Cynthia Siu

Weight effects associated with antipsychotics: A comprehensive database analysis

BACKGROUND Available data on atypical antipsychotic-induced weight gain are limited by a number of methodological factors. The objective of this report is to evaluate short-term (N=1742) and long-term (N=1649) weight effects in patients receiving standard doses of amisulpride, haloperidol, olanzapine, risperidone, ziprasidone, and placebo based on 21 randomized, placebo-controlled, parallel-group studies from an integrated clinical trial database. METHOD Analyses of the integrated ziprasidone schizophrenia trials database were performed to estimate the weighted average of weight change and the percentage of subjects experiencing weight gain (or weight loss) across studies for each agent studied, based on fixed- and random-effects models. Durations of treatment exposure in long-term trials were controlled by well-defined time windows (6 month: 150 to 210 days; 1 year: 330 to 390 days). Weight gain or loss was defined using a 7% change from baseline threshold. RESULTS During long-term therapy with 1-year treatment duration, incidence of weight gain for subjects treated with ziprasidone (17%) was not significantly different from the placebo (13%) or haloperidol (41%) groups based on 95% confidence interval. In contrast, significantly greater weight gain incidence was observed for the olanzapine (57%) and risperidone (39%) groups compared to placebo. Median weight change of +0.49, -0.18, +1.50 and +0.55 lb/month was observed for haloperidol, ziprasidone, olanzapine and risperidone subjects, respectively, indicating differential weight change patterns compared to placebo (-0.32). Similar results were observed for the short-term (4-12 weeks) and 6-month treatment exposure cohorts. CONCLUSIONS Our results confirm significant differences in long-term weight effects among atypical antipsychotics, consistent with findings from prior meta-analysis of antipsychotic-induced weight gain [Allison, D.B., Mentore, J.L., Heo, M., Chandler, L.P., Capelleri, J.C., Infante, M.C., Weiden, P.J., 1999. Antipsychotic induced weight gain: a comprehensive research synthesis. Am J Psychiatry 156, 1686-1696] and the CATIE schizophrenia study [Lieberman, J.A., Stroup, T.S., McEvoy, J.P., et al., 2005. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 353, 1209-1223].

Characteristics of the MATRICS Consensus Cognitive Battery in a 29-site antipsychotic schizophrenia clinical trial

OBJECTIVE The Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Project produced a battery of tests, the MATRICS Consensus Cognitive Battery (MCCB), designed to assess cognitive treatment effects in clinical trials of patients with schizophrenia. In validation studies, the MCCB demonstrated excellent reliability, minimal practice effects and significant correlations with measures of functional capacity. This study addresses whether the MCCB demonstrates these favorable characteristics when administered in the context of the type of large multi-site industry trial for which it was designed. METHODS In a clinical trial comparing risperidone and lurasidone, 323 clinically-stable outpatients with schizophrenia at 29 sites were assessed with MCCB at screening and a median of 15days later at baseline. A measure of functional capacity, the UCSD Performance-based Skills Assessment-Brief (UPSA-B) was administered at baseline. RESULTS All 323 (100%) patients had sufficient data for computing a composite score according to the MCCB criteria. The test-retest reliability of the MCCB composite score was excellent (ICC=0.88). The severity of cognitive impairment was T=24.7 (SD=12.1) at screening and T=26.7 (SD=12.4) at baseline. The MCCB composite score demonstrated a large correlation with the UPSA-B composite score (r=.60, df=304, p<.001). The practice effect on the composite score was small (z=0.18). DISCUSSION In the context of a 29-site antipsychotic trial in stable outpatients with schizophrenia, the MCCB is sensitive to cognitive deficits in all domains, demonstrates excellent test-retest reliability and small practice effects, and is strongly correlated with a leading measure of functional capacity.

Improvement in cognitive function following a switch to ziprasidone from conventional antipsychotics, olanzapine, or risperidone in outpatients with schizophrenia

OBJECTIVE To assess changes in cognitive function in stable outpatients with schizophrenia switched to ziprasidone from conventional antipsychotics (n = 108), olanzapine (n = 104), or risperidone (n = 58) because of suboptimal efficacy or poor tolerability. METHODS In three separate 6-week trials, patients received ziprasidone 40 mg b.i.d. for 2 days, followed by 20-80 mg b.i.d. for the next 40 days. Before switching, and at endpoint, patients were evaluated with tests of working and secondary verbal memory, vigilance, visuomotor speed, verbal fluency, and executive functioning. Principal components factor analysis was performed to test for clustering of cognitive variables. RESULTS Significant improvements were seen at endpoint in secondary verbal memory (in all three groups), vigilance (in patients switched from conventional antipsychotics or risperidone), executive function (in patients switched from conventional antipsychotics or risperidone), and verbal fluency. Factor analysis on baseline scores suggested reduction of the cognitive variables to three factors: verbal skills, attention and short-term memory, and executive functioning. Analysis of z-transformed mean change in factor scores showed significant improvement in verbal skills and global score following the switch from conventional antipsychotics, olanzapine, or risperidone. CONCLUSIONS Patients requiring a change in antipsychotic therapy may exhibit cognitive improvement following a switch to ziprasidone.

