Development of a population pharmacokinetic model for the novel long-acting injectable antipsychotic risperidone ISM®.

AIMS: The aims of this study were to develop a population pharmacokinetic (PK) model for risperidone ISM® and to investigate the relationships between active moiety exposure, as described by apparent clearance (CL40), and several covariates using all data from five clinical studies. METHODS: A population PK model was developed using active moiety concentrations from a study in healthy volunteers and two studies in patients with schizophrenia. Data from a comparative bioavailability study in medically stable patients and a Phase III study in patients with acute exacerbation of schizophrenia were then incorporated, using empirical Bayesian feedback and model refinement in NONMEM. Finally, covariate analysis was performed on CL40. RESULTS: The final model adequately described the pharmacokinetics of 6288 active moiety concentrations in 17 healthy volunteers and 430 patients with schizophrenia. This one-compartment disposition model had a complex absorption process, combining a small amount immediately entering the central active moiety compartment, two first-order absorption processes and a combined zero-order and first order process, with first-order elimination from the central compartment. Significant covariates on CL40 were BMI and sex. Goodness-of-fit (GOF) plots and visual predictive checks (VPC) confirmed acceptable description of the data. CONCLUSIONS: The population PK model adequately described active moiety concentrations from five clinical studies after risperidone ISM® administration. Relationships between active moiety exposure and covariates were defined in order to facilitate simulations for future studies. The model showed that risperidone ISM® rapidly achieves therapeutic plasma levels within the first hours after the first injection that are maintained sustainedly throughout the whole dosing interval following once-monthly gluteal injections of 100 mg and 75 mg.

Antipsychotic agents in anxiety disorders: An umbrella review.

BACKGROUND: Although not approved for the treatment of anxiety disorders (except trifluoperazine) there is ongoing off-label, unapproved use of first-generation antipsychotics (FGAs) and second-generation antipsychotics (SGAs) for anxiety disorders. There have been systematic reviews and meta-analyses on the use of antipsychotics in anxiety disorders, most of which focused on SGAs. OBJECTIVE: The specific aims of this umbrella review are to: (1) Evaluate the evidence of efficacy of FGAs and SGAs in anxiety disorders as an adjunctive treatment to traditional antidepressant treatments and other nonantipsychotic medications; (2) Compare monotherapy with antipsychotics to first-line treatments for anxiety disorders in terms of effectiveness, risks, and side effects. The review protocol is registered on PROSPERO (CRD42021237436). METHODS: An initial search was undertaken to identify systematic reviews and meta-analyses from inception until 2020, with an updated search completed August 2021 and January 2023. The searches were conducted in PubMed, MEDLINE (Ovid), EMBASE (Ovid), APA PsycInfo (Ovid), CINAHL Complete (EBSCOhost), and the Cochrane Library through hand searches of references of included articles. Review quality was measured using the AMSTAR-2 (A MeaSurement Tool to Assess Systematic Reviews) scale. RESULTS: The original and updated searches yielded 1796 and 3744 articles respectively, of which 45 were eligible. After final review, 25 systematic reviews and meta-analyses were included in the analysis. Most of the systematic reviews and meta-analyses were deemed low-quality through AMSTAR-2 with only one review being deemed high-quality. In evaluating the monotherapies with antipsychotics compared with first-line treatments for anxiety disorder there was insufficient evidence due to flawed study designs (such as problems with randomization) and small sample sizes within studies. There was limited evidence suggesting efficacy of antipsychotic agents in anxiety disorders other than quetiapine in generalized anxiety disorder (GAD). CONCLUSIONS: This umbrella review indicates a lack of high-quality studies of antipsychotics in anxiety disorders outside of the use of quetiapine in GAD. Although potentially effective for anxiety disorders, FGAs and SGAs may have risks and side effects that outweigh their efficacy, although there were limited data. Further long-term and larger-scale studies of antipsychotics in anxiety disorders are needed.

Early non-response as a predictor of later non-response to antipsychotics in schizophrenia: a randomized trial.

