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Some, but not all, studies have found longer duration of untreated psychosis (DUP) to be associated with poor response to treatment and more severe negative symptoms in schizophrenia. The aim of the current analysis was to investigate these parameters in a large cohort of patients in their first psychotic episode. The OPTiMiSE cohort included 446 patients with DUP up to two years, who were administered amisulpride for 4 weeks (Phase I). Patients who did not meet Andreasen remission criteria were randomized to double-blind continuation of amisulpride or olanzapine for 6 additional weeks in a blinded study (Phase II). Analyses showed that shorter DUP was associated with lower baseline CGI scores (p0.001, r = 0.184), PANSS total (p = 0.025, r = 0.106) and PANSS negative subscale scores (p = 0.023, r = 0.107). Remitters had a significantly shorter mean DUP compared to non-remitters both in Phase I (24.5 weeks ±24.3 vs. 35 weeks ± 32.2, p = 0.01, t=-2.521) and in Phase II (24.3 weeks ± 26.4 vs. 38.3 weeks ± 31.3, p = 0.031, t=-2.194). Logistic regression analyses showed a significant effect of DUP on treatment response both in phase I (p = 0.008) and phase II (p = 0.041). Linear regression analyses found that DUP significantly affects PANSS Total change at the end of phase I (p = 0.028) but not at the end of phase II (p = 0.236). Based on these findings, it is possible to conclude that shorter DUP is associated with better response to treatment, particularly during the first weeks after treatment initiation. These findings highlight the need for early identification of the first psychotic episode.

Newer, "atypical" antipsychotics carry a lower risk of motor side-effects than older, "typical" compounds. It has been proposed that a ~100-fold faster dissociation from the dopamine D2 receptor (D2R) distinguishes atypical from typical antipsychotics. Furthermore, differing antipsychotic D2R affinities have been suggested to reflect differences in dissociation rate constants (koff), while association rate constants (kon) were assumed to be similar. However, it was recently demonstrated that lipophilic accumulation of ligand in the cell interior and/or membrane can cause underestimation of koff, and as high-affinity D2R antagonists are frequently lipophilic, this may have been a confounding factor in previous studies. In the present work, a functional electrophysiology assay was used to measure the recovery of dopamine-mediated D2R responsivity from antipsychotic antagonism, using elevated concentrations of dopamine to prevent the potential bias of re-binding of lipophilic ligands. The variability of antipsychotic kon was also reexamined, capitalizing on the temporal resolution of the assay. kon was estimated from the experimental recordings using a simple mathematical model assumed to describe the binding process. The time course of recovery from haloperidol (typical antipsychotic) was only 6.4- to 2.5-fold slower than that of the atypical antipsychotics, amisulpride, clozapine, and quetiapine, while antipsychotic kons were found to vary more widely than previously suggested. Finally, affinities calculated using our kon and koff estimates correlated well with functional potency and with affinities reported from radioligand binding studies. In light of these findings, it appears unlikely that typical and atypical antipsychotics are primarily distinguished by their D2R binding kinetics.

