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Schizophrenia is a chronic mental illness that requires lifelong antipsychotic treatment. Therapy discontinuation, often due to poor adherence, increases the risk of relapses after both first and subsequent psychotic episodes. Long-acting injectable (LAI) antipsychotic drugs (APDs) have been introduced to increase therapeutic adherence, reducing blood-level variability compared to corresponding oral preparations. To compare the effectiveness of three LAI-APDs: aripiprazole (Apr) prolonged release once monthly (OM) haloperidol decanoate (Hal-D) and paliperidone palmitate (PP-OM). We retrospectively collected data for all patients with schizophrenia or other psychoses (n=217) treated with the three LAI-APDs for the first time from January 1, 2012 to October 31, 2016: n=48 with Apr-OM, n=55 with Hal-D, and n=114 with PP-OM. After 6 and 12 months of LAI treatments, we assessed clinical and functioning improvement, urgent consultations, psychiatric hospitalizations, adverse effects, and dropout. We compared urgent consultations and psychiatric hospitalizations required by the same patient 6 and 12 months before and after LAI implementation. Data were statistically analyzed. The three LAI groups differed significantly only for \"need for economic support from social service\" (more frequent in the Hal-D group) and \"schizoaffective disorder\" (prevalent in the Apr-OM group). Apr-OM was prescribed at the maximum dose required by the official guidelines, whereas the other two LAIs were prescribed at lower doses. After 6 and 12 months' treatment with the three LAI-APDs, we registered similar and significant reductions in both urgent consultations and psychiatric hospitalizations ( <0.001) and overlapping clinical and functioning improvement-scale scores ( <0.001), and 14.28% of patients dropped out, with no difference among the three LAI-APDs. Different kinds of adverse effects, though similar for number and severity, were reported in the three LAI groups. Our results suggest that both first- and second-generation LAI-APDs represent important therapeutic options, useful for improving schizophrenia's clinical course and its economic burden. Our study, which offers a wide and comprehensive observation of real-world clinical settings, combined an effectiveness evaluation through mirror analysis performed for each individual patient to a subsequent comparison among the three LAI-APDs, allowing us a more complete evaluation of clinical efficacy.

Background In the last decade, olanzapine became widely used in mental health service worldwide even after being criticized for its metabolic side effects. Patients with schizophrenia on olanzapine were usually found to stay on their medications longer than the other second‐generation antipsychotics (SGAs) except clozapine. The reason for this is unknown. Objective This prospective study compared the influences of olanzapine and other SGAs except clozapine on improving insight and medication discontinuation rate in schizophrenia. Methods A total of 148 patients with schizophrenia medically indicated for initiation of treatment with olanzapine or other SGAs were evaluated for symptoms, insight, attitudes toward medication, side effects, body weight and fasting lipid and glucose parameters at admission and before discharge, and follow‐up calls one‐year after discharge documented whether they were regularly taking prescribed psychotropic medication or not. Results After an average of 72.8 days of inpatient treatment, the olanzapine and other SGAs group exhibited similar levels of symptom improvement with an average reduction of 28.7 in the Positive and Negative Syndrome Scale (PANSS) total score. The Olanzapine group exhibited better improvement in insight assessed using the G12 item of PANSS and Insight and Treatment Attitudes Questionnaire (ITAQ), more metabolic side effects indexed with total cholesterol, triglycerides levels and weight gain, and a lower medication discontinuation rate than the other SGAs group. Conclusion Although general symptom improvement was similar, olanzapine significantly improved insight and presented less medication discontinuation compared to other SGAs, which might partially explain why patients on olanzapine stayed longer on their medications.

SummaryOur systematic review and meta-analysis of observational studies indicated that the use of antipsychotics was associated with a nearly 1.5-fold increase in the risk of fracture. First-generation antipsychotics (FGAs) appeared to carry a higher risk of fracture than second-generation antipsychotics (SGAs).IntroductionThe risk of fractures associated with the use of antipsychotic medications has inconsistent evidence between different drug classes. A systematic review and meta-analysis was conducted to evaluate whether there is an association between the use of antipsychotic drugs and fractures.MethodsSearches were conducted through the PubMed and EMBASE databases to identify observational studies that had reported a quantitative estimate of the association between use of antipsychotics and fractures. The summary risk was derived from random effects meta-analysis.ResultsThe search yielded 19 observational studies (n = 544,811 participants) with 80,835 fracture cases. Compared with nonuse, use of FGAs was associated with a significantly higher risk for hip fractures (OR 1.67, 95% CI, 1.45–1.93), and use of second generation antipsychotics (SGAs) was associated with an attenuated but still significant risk for hip fractures (OR 1.33, 95% CI, 1.11–1.58). The risk of fractures associated with individual classes of antipsychotic users was heterogeneous, and odds ratios ranged from 1.24 to 2.01. Chlorpromazine was associated with the highest risk (OR 2.01, 95% CI 1.43–2.83), while Risperidone was associated with the lowest risk of fracture (OR 1.24, 95% CI 0.95–1.83).ConclusionsFGA users were at a higher risk of hip fracture than SGA users. Both FGAs and SGAs were associated with an increased risk of fractures, especially among the older population. Therefore, the benefit of the off-label use of antipsychotics in elderly patients should be weighed against any risks for fracture.

