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Many articles suggest that clozapine was strongly associated with a higher incidence of new-onset diabetes mellitus, and the issue has remained unsettled. Many articles have compared clozapine with FGAs, but few have compared clozapine with SGAs. We aimed to compare the risk of new-onset diabetes mellitus in adults with schizophrenia treated with clozapine and other SGAs. We conducted a comprehensive search of databases from their inception up until August 26, 2023. The specific databases include PubMed, Embase and others. We included non-randomized controlled trials involving the use of SGAs such as clozapine, olanzapine, risperidone, quetiapine, amisulpride, and zotepine, with a focus on new-onset diabetes mellitus as an outcome. We utilized odds ratio with 95 % credible intervals (95 % CI) as our effect size measures. The study protocol is registered with PROSPERO, number CRD42024511280. We included 7 studies with sufficient data to include in the meta-analysis. A total of eight studies with 641,48 participants met the eligibility criteria. The OR of the incidence rates of new-onset diabetes between clozapine and olanzapine was 0.95 (95 % CI:[0.82–1.09]), between clozapine and risperidone was 1.25 (95 % CI: [1.09–1.44]), between clozapine and quetiapine was 1.44 (95 % CI: [0.92–2.25]). In patients with schizophrenia, clozapine has been found to have a higher rate of new-onset diabetes mellitus compared to risperidone. However, there was no significant difference in incidence rate between clozapine versus olanzapine and quetiapine. These findings can assist clinicians in balancing the risks and benefits of those drugs. • Differences in the incidence of new-onset diabetes caused by second-generation antipsychotics were compared. • Clozapine and olanzapine cause a similar incidence of new-onset diabetes. • Clozapine is more likely to cause new-onset diabetes than risperidone. • Explored relationship between therapy duration and incidence [ABSTRACT FROM AUTHOR]

PDE10A inhibition represents a potential mechanism for treating schizophrenia. PDE10A inhibitors increase cyclic nucleotides in striatal neurons, thereby mimicking the effects of dopamine receptor D2 antagonists and D1 agonists. We evaluated the PDE10A inhibitor MK-8189 for treating schizophrenia. Randomized, double-blind, placebo and active-controlled, phase 2a, multicenter, inpatient trial in adults experiencing an acute episode of schizophrenia. Participants were randomized 2:2:1 to once-daily MK-8189 12 mg, placebo, or risperidone 6 mg (active control) for 4-weeks. The primary outcome was change-from-baseline in total score on the Positive and Negative Syndrome Scale (PANSS) at 4 weeks. The number of treated participants was 90 for MK-8189, 89 for placebo, and 45 for risperidone. MK-8189 demonstrated a trend towards improvement versus placebo for change-from-baseline in PANSS total score after 4 weeks (difference = −4.7 [95 % CI: −9.8,0.5], P = 0.074). The active control risperidone was superior to placebo on PANNS total score (difference = −7.3 [95 % CI: −14.0,−0.6], P = 0.033), demonstrating assay sensitivity, while MK-8189 and risperidone did not significantly differ (difference = 2.6 [95 % CI: −4.0,9.2], P = 0.440). MK-8189 had a nominally significant effect on PANSS positive subscale score compared to placebo (difference = −2.2 [95 % CI: −3.8,−0.5], P = 0.011). Discontinuation of MK-8189 treatment due to an adverse event was low (<10 %). Extrapyramidal symptoms occurred with MK-8189 but were mostly mild and transient. Compared with placebo, MK-8189 reduced body weight while risperidone increased weight. These findings suggest that PDE10A inhibition may produce antipsychotic effects and associated weight loss and that further trials with PDE10A inhibitors are warranted. Clinicaltrials.gov identifier: NCT03055338 [ABSTRACT FROM AUTHOR]

Endothelial inflammation may be involved in the pathogenesis of schizophrenia, and cellular adhesion molecules (CAMs) on endothelial cells may facilitate leukocyte binding and transendothelial migration of cells and inflammatory factors. The aim of the present study was to assess levels of soluble cellular adhesion molecules, including intercellular adhesion molecule (ICAM)-1, vascular adhesion molecule (VCAM)-1, mucosal addressin cell adhesion molecule (MADCAM), junctional adhesion molecule (JAM-A) and neural cadherin (N-CAD) in patients with schizophrenia compared to healthy controls. The study population consists of 138 patients with schizophrenia-spectrum disorder, of whom 54 were drug-naïve, compared to 317 general population controls. The potential confounders age, gender, smoking and body mass index (BMI) were adjusted for in linear regression models. The total patient group showed significantly higher levels of ICAM-1 (p < 0.001) and VCAM-1 (p < 0.001) compared to controls. Previously medicated patients showed higher ICAM-1 levels compared to drug-naïve patients (p = 0.042) and controls (p < 0.001), and elevated VCAM-1 levels compared to controls (p < 0.001). Drug-naive patients had elevated levels of VCAM-1 (p = 0.031) compared to controls. In our study, patients with schizophrenia – including the drug-naïve – have higher levels of soluble CAMs compared to healthy controls. These findings suggest activation of the endothelial system as in inflammation. [ABSTRACT FROM AUTHOR]

Several studies have indicated that the plasma concentration of risperidone increases 3–5-fold during the acute-phase reaction (APR) of inflammation or infection. Psychiatric symptoms are present or deteriorate when the dose is lowered; thus, the complex effects of inflammation on the pharmacokinetics of risperidone need to be examined. We established a APR model in rabbits induced by lipopolysaccharide (LPS) and studied the effect of APR on pharmacokinetics, distribution and disposition of risperidone in vivo and in vitro. Following intramuscular administration, the plasma exposures for risperidone and its active metabolite (9-hydroxyrisperidone) were increased approximately 6-fold on day 2 of inflammation. The exposure values did not change between day 2 and 5 of inflammation, nor did the metabolite-to-parent ratio before and during inflammation. Following oral administration, the increase of risperidone exposure was twice as high as that following intramuscular administration during APR. However, the concentration of risperidone and 9-hydroxyrisperidone in brain tissue was similar between the inflammatory and control groups. Moreover, the plasma protein binding (PPB) of risperidone and 9-hydroxyrisperidone associated with inflammation were all increased to >99 %. In addition, risperidone and 9-hydroxyrisperidone were not substrates of the key transporters, OATP1B3, OCT2, OAT3, MATE-1, or MATE-2 K. The expression of progesterone X receptor and P-glycoprotein was inhibited by LPS. During APR, reduced expression of P-glycoprotein and increased PPB were responsible for increased exposure in plasma, while maintaining stable concentrations in the brain, and risperidone does not need to be dose-adjusted so as to achieve psychopharmacological outcomes. [ABSTRACT FROM AUTHOR]

