Efficacy and Acceptability of Antidepressants in Acute Depression – What Does the Largest Ever Research Study on Antidepressants Tell Us?

Posted on:March 23, 2018
Last Updated: November 10, 2023
Time to read: 10 minutes

Antidepressants are widely used treatments for major depressive disorder. However, there is considerable debate on their effectiveness because their short-term benefits are modest and the long-term benefits and harms are under-researched.

In 1998, Irving Kirsch published a meta-analysis of 19 placebo-controlled double-blind clinical trials [1]. In this publication, the mean change in depressive scores was compared between placebo and antidepressant. Here, it was shown that the placebo response was calculated to be responsible for 75% of the response to active antidepressant medication. [1]

This article reached a controversial conclusion, and the methodology was criticised, whereby the analysis was subject to significant clinical, methodological and statistical heterogeneity. [2]

However, in 2008, Kirsch repeated his work using a different set of clinical trials by requesting the FDA to divulge unpublished research from pharmaceutical companies [3]. In this data set, the placebo response was shown to be responsible for 82% of the response observed with antidepressant therapy.

Drug–placebo differences in antidepressant efficacy increase as a function of baseline severity, but are relatively small even for severely depressed patients. The relationship between initial severity and antidepressant efficacy is attributable to decreased responsiveness to placebo among very severely depressed patients, rather than to increased responsiveness to medication (Kirsch et al 2008).

Fournier and colleagues then supported the observation that antidepressants show a magnitude of benefit only for cases of severe depression (HDRS>25). [4]

The magnitude of benefit of antidepressant medication compared with placebo increases with severity of depression symptoms and may be minimal or nonexistent, on average, in patients with mild or moderate symptoms. For patients with very severe depression, the benefit of medications over placebo is substantial.

The efficacy of antidepressants has therefore been debated for at least a decade.

In February 2018, a systematic review and network meta-analysis was published by Cipriani and colleagues, which compared the efficacy and acceptability of antidepressants to treat major depressive disorder. [5]

This network meta-analysis was more extensive and included a comprehensive list of 21 antidepressants and placebo which were compared by using the most advanced statistical methodology for network meta-analysis to date.