raclopride and Psychotic-Disorders

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

Response to typical antipsychotic medication has been associated with achieving a level of striatal dopamine D2 receptor occupancy in the range of 65% to 70%. We undertook this study to determine whether response to the atypical antipsychotic olanzapine occurs at lower levels of D2 receptor occupancy.. Eighteen patients who presented with a first episode of psychosis were randomized to receive olanzapine 5 mg daily or haloperidol 2 mg daily in a double-blind design. We acquired positron emission tomography (PET) scans using the D2 ligand [11C]raclopride within the first 15 days of treatment to determine the percentage of D2 receptors occupied by the medication. According to response, dosage was then adjusted to a maximum dosage of 20 mg daily of either drug. PET scans were repeated after 10 to 12 weeks of treatment.. At the first PET scan, the 8 olanzapine-treated patients had significantly lower D2 receptor occupancies (mean 63.4%, SD 7.3) than those observed in the 10 patients treated with haloperidol (mean 73.0%, SD 6.1). When patients were rescanned following dosage adjustment, mean D2 receptor occupancies were greater than 70% in both groups. D2 receptor occupancies did not differ significantly between the olanzapine-treated group (mean 72.0%, SD 5.7) and the haloperidol-treated group (mean 78.7%, SD 7.6).. These results suggest that, in patients being treated for a first episode of psychosis, olanzapine has its antipsychotic effect at approximately the same levels of D2 receptor occupancy as are achieved with low dosages of haloperidol.

Topics: Acute Disease; Adolescent; Adult; Antipsychotic Agents; Benzodiazepines; Corpus Striatum; Dose-Response Relationship, Drug; Double-Blind Method; Female; Haloperidol; Humans; Male; Olanzapine; Positron-Emission Tomography; Psychotic Disorders; Raclopride; Receptors, Dopamine D2; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

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

Clozapine, risperidone, and other new "atypical" antipsychotic agents are distinguished from traditional neuroleptic drugs by having clinical efficacy with either no or low levels of extrapyramidal symptoms (EPS). Preclinical models have focused on striatal dopamine systems to account for their atypical profile. In this study, we examined the effects of clozapine and risperidone on amphetamine-induced striatal dopamine release in patients with psychotic disorders. A novel 11C-raclopride/PET paradigm was used to derive estimates of amphetamine-induced changes in striatal synaptic dopamine concentrations and patients were scanned while antipsychotic drug-free and during chronic treatment with either clozapine or risperidone. We found that amphetamine produced significant reductions in striatal 11C-raclopride binding during the drug-free and antipsychotic drug treatment phases of the study which reflects enhanced dopamine release in both conditions. There were no significant differences in % 11C-raclopride changes between the two conditions indicating that these atypical agents do not effect amphetamine-related striatal dopamine release. The implications for these data for antipsychotic drug action are discussed.

Topics: Adult; Amphetamine; Antipsychotic Agents; Clozapine; Dopamine Antagonists; Dopamine Uptake Inhibitors; Female; Humans; Image Processing, Computer-Assisted; Male; Middle Aged; Neostriatum; Psychotic Disorders; Raclopride; Risperidone; Salicylamides; Tomography, Emission-Computed

The clinical benefit of the atypical antipsychotic drug clozapine may be related to a combined effect on D2 and 5-HT2 receptors. To examine the basis for this hypothesis, positron emission tomography (PET) and the radioligand [11C]N-methylspiperone were used to determine cortical 5-HT2 receptor occupancy in three psychotic patients treated with 125 mg, 175mg and 200mg clozapine daily. The uptake of [11C]N-methylspiperone in the frontal cortex was very low compared to that in neuroleptic naive schizophrenic patients. 5-HT2 receptor occupancy calculated in the clozapine treated patients was 84%, 87% and 90%. The results show that clinical treatment with clozapine induces a high 5-HT2 receptor occupancy in psychotic patients at a low dose level.

