Highlight
The PAX-BD trial investigated pramipexole added to mood stabilisers for treatment-resistant bipolar depression, offering preliminary evidence of improved mood symptoms and psychosocial function without significant primary outcome benefit. The drug was generally well tolerated but associated with increased hypomanic symptoms, mitigated by concurrent antipsychotics. Study limitations included small sample size and COVID-19-related challenges.
Study Background
Bipolar depression represents a significant clinical challenge due to its treatment resistance and limited therapeutic options. The National Institute for Health and Care Excellence (NICE) currently offers few recommendations specifically for treatment-resistant bipolar depression, underscoring an unmet need for effective interventions. Pramipexole, a dopamine agonist primarily used in Parkinson’s disease, has demonstrated antidepressant potential in two small pilot studies for bipolar depression, suggesting that dopaminergic modulation could be a promising strategy.
Study Design
The PAX-BD trial was a multicenter, randomized, double-blind, placebo-controlled study conducted across 21 National Health Service trusts and Health Boards in England and Scotland. It enrolled adult patients (aged ≥18 years) diagnosed with treatment-resistant bipolar depression already receiving secondary mental health care. The target sample size was 290, but the study closed early due to recruitment difficulties during the COVID-19 pandemic, resulting in 39 participants randomized (18 to pramipexole, 21 to placebo) and 36 participants included in the primary analysis.
Participants underwent a pre-randomisation phase to optimise mood stabiliser and antipsychotic regimens. Following this, pramipexole or matched placebo was administered orally once daily, titrated from 0.25 mg up to a maximum of 2.5 mg based on efficacy and tolerability over 12 weeks, with assessments continuing up to 52 weeks.
The primary endpoint was reduction in depressive symptoms measured by the Quick Inventory for Depressive Symptomatology (QIDS). Secondary outcomes included anxiety measured by the Generalized Anxiety Disorder-7 scale, psychosocial functioning (Work and Social Adjustment Scale), hypomanic/manic symptoms (Altman Self-Rating Scale of Mania), medication tolerability, quality of life, capability well-being, and health economic endpoints.
Key Findings
At 12 weeks, pramipexole showed a greater reduction in depressive symptoms compared to placebo [mean change 4.4 (SD 4.8) vs. 2.1 (5.1)], corresponding to a moderate effect size (Cohen’s d = -0.72); however, this difference did not reach statistical significance (95% CI: -0.4 to 6.3; p=0.087). Despite the lack of significance in the primary endpoint, notable statistically significant secondary benefits emerged:
- At 36 weeks, pramipexole-treated patients showed sustained reductions in depressive symptoms.
- Response and remission rates at trial exit were higher in the pramipexole group.
- Psychosocial functioning notably improved with pramipexole.
- Health-related quality of life and capability well-being metrics demonstrated significant annual gains.
The safety profile was acceptable, with generally good tolerability. However, pramipexole was associated with an increased incidence of hypomanic or manic symptoms. This adverse effect was less pronounced when pramipexole was coadministered with antipsychotic treatment, suggesting a protective interaction. Furthermore, pramipexole tended to reduce overall healthcare and social care costs, indicating potential economic benefits.
Expert Commentary
The PAX-BD trial provides valuable preliminary data on the dopaminergic agent pramipexole in a difficult-to-treat bipolar depression subset. Although the primary endpoint did not attain significance—likely due in part to underpowering—the observed secondary outcomes imply meaningful clinical benefits. The increase in hypomanic symptoms aligns with pramipexole’s dopaminergic mechanism and highlights the necessity of careful monitoring and potentially the strategic use of antipsychotics to mitigate risk.
Limitations such as the small sample size, participant selection limited to secondary care settings, and the disruptions caused by the COVID-19 pandemic restrict the generalizability of results. Additionally, assessments were limited to English-speaking individuals, potentially excluding diverse populations.
Notably, the trial’s design highlights how co-administration strategies—pramipexole with antipsychotics—may optimize efficacy and safety, underscoring an avenue for future research. The biological plausibility of dopamine agonists exerting antidepressant effects in bipolar disorder is supported by neurobiological models linking dopaminergic dysregulation with mood symptoms.
Conclusion
The PAX-BD trial does not provide sufficient evidence to recommend pramipexole in routine clinical practice for treatment-resistant bipolar depression due to nonsignificant primary outcome results. Nonetheless, positive findings in secondary outcomes, psychosocial function, and patient quality of life suggest that pramipexole may hold therapeutic potential. Future trials with larger sample sizes and longer durations are warranted to confirm these benefits and clarify the role of concomitant antipsychotic treatment.
Funding and Trial Registration
This study was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 16/154/01) and published in Health Technology Assessment; Vol. 29, No. 21. The clinical trial is registered as ISRCTN72151939 and EudraCT 2018-2869-18.
References
McAllister-Williams H, et al. Pramipexole in addition to mood stabilisers for treatment-resistant bipolar depression: the PAX-BD randomised double-blind placebo-controlled trial. Health Technol Assess. 2025 May;29(21):1-216. doi: 10.3310/HBFC1953. PMID: 40455248; PMCID: PMC12146921.
