February 21, 2018
3 min read

Antidepressants more effective than placebo for major depression

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Andrea Cipriani

Twenty-one commonly used antidepressant medications appeared more effective than placebo for the treatment of major depressive disorder in adults, according to findings from an international study.

“There is a long-lasting debate and concern about [antidepressants’] efficacy and effectiveness, because short-term benefits are, on average, modest; and because long-term balance of benefits and harms is often understudied,” Andrea Cipriani, MD, PhD, of the department of psychiatry, University of Oxford, and Oxford Health NHS Foundation Trust, and colleagues wrote in The Lancet. “Therefore, innovation in psychopharmacology is of crucial importance, but the identification of new molecular targets is difficult, primarily because of the paucity of knowledge about how antidepressants work.”

The researchers conducted a network meta-analysis and systematic review of all double-blind, randomized controlled trials that compared antidepressants with placebo, or with another antidepressant, for the acute treatment of adults with major depressive disorder over 8 weeks. The primary outcomes were efficacy and acceptability. They included clinical trials that compared 21 commonly used antidepressant medications or placebo in their network meta-analysis; overall, 87,052 participants received an antidepressant drug and 29,425 received placebo.

In total, researchers included 522 trials comprising 116,477 participants in their study. The results showed that all 21 antidepressant medications were more effective than placebo, with odds ratios ranging between 2.13 for amitriptyline and 1.37 for reboxetine.

"The evidence of this study, the largest meta-analysis ever carried out in psychiatry, supports the use of commonly prescribed antidepressants to treat adults with moderate to severe major depression, which is a huge global unmet medical need,” Cipriani told Healio Psychiatry. “There are clinically important differences in efficacy and acceptability between drugs that should inform shared decision-making between patients and clinicians.”

In terms of acceptability, the only antidepressants linked to fewer dropouts than placebo were agomelatine (OR = 0.84; 95% CI 0.72–0.97) and fluoxetine (OR = 0.88; 95% CI, 0.8–0.96); placebo was only considered more acceptable than clomipramine (OR = 1.3; 95% CI, 1.01–1.68). In head-to-head studies, researchers observed that agomelatine, amitriptyline, escitalopram, mirtazapine, paroxetine, venlafaxine and vortioxetine were the most effective antidepressants, whereas fluoxetine, fluvoxamine, reboxetine and trazodone were the least effective. For acceptability, agomelatine, citalopram, escitalopram, fluoxetine, sertraline and vortioxetine were the most tolerable, whereas amitriptyline, clomipramine, duloxetine, fluvoxamine, reboxetine, trazodone and venlafaxine were observed as the least tolerable. Overall, 9% of the trials included in this meta-analysis were considered as high-risk of bias, 73% as moderate and 18% as low.

“Our study brings together the best available evidence to inform and guide doctors and patients in their treatment decisions. Antidepressants can be an effective tool to treat major depression, but this does not necessarily mean that antidepressants should always be the first line of treatment,” Cipriani said in a press release. “Medication should always be considered alongside other options, such as psychological therapies, where these are available. Patients should be aware of the potential benefits from antidepressants and always speak to their doctors about the most suitable treatment for them individually.”

Although important, these results do not answer the question about the long-term effects of antidepressants, and a network meta-analysis approach cannot be used on the individual patient level, Sagar V. Parikh, MD, department of psychiatry, University of Michigan, and Sidney H. Kennedy, MD, department of psychiatry, University of Toronto, wrote in an accompanying comment.

“Ultimately, the field requires different research strategies to identify response at the level of the individual patient, not just network meta-analysis with larger sample sizes. Nevertheless, Cipriani and colleagues have made a major contribution,” they wrote. “The demonstration of the extent of antidepressant superiority over placebo reassures patients and health care professionals of the efficacy of treatment despite high placebo response rates.” – by Savannah Demko

Disclosures: Cipriani reports support from the National Institute for Health Research Oxford Cognitive Health Clinical Research Facility. Please see the study for all other authors’ relevant financial disclosures. Parikh reports funding from Assurex Health, Canadian Institutes of Health Research, James and Ethel Flinn Foundation and Ontario Brain Institute. He reports honoraria from the Canadian Network for Mood and Anxiety Treatments, Lundbeck, Mensante Corporation and Takeda. He also holds minor equity in Mensante. Kennedy reports funding from Abbott, Canadian Institutes for Health Research, the Ontario Brain Institute and Ontario Research Fund. He reports honoraria from Allergan, Bristol-Myers Squibb, Lundbeck, Otsuka, Pfizer, Servier, Sunovion and Xian-Janssen.

Editors note: The headline was revised on Feb. 22.