Meta-Regression Analysis of Placebo Response in Antipsychotic Trials, 1970-2010

OBJECTIVE Large placebo response presents a major challenge for psychopharmacologic drug development and contributes to the increasing failure of psychiatric trials. The objective of this meta-regression analysis was to identify potential contributors to placebo response in randomized controlled trials of antipsychotic treatment in schizophrenia. METHOD The authors extracted trial design and clinical variables from eligible randomized controlled trials (N=50) identified through searches of MEDLINE (1960-2010) and other sources. Standardized mean change (SMC) was used as the effect size measure for placebo response, based on change scores on the Brief Psychiatric Rating Scale or the Positive and Negative Syndrome Scale from baseline to endpoint (2 to 12 weeks). RESULTS The results suggest significant heterogeneities (Q=387.83, df=49) in the magnitude of placebo response (mean SMC, -0.33, range -1.4 to 0.9) and in study quality. Both placebo SMC and study quality increased over time. Younger age, shorter duration of illness, greater baseline symptom severity, and shorter trial duration were significantly associated with greater placebo response, while country (United States compared with other countries) was not. More study sites, fewer university or Veterans Affairs treatment settings, and a lower percentage of patients assigned to receive placebo were associated with a greater placebo response, but these were not independent of publication year. Study quality affected the variability but not mean levels of placebo response. CONCLUSIONS This study identified important patient characteristics and trial design factors affecting the level of placebo response and hence the likelihood of detecting efficacy signals in randomized controlled trials. Future studies should test whether controlling these factors improves the detection of an antipsychotic effect.

Ziprasidone and haloperidol in the treatment of acute exacerbation of schizophrenia and schizoaffective disorder: comparison of intramuscular and oral formulations in a 6-week, randomized, blinded-assessment study

RationaleConventional intramuscular (IM) antipsychotics used in managing acute exacerbation of schizophrenia are associated with side effects such as acute dystonia.ObjectivesTo compare the efficacy and tolerability of sequential IM/oral ziprasidone with haloperidol in acute exacerbation of schizophrenia or schizoaffective disorder.MethodsIn a 6-week, multicenter, parallel-group, flexibly dosed study, patients were randomized to ziprasidone (IM up to 3 days, then oral 40–80 mg, b.i.d.) or haloperidol (IM up to 3 days, then oral 5–20 mg/day). Assessments were rater-blinded.ResultsAt the end of IM treatment, patients receiving ziprasidone (n=427) showed significantly improved Brief Psychiatric Rating Scale Total (BPRS total) scores compared with those receiving haloperidol (n=138) [least-squares (LS) mean change −6.14 for ziprasidone versus −4.13 for haloperidol, P<0.0018]. At endpoint, there were no significant between-group differences in BPRS total scores. There was a significantly greater improvement in BPRS negative subscale scores in ziprasidone-treated patients, both at the end of IM treatment (LS mean change −1.15 for ziprasidone and −0.28 for haloperidol, P<0.0001) and at study endpoint (LS mean change −2.94 for ziprasidone and −2.24 for haloperidol, P<0.0001). Haloperidol-treated patients exhibited significantly greater increases in Extrapyramidal Symptom Rating Scale at end of IM treatment and at endpoint (P<0.0001). They also had significantly higher ratings on the Barnes Akathisia Scale (P<0.0001) and the Movement Disorder Burden Score (P<0.005), as well as higher incidences of movement disorder-related adverse events.ConclusionsSequential IM and oral ziprasidone offers important efficacy and tolerability advantages over haloperidol in acute schizophrenia.

Understanding the relationship between baseline BMI and subsequent weight change in antipsychotic trials: Effect modification or regression to the mean?

The purpose of this study was to examine whether prior evidence of an inverse relationship between initial body weight and subsequent antipsychotic-induced weight change represents true effect modification or a statistical artifact, regression to the mean (RTM). We conducted a post-hoc analysis after pooling seven randomized, placebo- or active-controlled trials of ziprasidone and other antipsychotic agents. ANCOVA was applied to evaluate treatment-by-baseline body mass index (BMI) range interaction effect on weight change. Regression analysis was applied to estimate the potential bias due to RTM. Statistical interaction tests between baseline BMI ranges and treatment assignments (haloperidol, olanzapine, risperidone, or ziprasidone, versus placebo) were not significant within studies or across studies. Correlation between baseline and follow-up measurements of body weight in placebo-treated subjects was less than perfect (r=0.87, 6-month cohort), leading to RTM. Consistent with predictions based on RTM, the greatest weight change, on average, was observed in subgroups with baseline weights differing the most from the population mean. Our findings suggest that the previously observed correlation between baseline BMI and weight change subsequent to antipsychotic treatment reflects in part RTM, and not effect modification. This class of drugs appears to cause similar weight gain in both high and low baseline BMI groups.

Effect of lurasidone on neurocognitive performance in patients with schizophrenia: a short-term placebo- and active-controlled study followed by a 6-month double-blind extension.