Background Despite nearly fifty years of pharmacological research, the treatment of schizophrenia remains a challenge and clinical outcomes are still far from optimal. One of the major shortcomings in the current treatment of schizophrenia is that we have no valid criteria in clinical practice to predict who will respond to antipsychotic treatment and how long the treatment should be maintained before changing therapeutic strategy. The identification of blood-based biological markers of drug response with a good sensitivity and specificity would enable physicians to use these tests prior to choosing the antipsychotic treatment and therefore help the practitioner in his daily clinical practice. Methods Through a European consortium on Optimization of Treatment and Management of Schizophrenia in Europe (OPTiMiSE), we conducted a transcriptome analysis on 163 subjects with first episode psychosis. Patients were all treated for four weeks with amisulpride. Blood samples were collected at inclusion and after treatment and total RNA was analyzed by RNA-Seq for each patient before and after treatment as well as according to treatment outcome. After quality control, the detection of differentially expressed genes have been achieved using the DESeq. 2 package and in regards to biological processes and symptom improvement, with the aim of characterizing a biological signature of treatment response in first-episode psychosis. Results The transcription level of 10,683 expressed genes has been analyzed in peripheral blood mononuclear cells. We detected 499 and 84 genes that were differentially expressed after 4-week treatment with amisulpride in remitted and non-remitted patients, respectively, showing enrichment in differentially expressed genes in remitters when compared to non-remitters (p=0.02). We also found that for some of these genes, the expression level was significantly correlated with clinical outcome. A second analysis revealed that 39 of the 499 differentially expressed genes had a different expression level before amisulpride treatment between patients who will be in remission after 4-week treatment, suggesting these genes may help in predicting treatment response. Discussion We demonstrated here that amisulpride treatment affects gene expression in peripheral blood mononuclear cells, mainly in patients who will be in remission after four weeks of treatment, and that gene expression may be associated with symptom improvement. Further replications on independent samples are needed to confirm molecular mechanisms associated with clinical outcome and should help both in the identification of biological signatures of treatment response as well as in the development of new therapeutic strategies.

The European First Episode Schizophrenia Trial (EUFEST) included first-episode schizophrenia patients, assessing the efficacy of five antipsychotic drugs (haloperidol, amisulpride, olanzapine, quetiapine and ziprasidone) over one year. Baseline frequency of extrapyramidal symptoms (EPS) in this group of patients (n=490) was as follows: parkinsonism 10.8%, akathisia 10.0%, dystonia 1.8%, and dyskinesia 0.6%. The frequency of parkinsonism at baseline was greater in patients with a brief prior exposure to antipsychotics (≤2 weeks) compared with antipsychotic-naïve ones, and was positively correlated with the intensity of negative symptoms and negatively with depressive symptoms. After one month of treatment, the increase of parkinsonism was highest in patients receiving haloperidol (+13%), that of akathisia in patients treated with ziprasidone (+14%), and 10.1% of the patients were taking anticholinergic drugs, most frequently in the haloperidol group (24%). In 291 patients remaining on treatment after one year, both parkinsonism and akathisia had decreased: the frequency of parkinsonism was 3%, highest in the haloperidol group (9.1%), that of akathisia was 3%, highest in the quetiapine group (7.5%), and 4% of patients were taking anticholinergic drugs, most frequently those receiving haloperidol (10.5%). The results obtained suggest that in first-episode schizophrenia patients during the first year of antipsychotic treatment (in this case amisulpride, haloperidol in low doses, olanzapine, quetiapine and ziprasidone), EPS were present as manageable clinical problems.

Induction of motor disorders is considered the clinical landmark differentiating typical from atypical antipsychotics, and has been mainly correlated to dopamine D2 receptors blockade in striatum. This view is challenged by benzamides, such as amisulpride, which display low liability for motor side effects despite being D2/D3 receptors high-affinity blocking agents. These effects have been explained with the prominent presynaptic action of amisulpride or with the fast dissociation at D2 receptors, but there is scarce information on the effects of amisulpride on postsynaptic signaling. We carried out a molecular imaging study of gene expression after acute administration of haloperidol (0.8 mg/kg), amisulpride (10 or 35 mg/kg), or vehicle, focusing on postsynaptic genes that are key regulators of synaptic plasticity, such as Arc, c-fos, Zif-268, Norbin, Homer. The last one has been associated to schizophrenia both in clinical and preclinical studies, and is differentially induced by antipsychotics with different D2 receptors affinity. Topography of gene expression revealed that amisulpride, unlike haloperidol, triggers transcripts expression peak in medial striatal regions. Correlation analysis of gene expression revealed a prevalent correlated gene induction within motor corticostriatal regions by haloperidol and a more balanced gene induction within limbic and motor corticostriatal regions by amisulpride. Despite the selective dopaminergic profile of both compounds, our results demonstrated a differential modulation of postsynaptic molecules by amisulpride and haloperidol, the former impacting preferentially medial regions of striatum whereas the latter inducing strong gene expression in lateral regions. Thus, we provided a possible molecular profile of amisulpride, putatively explaining its "atypical atypicality".

