NiFe-based Prussian blue analogue nanopolygons hybridized with functionalized glyoxal polymer as a voltammetric platform for the determination of amisulpride in biological samples.

A novel voltammetric platform based on pencil graphite electrode (PGE) modification has been proposed, containing bimetallic (NiFe) Prussian blue analogue nanopolygons decorated with electro-polymerized glyoxal polymer nanocomposites (p-DPG NCs@NiFe PBA Ns/PGE). Cyclic voltammetry (CV), electrochemical impedance spectroscopy (EIS), and square wave voltammetry (SWV) were utilized to investigate the electrochemical performance of the proposed sensor. The analytical response of p-DPG NCs@NiFe PBA Ns/PGE was evaluated through the quantity of amisulpride (AMS), one of the most common antipsychotic drugs. Under the optimized experimental and instrumental conditions, the method showed linearity over the range from 0.5 to 15 × 10-8 mol L-1 with a good correlation coefficient (R = 0.9995) and a low detection limit (LOD) reached, 1.5 nmol L-1, with excellent relative standard deviation for human plasma and urine samples. The interference effect of some potentially interfering substances was negligible, and the sensing platform demonstrated an outstanding reproducibility, stability, and reusability. As a first trial, the proposed electrode aimed to shed light on the AMS oxidation mechanism, where the oxidation mechanism was monitored and elucidated using the FTIR technique. It was also found that the prepared p-DPG NCs@NiFe PBA Ns/PGE platform had promising applications for the simultaneous determination of AMS in the presence of some co-administered COVID-19 drugs, which could be attributed to the large active surface area, and high conductivity of bimetallic nanopolygons.

Amisulpride as a potential disease-modifying drug in the treatment of tauopathies.

INTRODUCTION: Hyperphosphorylation and aggregation of the microtubule-associated protein tau cause the development of tauopathies, such as Alzheimer's disease and frontotemporal dementia (FTD). We recently uncovered a causal link between constitutive serotonin receptor 7 (5-HT7R) activity and pathological tau aggregation. Here, we evaluated 5-HT7R inverse agonists as novel drugs in the treatment of tauopathies. METHODS: Based on structural homology, we screened multiple approved drugs for their inverse agonism toward 5-HT7R. Therapeutic potential was validated using biochemical, pharmacological, microscopic, and behavioral approaches in different cellular models including tau aggregation cell line HEK293 tau bimolecular fluorescence complementation, primary mouse neurons, and human induced pluripotent stem cell-derived neurons carrying an FTD-associated tau mutation as well as in two mouse models of tauopathy. RESULTS: Antipsychotic drug amisulpride is a potent 5-HT7R inverse agonist. Amisulpride ameliorated tau hyperphosphorylation and aggregation in vitro. It further reduced tau pathology and abrogated memory impairment in mice. DISCUSSION: Amisulpride may be a disease-modifying drug for tauopathies.

Amisulpride withdrawal akathisia responding to aripiprazole with propranolol in first-onset psychosis: a case report.

BACKGROUND: Akathisia tends to develop as an early complication of antipsychotic treatment in a dose-dependent manner. Although withdrawal akathisia has been reported after the discontinuation or dose reduction of typical antipsychotic drugs, akathisia following atypical antipsychotic drug withdrawal remains a rare phenomenon. CASE PRESENTATION: A 24-year-old woman with an acute psychotic episode was admitted and initially treated with aripiprazole. The aripiprazole dose was titrated up to 30 mg/day over 9 days and maintained for the next 3 days; however, her psychotic symptoms persisted without change. She was switched to amisulpride, with the dose increased over 2 weeks to 1000 mg/day. Subsequently, although the patient's psychotic episode subsided, her serum prolactin levels increased markedly. After discharge, the amisulpride dose was increased to 1200 mg/day owing to auditory hallucinations and was maintained with quetiapine (100-200 mg/day) and benztropine (1 mg/day) for 13 weeks. Given the potential for hyperprolactinemia as a side effect, the amisulpride dose was reduced to 800 mg/day concurrently with the discontinuation of benztropine; however, these changes resulted in severe restlessness without other extrapyramidal symptoms. The withdrawal akathisia disappeared over 2 weeks after switching to aripiprazole (10 mg/day) with propranolol (40 mg/day) and the patient's prolactin levels had normalized after 6 months of aripiprazole monotherapy. CONCLUSIONS: The present case highlights the potential for the development of withdrawal akathisia when the dose of amisulpride is tapered abruptly. Thus, a slow tapering and careful monitoring are recommended when switching from amisulpride to other antipsychotic drugs. Furthermore, this case suggests that changing the regimen to aripiprazole with propranolol may be a potential option for amisulpride withdrawal akathisia superimposed on pre-existing hyperprolactinemia.

