An Underutilized Option for Bipolar Depression
When we find ourselves in the half-tested world of off-label therapies, what’s a psychiatrist to do?
RESEARCH UPDATE
It is not unusual to exhaust the FDA-approved therapies for bipolar depression. That is when we find ourselves in the half-tested world of off-label therapies. I have tried most of them, from anti-inflammatories to melatonin agonists, and the one that I have seen the biggest difference with is the dopamine agonist pramipexole.
Pramipexole acts preferentially on the D3 dopamine receptors in the nucleus accumbens, also known as the “pleasure center.” What that suggests is that it is uniquely suited to address two cardinal symptoms of depression: low motivation and anhedonia. In two small, randomized controlled trials, pramipexole treated bipolar depression when added to a mood stabilizer, and the effect size was large (0.77-1.1).1-3
Pramipexole also worked in controlled trials of unipolar depression, so it is a good choice when the patient’s diagnosis is unclear, such as those who don’t have full hypomania but have a family history of bipolar disorder and moods that seem to worsen with antidepressants.4
Safety and tolerability
Tolerability is one of pramipexole’s strong suits. It does not tend to cause weight gain, sexual dysfunction, or cognitive problems. The main adverse effects are nausea, which usually improves with time, and fatigue, which rarely lasts into the morning.3
Medically, pramipexole is less risky than most conventional choices for bipolar depression. There is a possible risk of congestive heart failure, and though the studies are mixed on that it is concerning enough to warrant caution in those with heart disease.5,6 Edema can be seen in those of advanced age or compromised vascular function, and its appearance should prompt a consultation with the primary care provider and a reduction or cessation of the medication.7 Orthostatic hypotension is another cardiovascular risk to watch out for on pramipexole.
The two psychiatric risks to worry about on pramipexole are hallucinations and compulsive behavior.
Hallucinations
Pramipexole does not seem to cause overt psychosis but can cause hallucinations, particularly visual ones. Patients see shadows or small creatures, usually with good insight and little distress about it. This adverse effect is rare in the mood disorder population (< 1%) and there are no reports of delusions on the drug. Nor has pramipexole exacerbated psychosis in schizophrenia, where it has been studied for negative symptoms, extrapyramidal symptoms, and hyperprolactinemia.3
In contrast, it is patients with Parkinson disease (PD) who have the greatest risk of hallucinations on pramipexole, where it is often used with FDA approval to relieve motoric symptoms. Problems with compulsivity, such as pathological gambling, are also more common in the PD population.3
Compulsivity
Pramipexole’s ability to increase hedonic drive is a blessing and a curse. On the one hand, it can make a patient more active and motivated. Rarely, that can morph into benign compulsivity. Bookshelves are sorted alphabetically, closets compartmentalized into tidy bins, and garages turn spick and span. Patients are more often amused than bothered by these tendencies, which they prefer hands-down over their recent depression. Taken too far, however, and problems start to happen. Pathological gambling is the most notorious, but more often it crops up as overspending on Amazon and eBay, excessive masturbation, or binge eating.3
The neurologic term for this syndrome is hedonistic homeostatic dysregulation (HDD). It is seen with other D3 agonists, such as aripiprazole which carries a warning about “uncontrollable urges to gamble, binge eat, shop, and have sex.” HDD is distinct from mania, and there are no reports of HDD in the 504 subjects who participated in the mood disorder studies.4 Though rare, it is worth asking about in practice as it can lead to severe problems and patients may not associate it with the drug. The cases I have seen were not associated with manic features and improved with dose reduction or complete cessation of the treatment.
How to use it
Pramipexole works as monotherapy in unipolar depression, but in bipolar disorder it should be taken in concert with a mood stabilizer. That could be lithium, valproate, or, in bipolar II patients, lamotrigine. It can also be taken with an antipsychotic, as most of these antagonize a different dopamine receptor (D2). Some, particularly haloperidol, are inverse agonists at the pramipexole site, D3 (ie, they have the opposite effect there), but pramipexole has been studied in haloperidol-treated patients with good effect. A few antipsychotics might synergize D3 effects of pramipexole, such as aripiprazole, brexpiprazole, cariprazine, and lumateperone, which are partial D3 agonists.
