Acute Symptoms Of Schizophrenia Research Articles

412. Efficacy of Karxt on Negative Symptoms in Acute Schizophrenia: A Post Hoc Analysis of Participants With Prominent Negative Symptoms

412. Efficacy of Karxt on Negative Symptoms in Acute Schizophrenia: A Post Hoc Analysis of Participants With Prominent Negative Symptoms

Does short-term antipsychotic discontinuation of up to 3 weeks worsen symptoms in acute schizophrenia? A pooled analysis of placebo washout data.

This study aimed to examine symptom changes during short-term discontinuation of antipsychotics up to 3 weeks including the placebo washout phase in acute schizophrenia. The data from three double-blind, randomized, controlled trials comparing lurasidone versus placebo in patients with acute exacerbation of schizophrenia were analyzed. Symptom severity was assessed using the Positive and Negative Syndrome Scale (PANSS) total and the Clinical Global Impression-Severity scale (CGI-S) scores. The scores before and after the antipsychotic discontinuation phase were compared, and factors associated with score changes were explored. Among 2154 patients participating in the trials, 600 who received antipsychotic monotherapy and completed the antipsychotic discontinuation phase were included in the analysis. No patients received clozapine. The mean duration of the discontinuation phase was 5.9 ± 2.5 days. The PANSS total and CGI-S scores significantly changed from 94.0 ± 9.5 to 95.4 ± 10.5 (P < 0.001) and from 4.9 ± 0.6 to 4.9 ± 0.7 (P=0.041), respectively, during this phase; however, the absolute difference was minimal. The score changes were not associated with the type or dose of prior antipsychotics, or the duration or strategy (abrupt vs gradual) of antipsychotic discontinuation. Symptoms may not worsen to a clinically meaningful degree after short-term discontinuation of non-clozapine antipsychotics up to 3 weeks in patients with acute exacerbation of schizophrenia, suggesting that antipsychotic efficacy persists at least several days after discontinuation. This finding supports once-daily dosing regimen of antipsychotics and abrupt antipsychotic discontinuation when switching to another antipsychotic.

Paliperidone palmitate vs. paliperidone extended-release for the acute treatment of adults with schizophrenia: a systematic review and pairwise and network meta-analysis

Is paliperidone palmitate (PP) a useful treatment option for adults with acute symptoms of schizophrenia? We conducted a systematic review and a random-effects pairwise and network meta-analysis that compared PP (25−150 mg equivalent) with paliperidone extended-release (PAL-ER, 3−12 mg/d) regarding their efficacy and safety in adults with acute symptoms of schizophrenia. The outcomes were the total score of the Positive and Negative Syndrome Scale (PANSS-T) at week 6 (the primary outcome for efficacy) and all-cause discontinuation(the primary outcome for acceptability), discontinuation due to inefficacy, discontinuation due to adverse events, discontinuation due to the withdrawal of consent, and the incidence of individual adverse events. Five studies on PP and seven studies on PAL-ER, which involved 4970 individuals in total, were included in this study. For the primary outcomes, we only included data from the treatment arms that used 100 or 150 mg equivalent as an initial dose of PP and data from the treatment arms that used 6, 9, or 12 mg as an initial dose of PAL-ER. The pairwise meta-analyses showed that both PP and PAL-ER outperformed placebo regarding PANSS-T at week 6 and all-cause discontinuation. However, there were no statistically significant differences in these outcomes between the effect sizes of PP and that of PAL-ER. Both PP and PAL-ER increased blood prolactin levels in both females and males compared with placebo. PAL-ER significantly increased blood prolactin in both females and males compared with PP. There were no statistically significant differences in other outcomes between the effect sizes of PP and that of PAL-ER. Similar results in all outcomes were observed in the network meta-analyses. In conclusion, PP might be a useful treatment option for adults with acute symptoms of schizophrenia. A noninferiority study that directly compares PP with PAL-ER for acute schizophrenia, conducted according to the recommended regimen, is required to provide solid evidence.

Clozapine: An Updated Overview of Pharmacogenetic Biomarkers, Risks, and Safety-Particularities in the Context of COVID-19.