Topics: Adult; Antipsychotic Agents; Clozapine; Dopamine Agonists; Female; Humans; Male; Middle Aged; Prefrontal Cortex; Psychotic Disorders; Raclopride; Receptors, Serotonin; Salicylamides; Schizophrenia; Spiperone; Tomography, Emission-Computed

Between unaffected mental health and diagnosable psychiatric disorders, there is a vast continuum of functioning. The hypothesized link between striatal dopamine signaling and psychosis has guided a prolific body of research. However, it has been understudied in the context of multiple interacting factors, subclinical phenotypes, and pre-postsynaptic dynamics.. This work investigated psychotic-like experiences and D2/3 dopamine postsynaptic receptor availability in the dorsal striatum, quantified by in vivo [11C]-raclopride positron emission tomography, in a sample of 24 healthy male individuals. Additional mediation and moderation effects with childhood trauma and key dopamine-regulating genes were examined.. An inverse relationship between nondisplaceable binding potential and subclinical symptoms was identified. D2/3 receptor availability in the left putamen fully mediated the association between traumatic childhood experiences and odd beliefs, that is, inclinations to see meaning in randomness and unfounded interpretations. Moreover, the effect of early adversity was moderated by a DRD2 functional variant (rs1076560). The results link environmental and neurobiological influences in the striatum to the origination of psychosis spectrum symptomology, consistent with the social defeat and diathesis-stress models.. Adversity exposure may affect the dopamine system as in association with biases in probabilistic reasoning, attributional style, and salience processing. The inverse relationship between D2/3 availability and symptomology may be explained by endogenous dopamine occupying the receptor, postsynaptic compensatory mechanisms, and/or altered receptor sensitivity. This may also reflect a cognitively stabilizing mechanism in non-help-seeking individuals. Future research should comprehensively characterize molecular parameters of dopamine neurotransmission along the psychosis spectrum and according to subtype profiling.

Topics: Adult; Adult Survivors of Child Adverse Events; Adverse Childhood Experiences; Dopamine; Dopamine D2 Receptor Antagonists; Female; Humans; Male; Neostriatum; Positron-Emission Tomography; Psychological Trauma; Psychotic Disorders; Raclopride; Receptors, Dopamine D2; Receptors, Dopamine D3

To assess the impact of reducing the dose of antipsychotics on cognition and dopaminergic D. Open-label prospective PET [. A tertiary care center outpatient setting.. Thirty-seven clinically stable participants with schizophrenia or schizoaffective disorder, aged 50 years or greater, and having been treated with olanzapine or risperidone monotherapy at the same dose for at least 6 months.. Gradual reduction in their olanzapine or risperidone daily dose of up to 40%.. Clinical and cognitive assessments, and [. Reducing the antipsychotic dose resulted in an increase in D. Our findings suggest that optimizing D

Topics: Aged; Antipsychotic Agents; Benzodiazepines; Cognitive Dysfunction; Corpus Striatum; Female; Humans; Male; Middle Aged; Olanzapine; Positron-Emission Tomography; Psychotic Disorders; Raclopride; Receptors, Dopamine D2; Risperidone; Schizophrenia

Cannabis use in adolescence is emerging as a risk factor for the development of psychosis. In animal studies, Δ9-tetrahydrocannabinol (THC), the psychoactive component of cannabis, modulates striatal dopaminergic neurotransmission. Alterations in human striatal dopaminergic function have also been reported both in psychosis and in stimulant use. We sought to examine whether striatal dopamine D(2)/D(3) receptor availability was altered in volunteers with a history of cannabis use using a database of previously acquired [(11)C]-raclopride positron emission tomography (PET) scans. Ten [(11)C]-raclopride scans from volunteers with a history of cannabis use were compared to ten control scans using a functional striatal subdivision region of interest (ROI) analysis. No significant differences in either overall striatal BP(ND) values or BP(ND) values in any functional striatal subdivision were found between the two groups. There was also no correlation between lifetime frequency of cannabis use and BP(ND) values. Limbic striatal BP(ND) values were ten percent lower in current nicotine cigarette smokers. These findings suggest that, unlike other drugs of abuse, a history of cannabis use is not associated with alterations in striatal dopamine D(2)/D(3) receptor availability.

