Age and sex as moderators of the placebo response – an evaluation of systematic reviews and meta-analyses across medicine.

Predictors of the placebo response (PR) in randomized controlled trials (RCT) have been searched for ever since RCT have become the standard for testing novel therapies and age and gender are routinely documented data in all trials irrespective of the drug tested, its indication, and the primary and secondary end points chosen. To evaluate whether age and gender have been found to be reliable predictors of the PR across medical subspecialties, we extracted 75 systematic reviews, meta-analyses, and meta-regressions performed in major medical areas (neurology, psychiatry, internal medicine) known for high PR rates. The literature database used contains approximately 2,500 papers on various aspects of the genuine PR. These ‘meta-analyses’ were screened for statistical predictors of the PR across multiple RCT, including age and gender, but also other patient-based and design-based predictors of higher PR rates. Retrieved papers were sorted for areas and disease categories. Only 15 of the 75 analyses noted an effect of younger age to be associated with higher PR, and this was predominantly in psychiatric conditions but not in depression, and internal medicine but not in gastroenterology. Female gender was associated with higher PR in only 3 analyses. Among the patient-based predictors, the most frequently noted factor was lower symptom severity at baseline, and among the design- based factors, it was a randomization ratio that selected more patients to drugs than to placebo, more frequent study visits, and more recent trials that were associated with higher PR rates. While younger age may contribute to the PR in some conditions, sex does not. There is currently no evidence that the PR is different in the elderly. PR are, however, markedly influenced by the symptom severity at baseline, and by the likelihood of receiving active treatment in placebo- controlled trials.