Cholinergic and dopaminergic effects on prediction error and uncertainty responses during sensory associative learning.

Navigating the physical world requires learning probabilistic associations between sensory events and their change in time (volatility). Bayesian accounts of this learning process rest on hierarchical prediction errors (PEs) that are weighted by estimates of uncertainty (or its inverse, precision). In a previous fMRI study we found that low-level precision-weighted PEs about visual outcomes (that update beliefs about associations) activated the putative dopaminergic midbrain; by contrast, precision-weighted PEs about cue-outcome associations (that update beliefs about volatility) activated the cholinergic basal forebrain. These findings suggested selective dopaminergic and cholinergic influences on precision-weighted PEs at different hierarchical levels. Here, we tested this hypothesis, repeating our fMRI study under pharmacological manipulations in healthy participants. Specifically, we performed two pharmacological fMRI studies with a between-subject double-blind placebo-controlled design: study 1 used antagonists of dopaminergic (amisulpride) and muscarinic (biperiden) receptors, study 2 used enhancing drugs of dopaminergic (levodopa) and cholinergic (galantamine) modulation. Pooled across all pharmacological conditions of study 1 and study 2, respectively, we found that low-level precision-weighted PEs activated the midbrain and high-level precision-weighted PEs the basal forebrain as in our previous study. However, we found pharmacological effects on brain activity associated with these computational quantities only when splitting the precision-weighted PEs into their PE and precision components: in a brainstem region putatively containing cholinergic (pedunculopontine and laterodorsal tegmental) nuclei, biperiden (compared to placebo) enhanced low-level PE responses and attenuated high-level PE activity, while amisulpride reduced high-level PE responses. Additionally, in the putative dopaminergic midbrain, galantamine compared to placebo enhanced low-level PE responses (in a body-weight dependent manner) and amisulpride enhanced high-level precision activity. Task behaviour was not affected by any of the drugs. These results do not support our hypothesis of a clear-cut dichotomy between different hierarchical inference levels and neurotransmitter systems, but suggest a more complex interaction between these neuromodulatory systems and hierarchical Bayesian quantities. However, our present results may have been affected by confounds inherent to pharmacological fMRI. We discuss these confounds and outline improved experimental tests for the future.

The Opioid Interactions of the Antipsychotic Medications Risperidone and Amisulpride in Mice and Their Potential Use in the Treatment of Other Non-Psychotic Medical Conditions.

Pain is defined as an unpleasant sensory and emotional experience associated with actual or potential tissue damage. The opioid epidemic in the USA has highlighted the need for alternative treatments for pain. Following reports on the opioid interactions of various antipsychotic medications, we speculated that the involvement of the opioid system in some of the antipsychotics' mechanism of action may suggest their potential use in the treatment of pain. Risperidone is a neuroleptic with a potent dopamine D2 and serotonin 5-HT2 receptor-blocking activity as well as a high affinity for adrenergic and histamine H1 receptors. Amisulpride is a neuroleptic which selectively blocks dopamine D2 and D3 receptors. Both had a potent antinociceptive effect on ICR mice tested with a tail flick assay. That effect on both medications was antagonized by naloxone, indicating that at least some of the antinociceptive effects were mediated by an opioid mechanism of action. Further investigation found that ß-Funaltrexamine hydrochloride (ß-FNA), naloxonazine, and nor-Binaltorphimine dihydrochloride (nor-BNI) reversed the antinociceptive effect of both risperidone and amisulpride. Naltrindole at a dose that blocked [D-Pen2,D-Pen5]enkephalin (DPDPE, δ analgesia) blocked notably amisplride effect and only partially reversed that of risperidone. Risperidone induced an antinociceptive effect, implying involvement of µ and κ-opioid and δ-opioid mechanisms. Amisulpride-induced antinociception was mediated through selective involvement of all three opioid receptor subtypes. These findings emphasize the need for clinical trials to assess the possibility of extending the spectrum of medications available for the treatment of pain.

A novel and sensitive method for determination of amisulpride in human plasma by two-dimensional liquid chromatography.

