Evidence for solanidine as a dietary CYP2D6 biomarker: Significant correlation with risperidone metabolism.

AIMS: The extensive variability in cytochrome P450 2D6 (CYP2D6) metabolism is mainly caused by genetic polymorphisms. However, there is large, unexplained variability in CYP2D6 metabolism within CYP2D6 genotype subgroups. Solanidine, a dietary compound found in potatoes, is a promising phenotype biomarker predicting individual CYP2D6 metabolism. The aim of this study was to investigate the correlation between solanidine metabolism and the CYP2D6-mediated metabolism of risperidone in patients with known CYP2D6 genotypes. METHODS: The study included therapeutic drug monitoring (TDM) data from CYP2D6-genotyped patients treated with risperidone. Risperidone and 9-hydroxyrisperidone levels were determined during TDM, and reprocessing of the respective TDM full-scan high-resolution mass spectrometry files was applied for semi-quantitative measurements of solanidine and five metabolites (M402, M414, M416, M440 and M444). Spearman's tests determined the correlations between solanidine metabolic ratios (MRs) and the 9-hydroxyrisperidone-to-risperidone ratio. RESULTS: A total of 229 patients were included. Highly significant, positive correlationswere observed between all solanidine MRs and the 9-hydroxyrisperidone-to-risperidone ratio (ρ > 0.6, P < .0001). The strongest correlation was observed for the M444-to-solanidine MR in patients with functional CYP2D6 metabolism, i.e., genotype activity scores of 1 and 1.5 (ρ 0.72-0.77, P < .0001). CONCLUSION: The present study shows strong, positive correlations between solanidine metabolism and CYP2D6-mediated risperidone metabolism. The strong correlation within patients carrying CYP2D6 genotypes encoding functional CYP2D6 metabolism suggests that solanidine metabolism may predict individual CYP2D6 metabolism, and hence potentially improve personalized dosing of drugs metabolized by CYP2D6.

Uso de antipsicóticos atípicos no tratamento da esquizofrenia no Sistema Único de Saúde do Brasil: estudo de coorte, 2008-2017 / Uso de antipsicóticos atípicos en el tratamiento de la esquizofrenia en el Sistema Único de Salud de Brasil: estudio de 2008 a 2017 / Use of atypical antipsychotics in the treatment of schizophrenia in the Brazilian National Health System: a cohort study, 2008-2017

Objective: to investigate sociodemographic and clinical characteristics of users of atypical antipsychotics receiving care via the Specialized Component of Pharmaceutical Assistance (Componente Especializado da Assistência Farmacêutica - CEAF), for the treatment of schizophrenia in Brazil, between 2008 and 2017. Methods: this was a retrospective cohort study using records of the authorizations for high complexity procedures retrieved from the Outpatient Information System of the Brazilian National Health System, from all Brazilian states. Results: of the 759,654 users, 50.5% were female, from the Southeast region (60.2%), diagnosed with paranoid schizophrenia (77.6%); it could be seen a higher prevalence of the use of risperidone (63.3%) among children/adolescents; olanzapine (34.0%) in adults; and quetiapine (47.4%) in older adults; about 40% of children/adolescents were in off-label use of antipsychotics according to age; adherence to CEAF was high (82%), and abandonment within six months was 24%. Conclusion: the findings expand knowledge about the sociodemographic and clinical profile of users and highlight the practice of off-label use.

Objetivo: investigar las características sociodemográficas y clínicas de los usuarios de antipsicóticos atípicos, atendidos por el Componente Especializado de Asistencia Farmacéutica (CEAF) para el tratamiento de la esquizofrenia en Brasil, de 2008 a 2017. Métodos: estudio de cohorte retrospectivo utilizando registros de autorizaciones de trámites de alta complejidad del Sistema de Información Ambulatorio del SUS, de todos los estados brasileños. Resultados: de los 759.654 usuários identificados, el 50,5% era del sexo feminino de la región Sudeste (60,2%), diagnosticadas con esquizofrenia paranoide (77,6%). Hubo una mayor prevalencia de risperidona (63,3%) entre niños y adolescentes; de olanzapina (34,0%) en adultos; y quetiapina (47,4%) en ancianos. Alrededor del 40% de los niños/adolescentes estaba bajo uso no autorizado de antipsicóticos según la edad. La adherencia al CEAF fue alta (82%), y la deserción a los seis meses fue del 24%. Conclusión: los hallazgos amplían el conocimiento sobre el perfil sociodemográfico y clínico de los usuarios y destacan la práctica del uso off-label.

