A positron emission tomography study of quetiapine in schizophrenia: a preliminary finding of an antipsychotic effect with only transiently high dopamine D2 receptor occupancy

BACKGROUND: Quetiapine is a new atypical antipsychotic medication. As such, relatively little has been published regarding its in vivo effects at the dopamine type 2 (D2) and serotonin type 2a (5-HT2a) receptor systems. The following study was undertaken to explore these effects across the clinical dose range and relate this information to its clinical profile. METHODS: Twelve patients with schizophrenia were randomly assigned to doses of 150 to 600 mg/d (n=3, at 150, 300, 450, and 600 mg/d) of quetiapine. After 3 weeks of treatment, D2 and 5-HT2a occupancy were measured using positron emission tomography (PET) imaging, 12 to 14 hours after the last dose. Clinical efficacy and adverse effect ratings were obtained at baseline, at the time of PET scanning, and at 12 weeks. Two additional patients were included to examine the effects of the drug 2 to 3 hours after last dose. RESULTS: Quetiapine was an effective antipsychotic and improved the extrapyramidal symptoms and prolactin level elevation noted at baseline. It achieved these results with minimal (0%-27%) D2 occupancy 12 hours after the last dose. Study of the additional subjects revealed that quetiapine does give rise to transiently high (58%-64%) D2 occupancy 2 to 3 hours after a single dose that then decreases to minimal levels in 12 hours. CONCLUSIONS: Quetiapine shows a transiently high D2 occupancy, which decreases to very low levels by the end of the dosing interval. Quetiapine's low D2 occupancy can explain its freedom from extrapyramidal symptoms and prolactin level elevation. The data suggest that transient D2 occupancy may be sufficient for its antipsychotic effect. Future studies controlling for nonpharmacological effects as well as activities on other receptors will be necessary to confirm this suggestion.     

Prediction and assessment of extrapyramidal side effects induced by risperidone based on dopamine D(2) receptor occupancy

In the present study, we attempted to predict the risk of extrapyramidal side effects of a selective monoaminergic antagonist, risperidone, by analyzing the correlation between the dopamine D(2) receptor occupancy and the degree of extrapyramidal side effects of the drug. The occupancies of D(2) and 5-HT(2) receptors at various doses of risperidone were calculated by means of a receptor occupancy theory. The extrapyramidal side effects after administration of risperidone were attempted to predict by theoretical analysis of the correlation between the calculated occupancies and the evidence of extrapyramidal symptoms using a ternary complex model. The pharmacokinetic/pharmacodynamic analysis utilized the data concerning the pharmacokinetics of risperidone and 9-hydroxyrisperidone (active metabolite), their binding affinities with D(2) and 5-HT(2) receptors, and the clinical evidence of extrapyramidal symptoms (Extrapyramidal Symptom Rating Scale: ESRS), gathered from the literature. The mean occupancy of 5-HT(2) receptors after the administration of regular doses of risperidone was suggested to be more than 90%, whereas the mean occupancy of D(2) receptors varied between 50-80%, depending on the dose. The correlation between the occupancy of D(2) receptors and the extrapyramidal symptoms could be successfully analyzed with a ternary complex model, showing the predictability of the model for the extrapyramidal side effects of risperidone. Since the estimated risk of the extrapyramidal side effects varied with the dose, the present method of predicting the extrapyramidal side effects of risperidone may provide a basis for developing a rational dosing regimen for the drug.     

