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Background: When schizophrenia patients have insufficient response to clozapine, pharmacological augmentation is often applied. This meta-analysis summarizes available evidence on efficacy of pharmacological augmentation of clozapine treatment in schizophrenia spectrum disorder., Methods: Only double-blind randomized controlled studies were included. Primary outcome measure was total symptom severity, and secondary outcome measures were subscores for positive and negative symptoms. Effect sizes were calculated from individual studies and combined to standardized mean differences (Hedges's g)., Results: Twenty-nine studies reporting on 15 different augmentations were included. Significant better efficacy than placebo on total symptom severity was observed for lamotrigine, citalopram, sulpiride, and CX516 (a glutamatergic agonist). The positive effect of lamotrigine disappeared after outlier removal. The other positive findings were based on single studies. Significantly better efficacy on positive symptom severity was observed for topiramate and sulpiride. The effect of topiramate disappeared after outlier removal. Results for sulpiride were based on a single randomized controlled trial. Citalopram, sulpiride, and CX516 showed better efficacy for negative symptoms than placebo, all based on single studies., Conclusions: Evidence for efficacy of clozapine augmentation is currently scarce. Efficacy of lamotrigine and topiramate were both dependent on single studies with deviating findings. The effect of citalopram, sulpiride, and CX516 were based on single studies. Thus, despite their popularity, pharmacological augmentations of clozapine are not (yet) demonstrated to be superior to placebo.

Objective: To compare the effects of haloperidol, amisulpride, olanzapine, quetiapine, and ziprasidone on hostility in first-episode schizophrenia, schizoaffective disorder, or schizophreniform disorder., Method: We used the data acquired in the European First-Episode Schizophrenia Trial, an open, randomized trial (conducted in 14 countries) comparing 5 antipsychotic drugs in 498 patients aged 18-40 years with first-episode schizophrenia, schizoaffective disorder, or schizophreniform disorder. DSM-IV diagnostic criteria were used. Patients were assessed between December 23, 2002 and January 14, 2006. Most subjects joined the study as inpatients and then continued with follow-ups in outpatient clinic visits. The Positive and Negative Syndrome Scale (PANSS) was administered at baseline and at 1, 3, 6, 9, and 12 months after randomization. We analyzed the scores on the PANSS hostility item in a subset of 302 patients showing at least minimal hostility (a score > 1) at baseline. We hypothesized (1) that the treatments would differ in their efficacy for hostility and (2) that olanzapine would be superior to haloperidol. Our primary statistical analysis tested the null hypothesis of no difference among the treatment groups in change in hostility over time. Secondary analysis addressed the question of whether the effects on hostility found in the primary analysis were specific to this item. All our analyses were post hoc., Results: The primary analysis of hostility indicated an effect of differences between treatments (F(4,889) = 4.02, P = .0031). Post hoc treatment-group contrasts for hostility change showed that, at months 1 and 3, olanzapine was significantly superior (P < .05) to haloperidol, quetiapine, and amisulpride in reducing hostility. Secondary analyses demonstrated that these results were at least partly specific to hostility., Conclusions: Both hypotheses were supported. Olanzapine appears to be a superior treatment for hostility in early phases of therapy for first-episode schizophrenia, schizoaffective disorder, and schizophreniform disorder. This efficacy advantage of olanzapine must be weighed against its adverse metabolic effects and propensity to cause weight gain., Trial Registration: ISRCTN Register Identifier: ISRCTN68736636., (© Copyright 2011 Physicians Postgraduate Press, Inc.)

