A clinical trial inclusion criteria to enrich for patients presenting with canonical symptom structure in bipolar depression.

Clinical drug development in psychiatry is challenging due to heterogeneous patient populations and the uncertainty of measuring neuropsychiatric constructs with symptom rating scales. Here we describe the development and implementation of an enrichment algorithm that identifies canonical versus anomalous symptom presentations, at the individual subject level, based on MADRS ratings obtained at screening and baseline. Data from 5 randomized, placebo-controlled, phase 3 trials in bipolar I disorder was used (N = 2026 subjects and 15,239 MADRS assessments). A variance-covariance difference (VCD) vector was developed to encode individual symptom structure using the 10 items of MADRS from the two sequential assessments. An anomaly score, calculated from each subject's VCD vector was derived by isolation forest to quantify the degree of disparity from the hypothesized canonical item structure. A retrospective application of the algorithm reliably identified a threshold anomaly score above which the psychometric properties of MADRS deteriorate. Consistent with increasing the certainty of MADRS ratings, subjects with a canonical symptom structure at baseline demonstrated greater effect sizes post-baseline in a phase 2 placebo-controlled trial of non-racemic amisulpride (SEP-4199) for bipolar depression, analyzed retrospectively. Our analyses show that the developed algorithm can reduce the symptom structure heterogeneity at baseline and thus improve the measurement certainty of psychiatric symptoms in clinical trials. This novel enrichment method has been prospectively implemented in a Phase 3 clinical study of SEP-4199 and is consistent with regulatory guidelines aimed at increasing the statistical power and lowering patient-burden in clinical trials. Clinical Trials Registry: NCT00868452, NCT00868699, NCT01284517, NCT01986101, NCT03543410, NCT05169710.

Comparative Effectiveness of Amisulpride and Clozapine in the Treatment of Schizophrenia: A Systematic Review and Meta-Analysis.

In approximately one-third of individuals with schizophrenia, the illness demonstrates a poor response to standard antipsychotic treatments. Although a relatively small proportion fails to achieve remission after the initial exposure to either first- or second-generation antipsychotic drugs, the condition often becomes progressively more resistant to medication following subsequent relapses. We conducted comprehensive searches in databases such as PubMed and PubMed Central, extracting and assessing data quality using the Cochrane risk-of-bias tool for randomized clinical trials (RCTs). A random effects model was employed to calculate the pooled prevalence and explore heterogeneity, utilizing the I2 statistic. Subgroup analyses differentiated between experimental and placebo groups, while sensitivity analyses assessed the robustness of our findings, and publication bias was examined. Our meta-analysis included a sample size of 323 patients from seven studies out of the 10 selected articles. The pooled sample evaluated the effectiveness of amisulpride and clozapine in treating schizophrenia, with Positive and Negative Syndrome Scale (PANSS)-positive and PANSS-negative scores used in the subgroup analysis. The analysis revealed a heterogeneity of 78% and a statistically significant p-value of <0.05, favoring amisulpride and clozapine for treating schizophrenia either as monotherapy or in combination. These findings indicate that the effectiveness of these drugs is statistically significant. Our study underscores the necessity of conducting larger RCTs to further elucidate the optimal dosage and guideline criteria for prescribing amisulpride, clozapine, or their combination for patients resistant to first- and second-generation antipsychotics.

Effect of amisulpride on the expression of serotonin receptors, neurotrophic factor BDNF and its receptors in mice with overexpression of the aggregation-prone [R406W] mutant tau protein.