A novel and sensitive heart-cutting two-dimensional liquid chromatography with ultraviolet detection method (2D-LC-UV) was developed and validated for determination of amisulpride in human plasma. The 2D-LC system consists of a first dimensional (1 D) LC column and a middle transfer column as well as a second-dimensional (2 D) LC column. After simple protein precipitation, the sample was directly injected into the introduction valve of the 2D-LC system. The 1 D column, playing a role of primary separation and preconcentration for complex plasma matrices, transferred the targets to the intermediate column. Following capture of targets on the middle column online, the analytes were transferred to the 2 D separation column by a six-port valve. The 2 D column, avoiding interference from the plasma matrix, completed further separation and quantification. An assistant pump was optimized for primary enrichment as well as final elution in the heart-cutting mode. The analytical time of amisulpride was 7.401 min. The accuracy was between 0.48 and 8.49%, while the intra- and inter-day precisions ranged from 0.9 to 3.1% and from 1.7% to 3.3%, respectively. The linear range of amisulpride was 48.15-2,407.59 ng/ml, while the extraction recovery was 98.7-101.3%. The strategy established in the study, which was successfully applied to therapeutic drug monitoring of amisulpride for routine clinical detection, displays high sensitivity, good repeatability, convenience and low cost.

Prediction of Self-Report Cognitive Function for the Symptomatic Remission in Schizophrenia Treated with Amisulpride: a Multicenter, 8-Week Case-Control Study.

This study aimed to determine whether self-report cognitive function is a predictor of symptomatic remission in amisulpride-treated schizophrenia. Patients with DSM-IV schizophrenia diagnoses who received amisulpride treatment, were recruited. Each patient received amisulpride with a flexible-dose strategy of 400-800 mg daily for eight weeks. Remission was defined by a shorter version of the Positive and Negative Symptom Scale(PANSS)criteria, which includes six items (PANSS-6) with scores of less than three in each item(criteria A) or total six scores of less than fourteen(criteria B). Three hundred and three patients completed the study in 15 hospitals in China. By criteria A, 244 (80.5%) achieved symptomatic remission at endpoint, and 258 (85.1%) by criteria B. Duration of illness (DOI) (criteria A: t = 2.31, P = 0.025,criteria B:t = 2.24,p = 0.026) and perceived deficits questionnaire at baseline (PDQ20 Day0) (criteria A: t = 3.32, P = 0.001,criteria B:t = 2.76,p = 0.006) in remission groups were less than that in non-remission groups. Logistic regression analysis took into account sex, age, age-onset, DOI, and PDQ20(Day0), and showed that PDQ20(Day0) was a predictor for symptomatic remission in criteria A (B = - 0.02, P = 0.014) and criteria B (B = - 0.03, P = 0.005). The odds ratio (OR) of achieving remission will be reduced by 2% in criteria A and 3% in criteria B. There were no significant differences in gender composition, age, BMI, education level, age-onset, a daily dose of amisulpride and the percentage of PDQ20 Improvement between remission and nonremission in criteria A or criteria B. Receiver operating characteristic(ROC) curves were found for PDQ20(Day0) to define the precise scores to predict remission of schizophrenia (criteria A:AUC = 0.614, S.E. = 0.041, 95% CI = 0.535-0.694, p = 0.007; criteria B:AUC = 0.633, S.E. = 0.045, 95% CI = 0.545-0.721, p = 0.005). Our data suggest that an early self-report cognitive function in amisulpride-treated schizophrenia is important in predicting for symptomatic remission, the fewer scores of PDQ20 at baseline mean the patients have less daily cognitive difficulty, the more likely the patient is to achieve symptomatic remission.

Effect of haloperidol and amisulpride on the production of malondialdehyde in reaction to free radical attack on deoxyrybosis.

Knowledge of free radicals has a huge impact on the development of medicine not only because of diseases caused by reactive oxygen species, but also because of their harmful role in the pharmacotherapy of various diseases. Hence, many researchers are looking for both the mechanisms responsible for induction of oxidative stress in the body, and an effective method to scavenge free radicals. AIM: The aim of our study was to test the in vitro antioxidant properties of two known neuroleptics - haloperidonol and amisulpride, which are commonly used in the treatment of schizophrenia. MATERIALS AND METHODS: The study took advantage of the properties of hydroxyl radical degrading deoxyrybosis to malondialdehyde (MDA). Fenton reaction was used to produce the free radical. For this purpose, deoxyrybosis was incubated under appropriate conditions with FeSO4 (0.5mM), EDTA (1mM), H2O2 (14mM) and haloperidol or amisulpride at 1, 5, 20 or 50 umol/l concentrations. A clean system (containing no medicines) was a positive control. Thiobarbituric acid (TBA) was subsequently added to the reaction mixtures in the presence of trichloroacetic acid. RESULTS: The study took advantage of the properties of hydroxyl radical degrading deoxyrybosis to malondialdehyde (MDA). Fenton reaction was used to produce the free radical. For this purpose, deoxyrybosis was incubated under appropriate conditions with FeSO4 (0.5mM), EDTA (1mM), H2O2 (14mM) and haloperidol or amisulpride at 1, 5, 20 or 50 umol/l concentrations. A clean system (containing no medicines) was a positive control. Thiobarbituric acid (TBA) was subsequently added to the reaction mixtures in the presence of trichloroacetic acid. CONCLUSIONS: The results demonstrated that both haloperidol and amisulpride inhibit the degradation of deoxyrybosis to MDA, so they show antioxidant properties under the test conditions.