BACKGROUND: It remains a challenge to predict the long-term response to antipsychotics in patients with schizophrenia who do not respond at an early stage. This study aimed to investigate the optimal predictive cut-off value for early non-response that would better predict later non-response to antipsychotics in patients with schizophrenia. METHODS: This multicenter, 8-week, open-label, randomized trial was conducted at 19 psychiatric centers throughout China. All enrolled participants were assigned to olanzapine, risperidone, amisulpride, or aripiprazole monotherapy for 8 weeks. The positive and negative syndrome scale (PANSS) was evaluated at baseline, week 2, week 4, and week 8. The main outcome was the prediction of nonresponse. Nonresponse is defined as a < 20% reduction in the total scores of PANSS from baseline to endpoint. Severity ratings of mild, moderate, and severe illness corresponded to baseline PANSS total scores of 58, 75, and 95, respectively. RESULTS: At week 2, a reduction of < 5% in the PANSS total score showed the highest total accuracy in the severe and mild schizophrenia patients (total accuracy, 75.0% and 80.8%, respectively), and patients who were treated with the risperidone and amisulpride groups (total accuracy, 82.4%, and 78.2%, respectively). A 10% decrease exhibited the best overall accuracy in the moderate schizophrenia patients (total accuracy, 84.0%), olanzapine (total accuracy, 79.2%), and aripiprazole group (total accuracy, 77.4%). At week 4, the best predictive cut-off value was < 20%, regardless of the antipsychotic or severity of illness (total accuracy ranging from 89.8 to 92.1%). CONCLUSIONS: Symptom reduction at week 2 has acceptable discrimination in predicting later non-response to antipsychotics in schizophrenia, and a more accurate predictive cut-off value should be determined according to the medication regimen and baseline illness severity. The response to treatment during the next 2 weeks after week 2 could be further assessed to determine whether there is a need to change antipsychotic medication during the first four weeks. TRIAL REGISTRATION: This study was registered on Clinicaltrials.gov (NCT03451734).

Effect of 5-HT1A Receptor Partial Agonists of the Azapirone Class as an Add-On Therapy on Psychopathology and Cognition in Schizophrenia: A Systematic Review and Meta-Analysis.

BACKGROUND: There are ongoing efforts to examine the effect of 5-HT1A receptor partial agonists as an add-on therapy for several symptoms of schizophrenia. By conducting a systematic review and meta-analysis, we evaluated whether augmentation with 5-hydroxtrypatamine (5-HT)1A partial agonists of the azapirone class improves psychotic symptoms and attention/processing speed, a key domain of cognition, in patients with schizophrenia. METHODS: A literature search was performed from 1987 to February 25, 2022, to identify randomized controlled trials. The standardized mean difference (SMD) with 95% confidence intervals (CI) was calculated when there were 2 or more studies. Seven studies, involving 435 patients, met the inclusion criteria. RESULTS: Random-effects model meta-analyses revealed that add-on therapy with buspirone or tandospirone had a significant beneficial effect on overall psychotic symptoms (SMD = -1.13, 95% CI = -1.98 to -0.27) and positive symptoms (SMD = -0.72, 95% CI =-1.31 to -0.12), while the effect on negative symptoms did not reach statistical significance (SMD = -0.93, 95% CI = -1.90 to 0.04). A significant positive effect was also observed on attention/processing speed (SMD = 0.37, 95% CI = 0.12 to 0.61). CONCLUSIONS: These findings support the idea that some compounds that stimulate 5-HT1A receptors provide an effective pharmacologic enhancer in the treatment of schizophrenia. Further clinical trials are warranted to determine the benefits of the adjunctive use of 5-HT1A partial agonists in ameliorating symptoms and improving functional outcomes in patients with schizophrenia or other psychiatric disorders.

Lurasidone and risk of metabolic syndrome: results from short and long-term studies in patients with bipolar depression.

OBJECTIVE: The elevated prevalence of metabolic syndrome (MetS) in patients with depression has been associated with increased mortality. This post hoc analysis assessed the effect of treatment with lurasidone on risk of MetS in patients with bipolar depression. METHODS: Data used in the current analyses consisted of 3 double-blind (DB), placebo-controlled, 6-week studies in adults with bipolar I depression (N = 1192), consisting of 1 monotherapy, and 2 adjunctive trials (lithium or valproate). Also analyzed was a 6-month open-label (OL) extension study (monotherapy, N = 316; adjunctive therapy, N = 497); and a 5-month, OL, stabilization phase followed by randomization to a 28-week DB, placebo-controlled, adjunctive therapy study with lurasidone (N = 490). MetS was defined based on NCEP ATP III criteria (2005 revision). RESULTS: The proportion of patients with new-onset MetS was similar for lurasidone vs placebo in the short-term studies (monotherapy, 13.9% vs 15.3%; adjunctive therapy, 13.6% vs 11.0%); and remained stable during both the 6-month extension phase study (monotherapy, 15.2%; adjunctive therapy, 16.9%), and the 5-month stabilization study (adjunctive therapy, 12.2%). After 28 weeks of DB treatment (following 5-month treatment in the stabilization study), new onset MetS was observed at endpoint (OC) in 26.2% of the lurasidone group, and 30.8% of the placebo group. CONCLUSIONS: This post hoc analysis found that both short and long-term treatment with lurasidone was associated with a relatively low risk for the development of MetS in patients with bipolar I disorder. These findings are consistent with similar analyses in patients with schizophrenia.

