pyrimidinones and Schizophrenia

Aripiprazole has a unique pharmacological profile that includes partial agonism at D(2) receptors, antagonism at 5-HT(2) receptors, and partial agonism at 5-HT(1A) receptors. The authors conducted a positron emission tomography (PET) study to characterize the simultaneous effects of aripiprazole at the D(2), 5-HT(2), and 5-HT(1A) receptors in patients with schizophrenia or schizoaffective disorder.. Twelve patients who had previously received antipsychotic treatment were randomly assigned to receive 10 mg, 15 mg, 20 mg, or 30 mg of aripiprazole. After at least 14 days of treatment, participants underwent high-resolution PET scans using [(11)C]raclopride, [(18)F]setoperone, and [(11)C]WAY100635.. Very high occupancy was observed at striatal D(2) receptors (average putamen, 87%; caudate, 93%; and ventral striatum, 91%), lower occupancy at 5-HT(2) receptors (54%-60%), and even lower occupancy at 5-HT(1A) receptors (16%). D(2) occupancy levels were significantly correlated with plasma drug concentrations, and even the lowest dose (10 mg) led to 85% D(2) occupancy. Extrapyramidal side effects were seen only in two of the four participants with occupancies exceeding 90%.. Aripiprazole exhibits a unique occupancy profile as compared with other conventional and atypical antipsychotics. The threshold for response appears to be higher than 60%, extrapyramidal side effects appear to be uncommon even at occupancies that exceed the conventional extrapyramidal side effects threshold of 80%, and 5-HT(2) occupancy is lower than D(2) occupancy. Implications for aripiprazole's mechanism of action are discussed.

Topics: Adult; Antipsychotic Agents; Aripiprazole; Basal Ganglia; Basal Ganglia Diseases; Carbon Radioisotopes; Caudate Nucleus; Cerebral Cortex; Dopamine D2 Receptor Antagonists; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fluorine Radioisotopes; Humans; Male; Piperazines; Positron-Emission Tomography; Psychotic Disorders; Putamen; Pyridines; Pyrimidinones; Quinolones; Raclopride; Receptor, Serotonin, 5-HT1A; Receptors, Dopamine; Receptors, Dopamine D2; Schizophrenia; Serotonin 5-HT1 Receptor Agonists; Treatment Outcome

There have been conflicting reports as to whether olanzapine produces lower occupancy of striatal dopamine D(2)/D(3) receptor than typical antipsychotic drugs and preferential occupancy of extrastriatal dopamine D(2)/D(3) receptors. We performed [(18)F] fallypride PET studies in six schizophrenic subjects treated with olanzapine and six schizophrenic subjects treated with haloperidol to examine the occupancy of striatal and extrastriatal dopamine receptors by these antipsychotic drugs. [(18)F] setoperone PET studies were performed in seven olanzapine-treated subjects to determine 5-HT(2A) receptor occupancy. Occupancy of dopamine D(2)/D(3) receptors by olanzapine was not significantly different from that seen with haloperidol in the putamen, ventral striatum, medial thalamus, amygdala, or temporal cortex, that is, 67.5-78.2% occupancy; olanzapine produced no preferential occupancy of dopamine D(2)/D(3) receptors in the ventral striatum, medial thalamus, amygdala, or temporal cortex. There was, however, significantly lower occupancy of substantia nigra/VTA dopamine D(2)/D(3) receptors in olanzapine-treated compared to haloperidol-treated subjects, that is, 40.2 vs 59.3% (p=0.0014, corrected for multiple comparisons); in olanzapine-treated subjects, the substantia nigra/VTA was the only region with significantly lower dopamine D(2)/D(3) receptor occupancy than the putamen, that is, 40.2 vs 69.2% (p<0.001, corrected for multiple comparison). Occupancy of 5-HT(2A) receptors was 85-93% in the olanzapine- treated subjects. The results of this study demonstrated that olanzapine does not produce preferential occupancy of extrastriatal dopamine D(2)/D(3) receptors but does spare substantia nigra/VTA receptors. Sparing of substantia nigra/VTA dopamine D(2)/D(3) receptor occupancy may contribute to the low incidence of extrapyramidal side effects in olanzapine-treated patients.

