We examined the effect of early treatment response on the Quick Inventory of Depressive Symptomatology (QIDS-SR 16) within 2 weeks following randomization on the eventual treatment outcome at 6 weeks in a doubleblind study of subjects with major depressive disorder randomly assigned to a combination treatment (buspirone 15 mg with melatonin SR 3 mg), buspirone 15 mg, or placebo (Clinicaltrials.org: NCT 007005003). The extent of QIDS-SR 16 score improvement between baseline and week 2 was significantly associated with higher treatment response rates at week 6 (≥50% QIDS-SR 16 improvement from baseline) regardless of treatment assignment. Thirty-two of 123 subjects (26.0%) were QIDS-SR 16 treatment responders by week 2 and were excluded in a post-hoc analysis of five clinical metrics: QIDS-SR 16 , the Inventory of Depressive Symptomatology (IDS-c30), clinical global impression of severity and improvement scales, and Hamilton rating scale for anxiety. The effect size favoring the combination-treatment over buspirone and/or placebo increased on each of the 5 clinical metrics in the remaining 91 subjects with < 50% QIDS-SR 16 improvement at week 2. For instance, the effect size favoring the combination treatment over the pooled buspirone and placebo groups improved from 0.33 in the mITT population to 0.64 for the QIDS-SR 16 , and from 0.37 to 0.58 for the IDS-c30. Further, the statistical significance favoring the combination treatment improved from p = .055-.017 for the QIDS-SR 16. This was a post-hoc analysis of a small MDD study, but it is clear that future studies need to explore the mediating factors that affect signal detection and influence individual treatment response.

Ratings surveillance is used in clinical trials to assure ratings reliability of site-based scores. One surveillance method employs audio-digital recordings of site-based clinician interviews to obtain remote, site-independent scores for assessment of paired scoring concordance and interview quality. We examined the utility of this surveillance strategy using paired site-independent scores derived from recorded site-based Montgomery-Asberg depression rating scale (MADRS) interviews obtained from patients with major depressive disorder (MDD) participating in 5 clinical trials.High correlations were noted between the 3736 paired site-based and site-independent scores across all visits. Some rater “outliers” were identified whose ratings performance improved following remediation. In 3 studies with available outcome data, the blinded remote ratings yielded a high predictive value (91.2%) for replicating treatment response rates.The magnitude of the total MADRS scores affected the directionality of paired scoring deviations in each of the 5 studies. Across all visits, site-based raters scored the more severe MADRS scores (≥30) higher than site-independent raters and the less severe MADRS scores (<20) lower than site-independent raters. Individual MADRS items were similarly affected by the directionality of symptom severity.This analysis affirms the utility of audio-digital recording of site-based interviews as a surveillance strategy for quality assurance (monitoring and remediation). In addition, the high predictive value of blinded remote ratings to replicate site-based treatment outcomes may be useful to affirm primary site-based results when there is a potential of functional unblinding. The use of remote ratings as a primary measure beyond its utility for quality assurance needs further exploration.

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