Objective: Atypical antipsychotics are increasingly drugs of first choice in schizophrenia. Amisulpride, a new atypical antipsychotic, is reported to be effective for both positive and negative symptoms of schizophrenia in Western countries but Indian experience is limited. The aim of the present study was therefore to conduct a trial of amisulpride versus olanzapine in Indian schizophrenia patients., Methods: Eighty adult patients of either sex were randomized to receive standard doses of the two drugs orally, in a single blind manner, for 12 weeks, with follow up at 4 and 8 weeks. Effectiveness was assessed by changes in scores on the Brief Psychiatric Rating Scale (BPRS), Scale for Assessment of Positive Symptoms (SAPS), Scale for Assessment of Negative Symptoms (SANS), and physician-administered Clinical Global Impression (CGI) scale. Tolerability was assessed by treatment-emergent adverse drug reactions (ADRs)., Results: Evaluable were 39 patients on amisulpride and 38 on olanzapine. The groups were comparable at baseline with respect to demographics, illness duration and rating scores. Final BPRS score was lower for olanzapine (33.2 +/- 9.44) than for amisulpride (37.7 +/- 9.67). SAPS and SANS scores and CGI rating improved individually in both arms but remained comparable between groups throughout the study period, but olanzapine reduced SAPS score to a greater extent. ADRs were encountered in 67.5% and 47.5% of patients (p = 0.113) on amisulpride and olanzapine, respectively. Tremor and insomnia were more frequent with amisulpride, while olanzapine caused more weight gain and sedation. No serious ADRs occurred., Conclusions: Amisulpride, although comparable to olanzapine on some measures, did not match the improvement seen with the latter drug in BPRS and SAPS scores. Despite differences in ADR profiles, overall tolerability was satisfactory for both drugs. In Indian patients, amisulpride should therefore be an alternative to olanzapine to a limited extent, such as when weight gain and sedation are undesirable.

Introduction: Hyperprolactinemia is a well-recognized side effect of antipsychotic treatment. Cabergoline, a dopamine agonist, has been introduced on the market to treat hyperprolactinemia, even secondary to antipsychotic use., Case Report: In this article, we described two schizophrenic patients who received cabergoline to treat their antipsychotic-induced hyperprolactinemia and developed a subsequent psychotic exacerbation. The first patient received amisulpride as antipsychotic medication, and the second one took risperidone and fluoxetine for her psychotic and depressive symptoms, respectively. Both patients improved significantly their psychotic symptoms in 1 week without changing their former antipsychotic regimens., Discussion: To the best of our knowledge, we found no previous report of cabergoline-induced psychotic exacerbation in schizophrenic patients who received antipsychotics. We brought up questions whether schizophrenic patients on amisulpride or with the addition of fluoxetine may have higher risk to experience psychotic worsening. We also highlighted the possible role of dose-dependent nature in cabergoline-induced psychotic exacerbation, suggesting that the single starting dose of 0.5 mg or higher might be unsafe in schizophrenic patients., Conclusion: These cases suggest that cabergoline, like other dopaminergic agents, should be used with caution in psychotic patients and the dose should be as low as possible.

It has been argued that the efficacy superiority found in meta-analyses for some of the atypical antipsychotics is an artifact of higher dropout rates due to side effects in the haloperidol group combined with last-observation-carried-forward (LOCF) analyses. We therefore reanalyzed a number of pivotal studies comparing new generation antipsychotics (NGAs) and conventional antipsychotics (CAs). A total of 5 studies (n = 1271) comparing amisulpride and 3 studies (n = 2454) comparing olanzapine with CAs were reanalyzed using original patient data. We applied 4 different models: LOCF, completer analysis, LOCF but excluding dropouts due to adverse events, and LOCF but excluding all dropouts with the exception of dropouts related to efficacy. Effect sizes expressed as standardized mean differences between NGAs and CAs based on the 4 different analysis models were compared. The overall results were not different irrespective of the model used. Single studies, however, showed higher effect sizes when LOCF instead of other models was used. Overall, it does not seem that higher dropout rates due to side effects in the haloperidol groups together with LOCF analyses consistently biased the results in favor of amisulpride and olanzapine. Because the results of the single studies, however, showed that this may occasionally be the case, future studies should look at the data from different angles applying sensitivity analyses, and they may use alternative statistics such as mixed models, which need to be developed further. Ultimately, strategies to reduce dropout rates are needed.

Objective: The aim of the study was to evaluate the efficacy of olanzapine (5 and 20 mg/day) over a 6-month period in chronic schizophrenic patients experiencing predominantly negative symptoms., Method: Two hundred and forty-four patients participated in a 6-month multicenter double-blind trial of placebo (n = 34), olanzapine 5 mg/day (n = 70), olanzapine 20 mg/day (n = 70), or amisulpride 150 mg/day (n = 70). Primary measure was the scale for the assessment of negative symptoms., Results: Olanzapine 5 mg/day showed significantly greater improvement than placebo in negative symptoms and in the Positive and Negative Syndrome Scale total score. Baseline positive symptoms were low at baseline and changed minimally. The neurological tolerance of olanzapine, amisulpride and placebo were comparable., Conclusion: Olanzapine 5 mg/day was effective in treating negative symptoms in a group of schizophrenic with predominantly negative symptoms during the stabilization phase. Improvement in positive symptoms or extrapyramidal symptoms (EPS) was unlikely to explain this result while improvement in depression may have partially contributed.