Topics: Adult; Antipsychotic Agents; Benzamides; Benzodiazepines; Brain Chemistry; Corpus Striatum; Dopamine Antagonists; Female; Haloperidol; Humans; Image Processing, Computer-Assisted; Male; Middle Aged; Olanzapine; Positron-Emission Tomography; Pyrimidinones; Pyrrolidines; Radiopharmaceuticals; Receptor, Serotonin, 5-HT2A; Receptors, Dopamine D3; Schizophrenia; Serotonin Antagonists

Ziprasidone is an atypical antipsychotic drug that shows a higher affinity for serotonin 5-HT(2) receptors compared with dopamine D(2) receptors in vitro. The affinity of ziprasidone for these receptors in vivo in patients was examined in a positron emission tomography (PET) study.. The authors conducted a PET study to evaluate D(2) occupancy (using [(11)C]raclopride) and 5-HT(2) occupancy (using [(18)F]setoperone) in brain regions of interest in 16 patients with schizophrenia or schizoaffective disorder randomly assigned to receive 40, 80, 120, or 160 mg/day of ziprasidone, which reflected the recommended dose range. PET scanning was done after 3 weeks of administration and at trough plasma levels, i.e., 12-16 hours after the last dose.. The mean 5-HT(2) receptor occupancy was significantly higher than the mean D(2) receptor occupancy (mean=76%, SD=15%, and mean=56%, SD=18%, respectively). The estimated plasma ziprasidone concentration associated with 50% maximal 5-HT(2) receptor occupancy was almost four times lower than that for D(2) receptor occupancy.. These data affirm that ziprasidone is similar to other novel antipsychotics in having greater 5-HT(2) than D(2) receptor occupancy at therapeutic doses and suggest that the optimal effective dose of ziprasidone is closer to 120 mg/day than to the lower doses suggested by previous PET studies. The relatively high D(2) receptor occupancy, even at trough plasma levels, suggests that ziprasidone is more similar to risperidone and olanzapine in receptor occupancy profile than to clozapine and quetiapine. Since ziprasidone plasma levels show significant (more than twofold) variation within a single dose cycle, studies that are aimed at peak plasma levels (6 hours after the last dose) and that examine extrastriatal regions are required to fully characterize the in vivo occupancy profile of ziprasidone.

Topics: Adult; Antipsychotic Agents; Brain; Corpus Striatum; Drug Administration Schedule; Female; Humans; Male; Piperazines; Psychotic Disorders; Pyrimidinones; Raclopride; Receptors, Dopamine D2; Receptors, Serotonin, 5-HT2; Schizophrenia; Thiazoles; Tomography, Emission-Computed

Olanzapine is a new atypical antipsychotic recently introduced for the treatment of schizophrenia. The purpose of this study was to investigate olanzapine's binding to the serotonin 5-HT2 and dopamine D2 receptors in schizophrenic patients being treated with clinically relevant doses.. Twelve patients with schizophrenia were randomly assigned to 5, 10, 15, or 20 mg/day of olanzapine in a prospective fashion. Three other subjects taking 30-40 mg/day were also included. Once steady-state plasma levels were achieved, dopamine D2 and serotonin 5-HT2 receptors were assessed by using [11C]raclopride and [18F]setoperone positron emission tomography imaging, respectively. Ratings of clinical status, extrapyramidal side effects, and prolactin levels were also obtained.. Olanzapine induced near saturation of the 5-HT2 receptors, even at 5 mg/day. Its D2 occupancy increased with dose: patients taking 5-20 mg/day showed 43%-80% D2 occupancy, while patients taking 30-40 mg/day showed 83%-88%.. Olanzapine is a potent 5-HT2 blocker and shows a higher 5-HT2 than D2 occupancy at all doses. However, its D2 occupancy is higher than that of clozapine and similar to that of risperidone. In the usual clinical dose range of 10-20 mg/day, its occupancy varies from 71% to 80%, and this restricted range may explain its freedom from extrapyramidal side effects and prolactin elevation. However, doses of 30 mg/day and higher are associated with more than 80% D2 occupancy and may have a higher likelihood of prolactin elevation and extrapyramidal side effects.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Carbon Radioisotopes; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fluorine Radioisotopes; Humans; Male; Olanzapine; Pirenzepine; Prolactin; Pyrimidinones; Raclopride; Receptors, Dopamine D2; Receptors, Serotonin; Salicylamides; Schizophrenia; Tomography, Emission-Computed; Treatment Outcome

Topics: Brain; Butyrophenones; Humans; Isoxazoles; Piperidines; Pyrimidinones; Randomized Controlled Trials as Topic; Receptors, Serotonin; Risperidone; Ritanserin; Schizophrenia; Schizophrenic Psychology; Serotonin Antagonists