Topics: Adult; Alcohol Drinking; Cannabis; Carbon Isotopes; Corpus Striatum; Female; Humans; Limbic System; Male; Marijuana Abuse; Nicotine; Positron-Emission Tomography; Psychotic Disorders; Raclopride; Receptors, Dopamine D2; Receptors, Dopamine D3; Synaptic Transmission

It is generally held that the elderly are more sensitive to motor side effects of antipsychotics, although the mechanisms for such an effect are not fully understood. The objective of this study was to examine whether this sensitivity is due to a central pharmacokinetic (i.e., higher occupancy for a given plasma level) or pharmacodynamic (i.e., greater functional effects for a given occupancy) effect.. Cross-sectional.. Centre for Addiction and Mental Health, Toronto, Ontario, Canada.. Thirteen subjects aged 50 (mean +/- standard deviation age: 62 +/- 9 years) with schizophrenia or schizoaffective disorder who were receiving risperidone.. Dopamine D2 binding potential in the striatum, using [C]raclopride positron emission tomography scan. D2 receptor occupancy was calculated, using age-corrected measure from healthy individuals and region of interest analysis.. The authors observed the expected nonlinear relationship between total risperidone and 9-hydroxyrisperidone plasma level and striatal D2 receptor occupancy. The estimated plasma level of risperidone plus 9-hydroxyrisperidone associated with 50% maximal receptor occupancy was 7.3 ng/mL, which is similar to what has been reported in younger patients. However, extrapyramidal side effects (EPS) were observed in seven subjects at D2 occupancy of 34%-79%, occupancy levels that are lower than previously reported for younger patients in whom EPS are rare at occupancies lower than 80%.. The observation of greater functional effect (EPS in this case) for a given drug occupancy than the younger patients supports a pharmacodynamic mechanism for age-related antipsychotic drug sensitivity. This finding has important implications for dosing of antipsychotics in older patients with schizophrenia.

Topics: Aged; Aged, 80 and over; Antipsychotic Agents; Basal Ganglia Diseases; Case-Control Studies; Cross-Sectional Studies; Dopamine Antagonists; Female; Humans; Isoxazoles; Male; Middle Aged; Ontario; Paliperidone Palmitate; Positron-Emission Tomography; Psychiatric Status Rating Scales; Psychotic Disorders; Pyrimidines; Raclopride; Receptors, Dopamine D2; Risperidone; Schizophrenia; Treatment Outcome

Drugs that increase dopamine levels in the brain can cause psychotic symptoms in healthy individuals and worsen them in schizophrenic patients. Psychological stress also increases dopamine release and is thought to play a role in susceptibility to psychotic illness. We hypothesized that healthy individuals at elevated risk of developing psychosis would show greater striatal dopamine release than controls in response to stress. Using positron emission tomography and [(11)C]raclopride, we measured changes in synaptic dopamine concentrations in 10 controls and 16 psychometric schizotypes; 9 with perceptual aberrations (PerAb, ie positive schizotypy) and 7 with physical anhedonia (PhysAn, ie negative schizotypy). [(11)C]Raclopride binding potential was measured during a psychological stress task and a sensory-motor control. All three groups showed significant increases in self-reported stress and cortisol levels between the stress and control conditions. However, only the PhysAn group showed significant stress-induced dopamine release. Dopamine release in the entire sample was significantly negatively correlated with smooth pursuit gain, an endophenotype linked to frontal lobe function. Our findings suggest the presence of abnormalities in the dopamine response to stress in negative symptom schizotypy, and provide indirect evidence of a link to frontal function.

Topics: Adult; Dopamine; Dopamine Antagonists; Female; Frontal Lobe; Hormones; Humans; Linear Models; Male; Maternal Behavior; Neostriatum; Neuropsychological Tests; Positron-Emission Tomography; Psychiatric Status Rating Scales; Psychotic Disorders; Pursuit, Smooth; Raclopride; Radiopharmaceuticals; Receptors, Dopamine D2; Risk; Schizotypal Personality Disorder; Stress, Psychological