Quetiapine Moderates Doxorubicin-Induced Cognitive Deficits: Influence of Oxidative Stress, Neuroinflammation, and Cellular Apoptosis.

Chemotherapy is considered a major choice in cancer treatment. Unfortunately, several cognitive deficiencies and psychiatric complications have been reported in patients with cancer during treatment and for the rest of their lives. Doxorubicin (DOX) plays an important role in chemotherapy regimens but affects both the central and peripheral nervous systems. Antipsychotic drugs alleviate the behavioral symptoms of aging-related dementia, and the atypical class, quetiapine (QUET), has been shown to have beneficial effects on various cognitive impairments. The present investigation aimed to determine the possible mechanism underlying the effect of thirty-day administrations of QUET (10 or 20 mg/kg, p.o.) on DOX-induced cognitive deficits (DICDs). DICDs were achieved through four doses of DOX (2 mg/kg, i.p.) at an interval of seven days during drug treatment. Elevated plus maze (EPM), novel object recognition (NOR), and Y-maze tasks were performed to confirm the DICDs and find the impact of QUET on them. The ELISA tests were executed with oxidative [malondialdehyde (MDA), catalase, and reduced glutathione (GSH)], inflammatory [cyclooxygenase-2 (COX-2), nuclear factor kappa B (NF-κB), and tumor necrosis factor-alpha (TNF-α)], and apoptosis [B-cell lymphoma 2 (Bcl2), Bcl2 associated X protein (Bax), and Caspase-3] markers were assessed in the brain homogenate to explore the related mechanisms. DICD lengthened the transfer latency time in EPM, shortened the exploration time of the novel object, reduced the discrimination ability of the objects in NOR, and lowered the number of arm entries and time spent in the novel arm. QUET alleviated DICD-related symptoms. In addition, QUET reduced neuronal oxidative stress by reducing MDA and elevating GSH levels in the rat brain. Moreover, it reduced neuronal inflammation by controlling the levels of COX-2, NF-κB, and TNF-α. By improving the Bcl-2 level and reducing both Bax and Caspase-3 levels, it protected against neuronal apoptosis. Collectively, our results supported that QUET may protect against DICD, which could be explained by the inhibition of neuronal inflammation and the attenuation of cellular apoptosis protecting against oxidative stress.

Safety and effectiveness of lurasidone in adolescents with schizophrenia: results of a 2-year, open-label extension study.

BACKGROUND: Minimal long-term benefit: Risk data are available regarding antipsychotic treatments for schizophrenia in pediatric populations. This study evaluated the long-term safety, tolerability, and effectiveness of lurasidone in adolescents with schizophrenia. METHODS: Patients aged from 13 to 17 who completed 6 weeks of double-blind (DB), placebo-controlled treatment with lurasidone were enrolled in a 2-year, open-label (OL), flexible dose (20-80 mg/day) lurasidone treatment study. Safety was assessed via spontaneous reporting, rating scales, body weight measurement, metabolic, and prolactin testing. Effectiveness measures included the Positive and Negative Syndrome Scale (PANSS) total score. RESULTS: About 271 patients completed 6 weeks of DB treatment and entered the 2-year OL extension study. Altogether, 42.4% discontinued prematurely, 10.7% due to adverse events. During OL treatment, the most common adverse events were headache (24.0%); anxiety (12.9%), schizophrenia, and nausea (12.5%); sedation/somnolence (12.2%); and nasopharyngitis (8.9%). Minimal changes were observed on metabolic parameters and prolactin. Mean change from DB baseline in weight at week 52 and week 104 was +3.3 kg and + 4.9 kg, respectively, compared to an expected weight gain of +3.4 kg and + 5.7 kg, respectively, based on the sex- and age-matched US Center for Disease Control normative data. Continued improvement was observed in PANSS total score, with mean change from OL baseline of -15.6 at week 52 and -18.4 at week 104. CONCLUSION: In adolescents with schizophrenia, long-term lurasidone treatment was associated with minimal effects on body weight, lipids, glycemic indices, and prolactin. Continued improvement in symptoms of schizophrenia was observed over 2 years of lurasidone treatment.