Examining the heterogeneity of negative symptoms of schizophrenia contributes to the identification of available treatment targets. Generally, prior evidence classified three to four symptom treatment response trajectory groups over the course of positive symptoms, yet, no evidence exists regarding the heterogeneity of medium-term response to predominant negative symptoms. The current post-hoc analysis aims to identify the heterogeneity in negative symptom treatment response trajectories among patients with predominant negative symptoms who received either cariprazine or risperidone for 26 weeks. Treatment response was analyzed based on the: the Positive and Negative Syndrome Scale Factor Score for Negative Symptoms (PANSS-FSNS), and the Clinical Global Impression Severity (CGI S) and Improvement (CGI I) scales. To identify subgroups of patients with a similar course of treatment response, group-based trajectory modelling was utilized. Results demonstrated that in comparison with competing models, a single trajectory best described the treatment response of patients with predominant negative symptoms. The results indicate that patients with predominant negative symptoms with over ten years of schizophrenia respond rapidly to adequate treatment and follow a course of steady improvement. [ABSTRACT FROM AUTHOR]

Antipsychotic medications are generally effective in ameliorating psychotic symptoms in schizophrenia spectrum disorders (SSDs). Identifying predictors associated with poor treatment response is important for a personalized treatment approach. Childhood trauma (CT) may have a general and differential effect on the effectiveness of different types of antipsychotics in SSDs. The Bergen-Stavanger-Trondheim-Innsbruck (BeSt InTro) study is a pragmatic, researcher-initiated, semi-randomized trial. The present study aimed to investigate symptom change (the Positive and Negative Syndrome Scale) from baseline to 1, 3, 6, 12, 26, 39 and 52 weeks of antipsychotic treatment (amisulpride, aripiprazole and olanzapine) by group (CT/no CT). Participants (n = 98) with diagnoses within the schizophrenia spectrum (F20-29 in the International Classification of Diseases - 10th Revision) were randomized to receive amisulpride, aripiprazole or olanzapine, and for this study categorized into groups of none and low CT, and moderate to severe CT according to thresholds defined by the Childhood Trauma Questionnaire Short-Form manual. CT in SSDs predicted an overall slower treatment response and less antipsychotic effectiveness after 26 weeks of treatment, which was statistically nonsignificant at 52 weeks. Secondary analyses showed a differential effect of CT related to type of antipsychotic medication: patients with SSDs and CT who received olanzapine showed less antipsychotic effectiveness throughout 52 weeks of treatment. The intention-to-treat and per-protocol analyses were convergent. Our findings indicate that in patients with SSD and CT, delayed response to antipsychotics could be expected, and a longer evaluation period before considering change of medication may be recommended. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Increased dopaminergic activity in the striatum underlies the neurobiology of psychotic symptoms in schizophrenia (SZ). Beyond the impaired connectivity among the limbic system, the excess of dopamine could lead to inflammation and oxidative/nitrosative stress. It has been suggested that atypical antipsychotic drugs attenuate psychosis not only due to their modulatory activity on the dopaminergic/serotonergic neurotransmission but also due to their anti-inflammatory/antioxidant effects. In such a manner, we assessed the effects of the atypical antipsychotic risperidone (RISP) on the structural neuroplasticity and biochemistry of the striatum in adult rats with neonatal ventral hippocampus lesion (NVHL), which is a developmental SZ-related model. RISP administration (0.25 mg/kg, i.p.) ameliorated the neuronal atrophy and the impairments in the morphology of the dendritic spines in the spiny projection neurons (SPNs) of the ventral striatum (nucleus accumbens: NAcc) in the NVHL rats. Also, RISP treatment normalized the pro-inflammatory pathways and induced the antioxidant activity of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) in this model. Our results point to the neurotrophic, anti-inflammatory, and antioxidant effects of RISP, together with its canonical antipsychotic mechanism, to enhance striatum function in animals with NVHL. [ABSTRACT FROM AUTHOR]

Schizophrenia is a complex psychiatric disorder where genetic, epigenetic, and environmental factors play a role in disease onset, course of illness, and treatment outcome. Pharmaco(epi)genetic research presents an important opportunity to improve patient care through prediction of medication side effects and response. In this narrative review, we discuss the current state of research and important progress of both genetic and epigenetic factors involved in antipsychotic response, over the past five years. The review is largely focused on the following frequently prescribed antipsychotics: olanzapine, risperidone, aripiprazole, and clozapine. Several consistent pharmacogenetic findings have emerged, in particular pharmacokinetic genes (primarily cytochrome P450 enzymes) and pharmacodynamic genes involving dopamine, serotonin, and glutamate neurotransmission. In addition to studies analysing DNA sequence variants, there are also several pharmacoepigenetic studies of antipsychotic response that have focused on the measurement of DNA methylation. Although pharmacoepigenetics is still in its infancy, consideration of both genetic and epigenetic factors contributing to antipsychotic response and side effects no doubt will be increasingly important in personalized medicine. We provide recommendations for next steps in research and clinical evaluation. [ABSTRACT FROM AUTHOR]

Long-acting injectable antipsychotics (LAI-APs) remain underutilized. One reason is the concern that LAI-APs might cause serious adverse events such as neuroleptic malignant syndrome (NMS) and lead to prolonged symptoms compared with oral treatment. Because the risk of NMS associated with LAI second-generation antipsychotics (LAI-SGAs) remains unclear, we compared reporting frequency, time to onset, and mortality of NMS between LAI- and oral SGAs using data from a Japanese spontaneous adverse event reporting database between April 2004 and September 2019. Of 5791 patients reporting adverse events due to LAI-SGAs or the equivalent oral SGAs, 768 (13%) developed NMS. LAI aripiprazole and LAI paliperidone were associated with a significantly lower reporting frequency of NMS than the equivalent oral SGAs (adjusted reporting odds ratio [95% confidence interval]: 0.35 [0.19-0.63] and 0.40 [0.27-0.59], respectively). Between 42% and 62% of the NMS associated with LAI- and oral SGAs other than LAI risperidone occurred within 30 days after initiation. The proportion of mortality due to NMS associated with oral aripiprazole was 13.1% and no deaths occurred in patients with NMS associated with LAI aripiprazole. The proportions of mortality due to NMS associated with oral risperidone/paliperidone, LAI risperidone, and LAI paliperidone were 8.8%, 4.2%, and 3.4%, respectively. Our findings showed that LAI-SGAs were not associated with a higher reporting frequency and mortality of NMS compared with oral SGAs, although clinicians need to closely monitor the occurrence of NMS not only during oral SGA treatment, but also, and in particular, in the early stage of LAI-SGA treatment. [ABSTRACT FROM AUTHOR]

