Functional neuroanatomical substrates of altered reward processing in major depressive disorder revealed by a dopaminergic probe

Context: The pathophysiology of major depressive disorder (MDD) includes disturbances in several neuroanatomical substrates and neuro transmitter 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; t(21)=2.74, P=.01), with altered brain activation in the ventrolaterial prefrontal cortex and the orbitofrontal cortex and the caudate and putamen (F-1,F-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.