The serotonin theory of depression: a systematic umbrella review of the evidence

Abstract

The serotonin hypothesis of depression is still influential. We aimed to synthesise and evaluate evidence on whether depression is associated with lowered serotonin concentration or activity in a systematic umbrella review of the principal relevant areas of research. PubMed, EMBASE and PsycINFO were searched using terms appropriate to each area of research, from their inception until December 2020. Systematic reviews, meta-analyses and large data-set analyses in the following areas were identified: 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. Studies of depression associated with physical conditions and specific subtypes of depression (e.g. bipolar depression) were excluded. Two independent reviewers extracted the data and assessed the quality of included studies using the AMSTAR-2, an adapted AMSTAR-2, or the STREGA for a large genetic study. The certainty of study results was assessed using a modified version of the GRADE. We did not synthesise results of individual meta-analyses because they included overlapping studies. The review was registered with PROSPERO (CRD42020207203). 17 studies were included: 12 systematic reviews and meta-analyses, 1 collaborative meta-analysis, 1 meta-analysis of large cohort studies, 1 systematic review and narrative synthesis, 1 genetic association study and 1 umbrella review. Quality of reviews was variable with some genetic studies of high quality. Two meta-analyses of overlapping studies examining the serotonin metabolite, 5-HIAA, showed no association with depression (largest n = 1002). One meta-analysis of cohort studies of plasma serotonin showed no relationship with depression, and evidence that lowered serotonin concentration was associated with antidepressant use (n = 1869). Two meta-analyses of overlapping studies examining the 5-HT1A receptor (largest n = 561), and three meta-analyses of overlapping studies examining SERT binding (largest n = 1845) showed weak and inconsistent evidence of reduced binding in some areas, which would be consistent with increased synaptic availability of serotonin in people with depression, if this was the original, causal abnormaly. However, effects of prior antidepressant use were not reliably excluded. One meta-analysis of tryptophan depletion studies found no effect in most healthy volunteers (n = 566), but weak evidence of an effect in those with a family history of depression (n = 75). Another systematic review (n = 342) and a sample of ten subsequent studies (n = 407) found no effect in volunteers. No systematic review of tryptophan depletion studies has been performed since 2007. The two largest and highest quality studies of the SERT gene, one genetic association study (n = 115,257) and one collaborative meta-analysis (n = 43,165), revealed no evidence of an association with depression, or of an interaction between genotype, stress and depression. The main areas of serotonin research provide no consistent evidence of there being an association between serotonin and depression, and no support for the hypothesis that depression is caused by lowered serotonin activity or concentrations. Some evidence was consistent with the possibility that long-term antidepressant use reduces serotonin concentration.

Sex differences in peripheral monoamine transmitter and related hormone levels in chronic stress mice with a depression-like phenotype

“…The monoamine hypothesis plays an important role in the pathogenesis of depression, which believes that depression is closely related to the low level of monoamine such as NE and 5-HT in brain. Although the serotonin hypothesis of depression is still influential, a recent systematic umbrella review of the principal relevant areas of research on whether depression is associated with lowered serotonin concentration or activity suggested that peripheral serotonin levels have no correlation with depression and might not be useful as a biomarker ( Frank et al, 2000 , Moncrieff et al, 2022 ). The clinical relevance of peripheral monoamine measure warrants further investigation.…”

Mental Gravity: A novel theory of self, brain, mind and depression

“…At a practical level, the MG theory of depression could help treatment move beyond the serotonin hypothesis and the use of Specific Serotonin Reuptake Inhibitors (SSRI's) which is currently controversial (Moncrieff et al, 2022). Serotonin is implicated in rats' depression-like responses to hypergravity environments (Abe et al, 2010).…”

Serotonin as a Biocultural Molecule: Circular Causality, Stress, and Psychopathology

“…In fact, successfully applying a reductionist approach "often depends on on using the higher order phenomena to guide the search for lower level explanations and to recognize an adequate explanation when it has been found" (Kirmayer & Gold, 2012, p. 309). This might be a reason why the "chemical imbalance" hypotheses never seem to hold up to experimental scrutiny, in spite of being commonly held view by health professionals and layperson alike (Moncrieff et al, 2022).…”

“…The depressogenic effect of amine-depleting drugs, such as reserpine, and the use of serotonin reuptake inhibitors to treat mood disorders, including major depressive disorder, led to favoring this neurotransmitter in mechanistic explanations of mood regulation (Cowen & Browning, 2015;Vaswani et al, 2003). While this monoaminergic theory of depression has long been viewed as overly simplistic (Cowen, 2008;Moncrieff et al, 2022), the role of 5-HT in different manifestations of distress has expanded considerably. In part, this is due to the application of selective serotonin reuptake inhibitors (SSRIs) to treat more and more disorders (Vaswani et al, 2003); currently, there is evidence of low-to-moderate quality of positive effect of SSRIs in the treatment of depressive disorders (Arroll et al, 2009;Purgato et al, 2014;Wilkinson & Izmeth, 2016), obsessive-compulsive disorder (Soomro et al, 2008), various anxiety disorders (Bighelli et al, 2018;Williams et al, 2017), and post-traumatic disorder (Williams et al, 2022).…”