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Background: Among psychiatric illnesses, schizophrenia remains a chronic debilitating disorder. Although newer atypical antipsychotics have shown better improvement in schizophrenia patients, they are still lacking conclusive evidence-based studies. Aims and Objectives: The comparative evaluation of amisulpride versus olanzapine in terms of therapeutic efficacy and their cost in schizophrenia patients. Materials and Methods: This was a prospective, randomized, open-label comparative study. Patients diagnosed with schizophrenia were randomly allocated into two treatment arms. One group (n = 50) was treated with olanzapine, and another group (n = 50) was treated with amisulpride. Patients were followed up for 12 weeks. Positive and negative syndrome scale score assessments were done to evaluate the efficacy parameter. Antipsychotic drug costs were also studied. Results: In the treatment duration, it was observed that the positive and negative syndrome scores were 42.7% in the olanzapine-administered group, whereas the score was 33.8% in patients treated with amisulpride. The reduction in clinical global impression (CGI) score was 57% in the olanzapine group and 37% in the amisulpride group. The cost range for amisulpride was (Rs) 52.5-115.9 and for olanzapine was (Rs) 6.7-13.1 per positive and negative syndrome score improvement. Conclusion: A significant decrease in positive and negative syndrome scores and CGI scores was evident in both groups treated with amisulpride and olanzapine, but olanzapine is more efficacious and cost-effective than amisulpride. [ABSTRACT FROM AUTHOR]

Background: Recent studies have shown that liver enzyme abnormalities were not only seen with typical antipsychotics (APs) but also with atypical antipsychotics (AAPs). During the last 20 years, the hepatotoxicity of various antipsychotics received much attention. However, systematic evaluations of hepatotoxicity associated with APs are limited. Methods: All drug related hepatic disorders cases were retrieved from the FDA Adverse Event Reporting System (FAERS) database using standardized MedDRA queries (SMQ) from the first quarter of 2017 to the first quarter of 2022. Patient characteristics and prognosis were assessed. In this study, a case/non-case approach was used to calculate reporting odds ratio (RORs) and 95% confidence intervals (CIs). We calculated the drug-induced liver injury (DILI) RORs for each AAPs. Results: A total of 408 DILI cases were attributed to AAPs during the study period. 18.6% of these were designated as serious adverse event (SAE), which include death (19.74%), hospitalization (68.42%), disability (2.63%), and life-threatening (9.21%) outcomes. The RORs values in descending order were: quetiapine (ROR = 0.782), clozapine (ROR = 0.665), aripiprazole (ROR = 0.507), amisulpride (ROR = 0.308), paliperidone (ROR = 0.212), risperidone (ROR = 0.198), ziprasidone (0.131). Conclusion: The result found in our study was that all AAPs didn't have a significant correlation with increased hepatotoxicity. Future analysis of the FAERS database in conjunction with other data sources will be essential for continuous monitoring of DILI. [ABSTRACT FROM AUTHOR]

Nonracemic amisulpride (SEP‐4199) is an investigational 85:15 ratio of aramisulpride to esamisulpride and currently in clinical trials for the treatment of bipolar depression. During testing of SEP‐4199, a pharmacokinetic/pharmacodynamic (PK/PD) disconnect was discovered that prompted the development of a controlled‐release (CR) formulation with improved therapeutic index for QT prolongation. Observations that supported the development of a CR formulation included (i) plasma concentrations of amisulpride enantiomers were cleared within 24‐hours, but brain dopamine D2 receptor (D2R) occupancies, although achieving stable levels during this time, required 5 days to return to baseline; (ii) nonracemic amisulpride administered to non‐human primates produced significantly greater D2R occupancies during a gradual 6‐hour administration compared with a single bolus; (iii) concentration–occupancy curves were left‐shifted in humans when nonracemic amisulpride was gradually administered over 3 and 6 hours compared with immediate delivery; (iv) CR solid oral dose formulations of nonracemic amisulpride were able to slow drug dissolution in vitro and reduce peak plasma exposures in vivo in human subjects. By mathematically solving for a drug distribution step into an effect compartment, and for binding to target receptors, the discovery of a novel PK/PD model (termed here as Distribution Model) accounted for hysteresis between plasma and brain, a lack of receptor saturation, and an absence of accumulation of drug occupancy with daily doses. The PK/PD disconnect solved by the Distribution Model provided model‐informed drug development to continue in Phase III using the non‐bioequivalent CR formulation with diminished QT prolongation as dose‐equivalent to the immediate release (IR) formulation utilized in Phase II. [ABSTRACT FROM AUTHOR]