Long-acting injectable risperidone represents the first clinically available depot atypical antipsychotic. The present study used positron emission tomography (PET) to evaluate its dopamine D(2) binding profile at doses of 25, 50, or 75 mg administered every 2 weeks.. After achieving stabilization with one of the doses, nine patients with a diagnosis of schizophrenia or schizoaffective disorder underwent [(11)C]raclopride PET to measure D(2) occupancy. Participants were scanned twice during the 2-week injection interval: within 3 days after injection (postinjection) and within 5 days before the next injection (preinjection). At the same time, plasma was collected for measurements of risperidone plus 9-hydroxyrisperidone.. Mean post- and preinjection D(2) occupancy levels for the 25-, 50-, and 75-mg doses were 71.0% and 54.0%, 74.4% and 65.4%, and 81.5% and 75.0%, respectively. There was a significant correlation between dose and plasma concentrations of risperidone plus 9-hydroxyrisperidone, and the estimated plasma concentration associated with 50% D(2) occupancy (ED(50)) was 11.06 ng/ml. Prolactin levels were not correlated with drug levels or D(2) occupancy.. All three doses of injectable risperidone showed peak D(2) occupancy levels above the 65% threshold associated with optimal clinical response; the 75-mg dose approximated the 80% threshold linked to increased risk of extrapyramidal symptoms. Doses of 25 or 50 mg should provide therapeutic efficacy while minimizing the risk of extrapyramidal symptoms.

Topics: Adult; Antipsychotic Agents; Basal Ganglia Diseases; Brain; Carbon Radioisotopes; Corpus Striatum; Delayed-Action Preparations; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Injections; Isoxazoles; Male; Middle Aged; Paliperidone Palmitate; Positron-Emission Tomography; Prolactin; Psychotic Disorders; Pyrimidines; Raclopride; Receptors, Dopamine D2; Risperidone; Schizophrenia

The aim was to test the dopamine hypothesis of schizophrenia in a further analysis of D(2)-like dopamine binding using the radioligand [(11)C]raclopride and high resolution 3-dimensional (3D) PET. Eighteen drug-naive patients with schizophrenia and seventeen control subjects were examined. The D(2) binding potential (BP) in the putamen, the caudate and the thalamus was calculated using the simplified reference tissue model. The volume of regions of interest was controlled for by MRI. Symptoms were rated with the Positive and Negative Syndrome Scale for Schizophrenia (PANSS). No significant group differences were found for D(2) BP in the putamen or in the caudate and there was no significant hemispheric difference for any region. In the right thalamus the D(2) BP was significantly lower in patients as compared to control subjects, whereas a numerical difference did not reach statistical significance for the left thalamus. There was no significant correlation between D(2) BP and total PANSS score in any region. There was a highly significant age effect in the caudate and in the putamen, but not in the thalamus. In this relatively large PET study of exclusively drug-naive schizophrenic patients, a lower D(2) BP in the right thalamus was found in the patient group. This finding is in agreement with two previous studies in Sweden and in Japan using the high-affinity radioligand [(11)C]FLB 457 and provide further support for a role of dopamine in the thalamus related to the pathophysiology of schizophrenia.

Topics: Adolescent; Adult; Antipsychotic Agents; Brain; Caudate Nucleus; Corpus Striatum; Dominance, Cerebral; Dopamine Antagonists; Female; Humans; Image Processing, Computer-Assisted; Male; Middle Aged; Positron-Emission Tomography; Psychiatric Status Rating Scales; Psychotic Disorders; Putamen; Raclopride; Radioligand Assay; Receptors, Dopamine D2; Reference Values; Schizophrenia; Schizophrenia, Paranoid; Thalamus

Clozapine, the prototype of atypical antipsychotics, remains unique in its efficacy in the treatment of refractory schizophrenia. Its affinity for dopamine D(4) receptors, serotonin 5-HT(2A) receptor antagonism, effects on the noradrenergic system, and its relatively moderate occupancy of D(2) receptors are unlikely to be the critical mechanism underlying its efficacy. In an attempt to elucidate the molecular/synaptic mechanism underlying clozapine's distinctiveness in refractory schizophrenia, the authors studied the in vivo D(1) and D(2) receptor profile of clozapine compared with other atypical antipsychotics.. Positron emission tomography with the radioligands [(11)C]SCH23390 and [(11)C]raclopride was used to investigate D(1) and D(2) receptor occupancy in vivo in 25 schizophrenia patients receiving atypical antipsychotic treatment with clozapine, olanzapine, quetiapine, or risperidone.. Mean striatal D(1) occupancies ranged from 55% with clozapine to 12% with quetiapine (rank order: clozapine > olanzapine > risperidone > quetiapine). The striatal D(2) occupancy ranged from 81% with risperidone to 30% with quetiapine (rank order: risperidone > olanzapine > clozapine > quetiapine). The ratio of striatal D(1)/D(2) occupancy was significantly higher for clozapine (0.88) relative to olanzapine (0.54), quetiapine (0.41), or risperidone (0.31).. Among the atypical antipsychotics, clozapine appears to have a simultaneous and equivalent occupancy of dopamine D(1) and D(2) receptors. Whether its effect on D(1) receptors represents agonism or antagonism is not yet clear, as this issue is still unresolved in the preclinical arena. This distinctive effect on D(1)/D(2) receptors may be responsible for clozapine's unique effectiveness in patients with schizophrenia refractory to other typical and atypical antipsychotics.