Objetivo: investigar características sociodemográficas e clínicas de usuários de antipsicóticos atípicos assistidos pelo Componente Especializado da Assistência Farmacêutica (CEAF), para tratamento da esquizofrenia no Brasil, de 2008 a 2017. Métodos: estudo de coorte retrospectivo utilizando registros das autorizações de procedimentos de alta complexidade do Sistema de Informações Ambulatoriais do Sistema Único de Saúde, de todos os estados brasileiros. Resultados: dos 759.654 usuários, 50,5% eram do sexo feminino, da região Sudeste (60,2%), diagnosticados com esquizofrenia paranoide (77,6%); observou-se maior prevalência de uso da risperidona (63,3%) entre crianças/adolescentes; de olanzapina (34,0%), em adultos; e quetiapina (47,4%), nos idosos; cerca de 40% das crianças/ adolescentes estavam sob uso off-label de antipsicóticos segundo a idade; a adesão ao CEAF foi alta (82%), e o abandono em seis meses foi de 24%. Conclusão: os achados ampliam o conhecimento sobre perfil sociodemográfico e clínico dos usuários e destacam a prática do uso off-label.

Striatal glutamate, subcortical structure and clinical response to first-line treatment in first-episode psychosis patients.

INTRODUCTION: Recent studies have observed that patients with treatment-resistant schizophrenia as well as patients with schizophrenia who do not respond within a medication trial exhibit excess activity of the glutamate system. In this study we sought to replicate the within-trial glutamate abnormality and to investigate the potential for structural differences and treatment-induced changes to improve identification of medication responders and non-responders. METHODS: We enrolled 48 medication-naïve patients in a 4-week trial of risperidone and classified them retrospectively into responders and non-responders using clinical criteria. Proton magnetic resonance spectroscopy and T1-weighted structural MRI were acquired pre- and post-treatment to quantify striatal glutamate levels and several measures of subcortical brain structure. RESULTS: Patients were classified as 29 responders and 19 non-responders. Striatal glutamate was higher in the non-responders than responders both pre- and post-treatment (F1,39 = 7.15, p = .01). Volumetric measures showed a significant group x time interaction (t = 5.163, <1%FDR), and group x time x glutamate interaction (t = 4.23, <15%FDR) were seen in several brain regions. Striatal volumes increased at trend level with treatment in both groups, and a positive association of striatal volumes with glutamate levels was seen in the non-responders. CONCLUSIONS: Combining anatomic measures with glutamate levels offers the potential to enhance classification of responders and non-responders to antipsychotic medications as well as to provide mechanistic understanding of the interplay between neuroanatomical and neurochemical changes induced by these medications. Ethical statement The study was approved by the Ethics and Scientific committees of the Instituto Nacional de Neurología y Neurocirugía in Mexico City. All participants over 18 years fully understood and signed the informed consent; in case the patient was under 18 years, informed consent was obtained from both parents. Participants did not receive a stipend.

Combination Therapy of Long-Acting Injectable Second-Generation Antipsychotics and Oral Antipsychotics: A Retrospective Chart Review and Prescribers' Attitude Survey.