Despite recent emphasis on the measurement and treatment of negative symptoms, studies of the Scale for the Assessment of Negative Symptoms (SANS) identify different symptom clusters, offer mixed support for its psychometric properties and suggest that it is shortened. The current study objective is to examine the psychometric properties of the SANS and the feasibility of a short research version of the SANS. Data were re-analyzed from three clinical trials that compared placebo and amisulpride to 60 days. Participants had chronic schizophrenia and predominantly negative symptoms (n=487). Baseline data were examined with exploratory factor analysis and Item Response Theory (IRT) to identify a short SANS. The short and original SANS were compared: with confirmatory factor analysis at endpoint; and on symptom response with mixed modeling to compare. Results showed that at baseline the SANS consisted of three factors labeled Affective-flattening, Asociality and Alogia-inattentiveness. IRT suggested a short SANS with 11 items and 3 response options. Comparisons of the original and short SANS showed: the short version was a better fit to the data based on confirmatory factor analysis at endpoint; similar significant (p

Objective: This comprehensive review and meta-analysis compared the effectiveness of olanzapine and other antipsychotics in schizophrenia treatment, defining effectiveness as time to all-cause medication discontinuation (primary) and as all-cause treatment discontinuation rates. This study examined randomized clinical trials (RCTs) and observational non-interventional studies. Experimental procedures: Schizophrenia studies that compared olanzapine with individual first- (FGAs) and/or second-generation antipsychotics (SGAs) were included in the meta-analyses. Hazard ratios (HR), risk ratios (RR), and their associated 95% confidence intervals were extracted for RCTs and observational studies. Sensitivity analyses assessed the impact of sources of funding, dose of olanzapine, and allocation concealment method on final results. Results: There were 60 RCTs (N=33,360) and 27 observational studies (N=202,591) included. On time to all-cause medication discontinuation, olanzapine was significantly better than aripiprazole, quetiapine, risperidone, ziprasidone and perphenazine for RCTs and better than amisulpride, risperidone, haloperidol, and perphenazine for observational studies. There were no significant differences between olanzapine and clozapine in RCTs or observational studies. All-cause discontinuation rates in RCTs were significantly lower for olanzapine compared to all comparators except amisulpride and clozapine. In observational studies, olanzapine was less effective than clozapine. Industry-sponsored studies favored olanzapine when compared to haloperidol and perphenazine; higher dose of olanzapine favored quetiapine and perphenazine when compared to olanzapine; method of allocation concealment did not generally affect the results. Conclusion: Using a global measure of medication effectiveness (time to all-cause medication discontinuation), olanzapine appears to be more effective – in both RCTs and observational studies – than most SGAs and FGAs, except for clozapine.

The competing hypotheses that the action onset to antipsychotic medication assumes a course of early- or a delayed-response have been tested in positive and not negative symptoms in schizophrenia. The current study aims to test the early- and delayed-onset hypotheses with regard to negative symptoms. Data were re-analyzed from three clinical trials that compared placebo or amisulpride for up to 60 day. Participants had predominantly negative symptoms of schizophrenia (n=487). Response was examined with the incremental percentage Scale for the Assessment of Negative Symptoms (SANS) reduction over time. Response to the treatment, visit and treatment–visit interaction was assessed with mixed-modeling. Effect size differences on response between the amisulpride and placebo groups were reported at each visit. Across trials, mixed modeling showed that the incremental SANS reductions by the treatment–visit interaction that tests the action–onset hypothesis were not statistically significantly different across periods. The effect size differences of medication less placebo in the incremental percent SANS reduction showed non-significant differences based on overlapping confidence intervals with a moderate improvement at 8–14 day (ES=.33; 95% CI: −.07,.31), the least improvement at 28–30 day (ES=.12; 95% CI: −.07,.31), and a moderate improvement at 42–60 day to (ES=.39, 95%, CI: .19,.60). Generally, early- and delayed-response differences to antipsychotic were limited.

