Evaluation of SCH 39166 as PET ligand for central D1 dopamine receptor binding and occupancy in man

SCH 39166 is the first selective D₁-dopamine receptor antagonist developed for clinical trials in schizophrenia. SCH 39166 was evaluated as a radioligand for PET, labeled with¹¹C, and as a D₁-dopamine receptor antagonist after single oral doses in healthy men. After intravenous injection of [¹¹C]SCH 39166 distribution of radioactivity in brain grossly reflected D₁-dopamine receptor density. The putamen to cerebellum ratio at equilibrium was low (1.54±0.18 SD), which makes [¹¹C]SCH 39166 less suitable as a radioligand for applied PET studies. Saturability of specific binding was demonstrated after IV injection of [¹¹C]SCH 39166 with low specific radioactivity. Stereospecificity of binding was examined using the stereoisomer [¹¹C]SCH 39165. D₁-Receptor occupancy was demonstrated with [¹¹C]SCH 39166 2 h after administration of single oral doses of unlabeled SCH 39166 to each of three healthy subjects (25, 100 and 400 mg). There was a substantial reduction of specific [¹¹C]SCH 39166 uptake in the putamen after all doses. Single oral doses of 100 mg induced approximately 70% D₁-dopamine receptor occupancy in the basal ganglia, which should be sufficient to investigate the antipsychotic potential of D₁-dopamine receptor antagonism in clinical studies.     

PET analysis of human dopamine receptor subtypes using 11C-SCH 23390 and 11C-raclopride

Tracer doses of ¹¹C-SCH 23390 and ¹¹C-raclopride, selective D1-dopamine and D2-dopamine receptor antagonists, respectively, were injected intravenously into three healthy male volunteers and two drug-treated schizophrenic patients. Regional radioactivity in brain and plasma was followed during 1 h by positron emission tomography (PET). After injection of both ligands a high accumulation of radioactivity was observed in the dopamine-rich caudate putamen. Experiments with ¹¹C-SCH 23390, but not ¹¹C-raclopride, showed a conspicuous accumulation of radioactivity also in the neocortex. None of the ligands accumulated in the dopamine-poor cerebellum. Specific binding of ¹¹C-raclopride in the putamen was reduced by more than 80% in schizophrenic patients treated with antipsychotic doses of sulpiride or cis(Z)-flupentixol decanoate. ¹¹C-SCH 23390 binding was slightly reduced in both the cortex and the putamen after treatment with cis(Z)-flupentixol decanoate but not after sulpiride. The results indicate that clinical antipsychotic drug treatment with sulpiride and cis(Z)-flupentixol decanoate causes a substantial blockade of D2-dopamine receptors in the basal ganglia but has only a minor effect on D1-dopamine receptors.     

PET examination of [11C]NNC 687 and [11C]NNC 756 as new radioligands for the D1-dopamine receptor

The benzazepines NNC 687 and NNC 756 have in animal studies been described as selective D₁-dopamine receptor antagonists. Both compounds have been labeled with¹¹C for examination by positron emission tomography (PET). In the present study central receptor binding was studied in monkeys and healthy men. After IV injection of both radioligands in Cynomolgus monkeys radioactivity accumulated markedly in the striatum, a region with a high density of D₁-dopamine receptors. This striatal uptake was displaced by high doses of the selective D₁-antagonist SCH 23390 (2 mg/kg) but not by the 5HT₂-antagonist ketanserin (1.5 mg/kg) or the selective D₂-antagonist raclopride (3 mg/kg). The cortical uptake after injection of [¹¹C]NNC 687 was not reduced in displacement experiments with ketanserin. The cortical uptake of [¹¹C]NNC 756 was reduced in displacement and protection experiments with ketanserin by 24–28% (1.5 mg/kg), whereas no reduction could be demonstrated on striatal uptake. In healthy males both compounds accumulated markedly in the striatum. For [¹¹C]NNC 687 the ratio of radioactivity in the putamen to cerebellum was about 1.5. For [¹¹C]NNC 756 the ratio was about 5. This ratio of 5 for [¹¹C]NNC 756 is the highest obtained so far for PET radioligands for the D₁-dopamine receptor.     