Serotonin 5-HT7 receptors (5-HT7R) are attracting increasing attention as important participants in the mechanisms of Alzheimer's disease and as a possible target for the treatment of various tau pathologies. In this study, we investigated the effects of amisulpride (5-HT7R inverse agonist) in C57BL/6J mice with experimentally induced expression of the gene encoding the aggregation-prone human Tau[R406W] protein in the prefrontal cortex. In these animals we examined short-term memory and the expression of genes involved in the development of tauopathy (Htr7 and Cdk5), as well as biomarkers of neurodegenerative processes - the Bdnf gene and its receptors TrkB (the Ntrk2 gene) and p75NTR (the Ngfr gene). In a short-term memory test, there was no difference in the discrimination index between mice treated with AAV-Tau[R406W] and mice treated with AAV-EGFP. Amisulpride did not affect this parameter. Administration of AAV-Tau[R406W] resulted in increased expression of the Htr7, Htr1a, and Cdk5 genes in the prefrontal cortex compared to AAV-EGFP animals. At the same time, amisulpride at the dose of 10 mg/kg in animals from the AAV-Tau[R406W] group caused a decrease in the Htr7, Htr1a genes mRNA levels compared to animals from the AAV-Tau[R406W] group treated with saline. A decrease in the expression of the Bdnf and Ntrk2 genes in the prefrontal cortex was revealed after administration of AAV-Tau[R406W]. Moreover, amisulpride at various doses (3 and 10 mg/kg) caused the same decrease in the transcription of these genes in mice without tauopathy. It is also interesting that in mice of the AAV-EGFP group, administration of amisulpride at the dose of 10 mg/kg increased the Ngfr gene mRNA level. The data obtained allow us to propose the use of amisulpride in restoring normal tau protein function. However, it should be noted that prolonged administration may result in adverse effects such as an increase in Ngfr expression and a decrease in Bdnf and Ntrk2 expression, which is probably indicative of an increase in neurodegenerative processes.

Association of amisulpride and recovery room length of stay among patients with postoperative nausea and vomiting following outpatient surgery.

STUDY OBJECTIVE: Postoperative nausea and vomiting (PONV) is a common sequela of surgery in patients undergoing general anesthesia. Amisulpride has shown promise in its ability to treat PONV. The objective of this study was to determine if amisulpride is associated with significant changes in PACU efficiency within a fast-paced ambulatory surgery center. METHODS: This was a retrospective cohort study of 816 patients at a single ambulatory surgery center who experienced PONV between 2018 and 2023. The two cohorts analyzed were patients who did or did not have amisulpride among their anti-emetic regimens in the PACU during two distinct time periods (before and after amisulpride was introduced). The primary outcome of the study was PACU length of stay. Both unmatched analysis and a linear multivariable mixed-effects model fit by restricted maximum likelihood (random effect being surgical procedure) were used to analyze the association between amisulpride and PACU length of stay. We performed segmented regression to account for cohorts occurring during two time periods. RESULTS: Unmatched univariate analysis revealed no significant difference in PACU length of stay (minutes) between the amisulpride and no amisulpride cohorts (115 min vs 119 min, respectively; P = 0.07). However, when addressing confounders by means of the mixed-effects multivariable segmented regression, the amisulpride cohort was associated with a statistically significant reduction in PACU length of stay by 26.1 min (P < 0.001). CONCLUSIONS: This study demonstrated that amisulpride was associated with a significant decrease in PACU length of stay among patients with PONV in a single outpatient surgery center. The downstream cost-savings and operational efficiency gained from this drug's implementation may serve as a useful lens through which this drug's widespread implementation may further be rationalized.

Amisulpride as the antipsychotic of choice in severe psychotic disorder with comorbid impaired glucose tolerance.

Antipsychotics are the mainstay treatment for the majority of severe mental illnesses. Such patients are also more prone to develop medical comorbidities, which complicate the treatment decisions. It is estimated that up to 40% of individuals with schizophrenia have impaired glucose tolerance (IGT) or diabetes, which can be attributed to a combination of genetic, lifestyle, and medication-related factors. Some widely used antipsychotic medications like olanzapine, risperidone, and clozapine have been associated with an increased risk of weight gain, insulin resistance, and other metabolic abnormalities, which can worsen IGT and increase the risk of developing diabetes. Among second-generation antipsychotics (SGAs), amisulpride, aripirazole, and ziprasidone have a fairly low potency to cause obesity and hyperglycemia. In this context, clinicians must balance the benefits and risks of different antipsychotic medications and consider the individual's specific needs and preferences. Here, we shall discuss three cases, to ascertain how the use of amisulpride helped in glycemic control, and also reflect on probable etiologies leading to deranged glucose levels.