Alterations in polyunsaturated fatty acids (PUFAs), including omega-3 and omega-6, have been implicated in the pathophysiology of psychotic disorders, but little is known about their associations with neuropsychological functioning. The present study includes 46 recent-onset psychosis patients who participated in a larger (n = 50) double blind, placebo-controlled randomized clinical trial comparing 16 weeks of treatment with either risperidone + fish oil (FO) (EPA 740 mg and DHA 400 mg daily) or risperidone + placebo and completed neuropsychological assessments at the baseline timepoint. We investigated the relationship between baseline omega-3 (i.e., eicosapentaenoic acid, EPA; docosapentaenoic acid, DPA and docosahexaenoic acid, DHA) and omega-6 (i.e., arachidonic acid, AA) PUFA with baseline MATRICS Consensus Cognitive Battery (MCCB) and Brief Psychiatric Rating Scale (BPRS) scores. Twenty-five patients had neuropsychological data available at 16 weeks following participation in the clinical trial, which included 12 patients assigned to risperidone + FO and 13 patients assigned to risperidone + placebo. At baseline both higher DHA and EPA correlated significantly with better social cognition after controlling for functioning on other neuropsychological domains, total BPRS score, AA level and substance use. Also, at baseline higher AA correlated significantly with hostility/uncooperativeness after controlling for DHA + EPA + DPA, overall neuropsychological functioning and substance use. Patients treated with risperidone + FO demonstrated a significant longitudinal increase in social cognition that was significantly higher at 16 weeks compared to patients treated with risperidone + placebo. DHA also correlated significantly with social cognition at the 16-week timepoint. This study provides novel evidence for a differential role of omega-3 vs. omega-6 PUFA in neuropsychological deficits and symptoms in recent-onset psychosis and its treatment. [ABSTRACT FROM AUTHOR]

This cross-sectional study examines the differences in cortical volume and gray-to-white matter contrast (GWC) in first episode schizophrenia patients (SCZ) compared to healthy control participants (HC) and in SCZ patients as a function of exposure to second generation antipsychotic medication. We hypothesize 1) SCZ exhibit regionally lower cortical volumes relative to HCs, 2) cortical volume will be greater with longer exposure to second generation antipsychotics prior to the MRI scan, and 3) lower GWC with longer exposure to second generation antipsychotics prior to the MRI scan, suggesting more blurring from greater intracortical myelin. To accomplish this, MRI scans from 71 male SCZ patients treated with second generation oral risperidone and 42 male HCs were examined. 3D T1-weighted MPRAGE images collected at 1.5T were used to estimate cortical volume and GWC by sampling signal intensity at 30% within the cortical ribbon. Average cortical volume and GWC were calculated and compared between SCZ and HC. Cortical volume and GWC in SCZ patients were correlated with duration of medication exposure for the time period prior to the scan. First-episode SCZ patients had significantly lower cortical volume compared to HCs in bilateral temporal, superior and rostral frontal, postcentral gyral, and parahippocampal regions. In SCZ patients, greater cortical volume was associated with (log-transformed) duration of second-generation antipsychotic medication exposure in bilateral precuneus, right lingual, and right superior parietal regions. Lower GWC was correlated with longer duration of medication exposure bilaterally in the superior frontal lobes. In summary, second generation antipsychotics may increase cortical volume and decrease GWC in first episode SCZ patients. [ABSTRACT FROM AUTHOR]

The default mode network (DMN) has been consistently detected abnormally in schizophrenia. However, the effects of antipsychotics on this network are still under debate, and inconsistent findings may be due to the functional heterogeneity within the DMN, especially in the component regions of the posteromedial cortex (PMC). Here, we conducted a longitudinal research on the resting-state functional connectivity of the PMC subdivisions on 33 treatment-naive first-episode patients with schizophrenia at baseline and after 8 weeks of risperidone treatment through resting-state functional magnetic resonance imaging. At baseline, the patients demonstrated decreased connectivity of the three PMC seeds with several brain regions (target regions) compared with healthy controls. We then tested the effect of antipsychotic treatment on the functional connectivity between the three seeds and the target regions. We found that, one of the three seeds encompassed in PMC, namely, posterior cingulate cortex (PCC), was observed to have increased functional connectivity with the bilateral thalamus and the left lingual gyrus (LG). On the contrary, the functional connectivity between the target regions and the two remaining seeds, namely, the retrosplenial cortex and precuneus, was unaffected by risperidone treatment. Correlation analysis revealed a positive correlation between longitudinal change of PCC-LG connectivity and symptom improvement. These findings indicated the heterogeneity of the PMC in response to antipsychotic treatment and suggested the role of PCC as a treatment biomarker for schizophrenia. [ABSTRACT FROM AUTHOR]

Abnormal interactions between the striatum and salience network (SN) are considered as etiological and treatment-sensitive marker in schizophrenia. However, whether alterations in the intrinsic dynamics as reflected by resting-state functional connectivity (RSFC) between the striatum and salience network may predict treatment response to the widely used antipsychotic treatment strategies (risperidone, monotherapy) has not been examined systematically. To this end, treatment-naive first-episode schizophrenia patients (n = 41) underwent task-free resting-state fMRI assessment before (baseline) and after 8 weeks of risperidone monotherapy (n = 38). Intrinsic connectivity between striatal sub-regions and core salience processing nodes were examined and compared to carefully matched healthy controls (HC) to determine disorder-specific and treatment-predictive neural markers. Findings demonstrate hypo-connectivity of both ventral and dorsal striatal-SN pathways in patients at baseline. Importantly, specifically the dorsal striatal pathway at baseline could predict negative symptoms improvement in patients; while ventral striatal pathways could predict positive symptoms improvement. Together, results indicate that distinct striatal-SN pathways represent specific treatment-success markers for the effects of risperidone, suggesting that alterations in dorsal versus ventral striatal network markers may represent brain-based markers for specific symptomatologic improvements following risperidone mono-therapy. [ABSTRACT FROM AUTHOR]

