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

J Clin Psychiatry. 2017 Mar;78(3):317-323. doi: 10.4088/JCP.15m09972.

Abstract

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 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.

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.

Trial registration: ClinicalTrials.gov identifiers: NCT00840034, NCT01173601, NCT01187407, NCT01185340, NCT00795821.

Publication types

  • Dataset

MeSH terms

  • Adrenergic Uptake Inhibitors / adverse effects
  • Adrenergic Uptake Inhibitors / therapeutic use*
  • Adult
  • Clinical Trials as Topic
  • Depressive Disorder, Major / drug therapy*
  • Depressive Disorder, Major / physiopathology*
  • Depressive Disorder, Major / psychology
  • Depressive Disorder, Treatment-Resistant / drug therapy*
  • Depressive Disorder, Treatment-Resistant / physiopathology*
  • Depressive Disorder, Treatment-Resistant / psychology
  • Drug Therapy, Combination
  • Humans
  • Morpholines / adverse effects
  • Morpholines / therapeutic use*
  • Norepinephrine / physiology*
  • Phenylethyl Alcohol / adverse effects
  • Phenylethyl Alcohol / analogs & derivatives*
  • Phenylethyl Alcohol / therapeutic use
  • Prognosis
  • Psychiatric Status Rating Scales
  • Psychometrics
  • Selective Serotonin Reuptake Inhibitors / adverse effects
  • Selective Serotonin Reuptake Inhibitors / therapeutic use

Substances

  • Adrenergic Uptake Inhibitors
  • Morpholines
  • Serotonin Uptake Inhibitors
  • alpha-((5-fluoro-2-methoxyphenyl)methyl)-alpha-(tetrahydro-2H-pyran-4-yl)-2-morpholinemethanol
  • Phenylethyl Alcohol
  • Norepinephrine

Associated data

  • ClinicalTrials.gov/NCT00795821
  • ClinicalTrials.gov/NCT00840034
  • ClinicalTrials.gov/NCT01173601
  • ClinicalTrials.gov/NCT01185340
  • ClinicalTrials.gov/NCT01187407
  • ClinicalTrials.gov/NCT01187407
  • ClinicalTrials.gov/NCT00840034
  • ClinicalTrials.gov/NCT01173601
  • ClinicalTrials.gov/NCT01185340
  • ClinicalTrials.gov/NCT00795821