Background: Shared decision-making (SDM) has yet to be successfully adopted into routine use in psychiatric settings amongst people living with severe mental illnesses. Suboptimal rates of SDM are particularly prominent amongst patients with psychotic illnesses during antipsychotic treatment choices. Many interventions have been assessed for their efficacy in improving SDM within this context, although results have been variable and inconsistent. Aims: To generate an in-depth understanding of how, why, for whom, and to what extent interventions facilitating the application of SDM during antipsychotic treatment choices work and the impact of contextual factors on intervention effectiveness. Methods: This review will use realist review methodology to provide a causal understanding of how and why interventions work when implementing SDM during antipsychotic treatment choices. The cohort of interest will be those experiencing psychosis where ongoing treatment with an antipsychotic is clinically indicated. The review will take place over five stages; (1) Locating existing theories, (2) Searching for evidence, (3) Selecting articles, (4) Extracting and organising data and (5) Synthesizing evidence and drawing conclusions. An understanding of how and why interventions work will be achieved by developing realist programme theories on intervention effectiveness through iterative literature reviews and engaging with various stakeholder groups, including patient, clinician and carer representatives. Discussion: This is the first realist review aiming to identify generative mechanisms explaining how and why successful interventions aimed at improving SDM within the parameters outlined work and in which contexts desired outcomes are most likely to be achieved. Review findings will include suggestions for clinicians, policy and decision-makers about the most promising interventions to pursue and their ideal attributes. [ABSTRACT FROM AUTHOR]

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.

Abstract Psychiatric drugs do not vanish after being carried to wastewater treatment plants by the urine or feces of patients and, a variable portion of their dose and also unused or expired drugs are lost to the environment. This is because the technology of plants is not intended to eradicate pharmaceuticals and their metabolites. Above all, psychotropics can change population dynamics and behavior at lower doses. We believe that antipsychotics have not gotten enough attention when it comes to drug pollution and that their importance as environmental pollutants has been underestimated. An innovative approach to eliminating pharmaceutical pollutants from water is the application of advanced oxidation methods. Among these oxidation methods are photocatalysis, ozonation, UV/hydrogen peroxide oxidation, and photo-Fenton oxidation. Photocatalytic degradation of pharmaceuticals is now the most widely used method since it is affordable and ecologically beneficial due to the reusable nature of the photocatalyst. When light is absorbed during photocatalytic degradation, electrons in the valence band (VB) get excited and migrate into the conduction band (CB). Consequently, hydroxyl radicals (•OH) are produced by VB’s holes carrying out oxidation processes on photocatalyst surfaces. The charge difference between the two bands encourages reduction reactions by CB electrons at the surface. To perform successfully, a photocatalyst has to have enough surface-active sites, a favorable band edge location, modest bandgap energy, increased charge separation, and charge transfer. Due to the above-mentioned concerns, the investigation and analysis of the photocatalytic degradation of six psychiatric drugs—carbamazepine, sertraline, amisulpride, amitriptyline, diazepam, and alprazolam—are the main objectives of this review.

A major effort of the pharmaceutical industry has been to identify and market drug treatments that are effective in ameliorating the symptoms of psychotic illness but without the limitations of the current treatments acting at dopamine D2 receptors. These limitations include the induction of a range of adverse effects, the inadequate treatment response of a substantial proportion of people with schizophrenia, and the generally poor response to negative and cognitive features of the disease. Recently introduced drug treatments have gone some way to avoiding the first of these, with a reduced propensity for weight gain, cardiovascular risk and extrapyramidal motor effects. Despite claims of some small improvements in negative symptoms, these drugs have not demonstrated substantial increases in efficacy. Of the drugs currently in development as antipsychotic agents, several are misleadingly described as having novel 'non-dopaminergic' mechanisms that may offer improvements in addressing the limitations of adverse effects and efficacy. It will be argued, using the trace amine-associated receptor 1 agonist as an example, that several of these new drugs still act primarily through modulation of dopaminergic neurotransmission and, in not addressing the primary pathology of schizophrenia, are therefore unlikely to have the much-needed improvements in efficacy required to address the unmet need associated with resistance to current treatments. [ABSTRACT FROM AUTHOR]

Aims: This study aimed to assess the frequency of dosing inconsistencies in prescription data and the effect of four dosing assumption strategies on adherence estimates for antipsychotic treatment. Methods: A retrospective cohort, which linked prescription and dispensing data of adult patients with ≥1 antipsychotic prescription between 2015‐2016 and followed up until 2019, in Catalonia (Spain). Four strategies were proposed for selecting the recommended dosing in overlapping prescription periods for the same patient and antipsychotic drug: (i) the minimum dosing prescribed; (ii) the dose corresponding to the latest prescription issued; (iii) the highest dosing prescribed; and (iv) all doses included in the overlapped period. For each strategy, one treatment episode per patient was selected, and the Continuous Medication Availability measure was used to assess adherence. Descriptive statistics were used to describe results by strategy. Results: Of the 277 324 prescriptions included, 76% overlapped with other prescriptions (40% with different recommended dosing instructions). The number and characteristics of patients and treatment episodes (18 292, 18 303, 18 339 and 18 536, respectively per strategy) were similar across strategies. Mean adherence was similar between strategies, ranging from 57 to 60%. However, the proportion of patients with adherence ≥90% was lower when selecting all doses (28%) compared with the other strategies (35%). Conclusion: Despite the high prevalence of overlapping prescriptions, the strategies proposed did not show a major effect on the adherence estimates for antipsychotic treatment. Taking into consideration the particularities of antipsychotic prescription practices, selecting the highest dose in the overlapped period seemed to provide a more accurate adherence estimate. [ABSTRACT FROM AUTHOR]

