Antipsychotics In Schizophrenia Research Articles

P.577 ADVANCE: phase 2, randomised, double-blind, placebo-controlled study of adjunctive pimavanserin in patients with negative symptoms of schizophrenia

Due to the paucity of previous studies, we wanted to elucidate the pharmacoepidemiology of antipsychotics in schizophrenia in a general population sample, and the association between long-term antipsychotic use and outcomes.The sample included 53 schizophrenia subjects from the Northern Finland Birth Cohort 1966 with at least ten years of follow-up (mean 18.6 years since illness onset). Data on lifetime medication and outcomes (remission, Clinical Global Impression [CGI], Social and Occupational Functioning Assessment Scale [SOFAS]) were collected from medical records, interviews, and national registers.During the first two years 22 (42%), between two to five years 17 (32%), and between five to ten years 14 (26%) subjects had used antipsychotics less than half of the time. Drug-free periods became rarer during the follow-up. The mean lifetime daily dose of antipsychotics was 319 mg in chlorpromazine equivalents. A high lifetime average and cumulative dose and antipsychotic polypharmacy were associated with a poorer outcome in all measures, whereas having no drug-free periods was associated with a better SOFAS score and a low proportion of time on antipsychotics with a better CGI score.In our population-based sample, the use of antipsychotics increased during the first five years of illness and was relatively stable after that. Our results suggest that both low dose and proportion of use, and having no drug-free periods, are associated with better outcomes, which concords with current treatment recommendations and algorithms. High long-term doses and polypharmacy may relate to poor outcomes.

Neuroanatomical Features That Predict Response to Electroconvulsive Therapy Combined With Antipsychotics in Schizophrenia: A Magnetic Resonance Imaging Study Using Radiomics Strategy.

ObjectiveNeuroimaging-based brain signatures may be informative in identifying patients with psychosis who will respond to antipsychotics. However, signatures that inform the electroconvulsive therapy (ECT) health care professional about the response likelihood remain unclear in psychosis with radiomics strategy. This study investigated whether brain structure-based signature in the prediction of ECT response in a sample of schizophrenia patients using radiomics approach.MethodsThis high-resolution structural magnetic resonance imaging study included 57 patients at baseline. After ECT combined with antipsychotics, 28 and 29 patients were classified as responders and non-responders. Features of gray matter were extracted and compared. The logistic regression model/support vector machine (LRM/SVM) analysis was used to explore the predictive performance.ResultsThe regularized multivariate LRM accurately discriminated responders from non-responders, with an accuracy of 90.91%. The structural features were further confirmed in the validating data set, resulting in an accuracy of 87.59%. The accuracy of the SVM in the training set was 90.91%, and the accuracy in the validation set was 91.78%.ConclusionOur results support the possible use of structural brain feature-based radiomics as a potential tool for predicting ECT response in patients with schizophrenia undergoing antipsychotics, paving the way for utilization of markers in psychosis.

T213. TREND OF LONG-ACTING INJECTABLE ANTIPSYCHOTICS USE IN ASIA: FINDINGS FROM REAP ANTIPSYCHOTIC STUDIES

BackgroundResearch on Asian Prescription Pattern (REAP) is the largest and the longest lasting international collaborative research in psychiatry in Asia since 2001. At present, four studies on antipsychotics in schizophrenia, two antidepressants, one bipolar disorder and one mood disorder were completed. Previous studies have examined the use of Long-acting Injectable (LAI) antipsychotic in patients with schizophrenia and revealed major differences across countries. The aim of the study is to investigate the prescription trend of LAI antipsychotic use in four REAP schizophrenia surveys.MethodsWe analyzed the results from four times of REAP studies (AP1 to AP4, 2001, 2004, 2009 and 2016), to compare the trend of LAI prescriptions rates in China, Hong Kong, Japan, Korea, Singapore, and Taiwan, and also the rate of LAI use among 15 Asian countries in AP4.ResultsA total of 10505 patients were analyzed, with an average rate of 14.6% of patients received LAI antipsychotic treatment. For comparison of AP1 to AP4, there was a wide variation in the rate of LAI use among the six countries, with the highest prescription rate in Singapore (68.1%) and the lowest in Korea (1.6 %). Korean patients received no LAIs treatment in the first two surveys, and the rates in China and Japan were also very low. While in Hong Kong and Singapore, the rates were much higher. In AP4 survey, India, Malaysia, Thailand, Pakistan and Sri Lanka have a higher rate of LAI use, while in Indonesia, Myanmar, the rate is much lower. Vietnam does not use LAI at all. The prescription trend was also diverse, which increased in Korea and Japan and decreased in China, Hong Kong and Singapore. The overall prescription trend of LAI was in decrease. Besides, when analyzing cases with only using second generation antipsychotics, the usage of LAI was increased.DiscussionPrevious studies identified several factors associated with prescription of LAI, including demographic and clinical characteristics of patients, patients’ and physicians’ attitude towards LAI, availability of LAI, insurance coverage and related cultural factors. The prescription trend of first generation LAI was decreased in most of the six countries; on the other hand, second generation LAI usages maintain steady level and even slightly increased. In conclusion, LAI antipsychotic is still underuse in Asia, especially in some countries such as Korea, China, Japan, Indonesia and Myanmar. Various factors that influenced the prescription rate of LAI antipsychotic should be addressed further.

