Amisulpride: a review of its use in the management of schizophrenia.

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, amisupride 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 < or =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 (< or =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 < or =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.     

Spotlight on amisulpride in schizophrenia

Amisulpride, a substituted benzamide derivative, is a second-generation (atypical) antipsychotic. At low doses, it enhances dopaminergic neurotransmission by preferentially blocking presynaptic dopamine D(2)/D(3) autoreceptors. At higher doses, amisulpride antagonises postsynaptic D(2) and D(3) 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 < or = 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 (< or = 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 < or = 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.     

Practical issues with amisulpride in the management of patients with schizophrenia

Amisulpride is an atypical antipsychotic with a significantly greater effect size than first-generation, typical antipsychotics, and efficacy at least similar to that of olanzapine and risperidone in large-scale clinical trials in schizophrenia. Amisulpride provides greater improvement in positive and negative symptoms of schizophrenia, a better long-term outcome than typical antipsychotics, and distinct tolerability advantages over typical antipsychotics, which are reported to cause extrapyramidal symptoms (EPS) in 20-50% of patients. In addition, amisulpride is associated with significantly less weight gain than olanzapine and risperidone, does not increase body mass index, and favourably influences lipid profiles. In many patients with schizophrenia, adverse events impair adherence to treatment, and switching from typical or atypical antipsychotic therapy to amisulpride may be clinically appropriate. Observational drug-utilization studies suggest that many physicians switch to amisulpride because of fewer EPS and/or less weight gain and improved patient adherence. Cross-tapering (over 4 weeks), rather than abrupt cessation of pre-switch treatment, is preferred. Amisulpride has a low risk of drug-drug interactions, and, during cross-tapering, patients can remain on concurrent treatments (e.g. anticholinergics and antiparkinsonian agents) until the effective dosage has been reached. An appropriate amisulpride starting dose is 800 mg/day for patients with acute psychotic exacerbations, 400-800 mg/day for patients with predominantly positive symptoms, and 100-300 mg/day for predominantly negative symptoms. Amisulpride may be particularly suitable for clozapine-augmentation therapy in patients with refractory schizophrenia. Indeed, amisulpride is more effective than quetiapine as augmentation therapy in patients partially responsive to clozapine, and several prospective open-label studies and case series have reported promising results for amisulpride/clozapine combination therapy. In three prospective studies, addition of amisulpride 200-800 mg/day to clozapine significantly reduced mean scores on the Brief Psychiatric Rating Scale (BPRS) total (-33% to -35%), Clinical Global Impression (CGI)-Severity scale (-31%), Positive and Negative Syndrome Scale total (-22%), and Scale for the Assessment of Negative Symptoms (-34%). The proportion of responders (CGI score > or =3 or BPRS improvement >20%) was 71-86%. Retrospective case-series analyses have also reported improved psychopathological state, reduced adverse events, and lower clozapine dosage requirement with use of this combination. The pharmacological and clinical profiles of amisulpride suggest that this agent is a viable clinical option when a change of antipsychotic therapy is required in patients with schizophrenia because of lack of efficacy, adverse events and poor adherence to treatment, or for augmentation of clozapine in treatment-resistant illness.     

Acute phase of schizophrenia: impact of atypical antipsychotics

The acute phase of schizophrenia is characterized by the presence of positive, negative and affective symptoms. After recovery, patients still may suffer distressing residual symptoms; they also carry a high risk of relapse which may be associated with further deterioration in their condition. Prompt, early and continued treatment with an effective, well-tolerated antipsychotic agent, is therefore crucial. Typical antipsychotics are poorly tolerated, leading to lack of compliance and relapse. They also lack efficacy in controlling negative and affective symptoms. Atypical compounds such as amisulpride or risperidone are better tolerated. In addition, when compared with either haloperidol or risperidone, amisulpride has been shown to be at least as effective in controlling positive symptoms and significantly superior in alleviating negative symptoms. The onset of action of amisulpride appears more rapid than that of haloperidol. Amisulpride therefore fulfils all the requirements of a first-line agent for the treatment of the acute phase of schizophrenia.     

