Authors' objectives: 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. 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. Patients with bipolar disorder are symptomatic around 50% of the time, the vast majority of which relates to depressive symptoms. Current National Institute for Health and Care Excellence (NICE) guidelines for the management of bipolar depression (BD) include just three medication options: lamotrigine, quetiapine and olanzapine (with or without fluoxetine). Quetiapine and olanzapine are often poorly tolerated due to weight gain and sedation. Lamotrigine has a relatively small effect size and requires slow dose titration. British Association for Psychopharmacology (BAP) guidelines include a fourth option: lurasidone. However, BD often does not respond to these options leading patients to suffer from ‘treatment-resistant bipolar depression’ (TRBD). Rates of TRBD are unknown, however, around 50% of patients remain depressed at 6 months, and 30% at a year, because of treatment non-response, intolerance or non-acceptance. In addition, around 70% of currently depressed bipolar disorder patients in the UK are on at least one antidepressant despite little evidence that they are effective. Pramipexole is currently used to treat patients with Parkinson’s disease and has been shown to improve depressive symptoms in these patients, with two small pilot randomised controlled trials in BD also being positive. Primary objective To evaluate the clinical effectiveness of pramipexole versus placebo alongside standard mood-stabilising medication, over 12 weeks, in the management of TRBD.

Authors' results and conclusions: 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. 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. Fifty-one participants were recruited to pre-randomisation of whom 39 progressed to randomisation (dropout rate = 24%). Completion rates for self-rated online scales were around 80%. Thirty-six participants provided primary outcome data at 12 weeks and comprised the analysis population (drop-out rate = 7.7%), 16 in the pramipexole [2.18 mg/day (0.58) mean (SD)] and 20 in the placebo arms [2.25 mg/day (0.55)]. Despite the small sample size, the two arms were well matched on demographics, illness characteristics and current medication except that the pramipexole arm had a lower QIDS-SR baseline score at randomisation [pramipexole = 15.1 (5.2) vs. placebo = 17.3 (4.7): mean (SD)]. At 12 weeks, the reduction in QIDS-SR score from baseline was twice as high in the pramipexole arm compared with the placebo arm [4.4 (4.8) vs. 2.1 (5.1)]. However, ANCOVA adjusting for baseline differences in QIDS-SR was not significant [95% confidence interval (CI) −0.4 to 6.3; p = 0.0865]. Observation of the data suggested that the peak effect of the drug may have occurred beyond 12 weeks. ANCOVA demonstrated a significant advantage of 6.28 points lower for pramipexole at 36 weeks post randomisation. Similarly, while there was no significant difference in response (QIDS-SR reduction from baseline > 50%) and remission (QIDS-SR score ≤ 5) at 12 weeks, there was an advantage of pramipexole for response (46% vs. 6%; p = 0.026) and remission (31% vs. 0%; p = 0.030) rates at exit from the trial. Secondary analysis indicated significant improvements in psychosocial function at 36 and 48 weeks. There were decreases in anxiety symptoms at 36 weeks (p = 0.087) and an increase in the ability to experience pleasure at 6 weeks (p = 0.062) for participants in the pramipexole arm was not significant. Pramipexole was associated with a significant increase in manic/hypomanic symptoms at 12 weeks, but there was no significant increase in impulse control symptoms (though a higher proportion of participants in the pramipexole vs. placebo arm experienced at least one AE related to impulse control problems). There was one SAE in the pramipexole arm assessed as related to the study medication: mania that led to hospitalisation. Of 290 AEs occurring across both treatment arms, 265 (91%) required no action, 22 (8%) had treatment interrupted/dose reduced and 3 (1%) had Investigative Medicinal Product withdrawn. There were more mild and moderate AEs in the pramipexole arm, mostly of known psychiatric, nervous system and gastrointestinal side effects. Overall, tolerability and acceptability of study medication were similar between treatment arms. Around half of the randomised participants were taking an antipsychotic. Comparing those who were and were not taking one in combination with pramipexole, it appears that the reduction in depressive symptoms was similar, but the severity of hypomanic symptoms may have been less. Health economic analysis showed significant increase in HRQoL and capability well-being, and tendency towards reduced health and social care costs with high probability (70–90%) of cost-effectiveness for all health economic outcome measures over 48 weeks from the health and social care perspective. Sensitivity analyses confirmed the main findings. Qualitative analysis identified barriers to recruitment and retention including the complexity of BD, difficulty accessing eligible participants, inadequate research prioritisation and the COVID-19 pandemic. Participants’ concerns included receiving placebo, side effects of pramipexole, the burden of managing trial medication, using technology and/or engaging with safety monitoring for 48 weeks. Facilitators included positive relationships with care teams, central team support, responsive protocol amendments, and a strong desire for effective treatment. Lessons for future trials using semiremote methodology include using mass trial promotion strategies, reducing patient burden and fostering greater collaboration between trial staff and clinicians. The trial was conducted during the COVID-19 pandemic and was terminated early due to funding reasons. Therefore, the sample size was much more limited, and the follow-up of some participants was shorter than planned. 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. This may have resulted from the early closure of the study and hence small sample size. Despite this, there were suggestions of positive effects of pramipexole on mood, psychosocial function and quality of life. However, use of the medication was complicated by the need for complex dose titration and high rates of hypomanic and impulse control symptoms, which would make implementation in routine practice challenging. Further research is required to definitively address whether pramipexole is an effective safe and cost-effective treatment for TRBD. In addition, further studies should explore the impact of coadministration of an antipsychotic alongside pramipexole.

Authors' methods: 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. Twenty-one National Health Service trusts and Health Boards across England and Scotland. 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. 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. 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. 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. Randomised, double-blind, placebo-controlled trial, conducted within secondary care settings in 21 NHS Trusts and Health Boards across England and Scotland. The trial included two stages: pre-randomisation to adjust antipsychotics and commencing mood-stabilising medication (where required) and ensuring participant engagement with study procedures, prior to randomisation. Eligibility criteria Inclusion criteria: pre-randomisation stage Under secondary care mental health services. Decision made by the patient’s clinical team that a change in medication is indicated. Current diagnosis of bipolar disorder (type I or II). Currently meeting criteria for a major depressive episode with a Quick Inventory of Depressive Symptoms, Self-Rated (QIDS-SR) score > 10. Suffering from TRBD defined as the failure (non-response, intolerance and/or refused/clinically not indicated) of ≥ 2 NICE or BAP recommended mediations for BD (quetiapine, olanzapine, lamotrigine or lurasidone) in the current episode of depression. Aged 18 or over. Willing and able to provide written informed consent. Able to follow the trial prescription instructions and manage 8 week supplies of trial medication. If female and of child-bearing potential, must have a negative pregnancy test [urine beta-human chorionic gonadotropin (β-hCG)] and required to use a highly effective contraceptive method throughout the trial.

Project Status: Completed

URL for project: https://www.journalslibrary.nihr.ac.uk/programmes/hta/16/154/01

Year Published: 2025

URL for published report: https://www.journalslibrary.nihr.ac.uk/hta/HBFC1953

URL for additional information: English

English language abstract: An English language summary is available

Publication Type: Full HTA

Country: England, United Kingdom

DOI: 10.3310/HBFC1953

Organisation Name: NIHR Health Technology Assessment programme

Contact Address: NIHR Journals Library, National Institute for Health and Care Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK

Contact Name: journals.library@nihr.ac.uk

Contact Email: journals.library@nihr.ac.uk