Steven J. Romano

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].

Improvement in indices of health status in outpatients with schizophrenia switched to ziprasidone.

Side effect and health status changes were measured in 3 studies in which outpatients experiencing suboptimal efficacy or tolerability with their current antipsychotic were switched to 6 weeks of open-label ziprasidone. The studies differed only in the patient’s prior antipsychotic; 1 study group was on olanzapine (n = 104), a second on risperidone (n = 58), and third on a conventional antipsychotic (n = 108). Baseline and end point health status measures included weight and height, nonfasting cholesterol, and triglyceride levels, prolactin levels, and extrapyramidal side effects. Improvements in health indices and side effects were seen among all 3 groups, but the specific benefits depended on the preswitch antipsychotic. For example, patients switched from olanzapine experienced a mean weight loss of 1.76 kg (P < 0.0001), those switched from risperidone had a lesser reduction in weight (−0.86 kg; P = 0.015), and those switched from conventionals had a nonsignificant increase (+0.27 kg; P = 0.3). Prolactin levels decreased among those switched from risperidone (P < 0.0001) or conventionals (P = 0.05), but not for patients switched from olanzapine. EPS improved among those switched from conventionals (P < 0.0001) and to a lesser extent among those switched from risperidone (P < 0.01), but not in those changed from olanzapine (NS). Thus, in these studies, switching to ziprasidone in patients with continuing symptoms or side effects on their current medication was often associated with improved health status indices, lowered prolactin levels, or less EPS, with the magnitude benefit consistent with the known side-effect profile of the preswitch antipsychotic.

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.

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.

Rapid antipsychotic response with ziprasidone predicts subsequent acute manic/mixed episode remission

OBJECTIVE To assess rapid antipsychotic efficacy with oral ziprasidone monotherapy in bipolar acute manic/mixed episodes with psychotic features, and predictive value of rapid antipsychotic response for subsequent acute manic/mixed episode remission. METHODS Pooled analysis of two 3-week, randomized, double-blind, placebo-controlled trials of ziprasidone (40-160mg/d) in inpatients with bipolar I disorder, and a current manic or mixed episode, with (n=152) or without (n=246) psychotic features. Psychosis improvement was evaluated by change in SADS-C psychosis score (sum of delusions, hallucinations, and suspiciousness items). Rapid antipsychotic response (>or=50% decrease in SADS-C psychosis score by Day 4) and acute manic episode response and remission (endpoint >or=50% MRS decrease, and a MRS score <or=12, respectively) were analyzed. RESULTS Significantly greater antipsychotic effects were observed by Day 4 with ziprasidone treatment (vs. placebo) and the magnitude of improvement increased significantly with time, in all subjects, in the subgroup of all psychotic subjects, and psychotic subjects with low baseline agitation (p<0.05). Rapid antipsychotic response predicted subsequent acute manic episode remission independent of ziprasidone or placebo treatment received (p<0.001, ROC AUC=0.71) with significant improvement in accuracy of MRS remission prediction when compared to models using early changes in MRS score alone (p=0.01). LIMITATIONS Post hoc analysis, use of 3 SADS-C psychosis items to assess psychosis. CONCLUSIONS The predictive value of rapid (Day 4) improvement in psychotic symptoms for subsequent (Day 21) remission of acute manic/mixed symptoms may facilitate enhanced therapeutics, in view of the current practice of brief hospitalization for patients with acute manic/mixed episodes with psychotic features.

Improvement in Prosocial Functioning After a Switch to Ziprasidone Treatment

BACKGROUND Cognitive, social, and affective impairments are major features of schizophrenia, despite not being represented in the formal diagnostic criteria. These impairments are associated with major reductions in quality of life for patients with schizophrenia. Treatment with newer antipsychotic medications has been reported to improve all of these areas of functioning, but most studies have not examined the direct association between changes in cognitive functioning and other aspects of the illness. OBJECTIVES The goal of this analysis was to examine relationships between cognitive and affective symptoms and their impact on social impairments in patients switched to ziprasidone treatment. METHODS In this study, which is a re-analysis of previously published data, 270 patients were switched from previous treatment with conventional antipsychotics, risperidone, or olanzapine to treatment with ziprasidone. Patients were tested with a cognitive assessment battery, rated with the Positive and Negative Syndrome Scale (PANSS), and received other assessments of safety and tolerability. PANSS scores were divided into factors based on previously published factor analyses, with a focus on the cognitive, prosocial, and anxiety-depression factors. RESULTS Statistically significant improvements for global cognitive functioning and the three PANSS subscales were found across the studies. When the data were pooled for a path analysis, changes in cognitive functioning indexed by the PANSS cognitive subscales was the primary predictor of improvements in PANSS prosocial functions, with changes in anxiety-depression accounting for much less variance. CONCLUSION These results suggest a direct relationship between improvements in cognitive and prosocial functioning in patients with schizophrenia and indicate that treatments that enhance cognitive functioning, such novel antipsychotics, have the potential to improve aspects of outcome in schizophrenia even in short-term treatment studies. This issue should be addressed in future double-blind studies of the effects of atypical medications in schizophrenia.