Relationship between dopamine D(2) occupancy, clinical response, and side effects: a double-blind PET study of first-episode schizophrenia

OBJECTIVE: Since all antipsychotics block dopamine D(2) receptors, the authors investigated how well D(2) receptor occupancy in vivo predicts clinical response, extrapyramidal side effects, and hyperprolactinemia. METHOD: In a double-blind study, 22 patients with first-episode schizophrenia were randomly assigned to 1.0 or 2. 5 mg/day of haloperidol. After 2 weeks of treatment, D(2) receptor occupancy was determined with [(11)C]raclopride and positron emission tomography, and clinical response, extrapyramidal side effects, and prolactin levels were measured. Patients who showed adequate responses continued taking their initial doses, those who did not respond had their doses increased to 5.0 mg/day, and evaluations were repeated at 4 weeks for all patients. RESULTS: The patients showed a wide range of D(2) occupancy (38%-87%). The degree of receptor occupancy predicted clinical improvement, hyperprolactinemia, and extrapyramidal side effects. The likelihood of clinical response, hyperprolactinemia, and extrapyramidal side effects increased significantly as D(2) occupancy exceeded 65%, 72%, and 78%, respectively. CONCLUSIONS: The study confirms that D(2) occupancy is an important mediator of response and side effects in antipsychotic treatment. The data are consistent with a "target and trigger" hypothesis of antipsychotic action, i.e., that the D(2) receptor specificity of antipsychotics permits them to target discrete neurons and that their antagonist properties trigger within those neurons intracellular changes that ultimately beget antipsychotic response. While limited to haloperidol, the relationship between D(2) occupancy and side effects in this study helps explain many of the observed clinical differences between typical and atypical antipsychotics.     

Differential effects of aripiprazole on D(2), 5-HT(2), and 5-HT(1A) receptor occupancy in patients with schizophrenia: a triple tracer PET study

OBJECTIVE: 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. METHOD: 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. RESULTS: 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%. CONCLUSIONS: 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.     

In vivo determination of striatal dopamine D2 receptor occupancy in patients treated with olanzapine.

In vivo studies of dopamine D2 receptor occupancy with atypical antipsychotics have suggested good clinical efficacy at occupancy rates less than those observed with typical neuroleptics, and few extrapyramidal side effects (EPS), possibly even at high levels of D2 occupancy. We used [123I]IBZM-SPECT to investigate striatal D2 receptor occupancy in 10 schizophrenic patients who were treated with both a low (5 mg) and a high dose (20 mg) of the novel antipsychotic olanzapine without concomitant medications. The mean D2 occupancy at 5 mg was 59.8% (range 33-81%); the mean D2 occupancy at 20 mg was 82.8% (range 56-97%). Although the D2 occupancy rates on 5 and 20 mg olanzapine were significantly different (P < 0.001), there were no significant differences in clinical ratings for psychiatric symptoms or extrapyramidal side effects between the two doses of olanzapine. These data suggest that: (1) olanzapine doses below those used routinely occupy D2 receptors at levels approaching those associated with therapeutic response; (2) higher doses produce relatively high levels of D2 occupancy rates; and (3) EPS are mild even at relatively high levels of D2 occupancy.     

Is regionally selective D2/D3 dopamine occupancy sufficient for atypical antipsychotic effect? an in vivo quantitative [123I]epidepride SPET study of amisulpride-treated patients

OBJECTIVE: Atypical antipsychotic drug treatment is clinically effective with a low risk of extrapyramidal symptoms. Explanations for the mechanism underlying this beneficial therapeutic profile of atypical over typical antipsychotic agents include 1) simultaneous antagonism of dopamine D(2) and serotonin 5-HT(2A) receptors or 2) selective action at limbic cortical dopamine D(2)-like receptors with modest striatal D(2) receptor occupancy. Amisulpride is an atypical antipsychotic drug with selective affinity for D(2)/D(3) dopamine receptors and provides a useful pharmacological model for examining these hypotheses. The authors' goal was to evaluate whether treatment with amisulpride results in "limbic selective" D(2)/D(3) receptor blockade in vivo. METHOD: Five hours of dynamic single photon emission tomography data were acquired after injection of [(123)I]epidepride (approximately 150 MBq). Kinetic modeling was performed by using the simplified reference region model to obtain binding potential values. Estimates of receptor occupancy were made relative to a healthy volunteer comparison group (N=6). RESULTS: Eight amisulpride-treated patients (mean dose=406 mg/day) showed moderate levels of D(2)/D(3) receptor occupancy in the striatum (56%), and significantly higher levels were seen in the thalamus (78%) and temporal cortex (82%). CONCLUSIONS: Treatment with amisulpride results in a similar pattern of limbic cortical over striatal D(2)/D(3) receptor blockade to that of other atypical antipsychotic drugs. This finding suggests that modest striatal D(2) receptor occupancy and preferential occupancy of limbic cortical dopamine D(2)/D(3) receptors may be sufficient to explain the therapeutic efficacy and low extrapyramidal symptom profile of atypical antipsychotic drugs, without the need for 5-HT(2A) receptor antagonism.     