Background: clozapine (CLZ) use is precarious due to its neurological, cardiovascular, and hematological side effects; however, it is the gold standard in therapy-resistant schizophrenia (TRS) in adults and is underused. Objective: to examine the most recent CLZ data on (a) side effects concerning (b) recent pharmacological mechanisms, (c) therapy benefits, and (d) the particularities of the COVID-19 pandemic. Data sources: a search was performed in two databases (PubMed and Web of Science) using the specific keywords “clozapine” and “schizophrenia”, “side effects”, “agranulocytosis”, “TRS”, or “bipolar affective disorder (BAF)” for the last ten years. Study eligibility criteria: clinical trials on adults with acute symptoms of schizophrenia or related disorders. Results: we selected 37 studies, randomized controlled trials (RCTs), and clinical case series (CCS), centered on six main topics in the search area: (a) CLZ in schizophrenia, (b) CLZ in bipolar disorder, (c) side effects during the clozapine therapy, (d) CLZ in pregnancy, (e) CLZ in early-onset schizophrenia, and (f) CLZ therapy and COVID-19 infection. Limitations: we considered RCTs and CCS from two databases, limited to the search topics. Conclusions and implications of key findings: (a) clozapine doses should be personalized for each patient based on pharmacogenetics testing when available; the genetic vulnerability postulates predictors of adverse reactions’ severity; patients with a lower genetic risk could have less frequent hematological monitoring; (b) a CLZ-associated risk of pulmonary embolism imposes prophylactic measures for venous thromboembolism; (c) convulsive episodes are not an indication for stopping treatment; the plasma concentration of clozapine is a better side effect predictor than the dosage; (d) COVID-19 infection may enhance clozapine toxicity, generating an increased risk of pneumonia. Therapy must be continued with the proper monitoring of the white blood count, and the clozapine dose decreased by half until three days after the fever breaks; psychiatrists and healthcare providers must act together.

Comparative Efficacy and Tolerability of 32 Oral Antipsychotics for the Acute Treatment of Adults With Multi-Episode Schizophrenia: A Systematic Review and Network Meta-Analysis.

(Reprinted with permission from the Lancet 2019; 394: 939-51).

What Antipsychotic Dose Is Most Effective?

Back to table of contents Previous article Next article Clinical & ResearchFull AccessWhat Antipsychotic Dose Is Most Effective?Nick ZagorskiNick ZagorskiSearch for more papers by this authorPublished Online:10 Jan 2020https://doi.org/10.1176/appi.pn.2020.1b3AbstractA large meta-analysis calculated optimal doses for 19 different antipsychotics and found that for several medications, doses above the maximum licensed dose might be most effective. Combining clinical data from 68 separate studies, a research team has estimated the most effective dose for 19 different antipsychotic medications, including both oral and long-acting injectable (LAI) formulations. The researchers also calculated the dose equivalents of these 19 medications to guide physicians who may be considering switching patients from one antipsychotic to another. This meta-analysis was published in December 2019 in AJP in Advance.The minimum and maximum effective doses of antipsychotic drugs are not well understood, wrote Stefan Leucht, M.D., of the Technical University of Munich and colleagues. Though approved medications are licensed within a specific range of doses, these amounts are usually calculated early in the drug development process and may not reflect the optimal range for patients.Leucht and colleagues identified clinical trials that compared multiple doses of the same antipsychotics relative to placebo in people with acute schizophrenia symptoms. They then calculated how well symptoms improved in those taking different doses of the following medications: amisulpride, aripiprazole (oral and LAI), asenapine, brexpiprazole, cariprazine, clozapine, haloperidol, iloperidone, lurasidone, olanzapine (oral and LAI), paliperidone (oral and LAI), quetiapine, risperidone (oral and LAI), sertindole, and ziprasidone.he dose-response profiles for these 19 medications fell into two major classes. The first were antipsychotics whose effects plateaued or started dropping at higher tested doses, suggesting the optimal dose is within the currently licensed range. These medications included the following: amisulpride, oral and LAI aripiprazole, asenapine, brexpiprazole, cariprazine, haloperidol, oral olanzapine (when given to patients with predominantly negative symptoms), quetiapine, and oral and LAI risperidone.In some instances, the most effective dose was well below the upper prescribing limits. For example, the most effective dose of oral risperidone—which is approved up to 16 mg/day—is 6.3 mg/day, according to the analysis.“Clinicians often use relatively high doses of antipsychotics in practice,” Leucht told Psychiatric News. “Our analysis shows that for many antipsychotics such doses are not generally recommendable.”For the other medications—including clozapine, iloperidone, lurasidone, oral olanzapine (in patients with predominantly positive symptoms), LAI olanzapine, oral and LAI paliperidone, sertindole, and ziprasidone—there was no indication that the dose-response was plateauing. The authors said that this finding suggests that doses above the licensed limit might be more effective.Leucht cautioned that the dosing analysis considered only symptom improvements and that patients prescribed higher doses of these medications might experience worse side effects. Further controlled studies on dosing are needed to assess the risk-benefit profile of these antipsychotics at elevated doses, he said.“Clinicians need to be aware that if they go beyond the officially licensed doses, they are applying the drug ‘off label’ and should be careful in this regard.”Leucht also noted that the dose estimates for clozapine, haloperidol, LAI aripipazole, LAI olanzapine, and LAI risperidone were each based on a single dosing study, so the data should be interpreted with caution.The researchers also calculated the dose equivalencies of the antipsychotics, using haloperidol, olanzapine, and risperidone as reference drugs (for example, 1 mg of risperidone = x amount of the other medications). These equivalencies can help physicians considering prescribing a different medication, but the researchers cautioned that physicians should look at the full profiles of each medication and not just rely on the conversion calculator. For example, 20 mg/day olanzapine corresponds to 8.25 mg/day risperidone, but an 8.25 mg/day dose of risperidone may be less effective than the optimal level of 6.3 mg/day.“We stress that our results provide some guidance based on ‘average’ patients with chronic illness,” Leucht and colleagues wrote in the article. “The dose-response relationships in specific populations, such as first-episode patients, elderly patients (who need lower doses), and patients with treatment-resistant illness, are likely to be different.” Physicians should use these data as a starting point and then base individual dosing decisions on the properties of each medication, patient characteristics, and any other treatments that might influence antipsychotic response, they concluded.The authors reported no funding information in the article. ■ “Dose-Response Meta-Analysis of Antipsychotic Drugs for Acute Schizophrenia” is posted here. ISSUES NewArchived