Chronic form of Pisa syndrome after prolonged exposure to low-dose amisulpride treatment.

Pisa syndrome is a movement problem defined by tonic, sustained lateral flexion with a slight posterior rotation of the trunk. It seems to be a side effect of antipsychotic medicine in most cases. The clinical duration of Pisa syndrome can be acute, chronic, or recurrent. As far as we know, no reports are available in the literature on the chronic form of Pisa syndrome caused by low-dose amisulpride. A case of refractory tardive dystonia form of Pisa syndrome during treatment with stable low-dose amisulpride is presented in this report. Long-term, low-dosage amisulpride therapy may induce tardive dystonia even in patients with no other risk factors for dystonia.

Amisulpride and l-DOPA modulate subcortical brain nuclei connectivity in resting-state pharmacologic magnetic resonance imaging.

The precise understanding of the dopaminergic (DA) system and its pharmacological modifications is crucial for diagnosis and treatment of neuropsychiatric disorders, as well as for understanding basic processes, such as motivation and reward. We probed the functional connectivity (FC) of subcortical nuclei related to the DA system according to seed regions defined according to an atlas of subcortical nuclei. We conducted a large pharmaco-fMRI study using a double-blind, placebo-controlled design, where we examined the effect of l -DOPA, a dopamine precursor, and amisulpride, a D2/D3-receptor antagonist on resting-state FC in 45 healthy young adults using a cross-over design. We examined the FC of subcortical nuclei with connection to the reward system and their reaction to opposing pharmacological probing. Amisulpride increased FC from the putamen to the precuneus and from ventral striatum to precentral gyrus. l -DOPA increased FC from the ventral tegmental area (VTA) to the insula/operculum and between ventral striatum and ventrolateral prefrontal cortex and it disrupted ventral striatal and dorsal caudate FC with the medial prefrontal cortex. In an exploratory analysis, we demonstrated that higher self-rated impulsivity goes together with a significant increase in VTA-mid-cingulate gyrus FC during l -DOPA-challenge. Therefore, our DA challenge modulated distinct large-scale subcortical connectivity networks. A dopamine-boost can increase midbrain DA nuclei connectivity to the cortex. The involvement of the VTA-cingulum connectivity in dependence of impulsivity has implications for diagnosis and therapy in disorders like ADHD.

A systematic review and combined meta-analysis of concentration of oral amisulpride.

AIMS: Amisulpride, a first-line schizophrenia treatment, has shown large interindividual variability in plasma/serum levels, often outside the reference range (100-320 ng/mL). This study aims to clarify the impact of dose, sex, age and related factors for the interpatient variability in amisulpride plasma/serum concentration. METHODS: Both English and Chinese databases were searched from their inception to May 16, 2019, using the terms: amisulpride and (plasma OR serum OR blood OR "drug monitoring" OR concentration). Studies reporting concentrations and either a dose, associated factor, clinical outcome or side effect were included. RESULTS: Fourteen studies with 1628 participants were eventually included. Eligible articles yielded data on drug concentration and dose, averaging 333.9 (95% confidence interval [CI]: 294.5-373.3) ng/mL and 636.2 (95% CI: 549.7-722.6) mg/d, respectively. The calculated mean concentration-to-dose (C/D) ratio was 0.60 (95% CI: 0.52-0.67) (ng/mL)/mg. Subgroup analysis suggested that female patients on combined lithium-amisulpride have higher concentration levels and C/D ratios. Age was slight positive associated with C/D ratio while not for plasma level. Smoker patients have high concentration level than nonsmoking patients but not for C/D. Responsive and nonresponsive groups did not differ in concentration and C/D. CONCLUSION: Pooled concentration levels of amisulpride were higher than recommended with wide individual variation, especially in older patients, female patients and patients taking amisulpride combined with lithium. The specific therapeutic reference range for amisulpride may require reconstruction, which should consider the influence of age, sex, kidney function, drug-drug interactions, different dose regimens and sampling times in future study.

Efficacy of amisulpride on postoperative nausea and vomiting: a systematic review and meta-analysis.

