Treatment Of Acute Schizophrenia Research Articles

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.

High- v. low-dose quetiapine in schizophrenia: meta-analysis

Aims and methodTo study the difference between high- and low-dose quetiapine in acute treatment of schizophrenia. Data available from published double-blind fixed-dose trials were combined and analysed.ResultsThere was no statistically significant difference between high- (750–800 mg/day) and low-dose (300–400 mg/day) quetiapine in terms of the response rate, change in positive symptoms score and the discontinuation rates either as a result of lack of response or adverse effects.Clinical implicationsCombined evidence from fixed-dose trials does not support the prevalent practice of targeting the higher dose of quetiapine for optimal treatment response in schizophrenia.

Iloperidone for the treatment of schizophrenia

Iloperidone is a recently approved antipsychotic agent indicated for the acute treatment of schizophrenia in adults. Iloperidone is characterized as a serotonin 5-HT(2A) and dopamine D(2) receptor antagonist, which makes its core mechanism of action similar to other second-generation antipsychotic agents. The affinity (or lack thereof) of iloperidone for other receptors (e.g., histamine, muscarinic, α(1)-adrenoceptors, serotonin) results in a unique side effect and perhaps response profile that may make it an additional option for patients who have previously not tolerated or adequately responded to other available agents. Iloperidone has been studied in over 3,200 patients throughout its development. Its efficacy appears to be similar to haloperidol, risperidone and ziprasidone. It appears to be safe with minimal extrapyramidal side effects, weight gain and prolactin elevation. A cautious dosing and titration schedule is recommended at the initiation of therapy due to the potential for orthostatic hypotension and dizziness. Drug interactions through the CYP3A4 and CYP2D6 enzymes, along with the potential for QT prolongation, may influence its use in certain patients. Genetic studies conducted during drug development may facilitate the clinical use of pharmacogenomic tests to aid clinicians in optimizing the risk-benefit ratio of iloperidone. The purpose of this review is to summarize the chemistry, pharmacology and clinical aspects of iloperidone, with the goals of identifying key scientific and clinical issues for its use, as well as assessing the potential utility of iloperidone for the treatment of schizophrenia.

Iloperidone: a new option for the treatment of schizophrenia

Schizophrenia is a debilitating condition associated with high morbidity and mortality. While currently available atypical antipsychotic agents have significantly advanced the treatment of schizophrenia, there is still a great unmet need for new, effective and better-tolerated therapies. Iloperidone, a D2/5-HT2 receptor antagonist, has been recently approved by the US FDA for the acute treatment of schizophrenia in adults. Iloperidone has been shown to be effective in the treatment of schizophrenia in four short-term (4–6 weeks) and three long-term (52 weeks) studies with over 3000 patients exposed to treatment. Results also indicated a reassuring safety profile, particularly regarding extrapyramidal symptoms, akathisia and prolactin elevation, with a modest effect on weight gain and no medically important changes in cholesterol, triglycerides and glucose. As other antipsychotics, iloperidone has been shown to prolong the QTc interval. Since none of the current therapies work for every patient, a pharmacogenetic approach was used to identify genetic markers associated with increased response to iloperidone, suggesting a personalized therapeutic option for this drug. In addition, a long-term 4-week injectable formulation is being developed that may assist with patient compliance. Key development findings for iloperidone are presented here.

Asenapine for schizophrenia and bipolar disorder: a review of the efficacy and safety profile for this newly approved sublingually absorbed second-generation antipsychotic