BACKGROUND: Although long-acting injectable antipsychotics (LAI-APs) have been considered as a monotherapeutic option in the maintenance treatment of schizophrenia, it has been recently reported that the combination therapy of LAI-APs and oral antipsychotics (OAPs) is common. METHODS: We conducted a retrospective chart review to examine the situation of the combination therapy of LAI second-generation antipsychotics (LAI-SGAs) and OAPs, and a questionnaire survey to investigate prescribers' attitudes toward the combination therapy. We included patients who received any LAI-SGAs for 1 month or longer and classified them into monotherapy and combination therapy groups. We collected information on age, sex, primary psychiatric diagnosis, and concomitant psychotropic medications. RESULTS: Of the 132 patients, 39 (29.5%) received the combination therapy of LAI-SGAs and OAPs. Long-acting injectable risperidone was significantly associated with receiving the combination therapy compared with LAI aripiprazole. Olanzapine was the most common OAP in combination with LAI-SGAs. Only 8 patients (20.5%) concurrently received the same type of OAPs as LAI-SGAs. More than 60% of the patients received OAP polypharmacy before the initiation of LAI-SGAs. The psychiatrists in charge prescribed LAI-SGAs mainly because of a concern about adherence, and OAPs mainly because of insufficient dose of LAI-SGAs, to patients in the combination therapy group. They estimated that adherence to OAPs in two thirds of the patients in the combination therapy group was 80% or higher. CONCLUSIONS: The present study showed that the combination therapy of LAI-SGAs and OAPs is often conducted in real-world clinical practice. Considering the reason for the introduction of LAI-APs, clinicians should carefully monitor patients' adherence to OAPs concurrently used with LAI-APs.

Long-term efficacy and safety of once-monthly Risperidone ISM® in the treatment of schizophrenia: Results from a 12-month open-label extension study.

OBJECTIVE: To evaluate long-term efficacy, safety and tolerability of Risperidone ISM® in patients with schizophrenia, a multicenter, open-label extension of the PRISMA-3 study was conducted. METHODS: Eligible placebo (unstable) and Risperidone ISM® (stabilized) rollover patients from a previous 12-week double-blind phase and de novo stable patients received once-monthly intramuscular injections of Risperidone ISM® 75 or 100 mg for 12 months. The long term-efficacy assessment included the Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression-Severity (CGI-S) and Clinical Global Impression-Improvement (CGI-I) scales. Safety evaluation included treatment-emergent adverse events (TEAEs), injection site reactions (ISR), laboratory tests and several safety scales. RESULTS: Altogether, 215 patients entered the study (55 unstable, 119 stabilized and 41 stable patients). Most patients (74.9%) completed, and discontinuation rates were broadly similar across the study subgroups, mainly due to withdrawal of consent (12.1%). PANSS total and subscales scores decreased from baseline to endpoint in all groups, with the largest decrease for unstable patients. Improvement from baseline to 12 months was also shown for CGI-S and CGI-I scores for both unstable and stabilized patients; the CGI-S and CGI-I scores remained almost unchanged for the stable group. At least one treatment-related TEAE was reported in 39.1% of patients; the most common were headache (12.1%), hyperprolactinemia (9.8%) and asthenia (5.1%). ISR were reported in 8 (0.3%) patients; injection site pain score was low across the 2355 doses assessed. CONCLUSION: Risperidone ISM® is an effective, safe, and well-tolerated long-term treatment of schizophrenia in adults, regardless of the initial disease severity or whether patients were previously treated with Risperidone ISM® during an acute exacerbation or switched from stable doses of oral risperidone.

A Double-Blind, Placebo-Controlled Trial of Bupropion Add-on to Olanzapine or Risperidone in Overweight Individuals With Schizophrenia.

BACKGROUND: Weight gain due to antipsychotics is a challenging clinical problem because, to date, no effective pharmacological strategies have been found. Bupropion is often used in people with schizophrenia for smoking cessation and is well tolerated. However, studies on its use as weight loss treatment are scarce. The aim of the study was to examine the effectiveness of bupropion as a single weight loss treatment in overweight individuals maintained on long-term olanzapine or risperidone. METHODS: This randomized, double-blind, placebo-controlled, 8-week study included 26 overweight (body mass index ≥27 kg/m2) individuals with schizophrenia maintained on olanzapine (10-20 mg/d) or risperidone (2-4 mg/d). Participants were randomly allocated to a study group that received bupropion (150-300 mg/d) or to a placebo group. The positive and Negative Syndrome Scale and the Clinical Global Impression-Severity Scale were used to assess severity of psychosis at baseline and end of study (8 weeks). RESULTS: Bupropion addition, but not placebo, was associated with a significant reduction in body weight. Severity of psychotic symptoms was not altered in either group. CONCLUSIONS: The results demonstrate the efficacy of bupropion, compared with placebo, in patients maintained on chronic treatment with olanzapine or risperidone, both known to be major contributors to significant weight gain.