A PET study of dopamine D2 and serotonin 5-HT2 receptor occupancy in patients with schizophrenia treated with therapeutic doses of ziprasidone

OBJECTIVE: 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. METHOD: 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. RESULTS: 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. CONCLUSIONS: 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.     

Subjective experience and D2 receptor occupancy in patients with recent-onset schizophrenia treated with low-dose olanzapine or haloperidol: a randomized,double-blind study

OBJECTIVE: The authors tested the hypothesis that a dopamine D(2) receptor occupancy level between 60% and 70% in patients with recent-onset schizophrenia would result in optimal subjective experience. In addition, they sought preliminary evidence on whether subjective experience is better with low-dose olanzapine than with low-dose haloperidol. METHOD: Subjects (N=24) who met DSM-IV criteria for schizophrenia were randomly assigned to 6 weeks of double-blind treatment with either olanzapine, 7.5 mg/day, or haloperidol, 2.5 mg/day. Subjective experience, psychopathology, and extrapyramidal symptoms were assessed at baseline and at endpoint. After 6 weeks, D(2) receptor occupancy was assessed with [(123)I]iodobenzamide single photon emission computed tomography. RESULTS: The two study groups were similar at baseline. After 6 weeks, patients receiving olanzapine had a significantly lower mean dopamine D(2) receptor occupancy (51.0%, range=36%-67%) than those given haloperidol (65.5%, range=45%-75%). Receptor occupancy between 60% and 70% was associated with optimal subjective experience, and subjective experience improved significantly in the haloperidol group. CONCLUSIONS: A level of D(2) receptor occupancy between 60% and 70% is optimal for subjective experience of patients with recent-onset schizophrenia. Substantial interindividual variation in D(2) receptor occupancy was seen at fixed low-dose levels of olanzapine and haloperidol. Olanzapine, 7.5 mg/day, showed no superior subjective response over haloperidol, 2.5 mg/day. Olanzapine may need to be dosed higher than 7.5 mg/day for most patients with recent-onset schizophrenia, and haloperidol needs to be individually titrated in the very low dose range to reach optimal occupancy.     

In vivo occupation of dopamine D1, D2 and serotonin (5-HT)2A receptors by sertindole in the rat brain.

OBJECTIVE: To determine the in vivo occupation of dopamine D1, D2 and serotonin (5-HT)2A receptors by novel antipsychotic agent sertindole using N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), an irreversible antagonist at these receptor sites. DESIGN: Animal study. INTERVENTIONS: Intraperitoneal administration to Wistar rats of 1 of 4 test compounds: a control compound of 0.15% tartaric acid, or a compound of either sertindole (0.5 mg/kg or 2.0 mg/kg) or clozapine (20 mg/kg) dissolved in 0.15% tartaric acid 1 hour before intraperitoneal administration of EEDQ (8 mg/kg) or ethanol/water solution. RESULTS: Sertindole exhibited little or no effect on D1 and D2 binding sites in vivo. On the other hand, sertindole occupied 5-HT2A receptors more extensively and firmly than EEDQ. This study indicates that sertindole is characterized by high occupancy of 5-HT2A receptors and by low or minimum occupancy of D1 and D2 receptors. CONCLUSIONS: These characteristics are very similar to atypical antipsychotic agents such as clozapine. Sertindole's low liability to cause extrapyramidal side effects (EPS) may be related to greater long-term binding for 5-HT2A receptors relative to D2 receptors.     

