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 (DSMIIIR) 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 The drug was withdrawn prematurely in ten patients because of deterioration or refusal to take SCH 39166.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.

Schizophrenic patients were treated with fixed doses of sulpiride (800 mg) or chlorpromazine (400 mg) during eight weeks using a double-blind design. In order to examine relationships between pharmacokinetic, clinical and biochemical parameters in relation to treatment the following variables were recorded before and 1, 2, 4 and 8 weeks after treatment. Concentrations of sulpiride, CPZ, 7-OH-CPZ, nor,-CPZ were determined in serum and CSF using liquid chromatography and mass fragmentography. Clinical variables were psychotic morbidity and side effects as evaluated by CPRS, NOSIE and side effect ratings. Monoaminergic variables were concentrations of the major cerebral monoamine metabolites, HVA, 5-HIAA and MOPEG in the cerebrospinal fluid as measured by mass fragmentography. Prolactin levels in serum and CSF were measured by radioimmunoassay.During steady state, concentrations of sulpiride in serum varied fourfold between patients and CPZ twentyfold. Drug concentrations in serum and CSF were highly correlated in CPZ-but not in sulpiride-treated patients. Although sulpiride passed into the CSF, transport between serum and CSF was restricted. In the sulpiride group, improvement of psychotic morbidity and HVA elevation in CSF tended to be negatively related to the drug concentrations in serum. Sulpiride-treated patients with extrapyramidal side effects had significantly higher drug concentrations in serum.In CPZ-treated patients, improvement of psychotic morbidity, HVA elevation and prolactin elevation all tended to be positively correlated to drug concentrations in serum and CSF. CPZ-treated patients with extrapyramidal side effects also had significantly higher CPZ concentrations in serum.In both treatment groups, the MOPEG reduction in CSF tended to be correlated to improvement of psychotic morbidity.The study supplied clinical evidence for the view that antipsychotic drugs belonging to the phenothiazine and benzamide series induce antipsychotic effects in schizophrenic patients in a graded fashion which is proportional to the degree of interaction with the central dopaminergic mechanisms. The results also support the view that sulpiride has a more selective effect on central dopaminergic mechanisms than chlorpromazine.In the schizophrenic patients studied and with the doses used, sulpiride concentrations tended to be maximal with regard to clinical and biochemical effects. For CPZ on the other hand, drug concentrations in some patients seemed to be too low to induce optimal effects.

Schizophrenic patients were treated with the dopamine (DA)-2 receptor blocking drug sulpiride (800 mg daily) or the non-selective DA receptor blocking compound chlorpromazine (400 mg daily). Samples of lumbar cerebrospinal fluid (CSF) and blood were drawn before and after 1 , 2 , 4 and 8 weeks of treatment. Concentrations of the monoamine metabolites HVA, MOPEG and 5-HIAA in CSF and of prolactin (PRL) in CSF and serum were determined.In both treatment groups there were significant and similar elevations of HVA concentrations. HVA levels reached peaks after 1 to 2 weeks treatment and subsequently declined almost to the pretreatment level after 8 weeks. CSF and serum levels of PRL reached maximal levels within 2 weeks and remained stable at that level in both treatment groups. There were significantly higher PRL levels in sulpiride-than in chlorpromazine-treated patients, Women had higher PRL elevations in CSF in both treatment groups. The HVAPRL ratio in CSF was significantly reduced in the sulpiride but not in the chlorpromazine group. After 1 week there was a significantly elevated 5-HIAA level in the chlorpromazine but not in the sulpiride group. In both groups, the MOPEG concentrations were significantly reduced in relation to pretreatment levels. The reduction was significantly more pronounced in the chlorpromazine group.The results indicate that sulpiride affects central DA metabolism in a similar way as chlorpromazine when administered in doses that induce antipsychotic effects. After both drugs evidence was obtained for the development of tolerance to the effect on the receptors that regulate HVA levels in the CSF but not to receptors regulating PRL release. The different effects of the drugs on PRL, 5-HIAA and MOPEG levels indicate that sulpiride has a more specific effect than chlorpromazine on dopaminergic mechanisms.

To evaluate the clinical potential of sulpiride for the treatment of schizophrenic patients, a double‐blind study was performed comparing fixed doses of sulpiride (800 mg daily) and chlorpromazine (400 mg daily). Twentyfive schizophrenic (RDC) patients participated in each treatment group. Antipsychotic effects were evaluated by CPRS and NOSIE ratings before and after 1, 2, 4 and 8 weeks of treatment. Interrater reliabilities for CPRS items and subscales were satisfactory. Treatment with sulpiride or chlorpromazine resulted in a significant reduction of psychotic morbidity as estimated by CPRS and global ratings. CPRS scores reflecting autism were significantly reduced in all ratings of sulpiride‐treated patients, but only after four weeks in the chlorpromazine group. Total NOSIE scores indicated improvement in both treatment groups. A significant difference in favour of sulpiride was obtained for the NOSIE subscale “retardation”. Extrapyramidal side effects occurred at a similar frequency in both treatment groups. Autonomic side effects occurred to a greater extent in chlorpromazine‐treated patients. Lactation was reported only in four sulpiride‐treated patients. Liver transaminase enzymes in serum were markedly elevated only in chlorpromazine‐treated patients. The results indicate that sulpiride has a marked antipsychotic effect which is at least not inferior to that of chlorpromazine. A better effect on autistic components of behaviour was demonstrated for sulpiride. The results indicate a higher risk of lactation but a lower risk of anticholinergic side effects and liver toxicity for treatment with sulpiride than with chlorpromazine.

Schizophrenic patients were treated with fixed doses of sulpiride (800 mg/day) or chlorpromazine (CPZ) (400 mg/day) over a period of 8 weeks using a double-blind design. There were 25 patients in each group and all the patients were in an acute phase of their disease. They all fulfilled the Research Diagnostic Criteria (RDC) for schizophrenia. Depressive symptoms as rated according to the Comprehensive Psychopathological Rating Scale (CPRS) were present in the patients before treatment was started. The depressive and psychotic symptoms in both groups decreased in parallel during the whole period of treatment. Patients in the sulpiride group recovered more quickly from depressive symptoms than patients in the CPZ group. It was also found that patients with low concentrations of sulpiride or CPZ in serum recovered more completely from depressive symptoms and had fewer extrapyramidal side effects than patients with high drug concentrations.