No abstract

According to a systematic review on the use of selective serotonin reuptake inhibitors (SSRIs) in adult depression that was recently published in BMC Psychiatry, the results of which have been widely disseminated in lay media, these drugs increase the risk for serious adverse events (SAEs) while exerting poor antidepressant efficacy. A cursory analysis, however, suggests the analysis of SAEs conducted by the authors to be marred by both methodological inaccuracies and blatant errors. After having corrected for these apparent mistakes, we conducted a sensitivity analysis in which we also accounted for a possible moderating effect of age; while this suggests SSRIs to be safe drugs in the non-elderly, they do confirm what is already known, that is, that they may enhance the risk for SAEs in the old. Given the loose definition of SAE, including also innocuous phenomena, the possible clinical significance of the latter observation, however, remains unclear until the nature and actual impact of the SAEs in question have been clarified. Moreover, with respect to efficacy, we find the paper in BMC Psychiatry misleading: first, the authors seem unaware of the well-established shortcomings associated with the conventional efficacy parameter on which their analysis is based, second, they have included suboptimal SSRI doses and third, they have missed some pivotal trials. Unless there are explanations for the many peculiarities in this paper that have escaped us, and which may be satisfactorily clarified by the authors, it seems important that the conclusions presented in this paper be publicly rectified.

It has been suggested that the superiority of antidepressants over placebo in controlled trials is merely a consequence of side effects enhancing the expectation of improvement by making the patient realize that he/she is not on placebo. We explored this hypothesis in a patient-level post hoc-analysis including all industry-sponsored, Food and Drug Administration-registered placebocontrolled trials of citalopram or paroxetine in adult major depression that used the Hamilton Depression Rating Scale (HDRS) and included a week 6 symptom assessment (n = 15). The primary analyses, which compared completers on active treatment without early adverse events to completers on placebo (with or without adverse events) with respect to reduction in the HDRS depressed mood item showed larger symptom reduction in patients given active treatment, the effect sizes being 0.48 for citalopram and 0.33 for paroxetine. In actively treated subjects reporting early adverse events, who also outperformed those given placebo, the severity of the adverse events did not predict response. Several sensitivity analyses, for example, including (i) those using change of the sum of all HDRS-17 items as effect parameter, (ii) those excluding all subjects with adverse events (that is, also those on placebo) and (iii) those based on the intention-to-treat population, were all in line with the primary analyses. The finding that both paroxetine and citalopram are clearly superior to placebo also when not producing adverse events, as well as the lack of association between adverse event severity and response, argue against the theory that antidepressants outperform placebo solely or largely because of their side effects.

Oft-cited trial-level meta-analyses casting doubt on the usefulness of antidepressants have been based on re-analyses of to what extent the active drug has outperformed placebo in reducing the sum score of the Hamilton Depression Rating Scale (HDRS-17-sum) in clinical trials. Recent studies, however, suggest patient-level analyses of individual HDRS items to be more informative when assessing the efficacy of an antidepressant. To shed further light on both symptom-reducing and symptom-aggravating effects of a serotonin and noradrenaline reuptake inhibitor, duloxetine, when used for major depression in adults, we hence applied this approach to re-analyse data from 13 placebo-controlled trials. In addition, using patient-level data from 28 placebo-controlled trials of selective serotonin reuptake inhibitors (SSRIs), the response profile of duloxetine was compared to that of these drugs. Duloxetine induced a robust reduction in depressed mood that was not dependent on baseline severity and not caused by side-effects breaking the blind. A beneficial effect on depressed mood was at hand already after one week; when outcome was assessed using HDRS-17-sum as effect parameter, this early response was however masked by a concomitant deterioration with respect to adverse event-related items. No support for a suicide-provoking effect of duloxetine was obtained. The response profile of duloxetine was strikingly similar to that of the SSRIs. We conclude that the use of HDRS-17-sum as effect parameter underestimates the true efficacy and masks an early effect of duloxetine on core symptoms of depression. No support for major differences between duloxetine and SSRIs in clinical profile were obtained.

The net effect of SSRIs on suicidality appears beneficial in people above the age of 24 and neutral in those aged 18-24. Declaration of interest F.H. has received speaker's fees from Servier. E.E. has previously been on the advisory boards and/or received speaker's honoraria and/or research grants from Eli Lilly, GlaxoSmithKline, Servier and Lundbeck.