Background: Schizophrenic patients exhibit impairments in prepulse inhibition (PPI) and habituation of the acoustic startle response (ASR). Recent studies suggested that PPI deficits and habituation deficits are normalized after antipsychotic treatment. Despite clear evidence of gating and habituation mechanisms in animal models, it is still unknown which neurotransmitter systems are involved in schizophrenic patients. Thus, we compared the effects of a combined 5-HT2A/D2 and a pure D2/D3 antagonist on PPI and habituation of ASR in patients with schizophrenia., Methods: The ASR was measured in 37 acute schizophrenic patients who were randomized and double-blinded as to treatment with amisulpride or olanzapine. Patients were assessed during the first week and after four and eight weeks of treatment. Twenty healthy matched control subjects were examined likewise., Results: Schizophrenic patients showed a significant PPI deficit and significantly decreased startle amplitude at baseline. The gating deficit disappeared after antipsychotic treatment in both treatment groups. Amisulpride sensitized the startle amplitude, whereas startle amplitude was not changed by olanzapine. After correcting for startle amplitude, patients did not show a habituation deficit; however, amisulpride accelerated habituation, whereas olanzapine had no effect., Conclusions: Our findings suggest that the PPI-restoring effect of antipsychotics is probably attributed to a dopamine D2 receptor blockade.

Background: The efficacy of antipsychotics can be evaluated using the dimensional models of schizophrenic symptoms. The D2/D3-selective antagonist amisulpride has shown similar efficacy and tolerability to other atypical antipsychotics. The aim of the present study was to determine the efficacy of amisulpride on the dimensional model of schizophrenic symptoms and tolerability in latin schizophrenic patients., Method: Eighty schizophrenic patients were enrolled and 70 completed a prospective open-label 3-month study with amisulpride. The schizophrenic symptoms, psychosocial functioning and side-effects were evaluated with standardized scales., Results: The patients showed significant improvement in the five dimensions evaluated. Amisulpride (median final dose 357.1 mg/d) was well-tolerated without treatment-emergent extrapyramidal side-effects., Conclusion: Amisulpride showed efficacy on different psychopathological dimensions and was well tolerated, leading to consider this drug a first line choice for the treatment of schizophrenia.

Combined serotonin-2A (5-HT(2A)) and dopamine-2 (D2) receptor blockade has been proposed as a candidate mechanism by which second-generation antipsychotics (SGAs) improve both cognition and negative symptoms in schizophrenic patients, in contrast to antipsychotics of the first generation. The SGA amisulpride, however, only binds to D2/D3 receptors, which makes it an interesting tool to test this assumption. In a randomized controlled trial, 52 schizophrenic patients were allocated to treatment with either olanzapine (10-20 mg/day) or amisulpride (400-800 mg/day). A comprehensive neuropsychological test battery and clinical ratings were used to assess participants at inclusion and after 4 and 8 weeks. Cognitive improvements of moderate size were observed, with effect sizes similar to those obtained in previous studies on the cognitive effects of SGAs. Importantly, amisulpride was not inferior to olanzapine for any cognitive domain. Combined 5-HT(2A)/D2 receptor blockade is probably not necessary for cognitive improvement by SGAs.

Objective: This research examines how successful recommended longterm medical treatment of schizophrenic patients is following their discharge from inpatient treatment by evaluating the yearly rehospitalization rates., Methods: The sample consisted of 76 patients with schizophrenia who were admitted for the first time into Bezirkskrankenhaus Augsburg within a year. The recommended long-term medical treatment with conventional or atypical antipsychotics of patients after discharge and the one year rehospitalization rate depending on the medical treatment at time of discharge were examined., Results: After discharge from hospital more than 50 % of the observed patients were treated with atypical antipsychotics like olanzapine, risperidone or amisupride. Only 9 % were discharged with conventional neuroleptics. 38 % of the 76 observed patients had to be readmitted., Conclusions: This research shows that the beneficial properties of modern atypical antipsychotics are less favourable on a lower rehospitalization rate than expected.

