pyrimidinones and Depressive-Disorder

Changes in serotonin (5-HT)2 receptor densities were reported in depression by postmortem studies and following treatment with tricyclic antidepressants in animal studies. Here, 5-HT2 receptors were studied in vivo in depressed patients.. Cortical 5-HT2 receptors were investigated prospectively using positron-emission tomography and [18F]-setoperone in 7 depressed patients, before and after at least 3 weeks of clomipramine (CMI), 150 mg daily. They were compared to 7 age-matched controls.. There was no significant difference between the untreated patients and the controls, except in the frontal region, where the [18F]-setoperone specific binding was slightly lower in patients. After CMI treatment, depression scores significantly improved and [18F]-setoperone specific binding decreased in cortical regions, suggesting receptor occupancy and/or receptor regulation, by CMI; however, no clinical score correlated with the 5-HT2 receptor measurements either in the untreated or in the treated conditions.. These data substantiate the view that tricyclic antidepressants such as clomipramine significantly interact with cortical 5-HT2 serotoninergic receptors in actual therapeutic situations.

Topics: Adult; Aged; Antidepressive Agents; Binding Sites; Brain; Clomipramine; Depressive Disorder; Female; Fluorine Radioisotopes; Humans; Male; Middle Aged; Pyrimidinones; Receptors, Serotonin; Tomography, Emission-Computed

In the cortex of animals, serotonin (5-HT) levels increase after several weeks of treatment with selective serotonin reuptake inhibitors (SSRIs). Studies using an intrasubject design to examine the effects of SSRI treatment on 5-HT(2A) receptors in the cortex of drug-free depressed patients are needed. In theory, agonist stimulation of 5-HT(2A) receptors could be relevant to SSRI treatment by promoting neuronal growth and survival as well as direct elevation of mood. The objective of this study was to evaluate the effect of 6 weeks of paroxetine treatment on 5-HT(2A) receptors in depressed patients.. After a medication-free period of at least 3 months, 19 depressed patients were treated for 6 weeks with paroxetine, 20 mg/day. The authors used [(18)F]setoperone and positron emission tomography to assess 5-HT(2A) receptor binding potential in the patients before and after treatment and in 19 age-matched healthy subjects.. 5-HT(2A) binding potential declined with age in all cortical regions in the depressed and healthy subjects. There was a significant interaction between age and treatment effect on 5-HT(2A) binding potential in all cortical regions. Subjects aged 20 to 30 years had a 10% decrease in 5-HT(2A) binding potential after treatment, whereas subjects aged 30 to 40 had no change. No regional differences in 5-HT(2A) binding potential between depressed and healthy subjects were found.. 5-HT(2A) receptors down-regulate in young depressed subjects after treatment with paroxetine, but this down-regulation attenuates with age. This suggests that over 6 weeks paroxetine treatment increases 5-HT agonism on 5-HT(2A) receptors in the cortex of young patients with depression.

Topics: Adolescent; Adult; Age Factors; Cerebral Cortex; Depressive Disorder; Down-Regulation; Female; Fluorine Radioisotopes; Humans; Male; Paroxetine; Pyrimidinones; Receptor, Serotonin, 5-HT2A; Receptors, Serotonin; Selective Serotonin Reuptake Inhibitors; Tomography, Emission-Computed; Treatment Outcome

Postmortem and brain imaging studies that measured brain serotinin(2) (5-HT(2)) receptors in major depression reported an increase, decrease, and no change compared with controls. In this study, we assessed brain 5-HT(2) receptors in 20 depressed patients (mean +/- SD age, 40.1 +/- 9.5 years; range, 22-60 years) and 20 healthy controls similar in age (37.2 +/- 12.6 years; range, 19-59 years) using positron emission tomography and setoperone labeled with fluorine 18 ([(18)F]setoperone).. Patients with DSM-IV major depression and healthy controls underwent scanning with [(18)F]setoperone. All study subjects were drug free for at least 2 weeks. The 5-HT(2) binding images were created using region-to-cerebellum ratios. The differences in 5-HT(2) receptor binding potential between the two groups were determined with statistical parametric mapping software and region of interest analysis.. There was a significant negative correlation between 5-HT(2) receptor binding potential and age in both patients and controls, and the magnitude of this correlation was similar in both groups. Both statistical parametric mapping and region of interest analyses showed that, compared with healthy controls, depressed patients had significantly lower 5-HT(2) receptor binding potential in frontal, temporal, parietal, and occipital cortical regions. Statistical parametric mapping analysis showed that the mean decrease in 5-HT(2) receptor binding potential for the entire cluster in these regions was 22%, and it ranged from 22% to 27% for local maxima within the clusters of significant voxels.. This study suggests that brain 5-HT(2) receptors are decreased in patients with major depression.