Is amoxapine an atypical antipsychotic? Positron-emission tomography investigation of its dopamine2 and serotonin2 occupancy.

BACKGROUND: All currently available atypical antipsychotics have, at clinically relevant doses: i) high serotonin (5-HT)2 occupancy; ii) greater 5-HT2 than dopamine (D)2 occupancy; and iii) a higher incidence of extrapyramidal side effects when their D2 occupancy exceeds 80%. A review of pharmacologic and behavioral data suggested that amoxapine should also conform to this profile; therefore, we undertook a positron-emission tomography (PET) study of its 5-HT2 and D2 occupancy. METHODS: Seven healthy volunteers received 50-250 mg/day of amoxapine for 5 days and then had [11C]-raclopride and [18F]-setoperone PET scans. RESULTS: 5-HT2 receptors showed near saturation at doses of 100 mg/day and above. The D2 receptor occupancies showed a dose-dependent increase, never exceeding 80%; at all doses 5-HT2 occupancy exceeded D2 occupancy. CONCLUSIONS: PET data show that amoxapine's profile is very similar to that of the established atypical antipsychotics. These data, together with amoxapine's in vitro pharmacologic profile, effectiveness in animal models, and efficacy in psychotic depression raise the possibility of amoxapine as an "atypical" antipsychotic agent in the treatment of schizophrenia.     

Receptor occupancy and antipsychotic drug action measured by PET and SPECT]

Positron emission tomography (PET) and single photon emission computed tomography (SPECT) studies have demonstrated consistent findings of high dopamine D2 receptor occupancy (> 65-70%) in patients treated with antipsychotic drugs. Further, the risk of extrapyramidal side effects has been shown high in patients with occupancy above 80%. On the basis of these findings, an optimal interval for D2 receptor occupancy between 70% and 80% has been suggested. It has also been shown that several atypical antipsychotics induce marked occupancy of central 5-HT2 and D2 receptors in vivo. However, a low D2 occupancy has been observed in patients with clinical dose of clozapine or quetiapine. The antipsychotic effect of these atypical drugs with a low D2 receptor occupancy has been widely discussed with respect to actions on other receptor systems, limbic selectivity of antipsychotic action and episodic transient occupancy. The recent advances in PET/SPECT and developments of new radioligands have made it possible to evaluate antipsychotic drug actions directly in humans. The empirical data from occupancy measurements will enable us to open future directions of investigation of antipsychotic action and improvement of antipsychotic treatment.     

Dopamine D2 receptor occupancy with risperidone or olanzapine during maintenance treatment of schizophrenia: A cross-sectional study

In treating schizophrenia, it has been established that 65-80% occupancy of dopamine D2 receptors optimizes therapeutic efficacy while minimizing risks of extrapyramidal symptoms. However, it is unclear as to whether it is necessary to keep D2 receptor occupancy within this therapeutic window to maintain response. In this study, daily peak and trough D2 receptor occupancy levels were estimated in clinically stable patients with schizophrenia (DSM-IV) who were receiving risperidone or olanzapine. Using two collected plasma samples, plasma antipsychotic concentrations at peak and trough were estimated with population pharmacokinetic techniques. Corresponding dopamine D2 receptor occupancy levels were then estimated, using a recently developed model. 35 subjects with stable schizophrenia completed the study (mean±SD age, 48.8±13.8years; male [N=14]; Asians [N=23], Caucasians [N=12]; risperidone [N=20] at 3.2±2.3mg/day, and olanzapine [N=15] at 9.2±4.9mg/day) between September and December 2010. 48.6% (N=17) did not achieve a continuous blockade of ≥65%. Moreover, 11.4% (N=4) did not achieve the 65% threshold at estimated peak concentrations. In conclusion, approximately half the subjects with stable schizophrenia did not achieve estimated continuous blockade of D2 receptor occupancy of ≥65%. The results suggest that sustained D2 receptor occupancy levels of ≥65% may not always be necessary for the maintenance treatment of schizophrenia.     