Aim: 6-month multicentre, observational, open study evaluated the efficacy and tolerability of the new generation antipsychotic drug amisulpride in patients with acute schizophrenia., Method: 99 patients were included in the study, 72 (72%) completed the 6-month observation., Results: Marked improvement in CGI after 6 months of treatment was observed in 56 (56%) patients. Therapy with amisulpride reduced both positive (20% reduction of positive symptoms in the PANSS positive subscale in 78%) and negative symptoms (20% reduction of negative symptoms in the PANSS negative subscale in 77%)., Conclusion: Amisulpride was well tolerated, adverse events responsible for premature withdrawal from the study were observed only in 6% patients.

Clinician choice of an atypical antipsychotic may depend on a number of factors such as perceived efficacy, tolerability and cost. It is also important that the choice of treatment takes into consideration the previous response to treatment, experience of side-effects and personal clinical characteristics. The receptor-affinity profiles of the atypical antipsychotics differ; with the exception of amisulpride, a selective D2/D3 antagonist, all the atypical antipsychotics exhibit a greater affinity for the serotonin-2A receptors than dopamine receptors. However, there is no evidence that the variation in receptor affinities is relevant to efficacy. Indeed, the crucial factor may be fast dissociation from low affinity for the D2 receptor. Tolerability also varies between the atypical antipsychotics and the side-effect profile may be related to the receptor-affinity profile of the individual drugs. Extrapyramidal side-effects are generally less of a problem with most atypical drugs than with conventional drugs, but weight gain, loss of glycaemic control, sedation and hyperprolactinaemia remain problematic in some patients. Amisulpride is effective for the treatment of both positive and negative symptoms, and is well tolerated with regard to weight gain, glucose tolerance and sedation. In two clinical trials, the AMIRIS and SOLIANOL studies, amisulpride demonstrated clear advantages over some other atypical antipsychotics with respect to negative symptoms, depressive symptoms and weight gain.

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.

Objective: To report on a trial of adding amisulpride to clozapine., Methods: Description of six cases., Results: Six patients who had been on clozapine were commenced on amisulpride. All patients had had unwanted effects with clozapine, particularly sedation, hypersalivation, or weight gain. Five patients reported a high level of satisfaction with the regimen, having a reduction in the level of sedation and improvement in levels of motivation and energy, without recurrence of positive symptoms., Conclusion: The combined use of amisulpride and clozapine would appear to be an appropriate and beneficial treatment.

Several recent studies, albeit limited in sample number, design and generalizability, have suggested that augmentation of atypical antipsychotic medication (such as clozapine and olanzapine) with sulpiride, a substituted benzamide antipsychotic medication, may play a role in the management of treatment-resistant psychotic conditions. The objective of this study was to investigate any change in clinical symptomatology or side-effect profile in treatment-resistant schizophrenia patients receiving sulpiride in addition to olanzapine. Seventeen patients with treatment-resistant chronic schizophrenia, who were receiving olanzapine monotherapy for at least 6 months before study commencement, were randomized in a 1:1 fashion to receive either adjunctive treatment with sulpiride (study group) or to continue their pre-study treatment with olanzapine with no medication augmentation (control group), each for a period of 8 weeks. Changes in measures of positive and negative symptoms, anxiety, depression and extrapyramidal symptoms were assessed at baseline and at 8 weeks. Study observations indicated no significant differences in the changes in positive or negative symptomatology between patients receiving a combined regimen of olanzapine with sulpiride (600 mg/ day) augmentation and controls. However, a significantly greater improvement of depressive symptomatology (P < 0.05; as assessed by the Hamilton Scale for Depression) was noted in the sulpiride augmentation group. These data indicate improvement in depressive symptomatology with sulpiride augmentation of olanzapine in treatment-resistant chronic schizophrenia patients.

Background: The clinical outcome of patients suffering from schizophrenic psychoses has been considerably improved by atypical antipsychotics like clozapine and amisulpride. In patients whose symptomatology cannot be ameliorated by monotherapy, it might be necessary to combine two atypical antipsychotics. While clozapine interacts with a variety of neurotransmitter receptors, amisulpride predominantly binds with high affinity to D3/D2-dopamine receptors. Combination can be considered if a supplementary dopamine-receptor blockade is desired., Methods: We report on the therapy of 15 patients using a combination regimen of amisulpride and clozapine. Data were collected from patient records. The case reports document previous treatment attempts, describe the reason for the combination therapy, and determine its effect., Results: Major (six cases) or at least marked (eight cases) improvement of previously treatment-resistant positive and negative symptoms could be achieved by using a mean clozapine dose of 375 mg/day (serum level 0.38 mg/l) and an amisulpride dose of 527 mg/day. Additionally, by reducing the clozapine dose compared to monotherapy by 24 %, a significant reduction of side effects was observed., Conclusions: The combination of amisulpride with clozapine considerably enriches the therapeutic arsenal in cases of severe schizophrenic psychoses. Additional prospective studies are needed in order to systematically evaluate this new treatment strategy.

