09 Oct Placebo Responses to Anti-Psychotic Medications Increasing

MedicalResearch.com Interview with:
Bret R Rutherford, MD
Assistant Professor ,Clinical Psychiatry Columbia University College of Physicians and Surgeons
Division of Geriatric Psychiatry
New York State Psychiatric Institute
New York, NY 10032

Medical Research: What are the main findings of the study?

Dr. Rutherford: In this meta-analysis of 105 trials of acute antipsychotic drugs for schizophrenia, the placebo response was shown to be significantly increasing from 1960 to the present. Conversely, the treatment change associated with effective dose medication significantly decreased over the same time period. The average participant of a randomized clinical trial (RCT) receiving an effective dose of medication in the 1960s improved by 13.8 points in the BPRS, whereas this difference diminished to 9.7 BPRS points by the 2000s. The consequence of these divergent trends was a significant decrease in drug-placebo differences from 1960 to the present.

Medical Research: What was most surprising about the results?

Dr. Rutherford: Contrary to our hypotheses, the intensity of therapeutic contact (i.e., the number of scheduled visits) did not significantly influence the pre-post treatment change observed or affect average drug-placebo differences in our sample of trials of antipsychotic drugs. One reason for this may be that much of the treatment provided in these trials occurs within an inpatient setting, in which all patients benefit from a therapeutic milieu and attention from health care providers regardless of how frequent their visits with research staff. Alternatively, it may be the case that the supportive provision of empathy, a coherent narrative to understand one’s illness, and a therapeutic relationship are less effective in the treatment of schizophrenia.

Medical Research: What should clinicians and patients take away from your report?

Dr. Rutherford: The results from our meta-analysis confirm that the placebo response rates have been increasing over time in antipsychotic drug trials, while the change observed in medication-treated patients has been decreasing. Possible causes include decreased baseline symptom severity of study participants and a change in the treatment settings within which studies are conducted. The methodological changes to improve signal detection in RCTs of antipsychotic drugs suggested by our meta-analysis would be to recruit more severely ill patients, limit study duration to no longer than 8-12 weeks, dispense with single-blind placebo lead-in periods, and maximize the probability of being assigned to placebo as opposed to active medication.

Medical Research: What recommendations do you have for future research as a result of this study?

Dr. Rutherford: More research on study design would be interesting as a result of this study. Comparing our findings with what is known about placebo response in other disorders such as major depressive disorder, we find that a picture of placebo response emerges in which a substantial portion is caused by general methodological factors rather than the nature of the illness under study. For example, a common trend in both antidepressant and antipsychotic drug trials has been a shift over time from smaller, academic, single-site trials to larger, commercial, multicenter trials. These changes in RCT conduct have significant advantages, such as the increased statistical power conferred by larger samples. However, increased measurement error associated with multicenter clinical trails may lead to decreased effect sizes for medication and may partially offset the benefits of a larger sample size.

Second, whereas academic investigators may be biased by their interest in a positive research outcome, commercial sites, particularly those operated by contract research organizations have arguably more powerful financial incentives to enroll patients, which can result in the inflation of baseline scores by raters followed by a rapid decrease in scores once the restrictive entrance criterion has been passed. Some data suggest that using centralized raters may help control these potential biases and consequently improve inter-rater reliability, reduce biases toward inflation of baseline scores and observing improvement, and eliminate the effects of repeated assessments by the same clinician.

Citation:

Last Updated on October 9, 2014 by Marie Benz MD FAAD