999; 57:507–533.
9. Loke YK et al. Meta-analysis: gastrointestinal bleeding due to interaction between selective serotonin uptake inhibitors and non-steroidal anti-inflammatory drugs. Aliment Pharmacol Ther 2008; 27:31–40.
10. Williams LJ et al. Selective serotonin reuptake inhibitor use and bone mineral density in women with a history of depression. Int Clin Psychopharmacol 2008; 23:84–87.
11. Spina E et al. Clinically relevant pharmacokinetic drug interactions with second-generation antidepressants: an update. Clin Ther 2008; 30:1206–1227.
12. Montastruc F et al. The importance of drug-drug interactions as a cause of adverse drug reactions: a pharmacovigilance study of serotoninergic reuptake inhibitors in France. Eur J Clin Pharmacol 2012; 68:767–775.
13. Livingston MG et al. Monoamine oxidase inhibitors. An update on drug interactions. Drug Saf 1996; 14:219–227.
14. Wimbiscus M et al. MAO inhibitors: risks, benefits, and lore. Cleve Clin J Med 2010; 77:859–882.
15. Lin JH et al. Inhibition and induction of cytochrome P450 and the clinical implications. Clin Pharmacokinet 1998; 35:361–390.
16. Richelson E. Pharmacokinetic interactions of antidepressants. J Clin Psychiatry 1998; 59 Suppl 10:22–26.
17. Greenblatt DJ et al. Drug interactions with newer antidepressants: role of human cytochromes P450. J Clin Psychiatry 1998; 59 Suppl 15:19–27.
18. Taylor D. Pharmacokinetic interactions involving clozapine. Br J Psychiatry 1997; 171:109–112.
19. Dolder CR et al. Agomelatine treatment of major depressive disorder. Ann Pharmacother 2008; 42:1822–1831.
20. Chen G et al. Pharmacokinetic drug interactions involving vortioxetine (Lu AA21004), a multimodal antidepressant. Clin Drug Invest 2013; 33:727–736.

Cardiac effects of antidepressants

Selective serotonin reuptake inhibitors are generally recommended in cardiac disease but beware antiplatelet activity and cytochrome-medicated interactions with coadministered cardiac drugs. Mirtazapine is a suitable alternative.²⁸ SSRIs may protect against myocardial infarction,^53,54 and untreated depression worsens prognosis in cardiovascular disease.⁵⁵ Post myocardial infarction (MI), SSRIs and mirtazapine have either a neutral or beneficial effect on mortality.⁵⁶ Treatment of depression with SSRIs should not therefore be withheld post MI. Protective effects of treatment of depression post MI appear to relate to antidepressant administration possibly because of an anticoagulant effect or because of indirect reduction in arrhythmia frequency.^41,57 CBT may be ineffective in this respect.⁵⁸ Note that the antiplatelet effect of SSRIs may have adverse consequences too: upper GI bleeding is more common in those taking SSRIs.⁵⁹ See Table 4.17 for an overview.

Table 4.17 Summary of cardiac effects of antidepressants

References

1. Dolder CR et al. Agomelatine treatment of major depressive disorder. Ann Pharmacother 2008; 42:1822–1831.
2. Kozian R et al. [QTc prolongation during treatment with agomelatine]. Psychiatr Prax 2010; 37:405–407.
3. Roose SP et al. Pharmacologic treatment of depression in patients with heart disease. Psychosom Med 2005; 67 Suppl 1:S54–S57.
4. Dwoskin LP et al. Review of the pharmacology and clinical profile of bupropion, an antidepressant and tobacco use cessation agent. CNS Drug Rev 2006; 12:178–207.
5. Castro VM et al. QT interval and antidepressant use: a cross sectional study of electronic health records. BMJ 2013; 346:f288.
6. Eisenberg MJ et al. Bupropion for smoking cessation in patients hospitalized with acute myocardial infarction: a randomized, placebocontrolled trial. J Am Coll Cardiol 2013; 61:524–532.
7. Rasmussen SL et al. Cardiac safety of citalopram: prospective trials and retrospective analyses. J Clin Psychopharmacol 1999; 19:407–415.
8. Catalano G et al. QTc interval prolongation associated with citalopram overdose: a case report and literature review. Clin Neuropharmacol 2001; 24:158–162.
9. Lesperance F et al. Effects of citalopram and interpersonal psychotherapy on depression in patients with coronary artery disease: the Canadian Cardiac Randomized Evaluation of Antidepressant and Psychotherapy Efficacy (CREATE) trial. JAMA 2007; 297:367–379.
10. Astrom-Lilja C et al. Drug-induced torsades de pointes: a review of the Swedish pharmacovigilance database. Pharmacoepidemiol Drug Saf 2008; 17:587–592.
11. Zivin K et al. Evaluation of the FDA warning against prescribing citalopram at doses exceeding 40 mg. Am J Psychiatry 2013; 170: 642–650.
12. Sharma A et al. Pharmacokinetics and safety of duloxetine, a dual-serotonin and norepinephrine reuptake inhibitor. J Clin Pharmacol 2000; 40:161–167.
13. Schatzberg,AF. Efficacy and tolerability of duloxetine, a novel dual reuptake inhibitor, in the treatment of major depressive disorder. J Clin Psychiatry 2003; 64 Suppl 13:30–37.
14. Detke MJ et al. Duloxetine, 60 mg once daily, for major depressive disorder: a randomized double-blind placebo-controlled trial. J Clin Psychiatry 2002; 63:308–315.
15. Colucci VJ et al. Heart failure worsening and exacerbation after venlafaxine and duloxetine therapy. Ann Pharmacother 2008; 42:882–887.
16. Stuhec M. Duloxetine-induced life-threatening long QT syndrome. Wien Klin Wochenschr 2013; 125:165–166.
17. Orozco BS et al. Duloxetine: an uncommon cause of fatal ventricular arrhythmia. Clin Toxicol 2014; 51:672–672.
18. Fisch C. Effect of fluoxetine on the electrocardiogram. J Clin Psychiatry 1985; 46:42–44.
19. Ellison JM et al. Fluoxetine-induced bradycardia and syncope in two patients. J Clin Psychiatry 1990; 51:385–386.
20. Roose SP et al. Cardiovascular effects of fluoxetine in depressed patients with heart disease. Am J Psychiatry 1998; 155:660–665.
21. Strik JJ et al. Efficacy and safety of fluoxetine in the treatment of patients with major depression after first myocardial infarction: findings from a double-blind, placebo-controlled trial. Psychosom Med 2000; 62:783–789.
22. Strik JJ et al. Cardiac side-effects of two selective serotonin reuptake inhibitors in middle-aged and elderly depressed patients. Int Clin Psychopharmacol 1998; 13:263–267.
23. Stirnimann G et al. Brugada syndrome ECG provoked by the selective serotonin reuptake inhibitor fluvoxamine. Europace 2010; 12:282–283.
24. Warrington SJ et al. The cardiovascular effects of antidepressants. Psychol Med Monogr Suppl 1989; 16:i–40.
25. Stern H et al. Cardiovascular effects of single doses of the antidepressants amitriptyline and lofepramine in healthy subjects. Pharmacopsychiatry 1985; 18:272–277.
26. Waring WS et al. Acute myocarditis after massive phenelzine overdose. Eur J Clin Pharmacol 2007; 63:1007–1009.
27. Montgomery SA. Safety of mirtazapine: a review. Int Clin Psychopharmacol 1995; 10 Suppl 4:37–45.
28. Honig A et al. Treatment of post-myocardial infarction depressive disorder: a randomized, placebo-controlled trial with mirtazapine. Psychosom Med 2007; 69:606–613.
29. Moll E et al. Safety and efficacy during long-term treatment with moclobemide. Clin Neuropharmacol 1994; 17 Suppl 1:S74–S87.
30. Hilton S et al. Moclobemide safety: monitoring a newly developed product in the 1990s. J Clin Psychopharmacol 1995; 15:76S–83S.
31. Downes MA et al. QTc abnormalities in deliberate self-poisoning with moclobemide. Intern Med J 2005; 35:388–391.
32. Kuhs H et al. Cardiovascular effects of paroxetine. Psychopharmacology (Berl) 1990; 102:379–382.
33. Roose SP et al. Comparison of paroxetine and nortriptyline in depressed patients with ischemic heart disease. JAMA 1998; 279:287–291.
34. Mucci M. Reboxetine: a review of antidepressant tolerability. J Psychopharmacol 1997; 11:S33–S37.
35. Holm KJ et al. Reboxetine: a review of its use in depression. CNS Drugs 1999; 12:65–83.
36. Fleishaker JC et al. Lack of effect of reboxetine on cardiac repolarization. Clin Pharmacol Ther 2001; 70:261–269.
37. Shapiro PA et al. An open-label preliminary trial of sertraline for treatment of major depression after acute myocardial infarction (the SADHAT Trial).Sertraline Anti-Depressant Heart Attack Trial. Am Heart J 1999; 137:1100–1106.
38. Glassman AH et al. Sertraline treatment of major depression in patients with acute MI or unstable angina. JAMA 2002; 288:701–709.
39. Winkler D et al. Trazodone-induced cardiac arrhythmias: a report of two cases. Hum Psychopharmacol 2006; 21:61–62.
40. Jiang W et al. Safety and efficacy of sertraline for depression in patients with CHF (SADHART-CHF): a randomized, double-blind, placebocontrolled trial of sertraline for major depression with congestive heart failure. Am Heart J 2008; 156:437–444.
41. Leftheriotis D et al. The role of the selective serotonin re-uptake inhibitor sertraline in nondepressive patients with chronic ischemic heart failure: a preliminary study. Pacing Clin Electrophysiol 2010; 33:1217–1223.
42. Service JA et al. QT prolongation and delayed atrioventricular conduction caused by acute ingestion of trazodone. Clin Toxicol (Phila) 2008; 46:71–73.
43. Dattilo PB et al. Prolonged QT associated with an overdose of trazodone. J Clin Psychiatry 2007; 68:1309–1310.
44. Hippisley-Cox J et al. Antidepressants as risk factor for ischaemic heart disease: case-control study in primary care. BMJ 2001; 323:666–669.
45. Whyte IM et al. Relative toxicity of venlafaxine and selective serotonin reuptake inhibitors in overdose compared to tricyclic antidepressants. QJM 2003; 96:369–374.
46. van Noord C et al. Psychotropic drugs associated with corrected QT interval prolongation. J Clin Psychopharmacol 2009; 29:9–15.
47. Khawaja IS et al. Cardiovascular effects of selective serotonin reuptake inhibitors and other novel antidepressants. Heart Dis 2003; 5:153–160.
48. Pfizer Limited. Summary of Product Characteristics. Efexor XL 75 mg hard prolonged release capsules. https://www.medicines.org.uk/
49. Letsas K et al. QT interval prolongation associated with venlafaxine administration. Int J Cardiol 2006; 109:116–117.
50. Taylor D et al. Volte-face on venlafaxine—reasons and reflections. J Psychopharmacol 2006; 20:597–601.
51. Citrome L. Vortioxetine for major depressive disorder: a systematic review of the efficacy and safety profile for this newly approved antidepressant—what is the number needed to treat, number needed to harm and likelihood to be helped or harmed? Int J Clin Pract 2014; 68:60–82.
52. Takeda Pharmaceuticals America Inc. Highlights of Prescribing Information. Brintellix (vortioxetine) tablets. http://www.us.brintellix.com/
53. Sauer WH et al. Selective serotonin reuptake inhibitors and myocardial infarction. Circulation 2001; 104:1894–1898.
54. Sauer WH et al. Effect of antidepressants and their relative affinity for the serotonin transporter on the risk of myocardial infarction. Circulation 2003; 108:32–36.
55. Davies SJ et al. Treatment of anxiety and depressive disorders in patients with cardiovascular disease. BMJ 2004; 328:939–943.
56. Taylor D et al. Pharmacological interventions for people with depression and chronic physical health problems: systematic review and meta-analyses of safety and efficacy. Br J Psychiatry 2011; 198:179–188.
57. Chen S et al. Serotonin and catecholaminergic polymorphic ventricular tachycardia: a possible therapeutic role for SSRIs? Cardiovasc J Afr 2010; 21:225–228.
58. Berkman LF et al. Effects of treating depression and low perceived social support on clinical events after myocardial infarction: the Enhancing Recovery in Coronary Heart Disease Patients (ENRICHD) Randomized Trial. JAMA 2003; 289:3106–3116.
59. Dalton SO et al. Use of selective serotonin reuptake inhibitors and risk of upper gastrointestinal tract bleeding: a population-based cohort study. Arch Intern Med 2003; 163:59–64.

Further reading

Tousoulis D et al. Role of depression in heart failure—choosing the right antidepressive treatment. Int J Cardiol 2010; 140:12–18.

Antidepressant-induced arrhythmia

Depression confers an increased of risk of cardiovascular disease¹ and sudden cardiac death,² perhaps because of platelet activation,³ decreased heart rate variability,⁴ reduced physical activity,⁵ an association with an increased risk of diabetes and/or other factors.