Psychiatric drugs do not vanish after being carried to wastewater treatment plants by the urine or feces of patients and, a variable portion of their dose and also unused or expired drugs are lost to the environment. This is because the technology of plants is not intended to eradicate pharmaceuticals and their metabolites. Above all, psychotropics can change population dynamics and behavior at lower doses. We believe that antipsychotics have not gotten enough attention when it comes to drug pollution and that their importance as environmental pollutants has been underestimated. An innovative approach to eliminating pharmaceutical pollutants from water is the application of advanced oxidation methods. Among these oxidation methods are photocatalysis, ozonation, UV/hydrogen peroxide oxidation, and photo-Fenton oxidation. Photocatalytic degradation of pharmaceuticals is now the most widely used method since it is affordable and ecologically beneficial due to the reusable nature of the photocatalyst. When light is absorbed during photocatalytic degradation, electrons in the valence band (VB) get excited and migrate into the conduction band (CB). Consequently, hydroxyl radicals (•OH) are produced by VB's holes carrying out oxidation processes on photocatalyst surfaces. The charge difference between the two bands encourages reduction reactions by CB electrons at the surface. To perform successfully, a photocatalyst has to have enough surface-active sites, a favorable band edge location, modest bandgap energy, increased charge separation, and charge transfer. Due to the above-mentioned concerns, the investigation and analysis of the photocatalytic degradation of six psychiatric drugs—carbamazepine, sertraline, amisulpride, amitriptyline, diazepam, and alprazolam—are the main objectives of this review. [ABSTRACT FROM AUTHOR]

Introduction: The RISKMet project aims to: (1) identify risk factors for metabolic syndrome (MetS) by comparing patients with and without MetS; (2) characterise patients treated with second-generation antipsychotics (SGAs) about MetS diagnosis; (3) study behavioural patterns, including physical activity (PA) and dietary habits, in patients and healthy individuals using a prospective cohort design. Method: The RISKMet project investigates MetS in individuals treated with SGAs, focusing on both adult and paediatric populations. The study utilizes a case-control design to examine potential risk factors for MetS, categorizing participants as MetS+ considered as "Cases" and MetS- considered as "Controls" matched by sex and age. The evaluation of factors such as MetS, lifestyle habits, and environmental influences is conducted at two time points, T0 and T3, after 3 months. Subsequently, the project aims to assess body parameters, including physical examinations, and blood, and stool sample collection, to evaluate metabolic markers and the impact of SGAs. The analysis includes pharmacological treatment data and genetic variability. Behavioural markers related to lifestyle, eating behaviour, PA, and mood are assessed at both T0 and T3 using interviews, accelerometers, and a mobile app. The study aims to improve mental and physical well-being in SGA-treated individuals, establish a biobank for MetS research, build an evidence base for physical health programs, and develop preventive strategies for SGA-related comorbidities. Conclusions: This project innovates MetS monitoring in psychiatry by using intensive digital phenotyping, identifying biochemical markers, assessing familial risks, and including genetically similar healthy controls. Study registration number: ISRCTN18419418 at www.isrctn.com. [ABSTRACT FROM AUTHOR]

Background: Treatment effects of conventional approaches with antipsychotics or psychosocial interventions are limited when it comes to reducing negative and cognitive symptoms in schizophrenia. While there is emerging clinical evidence that new, augmented protocols based on theta-burst stimulation can increase rTMS efficacy dramatically in depression, data on similar augmented therapies are limited in schizophrenia. The different patterns of network impairments in subjects may underlie that some but not all patients responded to given stimulation locations. Methods: Therefore, we propose an augmented theta-burst stimulation protocol in schizophrenia by stimulating both locations connected to negative symptoms: (1) the left dorsolateral prefrontal cortex (DLPFC), and (2) the vermis of the cerebellum. Ninety subjects with schizophrenia presenting negative symptoms and aging between 18 and 55 years will be randomized to active and sham stimulation in a 1:1 ratio. The TBS parameters we adopted follow the standard TBS protocols, with 3-pulse 50-Hz bursts given every 200 ms (at 5 Hz) and an intensity of 100% active motor threshold. We plan to deliver 1800 stimuli to the left DLPFC and 1800 stimuli to the vermis daily in two 9.5-min blocks for 4 weeks. The primary endpoint is the change in negative symptom severity measured by the Positive and Negative Syndrome Scale (PANSS). Secondary efficacy endpoints are changes in cognitive flexibility, executive functioning, short-term memory, social cognition, and facial emotion recognition. The difference between study groups will be analyzed by a linear mixed model analysis with the difference relative to baseline in efficacy variables as the dependent variable and treatment group, visit, and treatment-by-visit interaction as independent variables. The safety outcome is the number of serious adverse events. Discussion: This is a double-blind, sham-controlled, randomized medical device study to assess the efficacy and safety of an augmented theta-burst rTMS treatment in schizophrenia. We hypothesize that social cognition and negative symptoms of patients on active therapy will improve significantly compared to patients on sham treatment. Trial registration: The study protocol is registered at "ClinicalTrials.gov" with the following ID: NCT05100888. All items from the World Health Organization Trial Registration Data Set are registered. Initial release: 10/19/2021. [ABSTRACT FROM AUTHOR]

