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

Although preclinical studies clearly indicate an effect of 5-HTTLPR genotype on 5-HT transporter (5-HTT) expression, studies in humans provided inconclusive results, hypothetically due to environmental factors and differences in individual behavior. For example, nicotine and other constituents of tobacco smoke elevate serotonin (5-HT) levels in the brain and may thereby cause homeostatic adaptations in 5-HTT availability that moderate effects of 5-HTTLPR genotype. To test whether 5-HTT availability in the midbrain is affected by smoking status and 5-HTTLPR genotype, we pooled data from prior studies on in vivo 5-HTT availability (BP

Topics: Adult; Benzylamines; Brain; Carbon Radioisotopes; Depressive Disorder, Major; Female; Genotype; Humans; Male; Middle Aged; Obsessive-Compulsive Disorder; Polymorphism, Genetic; Positron-Emission Tomography; Serotonin Plasma Membrane Transport Proteins; Smoking

Symptoms of anxiety are highly comorbid with major depressive disorder (MDD) and are known to alter the course of the disease. To help elucidate the biological underpinnings of these prevalent disorders, we previously examined the relationship between components of anxiety (somatic, psychic and motoric) and serotonin 1A receptor (5-HT

Topics: Adolescent; Adult; Anxiety; Benzylamines; Brain; Brain Mapping; Carbon Radioisotopes; Cohort Studies; Comorbidity; Depressive Disorder, Major; Female; Humans; Male; Middle Aged; Piperazines; Positron-Emission Tomography; Pyridines; Radiopharmaceuticals; Receptor, Serotonin, 5-HT1A; Serotonin; Serotonin Plasma Membrane Transport Proteins; Young Adult

The lower-expressing (S') alleles of the serotonin transporter (5-HTT) gene promoter polymorphism (5-HTTLPR) are linked to mood and anxiety related psychopathology. However, the specific neural mechanism through which these alleles may influence emotional and cognitive processing remains unknown. We examined the relationship between both 5-HTTLPR genotype and in vivo 5-HTT binding quantified via PET with amygdala reactivity to emotionally negative stimuli. We hypothesized that 5-HTT binding in both raphe nuclei (RN) and amygdala would be inversely correlated with amygdala reactivity, and that number of S' alleles would correlate positively with amygdala reactivity.. In medication-free patients with current major depressive disorder (MDD; N=21), we determined 5-HTTLPR genotype, employed functional magnetic resonance imaging (fMRI) to examine amygdala responses to negative emotional stimuli, and used positron emission tomography with [(11)C]DASB to examine 5-HTT binding.. [(11)C]DASB binding in RN and amygdala was inversely correlated with amygdala response to negative stimuli. 5-HTTLPR S' alleles were not associated with amygdala response to negative emotional stimuli.. Primary limitations are small sample size and lack of control group.. Consistent with findings in healthy volunteers, 5-HTT binding is associated with amygdala reactivity to emotional stimuli in MDD. 5-HTT binding may be a stronger predictor of emotional processing in MDD as compared with 5-HTTLPR genotype.

Topics: Adult; Alleles; Amygdala; Benzylamines; Carbon Radioisotopes; Depressive Disorder, Major; Emotions; Female; Functional Neuroimaging; Genotype; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Polymorphism, Genetic; Positron-Emission Tomography; Promoter Regions, Genetic; Radioligand Assay; Raphe Nuclei; Serotonin Plasma Membrane Transport Proteins