The Steady-State Comparative Bioavailability of Intramuscular Risperidone ISM and Oral Risperidone: An Open-Label, One-Sequence Study.

INTRODUCTION: This open-label, one-sequence study evaluated the steady-state comparative bioavailability of risperidone in situ microimplants (ISM®) and oral risperidone in patients stabilized on oral risperidone treatment. METHODS: Repeat oral administration of once daily 4 mg risperidone for 7 days was followed by 4 monthly (once every four weeks) intramuscular (IM) doses of risperidone ISM 100 mg. Mean steady-state concentration versus time profiles for risperidone, 9-OH risperidone, and risperidone active moiety was characterized. RESULTS: A total of 104 subjects were enrolled, 81 were included in the safety population and 58 completed the study. Intersubject variability for the steady-state concentrations versus time profiles for risperidone active moiety presented a greater variability range for oral risperidone versus risperidone ISM (% coefficient of variation [CV] range: 40-65% and 38-52%, respectively). Minimum plasma concentration at steady-state (Cmin, ss) and fluctuation in plasma concentrations (Fluc) of risperidone active moiety after risperidone ISM administration met bioequivalence criteria compared to the reference oral risperidone (geometric mean ratio [GMR] = 1.09 and 0.96, respectively; both 90% CIs were within 0.80-1.25). Area under the curve during the dosing interval (AUCtau), maximum plasma concentration at steady-state (Cmax, ss) and average plasma concentration (Cave) were only slightly higher (GMR [90% CI] = 1.25 [1.16-1.34], 1.17 [1.08-1.27], and 1.25 [1.16-1.34], respectively). Overall, once daily oral risperidone 4 mg and once monthly IM risperidone ISM 100 mg were generally safe and well tolerated in the participating subjects with schizophrenia previously stabilized with oral risperidone. CONCLUSION: The rapid release of risperidone ISM allows the achievement of the desired levels similar to those observed at the steady-state after oral risperidone treatment. Therefore, direct switch after 24 hours from the last oral risperidone dose to risperidone ISM treatment can be done in schizophrenia patients with no time lag, maintaining steady-state levels of the active moiety throughout treatment and without the need for oral risperidone supplementation or loading doses.

PANSS Individual Item and Marder Dimension Analyses From a Pivotal Trial of RBP-7000 (Monthly Extended-Release Risperidone) in Schizophrenia Patients.

Background: Positive and Negative Syndrome Scale (PANSS) data from a pivotal phase 3 study in participants with schizophrenia of RBP-7000, a recently marketed long-acting subcutaneous injectable risperidone formulation, were examined to determine if dose-response relationships existed for different items of the PANSS.Methods: Changes in the 30 PANSS items were analyzed individually and using the 5 factor-analysis-derived dimensions defined by Marder and colleagues. Subgroups of patients who could benefit from the RBP-7000 120 mg dose were investigated.Results: 337 participants were randomized and received study medication (RBP-7000 90 mg n = 111, RBP-7000 120 mg n = 114, placebo n = 112). Dose-dependent responses were observed in items from the study-specified PANSS positive and general psychopathology exploratory subscales. Dose-dependent responses were observed across all 5 Marder dimensions, with the largest effect sizes observed with the 120 mg dose in the uncontrolled hostility/excitement (UHE) and anxiety/depression dimensions. Participants with baseline UHE dimension scores ≥ 9 demonstrated greater improvement in PANSS total score at the 120 mg dose compared to the 90 mg dose.Conclusions: RBP-7000 demonstrated efficacy across both the primary and exploratory PANSS study endpoints and the post hoc Marder dimensions. Schizophrenia patients with higher baseline Marder UHE scores may benefit from initiation of treatment at the 120 mg dose.Trial Registration: ClinicalTrials.gov identifier: NCT02109562.