The tremendous advances in understanding the neurobiological circuits involved in schizophrenia have not translated into more effective treatments. An alternative strategy is to use a recently published 'Quantitative Systems Pharmacology' computer-based mechanistic disease model of cortical/subcortical and striatal circuits based upon preclinical physiology, human pathology and pharmacology. The physiology of 27 relevant dopamine, serotonin, acetylcholine, norepinephrine, gamma-aminobutyric acid (GABA) and glutamate-mediated targets is calibrated using retrospective clinical data on 24 different antipsychotics. The model was challenged to predict quantitatively the clinical outcome in a blinded fashion of two experimental antipsychotic drugs; JNJ37822681, a highly selective low-affinity dopamine D(2) antagonist and ocaperidone, a very high affinity dopamine D(2) antagonist, using only pharmacology and human positron emission tomography (PET) imaging data. The model correctly predicted the lower performance of JNJ37822681 on the positive and negative syndrome scale (PANSS) total score and the higher extra-pyramidal symptom (EPS) liability compared to olanzapine and the relative performance of ocaperidone against olanzapine, but did not predict the absolute PANSS total score outcome and EPS liability for ocaperidone, possibly due to placebo responses and EPS assessment methods. Because of its virtual nature, this modeling approach can support central nervous system research and development by accounting for unique human drug properties, such as human metabolites, exposure, genotypes and off-target effects and can be a helpful tool for drug discovery and development.

Topics: Antipsychotic Agents; Computer Simulation; Humans; Models, Neurological; Neostriatum; Piperidines; Prospective Studies; Pyridazines; Pyrimidinones; Schizophrenia; Treatment Outcome

The authors compared serotonin receptor binding in patients with schizophrenia and healthy comparison subjects.. They used positron emission tomography with [(18)F]setoperone to examine six patients with schizophrenia who had never been given neuroleptics and seven age-matched subjects who did not have schizophrenia.. A nondirected voxel-based analysis of the subjects' entire search volume found that serotonin 2A binding potential in the frontal cortex index was significantly smaller (by 16.3%) in patients with schizophrenia than in healthy subjects.. The authors conclude that the decrease in serotonin receptor densities previously reported in postmortem studies of subjects with schizophrenia are present at the onset of the illness, before exposure to neuroleptics.

Topics: Adolescent; Adult; Antipsychotic Agents; Brain; Female; Fluorine Radioisotopes; Frontal Lobe; Humans; Male; Pyrimidinones; Radionuclide Imaging; Receptor, Serotonin, 5-HT2A; Receptors, Serotonin; Schizophrenia

Several postmortem studies have reported regionally localized decreases in serotonin(2A) receptors (5-HT(2A)R) in schizophrenia. This was not confirmed by two recent [18F]setoperone positron emission tomography (PET) studies. In these two studies relatively large regions of interest (ROIs) were used; hence, 5-HT(2A)R changes may have been missed in some brain areas. Therefore, data from one study were analyzed on a voxel-by-voxel basis using Statistical Parametric Mapping (SPM). We also used this method to examine the relationship between 5-HT(2A)R binding potential (BP) and five PANSS-derived factors: negative, positive, activation, dysphoric and autistic preoccupation. Thirteen schizophrenic patients (10 antipsychotic-naïve, 3 antipsychotic-free; 11 M, 2 F; age 31+/-7 years) and 35 age-matched control subjects (15 M, 20 F; age 30+/-7 years) were scanned. The 5-HT(2A)R BP was determined for each voxel using the pseudoequilibrium ratio method on PET data obtained between 65 and 90 min after [18F]setoperone bolus injection. The resulting parametric 5-HT(2A)R BP images were spatially normalized using a ligand specific template. Analyses of covariance were done using SPM99 with age as covariate. In tests for the effect of schizophrenia and for partial correlations between 5-HT(2A)R BP and the five factors, corrected P values <0.05 at cluster or voxel level were considered significant. No significant differences were detected between patients and control subjects, and no significant correlations were observed between 5-HT(2A)R BP and any of the five factors. Thus, in agreement with the previous ROI studies, voxel-by-voxel analysis confirmed the lack of substantial 5-HT(2A)R BP differences between schizophrenic patients and control subjects.

Topics: Adult; Age Factors; Analysis of Variance; Brain; Case-Control Studies; Contrast Media; Female; Fluorine Radioisotopes; Humans; Male; Psychiatric Status Rating Scales; Pyrimidinones; Receptor, Serotonin, 5-HT2A; Receptors, Serotonin; Schizophrenia; Schizophrenic Psychology; Serotonin Antagonists; Tomography, Emission-Computed