Biomarkers that predict suicidal behavior, especially highly lethal behavior, are urgently needed. In cross-sectional studies, individuals with depression who attempt suicide have lower midbrain serotonin transporter binding potential compared with those who do not attempt suicide, and higher serotonin1A binding potential in the raphe nuclei (RN) is associated with greater lethality of past suicide attempts and suicidal intent and ideation.. To determine whether serotonin transporter binding potential in the lower midbrain predicts future suicide attempts and whether higher RN serotonin1A binding potential predicts future suicidal ideation and intent and lethality of future suicide attempts.. In this prospective 2-year observational study, a well-characterized cohort of 100 patients presenting for treatment of a major depressive episode of at least moderate severity underwent positron emission tomography using carbon 11-labeled N-(2-(1-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl))-N-(2-pyridyl)-cyclohexanecarboxamide ([11C]WAY-100635), a serotonin1A antagonist; a subset of 50 patients also underwent imaging with carbon 11-labeled 3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)- benzonitrile ([11C]DASB), a serotonin transporter radioligand. Imaging was performed at Columbia University Medical Center from May 3, 1999, to March 11, 2008. Follow-up was completed on May 28, 2010, and data were analyzed from August 1, 2013, to March 1, 2016.. Patients were treated naturalistically in the community and followed up for 2 years with documentation of suicidal behavior, its lethality, and suicidal ideation and intent.. Suicide attempt or suicide.. Of the 100 patients undergoing follow-up for more than 2 years (39 men; 61 women; mean [SD] age, 40.2 [11.2] years), 15 made suicide attempts, including 2 who died by suicide. Higher RN serotonin1A binding potential predicted more suicidal ideation at 3 (b = 0.02; t = 3.45; P = .001) and 12 (b = 0.02; t = 3.63; P = .001) months and greater lethality of subsequent suicidal behavior (b = 0.08; t = 2.89; P = .01). Exploratory analyses suggest that the serotonin1A binding potential of the insula (t = 2.41; P = .04), anterior cingulate (t = 2.27; P = .04), and dorsolateral prefrontal cortex (t = 2.44; P = .03) were also predictive of lethality. Contrary to our hypotheses, suicidal intent was not predicted by serotonin1A binding potential in any brain region (F1,10 = 0.83; P = .38), and midbrain serotonin transporter binding potential did not predict future attempts (log-rank χ21 = 0.4; P = .54), possibly owing to low power.. Greater RN serotonin1A binding potential predicted higher suicidal ideation and more lethal suicidal behavior during a 2-year period. This effect may be mediated through less serotonin neuron firing and release, which affects mood and suicidal ideation and thereby decision making.

Topics: Adult; Benzylamines; Brain; Brain Mapping; Carbon Radioisotopes; Depressive Disorder, Major; Female; Follow-Up Studies; Humans; Male; Middle Aged; Piperazines; Positron-Emission Tomography; Prospective Studies; Pyridines; Receptor, Serotonin, 5-HT1A; Serotonin Plasma Membrane Transport Proteins; Suicidal Ideation; Suicide; Suicide, Attempted

Suffering from anhedonia, patients with major depressive disorder (MDD) exhibit alterations in several parts of the serotonergic neurotransmitter system, which are in turn involved in reward processing. However, previous investigations of the serotonin transporter (SERT) focused on regional differences with varying results depending on the clinical syndrome. Here, we aimed to describe the serotonergic system of MDD patients on a network level by evaluating SERT associations across brain regions. Twenty medication free patients with major depression and 20 healthy controls underwent positron emission tomography using the radioligand [(11) C]DASB. SERT binding potentials (BPND ) were quantified voxel-wise with the multilinear reference tissue model 2. In addition, SERT BPND was extracted from the dorsal raphe nucleus (DRN) as an indicator of midbrain serotonergic neurotransmission. Whole-brain linear regression analysis was applied to evaluate the association of DRN SERT bindings to those in projection areas, which was followed by ANCOVA to assess differences in interregional relationships between patients and controls. Although both groups showed widespread positive correlations, group differences were restricted to decreased SERT associations between the DRN and the ventral striatum (right and left respectively: t=5.85, P<0.05 corrected and t=5.07, P<0.1 corrected) when comparing MDD patients (R(2)=0.11 and 0.24) to healthy subjects (R(2)=0.72 and 0.66, P<0.01 and 0.05 corrected). Adjusting for age and sex did not change these findings. This study indicates a disturbed regulation between key regions involved in reward processing via the SERT. Our interregional approach highlights the importance of evaluating pathophysiological alterations on a network level to gain complementary information in addition to regional investigations.