Determining the release kinetics of risperidone controlled release matrices to treat schizophrenia.

Risperidone is an atypical antipsychotic agent clinically used to treat schizophrenia, bipolar diseases, and autism. Usually, the frequency of doses is twice daily. In the present study, risperidone controlled release matrices formulated using hydrophilic and hydrophobic polymers. The tablets were prepared by direct compression. The pre-compression and post-compression properties were assessed, along with swelling studies. The morphology of particles observed using scanning electron microscopy (SEM) and Fourier transform infrared spectroscopy (FT-IR). The stability study on the drug was performed using thermal gravimetric analysis (TGA) and differential thermal analysis (DTA). The optimized formulation was prepared with the help of hydrophilic polymer K100M (40% ratio). Furthermore, release kinetics had investigated. The release pattern of optimized formulation FT5 fitted best to zero-order kinetics and showed excellent release characteristics. The model-independent approach had been used, formulations FT6 and FT8 showed resemblance with FT5 in all three media, respectively. The once daily formulation of risperidone could be beneficial for schizophrenia patients and their caregivers and will improve patient compliance.

Childhood dystonic reactions in the middle Black Sea region.

ABSTRACT: Acute dystonic reactions are a worrying reason for presentation to the pediatric emergency department and the pediatric neurology clinic in childhood. It must be diagnosed and treated quickly. The aim of this study was to examine the clinical presentations, etiological factors, and prognosis of patients presenting to our regional tertiary pediatric neurology clinic with a diagnosis of acute dystonic reactions in children.Nine pediatric patients who were treated for acute dystonic reactions between May, 2018 and May, 2020 and had adequate follow-up were included in the study. Medical record data were reviewed age, gender, etiology, features of family, treatment, and results.Three of the patients were female and 6 were male. Their average age was 11 years (4-17). All patients were evaluated as a drug-induced acute dystonic reaction. Of the 9 patients, 5 were due to metoclopramide, 3 were due to risperidone, and 1 was due to aripiprazole. It was learned that a similar situation against other drugs developed in the family history of 3 patients. As a treatment, all of them were intramuscularly applied biperiden suitable for their weight and 30 minutes dramatic improvement was observed. Additional dose had to be administered in only 1 case. All cases were discharged for 24 hours. No problem was observed in their follow-up.Drug-induced acute dystonic reaction can be diagnosed and has a clinical picture that completely resolves when effective treatment is applied. However, it should not be forgotten that it can reach life-threatening dimensions clinically.

Altered Antioxidant Defenses in Drug-Naive First Episode Patients with Schizophrenia Are Associated with Poor Treatment Response to Risperidone: 12-Week Results from a Prospective Longitudinal Study.

Abnormal redox regulation is thought to contribute to schizophrenia (SCZ). Accumulating studies have shown that the plasma antioxidant enzyme activity is closely associated with the course and outcome in antipsychotics-naïve first-episode (ANFE) patients with SCZ. The main purpose of this study was to investigate the effect of risperidone on oxidative stress markers in ANFE patients and the relationship between risperidone response and changes in oxidative stress markers. Plasma activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) enzyme, total antioxidant status (TAS), and malondialdehyde (MDA) levels were measured in 354 ANFE patients and 152 healthy controls. The clinical symptoms were evaluated by the Positive and Negative Syndrome Scale (PANSS). Patients received risperidone monotherapy for 12 weeks and oxidative stress markers and PANSS were measured at baseline and at follow-up. Compared with healthy controls, the patients exhibited higher activities of SOD, CAT, and TAS levels, but lower MDA levels and GPx activity. A comparison between 168 responders and 50 non-responders at baseline and 12-week follow-up showed that GPx activity decreased in both groups after treatment. Moreover, GPx activity decreased less in responders and was higher in responders than in non-responders at follow-up. These results demonstrate that the redox regulatory system and antioxidant defense enzymes may have predictive value for the response of ANFE patients to risperidone treatment.