Amisulpride: progress and outcomes

Amisulpride is a unique atypical antipsychotic that selectively blocks D2 and D3 receptors presynaptically in the frontal cortex, possibly enhancing dopaminergic transmission, and postsynaptically in the limbic areas, possibly reducing it. Thus dopaminergic over-activity in the frontal cortex, and under-activity in the limbic areas, can be treated simultaneously, alleviating both positive and negative symptoms of schizophrenia, respectively. In acute schizophrenia, amisulpride is at least as effective as haloperidol, with a greater number of patients responding to treatment as determined by Clinical Global Impression (CGI scores (p = 0.014). In addition, amisulpride is associated with a lower incidence of extrapyramidal symptoms (EPS) as determined by Simpson-Angus scores (SAS) when compared with haloperidol (p = 0.0053). Amisulpride showed similar efficacy to risperidone as determined by the Brief Psychiatric Rating Scale (BPRS) and the Positive and Negative Symptom Score (PANSS) positive subscale; a trend towards greater improvement of negative symptoms as determined by PANSS negative subscale compared with risperidone; and similar levels of EPS. Amisulpride uniquely benefits patients with negative symptoms and is the only antipsychotic to demonstrate efficacy in patients with predominantly negative symptoms. Amisulpride maintains its efficacy when used for medium/long-term treatment as demonstrated in studies of up to 12 months. Amisulpride demonstrates greater improvement in controlling symptoms compared to haloperidol. In terms of the relevance of the effects, a superiority is observed for quality of life, social adaptation and functioning as measured by the Quality of Life Scale (QLS), Clinical Glocal Impression scale (CGI) and Functional Status Questionnaire (FSQ) scales. Amisulpride also has one of the lowest potentials of all the antipsychotic agents for weight gain. The clinical evidence for amisulpride supports its earlier pre-clinical potential, showing it to be an atypical antipsychotic agent with specific clinical advantages.     

A review of the pharmacokinetics,tolerability and pharmacodynamics of amisulpride in healthy volunteers

Amisulpride binds selectively to dopamine D(2) and D(3) receptors in the limbic system. Low doses of amisulpride preferentially block presynaptic D(2)/D(3)-dopamine autoreceptors, thereby enhancing dopaminergic transmission, whereas higher doses block postsynaptic receptors, thus inhibiting dopaminergic hyperactivity. Amisulpride is clinically effective on the negative symptoms of acute schizophrenia exacerbations at low dosages (50-300 mg/day), and also on the positive symptoms of the disease at high dosages (400-800 mg/day). Nineteen clinical studies involving 358 volunteers have investigated the pharmacokinetics, pharmacodynamics and tolerability of amisulpride. Amisulpride shows linear pharmacokinetics, a bioavailability of 48%, low protein binding (17%) and an elimination half-life of approximately 12 h. It is predominantly eliminated in the urine as the parent compound. It exhibits no significant detrimental effects in psychometric or memory tests up to the dose of 400 mg/day, inducing only mild impairment at high doses, whereas EEG data suggest an alertness-enhancing effect at low doses (相似文献   