Risperidone in the treatment of behavioral disturbances in children and adolescents with borderline intellectual functioning: a double-blind, placebo-controlled pilot trial

Risperidone, an antipsychotic agent with combined serotonin (5-HT2A) and dopamine (D2) receptor-blocking properties, is associated with fewer extrapyramidal side effects in adults than conventional neuroleptics. Approved in 1993 for the treatment of schizophrenia, recent studies have highlighted its potential in other conditions, such as the management of behavioral disturbances. This phase II, double-blind, placebo-controlled study evaluated the efficacy and tolerability of risperidone in the treatment of persistent behavioral disturbances in children with borderline intellectual functioning. Thirteen patients (6-14 years) with low IQ (66-85) were enrolled in and completed the 4-week study. Risperidone, in daily doses of > or = 0.01 mg/kg (mean dose at treatment endpoint = 0.05 mg/kg; mean total dose = 1.2 mg/day), was significantly more effective than placebo in improving Aberrant Behavioral Checklist (ABC) symptom cluster scores for irritation (p < 0.05) and hyperactivity (p < 0.01), Clinical Global Impression score (p < 0.05), the Visual Analogue Scale score for individual target symptom (p < 0.001), and Personal Assessment Checklist scores for social relationships (p < 0.05) and occupational attitudes (p < 0.05). In addition, the improvement in total ABC score in the risperidone-treated group was clinically relevant (65% improvement vs. baseline), whereas the placebo-treated patients only improved 7% versus baseline. There was no difference between risperidone- and placebo-treated groups with respect to the occurrence of extrapyramidal side effects, and risperidone was well tolerated. In conclusion, short-term risperidone treatment was well tolerated and significantly more effective than placebo in controlling behavioral disturbances in children with low IQ.     

Increased dopamine d(2) receptor occupancy and elevated prolactin level associated with addition of haloperidol to clozapine

OBJECTIVE: The authors added haloperidol, a potent D(2) blocker, to ongoing treatment with clozapine in patients with schizophrenia to determine the effects of this combination on dopamine D(2) receptor blockade, prolactin level, and extrapyramidal side effects. METHOD: At baseline and 4-8 weeks after the addition of haloperidol (4 mg/day) to ongoing clozapine treatment, five patients were examined for prolactin elevation, extrapyramidal side effects, drug plasma levels, and D(2) receptor occupancy measured with [(11)C]raclopride and positron emission tomography imaging. RESULTS: Adding haloperidol significantly increased D(2) receptor occupancy, from a mean of 55% to 79%, and significantly increased the prolactin level. One patient developed akathisia, and another manifested mild extrapyramidal side effects. CONCLUSIONS: Adding a modest dose of haloperidol to clozapine results in the high D(2) receptor occupancy and sustained prolactin elevation usually associated with typical antipsychotics. These findings suggest that the lack of prolactin elevation associated with clozapine derives mainly from low D(2) receptor occupancy and not from the medication's effects on other receptors.     

A PET study evaluating dopamine D2 receptor occupancy for long-acting injectable risperidone

OBJECTIVE: 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. METHOD: 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. RESULTS: 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. CONCLUSIONS: 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.     