M201. MODERATORS OF WEIGHT GAIN IN RANDOMIZED CONTROLLED TRIALS OF SCHIZOPHRENIA – A META-REGRESSION ANALYSIS

BackgroundWeight gain is an important side effect of antipsychotics. Meta-analyses of randomized controlled trials indicate differences between the multiple antipsychotics in propensity to cause weight gain. However, antipsychotic-associated weight gain, in randomized controlled trials as well as in real life situations, might also depend on population characteristics and treatment-related factors.As a preparatory work for a systematic review and network-meta-analysis on metabolic side effects of antipsychotics (presented in another poster at this conference), we conducted a meta-regression analysis of potential moderators of weight gain.MethodsWe selected acute phase short-term, acute phase long-term as well as relapse prevention studies (all found by systematic reviews conducted by our group in the past) from our database of randomized controlled trials of antipsychotics in schizophrenia.We conductedi) meta-regression-analyses based on pairwise meta-analysis of the mean difference (MD) in change in weight (kg) between patients exposed to antipsychotics and placebo, andii) meta-regression-analyses based on single-arm meta-analysis of the change in weight (kg).We examined the moderators baseline weight, study duration, percentage women, and publication year.We conducted the analyses for all drugs pooled, placebo and per individual drug. For presentation of the results we focus on the drugs aripiprazole, haloperidol, quetiapine, olanzapine, and risperidone, because these are popular drugs in clinical practice, they differ in their receptor-binding profiles and multiple studies are available for these drugs.We conducted the analysis in R using the commands metacont, metagen and metareg from the package meta.ResultsThe dataset comprises 603 randomized controlled trials with 141 584 patients that examined 40 different antipsychotics. Trial duration varied between 3 and 156 weeks (median 8 weeks). 168 studies with 49 670 patients reported on change in body weight.We found no effect of baseline weight on antipsychotic-associated weight gain, however on placebo, lower baseline weight was associated with more weight loss.Moreover, on antipsychotics, higher percentage of women was associated with less weight gain, and, on placebo, higher percentage of women was associated with more weight loss.Longer study duration was not associated with increased weight gain. On placebo, longer studies were associated with more weight loss.There was no effect of publication year.DiscussionSurprisingly, we found no moderating effect of baseline weight and study duration on weight gain. However, our data suggests that men and women could have different risk of weight gain. Moreover, weight loss after switching to placebo might be higher in women and patients with less baseline weight. For interpretation, it must be noted that meta-regressions are observational evidence and thus prone to confounding. In addition, the scatter plots, presented on the poster, need to be considered to judge the robustness and magnitude of the moderated effects. Additional meta-regressions (planned to present on the poster) should address further potential moderators, such as antipsychotic dose, ethnicity, previous antipsychotic exposure and dropout rates.

Association of MTHFR 677C > T genetic polymorphism with extrapyramidal side effects of antipsychotic treatment

Several studies have revealed a positive association between methylenetetrahydrofolate reductase (MTHFR) single nucleotide polymorphism 677C > T and schizophrenia. In T-allele carriers the functional activity of MTHFR is reduced contributing to hyperhomocysteinemia development, methionine deficiency and as a consequence - redox dysregulation and the alteration of dopamine synthesis. The aim of this study was to investigate the association of MTHFR677C > T with the severity of extrapyramidal side effects of antipsychotics in schizophrenia. The average score on the Simpson-Angus scale (SAS) in a group of patients with MTHFR 677 T-allele (n = 30; 13.27 ± 5.10, M ± SD) was statistically significantly higher (t = −2.40; p = 0.02) than in the comparison group of wild genotype MTHFR 677 CC carriers (n = 31; 9.84 ± 6.03, M ± SD), confirming the working hypothesis about a possible association of the MTHFR677 T-allele carriage with the development of extrapyramidal side effects of antipsychotics.

