Amisulpride - A review of its use in the management of schizophrenia

Amisulpride, a substituted benzamide derivative, is a second-generation (at ypical) antipsychotic. At low doses, it enhances dopaminergic neurotransmis sion by preferentially blocking presynaptic dopamine D-2/D-3 autoreceptors. At higher doses, amisulpride antagonises postsynaptic dopamine D-2 and D-3 receptors, preferentially in the limbic system rather than the striatum, t hereby reducing dopaminergic transmission. In patients with acute exacerbations of schizophrenia, the recommended dosa ge of amisulpride is 400 to 800 mg/day, although dosages less than or equal to 1200 mg day may be administered. In comparative trials, amisulpride adm inistered within this range (400 to 1200 mg/day) was as effective as halope ridol 5 to 40 mg/day, flupenthixol 25 mg/day and risperidone 8 mg/day in pa tients with acute exacerbations of schizophrenia with predominantly positiv e symptoms. Amisulpride was more effective than haloperidol but equally eff ective as risperidone in controlling negative symptoms. Amisulpride 400 to 800 mg/day was more effective than haloperidol, risperidone and flupenthixo l in controlling affective symptoms in these patients. In randomised, double-blind trials involving patients with predominantly ne gative symptoms of schizophrenia, amisulpride 50 to 300 mg/day was more eff ective than placebo. Amisulpride is effective as maintenance therapy in patients with chronic sc hizophrenia. Long-term treatment with amisulpride was associated with impro vements in quality of life and social functioning. Amisulpride is generally well tolerated. In well-controlled trials, the neu rological tolerability profile (including ratings on extrapyramidal symptom scales) of amisulpride 400 to 1200 mg/day was superior to that of the conv entional antipsychotics (haloperidol or flupenthixol), but was similar to t hat of the atypical antipsychotic risperidone. At low dosages of amisulprid e (less than or equal to 300 mg/day), the incidence of adverse events (incl uding extrapyramidal symptoms) reported with amisulpride was similar to tha t with placebo. Conclusion: In comparative trials, amisulpride 400 to 1200 mg/day showed ef ficacy in reducing overall symptomatology and positive symptoms similar to that of conventional antipsychotics and newer atypical antipsychotics in pa tients with acute exacerbations of schizophrenia. Moreover, its effective a lleviation of negative and affective symptoms, its lower association with e xtrapyramidal symptoms and loss of cognitive function than conventional ant ipsychotics and its long-term efficacy justifies consideration of the use o f higher dosages of amisulpride in this group of patients. Consequently, th e dosage of amisulpride that is recommended in patients with acute exacerba tions of schizophrenia is 400 to 800 mg/day, although dosages less than or equal to 1200 mg/day may be administered. Lower dosages of amisulpride (50 to 300 mg/day) should be considered for the management of patients with neg ative symptoms of schizophrenia. Amisulpride is a first-line treatment opti on in the management of schizophrenia in the acute phase and for the mainte nance of treatment response. Amisulpride binds selectively and with high affinity to dopamine D-2 and D- 3 receptor subtypes with preferential binding to limbic structures rather t han the striatum, Amisulpride has little affinity for other dopamine recept or subtypes (D-1, D-4 or D-5) or other neurotransmitter receptors (serotoni n, histamine, muscarinic, adrenergic). In animals, low doses of amisulpride facilitate presynaptic dopamine receptor-mediated behaviours, whereas high er doses decrease behaviours associated with postsynaptic receptor activati on. Single oral doses of amisulpride of up to 400mg and multiple doses of amisu lpride (50 mg/day for 4 days) were devoid of detrimental effects on psychom etric and/or cognitive performance in healthy volunteers. Amisulpride incre ased prolactin levels in volunteers. Consistent with its lack of effects on the alpha -adrenergic and cholinergic system, amisulpride produced minor o r no neurocardiac effects. After single oral doses of amisulpride 50mg, the peak plasma amisulpride co ncentration was approximately 56 mug/L at 4 hours. An earlier lower peak (4 2 mug/L) was detected 1 hour earlier. Amisulpride distributes widely and ra pidly to tissues (volume of distribution 5.8 L/kg) and is minimally bound t o plasma protein (17%). Absolute