Clozapine (CZ) is a prescribed benzodiazepine psychiatric drug that is often possessed as an illicit drug and is associated with drug-facilitated sexual assaults (DFSA) due to its strong sedative capabilities. Hence, we propose an electrified liquid–liquid interface (eLLI) based transducing element as an alternative electroanalytical platform for rapid screening of CZ in soft and hard drinks which is habitually associated with DFSA crimes. First, molecular partitioning and the effect of chemical composition, pH, and the presence of ethanol in the biphasic configuration of the aqueous phase on the interfacial behaviour and analytical performance of the CZ at the eLLI have been investigated with voltammetry. Next, the electrochemical profiles of various soft and hard drinks were studied at the eLLI. The eLLI-based CZ sensor has shown a broad dynamic range (15–150 μM), lower detection limits (1μM), and adequate reliability towards rapid CZ screening in spiked soft and hard drink samples with reference to the standard chromatographic analysis. [ABSTRACT FROM AUTHOR]

Rationale: The precise diagnosis and treatment of cognitive impairment remains a major challenge in the field of schizophrenia (SCZ) research. Synaptic dysfunction and loss are thought to be closely related to the occurrence and development of SCZ and may be involved in cognitive dysfunction. Objectives: The purpose of this study was to investigate whether neuronal pentraxins (NPTXs) plays a role in the etiology of SCZ and provide evidence of its possible therapeutic value a new target for drug development. Methods: We recruited 275 participants, of whom 148 were SCZ from psychiatric hospital and 127 healthy control (HC) subjects from communities. Plasma concentrations of NPTXs were measured in HC and SCZ at baseline and after 8 weeks of antipsychotic treatment. The MATRICS Cognitive Consensus Battery was used to evaluate cognitive function. Furthermore, the brain is parcellated into 246 subregions using the Brainnetome atlas, and we extracted regional white matter volumes from magnetic resonance images of the SCZ groups. Results: Plasma NPTX2 levels were significantly lower in SCZ compared with HC subjects, but were significantly raised in SCZ after 8 weeks of antipsychotic treatment compared to baseline. In addition, baseline plasma NPTX2 levels were positively correlated with cognitive performance. Conclusions: These findings indicate that NPTX2 may reveal novel aspects of disease etiology and act as a promising target for new drug development. [ABSTRACT FROM AUTHOR]

Background: Patients with autism spectrum disorder (ASD) may experience severe psychiatric symptoms, often unresponsive to conventional pharmacological therapies, highlighting the need for more effective alternatives. Aims: This study aims to map and synthesize evidence on the use of clozapine as a therapeutic option for managing severe psychiatric symptomatology co-occurring with ASD. Methods: We conducted a scoping review on multiple sources following the JBI guidelines. The search strategy was inclusive, targeting both peer-reviewed publications and gray literature presenting empirical data on the use of clozapine therapy for patients with ASD accompanied by comorbid psychiatric symptoms. Two independent evaluators performed the selection of studies, data extraction, and critical appraisal. Results: The review included 46 studies, encompassing 122 ASD individuals who received clozapine therapy. The sources of evidence comprise 31 case reports, 8 case series, 6 retrospective observational studies, and 1 quasi-experimental prospective study. The tables present the findings along with a narrative summary. Clozapine treatment demonstrated benefits in four groups of severe and treatment-resistant psychiatric symptoms in ASD patients: disruptive behaviors, psychotic symptoms, catatonia, and mood symptoms. Although side effects were common, tolerability was generally satisfactory. However, severe adverse events, such as seizures, moderate neutropenia, and myocarditis, underscore the need for intensive clinical monitoring. Conclusions: While clozapine shows promise as a pharmacological intervention for severe psychopathologies in ASD, more rigorous clinical studies are required to elucidate its efficacy and safety in this population. The limited robustness of the evidence calls for caution, signaling an early research stage into this topic. [ABSTRACT FROM AUTHOR]