Breastfeeding practices among women taking second-generation antipsychotics: findings from the National Pregnancy Registry for Atypical Antipsychotics.

The purpose of this study is to examine initiation rates of breastfeeding and other breastfeeding outcomes among women taking second generation antipsychotics (SGAs). Participants were enrolled in the National Pregnancy Registry for Atypical Antipsychotics; an ongoing prospective cohort study enrolling women age 18-45 years who are exposed and unexposed to SGAs during pregnancy. A 3-month postpartum interview collects information regarding breastfeeding behaviors. Specifically, women are asked the following questions about ever breastfeeding, still breastfeeding at 3 months postpartum, and whether women are breastfeeding exclusively, bottle-feeding exclusively, or breast and bottle feeding. Descriptive statistics were used to summarize demographic variables and breastfeeding practices. Rates of breastfeeding initiation and continuation were higher among participants who did not use SGAs. Among women not on SGAs, 88.2% of women reported "ever breastfeeding" compared to 59.3% of women on an SGA. At 3 months postpartum, 47% of women on a non-SGA were exclusively breastfeeding compared to 23% of women on an SGA. While the majority of women on an SGA initiated breastfeeding, breastfeeding rates were considerably lower than for women who were not on a SGA. More research is needed on the safety of lactation and use of combinations of psychotropics for women in pregnancy and postpartum.

Reproductive safety of aripiprazole: data from the Massachusetts General Hospital National Pregnancy Registry for Atypical Antipsychotics.

Aripiprazole has become one of the most commonly prescribed psychotropics, making a more comprehensive understanding of its reproductive safety profile a priority. The goal of the current analysis was to determine the risk of major malformations in infants exposed during the first trimester of pregnancy to aripiprazole compared to infants whose mothers had psychiatric diagnoses but did not use an atypical antipsychotic during pregnancy. The National Pregnancy Registry for Atypical Antipsychotics is a prospective pharmacovigilance program in which pregnant women are enrolled and interviewed during pregnancy and the postpartum period. Medical records are assessed to confirm presence or absence of major malformations. Pregnant women ages 18-45 with psychiatric diagnoses are enrolled. As of April 2020, N = 848 women who had delivered infants were eligible for analyses. A total of 158 women with first trimester exposure to aripiprazole were compared to 690 controls. For 163 infants born to women in the exposed group, seven major malformations were confirmed (4.29%), compared to fourteen of the 690 unexposed infants (1.99%). The unadjusted odds ratio for major malformations between aripiprazole-exposed and unexposed infants was 2.21 (95% confidence interval [CI] = (0.88, 5.57) The adjusted odds ratio for major malformations was 1.35 (95% confidence interval [CI] = (0.43, 4.20). After adjustment for confounding variables, the risk of major malformations after first trimester exposure to aripiprazole was not significant compared to controls. While these results are reassuring, they are limited by relatively small numbers of participants. Future analyses with larger numbers are expected to provide more of a complete and precise reproductive safety profile regarding aripiprazole use during pregnancy. Trial registration: clinicaltrials.gov NCT01246765.

Efficacy and safety of cariprazine in bipolar I depression: A double-blind, placebo-controlled phase 3 study.

OBJECTIVE: To assess the efficacy, safety, and tolerability of cariprazine in the treatment of the depressed phase of bipolar I disorder in adults (NCT02670538). METHODS: In this phase 3 double-blind placebo-controlled study, adult patients with bipolar I disorder according to the Diagnostic and Statistical Manual - 5th Edition criteria and a current depressive episode were randomized to placebo (n = 167), cariprazine 1.5 mg/day (n = 168) or cariprazine 3.0 mg/day (n = 158). Efficacy parameters were changes in the Montgomery-Åsberg Depression Rating Scale (MADRS) total scores (primary) and Clinical Global Impressions - Severity (CGI-S) scores (secondary) from baseline to Week 6 compared to placebo. A mixed-model for repeated measures was used to estimate the least-squares mean differences (LSMD); P-values were adjusted for multiplicity. Adverse events (AEs), laboratory results, vital signs, and suicide risk were monitored. RESULTS: Cariprazine 1.5 mg/day significantly reduced depressive symptoms on the primary (MADRS LSMD = -2.5; adjusted P = .0417) and secondary (CGI-S LSMD = -0.3; adjusted P = .0417) efficacy parameters vs placebo; differences were not statistically significant for cariprazine 3.0 mg/day. Common treatment-emergent AEs (≥5% in either cariprazine group and at least twice the incidence of placebo) were akathisia, restlessness, nausea, and fatigue. Mean metabolic parameter changes were low and generally comparable among groups; mean weight increases were ≤0.5 kg for all groups. CONCLUSIONS: Cariprazine 1.5 mg/day significantly reduced depressive symptoms in adults with bipolar I depression compared to placebo, but differences were not significant for cariprazine 3.0 mg/day. The safety and tolerability profiles were similar to previous studies of cariprazine.

