Examining alternative core symptom inclusion criteria in randomized placebo-controlled trials for acute major depression

Examining alternative core symptom inclusion criteria in randomized placebo-controlled trials for acute major depression

Clinical trials testing the effectiveness of antidepressant medication usually have to compare the active medication to an inactive placebo pill. Despite many successful trials demonstrating the effectiveness of antidepressant medications, a given drug may still fail to separate from placebo. After several decades of clinical trials, placebo response rates have not decreased. This suggests a need to better understand factors that contribute to high placebo response rates.Clinical trials typically have a long list of inclusion and exclusion criteria used to select patients. Virtually all antidepressant trials specify a minimum depression symptom score required to participate in a trial (e.g., a score of 18 or more on the Hamilton Depression Rating Scale; HAMD-17). This practice is problematic for two reasons: (1) it does not appear to have decreased placebo response rates over time, and (2) scales such as the HAMD-17 include items that assess symptoms which are rare or infrequent in outpatient samples. The latter point is particularly problematic because an antidepressant cannot outperform placebo on symptoms/items which were absent or minimal to begin with.According to the diagnostic criteria for Major Depressive Disorder (MDD), there are only two symptoms that are necessary to make a diagnosis: depressed mood, and lack of interest/pleasure. Not surprisingly, in MDD trials, scores on the HAMD-17 items that measure these symptoms are higher than most other symptoms because, by definition, at least one of them is necessary for a diagnosis of MDD. As such, when it comes to designing an clinical trial, these two items may be a better index of depression severity rather than total HAMD-17 scale scores.The purpose of this study is to re-analyse data from 10 randomized placebo-controlled antidepressant trials to examine whether the use more strict inclusion criteria derived from the HAMD-17 scale items that assess core depressive symptoms (depressed mood, item 1, and lack of interest, item 7) would have resulted in larger drug-placebo differences.The main outcome of interest is whether depression scores decreased by 50% or more by the end of the trial (i.e., a treatment response).We expect to find that as scores on these items increase, patients will have lower placebo response rates compared to the sample overall. As a result, drug-placebo differences will be larger.If this is confirmed here and with additional research, the results would suggest that drug developers could design trials with lower placebo response rates simply by altering the inclusion criteria slightly. This would potentially help increase the chances that new medication trials are successful against placebo, thus helping make new treatments available to patients suffering from MDD.

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