pyrimidinones and Depressive-Disorder--Major

Dysfunctional attitudes are negatively biased assumptions and beliefs regarding oneself, the world, and the future. In healthy subjects, increasing serotonin (5-HT) agonism with a single dose of d-fenfluramine lowered dysfunctional attitudes. To investigate whether the converse, a low level of 5-HT agonism, could account for the higher levels of dysfunctional attitudes observed in patients with major depression or with self-injurious behavior, cortex 5-HT(2) receptor binding potential and dysfunctional attitudes were measured in patients with major depressive disorder, patients with a history of self-injurious behavior, and healthy comparison subjects (5-HT(2) receptor density increases during 5-HT depletion).. Twenty-nine healthy subjects were recruited to evaluate the effect of d-fenfluramine or of clonidine (control condition) on dysfunctional attitudes. Dysfunctional attitudes were assessed with the Dysfunctional Attitude Scale 1 hour before and 1 hour after drug administration. In a second experiment, dysfunctional attitudes and 5-HT(2) binding potential were measured in 22 patients with a major depressive episode secondary to major depressive disorder, 18 patients with a history of self-injurious behavior occurring outside of a depressive episode, and another 29 age-matched healthy subjects. Cortex 5-HT(2) binding potential was measured with [(18)F]setoperone positron emission tomography.. In the first experiment, dysfunctional attitudes decreased after administration of d-fenfluramine. In the second experiment, in the depressed group, dysfunctional attitudes were positively associated with cortex 5-HT(2) binding potential, especially in Brodmann's area 9 (after adjustment for age). Depressed subjects with extremely dysfunctional attitudes had higher 5-HT(2) binding potential, compared to healthy subjects, particularly in Brodmann's area 9.. Low levels of 5-HT agonism in the brain cortex may explain the severely pessimistic, dysfunctional attitudes associated with major depression.

Topics: Adolescent; Adult; Attitude; Brain Mapping; Cerebral Cortex; Clonidine; Depressive Disorder, Major; Female; Fenfluramine; Humans; Male; Personality Inventory; Pyrimidinones; Receptors, Serotonin; Reference Values; Self-Injurious Behavior; Tomography, Emission-Computed

Brain serotonin(2) (5-hydroxytryptamine(2); 5-HT(2)) receptors were considered potential targets for therapeutic efficacy of electroconvulsive therapy (ECT), but pre-clinical studies showed that electroconvulsive shock up-regulates 5-HT(2) receptors in contrast to antidepressant medications, which down-regulate brain 5-HT(2) receptors. Positron emission tomography (PET) studies in individuals with depression confirmed that antidepressant medications reduce brain 5-HT(2) receptors, but the effects of ECT on these receptors in individuals with depression are unknown.. To determine if a course of ECT alters brain 5-HT(2) receptors in individuals with depression and whether such changes correlate with improvement in symptoms.. Fifteen people with major depression, refractory to antidepressant therapy and referred for a course of ECT, had an [18F]setoperone scan during baseline drug-free washout period and another after a course of ECT. We assessed changes in brain 5-HT(2) receptors with ECT and their relationship to therapeutic outcome.. Widespread reduction in brain 5-HT(2) receptors was observed in all cortical areas with changes slightly more prominent in the right hemisphere. There was a trend for correlation between reduction in brain 5-HT(2) receptors in right parahippocampal gyrus, right lingual gyrus and right medial frontal gyrus, and improvement in depressive symptoms.. Unlike in rodents, and similar to antidepressants, ECT reduces brain 5-HT(2) receptors in individuals with depression. The ability of ECT to further down-regulate brain 5-HT(2) receptors in antidepressant non-responsive individuals may explain its efficacy in those people with antidepressant refractory depression.

Topics: Adolescent; Adult; Aged; Brain Mapping; Contrast Media; Depressive Disorder, Major; Down-Regulation; Electroconvulsive Therapy; Female; Humans; Male; Middle Aged; Pyrimidinones; Receptors, Serotonin, 5-HT2; Treatment Outcome; Young Adult