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Altered Response to Dextroamphetamine

Lescia K. Tremblay, BSc; Claudio A. Naranjo, MD; Laura Cardenas, MD; Nathan Herrmann, MD; Usoa E. Busto, PharmD

Arch Gen Psychiatry. 2002;59:409-416.

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 R² = 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.

From the Psychopharmacology Research Program, Sunnybrook & Women's College Health Sciences Centre–Sunnybrook Campus (Ms Tremblay and Drs Naranjo, Herrmann, and Busto), the Centre for Addiction and Mental Health, Addiction Research Centre Site (Drs Cardenas and Busto), and the Departments of Pharmacology (Drs Cardenas, Herrmann, and Busto), Psychiatry (Drs Naranjo and Herrmann), Medicine (Drs Naranjo and Herrmann), and Pharmaceutical Sciences (Ms Tremblay and Dr Busto), University of Toronto, Toronto, Ontario.

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