Douglas Vanderburg

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.

Sertraline Treatment of Children and Adolescents With Posttraumatic Stress Disorder: A Double-Blind, Placebo-Controlled Trial

OBJECTIVE The aim of this study was to evaluate the safety and efficacy of sertraline in children and adolescents who met Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) criteria for posttraumatic stress disorder (PTSD). METHOD Children and adolescents (6-17 years old) meeting DSM-IV criteria for PTSD were randomized to 10 weeks of double-blind treatment with sertraline (50-200  mg/day) or placebo. The primary efficacy measure was the University of California, Los Angeles Post-Traumatic Stress Disorder Index for DSM-IV (UCLA PTSD-I). RESULTS A total of 131 patients met entry criteria and were randomized to sertraline (n = 67; female, 59.7%; mean age, 10.8; mean UCLA PTSD-I score, 43.8 ± 8.5) or placebo (n = 62; female, 61.3%; mean age, 11.2; mean UCLA PTSD-I score, 42.1 ± 8.8). There was no difference between sertraline and placebo in least squares (LS) mean change in the UCLA PTSD-I score, either on a completer analysis (-20.4 ± 2.1 vs. -22.8 ± 2.1; p = 0.373) or on an last observation carried forward (LOCF) end point analysis (-17.7 ± 1.9 vs. -20.8 ± 2.1; p = 0.201). Attrition was higher on sertraline (29.9%) compared to placebo (17.7%). Discontinuation due to adverse events occurred in a 7.5% treated with sertraline and 3.2% treated with placebo. CONCLUSIONS Sertraline was a generally safe treatment in children and adolescents with PTSD, but did not demonstrate efficacy when compared to placebo during 10 weeks of treatment. ClinicalTrials.gov Identifier: NCT00150306.

Efficacy, Long-Term Safety, and Tolerability of Ziprasidone in Children and Adolescents with Bipolar Disorder

OBJECTIVE The purpose of this study was to evaluate the short- and long-term efficacy and safety of ziprasidone in children and adolescents with bipolar I disorder. METHODS Subjects 10-17 years of age with a manic or mixed episode associated with bipolar I disorder participated in a 4 week, randomized, double-blind, placebo-controlled multicenter trial (RCT) followed by a 26 week open-label extension study (OLE). Subjects were randomized 2:1 to initially receive flexible-dose ziprasidone (40-160 mg/day, based on weight) or placebo. Primary outcome was the change in Young Mania Rating Scale (YMRS) scores from baseline. Safety assessments included weight and body mass index (BMI), adverse events (AEs), vital signs, laboratory measures, electrocardiograms, and movement disorder ratings. RESULTS In the RCT, 237 subjects were treated with ziprasidone (n=149; mean age, 13.6 years) or placebo (n=88; mean age, 13.7 years). The estimated least squares mean changes in YMRS total (intent-to-treat population) were -13.83 (ziprasidone) and -8.61 (placebo; p=0.0005) at RCT endpoint. The most common AEs in the ziprasidone group were sedation (32.9%), somnolence (24.8%), headache (22.1%), fatigue (15.4%), and nausea (14.1%). In the OLE, 162 subjects were enrolled, and the median duration of treatment was 98 days. The mean change in YMRS score from the end of the RCT to the end of the OLE (last observation carried forward) was -3.3 (95% confidence interval, -5.0 to -1.6). The most common AEs were sedation (26.5%), somnolence (23.5%), headache (22.2%), and insomnia (13.6%). For both the RCT and the OLE, no clinically significant mean changes in movement disorder scales, BMI z-scores, liver enzymes, or fasting lipids and glucose were observed. One subject on ziprasidone in the RCT and none during the OLE had Fridericia-corrected QT interval (QTcF) ≥ 460 ms. CONCLUSION These results demonstrate that ziprasidone is efficacious for treating children and adolescents with bipolar disorder. Ziprasidone was generally well tolerated with a neutral metabolic profile. CLINICAL TRIALS REGISTRY NCT00257166 and NCT00265330 at ClinicalTrials.gov.

Ziprasidone in Adolescents with Schizophrenia: Results from a Placebo-Controlled Efficacy and Long-Term Open-Extension Study