Topics: Adult; Benzylamines; Brain; Brain Mapping; Carbon Radioisotopes; Depressive Disorder, Major; Dorsal Raphe Nucleus; Female; Humans; Male; Positron-Emission Tomography; Radiopharmaceuticals; Regression Analysis; Serotonin Plasma Membrane Transport Proteins; Signal Processing, Computer-Assisted; Smoking; Ventral Striatum

To study 5-HT transport and 5-HT1A receptors in temporal lobe epilepsy (TLE) and depression.. Thirteen patients had PET with [(11)C]DASB for 5-HTT and [(18)F]FCWAY for 5-HT1A receptor binding, MRI, and psychiatric assessment. Sixteen healthy volunteers had [(11)C]DASB, 19 had [(18)F]FCWAY, and 6 had both PET studies. We used a reference tissue model to estimate [(11)C]DASB binding. [(18)F]FCWAY volume of distribution was corrected for plasma-free fraction. Images were normalized to common space. The main outcome was the regional asymmetry index. Positive asymmetry indicates relative reduced binding (reflecting transporter activity) ipsilateral to epileptic foci.. Mean regional [(11)C]DASB binding and asymmetry did not differ between patients and controls. [(18)F]FCWAY asymmetry was significantly greater for patients than controls in hippocampus, amygdala, and fusiform gyrus. On analysis of variance with region as a repeated measure, depression diagnosis had a significant effect on [(11)C]DASB asymmetry, with significantly higher [(11)C]DASB asymmetry in insular cortex (trend for fusiform gyrus). In insular cortex, patients had a significant correlation between [(18)F]FCWAY asymmetry and [(11)C]DASB asymmetry.. Our study showed increased [(11)C]DASB asymmetry in insula and fusiform gyrus, and relatively reduced transporter activity, in subjects with both TLE and depression, as compared to subjects with TLE alone, implying reduced reuptake and thus increased synaptic 5-HT availability. This finding may represent a compensatory mechanism for 5-HT1A receptor loss. Altered serotonergic mechanisms have an important role in TLE and concomitant depression.

Topics: Adult; Age of Onset; Analysis of Variance; Anticonvulsants; Benzylamines; Cerebral Cortex; Cyclohexanes; Data Interpretation, Statistical; Depression; Depressive Disorder, Major; Diagnostic and Statistical Manual of Mental Disorders; Epilepsy, Temporal Lobe; Female; Functional Laterality; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Piperazines; Positron-Emission Tomography; Psychiatric Status Rating Scales; Radiopharmaceuticals; Receptor, Serotonin, 5-HT1A; Serotonin Plasma Membrane Transport Proteins; Sex Characteristics

Antidepressants used for treatment of depression exert their efficacy by blocking reuptake at serotonin transporters (5-HTT) and/or norepinephrine transporters (NET). Recent studies suggest that serotonin and norepinephrine reuptake inhibitors that block both 5-HTT and NET have better tolerability than tricyclic antidepressants and may have higher efficacy compared to selective serotonin reuptake inhibitors. Previous positron emission tomography (PET) studies have reported >80% 5-HTT occupancy with clinical doses of antidepressants, but there has been no report of NET occupancy in patients treated with antidepressants. In the present study, we investigated both 5-HTT and NET occupancies by PET using radioligands [(11)C]DASB and (S,S)-[(18)F]FMeNER-D(2), in six patients, each with major depressive disorder (MDD), using various doses of milnacipran. Our data show that mean 5-HTT occupancy in the thalamus was 33.0% at 50 mg, 38.6% at 100 mg, 60.0% at 150 mg and 61.5% at 200 mg. Mean NET occupancy in the thalamus was 25.3% at 25 mg, 40.0% at 100 mg, 47.3% at 125 mg and 49.9% at 200 mg. Estimated ED(50) was 122.5 mg with the dose for 5-HTT and 149.9 mg for NET. Both 5-HTT and NET occupancies were observed in a dose-dependent manner. Both 5-HTT and NET occupancies were about 40% by milnacipran at 100 mg, the dose most commonly administered to MDD patients.