Dose-Response Meta-Analysis of Antipsychotic Drugs for Acute Schizophrenia.

The dose-response relationships of antipsychotic drugs for schizophrenia are not well defined, but such information would be important for decision making by clinicians. The authors sought to fill this gap by conducting dose-response meta-analyses. A search of multiple electronic databases (through November 2018) was conducted for all placebo-controlled dose-finding studies for 20 second-generation antipsychotic drugs and haloperidol (oral and long-acting injectable, LAI) in people with acute schizophrenia symptoms. Dose-response curves were constructed with random-effects dose-response meta-analyses and a spline model. The outcome measure was total score reduction from baseline on the Positive and Negative Syndrome Scale or the Brief Psychiatric Rating Scale. The authors identified 95% effective doses, explored whether higher or lower doses than the currently licensed ones might be more appropriate, and derived dose equivalencies from the 95% effective doses. Sixty-eight studies met the inclusion criteria. The 95% effective doses and the doses equivalent to 1 mg of oral risperidone, respectively, were as follows: amisulpride for patients with positive symptoms, 537 mg/day and 85.8 mg; aripiprazole, 11.5 mg/day and 1.8 mg; aripiprazole LAI (lauroxil), 463 mg every 4 weeks and 264 mg; asenapine, 15.0 mg/day and 2.4 mg; brexpiprazole, 3.36 mg/day and 0.54 mg; haloperidol, 6.3 mg/day and 1.01 mg; iloperidone, 20.13 mg/day and 3.2 mg; lurasidone, 147 mg/day and 23.5 mg; olanzapine, 15.2 mg/day and 2.4 mg; olanzapine LAI, 277 mg every 2 weeks and 3.2 mg; paliperidone, 13.4 mg/day and 2.1 mg; paliperidone LAI, 120 mg every 4 weeks and 1.53 mg; quetiapine, 482 mg/day and 77 mg; risperidone, 6.3 mg/day and 1 mg; risperidone LAI, 36.6 mg every 2 weeks and 0.42 mg; sertindole, 22.5 mg/day and 3.6 mg; and ziprasidone, 186 mg/day and 30 mg. For amisulpride and olanzapine, specific data for patients with predominant negative symptoms were available. The authors have made available on their web site a spreadsheet with this method and other updated methods that can be used to estimate dose equivalencies in practice. In chronic schizophrenia patients with acute exacerbations, doses higher than the identified 95% effective doses may on average not provide more efficacy. For some drugs, higher than currently licensed doses might be tested in further trials, because their dose-response curves did not plateau.

Comparative efficacy and tolerability of 32 oral antipsychotics for the acute treatment of adults with multi-episode schizophrenia: a systematic review and network meta-analysis