Tricyclic antidepressants have established arrhythmogenic activity which arises as a result of potent blockade of cardiac sodium channels and variable activity at potassium channels.⁶ ECG changes produced include PR, QRS and QT prolongation and the Brugada syndrome.⁷ Nortriptyline has been associated in one study with an increased risk of cardiac arrest⁸ although a large cohort study did not confirm this finding.⁹ In patients taking tricyclics, ECG monitoring is a more meaningful and useful measure of toxicity than plasma level monitoring. Lofepramine, for reasons unknown, seems to lack the arrhythmogenicity of other TCAs, despite its major metabolite, desipramine, being a potent potassium channel blocker.¹⁰

There is limited evidence that venlafaxine is a sodium channel antagonist¹¹ and a weak antagonist at hERG potassium channels. Arrhythmia is a rare occurrence even after massive overdose^12–15 and ECG changes no more common than with SSRIs.¹⁶ No ECG changes are seen in therapeutic dosing¹⁷ and sudden cardiac death is no more common than with fluoxetine or citalopram.^9,18 Moclobemide,¹⁹ citalopram,^20,21 escitalopram,²² bupropion (amfebutamone),²³ trazodone^24,25 and sertraline,²⁶ amongst others,¹ have been reported to prolong the QTc interval in overdose but the clinical consequences of this are uncertain. QT changes are not usually seen at normal clinical doses.^27,28 An association between SSRIs and QT changes in normal dosing can be shown²⁹ but this seems largely to be driven by the effects of citalopram and escitalopram³⁰ . The effect is dose related³⁰ but modest.²⁹ Neither a large database study⁹ nor a large cohort study³¹ found any association between citalopram treatment and arrhythmia or cardiac mortality in routine clinical practice; in fact, higher doses of citalopram (> 40 mg) were associated with fewer adverse outcomes than lower doses.³¹ Vortioxetine seems to have no effect on QT;^32,33 similarly, agomelatine has no effect, even at supratherapeutic doses.³⁴

There is clear evidence for the safety of sertraline³⁵ and mirtazapine³⁶ (and to a lesser extent, citalopram,³⁶ fluoxetine³⁷ and bupropion³⁸ ) in subjects at risk of arrhythmia due to recent myocardial infarction. Another study supports the safety of citalopram in patients with coronary artery disease³⁹ (although citalopram is linked to a risk of torsades de pointes⁴⁰ ).

Relative cardiotoxicity of antidepressants is difficult to establish with any precision. Yellow Card (ADROIT) data suggest that all marketed antidepressants are associated with arrhythmia (ranging from clinically insignificant to life threatening) and sudden cardiac death. For a substantial proportion of drugs, these figures are more likely to reflect coincidence rather than causation. The Fatal Toxicity Index (FTI) may provide some means for comparison. This is a measure of the number of overdose deaths per million (FP10) prescriptions issued. FTI figures suggest high toxicity for tricyclic drugs (especially dosulepin but not lofepramine), medium toxicity for venlafaxine and moclobemide, and low toxicity for SSRIs, mirtazapine and reboxetine.^41–45 However, FTI does not necessarily reflect only cardiotoxicity (antidepressants variously cause serotonin syndrome, seizures and coma) and is, in any case, open to other influences. This is best evidenced in the change in FTI over time. A good example here is nortriptyline, the FTI of which has been estimated at 0.6¹⁶ and 39.2¹² and several values in between.^41,42,44 This change probably reflects changes in the type of patient prescribed nortriptyline. There is good evidence that venlafaxine is relatively more often prescribed to patients with more severe depression and who are relatively more likely to attempt suicide.^46–48 This is likely to inflate venlafaxine's FTI and erroneously suggest greater inherent toxicity. On the other hand, drugs with consistently low FTIs can probably be assumed to have very low risk of arrhythmias.

Citalopram and escitalopram have very low overdose toxicity despite QT prolongation occurring in about one-third of reported overdoses.⁴⁹ Standard doses of citalopram may be linked to an increased risk of cardiac arrest⁸ but other data suggest no increased risk of arrhythmia or death with standard and higher licensed doses of citalopram and escitalopram.³¹ Citalopram and escitalopram are probably the most cardiotoxic of the SSRIs but their toxicity is modest at worst, insignificant at best.

Summary

• Tricyclics (but not lofepramine) have an established link to ion channel blockade and cardiac arrhythmia.
• Non-tricyclics generally have a very low risk of inducing arrhythmia.
• Sertraline is recommended post MI, but other SSRIs and mirtazapine are also likely to be safe.
• Bupropion, citalopram, escitalopram, moclobemide, lofepramine and venlafaxine should be used with caution or avoided in those at risk of serious arrhythmia (those with heart failure, left ventricular hypertrophy, previous arrhythmia or MI). An ECG should be performed at baseline and 1 week after every increase in dose if any of these drugs are used in at-risk patients.
• TCAs (with the exception of lofepramine) are best avoided completely in patients at risk of serious arrhythmia. If use of a TCA cannot be avoided, an ECG should be performed at baseline, 1 week after each increase in dose and periodically throughout treatment. Frequency will be determined by the stability of the cardiac disorder and the TCA (and dose) being used; advice from cardiology should be sought.
• The arrhythmogenic potential of TCAs and other antidepressants is dose­related. Consideration should be given to ECG monitoring of all patients prescribed doses towards the top of the licensed range and those who are prescribed other drugs that through pharmacokinetic (e.g. fluoxetine) or pharmacodynamic (e.g. diuretics) mechanisms may add to the risk posed by the TCA.

References

1. Taylor D. Antidepressant drugs and cardiovascular pathology: a clinical overview of effectiveness and safety. Acta Psychiatr Scand 2008; 118:434–442.
2. Whang W et al. Depression and risk of sudden cardiac death and coronary heart disease in women: results from the Nurses' Health Study. J Am Coll Cardiol 2009; 53:950–958.
3. Ziegelstein RC et al. Platelet function in patients with major depression. Intern Med J 2009; 39:38–43.
4. Glassman AH et al. Heart rate variability in acute coronary syndrome patients with major depression: influence of sertraline and mood improvement. Arch Gen Psychiatry 2007; 64:1025–1031.
5. Whooley MA et al. Depressive symptoms, health behaviors, and risk of cardiovascular events in patients with coronary heart disease. JAMA 2008; 300:2379–2388.
6. Thanacoody HK et al. Tricyclic antidepressant poisoning : cardiovascular toxicity. Toxicol Rev 2005; 24:205–214.
7. Sicouri S et al. Sudden cardiac death secondary to antidepressant and antipsychotic drugs. Expert Opin Drug Saf 2008; 7:181–194.
8. Weeke P et al. Antidepressant use and risk of out-of-hospital cardiac arrest: a nationwide case-time-control study. Clin Pharmacol Ther 2012; 92:72–79.
9. Leonard CE et al. Antidepressants and the risk of sudden cardiac death and ventricular arrhythmia. Pharmacoepidemiol Drug Saf 2011; 20:903–913.
10. Hong HK et al. Block of the human ether-a-go-go-related gene (hERG) K+ channel by the antidepressant desipramine. Biochem Biophys Res Commun 2010; 394:536–541.
11. Khalifa M et al. Mechanism of sodium channel block by venlafaxine in guinea pig ventricular myocytes. J Pharmacol Exp Ther 1999; 291:280–284.
12. Colbridge MG et al. Venlafaxine in overdose—experience of the National Poisons Information Service (London centre). J Toxicol Clin Toxicol 1999; 37:383.
13. Blythe D et al. Cardiovascular and neurological toxicity of venlafaxine. Hum Exp Toxicol 1999; 18:309–313.
14. Combes A et al. Conduction disturbances associated with venlafaxine. Ann Intern Med 2001; 134:166–167.
15. Isbister GK. Electrocardiogram changes and arrhythmias in venlafaxine overdose. Br J Clin Pharmacol 2009; 67:572–576.
16. Whyte IM et al. Relative toxicity of venlafaxine and selective serotonin reuptake inhibitors in overdose compared to tricyclic antidepressants. QJM 2003; 96:369–374.
17. Feighner JP. Cardiovascular safety in depressed patients: focus on venlafaxine. J Clin Psychiatry 1995; 56:574–579.
18. Martinez C et al. Use of venlafaxine compared with other antidepressants and the risk of sudden cardiac death or near death: a nested case-control study. BMJ 2010; 340:c249.
19. Downes MA et al. QTc abnormalities in deliberate self-poisoning with moclobemide. Intern Med J 2005; 35:388–391.
20. Kelly CA et al. Comparative toxicity of citalopram and the newer antidepressants after overdose. J Toxicol Clin Toxicol 2004; 42:67–71.
21. Grundemar L et al. Symptoms and signs of severe citalopram overdose. Lancet 1997; 349:1602.
22. Mohammed R et al. Prolonged QTc interval due to escitalopram overdose. J Miss State Med Assoc 2010; 51:350–353.
23. Isbister GK et al. Bupropion overdose: QTc prolongation and its clinical significance. Ann Pharmacother 2003; 37:999–1002.
24. Service JA et al. QT prolongation and delayed atrioventricular conduction caused by acute ingestion of trazodone. Clin Toxicol (Phila) 2008; 46:71–73.
25. Dattilo PB et al. Prolonged QT associated with an overdose of trazodone. J Clin Psychiatry 2007; 68:1309–1310.
26. de Boer RA et al. QT interval prolongation after sertraline overdose: a case report. BMC Emerg Med 2005; 5:5.
27. van Noord C et al. Psychotropic drugs associated with corrected QT interval prolongation. J Clin Psychopharmacol 2009; 29:9–15.
28. van Haelst IM et al. QT interval prolongation in users of selective serotonin reuptake inhibitors in an elderly surgical population: a crosssectional study. J Clin Psychiatry 2014; 75:15–21.
29. Beach SR et al. Meta-analysis of selective serotonin reuptake inhibitor-associated QTc prolongation. J Clin Psychiatry 2014; 75:e441–449.
30. Castro VM et al. QT interval and antidepressant use: a cross sectional study of electronic health records. BMJ 2013; 346:f288.
31. Zivin K et al. Evaluation of the FDA warning against prescribing citalopram at doses exceeding 40 mg. Am J Psychiatry 2013; 170:642–650.
32. Dubovsky SL. Pharmacokinetic evaluation of vortioxetine for the treatment of major depressive disorder. Expert Opin Drug Metab Toxicol 2014; 10:759–766.
33. Alam MY et al. Safety, tolerability, and efficacy of vortioxetine (Lu AA21004) in major depressive disorder: results of an open-label, flexibledose, 52-week extension study. Int Clin Psychopharmacol 2014; 29:36–44.
34. Donazzolo Y et al. Evaluation of the effects of therapeutic and supra-therapeutic doses of agomelatine on the QT/QTc interval—A phase I, randomised, double-blind, placebo-controlled and positive-controlled, cross-over thorough QT/QTc study conducted in healthy volunteers. J Cardiovasc Pharmacol 2014; 64:440–451.
35. Glassman AH et al. Sertraline treatment of major depression in patients with acute MI or unstable angina. JAMA 2002; 288:701–709.
36. van Melle JP et al. Effects of antidepressant treatment following myocardial infarction. Br J Psychiatry 2007; 190:460–466.
37. Strik JJ et al. Efficacy and safety of fluoxetine in the treatment of patients with major depression after first myocardial infarction: findings from a double-blind, placebo-controlled trial. Psychosom Med 2000; 62:783–789.
38. Rigotti NA et al. Bupropion for smokers hospitalized with acute cardiovascular disease. Am J Med 2006; 119:1080–1087.
39. Lesperance F et al. Effects of citalopram and interpersonal psychotherapy on depression in patients with coronary artery disease: the Canadian Cardiac Randomized Evaluation of Antidepressant and Psychotherapy Efficacy (CREATE) trial. JAMA 2007; 297:367–379.
40. Astrom-Lilja C et al. Drug-induced torsades de pointes: a review of the Swedish pharmacovigilance database. Pharmacoepidemiol Drug Saf 2008; 17:587–592.
41. Crome P. The toxicity of drugs used for suicide. Acta Psychiatr Scand Suppl 1993; 371:33–37.
42. Cheeta S et al. Antidepressant-related deaths and antidepressant prescriptions in England and Wales, 1998-2000. Br J Psychiatry 2004; 184:41–47.
43. Buckley NA et al. Fatal toxicity of serotoninergic and other antidepressant drugs: analysis of United Kingdom mortality data. BMJ 2002; 325:1332–1333.
44. Buckley NA et al. Greater toxicity in overdose of dothiepin than of other tricyclic antidepressants. Lancet 1994; 343:159–162.
45. Morgan O et al. Fatal toxicity of antidepressants in England and Wales, 1993-2002. Health Stat Q 2004:18–24.
46. Egberts ACG et al. Channeling of three newly introduced antidepressants to patients not responding satisfactorily to previous treatment. J Clin Psychopharmacol 1997; 17:149–155.
47. Mines D et al. Prevalence of risk factors for suicide in patients prescribed venlafaxine, fluoxetine, and citalopram. Pharmacoepidemiol Drug Saf 2005; 14:367–372.
48. Chan AN et al. A comparison of venlafaxine and SSRIs in deliberate self-poisoning. J Med Toxicol 2010; 6:116–121.
49. Hasnain M et al. Escitalopram and QTc prolongation. J Psychiatry Neurosci 2013; 38:E11.