Several postmortem studies have reported a decreased density of serotonin 5-HT2 receptors in the prefrontal cortex in schizophrenia. The purpose of this study was to investigate this in patients with schizophrenia by means of [18F]setoperone and positron emission tomography (PET) imaging.. Thirteen neuroleptic-free patients with schizophrenia, 10 of whom were also neuroleptic-naive, were compared with a group of 26 normal subjects in the same age range. The density of 5-HT2 receptors was assessed with the use of [18F]setoperone and PET in standardized cortical regions of interest.. Increasing age was associated with similar declines in 5-HT2 receptors in all cortical regions in the patient group and in the normal comparison group. After control for the effect of age, there was no statistically significant difference between the patients and the comparison subjects in 5-HT2 receptor density in any of the cortical regions.. This study failed to find the decrease in 5-HT2 receptors reported in postmortem studies of schizophrenia. The study had the power to detect a decrease of 25% or more in 5-HT2 receptors, which was anticipated on the basis of the previous postmortem studies. Thus, a primary serotonergic abnormality in schizophrenia, if one exists, is either small or unlikely to be at the level of the 5-HT2 receptors. This finding does not rule out a therapeutic role for 5-HT2 antagonists in schizophrenia, but it does suggest that the therapeutic contribution is likely to be an indirect one.

Topics: Antipsychotic Agents; Brain Chemistry; Cerebral Cortex; Contrast Media; Fluorine Radioisotopes; Humans; Prefrontal Cortex; Pyrimidinones; Receptors, Serotonin; Schizophrenia; Tomography, Emission-Computed

Dopamine D2 receptor occupancy measurements provide a valid predictor of antipsychotic response, extrapyramidal side effects, and elevation of prolactin levels. The new antipsychotics clozapine, risperidone, and olanzapine obtain antipsychotic response with few extrapyramidal side effects and little prolactin elevation. The purpose of this study was to compare the D2 and serotonin 5-HT2 receptor occupancies of these drugs in patients receiving multiple-dose, steady-state regimens.. Forty-four patients with schizophrenia (16 taking risperidone, 2-12 mg/day; 17 taking olanzapine, 5-60 mg/day; and 11 taking clozapine, 75-900 mg/day) had their D2 and 5-HT2 occupancies determined with the use of [11C]raclopride and [18F]setoperone, respectively, and positron emission tomography imaging.. Clozapine showed a much lower D2 occupancy (16%-68%) than risperidone (63%-89%) and olanzapine (43%-89%). Risperidone and olanzapine gave equal D2 occupancies at doses of 5 and 20 mg/day, respectively. All three drugs showed greater 5-HT2 than D2 occupancy at all doses, although the difference was greatest for clozapine.. Clozapine, at doses known to be effective in routine clinical settings, showed a D2 occupancy clearly lower than that of typical antipsychotics, while risperidone and olanzapine at their usual clinical doses gave the same level of D2 occupancy as low-dose typical antipsychotics. The results also suggest that some previous clinical comparisons of antipsychotics may have been confounded by different levels of D2 occupancy. Clinical comparisons of these drugs, matching for D2 occupancy, may provide a better measure of their true "atypicality" and will help in understanding the contribution of non-D2 receptors to antipsychotic effects.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Carbon Radioisotopes; Clozapine; Drug Administration Schedule; Female; Fluorine Radioisotopes; Humans; Male; Middle Aged; Olanzapine; Pirenzepine; Pyrimidinones; Raclopride; Receptors, Dopamine D2; Receptors, Serotonin; Risperidone; Salicylamides; Schizophrenia; Tomography, Emission-Computed

This study examined the binding to cortical serotonin 5-HT2A receptors of conventional doses of the typical neuroleptic chlorpromazine in comparison with clozapine, the prototype atypical antipsychotic, and amisulpride, a specific dopamine D2-D3 blocker.. Seventeen schizophrenic patients treated with chlorpromazine (75-700 mg/day), four treated with clozapine (200-600 mg/day), and five treated with amisulpride (200-1200 mg/day) were studied. Cortical 5-HT2A binding was estimated by reference to the values for 14 antipsychotic-free schizophrenic subjects with the use of positron emission tomography and [18F]setoperone, a high-affinity radioligand for cortical 5-HT2A receptors.. A dose-dependent decrease in the number of available cortical binding sites for [18F] setoperone was demonstrated in the chlorpromazine group; for the highest dose, there was a virtual lack of sites available for binding. A very low percentage of available binding sites was also observed in the clozapine-treated patients at all doses. This suggests a high level of 5-HT2A blockade with both clozapine and high doses of chlorpromazine. No significant binding of amisulpride to 5-HT2A receptors was detected.. A high level of 5-HT2A receptor blockade does not appear specific to clozapine in comparison with high doses of chlorpromazine, suggesting that the distinct clinical profiles of both drugs are unrelated to 5-HT2A blockade itself.

