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Lescia K. Tremblay, PhD; Claudio A. Naranjo, MD; Simon J. Graham, PhD; Nathan Herrmann, MD; Helen S. Mayberg, MD; Stephanie Hevenor, BSc; Usoa E. Busto, PharmD

Arch Gen Psychiatry. 2005;62:1228-1236.

Context  The pathophysiology of major depressive disorder (MDD) includes disturbances in several neuroanatomical substrates and neurotransmitter systems. The challenge is to elucidate the brain mechanisms of MDD behavioral symptoms, chiefly those of anhedonia.

Objectives  To visualize the neuroanatomical substrates implicated in altered reward processing in MDD, using functional magnetic resonance imaging in combination with a dopaminergic probe (a 30-mg dose of oral dextroamphetamine sulfate) to stimulate the brain reward system; and to test the hypothesis that a hypersensitive response to dextroamphetamine in MDD involves the prefrontal cortex and the striatum.

Design and Interventions  Among subjects with MDD and healthy control subjects, functional magnetic resonance imaging data were collected before and after single-blind administration of dextroamphetamine.

Setting  Subjects were recruited through local newspaper advertisements and by word of mouth.

Participants  Twelve depressed subjects (mean age, 34.83 years; male-female ratio, 6:6) met criteria for MDD according to the DSM-IV, were not taking antidepressants, and had no comorbid Axis I disorders. Twelve control subjects (mean age, 29.33 years; male-female ratio, 5:7) were healthy volunteers without a history of Axis I disorders.

Main Outcome Measures  Functional magnetic resonance imaging blood oxygen level–dependent activation was measured during a controlled task, and dextroamphetamine-induced subjective effects were assessed using the Addiction Research Center Inventory.

Results  Subjects with MDD had a hypersensitive response to the rewarding effects of dextroamphetamine (2-fold increase; t₂₁ = 2.74, P = .01), with altered brain activation in the ventrolateral prefrontal cortex and the orbitofrontal cortex and the caudate and putamen (F_1,44 = 11.93, P = .001).

Conclusion  Dopamine-related neuroanatomical substrates are involved in altered reward processing in MDD, shedding light on the neurobiology of the anhedonic symptoms in MDD and suggesting these substrates as future therapeutic targets.

Author Affiliations: Neuropsychopharmacology Research Program, Sunnybrook and Women’s College Health Sciences Centre, Sunnybrook Campus (Drs Tremblay, Naranjo, Herrmann, and Busto); Clinical Neuroscience Department, Centre for Addiction and Mental Health (Drs Tremblay and Busto); Rotman Research Institute (Drs Graham and Mayberg and Ms Hevenor); and Departments of Pharmaceutical Sciences (Drs Tremblay and Busto), Pharmacology (Drs Naranjo, Herrmann, and Busto), Medical Biophysics (Dr Graham), Psychiatry (Drs Naranjo, Herrmann, and Mayberg), and Medicine (Drs Naranjo, Herrmann, and Busto), University of Toronto; Toronto, Ontario.

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