Maturitas 77 (2014) 118–123

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Maturitas journal homepage: www.elsevier.com/locate/maturitas

Review

Prescribing selective serotonin reuptake inhibitors in older age Anya Topiwala, Leonidas Chouliaras, Klaus P. Ebmeier ∗ Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford OX3 7JX, UK

a r t i c l e

i n f o

Article history: Received 15 November 2013 Received in revised form 21 November 2013 Accepted 23 November 2013

Keywords: Major depressive disorder Antidepressants Randomized controlled trials Side effects Risks Suicide

a b s t r a c t Apart from commercial reasons, two motivations have led to the introduction of SSRIs to replace the first and second generation antidepressants already available. One was the search for a more rational treatment, based on specific mechanisms, the other the development of effective treatments with fewer side effects, particularly for older patients, who have a greater sensitivity to cardio-vascular and central nervous system effects. The first has been frustrated up to a point, in that SSRIs and other single mechanism drugs do not appear to be more effective than the earliest relatively non-specific antidepressants. The second has been fulfilled, in that SSRIs generally are better tolerated in older patients and in overdose. However, there is a spectrum of other side effects that are particularly relevant in older age and that need attention when treating depression in this particular patient group. © 2013 Elsevier Ireland Ltd. All rights reserved.

Contents 1. 2.

3.

4.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Acute treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.1. Placebo-controlled trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.2. Head to head studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Relapse prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Side effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Common SSRI side effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Electrolyte disturbances . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. SSRIs, cardiotoxicity and the case of citalopram . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5. Gastrointestinal bleeding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.6. Falls, bone loss and fractures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.7. Serotonin syndrome, neuroleptic malignant syndrome, extrapyramidal side effects and akathisia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.8. SSRIs and tamoxifen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.9. Other SSRI side effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Contributors and their role . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Competing interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Provenance and peer review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

119 119 119 119 119 120 120 120 120 120 120 120 121 121 121 121 121 121 121 121 121 121 121

Abbreviations: CGI, Clinical Global Impression (scale); CI, confidence interval; CYP219, Cytochrome P450 2C19; EPSE, extrapyramidal side effects; FDA, US Food and Drug Administration; HAM-D, Hamilton Depression Rating scale; MADRS, Montgomery-Åsberg Depression Rating scale; MHRA, Medicines and Healthcare products Regulatory Agency; NNT, numbers needed to treat; OR, odds ratio; PPIs, proton pump inhibitors; QTc, QT interval corrected (for heart rate); RCT, randomized controlled trial; RR, risk ratio; SNRI (s), serotonin–norepinephrine reuptake inhibitor(s); SSRI(s), serotonin reuptake inhibitor(s); TCA(s), tricyclic antidepressants(s). ∗ Corresponding author. Tel.: +44 1865 226469; fax: +44 1865 793101. E-mail address: [email protected] (K.P. Ebmeier). 0378-5122/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.maturitas.2013.11.006

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1. Introduction Depression is common in older adults, affecting up to 9.3% of those over 75 years [1]. Pharmacodynamic and pharmacokinetic changes occur with age, so that results from antidepressant trials with selective serotonin reuptake inhibitors (SSRIs) in younger patients cannot be directly extrapolated. Despite this, older participants are often excluded from efficacy studies out of principle or for reasons of multimorbity. Fortunately, some problems with SSRIs that occur in young patients, such as the emergence of suicidal thoughts and acts, are not observed in older patients, thus making the cost benefit analysis more favorable [2]. In the following review, we will describe specific issues of efficacy and side effects of SSRIs, as they apply to older patients.