Olanzapine: an updated review of its use in the management of schizophrenia

Olanzapine, a thienobenzodiazepine derivative, is a second generation (atypical) antipsychotic agent which has proven efficacy against the positive and negative symptoms of schizophrenia. Compared with conventional antipsychotics, it has greater affinity for serotonin 5-HT2A than for dopamine D2 receptors. In large, well controlled trials in patients with schizophrenia or related psychoses, olanzapine 5 to 20 mg/day was significantly superior to haloperidol 5 to 20 mg/day in overall improvements in psychopathology rating scales and in the treatment of depressive and negative symptoms, and was comparable in effects on positive psychotic symptoms. The 1-year risk of relapse (rehospitalisation) was significantly lower with olanzapine than with haloperidol treatment. In the first double-blind comparative study (28-week) of olanzapine and risperidone, olanzapine 10 to 20 mg/day proved to be significantly more effective than risperidone 4 to 12 mg/day in the treatment of negative and depressive symptoms but not on overall psychopathology symptoms. In contrast, preliminary results from an 8-week controlled study suggested risperidone 2 to 6 mg/day was superior to olanzapine 5 to 20 mg/day against positive and anxiety/depressive symptoms (p < 0.05), although consistent with the first study, both agents demonstrated similar efficacy on measures of overall psychopathology. Improvements in general cognitive function seen with olanzapine treatment in a 1-year controlled study of patients with early-phase schizophrenia, were significantly greater than changes seen with either risperidone or haloperidol. However, preliminary results from an 8-week trial showed comparable cognitive enhancing effects of olanzapine and risperidone treatment in patients with schizophrenia or schizoaffective disorder. Several studies indicate that olanzapine has benefits against symptoms of aggression and agitation, while other studies strongly support the effectiveness of olanzapine in the treatment of depressive symptomatology. Olanzapine is associated with significantly fewer extrapyramidal symptoms than haloperidol and risperidone. In addition, olanzapine is not associated with a risk of agranulocytosis as seen with clozapine or clinically significant hyperprolactinaemia as seen with risperidone or prolongation of the QT interval. The most common adverse effects reported with olanzapine are bodyweight gain, somnolence, dizziness, anticholinergic effects (constipation and dry mouth) and transient asymptomatic liver enzyme elevations. In comparison with haloperidol, the adverse events reported significantly more frequently with olanzapine in > or = 3.5% of patients were dry mouth, bodyweight gain and increased appetite and compared with risperidone, only bodyweight gain occurred significantly more frequently with olanzapine. The high acquisition cost of olanzapine is offset by reductions in other treatment costs (inpatient and/or outpatient services) of schizophrenia. Pharmacoeconomic analyses indicate that olanzapine does not significantly increase, and may even decrease, the overall direct treatment costs of schizophrenia, compared with haloperidol. Compared with risperidone, olanzapine has also been reported to decrease overall treatment costs, despite the several-fold higher daily acquisition cost of the drug. Olanzapine treatment improves quality of life in patients with schizophrenia and related psychoses to a greater extent than haloperidol, and to broadly the same extent as risperidone. CONCLUSIONS: Olanzapine demonstrated superior antipsychotic efficacy compared with haloperidol in the treatment of acute phase schizophrenia, and in the treatment of some patients with first-episode or treatment-resistant schizophrenia. The reduced risk of adverse events and therapeutic superiority compared with haloperidol and risperidone in the treatment of negative and depressive symptoms support the choice of olanzapine as a first-line option in the management of schizophrenia in the acute phase and for the maintenance of treatment response.     

Quetiapine. A review of its use in the management of schizophrenia

Quetiapine (Seroquel), a dibenzothiazepine derivative, is an atypical antipsychotic with demonstrated efficacy in acute schizophrenia. In short-term, randomised, double-blind trials, it was usually more effective than placebo, and was generally effective against both positive and negative symptoms. Overall, quetiapine (up to 750 mg/day) was at least as effective as chlorpromazine (up to 750 mg/day) and had similar efficacy to haloperidol (up to 16 mg/day) in patients with acute schizophrenia in randomised, double-blind trials; it was at least as effective as haloperidol 20 mg/day in patients with schizophrenia unresponsive or partially responsive to previous antipsychotic treatment. Improvements in overall psychopathology and positive and negative symptoms with quetiapine (up to 800 mg/day) were similar to those with risperidone (up to 8 mg/day) or olanzapine (15 mg/day) [interim analysis]. Efficacy was maintained for at least 52 weeks in open-label follow-up studies in adult and elderly patients. Quetiapine improved cognitive function versus haloperidol, and depressive symptoms and hostility/aggression versus placebo. Quetiapine is well tolerated. It is associated with placebo-level incidence of extrapyramidal symptoms (EPS) across its entire dose range, appears to have a low risk for EPS in vulnerable patient groups (e.g. the elderly, adolescents or patients with organic brain disorders) and has a more favourable EPS profile than risperidone. Irrespective of dose, quetiapine, unlike risperidone and amisulpride, does not elevate plasma prolactin levels compared with placebo, and previously elevated levels may even normalise. Quetiapine appears to have minimal short-term effects on bodyweight and a favourable long-term bodyweight profile. Preliminary studies indicate that there is a high level of patient acceptability and satisfaction with quetiapine. In conclusion, quetiapine has shown efficacy against both positive and negative symptoms of schizophrenia, and has benefits in improving cognitive deficits, affective symptoms and aggression/hostility. The beneficial effects of quetiapine have been maintained for at least 52 weeks. Quetiapine was effective and well tolerated in hard-to-treat patients, and may be of particular use in these individuals. It is at least as effective as standard antipsychotics and appears to have similar efficacy to risperidone and olanzapine. The relative risk/benefit profile of quetiapine compared with other atypical antipsychotics requires further research in head-to-head trials, although quetiapine's relatively benign tolerability profile distinguishes it from other commonly used atypical agents, particularly with respect to bodyweight, EPS and plasma prolactin levels. Overall, quetiapine has an excellent risk/benefit profile and is a suitable first-line option for the treatment of schizophrenia.     

