Intended for healthcare professionals


Antidepressants and the serotonin hypothesis of depression

BMJ 2022; 378 doi: (Published 15 August 2022) Cite this as: BMJ 2022;378:o1993
  1. Tony Kendrick, professor of primary care1,
  2. Susan Collinson, specialist TB case worker2
  1. 1Primary Care, Population Sciences and Medical Education, University of Southampton, Aldermoor Health Centre, Southampton, UK
  2. 2Homerton University Hospital NHS Foundation Trust, London, UK
  1. Correspondence to: T Kendrick A.R.Kendrick{at}

Antidepressants remain an effective treatment for depression, even without the “chemical imbalance” explanation

A recent umbrella review of evidence for the serotonin theory of depression1 was widely reported in UK media as showing that depression is not caused by low levels of serotonin or a “chemical imbalance” and therefore casting doubt on the use of selective serotonin reuptake inhibitor (SSRI) antidepressants by millions of people.2345

The review brought together existing systematic reviews, meta-analyses, and large dataset analyses on associations between depression and concentrations of serotonin and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) in body fluids; serotonin 5-HT1A receptor binding; serotonin transporter (SERT) levels measured by imaging or postmortem analysis; tryptophan depletion; SERT gene polymorphism; and SERT gene-environment interactions. It reported no consistent evidence to support the hypothesis that depression is caused by reduced serotonin activity, and called for acknowledgment that the theory is not empirically substantiated.1

The polarising debate that ensued risks undermining the evidence based treatment of depression and causing harm to people who take or need SSRI antidepressants. Critics of the review and its coverage noted that study selection was incomplete, as an omitted 2021 meta-analysis had concluded that changes in blood biochemistry, notably of L-tryptophan, were …

View Full Text

Log in

Log in through your institution


* For online subscription