Objective: The "atypical" profile of the new antipsychotics clozapine, olanzapine, quetiapine, and risperidone has been linked to combined antagonism of serotonin 2 (5-HT(2)) and dopamine 2 (D(2)) receptors. Although amisulpride is a highly selective D(3)/D(2) receptor antagonist, it is assumed to have atypical properties as well. The purpose of this article was to compare the atypical profile of amisulpride with that of the 5-HT(2)/D(2) antagonists., Method: Randomized controlled trials that compared amisulpride with conventional antipsychotics or placebo for patients with schizophrenia were identified and included in a meta-analysis. The mean effect sizes found for amisulpride were compared with those of an updated meta-analysis of the 5-HT(2)/D(2) antagonists., Results: Eighteen randomized controlled trials of amisulpride (N=2,214) were found. In 11 studies of acutely ill patients it proved to be consistently more effective than conventional antipsychotics for global schizophrenic symptoms (measured with the Brief Psychiatric Rating Scale) and negative symptoms. Amisulpride is to date the only atypical antipsychotic for which several studies of patients suffering predominantly from negative symptoms have been published. In four such studies amisulpride was significantly more effective than placebo. Three small studies with conventional antipsychotics as comparators showed only a trend in favor of amisulpride in this regard. Amisulpride was associated with clearly lower use of antiparkinsonian medication and with fewer dropouts due to adverse events than conventional antipsychotics., Conclusions: These results cast some doubt on the notion that combined 5-HT(2)/D(2) antagonism is the reason that the newer antipsychotic medications are effective for negative symptoms and have fewer extrapyramidal side effects.

Amisulpride is a second-generation antipsychotic, a substituted benzamide. It appears to be an effective agent in treating schizophrenia for what are characterised as positive and negative symptoms. The recommended doses are between 400 mg/day and 800 mg/day. Amisulpride demonstrates a good global safety profile, particularly when compared with first-generation antipsychotics, such as haloperidol. There are interesting studies that point towards amisulpride's antidepressant effect in dysthymia speculative on possible roles in affective psychoses and chronic fatigue syndrome.

Amisulpride is a dopamine D2/D3-selective antipsychotic drug with potent antipsychotic efficacy in acute exacerbations of schizophrenia. It also possesses substantial efficacy in chronic schizophrenic patients with enduring predominant negative symptoms. This unique property has been demonstrated in a series of short (6 weeks) and medium-/long-term (6-12 months) double-blind placebo-controlled studies. The patients in these studies were carefully selected and assessed to avoid confounding results with non-specific changes in other symptom domains. The results not only show effects on negative symptoms at the optimal dose of 100 mg/day, but also significant improvement in global functioning. The effect observed in short-term studies was maintained over longer treatment periods (6-12 months). Amisulpride was well tolerated with a safety profile similar to placebo. These results open a new therapeutic approach for negative symptoms, one of the most disabling aspects of schizophrenia.

Clinical expectations in schizophrenia treatment have greatly increased since the introduction of new atypical antipsychotics, but the choice of therapeutic strategy has become more complex and reference guidelines are scarce. This paper summarizes the consensus of a broad range of professionals after long-term commercialization in France of an atypical antipsychotic, amisulpride. Participants were from psychiatric hospitals, private clinics, out-patients settings and research; all were experienced with the drug. Discussions focused on the practical use of amisulpride, as, in addition to the double-blind trials information, it may be useful for psychiatrists of other countries to intuitively understand the therapeutic properties of amisulpride. The topics selected include acute psychotic episodes, short- and long-term follow-up, feasibility of treating the initial phase, the elderly and switching treatments. The French experience emphasizes the central role of amisulpride as a first-line treatment of schizophrenia., (Copyright 2001 S. Karger AG, Basel.)

