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. 2025 May;29(21):1–216. doi: 10.3310/HBFC1953

Pramipexole in addition to mood stabilisers for treatment-resistant bipolar depression: the PAX-BD randomised double-blind placebo-controlled trial.

Hamish McAllister-Williams, Nicola Goudie, Lumbini Azim, Victoria Bartle, Michael Berger, Chrissie Butcher, Thomas Chadwick, Emily Clare, Paul Courtney, Lyndsey Dixon, Nichola Duffelen, Tony Fouweather, William Gann, John Geddes, Sumeet Gupta, Beth Hall, Timea Helter, Paul Hindmarch, Eva-Maria Holstein, Ward Lawrence, Phil Mawson, Iain McKinnon, Adam Milne, Aisling Molloy, Abigail Moore, Richard Morriss, Anisha Nakulan, Judit Simon, Daniel Smith, Bryony Stokes-Crossley, Paul Stokes, Andrew Swain, Zoë Walmsley, Christopher Weetman, Allan H Young, Stuart Watson
PMCID: PMC12146921  PMID: 40455248

Abstract

BACKGROUND

There are limited options currently recommended in National Institute for Health and Care Excellence guidelines for the treatment of bipolar depression. Pramipexole has been shown to improve mood symptoms in two small pilot studies in such patients.

OBJECTIVES

Primary: to evaluate the clinical effectiveness of pramipexole versus placebo alongside routine mood-stabilising medications over 12 weeks in patients with treatment-resistant bipolar depression. Secondary: evaluate the impact of pramipexole on mood and anxiety, psychosocial function, cost-effectiveness, and safety and tolerability over 48 weeks.

DESIGN

Multicentre, randomised, placebo-controlled trial of pramipexole versus placebo in addition to standard-of-care mood stabilisers. Clinicians, researchers and participants were blinded throughout the duration of the study. Pre-randomisation stage (to adjust antipsychotics or commence mood stabilisers where required) before randomisation. Weekly online assessments of mood and anxiety from randomisation to week 52, with psychosocial function, quality of life and healthcare resource utilisation assessments conducted at regular intervals.

SETTING

Twenty-one National Health Service trusts and Health Boards across England and Scotland.

PARTICIPANTS

Patients aged 18 years and over with a diagnosis of treatment-resistant bipolar depression currently under secondary care mental health services. Aim to randomise 290 participants.

INTERVENTIONS

Pramipexole or matched placebo orally once daily, titrated from 0.25 mg to maximum of 2.5 mg (salt weight) depending on efficacy and tolerability.

MAIN OUTCOME MEASURES

Depression - Quick Inventory for Depressive Symptomology; anxiety - Generalised Anxiety Disorder-7-item scale; psychosocial functioning - Work and Social Adjustment Scale; hypomania/mania - Altman Self-rating Scale of Mania; tolerability - Treatment Satisfaction Questionnaire for Medication; well-being and quality of life - EuroQol-5 Dimensions, five-level version, ICEpop CAPability measure for Adults and Oxford CAPabilities questionnaire-Mental Health tools.

RESULTS

Thirty-nine participants randomised (18 to pramipexole and 21 to placebo) with 36 providing data for the primary analysis. Pramipexole led to greater reductions in depressive symptoms at 12 weeks compared to placebo [4.4 (4.8) vs. 2.1 (5.1)]: a medium-sized (d = -0.72) but not statistically significant difference (95% confidence interval -0.4 to 6.3; p = 0.087). There were some statistically significant positive effects of pramipexole on secondary outcomes (reduction in depressive symptoms at 36 weeks, response and remission rates at trial exit, psychosocial function). Pramipexole was associated with an increased rate of hypomania/manic symptoms, but this appeared to be reduced by coadministration with an antipsychotic. General tolerability of pramipexole was good. There were significant annual gains in health-related quality of life and capability-well-being and tendency towards reduced health and social care costs.

LIMITATIONS

Small sample size and variable follow-up period due to recruitment during COVID-19 pandemic and the trial closing early. Participants limited to those in secondary care mental health services. All assessments only available in English.

CONCLUSIONS

No change in clinical practice can be recommended as there was not a significant difference between pramipexole and placebo on the primary efficacy outcome measure. However, there was evidence of positive effects of pramipexole on mood, psychosocial function and quality of life.

FUTURE WORK

Replication in a larger population and research to investigate the impact of coadministration of antipsychotics alongside pramipexole.

TRIAL REGISTRATION

This trial is registered as ISRCTN72151939 and EudraCT 2018-2869-18.

FUNDING

This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 16/154/01) and is published in full in Health Technology Assessment; Vol. 29, No. 21. See the NIHR Funding and Awards website for further award information.

Plain language summary

Patients with bipolar disorder have symptoms (depression or elevated mood) around 50% of the time and mostly these are depressive. There are few recommended treatments for bipolar depression, they do not always work, and often come with side effects like weight gain and drowsiness. There is a suggestion that pramipexole (currently used to treat Parkinson’s disease) may help treat bipolar depression. The PAX-BD trial aimed to test this, as well as seeing if it is safe and cost-effective over 48 weeks. Those eligible for the trial were randomly allocated to receive either pramipexole or placebo. Neither the treating team nor the participants knew which treatment they were receiving. Unfortunately, only 39 participants entered the trial due to the trial being closed early. While pramipexole did lead to a greater reduction in depressive symptoms compared to placebo at 12 weeks, the difference was not statistically significant, possibly due to there being too few participants in the trial. However, there were some statistically significant beneficial effects of pramipexole on mood, everyday functioning and quality of life later in the trial. On the downside, pramipexole appeared to increase the risk that participants experienced symptoms of elevated mood. There was evidence that pramipexole may be a cost-effective treatment. However, because of the trial being small in size, the results are not definitive and we cannot conclude that pramipexole should routinely be used for people with bipolar depression. Further research is required to give a clearer answer. A patient and public involvement group worked on the trial and provided valuable input into its design and conduct, and we learnt more about how such input can be improved in future trials. We also learnt more about what can help and hinder people taking in part in studies like PAX-BD.

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