2. Efficacy 2.1. Acute treatment 2.1.1. Placebo-controlled trials Currently, there is insufficient evidence to conclude that SSRIs increase remission (defined as Hamilton Depression Rating Scale (HAM-D) score ≤7/10 depending on version or Montgomery–Åsberg Depression Rating Scale (MADRS) ≤12) rates in depression (OR 1.29, 0.93–1.80) in those over 55 years [3]. The only positive meta-analysis used data solely from sponsorconducted trials [4]. However, SSRIs are efficacious in achieving a response (≥50% decrease in HAM-D, MADRS or Clinical Global Impression (CGI) score) in depressive symptoms in the elderly (OR 1.61 (1.18–2.2) [3]. The number needed to treat (NNT = 10, [3]) appears to be slightly higher than for younger adults ( 2 years) and those with short-term (≤2 years) depression. 2.1.1.3. Escitalopram. Two studies have failed to show a benefit of escitalopram over placebo in achieving remission or even a response of depressive symptoms [10,14]. 2.1.1.4. Citalopram. One study supports the use of citalopram over placebo in severe old age depression. [15] reported remission rates of 35% in subjects with severe depression (HAMD > 24) compared with 19% in those receiving placebo. 2.1.1.5. Sertraline. Sertraline also seems to be efficacious in treating depression in older adults [16]. After eight weeks of 50 or 100 mg sertraline, patients experienced significantly greater improvements than those receiving placebo on the Hamilton depression scale (−7.4 points (SD = 6.3) vs. −6.6 points (SD = 6.4) and CGI scale (over a shorter time period). 2.1.1.6. Fluvoxamine. Wakelin et al. found an improvement on HAMD and CGI scales in severely depressed elderly treated with four weeks of fluvoxamine (p < 0.05) [17]. 2.1.1.7. Comorbidity. There is some evidence for the use of SSRIs in elderly subjects with comorbid physical conditions. In a metaanalysis of controlled trials, Taylor et al. found that SSRIs showed a significant advantage over placebo: risk ratio (RR) = 0.81 (95% CI 0.73–0.91) for depression remission (RR = 0.83 (95% CI 0.71–0.97), response and in improving quality of life [18]. In older adults with dementia and comorbid depression, there is limited evidence for the efficacy of sertraline [19] and citalopram [20] in treating depressive symptoms. Banerjee et al. demonstrated improvements in the Cornell Scale for Depression in Dementia scores after 12 weeks of 150 mg sertraline. Whether SSRIs improve cognitive performance in such patients is still unclear, with one study reporting positive results [20] and another negative results [21]. 2.1.2. Head to head studies 2.1.2.1. Tricyclic antidepressants (TCAs). A meta-analysis concluded that SSRIs and TCAs were comparable in achieving remission of late life depression [3]. Individual RCTs finding no appreciable difference between the two antidepressant classes have compared: sertraline and imipramine [22], paroxetine and clomipramine [23], citalopram and amitriptyline [24], and fluoxetine and trimipramine [25]. Direct analyses of SSRIs and tricyclics in depressed elderly with comorbid physical health problems also failed to distinguish between them [18]. Kok [3] made similar inferences when considering the lower bar of improvement of depressive symptomatology. However, Bondareff [26] did report a significant advantage of sertraline over nortriptyline in secondary efficacy measures (post-treatment measures of cognitive function, memory, and quality of life) and Culang-Reinlieb et al. [27] found that patients treated with sertraline improved more in verbal learning than patients treated with nortriptyline. 2.1.2.2. Other antidepressants. There is a paucity of evidence for a superior efficacy of SSRIs over other classes of antidepressants [3]. In fact in a pooled analysis of four head to head studies of agomelatine vs. SSRIs, [28] found that final HAM-D-17 score was significantly lower in patients treated with agomelatine than in patients treated with SSRIs (p = 0.014). SSRIs appear to be equally efficacious in treating elderly depression as: trazodone [29], tianeptine [30], moclobemide [31], venlafaxine [32], mirtazapine [19], and bupropion [33]. One study reported that SSRIs produced a greater