Amisulpride improves depressive symptoms in acute exacerbations of schizophrenia: comparison with haloperidol and risperidone.

The Brief Psychiatric Rating Scale (BPRS) anxiety/depression subscore has been used to assess affective symptoms in three studies (n = 612) comparing amisulpride (400-800 mg/day, n = 339) with haloperidol (15-20 mg/day, n = 160) and risperidone (8 mg/day, n = 113) in the treatment of acute exacerbations of schizophrenia. At endpoint, the mean improvement in the anxiety/depression subscore showed a significant (P = 0.011) difference in favour of amisulpride (5.6+/-6.1) compared with haloperidol (4.4+/-5.5) and risperidone (3.7+/-4.7). Amisulpride provided a significantly greater improvement compared both to haloperidol and risperidone in more severely depressed patients (BPRS anxiety/depression subscore > or = 16 at baseline, P = 0.001). This significant advantage in favour of amisulpride is seen from the 2nd week of treatment.     

Amisulpride vs. risperidone in chronic schizophrenia: results of a 6-month double-blind study.

This multicenter, double-blind, randomized study evaluated the efficacy, safety and functional effects of two atypical antipsychotics, amisulpride and risperidone, in patients with chronic schizophrenia (DSM IV) with a recent worsening of symptoms. It was planned as a non-inferiority trial. 309 patients received amisulpride (400-1,000 mg/day) or risperidone (4-10 mg/day) for six months. Amisulpride was demonstrated to be not inferior to risperidone with respect to the decrease in Positive and Negative Syndrome Scale (PANSS) total score from baseline (90% 2-sided confidence interval (-5.6; 4.0)). Symptomatic improvement measured with the Brief Psychiatry Rating Scale (BPRS), the PANSS positive subscale, and the Bech Rafaelsen Melancholia Scale was similar in both groups. Amisulpride was significantly (p <.05) superior to risperidone in terms of response (>/=50% improvement in PANSS and BPRS total scores or "very much/much improved" on the Clinical Global Impression Scale) and also demonstrated better functional effects and subjective response. Both treatments were well tolerated and had a similar low incidence of extrapyramidal symptoms; however, amisulpride was associated with less weight gain and endocrine/sexual symptoms.     

A double-blind,randomised comparative trial of amisulpride versus olanzapine in the treatment of schizophrenia: short-term results at two months

OBJECTIVE: To compare the efficacy and safety of the atypical antipsychotics amisulpride and olanzapine in the treatment of acute psychotic exacerbations of schizophrenia. DESIGN AND SETTING: A multinational, double-blind randomised clinical trial. PATIENTS AND TREATMENT: Three hundred and seventy-seven patients with predominantly positive symptomatology were treated for six months with either amisulpride (200-800 mg/d) or olanzapine (5-20 mg/d). MAIN OUTCOME MEASURES: Short-term results were analysed after two months of treatment. The primary efficacy measure was the change of score on the Brief Psychiatric Rating Scale (BPRS). Other measures of efficacy and safety were also evaluated. RESULTS: Psychotic symptoms, as measured on the BPRS score, improved with both treatments, amisulpride being equivalent to olanzapine. All BPRS factor scores, as well as depressive symptoms, improved to a similar extent with both treatments. Less than five per cent of patients withdrew for adverse events, and there was no evidence for the emergence of extrapyramidal symptoms with either treatment. Statistically significant greater weight gain (2.7 +/- 3.9 kg) was observed during the study in the olanzapine group, compared with the amisulpride group (0.9 +/- 3.2 kg, p < 0.0001). CONCLUSIONS: Amisulpride and olanzapine show equivalent efficacy at 2 months in the treatment of acute psychotic exacerbations of schizophrenia. Amisulpride offers a significant advantage in preserving body weight.     

