The second-generation antipsychotic drug aripiprazole modulates the serotonergic system in pancreatic islets and induces beta cell dysfunction in female mice

Aims/hypothesis Second-generation antipsychotic (SGA) drugs have been associated with the development of type 2 diabetes and the metabolic syndrome in patients with schizophrenia. In this study, we aimed to investigate the effects of two different SGA drugs, olanzapine and aripiprazole, on metabolic state and islet function and plasticity. Methods We analysed the functional adaptation of beta cells in 12-week-old B6;129 female mice fed an olanzapine- or aripiprazole-supplemented diet (5.5–6.0 mg kg−1 day−1) for 6 months. Glucose and insulin tolerance tests, in vivo glucose-stimulated insulin secretion and indirect calorimetry were performed at the end of the study. The effects of SGAs on beta cell plasticity and islet serotonin levels were assessed by transcriptomic analysis and immunofluorescence. Insulin secretion was assessed by static incubations and Ca2+ fluxes by imaging techniques. Results Treatment of female mice with olanzapine or aripiprazole for 6 months induced weight gain (p<0.01 and p<0.05, respectively), glucose intolerance (p<0.01) and impaired insulin secretion (p<0.05) vs mice fed a control chow diet. Aripiprazole, but not olanzapine, induced serotonin production in beta cells vs controls, likely by increasing tryptophan hydroxylase 1 (TPH1) expression, and inhibited Ca2+ flux. Of note, aripiprazole increased beta cell size (p<0.05) and mass (p<0.01) vs mice fed a control chow diet, along with activation of mechanistic target of rapamycin complex 1 (mTORC1)/S6 signalling, without preventing beta cell dysfunction. Conclusions/interpretation Both SGAs induced weight gain and beta cell dysfunction, leading to glucose intolerance; however, aripiprazole had a more potent effect in terms of metabolic alterations, which was likely a result of its ability to modulate the serotonergic system. The deleterious metabolic effects of SGAs on islet function should be considered while treating patients as these drugs may increase the risk for development of the metabolic syndrome and diabetes. Graphical abstract

FORMULATION DEVELOPMENT AND EVALUATION OF CLOZAPINE TRANSDERMAL PATCHES

The Clozapine is available in the form of 25 Yellow Tablets of 100mg. Clozapine is very famous in now-a-days due to its use of optimisation in transdermal metric basically for experimental process and design.it is used for the improvement of bioavailability. The medications are demonstrated for mitigating the risk of recurrent suicidal behaviour in schizophrenia patients or schizoaffective disorder who really are evaluated to be at persistent risk of convolutional suicidal behaviour in a historical and controlled experimental state. The paper provides a brief analysis of Clozapine drugs Usage, Formulation and Evaluation. The drugs were used upon animals at first to test the effects. There are several side effects of Clozapine that includes High fever and also symptoms like flu, Weakness and dizziness, allergy in skin and red spots, Sometimes itching problems in vaginal, in serious problems it can also create breathing problems and worsening cough. This is known as the Second Generation Antipsychotic that helps in balancing the dopamine and serotonin that improves the cognitive functions like mood, thinking and behaviour of an individual. Clozapine is restricted to use however it is used under one particular condition i.e. when the person suffering from Schizophrenia does not respond to other medications, have suicidal incidents or have positive symptoms. Furthermore, considerable clinical study has proven that clozapine seems to be more efficacious than just about any other antipsychotic drug throughout therapeutic interventions and therefore it clearly outperforms some other antipsychotics with in treatment of recurrent schizoaffective disorder. KEYWORDS: schizophrenia, transdermal, clozapine, antipsychotic

Antipsychotic utilisation and persistence in Australia: A nationwide 5-year study

