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

Serotonergic dysfunction may contribute to negative mood states in affective disorders. Some in vivo imaging studies showed reduced availability of serotonin transporters (5-HTT) in the brainstem and thalamus of patients with major depression. We tested the hypothesis that 5-HTT availability is reduced in unmedicated unipolar patients with major depression compared to healthy control subjects matched for gender, age, genotype and smoking status. Availability of 5-HTT was measured in vivo with positron emission tomography and [(11)C]-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile (DASB) in the midbrain, thalamus and amygdala. DASB binding was correlated with the severity of depression (Beck's Depression Inventory), anxiety (Spielberger's State-Trait Anxiety Inventory) and personality traits (Temperament and Character Inventory). Patients with major depression displayed reduced 5-HTT availability in the thalamus (P=0.005). In patients, low serotonin transporter availability correlated with high anxiety (thalamus: r=-0.78, P=0.004; midbrain: r=-0.78, P=0.004; amygdala: r=-0.80, P=0.003). Correlations with severity of depression were weaker and did not survive correction for multiple testing. These results support the hypothesis that central serotonergic dysfunction is associated with negative mood states in affective disorders. In the thalamus, a low serotonin reuptake capacity may interfere with thalamic control of cortical excitability and contribute to anxiety rather than depression per se in major depression.

Topics: Anxiety; Benzylamines; Brain; Carbon Radioisotopes; Cerebellum; Depressive Disorder; Humans; Interviews as Topic; Positron-Emission Tomography; Radiography; Serotonin Plasma Membrane Transport Proteins; Thalamus

Personality trait is thought to be one of the important factors for vulnerability to depression. The relation between serotonin transporter (5-HTT) polymorphism and anxiety-related personality has been investigated in genetic research. In this study, we investigated the relation between in vivo regional 5-HTT binding in the brain and personality inventory measures in normal male volunteers.. Thirty-one healthy male volunteers underwent positron emission tomography scans with (11)C-labeled 3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl) benzonitrile ([(11)C]DASB) to measure 5-HTT and completed revised NEO Personality Inventory. Correlation of [(11)C]DASB binding potentials (BP) with personality inventory measures was calculated using region-of-interest analysis and statistical parametric mapping based on the BP images.. Neuroticism was positively correlated with 5-HTT binding in the thalamus (p = .004). No significant correlation was observed in any other brain region. Within the neuroticism dimension, the facet of depression was positively correlated with 5-HTT binding in the thalamus (p = .001).. Subjects with higher thalamic 5-HTT binding are more likely to express higher levels of neuroticism and depressive feeling. Serotonin transporter binding in the thalamus might be a marker of vulnerability to depression.

Topics: Adult; Benzylamines; Biomarkers; Brain; Carbon Radioisotopes; Depressive Disorder; Disease Susceptibility; Humans; Male; Neurotic Disorders; Personality; Personality Inventory; Positron-Emission Tomography; Risk Factors; Serotonin Plasma Membrane Transport Proteins; Sex Factors; Thalamus

Early post-mortem data suggest that damage to brain serotonin neurones might play a role in some features (e.g., depression) of Parkinson's disease (PD). However, it is not known whether such damage is a typical characteristic of living patients with PD or whether the changes are regionally widespread. To address this question we measured, by positron emission tomography imaging, levels of the brain serotonin transporter (SERT), a marker for serotonin neurones, as inferred from binding of [11C]-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile (DASB), a second generation SERT radioligand, in subcortical and cerebral cortical brain areas of clinically advanced non-depressed (confirmed by structured psychiatric interview) patients with PD. SERT binding levels in PD were lower than those in controls in all examined brain areas, with the changes statistically significant in orbitofrontal cortex (-22%), caudate (-30%), putamen (-26%), and midbrain (-29%). However, only a slight non-significant reduction (-7%) was observed in dorsolateral pre-frontal cortex, an area implicated in major depression. Our imaging data suggests that a modest, regionally widespread loss of brain serotonergic innervation might be a common feature of advanced PD. Further investigation will be required to establish whether SERT binding is more or less decreased in those patients with PD who also have major depressive disorder.

Topics: Aged; Benzylamines; Binding, Competitive; Biomarkers; Brain; Brain Chemistry; Carbon Radioisotopes; Depressive Disorder; Down-Regulation; Female; Humans; Male; Middle Aged; Parkinson Disease; Positron-Emission Tomography; Predictive Value of Tests; Serotonin; Serotonin Plasma Membrane Transport Proteins; Synaptic Transmission

Lowering of brain serotonin by acute tryptophan depletion (TD) frequently leads to transient symptoms of depression in vulnerable individuals but not in euthymic healthy subjects with a negative family history of depression. The effects of TD on regional serotonin transporter binding potential (5-HTT BP), an index of 5-HTT density and affinity, were studied in healthy individuals using 3-(11)C-amino-4-(2-dimethylaminomethylphenylsulfanyl)benzonitrile ([11C]DASB) positron emission tomography (PET). Adaptive decreases in 5-HTT density and/or affinity during TD would be a possible compensatory mechanism to maintain sufficient extracellular serotonin levels during TD, thereby preventing a depressive relapse.. Regional noninvasive 5-HTT BP was found in 25 healthy subjects using [11C]DASB PET. Fourteen subjects were scanned twice, once after TD and once after sham depletion, and 11 other healthy subjects were scanned twice to measure test-retest reliability of the method.. None of the healthy subjects experienced depressive symptoms during TD and there was no difference in regional 5-HTT BP during TD as compared with sham depletion.. Acute changes in 5-HTT density or affinity are unlikely to play a role in protecting healthy subjects against mood symptoms during TD. Other mechanisms that may be associated with greater resilience against acute lowering of extracellular serotonin should be explored to gain further insight into the neurochemical basis of different vulnerabilities to short-term depressive relapse.

Topics: Adult; Benzylamines; Brain; Carbon Radioisotopes; Depressive Disorder; Female; Humans; Male; Middle Aged; Positron-Emission Tomography; Secondary Prevention; Serotonin; Serotonin Plasma Membrane Transport Proteins; Tryptophan