Drug Attitude, Insight, and Patient's Knowledge About Prescribed Antipsychotics in Schizophrenia: A Cross-Sectional Survey.

IntroductionWhile patients’ perspectives toward pharmacotherapy are expected to be directly influenced by their motivation and understanding of the treatment that they are currently receiving, no study has comprehensively investigated the impact of insight into illness and knowledge for the ongoing pharmacotherapy on the attitude towards drug treatment among patients with schizophrenia.Materials and MethodsOne hundred forty-eight Japanese outpatients diagnosed with schizophrenia, according to the International Classification of Diseases 10th edition, were included (mean±SD age, 47.3±12.4 years; 90 men (60.8%)). Attitudes toward antipsychotic treatment and insight into illness were assessed with the Drug Attitude Inventory-10 (DAI-10) and the VAGUS, respectively. In addition, a multiple-choice questionnaire that was designed to examine patients’ knowledge about therapeutic effects, types, and implicated neurotransmitters of antipsychotic drugs they were receiving was utilized.ResultsThe mean±SD of DAI-10 score was 4.7±4.2. The multiple regression analysis found that lower Positive and Negative Syndrome Scale (PANSS) scores, higher VAGUS scores, and longer illness duration were significantly associated with higher DAI-10 scores (β=−0.226, P=0.009; β=0.250, P=0.008; β=0.203, P=0.034, respectively). There was a significant difference in the DAI-10 scores between the subjects who gave more accurate answers regarding the effects of their primary antipsychotic and those who did not (mean±SD, 5.57±4.38 vs 4.13±4.04, P=0.043); however, this finding failed to survive the multiple regression analysis.ConclusionBetter insight into illness and treatment, lower illness severity, longer illness duration, and possibly greater knowledge about the therapeutic effects of medications may lead to better attitudes towards pharmacotherapy among patients with schizophrenia, which has an important implication for this typically chronic mental condition requiring long-term antipsychotic treatment to sustain stability.

Predicting response to electroconvulsive therapy combined with antipsychotics in schizophrenia using multi-parametric magnetic resonance imaging

Electroconvulsive therapy (ECT) has been shown to be effective in schizophrenia, particularly when rapid symptom reduction is needed or in cases of resistance to drug treatment. However, there are no markers available to predict response to ECT. Here, we examine whether multi-parametric magnetic resonance imaging (MRI)-based radiomic features can predict response to ECT for individual patients. A total of 57 treatment-resistant schizophrenia patients, or schizophrenia patients with an acute episode or suicide attempts were randomly divided into primary (42 patients) and test (15 patients) cohorts. We collected T1-weighted structural MRI and diffusion MRI for 57 patients before receiving ECT and extracted 600 radiomic features for feature selection and prediction. To predict a continuous improvement in symptoms (ΔPANSS), the prediction process was performed with a support vector regression model based on a leave-one-out cross-validation framework in primary cohort and was tested in test cohort. The multi-parametric MRI-based radiomic model, including four structural MRI feature from left inferior frontal gyrus, right insula, left middle temporal gyrus and right superior temporal gyrus respectively and six diffusion MRI features from tracts connecting frontal or temporal gyrus possessed a low root mean square error of 15.183 in primary cohort and 14.980 in test cohort. The Pearson's correlation coefficients between predicted and actual values were 0.671 and 0.777 respectively. These results demonstrate that multi-parametric MRI-based radiomic features may predict response to ECT for individual patients. Such features could serve as prognostic neuroimaging biomarkers that provide a critical step toward individualized treatment response prediction in schizophrenia.