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improvement than mianserin [34,35], but others have not corroborated this [41]. 2.2. Relapse prevention A recent Cochrane review [36] found no significant difference in relapse rates between depression remitters given antidepressants compared to those given a placebo at 6, 18 or 24 months. At 12 months there was a benefit (NNT 5, RR 0.67 (0.55–0.82)) but not when considering only trials using SSRIs. At 36 months one trial demonstrated a benefit of active treatment. Three studies looked specifically at SSRIs. [37] found a clear benefit in delaying relapse (defined by increase in MADRS to >22 or lack of efficacy judged by investigator) of treating remitters with escitalopram (RR of 4.4). Similarly, [38] reported only 19/60 patients treated with citalopram vs. 41/61 given placebo relapsed, and the time to recurrence was significantly greater with citalopram. However, [39] failed to demonstrate the relapse prevention properties of SSRIs in their study. Two years after remittance there was no significant difference in relapse rates between sertraline treated and placebo treated patients. 3. Side effects 3.1. Introduction Various studies have shown that SSRIs are better tolerated in older people compared with tricyclic antidepressants (TCAs) or serotonin-norepinephrine inhibitors (SNRIs). This is due to their side effect profile and to less clinically significant drug interactions with other compounds [40]. In a double-blind RCT in frail older patients, sertraline was better tolerated than venlafaxine [41]. Similarly, in another double-blind RCT in older patients with depressive symptoms, paroxetine was better tolerated than nortriptyline, with discontinuation rates of 16% and 33%, respectively [42]. Amongst SSRIs, fluvoxamine has been associated with the highest discontinuation rate, followed by fluoxetine and sertraline, while citalopram and escitalopram appear to be the best tolerated [40]. Interestingly, the susceptibility of an older individual to side effects of SSRIs may be associated with genetic variation in the serotonin transporter and receptor genes [43]. SSRIs inhibit cytochrome P450 enzymes and thus may interact with any other compounds metabolized by cytochrome P450 enzymes [44]. 3.2. Common SSRI side effects The most commonly reported side effects of SSRIs are nausea, dry mouth, constipation, diarrhea, anorexia, drowsiness, dizziness, lethargy, sleep disturbance, tremor and anxiety with their respective prevalence ranging from 1 to 17% [45]. In a recent metaanalysis, SSRIs were shown to be better tolerated than TCAs, with commonest side effects of nausea and vomiting (17%) [46]. In a further study examining side effects of citalopram in relation to age, bradycardia was more prevalent in the older patients, while gastrointestinal side effects, sweating and headache were less likely to be present in participants over 60 years old [47]. The authors suggest that the different side effect profile in older patients may be related to the sensitivity of the serotonergic system being altered with age [47]. 3.3. Electrolyte disturbances Hyponatraemia, reported in 0.5–1% of older patients treated with SSRIs, is the most common electrolyte disturbance and is linked to inappropriate release of antidiuretic hormone [46,48].

