Study finds antidepressants to be more effective than placebos

Meta-analysis of 522 trials compared 21 commonly used antidepressants and concluded all of them to be more effective than placebos for the short-term treatment of acute depression in adults, with effectiveness ranging from small to moderate for different drugs.

The trials analysed were all double-blind, randomised controlled trials (RCTs) with a total of 116,477 participants. The study includes the largest amount of previously unpublished data to date, all of which is now freely available online.

"Our study brings together the best available evidence to inform and guide doctors and patients in their treatment decisions. We found that the most commonly used antidepressants are more effective than placebos, with some more effective than others. Our findings are relevant for adults experiencing a first or second episode of depression – the typical population seen in general practice." says lead author Dr Andrea Cipriani, University of Oxford and the NIHR Oxford Health Biomedical Research Centre.

"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 the doctors about the most suitable treatment for them individually," Cipriani concludes.

Large-scale worldwide illness

An estimated 350 million people have depression worldwide. The economic burden in the USA alone has been estimated at more than US$210 billion. Pharmacological and non-pharmacological treatments are available but owing to inadequate resources, antidepressants are more frequently used. However, there is considerable debate about their effectiveness.

As part of the study, the authors identified all double-blind RCTs that compared antidepressants with placebos, or with another antidepressant (head-to-head trials) for the acute treatment (over eight weeks) of major depression in adults aged 18 years or more. The authors then contacted pharma companies, original study authors, and regulatory agencies in order to supplement incomplete reports of the original papers, or provide data for unpublished studies.

The primary outcomes were efficacy (number of patients who responded to treatment, ie who had a reduction in depressive symptoms of 50% or more on a validated rating scale over eight weeks) and acceptability (proportion of patients who withdrew from the study for any reason by week eight).

Overall, 522 double-blind RCTs carried out between 1979 and 2016 that compared 21 commonly used antidepressants or placebos were included in the meta-analysis; the largest ever in psychiatry. A total of 87,052 participants had been randomly assigned to receive a drug, and 29,425 to receive placebos. The majority of patients had moderate-to-severe depression.

All 21 antidepressants were more effective than placebos and only one drug (clomipramine) was less acceptable than placebo.

Antidepressants effective to varying degrees

Some antidepressants were more effective than others, with agomelatine, amitriptyline, escitalopram, mirtazapine, paroxetine, venlafaxine, and vortioxetine proving most effective, and fluoxetine, fluvoxamine, reboxetine, and trazodone being the least effective. The majority of the most effective antidepressants are now off patent and available in generic form.

Antidepressants also differed in terms of acceptability, with agomelatine, citalopram, escitalopram, fluoxetine, sertraline, and vortioxetine proving most tolerable, and amitriptyline, clomipramine, duloxetine, fluvoxamine, reboxetine, trazodone, and venlafaxine being the least tolerable.

The authors note that the data included in the meta-analysis covers eight weeks of treatment, so may not necessarily apply to longer term drug treatment. The differences in efficacy and acceptability between different antidepressants were smaller when data from placebo-controlled trials were also considered.

Effects may not extend to bipolar condition

In order to ensure that the trials included in the meta-analysis were comparable, the authors excluded studies with patients who also had bipolar depression, symptoms of psychosis or treatment resistant depression, meaning that the findings may not apply to these patients.

"Antidepressants are effective drugs, but, unfortunately, we know that about one third of patients with depression will not respond. With effectiveness ranging from small to moderate for available antidepressants, it’s clear there is still a need to improve treatments further," adds Dr Cipriani, .

Nothing is perfect

78% of the 522 trials were funded by pharma companies, and the authors retrieved unpublished information for 52% of the trials included in the meta-analysis. Overall, 9% of the trials were rated as high risk of bias, 78% as moderate, and 18% as low. The design of the network meta-analysis and inclusion of unpublished data is intended to reduce the impact of individual study bias as much as possible. Although this study included a significant amount of unpublished data, a certain amount could still not be retrieved.

"Antidepressants are routinely used worldwide yet there remains considerable debate about their effectiveness and tolerability. By bringing together published and unpublished data from over 500 double blind randomised controlled trials, this study represents the best currently available evidence base to guide the choice of pharmacological treatment for adults with acute depression. The large amount of data allowed more conclusive inferences and gave the opportunity also to explore potential biases," says co-author Professor John Ioannidis, from the Departments of Medicine, Health Research and Policy, Biomedical Data Science, and Statistics, Stanford University, USA.

The international study was published in The Lancet.

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