Topics: Adult; Antidepressive Agents; Benzylamines; Brain; Brain Mapping; Carbon Radioisotopes; Cyclopropanes; Depressive Disorder, Major; Dose-Response Relationship, Drug; Female; Fluorine Radioisotopes; Gas Chromatography-Mass Spectrometry; Humans; Male; Middle Aged; Milnacipran; Morpholines; Norepinephrine Plasma Membrane Transport Proteins; Positron-Emission Tomography; Protein Binding; Serotonin Plasma Membrane Transport Proteins

Recent mathematical models suggest restored serotonergic burst-firing to underlie the antidepressant effect of selective serotonin reuptake inhibitors (SSRI), resulting from down-regulated serotonin transporters (SERT) in terminal regions. This mechanism possibly depends on the interregional balance between SERTs in the raphe nuclei and in terminal regions before treatment. To evaluate these hypotheses on a systems level in humans in vivo, we investigated SERT availability and occupancy longitudinally in patients with major depressive disorder using positron emission tomography (PET) and the radioligand [11C]DASB. Measurements were performed before and after a single oral dose, as well as after three weeks (mean 24.73±3.3 days) of continuous oral treatment with either escitalopram (10 mg/day) or citalopram (20 mg/day). Data were analyzed using voxel-wise linear regression and ANOVA to evaluate SERT binding, occupancy and binding ratios (SERT binding of the entire brain compared to SERT binding in the dorsal and median raphe nuclei) in relation to treatment outcome. Regression analysis revealed that treatment response was predicted by pre-treatment SERT binding ratios, i.e., SERT binding in key regions of depression including bilateral habenula, amygdala-hippocampus complex and subgenual cingulate cortex in relation to SERT binding in the median but not dorsal raphe nucleus (p<0.05 FDR-corrected). Similar results were observed in the direct comparison of responders and non-responders. Our data provide a first proof-of-concept for recent modeling studies and further underlie the importance of the habenula and subgenual cingulate cortex in the etiology of and recovery from major depression. These findings may indicate a promising molecular predictor of treatment response and stimulate new treatment approaches based on regional differences in SERT binding.

Topics: Adult; Benzylamines; Carbon Radioisotopes; Depressive Disorder, Major; Female; Humans; Male; Middle Aged; Positron-Emission Tomography; Radiopharmaceuticals; Raphe Nuclei; Selective Serotonin Reuptake Inhibitors; Serotonin Plasma Membrane Transport Proteins; Tomography, Emission-Computed, Single-Photon; Young Adult

Topics: Adolescent; Adult; Benzylamines; Bipolar Disorder; Brain Mapping; Carbohydrate Epimerases; Carbon Isotopes; Depressive Disorder, Major; Female; Genome-Wide Association Study; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Polymorphism, Single Nucleotide; Positron-Emission Tomography; Protein Binding; Serotonin Plasma Membrane Transport Proteins; Thalamus; Young Adult