Real-world data on new users of atypical antipsychotics: characterisation, prescription patterns, healthcare costs and early cardio-metabolic occurrences from a large Italian database.

PURPOSE: To describe new users of atypical antipsychotics (APs) in terms of sociodemographic characteristics, cardio-metabolic risk profile, prescription patterns, healthcare costs and cardio-metabolic events over the 24 months after treatment initiation. METHODS: Atypical AP new users were selected from the ReS database and grouped into three: patients already affected by cardio-metabolic diseases (group A), patients without these clinical conditions but with predisposing conditions (group B) and patients without cardio-metabolic diseases and predisposing conditions (group C). Annual prescription patterns and healthcare costs were analysed. Subjects of groups B and C were matched with controls to compare the occurrences of cardio-metabolic events over 24 months. RESULTS: Thirty-two thousand thirty-four new users of atypical APs were selected (median age 69). The 22.3% had cardio-metabolic diseases, 14.8% had predisposing conditions and 62.9% had none of these. The 99.3% received monotherapy. The mean annual cost per patient was €2785, and the median cost was €1108. After 24 months, a cardio-metabolic event occurred in 11.5% of group B vs. 8.7% of the controls (p < .01), and in 5.0% of group C vs. 2.1% of the controls (p < .01). CONCLUSION: Patients treated with atypical AP were on average old and, in a non-negligible amount, with cardio-metabolic disease or predisposing conditions. New users of atypical APs showed a significantly higher likelihood to develop a cardio-metabolic event early after treatment initiation.

Comparison of Lurasidone Versus Quetiapine for the Treatment of Delirium in Critically Ill Patients.

OBJECTIVE: To evaluate the efficacy and safety of lurasidone compared with quetiapine for treatment of delirium in critically ill patients. DESIGN: Prospective, observational cohort study. SETTING: Single-center community teaching hospital. PATIENTS: Forty adult intensive care unit (ICU) patients with delirium (Confusion Assessment Method in the ICU positive), tolerating enteral nutrition, and without active alcohol withdrawal or prior use of atypical antipsychotics. INTERVENTIONS: Patients were treated at the discretion of the prescriber with either lurasidone or quetiapine for delirium. Dose escalation and/or discontinuation were determined at the discretion of individual providers. RESULTS: Baseline characteristics differed with a higher severity of illness in patients in the quetiapine group (n = 20) and a higher baseline QTc interval in the lurasidone group (n = 20). No significant difference was seen in the time to delirium resolution (3.2 vs 3.4 days), average daily haloperidol requirements (5.7 vs 6.9 mg), hospital length of stay (LOS; 23.6 vs 27.9 days), or ICU LOS (12.1 vs 14.2 days). Lurasidone was associated with fewer ventilator support days (4.0 [interquartile range, IQR: 2.3-6.8] days vs 7 [IQR: 4.0-9.8; P = .0295] days) but also a fewer number of delirium-free days (0 [IQR: 0-1.0] days vs 2 [IQR: 0-3.0; P = .0231] days). Additionally, no difference was seen for ICU mortality (20% vs 20%), percentage of time oversedated (2.8% vs 2.7%), or incidence of QTc prolongation (10.0% vs 10.0%). CONCLUSIONS: Lurasidone for the treatment of delirium in critically ill patients did not differ in the time to delirium resolution when compared to quetiapine. Additionally, the incidence of QTc prolongation between agents does not appear to be different. Future randomized trials should evaluate dose escalation schemes and a larger proportion of patients to evaluate differences in mortality, efficacy, and life-threatening arrhythmias associated with atypical antipsychotic use.

A propensity score matching analysis for cardio metabolic risk of antipsychotics in patients with schizophrenia using Japanese claims data.