The effect of bezafibrate in preventing glucolipid abnormalities induced by the antipsychotic risperidone

The present study aimed to investigate the effect of bezafibrate on glucolipid abnormalities induced by antipsychotics in schizophrenia. Patients in the treatment group (group A) were treated with antipsychotics and a daily dose of 200 mg bezafibrate for 12 weeks, and patients in the control group (group B) were treated with antipsychotics; sugar, fat and weight changes before and after the treatment were compared between the two groups. Before treatment the differences in TG, TC, LDL-C, HDL-C, body weight and blood glucose between groups A and B were not statistically significant. However, in group B, levels of TG, TC, LDL-C, body weight and blood glucose after treatment showed statistically significant increases, although levels of HDL-C did not register any statistically significant change. By contract, in group A, there were no statistically significant changes in any of the variables measured. Bezafibrate can prevent an increase in sugar, fat and weight gain in treating schizophrenia patients with antipsychotics, and low doses of bezafibrate are safe in the antipsychotic treatment for schizophrenia.

When the drugs don't work: the potential of glutamatergic antipsychotics in schizophrenia - ADDENDUM.

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Therapy of Schizoaffective Disorder and Paranoid Schizophrenia with Episodic Course

Background. The use of atypical antipsychotics in schizophrenia contributes to the reduction of psychotic, affective, negative and cognitive disorders.Aims. To evaluate the effectiveness of ziprasidone therapy in patients with schizoaffective disorder and paranoid schizophrenia with episodic course.Materials and methods. In accordance with ICD-10 there were 14 (63.6 %) people with schizoaffective disorder (F25), 8 (36.4 %) people with paranoid schizophrenia, episodic course (F20.x1). Treatment with ziprasidone lasted 42 days. The dose of ziprasidone in 6 patients (27.3 %) was 80 mg, in 10 patients (45.5 %) – 120 mg, in 6 patients (27.3 %) – 160 mg. Evaluation of the effectiveness of ziprasidone therapy was carried out using psychometric scales (PANSS, General clinical impression scale to assess the effectiveness of therapy – CGI-S, CGI-I), adverse events were registered with the UKU scale.Results. The number of respondents was 19 (86.3 %) (reduction of the total score on the PANSS scale > 20 % of the pre-treatment level). Ziprasidone was effective in patients with schizoaffective disorder with a significant decrease in total score on PANSS subscales to the 14 th day of therapy (p < 0.05), with paranoid schizophrenia with episodic course – by the 21st day (p < 0.01). According to the CGI-S scale at the end of therapy, “borderline condition” was observed in 10 patients (52.6 %), mild severity – in 3 (15.8 %), normal condition – in 6 (31.6 %). CGI-I scale showed a significant improvement in 10 patients (52.6 %), marked improvement – in 9 patients (47.4 %). Among the mild adverse events that do not require discontinuation of the drug, we noted: weakness – in 3 patients (15.8 %), drowsiness – in 3 (15.8 %), impaired concentration – in 2 (10.5 %), orthostatic dizziness – in 2 (10.5 %), galactorrhea – in 1 (5.3 %).Conclusions. Ziprasidone is an effective antipsychotic drug that has a safe tolerability profile. It can be used in patients with schizoaffective disorders and paranoid schizophrenia with episodic course.

Long-acting atypical antipsychotics in schizophrenia: A systematic review and meta-analyses of effects on functional outcome.

Impairment in psychosocial function is common in schizophrenia. Long-acting injectable atypical antipsychotics are thought to enhance psychosocial function by boosting adherence. However, no systematic review has examined the effects of long-acting injectable atypical antipsychotics on psychosocial function in clinical trials. We searched major databases including Medline/PubMed, PsychINFO, EMBASE, CINAHL, Scopus, Web of Science, Cochrane Central Register of Controlled Trials and Clinical Trial Registries for randomised controlled trials that compared long-acting injectable atypical antipsychotics to placebo, oral antipsychotic medications or long-acting injectable atypical antipsychotics for all years till 2018, with no language limits. We performed a systematic review of findings on change in psychosocial function and its predictors in the included reports. Data on change in psychosocial functioning were meta-analysed using a random-effects model. A total of 26 studies were included in systematic review, and 19 studies with 8616 adults, 68.1% males were meta-analysed. Long-acting injectable atypical antipsychotics were superior to placebo (standardised mean difference = 0.39; 95% confidence interval = [0.32, 0.47]; p < 0.001; I2 = 0%; 9 studies) and oral antipsychotic medications (standardised mean difference = 0.16; 95% confidence interval = [0.01, 0.31]; p = 0.04; I2 = 77%; 10 studies) for improved psychosocial function and superiority was maintained in short- and long trials. Poor psychosocial function was predicted by longer treatment duration, severe symptoms, poor cognition and poor insight. Functioning was assessed by either a single or a combination of measures, but was not the primary outcome in most studies. Other sources of bias include poor blinding and reporting of randomisation. Long-acting injectable atypical antipsychotics are beneficial for recovery of psychosocial function in comparison with placebo, but the magnitude of superiority over oral antipsychotic treatment was small. Severe psychopathology at baseline predicted poor psychosocial function. Future effectiveness trials in which post-randomisation involvement is kept to a minimum, and psychosocial function is included as primary outcome a priori, are needed to capture the real-world impact of long-acting injectable atypical antipsychotics and to address methodological biases.