Topics: Adult; Age Factors; Brain; Cerebellum; Depressive Disorder; Female; Fluorine Radioisotopes; Frontal Lobe; Humans; Male; Middle Aged; Occipital Lobe; Parietal Lobe; Pyrimidinones; Receptors, Serotonin; Sex Factors; Temporal Lobe; Tomography, Emission-Computed

Widespread disturbances of serotonin (5-HT) are implicated in the pathophysiology of depression. Of 5-HT receptor abnormalities reported, the most replicated finding is increased 5-HT2 receptor binding in the postmortem prefrontal cortex of depressed suicide victims. The extent to which these findings exist in depressed persons without recent suicide attempts is uncertain. The objective of this study was to evaluate 5-HT2 receptors in depressed patients who were medication-free and who had not made recent suicide attempts.. With the use of [18F]setoperone and positron emission tomography (PET), 5-HT2 receptor binding potential was assessed in 14 depressed and 19 healthy subjects. Exclusion criteria for depressed patients included use of antidepressant medication within the past 6 months, a history of suicide attempts within the past 5 years, other current axis I disorders including bipolar disorder, and the presence of psychotic symptoms. The 5-HT2 (setoperone) binding potential in the two groups of subjects was compared by analysis of covariance with age as the covariate.. Age had a significant effect on 5-HT2 binding potential, but depression did not. The interaction of age and depression was not significant.. The 5-HT2 binding potential is not increased in untreated depressed subjects who have not made recent suicide attempts. This negative finding does not rule out the possibility that there is a role for 5-HT2 receptors in treatment or that 5-HT2 receptors are increased in highly suicidal states.

Topics: Adolescent; Adult; Age Factors; Depressive Disorder; Female; Fluorine Radioisotopes; Humans; Male; Middle Aged; Prefrontal Cortex; Pyrimidinones; Receptors, Serotonin; Research Design; Suicide, Attempted; Tomography, Emission-Computed

The neuroreceptor changes involved in therapeutic efficacy of various antidepressants remain unclear. Preclinical studies have shown that long-term administration of various antidepressants causes down-regulation of brain serotonin 2 (5-HT2) receptors in rodents, but it is unknown if similar changes occur following antidepressant treatment in depressed patients. Our purpose, therefore, was to assess the effects of treatment with desipramine hydrochloride on brain 5-HT2 receptors in depressed patients using positron emission tomography (PET) and fluorine-18 (18F)-labeled setoperone.. Eleven patients who met DSM-IV criteria for major depression as determined by a structured clinical interview for DSM-III-R diagnosis and suitable for treatment with desipramine were recruited. Ten patients underwent a PET scan before and another after 3 to 4 weeks of treatment with desipramine.. Eight of the 10 patients responded to desipramine treatment as indicated by more than 50% decrease in Hamilton Depression Rating Scale scores. Depressed patients showed a significant decrease in 5-HT2 receptor binding as measured by setoperone binding in frontal, temporal, parietal, and occipital cortical regions following desipramine treatment. The decrease in 5-HT2 receptor binding was observed bilaterally and was particularly prominent in frontal cortex.. Depressed patients showed a significant reduction in available 5-HT2 receptors in the brain following desipramine treatment, but it is unknown if this change in 5-HT2 receptors is due to clinical improvement or an effect of desipramine that is unrelated to clinical status.

Topics: Antidepressive Agents, Tricyclic; Brain; Depressive Disorder; Desipramine; Down-Regulation; Fluorine Radioisotopes; Fluorodeoxyglucose F18; Frontal Lobe; Humans; Occipital Lobe; Pyrimidinones; Receptors, Serotonin; Tomography, Emission-Computed

To investigate adaptative changes of 5-HT2A receptors induced by SSRIs, six patients chronically treated for a depressive episode (four with fluoxetine, two with fluvoxamine) were studied with PET and [18F]setoperone. They were compared to eight untreated depressive patients. The mean frontal to cerebellum radioactivity concentration ratio, an index of the [18F]setoperone specific binding to 5-HT2A receptors, was higher in treated than in untreated patients, when age was taken into account. This suggests that chronic treatment by SSRIs could induce an up-regulation of the 5-HT2A receptors, and that 5-HT2A receptor down-regulation is not a common mechanism for the therapeutic effects of all serotoninergic antidepressive drugs.

Topics: Adult; Antidepressive Agents; Depressive Disorder; Female; Fluorine Radioisotopes; Frontal Lobe; Humans; Male; Middle Aged; Pyrimidinones; Receptor, Serotonin, 5-HT2A; Receptors, Serotonin; Selective Serotonin Reuptake Inhibitors; Tomography, Emission-Computed