Background: Cognitive deficits of schizophrenia are predictors of poor function, but antipsychotic medication has limited efficacy for cognitive deficits. These deficits in learning and memory may result from activity of pro-inflammatory cytokines, which microglia produce. The microglia inhibitor minocycline might arrest this cytokine damage to the hippocampus and reverse the cognitive deficits of schizophrenia.Methods: A double-blind, placebo-controlled study involved 75 patients with schizophrenia who randomly received low dose (100 mg/day) or high dose minocycline (200 mg/day) or placebo added to risperidone. MATRICS Consensus Cognitive Battery (MCCB) was used to assess the cognitive functioning, and serum levels of Interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) were assessed.Results: Minocyclinehigh dose group was significantly superior to minocyclinelow dose or placebo group not only for the improvements in cognitive tests' scores as well (P < 0.05), but for IL-1β and IL-6 serum levels reduction (P < 0.01). The amelioration of cognitive deficits with minocycline correlated not only with the remission of negative symptoms, but also with the reduction in serum levels of IL-1β and IL-6.Conclusions: Minocycline adjunctive treatment was effective in improving cognitive deficits of patients with schizophrenia. The beneficial effect of minocycline may be related to reducing pro-inflammatory cytokines through microglia inhibition. [ABSTRACT FROM AUTHOR]

Objective: To explore pharmacogenetic relationships of NRG1 genotypes with neurocognitive performance and clinical symptoms after 12 week treatment of risperidone in Chinese Han first-episode schizophrenia.Methods: A cohort of 221 patients with schizophrenia were recruited for this research. Finally 177 untreated first-episode patients were clinically evaluated with the Positive and Negative Syndrome Scale (PANSS), Raven's Standard Progressive Matrices (RSPM), Digit Vigilance Test (DVT), Digit Span (DS), underwent genotyping for five polymorphisms of NRG1, and completed a 12-week prospective study of risperidone monotherapy.Results: 1. After risperidone treatment of 12 weeks, the total scores, positive score, negative score and general score of PANSS decreased significantly; the scores of RSPM, DVT and DS increased significantly. 2. No significant association with PANSS scores at baseline or change in scores after 12 weeks'treatment was found with any of the five SNPs. There was also neither significant association of DVT, DS or RSPM at baseline with any of the five SNPs. 3. After risperidone treatment of 12 weeks, rs3924999 and rs35753505 showed significant association with change in DVT and in RSPM in which there were significant differences among different genotype groups.Conclusion: This study suggested pharmacogenetic relationships between NRG1 variants and changes in cognition response with exposure to 12 weeks of treatment with risperidone. Two variants, rs3924999 and rs35753505, in the NRG1 gene were associated with the changes in attention and reasoning ability after risperidone treatment of 12 weeks. [ABSTRACT FROM AUTHOR]

Magnetic Resonance Spectroscopy is a popular approach to probe brain chemistry in schizophrenia (SZ), but no consensus exists as to the extent of alterations. This may be attributable to differential effects of populations studied, brain regions examined, or antipsychotic medication effects. Here, we measured neurometabolites in the anterior cingulate cortex (ACC) and hippocampus, two structurally dissimilar brain regions implicated in the SZ pathophysiology. We enrolled 61 SZ with the goal to scan them before and after six weeks of treatment with risperidone. We also scanned 31 matched healthy controls twice, six weeks apart. Using mixed effect repeated measures linear models to examine the effect of group and time on metabolite levels in each voxel, we report an increase in hippocampal glutamate + glutamine (Glx) in SZ compared to controls (p = 0.043), but no effect of antipsychotic medication (p = 0.330). In the ACC, we did not find metabolite alterations or antipsychotic medication related changes after six weeks of treatment with risperidone. The coefficients for the discriminant function (differentiating SZ from HC) in the ACC were greatest for NAA (-0.83), and in the hippocampus for Glx (0.76), the same metabolites were associated with greater treatment response in patients at trend level. Taken together, our data extends the existing literature by demonstrating regionally distinct metabolite alterations in the same patient group and suggests that antipsychotic medications may have limited effects on metabolite levels in these regions. [ABSTRACT FROM AUTHOR]

Background: In contrast to over 30 studies reporting neurotoxicity associated with the first-generation antipsychotics (FGAs), several published studies have reported multiple neuroprotective effects associated with the second generation antipsychotics (SGAs). This prompted us to conduct a review of the reported neuroprotective mechanisms of the SGA class of antipsychotics compared to the FGAs.Methods: A PubMed search was conducted using the keywords antipsychotic, neuroprotection, neuroplasticity, neurogenesis, neurotoxicity, toxicity, brain volume, neuroinflammation, oxidative stress, myelin, and oligodendrocyte. No restrictions were placed on the date of the articles or language. Studies with a clearly described methodology were included.Results: Animal, cell culture, and human clinical studies were identified. Twenty-four reports met the criteria for the search. All studies included at least one SGA (aripiprazole, clozapine, lurasidone, olanzapine, paliperidone, perospirone, quetiapine, risperidone, and/or ziprasidone). A few also included FGAs as a comparator (predominantly haloperidol). All studies demonstrated at least one neuroprotective mechanism of one or more SGAs, while some studies also showed that FGAs ranged from having no neuroprotective effects to actually exerting neurotoxic effects leading to neuronal death.Conclusions: A review of the literature suggests that in addition to their antipsychotic efficacy and low motoric side effects, SGAs exert measurable neuroprotective effects mediated via multiple molecular mechanisms and often in a dose-dependent manner. The neuroprotective effects of SGAs range from preventative to restorative and may play a salutary role in ameliorating the neurodegenerative effects of psychosis. [ABSTRACT FROM AUTHOR]

Second-generation antipsychotics are associated with moderate benefits in terms of improved schizophrenia symptoms, but also with higher rates of side-effects such as excessive weight gain (WG); a consensus on their efficacy has not been reached. To date, no study has evaluated the interplay of treatments and side-effects in a single framework, which is a critical step to clarify the role of side-effects in explaining the efficacy of these antipsychotics. We used recent methods for mediation and interaction to clarify the role of WG in explaining the effects of second-generation drugs on schizophrenia symptoms. We used data from 1460 participants in the CATIE trial, assigned to either perphenazine (first-generation comparison drug), olanzapine, quetiapine, risperidone, or ziprasidone. The primary outcome was an individual's score on the Positive and Negative Syndrome Scale (PANSS) for symptoms of schizophrenia after 9 months, separately evaluated as positive (PANSS+), negative (PANSS-), and total PANSS score. WG after 6 months was investigated as a potential mediator and effect modifier. Results showed that, by limiting WG, patients would benefit of a considerably better improvement in terms of PANSS symptoms. In the scenario of weight change being controlled between -2% and 1% for all participants, patients assigned to olanzapine would experience the highest significant improvements in both PANSS+ (-2.66 points; 95% CI: -4.98, -0.35), PANSS- (-1.59; 95% CI: -4.31, 1.14), and total PANSS (-6.11; 95% CI: -13.13, 0.92). In conclusion, occurrence of excessive WG hampers the potentially beneficial effects of second-generation antipsychotics, thus suggesting future directions for treatment and interventions. [ABSTRACT FROM AUTHOR]