Effectiveness of Long-Acting Injectable Antipsychotics in Schizophrenia: A Literature Review and Bayesian Meta-Analysis Informing Economic Considerations

BACKGROUND: Although the use of long-acting injectable antipsychotics (LAIs) is considered an important option in the management of schizophrenia two recent meta-analysis, which aimed to compare LAIs vs oral antipsychotics (OAPs) in terms of relapse rate, showed discordant results.AIM: To investigate factors affecting the efficacy of antipsychotics in terms of relapse prevention in the real-world and to estimate the management cost of an episode of relapse.METHODS: We conducted a literature search using MEDLINE/PubMed with the aim to extract efficacy, effectiveness and adherence data of LAIs and OAPs. The primary outcome was the relative risk (RR) of relapse between two strategies. The extracted RR were included in a series of Bayesian statistical models based on the starting hypotheses. The RR rates obtained from the meta-analysis have been used as input for an economic evaluation of the total costs associated with the management of the patient with schizophrenia from the Italian NHS perspective.RESULTS: The literature search identified 34 studies which met the inclusion criteria and were analyzed. According to the model that best explains the data, in the real-world setting the effectiveness with LAIs is greater than with OAPs, with a more pronounced effect for SGAs than for FGAs. Taking into account generation, route and frequency of administration, the RR decreased with lower administration frequency, with SGA LAI administered once every 90 days which is associated with the greatest reduction in the risk of relapse (-85%). When the results of the meta-analysis are used to feed an economic evaluation the results show that the SGA administered every 90 days is the strategy with the least expected cumulative cost both at 1 (€ 3,509) and 5 years (€ 19,690).CONCLUSION: SGA LAIs administered every 90 days seems to be the best option for the treatment of patient with schizophrenia from both the clinical and economic perspectives.An erratum to this article is available online at: https://doi.org/10.7175/fe.v20i1.1406

Adjunctive Metformin for Antipsychotic-Induced Dyslipidemia: A Meta-Analysis of Randomized, Double-Blind, Placebo-Controlled Trials

Background: Antipsychotic-induced dyslipidemia could increase the risk of cardiovascular diseases. This is a meta-analysis of randomized double-blind placebo-controlled trials (RCTs) to examine the efficacy and safety of adjunctive metformin for dyslipidemia induced by antipsychotics in schizophrenia. Methods: The standardized mean differences (SMDs) and risk ratios (RRs) with their 95% confidence intervals (CIs) were calculated using the random-effects model with the RevMan 5*3 version software. The primary outcome was the change of serum lipid level. Results: Twelve studies with 1,215 schizophrenia patients (592 in metformin group and 623 in placebo group) were included and analyzed. Adjunctive metformin was significantly superior to placebo with regards to low density lipoprotein cholesterol [SMD: -0*37 (95%CI:-0*69, -0*05), P=0*02; I2=78%], total cholesterol [SMD: -0*47 (95%CI:-0*66, -0*29), P<0*00001; I2=49%], triglyceride [SMD: -0*33 (95%CI:-0*45, -0*20), P<0*00001; I2=0%], and high density lipoprotein cholesterol [SMD: 0*29 (95%CI:0*02, 0*57), P=0*03; I2=69%]. The superiority of metformin in improving LDL-C level disappeared in a sensitivity analysis and 80% (8/10) of subgroup analyses. Metformin was significantly superior to placebo with regards to decrease in body weight, body mass index, glycated hemoglobin A1c, fasting insulin, and homeostasis model assessment-insulin resistance (P=0*002 to 0*01), but not regarding changes in waist circumference, waist-to-hip rate, leptin, fasting glucose, and blood pressure (P=0*07 to 0*33). The rates of discontinuation due to any reason [RR: 0*97 (95%CI: 0*66, 1*43), P=0*89; I2=0%] was similar between the two groups. Conclusions: Adjunctive metformin could be useful to improve total cholesterol and triglyceride levels, but it was not effective in improving LDL-C level in schizophrenia. Funding Statement: The study was supported by the National Key and Development Plan Precision Medical Research 2016 Project (2016YFC0906302) and Science and Technology Program of Guangzhou (201807010064). Declaration of Interests: The authors declare no conflicts of interest. Ethics Approval Statement: Review registration: CRD42019125861.

