Personality change during depression treatment: a placebo-controlled trial

Arch Gen Psychiatry. 2009 Dec;66(12):1322-30. doi: 10.1001/archgenpsychiatry.2009.166.


Context: High neuroticism is a personality risk factor that reflects much of the genetic vulnerability to major depressive disorder (MDD), and low extraversion may increase risk as well. Both have been linked to the serotonin system.

Objectives: To test whether patients with MDD taking selective serotonin reuptake inhibitors (SSRIs) report greater changes in neuroticism and extraversion than patients receiving inert placebo, and to examine the state effect hypothesis that self-reported personality change during SSRI treatment is merely a change of depression-related measurement bias.

Design: A placebo-controlled trial.

Setting: Research clinics. Patients Adult patients with moderate to severe MDD randomized to receive paroxetine (n = 120), placebo (n = 60), or cognitive therapy (n = 60).

Outcome measures: NEO Five-Factor Inventory and Hamilton Rating Scale for Depression.

Results: Patients who took paroxetine reported greater personality change than placebo patients, even after controlling for depression improvement (neuroticism, P < .001; extraversion, P = .002). The advantage of paroxetine over placebo in antidepressant efficacy was no longer significant after controlling for change in neuroticism (P = .46) or extraversion (P = .14). Patients taking paroxetine reported 6.8 times as much change on neuroticism and 3.5 times as much change on extraversion as placebo patients matched for depression improvement. Although placebo patients exhibited substantial depression improvement (Hamilton Rating Scale for Depression score, -1.2 SD, P < .001), they reported little change on neuroticism (-0.18 SD, P = .08) or extraversion (0.08 SD, P = .50). Cognitive therapy produced greater personality change than placebo (P </= .01); but its advantage on neuroticism was no longer significant after controlling for depression (P = .14). Neuroticism reduction during treatment predicted lower relapse rates among paroxetine responders (P = .003) but not among cognitive therapy responders (P = .86).

Conclusions: Paroxetine appears to have a specific pharmacological effect on personality that is distinct from its effect on depression. If replicated, this pattern would disconfirm the state effect hypothesis and instead support the notion that SSRIs' effects on personality go beyond and perhaps contribute to their antidepressant effects.

Publication types

  • Comparative Study
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Cognitive Behavioral Therapy / methods*
  • Depressive Disorder, Major / diagnosis
  • Depressive Disorder, Major / drug therapy*
  • Depressive Disorder, Major / therapy
  • Extraversion, Psychological
  • Humans
  • Neurotic Disorders
  • Observer Variation
  • Paroxetine / pharmacology
  • Paroxetine / therapeutic use*
  • Personality / classification
  • Personality / drug effects*
  • Personality Inventory / statistics & numerical data
  • Placebos
  • Psychiatric Status Rating Scales / statistics & numerical data
  • Selective Serotonin Reuptake Inhibitors / pharmacology
  • Selective Serotonin Reuptake Inhibitors / therapeutic use*
  • Severity of Illness Index
  • Treatment Outcome


  • Placebos
  • Serotonin Uptake Inhibitors
  • Paroxetine