Antidepressants and the serotonin hypothesis of depression

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 …