McAllister-Williams RH, Goudie N, Azim L, Bartle V, Berger M, Butcher C, Chadwick T, Clare E, Courtney P, Dixon L, Duffelen N, Fouweather T, Gann W, Geddes J, Gupta S, Hall B, Helter T, Hindmarch P, Holstein EM, Lawrence W, Mawson P, McKinnon I, Milne A, Molloy A, Moore A, Morriss R, Nakulan A, Simon J, Smith D, Stokes-Crossley B, Stokes PR, Swain A, Taiwo A, Walmsley Z, Weetman C, Young AH, and Watson S
Background: Options for 'treatment-resistant bipolar depression' (TRBD) are limited. Two small, short-term, trials of pramipexole suggest it might be an option., Aims: To evaluate the clinical effectiveness and safety of pramipexole in the management of TRBD., Methods: A multi-centre randomised, double-blind controlled trial including participants ⩾18 years old with TRBD (failure to respond, tolerate or clinical contraindication/patient refusal of ⩾2 of quetiapine, olanzapine, lamotrigine or lurasidone) randomised 1:1 to pramipexole (max 2.5 mg/day salt weight) or placebo added to ongoing mood stabiliser ( n = 39). Primary outcome: Quick Inventory of Depressive Symptoms, Self-rated (QIDS-SR) at 12 weeks. Up to 48 weeks follow-up., Results: Pramipexole ( n = 18) was associated with a greater reduction in QIDS-SR score at 12 weeks versus placebo ( n = 21, 4.4 (4.8) vs 2.1 (5.1)): a medium sized ( d = -0.72) but not statistically significant difference (95% CI: -0.4 to 6.3, p = 0.087). Similarly, there was a non-significant approximate 2-point ( d = -0.76) improvement in pleasure at 6 weeks (95% CI: -0.11 to 4.20). Significant advantages of pramipexole on QIDS-SR score (6.28 points: 95% CI: 1.85-10.71) and psychosocial function (5.36 points: 95% CI: 0.38-10.35) were seen at 36 weeks post-randomisation, and on the response (46% vs 6%; p = 0.026) and remission (31% vs 0%; p = 0.030) rates at trial exit (48 weeks or last available data after 16 weeks for those affected by the early study closure). Hypomania ratings were significantly higher at 12 weeks. Otherwise, pramipexole was well tolerated., Conclusions: Clinically large, but statistically non-significant, effects of pramipexole on depression at 12 weeks, with significant longer-term benefits on mood and function were observed. Pramipexole use was complicated by dose titration and increased hypomanic symptoms. The small sample size limits interpretation. Furthermore, larger randomised placebo-controlled trials are warranted., Competing Interests: Declaration of conflicting interestThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: R Hamish McAllister-Williams reports acting as TSC chair for the NIHR HTA-funded SNAPPER trial and DMC chair for the EU-funded PReDicT study; Director of Education for British Association for Psychopharmacology; receiving support for meetings via Janssen-Cilag; receiving payments/consultation fees from LivaNova, Janssen-Cilag, Sage Therapeutics, P1Vital, Takeda and Lundbeck. Michael Berger reports being co-PI on a research grant with payments made to the Medical University of Vienna by the WWTF (Vienna Science and Technology Fund). Thomas Chadwick reports payments from NIHR HTA and the following: Member of Programme Steering Committee (ODDESSI: Open Dialogue: Development and Evaluation of a Social Network Intervention for Severe Mental Illness – University College London); Chair of Data Monitoring and Ethics Committee (SCENE: Improving quality of life and health outcomes of patients with psychosis through a new structured intervention for expanding social networks – Queen Mary University of London); Member of Data Monitoring and Ethics Committee (SUMMIT: Supporting Mothers’ Mental health with Interpersonal Therapy – University College London). Sumeet Gupta reports receiving support/ payments/consultation fees from Janssen and Mylan. Aisling Molloy reports participation in the PAX-BD trial management group from 2021 to 2022, payment for writing an article on safe prescribing of lithium in primary care via Prescriber journal, pending payment for review of MPharm bipolar and unipolar depression slides from Sunderland University. Richard Morriss reports payments made to institutions from the NIHR HTA programme, UKRI-MRC, UKRI-ESPRC, Wellcome Trust, Magstim plc, Electromedical Products Inc, P1Vital Ltd, and membership of 2 DMEC committees as personal payment from Novartis plc. Judit Simon reports being PI/co-I on research grants with payments made to the Medical University of Vienna from the NIHR, EC Horizon 2020, EC Horizon Europe, ECNP, LBG, WWTF, FWF, and advisory honoraria received by the EBC in the past 5 years. Paul RA Stokes reports grant funding to his institution from NIHR as a co-applicant on the PAX-BD trial. Dr Stokes reports grant funding from the Medical Research Council UK, H. Lundbeck A/S and King’s Health Partners made to his institution, funding from NIHR, non-financial support from Janssen Research and Development LLC for an MRC-funded study led by Dr Stokes, editorial honoraria and non-financial support from Frontiers in Psychiatry outside the submitted work. Dr Stokes is the NIHR CRN Deputy National Specialty Lead for Mental Health, NIHR CRN South London Speciality Lead for Mental Health, a member of the UK Advisory Council for the Misuse of Drugs (ACMD), and Speciality Chief Editor, Mood Disorders section, Frontiers in Psychiatry. Allan H Young reports acting as PI on the following studies Restore-Life VNS registry study; ESKETINTRD3004; The Effects of Psilocybin on Cognitive Function in Healthy Participants; P-TRD, as UK CI Compass; COMP006; COMP007; Novartis MDD study MIJ821A1220, conducting paid lectures and advisory boards for the following companies with drugs used in affective and related disorders: Astrazenaca, Boehringer Ingelheim, Eli Lilly, LivaNova, Lundbeck, Sunovion, Servier, Livanova, Janssen, Allegan, Bionomics, Sumitomo Dainippon Pharma, COMPASS, Sage, Novartis, Neurocentrx, being a Trustee Drug Safety Research Unit, Editor of Journal of Psychopharmacology and Deputy Editor BJ Psych Open, and being on the Executive Committee for British Association Psychopharmacology and Intl Soc for Affective Disorders. Stuart Watson reports honoraria payments from the British Association of Psychopharmacology mood disorders certificate teaching and NIHR HTA board funding. All other authors report no relevant conflict of interest.