Omega-3 treatment studies for multi-episode schizophrenia or clinical high risk for conversion to psychosis states have had variable, and often negative, results. To examine adjunctive omega-3 treatment for recent onset psychosis, participants aged 15-40 years with recent onset schizophrenia-spectrum (n = 46) or bipolar (n = 4) disorders and current psychotic symptoms were treated for 16 weeks with risperidone and randomly-assigned omega-3 (EPA 740 mg and DHA 400 mg daily) or matching placebo. The primary outcome measure was the Brief Psychiatric Rating Scale (BPRS) total score. Mean lifetime antipsychotic exposure was 18.1 days. Length of time in treatment, risperidone dose and number of omega-3/placebo capsules taken did not differ between conditions. Longitudinal analysis of the total BPRS score revealed a trend level (p = 0.0826) treatment effect favoring omega-3 treatment. Lorazepam was an allowed concomitant medication. Among the subgroup (N = 23) who did not receive lorazepam, the treatment effect on BPRS total scores favoring omega-3 was significant (p = 0.0406) and factor scores analyses revealed a substantial decrease in depression-anxiety with omega-3 but no change with placebo (treatment-by-time interaction, p = 0.0184). Motor side effects did not differ between conditions. Analysis of Systematic Assessment for Treatment Emergent Events assessments revealed fewer adverse events overall with omega-3 compared with placebo with the largest differences between conditions (all favoring omega-3) on confusion, anxiety, depression, irritability, and tiredness/fatigue. These results suggest that omega-3 adjuvant treatment is a potential option for depression and anxiety symptoms of people with recent onset psychosis. Further research is needed to confirm this potential. Clinical trial registration: NCT01786239. [ABSTRACT FROM AUTHOR]

Although currently approved antipsychotics exert efficacy on positive symptoms of schizophrenia, treatments for negative symptoms remain a major unmet need. Post hoc analyses were used to investigate the possible efficacy of cariprazine in patients with moderate/severe negative symptoms of schizophrenia and no predominance of positive symptoms. Data were pooled from 2 randomized, double-blind, placebo- and active-controlled cariprazine studies in patients with acute schizophrenia (NCT00694707, NCT01104766). Analyses included data from a subset of patients with a Positive and Negative Syndrome Scale factor score for negative symptoms (PANSS-FSNS) ≥24, PANSS factor score for positive symptoms (PANSS-FSPS) ≤19, and scores of ≥4 on ≥2 of 3 PANSS items (blunted affect [N1], passive/apathetic social withdrawal [N4], lack of spontaneity/flow of conversation [N6]). Changes from baseline to week 6 in PANSS-FSNS were evaluated in the following treatment groups: placebo (n = 79), cariprazine 1.5-3 (n = 94) and 4.5-6 mg/d (n = 66), risperidone 4 mg/d (n = 34), or aripiprazole 10 mg/d (n = 44). Significant differences were observed versus placebo for cariprazine (1.5-3 mg/d, P = .0179; 4.5-6 mg/d, P = .0002) and risperidone (P = .0149), but not aripiprazole (P = .3265), and versus aripiprazole for cariprazine 4.5-6 mg/d (P = .0197). After adjusting for positive symptom changes, differences versus placebo remained statistically significant for cariprazine (1.5-3 mg/d, P = .0322; 4.5-6 mg/d, P = .0038) but not for risperidone (P = .2204). PANSS-FSNS response (≥20% reduction from baseline) rates were significantly higher with cariprazine (1.5-3 mg/d = 54.3%, P = .0194; 4.5-6 mg/d = 69.7%, P = .0001) than placebo (35.4%). In patients with acute schizophrenia and moderate/severe negative symptoms, cariprazine was associated with significantly greater improvement in negative symptoms compared with placebo and aripiprazole, warranting further exploration of the efficacy of cariprazine on negative symptoms. [ABSTRACT FROM AUTHOR]

Introduction: Evidence about the anti-inflammatory properties of antipsychotics has grown. However, no previous studies have compared the immunomodulatory effect of risperidone and aripiprazole.Objectives: The main aim of the present work is to compare the anti-inflammatory effect of risperidone and aripiprazole on a large array of serum cytokines at 3 months following the onset of treatment.Methods: This is a prospective, randomized, open-label study. Patients were randomly assigned to risperidone or aripiprazole. From this randomization, 75 patients and 75 healthy volunteers that matched with the selected patients were picked for entry in this study. Serum concentrations of 21 cytokines/chemokines were measured at baseline and 3 months following the initiation of antipsychotic medication.Results: Those patients who were randomly assigned to risperidone had higher levels of IL-8 (p = 0.000) and MIP-1β (p = 0.007) than healthy volunteers at baseline, whereas no differences were found between patients initially assigned to aripiprazole and healthy volunteers. Three months following the onset of medication several cytokines decreased significantly: IL-8, MIP-1β, Fractalkine, TNF-α, IL-7, IL-13, IL-17α, IL-23, IL-21 (all ps < 0.01). No differences were found in the percentages of change between both treatments. The effect size of the two antipsychotics was similar, except for TNF-α, IL-13, IL-17α and Fractalkine, in which aripiprazole seems to have a greater effect size than risperidone, whereas risperidone seems to have a greater effect size than aripiprazole on MIP-1β.Conclusions: This is the first study that has compared the immunomodulatory effect of risperidone and aripiprazole, finding that the anti-inflammatory effect of both treatments was similar. [ABSTRACT FROM AUTHOR]

Objective: Antipsychotic blood levels (ABLs) may help identify patients at risk for treatment failure. Reference ranges (RR) for plasma concentrations of ABLs that account for between-patient variability were developed for risperidone and olanzapine based on population pharmacokinetic models. The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) collected clinical outcomes and ABLs, allowing testing of the relationship of ABLs with outcomes.Methods: ABLs from 694 patients who were randomized to olanzapine or risperidone were compared to the 80% RRs and were assessed as below or within/above the RR. Treatment failure was defined per any of these criteria: (1) emergency room visit for psychiatric reasons, (2) hospitalization for psychiatric reasons, (3) adverse event of completed suicide, suicidal ideation, or suicide attempt, (4) assaultive behavior, (5) arrested or jailed, (6) 2-point increase from baseline in Clinical Global Impression-Severity score, (7) 25% increase in Positive and Negative Syndrome Scale total score. Patients assessed with treatment failure within 100 days of drug concentration measurement were analyzed.Results: Treatment failure occurred in 126 of 323 patients. The proportion of patients with ABLs below RR was 18.3% (59/323) compared to 10% expected in a fully adherent population. Among the 59 with ABLs below RR, 50.8% had treatment failure (compared to 36.4% for the 264 with ABLs within/above RR). The difference between groups was significant (odds ratio = 1.810; 95% CI = 1.025, 3.197; p = 0.0408).Conclusions: Analysis of CATIE data showed that ABLs within the context of RRs may identify patients with higher risk of relapse. [ABSTRACT FROM AUTHOR]