Topics: Adolescent; Adult; Antipsychotic Agents; Benzazepines; Benzodiazepines; Carbon Radioisotopes; Clozapine; Corpus Striatum; Dibenzothiazepines; Female; Humans; Male; Middle Aged; Olanzapine; Prolactin; Psychotic Disorders; Quetiapine Fumarate; Raclopride; Receptors, Dopamine D1; Receptors, Dopamine D2; Risperidone; Schizophrenia; Tomography, Emission-Computed; Treatment Outcome

Blockade of central alpha1-adrenoceptors has been implicated as a possible factor contributing to the atypical antipsychotic profile of clozapine. Thus, in the present study we examined the effects of concomitant alpha1-adrenoceptor and dopamine D2 receptor blockade on conditioned avoidance response performance, as an index of antipsychotic-like activity, and on the induction of catalepsy, as a test for extrapyramidal side effect liability, in rats. It was found that pretreatment with the alpha1-adrenoceptor antagonist prazosin (0.2mg kg(-1) s.c.) caused an enhancement of a suppression of conditioned avoidance response in the presence of the dopamine D2 receptor antagonist raclopride (0.05-0.20 mg kg(-1) s.c.). The effect was most prominent at a subthreshold dose of raclopride (0.05 mg kg(-1)). At these doses, prazosin or raclopride by themselves, or in combination, did not produce catalepsy. In addition, pretreatment with prazosin (0.2mgkg(-1) s.c.) did not alter the catalepsy produced by a higher dose of raclopride (1.0 mg kg(-1) s.c.). It is suggested that, in the presence of low dopamine D2 receptor occupancy, additional alpha1-adrenoceptor blockade might improve antipsychotic efficacy, and thereby improve the therapeutic window with regard to parkinsonism.

Topics: Adrenergic alpha-1 Receptor Antagonists; Animals; Antipsychotic Agents; Avoidance Learning; Catalepsy; Conditioning, Psychological; Disease Models, Animal; Dopamine D2 Receptor Antagonists; Dose-Response Relationship, Drug; Drug Interactions; Male; Prazosin; Psychotic Disorders; Raclopride; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic, alpha-1; Receptors, Dopamine D2

Previous studies have shown D2-like dopamine receptor involvement in the regulation of phospholipid methylation (PLM), while others have documented impaired methionine and folate metabolism in schizophrenia. Utilizing [14C]formate labeling in cultured neuroblastoma cell lines, we now show that D4 dopamine receptors (D4R) mediate the stimulatory effect of dopamine (DA) on PLM. The effect of DA was potently blocked by highly D4R-selective antagonists and stimulated by the D4R-selective agonist CP-226269. DA-stimulated PLM was dependent upon the activity of methionine cycle enzymes, but DA failed to increase PLM in [3H]methionine labeling studies, indicating that a methionine residue in the D4R might be involved in mediating PLM. A direct role for MET313, located on transmembrane helix No. 6 immediately adjacent to phospholipid headgroups, was further suggested from adenosylation, site-directed mutagenesis and GTP-binding results. A comparison of PLM in lymphocytes from schizophrenia patients vs control samples showed a four-fold lower activity in the schizophrenia group. These findings reveal a novel mechanism by which the D4R can regulate membrane composition. Abnormalities in D4R-mediated PLM may be important in psychiatric illnesses such as schizophrenia.

