Higher 5-HT1A autoreceptor binding as an endophenotype for major depressive disorder identified in high risk offspring - A pilot study.

Higher serotonin-1A (5-HT1A) receptor binding potential (BPF) has been found in major depressive disorder (MDD) during and between major depressive episodes. We investigated whether higher 5-HT1A binding is a biologic trait transmitted to healthy high risk (HR) offspring of MDD probands. Data were collected contemporaneously from: nine HR, 30 depressed not-recently medicated (NRM) MDD, 18 remitted NRM MDD, 51 healthy volunteer (HV) subjects. Subjects underwent positron emission tomography (PET) using [11C]WAY100635 to quantify 5-HT1A BPF, estimated using metabolite, free fraction-corrected arterial input function and cerebellar white matter as reference region. Multivoxel pattern analyses (MVPA) of PET data evaluated group status classification of individuals. When tested across 13 regions of interest, an effect of diagnosis is found on BPF which remains significant after correction for sex, age, injected mass and dose: HR have higher BPF than HV (84.3% higher in midbrain raphe, 40.8% higher in hippocampus, mean BPF across all 13 brain regions is 49.9% ±â€¯11.8% higher). Voxel-level BPF maps distinguish HR vs. HV. Elevated 5-HT1A BPF appears to be a familially transmitted trait abnormality. Future studies are needed to replicate this finding in a larger cohort and demonstrate the link to the familial transmission of mood disorders.

Will imaging individual raphe nuclei in males with major depressive disorder enhance diagnostic sensitivity and specificity?

BACKGROUND: Positron emission tomography (PET) studies in major depressive disorder (MDD) have reported higher serotonin 1A (5-HT1A ) autoreceptor binding in the raphe. In males, the difference is so large that it can potentially be used as the first biological marker for MDD. However, the raphe includes several nuclei, which project to different regions of the brain and spinal cord and may be differentially involved in disease. We aimed to identify 5-HT1A differences in individual raphe nuclei using PET in order to determine whether use of subnuclei would provide greater sensitivity and specificity of diagnosing MDD. METHODS: We identified individual nuclei using a hybrid set-level technique on an average [11 C]-WAY100635 PET image derived from 52 healthy volunteers (HV). We delineated three nuclei: dorsal raphe nucleus (DRN), median raphe nucleus (MRN), and raphe magnus (RMg). An atlas image of these nuclei was created and nonlinearly warped to each subject (through an associated MRI) in a separate sample of 41 males (25 HV, 16 MDD) who underwent [11 C]-WAY100635 PET. RESULTS: 5-HT1A binding was elevated in DRN in MDD (P < .01), and was not different in the RMg and MRN between groups. Receiver operating characteristic (ROC) curves showed that combining DRN and MRN produces highest sensitivity (94%) and specificity (84%) to identify MDD. CONCLUSION: In agreement with postmortem studies, we found higher 5-HT1A autoreceptor binding in MDD selectively in the DRN. 5-HT1A autoreceptor binding in the combined DRN and MRN is a better biomarker for MDD than in the raphe as a whole.