Lack of apparent antipsychotic effect of the D1-dopamine recepotr antagonist SCH39166 in acutely ill schizophrenic patients

SCH 39166 is the first selective D₁ dopamine receptor antagonist developed for the treatment of schizophrenic patients. To examine potential antipsychotic effect, tolerability and safety, SCH 39166 was given orally to 17 acutely ill drug free schizophrenic patients (DSMIII_R) in an open 4-week study. Doses were escalated from 10 to 100 mg b.i.d. according to a fixed schedule over 17 days and remained at 100 mg b.i.d. for another 11 days. The drug was withdrawn prematurely in ten patients because of deterioration or refusal to take SCH 39166. In the nine patients participating for more than 2 weeks, none had an apparent reduction of BPRS or CGI scores. Side effects were agitation, akathisia and emesis in single patients. After withdrawal of SCH 39166 of the patients improved when treated with classical neuroleptics or clozapine. The result of the study does not support the prediction that selective D₁ dopamine receptor antagonism will produce antipsychotic effects in schizophrenia     

[11C]Ro 15-4513, a ligand for visualization of benzodiazepine receptor binding

Ro 15-4513, a partial inverse agonist at the benzodiazepine (BZ) receptor site was labelled with¹¹C and used for in vitro autoradiography on human post mortem brain sections and for positron emission tomography (PET) on Cynomolgus monkeys. The total radiochemical yield of [¹¹C]Ro 15-4513 was 30–40% with an overall synthesis time of 40 min. The specific radioactivity was about 1000 Ci/mmol at end of synthesis. In vitro autoradiography showed that [¹¹C]Ro 15-4513 bound specifically predominately in the neocortex of the human brain. Specific binding was also demonstrated in the basal ganglia and the cerebellar cortex. Flumazenil (Ro 15-1788) and clonazepam inhibited the binding in cerebral regions, but a significant proportion in the cerebellum was not inhibited by these agents. This proportion may represent ₆-containing BZ receptors. PET examination of [¹¹C]Ro 15-4513 binding in Cynomolgus monkeys demonstrated high uptake of radioactivity in neocortex. The uptake of radioactivity was markedly displaced by high doses of Ro 15-4513 or clonazepam. [¹¹C]Ro 15-4513 should be a useful ligand to examine BZ receptor characteristics in the living human brain by PET.     

Oral administration of NNC 756 — a placebo controlled PET study of D1-dopamine receptor occupancy and pharmacodynamics in man

NNC 756 is a new benzazepine with high affinity and selectivity for D₁-dopamine receptors. In a double-blind, placebo controlled, cross-over study, positron emission tomography and the radioligand [¹¹C]SCH 23390 were used to determine central D₁-do-pamine receptor occupancy after a single oral dose of 80 mg NNC 756 in three healthy men. NNC 756 induced 75, 66 and 47% occupancy of D₁-dopamine receptors in the putamen of at 1.5 h after drug administration and 46, 36 and 24% after 7.5 h. There was a hyperbolic relationship between the occupancy values and the serum concentrations. The K_i value for the hyperbola was 6.4 ng/ml (±SD 1.4). The occupancy at 1.5 h is on the same level as that shown to induce effects in animal models for prediction of antipsychotic effect. Restlessness (akathisia) appeared in two subjects and nausea in one subject at time of peak drug concentration in serum. The oral dose level of 80 mg should be appropriate to investigate the potential antipsychotic effect of NNC 756.     

Receptor binding of N-(methyl-11C) clozapine in the brain of rhesus monkey studied by positron emission tomography (PET)

By means of positron emission tomography the uptake and kinetics of N-(methyl-¹¹C)clozapine in different brain regions have been studied in Rhesus monkeys. ¹¹C-clozapine rapidly entered the brain and maximum radioactive uptake was seen 5–12 min after administration. Highest uptake was measured in the striatum. Other regions with an uptake higher than in the cerebellum were thalamus and mesencephalon. The radioactivity from different brain regions decreased with an elimination half-life of about 5 h and parallelled the plasma kinetics of unlabelled clozapine. The striatum/cerebellum ratio of ¹¹C-clozapine-derived radioactivity remained constant during the period studied and did not change after pretreatment with atropine. In contrast, the striatum/cerebellum ratio was somewhat lower after pretreatment with N-methylspiperone (NMSP), indicating competition for the same binding sites in the striatum. After pretreatment with increasing doses of clozapine, a dose-dependent protection of binding sites in the striatum for ¹¹C-NMSP was seen. It is concluded that clozapine is more loosely bound to dopamine receptors in the striatum than N-methylspiperone and that the kinetics of clozapine in the brain parallel that in the plasma. The binding properties of clozapine within the brain may explain some of the clinical properties of the drug.     