BACKGROUND: The aim of this study was to evaluate the cardio-metabolic risk in schizophrenia patients treated by atypical antipsychotic drugs compared with that in those treated without atypical antipsychotic drugs using a nationwide insurance claims database and medical examination database in Japan. METHODS: Eligible patients were defined as those meeting the following two criteria: (i) A diagnosis of schizophrenia (ICD-10 code: F20) was made between 1 January 2005 and 31 December 2017, with data available for at least 6 months before the diagnosis was made (index month), and (ii) health check-up data were available within ±3 months of the index month. The primary endpoint was changes in cardio-metabolic risk based on the Suita score at 1 year, and the secondary endpoints were changes in medical examination data related to cardio-metabolic risk (total cholesterol [TC], triglyceride, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, body mass index [BMI], and hemoglobin A1c) at 1 year. The primary endpoint was evaluated by multivariate analysis, with the cumulative chlorpromazine equivalent amount and the baseline Suita score added as covariates. RESULTS: One-hundred eighty five pairs of propensity score (PS)-matched patients were evaluated. Patients receiving atypical antipsychotic drugs exhibited a greater change in the Suita score and a risk of coronary heart disease based on the Suita score of 0.530 and 0.098%, respectively, than patients not receiving atypical antipsychotic drugs, but there was no significant difference (p = 0.412 and 0.610). The significant changes in TC and BMI were determined as 6.525 mg/dL and 0.380 kg/m2 greater, respectively, in patients treated with atypical antipsychotic drugs (p = 0.037 and 0.011). CONCLUSIONS: There were no significant increases in changes in the Suita score at 1 year by treatment with atypical antipsychotic drugs compared with treatment without atypical antipsychotic drugs. However, the TC and BMI were significantly higher in patients treated with atypical antipsychotic drugs.

The use of olanzapine as an antiemetic in palliative medicine: a systematic review of the literature.

BACKGROUND: Olanzapine is an atypical antipsychotic that has affinity for many central nervous system receptors. Its efficacy is supported by several studies in the prevention and treatment of chemotherapy-induced nausea and vomiting. No recommendations exist on the antiemetic use of olanzapine in the palliative care setting. The aim of this work is to complete the initial work of Fonte et al. published in 2015, to determine whether the literature supports the use of olanzapine as an antiemetic in palliative situations and, in practice, to propose a therapeutic schema adapted to the palliative setting. METHODS: Systematic review of the literature according to the PRISMA criteria. We searched the PubMed, Cochrane, RefDoc, EMBase databases and the gray literature databases. The bibliographic search was conducted between November 2016 and August 2017. RESULTS: Thirteen articles were included: 2 case studies, 3 case series, 3 retrospective studies, 2 prospective studies, 2 literature reviews. All studies concluded on the efficacy of olanzapine as an antiemetic in the palliative care setting. No serious adverse effects were reported. Based on the data from the literature review, we propose a therapeutic scheme adapted to the palliative care context. CONCLUSION: Action of olanzapine on many receptors and its tolerance profile make it an interesting antiemetic treatment in palliative medicine. But to date, studies are scarce and have a low statistical power. Further investigation is therefore needed to determine the benefit of this treatment in palliative care patients, compared to usual treatments.

Adverse reaction reports of neuroleptic malignant syndrome induced by atypical antipsychotic agents in the Japanese Adverse Drug Event Report (JADER) database.

AIM: This study evaluates reports on neuroleptic malignant syndrome (NMS) as an adverse event associated with the use of atypical antipsychotic agents (AAA) in Japan. We examined NMS occurrence following monotherapy and combination therapy with AAA in real clinical practice using the Japanese Adverse Drug Event Report database. METHODS: Adverse drug reaction reports associated with the use of one or more AAA or haloperidol were analyzed. The odds ratios of NMS occurrence after monotherapy and combination therapy with AAA without typical antipsychotic agents (TAA) relative to those after haloperidol monotherapy were estimated using multiple logistic regression. RESULTS: Associated with the use of one or more AAA without TAA were 721 events of NMS in 11 071 cases. NMS occurrence after monotherapy with most AAA and their combinations had lower odds ratios than that after haloperidol use. However, the odds ratios after blonanserin monotherapy and combination therapies with quetiapine and zotepine, and risperidone and zotepine were estimated higher than 1. CONCLUSION: Monotherapy or combination therapy with most AAA without TAA was not likely to cause NMS as an adverse reaction compared to haloperidol monotherapy. However, blonanserin monotherapy and combination therapies with quetiapine and zotepine, and risperidone and zotepine, possibly increase the report of NMS. Our results may provide useful information for medications such as AAA that are clinically used to treat mental disorders, though further research with more data are needed to clarify this.

Contribution of parasympathetic muscarinic augmentation of insulin secretion to olanzapine-induced hyperinsulinemia.

