Typical and atypical antipsychotic occupancy of D2 and S2 receptors: An autoradiographic analysis in rat brain

In thin sections of rat brain, [3H]spiperone binds to D2 sites in the basal ganglia (caudate-putamen, nucleus accumbens, olfactory tubercle) and S2 sites in the claustrum and motor cortex. The in vitro displacement of [3H]spiperone from these regions was quantified autoradiographically with the "atypical" neuroleptics clozapine and thioridazine, which ameliorate psychosis, a "typical" neuroleptic, haloperidol, which also induces extrapyramidal side effects, or with metoclopramide, which induces extrapyramidal side effects but is an ineffective antipsychotic. Whereas metoclopramide was equipotent at D2 sites, haloperidol was less potent and clozapine and thioridazine more potent by 2- to 3-fold at competing for D2 sites in the nucleus accumbens or olfactory tubercle than in the caudate-putamen. As measured autoradiographically or with tissue homogenates, clozapine, thioridazine, and five other atypical neuroleptics were 4- to 800-times more potent at competing for S2 sites in the frontal cortex than for D2 sites in the basal ganglia. A preference of atypical antipsychotics for D2 receptors in the nucleus accumbens and olfactory tubercle and for the S2 receptor may explain the relative lack of extrapyramidal side effects produced by these compounds.     

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.     

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.     

Central D2-dopamine receptor occupancy in schizophrenic patients treated with antipsychotic drugs

Using positron emission tomography and the carbon 11-labeled ligand raclopride, central D2-dopamine receptor occupancy in the putamen was determined in psychiatric patients treated with clinical doses of psychoactive drugs. Receptor occupancy in drug-treated patients was defined as the percent reduction of specific carbon 11-raclopride binding in relation to the expected binding in the absence of drug treatment. Clinical treatment of schizophrenic patients with 11 chemically distinct antipsychotic drugs (including both classic and atypical neuroleptics such as clozapine) resulted in a 65% to 85% occupancy of D2-dopamine receptors. In a depressed patient treated with the tricyclic antidepressant nortriptyline, no occupancy was found. The time course for receptor occupancy and drug levels was followed after withdrawal of sulpiride or haloperidol. D2-dopamine receptor occupancy remained above 65% for many hours despite a substantial reduction of serum drug concentrations. In a sulpiride-treated patient, the dosage was reduced in four steps over a nine-week period and a curvilinear relationship was demonstrated between central D2-dopamine receptor occupancy and serum drug concentrations. The results demonstrate that clinical doses of all the currently used classes of antipsychotic drugs cause a substantial blockade of central D2-dopamine receptors in humans. This effect appears to be selective for the antipsychotics, since it was not induced by the antidepressant nortriptyline.     

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.     

Antipsychotic occupancy of dopamine receptors in schizophrenia

Antipsychotic drugs were introduced in the early 50s on the basis of clinical observations in patients with schizophrenia. Experimental studies later revealed that antagonism at the D(2) dopamine receptor is a common characteristic of all antipsychotic drugs. In the 80s, the advent of brain imaging technologies such as positron emission tomography (PET) allowed for direct noninvasive studies of drug binding in treated patients. The concept receptor occupancy is defined as the fraction (%) of a receptor population that is occupied during treatment with an unlabelled drug. With regard to antipsychotic drugs, the radioligand [(11) C]-raclopride has been the most widely used for binding to the D(2) /D(3) -dopamine receptors. The present review discusses the contribution from molecular imaging to the current understanding of mechanism of action (MoA) of antipsychotic drugs. Consistent initial PET-findings of high D2-receptor occupancy in the striatum of patients responding to different antipsychotic drug treatments provided clinical support for the dopamine hypothesis of antipsychotic drug action. It has subsequently been demonstrated that patients with extrapyramidal syndromes (EPS) have higher occupancy (above 80%) than patients with good response but no EPS (65-80%). The PET-defined interval for optimal antipsychotic drug treatment has been implemented in the evolvement of dose recommendations for classical as well as more recently developed drugs. Another consistent finding is lower D(2) -occupancy during treatment with the prototype atypical antipsychotic clozapine. The MoA of clozapine remains to be fully understood and may include nondopaminergic mechanisms. A general limitation is that currently available PET-radioligands are not selective for any of the five dopamine receptor subtypes. Current attempts at developing such ligands may provide the tools required to refine further the MoA of antipsychotic drugs.     