Savoxepine: striatal dopamine-D2 receptor occupancy in human volunteers measured using positron emission tomography (PET)

Summary The extent and duration of striatal dopamine-D₂ receptor occupancy by savoxepine in humans has been studied using positron emission tomography with [¹¹C]-raclopride, in order to investigate why the anticipated favourable ratio between its extrapyramidal and antipsychotic effects was not achieved in practice.After 0.25 mg savoxepine, striatal D₂ receptor occupancy peaked at 50–60% after 24–36 h and disappeared within 6 days. After doses of 0.1 mg to 0.5 mg, D₂ receptor occupancy in the putamen and caudate nucleus increased from 20 to 70% 3–7 h after administration and amounted to 40 to 75% at the peak time (20–29 h).This suggests that cumulative D₂ receptor blockade would occur if equal or increasing doses of savoxepine were given repeatedly. Extrapyramidal adverse-effects would be likely to occur under such circumstances. An adequate test of the theory that preference for hippocampal dopamine D₂ receptors with afford a good therapeutic ratio requires an alternative dosing regimen.     

Differential effects of the D1-DA receptor antagonist SCH39166 on positive and negative symptoms of schizophrenia

In the present open study the effects of the D₁-dopamine antagonist SCH 39166 on positive and negative symptoms of schizophrenia (DSM-IIIR) were investigated. SCH 39166 was given orally according to a fixed dosage schedule (day 1: 25 mg b.i.d; day 4: 50 mg b.i.d.; day 7: 100 mg b.i.d; day 18: 200 mg b.i.d.; day 21: 225 mg b.i.d.). Seven patients completed 2 weeks, and five patients completed the study. The reason for premature withdrawal was lack of efficacy or refusal to take SCH 39166. In none of the patients a reduction of the BPRS or CGI score was found. As measured with the PANSS, a significant reduction was observed in the score of the negative subscale, whereas the positive symptoms scale and general psychopathology score remained unaffected. Akathisia, rigidity and hypokinesia were reported occasionally, although only mild in severity. The results of the present study do not support the hypothesis that D₁-dopamine antagonists are clinically effective antipsychotics in schizophrenia, considering the fact that SCH 39166 had no effect on positive symptoms. The present study provides circumstantial evidence for an effect of SCH 39166 on negative symptoms.     

An open trial of the D1 antagonist SCH 39166 in six cases of acute psychotic states

Six psychotic patients were included in a four-week study of the effects of the D₁ selective antagonist SCH 39166 given as monotherapy. Four had a diagnosis of schizophrenia, and two suffered from a schizoaffective disorder. All presented with an acute psychotic exacerbation at the beginning of the trial. SCH 39166 was progressively increased from 50 mg/day to 600 mg/day. In the four schizophrenic patients, the BPRS worsened, and three out of the four failed to complete the study because of this. Three schizophrenic patients were aggressive or violent after abrupt discontinuation of treatment. In the two patients with schizoaffective disorder the BPRS improved during the trial, but they had an acute relapse immediately after treatment discontinuation. Extrapyramidal symptoms improved in three of the six patients, and worsened in one.     

D1 dopamine receptor binding in mood disorders measured by positron emission tomography

D₁ dopamine receptor binding in mood disorders was studied by positron emission tomography (PET) using¹¹C-SCH23390. Ten patients with bipolar mood disorders and 21 normal controls were studied in the drug-free state. The patients were in euthymic (N=6), depressed (N=3) and manic (N=1) states. Regional radioactivity in the brain was followed for 40 min by PET. A two-compartment model was used to obtain the binding potential (k₃/k₄) for the striatum and frontal cortex. The binding potentials for the frontal cortex for the patients were significantly lower than those for normal controls, whereas those for striatum were not significantly different. These findings suggest that D₁ dopamine receptors in the frontal cortex may be in a different state in patients with bipolar mood disorders.Preliminary results of this study were presented at the 17th Congress of Collegium Internationale Neuro-Psychopharmacologicum, Kyoto International Conference Hall, Kyoto, Japan, September 10–14, 1990     

