Brain reward system activity in major depression and comorbid nicotine dependence.

Major depressive disorder (MDD) and nicotine dependence are highly comorbid. MDD patients may use nicotine to ameliorate depressive symptoms. The pathophysiology of the comorbidity of these two disorders is unknown. We hypothesized that a dysfunctional dopaminergic brain reward system (BRS) might be a neurobiological link between MDD and nicotine dependence and that smoking modulates the activity of the BRS by enhancing dopaminergic activity and relieving some depressive symptoms. Eighteen nicotine-dependent, nonmedicated subjects with Diagnostic and Statistical Manual of Mental Disorders (4th edition) diagnosis of MDD and 16 nicotine-dependent, control subjects participated in a double-blind, placebo-controlled, randomized parallel study. A single 30-mg oral dose of d-amphetamine (d-amph) was used to release dopamine and probe the activity of the BRS. The d-amph-mediated physiological and rewarding effects were assessed at baseline and post-treatment using standardized and validated questionnaires. Our results show that d-amph significantly increased blood pressure (p < 0.001). Subjective rewarding d-amph effects increased in both groups. Negative subjective effects were reported while on placebo during nonsmoking sessions. A significant correlation between depression severity (Hamilton depression scale) and d-amph rewarding effects was found in MDD smoker subjects (Addiction Research Center Inventory composite: r = 0.89, p < 0.000; profile of mood states composite: r = 0.71, p < 0.003; and visual analog scales composite: r = 0.78, p < 0.005). These data show that smoking did not modify the response to d-amph in MDD or control subjects, but decreased overall negative mood state during placebo sessions. Severity of depression was significantly correlated with increased rewarding effects of d-amph. Thus, although the BRS may be dysfunctional in MDD subjects, chronic nicotine use does not modify response to d-amph.