By Jean Balchin 22/02/2018

A major meta-analysis study comparing commonly used antidepressants has concluded that all are more effective than placebo for the short-term treatment of acute depression in adults, with effectiveness ranging from small to moderate for different drugs.

What is depression?

According to the American Psychiatric Association, depression

“is a common and serious medical illness that negatively affects how you feel, the way you think and how you act. Fortunately, it is also treatable. Depression causes feelings of sadness and/or a loss of interest in activities once enjoyed. It can lead to a variety of emotional and physical problems and can decrease a person’s ability to function at work and at home.”

The meta-analysis

Published in The Lancet, the international study comprises a network meta-analysis of 522 double-blind, randomised controlled trials comprising a total of 116477 participants. This study constitutes the largest amount of unpublished data to date.

“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 placebo, 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. 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. 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,” says lead author Dr Andrea Cipriani, University of Oxford and the NIHR Oxford Health Biomedical Research Centre.

It is estimated that at least 350 million people worldwide have depression. Quite apart from the emotional and social repercussions of this fact, the economic burden in the USA alone has been estimated to be more than US$210 billion. Both pharmacological (medication) and non-pharmacological (counselling etc) treatments are available but because of inadequate resources, antidepressants are used more frequently than psychological interventions. There has been considerable debate about their effectiveness over the years.

How was the meta-analysis conducted?

The authors examined the data and identified all double-blind, randomised controlled trials (RCTs) comparing antidepressants with placebo, or with another antidepressants (head-to-head trials) for the acute treatment (over 8 weeks) of major depression in adults aged 18 years or more. In a double-blind trial, neither the subjects nor the experimenters know which subjects are in the test and control groups during the actual course of the experiments.

The relevant pharmaceutical companies, original study authors, and regulatory agencies were then contacted in order to supplement incomplete reports of the original papers, or provide data for unpublished studies.

Fluoxetine, a common antidepressant. Also known as Prozac.

The primary outcomes were

  • efficacy (number of patients who responded to treatment, i.e. who had a reduction in depressive symptoms of 50% or more on a validated rating scale over 8 weeks) and
  • acceptability (proportion of patients who withdrew from the study for any reason by week 8).

In the largest ever meta-analysis in psychiatry, 522 double-blind RCTs done between 1979 and 2016 comparing 21 commonly used antidepressants or placebo were examined. A total of 87052 participants had been randomly assigned to receive a drug, and 29425 to receive placebo. The majority of patients had moderate-to-severe depression.

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

Effectiveness and acceptability

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. Amitriptyline, clomipramine, duloxetine, fluvoxamine, reboxetine, trazodone, and venlafaxine were considered the least tolerable.


One limitation of this study however, is that the data included in the meta-analysis only covers 8-weeks of treatment, so may not necessarily apply to longer term antidepressant use. Moreover, the differences in efficacy and acceptability between different antidepressants were smaller when data from placebo-controlled trials must also be kept in mind.

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 depression that resisted treatment. Thus, these 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, a consultant psychiatrist at Oxford Health NHS Foundation Trust. 

409 (78%) of 522 trials were funded by pharmaceutical companies, and the authors retrieved unpublished information for 274 (52%) of the trials included in the meta-analysis. Overall, 46 (9%) trials were rated as high risk of bias, 380 (78%) as moderate, and 96 (18%) as low.

The impact of individual study bias was negated significantly by the design of the network meta-analysis and inclusion of unpublished data. However, 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.

Moreover, the authors did not have access to individual-level data, so were only able to analyse group differences. Thus they could not look at the effectiveness or acceptability of antidepressants in relation to age, sex, severity of symptoms, duration of illness or other individual-level characteristics.

The findings from this study contrast with a similar analysis in children and adolescents, which concluded that fluoxetine was probably the only antidepressant that might reduce depressive symptoms.

According to the authors, this difference may result from the fact that depression in young people is often the result of different mechanisms or causes. Fundamentally, because of the relatively few number of studies in young people there is great uncertainty around the risks and benefits of using any antidepressants for the treatment of depression in children and adolescents.

You can read this study here.

Where to get help

If you are worried about your or someone else’s mental health, the best place to get help is your GP or local mental health provider. However, if you or someone else is in danger or endangering others, call 111.

If you need to talk to someone, the following free helplines operate 24/7:

LIFELINE: 0800 543 354
NEED TO TALK? Call or text 1737
SAMARITANS: 0800 726 666
YOUTHLINE: 0800 376 633 or text 234

There are lots of places to get support. For others, click here.