Early Placebo Improvement Is a Marker for Subsequent Placebo Response in Long-Acting Injectable Antipsychotic Trials for Schizophrenia: Combined Analysis of 4 RCTs.

Placebo effects remain largely unexplored in clinical trials of long-acting injectable (LAI) antipsychotics for schizophrenia. This study aims to characterize patients showing improvements after placebo injections and to search for criteria for the prediction of subsequent response based on the magnitude of score changes after the first week of treatment. Data from 450 patients with schizophrenia (DSM-IV) who received placebo injections in 4 double-blind randomized controlled trials evaluating efficacy of LAI paliperidone palmitate obtained through the Yale University Open Data Access (YODA) project were analyzed. These 4 studies were conducted from October 2003 to March 2008. Multiple logistic regression analyses were conducted to examine associations between placebo response and demographic and clinical characteristics. The predictive power of improvement at week 1 for response at week 9 was investigated; sensitivity and specificity of incremental 5% cutoff points between a 5% and 25% reduction in Positive and Negative Syndrome Scale (PANSS) total score at week 1 were calculated. Percent reduction in the PANSS total score at week 1 and a lower PANSS G12 item score (ie, better in judgment and insight) at baseline were significantly associated with placebo response at week 9 (odds ratio [OR] = 1.063; 95% CI, 1.040-1.087, P < .001; and OR= 0.739; 95% CI, 0.553-0.986, P = .040, respectively, in the per-protocol analysis). Cutoffs of a 10% (accuracy = 0.724 in the per-protocol analysis) and 15% (accuracy = 0.722 in the last-observation-carried-forward analysis) reduction in the PANSS total score at week 1 showed the highest predictive power. The appreciation that longer-term response following placebo injections can be predicted by a 10%-15% PANSS total score reduction at week 1 could guide the design of future clinical trials of LAI antipsychotics in schizophrenia to identify and exclude potential placebo responders early during the course of the study.

N-3 polyunsaturated fatty acids and clozapine abrogates poly I: C-induced immune alterations in primary hippocampal neurons

The viral mimetic polyinosinic:polycytidylic acid (poly I:C) is an important tool to study the consequences of viral infection to the development of neuropsychiatric disorders. Here, based on the premise of omega-3 polyunsaturated fatty acids (n3 PUFAs) as supplemental treatment to antipsychotics in schizophrenia, we investigated the involvement of NFkB pathway in the effects of n3 PUFAs or of the atypical antipsychotic clozapine in hippocampal poly I:C-challenged neurons. Primary hippocampal neuronal cultures were exposed to n3 PUFAs (DHA4.35 μM/EPA7.10 μM, DHA 8.7 μM/EPA14.21 μM or DHA17.4 μM/EPA28.42 μM) or clozapine (1.5 or 3 μM) in the presence or absence of poly I:C. MTT assay revealed that poly I:C-induced reduction in cell viability was prevented by n3 PUFAs or clozapine. N3 PUFAs (DHA 8.7 μM/EPA14.21 μM) or clozapine (3 μM) significantly reduced poly I:C-induced increase in iNOS, NFkB (p50/p65), IL-6 and nitrite when compared to non-treated cells. Only n3 PUFAs prevented poly I:C-induced deficits in BDNF. On the other hand, poly I:C caused a marked reduction in DCX immunoexpression, which was prevented only by clozapine. Thus, n3 PUFAs and clozapine exert in vitro neuroprotective effects against poly I:C immune challenge in hippocampal neurons, by mechanisms possibly involving the inhibition of canonical NFkB pathway. The present study adds further evidences to the mechanisms underlying n3 PUFAs and clozapine neuroprotective effects against viral immune challenges. Since n3 PUFAs is a safe strategy for use during pregnancy, our results also add further evidence for the use of this supplement in order to prevent alterations induced by viral hits during this developmental period.

Maximizing response to first-line antipsychotics in schizophrenia: a review focused on finding from meta-analysis.