Atypical antipsychotic drugs have been associated with the development of obesity and diabetes. In particular, olanzapine can induce peripheral insulin resistance and compensatory hyperinsulinemia independent of weight gain or psychiatric disease. To determine if this compensatory increase in insulin is mediated by parasympathetic muscarinic stimulation, we randomized 15 healthy subjects 2:1 to receive double-blind olanzapine or placebo for 9 days under diet- and activity-controlled inpatient conditions. Before and after 7 days of study drug administration, subjects underwent frequently sampled intravenous glucose tolerance tests with either saline or atropine infused on subsequent days to assess insulin secretion and hepatic insulin extraction in the absence or presence of muscarinic blockade. We found that olanzapine led to an increase in the acute insulin response to glucose, which was not seen with placebo, and was attenuated in the olanzapine group by atropine. Deconvolution of C-peptide data confirmed an increase in insulin secretion with olanzapine, which was blocked by atropine, with a modest reduction in hepatic insulin extraction with olanzapine. These results support the contribution of muscarinic augmentation of insulin secretion to olanzapine-induced hyperinsulinemia, and provide a mechanism for the compensatory hyperinsulinemia that normally serves to prevent deterioration of glucose tolerance under conditions of metabolic challenge.

Safety and Effectiveness of Long-Term Treatment with Lurasidone in Older Adults with Bipolar Depression: Post-Hoc Analysis of a 6-Month, Open-Label Study.

OBJECTIVE: To evaluate the safety and effectiveness of 6 months of treatment with lurasidone in older adults with a diagnosis of bipolar I depression. DESIGN: Post-hoc analysis of a multicenter, 6-month, open-label extension study. SETTING: Outpatient. PARTICIPANTS: Patients aged 55 to 75 years with a DSM-IV-TR diagnosis of bipolar I depression who had completed 6 weeks of double-blind, placebo-controlled treatment with either lurasidone monotherapy (1 study) or adjunctive therapy with lithium or valproate (2 studies). INTERVENTION: Flexible doses of lurasidone, 20 to 120 mg/day, either as monotherapy, or adjunctive with lithium or valproate. MEASUREMENTS: Effectiveness was assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS; change from open-label-baseline to month-6, observed case analysis). RESULTS: A total of 141 older adults entered the extension study (monotherapy, N = 55; 39%; adjunctive therapy, N = 86; 61%). At the end of 6 months of open-label treatment with lurasidone, as monotherapy or adjunctive therapy, minimal changes were observed in the older adult sample in mean weight (-1.0 kg and -0.4 kg, respectively); and median total cholesterol (-2.0 mg/dL and +6.0 md/dL, respectively), triglycerides (+2.5 mg/dL and +6.0 mg/dL, respectively), and HbA1c (0.0% and -0.1%, respectively). Patients treated with 6 months of lurasidone showed a mean improvement on the MADRS in both the monotherapy (-6.2) and adjunctive therapy (-6.7) groups. CONCLUSIONS: Results of these post-hoc analyses found that up to 7.5 months of lurasidone treatment for bipolar depression in older adults was associated with minimal effects on weight and metabolic parameters, with low rates of switching to hypomania or mania, and was well tolerated. The antidepressant effectiveness of lurasidone in this age group was maintained over the 6-month treatment period.

Expression of Serotonin2C Receptors in Pyramidal and GABAergic Neurons of Rat Prefrontal Cortex: A Comparison with Striatum.

The prefrontal cortex (PFC) is enriched in several serotonin receptors, including 5-HT1A-R, 5-HT2A-R, and 5-HT3-R. These receptors modulate PFC activity due to their expression in large neuronal populations (5-HT1A-R, 5-HT2A-R) or in selected GABAergic populations (5-HT3-R). They are also relevant for antidepressant and antipsychotic drug action. Less is known about the localization of 5-HT2C-R, for which atypical antipsychotics show high affinity. Here, we report on the cellular distribution of 5-HT2C-R in rat PFC and striatum, using double in situ hybridization histochemistry. In PFC, 5-HT2C-R are expressed in pyramidal (VGLUT1-positive) and GABAergic (GAD-positive) neurons, including parvalbumin-positive neurons. There is a marked dorso-ventral gradient in the proportion of VGLUT1-positive cells expressing 5-HT2C-R (9% in the cingulate cortex, 61% in the tenia tecta and 66% in the piriform cortex), less marked for GABAergic neurons (13-27%). There is also a laminar gradient, with more cells expressing 5-HT2C-R in deep (V-VI) than in intermediate (II-III) layers. In common with 5-HT3-R, layer I GABAergic cells express 5-HT2C-R. The proportion of 5-HT2C-R-expressing striatal neurons was 23% (dorsolateral caudate-putamen), 37% (ventromedial caudate-putamen), 53% (nucleus accumbens-core), and 49% (nucleus accumbens-shell). These results help to better understand the serotonergic modulation of PFC-based networks, including basal ganglia circuits, and atypical antipsychotic drug action.