Antidepressant-induced hyponatraemia

Most antidepressants have been associated with hyponatraemia; the onset is usually within 30 days (median 11 days) of starting treatment^1–3 and is probably not doserelated.^1,4 The most likely mechanism of this adverse effect is the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Hyponatraemia is a potentially serious adverse effect of antidepressants that demands careful monitoring,⁵ particularly in those patients at greatest risk (see 'Monitoring' below).

Antidepressants

No antidepressant has been shown not to be associated with hyponatraemia and most have a reported association.⁶ It has been suggested that serotonergic drugs are relatively more likely to cause hyponatraemia,^7,8 although this is disputed.⁹ The most recent analyses suggest SSRIs are more likely to cause hyponatraemia than TCAs or mirtazapine,¹⁰ and that older women who are co-prescribed other medication known to reduce plasma sodium are at greatest risk.¹¹ Only one (agomelatine) of the more recently introduced serotonergic drugs appears to be free of this effect—cases of hyponatraemia have been described with mirtazapine^12–14 (although the reported incidence is very low¹¹), escitalopram^15,16 and duloxetine.⁴ Vortioxetine has also been linked to hyponatraemia,¹⁷ as has desvenlafaxine¹⁸. Noradrenergic antidepressants are also clearly linked to hyponatraemia^19–25 (albeit at a lower frequency). There are notably few reports for MAOIs^26,27 and none for agomelatine. CYP2D6 poor metabolisers may be at increased risk²⁸ of antidepressant-induced hyponatraemia although evidence is somewhat inconsistent.²⁹

Monitoring^1,11,30–34

All patients taking antidepressants should be observed for signs of hyponatraemia (dizziness, nausea, lethargy, confusion, cramps, seizures). Serum sodium should be determined (at baseline and 2 and 4 weeks, and then 3-monthly³⁵) for those at high risk of drug-induced hyponatraemia. High-risk factors are as follows:

• extreme old age (> 80 years)
• female gender
• history of hyponatraemia/low baseline Na concentration
• co-therapy with other drugs known to be associated with hyponatraemia (e.g. diuretics, NSAIDs, carbamazepine, cancer chemotherapy, calcium antagonists, angiotensin converting enzyme [ACE] inhibitors)
• reduced renal function (glomerular filtration rate [GFR] < 50 mL/minute)
• medical co-morbidity (e.g. hypothyroidism, diabetes, chronic obstructive pulmonary disease [COPD], hypertension, head injury, congestive cardiac failure [CCF], cerebrovascular accident [CVA], various cancers).

Note that hyponatraemia is common in elderly patients so monitoring is essential.^11,36,37

Treatment³⁷

It may be possible to manage mild hyponatraemia with fluid restriction.³¹ Some suggest increasing sodium intake,⁴ although this is likely to be impractical. If symptoms persist, the antidepressant should be discontinued.

• The normal range for serum sodium is 136–145 mmol/L.
• If serum sodium is > 125 mmol/L, monitor sodium daily until normal. Symptoms include headache, nausea, vomiting, muscle cramps, restlessness, lethargy, confusion and disorientation. Consider withdrawing the offending antidepressant.
• If serum sodium is < 125 mmol/L, refer to specialist medical care. There is an increased risk of life-threatening symptoms such as seizures, coma and respiratory arrest. The antidepressant should be discontinuted immediately. (Note risk of discontinuation symptoms which may complicate the clinical picture.) Note also that rapid correction of hyponatraemia may be harmful.¹⁴

Restarting treatment

• For those who develop hyponatraemia with an SSRI, there are many case reports of recurrent hyponatraemia on rechallenge with the same or a different SSRI, and relatively fewer reports of recurrence occurring with an antidepressant from another class.^11,12 There are also case reports of successful rechallenge.¹
• Consider withdrawing other drugs associated with hyponatraemia (risk increases exponentially when antidepressants are combined with diruetics, etc.³).
• Prescribe a drug from a different class. Consider noradrenergic drugs such as nortriptyline and lofepramine, mirtazapine or an MAOI such as moclobemide. Agomelatine is also an option. Begin with a low dose, increasing slowly, and monitor closely. If hyponatraemia recurs and continued antidepressant use is essential, consider water restriction and/or careful use of demeclocycline (see BNF).
• Consider ECT.

Other prescribed drugs

Carbamazepine has a well-known association with SIADH. Note also that antipsychotic use has been linked to hyponatraemia^38–40 (see section on 'Antipsychotics and hyponatraemia' in Chapter 2). Other commonly prescribed drugs such as thiazide diuretics, NSAIDs, tramadol, omeprazole and trimethoprim can also cause hyponatraemia.^2,32

References

1. Egger C et al. A review on hyponatremia associated with SSRIs, reboxetine and venlafaxine. Int J Psychiatry Clin Pract 2006; 10:17–26.
2. Liamis G et al. A review of drug-induced hyponatremia. Am J Kidney Dis 2008; 52:144–153.
3. Letmaier M et al. Hyponatraemia during psychopharmacological treatment: results of a drug surveillance programme. Int J Neuropsychopharmacol 2012; 15:739–748.
4. Kruger S et al. Duloxetine and hyponatremia: a report of 5 cases. J Clin Psychopharmacol 2007; 27:101–104.
5. Mohan S et al. Prevalence of hyponatremia and association with mortality: results from NHANES. Am J Med 2013; 126:1127–1137.
6. Thomas A et al. Hyponatraemia and the syndrome of inappropriate antidiuretic hormone secretion associated with drug therapy in psychiatric patients. CNS Drugs 1995; 5:357–369.
7. Movig KL et al. Serotonergic antidepressants associated with an increased risk for hyponatraemia in the elderly. Eur J Clin Pharmacol 2002; 58:143–148.
8. Movig KL et al. Association between antidepressant drug use and hyponatraemia: a case-control study. Br J Clin Pharmacol 2002; 53:363–369.
9. Kirby D et al. Hyponatraemia and selective serotonin re-uptake inhibitors in elderly patients. Int J Geriatr Psychiatry 2001; 16:484–493.
10. De Picker L et al. Antidepressants and the risk of hyponatremia: a class-by-class review of literature. Psychosomatics 2014; April 21 (epub ahead of print).
11. Dirks AC et al. Recurrent hyponatremia after substitution of citalopram with duloxetine. J Clin Psychopharmacol 2007; 27:313.
12. Bavbek N et al. Recurrent hyponatremia associated with citalopram and mirtazapine. Am J Kidney Dis 2006; 48:e61–e62.
13. Ladino M et al. Mirtazapine-induced hyponatremia in an elderly hospice patient. J Palliat Med 2006; 9:258–260.
14. Cheah CY et al. Mirtazapine associated with profound hyponatremia: two case reports. Am J Geriatr Pharmacother 2008; 6:91–95.
15. Grover S et al. Escitalopram-associated hyponatremia. Psychiatry Clin Neurosci 2007; 61:132–133.
16. Covyeou JA et al. Hyponatremia associated with escitalopram. N Engl J Med 2007; 356:94–95.
17. Takeda Pharmaceuticals America Inc. Highlights of Prescribing Information. Brintellix (vortioxetine) tablets. http://www.us.brintellix.com/
18. Lee G et al. Syndrome of inappropriate secretion of antidiuretic hormone due to desvenlafaxine. Gen Hosp Psychiatry 2013; 35:574.e571–573.
19. O'Sullivan D et al. Hyponatraemia and lofepramine. Br J Psychiatry 1987; 150:720–721.
20. Wylie KR et al. Lofepramine-induced hyponatraemia. Br J Psychiatry 1989; 154:419–420.
21. Ranieri P et al. Reboxetine and hyponatremia. N Engl J Med 2000; 342:215–216.
22. Miller MG. Tricyclics as a possible cause of hyponatremia in psychiatric patients. Am J Psychiatry 1989; 146:807.
23. Colgate R. Hyponatraemia and inappropriate secretion of antidiuretic hormone associated with the use of imipramine. Br J Psychiatry 1993; 163:819–822.
24. Koelkebeck K et al. A case of non-SIADH-induced hyponatremia in depression after treatment with reboxetine. World J Biol Psychiatry 2009; 10:609–611.
25. Kate N et al. Bupropion-induced hyponatremia. Gen Hosp Psychiatry 2013; 35:681.
26. Mercier S et al. Severe hyponatremia induced by moclobemide (in French). Therapie 1997; 52:82–83.
27. Peterson JC et al. Inappropriate antidiuretic hormone secondary to a monamine oxidase inhibitor. JAMA 1978; 239:1422–1423.
28. Kwadijk-de GS et al. Variation in the CYP2D6 gene is associated with a lower serum sodium concentration in patients on antidepressants. Br J Clin Pharmacol 2009; 68:221–225.
29. Stedman CA et al. Cytochrome P450 2D6 genotype does not predict SSRI (fluoxetine or paroxetine) induced hyponatraemia. Hum Psychopharmacol 2002; 17:187–190.
30. Jacob S et al. Hyponatremia associated with selective serotonin-reuptake inhibitors in older adults. Ann Pharmacother 2006; 40: 1618–1622.
31. Roxanas M et al. Venlafaxine hyponatraemia: incidence, mechanism and management. Aust NZ J Psychiatry 2007; 41:411–418.
32. Reddy P et al. Diagnosis and management of hyponatraemia in hospitalised patients. Int J Clin Pract 2009; 63:1494–1508.
33. Siegler EL et al. Risk factors for the development of hyponatremia in psychiatric inpatients. Arch Intern Med 1995; 155:953–957.
34. Mannesse CK et al. Characteristics, prevalence, risk factors, and underlying mechanism of hyponatremia in elderly patients treated with antidepressants: a cross-sectional study. Maturitas 2013; 76:357–363.
35. Arinzon ZH et al. Delayed recurrent SIADH associated with SSRIs. Ann Pharmacother 2002; 36:1175–1177.
36. Fabian TJ et al. Paroxetine-induced hyponatremia in the elderly due to the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). J Geriatr Psychiatry Neurol 2003; 16:160–164.
37. Sharma H et al. Antidepressant-induced hyponatraemia in the aged. Avoidance and management strategies. Drugs Aging 1996; 8:430–435.
38. Ohsawa H et al. An epidemiological study on hyponatremia in psychiatric patients in mental hospitals in Nara Prefecture. Jpn J Psychiatry Neurol 1992; 46:883–889.
39. Leadbetter RA et al. Differential effects of neuroleptic and clozapine on polydipsia and intermittent hyponatremia. J Clin Psychiatry 1994; 55 Suppl B:110–113.
40. Collins A et al. SIADH induced by two atypical antipsychotics. Int J Geriatr Psychiatry 2000; 15:282–283.

Further reading

Spasovski G et al. Clinical practice guideline on diagnosis and treatment of hyponatraemia. Eur J Endocrinol 2014; 170:G1–47.

Antidepressants and hyperprolactinaemia

Prolactin release is controlled by endogenous dopamine but is also indirectly modulated by serotonin via stimulation of 5HT_1c and 5HT₂ receptors.^1,2 Long-standing increased plasma prolactin (with or without symptoms) is very occasionally seen with antidepressant use.³ Where antidepressant-induced hyperprolactinaemia does occur, rises in prolactin are usually small and short-lived⁴ and so symptoms are very rare. There is no association between SSRI use and breast cancer.⁵ Routine monitoring of prolactin is not recommended but where symptoms suggest the possibility of hyperprolactinaemia then measurement of plasma prolactin is essential. Where symptomatic hyperprolactinaemia is confirmed, a switch to mirtazapine is recommended (see Table 4.18 below), although there is also evidence that switching to an alternative SSRI can resolve symptoms.^6,7

Some details of associations between antidepressants and increased prolactin are given in Table 4.18.

