Bipolar affective disorder (BPD, manic-depressive illness) is a common, severe, chronic and often life-threatening illness. Increasingly, the depressive phase of the illness is recognized as contributing much of the morbidity and mortality. Impairment in physical and social functioning resulting from depression can be just as severe as other chronic medical illnesses. Suicide is the cause of death in 10-20% of individuals with either bipolar or recurrent depressive disorders. The treatments for acute unipolar depression have been extensively researched. However, despite the availability of a wide range of antidepressant drugs, clinical trials indicate that 30% to 40% of (unipolar) depressed patients fail to respond to first-line antidepressant treatment, despite adequate dosage, duration, and compliance. Very few studies have examined the efficacy of somatic treatments for the acute phase of bipolar depression. Thus, there is a clear need to develop novel and improved therapeutics for bipolar depression. A deficiency of dopamine systems stands as a prime candidate for involvement in the pathophysiology of depression. Preliminary studies suggest that pramipexole (Mirapex), a dopaminergic-agent that is FDA-approved for Parkinson?s disease, may have antidepressant properties in unipolar and bipolar patients as well as neurotrophic properties. In this study, we propose to investigate the potential efficacy of pramipexole, which enhances dopaminergic throughput via D2 and D3 receptors and exerts robust neurotrophic effects via direct intracellular mechanisms. This is a 6-week randomized double-blind, placebo-controlled add-on study that will examine the efficacy of pramipexole in acutely depressed Bipolar II patients. This study has three phases. The first phase is the washout phase that will last for 14 days. The second phase is a 6-week double-blind acute phase in which the efficacy and tolerability of adjunctive pramipexole and placebo are compared. Patients who complete the 6-week double-blind phase will receive either open-label pramipexole or clinical treatment. Acute efficacy will be determined by demonstrating a greater response rate using specified criteria. Patients, ages 18 to 70, with a diagnosis of Bipolar II disorder, depressed (without psychotic features), will be randomized to double-blind treatment to receive either pramipexole (0.375-4.5 mg/day) or placebo in combination with a mood stabilizer for a period of 6 weeks. Following this acute period, the patients will receive either open-label pramipexole or treatment as clinically indicated. Approximately 100 patients with acute Bipolar II depression will be enrolled in the study. Imaging and pharmacokinetic studies will be obtained during the study. So far, twenty one patients with DSM-IV bipolar II disorder, depressive phase were randomly assigned to treatment with pramipexole (N=10) or placebo (N=11). Primary efficacy was assessed by change from baseline in scores of the Montgomery-Asberg Depression rating scale. All subjects except for one in each group completed the study. The Analysis of Covariance (ANCOVA) for total Montgomery-Asberg Depression Rating Scale (MADRS) scores showed a significant treatment effect with no time effect or interaction between treatment and time. Response (>50 decrease in MADRS from baseline) occurred in 60% of patients taking pramipexole and 9% taking placebo (p=.02). Mean percentages in improvement from baseline MADRS depression ratings were greater with pramipexole (47%) than placebo (12.4%) (p<.05). One subject on pramipexole and two on placebo developed hypomanic symptoms. The dopamine agonist pramipexole was found to have significant antidepressant effects in patients with bipolar II depression. This suggests that a deficiency in the dopaminergic system may be involved in the pathophysiology of this disorder. Brain neuroimaging investigation is currently undergoing to determine volumetric (MRI), functional (PET), and neurochemical (MRS) changes related with the administration and antidepressant response associated to pramipexole.