Comparing HAMD17 and HAMD subscales on their ability to differentiate active treatment from placebo in randomized controlled trials

Abstract

BackgroundThe 17-item Hamilton depression rating scale (HAMD17) is the standard efficacy outcome in antidepressant clinical trials. It is criticized for multidimensionality and poorly discriminating treatment from placebo. HAMD subscales may overcome these limitations and reduce the sample size of clinical trials. This study compared the discriminative performance of the HAMD17 and three established HAMD subscales (Bech, Maier-Philipp, Gibbons) across a range of antidepressants with different mechanisms of action. MethodsWe analyzed data from 24 clinical trials including 3692 patients randomized to tricyclic or tetracyclic antidepressants (TCAs or TeCAs), selective serotonin reuptake inhibitors (SSRIs) or placebo. Data were analyzed using a mixed model for repeated measurements (MMRM). Standardized effect sizes for the HAMD17 and subscales were derived for every time-point, and their effect on sample size was evaluated. ResultsFor TCAs and TeCAs vs. placebo, the HAMD17 consistently provided the highest standardized effects. The sample size to establish efficacy at week six was >25 percent smaller than for any of the subscales. However, for SSRIs vs. placebo, the HAMD17 provided slightly smaller standardized effects and was the least efficient outcome. There were no relevant differences between the subscales. LimitationsData were derived exclusively from mirtazapine trials. Conclusions are restricted to clinical trial settings. ConclusionsComparative performance of the HAMD17 and various subscales strongly depends on type of antidepressant. Results support using HAMD17 as primary endpoint in clinical trials, but it will be beneficial to pro-actively include subscales as additional endpoints to successfully establish treatment effects of new antidepressants.