Amisulpride is a substituted benzamide derivative with selective binding to the D2/D3 dopamine receptor. In patients, a beneficial effect on negative signs has been demonstrated for doses up to 300 mg daily. On the other hand, amisulpride demonstrate efficacy in the treatment of classical form of schizophrenia at higher doses (400 to 800 mg/day up to 1,200 mg/day at the maximum). Five studies that included acutely ill schizophrenic patients are reviewed. All were double blind, randomized parallel group studies and the primary efficacy criterion was the BPRS total score. In these study amisulpride was at least as efficacious as haloperidol (10-30 mg), risperidone (8 mg daily), or flupentixol (25 mg daily) in controlling positive symptoms, but was significantly more effective than haloperidol on secondary negative symptoms. When quality of life (QLS) was assessed, amisulpride led to a better improvement than haloperidol. In the long term treatment of schizophrenia, amisulpride maintained antipsychotic efficacy over a 12-month period in an open randomized study. In this study, amisulpride led to a better improvement on Global Assessment of Functioning than haloperidol, the standard reference drug. Furthermore, amisulpride has a favorable benefit/risk profile and induces fewer extrapyramidal side effects than haloperidol the standard reference drug. Therefore, amisulpride is proposed for first-line treatment of schizophrenia in acute exacerbations. It contributes to favor a better social rehabilitation of schizophrenic patients.

Amisulpride is a benzamide derivative atypical antipsychotic characterized by selective blockade of dopamine D3 and D2 receptors, limbic selectivity and preferential blockade of dopamine autoreceptors at low doses. Its efficacy on predominant negative symptoms of schizophrenia at low doses, and on the positive symptoms at doses from 400 to 1,200 mg/day has been demonstrated in several controlled studies. The aim of our study was to assess the use in psychiatric clinical practice under naturalistic conditions, efficacy and safety of amisulpride and patient's ability to cope with social skills during a 3-month period of treatment with a follow-up at 6 months. A total of 445 patients (293 men and 152 women), between 18 and 45 years of age, were included in the study DSM III-R criteria of schizophrenia, paranoid type (295.3), or schizophreniform disorder (295.4) were required for inclusion. The patients received amisulpride with flexible dosage between 600 and 1,200 mg/d during a 3-month period (792 mg/d +/- 318). Evaluation was based on the Brief Psychiatric Rating Scale (BPRS), on the Positive And Negative Symptoms Scale (PANSS), and on Clinical Global Improvement scale, completed at D0, D14, D28, D60 and D90. Safety was also assessed with a comprehensive statement of adverse events and with the Simpson-Angus scale of extra pyramidal symptoms. A scale of social adaptation (Echelle d'Adaptation PsychoSociale) was completed at D0, D90 and D180. During the 3-month period of treatment, 124 patients (27.9%) dropped out the trial, including 24 cases of inefficacy and 27 cases of concomitant events. Intent-to-treat analysis showed a significant improvement of BPRS scores (40.2 vs 67.6; p < 0.0001), of positive PANSS scores (13.9 vs 27.7; p < 0.0001), and negative PANSS scores (17.45 vs 28.3; p < 0.0001) between D0 and D90. CGI results confirmed these figures. Follow-up assessment at D180 showed a sustained response on BPRS ans PANSS scores. Amisulpride was well tolerated in the study, with 21% of patients reporting adverse events, in majority psychiatric or endocrine disturbances. Only seven adverse events were assessed as serious. Extra pyramidal symptoms remained low during the study, as measured with Simpson-Angus scale. The EAPS scale showed a significant improvement of social adaptation during the treatment, with a sustained response during the 3-month follow-up period. In conclusion, 600-1 200 mg/d of amisulpride is an effective and well tolerated treatment of schizophrenic disorders, as demonstrated through this 3-month study carried in a large sample of 445 patients. Besides results suggest that under treatment with amisulpride in schizophrenic patients patients' ability to social adaptation can be improved, which could facilitate their rehabilitation.