Objective: This study was to examine the alterations in metabolic parameters, anti-oxidant superoxide dismutase (SOD), inflammatory marker high-sensitivity C-reactive protein (hs-CRP) and microbiota after 24-week risperidone treatment in drug naïve, normal weight, first episode schizophrenia patients; the study further examined the relationship between metabolic changes and changes in microbiota.Methods: Forty-one patients completed the 24-week study and 41 controls were enrolled in this study. Metabolic parameters, SOD, hs-CRP and the copy numbers of 5 fecal bacteria were measured at baseline (both groups) and at different time points (patients only).Results: Patients had significantly lower numbers of fecal Bifidobacterium spp., Escherichia coli, Lactobacillus spp. compared with healthy controls (HC) (ps < 0.001); in contrast, the numbers of fecal Clostridium coccoides group were significantly higher in the patient group compared with HC (p < 0.001). After 24-week risperidone treatment, there were significant increases in body weight, BMI, fasting blood-glucose, triglycerides, LDL, hs-CRP, SOD and HOMA-IR (p < 0.001), significant increases in the numbers of fecal Bifidobacterium spp. and E. coli (ps < 0.001), and significant decreases in the numbers of fecal Clostridium coccoides group and Lactobacillus spp. (ps < 0.001). Hierarchical multiple linear regression analysis shows that after controlling for potential confounding variables, only the changes in fecal Bifidobacterium spp., among 4 types of fecal bacteria, entered into the model and significantly correlated with the changes in weight (unstandardized coefficient B = 4.413, R2 change = 0.167, p = 0.009) and BMI (B = 1.639, R2 change = 0.172, p = 0.008) after 24-week treatment.Conclusion: Drug naïve, first episode schizophrenia patients show abnormalities in microbiota composition. Risperidone treatment causes significant changes in certain fecal bacteria, which are likely associated with antipsychotic medication induced metabolic changes. [ABSTRACT FROM AUTHOR]

Introduction: Discontinuation of the initial oral antipsychotic prescribed for a first episode of psychosis (FEP) can derail outcome. Our objective was to examine the rate of and time to all-cause discontinuation of the first antipsychotic prescribed and the factors influencing such discontinuation.Methods: In a sample of 390 FEP patients, we estimated the rate of and time to discontinuation of the initial antipsychotic over a one-year period. The effects of a number of putative predictors of discontinuation were estimated using regression analyses.Results: Rate of discontinuation of the first antipsychotic was 72%, with no difference between the 3 investigated antipsychotics (olanzapine (73%), risperidone (68%) and aripiprazole (75%)), (χ2 (2) = 1.89, p = 0.388). Mean time to discontinuation was 7.2 (4.6) months and was not different among the three antipsychotics (Log-rank χ2 (2) = 0.257, p = 0.879). Binary logistic regression showed that higher positive and negative symptoms remission and baseline functioning were associated with lower rates of discontinuation (Nagelkerke R2 = 0.36, χ2 (10) = 66.9, p < 0.001). Multiple linear regression showed the same predictors, in addition to male gender and less weight gain per month of exposure to the initial antipsychotic, to be associated with longer time to discontinuation (adjusted R2 = 0.336, F (9, 219) = 13.8, p < 0.001).Conclusion: Discontinuation of the initial antipsychotic is a major concern in the course of treating FEP. Symptom relief, better functioning and lower side effects appear to be the major factors associated with continuing an antipsychotic medication. [ABSTRACT FROM AUTHOR]

Sex seems to matter. Factors influencing the effect of aripiprazole on prolactin levels in patients treated with risperidone or paliperidone. Prolactin, Risperidone, Aripiprazole, Gender, Paliperidone. [Extracted from the article]

Objective: Cannabis use disorders (CUDs) are highly comorbid in patients with schizophrenia and associated with poor outcome. Clozapine has been put forward as the first choice antipsychotic in this patient group. However, little is known about the mechanisms underlying the assumed superiority of clozapine.Methods: A total of 38 patients with DSM-IV schizophrenia (30 with and 8 without a DSM-IV CUD) and 20 healthy comparison subjects were included between April 2009 and June 2012. Patients were randomized to antipsychotic treatment with clozapine or risperidone. At baseline and after 4weeks of medication, brain response to cannabis-related, positive and neutral images was measured using functional MRI. Neural correlates of cue reactivity were assessed in the following regions of interest: amygdala, ventral striatum, insula, thalamus, orbitofrontal cortex and anterior cingulate cortex. Subjective craving was assessed using self-report questionnaires (OCDUS and MCQ).Results: At baseline, patients with a comorbid CUD showed higher subjective craving and greater activation in response to cannabis-related images compared to patients without a CUD and healthy controls in most regions of interest. Clozapine treated patients reported a greater reduction in craving (F(1,28)=6.0, p=0.04) and showed a larger decrease in amygdala activation during cannabis-related images compared to risperidone treated patients (T=3.94, pFWE=0.006). In addition, significant correlations were found between subjective craving and thalamus and insula activation during cannabis-related images.Conclusion: These findings provide evidence that clozapine is superior to risperidone in decreasing subjective craving and cue reactivity for cannabis-related images probably due to a differential effect on dopaminergic neurotransmission.Trial Registration: 'Nederlands trial register' (http://www.trialregister.nl), nr NTR1761, http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=1761. [ABSTRACT FROM AUTHOR]

Imbalance in neural excitation and inhibition is associated with behavioral dysfunction in individuals with schizophrenia and at risk for this illness. We examined whether targeting increased neural activity with the antiepileptic agent, levetiracetam, would benefit memory performance in a preclinical model of schizophrenia that has been shown to exhibit hyperactivity in the hippocampus. Adult rats exposed to ketamine subchronically during late adolescence showed impaired hippocampal-dependent memory performance. Treatment with levetiracetam dose-dependently improved memory performance of the ketamine-exposed rats. In contrast, the antipsychotic medication risperidone was not effective in this assessment. Levetiracetam remained effective when administered concurrently with risperidone, supporting potential viability of adjunctive therapy with levetiracetam to treat cognitive deficits in schizophrenia patients under concurrent antipsychotic therapy. In addition to its pro-cognitive effect, levetiracetam was also effective in attenuating amphetamine-induced augmentation of locomotor activity, compatible with the need for therapeutic treatment of positive symptoms in schizophrenia. [ABSTRACT FROM AUTHOR]

