01. Treatment-Resistant Bipolar Depression: Is Adjunctive Pramipexole An Option?

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Pramipexole for Treatment-Resistant Bipolar Depression

Bipolar depression can be incredibly stubborn. Patients with bipolar disorder spend roughly half their time symptomatic and the vast majority of that is depressive.

For many, standard treatments just don’t offer enough relief. What do we do when we’ve run the gamut of FDA-approved medications for bipolar depression and our patient is still struggling

Today, we’re going to dive into a recent study, the PAX-BD trial which explored pramipexole as an add-on treatment for these very patients.

Defining Treatment Resistance Bipolar Depression

In this study, treatment-resistant bipolar depression was pragmatically defined. Patients had not responded to, couldn’t tolerate, or refused at least two commonly recommended medications, such as:

• Quetiapine
• Olanzapine (with or without fluoxetine)
• Lamotrigine
• Lurasidone

This issue isn’t minor. About half of those with bipolar depression remain depressed at six months and one-third remain symptomatic throughout the year. Treatment non-response, intolerance, or non-acceptance significantly contributes to the overall financial and emotional burden of bipolar disorder. Antidepressants, though commonly used, have questionable efficacy in bipolar depression. Finding effective, well-tolerated options is critical.

Rationale for Pramipexole in Bipolar Depression

You might know pramipexole as a dopamine agonist primarily used in Parkinson’s disease. The hypothesis here is that bipolar depression involves a hypodopaminergic state. Preclinical studies indicate pramipexole can increase hippocampal neurogenesis—a common antidepressant mechanism. And importantly, previously smaller trials in bipolar depression showed some positive signals.

The PAX-BD trial aimed to rigorously test this in a larger placebo-controlled setting.

Study Design and Primary Outcome

This multicenter, randomized, double-blind, placebo-controlled trial included patients with bipolar I or II depression actively taking mood stabilizers like lithium, valproate, carbamazepine, or lamotrigine. Participants received either pramipexole (up to 2.5 mg/day) or placebo added to existing stabilizers. The primary outcome was the change in self-rated depressive symptoms (QIDS-SR) at 12 weeks.

12-Week Results: Large Clinical Effect Without Statistical Significance

At 12 weeks, the pramipexole group showed a greater reduction in QIDS-SR scores, an average decrease of 4.4 points compared to the placebo group, an average reduction of 2.1 points. This represents a clinically large reduction with a good effect size. However, it did not reach statistical significance at 12 weeks.

I wouldn’t let that non-significant p-value at 12 weeks overshadow the findings. The study was actually stopped early by the funder due to slow recruitment heavily impacted by the COVID-19 pandemic.

This meant they randomized only 39 participants instead of their intended enrollment. The researchers suggest the small sample size is the most likely reason the primary outcome didn’t hit statistical significance despite the good clinical improvement.

Promising Long-Term Outcomes

The longer-term outcome showed promise but due to dropouts over time the data may suffer from attrition bias. At 36 weeks, pramipexole showed a statistically significant greater reduction in QIDS-SR scores compared to placebo and depression response and remission rates were statistically significant.

Patients on pramipexole also had significant improvements in psychosocial function at 36 and 48 weeks and response and remission rates were better compared to placebo. It’s possible that the full therapeutic effects of pramipexole might unfold over a more extended period than just 12 weeks implying that we need to think about longer-term trials for these patients.

Small Sample Size Limited Conclusions

Now, while promising, the study also highlights a few more areas for careful clinical consideration. Small sample size is the study’s biggest limitation.

The early closure led to very small numbers at later followup points and the small size could’ve also contributed to baseline imbalances in patient characteristics between the groups. So while the longer-term results are statistically significant, they come from a much smaller subset of participants who stayed in the trial longer.

Safety Considerations: Hypomania and Mania Risk

Hypomania and mania risk is a key safety point. Self-rated manic symptoms with the ASRM score were significantly higher in the pramipexole group at 12 weeks by 1.2 points after adjusting for baseline differences in the groups but this evened out between the two groups at later timepoints.

There were no differences in the observer-rated YMRS scores at week 12. And although rare, one serious adverse event of a manic relapse with psychotic symptoms and hospitalization was deemed related to pramipexole.

Overall, adverse events related to hypomania or mania were more common in the pramipexole arm, 44% of participants versus 29% in placebo.

So a clinical pearl if you’re going to try pramipexole for your patient. Vigilant monitoring for hypomanic or manic symptoms is essential especially in the early treatment phase.

