n-n-dimethyl-2-(2-amino-4-cyanophenylthio)benzylamine and Seasonal-Affective-Disorder

We have recently shown that the emergence and severity of seasonal affective disorder (SAD) symptoms in the winter is associated with an increase in cerebral serotonin (5-HT) transporter (SERT) binding. Intriguingly, we also found that individuals resilient to SAD downregulate their cerebral SERT binding in the winter. In the present paper, we provide an analysis of the SERT- and 5-HT dynamics as indexed by 5-HT

Topics: Adult; Benzylamines; Brain; Brain Mapping; Down-Regulation; Female; Humans; Longitudinal Studies; Male; Piperidines; Positron-Emission Tomography; Radiopharmaceuticals; Receptors, Serotonin, 5-HT4; Resilience, Psychological; Seasonal Affective Disorder; Seasons; Serotonin Plasma Membrane Transport Proteins; Sex Factors

Cross-sectional neuroimaging studies in non-depressed individuals have demonstrated an inverse relationship between daylight minutes and cerebral serotonin transporter; this relationship is modified by serotonin-transporter-linked polymorphic region short allele carrier status. We here present data from the first longitudinal investigation of seasonal serotonin transporter fluctuations in both patients with seasonal affective disorder and in healthy individuals. Eighty (11)C-DASB positron emission tomography scans were conducted to quantify cerebral serotonin transporter binding; 23 healthy controls with low seasonality scores and 17 patients diagnosed with seasonal affective disorder were scanned in both summer and winter to investigate differences in cerebral serotonin transporter binding across groups and across seasons. The two groups had similar cerebral serotonin transporter binding in the summer but in their symptomatic phase during winter, patients with seasonal affective disorder had higher serotonin transporter than the healthy control subjects (P = 0.01). Compared to the healthy controls, patients with seasonal affective disorder changed their serotonin transporter significantly less between summer and winter (P < 0.001). Further, the change in serotonin transporter was sex- (P = 0.02) and genotype- (P = 0.04) dependent. In the patients with seasonal affective disorder, the seasonal change in serotonin transporter binding was positively associated with change in depressive symptom severity, as indexed by Hamilton Rating Scale for Depression - Seasonal Affective Disorder version scores (P = 0.01). Our findings suggest that the development of depressive symptoms in winter is associated with a failure to downregulate serotonin transporter levels appropriately during exposure to the environmental stress of winter, especially in individuals with high predisposition to affective disorders.media-1vid110.1093/brain/aww043_video_abstractaww043_video_abstract.

Topics: Adult; Benzylamines; Carbon Radioisotopes; Case-Control Studies; Estradiol; Female; Humans; Longitudinal Studies; Male; Neuroimaging; Positron-Emission Tomography; Progesterone; Psychiatric Status Rating Scales; Radioligand Assay; Seasonal Affective Disorder; Seasons; Serotonin Plasma Membrane Transport Proteins; Tryptophan; Young Adult

Seasonal affective disorder (SAD) is highly prevalent with rates of 1-6% and greater prevalence at more extreme latitudes; however, there are almost no direct brain investigations of this disorder. In health, serotonin transporter binding potential (5-HTT BPND), an index of 5-HTT levels, is greater throughout the brain in fall-winter compared with spring-summer. We hypothesized that in SAD, this seasonal variation would be greater in brain regions containing structures that regulate affect such as the prefrontal and anterior cingulate cortices (PFC and ACC). Furthermore, given the dimensional nature of SAD symptoms, it was hypothesized that seasonal fluctuation of 5-HTT BPND in the PFC and ACC would be greatest in severe SAD. Twenty SAD and twenty healthy participants underwent [(11)C]DASB positron emission tomography scans in summer and winter to measure seasonal variation in [(11)C]DASB 5-HTT BPND. Seasonal increases in [(11)C]DASB 5-HTT BPND were greater in SAD compared with healthy in the PFC and ACC, primarily due to differences between severe SAD and healthy (severe SAD vs healthy; Mann-Whitney U, U=42.5 and 37.0, p=0.005 and 0.003, respectively; greater magnitude in severe SAD of 35.10 and 14.23%, respectively), with similar findings observed in other regions (U=40.0-62.0, p=0.004-0.048; greater magnitude in severe SAD of 13.16-17.49%). To our knowledge, this is the first brain biomarker identified in SAD. This creates a new opportunity for phase 0 studies to target this phenotype and optimize novel prevention/treatment strategies for SAD.

Topics: Adult; Benzylamines; Carbon Radioisotopes; Case-Control Studies; Female; Humans; Magnetic Resonance Imaging; Male; Positron-Emission Tomography; Protein Binding; Seasonal Affective Disorder; Seasons; Serotonin Plasma Membrane Transport Proteins; Statistics, Nonparametric; Surveys and Questionnaires; Young Adult