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Sulpiride is a benzamide derivative, structurally distinct from other standard antipsychotics, which binds selectively to central and peripheral dopamine D2-and D3-receptors. In animals, sulpiride displays neuropharmacological and behavioural actions that are variously considered predictive of typical and atypical antipsychotic activity. Atypical properties include a lack of sedative and cataleptogenic effects and failure to antagonise apomorphine-induced stereotypy. In common with other dopamine D2-receptor antagonists, sulpiride has a pronounced prolactin-stimulating effect.Sulpiride displays an apparent spectrum of clinical activity which differs from that of conventional antipsychotics, with sedative effects predominating at higher doses and activating effects at lower doses. Antipsychotic activity occurs over a dosage range of 400 to 3200 mg/day, with negative symptoms responding best to low dosages (≤ 800 mg/day) and positive symptoms to higher dosages (≥ 1200 mg/day). In terms of its global antipsychotic efficacy, sulpiride compares similarly with most conventional antipsychotics. Extrapyramidal effects (akathisia, acute dystonia and parkinsonism) have been associated with sulpiride, occurring in 12.8% of patients receiving doses ≤ 1200 mg/day; tardive dyskinesia appears to be rare. Male impotence, galactorrhoea and amenorrhoea are presumably related to the hyperprolactinaemic effect of the drug.As a disinhibiting antipsychotic, sulpiride is indicated for the treatment of acute and chronic schizophrenia with prominent autistic and affective symptoms. The wide therapeutic dose range and lack of sedative effect of low dose sulpiride may be beneficial in maintenance therapy of remitted schizophrenic outpatients. With its relatively low propensity to cause extrapyramidal symptoms and tardive dyskinesia, sulpiride also offers advantages in the treatment of schizophrenic patients who are intolerant of conventional antipsychotics.In contrast to the classical antipsychotic drugs such as haloperidol and chlorpromazine, sulpiride shows selective affinity for the dopamine D2- and D3-receptor subgroups, with little affinity for other brain receptors. Peripheral dopamine receptors in blood vessels and gastrointestinal smooth muscle are also antagonised by sulpiride. Pharmacodynamic properties distinguishing sulpiride as an atypical antipsychotic include lack of inhibition of dopamine-induced stimulation of adenylate cyclase, induction of weak catalepsy, weak antagonism of apomorphine-induced locomotion and lack of inhibition of apomorphine-induced behaviour in animal models. In humans, disinhibitory properties and lack of sedation are noted. As with other dopamine D2-receptor antagonists, sulpiride has a pronounced stimulatory effect on prolactin release from the pituitary gland.Sulpiride has stereoselective properties, and S-sulpiride appears to be the more active of the 2 enantiomers. However, racemic sulpiride is usually used for the treatment of schizophrenia.The low oral bioavailability of sulpiride is probably due to its incomplete absorption from the gastrointestinal tract. Food tends to decrease the gastrointestinal absorption of sulpiride, as do drugs which increase gastric pH. Distribution and elimination follow linear pharmacokinetics. Sulpiride has low lipid solubility and penetrates the cerebrospinal fluid poorly. Very little metabolism occurs and renal clearance is high, resulting in accumulation of sulpiride in patients with renal dysfunction.The relationship between plasma sulpiride concentration and clinical efficacy is equivocal.Dose-finding studies suggest that sulpiride is partially selective towards the negative symptoms of schizophrenia at low dosages (400 to 1000 mg/day), with more overt activity against positive symptoms being apparent at higher dosages (> 1000 mg/day). The activating or disinhibitory effect ascribed to low dose sulpiride may be offset at higher doses by a possible deactivating effect.The antipsychotic efficacy of sulpiride 400 to 1400 mg/day has been established in a limited number of double-blind placebo-controlled comparisons of ≤ 3 months' duration in patients with chronic schizophrenia. In patients with prominent negative symptoms, sulpiride 400 mg/day improved affective blunting, poverty of speech and socially detrimental behaviour. When used prophylactically in remitted schizophrenic outpatients, sulpiride 100 to 600 mg/day extended the duration of remission and reduced the relapse rate over a 1-year period.In controlled clinical trials of 1 to 4 months' duration, sulpiride ≤ 3200 mg/day (usually ≤ 1200 mg/day) has shown comparable overall antipsychotic activity to bromperidol 7 to 36 mg/day, chlorpromazine 150 to 600 mg/day, haloperidol 3 to 40 mg/day, perphenazine 4 to 48 mg/day, trifluoperazine 15 to 45 mg/day and zuclopenthixol 25 to 150 mg/day in patients with acute or chronic schizophrenia. A moderate to marked improvement in global psychotic morbidity was reported in ≈ 30 to 50% of chronic schizophrenic patients receiving sulpiride in these trials.In hospitalised patients with either acute schizophrenic episodes or chronic schizophrenia, sulpiride 300 to 1200 mg/day tended to produce a greater improvement in global psychotic morbidity than chlorpromazine 150 to 600 mg/day. Although sulpiride was as active as chlorpromazine against positive psychotic symptoms in patients with acute schizophrenic episodes, it proved superior to the latter in ameliorating autistic symptoms. In hospitalised patients with paranoid or hebephrenic schizophrenia, the antipsychotic action of sulpiride 100 to 2300 (mean 1000) mg/day appeared to be more rapid and wider-ranging than that of haloperidol 0.5 to 10.5 (mean 5.0) mg/day, encompassing depressive and anxious as well as hostile-paranoid symptoms. Among patients with chronic schizophrenia and prominent negative symptoms of apathy and anergia, the response rates to sulpiride 300 to 1200 mg/day and perphenazine 12 to 48 mg/day were comparable; sulpiride, however, appeared to have the more rapid onset of action. Among patients with schizophrenic and schizoaffective psychoses, sulpiride 200 to 1800 mg/day was reported to show greater activity than perphenazine 8 to 80 mg/day against symptoms of depression, somatic concerns and psychomotor retardation.Extrapyramidal symptoms, believed to depend on the extent of dopamine D2-receptor occupancy, occurred in 12.8% of 2851 patients receiving sulpiride in 65 clinical studies. Tardive dyskinesia and neuroleptic malignant syndrome have rarely been associated with sulpiride therapy. Endocrine effects have been reported less often than expected from the pharmacodynamic data.Sulpiride has a low toxicity profile on overdose. Caution is advised in patients receiving sulpiride in conjunction with alcohol (ethanol), levodopa, antihypertensive agents or central depressants.The dosage of sulpiride is adjusted according to the most prominent psychiatric symptoms in patients with acute or chronic psychosis: 200 to 600 mg/day in patients with predominantly negative symptoms and 800 to 1600 mg/day in those with mainly positive symptoms. Dosage adjustment is required in patients with severe renal failure.