Determinants of antipsychotic response in schizophrenia: implications for practice and future clinical trials.

BACKGROUND: Response to antipsychotics in schizophrenia is highly variable, and determinants are not well understood or used to design clinical trials. OBJECTIVE: We aimed to understand determinants of response to antipsychotic treatment. METHOD: Supported by the Innovative Medicines Initiative, as part of a large public-private collaboration (NEWMEDS), we assembled the largest dataset of individual patient level information from randomized placebo-controlled trials of second-generation antipsychotics conducted in adult schizophrenia patients by 5 large pharmaceutical companies. The dataset included all placebo-controlled trials of risperidone, paliperidone, ziprasidone, sertindole, olanzapine, and quetiapine. We examined patient and trial-design-related determinants of outcome as measured by change on the Positive and Negative Syndrome Scale in 29 placebo-controlled trials (drug, n =6,971; placebo, n = 2,200) and initial findings confirmed in additional data from 5 separate trials (drug, n =1,699; placebo, n = 580). RESULTS: While it is conventional for trials to be 6 weeks long, drug-placebo differences were observable at week 4 with nearly the same sensitivity, and dropout rates were lower. Having any of these attributes was associated with significantly greater drug versus placebo differences in symptom improvement and rates of study completion: being female (P ≤ .04), being a young adult patient who is a few years beyond the first episode (P ≤ .03), having prominent positive and negative symptoms (P ≤ .03), and living in Eastern Europe versus North America (P ≤ .04). Contrary to prevalent clinical opinion, age at onset and use of benzodiazepines did not show a differential treatment response, and patients just above PANSS inclusion threshold were not overrepresented. CONCLUSIONS: Proof-of-concept trials can be shorter and efficiency improved by including an even distribution of sexes and of patients with prominent symptomatology, thus reducing patient exposure to placebo and experimental treatments.

Combining efficacy and completion rates with no data imputation: a composite approach with greater sensitivity for the statistical evaluation of active comparisons in antipsychotic trials.

Outcomes in RCT's of antipsychotic medications are often examined using last observation carried forward (LOCF) and mixed effect models (MMRM), these ignore meaning of non-completion and thus rely on questionable assumptions. We tested an approach that combines into a single statistic, the drug effect in those who complete trial and proportion of patients in each treatment group who complete trial. This approach offers a conceptually and clinically meaningful endpoint. Composite approach was compared to LOCF (ANCOVA) and MMRM in 59 industry sponsored RCT's. For within study comparisons we computed effect size (z-score) and p values for (a) rates of completion, (b) symptom change for complete cases, which were combined into composite statistic, and (c) symptom change for all cases using last observation forward (LOCF). In the 30 active comparator studies, composite approach detected larger differences in effect size than LOCF (ES=.05) and MMRM (ES=.076). In 10 of the 49 comparisons composite lead to significant differences (p ≤ .05) where LOCF and MMRM did not. In 3 comparisons LOCF was significant, in 2 MMRM lead to significant differences whereas composite did not. In placebo controlled trials, there was no meaningful difference in effect size between composite and LOCF and MMRM when comparing placebo to active treatment, however composite detected greater differences than other approaches when comparing between active treatments. Composite was more sensitive to effects of experimental treatment vs. active controls (but not placebo) than LOCF and MMRM thereby increasing study power while answering a more relevant question.

Issues and perspectives in designing clinical trials for negative symptoms in schizophrenia.

A number of pharmacological agents for treating negative symptoms in schizophrenia are currently in development. Unresolved questions regarding the design of clinical trials in this area were discussed at an international meeting in Florence, Italy in April 2012. Participants included representatives from academia, the pharmaceutical industry, and the European Medicines Agency (EMA). Prior to the meeting, participants submitted key questions for debate and discussion. Responses to the questions guided the discussion during the meeting. The group reached agreement on a number of issues: (1) study subjects should be under the age of 65; (2) subjects should be excluded for symptoms of depression that do not overlap with negative symptoms; (3) functional measures should not be required as a co-primary in negative symptom trials; (4) information from informants should be included for ratings when available; (5) Phase 2 negative symptom trials should be 12weeks and 26weeks is preferred for Phase 3 trials; (6) prior to entry into a negative symptom study, subjects should demonstrate clinical stability for a period of 4 to 6months by collection of retrospective information; and (7) prior to entry, the stability of negative and positive symptoms should be confirmed prospectively for four weeks or longer. The participants could not reach agreement on whether predominant or prominent negative symptoms should be required for study subjects.