This double-blind study evaluated change in cognitive performance and functional capacity in lurasidone and quetiapine XR-treated schizophrenia patients over a 6-week, placebo-controlled study, followed by a 6-month, double-blind extension. Cognitive performance and functional capacity were assessed with the CogState computerized cognitive battery and the UPSA-B. Analyses were conducted for all subjects, as well as the subsample whose test scores met prespecified validity criteria. No statistically significant differences were found for change in the composite neurocognitive score for lurasidone (80 mg/day and 160 mg/day) groups, quetiapine XR and placebo in the full sample at week 6. For the evaluable sample (N = 267), lurasidone 160 mg was superior to both placebo and quetiapine on the neurocognitive composite, while lurasidone 80 mg, quetiapine XR, and placebo did not differ. UPSA-B scores were superior to placebo at 6 weeks for all treatments. In the double-blind extension study, analysis of the full sample showed significantly better cognitive performance in the lurasidone (40-160 mg) group compared to the quetiapine XR (200-800 mg) group at both 3 and 6 months. Cognitive and UPSA-B total scores were significantly correlated at baseline and for change over time. This is the first study to date where the investigational treatment was superior to placebo on both cognitive assessments and a functional coprimary measure at 6 weeks, as well as demonstrated superiority to an active comparator on cognitive assessments at 6 weeks and at 6 months of extension study treatment. These findings require replication, but are not due to practice effects, because of the placebo and active controls.

Metabolic risk factors in first-episode schizophrenia: baseline prevalence and course analysed from the European First-Episode Schizophrenia Trial

Available data on antipsychotic-induced metabolic risks are often constrained by potential confounding effects due to prior antipsychotic treatment. In this study, we assessed the baseline prevalence of metabolic abnormalities and changes following treatment with five commonly-used antipsychotic drugs (haloperidol, amisulpride, olanzapine, quetiapine or ziprasidone) in first-episode, partially antipsychotic-naive patients with schizophrenia in the European first-episode schizophrenia trial (EUFEST). Overall baseline prevalence of metabolic syndrome (MetS) was 6.0%, with similar rates observed in the antipsychotic-naive patients (5.7%, 9/157) and in the other patients with only a brief prior exposure to antipsychotics (6.1%, 20/326). These results are consistent with the MetS prevalence rate estimated in a general population of similar age. Examination of individual risk factors showed 58.5% of subjects had one or more elevated metabolic risks at baseline: 28.5% demonstrated suboptimal HDL; 24.2% hypertension; 17.7% hypertriglyceridemia; 8.2% abdominal obesity; 7.3% hyperglycaemia. Increase in body weight (kg/month) occurred in patients treated with haloperidol (0.62 S.E. 0.11), amisulpride (0.76 S.E. 0.08), olanzapine (0.98 S.E. 0.07) and quetiapine (0.58 S.E. 0.09), which was significantly greater than that in the ziprasidone group (0.18 S.E. 0.10). The incidence rate of new diabetes cases over a 52-wk follow-up period was 0.82% (4/488). More patients experienced worsening rather than improvement of hypertriglyceridemia or hyperglycaemia in all treatment groups. Our findings suggest that in first-episode, partially antipsychotic-naive patients, the baseline prevalence rate of MetS appears to be no higher than that in the general population, but serious underlying individual risk factors nevertheless existed.

Remission in schizophrenia: 196-week, double-blind treatment with ziprasidone vs . haloperidol

To compare the remission rate and its time-course over 196 wk of double-blind treatment with an atypical antipsychotic, ziprasidone (80-160 mg/d given b.i.d., or 80-120 mg/d given q.d.), or a conventional antipsychotic, haloperidol (5-20 mg/d). Outcome assessments included attainment of remission (Andreasen criteria) by longitudinal analysis. Positive and Negative Syndrome Scale (PANSS) scores, Global Assessment of Functioning Scale (GAF) scores, and quality-of-life (QLS) were also assessed in the initial 40-wk study phase (n=599) and the 3-yr extension study (n=186). Discontinuation rates in the initial 40-wk core and follow-up extension studies were comparable between groups: 64% and 65% for the 80-160 mg/d ziprasidone group, 65% and 58% for the 80-120 mg/d ziprasidone group, and 60% and 66% for the 5-20 mg/d haloperidol group, respectively. Mean change scores from baseline to LOCF endpoint (week 40 or early termination) for PANSS negative and GAF (primary efficacy variables) were not statistically significantly different between ziprasidone and haloperidol. During the 3-yr extension study, ziprasidone-treated subjects (80-160 mg/d) were more likely to achieve remission (51%) than haloperidol-treated (40%) subjects (p=0.04), while there was a favourable trend associated with 80-120 mg/d ziprasidone (48%). Compared to the haloperidol group, subjects assigned to the 80-160 mg/d ziprasidone group showed a gradual and persistent improvement in remission (p=0.006) and quality-of-life (p=0.004) in the longitudinal analyses. Significant differences in the trajectory of PANSS total and GAF scores favouring the 80-160 mg/d ziprasidone group were also observed. In this long-term, double-blind study, ziprasidone treatment was more likely to result in remission than haloperidol treatment, and was associated with greater improvement in quality-of-life.

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.