Higher serotonin 1A binding in a second major depression cohort: Modeling and reference region considerations

Background: Serotonin 1A receptors (5-HT_1A) are implicated in major depressive disorder (MDD). We previously reported higher 5-HT_1A binding potential (BP_F) in antidepressant naive MDD subjects compared with control subjects, while other studies report lower BP _ND. Discrepancies can be related to differences in study population or methodology. We sought to replicate our findings in a novel cohort and determine whether choice of reference region and outcome measure could explain discrepancies. Methods: Nine new control subjects and 22 new not recently medicated (NRM) MDD subjects underwent positron emission tomography. BP _F and BP_ND were determined using a metabolite and free fraction corrected arterial input function. BP_ND was also determined using cerebellar gray matter (CGM) and cerebellar white matter (CWM) reference regions as input functions. Results: BP_F was higher in thenewNRMcohort (p =.037) compared withnewcontrol subjects, comparable to the previous cohort (p <.04). Cohorts were combined to examine the reference region and outcome measure. BP_F was higher in theNRMcompared with control subjects (p=.0001). Neither BPND usingCWM(p=.86) nor volume of distribution (V_T) (p=.374) differed between groups. When CGM was used, the NRM group had lower 5-HT1A BPND compared with control subjects (p =.03); CGM V_T was higher in NRM compared with control subjects (p =.007). Conclusions: Choice of reference region and outcome measure can produce different 5-HT_1A findings. Higher 5-HT_1A BP_F in MDD was found with the method with fewest assumptions about nonspecific binding and a reference region without receptors.