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

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.