AIM AND BACKGROUND: Postoperative nausea and vomiting (PONV) remains a significant clinical problem for surgical patients. Amisulpride is a well-studied D2/D3 antagonist that has the potential to be used for preventing and treating PONV. Our aim was to assess the efficacy and safety of amisulpride for prevention and treatment of PONV through a systematic review and meta-analysis. METHOD: A systematic literature search was performed using MEDLINE, EMBASE, PUBMED, clinicaltrials.gov, and the Cochrane Central Register of Controlled Trials from their inception to Feb 15th, 2019. The efficacy outcome was the incidence of complete response, defined as no emesis and no rescue antiemetic use in a 24-h period after study drug administration. The safety outcomes were the adverse effects associated with amisulpride. RESULTS: Five studies comprising 3243 patients met inclusion critieria. Compared with placebo, amisulpride showed a significantly improved incidence of complete response [relative risk (RR): 1.30; 95% confidence interval (CI): 1.20-1.41; P < 0.00001, I2 = 0%] with firm evidence from the trial sequential analysis. Particularly, the amisulpride at 5 mg dose indicated a significant benefit than placebo [relative risk (RR): 1.28; 95% confidence interval (CI): 1.18-1.39; P < 0.00001, I2 = 4%]. The adverse event profile of amisulpride was generally similar to the placebo. CONCLUSION: Based on our findings, low-dose, intravenous amisulpride is safe and efficacious for the prevention and treatment of PONV compared to placebo. Further studies are needed to explore the optimal dose and timing. CLINICAL TRIAL REGISTRATION: PROSPERO: CRD42019121483.

A randomized double-blind controlled trial to assess the benefits of amisulpride and olanzapine combination treatment versus each monotherapy in acutely ill schizophrenia patients (COMBINE): methods and design.

This report presents the rationale and design of a multi-center clinical trial that examines the efficacy and safety of antipsychotic combination treatment in acutely ill schizophrenia patients compared to antipsychotic monotherapy. Antipsychotic combination treatment is common in clinical practice worldwide, despite clinical guidelines generally not recommending such practice due to lacking evidence for its efficacy and safety. Olanzapine has a related chemical structure and comparable receptor-binding profile as clozapine, which demonstrated superior efficacy in combination studies, but has a more unfavorable side-effect profile compared to olanzapine. Amisulpride and olanzapine have shown promising therapeutic efficacy in meta-analyses in monotherapy for people with schizophrenia. Combining amisulpride and olanzapine, complementary receptor-binding properties may enhance efficacy and possibly reduce (or at least not augment) side effects due to the different receptor profiles and metabolization pathways. Accordingly, we hypothesize that patients treated with amisulpride plus olanzapine show greater improvement on the Positive and Negative Syndrome Scale total score after 8 weeks versus either monotherapy. A randomized, double-blind controlled trial is performed at 16 German centers comparing flexibly dosed monotherapy of oral amisulpride (400-800 mg/day), and olanzapine (10-20 mg/day) and amisulpride-olanzapine co-treatment. Sample size was calculated to be n = 101 per treatment arm, assuming an effect size of 0.500 and a two-sided alpha = 0.025 and beta = 0.90. Recruitment for this trial started in June 2012. Until December 2018, 328 patients have been randomized. Trial conduct has been extended to reach the projected sample size. Publication of the study results is expected in 2019 informing an evidence-based recommendation regarding specific antipsychotic combination treatment.

c-Fos and FosB/ΔFosB colocalizations in selected forebrain structures after olanzapine, amisulpride, aripiprazole, and quetiapine single administration in rats preconditioned by two different mild stressors sequences.