Furthermore, in a case control study of participants receiving fluoxetine compared with paroxetine, fluoxetine was almost twice as likely to induce hyponatraemia [48], with a low body weight being a particular risk factor. Typically, this side effect is detected on average within three weeks after starting treatment with an SSRI antidepressant and is associated with general physiological changes in the elderly, such as altered renal function, reduced subjective sensations of thirst, increased antidiuretic hormone secretion, as well as medical comorbidities and concomitant drug use [49]. Interestingly, Kerby et al. [50] have found that in older inpatients receiving sertraline or venlafaxine, hyponatraemia can be as frequent as 39% compared with a 10% prevalence in inpatient controls. 3.4. SSRIs, cardiotoxicity and the case of citalopram Bradycardia and other cardiac arrhythmias have been linked with the use of SSRIs, mainly in older patients or in those with preexisting cardiac disease [51]. This is thought to result from a direct effect on sodium and calcium channels. Additionally, in patients receiving concomitant beta-blockers, SSRIs can increase the blood level of the former [52]. In 2011, the company marketing citalopram in the US published a guideline suggesting that, based on unpublished trials, doses of 60 mg are associated with QTc interval prolongation and increased risk for torsade de pointes arrhythmia. It was further suggested that citalopram should not be used at all in patients with congenital long QT syndrome. Correction of electrolyte abnormalities should be performed before the initiation of treatment and ECG monitoring should be performed in patients with heart problems or concomitant medications that may prolong the QT interval. It was advised that patients who experience symptoms of an abnormal heart rate should seek medical attention immediately. Later on, the FDA in the US and the MHRA in the UK issued safety communications informing of abnormal heart rhythms associated with high doses of citalopram and escitalopram and suggested that citalopram should no longer be used in doses greater than 40 mg. Along with the aforementioned recommendations it was advised that a maximum dose of 20 mg citalopram should be administered in patients with hepatic impairment, patients >65 years (>60 according to the FDA), patients who are CYP219 poor metabolizers or are taking cimetidine, because those factors increase the blood levels of citalopram and thus increase the risk of affecting the electrical activity of the heart. It was further suggested that the maximum dose of escitalopram in people >65 years old should be 10 mg [10]. Meanwhile, a study reviewing published evidence and case reports, concluded that there was not enough evidence for the above recommendation. They encouraged publication of further findings relating to citalopram including cardiac side effects, as most of the available data on citalopram cardiotoxicity is based on overdose cases [53]. The latest evidence, from a cohort study involving 618,450 patients receiving citalopram, found no association between citalopram and fatal cardiac arrhythmias [54]. 3.5. Gastrointestinal bleeding SSRIs have been linked with upper gastrointestinal bleeding [55,56] at a risk comparable to the use of low dose of ibuprofen [57]. SSRIs can interact with non-steroidal anti-inflammatory drugs increasing the risk of such bleeding [56,57] while concomitant use of proton pump inhibitors (PPIs) may reduce that risk [58]. The mechanistic explanations behind the association of SSRI treatment and bleeding have been investigated in vitro and in vivo studies, and imply that the SSRI-related reduction of serotonin in platelets may inhibit their aggregation and thus predispose to excessive bleeding [59]. SSRIs are also associated with an increased frequency of

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uncomplicated peptic ulcers [60] and helicobacter pylori infection may increase the risk of SSRI-related bleeding [61]. Some casecontrol studies and reviews of available evidence have failed to find a significant correlation between SRRIs and gastrointestinal bleeding [62–64]. It has been suggested that such associations may be limited to older patients or patients at high risk, such as those with liver failure [65]. 3.6. Falls, bone loss and fractures A case control study in subjects over 66 years old found an association between hip fractures and the use of SSRIs (fluoxetine, fluvoxamine, paroxetine and sertraline) with an OR of 2.4 [66]. In particular, the risk was higher for new users (started in the last 30 days) compared with continuous users [66]. A retrospective cohort study also found an association between SSRI treatment and increased risk of falls in older nursing home residents [67]. In addition, long-term SSRI treatment has been linked to osteoporosis in late-life and thus an increased risk of fractures [68]. A recent study in middle-aged women, however, failed to show an association between SSRI treatment and annual changes in bone density [69]. 3.7. Serotonin syndrome, neuroleptic malignant syndrome, extrapyramidal side effects and akathisia Serotonin syndrome and the neuroleptic malignant syndrome represent rare, but potentially fatal side effects of SSRIs. Increased levels of serotonin in the intrasynaptic space may rarely induce a group of symptoms known as the serotonin syndrome [70]. This is more likely with TCAs, but has also been reported as a result of SSRI treatment. Serotonin syndrome involves mental state changes, agitation, confusion, hyperactivity, muscle spasms, shivering, clonus, myoclonus, ocular oscillations, tremors, and hyperreflexia [70]. Even more rarely, SSRIs can cause the so called neuroleptic malignant syndrome, which typically presents with altered level of consciousness, bradykinesia, temperature dysregulation (usually hyperpyrexia) diaphoresis, tachycardia, hypertension and raised creatinine phosphokinase. Additionally, serotonergic inhibition of dopaminergic neurotransmission by SSRIs (particularly dependent on their affinity for the 5-HT2c receptors, selectivity for serotonin, half-life and drug interaction with neuroleptics), can cause extrapyramidal symptoms (EPSEs) and akathisia. Most of the cases reported so far were associated with paroxetine or fluoxetine [71]. While EPSEs are rare in the general population, they can affect up to 6% of older patients treated with SSRIs [72].

