To examine the effect of esketamine nasal spray (ESK) plus newly initiated oral antidepressant (OAD) versus OAD plus placebo nasal spray (PBO) on the association between Montgomery–Åsberg Depression Rating Scale (MADRS) and 9-item Patient Health Questionnaire (PHQ-9) scores in adults with treatment-resistant depression (TRD).

Data from TRANSFORM-1 and TRANSFORM-2 (two similarly designed, randomized, active-controlled TRD studies) and SUSTAIN-1 (relapse prevention study) were analyzed. Group differences for mean changes in PHQ-9 total score from baseline were compared using analysis of covariance. Associations between MADRS and PHQ-9 total scores from TRANSFORM-1/TRANSFORM-2 were assessed using simple parametric, nonparametric, and multiple regression models.

In TRANSFORM-1/TRANSFORM-2 (ESK + OAD, n = 343; OAD + PBO, n = 222), baseline PHQ-9 mean scores were 20.4 for ESK + OAD and 20.6 for OAD + PBO (severe depression). At day 28, significant group differences were observed in least squares mean change (SE) in PHQ-9 scores from baseline (−12.8 [0.46] vs −10.3 [0.53], P < .001) and in clinically substantial change in PHQ-9 scores (≥6 points; 77.1% vs 64%, P < .001) in ESK + OAD and OAD + PBO groups, respectively. A nonlinear relationship between MADRS and PHQ-9 was observed; total scores demonstrated increased correlation over time. In SUSTAIN-1, 57.3% of patients receiving ESK + OAD (n = 89) versus 44.2% receiving OAD + PBO (n = 86) retained remission status (PHQ-9 score ≤4) at maintenance treatment end point (P = .044).

In adults with TRD, ESK + OAD significantly improved severity of depressive symptoms, and more patients achieved clinically meaningful changes in depressive symptoms based on PHQ-9, versus OAD + PBO. PHQ-9 outcomes were consistent with those of clinician-rated MADRS.

ClinicalTrials.gov: NCT02417064, NCT02418585, NCT02493868.