Antidepressants do work after all

In the current issue, Andrade and colleagues describe naturalistic outcomes following antidepressant therapy in 808 people with major depressive disorder (MDD) in India. The authors adopt a prospective observational design, in which they compare the change in depressive symptoms from initiation of first antidepressant therapy through a 6-week follow-up. With direct-topsychiatrist care being common in India, the authors were able to use the Montgomery–Åsberg Depression Rating Scale (MADRS) – a clinician part-rated assessment that is putatively sensitive to changes during treatment (Montgomery and Asberg, 1979) – within a representative, primary care cohort. Further, by recruiting 205 different psychiatrists across multiple regions of India, with each asked to recruit the same number of patients, the authors ensured that the diversity of the sample was considerable. Of the 98.8% of patients who were followed up at 6 weeks, the vast majority received treatment with desvenlafaxine, vilazodone or escitalopram. The primary clinical outcome (50% reduction of MADRS score) was met in 66.1% of the sample, whilst MADRS remission (score <10) was recorded in 36.7% of patients. In terms of tolerability, patient-rated adverse events were mostly described as absent (32.3%) or minor (46.0%), whilst only 0.9% reported that the treatment was worse than the illness. Noted limitations of the study include its observational design, lack of systematic recording of specific adverse events, non-random recruitment of the sample, and a comorbid mental health diagnosis (mostly anxiety disorders) for 14.9% of the sample. Despite these limitations, clinicians and patients should be encouraged by the key finding that two-thirds of patients responded to first-line antidepressant therapy when used in a routine, primary care setting. Indeed, clinical response might have been even greater if follow-up had been extended beyond 6 weeks and if no patients with comorbid anxiety disorders had been recruited. Moreover, desvenlafaxine – the most commonly prescribed antidepressant in the study – has relatively poor efficacy compared with other antidepressants (Cipriani et al., 2018), suggesting that different choices of antidepressants could improve outcomes even more. The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial was carried out in the United States and is frequently cited as a benchmark for response rates to antidepressant therapy (Rush et al., 2006). In STAR*D, 47% of patients responded to first-line therapy with citalopram, followed by more modest response rates to second-line therapies. Compared with the present (MDD-1) study, the more modest outcomes in STAR*D could in part be explained by the differences in study populations. Whereas MDD-1 recruited a naturalistic, primary care sample receiving their first ever antidepressant, STAR*D was a more tightly defined clinical trial population, most of whom had recurrent or resistant depression. Further, Andrade and colleagues speculate that depressed patients in India have a more favourable stress–support ratio and better trust in the medical system, which may help to explain the more promising outcomes from their study. A criticism of the MDD-1 study is that, lacking a control arm, we cannot say that any benefits of antidepressants were not strongly driven by ‘placebo’ effects. Critics of antidepressants have asserted that pharmacological benefits of antidepressants are overestimated due to non-scrutiny or nonpublication of negative clinical trials. In a 2008 meta-analysis of 35 clinical trials submitted to the US Food and Drug Agency, Kirsch and colleagues reported that drug–placebo differences increased as a function of initial severity, rising from almost no difference at moderate levels of initial depression to a relatively small difference for patients with very severe depression (Kirsch et al., 2008). Further, the relationship between initial depression severity and antidepressant efficacy was attributed to decreased responsiveness to placebo among very severely depressed patients, rather than increased responsiveness to antidepressants. More recently, however, this negative view of antidepressants has become difficult to sustain. A 2018 network metaanalysis of 421 studies – including 86 unpublished studies from trial registries and pharmaceutical company websites – found that all antidepressants were more efficacious than placebo in adults with MDD. The overall effect size of 0.3 is comparable to accepted interventions in chronic physical diseases, such as chronic obstructive pulmonary disease and multiple sclerosis (Leucht et al., 2012). Subsequent to this 2018 meta-analysis, a randomised controlled trial (RCT) of 655 patients in primary care showed that sertraline was more Antidepressants do work after all