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01-12-2021 | Mood Disorders | Study protocol

Study protocol for a randomised placebo-controlled trial of pramipexole in addition to mood stabilisers for patients with treatment resistant bipolar depression (the PAX-BD study)

Authors: Lumbini Azim, Paul Hindmarch, Georgiana Browne, Thomas Chadwick, Emily Clare, Paul Courtney, Lyndsey Dixon, Nichola Duffelen, Tony Fouweather, John R. Geddes, Nicola Goudie, Sandy Harvey, Timea Helter, Eva-Maria Holstein, Garry Martin, Phil Mawson, Jenny McCaffery, Richard Morriss, Judit Simon, Daniel Smith, Paul R. A. Stokes, Jenn Walker, Chris Weetman, Faye Wolstenhulme, Allan H. Young, Stuart Watson, R. Hamish McAllister-Williams

Published in: BMC Psychiatry | Issue 1/2021

Abstract

Background

Treatment Resistant Bipolar Depression (TRBD) is a major contributor to the burden of disease associated with Bipolar Disorder (BD). Treatment options for people experiencing bipolar depression are limited to three interventions listed by National Institute for Health and Care: lamotrigine, quetiapine and olanzapine, of which the latter two are often not well tolerated. The majority of depressed people with BD are therefore prescribed antidepressants despite limited efficacy. This demonstrates an unmet need for additional interventions. Pramipexole has been shown to improve mood symptoms in animal models of depression, in people with Parkinson’s Disease and two proof of principle trials of pramipexole for people with BD who are currently depressed.

Methods

The PAX-BD study, funded by the United Kingdom (UK) National Institute for Health Research, aims to extend previous findings by assessing the efficacy, safety and health economic impact of pramipexole in addition to mood stabilisers for patients with TRBD. A randomised, double-blind, placebo controlled design is conducted in a naturalistic UK National Health Service setting. An internal pilot study to examine feasibility and acceptability of the study design is included. Participants with TRBD are screened from National Health Service secondary care services in up to 40 mental health trusts in the UK, with the aim of recruiting approximately 414 participants into a pre-randomisation phase to achieve a target of 290 randomised participants. Primary safety and efficacy measures are at 12 weeks following randomisation, with follow up of participants to 52 weeks. The primary outcome is depressive symptoms as measured by Quick Inventory for Depressive Symptomatology – Self Report. Secondary outcomes include changes in anxiety, manic symptoms, tolerability, acceptability, quality of life and cost-effectiveness. Outcome measures are collected remotely using self-report tools implemented online, and observer-rated assessments conducted via telephone. ANCOVA will be used to examine the difference in rating scale scores between treatment arms, and dependent on compliance in completion of weekly self-report measures. A mixed effects linear regression model may also be used to account for repeated measures.

Trial registration

ISRCTN72151939. Registered on 28 August 2019, http://www.isrctn.com/ISRCTN72151939

Protocol Version: 04-FEB-2021, Version 9.0.

Available only for authorised users

Clemente AS, Diniz BS, Nicolato R, Kapczinski FP, Soares JC, Firmo JO, et al. Bipolar disorder prevalence: a systematic review and meta-analysis of the literature. Rev Bras Psiquiatr. 2015;37(2):155–61. https://doi.org/10.1590/1516-4446-2012-1693.CrossRefPubMed

Kessing LV, Vradi E, Andersen PK. Life expectancy in bipolar disorder. Bipolar Disord. 2015;17(5):543–8. https://doi.org/10.1111/bdi.12296.CrossRefPubMed

Judd LL, Akiskal HS, Schettler PJ, Endicott J, Maser J, Solomon DA, et al. The long-term natural history of the weekly symptomatic status of bipolar I disorder. Arch Gen Psychiatry. 2002;59(6):530–7. https://doi.org/10.1001/archpsyc.59.6.530.CrossRefPubMed

Judd LL, Akiskal HS, Schettler PJ, Coryell W, Endicott J, Maser JD, et al. A prospective investigation of the natural history of the long-term weekly symptomatic status of bipolar II disorder. Arch Gen Psychiatry. 2003;60(3):261–9. https://doi.org/10.1001/archpsyc.60.3.261.CrossRefPubMed

National Institute for Health and Care Excellence. Bipolar disorder: Assessment and management. NICE; 2014.