Effects of ABCB1 gene polymorphisms on autonomic nervous system activity during atypical antipsychotic treatment in schizophrenia.

BACKGROUND: There are interindividual differences in the adverse effects of atypical antipsychotics, which include autonomic nervous system (ANS) dysfunction. Accordingly, to clarify the interindividual differences in the adverse effects of specific atypical antipsychotics in schizophrenia, we investigated the association between ANS dysfunction and ATP-binding cassette transport sub-family B member 1 (ABCB1) gene polymorphisms in patients with schizophrenia. METHODS: In total, 233 Japanese patients with schizophrenia participated in this study. All of the participants received an atypical antipsychotic as monotherapy: 89 participants received risperidone, 69 olanzapine, 48 aripiprazole, and 27 quetiapine. ANS activity was assessed by means of a power spectral analysis of heart rate variability. Four single nucleotide polymorphisms (SNPs) in ABCB1 (rs1045642, rs1128503, rs2032582, and rs2235048) were genotyped using the TaqMan method. RESULTS: For aripiprazole, sympathetic and total autonomic nervous activities were significantly lower in the rs1045642 T allele carrier-rs2235048 C allele carrier group than in the rs1045642 non-T allele carrier-rs2235048 non-C allele carrier group. In addition, in the aripiprazole group, the T-C-T-A haplotype (rs1045642-rs2235048-rs1128503-rs2032582) was associated with decreased ANS activity. However, there were no significant associations between ANS activity and ABCB1 gene polymorphisms in the risperidone, olanzapine, and quetiapine groups. Multiple regression analysis revealed that sympathetic and total nervous activities were significantly associated with the ABCB1 rs1045642-rs2235048 genotype and the T-C-T-A haplotype (rs1045642-rs2235048-rs1128503-rs2032582). CONCLUSION: We suggest that ABCB1 genetic polymorphisms affect aripiprazole-related ANS dysfunction but do not affect risperidone-, olanzapine-, or quetiapine-related ANS dysfunction.

A weight-independent association between atypical antipsychotic medications and obstructive sleep apnea.

BACKGROUND: With increasing use of atypical antipsychotic (AAP) agents, the concern has been raised about the association between AAP agents and medical complications. Obstructive sleep apnea (OSA) is a common breathing disorder that adversely affects health and quality of life. Because the major risk factors for OSA are weight gain and obesity by altering the upper airway anatomy, an association between AAP and development of OSA is predictable. However, we hypothesized that AAP may promote OSA not only by weight gain but also because of its potential effects on upper airway muscle function. In the present study, we evaluated the possible association between AAP use and the severity of OSA. METHODS: A sample of patients using AAP for treatment of paradoxical insomnia was evaluated before and at least 8 weeks after AAP use. Patients were divided based on type of AAP use to olanzapine, risperidone, and quetiapine groups. Patients used olanzapine (5-10 mg), risperidone (2-4 mg), or quetiapine (100-200 mg) 2 h before bedtime. Before and after treatment, respiratory variables were recorded using polysomnography. BMI, neck circumference (NC), and waist circumference (WC) were measured before and after treatment period. RESULTS: There was no significant difference between pre- and post-treatment apnea index (0.2 ± 0.6 vs. 2.6 ± 4.3; p = 0.094) in olanzapine group. However, significant differences in hypopnea index (5.1 ± 5 vs. 30 ± 10.8; p < 0.0001) and AHI (5.3 ± 4.9 vs. 32.6 ± 9.6; p < 0.0001) were observed. Similar results were found in quetiapine and risperidone groups, except that in quetiapine group, apnea index was significantly increased after treatment period (0.7 ± 1.2 in pre-treatment vs. 3.1 ± 2.4 in post-treatment; p = 0.007). There were no significant changes in BMI, NC, and WC during treatment period in all three groups. CONCLUSION: While AAP medications are known cause of weight gain as a main risk factor of OSA, our finding demonstrated a weight-independent association between AAP medications and worsening respiration during sleep.