Stereoselective binding of 11C-labelled piquindone (Ro 22–1319) to dopamine-D2 receptors in the living human brain

The stereoenantiomers of piquindone (Ro 22–1319), a new antipsychotic pyrroloisoquinoline derivative, were labelled with the positron-emitting isotope ¹¹C. Only the (?)-enantiomer inherits most of the biological activity of racemic piquindone. The compounds were examined by positron emission tomography (PET) for dopamine-D2 receptor binding in the living brain of Cynomolgus monkeys and healthy human subjects. After i.v. administration of tracer doses the (?)-enantiomer but not the (+)-enantiomer was shown to accumulate markedly in the dopamine-D2 receptor rich caudate/putamen in both species. After (?) ¹¹C piquindone injection, radioactivity in the human caudate/putamen, and the putamen/cerebellar activity ratio increased to about 2 during the hour when radioactivity could be followed. (?)¹¹C piquindone binding in the monkey putamen was not easily displaceable by haloperidol. The results demonstrate that (?) but not (+)-¹¹C piquindone has a high affinity for dopamine-D2 receptors in the living human brain. The results are compatible with the view that clinical administration of piquindone produces a long-lasting effect on central dopamine-D2 receptors. (?)¹¹C Piquindone is a useful ligand for visualization of dopamine-D2 receptor binding by PET and for analysing relationships between antipsychotic effects of piquindone and blockade of specific binding sites in the brain of schizophrenic patients.     

Striatal dopamine D<Subscript>2</Subscript> receptors in medication-naive patients with major depressive disorder as assessed with [<Superscript>11</Superscript>C]raclopride PET

Rationale Among other monoamine neurotransmitters, dopamine is implicated in the pathophysiology of major depression. Experimental studies suggest the involvement of the mesolimbic dopamine system in the mechanism of action of antidepressant drugs. Previous in vivo imaging studies have studied striatal dopamine D₂ receptor availability in depression but the results are equivocal thus far. Objective To study the striatal and thalamic dopamine D₂ receptor availability in drug-naive patients with major depression was the aim of this study. Materials and methods Caudate, putamen, and thalamic dopamine D₂ receptor availability was estimated using positron emission tomography and [¹¹C]raclopride in 25 treatment-seeking drug-free patients (of whom 24 were drug-naive) with major depression (primary care patients) as well as in 19 demographically similar healthy control subjects. Receptor availability was expressed as the binding potential (BP_ND), and analyses were carried out based on both regional and voxel-level BP_ND estimates. Results No statistically significant differences in [¹¹C]raclopride BP_ND were observed between the groups either in the caudate nucleus (+1.7%, CI −4.8% to +8.3%), putamen (−1.0%, CI −7.2% to 5.1%), thalamus (−2.4%, CI −8.7% to 4.0%), or ventral striatum (−3.8%, CI −9.3% to +1.6%). In the patients, depressive symptoms were not associated with [¹¹C]raclopride BP_ND in any region. Conclusions The findings in this sample of treatment-seeking, drug-naive and predominantly first-episode patients with major depression do not support the involvement of striatal dopamine D₂ receptors in the pathophysiology of the illness, but do not exclude the potential importance of dopaminergic mechanisms in antidepressant drug action.     

Determination of plasma and brain concentrations of SCH 39166 and their correlation to conditioned avoidance behavior in rats

Plasma and brain concentrations of the dopamine D₁ receptor antagonist, SCH 39166, were measured and compared to behavioral activity in the conditioned avoidance response paradigm (CAR). SCH 39166 was administered at two behaviorally active doses (1 mg/kg, SC and 10 mg/kg, PO) and the time course for CAR activity was compared with the plasma and brain concentrations of unconjugated SCH 39166. Conjugation andN-demethylation of SCH 39166 after oral administration were also determined and first pass metabolism examined. Results from these studies demonstrated a similar time-dependent disappearance of unconjugated SCH 39166 from both the plasma and brain, independent of route of administration. Brain concentrations of SCH 39166 were approximately 5-fold higher than corresponding plasma concentrations, regardless of route. However, plasma and brain concentrations of unconjugated SCH 39166 were higher after SC administration of 1.0 mg/kg, than after PO administration of 10 mg/kg, suggesting a substantial first pass metabolism of SCH 39166. In addition, total (conjugated and unconjugated) plasma concentrations of SCH 39166 were at least 10-fold higher than unconjugated concentrations of SCH 39166 after PO administration of 10 mg/kg, demonstrating that a high proportion of drug was conjugated. Metabolism to theN-desmethyl analog, SCH 40853, was observed after PO administration of 10 mg/kg SCH 39166 and a high proportion of conjugation of the desmethyl analog was also seen. Finally, plasma concentrations of unconjugated SCH 39166 exhibited a high positive correlation (r=0.934,P<0.001) with brain concentrations of unconjugated SCH 39166. Behavioral activity in the CAR was also positively correlated with plasma concentrations (r=0.95,P<0.001) and brain concentrations (r=0.88,P<0.001) of unconjugated SCH 39166.     