Clozapine-Associated Leukopenia and Agranulocytosis in Western Cape, South Africa: A 3-Year Retrospective Cohort Study.

BACKGROUND: Clozapine may cause life-threatening hematological side effects (HSEs). Hematological side effect incidence data from Sub-Saharan Africa are lacking. Furthermore, clozapine reduces cellular immunity, and it is unknown whether clozapine is a risk factor for tuberculosis or whether HIV is a risk factor for developing HSEs. We assessed the incidence of HSEs in South Africans from the Western Cape Province on clozapine, and the secondary objective was to determine the association of HIV and tuberculosis with clozapine exposure. METHODS: We conducted a 24-week retrospective descriptive study of patients initiated on clozapine between January 2015 and December 2017 using anonymized data from the Provincial Health Data Centre. A control group of patients initiated on risperidone was selected. RESULTS: We identified 23,328 patients and included 5213 who had white blood cell monitoring (n = 1047 clozapine, n = 4166 risperidone). The incidence of leukopenia in patients on clozapine was 0.38% (95% confidence interval [CI], 0.01%-0.76%) measured over a 24-week period and was 0.41% in patients on risperidone (95% CI, 0.21%-0.6%) (P = 0.91). The incidence of agranulocytosis in patients on clozapine was 0.19% (95% CI, 0.00%-0.46%) measured over a 24-week period and was 0.24% in patients on risperidone (95% CI, 0.09%-0.39%) (P = 0.266). HIV-infected patients had a 7.46 times increased risk of developing leukopenia (95% CI, 3.37-16.48; P < 0.01). Patients who developed leukopenia had a 6.24 times increased risk of contracting tuberculosis (95% CI, 1.84-21.11; P < 0.01). CONCLUSIONS: Our incidence of clozapine-induced HSEs was lower than previously reported and not significantly different compared with risperidone. HIV infection was associated with HSEs. Patients with HSEs had an increased risk of developing tuberculosis.

Body mass index increase in preschoolers with heterogeneous psychiatric diagnoses treated with risperidone.

OBJECTIVE: Use of risperidone in preschool-aged children is growing, with rising concerns of adverse metabolic consequences. Longitudinal data on risperidone-related weight gain in preschoolers are scarce. We aimed to evaluate changes in body mass index (BMI) that are associated with risperidone treatment in preschoolers. METHOD: We analyzed naturalistic, longitudinal data on 141 preschool children (112 boys, 29 girls) receiving psychiatric care. Mean patient age at baseline was 5.0 years (SD=0.8) and average follow-up period was 1.3 years (SD=0.8), with >8 mean BMI measurements per patient. We studied the effect of risperidone exposure (n=78) on age-and-sex-standardized BMI (BMI Z-score) implementing mixed models with random subject intercepts to account for repeated measures, covarying for multiple confounders including demographics, stimulant treatment and psychiatric diagnoses. We employed similar models to study dose and duration effects. RESULTS: Risperidone treatment was significantly associated with an increase in BMI (effect size of exposure=0.45 SD (SE=0.06), t (949)=7.7, p<0.001) covarying for stimulant exposure and other confounders, independent of treatment indication. Females exhibited stronger effects (risperidone treatment × sex interaction t=2.32, p=0.02)). Risperidone daily dose was associated with increase in BMI (for each additional 1 mg, effect size=0.28 SD (SE=0.07), t(419)=3.76, p<0.001). CONCLUSION: Similar to older populations, risperidone treatment in preschoolers is associated with significant weight gain, with evidence for dose effects. Findings provide critical data that can inform clinicians.

Muscle Tissue as a Surrogate for In Vitro Drug Release Testing of Parenteral Depot Microspheres.