To describe the efficacy and safety of asenapine for the treatment of schizophrenia and bipolar disorder. The pivotal registration trials were accessed by querying http://www.pubmed.gov, http://www.fda.gov and http://www.clinicaltrials.govfor the search terms 'asenapine' or 'ORG 5222'. All available clinical reports of studies were identified, as well as preclinical animal and receptor affinity studies that describe potential mechanisms of action. Extensive documents available from the US Food and Drug Administration and Schering-Plough Corporation as posted on http://www.fda.gov provided much of this data. Product labelling also provided additional information. Descriptions of the principal results and calculation of number needed to treat (NNT) and number needed to harm (NNH) for relevant dichotomous outcomes were extracted from the study reports and synopses. Additional safety outcomes subject to NNH analysis were obtained from product labelling. A sublingual formulation of asenapine has received regulatory approval for the acute treatment of schizophrenia and manic/mixed episodes of bipolar I disorder. Bioavailability is 35% when taken sublingually, but < 2% if ingested. Similar to other second-generation antipsychotics, asenapine's binding profile includes 5-HT2A and D2 antagonism. Binding at the alpha-1 adrenergic and histamine H1 receptors predicts asenapine's propensity to cause orthostasis and sedation in some patients. Efficacy in the treatment of acute schizophrenia is supported by 2 of 4 completed phase II/III randomised, placebo and active-controlled 6-week trials, principally at a dose of 5 mg bid. Responder analysis for one of the studies reveals a NNT of asenapine vs. placebo of six for response as defined by a minimum of a 20% decrease in the Positive and Negative Syndrome Scale total score from baseline, and a NNT of 8 for the threshold of a 30% decrease. Efficacy in the treatment of manic or mixed episodes of bipolar I disorder is supported by 2 of 2 completed phase III randomised, placebo and active-controlled 3-week trials and by a 9-week extension trial. The dose tested in the bipolar trials was 10 mg bid. Longer-term studies have been completed in patients with schizophrenia or bipolar disorder, but complete results have not yet been published. Asenapine has a relatively favourable tolerability profile. For the patients with schizophrenia, the NNH values for asenapine vs. placebo for commonly observed adverse reactions were 13 (95% CI 8-30) for akathisia (10 mg bid), 20 (95% CI 13-50) for oral hypoesthesia (5 mg bid) and 13 (95% CI 8-32) for somnolence (5 mg bid). For patients with bipolar disorder, the NNH values for asenapine 5-10 mg bid vs. placebo were 6 (95% CI 5-9) for somnolence, 13 (95% CI 9-25) for dizziness, 20 (95% CI 13-56) for extra-pyramidal symptoms (EPS) other than akathisia and 25 (95% CI 16-71) for increased weight. Asenapine is associated with a lower frequency for EPS than haloperidol. Asenapine has a mild effect on the ECG QT interval similar to that seen with quetiapine. Asenapine's effect on prolactin is similar to that observed with olanzapine. Asenapine has a more favourable weight gain and metabolic profile compared with olanzapine. Asenapine sublingual tablets are a new option for the treatment of acute episodes of schizophrenia and for the treatment of acute manic or mixed episodes of bipolar I disorder. Although there is no evidence for asenapine's efficacy to be superior to currently available agents, asenapine's favourable weight and metabolic profile are of clinical interest. A caveat is that the data reviewed regarding asenapine are from its manufacturer. No independent studies of asenapine's efficacy or safety are available. Obstacles to the use of asenapine are the recommendations for twice daily dosing and the need to avoid food or liquids for 10 min after administration. As asenapine's bioavailability is very low if ingested, asenapine is unique among the antipsychotics, in that it needs to be swallowed to be covertly 'cheeked'.

Iloperidone

Iloperidone is an atypical antipsychotic that is approved for the treatment of adult patients with schizophrenia. In several large (n > 570 per trial), 4- or 6-week, double-blind, multinational, multicentre trials in adult patients with schizophrenia, recommended target dosages of oral iloperidone (6-12 mg twice daily) generally showed better efficacy than placebo, in terms of improvements in Positive and Negative Syndrome Scale (PANSS) total scores or Brief Psychiatric Rating Scale (BPRS) scores (primary endpoints) and also for most secondary endpoints, including PANSS subscale scores. In addition, pharmacogenomic studies identified single nucleotide polymorphisms (SNPs) that were associated with an enhanced response to iloperidone during acute treatment of schizophrenia. More limited data also support the role of these SNPs in enhancing responses to iloperidone during longer-term treatment. In a pooled analysis of three 52-week, double-blind, multinational, multicentre trials (n = 473), iloperidone treatment was shown to be equivalent to that with haloperidol, based on Kaplan-Meier estimates of the time to relapse (primary endpoint). Iloperidone was generally well tolerated and was associated with few extrapyramidal symptoms or changes in metabolic parameters in short- and longer-term clinical trials in adult patients with schizophrenia.

