mcn-5652 and Depressive-Disorder--Major

Physical or psychological adversity in childhood is associated with a higher risk for depression in adulthood, and with persistent serotonergic abnormalities in humans and in animal models. We hypothesized that reported childhood abuse would be associated with lower brain serotonin transporter (5-HTT) binding potential (BP(P), proportional to the number of available transporters) in adults. We examined healthy volunteers and subjects with major depressive disorder, a sample enriched for childhood abuse.. Regional brain 5-HTT BP(P) was measured using positron emission tomography (PET) with [(11)C]McN 5652 and a metabolite-corrected arterial input function in 43 healthy volunteers and 23 subjects in a major depressive episode, ten of whom reported a history of sexual and/or physical abuse before age 15, and 13 of whom did not. As only two healthy volunteers reported childhood abuse, primary analyses were restricted to the depressed sample, with healthy controls presented as comparators.. Depressed subjects reporting childhood abuse had lower 5-HTT BP(P) than nonabused depressed subjects across all brain regions examined (P = 0.017). The groups did not differ in relevant demographic or clinical variables. Genotype frequencies of a functional polymorphism in the 5-HTT gene promoter (5-HTTLPR) did not differ between the groups.. Reported childhood abuse is associated with lower 5-HTT BP(P) in this sample of subjects with major depression, consistent with other reports that childhood adversity can lower serotonergic function permanently. Lower 5-HTT BP(P) may represent a biological pathway through which early life stress predisposes to the development of subsequent psychiatric illness, including major depressive disorder.

Topics: Adult; Adult Survivors of Child Abuse; Brain; Carbon Radioisotopes; Depressive Disorder, Major; Female; Gene Frequency; Humans; Isoquinolines; Male; Neuropsychological Tests; Pilot Projects; Polymorphism, Genetic; Positron-Emission Tomography; Promoter Regions, Genetic; Sequence Analysis, DNA; Serotonin Plasma Membrane Transport Proteins

The authors examined effects of a triallelic functional polymorphism of the human serotonin-transporter-linked promoter region (5-HTTLPR) on in vivo expression of serotonin transporter in the brain in healthy volunteers and subjects with major depressive disorder.. Twenty-five medication-free subjects with DSM-IV major depressive disorder during a major depressive episode and 42 healthy volunteers were clinically evaluated and genotyped. Serotonin transporter binding potential (f(1)B(max)/K(d)) was determined by using positron emission tomography with the radiotracer [(11)C]McN 5652 and metabolite-corrected arterial input functions.. There was no difference in serotonin transporter binding potential by genotype in healthy volunteers or in subjects with major depressive disorder. Allelic frequencies did not differ between subjects with major depressive disorder and healthy volunteers.. Associations of the 5-HTTLPR polymorphism to clinical phenotypes appear to be due to developmental effects of 5-HTTLPR on expression and not due to its direct effect on serotonin transporter binding in adulthood.

Topics: Adult; Age Factors; Alleles; Brain; Carbon Radioisotopes; Depressive Disorder, Major; Female; Gene Expression; Gene Frequency; Genotype; Humans; Isoquinolines; Male; Phenotype; Polymorphism, Genetic; Positron-Emission Tomography; Promoter Regions, Genetic; Serotonin Plasma Membrane Transport Proteins

CSF analysis, neuroendocrine challenges, serotonin depletion studies, and treatment studies implicate the serotonergic system in the pathophysiology of major depressive disorder. On the basis of postmortem and imaging studies, the authors hypothesized that subjects with major depressive disorder in a major depressive episode have fewer serotonin transporter sites, compared with healthy subjects.. Serotonin transporter binding potential (f(1)B(max)/K(d)) was determined using positron emission tomography with [(11)C]McN 5652 in six brain regions in 25 medication-free subjects with DSM-IV major depressive disorder during a major depressive episode and in 43 healthy volunteer comparison subjects. All subjects had arterial lines placed to determine metabolite-corrected arterial input functions.. Serotonin transporter binding potential differed significantly by brain region and group. Post hoc analysis revealed lower binding potential in subjects with major depressive disorder, relative to the comparison subjects, in the amygdala and midbrain. The lower binding potential was more pronounced in the depressed subjects who had never received antidepressants. No correlation was found between binding potential in the midbrain and severity of depression or number of days without medication. Binding potential did not differ between suicide attempters and nonattempters.. Subjects in a major depressive episode have lower serotonin transporter binding potential in the amygdala and midbrain, compared to healthy subjects.

Topics: Adult; Ambulatory Care; Amygdala; Antidepressive Agents; Brain; Carbon Radioisotopes; Depressive Disorder, Major; Female; Hospitalization; Humans; Isoquinolines; Male; Mesencephalon; Positron-Emission Tomography; Psychiatric Status Rating Scales; Serotonin Plasma Membrane Transport Proteins; Severity of Illness Index; Suicide, Attempted

Alterations in the brain serotonin (5-HT) system have been found in patients with depression. We used the selective 5-HT transporter site ligand [11C](+)McN5652 and positron emission tomography (PET) to examine the hypothesis that alterations in 5-HT transporter levels may be present in selected regions of the brain in depressed patients.. Four drug free depressed patients and four healthy control subjects were studied using [11C](+)McN5652 and PET. The distribution volume (DV) ratio of the PET ligand in selected regions of interest (ROIs) compared to cerebellum were calculated for the ROIs.. Patients showed significantly larger DV ratios in the left frontal cortex (P=0.013) and right cingulate cortex (P=0.043) compared to control subjects.. The sample size was modest with gender differences between the subject groups. The PET agent, [11C](+)McN5652, may have a lower binding affinity for the 5-HT transporter in the cortical regions compared to other brain regions.. These findings suggest that 5-HT transporter sites may be increased in the frontal and cingulate cortices of depressed patients. These alterations in 5-HT transporter sites may be of pathophysiologic significance in the etiology of depression and its treatment.

Topics: Adult; Brain; Carbon Radioisotopes; Depressive Disorder, Major; Dominance, Cerebral; Female; Frontal Lobe; Gyrus Cinguli; Humans; Image Processing, Computer-Assisted; Isoquinolines; Male; Membrane Glycoproteins; Membrane Transport Proteins; Middle Aged; Nerve Tissue Proteins; Positron-Emission Tomography; Reference Values; Serotonin Plasma Membrane Transport Proteins