Probing brain reward system function in major depressive disorder: altered response to dextroamphetamine

Arch Gen Psychiatry. 2002 May;59(5):409-16. doi: 10.1001/archpsyc.59.5.409.


Background: The state of the brain reward system in major depressive disorder was assessed with dextroamphetamine, which probes the release of dopamine within the mesocorticolimbic system, a major component of the brain reward system, and produces measurable behavioral changes, including rewarding effects (eg, euphoria). We hypothesized that depressed individuals would exhibit an altered response to dextroamphetamine due to an underlying brain reward system dysfunction reflected by anhedonic symptoms.

Methods: In a double-blind, placebo-controlled, randomized, parallel study, the behavioral and physiological effects of a single 30-mg dose of oral dextroamphetamine sulfate were measured. Forty patients with a diagnosis of DSM-IV major depressive disorder who were not taking antidepressant medications (22 assigned to dextroamphetamine and 18 to placebo) were compared with 36 control subjects (18 assigned to dextroamphetamine and 18 to placebo) using validated self-report drug effect measurement tools (eg, the Addiction Research Center Inventory), heart rate, and blood pressure.

Results: Multiple regression analysis showed that severity of depression as measured by the Hamilton Rating Scale for Depression correlated highly with the rewarding effects of dextroamphetamine in the depressed group (model R(2) = 0.63; interaction P =.04). A subsequent analysis categorizing the depressed group into patients with severe symptoms (Hamilton score >23) and those with moderate symptoms revealed a significant interaction between drug and depression (P =.02). Patients with severe symptoms reported rewarding effects 3.4-fold greater than controls.

Conclusions: The results suggest the presence of a hypersensitive response is present in the brain reward system of depressed patients, which may reflect a hypofunctional state and may provide a novel pathophysiologic and therapeutic target for future studies.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Blood Pressure / drug effects
  • Brain / drug effects*
  • Brain / physiopathology
  • Depressive Disorder / diagnosis*
  • Depressive Disorder / physiopathology*
  • Dextroamphetamine / pharmacology*
  • Dopamine / physiology*
  • Double-Blind Method
  • Emotions / drug effects
  • Emotions / physiology
  • Euphoria / drug effects
  • Euphoria / physiology
  • Female
  • Heart Rate / drug effects
  • Humans
  • Limbic System / drug effects
  • Limbic System / physiopathology
  • Male
  • Middle Aged
  • Neural Pathways / drug effects*
  • Neural Pathways / physiopathology
  • Personality Inventory
  • Placebos
  • Psychiatric Status Rating Scales
  • Regression Analysis
  • Reward*
  • Severity of Illness Index


  • Placebos
  • Dextroamphetamine
  • Dopamine