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Dopamine Agonists for Bipolar Depression














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A relatively recent theory about bipolar disorder and depression is that it involves dysregulation of the dopamine system (see the article on this website). Therefore, anything that increases dopamine levels should treat bipolar depression. The following research is about the use of dopamine agonists to test this theory on treatment-resistant bipolar depression, specifically pramipexole (Mirapex), a drug developed to treat Parkinson's, which is characterized by depeleted dopamine.
















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Biol Psychiatry. 2004 Jul 1;56(1):54-60.

 
Pramipexole for bipolar II depression: a placebo-controlled proof of concept study.

Zarate CA Jr, Payne JL, Singh J, Quiroz JA, Luckenbaugh DA, Denicoff KD, Charney DS, Manji HK.

Laboratory of Molecular Pathophysiology, Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institute of Health, Department of Human and Health Services, Bethesda, Maryland, USA.

BACKGROUND: The original serotonergic and noradrenergic hypotheses do not fully account for the neurobiology of depression or mechanism of action of effective antidepressants. Research implicates a potential role of the dopaminergic system in the pathophysiology of bipolar disorder. The current study was undertaken as a proof of the concept that dopamine agonists will be effective in patients with bipolar II depression. METHODS: In a double-blind, placebo-controlled study, 21 patients with DSM-IV bipolar II disorder, depressive phase on therapeutic levels of lithium or valproate were randomly assigned to treatment with pramipexole (n = 10) or placebo (n = 11) for 6 weeks. Primary efficacy was assessed by the Montgomery-Asberg Depression Rating Scale. RESULTS: All subjects except for one in each group completed the study. The analysis of variance for total Montgomery-Asberg Depression Rating Scale scores showed a significant treatment effect. A therapeutic response (>50% decrease in Montgomery-Asberg Depression Rating Scale from baseline) occurred in 60% of patients taking pramipexole and 9% taking placebo (p =.02). One subject on pramipexole and two on placebo developed hypomanic symptoms. CONCLUSIONS: The dopamine agonist pramipexole was found to have significant antidepressant effects in patients with bipolar II depression.

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Pramipexole augmentation in the treatment of unipolar and bipolar depression: a retrospective chart review.

Sporn J, Ghaemi SN, Sambur MR, Rankin MA, Recht J, Sachs GS, Rosenbaum JF, Fava M.

Department of Psychiatry, Massachusetts General Hospital, USA. spornj@intra.NIMH.NIH.GOV

OBJECTIVE: To assess the effectiveness and safety of pramipexole as an adjunctive medication in refractory bipolar and unipolar depression in a naturalistic setting. METHODS: Retrospective chart review by psychiatrists on staff at a university hospital identified all patients who had received pramipexole. Response was based on moderate to marked improvement in the Clinical Global Impression-Improvement (CGI-I) scale. RESULTS: Pramipexole (mean dose 0.70 mg/d, mean duration 24.4 weeks) was effective in 6/12 (50.0%) of patients with bipolar depression, and 8/20 (40%) of patients with unipolar depression, mean duration of follow-up of 24.4 weeks. One case of transient hypomania was noted. Eight patients discontinued pramipexole due to lack of response and four due to side effects. CONCLUSIONS: Pramipexole, used as an adjunct to antidepressants or mood stabilizers, appeared to be effective and safe in the treatment of unipolar and bipolar depression. These uncontrolled, retrospective, naturalistic pilot data require confirmation by controlled research before conclusions can be made.

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Dopamine agonist shows bipolar II depression promise

Biol Psychiatry 2004; 56: 54–60

The dopamine agonist pramipexole appears to have significant antidepressant effects in patients with bipolar II disorder, reveal US study findings that support the involvement of the dopaminergic system in the treatment of depression.

"In recent years, there has been growing appreciation that the original serotonergic and noradrenergic hypotheses do not fully account for the neurobiology of depression or the mechanisms of effective treatments," say Carlos Zarate and colleagues from the National Institutes of Health in Bethesda, Maryland.

Recognizing that the dopaminergic system represents a "prime candidate on a number of theoretical grounds," the researchers assessed the effect of the dopamine antagonist pramipexole on bipolar II depression in 21 patients.

The patients were randomly assigned to receive treatment with either pramipexole (n=10) or placebo (n=11) for 6 weeks.

Analysis of total Montgomery-Asberg Depression Rating Scale scores showed a significant treatment effect with pramipexole, with 60% of patients achieving a therapeutic response, defined as a 50% or greater decrease in scores from baseline. This compared with just 9% of patients taking placebo.

