It is often assumed that the effects of antidepressants demonstrate that depression must be at least partially caused by a brain-based chemical abnormality, and that the apparent efficacy of SSRIs shows that serotonin is implicated. Many general practitioners also subscribe to this view and popular websites commonly cite the theory. Surveys suggest that 80% or more of the general public now believe it is established that depression is caused by a ‘chemical imbalance’. Although it has been questioned more recently, the serotonin theory of depression remains influential, with principal English language textbooks still giving it qualified support, leading researchers endorsing it, and much empirical research based on it. A link between lowered serotonin and depression was first suggested in the 1960s, and widely publicised from the 1990s with the advent of the Selective Serotonin Reuptake Inhibitor (SSRI) antidepressants. The idea that depression is the result of abnormalities in brain chemicals, particularly serotonin (5-hydroxytryptamine or 5-HT), has been influential for decades, and provides an important justification for the use of antidepressants. Some evidence was consistent with the possibility that long-term antidepressant use reduces serotonin concentration. 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.
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. No systematic review of tryptophan depletion studies has been performed since 2007. Another systematic review ( n = 342) and a sample of ten subsequent studies ( n = 407) found no effect in volunteers. 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). However, effects of prior antidepressant use were not reliably excluded. Two meta-analyses of overlapping studies examining the 5-HT 1A 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. 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 serotonin metabolite, 5-HIAA, showed no association with depression (largest n = 1002). Quality of reviews was variable with some genetic studies of high quality. 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. The review was registered with PROSPERO (CRD42020207203).
We did not synthesise results of individual meta-analyses because they included overlapping studies. The certainty of study results was assessed using a modified version of the GRADE. 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. Studies of depression associated with physical conditions and specific subtypes of depression (e.g. 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-HT 1A receptor binding serotonin transporter (SERT) levels measured by imaging or at post-mortem tryptophan depletion studies SERT gene associations and SERT gene-environment interactions. PubMed, EMBASE and PsycINFO were searched using terms appropriate to each area of research, from their inception until December 2020. 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. The serotonin hypothesis of depression is still influential.
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