Asenapine approved for treatment of schizophrenia, bipolar disorder

FDA and Schering-Plough Corporation on August 14 announced the approval of asenapine sublingual tablets for the acute treatment of schizophrenia and manic or mixed episodes associated with bipolar I disorder in adults. Schering-Plough expects the atypical antipsychotic drug to be available during

The Efficacy and Safety of Blonanserin Compared with Haloperidol in Acute-Phase Schizophrenia

Blonanserin is a novel atypical antipsychotic agent with potent dopamine D(2) and serotonin 5-HT(2) antagonist properties. It may potentially have a lower incidence of adverse events than other antipsychotic agents. To determine the efficacy and safety of three doses of blonanserin compared with placebo and haloperidol in patients with acute-phase schizophrenia. This was a 6-week, randomized, double-blind, placebo- and haloperidol-controlled, international, multicentre study. Patients with an acute exacerbation of their schizophrenia, with a Positive and Negative Syndrome Scale (PANSS) score >/=70 and a Clinical Global Impression - Severity of Illness (CGI-S) score >/=4 ('moderately ill') [with no decrease >/=20% or >/=1 point, respectively, during the wash-out period] were randomized into one of five treatment groups (blonanserin 2.5, 5 or 10 mg, haloperidol 10 mg or placebo once daily). Patients were assessed weekly for clinical efficacy, adverse events, extrapyramidal symptoms (EPS) and drug compliance, and were assessed biweekly for other safety variables. All 307 randomized patients received at least one dose of study medication and 228 (74.3%) completed the study. The mean reduction in PANSS total score at week 6 was significantly greater with all active treatments compared with placebo (-12.58; p < 0.001); blonanserin 10 mg was significantly superior to blonanserin 2.5 mg (-30.18 vs -20.6; p < 0.001), but blonanserin 5 mg (-27.19) and haloperidol 10 mg (-28.16) were not. All active treatments showed greater efficacy against the positive symptoms of schizophrenia, and blonanserin (5 and 10 mg) was more effective against the negative symptoms than haloperidol. Blonanserin was well tolerated at all doses and there was no evidence of clinically important weight gain, orthostatic hypotension, corrected QT interval prolongation or clinically relevant changes in laboratory test results. Haloperidol caused persistent elevation in prolactin levels, but this was not seen with any dose of blonanserin throughout the study period. There was a lower incidence of EPS with blonanserin 10 mg (26.6%) than with haloperidol 10 mg (53.3%). Blonanserin was effective in the treatment of acute schizophrenia and showed greater efficacy in negative symptoms compared with placebo and haloperidol. Blonanserin was well tolerated and its safety profile compared favourably with haloperidol, particularly with respect to prolactin elevation and EPS frequency.