Objectives: To evaluate the utilisation and persistence of antipsychotics for the treatment of schizophrenia in Australia. Methods: A retrospective study using the Australian Pharmaceutical Benefits Scheme database of a representative 10% sample. All adults with schizophrenia who were dispensed three or more supplies of oral (including clozapine) or long-acting injectable antipsychotics between 1 June 2015 and 31 May 2020 were included. Persistence time in treatment was evaluated using survival analysis and Cox hazard ratios. Results: In all, 26,847 adults with schizophrenia were studied. Oral second-generation antipsychotics were more frequently dispensed than the other antipsychotic groups studied. Median treatment persistence times were 18.3 months for second-generation antipsychotic long-acting injectables, 10.7 months for oral second-generation antipsychotics and were significantly lower for both formulations of first-generation antipsychotics at 5.2 months (long-acting injectables) and 3.7 months (oral). The median persistence time for clozapine was significantly longer than all other antipsychotics groups. Conclusions: Oral second-generation antipsychotics and second-generation antipsychotic long-acting injectables accounted for over 75% and 13% of all antipsychotics in Australia, respectively. Concerns over medication adherence and subsequent relapse have not translated into increased long-acting injectable usage despite their significantly longer persistence. Clozapine, the single most ‘persistent’ antipsychotic, was only used in 9% of people, although up to a third of all cases are likely to be treatment-resistant. Our data suggest clinicians should give consideration to the earlier use of second-generation antipsychotic long-acting injectables and clozapine, to ameliorate prognosis in schizophrenia.

Off-label antipsychotic use patterns among Texas Medicaid adults 2013–2016

Aim: To describe trends in off-label antipsychotic use among Texas Medicaid adults and examine whether demographic and clinical characteristics were associated with off-label use. Methods: Three diagnostic groups (i.e. no diagnosis, on label and off-label) were created based on mental health disorder diagnoses and related antipsychotic prescriptions. Results: During 2013–2016, the prevalence of off-label antipsychotic use decreased from 22.5% to 17.4% and the proportions of no mental health diagnosis remained stable (7.3–9.4%). Patients aged ≥25 years and second-generation antipsychotic users had significantly lower odds of receiving antipsychotics off-label or with no diagnosis. Conclusion: Compared with previous Medicaid database studies, the proportions of off-label antipsychotic use and antipsychotic use with no concurrent psychiatric diagnosis were notably lower.

Review: Influence of the CYP450 Genetic Variation on the Treatment of Psychotic Disorders

Second-generation antipsychotic metabolism is mainly carried out by the CYP450 superfamily, which is highly polymorphic. Therefore, knowing the influence of the different known CYP450 polymorphisms on antipsychotic plasmatic levels and, consequently, the biological effect could contribute to a deeper knowledge of interindividual antipsychotic treatment variability, prompting possible solutions. Considering this, this state of the art review aimed to summarize the current knowledge about the influence of the diverse characterized phenotypes on the metabolism of the most used second-generation antipsychotics. Forty studies describing different single nucleotide polymorphisms (SNPs) associated with the genes CYP1A2, CYP2D6, CYP3A4, CYP3A5, and ABCB1 and their influence on pharmacokinetics of olanzapine, clozapine, aripiprazole, risperidone, and quetiapine. Most of the authors concluded that although significant differences in the pharmacokinetic parameters between the different phenotypes could be observed, more thorough studies describing pharmacokinetic interactions and environmental conditions, among other variables, are needed to fully comprehend these pharmacogenetic interactions.

Risperidone-Induced Neutropenia in a Schizophrenic Patient: A Case Report and Literature Review

Neutropenia is an adverse effect of various pharmacological therapies, including antipsychotics. Among the second-generation antipsychotic (SGA) medications, clozapine is most notable for neutropenic adverse effect. Risperidone, another SGA drug, is linked mainly with metabolic adverse effects, but rarely, blood dyscrasia adverse reactions have been reported. Hence, we report the case of a 56-year-old African American woman who developed severe neutropenia following two weeks of oral risperidone treatment. Her neutrophil levels returned to normal limits following discontinuation of risperidone and switching to haloperidol.