SummaryBackgroundSchizophrenia is one of the most common, burdensome, and costly psychiatric disorders in adults worldwide. Antipsychotic drugs are its treatment of choice, but there is controversy about which agent should be used. We aimed to compare and rank antipsychotics by quantifying information from randomised controlled trials.MethodsWe did a network meta-analysis of placebo-controlled and head-to-head randomised controlled trials and compared 32 antipsychotics. We searched Embase, MEDLINE, PsycINFO, PubMed, BIOSIS, Cochrane Central Register of Controlled Trials (CENTRAL), WHO International Clinical Trials Registry Platform, and ClinicalTrials.gov from database inception to Jan 8, 2019. Two authors independently selected studies and extracted data. We included randomised controlled trials in adults with acute symptoms of schizophrenia or related disorders. We excluded studies in patients with treatment resistance, first episode, predominant negative or depressive symptoms, concomitant medical illnesses, and relapse-prevention studies. Our primary outcome was change in overall symptoms measured with standardised rating scales. We also extracted data for eight efficacy and eight safety outcomes. Differences in the findings of the studies were explored in metaregressions and sensitivity analyses. Effect size measures were standardised mean differences, mean differences, or risk ratios with 95% credible intervals (CrIs). Confidence in the evidence was assessed using CINeMA (Confidence in Network Meta-Analysis). The study protocol is registered with PROSPERO, number CRD42014014919.FindingsWe identified 54 417 citations and included 402 studies with data for 53 463 participants. Effect size estimates suggested all antipsychotics reduced overall symptoms more than placebo (although not statistically significant for six drugs), with standardised mean differences ranging from −0·89 (95% CrI −1·08 to −0·71) for clozapine to −0·03 (−0·59 to 0·52) for levomepromazine (40 815 participants). Standardised mean differences compared with placebo for reduction of positive symptoms (31 179 participants) varied from −0·69 (95% CrI −0·86 to −0·52) for amisulpride to −0·17 (−0·31 to −0·04) for brexpiprazole, for negative symptoms (32 015 participants) from −0·62 (−0·84 to −0·39; clozapine) to −0·10 (−0·45 to 0·25; flupentixol), for depressive symptoms (19 683 participants) from −0·90 (−1·36 to −0·44; sulpiride) to 0·04 (−0·39 to 0·47; flupentixol). Risk ratios compared with placebo for all-cause discontinuation (42 672 participants) ranged from 0·52 (0·12 to 0·95; clopenthixol) to 1·15 (0·36 to 1·47; pimozide), for sedation (30 770 participants) from 0·92 (0·17 to 2·03; pimozide) to 10·20 (4·72 to 29·41; zuclopenthixol), for use of antiparkinson medication (24 911 participants) from 0·46 (0·19 to 0·88; clozapine) to 6·14 (4·81 to 6·55; pimozide). Mean differences compared to placebo for weight gain (28 317 participants) ranged from −0·16 kg (−0·73 to 0·40; ziprasidone) to 3·21 kg (2·10 to 4·31; zotepine), for prolactin elevation (21 569 participants) from −77·05 ng/mL (−120·23 to −33·54; clozapine) to 48·51 ng/mL (43·52 to 53·51; paliperidone) and for QTc prolongation (15 467 participants) from −2·21 ms (−4·54 to 0·15; lurasidone) to 23·90 ms (20·56 to 27·33; sertindole). Conclusions for the primary outcome did not substantially change after adjusting for possible effect moderators or in sensitivity analyses (eg, when excluding placebo-controlled studies). The confidence in evidence was often low or very low.InterpretationThere are some efficacy differences between antipsychotics, but most of them are gradual rather than discrete. Differences in side-effects are more marked. These findings will aid clinicians in balancing risks versus benefits of those drugs available in their countries. They should consider the importance of each outcome, the patients' medical problems, and preferences.FundingGerman Ministry of Education and Research and National Institute for Health Research

The differential effects of a focus on symptoms versus recovery in reducing stigma of schizophrenia.

We extend investigations of the impact of the content of video contact with an individual with schizophrenia on stigma reduction. We examine whether differential impacts persist over a 2-week period and the extent to which they are mediated by perceived similarity and feelings of empathy and/or sympathy. We used a randomized control trial wherein participants were exposed to a video in which an individual described his recovery from schizophrenia, or the same person described acute symptoms of schizophrenia, or a no-video control condition. Outcomes included impressions of and preferred social distance to the person in the video and people in general with schizophrenia and well as perceptions of similarity and feelings of sympathy and empathy. We also measured an overt behaviour, seating distance, at 2-week follow-up. The recovery-focused material was generally more effective in improving impressions and reducing preferred level of social distance. Although the symptom-focused video resulted in great sympathy for the person, this did not translate into positive impressions or reduced social distance. Mediational analyses yielded findings consistent with the benefits of the recovery video being mediated by increased perceptions of similarity and lower feelings of sympathy. Exposure to the recovery-focused video resulted in less anxiety in anticipation of meeting the person in the video relative to the control condition. Video contact emphasizing potential for recovery from schizophrenia was more effective in reducing stigmatizing responses than contact highlighting acute symptoms. Increased sympathy does not necessarily translate into reductions in stigma.