In a previous study we showed that genetic variation in HTR2A, which encodes the serotonin 2A receptor, influenced outcome of citalopram treatment in patients with major depressive disorder. Since chronic administration of citalopram, which selectively and potently inhibits the serotonin transporter (5-HTT), putatively enhances serotonergic transmission, it is conceivable that genetic variation within HTR2A also influences pretreatment 5-HTT function or serotonergic transmission. The present study used positron emission tomography (PET) and the selective 5-HTT ligand, [11C]DASB, to investigate whether the HTR2A marker alleles that predict treatment outcome also predict differences in 5-HTT binding. Brain levels of 5-HTT were assessed in vivo using PET measures of the non-displaceable component of the [11C]DASB binding potential (BPND). DNA from 43 patients and healthy volunteers, all unmedicated, was genotyped with 14 single nucleotide polymorphisms located within or around HTR2A. Allelic association with BPND was assessed in eight brain regions, with covariates to control for race and ethnicity. We detected allelic association between [11C]DASB BPND in thalamus and three markers in a region spanning the 3' untranslated region and second intron of HTR2A (rs7333412, p=0.000045; rs7997012, p=0.000086; rs977003, p=0.000069). The association signal at rs7333412 remained significant (p<0.05) after applying corrections for multiple testing via permutation. Genetic variation in HTR2A that was previously associated with citalopram treatment outcome was also associated with thalamic 5-HTT binding. While further work is needed to identify the actual functional genetic variants involved, these results suggest that a relationship exists between genetic variation in HTR2A and either 5-HTT expression or central serotonergic transmission that influences the therapeutic response to 5-HTT inhibition in major depression.

Topics: Adult; Benzylamines; Bipolar Disorder; Brain Mapping; Carbon Radioisotopes; Depressive Disorder, Major; Female; Genome-Wide Association Study; Genotype; Humans; Linear Models; Male; Middle Aged; Polymorphism, Single Nucleotide; Positron-Emission Tomography; Protein Binding; Receptor, Serotonin, 5-HT2A; Serotonin Plasma Membrane Transport Proteins; Young Adult

Although brain serotonin transporter (5-HTT) density has been investigated in subjects with a history of major depressive episodes (MDE), there has never been an investigation of brain 5-HTT during a current MDE. Brain 5-HTT binding potential (BP) may have an important role during MDE due to major depressive disorder, because the 5-HTT regulates extracellular 5-HT. The BP is an index of receptor density. Carbon 11-labeled 3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile (DASB) positron emission tomography (PET) is the first brain imaging technique that can measure the 5-HTT BP in cortical and subcortical brain regions in vivo. The purposes of this study were to investigate 5-HTT BP during MDE and to determine the relationship between 5-HTT BP and negativistic dysfunctional attitudes during MDE. Dysfunctional attitudes are negatively biased assumptions and beliefs regarding oneself, the world, and the future. Our recent publication of increased serotonin2 BP in MDE with severely negativistic dysfunctional attitudes suggests that this subgroup of MDE subjects has very low levels of extracellular serotonin.. Regional 5-HTT BP was measured in 20 nonsmoking medication-free (> or =3 months) depressed subjects and 20 age-matched nonsmoking, medication-free, healthy subjects using [11C]DASB PET. Dysfunctional attitudes were measured using the Dysfunctional Attitudes Scale.. No difference in regional 5-HTT BP was found between MDE and healthy subjects; however, the subgroup of MDE subjects with highly negativistic dysfunctional attitudes had significantly higher 5-HTT BP compared with healthy subjects in brain regions mainly sampling serotonergic nerve terminals (prefrontal cortex, anterior cingulate, thalamus, bilateral caudate, and bilateral putamen; average, 21% greater; F(1,26), 5.6-12.2 [P values, .03-.002]). In the MDE subjects, increased 5-HTT BP was strongly associated with more negativistic dysfunctional attitudes in brain regions primarily sampling serotonergic nerve terminals (prefrontal cortex, anterior cingulate, thalamus, caudate, and putamen; r = 0.64-0.74 [P values, .003 to <.001]).. Serotonin transporters play an important role during depression. The magnitude of regional 5-HTT BP can provide a vulnerability to low levels of extracellular serotonin and symptoms of extremely negativistic dysfunctional attitudes.

Topics: Benzylamines; Brain; Carbon Radioisotopes; Depressive Disorder, Major; Humans; Membrane Glycoproteins; Membrane Transport Proteins; Negativism; Nerve Tissue Proteins; Positron-Emission Tomography; Psychiatric Status Rating Scales; Serotonin; Serotonin Plasma Membrane Transport Proteins