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Home Exclusive Mental Health Depression

Large systematic review finds no evidence for the serotonin hypothesis of depression

by Mane Kara-Yakoubian
July 22, 2022
in Depression, Psychopharmacology

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A large systematic umbrella review published in Molecular Psychiatry suggests a lack of consistent evidence linking serotonin and depression, concluding that there is no support for the hypothesis that depression is caused by lowered serotonin activity or concentration.

Decades of literature has argued that depression results from abnormalities in serotonin, a neurotransmitter involved in numerous psychological and physiological processes. This has served as the basis for the use of Selective Serotonin Reuptake Inhibitor (SSRI) antidepressants. That depression is caused by a chemical imbalance in the brain has widespread support from researchers, health care practitioners, and the general public. The seeming efficacy of SSRIs is believed to provide support for the involvement of serotonin in depression. Other explanations have suggested that antidepressants enhance a placebo effect or generally blunt emotion.

In this work, Joanna Moncrieff and colleagues conduct the first comprehensive review that synthesizes the relevant evidence to examine the serotonin hypothesis of depression. Umbrella reviews are one of the most effective ways of synthesizing information, as they involve the review of systematic reviews and meta-analyses. This review expanded these criteria to include large studies that aggregated data from individual studies, as well as one large-scale genetic study.

Other inclusion criteria included peer-reviewed studies involving people with depressive disorders (tryptophan depletion for experimental studies, with a control or sham condition), or those measuring mood as an outcome. In the case of more than five systematic reviews or large analyses, the authors included the most recent five. Animal studies, and studies exclusively focusing on depression in physical conditions (e.g., Parkinson’s disease), or subtypes of depression (e.g., postpartum depression, depression in bipolar disorder) were excluded.

The researchers did not apply any language or date restrictions. As well, the ten most recent studies at the time of the search (December 2020) were included to illustrate more recent findings for areas in which a systematic review or meta-analysis from the past decade could not be found.

The scoping review covered six areas of research that have provided support for the serotonin hypothesis of depression, including “serotonin and serotonin metabolite, 5-HIAA, concentrations in body fluids; serotonin 5-HT1A receptor binding; serotonin transporter (SERT) levels measured by imaging or at post-mortem; tryptophan depletion studies; SERT gene associations and SERT gene-environment interactions.” A total of 17 studies were included in this work.

Moncrieff and colleagues write that “the major strands of research on serotonin shows there is no convincing evidence that depression is associated with, or caused by, lower serotonin concentrations or activity.” Most studies revealed no differences in serotonin activity between people with depression and without. As well, the methods of reducing serotonin availability via tryptophan depletion did not lower mood among participants. Further, genetic studies reject a link between genotypes relating to the serotonin system and depression.

There is some weak evidence for the association between serotonin activity and depression from studies examining serotonin 5-HT1A receptors and levels of SERT. However, these results are likely mediated by prior use of antidepressants which have influenced the serotonin system.

The researchers add, “The idea that depression is the result of a chemical imbalance also influences decisions about whether to take or continue antidepressant medication and may discourage people from discontinuing treatment, potentially leading to lifelong dependence on these drugs.”

Moncrieff and colleagues conclude, “We suggest it is time to acknowledge that the serotonin theory of depression is not empirically substantiated.”

The systematic review, “The serotonin theory of depression: a systematic umbrella review of the evidence”, was authored by Joanna Moncrieff, Ruth E. Cooper, Tom Stockmann, Simone Amendola, Michael P. Hengartner, and Mark A. Horowitz.

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