Background Acute antipsychotic poisoning is correlated to a high prevalence of qt interval prolongation. Aim This study aimed to evaluate early qt interval prolongation predictors in acute antipsychotic-poisoned patients. Methodology This prospective cohort study enrolled 70 symptomatic patients with acute antipsychotic poisoning. Sociodemographic data, toxicological, clinical, investigation, and outcomes were collected and analyzed. The estimation of the corrected qt interval (QTc) was performed using Bazett's method. Primary outcome was normal or abnormal length of QTc interval. Secondary outcomes included duration of hospital stay, complete recovery and mortality. The corrected qt interval was analyzed by univariate and multivariate logistic regression analysis. Results Patients were divided into groups A (normal QTc interval up to 440 msec; 58.6% of cases) and B (prolonged QTc interval ≥ 440 msec; 41.4% of cases). Patients in group B had significantly high incidences of quetiapine intake, bradycardia, hypotension, hypokalemia, and long duration of hospital stay. By multivariate analysis, quetiapine [Odd's ratio (OR): 39.674; Confidence Interval (C.I:3.426–459.476)], bradycardia [OR: 22.664; C.I (2.534–202.690)], and hypotension [OR: 16.263; (C.I: 2.168–122.009)] were significantly correlated with prolonged QTc interval. Conclusion In acute antipsychotic poisoning, quetiapine, bradycardia, and hypotension are early clinical predictors for prolonged QTc interval. [ABSTRACT FROM AUTHOR]

Background: Dual disorders (DDs) involve the coexistence of a substance use disorder (SUD) with another mental illness, often from the psychotic and affective categories. They are quite common in clinical practice and present significant challenges for both diagnosis and treatment. This study explores the effectiveness of brexpiprazole, a third-generation antipsychotic, in an Italian sample of individuals diagnosed with schizophrenia spectrum disorder and a comorbid SUD. Methods: Twenty-four patients, diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) and enrolled in several Italian hospitals, underwent a psychometric assessment at baseline (T0) and one month (T1) after starting brexpiprazole treatment administered at a mean dosage of 2 mg/day. Results: Brexpiprazole demonstrated significant reductions in psychopathological burden (Positive and Negative Syndrome Scale/PANSS total score: p < 0.001). Positive (p = 0.003) and negative (p = 0.028) symptoms, substance cravings (VAS craving: p = 0.039), and aggression (MOAS scale: p = 0.003) were notably reduced. Quality of life improved according to the 36-item Short Form Health Survey (SF-36) subscales (p < 0.005). Conclusions: This study provides initial evidence supporting brexpiprazole's efficacy and safety in this complex patient population, with positive effects not only on psychopathology and quality of life, but also on cravings. Further studies involving larger cohorts of subjects and extended follow-up periods are needed. [ABSTRACT FROM AUTHOR]

The rapid fabrication is described of binary electrocatalyst based on a highly porous metal–organic framework with zirconium metal core (Zr-MOF) decorated over the graphitic carbon nitride (g-C3N4) nanosheets via facile ultrasonication method. It is used for the robust determination of antipsychotic drug chlorpromazine (CLP) from environmental samples. The electrochemical behaviour of 2D Zr-MOF@g-C3N4 was characterized by cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS) studies. The crystalline and porous nature of the composite was characterized by XRD and SEM analysis. The functional groups and surface characteristics were investigated by FT-IR, Raman and XPS. The major electrochemical properties of the Zr-MOF@g-C3N4 composite towards CLP detection were analyzed by CV, chronocoulometric (CC), chronoamperometric (CA) and differential pulse voltammetry (DPV) techniques. The composite exhibits a low detection limit (LOD) of 2.45 nM with a linear range of 0.02 to 2.99 µM and attractive sensitivity for CLP. The sensor system shows higher selectivity towards the possible interferences of CLP drug and exhibits better repeatability and stability. Finally, the fabricated sensor system shows a high recovery range varying from 96.2 to 98.9% towards the real samples. The proposed electrochemical probe might be a promising alternative to the prevailing diagnostic tools for the detection of CLP. [ABSTRACT FROM AUTHOR]

This is a rare side effect of amisulpride-induced phonic and motor tics that completely resolved within 2 weeks of stopping the drug. Naranjo adverse drug effect probability scale is eight, suggests that it's a probable causation of the tics.

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.