OBJECTIVE The purpose of this study was to evaluate the short- and long-term efficacy, safety, and tolerability of ziprasidone in adolescents with schizophrenia. METHODS Subjects ages 13-17 years with schizophrenia (American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 4th ed. [DSM-IV]) were enrolled in a 6 week, randomized, double-blind, placebo-controlled multicenter trial (RCT) followed by a 26 week open-label extension study (OLE). Subjects were randomized in a 2:1 ratio to flexible-dose oral ziprasidone (40-160 mg/day, based on weight) or placebo. Primary end-point was change from baseline in Brief Psychiatric Rating Scale-Anchored (BPRS-A) total score. Safety assessments included adverse events, vital signs, laboratory measures, electrocardiograms, weight and body mass index, and movement disorder ratings. RESULTS Planned interim analysis for the primary end-point in the RCT resulted in early termination of both studies because of futility. In the RCT, 283 subjects received ziprasidone (n=193) or placebo (n=90). In the intent-to-treat analysis population, the least squares mean (SE) BPRS-A score decrease from baseline at week 6 was not significantly different (p=0.15; -14.16 [0.78] for ziprasidone and -12.35 [1.05] for placebo). Per-protocol analysis was significant (p=0.02). In the OLE, 221 subjects entered the OLE and received ziprasidone for a median of 99 days. The mean (SD) change in BPRS-A score from end of RCT to end of OLE (last observation carried forward) was -6.9 (8.9). The most common treatment-emergent adverse events (≥ 10%) for all causalities during the RCT were somnolence and extrapyramidal disorders, and during OLE was somnolence only. No subjects had Fridericias corrected QT (QTcF) ≥ 500 ms in the RCT or OLE phases. One completed suicide occurred during the OLE phase. For RCT and OLE, no clinically significant changes were reported in metabolic indices and laboratory measures. CONCLUSIONS Ziprasidone failed to separate from placebo in treatment of schizophrenia in adolescents. Ziprasidone was generally well tolerated with an overall neutral weight and metabolic profile. CLINICAL TRIALS REGISTRY NCT00257192 and NCT00265382 at ClinicalTrials.gov .

Adjunctive oral ziprasidone in patients with acute mania treated with lithium or divalproex, part 1: results of a randomized, double-blind, placebo-controlled trial.

OBJECTIVE To assess the efficacy and safety of adjunctive ziprasidone in subjects with acute mania treated with lithium or divalproex, with an inadequate response to the mood stabilizer. METHOD The study enrolled subjects aged 18-65 years who had a primary DSM-IV diagnosis of bipolar I disorder, with the most recent episode manic or mixed, with or without rapid cycling, and a Young Mania Rating Scale (YMRS) score ≥ 18. Subjects were randomized under double-blind conditions to receive ziprasidone, 20 to 40 mg (n = 226) or 60 to 80 mg (n = 232), or placebo (n = 222) twice a day for 3 weeks in addition to their mood stabilizer. The primary efficacy variable was change in YMRS scores from baseline to 3 weeks. Secondary efficacy measures included the Montgomery-Asberg Depression Rating Scale, Positive and Negative Syndrome Scale, Clinical Global Impressions-Severity of Illness and -Improvement scales, and Global Assessment of Functioning. Computer-administered YMRS was included for quality control and to evaluate study performance. The study was conducted between April 2006 and December 2008. RESULTS Least-squares mean ± standard error changes in YMRS scores from baseline to week 3 were -10.2 ± 0.80 in the mood stabilizer + ziprasidone 60- to 80-mg group, -11.0 ± 0.80 in the mood stabilizer + ziprasidone 20- to 40-mg group, and -9.5 ± 0.80 in the mood stabilizer + placebo group. Mean treatment differences between adjunctive ziprasidone groups and placebo were not statistically significant on primary or secondary efficacy measures. Ziprasidone was well tolerated. CONCLUSIONS Adjunctive ziprasidone treatment failed to separate from mood stabilizer (lithium or divalproex) treatment on primary and secondary end points. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT00312494.

Placebo response trajectories in short-term and long-term antipsychotic trials in schizophrenia

Increasing rates of placebo response have eroded placebo-control group differences in randomized controlled trials, although the reasons for this trend remain unclear. Data were extracted from the placebo arms in two identically designed 6-week studies and one 52-week study in the ziprasidone clinical trial database. The objective of this analysis was to identify distinct patterns of placebo response trajectories that could capture individual variability in the time course of change during a 1-year trial using growth mixture latent class analyses. These long-term placebo response patterns were contrasted with two 6-week schizophrenia studies. The placebo response trajectory analysis that showed 58% (Group 4) had gradual improvement in the PANSS negative subscale score (p<0.05), fewer dropouts (p<0.05) and improvement in abnormal movements, contrasted with 3 other trajectory groups that showed worsening on these measures. Almost all subjects (98%) in this symptom improvement group were treated with conventional antipsychotics just prior to placebo treatment. In contrast, the trajectory analyses showed worsening of symptoms based on PANSS total score in the 1-year trial (+15.5, SEM 2.6). Some gradual improvement of symptoms (-14.0, SEM 1.6) was also noted in 67% (n=114) of patients in the 6-week short term trials. Our findings indicate that substantial heterogeneity in placebo response occurs in both short-term and long-term trials. The placebo response trajectories appeared to depend on the efficacy measure of symptom reduction chosen, prior antipsychotic use profile, and trial durations. Further research is warranted to examine the trajectory patterns of placebo responses in independent patient populations.

Intramuscular ziprasidone versus haloperidol for managing agitation in Chinese patients with schizophrenia.