IntroductionLong-acting injectable antipsychotics (LAIs) have emerged as a new therapeutic option to treat patients suffering a psychotic disorder. To date, there is a lack of studies regarding safety and clinical use pattern of LAIs in pregnant women.ObjectivesProvide evidence and real world clinical data of pregnant women with schizophrenia who have been treated with long-acting aripiprazole monohydrate (aripiprazole once monthly [AOM] condition) during their pregnancy.MethodsDescriptive real-world clinical experiences of pregnant women in treatment with AOM. The information was obtained by reviewing electronic medical records and by direct clinical observation management.ResultsThe first six case-series describing the pregnancy course of women with schizophrenia treated with AOM. All of them remained psychopathologically stable through pregnancy, and their infants became healthy with normal developmental milestones (Table 1).Table 1.Clinical characteristics of six case-reports.Mothers123456Maternal/Pregnancy outcomesAge(years)352935313830DiagnosisSchizophreniaSchizophreniaSchizophreniaSchizophreniaSchizophreniaSchizophreniaAOM(mg/days)400-300400-300400-300160300400Type of deliveryEutocic.Eutocic, pretermEutocicEutocicEutocicEutocicNeonatal outcomesWeight(grams)330018003140310229403400GenderFemaleFemaleMaleMaleMaleMaleDevelopmental Abnormalities(years)No(3)No(2)No( 0.17)No(2)No(2)No(1.5)ConclusionsThe favorable results in this case-series suggest that despite the lack of evidence on reproductive safety and treatment with AOM during pregnancy, this therapeutic option should be considered in pregnant women with schizophrenia. However, further research on the use of long-acting antipsychotics in pregnant women is needed.DisclosureNo significant relationships.

Second-generation antipsychotics (SGAs) are the cornerstone of treatment for schizophrenia because of their high clinical efficacy. However, SGA treatment is associated with severe metabolic alterations and body weight gain, which can increase the risk of type 2 diabetes and cardiovascular disease, and greatly accelerate mortality. Several underlying mechanisms have been proposed for antipsychotic-induced weight gain (AIWG), but some studies suggest that metabolic changes in insulin-sensitive tissues can be triggered before the onset of AIWG. In this review, we give an outlook on current research about the metabolic disturbances provoked by SGAs, with a particular focus on whole-body glucose homeostasis disturbances induced independently of AIWG, lipid dysregulation or adipose tissue disturbances. Specifically, we discuss the mechanistic insights gleamed from cellular and preclinical animal studies that have reported on the impact of SGAs on insulin signaling, endogenous glucose production, glucose uptake and insulin secretion in the liver, skeletal muscle and the endocrine pancreas. Finally, we discuss some of the genetic and epigenetic changes that might explain the different susceptibilities of SGA-treated patients to the metabolic side-effects of antipsychotics.

Background It is well established that the different antipsychotics used for schizophrenia symptoms differ substantially in their side effects. However, relatively little is known about the impact of these side effects on functioning from the patient’s perspective. We aimed to understand how key side effects of second-generation antipsychotics impact the functioning and quality of life (QoL) of patients with schizophrenia. Methods This is a cross-sectional, web-based survey of patient-reported side effect burden of antipsychotic drugs in adults with schizophrenia. The survey was deployed in the United States, Canada, Australia, Spain, Italy, Norway, and Denmark. It included sociodemographic and clinical questions, the Quality of Life Enjoyment and Satisfaction Questionnaire Short Form (Q-LES-Q-SF), and the Glasgow Antipsychotic Side-Effect Scale (GASS). Eight pre-defined key side effects classified as activating (“Shaky hands or arms,” “Restlessness,” and “Difficulty sleeping”), sedating (“Sleepy during the day”, “Feeling drugged or like a zombie,” and “Feeling dizzy/Fainted”) or other side effects (“Problems enjoying sex” and “Gaining weight”), and additional questions related to impacts on function and quality of life were asked. Results In total, 435 participants (mean age: 38 years, 53.8% female) were included. The total Q-LES-Q-SF score indicated overall medium satisfaction with their quality of life (score of 44.3; possible range 14–70). The most prevalent side effects were “Sleepy during the day” (83.2%), “Difficulty sleeping” (74.7%), “Dry mouth” (63.9%), “Problems enjoying sex” (53.4%) and “Gaining weight” (52.4%). Women reported the side effects of “Sleepy during the day”, “Problems enjoying sex” and “Gaining weight” more frequently than men. Key side effects impacted physical, social, occupational and psychological aspects of functioning. Patients with key side effects often felt frustrated by their experiences. Total Q-LES-Q-SF score showed a significant inverse correlation with the score of pre-defined groups of side effects indicating worse QoL in association with more severe key side effects in these patients. Conclusion Stable patients with schizophrenia taking second-generation antipsychotics live with many side effects, including activating and sedating side effects, sexual side effects, and weight gain. Presence of these side effects is associated with substantial impacts across all aspects of daily functioning and lower quality of life and satisfaction.