Long-term safety and efficacy of amisulpride in subchronic or chronic schizophrenia. Amisulpride Study Group

Amisulpride is an atypical antipsychotic with selective affinity for dopamine D2/3 receptors. In this long-term, open, randomised, multicentre trial, patients with chronic or subchronic schizophrenia received amisulpride (n =370) or haloperidol (n = 118) for 12 months. Dosage regimens were flexible (amisulpride 200-800 mg/day, haloperidol 5-20 mg/day). Improvement in mean Brief Psychiatric Rating Scale total score was significantly greater for amisulpride than haloperidol (17.0 versus 12.8, P = 0.01). Positive symptoms (Positive and Negative Syndrome Scale [PANSS] positive) improved in a similar way in each group but amisulpride caused a significantly better improvement in negative symptoms (PANSS negative) (7.1 versus 3.7, P < 0.0001). Improvements in Global Assessment of Functioning (GAF) and Quality of Life Scale (QLS) scores were also significantly greater in the amisulpride group (GAF -20.1 versus -13.6, P = 0.001; QLS -0.64 versus -0.30, P = 0.02). Adverse events were mainly psychiatric in nature, and occurred with similar frequency in each group (amisulpride 254/370, 69%; haloperidol 82/118, 70%). Extrapyramidal symptoms were more frequent for haloperidol (48/118, 41% versus 96/370, 26% for amisulpride), leading to a greater requirement for antiparkinsonian medication (haloperidol 66/118, 56% versus amisulpride 118/370, 32%). Haloperidol significantly aggravated parkinsonism, akathisia and involuntary movement compared to amisulpride. The overall incidence of endocrine events was comparable between groups (4% for amisulpride, 3% for haloperidol). Maintenance of efficacy was comparable in both treatment groups; 59% of amisulpride patients and 55% of haloperidol patients improved after 1 month of therapy remained improved throughout the study period. Amisulpride is effective following flexible long-term administration and significantly improves social functioning and quality of life.     

Improvement of acute exacerbations of schizophrenia with amisulpride: a comparison with haloperidol

Amisulpride is a substituted benzamide with high selectivity for dopaminergic D₂ and D₃ receptors. This study compared 800 mg/day amisulpride and 20 mg/day haloperidol in patients with acute exacerbations of schizophrenia. This multicenter, double-blind trial involved 191 patients allocated, after a 1 to 7-day wash-out period, to amisulpride (n = 95) or haloperidol (n = 96) for 6 weeks. Improvement of mean BPRS total score was 48% for amisulpride and 38% for haloperidol (NS), whereas improvement in the Negative PANSS subscale was greater in the amisulpride group (37%) compared to haloperidol (24%) (P = 0.038). CGI scores showed a higher number of responders in the amisulpride (62%) than in the haloperidol group (44%) (P = 0.014). More extrapyramidal symptoms measured with the Simpson-Angus scale were provoked in the haloperidol group (P = 0.0009). Amisulpride is at least as effective as haloperidol in the treatment of acute exacerbations of schizophrenia, and is more effective in the treatment of negative symptoms whilst causing less parkinsonism. Received: 13 December 1996/Final version: 12 March 1997     

No negative symptoms in healthy volunteers after single doses of amisulpride, aripiprazole, and haloperidol: a double-blind placebo-controlled trial