Topics: Amino Acid Sequence; Aminopyridines; Animals; Benzazepines; Binding Sites; Carbon Radioisotopes; CHO Cells; Clozapine; Cricetinae; Dopamine Agonists; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Formates; Guanosine 5'-O-(3-Thiotriphosphate); Humans; Methionine; Mutagenesis, Site-Directed; Neuroblastoma; Phospholipids; Phosphorylation; Piperidines; Psychotic Disorders; Pyridines; Pyrroles; Raclopride; Receptors, Dopamine D2; Receptors, Dopamine D4; Recombinant Proteins; S-Adenosylmethionine; Salicylamides; Schizophrenia; Transfection; Tumor Cells, Cultured

Previous studies of the relationship between plasma prolactin and clinical effects in patients treated with antipsychotic drugs have yielded inconsistent results. A possible explanation may be that most studies have not included subtherapeutic or low doses of antipsychotics. In this exploratory, double-blind study, the relationship between plasma prolactin concentration and central D2 receptor occupancy was examined in 13 schizophrenic patients treated with the experimental antipsychotic drug raclopride (2, 6, or 12 mg daily). D2 receptor occupancy was determined by positron emission tomography and was related to antipsychotic effect as measured by the Brief Psychiatric Rating Scale. Plasma prolactin concentration was increased in eight of nine patients with a D2 receptor occupancy greater than 50%, whereas it was normal among patients with a D2 receptor occupancy less than 50% (p < 0.01). Plasma prolactin concentration measured 4 hours after the morning dose of raclopride correlated significantly with plasma raclopride concentration (r = 0.92, p < 0.01), the degree of D2 receptor occupancy (r = 0.81,p < 0.01), and the antipsychotic effect (r = 0.79, p < 0.01). Further controlled studies that include low doses of antipsychotic drugs may warrant a reconciliation of plasma prolactin as a useful tool in clinical monitoring of antipsychotic drug treatment.

Topics: Adult; Antipsychotic Agents; Biological Availability; Brain; Dopamine Antagonists; Dose-Response Relationship, Drug; Double-Blind Method; Drug Monitoring; Female; Humans; Male; Prolactin; Psychiatric Status Rating Scales; Psychotic Disorders; Raclopride; Receptors, Dopamine D2; Salicylamides; Schizophrenia; Tomography, Emission-Computed; Treatment Outcome

Positron emission tomography (PET) studies of typical neuroleptics suggest that 60% to 80% of striatal D2 occupancy may be sufficient for optimal clinical treatment of psychosis. Therefore, striatal D2 occupancy may be used as an index to determine the optimal dose range. Toward this end, we determined the in vivo D2 profile of loxapine, using [11C]-raclopride and PET. Seven patients selected from a clinical population were scanned while taking steady-state oral loxapine from 10 to 100 mg/day. Their D2 receptor occupancy was estimated by comparing them to age-matched data from neuroleptic-naive patients. The D2 receptor occupancy ranged from 52% to 90%, and there was a very strong relationship between dose and D2 occupancy, suggesting that 15 to 30 mg/day of loxapine would produce, the putatively optimal, 60% to 80% striatal D2 blockade. This dose range is much lower than that used in most clinical settings and points to the potential efficacy of loxapine at lower doses.

Topics: Administration, Oral; Adult; Antipsychotic Agents; Carbon Radioisotopes; Corpus Striatum; Cross-Sectional Studies; Dopamine Antagonists; Female; Humans; Loxapine; Male; Psychotic Disorders; Raclopride; Receptors, Dopamine D2; Salicylamides; Tomography, Emission-Computed

Positron emission tomography and 11-C-labelled raclopride was used to determine central D2-dopamine receptor occupancy in three melperone treated patients. Treatment with melperone in daily doses of 250 and 300 mg for 3 to 6 weeks, resulted in a receptor occupancy above 70%. Thus, clinical doses of melperone as we previously demonstrated for several classical neuroleptics cause a substantial D2-dopamine receptor blockade in the human brain in vivo.

Topics: Adult; Antipsychotic Agents; Butyrophenones; Female; Humans; Male; Prolactin; Psychotic Disorders; Raclopride; Receptors, Dopamine; Receptors, Dopamine D2; Salicylamides; Schizophrenia; Tomography, Emission-Computed