Cortical 5-HT2A receptors in depression and suicide: a systematic review and meta-analysis of in vivo and post-mortem imaging studies.

Introduction: Major depressive disorder (MDD) is a leading cause of suicide and disability. Better understanding changes to serotonin_2A receptors (5-HT_2ARs) in MDD and suicide may help to improve treatments. We systematically reviewed and meta-analysed positron emission tomography (PET), single photon emission computed tomography (SPECT) and post-mortem radioligand binding studies of cortical 5-HT_2ARs in MDD and suicide.

Methods: Databases were searched from inception to August/September 2024. Binding data were extracted and pooled before random-effects meta-analyses of mean difference (Hedges' g) and variance were undertaken. Simple linear regression was performed to investigate the relationship between receptor binding and depression severity at baseline in PET and SPECT studies. We also assessed study quality and tested for evidence of publication bias.

Results: Data on 556 MDD patients or suicide victims and 526 controls from 31 studies were included. Cortical 5-HT_2AR binding was significantly lower in living MDD patients, who had not taken antidepressants for between one week and forever, than controls in frontal, prefrontal, cingulate, anterior cingulate and, upon sensitivity analysis, temporal cortex (Hedges' g = -0.40 to -0.57). In frontal and cingulate regions, binding effect size correlated with depression severity at baseline. There was study-level evidence of lower regional binding in never-medicated MDD patients than controls which, upon exploratory meta-analysis, reached significance in anterior cingulate cortex. Most PET or SPECT studies were of good or fair quality. The results of most post-mortem analyses were negative and included studies were of variable quality. There was limited evidence of publication bias.

Conclusion: In vivo 5-HT_2AR binding is reduced in MDD in frontal, cingulate and temporal cortex. This finding is based mainly on studies that used antagonist or inverse agonist radiotracers.