Table 4.18 Reported associations between antidepressants and increased prolactin

References

1. Emiliano AB et al. From galactorrhea to osteopenia: rethinking serotonin-prolactin interactions. Neuropsychopharmacology 2004; 29:833–846.
2. Rittenhouse PA et al. Neurons in the hypothalamic paraventricular nucleus mediate the serotonergic stimulation of prolactin secretion via 5-HT1c/2 receptors. Endocrinology 1993; 133:661–667.
3. Trenque T et al. Serotonin reuptake inhibitors and hyperprolactinaemia: a case/non-case study in the French pharmacovigilance database. Drug Saf 2011; 34:1161–1166.
4. Voicu V et al. Drug-induced hypoand hyperprolactinemia: mechanisms, clinical and therapeutic consequences. Expert Opin Drug Metab Toxicol 2013; 9:955–968.
5. Ashbury JE et al. Selective serotonin reuptake inhibitor (SSRI) antidepressants, prolactin and breast cancer. Front Oncol 2012; 2:177.
6. Mondal S et al. A new logical insight and putative mechanism behind fluoxetine-induced amenorrhea, hyperprolactinemia and galactorrhea in a case series. Therapeut Adv Psychopharmacol 2013; 3:322–334.
7. Strzelecki D et al. Hyperprolactinemia and bleeding following use of sertraline but not use of citalopram and paroxetine: a case report. Arch Psychiatry Psychother 2012; 1:45–48.
8. Taylor D et al. Antidepressant efficacy of agomelatine: meta-analysis of published and unpublished studies. BMJ 2014; 348:g1888.
9. Chu YS et al. Stimulatory and entraining effect of melatonin on tuberoinfundibular dopaminergic neuron activity and inhibition on prolactin secretion. J Pineal Res 2000; 28:219–226.
10. Whiteman PD et al. Bupropion fails to affect plasma prolactin and growth hormone in normal subjects. Br J Clin Pharmacol 1982; 13:745.
11. Meltzer HY et al. Effect of antidepressants on neuroendocrine axis in humans. Adv Biochem Psychopharmacol 1982; 32:303–316.
12. Price LH et al. Effects of tranylcypromine treatment on neuroendocrine, behavioral, and autonomic responses to tryptophan in depressed patients. Life Sci 1985; 37:809–818.
13. Laakmann G et al. Effects of mirtazapine on growth hormone, prolactin, and cortisol secretion in healthy male subjects. Psychoneuroendocrinology 1999; 24:769–784.
14. Laakmann G et al. Mirtazapine: an inhibitor of cortisol secretion that does not influence growth hormone and prolactin secretion. J Clin Psychopharmacol 2000; 20:101–103.
15. Schule C et al. The influence of mirtazapine on anterior pituitary hormone secretion in healthy male subjects. Psychopharmacology (Berl) 2002; 163:95–101.
16. Schule C et al. Reboxetine acutely stimulates cortisol, ACTH, growth hormone and prolactin secretion in healthy male subjects. Psychoneuroendocrinology 2004; 29:185–200.
17. Daffner-Bugia C et al. The neuroendocrine effects of venlafaxine in healthy subjects. Hum Psychopharmacol 1996; 11:1–9.
18. Sternbach H. Venlafaxine-induced galactorrhea. J Clin Psychopharmacol 2003; 23:109–110.
19. Demir EY et al. Hyperprolactinemia connected with venlafaxine: a case report. Anatol J Psychiatry 2014; 15:S10–S14.
20. Ashton AK et al. Hyperprolactinemia and galactorrhea induced by serotonin and norepinephrine reuptake inhibiting antidepressants. Am J Psychiatry 2007; 164:1121–1122.
21. Korkmaz S et al. Galactorrhea during duloxetine treatment: a case report. Turk J Psychiatry 2011; 22:200–201.
22. Sagud M et al. Effects of sertraline treatment on plasma cortisol, prolactin and thyroid hormones in female depressed patients. Neuropsychobiology 2002; 45:139–143.
23. Schlosser R et al. Effects of subchronic paroxetine administration on night-time endocrinological profiles in healthy male volunteers. Psychoneuroendocrinology 2000; 25:377–388.
24. Nadeem HS et al. Comparison of the effects of citalopram and escitalopram on 5-Ht-mediated neuroendocrine responses. Neuropsychopharmacology 2004; 29:1699–1703.
25. Egberts AC et al. Non-puerperal lactation associated with antidepressant drug use. Br J Clin Pharmacol 1997; 44:277–281.
26. Peterson MC. Reversible galactorrhea and prolactin elevation related to fluoxetine use. Mayo Clin Proc 2001; 76:215–216.
27. Morrison J et al. Galactorrhea induced by paroxetine. Can J Psychiatry 2001; 46:88–89.
28. Mahasuar R et al. Euprolactinemic galactorrhea associated with use of imipramine and escitalopram in a postmenopausal woman. Gen Hosp Psychiatry 2010; 32:341–343.
29. Fava GA et al. Prolactin, cortisol, and antidepressant treatment. Am J Psychiatry 1988; 145:358–360.
30. Orlander H et al. Imipramine induced elevation of prolactin levels in patients with HIV/AIDS improved their immune status. West Indian Med J 2009; 58:207–213.
31. Meltzer HY et al. Lack of effect of tricyclic antidepressants on serum prolactin levels. Psychopharmacology (Berl) 1977; 51:185–187.
32. Gadd EM et al. Antidepressants and galactorrhoea. Int Clin Psychopharmacol 1987; 2:361–363.
33. Anand VS. Clomipramine-induced galactorrhoea and amenorrhoea. Br J Psychiatry 1985; 147:87–88.
34. Fowlie S et al. Hyperprolactinaemia and nonpuerperal lactation associated with clomipramine. Scott Med J 1987; 32:52.
35. Mahableshwarkar AR et al. A randomized, double-blind, fixed-dose study comparing the efficacy and tolerability of vortioxetine 2.5 and 10 mg in acute treatment of adults with generalized anxiety disorder. Hum Psychopharmacol 2014; 29:64–72.
36. Baldwin DS et al. Vortioxetine (Lu AA21004) in the long-term open-label treatment of major depressive disorder. Curr Med Res Opin 2012; 28:1717–1724.

Further reading

Coker F et al. Antidepressant-induced hyperprolactinaemia: incidence, mechanisms and management. CNS Drugs 2010; 24:563–574.

Antidepressants and diabetes mellitus

There is an established link between diabetes and depression.¹ Prevalence rates of co-morbid depressive symptoms in diabetic patients have been reported to range from 9% to 60% depending on the screening method used. A diagnosis of diabetes is linked to an increased likelihood of antidepressant prescription.^2,3 Having diabetes doubles the odds of co-morbid depression.⁴ Patients with depression and diabetes have a high number of cardiovascular risk factors and increased mortality.^5,6 The presence of depression has a negative impact on metabolic control and likewise poor metabolic control may worsen depression.⁷

Considering all of this, the treatment of co-morbid depression in patients with diabetes is of vital importance and drug choice should take into account likely effects on metabolic control (see Table 4.19). Cochrane⁸ suggests that antidepressants are effective and moderately improve glycaemic control. Be aware, however, that the prescribing of antidepressants may be associated with reduced adherence to antidiabetic medication.⁹

Table 4.19 Effect of antidepressants on glucose homeostasis and weight

Recommendation: all patients with a diagnosis of depression should be screened for diabetes. In those who are diabetic:

• use SSRIs first line; most data support fluoxetine
• SNRIs are also likely to be safe but there are fewer supporting data
• avoid TCAs and MAOIs if possible due to their effects on weight and glucose homeostasis
• monitor blood glucose and HbA_1c carefully when antidepressant treatment is initiated, when the dose is changed and after discontinuation.

References

1. Katon WJ. The comorbidity of diabetes mellitus and depression. Am J Med 2008; 121 Suppl 2:S8–15.
2. Musselman DL et al. Relationship of depression to diabetes types 1 and 2: epidemiology, biology, and treatment. Biol Psychiatry 2003; 54:317–329.
3. Knol MJ et al. Antidepressant use before and after initiation of diabetes mellitus treatment. Diabetologia 2009; 52:425–432.
4. Anderson RJ et al. The prevalence of comorbid depression in adults with diabetes: a meta-analysis. Diabetes Care 2001; 24:1069–1078.
5. Katon WJ et al. Cardiac risk factors in patients with diabetes mellitus and major depression. J Gen Intern Med 2004; 19:1192–1199.
6. Katon WJ et al. The association of comorbid depression with mortality in patients with type 2 diabetes. Diabetes Care 2005; 28: 2668–2672.
7. Lustman PJ et al. Depression in diabetic patients: the relationship between mood and glycemic control. J Diabetes Complications 2005; 19:113–122.
8. Baumeister H et al. Psychological and pharmacological interventions for depression in patients with diabetes mellitus and depression. Cochrane Database Syst Rev 2012; 12:CD008381.
9. Caughey GE et al. Does antidepressant medication use affect persistence with diabetes medicines? Pharmacoepidemiol Drug Saf 2013; 22:615–622.
10. Maheux P et al. Fluoxetine improves insulin sensitivity in obese patients with non-insulin-dependent diabetes mellitus independently of weight loss. Int J Obes Relat Metab Disord 1997; 21:97–102.
11. Gulseren L et al. Comparison of fluoxetine and paroxetine in type II diabetes mellitus patients. Arch Med Res 2005; 36:159–165.
12. Lustman PJ et al. Sertraline for prevention of depression recurrence in diabetes mellitus: a randomized, double-blind, placebo-controlled trial. Arch Gen Psychiatry 2006; 63:521–529.
13. Gray DS et al. A randomized double-blind clinical trial of fluoxetine in obese diabetics. Int J Obes Relat Metab Disord 1992; 16 Suppl 4:S67–S72.
14. Knol MJ et al. Influence of antidepressants on glycaemic control in patients with diabetes mellitus. Pharmacoepidemiol Drug Saf 2008; 17:577–586.
15. Briscoe VJ et al. Effects of a selective serotonin reuptake inhibitor, fluoxetine, on counterregulatory responses to hypoglycemia in healthy individuals. Diabetes 2008; 57:2453–2460.
16. Andersohn F et al. Long-term use of antidepressants for depressive disorders and the risk of diabetes mellitus. Am J Psychiatry 2009; 166:591–598.
17. Derijks HJ et al. Influence of antidepressant use on glycemic control in patients with diabetes mellitus: an open-label comparative study. J Clin Psychopharmacol 2009; 29:405–408.
18. Kivimaki M et al. Antidepressant medication use, weight gain, and risk of type 2 diabetes: a population-based study. Diabetes Care 2010; 33:2611–2616.
19. Rubin RR et al. Antidepressant medicine use and risk of developing diabetes during the diabetes prevention program and diabetes prevention program outcomes study. Diabetes Care 2010; 33:2549–2551.
20. Echeverry D et al. Effect of pharmacological treatment of depression on A1C and quality of life in low-income Hispanics and African Americans with diabetes: a randomized, double-blind, placebo-controlled trial. Diabetes Care 2009; 32:2156–2160.
21. Gehlawat P et al. Diabetes with comorbid depression: role of SSRI in better glycemic control. Asian J Psychiatr 2013; 6:364–368.
22. Dhavale HS et al. Depression and diabetes: impact of antidepressant medications on glycaemic control. J Assoc Physicians India 2013; 61:896–899.
23. Mojtabai R. Antidepressant use and glycemic control. Psychopharmacology (Berl) 2013; 227:467–477.
24. Lustman PJ et al. Effects of nortriptyline on depression and glycemic control in diabetes: results of a double-blind, placebo-controlled trial. Psychosom Med 1997; 59:241–250.
25. McIntyre RS et al. The effect of antidepressants on glucose homeostasis and insulin sensitivity: synthesis and mechanisms. Expert Opin drug Saf 2006; 5:157–168.
26. Mumoli N et al. Clomipramine-induced diabetes. Ann Intern Med 2008; 149:595–596.
27. Goodnick PJ. Use of antidepressants in treatment of comorbid diabetes mellitus and depression as well as in diabetic neuropathy. Ann Clin Psychiatry 2001; 13:31–41.
28. McIntyre RS et al. Mood and psychotic disorders and type 2 diabetes: a metabolic triad. Can J Diabetes 2005; 29:122–132.
29. Raskin J et al. Duloxetine versus routine care in the long-term management of diabetic peripheral neuropathic pain. J Palliat Med 2006; 9:29–40.
30. Crucitti A et al. Duloxetine treatment and glycemic controls in patients with diagnoses other than diabetic peripheral neuropathic pain: a meta-analysis. Curr Med Res Opin 2010; 26:2579–2588.
31. Himmerich H et al. Changes in weight and glucose tolerance during treatment with mirtazapine. Diabetes Care 2006; 29:170.
32. Karaiskos D et al. Agomelatine and sertraline for the treatment of depression in type 2 diabetes mellitus. Int J Clin Pract 2013; 67:257–260.

Antidepressants and sexual dysfunction

Primary sexual disorders are common, although reliable normative data are lacking.¹ Reported prevalence rates vary depending on the method of data collection (low numbers with spontaneous reports, increasing with confidential questionnaires and further still with direct questioning).^1,2 Physical illness, psychiatric illness, substance misuse and prescribed drug treatment can all cause sexual dysfunction.^1,2 People with depression are more likely to be obese,³ have diabetes,⁴ and have cardiovascular disease than the general population, making them more likely to suffer sexual dysfunction.

Baseline sexual functioning should be determined, if possible (questionnaires may be useful), because sexual function affects quality of life and compliance (sexual dysfunction is one of the major causes of treatment dropout⁵). Complaints of sexual dysfunction may also indicate progression or inadequate treatment of underlying medical or psychiatric conditions. It may also be the result of drug treatment and intervention may greatly improve quality of life.⁶

Effects of depression

Both depression and the drugs used to treat it can cause disorders of desire, arousal and orgasm. The precise nature of the sexual dysfunction may indicate whether depression or treatment is the more likely cause. For example, 40–50% of people with depression report diminished libido and problems regarding sexual arousal in the month before diagnosis, but only 15–20% experience orgasm problems before taking an antidepressant.⁷ In general, the prevalence and severity of sexual dysfunction increase with the severity of depression.⁸ In some patients reporting sexual dysfunction before diagnosis, sexual functioning improves on treatment with antidepressants.⁹ A post hoc analysis of data from the STAR*D study revealed that sexual dysfunction was problematic in 21% of patients whose depression remitted with citalopram treatment compared with 61% of those whose depression did not remit.¹⁰ In any cohort of people with depression there will be some who do not have sexual dysfunction, and some who develop sexual dysfunction on antidepressants. Amongst those presenting with sexual dysfunction, some will see an improvement, some no change and some a worsening when taking on antidepressant.¹¹

Effects of antidepressant drugs

Antidepressants can cause sedation, hormonal changes, disturbance of cholinergic/adrenergic balance, peripheral α-adrenergic antagonism, inhibition of nitric oxide and increased serotonin neurotransmission, all of which can result in sexual dysfunction.¹² Sexual dysfunction has been reported as a side-effect of all antidepressants, although rates vary (see Table 4.20). The impact of antidepressants on sexual function is likely to be dose dependent. Individual susceptibility also varies and may be at least partially genetically determined.^13,14 All effects are reversible.