Lurasidone in the Treatment of Acute Schizophrenia

Lurasidone is a novel psychotropic agent with high affinity for D(2) and 5-HT(2A) receptors, as well as for receptors implicated in the enhancement of cognition and mood and the reduction of negative symptoms (5-HT(7), 5-HT(1A), and alpha(2c)). The objective of the study was to evaluate the safety and efficacy of lurasidone in patients hospitalized for an acute exacerbation of DSM-IV-defined schizophrenia. Patients were randomly assigned to 6 weeks of double-blind treatment with a fixed dose of lurasidone 80 mg (N = 90, 75.6% male, mean age = 39.7 years, mean baseline score on the Brief Psychiatric Rating Scale derived from the Positive and Negative Syndrome Scale [BPRSd] = 55.1) or placebo (N = 90, 77.8% male, mean age = 41.9 years, mean BPRSd score = 56.1). The primary efficacy measure was the BPRSd. The study was conducted from May to December 2004. At day 42, last-observation-carried-forward endpoint, treatment with lurasidone was associated with significant improvement compared to placebo on the BPRSd (least squares mean +/- SE = -8.9 +/- 1.3 vs. -4.2 +/- 1.4; p = .012), as well as on all secondary efficacy measures, including the PANSS total score (-14.1 +/- 2.1 vs. -5.5 +/- 2.2; p = .004) and the PANSS positive (-4.3 +/- 0.7 vs. -1.7 +/- 0.7; p = .006), negative (-2.9 +/- 0.5 vs. -1.3 +/- 0.5; p = .025), and general psychopathology (-7.0 +/- 1.1 vs. -2.7 +/- 1.2; p = .0061) subscales. Significant improvement was seen as early as day 3, based on BPRSd, PANSS, and Clinical Global Impressions-Severity of Illness assessments. Treatment with lurasidone was generally well tolerated and was not associated with adverse changes in metabolic or electrocardiogram parameters. There were no clinically significant differences between lurasidone and placebo in objective measures of extrapyramidal symptoms. The results of this study suggest that the novel psychotropic agent lurasidone is a safe and effective treatment for patients with an acute exacerbation of schizophrenia. (ClinicalTrials.gov) Identifier: NCT00088634.

Quetiapine Extended Release

Quetiapine is an atypical antipsychotic agent with well established efficacy and tolerability in the acute and maintenance treatment of adults with schizophrenia. The extended-release formulation of quetiapine (quetiapine XR) was developed to provide more convenient once-daily administration, as well as allowing simple and rapid dose escalation, with the aim of improving compliance (known to be a substantial issue in patients with schizophrenia). In several short-term clinical trials, oral quetiapine XR 400-800 mg once daily was generally effective across a range of symptoms in the acute treatment of schizophrenia. As a long-term maintenance treatment, quetiapine XR prevented relapse in patients with stable disease, with significantly longer times to relapse in patients treated with quetiapine XR compared with placebo. Quetiapine XR was generally well tolerated in clinical trials. According to pooled results from three 6-week trials, events occurring in >or=5% of quetiapine XR recipients with an incidence>or=2-fold that seen in placebo recipients were dry mouth, somnolence and dizziness. A generally low incidence of extrapyramidal symptoms (EPS) is seen in quetiapine XR recipients. The most common potentially EPS-associated adverse events seen with quetiapine treatment were akathisia, restlessness and tremor. Rates of worsening of Simpson-Angus Scale and Barnes Akathisia Rating Scale scores were not dissimilar among quetiapine XR, quetiapine immediate release and placebo.

Efficacy and safety of oral paliperidone extended-release tablets in the treatment of acute schizophrenia: pooled data from three 52-week open-label studies

Long-term efficacy and safety of paliperidone extended-release tablets (3-12 mg/day) were evaluated in pooled data from 52-week open-label extension (OLE) phases of three 6-week, placebo-controlled, double-blind (DB) trials involving 1083 schizophrenia patients. Forty-seven percent of patients completed the OLE phase. Outcome measures included Positive and Negative Syndrome Scale and Personal and Social Performance scale scores. Improvements observed on both scales in active treatment groups during the DB phases were maintained during the OLE phase. Most commonly (> or =10% patients) reported adverse events (AEs) were insomnia, headache, and akathisia. One or more serious AEs were reported by 16% of patients; two patients had a treatment-emergent AE that resulted in death (suicide). Extrapyramidal symptom-related AEs were reported by 25% of patients. Median maximum movement disorder rating scale scores indicated no severity change during the OLE. Mean (+/-SD) increase in body weight from OLE baseline to end point was 1.1+/-5.47 kg across treatment groups and there were no clinically meaningful changes for plasma glucose, insulin or lipid levels. This analysis shows that paliperidone extended-release can maintain improvements in symptoms and functioning and is generally well tolerated for up to 52 weeks in schizophrenia patients.

Olanzapine pamoate: a stick in time?

