Positron Emission Tomography Quantification of Serotonin-1A Receptor Binding in Medication-Free Bipolar Depression

Background: Little is known about the serotonin-1A receptor (5-HT1A) in bipolar depression despite altered 5-HT1A binding in major depressive disorder. Utilizing positron emission tomography (PET) and the radioligand N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexan ecarboxamide ([Carbonyl-C-11]WAY-100635), 5-HT1A binding was compared between depressed bipolar disorder (BD) and controls. Methods: Brain 5-HT1A binding potential (BP_F = B_max/K_D, where B_max = total available receptors, and 1/K_D = ligand affinity) was measured in 32 currently depressed, medication-free BD subjects and 47 controls. Participants were genotyped for the 5-HT1A promoter polymorphism C(-1019)G. Results: The bipolar depressed group demonstrated higher 5-HT1A BP_F across all regions of interest (ROIs; p = .022). Post hoc analyses indicated that male BD patients had higher 5-HT1A BP_F than male controls (p = .025), with higher 5-HT1A BP_F found in every region (by 102% in raphe nuclei and 29% to 50% in the forebrain ROIs); whereas, female subgroups did not differ in 5-HT1A BP_F (p = .32). Serotonin-1A BP_F did not correlate with depression severity. The GG genotype was overrepresented at trend level in the BD group (p = .057). Number of G-allele copies was associated with higher 5-HT1A BP_F in raphe (p = .0050), amygdala (p = .022), and hippocampus (p = .041). Conclusions: Higher 5-HT1A BP_F in bipolar depressed males suggests higher raphe autoreceptor binding, potentially causing less serotonin release and compensatory upregulation of forebrain postsynaptic 5-HT1A receptors. The raphe effect may be partly genetic. No difference in 5-HT1A BP_F between BD and control females may reflect greater effect of prior antidepressant exposure in BD females.