Adverse effects were similar for the two groups, with the exception of tremor, which tended to be more common among patients in the active treatment group. However, no serious side effects were noted, and no patients discontinued treatment because of an unwanted effect.

"In conclusion, the neurotrophic D2/D3 dopamine agonist pramipexole was effective in acute bipolar II depression and was associated with low switch rates into hypomania/mania," Zarate and team write in the journal Biological Psychiatry.

"These results suggest that agents that provide trophic support and enhance throughput through the circuits implicated in mediating motivation, hedonic drive, and motoric activity may be ideal treatments for bipolar depression."

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Pramipexole shows bipolar antidepressant effect

Am J Psychiatry 2004; 161: 564-566

The addition of the dopamine agonist pramipexole to mood stabilizers could enhance the treatment response of patients with bipolar depression who have not previously responded to therapy, data from a preliminary US trial show.

Recognizing that dopamine agonists "have gained increasing attention for their possible antidepressant effects," Joseph Goldberg, from The Zucker Hillside Hospital in Glen Oaks, New York, and colleagues assessed the effect of pramipexole in depressed outpatients with non-psychotic bipolar disorder.

Twenty-two such patients were randomly assigned to receive placebo or flexibly dosed pramipexole, at an average maximum dose of 1.7 mg/day, in addition to their existing mood stabilizers.

In all, 10 (83%) of the 12 patients given pramipexole completed the 6 weeks of treatment, compared with just six (60%) of the 10 patients treated with placebo.

Notably, 57% of patients taking pramipexole achieved a 50% or greater reduction in depressive symptoms, as measured on the Hamilton Depression Rating Scale, compared with just 20% of those given placebo. Indeed, the average reduction in HAMD scores was 48% for patients taking pramipexole versus 21% for placebo-treated individuals.

Superior improvements in Clinical Global Impression scores were also seen for patients treated with pramipexole in comparison with placebo, with average scores of 2.7 and 4.4, respectively.

The drug was generally well tolerated, with no patients discontinuing treatment because of unwanted effects, although one patient did become hypomanic during the sixth week of treatment, despite taking concomitant divalproex.

Reporting in the American Journal of Psychiatry, the researchers conclude: "Pramipexole was a safe and effective antidepressant among patients with bipolar depression."

They add that larger randomized, controlled trials are warranted to confirm their initial observations.
 
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1: Pharmacopsychiatry. 2001 Jul;34(4):137-41.


Adjunctive dopamine agonists in treatment-resistant bipolar II depression: an open case series.

Perugi G, Toni C, Ruffolo G, Frare F, Akiskal H.

Department of Psychiatry, University of Pisa, Italy. gperugi@psico.med.unipi.it

OBJECTIVE: Previous studies and case observations have suggested that dopamine agonists (DAAs) such as pramipexole (PPX) and ropinirole (RPN) might be effective for major depression, but their adjunctive use in treatment-resistant bipolar II depression has not yet been specifically addressed. METHOD: A chart review was conducted on 18 patients with a DSM-III-R bipolar NOS (Bipolar II) major depressive episode who were admitted to the day-hospital of the Department of Psychiatry at the University of Pisa. DAAs were added to ongoing treatments with conventional antidepressants and mood stabilizers to which patients had no responded after a period of at least 8 weeks. Clinical state and adverse effects were assessed at each visit. Final improvement in CGI scores of 1 or 2 were considered as responders. RESULTS: Mean DAA trial duration was 17.6 (sd = 7.8, range 4-34) weeks, with a mean final dose of 1.23+/-0.32 mg/day (range, 0.75-1.50mg/day) for PPX, and 2.97+/-0.99mg/day (range, 1.50-5.00mg/day) for RPN. DAAs were well tolerated and did not show any negative interaction with concomitant psychotropic medications. Only one patient became worse (final CGI = 5), and had to interrupt PPX due to nausea, increased agitation and irritability. Eight patients (44.4%) were considered responders (4 with PPX and 4 with RPN): 5 showed marked improvement (CGI = 1), and 3 showed moderate improvement (CGI = 2); another 5 (27.8%) manifested a transient response not sustained up to the end. The initial and final scores of CGI severity scale for all patients (responders and non-responders combined) were, respectively, 5.33+/-0.7 and 3.94+/-1.3 (mean +/- S.D). The mean change according to the CCI severity scale was statistically significant (t=4.74. p < 0.0002). CONCLUSION: From the results, PPX and RPN appear to be well tolerated and potentially useful in the adjunctive treatment of drug-resistant bipolar II depression.
















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