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.     

PET imaging of dopamine receptors in human basal ganglia: relevance to mental illness.

The development of PET and in vivo ligand-binding techniques over the past decade has allowed the analysis of dopamine receptor functions in the basal ganglia of human subjects. Using ligands selective for the different subtypes of dopamine receptors, their gross distribution, total number of binding sites and affinity have been determined in the caudate-putamen of the living human brain. Recent studies in young, drug-naive schizophrenic patients failed to demonstrate a consistent alteration in the densities or affinities of D2 dopamine receptors in the basal ganglia of these subjects, contradicting the view that elevated densities of D2 dopamine receptors are a major pathophysiological mechanism in this disorder. PET measurements of D2 dopamine receptor occupancy in relation to clinical antipsychotic drug treatment demonstrated that all chemically different categories of antipsychotic drugs induced a marked occupancy of D2 dopamine receptors. This effect was dose-dependent and fully reversible. It appeared earlier than the antipsychotic effect and was also present in neuroleptic-resistant patients. Resistance to neuroleptic drugs is in all probability related to heterogeneity of biological factors causing schizophrenia. Some, but not all, antipsychotic drugs also induced a significant D1 dopamine receptor occupancy. This effect was most marked for the unconventional drug clozapine, which showed about the same degree of D1 as D2 dopamine receptor blockade when given in clinical doses.     

Equivalent occupancy of dopamine D1 and D2 receptors with clozapine: differentiation from other atypical antipsychotics

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

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.     

Clozapine for refractory schizophrenia: an open study of 14 patients treated up to 2 years

Clozapine is a novel antipsychotic agent that selectively blocks mesolimbic--rather than nigrostriatal--dopamine receptors, causes fewer extrapyramidal symptoms than do other neuroleptics, and has superior antipsychotic efficacy in some patients. However, clozapine also causes agranulocytosis more frequently than do other neuroleptics. The evidence documenting the superior benefits obtained with clozapine has primarily involved short-term (4-6 weeks) trials, and the systematic evaluation of long-term clozapine use has been limited. In this study, 14 patients with refractory chronic schizophrenia were treated openly with clozapine up to 2 years; 8 did substantially better when given clozapine than they had when given other neuroleptics. That finding suggests that clozapine may provide a useful addition to the therapeutic armamentarium for the long-term treatment of schizophrenia, despite the increased risks and the need for frequent blood tests.     

Mechanism of new antipsychotic medications: occupancy is not just antagonism

Antagonism of D2-like dopamine receptors is the putative mechanism underlying the antipsychotic efficacy of psychotropic drugs. Positron emission tomographic studies suggest that the antipsychotic effect of dopamine receptor antagonists occurs within a therapeutic window between 60% and 80% (striatal) D2 receptor occupancy. The incidence of extrapyramidal side effects increases above the 80% threshold. However, the novel atypical antipsychotic drug, aripiprazole, occupies up to 95% of striatal D2-like dopamine receptors at clinical doses, and the incidence of extrapyramidal side effects with aripiprazole is no higher than with placebo. The most likely explanation for this finding is aripiprazole's weak partial agonism at D2-like dopamine receptors. This particular pharmacologic feature characterizes a new class of atypical antipsychotics that does not match the original concept of a therapeutic occupancy window for antagonist antipsychotics. When not involving pure antagonists, it implies a need to adjust the expected receptor occupancy (measured using positron emission tomography) for the therapeutic window.     

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.     

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 neurochemical basis for the antipsychotic activity of loxapine: interactions with dopamine D1, D2, D4 and serotonin 5-HT2 receptor subtypes.

Loxapine is a typical neuroleptic that shows great structural and functional homology to the atypical antipsychotic clozapine. Chronic loxapine treatment is usually associated with extrapyramidal symptoms (EPS), whereas clozapine treatment is not. Conversely, loxapine does not produce the agranulocytosis that often results from protracted clozapine treatment. Earlier studies of loxapine have usually implicated D2 receptor blockade as the cause of the tardive dyskinesia that occurs with chronic treatment. More recently, loxapine's ability to potentiate serotonergic neurotransmission has also been implicated. In this study, the pharmacological affinities of loxapine for the dopamine D1, D2, D4, as well as serotonin-2 (5-HT2) and NMDA receptor subtypes, were investigated through direct radioreceptor assays. The findings indicate that loxapine displays an extremely strong binding affinity for dopamine D4 and serotonin 5-HT2 receptors, which suggests that both serotonergic and dopaminergic mechanisms contribute to the antipsychotic drug action and EPS associated with loxapine in the treatment of schizophrenia.     