P.3.d.039 Paliperidone extended-release monotherapy suggested greater improvement of social functioning than polypharmacy in clinical practice

In this prospective multicentre, open-label, 6-month study (Paliperidone Palmitate Flexible Dosing in Schizophrenia [PALMFlexS]), tolerability, safety and treatment response with paliperidone palmitate (PP) were explored in patients with acute symptoms of schizophrenia following switching from previously unsuccessful treatment with oral antipsychotics. This pragmatic study was conducted in a large, more representative sample of the general schizophrenia population compared to randomized controlled pivotal trials, to specifically mimic real-world clinical situations. After initiation on Day 1 and Day 8, patients received PP once monthly at flexible doses (50–150 mg eq.) intramuscularly. The primary efficacy outcome was defined as the percentage of patients achieving ≥ 30% improvement in PANSS total score from baseline (BL) to last-observation-carried-forward (LOCF) endpoint (EP). Safety and tolerability assessments included Extrapyramidal Symptom Rating Scale (ESRS) total score and treatment-emergent adverse events (TEAEs). Overall, 212 patients received PP at least once after switching from oral antipsychotics, primarily due to lack of efficacy (45.8%). Significant improvements from BL in mean (SD) PANSS total score were observed from Day 8 onwards (BL to LOCF EP: − 31.0 [29.0]; p < 0.0001). At endpoint, two-thirds (66.7%) and 43.5% of patients achieved a ≥ 30% and ≥ 50% improvement in mean PANSS total score, respectively. PP was associated with significant improvements across secondary measures of symptom severity, subjective well-being, medication satisfaction, illness-related disorders of activity and participation, and patient functioning (p < 0.0001; BL to LOCF EP). PP was generally well tolerated, with significant reductions in ESRS total score (p < 0.0001) and mainly mild-to-moderate TEAEs. TEAEs reported in ≥ 5% of patients were injection-site pain (13.7%), insomnia (10.8%), psychotic disorder (10.4%), headache and anxiety (both 6.1%). The PALMFlexS study findings provide valuable pragmatic clinical data on PP treatment in patients with acute schizophrenia previously unsuccessfully treated with oral antipsychotics.

P.3.d.040 Previous oral aripiprazole dose (10 or 30 mg/day): effect on the efficacy and tolerability of aripiprazole once-monthly

In this prospective multicentre, open-label, 6-month study (Paliperidone Palmitate Flexible Dosing in Schizophrenia [PALMFlexS]), tolerability, safety and treatment response with paliperidone palmitate (PP) were explored in patients with acute symptoms of schizophrenia following switching from previously unsuccessful treatment with oral antipsychotics. This pragmatic study was conducted in a large, more representative sample of the general schizophrenia population compared to randomized controlled pivotal trials, to specifically mimic real-world clinical situations. After initiation on Day 1 and Day 8, patients received PP once monthly at flexible doses (50–150 mg eq.) intramuscularly. The primary efficacy outcome was defined as the percentage of patients achieving ≥ 30% improvement in PANSS total score from baseline (BL) to last-observation-carried-forward (LOCF) endpoint (EP). Safety and tolerability assessments included Extrapyramidal Symptom Rating Scale (ESRS) total score and treatment-emergent adverse events (TEAEs). Overall, 212 patients received PP at least once after switching from oral antipsychotics, primarily due to lack of efficacy (45.8%). Significant improvements from BL in mean (SD) PANSS total score were observed from Day 8 onwards (BL to LOCF EP: − 31.0 [29.0]; p < 0.0001). At endpoint, two-thirds (66.7%) and 43.5% of patients achieved a ≥ 30% and ≥ 50% improvement in mean PANSS total score, respectively. PP was associated with significant improvements across secondary measures of symptom severity, subjective well-being, medication satisfaction, illness-related disorders of activity and participation, and patient functioning (p < 0.0001; BL to LOCF EP). PP was generally well tolerated, with significant reductions in ESRS total score (p < 0.0001) and mainly mild-to-moderate TEAEs. TEAEs reported in ≥ 5% of patients were injection-site pain (13.7%), insomnia (10.8%), psychotic disorder (10.4%), headache and anxiety (both 6.1%). The PALMFlexS study findings provide valuable pragmatic clinical data on PP treatment in patients with acute schizophrenia previously unsuccessfully treated with oral antipsychotics.

A 3-Week, Open Label Study to Evaluate the Efficacy and Safety of Extended Release Quetiapine Fumarate in the Treatment of Agitation in Patients with Schizophrenia