There are many psychotropic drugs available for treatment of schizophrenia. The clinician's choice of the most effective first-line antipsychotic treatment for patients with schizophrenia should balance considerations of differential efficacy of antipsychotics against the relative risk of different side effects. We reviewed recent studies using meta-analytic techniques and additional studies of new antipsychotics which quantitatively evaluate the efficacy of side effects of first- and second-generation antipsychotics and studies of the efficacy on add-on secondary medications. We present an integrated summary of these results to guide a clinician's decision-making. Recent meta-analyses have suggested that antipsychotics are not equivalent in efficacy. Clozapine (effect size [SMD] 0.88 vs. placebo), amisulpride (effect size 0.6 vs placebo), olanzapine (effect size 0.59 vs. placebo), and risperidone (effect size 0.56 vs placebo) show small but statistically significant differences compared to a number of other antipsychotics on measures of overall efficacy (effect sizes 0.33-0.50). However, increasing placebo response remains a concern in interpreting these data. Amisulpride (effect size 0.47 vs placebo) and cariprazine (effect size in one trial compared to risperidone 0.29) have the strongest evidence indicating greater efficacy for treating primary negative symptoms relative to other antipsychotics. In terms of side effects, clozapine and olanzapine have among the highest weight gain potential and sertindole and amisulpride have more effects on QTc prolongation than other commonly used antipsychotics. Prolactin elevation is highest with paliperidone, risperidone, and amisulpride. Adjunctive treatment with an antidepressant drug may improve response in patients with schizophrenia who also have severe depressive or negative symptoms. For multi-episode patients with an inadequate response to an adequate dose and duration of the initial antipsychotic choice, switching to another antipsychotic, with a different receptor profile, may improve response, although evidence is very limited. In first-episode patients, a recent study on switching to another antipsychotic, with a different receptor profile after 4weeks demonstrated no beneficial effects. There is little evidence to support using doses above the therapeutic range other than in exceptional circumstances. Our review of recent studies using meta-analytic techniques has provided evidence that all antipsychotics are not equal in the severity of different side effects and in some measures of clinical efficacy. Comparative analysis and rankings from network meta-analyses can provide guidance to clinicians in choosing the most appropriate antipsychotic for first-line treatment, if used in conjunction with available information of the patient's history of previous clinical response or higher risks for specific side effects.

The acute efficacy of antipsychotics in schizophrenia: a review of recent meta-analyses.

Schizophrenia is the eighth leading cause of disability worldwide in people aged 15-44 years. Before antidopaminergic antipsychotics were introduced in the 1950s, no effective medications existed for the treatment of schizophrenia. This review summarizes key meta-analytic findings regarding antipsychotic efficacy in the acute treatment of schizophrenia, including clozapine in treatment-resistant patients. In the most comprehensive meta-analysis of randomized controlled trials conducted in multi-episode schizophrenia, antipsychotics outperformed placebo regarding total symptoms, positive symptoms, negative symptoms, depressive symptoms, quality of life and social functioning. Amongst these outcomes, the standardized mean difference for overall symptoms was largest, that is, 0.47 (95% credible interval = 0.42-0.51), approaching a medium effect size, being reduced to 0.38 when publication bias and small-trial effects were accounted for. A comparison of two meta-analyses indicated that first-episode patients, compared with multi-episode patients, were more likely to have at least minimal treatment response [⩾20% Positive and Negative Syndrome Scale (PANSS)/Brief Psychiatric Rating Scale (BPRS) score reduction: 81% versus 51%] and good response (⩾50% PANSS/BPRS score reduction: 52% versus 23%). In multi-episode schizophrenia, no response or worsening after 2 weeks of a therapeutic antipsychotic dose was highly predictive of not achieving a good response at endpoint (median treatment = 6 weeks: specificity = 86%; positive predictive value = 90%), suggesting a change in treatment should be considered in such cases. In first-episode psychosis, adequately dosed antipsychotic treatment trials for more than 2 weeks are recommended before using no response or worsening as a decision point for aborting a given antipsychotic. In clearly defined treatment-resistant schizophrenia, clozapine generally outperformed other antipsychotics, especially when dosed appropriately (target = 3-6 months' duration; trough clozapine level ⩾350-400 μg/L) with a response rate (⩾20% PANSS/BPRS) of 33% by 3 months of treatment. High antipsychotic doses and psychotropic combinations are unlikely to be superior to standard doses of antipsychotic monotherapy. Acute antipsychotic efficacy in schizophrenia depends on the targeted symptom domain (greater efficacy: total and positive symptoms, lesser efficacy: negative symptoms, depressive symptoms, social functioning and quality of life). Greater antipsychotic efficacy is associated with higher total baseline symptom severity, treatment-naïveté/first-episode status, shorter illness duration, and trials that are nonindustry sponsored and that have a lower placebo effect. The heterogeneity of antipsychotic response across individuals and key symptom domains, the considerable degree of nonresponse/treatment resistance in multi-episode patients, and the adverse effect potential of antipsychotics are major limitations, underscoring the need to develop new medications for the treatment of schizophrenia. Drug development should include matching patient subgroups, which are identified by means of clinical and biomarker variables, to mechanisms of action of novel medications, targeting specific symptom domains, and investigating mechanisms of action other than dopaminergic blockade.

