Intended for healthcare professionals

Feature Essay

The trouble with antidepressants: why the evidence overplays benefits and underplays risks—an essay by John B Warren

BMJ 2020; 370 doi: (Published 03 September 2020) Cite this as: BMJ 2020;370:m3200
  1. John B Warren, director
  1. Medicines Assessment, Ipswich, Suffolk, UK
  1. jbwarren5{at}

Widespread prescribing has not reduced mental disability or suicide, raising questions about the assessment of evidence on effectiveness and safety of antidepressants, writes John Warren

Depression can be severe and reduce life expectancy. Antidepressant prescribing has increased substantially in recent years so that one in eight UK adults, some 7.3 million people, now receive a prescription for antidepressants each year, and many take them long term.1 More than 60% of US residents taking antidepressants do so for more than two years.2

Although meta-analyses seem to support widespread use, concerns have been raised about the effectiveness and safety of the drugs. The conclusions of meta-analyses have been criticised because of manufacturers’ influence on trials,34 under-recognition of the placebo effect, inadequate attention to negative data, different methods used to assess risk and benefit, and lack of benefit on suicide. There are also concerns about limited safety databases and the huge commercial promotion of these drugs.

Analysis of the benefits and risks of drugs in psychiatry differs from other therapeutic areas. There are no reliable biomarkers of psychiatric disease and no primary endpoint to summarise safety and efficacy (an equivalent to mortality in cardiovascular or oncology trials). Psychiatry therefore depends on composite scales for diagnosis and to assess drug efficacy. As composite measures are rarely used for adverse events, trials are likely to overestimate benefit and underestimate risks, with serious implications for public health. Although prescribers will often see patients improve over time, questions remain about how much antidepressants contribute to this and whether long term treatment is safe.

Unclear mechanism of action

A common justification for using antidepressants is that they correct a chemical deficiency in the brain. The monoamine hypothesis, over 50 years old, implicates serotonergic, noradrenergic, and dopaminergic neurotransmission in the pathogenesis of depression.

Deficiency of the neurotransmitter dopamine explains …

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