OBJECTIVE: Olanzapine (OLA), amisulpride (AMI), aripiprazole (ARI), and quetiapine (QUE) belong to antipsychotics, which administration represents still most reliable way for the treatment of schizophrenic and bipolar disorders. The intention of the present study was to explore whether the acute administration of a particular antipsychotic, indicated by the presence of c-Fos, will: a) stimulate neurons already activated by a long lasting homogeneous or heterogeneous stress preconditioning, indicated by the FosB/ΔFosB (ΔFosB) expression, or b) have a stimulatory effect only on a not activated, so called silent neurons. The pattern of ΔFosB and c-Fos spatial relationship was investigated in three forebrain structures, including the septal ventrolateral nucleus (seVL), the striatal dorsolateral area (stDL), and the shell of the nucleus accumbens (shell). METHODS: The rats were divided into 10 groups and exposed to two types of stressors. Half of them was exposed to a sequence of homogeneous stressor - handling (HDL) and the other half to a heterogeneous stressor (CMS) daily for 20 days. CMS consisted of five types of stressors: crowding, air-puff, wet bedding, predator stress, and forced swimming applied in an unexpected order. On the 21st day of the experiment, the rats were free of the stress exposure and on the 22nd day, both groups of animals receive a single intraperitoneal injection of vehicle (4% DMSO in saline, 0.1 ml/100 g) or OLA (5 mg/kg), AMI (20 mg/kg), ARI (10 mg/kg), and QUE (15 mg/kg). 90 min after the drugs administration the animals were transcardially perfused, brains removed, cut into 30 µm thick coronal sections, and double stained: first with ΔFosB antibody linked with Alexa488 fluorescent dye and second with c-Fos antibody linked to Alexa596 one. Quantitative evaluation of ΔFosB and c-Fos colocalizations was performed on fluorescence photomicrographs transformed into a final picture containing only yellow, green, and red colored circles. RESULTS: The data of this investigation demonstrate that ΔFosB and c-Fos colocalizations occurred in each of the three areas investigated, i.e. seVL, stDL, and shell ones, in both HDL as well as CMS preconditioned rats. The levels of ΔFosB and c-Fos colocalizations varied in the individual forebrain areas studied. From the total 22 areas measured, level of c-Fos colocalization prevailed over ΔFosB in 18 ones. However, neither c-Fos nor ΔFosB reached 100% level of colocalization in any of the forebrain areas investigated. CONCLUSION: The present findings indicate that ΔFosB and c-Fos colocalizations occurred in each of the three areas investigated, i.e. seVL, stDL, and shell, in both HDL and CMS preconditioned rats, whereas the parallel occurrence of free c-Fos as well as c-Fos colocalized with ΔFosB might speak out for a possible involvement of the c-Fos activated by antipsychotics applied in dual, i.e. short- and long-lasting, functions.

Effect of amisulpride, olanzapine, quetiapine, and aripiprazole single administration on c-Fos expression in vasopressinergic and oxytocinergic neurons of the rat hypothalamic supraoptic nucleus.

OBJECTIVE: The goal of this study was to reveal the impact of four types of atypical antipsychotics including amisulpride (AMI), olanzapine (OLA), quetiapine (QUE), and aripiprazole (ARI), with different receptor-affinity profile and dissociation constant, on the activity of hypothalamic supraoptic nucleus (SON) vasopressinergic and oxytocinergic neurons. METHODS: Male Sprague Dawley rats received a single injection of vehicle (VEH) (0.1 ml/100g), AMI (20 mg/kg), OLA (5 mg/kg), QUE (15 mg/kg/) or ARI (10 mg/kg). Ninety min after treatment, the animals were fixed by transcardial perfusion, the brains removed, and cryocut into serial coronal sections of 35 µm thickness. The sections were processed for c-Fos staining using an avidin-biotin-peroxidase complex and visualized by nickel intensified diaminobenzidine to reach black end product. Afterwards, the sections were exposed to vasopressin (AVP) and oxytocin (OXY) antibodies and the reaction product visualized by biotin-labeled fluorescent Alexa Fluor 568 dye. The data were evaluated from c-Fos and AVP or OXY merged sections. RESULTS: The present study shows that all four antipsychotics applied induced c-Fos expression in the SON. With respect to the stimulation efficacy of the individual antipsychotics, estimated based on the quantity of c-Fos-labeled AVP and OXY neurons, could be a preferential action assigned to QUE over moderate effect of ARI and lower effect to OLA and reduced effect of AMI (VEH < AMI < OLA < ARI < QUE). CONCLUSION: The present data for the first time provide an insight into the quantitative pattern of brain activity within the clusters of SON AVP and OXY cells in response to different atypical antipsychotics single treatment.

Phenotypic factors associated with amisulpride-induced weight gain in first-episode psychosis patients (from the OPTiMiSE cohort).

OBJECTIVE: Antipsychotic-induced weight gain (AiWG) is a debilitating adverse effect of most antipsychotics. First-episode psychosis patients are particularly vulnerable to the detrimental consequences of AiWG. Amisulpride has good efficacy and tolerability. We here aimed to identify the phenotypic factors associated with amisulpride-induced weight gain in first-episode psychosis patients. METHOD: Data were collected from the Optimization of Treatment and Management of Schizophrenia in Europe trial. Multivariable regression models with various phenotypic variables (N = 305) were performed with absolute AiWG and clinically relevant AiWG (≥7% AiWG) as outcomes. RESULTS: Four weeks of amisulpride treatment increased body weight from 69.7 to 72.4 kg (P < 0.001). In the regression model of absolute AiWG, unemployment (ß = 0.94, P = 0.016), younger age (ß = -0.07, P = 0.031) and absence of current comorbid major depression disorder (ß = -1.61, P = 0.034) were positively associated with absolute AiWG. In the regression model of clinically relevant AiWG, unemployment (OR = 2.83, P = 0.001), schizophreniform disorder (OR = 2.00, P = 0.025) and low baseline weight (OR = 0.97, P = 0.032) increased the likelihood of clinically relevant AiWG. CONCLUSIONS: Clinicians prescribing amisulpride should consider the relatively high susceptibility to AiWG in unemployed first-episode patients with psychosis, in particular young subjects with a diagnosis of schizophreniform disorder. We advise to carefully monitor these patients and, when needed, implement weight-reducing strategies.