Not all of the sexual side-effects of antidepressants are undesirable:¹ serotonergic antidepressants including clomipramine are effective in the treatment of premature ejaculation¹⁵ and may also be beneficial in paraphilias.

Table 4.20 Sexual adverse effects of antidepressant drugs

Sexual side-effects can be minimised by careful selection of the antidepressant drug—see Table 4.20.

Treatment

A thorough assessment is essential to exclude physical causes such as diabetes and cardiovascular disease, and psychological and relationship difficulties. Spontaneous remission occurs in approximately 10% of cases and partial remission in a further 11%.⁵ If this does not happen, the dose may be reduced or the antidepressant discontinued where appropriate.

Drug 'holidays' or delayed dosing may be used,³⁹ as may dose reduction. This approach is problematic as the patient may relapse or experience antidepressant discontinuation symptoms. More logical is a switch to a different drug that is less likely to cause the specific sexual problem experienced (see Table 4.20). Note that agomelatine^40,41 and amfebutamone (bupropion—not licensed for depression in UK)^42,43 have probably the lowest risk of sexual dysfunction. Bupropion is widely used in the USA as a first-line antidepressant with minimal risk of sexual side-effects, and as an adjunct (antidote) in patients with SSRI-induced sexual dysfunction.⁴⁴ Preliminary data support the reduction of sexual side-effects in patients treated with duloxetine or SSRIs when mirtazapine is added.^45,46 Trazodone may have similar effects.⁴⁷ Selegiline transdermal patches (licensed for the treatment of depression in the USA) seem to be associated with a low risk of sexual side-effects.⁴⁸

Adjunctive or 'antidote' drugs may also be used (see section on 'Antipsychotics and sexual dysfunction' in Chapter 2 for further information).

Sildenafil is more effective than placebo at improving erectile function in men,⁴⁹ and in improving sexual function in women taking SSRIs.⁵⁰ Small RCTs support the modest efficacy of maca root⁵¹ and saffron.^52,53

A Cochrane review of the 'strategies for managing sexual dysfunction induced by antidepressant medication' found that the addition of sildenafil or tadalafil may improve sexual function in men and bupropion may be useful in women.⁵⁴

References

1. Baldwin DS et al. Effects of antidepressant drugs on sexual function. Int J Psychiatry Clin Pract 1997; 1:47–58.
2. Pollack MH et al. Genitourinary and sexual adverse effects of psychotropic medication. Int J Psychiatry Med 1992; 22:305–327.
3. Luppino FS et al. Overweight, obesity, and depression: a systematic review and meta-analysis of longitudinal studies. Arch Gen Psychiatry 2010; 67:220–229.
4. Kivimaki M et al. Antidepressant medication use, weight gain, and risk of type 2 diabetes: a population-based study. Diabetes Care 2010; 33:2611–2616.
5. Montejo AL et al. Incidence of sexual dysfunction associated with antidepressant agents: a prospective multicenter study of 1022 outpatients. Spanish Working Group for the Study of Psychotropic-Related Sexual Dysfunction. J Clin Psychiatry 2001; 62 Suppl 3:10–21.
6. Segraves RT. Effects of psychotropic drugs on human erection and ejaculation. Arch Gen Psychiatry 1989; 46:275–284.
7. Kennedy SH et al. Sexual dysfunction before antidepressant therapy in major depression. J Affect Disord 1999; 56:201–208.
8. Cheng JY et al. Depressive symptomatology and male sexual functions in late life. J Affect Disord 2007; 104:225–229.
9. Saiz-Ruiz J et al. Assessment of sexual functioning in depressed patients treated with mirtazapine: a naturalistic 6-month study. Hum Psychopharmacol 2005; 20:435–440.
10. Ishak WW et al. Sexual satisfaction and quality of life in major depressive disorder before and after treatment with citalopram in the STAR*D study. J Clin Psychiatry 2013; 74:256–261.
11. Werneke U et al. Antidepressants and sexual dysfunction. Acta Psychiatr Scand 2006; 114:384–397.
12. Clayton AH. Recognition and assessment of sexual dysfunction associated with depression. J Clin Psychiatry 2001; 62 Suppl 3:5–9.
13. Bishop JR et al. Serotonin 2A -1438 G/A and G-protein Beta3 subunit C825T polymorphisms in patients with depression and SSRI-associated sexual side-effects. Neuropsychopharmacology 2006; 31:2281–2288.
14. Bishop JR et al. The association of serotonin transporter genotypes and selective serotonin reuptake inhibitor (SSRI)-associated sexual side effects: possible relationship to oral contraceptives. Hum Psychopharmacol 2009; 24:207–215.
15. Waldinger MD. Premature ejaculation: definition and drug treatment. Drugs 2007; 67:547–568.
16. Harrison WM et al. Effects of antidepressant medication on sexual function: a controlled study. J Clin Psychopharmacol 1986; 6:144–149.
17. Beaumont G. Sexual side-effects of clomipramine (Anafranil). J Int Med Res 1977; 5:37–44.
18. Rickels K et al. Nefazodone: aspects of efficacy. J Clin Psychiatry 1995; 56 Suppl 6:43–46.
19. Sovner R. Anorgasmia associated with imipramine but not desipramine: case report. J Clin Psychiatry 1983; 44:345–346.
20. Gartrell N. Increased libido in women receiving trazodone. Am J Psychiatry 1986; 143:781–782.
21. Sullivan G. Increased libido in three men treated with trazodone. J Clin Psychiatry 1988; 49:202–203.
22. Thompson JW Jr. et al. Psychotropic medication and priapism: a comprehensive review. J Clin Psychiatry 1990; 51:430–433.
23. Lesko LM et al. Three cases of female anorgasmia associated with MAOIs. Am J Psychiatry 1982; 139:1353–1354.
24. Herman JB et al. Fluoxetine-induced sexual dysfunction. J Clin Psychiatry 1990; 51:25–27.
25. Gelenberg AJ et al. Mirtazapine substitution in SSRI-induced sexual dysfunction. J Clin Psychiatry 2000; 61:356–360.
26. Jacobsen FM. Fluoxetine-induced sexual dysfunction and an open trial of yohimbine. J Clin Psychiatry 1992; 53:119–122.
27. Lauerma H. Successful treatment of citalopram-induced anorgasmia by cyproheptadine. Acta Psychiatr Scand 1996; 93:69–70.
28. Demyttenaere K et al. Review: Bupropion and SSRI-induced side effects. J Psychopharmacol 2008; 22:792–804.
29. Waldinger MD et al. SSRIs and ejaculation: a double-blind, randomized, fixed-dose study with paroxetine and citalopram. J Clin Psychopharmacol 2001; 21:556–560.
30. Praharaj SK. Serotonin reuptake inhibitor induced sensory disturbances. Br J Clin Pharmacol 2004; 58:673–674.
31. Ilie CP et al. Painful ejaculation. BJU Int 2007; 99:1335–1339.
32. Tran QT et al. Priapism, ecstasy, and marijuana: is there a connection? Adv Urol 2008; 1. DOI:10.1155/2008/193694
33. Lee KU et al. Antidepressant-induced sexual dysfunction among newer antidepressants in a naturalistic setting. Psychiatry Invest 2010; 7:55–59.
34. Haberfellner EM. Sexual dysfunction caused by reboxetine. Pharmacopsychiatry 2002; 35:77–78.
35. Delgado PL et al. Sexual functioning assessed in 4 double-blind placeboand paroxetine-controlled trials of duloxetine for major depressive disorder. J Clin Psychiatry 2005; 66:686–692.
36. Kennedy SH et al. A double-blind comparison of sexual functioning, antidepressant efficacy, and tolerability between agomelatine and venlafaxine XR. J Clin Psychopharmacol 2008; 28:329–333.
37. Montejo A et al. The effects of agomelatine on sexual function in depressed patients and healthy volunteers. Hum Psychopharmacol 2011; 26:537–542.
38. Koesters M et al. Agomelatine efficacy and acceptability revisited: systematic review and meta-analysis of published and unpublished randomised trials. Br J Psychiatry 2013; 203:179–187.
39. Rothschild AJ. Selective serotonin reuptake inhibitor-induced sexual dysfunction: efficacy of a drug holiday. Am J Psychiatry 1995; 152:1514–1516.
40. Serretti A et al. Treatment-emergent sexual dysfunction related to antidepressants: a meta-analysis. J Clin Psychopharmacol 2009; 29:259–266.
41. Kennedy SH et al. A double-blind comparison of sexual functioning, antidepressant efficacy, and tolerability between agomelatine and venlafaxine XR. J Clin Psychopharmacol 2008; 28:329–333.
42. Clayton AH et al. Bupropion extended release compared with escitalopram: effects on sexual functioning and antidepressant efficacy in 2 randomized, double-blind, placebo-controlled studies. J Clin Psychiatry 2006; 67:736–746.
43. Clayton AH et al. Prevalence of sexual dysfunction among newer antidepressants. J Clin Psychiatry 2002; 63:357–366.
44. Balon R et al. Survey of treatment practices for sexual dysfunction(s) associated with anti-depressants. J Sex Marital Ther 2008; 34:353–365.
45. Ravindran LN et al. Combining mirtazapine and duloxetine in treatment-resistant depression improves outcomes and sexual function. J Clin Psychopharmacol 2008; 28:107–108.
46. Ozmenler NK et al. Mirtazapine augmentation in depressed patients with sexual dysfunction due to selective serotonin reuptake inhibitors. Hum Psychopharmacol 2008; 23:321–326.
47. Stryjer R et al. Trazodone for the treatment of sexual dysfunction induced by serotonin reuptake inhibitors: a preliminary open-label study. Clin Neuropharmacol 2009; 32:82–84.
48. Clayton AH et al. Symptoms of sexual dysfunction in patients treated for major depressive disorder: a meta-analysis comparing selegiline transdermal system and placebo using a patient-rated scale. J Clin Psychiatry 2007; 68:1860–1866.
49. Fava M et al. Efficacy and safety of sildenafil in men with serotonergic antidepressant-associated erectile dysfunction: results from a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry 2006; 67:240–246.
50. Nurnberg HG et al. Sildenafil treatment of women with antidepressant-associated sexual dysfunction: a randomized controlled trial. JAMA 2008; 300:395–404.
51. Dording CM et al. A double-blind, randomized, pilot dose-finding study of maca root (L. meyenii) for the management of SSRI-induced sexual dysfunction. CNS Neurosci Ther 2008; 14:182–191.
52. Modabbernia A et al. Effect of saffron on fluoxetine-induced sexual impairment in men: randomized double-blind placebo-controlled trial. Psychopharmacology (Berl) 2012; 223:381–388.
53. Kashani L et al. Saffron for treatment of fluoxetine-induced sexual dysfunction in women: randomized double-blind placebo-controlled study. Hum Psychopharmacol 2013; 28:54–60.
54. Taylor MJ et al. Strategies for managing sexual dysfunction induced by antidepressant medication. Cochrane Database Syst Rev 2013; 5:CD003382.

Further reading

Williams VS et al. Prevalence and impact of antidepressant-associated sexual dysfunction in three European countries: replication in a crosssectional patient survey. J Psychopharmacol 2010; 24:489–496.