Efficacy and safety of low-dose amisulpride versus olanzapine-fluoxetine combination in post-schizophrenic depression: A randomized controlled trial.

Post-schizophrenic depression (PSD) increases the morbidity, mortality, and health burden in patients with schizophrenia. However, treatment of PSD is challenging due to the lack of substantial evidence of standard clinical practice. This study was aimed at comparing the efficacy and safety of low-dose amisulpride versus olanzapine-fluoxetine combination (OFC) in PSD. This was a randomized controlled trial conducted in sixty patients with PSD fulfilling the eligibility criteria. Recruited patients were randomized to receive either amisulpride at low dose (i.e., 100-300 mg/day) or OFC (5/10 mg + 20 mg) for eight weeks. The Calgary Depression Scale for Schizophrenia (CDSS), the Clinical Global Impression-Severity (CGI-S) and serum BDNF levels were assessed at baseline and after eight weeks of treatment. The change in the CDSS scores from baseline over eight weeks was significant in both the amisulpride and OFC groups. However, the changes were not significant when compared between the groups. Similarly, the changes in CGI-S scores and serum BDNF levels were significant in each group; but non-significant between the groups. A significant negative correlation was found between the changes in the CDSS scores and the serum BDNF levels in each group. No significant adverse events were noted in either group. Thus, to conclude, low-dose amisulpride can be a potential monotherapy in PSD with a favourable clinical outcome and safety profile (ClinicalTrials.gov ID: NCT04876521).

Role of prolactin in the protective effect of amisulpride against 1,2-Diacetylbenzene's neurotoxicity.

Exposure to organic solvents is associated with various health problems, including neurodegenerative diseases. Among these solvents, 1,2-diethylbenzene is notable for its ability to produce a toxic metabolite, 1,2-Diacetylbenzene (DAB), which can cause memory impairment. Prolactin (PRL) is theorized to protect the central nervous system. Certain antipsychotic drugs, known for increasing PRL secretion, have shown to improve cognitive performance in psychotic Alzheimer's patients. Among these, amisulpride stands out for its high efficacy, limited side effects, and high selectivity for dopamine D2 receptors. In our study, we explored the potential of amisulpride to inhibit DAB-induced neurotoxicity via PRL activation. Our results show that amisulpride enhances the PRL/JAK/STAT, PI3K/AKT, and BDNF/ERK/CREB pathways, playing critical roles in PRL's neuroprotection pathways and memory formation. Additionally, amisulpride inhibited DAB-triggered NLRP3 inflammasome activation and apoptosis. Collectively, these findings suggest that amisulpride may be a promising therapeutic intervention for DAB-induced neurotoxicity, partly through activating the PRL pathway.

Bioequivalence of 200 mg Amisulpride Tablets in Healthy Chinese Volunteers under Fasting and Fed Conditions.

In this study, we compared the pharmacokinetics and safety of a new generic product and a branded reference product of amisulpride tablets. Additionally, we assessed the bioequivalence of the 2 products in healthy Chinese volunteers to acquire sufficient evidence for the marketing approval of the generic drug. Thirty volunteers under fasting and fed conditions were randomly administered a single dose of the test or reference drug orally, followed by a 7-day washout period. The pharmacokinetic parameters were obtained by the concentration-time profiles, including the area under the plasma concentration-time curve (AUC) over the dosing interval, AUC from time zero to infinity, maximum plasma concentration, time to achieve maximum plasma concentration, and elimination half-life. AUC from time zero to infinity of amisulpride in the postprandial group was reduced by approximately 25%, suggesting that a high-fat diet can affect this parameter. In the aspect of safety, no serious adverse events occurred. This study demonstrated that generic and reference products of amisulpride tablets were bioequivalent in healthy Chinese volunteers under fasting and fed conditions.

Formulation, optimization and evaluation of amisulpride-loaded niosomal intranasal gel for brain targeting.

