Altered serotonin 1A binding in major depression: A [carbonyl-C-11] WAY100635 positron emission tomography study

Background: Serotonin 1A receptors (5-HT_1A) are implicated in the pathophysiology of major depressive disorder (MDD) and in the action of selective serotonin reuptake inhibitors (SSRI). SSRI desensitize 5-HT _1A and down-regulate 5-HT transporters (5-HTT) with the latter persisting for weeks after discontinuation of SSRI. MDD subjects are more likely to be homozygous for the functional 5-HT_1A G(-1019) allele of the promoter polymorphism and are postulated to have higher 5-HT_1A than healthy volunteers (controls). We measure 5-HT_1A in MDD, assess the effects of antidepressant exposure (AE), and examine the role of the C(-1019)G polymorphism. Methods: Genotyped and determined 5-HT_1A binding potential (BP) by positron emission tomography (PET) using [carbonyl-C-11]-WAY- 100635 in 28 medication-free MDD subjects during a current major depressive episode and 43 controls. Results: No difference in BP between controls and MDD subjects (p = .235). There was a difference in BP comparing the controls, antidepressant naive (AN) MDD subjects, and subjects with AE across all regions (p = .013). Post hoc testing reveals higher BP in AN compared to controls (p = .008) and to AE (p = .007). The GG genotype is overrepresented in MDD subjects (p = .059), and BP appears higher with the G allele. Conclusions: AN have higher 5-HT_1A than controls and AE suggesting a model of depression characterized by an over expression of autoinhibitory somatodendritic 5-HT _1A receptors, perhaps due to the higher expressing G allele, that may result in reduced terminal field 5-HT release. AE appears to have long-term effects on 5-HT_1A.