Amisulpride is an atypical antipsychotic drug. Low doses increase dopaminergic transmission via presynaptic blockade and are effective in patients with predominantly negative (deficit) symptoms of schizophrenia. In three double-blind studies, two short-term and one medium/long-term, comparing amisulpride with placebo, 272 patients with schizophrenia were carefully selected for a predominance of negative symptoms (low severity of positive symptoms, depression and extrapyramidal side effects). Fixed daily doses of amisulpride (100 and 300 mg) were used in a 6-week dose-range finding study (104 patients). Daily doses of between 50 and 100 mg amisulpride were used in a second 6-week study (27 patients), and in a third study, 100 mg amisulpride was administered for 6 months (141 patients) with an extension of up to 1 year. Mean total scores for the Scale for the Assessment of Negative Symptoms (SANS) at baseline in the different treatment groups varied from 98 to 74, and improved significantly in the amisulpride groups (mean change from 24 to 40 points) compared with the placebo groups. Positive symptoms measured by the Scale for the Assessment of Positive Symptoms (SAPS) were low at baseline, and the change at the end of the studies was minimal. Extrapyramidal side effects were of low severity in these studies and parkinsonism scores for amisulpride were not different from placebo. Overall, these findings indicate that the improvement in negative symptoms was not linked to a concomitant improvement in positive symptoms, parkinsonism or depressive symptoms as would be expected in the case of secondary negative symptoms. The results of these studies thus confirm the efficacy of amisulpride in schizophrenic patients with primary negative or deficit symptoms at a dose of 100 mg/day.

Amisulpride is a benzamide derivative which displays a pharmacological profile distinct from that of classical neuroleptics such as haloperidol. In vitro, amisulpride selectively binds to dopamine (DA) receptors and is devoid of any affinity for serotonergic, alpha-adrenergic, histaminergic or muscarinic receptors. It has high and equal affinities for human D2 and D3 receptors, without affinity for D1 and D4 receptors. In vivo, in rats, amisulpride preferentially blocked D2 and D3 receptors localized in limbic structures in comparison with receptors found in the striatum. In addition, amisulpride selectively blocked presynaptic DA receptors. Thus, amisulpride antagonized apomorphine-induced effects (yawning, hypomotility) related to presynaptic DA receptor stimulation at very low doses (ED50 = 0.3-1 mg/kg, ip) compared to those needed to inhibit hypermotility and gnawing (60-80 mg/kg, ip) which involve post-synaptic DA receptor stimulation. The high affinity of amisulpride for D2 and D3 receptors, and its high degree of limbic selectivity may explain the lack of catalepsy in rats and the low incidence of neurological side effects in clinical studies. The enhancement of DA function produced by its selective presynaptic receptor DA blockade may account for the clinical efficacy of amisulpride against negative symptoms of schizophrenia.

The deficit forms of schizophrenia have given rise to important research and controversy for the last 15 years. It is now recognized that some negative symptoms in schizophrenia are part of a pure and primary deficit syndrome which could be related to decreased dopaminergic function and which is not well improved by standard antipsychotic drugs. Amisulpride is a substituted benzamide neuroleptic with an original pharmacologic profile. Prescription of high doses (600-1 200 mg/day) yields to an usual antipsychotic activity on positive symptoms, through the blockage of post-synaptic dopamine receptors. At low doses, amisulpride preferentially blocks presynaptic dopamine autoreceptors, with a poor affinity for striatal sites. Three recent double-blind placebo controlled studies have suggested an efficacy of low doses (50-300 mg/day) of amisulpride in deficit forms of schizophrenia. The first study was carried out in young never-treated schizophrenic patients, and showed a significant improvement of negative symptoms with a 6-week amisulpride treatment. In the second study, subjects with a long-course deficit schizophrenia were included after a 6-week wash-out period. Reduction of scores of negative symptoms (Andreasen's scale) was about twice as important in the amisulpride group compared to the placebo group, whereas positive symptoms, modest at inclusion, remained unchanged. Finally, the efficacy of amisulpride was shown in another double-blind long-term study over 6 months in patients with predominantly negative symptoms. The overall safety profile of amisulpride in these studies was good, in particular with a low incidence of extrapyramidal symptoms. Thus, amisulpride at low doses appeared to be a well tolerated treatment for various deficit forms of schizophrenia, with a short-term and long-term efficacy.