Olanzapine pamoate, a long-acting depot preparation of olanzapine, is being evaluated by regulatory agencies for the treatment of schizophrenia. Clinical trial information was accessed by on-line query of http://www.pubmed.gov, http://www.clinicaltrials.gov and http://www.fda.gov, along with an examination of poster presentations at scientific meetings held in 2008. Two double-blind randomised clinical trials of olanzapine pamoate were conducted and demonstrate efficacy for both the acute treatment of schizophrenia and for the maintenance of antipsychotic response. Long-term open-label studies provide additional information on safety. The overall tolerability profile for olanzapine pamoate is similar to that for the oral formulation; however, with the depot there is a risk of a postinjection delirium sedation syndrome which resembles an overdose of oral olanzapine and which occurs in 0.07% of injections, requiring patients to be observed for 3 h after injection. At present, there are no studies available that directly compare olanzapine pamoate with other antipsychotics other than oral olanzapine.

GENDER DIFFERENCES IN PREMORBID, ENTRY, TREATMENT, AND OUTCOME CHARACTERISTICS IN A TREATED EPIDEMIOLOGICAL SAMPLE OF 661 PATIENTS WITH FIRST EPISODE PSYCHOSIS

The question of which antipsychotic drug should be preferred for the treatment of schizophrenia is controversial, and conventional pairwise meta-analyses cannot provide a hierarchy based on the randomised evidence. We aimed to integrate the available evidence to create hierarchies of the comparative efficacy, risk of all-cause discontinuation, and major side-effects of antipsychotic drugs.We did a Bayesian-framework, multiple-treatments meta-analysis (which uses both direct and indirect comparisons) of randomised controlled trials to compare 15 antipsychotic drugs and placebo in the acute treatment of schizophrenia. We searched the Cochrane Schizophrenia Group's specialised register, Medline, Embase, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov for reports published up to Sept 1, 2012. Search results were supplemented by reports from the US Food and Drug Administration website and by data requested from pharmaceutical companies. Blinded, randomised controlled trials of patients with schizophrenia or related disorders were eligible. We excluded trials done in patients with predominant negative symptoms, concomitant medical illness, or treatment resistance, and those done in stable patients. Data for seven outcomes were independently extracted by two reviewers. The primary outcome was efficacy, as measured by mean overall change in symptoms. We also examined all-cause discontinuation, weight gain, extrapyramidal side-effects, prolactin increase, QTc prolongation, and sedation.We identified 212 suitable trials, with data for 43 049 participants. All drugs were significantly more effective than placebo. The standardised mean differences with 95% credible intervals were: clozapine 0·88, 0·73–1·03; amisulpride 0·66, 0·53–0·78; olanzapine 0·59, 0·53–0·65; risperidone 0·56, 0·50–0·63; paliperidone 0·50, 0·39–0·60; zotepine 0·49, 0·31–0·66; haloperidol 0·45, 0·39–0·51; quetiapine 0·44, 0·35–0·52; aripiprazole 0·43, 0·34–0·52; sertindole 0·39, 0·26–0·52; ziprasidone 0·39, 0·30–0·49; chlorpromazine 0·38, 0·23–0·54; asenapine 0·38, 0·25–0·51; lurasidone 0·33, 0·21–0·45; and iloperidone 0·33, 0·22–0·43. Odds ratios compared with placebo for all-cause discontinuation ranged from 0·43 for the best drug (amisulpride) to 0·80 for the worst drug (haloperidol); for extrapyramidal side-effects 0·30 (clozapine) to 4·76 (haloperidol); and for sedation 1·42 (amisulpride) to 8·82 (clozapine). Standardised mean differences compared with placebo for weight gain varied from −0·09 for the best drug (haloperidol) to −0·74 for the worst drug (olanzapine), for prolactin increase 0·22 (aripiprazole) to −1·30 (paliperidone), and for QTc prolongation 0·10 (lurasidone) to −0·90 (sertindole). Efficacy outcomes did not change substantially after removal of placebo or haloperidol groups, or when dose, percentage of withdrawals, extent of blinding, pharmaceutical industry sponsorship, study duration, chronicity, and year of publication were accounted for in meta-regressions and sensitivity analyses.Antipsychotics differed substantially in side-effects, and small but robust differences were seen in efficacy. Our findings challenge the straightforward classification of antipsychotics into first-generation and second-generation groupings. Rather, hierarchies in the different domains should help clinicians to adapt the choice of antipsychotic drug to the needs of individual patients. These findings should be considered by mental health policy makers and in the revision of clinical practice guidelines.None.

