Does negative affectivity predict differential response to an SSRI versus a non-SSRI antidepressant?

J Clin Psychiatry. 2014 Sep;75(9):e939-44. doi: 10.4088/JCP.14m09025.


Objective: This work tested the hypothesis that patients with high negative affectivity (NA) would have a better response to a serotonergic agent (escitalopram) than to one not thought to act directly on serotonin (bupropion).

Method: Data from a study conducted between August 2007 and July 2011 were reanalyzed retrospectively. Patients (N = 245) meeting criteria for major depressive disorder (MDD), diagnosed with DSM-IV-TR, were randomly assigned to double-blind treatment with bupropion extended-release, escitalopram, or the combination. Negative affectivity score was estimated using the guilt, hostility/irritability, and fear/anxiety items of the Hamilton Depression Rating Scale, the Montgomery-Asberg Depression Rating Scale, the Quick Inventory of Depressive Symptoms, and the Social Adjustment Scale. We felt that these items captured published descriptions of the NA construct. A Clinical Global Impressions-Severity of Illness (CGI-S) score ≤ 2 defined response. Because combined treatment addressed both serotonin and non-serotonin systems, patients treated with both medications did not test the hypothesis and so were excluded from the analyses.

Results: Analysis of covariance with treatment as a grouping variable, NA as covariate, and CGI-S as dependent variable showed a significant 2-way interaction between treatment and NA (F₁,₁₅₆ = 4.82, P < .03). In the low-NA group, response rates were similar between treatments (escitalopram: 28/42 [67%]; bupropion: 23/40 [58%]; NS), while there was a significant advantage for escitalopram in patients with high NA (escitalopram: 24/40 [60%]; bupropion = 14/41 [34%]; P = .017).

Conclusions: These data suggest that patients with high negative affectivity respond preferentially to antidepressants that selectively enhance serotonin neurotransmission. Although patients with low NA appear to benefit from serotonin enhancement as well, they also improved with bupropion, an antidepressant not thought to directly affect serotonin neurotransmission. These findings come from retrospective analyses using unproven approximation of NA, so no clinical inferences should be made before independent replication utilizing accepted NA measurement.

Trial registration: identifier: NCT00519428.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Affect*
  • Antidepressive Agents, Second-Generation / administration & dosage
  • Antidepressive Agents, Second-Generation / therapeutic use*
  • Bupropion / administration & dosage
  • Bupropion / therapeutic use*
  • Citalopram / administration & dosage
  • Citalopram / therapeutic use*
  • Delayed-Action Preparations
  • Depressive Disorder, Major / drug therapy*
  • Depressive Disorder, Major / psychology
  • Double-Blind Method
  • Drug Therapy, Combination
  • Female
  • Humans
  • Male
  • Psychiatric Status Rating Scales
  • Psychological Tests
  • Retrospective Studies
  • Selective Serotonin Reuptake Inhibitors / administration & dosage
  • Selective Serotonin Reuptake Inhibitors / therapeutic use*
  • Severity of Illness Index
  • Treatment Outcome


  • Antidepressive Agents, Second-Generation
  • Delayed-Action Preparations
  • Serotonin Uptake Inhibitors
  • Bupropion
  • Citalopram

Associated data