Objective: To evaluate the efficacy of extended-release quetiapine fumarate (XR) monotherapy once daily, in the treatment of patients with acute episodes of schizophrenia and agitation.Method: Our study was a 3-week open-label study conducted in adult in- or outpatients with schizophrenia. Quetiapine XR was initiated at 300 mg on day 1,600 mg on day 2, and 400–800 mg (at the investigator's discretion) on day 3 and onwards. The primary endpoint was the change from baseline in the Positive and Negative Syndrome Scale Excited Component (PANSS- EC) score. Secondary endpoints included change from baseline in PANSS-Positive, PANSS-Negative, PANSS-General Psychopathological (PANSS-G) subscale scores, total PANSS score, PANSS aggression, hostility and depression cluster scores, CGI-Severity of illness (CGI-S) and the absolute CGI-Improvement (CGI-I) scales. Tolerability was assessed based on reported adverse events (AEs), the Simpson-Angus Scale (SAS) and Barnes Akathisia Rating Scale (BARS) scores, laboratory measurements and electrocardiograms (ECGs).Results: Of 40 patients enrolled, 35 completed the study. At day 21, statistically significant improvements versus baseline were seen for the primary and all secondary endpoints assessed. The incidence of AEs was low, and all were mild to moderate in severity. No extrapyramidal symptoms (EPS) as measured by the SAS and BARS were reported, indicating that the treatment was well tolerated. Hospitalization was required in one out-patient due to a relapse of psychosis, but was not considered to be treatment related.Conclusion: Once-daily quetiapine fumarate XR (400–800 mg/day) was effective in reducing agitation and a broad range of symptoms in acute schizophrenia. Treatment, including rapid dose escalation, was generally well tolerated in this study.

Effects of the Adverse Life Events and Disrupted in Schizophrenia-1 (DISC1) Gene Polymorphisms on Acute Symptoms of Schizophrenia

The aim of this study was to evaluate the effects of traumatic childhood events and recent adverse life events, as well as the Disrupted in Schizophrenia-1 (DISC1) gene polymorphisms on types of last acute symptoms of patients with schizophrenia. Hundred patients with schizophrenia were given the Childhood Trauma Questionnaire, the Social Readjustment Rating Scale, Scale for Assessment of Positive Symptoms (SAPS), Scale for Assessment of Negative Symptoms (SANS), Brief Psychiatric Rating Scale (BPRS), and Calgary Depression Scale for Schizophrenia (CDSS). The patients' and healthy controls' DISC1 gene was evaluated for the -274G>C, c.791G>A, and c.2110A>T polymorphisms. There was no statistically significant difference with regard to the DISC1 gene polymorphisms between patient and healthy control groups. No significant relationship was found between the -274G>C, c.791G>A, and c.2110A>T haplotypes and development of different acute symptoms of schizophrenia. Having a recent stressful life event significantly affected SAPS (95% confidence interval [CI]=-67.547, -21.473; p=0.00) and BPRS-1 scores (95% CI=-51.405, -6.885; p=0.01), whereas emotional abuse at childhood significantly affected SANS scores (95% CI=-37.300, -10.401; p=0.00). This study shows that features of acute symptoms in schizophrenia are not influenced by the polymorphisms on the DISC1 gene, but are influenced by recent adverse life events and emotional abuse at childhood.

Enhanced MK-801-induced locomotion in Kir6.2 knockout mice

ATP-sensitive K+ (K-ATP) channels provide a unique link between cellular energetics and electrical excitability, and also act as a unifying molecular coordinator of the body's response to stress. Although the body's response to stress is implicated in the worsening or relapse of psychotic symptoms in schizophrenia, the role of K-ATP channels remains unclear. Therefore, the aim of the current study was to investigated the effect of K-ATP channels on schizophrenia-like symptoms induced by MK-801 using Kir6.2 (one pore-forming subunit of K-ATP) knockout mice. We demonstrated that Kir6.2 knockout enhanced locomotor activity significantly compared to the wild-type mice after MK-801 administration. Moreover, we found that depletion of Kir6.2 significantly increased the numbers of Arc-positive cells in cortex, hippocampus and striatum in basal state. MK-801 augmented the Arc expression in wild-type mice. Collectively, our findings in this study indicate that K-ATP channels are involved in the regulation of MK-801-induced acute symptoms of schizophrenia, which is associated with the neural excitability. In addition, our results may provide valuable information for the development of new treatments for schizophrenia.

The positive symptoms of acute schizophrenia and latent inhibition in humans and animals: Underpinned by the same process(es)?

Introduction. It has been suggested that the positive symptoms of acute schizophrenia are a consequence of a disruption of the process that produces latent inhibition (slower acquisition of conditioned responding after preexposure to the conditioned stimulus) and that this effect can be modelled by pro- and antipsychotic compounds in healthy participants and in nonhuman animals. This idea assumes that latent inhibition in humans and animals is underpinned by the same process(es). Method. First, we question the equivalence of human and animal latent inhibition. Second, we review the studies that have examined latent inhibition in populations with schizophrenia and in healthy populations after administration of amphetamine or haloperidol. Results. Theoretical analysis of the similarities and differences in latent inhibition effects, and the procedures used to generate them, in humans and animals renders the suggested equivalence between them unconvincing. The studies examining latent inhibition in populations with schizophrenia and in healthy populations after administration of amphetamine or haloperidol are marked by a number of methodological shortcomings and reveal discrepant results. Conclusions. The theoretical and empirical analyses provide little support for a common process underlying deficits of latent inhibition in patients exhibiting positive symptoms of acute schizophrenia, and such deficits in experimental models in healthy humans and infrahumans.