The effectiveness of available neuropsychiatric drugs in the era of an increasing number of patients is not sufficient, and the complexity of neuropsychiatric disease entities that are difficult to diagnose and therapeutically is increasing. Also, discoveries about the pathophysiology of neuropsychiatric diseases are promising, including those initiating a new round of innovations in the role of oxidative stress in the etiology of neuropsychiatric diseases. Oxidative stress is highly related to mental disorders, in the treatment of which the most frequently used are first- and second-generation antipsychotics, mood stabilizers, and antidepressants. Literature reports on the effect of neuropsychiatric drugs on oxidative stress are divergent. They are starting with those proving their protective effect and ending with those confirming disturbances in the oxidation–reduction balance. The presented publication reviews the state of knowledge on the role of oxidative stress in the most frequently used therapies for neuropsychiatric diseases using first- and second-generation antipsychotic drugs, i.e., haloperidol, clozapine, risperidone, olanzapine, quetiapine, or aripiprazole, mood stabilizers: lithium, carbamazepine, valproic acid, oxcarbazepine, and antidepressants: citalopram, sertraline, and venlafaxine, along with a brief pharmacological characteristic, preclinical and clinical studies effects.

Aims/hypothesisSecond-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.MethodsWe 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.ResultsTreatment 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/interpretationBoth 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.

The pharmacological treatment of cognitive impairments associated with schizophrenia is still a major unmet clinical need. Indeed, treatments with available antipsychotics generate highly variable cognitive responses among patients with schizophrenia. This has led to the general assumption that antipsychotics are ineffective on cognitive impairment, although personalized medicine and drug repurposing approaches might scale down this clinical issue. In this scenario, evidence suggests that cognitive improvement exerted by old and new atypical antipsychotics depends on dopaminergic mechanisms. Moreover, the newer antipsychotics brexpiprazole and cariprazine, which might have superior clinical efficacy on cognitive deficits over older antipsychotics, mainly target dopamine receptors. It is thus reasonable to assume that despite more than 50 years of elusive efforts to develop novel non-dopaminergic antipsychotics, dopamine receptors remain the most attractive and promising pharmacological targets in this field. In the present review, we discuss preclinical and clinical findings showing dopaminergic mechanisms as key players in the cognitive improvement induced by both atypical antipsychotics and potential antipsychotics. We also emphasize the concept that these mechanistic advances, which help to understand the heterogeneity of cognitive responses to antipsychotics, may properly guide treatment decisions and address the unmet medical need for the management of cognitive impairment associated with schizophrenia.

Introduction: Antipsychotic drugs are the cornerstone of the pharmacological treatment of psychotic disorders; however, even with Second-generation antipsychotics (SGA), adverse effects continue to be extremely accentuated and the treatment effectiveness is compromised by low adherence of the patient. Objectives: Taking into consideration the importance of adverse effects for psychotic therapeutics, this study aims to analyze the adverse effect of the Neuroleptic Malignant Syndrome (NMS) reported in EudraVigilance Database, associated with 3 widely used SGA, Risperidone, Quetiapine, and Clozapine. Methods: The EudraVigilance Database was analyzed from 09/01/2017 to 31/10/2020 about NMS, associated with Risperidone, Quetiapine, and Clozapine. NMS is the second most reported adverse effect inside the Nervous System Disorders SOC (System Organ Class). There were just considered NMS as suspected adverse effect. Results: It was observed a general tendency of reduction of NMS reports from 2017 to 2020 (most of them performed by healthcare professionals). Risperidone presented the highest level of reports during this period (more than 350), followed by Quetiapine and Clozapine. The NMS reports were predominantly referred to the male sex, from 18 to 64 years old. Risperidone presented the lowest number of fatal cases of NMS (1), in contrast with 3 reported with Quetiapine and Clozapine. A significant number of patients with Schizophrenia recovered from NMS. Conclusions: It is important to do clinical monitoring of the NMS, because it is rare, although it has life-threatening consequences. Pharmacovigilance databases are important tools to evaluate the safety of drugs and it must be more widely and efficiently promoted for healthcare and patients use. Disclosure: No significant relationships.