Aim: To develop stable non-ionic surfactant vesicles containing amisulpride (AMS) to improve brain uptake via nose to brain mechanism. Methods: Niosomes were developed using a modified ethanol injection technique, optimized using 32 factorial design and evaluated for the vesicle size (VS), percent encapsulation efficiency (EE), zeta potential (ZP) and % cumulative drug release (%CDR). Results: Optimized niosomes (Span-60: cholesterol ratio 0:1) showed 191.4 nm VS, 84.25% EE, -38.2 ZP and 81.31% CDR. In situ gel with these niosomes displayed 78% CDR. TEM analysis revealed spherical niosomes. Pharmacokinetic and brain tissue distribution studies in rats showed enhanced plasma and brain concentrations, indicating successful brain targeting. Conclusion: This strategy demonstrates improved AMS permeation via the nasal cavity, enhancing bioavailability for treating schizophrenia.

Schizophrenia is a serious mental illness causing intense symptoms like hallucinations and delusions. Medicines like amisulpride can help, but they have problems like not dissolving well. The brain's defenses also make it hard for medicines to work. People are trying to send medicine through the nose to avoid these problems. These researchers developed tiny carriers called niosomes to carry amisulpride to the brain via the nose. To further help with delivery of amisulpride to the brain, they added the niosomes to a gel that becomes solid inside the body. They found that the nisome-containing gel can keep medicine in the nose for a long time and is effective at delivering amisulpride to the brain.

Perioperative utility of amisulpride and dopamine receptor antagonist antiemetics-a narrative review.

Despite advances in antiemetics and protocolized postoperative nausea vomiting (PONV) management, it remains one of the most common postoperative adverse events. In patients who developed PONV despite antiemetic prophylaxis, giving a rescue treatment from the same class of medication is known to be of limited efficacy. Given the widespread use of 5-HT3 antagonists as PONV prophylaxis, another class of effective intravenous rescue antiemetic is in dire need, especially when prophylaxis fails, and rescue medication is utilized. Dopamine antagonists were widely used for the treatment of PONV but have fallen out of favor due to some of their side effect profiles. Amisulpride was first designed as an antipsychotic medication but was found to have antiemetic properties. Here we will review the historical perspective on the use of dopamine receptor antagonist antiemetics, as well as the evidence on the efficacy and safety of amisulpride.

Effects of a single dose of amisulpride on functional brain changes during reward- and motivation-related processing using task-based fMRI in healthy subjects and patients with major depressive disorder - study protocol for a randomized clinical trial.

BACKGROUND: Anhedonia and other deficits in reward- and motivation-related processing in psychiatric patients, including patients with major depressive disorder (MDD), represent a high unmet medical need. Neurobiologically, these deficits in MDD patients are mainly associated with low dopamine function in a frontostriatal network. In this study, alterations in brain activation changes during reward processing and at rest in MDD patients compared with healthy subjects are explored and the effects of a single low dose of the dopamine D2 receptor antagonist amisulpride are investigated. METHODS: This is a randomized, controlled, double-blind, single-dose, single-center parallel-group clinical trial to assess the effects of a single dose of amisulpride (100 mg) on blood-oxygenation-level-dependent (BOLD) responses during reward- and motivation-related processing in healthy subjects (n = 60) and MDD patients (n = 60). Using functional magnetic resonance imaging (fMRI), BOLD responses are assessed during the monetary incentive delay (MID) task (primary outcome). Exploratory outcomes include BOLD responses and behavioral measures during the MID task, instrumental learning task, effort-based decision-making task, social incentive delay task, and probabilistic reward task as well as changes in resting state functional connectivity and cerebral blood flow. DISCUSSION: This study broadly covers all aspects of reward- and motivation-related processing as categorized by the National Institute of Mental Health Research Domain Criteria and is thereby an important step towards precision psychiatry. Results regarding the immediate effects of a dopaminergic drug on deficits in reward- and motivation-related processing not only have the potential to significantly broaden our understanding of underlying neurobiological processes but might eventually also pave the way for new treatment options. TRIAL REGISTRATION: ClinicalTrials.gov NCT05347199. April 12, 2022.

A narrative review of non-racemic amisulpride (SEP-4199) for treatment of depressive symptoms in bipolar disorder and LB-102 for treatment of schizophrenia.