The effect of serotonin(1A) receptor agonism on antipsychotic drug-induced dopamine release in rat striatum and nucleus accumbens

Serotonin (5-HT)(1A) receptor agonism may be of interest in regard to both the antipsychotic action and extrapyramidal symptoms (EPS) of antipsychotic drugs (APD) based, in part, on the effect of 5-HT(1A) receptor stimulation on the release of dopamine (DA) in the nucleus accumbens (NAC) and striatum (STR), respectively. We investigated the effect of R(+)-8-hydroxy-2-(di-n-propylamino)-tetralin (R(+)-8-OH-DPAT) and n-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-n-(2-pyridinyl)cyclohe xanecarboxamide trihydrochloride (WAY100635), a selective 5-HT(1A) receptor agonist and antagonist, respectively, on basal and APD-induced DA release. In both STR and NAC, R(+)-8-OH-DPAT (0.2 mg/kg) decreased basal DA release; R(+)-8-OH-DPAT (0.05 mg/kg) inhibited DA release produced by the 5-HT(2A)/D(2) receptor antagonists clozapine (20 mg/kg), low dose risperidone (0.01 and 0. 03 mg/kg) and amperozide (10 mg/kg), but not that produced by high dose risperidone (0.1 and 1.0 mg/kg) or haloperidol (0.01-1.0 mg/kg), potent D(2) receptor antagonists. This R(+)-8-OH-DPAT-induced inhibition of the effects of clozapine, risperidone and amperozide was antagonized by WAY100635 (0.05 mg/kg). WAY100635 (0.1-0.5 mg/kg) alone increased DA release in the STR but not NAC. The selective 5-HT(2A) receptor antagonist M100907 (1 mg/kg) did not alter the effect of R(+)-8-OH-DPAT or WAY100635 alone on basal DA release in either region. These results suggest that 5-HT(1A) receptor stimulation inhibits basal and some APD-induced DA release in the STR and NAC, and that this effect is unlikely to be mediated by an interaction with 5-HT(2A) receptors. The significance of these results for EPS and antipsychotic action is discussed.     

In vivo determination of striatal dopamine D2 receptor occupancy in patients treated with olanzapine

In vivo studies of dopamine D₂ receptor occupancy with atypical antipsychotics have suggested good clinical efficacy at occupancy rates less than those observed with typical neuroleptics, and few extrapyramidal side effects (EPS), possibly even at high levels of D₂ occupancy. We used [¹²³I]IBZM-SPECT to investigate striatal D₂ receptor occupancy in 10 schizophrenic patients who were treated with both a low (5 mg) and a high dose (20 mg) of the novel antipsychotic olanzapine without concomitant medications. The mean D₂ occupancy at 5 mg was 59.8% (range 33–81%); the mean D₂ occupancy at 20 mg was 82.8% (range 56–97%). Although the D₂ occupancy rates on 5 and 20 mg olanzapine were significantly different (P<0.001), there were no significant differences in clinical ratings for psychiatric symptoms or extrapyramidal side effects between the two doses of olanzapine. These data suggest that: (1) olanzapine doses below those used routinely occupy D₂ receptors at levels approaching those associated with therapeutic response; (2) higher doses produce relatively high levels of D₂ occupancy rates; and (3) EPS are mild even at relatively high levels of D₂ occupancy.     

Double-blind olanzapine vs. haloperidol D2 dopamine receptor blockade in schizophrenic patients: a baseline-endpoint

The aim of this study was to compare in vivo striatal D2 dopamine receptor occupancy induced by olanzapine and haloperidol in schizophrenic patients using a baseline-endpoint [(123)I]IBZM single photon computed emission tomography (SPECT) design. The relationships of striatal D2 receptor occupancy with clinical efficacy and extrapyramidal symptoms (EPS) were also assessed. Twenty-seven inpatients with schizophrenia or schizophreniform disorder were included in a 4-week prospective, randomized, double-blind, parallel and comparative clinical trial. Thirteen patients were treated with haloperidol (10 mg/day) and 14 with olanzapine (10 mg/day). Ratings of clinical status and EPS were obtained weekly. The percentage of D2 receptor occupancy was estimated by using basal ganglia (striatum)/frontal cortex IBZM uptake ratios obtained from each patient before and after 4 weeks of maintained antipsychotic treatment. Olanzapine led to a mean striatal D2 receptor occupancy of 49% (range 28-69%), which was significantly lower than that induced by haloperidol (mean 64%, range 46-90%). The baseline-endpoint SPECT design used in this study revealed lower antipsychotic D2 occupancy percentage values than those reported in the literature, using other approaches. The degree of striatal D2 receptor occupancy correlated to the EPS, which predominantly appeared in patients on haloperidol. No relationship was found between the striatal D2 receptor occupancy and clinical improvement. Olanzapine induced a lower striatal D2 occupancy than haloperidol. This low striatal D2 occupancy, together with the lower incidence of EPS in olanzapine-treated patients, contributed to confirm the atypical behavior of this new antipsychotic drug. Nevertheless, conclusions based on SPECT-estimated percentages of antipsychotic D2 occupancy should be cautious, since the SPECT design could influence the results. In this regard, SPECT studies including baseline and endpoint examinations should be encouraged.     