Background: Adherence to antipsychotic medication and care discontinuity remain a challenge to healthcare practitioners providing care to patients with schizophrenia. Objective: This study used real-world data from a US hospital-based, all-payer database to examine clinical quality measures among patients with schizophrenia initiated on a long-acting injectable (LAI) or switched to a new oral antipsychotic medication (OAP) following a hospitalization. Methods: A retrospective cohort study using the PINC AI™ Healthcare Database compared two cohorts of patients with schizophrenia on post-index hospitalization clinical quality and care continuity endpoints. Patients initiated on an LAI (n = 7292) or switched to a new OAP (n = 31,956) during an index hospitalization between April 2017 and April 2020 were included. Propensity score weighting addressed differences in patient, hospital, and clinical characteristics between the two cohorts. Results: Patients who initiated an LAI experienced significantly greater adjusted 30-day antipsychotic medication continuation to index therapy, higher rate of 30-day outpatient follow-up care, longer mean time to discontinuation of index therapy, and lower risk of discontinuing their index treatment compared to patients who switched to a new OAP (all p values < 0.001). Probability of 30-day antipsychotic medication continuation was significantly higher for LAI initiators than for patients who switched to a new OAP, even after controlling for patient, clinical, and hospital characteristics (adjusted odds ratio = 1.2, 95% CI 1.1–1.3, p < 0.001). Conclusion: Patients who initiated an LAI in a hospital setting experienced better clinical quality and care continuity outcomes compared to patients who were switched to a new OAP. These findings may be useful in identifying solutions to help improve the quality of medication management post-hospital discharge among patients with schizophrenia. [ABSTRACT FROM AUTHOR]

Model‐informed precision dosing using virtual twins (MIPD‐VTs) is an emerging strategy to predict target drug concentrations in clinical practice. Using a high virtualization MIPD‐VT approach (Simcyp version 21), we predicted the steady‐state clozapine concentration and clozapine dosage range to achieve a target concentration of 350 to 600 ng/mL in hospitalized patients with treatment‐resistant schizophrenia (N = 11). We confirmed that high virtualization MIPD‐VT can reasonably predict clozapine concentrations in individual patients with a coefficient of determination (R2) ranging between 0.29 and 0.60. Importantly, our approach predicted the final dosage range to achieve the desired target clozapine concentrations in 73% of patients. In two thirds of patients treated with fluvoxamine augmentation, steady‐state clozapine concentrations were overpredicted two to four‐fold. This work supports the application of a high virtualization MIPD‐VT approach to inform the titration of clozapine doses in clinical practice. However, refinement is required to improve the prediction of pharmacokinetic drug–drug interactions, particularly with fluvoxamine augmentation. [ABSTRACT FROM AUTHOR]

Introduction The complex nature of neurocognitive impairment in schizophrenia has been discussed in light of the mixed effects of antipsychotic drugs, psychotic symptoms, dopamine D2 receptor blockade, and intelligence quotient (IQ). These factors have not been thoroughly examined before. Methods This study conducted a comprehensive re-analysis of the CATIE data using machine learning techniques, in particular Conditional Inference Tree (CTREE) analysis, to investigate associations between neurocognitive functions and moderating factors such as estimated trough dopamine D2 receptor blockade with risperidone, olanzapine, or ziprasidone, Positive and Negative Syndrome Scale (PANSS), and baseline IQ in 573 patients with schizophrenia. Results The study reveals that IQ, age, and education consistently emerge as significant predictors across all neurocognitive domains. Furthermore, higher severity of PANSS-negative symptoms was associated with lower cognitive performance scores in several domains. CTREE analysis, in combination with a genetic algorithm approach, has been identified as particularly insightful for illustrating complex interactions between variables. Lower neurocognitive function was associated with factors such as age>52 years, IQ<94/95,<12/13 education years, and more pronounced negative symptoms (score<26). Conclusions These findings emphasize the multifaceted nature of neurocognitive functioning in patients with schizophrenia, with the PANSS-negative score being an important predictor. This gives rise to a role in addressing negative symptoms as a therapeutic objective for enhancing cognitive impairments in these patients. Further research must examine nonlinear relationships among various moderating factors identified in this work, especially the role of D2 occupancy. [ABSTRACT FROM AUTHOR]

The aim of our study was to evaluate the efficacy of cariprazine augmentation of clozapine in treatment-resistant schizophrenia in a retrospective chart review. Among 916 medical records of schizophrenia patients, we identified 12 individuals treated with a combination of those drugs for a duration of 3–60 weeks [median 32 (10–40)]. Clinical Global Impression–Improvement (CGI-I) scores were used to measure the treatment response between the introduction of cariprazine augmentation of clozapine and the last point of observation. The majority of the patients presented treatment response (9/12 patients, 75%) after 4–16 weeks of therapy [median 6 (4–12)]. Treatment was associated with the decrease in positive, negative, affective, and anxiety symptom severity, as well as improvement of patient global functioning. One patient discontinued the treatment due to side effects (akathisia), and two patients halted the therapy due to the exacerbation of psychotic symptoms. Our study presents a thorough clinical description of the largest number of treatment-resistant schizophrenia patients medicated using cariprazine augmentation of clozapine in a “real-world” setting. Our results suggest that the use of this combination may lead to the improvement in a broad range of symptoms of patients with this condition. [ABSTRACT FROM AUTHOR]

