Efficacy of new-generation antidepressants assessed with the Montgomery-Asberg Depression Rating Scale, the gold standard clinician rating scale: A meta-analysis of randomised placebo-controlled trials

Abstract

Background: It has been claimed that efficacy estimates based on the Hamilton Depression Rating-Scale (HDRS) underestimate antidepressants true treatment effects due to the instrument's poor psychometric properties. The aim of this study is to compare efficacy estimates based on the HDRS with the gold standard procedure, the Montgomery-Asberg Depression Rating-Scale (MADRS).

Methods and findings: We conducted a meta-analysis based on the comprehensive dataset of acute antidepressant trials provided by Cipriani et al. We included all placebo-controlled trials that reported continuous outcomes based on either the HDRS 17-item version or the MADRS. We computed standardised mean difference effect size estimates and raw score drug-placebo differences to evaluate thresholds for clinician-rated minimal improvements (clinical significance). We selected 109 trials (n = 32,399) that assessed the HDRS-17 and 28 trials (n = 11,705) that assessed the MADRS. The summary estimate (effect size) for the HDRS-17 was 0.27 (0.23 to 0.30) compared to 0.30 (0.22 to 0.38) for the MADRS. The effect size difference between HDRS-17 and MADRS was thus only 0.03 and not statistically significant according to both subgroup analysis (p = 0.47) and meta-regression (p = 0.44). Drug-placebo raw score difference was 2.07 (1.76 to 2.37) points on the HDRS-17 (threshold for minimal improvement: 7 points according to clinician-rating and 4 points according to patient-rating) and 2.99 (2.24 to 3.74) points on the MADRS (threshold for minimal improvement: 8 points according to clinician-rating and 5 points according to patient-rating).

Conclusions: Overall there was no meaningful difference between the HDRS-17 and the MADRS. These findings suggest that previous meta-analyses that were mostly based on the HDRS did not underestimate the drugs' true treatment effect as assessed with MADRS, the preferred outcome rating scale. Moreover, the drug-placebo differences in raw scores suggest that treatment effects are indeed marginally small and with questionable importance for the average patient.

Fig 1. PRISMA study flowchart.

Literature search and study selection conducted by Cipriani et al. [6] is depicted in grey, our own further study selection for this particular analysis is depicted in black. RCTs: randomized controlled trials; HDRS-17: Hamilton Depression Rating Scale 17-item version, MADRS: Montgomery-Asberg Depression Rating Scale.

Fig 2. Meta-analytic results across all antidepressants and for individual antidepressants with sufficient number of trials (k≥3).

Horizontal lines denote the 95% confidence intervals of the point estimates. Meta-analytic results for trials using the HDRS-17 and the MADRS are depicted in grey and black, respectively. The vertical dashed line indicates the overall result (SMD = 0.29) from the Cipriani et al. [6] dataset as reported by Munkholm et al. [11].