Serotonin 2A receptor binding in healthy twins genetically predisposed to major depression in comparison with undisposed controls

Disturbances in serotonergic transmission is involved in the pathophysiology of depression. Previous PET studies have been inconsistent with regard to the direction and regional distribution of the 5-HT2A alterations in major depression. Genetic factors play an ethiological role in both major depression and personality profiles. In particular a high neuroticism score is known to be associated with an increased risk of developing major depression. We tested whether the regional cerebral 5-HT2A receptor binding differed between a group of genetically predisposed twins and a group of undisposed controls. Further, we tested if differences in personality traits of the neuroticism dimension, within the predisposed group, correlated to the regional 5-HT2A receptor binding. Twelve healthy twins (median age 44 (22–61)) genetically predisposed to depression and 12 healthy and undisposed volunteers (median age 46 (22–63)) were investigated with MRI and [18F]-altanserin PET. Female:male ratio was 9:3 in both groups reflecting the profile in depression. The steady-state binding potential (BP1) was determined in 19 brain regions using cerebellum as a reference region and metabolite corrected plasma concentration. All subjects completed the NEO-PI-R personality questionnaire, which evaluates the broad personality dimensions of neuroticism, extraversion, openness, agreeableness, and conscientiousness each based on 6 personality traits. Group comparisons between regional 5-HT2A receptor binding were performed using the Mann-Whitney test. In a multiple linear regression analysis of data from the predisposed group, the personality trait scores of the neurotiscims dimension were compared to the regional 5-HT2A receptor binding with adjustment for age and gender. The regional 5-HT2A receptor binding did not differ between the subjects genetically predisposed to depression and the undisposed controls. In the predisposed group, we found a trend towards a positive correlation between the cortical 5-HT2A receptor binding and the personality trait depression, a component of neuroticism. The trend (p<0.10) was found in the following limbic regions: 1. left anterior cingulate (r=0.66, p=0.051), 2. right entorhinal cortex (r=0.60, p=0.082), and 3. left enthorhinal cortex (r=0.62, p=0.070). In addition, a positive correlation between 5-HT2A receptor binding and the anxiety component of neuroticism was found in the right enthorhinal cortex (r=0.72, p=0.027). Our preliminary data did not show any significant difference between the subjects genetically predisposed to depression and the undisposed controls. In the predisposed group, a positive correlation between 5-HT2A receptor binding and the anxiety component of neuroticism was found in the right enthorhinal cortex. Furthermore, a trend towards a positive correlation between the personality trait depression and the 5-HT2A receptor binding was present in limbic regions. If reproduced in the larger sample, this suggests that in subjects at risk for major depression limbic 5-HT2A receptor binding may serve as a trait marker for major depression.