Despite the importance of drug release testing of parenteral depot formulations, the current in vitro methods still require ameliorations in biorelevance. We have investigated here the use of muscle tissue components to better mimic the intramuscular administration. For convenient handling, muscle tissue was used in form of a freeze-dried powder, and a reproducible process of incorporation of tested microspheres to an assembly of muscle tissue of standardized dimensions was successfully developed. Microspheres were prepared from various grades of poly(lactic-co-glycolic acid) (PLGA) or ethyl cellulose, entrapping flurbiprofen, lidocaine, or risperidone. The deposition of microspheres in the muscle tissue or addition of only isolated lipids into the medium accelerated the release rate of all model drugs from microspheres prepared from ester-terminated PLGA grades and ethyl cellulose, however, not from the acid-terminated PLGA grades. The addition of lipids into the release medium increased the solubility of all model drugs; nonetheless, also interactions of the lipids with the polymer matrix (ad- and absorption) might be responsible for the faster drug release. As the in vivo drug release from implants is also often faster than in simple buffers in vitro, these findings suggest that interactions with the tissue lipids may play an important role in these still unexplained observations.

The effect of risperidone on reward-related brain activity is robust to drug-induced vascular changes.

Dopamine (DA) mediated brain activity is intimately linked to reward-driven cerebral responses, while aberrant reward processing has been implicated in several psychiatric disorders. fMRI has been a valuable tool in understanding the mechanism by which DA modulators alter reward-driven responses and how they may exert their therapeutic effect. However, the potential effects of a pharmacological compound on aspects of neurovascular coupling may cloud the interpretability of the BOLD contrast. Here, we assess the effects of risperidone on reward driven BOLD signals produced by reward anticipation and outcome, while attempting to control for potential drug effects on regional cerebral blood flow (CBF) and cerebrovascular reactivity (CVR). Healthy male volunteers (n = 21) each received a single oral dose of either 0.5 mg, 2 mg of risperidone or placebo in a double-blind, placebo-controlled, randomised, three-period cross-over study design. Participants underwent fMRI scanning while performing the widely used Monetary Incentive Delay (MID) task to assess drug impact on reward function. Measures of CBF (Arterial Spin Labelling) and breath-hold challenge induced BOLD signal changes (as a proxy for CVR) were also acquired and included as covariates. Risperidone produced divergent, dose-dependent effects on separate phases of reward processing, even after controlling for potential nonneuronal influences on the BOLD signal. These data suggest the D2 antagonist risperidone has a wide-ranging influence on DA-mediated reward function independent of nonneuronal factors. We also illustrate that assessment of potential vascular confounds on the BOLD signal may be advantageous when investigating CNS drug action and advocate for the inclusion of these additional measures into future study designs.

Maintenance Treatment With Long-Acting Injectable Antipsychotics for People With Nonaffective Psychoses: A Network Meta-Analysis.

OBJECTIVE: This study compared relapse prevention and acceptability of long-acting injectable (LAI) antipsychotics in the maintenance treatment of adults with nonaffective psychoses. METHODS: The authors searched MEDLINE, Embase, PsycINFO, CINAHL, CENTRAL, and online registers for randomized controlled trials published until June 2020. Relative risks and standardized mean differences were pooled using random-effects pairwise and network meta-analysis. The primary outcomes were relapse rate and all-cause discontinuation ("acceptability"). The quality of included studies was rated with the Cochrane Risk of Bias tool, and the certainty of pooled estimates was measured with GRADE (Grading of Recommendations Assessment, Development, and Evaluation). RESULTS: Of 86 eligible trials, 78 (N=11,505) were included in the meta-analysis. Regarding relapse prevention, most of the 12 LAIs included outperformed placebo. The largest point estimates and best rankings of LAIs compared with placebo were found for paliperidone (3-month formulation) and aripiprazole. Moderate to high GRADE certainty for superior relapse prevention compared with placebo was also found for (in descending ranking order) risperidone, pipothiazine, olanzapine, and paliperidone (1-month formulation). In head-to-head comparisons of LAIs, only haloperidol was inferior to aripiprazole, fluphenazine, and paliperidone. For acceptability, most LAIs outperformed placebo, with moderate to high GRADE certainty for (in descending ranking order) zuclopenthixol, aripiprazole, paliperidone (3-month formulation), olanzapine, flupenthixol, fluphenazine, and paliperidone (1-month formulation). In head-to-head comparisons, only LAI aripiprazole had superior acceptability to other LAIs (bromperidol, fluphenazine, paliperidone [1-month formulation], pipothiazine, and risperidone). CONCLUSIONS: LAI formulations of paliperidone (3-month formulation), aripiprazole, olanzapine, and paliperidone (1-month formulation) showed the highest effect sizes and certainty of evidence for both relapse prevention and acceptability. Results from this network meta-analysis should inform frontline clinicians and guidelines.