Amisulpride prevents nausea and vomiting associated with highly emetogenic chemotherapy: a randomised, double-blind, placebo-controlled, dose-ranging trial.

PURPOSE: Chemotherapy-induced nausea and vomiting (CINV) remain significant clinical problems, especially in the delayed phase (24-120 h after chemotherapy). Amisulpride is a dopamine D2/D3-receptor antagonist previously shown to be an effective intravenous antiemetic. We conducted a randomised, double-blind study to characterise the dose response of oral amisulpride in delayed phase CINV. METHODS: Chemotherapy-naïve patients receiving cisplatin ≥ 70 mg/m2 or an anthracycline-cyclophosphamide regimen for breast cancer received, on day 1, 20 mg amisulpride and 8-16 mg ondansetron intravenously followed, once daily on days 2-4, by 10, 20 or 40 mg oral amisulpride or placebo. A control group receiving standard three-drug prophylaxis was enrolled for assay sensitivity purposes. The primary endpoint was complete response (CR), defined as no emesis or rescue medication use, in the delayed phase. RESULTS: Three hundred eighteen subjects were evaluable per protocol. CR rate (24-120 h) was 20% with placebo and 46% with 10 mg amisulpride (p = 0.006 after multiplicity adjustment); in the three-drug control group, it was 59%. Emesis, nausea and 0-120-h CR rate were significantly improved with 10 mg amisulpride compared to placebo. Higher doses of amisulpride were not more effective than 10 mg. In patients with acute phase CR, delayed phase CR rate was 44% for placebo, 75% for 10 mg amisulpride (p = 0.022) and 70% for the 3-drug control. No significant differences were seen between groups in safety parameters. CONCLUSIONS: Amisulpride 10 mg orally is safe and superior to placebo at preventing delayed CINV caused by highly emetogenic chemotherapy. TRIAL REGISTRATION: NCT01857232.

Spatial relationship between the c-Fos distribution and enkephalinergic, substance P, and tyrosine hydroxylase innervation fields after acute treatment with neuroleptics olanzapine, amisulpride, quetiapine, and aripiprazole in the rat septum.

OBJECTIVE: The aim of the present study was to demonstrate the spatial relationship between the c-Fos immunoreactive cells elicited by an acute treatment with neuroleptics including amisulpride (AMI), olanzapine (OLA), quetiapine (QUE), and aripiprazole (ARI) and enkephalinergic (ENK), substance P (SP), and tyrosine hydroxylase (TH) innervation fields in the rat septum. METHODS: Male Sprague Dawley rats received a single injection of OLA (5 mg), ARI (10 mg), AMI (20 mg), QUE (15 mg/kg/b.w.). Ninety min after antipsychotics administration, the animals were transcardially perfused with a fixative and the brains cryocut into serial coronal sections of 35 µm thickness. The sections were processed for c-Fos staining using an avidin-biotin-peroxidase complex and visualized by nickel intensified diaminobenzidine to reach black endproduct. Afterwards, the sections were exposed to ENK, SP, and TH antibodies and the reaction product visualized by biotin-labeled fluorescent AlexaFluor 564 dye. The data were evaluated from the sections either simultaneously illuminated with fluorescent and transmission microscope beams or after merging the separately illuminated sections in the Adobe Photoshop 7.0 software. RESULTS: ENK, SP, and TH displayed characteristic spatial images formed by a dense accumulation of immunoreactive fibers and terminals on the both sides of the septum. A dense plexus of axons formed by ENK and SP immunopositive terminals were situated predominantly in the lateral, while TH ones more medial portion of the septum. QUE and AMI activated distinct amount of c-Fos expression in cells located within the SP-immunoreactive principal innervation field. The OLA effect on the c-Fos expression was very pronounced in the ventral TH-labeled principal innervation field including the space between the ENK field ventral portion and the dorsal margin of the accumbens nucleus shell. Generally, the occurrence of c-Fos cells in the ENK-immunoreactive principal innervation field, in comparison with the surrounding septal area, was less abundant after all of the four antipsychotics treatments. CONCLUSION: The data of the present study indicate that ENK, SP, and TH innervation fields may influence separate populations of septal cells activated by AMI, OLA, QUE, and ARI and that each of these region-differently innervated cells may be associated with the functional heterogeneity of the individual lateral septal nuclei.