Noncompliance and poor outcome in patients with schizophrenia are closely related to the negative symptoms secondary to antipsychotics. No controlled study has evaluated whether amisulpride and aripiprazole induce negative symptoms. The aim of this study was to assess the effects of single doses of amisulpride, aripiprazole, haloperidol, and risperidone in healthy volunteers. Seventy-eight young volunteers took part in this double-blind, randomized, placebo-controlled, parallel study of four antipsychotics: 400 mg amisulpride, 10 mg aripiprazole, 3 mg haloperidol, and 2 mg risperidone. Assessments of negative symptoms were done 4 h after administration using both subjective rating scales (Neuroleptic Induced Deficit Syndrome Scale and Subjective Deficit Syndrome Scale) and an objective rating scale (Scale for the Assessment of Negative Symptoms). Risperidone only produced significant increases on the avolition score of the Neuroleptic Induced Deficit Syndrome Scale and blunted affect and alogia scores of the Scale for the Assessment of Negative Symptoms compared with placebo. The effect on blunted affect persisted after controlling for mental sedation. Amisulpride, aripiprazole, and haloperidol did not induce negative symptoms. Aripiprazole and risperidone induced mild extrapyramidal symptoms. The most common adverse events were somnolence and cognitive slowing. These data indicate that a single risperidone dose induces negative symptoms in normal volunteers, whereas amisulpride, aripiprazole, and haloperidol do not. These characteristics of antipsychotics should be considered when choosing optimal drugs for patients with psychosis.     

Amisulpride a selective dopamine antagonist and atypical antipsychotic: results of a meta-analysis of randomized controlled trials

The pharmacological profiles of the atypical antipsychotics, clozapine, olanzapine, quetiapine and risperidone, all show a combined serotonin (5-HT2) and dopamine type-2 (D2) receptor antagonism. Amisulpride, a highly selective dopamine D2/D3 receptor antagonist that binds preferentially to receptors in the mesolimbic system, is also an 'atypical' antipsychotic despite having a different receptor-affinity profile. A meta-analysis of 18 clinical trials was undertaken to compare the efficacy and safety of amisulpride with conventional antipsychotics. The improvement in mental state was assessed using the Brief Psychiatric Rating Scale (BPRS) or the Scale for the Assessment of Negative Symptoms (SANS). In a pooled analysis of 10 studies of acutely ill patients, amisulpride was significantly more effective than conventional neuroleptics with regard to improvement of global symptoms. Amisulpride is, to date, the only atypical antipsychotic for which several studies on patients suffering predominantly from negative symptoms have been published. In four such studies, amisulpride was significantly superior to placebo. Three small studies with conventional neuroleptics as a comparator showed only a trend in favour of amisulpride in this regard. Amisulpride was associated with fewer extrapyramidal side-effects and fewer drop-outs due to adverse events than conventional neuroleptics. These results clearly show that amisulpride is an 'atypical' antipsychotic, and they cast some doubt on the notion that combined 5-HT2-D2 antagonism is the only reason for the high efficacy against negative symptoms and fewer extrapyramidal side-effects.     

A Double-blind,Randomised Comparative Trial of Amisulpride Versus Olanzapine in the Treatment of Schizophrenia: Short-term Results at Two Months

Summary

Objective: To compare the efficacy and safety of the atypical antipsychotics amisulpride and olanzapine in the treatment of acute psychotic exacerbations of schizophrenia.

Design and setting: A multinational, double-blind randomised clinical trial.

Patients and treatment:Three hundred and seventy-seven patients with predominantly positive symptomatology were treated for six months with either amisulpride (200-800?mg/d) or olanzapine (5-20?mg/d).

Main outcome measures: Short-term results were analysed after two months of treatment. The primary efficacy measure was the change of score on the Brief Psychiatric Rating Scale (BPRS). Other measures of efficacy and safety were also evaluated.

Results: Psychotic symptoms, as measured on the BPRS score, improved with both treatments, amisulpride being equivalent to olanzapine. All BPRS factor scores, as well as depressive symptoms, improved to a similar extent with both treatments. Less than five per cent of patients withdrew for adverse events, and there was no evidence for the emergence of extrapyramidal symptoms with either treatment. Statistically significant greater weight gain (2.7?±?3.9?kg) was observed during the study in the olanzapine group, compared with the amisulpride group (0.9?±?3.2?kg, p?<?0.0001).