bioavailability of amisulpride is approxim ate to 50%. Metabolism of amisulpride is limited and the two main metabolit es are inactive. Amisulpride is primarily excreted in the urine. Eliminatio n is biphasic, with a terminal elimination half-life of approximately 12 ho urs. Renal clearance is approximately 20 L/h in healthy volunteers. In patients with acute exacerbations of schizophrenia with predominantly po sitive symptoms, amisulpride 400 to 1200 mg/day reduced overall symptomatol ogy [assessed by the Brief Psychiatric Rating Scale (BPRS) total scores] by 42 to 59% and positive symptom scores [assessed by the Positive and Negati ve Syndrome Scale (PANSS) positive subscore or Scale for the Assessment of Positive Symptoms (SAPS)] by 48 to 75%, a response rate not significantly d ifferent 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, dou ble-blind trials. Amisulpride 400 to 1200 mg/day reduced negative symptom s cores [assessed by negative PANSS subscore or Scale for Assessment of Negat ive Symptoms (SANS)] by 35 to 47% in these patients, a response rate that w as significantly higher than that of haloperidol but not significantly diff erent from that of risperidone. Amisulpride 400 to 800 mg/day reduced affec tive symptoms to a greater extent than haloperidol, risperidone and flupent hixol. Amisulpride 400 to 800 mg/day was associated with an earlier onset o f action than haloperidol. In patients with predominantly negative symptoms, low dosages of amisulprid e 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 rando mised, double-blind trials. In long-term studies, amisulpride 200 to 1200 mg/day was effective as maint enance therapy in patients with chronic schizophrenia with mixed symptoms. In a randomised, double-blind trial, low dosages of amisulpride (less than or equal to 300 mg/day) prevented an increase in both negative and positive symptom scores when administered as maintenance therapy to patients with p redominantly negative symptoms. Long-term amisulpride administration was as sociated with improvements in measures of quality of life and social functi oning. Amisulpride at low and high dosages is well tolerated. At low dosages (less than or equal to 300 mg/day), the incidence of adverse events was similar in amisulpride- and placebo-treated patients. At higher dosages (400 to 120 0 mg/day), the overall incidence of adverse events in amisulpride recipient s was similar to that in recipients of haloperidol, flupenthixol and risper idone. The most commonly reported adverse events associated with higher dos ages of amisulpride were extrapyramidal symptoms, insomnia, hyperkinesia, a nxiety, 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 A bnormal Involuntary Movement Scale (AIMS)] of amisulpride 400 to 1200 mg/da y was superior to that of the conventional antipsychotics (haloperidol or f lupenthixol), but was similar to that of the atypical antipsychotic risperi done. Ratings on extrapyramidal symptom scales were similar in recipients o f low-dosage amisulpride and placebo. The increase in bodyweight associated with amisulpride (200 to 1200 mg/day) was slightly greater than that assoc iated with haloperidol 5 to 30 mg/day in two long-term studies but lower th an 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 endo crine disorders was low in patients treated with higher dosages of amisulpr ide and similar to that observed in haloperidol and risperidone recipients. Pooled results from comparative trials showed that amisulpride had a satis factory cardiovascular profile and was not associated with any clinical abn ormalities in laboratory parameters including haematological and hepatologi cal tests. Data from a retrospective study showed that amisulpride was more cost effec tive than haloperidol in patients with schizophrenia in ambulatory care. Th is was mainly the result of lower hospitalisation costs. In addition, amisu lpride was more effective than haloperidol in improving measures of quality of life in medium- and long-term studies. An oral amisulpride dosage of 400 to 800 mg/day is recommended for acute ps ychotic episodes in patients with schizophrenia. The dosage may be increase d up to 1200 mg/day; however, tolerability data for dosages >1200 mg/day ar e not available. It is recommended that maintenance therapy should be estab lished 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 tw ice daily. Dosage reductions are recommended in patients with creatinine cl earance below 60 ml/min.