The ideal candidate for pramipexole is a patient with full bipolar depression who lacks mixed or psychotic features and has not recovered on FDA-approved options. Dosing is best at night, although a few find it “activating” and do better with morning dosing. Start with 0.125 mg to 0.25 mg qhs and raise by 0.25 mg every 5 to 7 days. Nausea is the most common reason for discontinuation, and effective antidotes include ondansetron (4 mg q8 hr prn), a proton-pump inhibitor like pantoprazole (40 mg qd), or ginger capsules (1 to 2 gram/day).8
Use a rating scale to monitor progress and follow up when the daily dose reaches 0.75 mg. A few are fully recovered at that point, but most are only 25% better and benefit from further titration. The usual dose is 1.5 mg qhs, though some go higher into the 2 mg to 3 mg range.
Pramipexole is not a mood stabilizer, and its long-term effects are largely untested. Open-label studies lasting up to 1.5 years in mood disorders offer some reassurance,9 and in my own experience the theoretical risks of tolerance, manic cycling, or psychosis have not occurred in patients who have remained on it for 10 to 15 years. The decision to discontinue pramipexole medication is a collaborative one, but I would wait 6 to 12 months after recovery before attempting to taper it off, which can be done over 1 to 2 months.
Dr Aiken is the Mood Disorders Section Editor for Psychiatric Times, the Editor in Chief of The Carlat Psychiatry Report, and the Director of the Mood Treatment Center. His written several books on mood disorders, most recently The Depression and Bipolar Workbook. He can be heard in the weekly Carlat Psychiatry Podcast with his co-host Kellie Newsome, PMH-NP.
Disclosures:
The author does not accept honoraria from pharmaceutical companies but receives royalties from PESI for The Depression and Bipolar Workbook and from W.W. Norton & Co. for Bipolar, Not So Much.
References:
1. Zarate CA Jr, Payne JL, Singh J, et al. Pramipexole for bipolar II depression: a placebo-controlled proof of concept study.Biol Psychiatry, 2004;56:54–60.
2. Goldberg JF, Burdick KE, Endick CJ. Preliminary randomized, double-blind, placebo-controlled trial of pramipexole added to mood stabilizers for treatment-resistant bipolar depression.Am J Psychiatry, 2004;161:564–566.
3. Aiken CB. Pramipexole in psychiatry: a systematic review of the literature.J Clin Psychiatry, 2007;68:1230–1236.
4. Tundo A, de Filippis R, De Crescenzo F. Pramipexole in the treatment of unipolar and bipolar depression. A systematic review and meta-analysis.Acta Psychiatr Scand, 2019;140:116–125.
5. Perez-Lloret S, Rey MV, Crispo J, et al. Risk of heart failure following treatment with dopamine agonists in Parkinson's disease patients.Expert Opin Drug Saf, 2014;13:351–360.
6. Montastruc F, Moulis F, Araujo M, Chebane L, Rascol O, Montastruc JL. Ergot and non-ergot dopamine agonists and heart failure in patients with Parkinson's disease.Eur J Clin Pharmacol, 2017;73:99–103.
7. Kleiner-Fisman G, Fisman DN. Risk factors for the development of pedal edema in patients using pramipexole.Arch Neurol, 2007;64:820–824.
8. Holman AJ, Myers RR. A randomized, double-blind, placebo-controlled trial of pramipexole, a dopamine agonist, in patients with fibromyalgia receiving concomitant medications.Arthritis Rheum, 2005;52:2495–2505.
9. Dell'Osso B, Ketter TA. Assessing efficacy/effectiveness and safety/tolerability profiles of adjunctive pramipexole in bipolar depression: acute versus long-term data.Int Clin Psychopharmacol, 2013;28:297–304.
