Pramipexole in unipolar and bipolar depression

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To review the evidence for this use of pramipexole in the treatment of unipolar and bipolar depression, a literature search on Embase and Medline was conducted in December 2003. The search was updated in July 2004. The reference sections of retrieved papers were searched for further relevant references.

There are limited data on the clinical use of pramipexole in affective disorders. Only two double-blind trials in bipolar depression and one in unipolar depression were retrieved. Most information is in the form of case reports and open studies. No dose-response relationships have been established and a wide range of doses has been employed in the reports.

In view of the fact that the evidence for the use of pramipexole is still limited at the time of writing, its routine clinical use cannot be recommended. The data appear promising, but further research is required to determine its role in affective disorders.

The monoamine hypothesis of depression has been the driving force behind antidepressant drug development for several decades. The theory holds that lower levels of serotonin, noradrenaline and dopamine may be involved in the pathophysiology of depression. The place of serotonin and noradrenaline in the clinical development of depression is well established. Most currently available antidepressants are thought to act via inhibition of the neuronal reuptake of either or both of these neuro-transmitters.

More recently, an increased interest in the role of dopamine in the aetiology of depression has developed. This interest derives in part from the dopamine hypothesis of reward. In simple terms, pleasurable activity is associated with release of dopamine in the brain reward system (BRS). Conversely, inactivation of dopamine function can lead to anhedonia, the inability to experience pleasure, which is a core feature of depression. Furthermore, psychostimulants such as amphetamine and cocaine in low doses enhance dopamine release and cause activation and euphoria in normal volunteers. In higher doses or when taken repeatedly, they cause grandiosity, dysphoria and delusions. The withdrawal of these drugs frequently results in depression and anhedonia.

Data from animal studies and from limited human data indicate that dopamine agonists have antidepressant properties. The forced swimming test is one of the methods used to screen for antidepressant activity. When rats are forced to swim in a closed space from which they cannot escape, they will eventually stop attempting to escape and become immobile. Time to immobility in the swim test may be prolonged not only by antidepressants, but also by dopamine agonists. Furthermore, the anti-immobility effect of antidepressants in the forced swim test may be enhanced by co-administration of dopamine agonists (Maj & Rogoz, 1999; Renard et al, 2001). In humans, the dopamine agonist bromocriptine has been shown to be as effective as imipramine in the treatment of depression (Willner, 1983). For a review of dopamine in depression, see Willner (1995) and Rampello et al (2000).

Only a limited number of antidepressant drugs have potent activity on dopaminergic transmission. Of the antidepressants currently in use in the UK, the tricycle antidepressants only have a very weak effect on dopamine reuptake, while venlafaxine and sertraline have more substantial, but still limited, dopaminergic effects, albeit at higher doses. Bupropion, amineptine and nomifensine are dopaminergic antidepressants that act partly via inhibition of dopamine reuptake. Bupropion is licensed in the UK only for smoking cessation. Amineptine has been withdrawn from major markets because of its propensity for addiction, while nomifensine, a selective dopamine reuptake inhibitor, was withdrawn due to the risk of acute haemolytic anaemia and intravascular hemolysis. There is no dopamine agonist currently licensed for the treatment of depression.

Pramipexole is a recently introduced dopamine D2/D3 agonist with preferential binding affinity to D3 receptors. It was licensed in the UK in 1998 at doses ranging from 0.375 to 4.5 mg per day for idiopathic Parkinson’s disease.

We conducted a literature search in December 2003 on Medline (1966-2003) and Embase (1980-2003) using the terms ‘pramipexole’, ‘dopamine agonists’, ‘bipolar disorder’ and ‘depression’. The search was updated in July 2004. The reference section of retrieved papers were hand-searched for further relevant references.

Conclusion
Data on the efficacy of pramipexole are still very limited. There is possibly a subgroup of patients who may respond preferentially to dopaminergic agents. At present, there is insufficient evidence to recommend the routine use of pramipexole. However, it may be considered as an alternative in patients with refractory unipolar and bipolar depression, in particular patients with marked motor retardation, hypersomnia, reduced sexual activity or melancholic features. It may also be considered as an option for the treatment of depression in patients wit Parkinson’s disease. There is no established dose and nausea is a dose-limiting adverse effect. The possibility of a manic switch, psychosis and other CNS manifestations should be borne in mind. Further studies are needed to establish the role of pramipexole in the treatment of unipolar and bipolar depression.

Full Text

Eromona Whiskey

Principal Pharmacist, Maudsley Hospital, Denmark Hill, London SE5 8AZ.

David Taylor

Chief Pharmacist, Maudsley Hospital, Denmark Hill, London, E-mail:

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