The purpose of this study is to examine the safety and effectiveness of the drug pramipexole
given in combination with lithium or divalproex for the short-term treatment of acute
depression in patients with bipolar disorder.
Bipolar disorder is a severe, chronic, and often life-threatening illness. Treatments for
acute unipolar depression have been extensively researched. However, despite the
availability of a wide range of antidepressant drugs, a significant proportion of depressed
patients fail to respond to first-line antidepressant treatment. Novel and improved
therapeutics for bipolar depression are needed. This study will evaluate the antidepressant
properties of pramipexole.
This study will be conducted in three phases. Phase 1 is a 14-day washout period in which
participants will be tapered off all their psychiatric medicines except divalproex or
lithium. Participants will also be asked to adhere to a low caffeine and low monoamine diet.
During Phase 2, participants will be randomly assigned to receive either pramipexole or
placebo (an inactive pill) for 6 weeks. Participants who respond to treatment will be given
either open-label pramipexole or another clinical treatment.
Participants will be screened with a medical history, physical examination,
electrocardiogram (EKG), blood and urine tests, and a psychiatric evaluation. Women of
childbearing potential will have a pregnancy test. Participants will have a physical exam
and EKG at study entry and study completion. Blood will be drawn at various times throughout
the study. Pulse and blood pressure measurements will be taken daily. Weekly interviews will
be conducted. Participants and a control group of healthy volunteers will undergo positron
emission tomography (PET) and magnetic resonance imaging (MRI) scans of the brain.
Bipolar affective disorder (BPD, manic-depressive illness) is a common, severe, chronic and
often life-threatening illness. Increasingly, it is being recognized that it is the
depressive phase of the illness, which contributes 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
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
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.
Male or female subjects, 18 to 70 years of age.
Female subjects of childbearing potential must be using a medically accepted means of
Each subject must understand the nature of the study and must sign an informed consent
Subjects must fulfill the criteria for Bipolar II disorder depressed without psychotic
features as defined in DSM-IV (296.89) based on clinical assessment and confirmed by
structured diagnostic interview SCID-P.
Subjects must have an initial score at Visit 1 and Visit 2 of at least 20 on the MADRS.
Subjects must have experienced, in the opinion of the investigator, at least two previous
hypomanic and two major depressive episodes as defined in DSM-IV.
Subjects must have failed to respond in the past to an adequate dose and duration of at
least one antidepressant (SSRI, bupropion, or venlafaxine) during an episode of major
Subjects must take VPA or lithium (valproate 50-125 microg/ml or lithium 0.6-1.2 mEq/L)
for at least 4 weeks prior to Visit 2. At least two blood levels of lithium and VPA must
be within therapeutic range (each at least 1 week apart) prior to Visit 2. If the subject
is not taking lithium or VPA, the research physician may start them on lithium or VPA at
Current major depressive episode no more than 24 months.
Presence of psychotic features
Participating in a clinical trial of another investigational drug within 1 month prior to
study entry (Visit 1).
Female subjects who are either pregnant or nursing.
Serious, unstable illnesses including hepatic, renal, gastroenterologic, respiratory,
cardiovascular (including ischemic heart disease), endocrinologic, neurologic,
immunologic, or hematologic disease.
Subjects with uncorrected hypothyroidism or hyperthyroidism.
Subjects with one or more seizures without a clear and resolved etiology.
Documented history of hypersensitivity or intolerance to pramipexole
DSM-IV substance abuse (except nicotine and caffeine) within the past 90 days and
substance dependence within the past 5 years.
Subjects with a DSM-IV rapid cycling course of illness in the past 12-months.
Treatment with an injectable depot neuroleptic within less than one dosing interval prior
to Visit 2.
Treatment with a reversible MAOI, guanethidine, or guanadrel within 1 week prior to Visit
Treatment with fluoxetine within 4 weeks prior to Visit 2.
Treatment with any other concomitant medication (Appendix B) 1 day prior to Visit 2.
Treatment with clozapine or ECT within 3 months prior to Visit 2.
Current diagnosis of schizophrenia or other psychotic disorder as defined in the DSM-IV.
Judged clinically to be at serious suicidal risk.
Patients will not be allowed to receive structured psychotherapy during the trial.