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.     

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.     

The effect of chronic treatment with typical and atypical antipsychotics on working memory and jaw movements in three- and eighteen-month-old rats

The effects of chronic treatment with typical and atypical antipsychotics on acquisition, working memory, motor activity, and rat tardive dyskinesia (TD) were studied in 3- and 18-month-old Sprague-Dawley rats. Acquisition and working memory were studied in eight-arm radial mazes. TD liability of antipsychotic drugs (APD) was evaluated in rat model of TD in which spontaneous repetitive jaw movements (RJM) occur during withdrawal from neuroleptic treatment. Motor behavior was assessed using the traverse beam test. D1 and D2 receptor occupancy was determined in the rat brain during treatment with typical and atypical antipsychotics. Chronic administration of clozapine, haloperidol, and risperidone impaired acquisition of the eight-arm radial maze in both young and aging rats while olanzapine had no effect. Retention tests showed that aging rats made more errors than the adults and that the antipsychotics haloperidol and risperidone significantly impaired retention in both age groups. Evaluation of motor behavior revealed that typical and atypical antipsychotics used in comparable doses in young rats had no effect on motor behavior, whereas in aging rats performance was impaired by clozapine, haloperidol, and risperidone but not by olanzapine. RJM responses were increased during washout from haloperidol treatment in young and aging rats whereas olanzapine, clozapine, and risperidone had no effect. D2 receptor occupancy in haloperidol- and risperidone-treated rats was above 70% while olanzapine and clozapine receptor occupancy was below 70%, which is the threshold for the appearance of extrapyramidal syndrome (EPS) and TD.     

Increasing D2 affinity results in the loss of clozapine's atypical antipsychotic action

Typical antipsychotics (haloperidol) give rise to severe motor side-effects while atypical antipsychotics like clozapine do not. Action at several neurotransmitter receptors have been implicated. To identify the critical mechanisms involved we synthesized an 8-C1 isomer of clozapine which showed an equivalent affinity to clozapine on multiple receptors (5-HT1A, 5-HT2, D1, D4, M1) but differed in having a 10-fold higher affinity at the dopamine D2/3 receptor. When tested in a series of animal models indicative of the typical/atypical distinction (catalepsy, striatal gene-induction, prolactin elevation) isoclozapine lost atypical properties and behaved like a typical antipsychotic. Simultaneous in vivo receptor occupancy studies confirmed that alterations in D2 receptor occupancy were most closely related to loss of atypicality by clozapine's isomer isoclozapine. The implications for the design of future antipsychotics is discussed.     

Striatal D2/D3 receptor occupancy, clinical response and side effects with amisulpride: an iodine-123-iodobenzamide SPET study

INTRODUCTION: Amisulpride appears to be an effective atypical agent for treating schizophrenia in a dose-dependent manner. METHODS: 29 patients suffering from schizophrenia or schizoaffective disorder were treated with a broad dose range of amisulpride (50-1 200 mg/day, mean: 455.2+/-278.8 mg/day). After 2 weeks, brain single photon emission tomography (SPET) scans were performed two hours after intravenous injection of 185 MBq [ (123)I]IBZM. Clinical evaluations and ratings of extrapyramidal symptoms were performed at baseline and after steady state treatment of two weeks with amisulpride. RESULTS: In patients treated with amisulpride, specific binding of [ (123)I]IBZM to D2 receptors was significantly decreased (p<0.001) compared to healthy controls. D2 receptor blockade correlated well with administered doses and plasma concentrations of amisulpride. Extrapyramidal side effects, which had to be treated with biperiden, were observed in 31% of the patients. Clinical response was very good, without correlation between the response and striatal D2 occupancy. DISCUSSION: Within the first two weeks of treatment with the atypical antipsychotic amisulpride a significant occupancy of striatal postsynaptic dopamine D2 receptors was achieved. At the same time amisulpride shows an excellent tolerability with good efficacy.