PAX-BD

PAX-BD was a major trial examining a novel treatment for bipolar disorder, funded by the National Institute for Health Research’s (NIHR) Health Technology Assessment (HTA) Board. The study was led from Newcastle, but patients will be recruited from other sites across the UK.

The PAX-BD study was unfortunately closed down early, prior to recruitment of a full sample of participants by the funder due to issues with the rate of recruitment. As a result, while there were some positive findings, conclusions from the study are somewhat limited.

Copies of the “Plain English Summary” and “Abstract” from the study’s “Final Report” submitted to the NIHR HTA Panel are shown below. Note that these are subject to alteration following peer review of the final report.

Plain English summary

Patients with bipolar disorder (BD) have symptoms (depression or elevated mood) around 50% of the time and mostly these are depressive. There are few current 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 were randomised 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 quite big enough to be 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, every-day 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 can’t conclude that pramipexole should routinely be used for people with bipolar depression. Further research is required to give a clearer answer.

A Patient & Public Involvement (PPI) 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.

Abstract

A randomised controlled trial of pramipexole versus placebo in addition to mood stabilisers for Treatment Resistant Bipolar Depression.

Background

There are limited options currently recommended in National Institute for Health and Social Care (NICE) 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 (TRBD). Secondary: evaluate the impact of pramipexole on mood and anxiety, psycho-social function, cost-effectiveness, and safety and tolerability over 48-weeks.

Design

Multi-centre, double-blind, randomised, placebo-controlled trial of pramipexole versus placebo in addition to standard of care mood stabilisers. Pre-randomisation stage (to adjust antipsychotics or commence mood stabilisers where required) before randomisation. Weekly on-line assessments of mood and anxiety from randomisation to week 52, with psychosocial function, quality of life and health care resource utilisation assessments conducted at regular intervals.

Setting

21 NHS trusts and Health Boards across England and Scotland

Participants

Patients aged 18 years and over with a diagnosis of TRBD currently under secondary care mental health services.

Interventions

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

Main outcome measures

Depression - Quick Inventory for Depressive Symptomology (QIDS-SR); Anxiety - Generalised Anxiety Disorder 7-item scale (GAD-7); Psychosocial functioning - Work and Social Adjustment Scale (WSAS); Hypomania/mania - Altman Scale for Rating Mania (ASRM); Tolerability - Treatment Satisfaction Questionnaire for Medication (TSQM); Well being and quality of life - EQ-5D-5L, ICECAP-A and OxCAP-MH 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, but this did not reach statistical significance (p=0.0865). 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 co-administration with an antipsychotic. General tolerability of pramipexole was good. There were significant annual gains in health-related quality of life and capability-wellbeing and tendency towards reduced health and social care costs.

Limitations

Small sample size and variable follow up period due 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

There is some evidence that pramipexole, over 48 weeks, in conjunction with mood stabilisers cost effectively improves mood, psychosocial function and quality of life in participants with TRBD.

Future work

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

Trial registration

ISRCTN72151939

EudraCT: 2018-2869-18

Funding details

This project was funded by the National Institute for Health Research (NIHR) HTA programme.