A new proposal for randomized start design to investigate disease-modifying therapies for Alzheimer disease.

Background The increasing prevalence of Alzheimer disease (AD) and lack of effective agents to attenuate progression have accelerated research and development of disease modifying (DM) therapies. The traditional parallel group design and single time point analysis used in the support of past AD drug approvals address symptomatic benefit over relatively short treatment durations. More recent trials investigating disease modification are by necessity longer in duration and require larger sample sizes. Nevertheless, trial design and analysis remain mostly unchanged and may not be adequate to meet the objective of demonstrating disease modification. Randomized start design (RSD) has been proposed as an option to study DM effects, but its application in AD trials may have been hampered by certain methodological challenges. Purpose To address the methodological issues that have impeded more extensive use of RSD in AD trial and to encourage other researchers to develop novel design and analysis methodologies to better ascertain DM effects for the next generation of AD therapies, we propose a stepwise testing procedure to evaluate potential DM effects of novel AD therapies. Methods Alzheimer Disease Assessment Scale-Cognitive Subscale (ADAS-cog) is used for illustration. We propose to test three hypotheses in a stepwise sequence. The three tests pertain to treatment difference at two separate time points and a difference in the rate of change. Estimation is facilitated by the Mixed-effects Model for Repeated Measures approach. The required sample size is estimated using Monte Carlo simulations and by modeling ADAS-cog data from prior longitudinal AD studies. Results The greatest advantage of the RSD proposed in this article is its ability to critically address the question on a DM effect. The AD trial using the new approach would be longer (12-month placebo period plus 12-month delay-start period; total 24-month duration) and require more subjects (about 1000 subjects per arm for the non-inferiority margin chosen in the illustration). It would also require additional evaluations to estimate the rate of ADAS-cog change toward the end of the trial. Limitations A regulatory claim of disease modification for any compound will likely require additional verification of a drug’s effect on a validated biomarker of Alzheimer’s pathology. Conclusions Incorporation of the RSD in AD trials is feasible. With proper trial setup and statistical procedures, this design could support the detection of a disease-modifying effect. In our opinion, a two-phase RSD with a stepwise hypothesis testing procedure could be a reasonable option for future studies.

Why Are Innovative Drugs Failing in Phase III

There is a disturbing trend in studies of new drugs for psychiatric disorders. A number of innovative and promising drugs that appear to show effectiveness in phase II trials fail in phase III. In some cases, the study sponsormay discontinue further development of the drug based on the results. It is possible that the phase II results weremisleading and that the program should have never moved to phase III because of a lack of efficacy or adverse effects. This commentary addresses an alternative explanation; that is, effective drugs are failing because of systematic problems in the methods for carrying out large, multinational phase III trials. If this is the case, it is vital for our field to address this problem because medications that can improve the lives of people with serious mental illness may never reach the clinic. In addition, the failure of these trials appears to have convinced some companies to limit investment in the CNS area and in psychiatry in particular, substantially decreasing the resources available for drug development. In phase II drug trials, the agent is administered to patients with a particular disease or condition. These studies usually include hundreds of patients and are essential for establishing the agent’s effect size, dose range, and general safety and tolerability profile. Phase III trials are much larger and can involve 300 to 3,000 participants. These studies can confirm the phase II findings and provide additional safety information. Recently, these trials have been global and have included as many as 200 different research sites. An important observation from a number of recently completed phase III trials is that the active drug resulted in similar symptom reduction as in the phase II trials. However, the placebo response was substantially greater, and the active drug did not separate from placebo. Another characteristic of these studies is that they often have aggressive timelines. Sites and contract research organizations are reimbursed based on the number of subjects who are randomized, and there is often pressure to meet deadlines.