High central D2-dopamine receptor occupancy as assessed with positron emission tomography in medicated but therapy-resistant schizophrenic patients.

We investigated whether the lack of therapeutic response to long-term and adequate neuroleptic treatment was due to a failure to achieve a blockade of cerebral dopamine receptors. Six chronic schizophrenic and medicated patients (DSM-III-R diagnosis, paranoid or disorganized type) were assessed with the Present State Examination and the Brief Psychiatric Rating Scale. According to the Chouinard Rating Scale there were little extrapyramidal symptoms, although no anticholinergic drugs were given. Plasma levels of the neuroleptics were determined and found in the therapeutic range or higher. Dopamine D2-receptor occupancy was determined with positron emission tomography using 11C-methylspiperone as ligand. There was a more than 95% blockade of the D2 receptors in the striatum. These results indicate that the lack of therapeutic response and extra-pyramidal side effects cannot be attributed to an incomplete blockade of cerebral D2 receptors and that the pathogenetic role of these receptors can be questioned in therapy-resistant schizophrenic patients.     

D2-dopamine receptor occupancy differs between patients with and without extrapyramidal side effects

To investigate whether the occurrence of extrapyramidal side effects was related to D2 dopamine receptor occupancy, iodobenzamide single positron emission computed tomography was carried out in 27 schizophrenic patients and 10 controls. Eighteen patients were treated with haloperidol; 9 patients were treated with clozapine. Our data suggest a relationship between D2 receptor occupancy and extrapyramidal side effects as well as the existence of a neuroleptic threshold of a striatal:frontal cortex ratio of 1.2, below which drug-induced exptrapyramidal side effects can be expected.     

A method to estimate in vivo D2 receptor occupancy by antipsychotic drugs.

A computational method is presented to estimate in vivo receptor occupancies of frequently used antipsychotic medications, which may provide a way to determine their central nervous system (CNS) effects in humans. The method can be used to estimate occupancies of several receptor types based on the daily dose of antipsychotic medication. Estimates of D2 receptor occupancy by haloperidol based on this equation were compared with those yielded by positron emission tomography (PET) measures in humans for the same compounds and dosages: the results of this comparison validated the approach.     

Typical antipsychotic drugs -- D(2) receptor occupancy and depressive symptoms in schizophrenia

We tested the hypothesis that the degree of striatal dopamine D(2) receptor blockade induced by typical antipsychotic treatment directly correlates with the presence and severity of depressive symptoms in schizophrenia. Clinical and [(123)I]-IBZM single-photon emission tomography (SPET) scan data obtained from 18 typical antipsychotic treated schizophrenic patients was analysed to evaluate the relationship between striatal D(2) receptor occupancy and the depressive subscale of the Brief Psychiatric Rating Scale (BPRS-D). Striatal D(2) receptor occupancy by typical antipsychotic drugs was significantly positively correlated with BPRS-D scores (r=0.52, p=0.025). This study suggests that high striatal dopamine D(2) blockade by typical antipsychotic drugs may contribute to the emergence of depressive symptoms in typical antipsychotic treated schizophrenic patients.     

The electroencephalographic sleep pattern in schizophrenic patients treated with clozapine or classical antipsychotic drugs

The effects of antipsychotic agents on sleep were tested by examining the nocturnal electroencephalographic recordings of 14 drug-naïve schizophrenic patients and comparing these with recordings from 12 patients treated with clozapine and 10 treated with classical neuroleptics (haloperidol: n=7; flupentixol: n=3). In both of the treated groups, sleep continuity measures and rapid eye movement (REM) density were significantly higher than in the drug-naïve group. Clozapine-treated patients showed significantly more stage two sleep, more stable non-REM sleep (stages two, three and four) and less stage one than patients treated with haloperidol or flupentixol. Clozapine had no effect on the amount of REM sleep. Although mean REM latency was almost twice as long in the clozapine compared with the other two groups, this difference was not statistically significant. The present study suggests considerable differences between the influence of typical and atypical antipsychotic agents on sleep. However, the results of this cross-sectional study should be confirmed using a longitudinal intraindividual approach.     