SSRIs and bleeding

Serotonin is released from platelets in response to vascular injury and promotes vasoconstriction and morphological changes in platelets that lead to aggregation.¹ Serotonin alone is a relatively weak platelet aggregator. SSRIs inhibit the serotonin transporter which is responsible for the uptake of serotonin into platelets. It might thus be predicted that SSRIs will deplete platelet serotonin, leading to a reduced ability to form clots and a subsequent increase in the risk of bleeding. SSRIs also increase gastric acid secretion and therefore may be irritant to the gastric mucosa.² Use of SSRIs seems to increase the risk of peptic ulcer.³

Several database studies have found that patients who take SSRIs are at significantly increased risk of being admitted to hospital with an upper GI bleed compared with ageand-sex matched controls.^4–7 This association holds when age, gender and the effects of other drugs such as aspirin and NSAIDs are controlled for. Co-prescription of low-dose aspirin at least doubles the risk of GI bleeding associated with SSRIs alone and co-prescription of NSAIDs approximately quadruples risk.⁸ Combined use of SSRIs and NSAIDs greatly increases the use of anti-acid drugs.⁹ The elderly and those with a history of GI bleeding are at greatest risk.^6,7,10 The risk may be greatest with SSRIs that have a high affinity for the serotonin transporter.^5,11 Risk decreases to the same level as controls in past users of SSRIs, indicating that bleeding is likely to be associated with treatment itself rather than some inherent characteristic of the patients being treated.⁵

The excess risk of bleeding is not confined to upper GI bleeds. The risk of lower GI bleeds may also be increased¹² and an increased risk of uterine bleeding has also been reported.¹³ SSRIs should be used cautiously in patients with cirrhosis or other risk factors for internal bleeding.¹⁴

Use of SSRIs in the perioperative period has been associated with a 20% increase in inpatient mortality (absolute risk 1:1000), although patient rather than drug factors could not be excluded as the cause.¹⁵ One study found that patients prescribed SSRIs who underwent orthopaedic surgery had an almost four-fold risk of requiring a blood transfusion.¹⁶ This equated to one additional patient requiring transfusion for every ten SSRI patients undergoing surgery and was double the risk of patients who were taking NSAIDs alone. It should be noted in this context that treatment with SSRIs has been associated with a 2.4-fold increase in the risk of hip fracture¹⁷ and a two-fold increase of fracture in old age.¹⁸ The combination of advanced age, SSRI treatment, orthopaedic surgery and NSAIDs clearly presents a very high risk. However, there does not seem to be an increased risk of bleeding in patients who undergo coronary artery bypass surgery.¹⁹ Similarly, the risk of post-partum haemorrhage does not seem to be increased,²⁰ although a review of 13 studies found an increased odds ratio (1.21–4.14) of perioperative bleeding with SSRIs.²¹ One study noted an increased risk of bleeding in women undergoing breast surgery²² and the authors suggest withholding SSRIs for 2 weeks prior to such planned surgery. Others conclude that there is insufficient evidence to support routine discontinuation of SSRIs prior to surgery and call for RCTs to be conducted in this area of care.²³ Venlafaxine may have similar effects²¹ but duloxetine may not affect bleeding risk.²⁴

It is likely that SSRIs are responsible for an additional three episodes of bleeding in every 1000 patient-years of treatment over the normal background incidence^5,13 but this figure masks large variations in risk (see Table 4.21). For example, one in 85 patients with a history of GI bleed will have a further bleed attributable to treatment with a SSRI.¹⁰ One database study suggests that gastroprotective drugs (proton pump inhibitors—PPIs) decrease the risk of GI bleeds associated with SSRIs (alone or in combination with NSAIDs) although not quite to control levels.⁶

Some studies have been prompted by the hypothesis that the increased risk of upper GI bleeds associated with SSRIs may be balanced by a decreased risk of embolic events. One database study failed to find a reduction in the risk of a first myocardial infarction in SSRI-treated patients compared with controls,²⁵ while another²⁶ found a reduction in the risk of being admitted to hospital with a first MI in smokers on SSRIs. The effect size in the second study was large: approximately one in ten hospitalisations were avoided in SSRI-treated patients.²⁶ This is similar to the effect size of other antiplatelet therapies such as aspirin.²⁷

In patients who take warfarin, SSRIs increase the risk of a non-GI bleed 2–3-fold (similar to the effect size of NSAIDs) but do not seem to increase the risk of a GI bleed.^28,29 This does not seem to be associated with any effect on the INR, making it difficult to identify those at highest risk.²⁹ In keeping with these findings, SSRI use in anticoagulated patients being treated for acute coronary syndromes may decrease the risk of minor cardiac events at the expense of an increased risk of a bleed.³⁰

Three large database studies have failed to find a reduction in the risk of an ischaemic stroke (or increase in the risk of haemorrhagic stroke) in SSRI users.^31–33 A single cohort study reported an increased risk of haemorrhagic stroke.³⁴ The absolute risk was small. A further nested case–control study showed an 11% increased odds of haemorrhagic stroke in people on SSRIs³⁵ (absolute risk 1:10,000 patient-years of treatment). Table 4.21 shows estimated relative odds/risk of bleeding events reported in more recent meta-analyses.

Table 4.21 Recent analyses of bleeding risk with SSRIs

Summary

• SSRIs increase the risk of GI, cerebral and perioperative bleeding (those undergoing orthopaedic or breast surgery may be at greatest risk).
• Risk is increased still further in those also receiving aspirin, NSAIDs or oral anticoagulants.
• Try to avoid SSRIs in patients receiving NSAIDs, aspirin or oral anticoagulants or with history of cerebral or GI bleeds.
• If SSRI use cannot be avoided, monitor closely and prescribe gastroprotective proton pump inhibitors.

References

1. Skop BP et al. Potential vascular and bleeding complications of treatment with selective serotonin reuptake inhibitors. Psychosomatics 1996; 37:12–16.
2. Andrade C et al. Serotonin reuptake inhibitor antidepressants and abnormal bleeding: a review for clinicians and a reconsideration of mechanisms. J Clin Psychiatry 2010; 71:1565–1575.
3. Dall M et al. There is an association between selective serotonin reuptake inhibitor use and uncomplicated peptic ulcers: a population-based case-control study. Aliment Pharmacol Ther 2010; 32:1383–1391.
4. de Abajo FJ et al. Association between selective serotonin reuptake inhibitors and upper gastrointestinal bleeding: population based casecontrol study. BMJ 1999; 319:1106–1109.
5. Dalton SO et al. Use of selective serotonin reuptake inhibitors and risk of upper gastrointestinal tract bleeding: a population-based cohort study. Arch Intern Med 2003; 163:59–64.
6. de Abajo FJ et al. Risk of upper gastrointestinal tract bleeding associated with selective serotonin reuptake inhibitors and venlafaxine therapy: interaction with nonsteroidal anti-inflammatory drugs and effect of acid-suppressing agents. Arch Gen Psychiatry 2008; 65:795–803.
7. Lewis JD et al. Moderate and high affinity serotonin reuptake inhibitors increase the risk of upper gastrointestinal toxicity. Pharmacoepidemiol Drug Saf 2008; 17:328–335.
8. Paton C et al. SSRIs and gastrointestinal bleeding. BMJ 2005; 331:529–530.
9. de Jong JC et al. Combined use of SSRIs and NSAIDs increases the risk of gastrointestinal adverse effects. Br J Clin Pharmacol 2003; 55:591–595.
10. van Walraven C et al. Inhibition of serotonin reuptake by antidepressants and upper gastrointestinal bleeding in elderly patients: retrospective cohort study. BMJ 2001; 323:655–658.
11. Verdel BM et al. Use of serotonergic drugs and the risk of bleeding. Clin Pharmacol Ther 2011; 89:89–96.
12. Wessinger S et al. Increased use of selective serotonin reuptake inhibitors in patients admitted with gastrointestinal haemorrhage: a multicentre retrospective analysis. Aliment Pharmacol Ther 2006; 23:937–944.
13. Meijer WE et al. Association of risk of abnormal bleeding with degree of serotonin reuptake inhibition by antidepressants. Arch Intern Med 2004; 164:2367–2370.
14. Weinrieb RM et al. A critical review of selective serotonin reuptake inhibitor-associated bleeding: balancing the risk of treating hepatitis C-infected patients. J Clin Psychiatry 2003; 64:1502–1510.
15. Auerbach AD et al. Perioperative use of selective serotonin reuptake inhibitors and risks for adverse outcomes of surgery. JAMA Intern Med 2013; 173:1075–1081.
16. Movig KL et al. Relationship of serotonergic antidepressants and need for blood transfusion in orthopedic surgical patients. Arch Intern Med 2003; 163:2354–2358.
17. Liu B et al. Use of selective serotonin-reuptake inhibitors of tricyclic antidepressants and risk of hip fractures in elderly people. Lancet 1998; 351:1303–1307.
18. Richards JB et al. Effect of selective serotonin reuptake inhibitors on the risk of fracture. Arch Intern Med 2007; 167:188–194.
19. Andreasen JJ et al. Effect of selective serotonin reuptake inhibitors on requirement for allogeneic red blood cell transfusion following coronary artery bypass surgery. Am J Cardiovasc Drugs 2006; 6:243–250.
20. Salkeld E et al. The risk of postpartum hemorrhage with selective serotonin reuptake inhibitors and other antidepressants. J Clin Psychopharmacol 2008; 28:230–234.
21. Mahdanian AA et al. Serotonergic antidepressants and perioperative bleeding risk: a systematic review. Expert Opin Drug Saf 2014; 13:695–704.
22. Jeong BO et al. Use of serotonergic antidepressants and bleeding risk in patients undergoing surgery. Psychosomatics 2014; 55:213–220.
23. Mrkobrada M et al. Selective serotonin reuptake inhibitors and surgery: to hold or not to hold, that is the question: comment on 'Perioperative use of selective serotonin reuptake inhibitors and risks for adverse outcomes of surgery'. JAMA Intern Med 2013; 173:1082–1083.
24. Perahia DG et al. The risk of bleeding with duloxetine treatment in patients who use nonsteroidal anti-inflammatory drugs (NSAIDs): analysis of placebo-controlled trials and post-marketing adverse event reports. Drug Healthcare patient Saf 2013; 5:211–219.
25. Meier CR et al. Use of selective serotonin reuptake inhibitors and risk of developing first-time acute myocardial infarction. Br J Clin Pharmacol 2001; 52:179–184.
26. Sauer WH et al. Selective serotonin reuptake inhibitors and myocardial infarction. Circulation 2001; 104:1894–1898.
27. Antiplatelet Trialists' Collaboration. Collaborative overview of randomised trials of antiplatelet therapy—I: Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ 1994; 308:81–106.
28. Schalekamp T et al. Increased bleeding risk with concurrent use of selective serotonin reuptake inhibitors and coumarins. Arch Intern Med 2008; 168:180–185.
29. Wallerstedt SM et al. Risk of clinically relevant bleeding in warfarin-treated patients—influence of SSRI treatment. Pharmacoepidemiol Drug Saf 2009; 18:412–416.
30. Ziegelstein RC et al. Selective serotonin reuptake inhibitor use by patients with acute coronary syndromes. Am J Med 2007; 120:525–530.
31. Bak S et al. Selective serotonin reuptake inhibitors and the risk of stroke: a population-based case-control study. Stroke 2002; 33:1465–1473.
32. Barbui C et al. Past use of selective serotonin reuptake inhibitors and the risk of cerebrovascular events in the elderly. Int Clin Psychopharmacol 2005; 20:169–171.
33. Kharofa J et al. Selective serotonin reuptake inhibitors and risk of hemorrhagic stroke. Stroke 2007; 38:3049–3051.
34. Smoller JW et al. Antidepressant use and risk of incident cardiovascular morbidity and mortality among postmenopausal women in the Women's Health Initiative study. Arch Intern Med 2009; 169:2128–2139.
35. Douglas I et al. The use of antidepressants and the risk of haemorrhagic stroke: a nested case control study. Br J Clin Pharmacol 2011; 71:116–120.
36. Hackam DG et al. Selective serotonin reuptake inhibitors and brain hemorrhage: a meta-analysis. Neurology 2012; 79:1862–1865.
37. Oka Y et al. Meta-analysis of the risk of upper gastrointestinal hemorrhage with combination therapy of selective serotonin reuptake inhibitors and non-steroidal anti-inflammatory drugs. Biol Pharm Bull 2014; 37:947–953.
38. Anglin R et al. Risk of upper gastrointestinal bleeding with selective serotonin reuptake inhibitors with or without concurrent nonsteroidal anti-inflammatory use: a systematic review and meta-analysis. Am J Gastroenterol 2014; 109:811–819.
39. Wang YP et al. Short-term use of serotonin reuptake inhibitors and risk of upper gastrointestinal bleeding. Am J Psychiatry 2014; 171:54–61.
40. Shin D et al. Use of selective serotonin reuptake inhibitors and risk of stroke: a systematic review and meta-analysis. J Neurol 2014; 261:686–695.
41. Jiang HY et al. Use of selective serotonin reuptake inhibitors and risk of upper gastrointestinal bleeding: a systematic review and meta-analysis. Clin Gastroenterol Hepatol 2014; 30 June (epub ahead of print).
42. Quinn GR et al. Effect of selective serotonin reuptake inhibitors on bleeding risk in patients with atrial fibrillation taking warfarin. Am J Cardiol 2014; 114:583–586.

Antidepressants: relative adverse effects—a rough guide

Table 4.22 shows approximate relative severity of common adverse effects of antidepressants.

Table 4.22 sCommon adverse effects of antidepressants

Anxiety spectrum disorders

Anxiety is a normal emotion that is experienced by everyone at some time. Symptoms can be psychological, physical, or a mixture of both. Intervention is required when symptoms become disabling or reduce quality of life.

There are several disorders within the overall spectrum of anxiety disorders, each with its own characteristic symptoms. These are outlined briefly in Table 4.23. Anxiety disorders can occur on their own, be co-morbid with other psychiatric disorders (particularly depression), be a consequence of physical illness such as thyrotoxicosis or be drug induced (e.g. by caffeine). Co-morbidity with other psychiatric disorders is very common.

Anxiety spectrum disorders tend to be chronic and treatment is often only partially successful. Note that people with anxiety disorders may be particularly prone to adverse effects.¹ High initial doses of SSRIs in particular may be poorly tolerated.

Benzodiazepines

Benzodiazepines provide rapid symptomatic relief from acute anxiety states.² All guidelines and consensus statements recommend that this group of drugs should only be used to treat anxiety that is severe, disabling or subjecting the individual to extreme distress. Because of their potential to cause physical dependence and withdrawal symptoms, these drugs should be used at the lowest effective dose for the shortest period of time (maximum 4 weeks), while medium-/long-term treatment strategies are put in place, and with caution in patients with substance misuse. For the majority of patients, these recommendations are sensible and should be adhered to. A very small number of patients with severely disabling anxiety may benefit from long-term treatment with a benzodiazepine and these patients should not be denied treatment. Benzodiazepines are, however, known to be overprescribed in the long term for treatment of both anxiety³ and depression,⁴ usually in place of more appropriate treatment.