Striatal D2 dopamine receptor binding characteristics in vivo in patients with alcohol dependence

Striatal D₂ dopamine receptor characteristics of nine male patients with alcohol dependence abstinent for 1–68 weeks and eight healthy male volunteers were studied in vivo with positron emission tomography. The selective D₂ receptor ligand [¹¹C]raclopride and equilibrium model was used for D₂ receptor density (B_max) and affinity (K_d) measurements. A trend for a decreased striatal D₂ receptor density and for reduced D₂ receptor affinity was observed in patients with alcohol dependence. These parameters were not statistically significantly different between alcoholics and controls, but the ratio between D₂ receptor density and affinity (B_max/K_d or the striatum/cerebellum ratio from the high specific activity scan) was highly significantly lower in alcoholics than that of controls. In conclusion, the low D₂ dopamine receptor B_max/K_d ratio (striatum/cerebellum ratio) indicates that specific aspects of striatal [¹¹C]raclopride binding in vivo are deviant in alcoholics compared to controls. The result is compatible with a reduced avidity of striatal dopamine D₂ receptors in alcoholics, which is in line with the idea that D₂ dopaminergic mechanisms are involved in the biology of alcohol dependence in man.     

Selective D1- and D2-dopamine receptor blockade both induces akathisia in humans — a PET study with [11C]SCH 23390 and [11C]raclopride

Pharmacological effects were recorded and time course for receptor binding in brain was followed by positron emission tomography after IV injection of the selective D₁-dopamine receptor antagonist SCH 23390 in four healthy subjects in doses of 310–810 µg. Akathisia, the syndrome of motor restlessness, appeared after the three highest doses. The akathisia was transient and occurred only when [¹¹C]SCH 23390 binding in the basal ganglia was at a high level with a central D₁-dopamine receptor occupancy of 45–59%. The D₂-dopamine receptor antagonist [¹¹C]raclopride was injected IV into 20 healthy subjects and 13 schizophrenic patients. Akathisia appeared in 14 healthy subjects and 7 patients and coincided with maximal [¹¹C]raclopride binding in the basal ganglia. The findings for [¹¹C]raclopride and [¹¹C]SCH 23390 are the first demonstration of a relationship between time courses for radioligand binding in the human brain and simultaneously induced pharmacological effects.     

Dose dependent occupancy of central dopamine D2 receptors by the novel neuroleptic CP-88,059-01: a study using positron emission tomography and11C-raclopride

Positron emission tomography (PET) and¹¹C-raclopride were used to measure the occupancy of central dopamine D₂ receptors by a new neuroleptic, CP-88,059-1. In a double blind dose escalation study, seven healthy male subjects received a predose of between 2 mg and 60 mg CP-88,059-1, 5 h before PET scanning. One additional subject was assigned to placebo predose. Receptor occupancy was defined as the percentage reduction in binding potential compared with that seen in the subject predosed with placebo and with that seen in seven unmedicated normal volunteers previously studied. Binding of¹¹C-raclopride decreased in a dose dependent manner, and 85% dopamine D₂ receptor occupancy was achieved with the highest dose of CP-88,059-1. The findings confirm that brain dopamine D₂ receptors are blocked by CP-88,059-1 and suggest that an effective antipsychotic dose will be between 20 mg and 40 mg. The study highlights the potential of positron emission tomography in the preclinical evaluation of new drugs.     

