Is the Noradrenergic Symptom Cluster a Valid Construct in Adjunctive Treatment of Major Depressive Disorder?

Objective: To identify symptoms potentially representative of a noradrenergic symptom cluster as possible predictors of response to the selective norepinephrine reuptake inhibitor (NRI) edivoxetine when used as monotherapy or adjunctive treatment in patients with DSM-IV-TR major depressive disorder (MDD). Methods: Pooled data from 4 adjunctive treatment trials (selective serotonin reuptake inhibitor [SSRI] + edivoxetine 6-18 mg/d vs SSRI + placebo; N = 2,066) and data from 1 monotherapy trial (edivoxetine 6-18 mg/d versus placebo; N = 495) were used to identify predictors of response related to noradrenergic symptoms using a resampling-based ensemble tree method. The trials were conducted from 2008 to 2013. Results: In the pooled adjunctive trials, no subgroup was identified that demonstrated a greater edivoxetine-placebo treatment difference than the overall patient cohort. In the edivoxetine monotherapy trial, no subgroup showing greater mean edivoxetineplacebo differences on the Montgomery-Asberg Depression Rating Scale versus the overall patient cohort was identified; a subgroup (67%) with high baseline Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ) total score (>= 28) showed statistically significantly (P =.02) greater mean edivoxetineplacebo differences on the Sheehan Disability Scale versus the overall patient cohort, and subgroups with baseline CPFQ total score >= 28 (65%), CPFQ cognition dimension score >= 16 (63%), or CPFQ physical dimension score = 13 (59%) showed statistically significantly (P <=.025) greater mean edivoxetine-placebo differences on the CPFQ total score versus the overall patient cohort. Conclusions: While we could not identify symptoms predictive of response to the selective NRI edivoxetine used as adjunctive treatment, impaired cognition and physical symptoms may predict greater improvement during monotherapy.