Pramipexole in Refractory Bipolar Depression
To the Editor: Pramipexole, a direct dopamine agonist with D3 receptor selectivity, recently approved by the FDA for the treatment of Parkinson’s disease (1), has been reported to be as effective as fluoxetine in the treatment of major depression (unpublished 1997 study by Corrigan and Evans) and an effective neuroleptic adjunct for the negative symptoms of schizophrenia (2). We report two cases of treatment-resistant bipolar depression where improvement followed augmentation with pramipexole.
Mr. A, a 50-year-old man with a 23-year history of bipolar I disorder and over 15 hospitalizations, had recurrent dysphoric manias and major depressions with reversed vegetative signs. There was a remote period of cocaine abuse and a dense family history of bipolar illness. Past manias had responded poorly to lithium, carbamazepine, and valproate monotherapies or combinations. Incidents of depression persisted despite regimens of bupropion; however, low doses of sertraline triggered mania. Depressions previously responded to ECT but resisted a course of 40 bilateral treatments. Mr. A’s condition was stable for over 1 year on a high-dose regimen of lamotrigine and clonazepam, until he was rehospitalized for anergic depression that was unresponsive to lithium augmentation. Pramipexole was begun at a dose of 0.25 mg/day and increased over 10 days to 0.75 mg/day. Within 1 week, marked improvement was noted in mood and activity. Euthymia was achieved, and Mr. A remained without side effects at his 8-week follow-up.
Mr. B, a 33-year-old artist with a 15-year history of bipolar I illness and alcohol abuse (in remission), had 14 hospitalizations for both psychotic depressions and manias. His episodes improved minimally with lithium, carbamazepine, valproate, verapamil, and gabapentin alone and in combination with adjunctive typical neuroleptics and benzodiazepines. Sertraline, tricyclics, and one course of ECT were ineffective for his depressions. Nortriptyline and venlafaxine each induced dysphoric mania and cycling. Bupropion plus lithium and lamotrigine provided substantial improvement until he developed a tolerance after 2 months.
Olanzapine, topiramate, and lamotrigine controlled mania and cycling until severe depression recurred, with reversed vegetative signs, prompting a trial of pramipexole. Mr. B was given a 1-mg/day dose of pramipexole; after 6 weeks, a marked antidepressant response occurred, and the drug was well tolerated except for transient, dose-related nausea. Subsequently, a brief depressive exacerbation resolved itself without medication changes. Mr. B’s functional improvement, with only low-grade depression and no cycling, continued through his 6-month follow-up.
The greater density of D3 receptors in the mesolimbic areas (3) involved in mood regulation may relate to pramipexole’s efficacy in psychomotor-retarded conditions (i.e., negative symptoms, Parkinson’s disease, depression). Controlled studies of pramipexole, in doses of 0.25–10.25 mg/day over 4–8 weeks (2, unpublished 1997 study by Corrigan and Evans), are encouraged to clarify dose-related acute and long-term efficacy in bipolar depression, possible side effects (e.g., insomnia, fatigue, dyskinesias, orthostatic hypotension, hallucinations), potential induction of mania/psychosis, and preferential response in atypical versus melancholic depression.
1. Parkinson Study Group: Safety and efficacy of pramipexole in early Parkinson disease: a randomized dose-ranging study. JAMA 1997; 278:125–130Crossref, Medline, Google Scholar
2. Kasper S, Barnas C, Heiden A, Volz HP, Laakmann G, Zeit H, Pfolz H: Pramipexole as adjunct to haloperidol in schizophrenia: safety and efficacy. Eur Neuropsychopharmacol 1997; 7:65–70Crossref, Medline, Google Scholar
3. Levesque D, Diaz J, Pilon C, Martres MP, Giros B, Souil E, Schott D, Morgat JL, Schwartz JC, Sokoloff P: Identification, characterization, and localization of the dopamine D3 receptor in rat brain using 7-[3H]hydroxy-N,N-di-n-propyl-2-aminotetralin. Proc Natl Acad Sci USA 1992; 89:8155–8159Google Scholar
