Neuroticism as a mediator of treatment response to SSRIs in major depressive disorder

J Affect Disord. 2008 Nov;111(1):67-73. doi: 10.1016/j.jad.2008.02.006. Epub 2008 Apr 2.


Background: Serotonin function has been implicated in both major depressive disorder and neuroticism. In the current investigation, we examined the hypothesis that any change in depression severity is mediated through the reduction of neuroticism, but only for those compounds which target serotonin receptors.

Methods: Ninety-three outpatients in the midst of a major depressive episode received one of three antidepressant medications, classified into two broad types: selective serotonin reuptake inhibitors (SSRIs) and non-SSRIs (i.e. reversible monoamine oxidase inhibitors [RIMAs] and noradrenergic and dopaminergic reuptake blockers [NDMs]). Patients completed the Hamilton Rating Scale for Depression, Beck Depression Inventory II and Revised NEO Personality Inventory prior to and following approximately 16 weeks of treatment. Structural equation modeling was used to test two models: a mediation model, in which neuroticism change is the mechanism by which SSRIs exert a therapeutic effect upon depressive symptoms, and a complication model, in which neuroticism change is a mere epiphenomenon of depression reduction in response to SSRIs.

Results: The mediation model provided a good fit to the data; the complication model did not. Patients treated with SSRIs demonstrated greater neuroticism change than those treated with non-SSRIs, and greater neuroticism change was associated with greater depressive symptom change. These effects held for both self-reported and clinician-rated depressive symptom severity.

Limitations: Replication within a randomized control trial with multiple assessment periods is required.

Conclusion: Neuroticism mediates changes in depression in response to treatment with SSRIs, such that any treatment effect of SSRIs occurs through neuroticism reduction.

Publication types

  • Clinical Trial
  • Comparative Study
  • Randomized Controlled Trial

MeSH terms

  • Adrenergic Uptake Inhibitors / therapeutic use
  • Adult
  • Ambulatory Care
  • Depressive Disorder, Major / diagnosis
  • Depressive Disorder, Major / drug therapy*
  • Depressive Disorder, Major / psychology
  • Female
  • Humans
  • Male
  • Monoamine Oxidase Inhibitors / therapeutic use
  • Neurotic Disorders / diagnosis
  • Neurotic Disorders / drug therapy*
  • Neurotic Disorders / psychology
  • Personality / classification*
  • Personality Inventory
  • Psychiatric Status Rating Scales
  • Serotonin Uptake Inhibitors / therapeutic use*
  • Severity of Illness Index
  • Treatment Outcome


  • Adrenergic Uptake Inhibitors
  • Monoamine Oxidase Inhibitors
  • Serotonin Uptake Inhibitors