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



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.



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 edivoxetine-placebo differences on the Montgomery-Asberg Depression Rating Scale versus the overall patient cohort was identified; a subgroup (67%) with high b​aseline Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ) total score (≥ 28) showed statistically significantly (P = .02) greater mean edivoxetine-placebo 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.



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.



ClinicalTrials.gov identifiers: NCT00840034, NCT01173601, NCT01187407, NCT01185340, NCT00795821.
Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285. vstauffer@lilly.com.|Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA.
Virginia L
VL
Stauffer
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA.
Peng
P
Liu
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA.|Dr Goldberger is now affiliated with AbbVie Pharmaceuticals in Lake Bluff, Illinois, and is no longer affiliated with Eli Lilly and Company, although she was at the time this research was done and when the manuscript was accepted for publication.
Celine
C
Goldberger
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA.|University of Texas Health Science Center, Houston, Texas, USA.
Lauren B
LB
Marangell
Department of Psychiatry, University of California, San Francisco, California, USA.
Craig
C
Nelson
Psychiatry and Neurosciences Research Center, French Institute of Health and Medical Research, Paris, France.
Philip
P
Gorwood
Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts, USA.
Maurizio
M
Fava
D018759:Adrenergic Uptake Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D000328:Adult; D002986:Clinical Trials as Topic; D003865:Major Depressive Disorder / Q000188:drug therapy* / Q000503:physiopathology* / Q000523:psychology; D061218:Depressive Disorder, Treatment-Resistant / Q000188:drug therapy* / Q000503:physiopathology* / Q000523:psychology; D004359:Drug Therapy, Combination; D006801:Humans; D009025:Morpholines / Q000009:adverse effects / Q000627:therapeutic use*; D009638:Norepinephrine / Q000502:physiology*; D010626:Phenylethyl Alcohol / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D011379:Prognosis; D011569:Psychiatric Status Rating Scales; D011594:Psychometrics; D017367:Selective Serotonin Reuptake Inhibitors / Q000009:adverse effects / Q000627:therapeutic use
D018759:Adrenergic Uptake Inhibitors; D009025:Morpholines; D009638:Norepinephrine; D010626:Phenylethyl Alcohol; D017367:Selective Serotonin Reuptake Inhibitors; C568831:alpha-((5-fluoro-2-methoxyphenyl)methyl)-alpha-(tetrahydro-2H-pyran-4-yl)-2-morpholinemethanol