Schizophrenia is a complex psychotic disorder with co-occurring conditions, including insulin resistance and type 2 diabetes (T2D). It is well established that T2D and its precursors (i.e., insulin resistance) are more prevalent in patients with schizophrenia who are treated with antipsychotics, as well as in antipsychotic-naïve patients experiencing their first episode of psychosis, compared with the general population. However, the mechanism(s) underlying the increased susceptibility, shared genetics, and possible cause–effect relationship between schizophrenia and T2D remain largely unknown. The objective of this narrative review was to synthesize important studies, including Mendelian randomization (MR) analyses that have integrated genome-wide association studies (GWAS), as well as results from in vitro models, in vivo models, and observational studies of patients with schizophrenia. Both GWAS and MR studies have found that schizophrenia and T2D/insulin resistance share genetic risk factors, and this may mediate a connection between peripheral or brain insulin resistance and T2D with cognition impairment and an increased risk of developing prediabetes and T2D in schizophrenia. Moreover, accumulating evidence supports a causal role for insulin resistance in schizophrenia and emphasizes the importance of a genetic basis for susceptibility to T2D in patients with schizophrenia before they receive psychotic treatment. The present findings and observations may have clinical implications for the development of better strategies to treat patients with schizophrenia, with both pharmacological (i.e., samidorphan, empagliflozin) and/or nonpharmacological (i.e., lifestyle changes) approaches. Additionally, this review may benefit the design of future studies by physicians and clinical investigators. [ABSTRACT FROM AUTHOR]

A vigorously debated issue in the psychiatric literature is whether long-acting injectable antipsychotics (LAIs) show clinical benefit over antipsychotics taken orally. In addressing this question, it is critical that systematic reviews incorporate risk of bias assessments of trial data in a robust way and are free of undue industry influence. In this paper, we present a case analysis in which we identify some of the design problems in a recent systematic review on LAIs vs oral formulations. This case illustrates how evidence syntheses that are shaped by commercial interests may undermine patient-centered models of recovery and care. We offer recommendations that address both the bioethical and research design issues that arise in the systematic review process when researchers have financial conflicts of interest. [ABSTRACT FROM AUTHOR]

Long-acting injectable (LAI) neuroleptics constitute an effective therapeutical alternative for individuals suffering from persistent mental illness. These injectable pharmaceuticals help patients manage their condition better and improve long-term outcomes by preventing relapses and improving compliance. This review aims to analyse the current formulation aspects of LAI neuroleptics, with particular emphasis on analysis of drug release profiles as a critical test to guarantee drug quality and relevant therapeutical activity. While there is no officially approved procedure for depot parenteral drug formulations, various dissolution tests which were developed by LAI manufacturers are described. In vitro dissolution tests also possess a critical function in the estimation of the in vivo performance of a drug formulation. For that reason, thorough inspection of the in vitro–in vivo correlation (IVIVC) is also discussed. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

This article explores the use of stem cell models and postmortem studies to investigate the neurodevelopment of the striatum in schizophrenia. Stem cell-derived neurons have been found to exhibit similar cellular characteristics to those observed in postmortem analyses. The authors of this study developed a method to directly compare stem cell-derived neurons with postmortem brain tissue from the same individuals, focusing on the striatum. They found that the stem cell-derived neurons exhibited schizophrenia-associated signatures similar to those seen in adult brain tissue, suggesting an accelerated developmental trajectory in schizophrenia. The study also contributes to the ongoing debate about the accuracy of postmortem human neurons as representations of disease processes in the living brain. [Extracted from the article]

Abstract 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.

This article's objective is to present the latest evidence and information on the management of postoperative nausea and vomiting (PONV). PONV continues to affect 30% of the surgical population causing patient dissatisfaction, extending length of stay, and increasing overall costs. This review includes the introduction of 2 new intravenous formulations of antiemetics (amisulpride, aprepitant), updates on nontraditional therapies, suggestions for combination prophylaxis, emerging data on rescue treatment, and considerations for special populations and settings. Both of the new antiemetics provide promising options for pharmacologic interventions for PONV with favorable safety profiles. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Rationale: Inadequate responses to current schizophrenia treatments have accelerated research into novel therapeutic approaches. Objectives: This study investigated the efficacy and tolerability of adjunctive L-theanine, an ingredient with neuroimmunomodulatory and neuroprotective properties, for chronic schizophrenia. Methods: Eighty chronic schizophrenia inpatients were equally assigned to receive risperidone (6 mg/day) plus either L-theanine (400 mg/day) or matched placebo in this 8-week, randomized, parallel-group, double-blind, placebo-controlled trial. The participants were assessed using the Positive and Negative Syndrome Scale (PANSS) by recording the results of subscales at baseline and weeks 4 and 8 to measure treatment efficacy. Additionally, the participants were assessed for the Hamilton Depression Rating Scale (HDRS) and adverse events, including the Extrapyramidal Symptom Rating Scale (ESRS). Results: Sixty patients, 30 in each group, were included in the analyses. All baseline demographic and clinical characteristics were comparable between the groups (p-values > 0.05). The reduction rates from baseline to endpoint in negative, general psychopathology, and total scores of PANSS were greater in the L-theanine group (p-values = 0.03, 0.01, and 0.04, respectively). Regarding general psychopathology scores, the reduction in the L-theanine group was also greater until week 4 (p-value < 0.01). The time × treatment interaction effect was significant on negative (p-value = 0.03), general psychopathology (p-value < 0.01), and total (p-value = 0.04) scores of PANSS, indicating additional improvements in the L-theanine group. The HDRS and side effects were comparable between the groups (p-values > 0.05). Conclusions: L-Theanine adjunct to risperidone safely and tolerably outperformed adjunctive placebo for schizophrenia, and promising evidence indicated its effects on primary negative symptoms, which need to be scrutinized in further studies. Trial registration: The study protocol was registered and published prospectively in the Iranian Registry of Clinical Trials (http://www.irct.ir; registration number: IRCT20090117001556N133) on 2020–12-12. [ABSTRACT FROM AUTHOR]