Enhanced Oral Absorption of Amisulpride Via a Nanostructured Lipid Carrier-Based Capsules: Development, Optimization Applying the Desirability Function Approach and In Vivo Pharmacokinetic Study.

Amisulpride (AMS), a second generation antipsychotic, suffers from low oral bioavailability (48%). This might be due to its pH-dependent solubility or being a substrate of P-glycoprotein efflux pump. Nanostructured lipid carriers (NLCs) were proposed in this study to enhance the oral absorption of AMS. AMS-NLCs were prepared by solvent evaporation technique according to (21.41.31) factorial design, whereas the type of solid lipid (tripalmitin or Gelucire® 43/1), lipid to drug ratio (7:1, 10:1, or 13:1) and type of external suspending medium (double distilled water, 0.5% TSP pH 12, 1% HPMC or 2.5% glycerin) were the independent variables. The average entrapment efficiency, particle size, polydispersity index, and zeta potential of the prepared formulations ranged from 29.01 to 69.06%, 184.9 to 708.75 nm, 0.21 to 0.59, and - 21 to - 33.55 mV, respectively. AMS-NLCs were optimized according to the desirability function to maximize the entrapment efficiency and minimize the particle size. Formulae G12, G10, and G7 with the highest desirability values of 0.915, 0.84, and 0.768, respectively, were chosen for further investigations. Novel AMS-NLCs capsules were prepared from the lyophilized formulations (TG7 and MG10) to enhance stability and increase patient compliance. The capsules were evaluated in terms of weight variation, content uniformity, and in vitro release pattern. The pharmacokinetics of AMS-NLCs capsules (formula TG7) were tested in rabbits compared to the commercial Amipride® tablets. The relative bioavailability of AMS-NLCs capsules was found to be 252.78%. In conclusion, the NLC-based capsules show potential to improve the oral bioavailability of AMS.

Optimization of maintenance therapy of Risperidone with CYP2D6 genetic polymorphisms through an extended translational framework-based prediction of target occupancies/clinical outcomes.

Risperidone, one of the second-generation antipsychotics, can efficiently target dopamine D2 and serotonin 5-HT2A receptors. There actually exists significant implication of CYP2D6 genetic polymorphisms on the metabolic kinetics of risperidone, little is known about the extent of CYP2D6 impacting human D2 and 5-HT2A receptor occupancies as well as the clinical efficacy and efficacy in schizophrenia treatment. Here we assessed the influences of CYP2D6 gene polymorphisms on human target occupancies/clinical outcomes and optimized the maintenance therapy of risperidone. A translational framework, previously developed using in vitro and in vivo information in rats, was used as the basis for integrating the effects of CYP2D6 genetic polymorphisms on target occupancies and clinical outcomes. D2 occupancy as a biomarker was related to Positive and Negative Syndrome Scale (PANSS) response and Simpson-Angus Scale (SAS). The population approach was applied to characterize pharmacokinetic and pharmacodynamic (PK/PD) profiles of risperidone. Non-compartment analysis method was performed to calculate the steady state PK/PD parameters of both risperidone and 9-hydroxyrisperidone. The predictive power of this extended translational framework was determined by comparing the predictions of target occupancies and clinical outcomes with the reported human values of risperidone at clinically suggested dosage of 4.0 mg/day. This extended translational framework was adequately used to predict human target occupancies and clinical outcomes. At the steady state, D2 ROs were 75.8%, 79.3% and 86.0% for CYP2D6 poor metabolizer (PM), intermediate metabolizer (IM) and extensive metabolizer (EM), respectively; 5-HT2A ROs were 96.4%, 97.2% and 98.4% for CYP2D6 PM, IM and EM, respectively; PANSS changes from placebo were -5.3, -7.7 and -11.3 for CYP2D6 PM, IM and EM, respectively; SAS changes from placebo were 0.13, 0.15 and 0.18 for CYP2D6 PM, IM and EM, respectively. The predictions of human D2, 5-HT2A RO, PANSS and SAS changes for risperidone with CYP2D6 genetic polymorphisms were well in line with the reported values in clinic. 5.0, 4.0 and 2.5 mg/day were the equivalent dosages of risperidone for CYP2D6 PM, IM and EM, respectively. The optimized maintenance therapy of risperidone was provided through the Three-Step method and the dosage range was 2.5-5.0 mg/day for three CYP2D6 gene groups in the present study. Taken together, our findings demonstrate that this extended translational framework not only differentiates the effects of CYP2D6 genetic polymorphisms on target occupancies and clinical outcomes, but also constitutes a scientific basis to optimize the maintenance therapy of neuropsychiatric patients in clinic.