NICE recommends that benzodiazepines should not be used to treat panic disorder.⁵ In other countries, alprazolam is widely used for this indication. Benzodiazepines should be used with care in post-traumatic stress disorder (PTSD).⁶

SSRIs/SNRIs

When used to treat generalised anxiety disorder (GAD), SSRIs should initially be prescribed at half the normal starting dose for the treatment of depression and the dose titrated upwards into the normal antidepressant dosage range as tolerated (initial worsening of anxiety may be seen when treatment is started⁷). The same advice applies to the use of venlafaxine and duloxetine. Response is usually seen within 6 weeks and continues to increase over time.⁸ The optimal duration of treatment has not been determined but should be at least 1 year.^9,10 Effective treatment of GAD may prevent the development of major depression.⁹ Fluoxetine is probably the most effective SSRI and sertraline the best tolerated.¹¹

When used to treat panic disorder, the same starting dose and dosage titration as in GAD should be used. Doses of clomipramine,¹² citalopram¹³ and sertraline¹⁴ towards the bottom of the antidepressant range give the best balance between efficacy and sideeffects, whereas higher doses of paroxetine (40 mg and above) may be required.¹⁵ Higher doses of all drugs may be effective when standard doses have failed. Onset of action may be as long as 6 weeks. Women may respond better to SSRIs than men.¹⁶ There is some evidence that augmentation with clonazepam leads to a more rapid response (but not a greater magnitude of response overall).¹⁵ The optimal duration of treatment is unknown, but should be at least 8 months;¹⁷ a large naturalistic study showed convincing evidence of benefit for at least 3 years.¹⁸ Less than half are likely to remain well after medication is withdrawn.¹⁹

Lower starting doses are also required in post-traumatic stress disorder (PTSD), although high doses (e.g. fluoxetine 60 mg) are often required for full effect. Response is usually seen within 8 weeks, but can take up to 12 weeks.¹⁹ Treatment should be continued for at least 6 months and probably longer.^10,20,21

Although the doses of SSRIs licensed for the treatment of obsessive compulsive disorder (OCD) are higher than those licensed for the treatment of depression (e.g. fluoxetine 60 mg, paroxetine 40–60 mg), lower (standard antidepressant) doses may be effective, particularly for maintenance treatment.²² Initial response is usually slower to emerge than in depression (can take 10–12 weeks). Treatment should continue for at least 1 year.¹⁰ The relapse rate in those who continue treatment for 2 years is half that of those who stop treatment after initial response (25–40% versus 80%).²³ In most people with OCD, the condition is persistent and symptom severity fluctuates over time.²⁴

Body dysmorphic disorder (BDD) should be treated initially with CBT. If symptoms are moderate to severe, adding an SSRI may improve outcome.²⁵ Buspirone may usefully augment the SSRI.²⁵

Standard antidepressant starting doses are well tolerated in social phobia,^26,27 and dosage titration may benefit some patients but is not always required. Response is usually seen within 8 weeks and treatment should be continued for at least a year and probably longer.²⁷ Note that NICE recommends CBT as first-line treatment for social anxiety.²⁸

All patients treated with SSRIs should be monitored for the development of akathisia, increased anxiety and the emergence of suicidal ideation; the risk is thought to be greatest in those < 30 years, those with co-morbid depression and those already known to be at higher risk of suicide.^25,29

Selective serotonin reuptake inhibitors should not be stopped abruptly, as patients with anxiety spectrum disorders are particularly sensitive to discontinuation symptoms (see section on 'Antidepressant discontinuation symptoms' in this chapter). The dose should be reduced slowly as tolerated over several weeks to months.

Pregabalin

Pregabalin is licensed for the treatment of GAD. Several large RCTs have demonstrated its efficacy and tolerability and comparable speed of onset of action to a benzodiazepine.³⁰ The dose of pregabalin in GAD is initially 150 mg, increased gradually to maximum of 600 mg in 2–3 divided doses. Pregabalin should not be stopped abruptly as it may precipitate rebound anxiety and seizures.

Psychological approaches

There is good evidence to support the efficacy of some psychological interventions in anxiety spectrum disorders.^10,31 Examples include exposure therapy in OCD and social phobia. Initial drug therapy may be required to help the patient become more receptive to psychological input. Some studies suggest that optimal outcome is achieved by combining psychological and drug therapies,⁵ but negative studies also exist.^32,33

A discussion of the evidence base for psychological interventions is outside the scope of these guidelines. Further information can be found at www.doh.gov.uk.³⁴ It is recognised that for many patients, psychological therapies are an appropriate first-line treatment, and indeed this is supported by NICE.⁵

Table 4.23 Characteristics and management of anxiety spectrum disorders

Summary of NICE guidelines for the treatment of generalised anxiety disorder⁵, panic disorder⁵ and OCD²⁵

• A 'stepped care' approach is recommended to help in choosing the most effective intervention.
• A comprehensive assessment is recommended that considers the degree of distress and functional impairment; the effect of any co-morbid mental illness, substance misuse or medical condition; and past response to treatment.
• Treat the primary disorder first.
• Psychological therapy is more effective than pharmacological therapy and should be used as first line where possible. Details of the types of therapy recommended and their duration can be found in the NICE guidelines.
• Pharmacological therapy is also effective. Most evidence supports the use of the SSRIs (sertraline as first line).
• Provide verbal and written information on the likely benefits and disadvantages of each mode of treatment.
• Consider combination therapy for complex anxiety disorders that are refractory to treatment.

Panic disorder

• Benzodiazepines should not be used.
• A SSRI should be used as first line. If SSRIs are contraindicated or there is no response, imipramine or clomipramine can be used.
• Self-help (based on CBT principles) should be encouraged.

Generalised anxiety disorder

• Benzodiazepines should not be used beyond 2–4 weeks.
• An SSRI should be used as first line.
• SNRIs and pregabalin are alternative choices.
• High-intensity psychological intervention and self-help (based on CBT principles) should be encouraged.

OCD (where there is moderate or severe functional impairment)

• Use an SSRI or intensive CBT.
• Combine the SSRI and CBT if response to single strategy is suboptimal.
• Use clomipramine if SSRIs fail.
• If response is still suboptimal, add an antipsychotic or combine clomipramine and citalopram.