Pharmacoeconomic analysis of using typical and atypical antipsychotics in schizophrenia

The aim: to provide a comprehensive pharmacoeconomic evaluation of the maintenance therapy with antipsychotics in outpatients diagnosed with schizophrenia.Materials and methods. The analysis was conducted by two mutually complementary steps: an epidemiological study on outpatients with schizophrenia, and a subsequent pharmacoeconomic modeling. Two medical technologies were evaluated and compared: treatment with classical antipsychotics (kA) and treatment with atypical antipsychotics (AA). For the clinical and economic analysis of these treatments, we used a number of indices derived from our retrospective study of patients’ medical records. The cost-effectiveness analysis, incremental analysis, and «budget impact» analysis were performed taking into account the direct and indirect costs of the treatments.Results. We determined the costs of managing outpatients with schizophrenia from the perspective of the healthcare budget and the social burdens; we also looked into the relevance and effectiveness of the current costs at various time intervals – 6, 12 and 24 months. As shown, the treatment strategies involving AA were more budget-consumptive than the kA treatments. even if the treatments were switched to the reproduced AA (up to 100% replacement), the costs would remain to be higher than those for the kA. The «cost-effectiveness» analysis related to «the proportion of stable patients» for the horizons of 6 and 12 months indicated that the reproduced AA would be more economically effective than the kA. However, when the observation period was increased to 24 months, this economic advantage of AA diminished, and the kA drugs had a lower CeR instead. For the «number of hospitalization-free days per year», the use of AA was more cost-effective only versus the 100% use of reproduced AA at the simulated horizon of 12 months. When the use of 100% reference AA or the combined use of reference + reproduced AA was simulated, the treatment with kA remained more economically effective, regardless of the simulated period.Conclusion. The pharmacoeconomic simulation of the antipsychotic therapy in outpatients with schizophrenia suggests the ways to optimize the treatment. Among them, (a) using AA for the treatment of at least 15.6% of patients (those who are employed); keeping the ≥60% use of kA to ensure the optimal resource-saving effect of the treatment; (b) using reproduced AA at the level of ≥70% (instead of the reference AA similar in efficacy and safety) to keep the treatment economically feasible.

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

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

Effect of Aerobic Exercise on Improving Symptoms of Individuals With Schizophrenia: A Single Blinded Randomized Control Study.

Introduction: Antipsychotic treatment can improve the symptoms of schizophrenia; however, residual symptoms after antipsychotic treatment are frequent. The effects of exercise on the symptoms of schizophrenic patients under antipsychotic treatment are inconclusive. The aim of this randomized case-control study was to examine the effects of aerobic exercise (AE) on the symptoms of schizophrenic patients receiving antipsychotic treatment.Methods: In total, 33 and 29 participants being treated with antipsychotics for schizophrenia were randomly assigned into the aerobic exercise (AE) group and the control group, respectively. The severities of schizophrenic symptoms were measured using the Chinese version of the Positive and Negative Syndrome Scale (PANSS) before, immediately after, and 3 months after the intervention in both groups.Results: In total, 24 participants (72.7%) in the AE group and 22 (75.9%) in the control group completed the study. The results indicated that the severities of positive symptoms and general psychopathology in the AE group significantly decreased during the 12 weeks of intervention but did not further significantly change during the 3-month follow-up period. The severities of negative symptoms in the AE group decreased significantly after 12 weeks of intervention and continued decreasing during the 3-month follow-up period. Interaction effects between time and group on the severities of symptoms on the negative and general psychopathology scales were observed.Conclusion: AE can improve the severities of symptoms on the negative and general psychopathology scales in individuals with schizophrenia being treated with antipsychotics.