Central D1- and D2-receptor occupancy during antipsychotic drug treatment

1. It has been unequivocally shown that antipsychotic compounds reduce dopaminergic transmission. A relationship in vitro between the potency for the antipsychotic effect and the blockade of D2-dopamine receptors has been shown. No such relationships have been demonstrated for any other central receptor population. 2. Positron emission tomography (PET) has made it possible to investigate interactions of psychotropic drugs with central receptors in the living human brain. Using the selective D2 receptor antagonist raclopride labelled with positron emitting isotope 11C, it has been shown that chemically distinct classical neuroleptics in conventional doses occupy a high degree (65-89%) of the D2-receptors in the human brain. The results substantiate the opinion that the antipsychotic effects is mediated by a blockade of D2-dopamine receptors. 3. The degree of binding to D1-receptors using the 11C-labelled D1-antagonist from Schering (SCH 23390) as the ligand was also determined. The D1-receptor occupancy seemed to be dependent on the type of the antipsychotic compound studied. 4. The atypical neuroleptic compound clozapine demonstrated a different binding profile than the classical neuroleptics. Thus, clozapine in conventional doses occupied D2-receptors to a smaller extent (40%, 40%, 65%) than classical neuroleptics. The occupation of D1-receptors was higher (40%, 42%) than that of classical compounds (0-36%). 5. The unique clinical profile of clozapine may be related to its potency on both D1- and D2-receptors. The distribution of D1-receptors varies from that of D2-receptors in the human brain which may be one reason for the importance of blocking both D1- and D2-receptors for a full antipsychotic response.     

ADH secretion in schizophrenic patients on antipsychotic drugs

The authors studied antidiuretic hormone (ADH) secretion in schizophrenics on antipsychotic drugs. The mean plasma level of ADH is lower among schizophrenics than among controls at comparable values of plasma osmolality. In regression analysis of the relationship between plasma ADH and plasma osmolality, the slope of the regression line is gentler and the threshold of ADH secretion is lower in schizophrenics than that in control subjects. The authors suggest that the relationship between plasma ADH and plasma osmolality may be different in schizophrenics receiving antipsychotic drugs than in controls.     

An animal model of extrapyramidal side effects induced by antipsychotic drugs: relationship with D2 dopamine receptor occupancy

1. Muscle rigidity was assessed quantitatively and objectively as increases in electromyographic (EMG) activity (muscle rigidity) in the hindlimb muscles of the rat following subcutaneous administration of haloperidol, fluphenazine and thioridazine. 2. Behavioural changes were assessed as increases in the catalepsy score, defined as the time taken for an animal to move off an inclined grid. 3. Increased tonic EMG activity, or the presence of catalepsy was related to the level of occupancy of dopamine D2 receptors in the striatum and substantia nigra of the brain, measured using ex vivo quantitative autoradiography. 4. Increases in tonic EMG activity and the induction of catalepsy were associated with >80% occupancy of striatal and nigral D2 receptors by fluphenazine, while haloperidol increased tonic EMG activity at D2 occupancies of >57%. 5. Thioridazine at doses ranging from 1-15 mg/kg failed to increase EMG activity and occupied <61% of striatal D2 receptors. 6. Overall the findings support the hypothesis that muscle rigidity is observed when a threshold level of D2 receptors in the striatum and substantia nigra are occupied by antipsychotic drugs. 7. This conclusion is consistent with the results of positron emission tomography (PET) studies in humans, and those from our past studies in rats using raclopride, chlorpromazine and clozapine, in which a threshold of approximately 70% striatal and nigral D2 receptor occupancy has been demonstrated.     

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.     

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.     

Serial [18F]N-methylspiroperidol PET studies to measure changes in antipsychotic drug D-2 receptor occupancy in schizophrenic patients

An indirect approach to the relationship among drug dose, plasma level, and the competition between a labeled neuroleptic drug [18F]N-methylspiroperidol (18F-NMS) for binding sites in striatal tissue in normal and schizophrenic subjects is described. The slope of the line plotting the ratio of activity in the striatum (As) to activity in the cerebellum (Ac) versus time up to 5 hr postinjection of 18F-NMS is taken as a marker of site occupancy. An inverse relation between labeled competitor uptake and drug plasma level has been demonstrated for the classes of antipsychotic drug studied. Striatal uptake studies showed a progressive increase in all subjects following drug withdrawal up to 156 hr postwithdrawal. Uptake and clearance of 18F-NMS in cerebellar tissue was not appreciably affected by antipsychotic medication or drug withdrawal.     

Extrastriatal dopamine D2 receptor occupancy in olanzapine-treated patients with schizophrenia

Olanzapine is described as a multi-acting receptor-targeted antipsychotic agent. Although regional differences of dopamine D₂ receptor occupancy, i.e., limbic selectivity, were reported for olanzapine, contradictory results were also reported. We measured dopamine D₂ receptor occupancy of olanzapine in extrastriatal regions in patients with schizophrenia using positron-emission tomography with [¹¹C]FLB457 and the plasma concentrations of olanzapine. Ten patients with schizophrenia taking 5–20 mg/day of olanzapine participated. Dopamine D₂ receptor occupancy in the temporal cortex ranged from 61.1 to 85.8%, and plasma concentration was from 12.7 to 115.4 ng/ml. The ED₅₀ value was 3.4 mg/day for dose and 10.5 ng/ml for plasma concentration. The ED₅₀ values obtained in this study were quite similar to those previously reported in the striatum. In conclusion, although the subjects and methods were different from previous striatal occupancy studies, these results suggest that limbic occupancy by olanzapine may not be so different from that in the striatum.     