Conclusions: Amisulpride and olanzapine show equivalent efficacy at 2 months in the treatment of acute psychotic exacerbations of schizophrenia. Amisulpride offers a significant advantage in preserving body weight.     

Clinical efficacy of olanzapine]

The treatment of schizophrenic patients who fail adequate trials of typical neuroleptics is a major challenge. For these patients, the availability of atypical antipsychotics is a useful therapeutic advance. Olanzapine shows a superior and broader spectrum of efficacy in the treatment of schizophrenia, particularly its negative symptoms, with a substantially more favorable safety profile than conventional antipsychotic agents (e.g., haloperidol). However, little information on the clinical effects of olanzapine is available in Japan. This article provides information on the efficacy of olanzapine for various symptoms of schizophrenic patients and drug safety. Olanzapine is significantly superior to haloperidol in positive, negative, and depressive symptoms of patients, and for tardive dyskinesia and extrapyramidal symptoms. Significantly greater improvement in avolition-apathy is achieved with olanzapine as compared to risperidone. These advantages are related to high affinity at the 5-HT2 binding site, no association with an alteration in dopamine A9 firing rates, and lower D2 striatal receptor blockade of olanzapine. Treatment with 10 mg/day olanzapine is more appropriate for positive symptoms, and 12.5-17.5 mg/day olanzapine is more effective for negative symptoms. Patients will need help adapting to a new level of functioning after a successful switch to olanzapine, and overcoming the disappointment that eventually occurs when the limitations of olanzapine become apparent.     

Risperidone versus haloperidol in the treatment of acute exacerbations of chronic inpatients with schizophrenia: a randomized double-blind study.

The purpose of this study was to compare the efficacy and safety of risperidone and haloperidol in treatment-resistant chronic schizophrenic patients. Subjects (n = 78) who met DSM-III criteria for schizophrenia were randomly assigned to receive 6 mg/day of risperidone or 20 mg/day of haloperidol for 12 weeks. Clinical efficacy was determined using the Positive and Negative Syndrome Scale (PANSS), and side-effects with the Treatment Emergent Symptom Scale (TESS). Risperidone produced a mean 39.8 +/- 24.1% reduction in total PANSS score compared to a mean 28.3 + 19.4% reduction in the haloperidol group (P < 0.05). Analysis of changes for the three subscores of the PANSS revealed that the general psychopathology and negative subscores were significantly improved in the risperidone group compared to the haloperidol group. As for the side-effects, the risperidone group showed a significantly lower TESS total score, as well as nervous system symptoms subscore and cardiovascular symptoms subscore, compared to the haloperidol group. Risperidone appears to be a more effective and better tolerated antipsychotic drug in treatment-refractory Chinese schizophrenia than haloperidol.     

Aripiprazole

Aripiprazole is a quinolinone derivative and the first of a new class of atypical antipsychotics. The drug has partial agonist activity at dopamine D(2) and serotonin 5-HT(1A) receptors, and is also an antagonist at 5-HT(2A) receptors. In patients with acute relapse of schizophrenia or schizoaffective disorder, aripiprazole 15 to 30 mg/day was at least as effective as haloperidol 10 mg/day and had similar efficacy to risperidone 6 mg/day in well designed, 4-week, placebo-controlled trials. Negative symptoms improved earlier in the aripiprazole than the risperidone group. Efficacy of aripiprazole was observed at week 1 in several trials and was sustained throughout the study periods. Aripiprazole was superior to placebo in a 26-week trial in patients with stable, chronic schizophrenia. In a 52-week trial involving patients with acute relapsing disease, aripiprazole was similar to haloperidol as assessed by time to failure to maintain response and was superior in ameliorating negative and depressive symptoms. The incidence of extrapyramidal symptoms during aripiprazole therapy was similar to that with risperidone and placebo but lower than with haloperidol. Compared with placebo, the proportion of patients with increased plasma prolactin levels and QTc prolongation was similar in patients treated with aripiprazole 15 to 30 mg/day but was significantly increased with haloperidol and risperidone.