Background: The efficacy of low doses of certain neuroleptics in improving negative symptoms is still controversial. This study assessed the efficacy of amisulpride, a benzamide which increases dopaminergic transmission at low doses via presynaptic dopamine receptor blockade, on negative symptoms of schizophrenia., Method: The study was designed as a parallel-group, double-blind, placebo-controlled trial. Patients had to fulfil DSM-III criteria for schizophrenia, Andreasen's criteria for negative schizophrenia, and to have a total score of at least 75 on the SANS; those treated with neuroleptics or antidepressants underwent a six-week placebo wash-out. One hundred and four in-patients were randomly assigned to amisulpride 100 mg/d, amisulpride 300 mg/d, or placebo for six weeks; 85 patients completed the study., Results: Both amisulpride doses were significantly more effective than placebo on the primary evaluation criterion (SANS total score, MANOVA P < 0.02). No significant changes were found in positive symptoms or in extrapyramidal symptoms., Conclusions: Negative symptoms can be improved by low doses of amisulpride, favouring the hypothesis of dopaminergic hypofunction as one of the causes of negative symptoms.

Although clozapine (CLZ) is effective in resistant schizophrenia, it fails in some cases leading to a therapeutic problem. Authors report a case of schizophrenia which resists several neuroleptic trials (including haloperidol, chlorpromazine and thioproperazine) and responds to a sequence of CLZ and amisulpride. These two atypical neuroleptics have the same main target (mesolimbic system) but have different and complementary affinities to neuromediator receptors: CLZ has strong serotoninergic and anticholinergic action, noradrenergic alpha 1 affinity and moderately active dopaminergic antagonism; amisulpride has a high and specific dopaminergic D2 antagonism when used at high posology. This clinical improvement can be related to "second treatment effect", described by Goldman in 1966: his study included two groups of refractory schizophrenic patients who received successively during two 6 months periods, 2 neuroleptics (fluphenazine and trifluperazine). Without initial therapeutic response, he noted a significant improvement only after change of neuroleptic medication. Tricyclic antidepressants may turn to be effective, after an initial failure, when they are given after an uneffective ECT trial. The same model may be applied and the clozapine-amisulpride sequence is proposed as an alternative treatment in resistant schizophrenia: even if CLZ is uneffective, it may produce carryover effects which ease the action of amisulpride. The hypothesis of an action on 5HT2-D2 antagonism is advanced. It leads to the general question of the opportunity of neuroleptic sequential prescription in resistant schizophrenia as a therapeutic option.

Based on recent quantitative EEG findings of increased slow activity in negative schizophrenia indicating organicity, it was hypothesized that neuroleptics decreasing delta/theta activity should be beneficial for schizophrenics with predominantly negative symptoms. Thus, a double-blind, clinical, psychometric and neurophysiological study was carried out in 40 hospitalized patients with unproductive schizophrenia (mean age: 31 years; ICD diagnoses: 295.0, 295.1 and 295.6) who were treated randomly either with the benzamide amisulpride (AMI; n = 19) or low doses of fluphenazine (FLU; n = 21). In the first 2 weeks the daily doses were 50 mg AMI or 2 mg FLU, respectively, from the third week on up to the sixth week 100 mg AMI and 4 mg FLU. Clinical evaluations, psychometry and EEG mapping were performed on day 1 (hours 0 and 4--acute effect), on day 14 (hour 0--subacute effect) and on day 42 (hours 0 and 4--chronic and superimposed effects). Three AMI patients discontinued therapy prematurely because of productive symptoms (days 14, 28 and 35), while in the FLU group 2 patients dropped out due to depressive symptoms (days 21, 28), 1 due to productive symptoms (day 35), 1 due to ineffectiveness (day 28), and 1 because of an akinetic crisis (day 6). Statistical evaluation demonstrated a significant improvement in the AMDP apathy and Andreasen SANS score in both groups with the patients remaining severely ill as rated by the CGI. FLU-treated patients needed significantly more anticholinergic medication than the AMI-treated group. Psychometric evaluation showed in regard to the noopsyche significant improvement after subacute, chronic and superimposed AMI, while FLU-treated patients showed significant improvement only after subacute treatment. AMI was significantly superior to FLU at the hours 0 and 4 of day 42. The thymopsyche improved after subacute, chronic and superimposed administration of both compounds with a significant superiority of AMI on days 14 and 42 (4 h postdrug). EEG mapping showed a decrease of delta/theta and increase of beta activity as well as an acceleration of the centroid after acute and superimposed AMI on day 42 as compared with baseline; FLU patients exhibited a decrease of delta/theta activity and an acceleration of the total centroid too, while alpha activity was augmented and beta activity tended to be reduced. Our study demonstrated that, in addition to the new benzamide AMI, FLU in low doses may also be regarded as a neuroleptic with activating properties and may be utilized in the treatment of schizophrenics with predominantly negative symptoms.