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 the new NRM cohort (p = .037) compared with new control subjects, comparable to the previous cohort (p = .04). Cohorts were combined to examine the reference region and outcome measure. BP, was higher in the NRM compared with control subjects (p = .0001). Neither BP using CWM (p = .86) nor volume of distribution (V(T)) (p = .374) differed between groups. When CGM was used, the NRM group had lower 5-HT(1A) BP(ND) 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.