INTRODUCTION: The challenges posed by treatment-resistant schizophrenia and depressive symptoms have led to ongoing difficulties despite the availability of antipsychotics and antidepressants. This review addresses the potential of amisulpride analogs, particularly SEP-4199, in addressing these challenges through enhanced efficacy and reduced side effects. AREAS COVERED: This review focuses on the pharmacological profile of amisulpride analogs, exemplified by LB-102 and its derivative SEP-4199. PubMed gathered articles (up to 10 March 2023) on 'amisulpride,' 'schizophrenia,' 'bipolar disorder,' and 'major depressive disorder;' ClinicalTrials.gov tracked SEP-4199 and LB-102 trials. LB-102, a newly identified N-methylated analog of amisulpride, exhibits enhanced lipophilicity at lower doses, as demonstrated in a phase 1 study, indicating significant promise for therapeutic applications. The discovery of SEP-4199, a non-racemic analog composed of R- and S-enantiomers in an 85:15 ratio, is discussed, emphasizing its potential to enhance antidepressant effects while minimizing extrapyramidal side effects via selective D2 receptor binding. Recent phase 2 trials have demonstrated SEP-4199's efficacy in treating depressive symptoms in bipolar disorder I, capitalizing on D2-mediated anti-anhedonic and D3-mediated reward effects. EXPERT OPINION: The development of SEP-4199 presents a potential breakthrough for managing depressive symptoms in bipolar disorder I. Further exploration of D2 and D3 receptor-mediated effects could lead to improved treatment strategies.

Population pharmacokinetics of Amisulpride in Chinese patients with schizophrenia with external validation: the impact of renal function.

Introduction: Amisulpride is primarily eliminated via the kidneys. Given the clear influence of renal clearance on plasma concentration, we aimed to explicitly examine the impact of renal function on amisulpride pharmacokinetics (PK) via population PK modelling and Monte Carlo simulations. Method: Plasma concentrations from 921 patients (776 in development and 145 in validation) were utilized. Results: Amisulpride PK could be described by a one-compartment model with linear elimination where estimated glomerular filtration rate, eGFR, had a significant influence on clearance. All PK parameters (estimate, RSE%) were precisely estimated: apparent volume of distribution (645 L, 18%), apparent clearance (60.5 L/h, 2%), absorption rate constant (0.106 h-1, 12%) and coefficient of renal function on clearance (0.817, 10%). No other significant covariate was found. The predictive performance of the model was externally validated. Covariate analysis showed an inverse relationship between eGFR and exposure, where subjects with eGFR= 30 mL/min/1.73 m2 had more than 2-fold increase in AUC, trough and peak concentration. Simulation results further illustrated that, given a dose of 800 mg, plasma concentrations of all patients with renal impairment would exceed 640 ng/mL. Discussion: Our work demonstrated the importance of renal function in amisulpride dose adjustment and provided a quantitative framework to guide individualized dosing for Chinese patients with schizophrenia.

Amisulpride attenuates 5-fluorouracil-induced cognitive deficits via modulating hippocampal Wnt/GSK-3ß/ß-catenin signaling in Wistar rats.

Chemotherapy-induced cognitive impairment (CICI) is a general term describing cognitive dysfunction during/after treatment with chemotherapeutic agents. CICI represents a significant medical problem due to its increasing prevalence with the lack of robust therapeutic approaches. This study aimed at investigating the effects of chronic treatment with amisulpride (5 mg/kg/day) in the management of 5-fluorouracil (5-FU)-induced cognitive deficits in Wistar rats. Rats received 5 intraperitoneal injections of 5-FU (25 mg/kg every 3 days). 5-FU treatment induced impairments in spatial learning (reduction in object location discrimination ratio) and non-spatial learning (reduction in novel object recognition discrimination ratio). Moreover, 5-FU induced a decrease in the activity of the Wnt/GSK-3ß/ß-catenin pathway with a decrease in brain-derived neurotrophic factor (BDNF) level in the hippocampus. These changes were associated with an increase in the expression of the pro-inflammatory cytokines; tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß), in hippocampal tissue sections accompanied by a decrease in the number of Ki-67 positive cells (indicating a decrease in proliferative capacity), a decrease in the Nissl's granules optical density (denoting neurodegeneration), a decrease in the number of viable intact neurons with an increase in the expression of ß-amyloid and caspase-3. Amisulpride enhanced Wnt/GSK-3ß/ß-catenin signaling, increased BDNF levels, and abrogated 5-FU-induced neuroinflammation, apoptosis, ß-amyloid accumulation, and neurodegenerative changes with an improvement of cognitive performance. This study draws attention to the pro-cognitive effects of amisulpride in 5-FU-exposed rats that could be attributed to enhancing hippocampal Wnt/GSK-3ß/ß-catenin signaling pathway, and this could offer a promising therapeutic option for subjects with CICI.