Topics: Adolescent; Adult; Amisulpride; Animals; Antipsychotic Agents; Cerebral Cortex; Chlorpromazine; Clozapine; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fluorine Radioisotopes; Humans; Male; Pyrimidinones; Receptor, Serotonin, 5-HT2A; Receptors, Serotonin; Schizophrenia; Sulpiride; Tomography, Emission-Computed

To investigate putative abnormalities of cortical 5-HT2A receptor density in schizophrenia, we used positron emission tomography and [18F]setoperone, a high-affinity 5-HT2A receptor radioligand, in 14 neuroleptic-free or -naive schizophrenic patients and in 15 normal controls. No significant difference between the groups was observed in the whole or regional cortical binding potential of [18F]setoperone, indicating an absence of major 5-HT2A receptor cortical density abnormalities in schizophrenics.

Topics: Adult; Cell Count; Cerebral Cortex; Female; Functional Laterality; Humans; Male; Pyrimidinones; Receptors, Serotonin; Schizophrenia; Tomography, Emission-Computed

Loxapine, a dibenzoxazepine antipsychotic, is closely related to clozapine and shares clozapine's high affinity for binding to serotonin 5-HT2 and dopamine D4 receptors. The purpose of this study was to document loxapine's 5-HT2 and D2 receptor occupancy in vivo in patients with psychoses.. Ten patients who were taking loxapine (10-100 mg/day) had their D2 and 5-HT2 receptors assessed by means of positron emission tomography with [11C]raclopride and [18F]setoperone, respectively.. The D2 receptor occupancy ranged from 43% to 90%; 5-HT2 occupancy varied from 27% to near saturation. Statistical comparison of the results showed that loxapine was equipotent in blocking 5-HT2 and D2 receptors.. Loxapine differs from typical neuroleptics in demonstrating a high degree of 5-HT2 receptor occupancy. However, it is not "atypical" like clozapine and risperidone, since its 5-HT2 occupancy is not higher than its D2 occupancy. The results demonstrate that a high level of 5-HT2 occupancy is not a sufficient condition for atypicality. If atypical antipsychotic action is predicated on a combination of 5-HT2 and D2 effects, then it requires > 80% 5-HT2 occupancy in conjunction with < 80% D2 occupancy.

Topics: Adult; Cerebellum; Corpus Striatum; Dopamine Antagonists; Female; Fluorine Radioisotopes; Humans; Loxapine; Male; Pyrimidinones; Raclopride; Receptors, Dopamine D2; Receptors, Serotonin; Salicylamides; Schizophrenia; Tomography, Emission-Computed

Alterations in phospholipid metabolism in blood elements have been proposed as the possible biochemical marker of schizophrenia. In the present study, we investigated the composition and membrane distribution of phospholipids in platelets of drug-free schizophrenic patients and controls. We have demonstrated that platelets of drug-free schizophrenics have significantly higher cytosolic Ca2+ levels in comparison with healthy controls. Platelets of drug-free schizophrenic patients have a lower content of phosphatidylinositol (PI). After thrombin activation, PI is the target of phospholipase C instead of phosphatidylinositol 4,5-bisphosphate (PIP2), which is hydrolyzed in platelets of controls. Alterations in the distribution of phospholipids were found in the plasma membrane of platelets of schizophrenic patients. We suggest that alterations in phospholipid metabolism might be evoked by a disturbance of calcium homeostasis in schizophrenic patients.

Topics: Adult; Blood Platelets; Calcium; Female; Flow Cytometry; Fluorescent Dyes; Homeostasis; Humans; Male; Phosphatidylinositol 4,5-Diphosphate; Phospholipids; Pyrimidinones; Schizophrenia; Thrombin

The new antipsychotic drug setoperone is pharmacologically characterized by its potent serotonin and moderate dopamine receptor blocking properties. Forty chronic schizophrenic patients were included and 34 completed this pilot study. Following a drug-free period of 1 week the patients received setoperone 5 mg t.i.d. After 1 month of treatment, the psychotic symptoms, as measured by the BPRS, improved by approximately 50% (P less than 0.001) as compared with the condition under previous neuroleptic medication. Blockade of serotonin receptors may be related to improvement of autistic behaviour, dysphoria, and parkinson-like symptoms. In residual schizophrenic patients, the need for dopamine blockade, which is normally correlated with the therapeutic effect on positive symptoms, can be reduced substantially.

Topics: Adult; Aged; Basal Ganglia Diseases; Female; Humans; Male; Middle Aged; Pilot Projects; Psychiatric Status Rating Scales; Pyrimidinones; Schizophrenia; Serotonin Antagonists