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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. [ABSTRACT FROM AUTHOR]

Forensic institutions throughout the world house patients with severe psychiatric illness and history of criminal violations. Improved medical care, hygiene, psychiatric treatment, and nutrition led to an unmatched longevity in this population, which previously lived, on average, 15 to 20 years shorter than the public at large. On the other hand, longevity has contributed to increased prevalence of age-related diseases, including neurodegenerative disorders, which complicate clinical management, increasing healthcare expenditures. Forensic institutions, originally intended for the treatment of younger individuals, are ill-equipped for the growing number of older offenders. Moreover, as antipsychotic drugs became available in 1950s and 1960s, we are observing the first generation of forensic detainees who have aged on dopamine-blocking agents. Although the consequences of long-term treatment with these agents are unclear, schizophrenia-associated gray matter loss may contribute to the development of early dementia. Taken together, increased lifespan and the subsequent cognitive deficit observed in long-term forensic institutions raise questions and dilemmas unencountered by the previous generations of clinicians. These include: does the presence of neurocognitive dysfunction justify antipsychotic dose reduction or discontinuation despite a lifelong history of schizophrenia and violent behavior? Should neurolipidomic interventions become the standard of care in elderly individuals with lifelong schizophrenia and dementia? Can patients with schizophrenia and dementia meet the Dusky standard to stand trial? Should neurocognitive disorders in the elderly with lifelong schizophrenia be treated differently than age-related neurodegeneration? In this article, we hypothesize that gray matter loss is the core symptom of schizophrenia which leads to dementia. We hypothesize further that strategies to delay or stop gray matter depletion would not only improve the schizophrenia sustained recovery, but also avert the development of major neurocognitive disorders in people living with schizophrenia. Based on this hypothesis, we suggest utilization of both receptor-dependent and independent therapeutics for chronic psychosis. [ABSTRACT FROM AUTHOR]

Sarcosine (N-methylglycine), a glutamatergic modulator, reduces the primary negative symptoms of schizophrenia. These beneficial changes might be mediated by trophic factors such as epidermal growth factor (EGF). We assessed associations between initial serum EGF levels or changes in serum EGF levels and symptom severity during the addition of sarcosine to stable antipsychotic treatment and thereby evaluated the associations between glutamatergic modulation, clinical changes and peripheral EGF concentrations. Fifty-eight subjects with a diagnosis of chronic schizophrenia with dominant negative symptoms, stably treated with antipsychotics, completed a prospective 6-month, randomized, double-blind, placebo-controlled study. Subjects received orally 2 g of sarcosine (n = 28) or placebo (n = 30) daily. Serum EGF levels and symptom severity (using the Positive and Negative Syndrome Scale (PANSS) and the Calgary Depression Scale for Schizophrenia (CDSS)) were assessed at baseline, 6-week and 6-month follow-up. Augmentation antipsychotic treatment with sarcosine had no effect on EGF serum levels at any time points. Only the sarcosine group showed a significant improvement in negative symptoms, general psychopathology subscales and the overall PANSS score. We found a reduction in serum EGF levels in the placebo group, but levels in the sarcosine remained stable during the study. Our data indicate that improvement in negative symptoms due to sarcosine augmentation is not directly mediated by EGF, but effective treatment may induce the production or block the decrease in EGF concentrations, which indicates the neuroprotective effect of treatment and confirms the relationship between neuroprotection and EGF levels. [ABSTRACT FROM AUTHOR]

This article discusses a case of clozapine-induced stuttering in a patient with treatment-resistant schizophrenia. Clozapine is an antipsychotic medication commonly used for schizophrenia, but it can have side effects, including rare cases of stuttering. The article emphasizes the importance of clinicians being aware of this side effect and the need for further research to understand the underlying causes. The case study describes the patient's history, treatment, and the resolution of stuttering after a dose reduction and the addition of an antiepileptic drug. The article concludes by highlighting the need for clinicians to be aware of clozapine-induced stuttering and the importance of future research in this area. [Extracted from the article]

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. 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. 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. [ABSTRACT FROM AUTHOR]