Negative symptoms in schizophrenia--the remarkable impact of inclusion definitions in clinical trials and their consequences.

BACKGROUND: Negative symptoms are an important target for intervention in schizophrenia. There is lack of clarity in defining appropriate patients for negative symptom trials. While regulators, drug developers and academics have expressed positions in this regard, the implications of these definitions are not yet tested in large-scale trials and there is no consensus. OBJECTIVES: We examined the extent to which various operational criteria for inclusion in negative symptoms in schizophrenia clinical trials can impact patient selection and examined the effectiveness of second generation antipsychotics (SGAs) in patients with various degrees of negative symptoms. METHOD: Using anonymized patient data from AstraZeneca, Janssen Pharmaceuticals, Eli Lilly, Lundbeck, and Pfizer from 20 placebo-controlled trials of SGAs in schizophrenia from the NewMeds repository, we applied different criteria for negative symptoms: prominent, predominant, and EMA criteria, which require predominant and core negative symptoms to be present and examined the impact of these on inclusion and outcome. RESULTS: Operational criteria for negative symptoms in trials vary greatly in their inclusion of patients from "typical" trial samples. Of the patients in our studies, 8.1% and 62.3% met criteria for prominent negative symptoms, 10.2% to 50.2% met criteria for predominant negative symptoms and 7.6% to 40.0% met EMA criteria at baseline. After 6weeks of active treatment, 8% and 33.1% of patients met criteria for prominent residual negative symptoms and 14.9% to 65% met criteria for prominent and 12.2% to 45.5% met EMA criteria. Patients with predominant or prominent negative symptoms showed marked improvement on second generation antipsychotics. CONCLUSIONS: Applying various operational criteria for selecting patients for negative symptoms trials provides a great variability in percentage of suitable patients calling into question the extent to which some definitions may be overly narrow.

Risperidone in the treatment of psychosis of Alzheimer disease: results from a prospective clinical trial.

OBJECTIVE: The objective of this study was to evaluate efficacy and safety of low-dose risperidone for treating psychosis of Alzheimer disease (AD). METHOD: The authors conducted a randomized, eight-week, double-blind, placebo-controlled, multicenter trial involving nursing home residents diagnosed with AD and psychosis. Four hundred seventy-three patients were randomly assigned to placebo (N = 238) or 1.0 to 1.5 mg risperidone per day (N = 235). Coprimary efficacy end points were: changes in scores on the Behavioral pathology in Alzheimer's Disease (BEHAVE-AD) Psychosis subscale and Clinical Global Impression of Change (CGI-C). Protocol-specified subgroup analyses were performed by demographics and dementia severity. RESULTS: Efficacy analysis included 416 patients. Both groups improved significantly on the BEHAVE-AD Psychosis subscale and CGI-C with no significant difference between groups. In the subgroups analyses, a statistically significant treatment by Mini-Mental Status Examination (MMSE) interaction on the CGI-C (F([2,381]) = 3.90, p = 0.021) was observed with patients with more severe dementia (MMSE <10) showing significant differences at end point favoring risperidone treatment (chi(2) ([1]) = 5.11, p = 0.024). Mean risperidone dose was 1.03 +/- 0.24 mg per day. All-cause discontinuation rates were 25% for both risperidone and placebo. Treatment-emergent adverse events occurred in 74% risperidone versus 64% placebo patients, with somnolence occurring significantly more frequently with risperidone (16.2% versus 4.6%). Nine (3.8%) risperidone- and six (2.5%) placebo patients died during or within 30 days after treatment. CONCLUSION: This trial did not confirm earlier findings in this population.