Iloperidone—A Second-Generation Antipsychotic for the Treatment of Acute Schizophrenia

Objective: To review the pharmacology, efficacy, and tolerability of iloperidone, a second-generation antipsychotic, in the treatment of acute schizophrenia in adults. Data Sources: English-language articles were obtained via MEDLINE (1966-March 2010) and International Pharmaceutical Abstracts (1970-March 2010) searches using the key words iloperidone, acute schizophrenia, atypical antipsychotics, second-generation antipsychotics, HP 873, P88–8991, P95–12113, and Fanapt. Bibliographies of selected articles were used to identify additional sources. Study Selection and Data Extraction: Available published articles reporting the results of human studies of iloperidone were reviewed for inclusion in this article. Additional information regarding pharmacology, adverse events, contraindications, and precautions was obtained from the manufacturer's prescribing information. Data Synthesis: Iloperidone is a second-generation antipsychotic approved for the treatment of acute schizophrenia in adults. Iloperidone is well absorbed upon oral administration, highly protein bound, and metabolized primarily by CYP3A4 and 2D6. Phase 3 clinical trials evaluating the efficacy of iloperidone demonstrated significantly higher response rates with iloperidone compared with placebo in the treatment of positive, negative, and cognitive symptoms associated with acute schizophrenia when the drug was given in doses up to 24 mg daily. Dizziness, dry mouth, and nausea were the most commonly reported adverse events and appear to be dose related. Additional adverse events occurring in 5% or more of patients include orthostatic hypotension, somnolence, tachycardia, fatigue, nasal congestion, and weight increase. Iloperidone should be titrated slowly over a 7-day interval to avoid the potential for orthostatic hypotension. Product labeling includes a black box warning against the use of iloperidone in dementia-related psychosis and precautions regarding QT interval prolongation. Conclusions: Iloperidone is an effective treatment for the symptoms of acute schizophrenia in adults. Additional studies are needed to assess comparative effectiveness with other pharmacologic treatments of schizophrenia, long-term efficacy, and long-term safety.

Hostility of drug-free patients with schizophrenia and n− 3 polyunsaturated fatty acid levels in red blood cells

Many reports suggest that n− 3 polyunsaturated fatty acids (PUFAs) influence the symptoms of psychiatric disorders. Moreover, it has also been reported that n− 3 PUFAs control aggression and hostility. Acute symptoms of schizophrenia such as aggression can be a formidable clinical problem resulting in hospitalization. However, few investigations have determined the relationships between acute symptoms of drug-free schizophrenia and n− 3 PUFAs. We recruited 75 inpatients with acute drug-free schizophrenia admitted to Chiba Psychiatric Medical Center, an emergency psychiatric hospital. Blood was sampled immediately after admission. The red blood cell (RBC) fatty acid composition and hostility score of Positive and Negative Syndrome Scale (PANSS) scores were measured. Multiple regression analysis showed that the concentrations of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and the ratio of EPA/arachidonic acid (AA) in RBC showed significant negative correlations with the hostility score of PANSS scores after adjustment for age and sex. AA, on the other hand, showed significant positive correlations. The tissue n− 3 PUFA and n− 6 PUFA levels were negatively and positively associated with the hostility score of PANSS scores, respectively, suggesting possible effects of PUFA levels on hostile behavior in patients with schizophrenia.

Measuring social functioning with the personal and social performance scale in patients with acute symptoms of schizophrenia: Interpretation of results of a pooled analysis of three Phase III trials of paliperidone extended-release tablets