A number of compounds aimed at improving cognition in schizophrenia have failed to demonstrate efficacy in Phase 2 clinical trials. Translational studies using biomarkers in surrogate populations, such as schizotypy, could be used to assess the efficacy of novel compounds. In this study, we aimed to validate the sensitivity and inter-site reliability of cognitive biomarkers (working memory (N-back), spatial working memory (SWM) and verbal fluency (VF) tasks) to detect the schizotypy phenotype and its reversal by psychotropic drugs. Healthy volunteers scoring high or average on a schizotypal personality measure (122 in each group) were randomized to receive a single dose of risperidone, amisulpride, nicotine or placebo in a double-blind, between-subject design. We found evidence for a poorer performance on N-back and VF tasks in the high schizotypy group, replicating previous research. This effect was counteracted by amisulpride on N-back: it improved working memory in high schizotypy group but impaired the controls. A similar pattern was seen in SWM and VF. We interpret this finding in the light of the dopamine enhancing action of amisulpride when given in low doses. In contrast, risperidone impaired both groups and nicotine had a beneficial effect for the low baseline performers only. These effects were consistent across sites. These data demonstrates the utility of biomarkers in detecting the effect of schizotypy and its reversal by drugs that enhance dopamine and cholinergic function. Studies using similar design could help the early assessment of potential of compounds designed to improve cognition in schizophrenia.

Antipsychotic discontinuation rates are a powerful indicator of medication effectiveness in schizophrenia. We examined antipsychotic discontinuation in the Schizophrenia Outpatient Health Outcomes (SOHO) study, a 3-year prospective, observational study in outpatients with schizophrenia in 10 European countries. Patients (n=7728) who started antipsychotic monotherapy were analyzed. Medication discontinuation for any cause ranged from 34% and 36% for clozapine and olanzapine, respectively, to 66% for quetiapine. Compared to olanzapine, the risk of treatment discontinuation before 36 months was significantly higher for quetiapine, risperidone, amisulpride, and typical antipsychotics (oral and depot), but similar for clozapine. Longer medication maintenance was associated with being socially active and having a longer time since first treatment contact for schizophrenia, whereas higher symptom severity, treatment with mood stabilizers, substance abuse, having hostile behaviour were associated with lower medication maintenance. Antipsychotic maintenance in SOHO was higher than the results of previous randomized studies.

The atypical antipsychotic drug amisulpride is a benzamide with specific antagonistic properties, which target dopamine D(2) and D(3) receptors, preferentially in the limbic system. Amisulpride is readily absorbed from the gastrointestinal tract, distributed to all body systems with little binding to plasma proteins. Elimination occurs mainly through the kidneys as unchanged drug. In contrast, hepatic metabolism is of minor significance and primarily yields two inactive metabolites. Very little is known about the plasma concentrations of amisulpride in patients at varying oral doses or about clinically relevant interactions with co-medication. The aim of the present investigation was to elucidate the factors, which affect amisulpride levels in schizophrenic patients. The plasma amisulpride levels of 85 patients with schizophrenia or schizoaffective disorder (mean age: 34.0+/-11.4 years; 40 women, 45 men) were assessed by high-performance liquid chromatography (HPLC) with fluorometric detection. The average daily dose of amisulpride was 772.3 mg (S.D. 346.7 mg) and the mean amisulpride plasma concentration was 424.4 ng/ml (S.D. 292.8 ng/ml). The interindividual variance of the amisulpride plasma concentration was high; furthermore, the plasma concentration increased linearly with the daily oral dose (r=0.50, p

Tolerability of combination of low-dose amisulpride with antidepressants in clinical practice in patient Faculty Hospital in Brno