Repetitive transcranial magnetic stimulation combined with olanzapine and amisulpride for treatment-refractory schizophrenia.

BACKGROUND: Treatment-refractory schizophrenia (TRS), accounting for approximately 30% of all schizophrenia cases, has poor treatment response and prognosis despite treatment with antipsychotic drugs. AIM: To analyze the therapeutic effectiveness of repetitive transcranial magnetic stimulation (rTMS) combined with olanzapine (OLZ) and amisulpride (AMI) for TRS and its influence on the patient's cognitive function. METHODS: This study enrolled 114 TRS patients who received treatment at the First Affiliated Hospital of Zhengzhou University between July 2019 and July 2022. In addition to the basic OLZ + AMI therapy, 54 cases of the control group (Con group) received modified electroconvulsive therapy, while 60 cases of the research group (Res group) received rTMS. Data on therapeutic effectiveness, safety (incidence of drowsiness, headache, nausea, vomiting, or memory impairment), Positive and Negative Symptom Scale, Montreal Cognitive Assessment Scale, and Schizophrenia Quality of Life Scale were collected from both cohorts for comparative analyses. RESULTS: The Res group elicited a higher overall response rate and better safety profile when compared with the Con group. Additionally, a significant reduction was observed in the post-treatment Positive and Negative Symptom Scale and Schizophrenia Quality of Life Scale scores of the Res group, presenting lower scores than those of the Con group. Furthermore, a significant increase in the Montreal Cognitive Assessment Scale score was reported in the Res group, with higher scores than those of the Con group. CONCLUSION: The treatment of TRS with rTMS and OLZ + AMI is effective and safe. Moreover, it can alleviate the patients' mental symptoms, improve their cognitive function and quality of life, and has a high clinical application value.

Amisulpride Decreases Tau Protein Hyperphosphorylation in the Brain of OXYS Rats.

AIM: In this study, OXYS rats of three ages (1, 3, and 6 months), a proven model of Alzheimer's disease (AD), at various stages of disease progression were used to thoroughly study the effects of amisulpride on behavior and tau protein phosphorylation. BACKGROUND: With the growing number of patients with AD, the problem of finding a cure is very acute. Neurodegeneration in AD has various causes, one of which is hyperphosphorylation of tau protein. OBJECTIVE: This study aimed to investigate whether amisulpride would affect pathological tau phosphorylation in AD. METHODS: We assessed the influence of chronic administration of amisulpride (3 weeks, 3 mg/kg per day, intraperitoneally)-a 5-HT7 receptor inverse agonist-on behavior and tau hyperphosphorylation in OXYS rats (at ages of 1, 3, and 6 months). RESULTS: Chronic administration of amisulpride dramatically decreased tau phosphorylation in the frontal cortex and hippocampus of 3-month-old OXYS rats. Additionally, in 1- and 3-month-old rats' hippocampi, amisulpride diminished the mRNA level of the Cdk5 gene encoding one of the main tau kinases involved in the 5-HT7 receptor-induced effect on tau phosphorylation. CONCLUSION: Thus, We found that chronic administration of amisulpride could reduce pathological tau hyperphosphorylation while reducing anxiety. We propose amisulpride to have therapeutic potential against AD and that it can be the most effective in the early stages of the disease.

Facial mimicry is not modulated by dopamine D2/3 and opioid receptor antagonism.