Antipsychotic drugs are associated with autonomic nervous system (ANS) dysfunction in patients with schizophrenia, but the effects of individual atypical antipsychotic drugs are not clear. This study investigated how four atypical antipsychotic drugs-risperidone, olanzapine, aripiprazole, and quetiapine-differ in their effects on ANS activity. A total of 241 Japanese patients with schizophrenia participated in this study. All of the participants received an atypical antipsychotic as monotherapy: 90 participants received risperidone, 68 olanzapine, 52 aripiprazole, and 31 quetiapine. ANS activity was assessed by means of a power spectral analysis of heart rate variability. The quetiapine group showed significantly diminished sympathetic and parasympathetic activity compared with the risperidone and aripiprazole groups and significantly lower sympathetic activity relative to olanzapine. In addition, multiple regression analysis showed that the type of antipsychotic drug significantly influenced ANS activity. We suggest that, among the antipsychotics examined-risperidone, olanzapine, aripiprazole and quetiapine-quetiapine has the strongest effect on ANS activity. [ABSTRACT FROM AUTHOR]

The purpose of this nationwide population-based study is to compare the long-term effectiveness of brand-name antipsychotics with generic antipsychotics for treating schizophrenia. We identified patients with schizophrenia who were prescribed antipsychotics from a random sample of one million records from Taiwan's National Health Insurance database, observed between January 1, 2000 and December 31, 2012. Only those with no prior use of antipsychotics for at least 180days were included. We selected patients who were prescribed brand-name risperidone (N=404), generic risperidone (N=145), brand-name sulpiride (N=334), or generic sulpiride (N=991). The effectiveness of the treatments researched in this study consisted of average daily doses, rates of treatment discontinuation, augmentation therapy, and psychiatric hospitalization. We found that compared to patients treated with generic risperidone, those treated with brand-name risperidone required lower daily doses (2.14mg vs. 2.61mg). However, the two groups demonstrated similar rates of treatment discontinuation, augmentation, and psychiatric hospitalization. On the other hand, in comparison with patients prescribed generic sulpiride, those treated with brand-name sulpiride not only required lower daily doses (302.72mg vs. 340.71mg) but also had lower psychiatric admission rates (adjusted hazard ratio: 0.24, 95% confidence interval: 0.10-0.56). In conclusion, for both risperidone and sulpiride, higher daily doses of the respective generic drugs were prescribed than with brand-name drugs in clinical settings. Furthermore, the brand-name sulpiride is more effective at preventing patients from hospitalization than generic sulpiride. These findings can serve as an important reference for clinical practices and healthcare economics for treating schizophrenic patients. [ABSTRACT FROM AUTHOR]

Background: The concept of dose equivalence of depot medication is important for many scientific and clinical purposes.Methods: A systematic literature search on four second-generation antipsychotics available as long-acting injectable drugs and haloperidol was conducted. We used the minimum effective dose method which is based on randomized fixed dose studies where the smallest dose which was significantly more efficacious than placebo in the primary outcome was declared as minimum effective dose. We calculated equivalent doses from acute phase studies but we also reported the minimum effective doses found in relapse prevention studies.Results: The acute phase minimum effective doses/olanzapine equivalents were: aripiprazole lauroxil 441mg (300mg aripiprazole)/4wks/0.71; aripiprazole 400mg/4weeks/0.95 (aripiprazole maintena); paliperidone palmitate 25mg/4weeks/0,06; risperidone 25mg/2weeks/0,12; RBP-7000 90mg/4weeks/0,21; olanzapine 210mg/2weeks/1.Conclusions: The minimum effective dose method is an operationalized and evidence-based approach for determining antipsychotic dose equivalence which can also be applied to long-acting injectable formulations. Doses may not have been chosen low enough to find the truly minimum effective dose. Comparisons with other methods will be necessary to come to ultimate conclusions. [ABSTRACT FROM AUTHOR]

Antipsychotic Induced Weight Gain (AIWG) is a common and severe side effect of many antipsychotic medications. Mitochondria play a vital role for whole-body energy homeostasis and there is increasing evidence that antipsychotics modulate mitochondrial function. This study aimed to examine the role of variants in nuclear-encoded mitochondrial genes and the mitochondrial DNA (mtDNA) in conferring risk for AIWG. We selected 168 European-Caucasian individuals from the CATIE sample based upon meeting criteria of multiple weight measures while taking selected antipsychotics (risperidone, quetiapine or olanzapine). We tested the association of 670 nuclear-encoded mitochondrial genes with weight change (%) using MAGMA software. Thirty of these genes showed nominally significant P-values (<0.05). We were able to replicate the association of three genes, CLPB, PARL, and ACAD10, with weight change (%) in an independent prospectively assessed AIWG sample. We analyzed mtDNA variants in a subset of 74 of these individuals using next-generation sequencing. No common or rare mtDNA variants were found to be significantly associated with weight change (%) in our sample. Additionally, analysis of mitochondrial haplogroups showed no association with weight change (%). In conclusion, our findings suggest nuclear-encoded mitochondrial genes play a role in AIWG. Replication in larger sample is required to validate our initial report of mtDNA variants in AIWG. [ABSTRACT FROM AUTHOR]

Purpose: To disentangle an association between tobacco smoking, smoking habits and pharmacokinetic patterns such as plasma concentrations of risperidone (RIS), its active metabolite 9-hydroxyrisperidone (9-OH-RIS) and the active moiety, AM, (RIS+9-OH-RIS) in a naturalistic sample.Methods: Plasma concentrations, dose adjusted plasma concentrations (C/D) of RIS, 9-OH-RIS and AM in patients out of a therapeutic drug monitoring (TDM) database were compared between smokers (n=401) and non-smokers (n=292).Results: Daily dosage of risperidone differed significantly with smokers receiving higher doses than patients in the control group (p=0.001). No differences were detected in plasma concentrations of the active moiety, RIS and 9-OH-RIS (p=0.8 for AM, p=0.646 for RIS and p=0.538 for 9-OH-RIS). However, dose corrected concentrations (C/D) of metabolite (C/D 9-OH-RIS) and active moiety (C/D AM) differed between significantly between groups (p=0.002 and p=0.007). After stratifying smokers to a group of moderate smokers (<20cigarettes/day) (RS1, n=109) and a group of heavy smokers (≥20cigarettes/day) (RS2, n=135), the comparison between non-smokers and both groups only showed lower values of C/D for 9-OH-RIS (p=0.011) for the group of moderate smokers while other pharmacokinetic parameters did not differ.Conclusions: Apart from the well-known induction of CYP1A2 activity by polycyclic aromatic hydrocarbons, smoking might exert an effect on other CYP isoenzymes as well. A possible interpretation proposes a slight inducing effect of smoking on risperidone metabolism most likely via CYP3A4. [ABSTRACT FROM AUTHOR]