Abstract Intramuscular (IM) antipsychotics are preferred for efficient control of agitation symptoms. Previous studies have demonstrated that IM ziprasidone is efficacious and safe for treatment of agitation in schizophrenia. However, clinicians now recognize that racial differences may contribute to altered therapeutic response and tolerability. This study compared the efficacy and tolerability of IM ziprasidone versus IM haloperidol for the management of agitation in Chinese subjects with schizophrenia. Subjects with acute schizophrenia were randomized to either ziprasidone (n = 189, 10 to 20 mg as required up to a maximum of 40 mg/d) or haloperidol (n = 187, 5 mg every 4 to 8 hours to a maximum of 20 mg/d) for 3 days. Psychiatric assessments and adverse events were assessed at baseline, 2, 4, 24, 48, and 72 hours. In the ziprasidone group, 2.1% of subjects discontinued versus 3.7% in the haloperidol group. The least squares mean change (SE) from baseline to 72 hours in Brief Psychiatry Rating Scale total score was −17.32 (0.7) for ziprasidone (n = 167) and −18.44 (0.7) for haloperidol (n = 152), with a 95% confidence interval treatment difference of −0.7 to 2.9. Fewer subjects experienced adverse events after ziprasidone (n = 54, 28.6%) than haloperidol (n = 116, 62.0%), with a notably higher incidence of extrapyramidal symptoms in the haloperidol group (n = 69, 36.9%) compared to the ziprasidone group (n = 4, 2.1%). For controlling agitation in schizophrenia in this Chinese study, ziprasidone had a favorable tolerability profile and comparable efficacy and safety compared to haloperidol.

Assessments of suicidality in double-blind, placebo-controlled trials of ziprasidone

OBJECTIVE A pooled analysis was conducted to identify possibly suicide-related adverse events in Pfizer-sponsored, phases 2-4, placebo-controlled, double-blind, adult and pediatric completed randomized controlled trials of ziprasidone and to evaluate the risk of suicidality with ziprasidone versus placebo. METHOD The trials included were initiated as early as June 1992, and the cutoff date for selection of the placebo-controlled trials in the Pfizer database was October 2, 2009. The US Food and Drug Administration (FDA)-defined search methodology was used to identify possibly suicide-related adverse events, and the Columbia Classification Algorithm of Suicide Assessment (primary outcome measure) was used to categorize them. The incidences of possibly suicide-related adverse events were calculated for individual classifications and for the predefined combined categories of suicidality (comprising classification codes 1-4) and suicidal behavior (comprising classification codes 1-3), along with the ziprasidone versus placebo relative risks and corresponding 95% CIs. Exact binomial 95% CIs were calculated for the individual treatment group incidences. RESULTS Suicidality events were identified in 52 among 5,123 subjects treated with either ziprasidone or placebo in 22 trials. No cases of completed suicide occurred in this analysis. There were no statistically significant differences between ziprasidone and placebo in any of the individual classification categories, combined suicidal behavior category (ziprasidone vs placebo relative risk = 0.67; 95% CI, 0.206-2.201), or combined suicidality risk category (ziprasidone vs placebo relative risk = 0.90; 95% CI, 0.514-1.563). CONCLUSIONS Results of our analyses, performed in accordance with the FDA-specified search strategy, reveal no significant differences in treatment-emergent suicidality risk in ziprasidone versus placebo subjects treated in controlled clinical trials.

Relating Spontaneously Reported Extrapyramidal Adverse Events to Movement Disorder Rating Scales

Background: While antipsychotic-induced extrapyramidal symptoms (EPS) and akathisia remain important concerns in the treatment of patients with schizophrenia, the relationship between movement disorder rating scales and spontaneously reported EPS-related adverse events (EPS-AEs) remains unexplored. Methods: Data from four randomized, placebo- and haloperidol-controlled ziprasidone trials were analyzed to examine the relationship between spontaneously reported EPS-AEs with the Simpson Angus Scale (SAS) and Barnes Akathisia Rating Scale (BARS). Categorical summaries were created for each treatment group to show the frequencies of subjects with EPS-AEs in each of the SAS and BARS categories at weeks 1, 3, and 6, and agreement between ratings was quantified by means of weighted kappa (κ). Results: In general, we found greater frequencies of EPS-AEs with increasing severity of the SAS and BARS scores. The EPS-AEs reported with a “none” SAS score ranged from 0 to 22.2%, with a “mild” SAS score from 3.3 to 29.0%, and with a “moderate” SAS score from 0 to 100%. No subjects in any treatment group reported “severe” SAS scores or corresponding EPS-AEs. Agreement between SAS scores and EPS-AEs was poor for ziprasidone and placebo (κ < 0.2) and only slightly better for haloperidol. The EPS-AEs reported with “non questionable” BARS scores ranged from 1.9 to 9.8%, with “mild moderate” BARS scores from 12.8 to 54.6%, and with “marked severe” scores from 0 to 100%. Agreement was modest for ziprasidone and placebo (κ < 0.4) and moderate for haloperidol (κ < 0.6). Conclusions: These findings may reflect either underreporting of AEs by investigators and subjects or erroneous rating scale evaluations.

Ziprasidone and the relative risk of diabetes

Kessing et al [1][1] describe the risks of diabetes in clinical practice from a large-cohort, observational study of Danish patients requiring antipsychotics. We believe that the relative risks of subsequent incident diabetes that they report for individual antipsychotics are at odds with