References

1. Nash JR et al. Pharmacotherapy of anxiety. HandbExp Pharmacol 2005:469-501.
2. Martin JL et al. Benzodiazepines in generalized anxiety disorder: heterogeneity of outcomes based on a systematic review and meta-analysis of clinical trials. J Psychopharmacol 2007; 21:774–782.
3. Benitez CI et al. Use of benzodiazepines and selective serotonin reuptake inhibitors in middle-aged and older adults with anxiety disorders: a longitudinal and prospective study. Am J Geriatr Psychiatry 2008; 16:5–13.
4. Demyttenaere K et al. Clinical factors influencing the prescription of antidepressants and benzodiazepines: results from the European Study of the Epidemiology of Mental Disorders (ESEMeD). J Affect Disord 2008; 110:84–93.
5. National Institute for Health and Clinical Excellence. Generalised anxiety disorder and panic disorder (with or without agoraphobia) in adults. Clinical Guideline 113, 2011. http://guidance.nice.org.uk/CG113
6. Davidson JR. Use of benzodiazepines in social anxiety disorder, generalized anxiety disorder, and posttraumatic stress disorder. J Clin Psychiatry 2004; 65 Suppl 5:29–33.
7. Scott A et al. Antidepressant drugs in the treatment of anxiety disorders. Adv Psychiatr Treatment 2001; 7:275–282.
8. Ballenger JC. Remission rates in patients with anxiety disorders treated with paroxetine. J Clin Psychiatry 2004; 65:1696–1707.
9. Davidson JR et al. A psychopharmacological treatment algorithm for generalised anxiety disorder (GAD). J Psychopharmacol 2010; 24:3–26.
10. Baldwin DS et al. Evidence-based pharmacological treatment of anxiety disorders, post-traumatic stress disorder and obsessive-compulsive disorder: a revision of the 2005 guidelines from the British Association for Psychopharmacology. J Psychopharmacol 2014; 28:403–439.
11. Baldwin D et al. Efficacy of drug treatments for generalised anxiety disorder: systematic review and meta-analysis. BMJ 2011; 342:d1199.
12. Caillard V et al. Comparative effects of low and high doses of clomipramine and placebo in panic disorder: a double-blind controlled study. French University Antidepressant Group. Acta Psychiatr Scand 1999; 99:51–58.
13. Wade AG et al. The effect of citalopram in panic disorder. Br J Psychiatry 1997; 170:549–553.
14. Londborg PD et al. Sertraline in the treatment of panic disorder. A multi-site, double-blind, placebo-controlled, fixed-dose investigation. Br J Psychiatry 1998; 173:54–60.
15. Pollack MH et al. Combined paroxetine and clonazepam treatment strategies compared to paroxetine monotherapy for panic disorder. J Psychopharmacol 2003; 17:276–282.
16. Clayton AH et al. Sex differences in clinical presentation and response in panic disorder: pooled data from sertraline treatment studies. Arch Womens Ment Health 2006; 9:151–157.
17. Rickels K et al. Panic disorder: long-term pharmacotherapy and discontinuation. J Clin Psychopharmacol 1998; 18:12S–18S.
18. Choy Y et al. Three-year medication prophylaxis in panic disorder: to continue or discontinue? A naturalistic study. Compr Psychiatry 2007; 48:419–425.
19. Michelson D et al. Continuing treatment of panic disorder after acute response: randomised, placebo-controlled trial with fluoxetine. The Fluoxetine Panic Disorder Study Group. Br J Psychiatry 1999; 174:213–218.
20. Davidson J et al. Efficacy of sertraline in preventing relapse of posttraumatic stress disorder: results of a 28-week double-blind, placebocontrolled study. Am J Psychiatry 2001; 158:1974–1981.
21. Stein DJ et al. Pharmacotherapy for post traumatic stress disorder (PTSD). Cochrane Database Syst Rev 2006 Jan 25;(1):CD002795–
22. Martenyi F et al. Fluoxetine v. placebo in prevention of relapse in post-traumatic stress disorder. Br J Psychiatry 2002; 181:315–320.
23. Expert Consensus Panel for Obsessive-Compulsive Disorder. Treatment of obsessive-compulsive disorder. J Clin Psychiatry 1997; 58 Suppl 4: 2–72.
24. Catapano F et al. Obsessive-compulsive disorder: a 3-year prospective follow-up study of patients treated with serotonin reuptake inhibitors OCD follow-up study. J Psychiatr Res 2006; 40:502–510.
25. National Institute for Health and Clinical Excellence. Obsessive-compulsive disorder: core interventions in the treatment of obsessivecompulsive disorder and body dysmorphic disorder. Clinical Guideline 31, 2005. http://www.nice.org.uk
26. Blomhoff S et al. Randomised controlled general practice trial of sertraline, exposure therapy and combined treatment in generalised social phobia. Br J Psychiatry 2001; 179:23–30.
27. Hood SD et al. Psychopharmacological treatments: an overview. In: Crozier WR, ed. International Handbook of Social Anxiety Concepts, Research and Interventions Relating to the Self and Shyness. Oxford: John Wiley and Sons Ltd; 2001.
28. Mayo-Wilson E et al. Psychological and pharmacological interventions for social anxiety disorder in adults: a systematic review and network meta-analysis. Lancet Psychiatry 2014; 1:368–376.
29. National Institute for Health and Clinical Excellence. Depression in adults: the treatment and management of depression in adults. Clinical Guideline 90, 2009. http://www.nice.org.uk/Guidance/cg90
30. Pollack MH. Refractory generalized anxiety disorder. J Clin Psychiatry 2009; 70 Suppl 2:32–38.
31. Roberts NP et al. Early psychological interventions to treat acute traumatic stress symptoms. Cochrane Database Syst Rev 2010: 4:CD007944.
32. van Apeldoorn FJ et al. Is a combined therapy more effective than either CBT or SSRI alone? Results of a multicenter trial on panic disorder with or without agoraphobia. Acta Psychiatr Scand 2008; 117:260–270.
33. Marcus SM et al. A comparison of medication side effect reports by panic disorder patients with and without concomitant cognitive behavior therapy. Am J Psychiatry 2007; 164:273–275.
34. Department of Health. Treatment choice in psychological therapies and counselling: evidence based clinical practice guideline. http://www. dh.gov.uk/
35. Goodwin RD et al. Psychopharmacologic treatment of generalized anxiety disorder and the risk of major depression. Am J Psychiatry 2002; 159:1935–1937.
36. Allgulander C et al. Efficacy of sertraline in a 12-week trial for generalized anxiety disorder. Am J Psychiatry 2004; 161:1642–1649.
37. Lenox-Smith AJ et al. A double-blind, randomised, placebo controlled study of venlafaxine XL in patients with generalised anxiety disorder in primary care. Br J Gen Pract 2003; 53:772–777.
38. Rosenthal M. Tiagabine for the treatment of generalized anxiety disorder: a randomized, open-label, clinical trial with paroxetine as a positive control. J Clin Psychiatry 2003; 64:1245–1249.
39. Pande AC et al. Pregabalin in generalized anxiety disorder: a placebo-controlled trial. Am J Psychiatry 2003; 160:533–540.
40. Mathew SJ et al. Open-label trial of riluzole in generalized anxiety disorder. Am J Psychiatry 2005; 162:2379–2381.
41. Schuurmans J et al. A randomized, controlled trial of the effectiveness of cognitive-behavioral therapy and sertraline versus a waitlist control group for anxiety disorders in older adults. Am J Geriatr Psychiatry 2006; 14:255–263.
42. Chessick CA et al. Azapirones for generalized anxiety disorder. Cochrane Database Syst Rev 2006; 3:CD006115.
43. Bakker A et al. SSRIs vs. TCAs in the treatment of panic disorder: a meta-analysis. Acta Psychiatr Scand 2002; 106:163–167.
44. Benjamin J et al. Double-blind, placebo-controlled, crossover trial of inositol treatment for panic disorder. Am J Psychiatry 1995; 152:1084–1086.
45. Otto MW et al. An effect-size analysis of the relative efficacy and tolerability of serotonin selective reuptake inhibitors for panic disorder. Am J Psychiatry 2001; 158:1989–1992.
46. Herring MP et al. The effect of exercise training on anxiety symptoms among patients: a systematic review. Arch Intern Med 2010; 170:321–331.
47. Lader M et al. A multicentre double-blind comparison of hydroxyzine, buspirone and placebo in patients with generalized anxiety disorder. Psychopharmacology (Berl) 1998; 139:402–406.
48. Montgomery S et al. Long-term treatment of anxiety disorders with pregabalin: a 1 year open-label study of safety and tolerability. Curr Med Res Opin 2013; 29:1223–1230.
49. Stein DJ et al. Agomelatine prevents relapse in generalized anxiety disorder: a 6-month randomized, double-blind, placebo-controlled discontinuation study. J Clin Psychiatry 2012; 73:1002–1008.
50. Stein DJ et al. Agomelatine in generalized anxiety disorder: an active comparator and placebo-controlled study. J Clin Psychiatry 2014; 75:362–368.
51. Mezhebovsky I et al. Double-blind, randomized study of extended release quetiapine fumarate (quetiapine XR) monotherapy in older patients with generalized anxiety disorder. Int J Geriatr Psychiatry 2013; 28:615–625.
52. Mahableshwarkar AR et al. A randomized, double-blind, fixed-dose study comparing the efficacy and tolerability of vortioxetine 2.5 and 10 mg in acute treatment of adults with generalized anxiety disorder. Hum Psychopharmacol 2014; 29:64–72.
53. Bidzan L et al. Vortioxetine (Lu AA21004) in generalized anxiety disorder: results of an 8-week, multinational, randomized, double-blind, placebo-controlled clinical trial. Eur Neuropsychopharmacol 2012; 22:847–857.
54. Rothschild AJ et al. Vortioxetine (Lu AA21004) 5 mg in generalized anxiety disorder: results of an 8-week randomized, double-blind, placebo-controlled clinical trial in the United States. Eur Neuropsychopharmacol 2012; 22:858–866.
55. Sheehan DV et al. Efficacy and tolerability of controlled-release paroxetine in the treatment of panic disorder. J Clin Psychiatry 2005; 66:34–40.
56. Bradwejn J et al. Venlafaxine extended-release capsules in panic disorder: flexible-dose, double-blind, placebo-controlled study. Br J Psychiatry 2005; 187:352–359.
57. Pollack M et al. A randomized controlled trial of venlafaxine ER and paroxetine in the treatment of outpatients with panic disorder. Psychopharmacology (Berl) 2007; 194:233–242.
58. Ferguson JM et al. Relapse prevention of panic disorder in adult outpatient responders to treatment with venlafaxine extended release. J Clin Psychiatry 2007; 68:58–68.
59. Buch S et al. Successful use of phenelzine in treatment-resistant panic disorder. J Clin Psychiatry 2007; 68:335–336.
60. Jakovljevic M et al. Olanzapine in the treatment-resistant, combat-related PTSD—a series of case reports. Acta Psychiatr Scand 2003; 107:394–396.
61. Otte C et al. Valproate monotherapy in the treatment of civilian patients with non-combat-related posttraumatic stress disorder: an openlabel study. J Clin Psychopharmacol 2004; 24:106–108.
62. Davidson JR et al. Mirtazapine vs. placebo in posttraumatic stress disorder: a pilot trial. Biol Psychiatry 2003; 53:188–191.
63. Bremner DJ et al. Treatment of posttraumatic stress disorder with phenytoin: an open-label pilot study. J Clin Psychiatry 2004; 65:1559–1564.
64. Davidson J et al. Treatment of posttraumatic stress disorder with venlafaxine extended release: a 6-month randomized controlled trial. Arch Gen Psychiatry 2006; 63:1158–1165.
65. Raskind MA et al. A parallel group placebo controlled study of prazosin for trauma nightmares and sleep disturbance in combat veterans with post-traumatic stress disorder. Biol Psychiatry 2007; 61:928–934.
66. Padala PR et al. Risperidone monotherapy for post-traumatic stress disorder related to sexual assault and domestic abuse in women. Int Clin Psychopharmacol 2006; 21:275–280.
67. Connor KM et al. Fluoxetine in post-traumatic stress disorder. Randomised, double-blind study. Br J Psychiatry 1999; 175:17–22.
68. Taylor FB. Tiagabine for posttraumatic stress disorder: a case series of 7 women. J Clin Psychiatry 2003; 64:1421–1425.
69. Pivac N et al. Olanzapine versus fluphenazine in an open trial in patients with psychotic combat-related post-traumatic stress disorder. Psychopharmacology (Berl) 2004; 175:451–456.
70. Filteau MJ et al. Quetiapine reduces flashbacks in chronic posttraumatic stress disorder. Can J Psychiatry 2003; 48:282–283.
71. Watts BV et al. Meta-analysis of the efficacy of treatments for posttraumatic stress disorder. J Clin Psychiatry 2013; 74:e541–550.
72. Carey P et al. Olanzapine monotherapy in posttraumatic stress disorder: efficacy in a randomized, double-blind, placebo-controlled study. Hum Psychopharmacol 2012; 27:386–391.
73. Feder A et al. Efficacy of intravenous ketamine for treatment of chronic posttraumatic stress disorder: a randomized clinical trial. JAMA Psychiatry 2014; 71:681–688.
74. Dell'Osso B et al. Serotonin-norepinephrine reuptake inhibitors in the treatment of obsessive-compulsive disorder: a critical review. J Clin Psychiatry 2006; 67:600–610.
75. Sousa MB et al. A randomized clinical trial of cognitive-behavioral group therapy and sertraline in the treatment of obsessive-compulsive disorder. J Clin Psychiatry 2006; 67:1133–1139.
76. Eriksson T. Anti-androgenic treatment of obsessive-compulsive disorder: an open-label clinical trial of the long-acting gonadotropin-releasing hormone analogue triptorelin. Int Clin Psychopharmacol 2007; 22:57–61.
77. Soomro GM et al. Selective serotonin re-uptake inhibitors (SSRIs) versus placebo for obsessive compulsive disorder (OCD). Cochrane Database Syst Rev 2008: 1:CD001765.
78. Skapinakis P et al. Antipsychotic augmentation of serotonergic antidepressants in treatment-resistant obsessive-compulsive disorder: a meta-analysis of the randomized controlled trials. Eur Neuropsychopharmacol 2007; 17:79–93.
79. Fineberg NA et al. Escitalopram prevents relapse of obsessive-compulsive disorder. Eur Neuropsychopharmacol 2007; 17:430–439.
80. Storch EA et al. Aripiprazole augmentation of incomplete treatment response in an adolescent male with obsessive-compulsive disorder. Depress Anxiety 2008; 25:172–174.
81. Denys D et al. Quetiapine addition in obsessive-compulsive disorder: is treatment outcome affected by type and dose of serotonin reuptake inhibitors? Biol Psychiatry 2007; 61:412–414.
82. Dold M et al. Antipsychotic augmentation of serotonin reuptake inhibitors in treatment-resistant obsessive-compulsive disorder: a metaanalysis of double-blind, randomized, placebo-controlled trials. Int J Neuropsychopharmacol 2013; 16:557–574.
83. Grant JE. Clinical practice: Obsessive-compulsive disorder. N Engl J Med 2014; 371:646–653.
84. Askari N et al. Granisetron adjunct to fluvoxamine for moderate to severe obsessive-compulsive disorder: a randomized, double-blind, placebo-controlled trial. CNS Drugs 2012; 26:883–892.
85. Ghaleiha A et al. Memantine add-on in moderate to severe obsessive-compulsive disorder: randomized double-blind placebo-controlled study. J Psychiatr Res 2013; 47:175–180.
86. Rodriguez CI et al. Randomized controlled crossover trial of ketamine in obsessive-compulsive disorder: proof-of-concept. Neuropsychopharmacology 2013; 38:2475–2483.
87. Afshar H et al. N-acetylcysteine add-on treatment in refractory obsessive-compulsive disorder: a randomized, double-blind, placebo-controlled trial. J Clin Psychopharmacol 2012; 32:797–803.
88. Simon NM et al. An open-label study of levetiracetam for the treatment of social anxiety disorder. J Clin Psychiatry 2004; 65:1219–1222.
89. Kinrys G et al. Valproic acid for the treatment of social anxiety disorder. Int Clin Psychopharmacol 2003; 18:169–172.
90. Mancini M et al. Use of duloxetine in patients with an anxiety disorder, or with comorbid anxiety and major depressive disorder: a review of the literature. Expert Opin Pharmacother 2010; 11:1167–1181.
91. Blanco C et al. A placebo-controlled trial of phenelzine, cognitive behavioral group therapy, and their combination for social anxiety disorder. Arch Gen Psychiatry 2010; 67:286–295.
92. Hansen RA et al. Efficacy and tolerability of second-generation antidepressants in social anxiety disorder. Int Clin Psychopharmacol 2008; 23:170–179.
93. Westenberg HG. Recent advances in understanding and treating social anxiety disorder. CNS Spectr 2009; 14:24–33.
94. Blanco C et al. Pharmacological treatment of social anxiety disorder: a meta-analysis. Depress Anxiety 2003; 18:29–40.
95. Stein MB et al. Efficacy of low and higher dose extended-release venlafaxine in generalized social anxiety disorder: a 6-month randomized controlled trial. Psychopharmacology (Berl) 2005; 177:280–288.
96. Aarre TF. Phenelzine efficacy in refractory social anxiety disorder: a case series. Nord J Psychiatry 2003; 57:313–315.
97. Pollack MH et al. A double-blind randomized controlled trial of augmentation and switch strategies for refractory social anxiety disorder. Am J Psychiatry 2014; 171:44–53.
98. Offidani E et al. Efficacy and tolerability of benzodiazepines versus antidepressants in anxiety disorders: a systematic review and meta-analysis. Psychother Psychosom 2013; 82:355–362.
99. Khan A et al. Extended-release quetiapine fumarate (quetiapine XR) as adjunctive therapy in patients with generalized anxiety disorder and a history of inadequate treatment response: a randomized, double-blind study. Ann Clin Psychiatry 2014; 26:3–18.

Benzodiazepines in the treatment of psychiatric disorders

Benzodiazepines are normally divided into two groups depending on their half-life: hypnotics (short half-life) or anxiolytics (long half-life). Although benzodiazepines have a place in the treatment of some forms of epilepsy and severe muscle spasm, and as premedicants in some surgical procedures, the vast majority of prescriptions are written for their hypnotic and anxiolytic effects. Benzodiazepines are also used for rapid tranquillisation (see section on 'Rapid tranquillisation' in Chapter 7) and, as adjuncts, in the treatment of depression and schizophrenia.

Benzodiazepines are commonly prescribed; a European study found that almost 10% of adults had taken a benzodiazepine over the course of a year.¹

Anxiolytic effect

Benzodiazepines reduce pathological anxiety, agitation and tension. Although useful in the short-term management of generalised anxiety disorder,^2,3 either alone or to augment SSRIs, benzodiazepines are clearly addictive; many patients continue to take these drugs for years⁴ with unknown benefits and many likely harms. Benzodiazepines may be less effective in the short term than hydroxyzine, an antihistamine that is not known to be addictive.⁵ If a benzodiazepine is prescribed, this should not routinely be for longer than 1 month.

The National Institute for Health and Care Excellence recommends that benzodiazepines should not be routinely used in patients with generalised anxiety disorder except as a short-term measure during crisis.⁶

Repeat prescriptions should be avoided in those with major personality problems whose difficulties are unlikely ever to resolve. Benzodiazepines should also be avoided, if possible, in those with a history of substance misuse.

Hypnotic effect

Benzodiazepines inhibit REM sleep and a rebound increase is seen when they are discontinued. There is a debate over the significance of this property.⁷

Benzodiazepines are effective hypnotics, at least in the short term. RCTs support the effectiveness of Z-hypnotics over a period of at least 6 months^8,9 but it is unclear if this holds true for benzodiazepine hypnotics.

Physical causes (pain, dyspnoea, etc.) or substance misuse (most commonly high caffeine consumption) should always be excluded before a hypnotic drug is prescribed. A high proportion of hospitalised patients are prescribed hypnotics.¹⁰ Care should be taken to avoid using hypnotics regularly or for long periods of time.