Menstrual Dysfunction in Women With Schizophrenia During Risperidone Maintenance Treatment.

BACKGROUND: A percentage of women patients with schizophrenia may suffer from menstrual dysfunction associated with antipsychotic medication. This study evaluated menstrual dysfunction in women with schizophrenia given maintenance risperidone, and investigated the association between menstrual dysfunction and the duration and dose of risperidone and clinical symptoms. METHODS: The data of 161 women were obtained from the Risperidone Maintenance Treatment in Schizophrenia study, including patients' characteristics, menstrual conditions, and duration and dosage of risperidone. Qualitative data regarding menstrual health were evaluated at baseline (clinical stabilization after 4-8 weeks maintenance treatment with a standard risperidone dose 4-8 mg/d) and follow-up interviews up to 52 weeks. RESULTS: At baseline, 73.2% (119/161) of the patients were eumenorrheic; specific rates of menstrual dysfunction were 14.3% (23/161) irregular menstruation, 6.8% (11/161) oligomenorrhea, and 5.0% (8/161) amenorrhea. At the end of follow-up, 16.0% (19/119) of those with eumenorrhea at baseline reported menstrual dysfunction. During the entire risperidone maintenance treatment, 37.9% (61/161) experienced menstrual dysfunction. The range of onset time from the beginning of risperidone treatment to menstrual dysfunction was 64 to 243 days. Risperidone dose was positively associated with menstrual dysfunction (r = 0.187, P = 0.046). The total Positive and Negative Syndrome Scale score was significantly associated with menstrual dysfunction (r = 0.274, P = 0.001). CONCLUSIONS: Attention should be given to menstrual dysfunction of women with schizophrenia that is an adverse effect of risperidone maintenance treatment. Menstrual dysfunction may occur early or late during maintenance treatment, partly depending on the dose.ClinicalTrials.govidentifier: NCT00848432.

A typical antipsychotic treatment induced gradually expanding white matter alterations in healthy individuals with persistent auditory verbal hallucinations-an artificially controlled pilot study.

OBJECTIVE: The aim of this study was to explore the effects of atypical antipsychotics (AaPs) on brain white matter (WM) tracts in healthy individuals with auditory verbal hallucinations (Hi-AVHs). METHODS: We analyzed neuroimaging, AVH symptoms, and cognitive assessment data obtained from 39 Hi-AVHs who reported being distressed by persistent AVHs and volunteered to receive AaP treatment. We used tract-based spatial statistics (TBSS) and t tests to explore AaP pharmacotherapy effects on AVH symptoms and brain WM alterations in Hi-AVH subjects. RESULTS: TBSS and t tests revealed WM alterations after AaP treatment, relative to pretreatment observations. Although AaPs alleviated AVH symptoms, WM alterations in these subjects expanded over 8 months of AaP treatment, encompassing most major WM tracts by the end of the observation period, including the corpus callosum, arcuate fasciculus, cortico-spinal tracts, anterior commissure, and posterior commissure. CONCLUSIONS: The worsening of AaP-associated WM alterations observed in this study suggest that AaPs may not be a good choice for the treatment of Hi-AVHs despite their ability to alleviate AVHs.