Antipsychotics may confer long term benefits and risks, including cardiovascular disease (CVD) risk. Several studies using routine clinical data have reported associations between antipsychotics and CVD but potential confounding factors and unclear classification of drug exposure limits their interpretation.Method: We used data from The Health Improvement Network, a large UK primary care database to determine relative risks of (CVD) comparing similar groups of people only prescribed olanzapine versus either risperidone or quetiapine. We included participants over 18 between 1995 and 2011. To assess confounding factors we created propensity scores for being prescribed each antipsychotic. We used propensity score matching and Poisson regression to calculate the CVD incidence rate ratios for olanzapine versus the other two drugs.Results: We identified 18,319 people who received a single antipsychotic during follow-up (n=5090 risperidone, 7797 olanzapine and 4613 quetiapine). In unmatched analyses, the CVD incidence rate ratio (IRR) for olanzapine versus risperidone was 0.63 (0.51-0.77) but the propensity score matched IRR was 0.78 (0.61-1.02). In the unmatched olanzapine versus quetiapine analysis the IRR adjusted for age and sex for olanzapine was 1.52 (1.16-1.98) but the propensity score matched analysis gave an IRR of 1.08 (0.79-1.46).Conclusions: After propensity score matching, we found no statistical differences in CVD incidence between olanzapine and either risperidone or quetiapine. Analyses which did not account for confounding factors produced very different results. Researchers must address confounding factors when designing observational studies to assess adverse outcomes of drugs, including antipsychotics. [ABSTRACT FROM AUTHOR]

Background: Several antipsychotics, especially risperidone, are known to increase serum prolactin. Hyperprolactinemia has been linked to the development of mammary gland tumors in animal studies. We therefore investigated the risk of breast cancer in a nationwide cohort of women using risperidone or other antipsychotics.Methods: All women, 18years or older, who initiated treatment with risperidone or any other antipsychotic between 2006 and 2012 were identified in Swedish nationwide registers. Patients with two consecutive dispensations of the same antipsychotic within 3months, no previous cancer diagnosis, and no previous dispensations of paliperidone were included. The final cohort consisted of 55976 women of whom 22908, 24524, and 8544 were exposed to risperidone, other atypical antipsychotics, and typical antipsychotics, respectively. A Cox regression model was used to estimate the hazard ratio (HR) and 95% confidence interval (CI) for the association between antipsychotics and breast cancer.Results: Patients were followed prospectively, the mean follow-up time ranging from 2.4 to 2.8years between treatment groups. After adjusting for age, there was no increased risk for breast cancer among risperidone users compared to patients exposed to another atypical antipsychotic (HR 0.94, 95% CI 0.72-1.22) or a typical antipsychotic (HR 1.25, 95% CI 0.94-1.66). Analyses stratified by tumor stage, using active treatment follow-up time, or including only treatment naïve patients did not reveal any noteworthy change in the results.Conclusion: Risperidone use does not confer an increased short-term risk of breast cancer compared to other antipsychotic agents. [ABSTRACT FROM AUTHOR]

The aim of this study was to compare the antioxidant activities of six atypical antipsychotic drugs: clozapine (CLZ), quetiapine, olanzapine (OLA), risperidone, ziprasidone, aripiprazole (ARI), as well as a typical antipsychotic drug, haloperidol. Several tests of antioxidant activity were used: protection of thiol groups against oxidation by peroxynitrite (PN) and 3-morpholinosydnonimine (SIN-1, generator of PN), oxidation of dihydrorhodamine 123 by PN, SIN-1 and hypochlorite (NaOCl), bleaching of fluorescein fluorescence by PN, 2,2'-azobis(2-amidinopropane) dihydrochloride (AAPH, generator of peroxyl radicals) and NaOCl, radical-scavenging activity with respect to 2,2'-azinobis(3-ethylbenzthiazoline-6-sulfonic acid) radical, 2,2-diphenyl-1-picrylhydrazyl free radical and the Ferric Reducing Antioxidant Potential. In most of the tests, OLA showed the highest antioxidant activity, followed by CLZ and in some cases ARI, other compounds being much less active or not active. OLA and CLZ exerted limited toxicity on mouse neuroblastoma Neuro-2A (N2A) cells and protected the cells against the toxic action of SIN-1, AAPH and NaOCl in the physiologically relevant concentration range of these oxidants. Both drugs reduced the PN-induced nitration of intracellular proteins. Given that schizophrenia is associated with oxidative and nitrosative stress, the direct antioxidant activity OLA and CLZ may contribute to the therapeutic action of these compounds. [ABSTRACT FROM AUTHOR]

Objective: We aimed to assess whether long-acting injectable antipsychotics (LAIs), which are initiated in a loading strategy or overlapping with oral antipsychotics (OAPs) and which cannot be stopped immediately, are associated with greater safety/tolerability issues than OAPs.Method: Systematic review and meta-analysis of randomized controlled trials (RCTs) comparing LAIs and OAPs, including only LAI-OAP pairs of the same OAP (allowing oral risperidone and paliperidone as comparators for either risperidone or paliperidone LAI). Primary outcome was treatment discontinuation due to adverse events. Secondary outcomes included serious adverse events, death, ≥1 adverse event and individual adverse event rates.Results: Across 16 RCTs (n=4902, mean age=36.4years, males=65.8%, schizophrenia=99.1%) reporting on 119 adverse event outcomes, 55 (46.2%) adverse events were reported by ≥2 studies allowing a formal meta-analysis. Out of all 119 reported adverse events, LAIs and OAPs did not differ significantly regarding 115 (96.6%). LAIs were similar to OAPs regarding the frequency of treatment discontinuation due to adverse events, serious adverse events, all-cause death and death for reasons excluding accident or suicide. Compared to OAPs, LAIs were associated with significantly more akinesia, low-density lipoprotein cholesterol change and anxiety. Conversely, LAIs were associated with significantly lower prolactin change.Conclusion: LAIs and OAPs did not differ on all serious and >90% of individual adverse events. However, more studies focusing on adverse event frequencies, severity and time course associated with LAI vs OAP formulations of the same antipsychotic are needed. Additionally, adverse events data for LAIs after stopping overlapping oral antipsychotic treatment are needed. [ABSTRACT FROM AUTHOR]