PET analysis of alcohol interaction with the brain disposition of [11C]flumazenil

Acute alcohol administration to rats has in preliminary studies been reported to drastically increase the binding of the benzodiazepine (BZ) receptor antagonist [³H]flumazenil (Ro 15-1788) to central BZ receptors. In the present study the effect of acute alcohol ingestion on the disposition of [¹¹C]flumazenil in the human brain and plasma was examined by positron emission tomography (PET) in four healthy volunteers. Neocortex, cerebellum and pons (reference region) were delineated using X-ray computerized tomography (CT). Alcohol did not increase either total radioactivity uptake or specific [¹¹C]flumazenil binding in neocortex or cerebellum. However, alcohol had a small but significant effect on [¹¹C]flumazenil in arterial blood. After alcohol the plasma radioactivity peak was higher, more narrow and occurred earlier than in the control experiments. The present experiments contradict the view that alcohol directly affects central BZ receptor binding in man. Thus the dramatic increase of flumazenil binding in rat brain reported previously could not be observed in the human brain.     

A PET study of D1-like dopamine receptor ligand binding

Rationale: Several positron emission tomography (PET) studies have shown that radioligand binding to D₂-like dopamine receptors competes with endogenous dopamine. Objective: The purpose of this PET study was to examine the effect of amphetamine and reserpine on D₁-like dopamine receptor binding. Methods: Three Cynomolgus monkeys were examined with the radioligands [¹¹C]SCH 23390 or [¹¹C]NNC 112 at baseline condition and after pretreatment with amphetamine (2 mg/kg IV). The B/F values (binding potential) in the striatum and the neocortex were calculated at transient equilibrium. In two monkeys, the effect of the long-lasting dopamine depletion after reserpine (1 mg/kg IV) was followed by a repeated Scatchard procedure in up to 77 days after drug administration. The Scatchard analysis was based on two PET measurements with high and low specific radioactivity and allowed the calculation of D₁-like dopamine receptor density (B_max) and apparent affinity (K_D ^app). Results: The effect of amphetamine on the B/F values was between –14 and 6%. These changes can be considered as within the range of the test-retest reliability. Thus, there was no evident effect of amphetamine-induced dopamine release on D₁-like dopamine receptor binding. Five hours after reserpine administration, there was no change in B_max or K_D ^app. At 3, 23, and 28 days after reserpine administration, the Scatchard analyses indicated a 13–20% reduction in B_max without any evident change in K_D ^app in both the striatum and the neocortex. Conclusions: The lack of evident effects of amphetamine and reserpine on D₁-like dopamine receptor binding is markedly different from the 20% amphetamine-induced decrease and 50% reserpine-induced increase that has been consistently reported for D₂-like dopamine receptor binding. The data indicated that D₁-like dopamine receptor occupancy of endogenous dopamine is low at physiological condition. It is thus unlikely that D₁-like dopamine receptor radioligands can be used to measure changes in the concentration of endogenous dopamine. Received: 8 March 1999 / Final version: 12 May 1999     

5-HT2 and D2 dopamine receptor occupancy in the living human brain

It has been suggested that a combined blockade of 5-HT₂ and D₂ dopamine receptors may be superior to D₂ dopamine antagonists alone in the treatment of schizophrenia. Risperidone, which has a high affinity for 5-HT₂ and D₂ dopamine receptors in vitro, is a new antipsychotic drug that has been developed according to this hypothesis. The aim of this study was to examine if risperidone indeed induces 5-HT₂ and D₂ dopamine receptor occupancy in vivo in humans. Central receptor occupancy was examined by positron emission tomography (PET) in three healthy men after oral administration of 1 mg risperidone. [¹¹C]N-methylspiperone ([¹¹C]NMSP) was used as a radioligand for determination of 5-HT₂ receptor occupancy in the neocortex. Both an equilibrium ratio analysis and a kinetic three-compartmental analysis indicated a 5-HT₂ receptor occupancy about 60%. [¹¹C]raclopride was used as a radioligand for determination of D₂ dopamine receptor occupancy in the striatum and the calculated occupancy was about 50%. This is the first quantitative determination of 5-HT₂ receptor occupancy induced by an antipsychotic drug in the living human brain. The results indicate that 5-HT₂ receptor occupancy should be very high at the dose level of 4–10 mg risperidone daily, as suggested for clinical use. Risperidone is thus an appropriate compound for clinical evaluation of the benefit of combined 5-HT₂ and D₂ dopamine receptor blockade in the treatment of schizophrenia.This paper was presented in part at the XVIIIth C.I.N.P. Congress, Nice, France, 28th June-2nd July 1992.