Efficacy and Tolerability of Oral Paliperidone Extended-Release Tablets in the Treatment of Acute Schizophrenia

To evaluate the efficacy and safety of an extended-release (ER) formulation of paliperidone in patients with an acute episode of schizophrenia, in the dosage range of 3 to 15 mg daily. A pooled analysis of 3 similarly designed 6-week, multicenter, double-blind, randomized, fixed-dose, placebo-controlled studies in 1326 patients with acute schizophrenia (Positive and Negative Syndrome Scale [PANSS] total score of 70-120) was performed. Patients were randomly assigned to receive 3, 6, 9, 12, or 15 mg daily of paliperidone ER or placebo. Efficacy and safety assessments were performed. The primary endpoint was change in PANSS total score from baseline to endpoint. PANSS total, PANSS subscale factor, and Personal and Social Performance scale scores significantly improved at endpoint for all doses of paliperidone ER relative to placebo (p <or= .001). A significantly greater proportion of paliperidone ER-treated patients at all doses achieved a clinical response compared with placebo (p <or= .001). Treatment-emergent adverse events (TEAEs) occurred in 66% to 77% of patients in the paliperidone ER groups and 66% of patients in the placebo group; serious TEAEs occurred in 6% of patients who received placebo and 5% to 6% of paliperidone ER-treated patients. Regardless of treatment group, median Simpson-Angus Rating Scale global, Abnormal Involuntary Movement Scale total, and Barnes Akathisia Rating Scale scores were 0 at both baseline and endpoint. There were no clinically relevant differences in measures of body weight gain, glucose handling, lipid metabolism, or proportion of patients with abnormal corrected QT intervals on electrocardiography and no important differences between the proportion of patients who received paliperidone ER or placebo who reported potentially glucose- or prolactin-related events. Paliperidone ER given once daily for 6 weeks appears to be a safe, well-tolerated, and effective treatment for patients with acute schizophrenia.

325 – Costs and outcomes associated with atypical antipsychotic treatment of acute schizophrenia

325 – Costs and outcomes associated with atypical antipsychotic treatment of acute schizophrenia

Asenapine,* administered as a fast-dissolving sublingual tablet, appears to be effective for the treatment of acute schizophrenia,

Asenapine,* administered as a fast-dissolving sublingual tablet, appears to be effective for the treatment of acute schizophrenia,

Comparison of ziprasidone and aripiprazole in acutely ill patients with schizophrenia or schizoaffective disorder: a randomized, double-blind, 4-week study

We compared the efficacy and safety of ziprasidone and aripiprazole in the treatment of acutely ill patients with schizophrenia. Patients were randomized to receive double-blind treatment with ziprasidone (80-160 mg/day), or aripiprazole (10-30 mg/day) for up to 4 weeks. Primary efficacy measures were the Clinical Global Impression of Severity scale (CGI-S) and Brief Psychiatric Rating Scale (BPRSd) total (derived from the Positive and Negative Syndrome Scale). Noninferiority for ziprasidone (N=125) relative to aripiprazole (N=128) was established for CGI-S score (P=0.007), but was not confirmed for BPRSd total score (P=0.248). Effect sizes for within-group improvement, however, were robust for both ziprasidone and aripiprazole (effect size range 1.0-1.1 for CGI-S; and range 1.1-1.2 for BPRSd total). A mixed model repeated measures analysis of BPRSd total score favored ziprasidone at day 4 compared with aripiprazole (P=0.04), with no significant differences between treatment groups at other visits (P=0.001 for interaction between treatment and visit). No statistically significant difference was found in CGI-S score between groups across all visits. Our findings suggest that ziprasidone and aripiprazole exhibit similar efficacy and tolerability profiles in the treatment of acute schizophrenia. Differences between the two drugs in the onset of therapeutic effect warrant further investigation.

