Confirmed: Antidepressants Work for Major Depression

Deborah Brauser

February 27, 2018

A large meta-analysis confirms that antidepressants are effective for major depressive disorder (MDD).

The study included 522 randomized controlled trials (RCTs) and compared 21 different antidepressants with placebo in more than 116,000 patients with MDD.

Results showed that each studied antidepressant was significantly more efficacious, defined as yielding a reduction of at least 50% in the total score of a standardized scale for depression, than placebo after 8 weeks.

During head-to-head comparisons among the class, patients who received agomelatine, escitalopram, and vortioxetine had both high response rates and low dropout rates, which led the investigators to name these drugs "more acceptable" than other antidepressants.

Compared with the other studied antidepressants, trazodone, fluvoxamine, and reboxetine had "generally inferior efficacy and acceptability profiles...making them less favorable options," write the investigators, led by Andrea Cipriani, MD, Department of Psychiatry, the University of Oxford, United Kingdom.

"Our study brings together the best available evidence to inform and guide doctors and patients in their treatment decisions," said Cipriani in a press release.

"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," he added. "Medications should always be considered alongside other options, such as psychological therapies, where these are available."

The findings were published online February 21 in the Lancet.

Ongoing Debate

"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," write the investigators.

As reported by Medscape Medical News, the researchers published findings in 2009 in the Lancet from a meta-analysis that assessed 12 new-generation antidepressants in head-to-head comparisons only.

"With the marketing of new antidepressants and increasing numbers of trials published every year, an updated systematic review and network meta-analysis was required to synthesize the evidence in this important clinical area," now write the investigators, with members from the United Kingdom, the United States, Japan, Switzerland, France, Germany, and the Netherlands.

They assessed both published and unpublished RCTs conducted from 1979 to January 2016, including both placebo-controlled and head-to-head studies. The final meta-analysis included 522 trials and 116,477 adult patients with MDD (62.3% women; mean age, 44 years).

The 21 antidepressants included in the trials were agomelatine, amitriptyline, bupropion, citalopram, clomipramine, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, levomilnacipran, milnacipran, mirtazapine, nefazodone, paroxetine, reboxetine, sertraline, trazodone, venlafaxine, vilazodone, and vortioxetine.

The primary outcomes were acceptability, determined on the basis of treatment discontinuations for any reason, and efficacy.

Relative Merits

When all of the trials were included, the difference in odds ratios (ORs) for efficacy between the antidepressants ranged from 1.15 to 1.55; they ranged from 0.64 to 0.83 for acceptability.

In the study drug–vs–placebo trials only, all of the antidepressants were significantly more effective after 8 weeks of treatment, with ORs ranging from 2.13 for amitriptyline to 1.37 for reboxetine.

Dropout rates were lower with agomelatine and fluoxetine than with placebo (ORs, 0.84 and 0.88, respectively). Dropout rates were higher with clomipramine (OR, 1.30).

In assessments of just the antidepressant-vs-antidepressant trials, the greatest effectiveness was found for the following seven drugs: agomelatine, amitriptyline, escitalopram, mirtazapine, paroxetine, venlafaxine, and vortioxetine (OR range, 1.19 - 1.96). The least effective were fluoxetine, fluvoxamine, reboxetine, and trazodone (OR range, 0.51 - 0.84).

The least amount of dropouts were shown for agomelatine, citalopram, escitalopram, fluoxetine, sertraline, and vortioxetine (OR range, 0.43 - 0.77), meaning they were the most acceptable to patients.

The most dropouts were associated with amitriptyline, clomipramine, duloxetine, fluvoxamine, reboxetine, trazodone, and venlafaxine (OR range, 1.30 - 2.32).

"These results should serve evidence-based practice and inform patients, physicians, guideline developers, and policy makers on the relative merits of the different antidepressants," write the investigators.

However, the results "must be tempered by the potential limitations of the methodology...and the uncertainties that might result from choice of dose or treatment setting," they add.

They also note that this analysis included adults only, and the findings "contrast with the efficacy of antidepressants in children and adolescents, for which fluoxetine is probably the only antidepressant that might reduce depressive symptoms."

"Major Contribution"

"Cipriani and colleagues have made a major contribution," write Sagar V. Parikh, MD, and Sidney H. Kennedy, MD, from the Departments of Psychiatry at the University of Michigan, Ann Arbor and the University of Toronto, Ontario, Canada, respectively, in an accompanying editorial.

However, "a key question — raised in 2009 — remains, what is the implication of superiority of outcomes at 8 weeks for long-term effects, particularly functional outcomes?" write the editorialists.

They add that although the methodology used is very good for aggregating data, it doesn't allow individual patient analysis or details on "who might preferentially respond or who might be more vulnerable to side-effects."

Still, the significant differences identified between the drugs in this analysis "are relevant to health-care economists and policy makers, clinicians, and patients," especially during talks about first treatment, write Parikh and Kennedy.

In addition, "the demonstration of the extent of antidepressant superiority over placebo reassures patients and health-care professionals of the efficacy of [this] treatment despite high placebo response rates."

The study was funded by the National Institute for Health Research Oxford Health Biomedical Research Center and the Japan Society for the Promotion of Science. A full list of disclosures for the other study authors and for the editorialists are in the original articles.

Lancet. Published online February 21, 2018. Full article, Editorial

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