Depression, I was wrong

Depression and serotonin

(UK, July 2022)

Moncrieff, J., Cooper, R.E., Stockmann, T. et al. The serotonin theory of depressiona systematic umbrella review of the evidence. Mol Psychiatry (2022).

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

We aimed to synthesise and evaluate evidence,

whether depression is associated with lowered serotonin

Studies included

17 studies, 12 systematic reviews and meta-analyses, 5 other relevant studies

Serotonin metabolite, 5-HIAA levels unchanged

Serotonin (neurotransmitter), quickly metabolized

Serotonin ----- MAO ------ 5-hydroxy indole acetic acid (5HIAA)

(5-hydroxyindoleacetic acid)

Plasma 5-HIAA, showed no association with depression

Cerebrospinal fluid 5-HIAA, showed no association with depression

Plasma serotonin

Showed no relationship with depression

Several studies of post-menopausal women,

revealed lower levels of plasma 5-HT in women with depression,

(p more than 0.05)

Serotonin receptors

5-HT1A post synaptic receptor

In depression (caused by reduced serotonin) expected to show increased activity of 5-HT1A receptors

Studies found either no difference in 5-HT1A receptors

(between people with depression and controls),

or a lower level of these receptors

Tryptophan depletion

Studies found no effect in healthy volunteers,

but weak evidence of an effect in those with a family history of depression

Studies of the Serotonin transporter (SERT) gene

Serotonin transporter (SERT) is the molecular target of selective serotonin reuptake inhibitors

As expected, antidepressant treatment reduces SERT

Amount or activity of SERT would be expected to be higher in people with depression

No evidence of an association with depression,

or of an interaction between genotype, stress and depression.

Effects of SSRIs on plasma serotonin

Lowered serotonin concentration was associated with antidepressant use

Sensitivity analyses revealed that antidepressants were strongly associated with lower serotonin levels independently of depression.

Discussion

This review suggests that the huge research effort based on the serotonin hypothesis has not produced convincing evidence of a biochemical basis to depression.

This is consistent with research on many other biological markers

We suggest it is time to acknowledge that the serotonin theory of depression is not empirically substantiated

Some evidence was consistent with the possibility that long-term antidepressant use reduces serotonin concentration.