Drugs

, Volume 61, Issue 14, pp 2123–2150 | Cite as

Amisulpride

A Review of its Use in the Management of Schizophrenia
Adis Drug Evaluation

Summary

Abstract

Amisulpride, a substituted benzamide derivative, is a second-generation (atypical) antipsychotic. At low doses, it enhances dopaminergic neurotransmission by preferentially blocking presynaptic dopamine D2/D3 autoreceptors. At higher doses, amisulpride antagonises postsynaptic dopamine D2 and D3 receptors, preferentially in the limbic system rather than the striatum, thereby reducing dopaminergic transmission.

In patients with acute exacerbations of schizophrenia, the recommended dosage of amisulpride is 400 to 800 mg/day, although dosages ≤1200 mg/day may be administered. In comparative trials, amisulpride administered within this range (400 to 1200 mg/day) was as effective as haloperidol 5 to 40 mg/day, flupenthixol 25 mg/day and risperidone 8 mg/day in patients with acute exacerbations of schizophrenia with predominantly positive symptoms. Amisulpride was more effective than haloperidol but equally effective as risperidone in controlling negative symptoms. Amisulpride 400 to 800 mg/day was more effective than haloperidol, risperidone and flupenthixol in controlling affective symptoms in these patients.

In randomised, double-blind trials involving patients with predominantly negative symptoms of schizophrenia, amisulpride 50 to 300 mg/day was more effective than placebo.

Amisulpride is effective as maintenance therapy in patients with chronic schizophrenia. Long-term treatment with amisulpride was associated with improvements in quality of life and social functioning.

Amisulpride is generally well tolerated. In well-controlled trials, the neurological tolerability profile (including ratings on extrapyramidal symptom scales) of amisulpride 400 to 1200 mg/day was superior to that of the conventional antipsychotics (haloperidol or flupenthixol), but was similar to that of the atypical antipsychotic risperidone. At low dosages of amisulpride (≤300 mg/day), the incidence of adverse events (including extrapyramidal symptoms) reported with amisulpride was similar to that with placebo.

Conclusion: In comparative trials, amisulpride 400 to 1200 mg/day showed efficacy in reducing overall symptomatology and positive symptoms similar to that of conventional antipsychotics and newer atypical antipsychotics in patients with acute exacerbations of schizophrenia. Moreover, its effective alleviation of negative and affective symptoms, its lower association with extrapyramidal symptoms and loss of cognitive function than conventional antipsychotics and its long-term efficacy justifies consideration of the use of higher dosages of amisulpride in this group of patients. Consequently, the dosage of amisulpride that is recommended in patients with acute exacerbations of schizophrenia is 400 to 800 mg/day, although dosages ≤1200 mg/day may be administered. Lower dosages of amisulpride (50 to 300 mg/day) should be considered for the management of patients with negative symptoms of schizophrenia. Amisulpride is a first-line treatment option in the management of schizophrenia in the acute phase and for the maintenance of treatment response.

Pharmacodynamic Properties

Amisulpride binds selectively and with high affinity to dopamine D2 and D3 receptor subtypes with preferential binding to limbic structures rather than the striatum. Amisulpride has little affinity for other dopamine receptor subtypes (D1, D4 or D5) or other neurotransmitter receptors (serotonin, histamine, muscarinic, adrenergic). In animals, low doses of amisulpride facilitate presynaptic dopamine receptor-mediated behaviours, whereas higher doses decrease behaviours associated with postsynaptic receptor activation.

Single oral doses of amisulpride of up to 400mg and multiple doses of amisulpride (50 mg/day for 4 days) were devoid of detrimental effects on psychometric and/or cognitive performance in healthy volunteers. Amisulpride increased prolactin levels in volunteers. Consistent with its lack of effects on the α-adrenergic and cholinergic system, amisulpride produced minor or no neurocardiac effects.

Pharmacokinetic Properties

After single oral doses of amisulpride 50mg, the peak plasma amisulpride con-centration was approximately 56 μg/L at 4 hours. An earlier lower peak (42 μg/L) was detected 1 hour earlier. Amisulpride distributes widely and rapidly to tissues (volume of distribution 5.8 L/kg) and is minimally bound to plasma protein (17%). Absolute bioavailability of amisulpride is ≈50%. Metabolism of amisulpride is limited and the two main metabolites are inactive. Amisulpride is primarily excreted in the urine. Elimination is biphasic, with a terminal elimination half-life of approximately 12 hours. Renal clearance is approximately 20 L/h in healthy volunteers.