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3.9. Other SSRI side effects Side effects of SSRI treatment reported in the general population but not particularly studied in the older patients involve weight gain and sexual dysfunction. Masand et al. have found that, in the general population, SSRIs are associated with a 3–4 kg weight increase, which could be managed with physical exercise and nutritional specialist support [77]. Sexual side effects of decreased libido, decreased arousal and decreased orgasm quality have been also associated with the use of SSRIs, but not particularly studied in the elderly, and their reported prevalence vary from 1.9 to 75% [46,78]. 4. Conclusion Overall, there is not enough evidence to conclude that SSRIs can achieve remission of depression in elderly patients. There is, however, a growing body of evidence supporting the notion that SSRIs are the treatment of choice in elderly depressed patients. The efficacy of SSRIs in achieving a response to depressive symptoms in the elderly seems to be comparable to other antidepressants and in parallel they appear to be safer, better tolerated and with fewer serious adverse effects. Nevertheless, there is a spectrum of side effects of SSRIs that are particularly relevant in the elderly, such as cardiotoxicity, electrolyte disturbances and predisposition to bleeding and to falls and fractures that need close monitoring and consideration when treating this patient group. Contributors and their role Anya Topiwala – First draft (part), revisions (whole). Leonidas Chouliaras – First draft (part), revisions (whole). Klaus P. Ebmeier – First draft (part), revisions (whole). Competing interest Anya Topiwala – none. Leonidas Chouliaras – none. Klaus P. Ebmeier –Dr Ebmeier reports consultation fees received from Lily in relation to AmyvidTM . Funding Anya Topiwala – UK Medical Research Council (G1001354) – Clinical Lecturer. Leonidas Chouliaras – National Institute for Health Research – Academic Clinical Fellow. Klaus P. Ebmeier – UK Medical Research Council (G1001354), the Gordon Edward Small’s Charitable Trust (SC008962), and the HDH Wills 1965 Charitable Trust. Provenance and peer review

3.8. SSRIs and tamoxifen SSRIs have a little known but potentially disastrous interaction with tamoxifen, a selective estrogen receptor modulator used in the treatment of estrogen-receptor positive breast cancers [73]. Depression affects up to 25% of breast cancer patients [74] and hence concomitant treatment using SSRIs and tamoxifen is common. Tamoxifen is a prodrug, metabolized to its active form endoxifen by the cytochrome P450 enzyme CYP2D6. SSRIs inhibit the latter and hence reduce the production of endoxifen. Correspondingly, paroxetine has been shown to significantly increase the risk of death from breast cancer [75]. In fact a 50% increase in the proportion of time patients take both drugs results in a 54% increase in the risk of death. This may be explained by paroxetine’s potent inhibition of CYP2D6 resulting in irreversible loss of the enzyme until more is synthesized. In contrast, SSRIs that are less powerful CYP2D6 inhibitors, such as citalopram, may be safer [76].

Commissioned and externally peer reviewed. Acknowledgements AT is a MRC-funded Clinical Lecturer in Psychiatry, LC a NIHRfunded Academic Clinical Fellow. References [1] Meeks TW, Vahia IV, Lavretsky H, Kulkarni G, Jeste DV. A tune in “a minor” can “b major”: a review of epidemiology, illness course, and public health implications of subthreshold depression in older adults. J Affect Disord 2011;129(1–3):126–42. [2] Martinez C, Rietbrock S, Wise L, et al. Antidepressant treatment and the risk of fatal and non-fatal self harm in first episode depression: nested case–control study. BMJ 2005;330(7488):389 [Epub 19 February 2005]. [3] Kok RM, Nolen WA, Heeren TJ. Efficacy of treatment in older depressed patients: a systematic review and meta-analysis of double-blind randomized controlled trials with antidepressants. J Affect Disord 2012;141(2–3):103–15.

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