Dopamine D2 receptor occupancy by olanzapine or risperidone in young patients with schizophrenia

A crucial characteristic of antipsychotic medication is the occupancy of the dopamine (DA) D2 receptor. We assessed striatal DA D2 receptor occupancy by olanzapine and risperidone in 36 young patients [31 males, 5 females; mean age 21.1 years (16-28)] with first episode schizophrenia, using [123I]iodobenzamide (IBZM) SPECT. The occupancy of DA D2 receptors was not significantly different between olanzapine and risperidone. However, in subgroups of most prescribed doses, DA D2 occupancy was higher in the risperidone 4-mg group (79%) compared to the olanzapine 15-mg group (62%). [123I]IBZM binding ratios decreased with olanzapine dose (r = -0.551; P < 0.01), indicating higher DA D2 receptor occupancy with higher olanzapine dose. Akathisia and positive symptoms were correlated with [123I]IBZM binding ratio (r = -0.442; P < 0.01; and r = -0.360; P < 0.05, respectively). Prolactin (PRL) levels were elevated in the risperidone, but not in the olanzapine group, at comparable D2 receptor occupancy levels. In the olanzapine group, PRL levels were correlated with [123I]IBZM binding ratio (r = -0.551; P < 0.01). In conclusion, both olanzapine and risperidone induce a high striatal D2 receptor occupancy, dependent on dose and group formation. The lower incidence of prolactin elevation with olanzapine, compared to risperidone, may not be attributed to a lower D2 receptor occupancy.     

An open pilot study combining risperidone and a selective serotonin reuptake inhibitor as initial antidepressant therapy

BACKGROUND: Atypical antipsychotics such as risperidone or olanzapine have been reported to be effective when added to a selective serotonin reuptake inhibitor (SSRI) in cases of depression in which treatment with an SSRI alone is not effective. It is possible that the combination of an SSRI and an atypical antipsychotic may be efficacious as an initial treatment for major depression. METHOD: Thirty-six subjects who fulfilled DSM-IV diagnostic criteria for major depressive disorder were given fluvoxamin, 50 or 75 mg/day, with risperidone, 0.5 or 1 mg/day, at the start of treatment. The dose of fluvoxamine was increased to 100 or 150 mg/day on the fourth day of the treatment and maintained thereafter. Hamilton Rating Scale for Depression (HAM-D) scores were obtained at base-line and every week for 6 weeks. Remission and response were defined, respectively, as > or = 75% and 50%-74% reduction from baseline in HAM-D score. RESULTS: Of 30 subjects who completed the 6-week study, 23 (76%) achieved remission, 5 (17%) achieved response, and 2 (7%) were nonresponsive. Of the 6 patients who did not complete the study, 3 showed remission, 1 showed response, and 2 showed minimal or no response by the time of dropout. The reported adverse effects were mild, and none of the 36 subjects enrolled in the study manifested or reported extrapyramidal symptoms, nausea, or vomiting. CONCLUSION: The results suggest that the combination of risperidone and fluvoxamine from the beginning of antidepressant therapy enhances the therapeutic response rate in depression.