Therapeutic Efficacy

In patients with acute exacerbations of schizophrenia with predominantly positive symptoms, amisulpride 400 to 1200 mg/day reduced overall symptomatology [assessed by the Brief Psychiatric Rating Scale (BPRS) total scores] by 42 to 59% and positive symptom scores [assessed by the Positive and Negative Syndrome Scale (PANSS) positive subscore or Scale for the Assessment of Positive Symptoms (SAPS)] by 48 to 75%, a response rate not significantly different from that produced by haloperidol 5 to 40 mg/day, flupenthixol 25 mg/day and risperidone 8 mg/day in long-term and short-term randomised, double-blind trials. Amisulpride 400 to 1200 mg/day reduced negative symptom scores [assessed by negative PANSS subscore or Scale for Assessment of Negative Symptoms (SANS)] by 35 to 47% in these patients, a response rate that was significantly higher than that of haloperidol but not significantly different from that of risperidone. Amisulpride 400 to 800 mg/day reduced affective symptoms to a greater extent than haloperidol, risperidone and flupenthixol. Amisulpride 400 to 800 mg/day was associated with an earlier onset of action than haloperidol.

In patients with predominantly negative symptoms, low dosages of amisulpride 50 to 300 mg/day significantly reduced negative symptom scores (assessed by SANS) by 32 to 46% compared with 8 to 23% in placebo recipients in randomised, double-blind trials.

In long-term studies, amisulpride 200 to 1200 mg/day was effective as maintenance therapy in patients with chronic schizophrenia with mixed symptoms. In a randomised, double-blind trial, low dosages of amisulpride (≤300 mg/day) prevented an increase in both negative and positive symptom scores when administered as maintenance therapy to patients with predominantly negative symptoms. Long-term amisulpride administration was associated with improvements in measures of quality of life and social functioning.

Tolerability

Amisulpride at low and high dosages is well tolerated. At low dosages (≤300 mg/day), the incidence of adverse events was similar in amisulpride-and placebo-treated patients. At higher dosages (400 to 1200 mg/day), the overall incidence of adverse events in amisulpride recipients was similar to that in recipients of haloperidol, flupenthixol and risperidone. The most commonly reported adverse events associated with higher dosages of amisulpride were extrapyramidal symptoms, insomnia, hyperkinesia, anxiety, bodyweight increase and agitation.

The incidence of extrapyramidal symptoms was dose related. The neurological tolerability profile [assessed according to the Simpson-Angus Scale (SAS; an extrapyramidal symptom scale), the Barnes Akathisia Scale (BAS) or the Abnormal Involuntary Movement Scale (AIMS)] of amisulpride 400 to 1200 mg/day was superior to that of the conventional antipsychotics (haloperidol or flupenthixol), but was similar to that of the atypical antipsychotic risperidone. Ratings on extrapyramidal symptom scales were similar in recipients of low-dosage amisulpride and placebo. The increase in bodyweight associated with amisulpride (200 to 1200 mg/day) was slightly greater than that associated with haloperidol 5 to 30 mg/day in two long-term studies but lower than that associated with risperidone 8 mg/day in an 8-week study.

Plasma prolactin levels were increased 3-fold after 12 months’ therapy with amisulpride in patients with schizophrenia. However, the incidence of endocrine disorders was low in patients treated with higher dosages of amisulpride and similar to that observed in haloperidol and risperidone recipients. Pooled results from comparative trials showed that amisulpride had a satisfactory cardiovascular profile and was not associated with any clinical abnormalities in laboratory parameters including haematological and hepatological tests.

Pharmacoeconomic and Quality-of-Life Studies

Data from a retrospective study showed that amisulpride was more cost effective than haloperidol in patients with schizophrenia in ambulatory care. This was mainly the result of lower hospitalisation costs. In addition, amisulpride was more effective than haloperidol in improving measures of quality of life in medium-and long-term studies.

Dosage and Administration

An oral amisulpride dosage of 400 to 800 mg/day is recommended for acute psychotic episodes in patients with schizophrenia. The dosage may be increased up to 1200 mg/day; however, tolerability data for dosages >1200 mg/day are not available. It is recommended that maintenance therapy should be established individually with the minimally effective dosage. For patients with predominantly negative symptoms of schizophrenia, oral dosages of 50 to 300 mg/day are recommended. Dosages above 400 mg/day should be administered twice daily. Dosage reductions are recommended in patients with creatinine clearance below 60 ml/min.

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© Adis International Limited 2001

Authors and Affiliations

  1. 1.Adis International LimitedMairangi Bay, Auckland 10New Zealand

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