Subjective experience and dopamine D2 receptor occupancy in patients treated with antipsychotics: clinical implications.

OBJECTIVES: This paper gives an overview of studies on the association between dopaminergic neurotransmission and the subjective experience of patients with schizophrenia. METHODS: We undertook a review of the literature. RESULTS: Dopaminergic neurotransmission may be relevant for subjective experience. Higher striatal D2 receptor occupancy by typical and atypical antipsychotics is related to worse subjective experience, more severe negative symptoms, and depression. Individuals with lower baseline dopamine function are at an increased risk for dysphoric responses during antipsychotic therapy with dopaminergic-blocking drugs. There is preliminary evidence that a window of striatal D2 receptor occupancy between 60% and 70% is optimal for the subjective experience of patients. These occupancies are often reached even with low dosages of antipsychotic drugs. CONCLUSIONS: Reaching an optimal dopamine D2 receptor occupancy is clinically relevant, since subjective experience associated with antipsychotic medication is related to medication compliance. Antipsychotic drug dosages often need to be lower than levels in common use.     

抗精神病药对首发精神分裂症患者认知功能及事件相关电位的影响

目的:观察抗精神病药对首发精神分裂症患者认知功能和事件相关电位P300的影响.方法:对67例患者(病例组),采用随机对照研究连续观察12周,其中利培酮组32例,奎硫平组35例,另选择正常对照组32名.进行阳性与阴性症状量表(PANSS)、韦氏记忆量表(WMS)和事件相关电位P300的测评.结果:首发精神分裂症患者在长时记忆、短时记忆、瞬时记忆及记忆商数(MQ)受损较为明显,与正常对照组比较差异有显著性(P＜0.05).P300电位成分中P2、N2及P3潜伏期明显延长,P2及P3波幅明显降低,与正常对照组比较差异均有显著性(P均＜0.05).奎硫平组及利培酮组患者治疗后WMS的再认、联想、理解及MQ均明显高于治疗前,两组患者治疗后WMS各项目之间比较差异均无显著性;两组患者在治疗前后P300各指标之间差异无显著性.结论:首发精神分裂症患者存在认知功能障碍,奎硫平与利培酮对首发精神分裂症患者认知功能的作用相当.     

Effects of antipsychotic drugs on memory functions of schizophrenic patients.

In this research we investigated the effects of 4 antipsychotic drugs with different anticholinergic components on different memory functions of schizophrenic patients. Drugs were administered in cumulative doses and memory was tested 90 min after each drug was administered. The results show that chlorpromazine and thioridazine impaired short-term verbal memory after 6 h of sequential administration. Trifluoperazine and haloperidol improved short-term verbal memory from the third to the fifth administration. Immediate memory, long-term memory and visual short-term memory were not impaired by any drug.     

Suggested minimal effective dose of risperidone based on PET-measured D2 and 5-HT2A receptor occupancy in schizophrenic patients.

OBJECTIVE: Multicenter trials with the novel antipsychotic risperidone have suggested a standard dose of 6 mg/day. However, a dose producing the highest response rate in fixed-dose studies is likely to exceed the minimal effective dose in most patients. The aim of this positron emission tomography (PET) study was to suggest a minimal effective dose of risperidone based on measurements of dopamine D2 and serotonin 5-HT2A receptor occupancy. METHOD: Eight first-episode or drug-free schizophrenic patients were treated with risperidone, 6 mg/day, for 4 weeks and then 3 mg/day for 2 weeks. PET was performed after 4 and 6 weeks, with [11C]raclopride to measure D2 receptor occupancy and [11C]N-methylspiperone to measure 5-HT2A receptor occupancy. RESULTS: Seven patients completed the study and responded to treatment with risperidone. No patient had extrapyramidal side effects at the time of inclusion in the study. At the 6-mg/day dose, mean D2 receptor occupancy was 82% (range = 79%-85%), 5-HT2A receptor occupancy was 95% (range = 86%-109%), and six patients had developed extrapyramidal side effects. After dose reduction to 3 mg/day, D2 receptor occupancy was 72% (range = 53%-78%), and 5-HT2A receptor occupancy was 83% (range = 65%-112%). Three patients had extrapyramidal side effects at this time. CONCLUSIONS: Treatment with risperidone, 6 mg/day, is likely to induce unnecessarily high D2 receptor occupancy, with a consequent risk of extrapyramidal side effects. High 5-HT2A receptor occupancy did not prevent extrapyramidal side effects completely. The authors previously suggested an optimal interval for D2 receptor occupancy of 70%-80%. To achieve this, resperidone, 4 mg/day, should be a suitable initial dose for antipsychotic effect with a minimal risk of extrapyramidal side effects in most patients.