RATIONALE: According to theories of embodied cognition, facial mimicry - the spontaneous, low-intensity imitation of a perceived emotional facial expression - is first an automatic motor response, whose accompanying proprioceptive feedback contributes to emotion recognition. Alternative theoretical accounts, however, view facial mimicry as an emotional response to a rewarding stimulus, and/or an affiliative signal, and thus reject the view of an automatic motor copy. OBJECTIVES: To contribute to this debate and further investigate the neural basis of facial mimicry, as well as its relation to reward processing, we measured facial reactions to dynamic happy and angry faces after pharmacologically manipulating the opioid and dopamine systems - respectively, thought to subserve 'liking' and 'wanting' of rewards. METHODS: In a placebo-controlled, double-blind experiment, 130 volunteers received in a between-subjects design 50 mg of the opioidergic antagonist naltrexone, 400 mg of the dopaminergic antagonist amisulpride, or placebo. RESULTS: Clear occurrence of facial mimicry, measured 4 h after drug intake with electromyography (EMG) of the zygomaticus major and corrugator supercilii muscles, was found. However, facial mimicry was not affected by either compound, as shown with both frequentist statistics, and a Bayesian asymptotic regression model. CONCLUSIONS: This null finding does not support the hypothesis that facial mimicry (of happiness) reflects an emotional response to a rewarding stimulus, leaving open the possibility of facial mimicry being an automatic motor copy. The results are relevant to the discussion about the psychological nature and the neural basis of facial mimicry, although they should be considered preliminary, given the challenges of interpreting null findings when targeting a novel effect of unknown size.

A 5-year retrospective study of amisulpride steady-state plasma concentration in patients with schizophrenia in real-life settings based on therapeutic drug monitoring data.

OBJECTIVE: Here, we present a retrospective analysis of the last 5 years' data collected in real-life settings as direct evidence to evaluate the optimal therapeutic window of amisulpride (AMI) for psychiatric patients. METHODS: Retrospective analysis of the therapeutic drug monitoring (TDM) results of AMI in outpatients and inpatients were obtained from the Xi'an Mental Health Center from 2017 to 2021. RESULTS: The interquartile (P25-P75) AMI concentrations ranged 212.20-574.25 ng/mL. The results showed that the proportion of outpatients who received TDM once was significantly higher than that of inpatients who received TDM once (P < 0.001), whereas the reverse was true for those who experienced TDM more than twice (P < 0.001). Higher estimated plasma concentrations were identified in inpatients, female patients, and patients over 59 years of age. Nearly 57.21% of the samples had high concentrations (>320 ng/mL). CONCLUSIONS: The optimal therapeutic reference range for AMI may require reconstruction to guide the use of AMI for the treatment of schizophrenia.

Does drug use affect the efficacy of amisulpride, aripiprazole and olanzapine in patients with schizophrenia spectrum disorders? Results from a pragmatic, randomised study.

OBJECTIVES: Drug use is prevalent in patients with schizophrenia spectrum disorders (SSD) but there is limited knowledge about the influence of drug use on the effectiveness of antipsychotic medication. This secondary explorative study compared the effectiveness of three antipsychotics in patients with SSD, with and without drug use. METHODS: The BeSt InTro multi-centre, head to head, rater-blinded randomised study compared amisulpride, aripiprazole and olanzapine over a 1-year follow-up period. All patients (n = 144) were aged ≥18 years and met the ICD-10 criteria for SSD (F20-29). Clinical symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS). The primary outcome was reduction of a PANSS positive subscale score. RESULTS: At baseline, 38% of all patients reported drug use in the last 6 months before inclusion, with cannabis as the main drug (85%), followed by amphetamine-type stimulants (45%), sedatives (26%), hallucinogens (19%), cocaine (13%), opiates (4%), GHB (4%), solvents (4%), analgesics (4%) and anabolic steroids (2%). The predominant pattern was the use of several drugs. There were no significant overall differences in the PANSS positive subscale score reduction for the three studied antipsychotics among patients either with or without drug use. In the drug use group, older patients treated with amisulpride showed a greater PANSS positive subscale score reduction during the treatment period compared to younger patients. CONCLUSION: The current study showed that drug use does not appear to affect the overall effectiveness of amisulpride, aripiprazole and olanzapine in patients with SSD. However, amisulpride may be a particularly suitable choice for older patients with drug use.

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.