Impulse Control Behaviors

Adverse events categorized as impulse control behaviors were reported by more participants on pramipexole, 33%, compared to placebo at 19%. These included:

• Gambling
• Internet gaming
• Excessive buying
• Eating
• Hair picking

This is a known issue for patients taking the drug for Parkinson’s, a dopamine effect. Be aware of this potential side effect and routinely screen for new impulse control behaviors.

Combining Pramipexole with Antipsychotics

Now, a fascinating nuance of this trial is the issue of antipsychotic co-treatment. The study initially prohibited antipsychotic use during the trial on the basis that pramipexole is a dopamine agonist and antipsychotics are dopamine antagonists. This severely hampered their recruitment.

This rule was later relaxed. The paper tentatively suggests that combining pramipexole with an antipsychotic might actually reduce the risk of manic symptoms without negatively impacting the depressive response based on the differences they saw between patients in the trial.

This makes sense pharmacologically given pramipexole’s higher affinity for D3 receptors and many antipsychotics’ greater affinity for D2 receptors. More research is needed here but it’s a critical clinical point. Perhaps combining antipsychotics and pramipexole could be beneficial for our patient.

Clinical Takeaways

So where does this leave us? The PAX-BD study despite its early termination and small sample size offers evidence that pramipexole may be an effective adjunctive treatment option for treatment-resistant bipolar depression.

For those truly challenging cases of bipolar depression that haven’t responded to multiple standard treatments, pramipexole is certainly an option to consider as an add-on. But remember to start with a low dose, titrate slowly and maintain careful vigilance for hypomania or mania and impulse control issues.

The authors conclude that a larger definitive trial is needed and that such a study is feasible with improved recruitment strategies and a more realistic sample size target. And crucially, future studies should definitely allow for co-administration of antipsychotics from the start.

Abstract

A randomised double-blind, placebo-controlled trial of pramipexole in addition to mood stabilisers for patients with treatment-resistant bipolar depression (the PAX-BD study)

Background:

Options for ‘treatment-resistant bipolar depression’ (TRBD) are limited. Two small, short-term, trials of pramipexole suggest it might be an option.

Aims:

To evaluate the clinical effectiveness and safety of pramipexole in the management of TRBD.

Methods:

A multi-centre randomised, double-blind controlled trial including participants ⩾18 years old with TRBD (failure to respond, tolerate or clinical contraindication/patient refusal of ⩾2 of quetiapine, olanzapine, lamotrigine or lurasidone) randomised 1:1 to pramipexole (max 2.5 mg/day salt weight) or placebo added to ongoing mood stabiliser (n = 39). Primary outcome: Quick Inventory of Depressive Symptoms, Self-rated (QIDS-SR) at 12 weeks. Up to 48 weeks follow-up.

Results:

Pramipexole (n = 18) was associated with a greater reduction in QIDS-SR score at 12 weeks versus placebo (n = 21, 4.4 (4.8) vs 2.1 (5.1)): a medium sized (d = −0.72) but not statistically significant difference (95% CI: −0.4 to 6.3, p = 0.087). Similarly, there was a non-significant approximate 2-point (d = −0.76) improvement in pleasure at 6 weeks (95% CI: −0.11 to 4.20). Significant advantages of pramipexole on QIDS-SR score (6.28 points: 95% CI: 1.85–10.71) and psychosocial function (5.36 points: 95% CI: 0.38–10.35) were seen at 36 weeks post-randomisation, and on the response (46% vs 6%; p = 0.026) and remission (31% vs 0%; p = 0.030) rates at trial exit (48 weeks or last available data after 16 weeks for those affected by the early study closure). Hypomania ratings were significantly higher at 12 weeks. Otherwise, pramipexole was well tolerated.

Conclusions:

Clinically large, but statistically non-significant, effects of pramipexole on depression at 12 weeks, with significant longer-term benefits on mood and function were observed. Pramipexole use was complicated by dose titration and increased hypomanic symptoms. The small sample size limits interpretation. Furthermore, larger randomised placebo-controlled trials are warranted.

Reference

McAllister-Williams RH, Goudie N, Azim L, et al. A randomised double-blind, placebo-controlled trial of pramipexole in addition to mood stabilisers for patients with treatment-resistant bipolar depression (the PAX-BD study). Journal of Psychopharmacology. 2025;39(2):106-120.