C.15.05 Schizophrenia: antipsychotics in the acute phase and beyond

The question of which antipsychotic drug should be preferred for the treatment of schizophrenia is controversial, and conventional pairwise meta-analyses cannot provide a hierarchy based on the randomised evidence. We aimed to integrate the available evidence to create hierarchies of the comparative efficacy, risk of all-cause discontinuation, and major side-effects of antipsychotic drugs.We did a Bayesian-framework, multiple-treatments meta-analysis (which uses both direct and indirect comparisons) of randomised controlled trials to compare 15 antipsychotic drugs and placebo in the acute treatment of schizophrenia. We searched the Cochrane Schizophrenia Group's specialised register, Medline, Embase, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov for reports published up to Sept 1, 2012. Search results were supplemented by reports from the US Food and Drug Administration website and by data requested from pharmaceutical companies. Blinded, randomised controlled trials of patients with schizophrenia or related disorders were eligible. We excluded trials done in patients with predominant negative symptoms, concomitant medical illness, or treatment resistance, and those done in stable patients. Data for seven outcomes were independently extracted by two reviewers. The primary outcome was efficacy, as measured by mean overall change in symptoms. We also examined all-cause discontinuation, weight gain, extrapyramidal side-effects, prolactin increase, QTc prolongation, and sedation.We identified 212 suitable trials, with data for 43 049 participants. All drugs were significantly more effective than placebo. The standardised mean differences with 95% credible intervals were: clozapine 0·88, 0·73–1·03; amisulpride 0·66, 0·53–0·78; olanzapine 0·59, 0·53–0·65; risperidone 0·56, 0·50–0·63; paliperidone 0·50, 0·39–0·60; zotepine 0·49, 0·31–0·66; haloperidol 0·45, 0·39–0·51; quetiapine 0·44, 0·35–0·52; aripiprazole 0·43, 0·34–0·52; sertindole 0·39, 0·26–0·52; ziprasidone 0·39, 0·30–0·49; chlorpromazine 0·38, 0·23–0·54; asenapine 0·38, 0·25–0·51; lurasidone 0·33, 0·21–0·45; and iloperidone 0·33, 0·22–0·43. Odds ratios compared with placebo for all-cause discontinuation ranged from 0·43 for the best drug (amisulpride) to 0·80 for the worst drug (haloperidol); for extrapyramidal side-effects 0·30 (clozapine) to 4·76 (haloperidol); and for sedation 1·42 (amisulpride) to 8·82 (clozapine). Standardised mean differences compared with placebo for weight gain varied from −0·09 for the best drug (haloperidol) to −0·74 for the worst drug (olanzapine), for prolactin increase 0·22 (aripiprazole) to −1·30 (paliperidone), and for QTc prolongation 0·10 (lurasidone) to −0·90 (sertindole). Efficacy outcomes did not change substantially after removal of placebo or haloperidol groups, or when dose, percentage of withdrawals, extent of blinding, pharmaceutical industry sponsorship, study duration, chronicity, and year of publication were accounted for in meta-regressions and sensitivity analyses.Antipsychotics differed substantially in side-effects, and small but robust differences were seen in efficacy. Our findings challenge the straightforward classification of antipsychotics into first-generation and second-generation groupings. Rather, hierarchies in the different domains should help clinicians to adapt the choice of antipsychotic drug to the needs of individual patients. These findings should be considered by mental health policy makers and in the revision of clinical practice guidelines.None.

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Med Check

Efficacy and tolerability of oral paliperidone extended-release tablets in the treatment of acute schizophrenia: pooled data from three 6-week placebo-controlled studies (PAL-SCH-303/304/305)

Efficacy and tolerability of oral paliperidone extended-release tablets in the treatment of acute schizophrenia: pooled data from three 6-week placebo-controlled studies (PAL-SCH-303/304/305)