Background: The safety and efficacy of paliperidone extended-release tablets (paliperidone ER) in patients with acute symptoms of schizophrenia have been described in 3 randomized, double-blind, 6-week, placebo-controlled, fixed-dose, Phase III clinical trials. The validity and reliability of the Personal and Social Performance (PSP) scale, both in patients with acute symptoms of schizophrenia and those with stabilized symptoms, have also been reported. Objective: The aim of this work was to estimate the treatment benefit of paliperidone ER compared with placebo in terms of improvements in personal and social functioning as measured by the PSP scale in 3 controlled clinical trials. Methods: Data were derived from 3 paliperidone ER multicenter Phase III pivotal studies of patients with acute symptoms of schizophrenia. Each study included a randomized, double-blind, placebo- and active-controlled, parallel-group, 6-week treatment period with an open-label extension of paliperidone ER treatment. Patients were randomized to receive paliperidone ER, olanzapine 10 mg, or placebo once daily. Paliperidone ER doses were 3, 9, and 15 mg/d in 1 study; 6, 9, and 12 mg/d in another; and 6 and 12 mg/d in the third. Collectively, 1306 intent-to-treat patients received placebo or paliperidone ER in these 3 trials. Most (61.7%) were white; 21.6% were black, 8.8% were Asian, and 7.9% were of another race. The mean age ranged from 36.3 to 39.4 years across treatment groups. Multiple analyses were applied to PSP data (for which higher scores indicate better personal and social functioning) from these paliperidone ER studies: between-group minimum important difference (MID) estimates; responder analyses; between-group cumulative frequency comparisons of PSP change from baseline to end point; and number-needed-to-treat (NNT) estimates. Results: Standardized differences and effect sizes between paliperidone ER and placebo in PSP mean change from baseline to end point ranged from 0.52 to 0.85 for all paliperidone ER doses. Observed between-group differences (paliperidone ER minus placebo) in PSP mean change from baseline to end point exceeded the between-group MID of 7 points at all paliperidone ER doses. The percentage of patients achieving at least one 10-point category improvement in the PSP was higher with all paliperidone ER doses (range, 49.6%–63.6%) than placebo (33.1%) ( P < 0.005). Across the distribution of all possible PSP scores, the percentage of patients achieving any level of change appeared to be greater for paliperidone ER than for placebo at all doses. Derived NNTs for improved personal and social functioning based on paliperidone ER trials ranged from 3.3 to 6.1. The improvement in personal and social functioning achieved by patients receiving paliperidone ER during the double-blind studies was maintained throughout the 52-week, open-label extension studies, as assessed using multiple definitions of response; subjects in the placebo arm during doubleblind treatment appeared to achieve and maintain improved functioning when switched to paliperidone ER for the extension studies. Conclusion: These results suggest that paliperidone ER had a meaningful treatment benefit with respect to improving personal and social functioning in these patients with acute symptoms of schizophrenia.

The role of effort, cognitive expectancy appraisals and coping style in the maintenance of the negative symptoms of schizophrenia

The aim of the present study was to assess the role of psychological factors, specifically effort, coping, and negative expectancy appraisals, in addition to executive functioning and depression, in accounting for negative symptoms broadly defined. Fifty inpatients with acute schizophrenia participated in a study with a cross-sectional design. All of the psychological variables had significant partial correlations with some of the measures of negative symptoms when depression was controlled. A series of multiple regression analyses indicated that executive functioning only made a significant unique contribution to the prediction of affective flattening, whereas psychological factors made unique contributions to the variance in each of the negative symptom subscales apart from affective flattening, as well as to the negative symptom total score, accounting for 9% to 19% of the variance. These results suggest that, in addition to neuropsychological variables, psychological variables are important for understanding negative symptoms in acute schizophrenia.

Reliability, validity and ability to detect change of the clinician-rated Personal and Social Performance scale in patients with acute symptoms of schizophrenia

ABSTRACTObjective: To describe the measurement properties of the Personal and Social Performance scale (PSP), a clinician-reported measure of severity of personal and social dysfunction, in subjects with acute symptoms of schizophrenia.Methods: Pooled data from three paliperidone extended-release clinical studies (n = 1665) and data from a separate noninterventional, cross-sectional, validation study (n = 299) were analyzed.Results: The PSP showed good interrater (intraclass correlation coefficient [ICC] = 0.87) and test–retest (ICCs > 0.90) reliability. Pearson correlation coefficient for association between baseline PSP and Positive and Negative Syndrome Scale (PANSS) total scores was −0.32 for subjects assessed by the same rater and −0.29 for subjects assessed by different raters, suggesting low overlap in measurement constructs between the PANSS and PSP. Spearman Rank correlation coefficient for association between baseline PSP and Clinical Global Impression-Severity (CGI-S) scores was −0.51 with the same rater and −0.15 with different raters. Hypothesized relationships between the PSP and the PANSS or CGI-S based on levels of disease severity were prospectively defined. These hypotheses were confirmed by analyses showing statistically significant differences between baseline mean PSP scores in subjects grouped by severity rating on the CGI-S (mild or less vs. at least moderate) (p < 0.001) and the PANSS (‘low symptom severity’ vs. ‘high symptom severity’) (p = 0.005). The PSP was sensitive to change based on statistically significant correlations between change in the PSP and change in the CGI-S (p < 0.001) and the PANSS (p < 0.001). Limitations of analyses include pooling data across studies, interrater reliability assessment in the validation study only, post hoc assessment of test–retest reliability in the paliperidone ER studies, different raters for the PSP and PANSS not specified in the paliperidone ER studies, PSP validity assessment based on the PANSS and the CGI-S as comparators rather than another social function instrument.Conclusion: These initial reliability and validity assessments suggest the PSP has promise as a measure of social functioning in patients with acute symptoms of schizophrenia.