Calabrese JR, Keck PE, Macfadden W, Minkwitz M, Ketter TA, Weisler RH, et al. A randomized, double-blind, placebo-controlled trial of quetiapine in the treatment of bipolar I or II depression. Am J Psychiatry. 2005;162(7):1351–60. https://doi.org/10.1176/appi.ajp.162.7.1351.CrossRefPubMed

Tohen M, Vieta E, Calabrese J, Ketter TA, Sachs G, Bowden C, et al. Efficacy of olanzapine and olanzapine-fluoxetine combination in the treatment of bipolar I depression. Arch Gen Psychiatry. 2003;60(11):1079–88. https://doi.org/10.1001/archpsyc.60.11.1079.CrossRefPubMed

Prescribing Observatory for Mental Health. Prescribing valproate for bipolar disorder. Topic 15a baseline audit report. Royal College of Psychiatrists; 2016.

Hidalgo-Mazzei D, Berk M, Cipriani A, Cleare AJ, Florio AD, Dietch D, et al. Treatment-resistant and multi-therapy-resistant criteria for bipolar depression: consensus definition. Br J Psychiatry J Ment Sci. 2019;214(1):27–35. https://doi.org/10.1192/bjp.2018.257.CrossRef

10.

Kupfer DJ, Frank E, Grochocinski VJ, Luther JF, Houck PR, Swartz HA, et al. Stabilization in the treatment of mania, depression and mixed states. Acta Neuropsychiatr. 2000;12(3):110–4. https://doi.org/10.1017/S0924270800035547.CrossRefPubMed

11.

McCrone P. Paying the price : the cost of mental health care in England to 2026. London: The King’s Fund; 2008.

12.

Young AH, Rigney U, Shaw S, Emmas C, Thompson JM. Annual cost of managing bipolar disorder to the UK healthcare system. J Affect Disord. 2011;133(3):450–6. https://doi.org/10.1016/j.jad.2011.06.016.CrossRefPubMed

13.

Willner P, Lappas S, Cheeta S, Muscat R. Reversal of stress-induced anhedonia by the dopamine receptor agonist, pramipexole. Psychopharmacology (Berl). 1994;115:454–62.CrossRef

14.

Kitagawa K, Kitamura Y, Miyazaki T, Miyaoka J, Kawasaki H, Asanuma M, et al. Effects of pramipexole on the duration of immobility during the forced swim test in normal and ACTH-treated rats. Naunyn Schmiedeberg's Arch Pharmacol. 2009;380(1):59–66. https://doi.org/10.1007/s00210-009-0405-0.CrossRef

15.

Chiu W-H, Depboylu C, Hermanns G, Maurer L, Windolph A, Oertel WH, et al. Long-term treatment with L-DOPA or pramipexole affects adult neurogenesis and corresponding non-motor behavior in a mouse model of Parkinson’s disease. Neuropharmacology. 2015;95:367–76. https://doi.org/10.1016/j.neuropharm.2015.03.020.CrossRefPubMed

16.

Breuer ME, Groenink L, Oosting RS, Buerger E, Korte M, Ferger B, et al. Antidepressant effects of pramipexole, a dopamine D3/D2 receptor agonist, and 7-OH-DPAT, a dopamine D3 receptor agonist, in olfactory bulbectomized rats. Eur J Pharmacol. 2009;616(1-3):134–40. https://doi.org/10.1016/j.ejphar.2009.06.029.CrossRefPubMed

17.

Duman RS, Nakagawa S, Malberg J. Regulation of adult neurogenesis by antidepressant treatment. Neuropsychopharmacol Off Publ Am Coll Neuropsychopharmacol. 2001;25(6):836–44. https://doi.org/10.1016/S0893-133X(01)00358-X.CrossRef

18.

Serafini G, Hayley S, Pompili M, Dwivedi Y, Brahmachari G, Girardi P, et al. Hippocampal neurogenesis, neurotrophic factors and depression: possible therapeutic targets? CNS Neurol Disord Drug Targets. 2014;13(10):1708–21. https://doi.org/10.2174/1871527313666141130223723.CrossRefPubMed

19.

Shen T, Ye R, Zhang B. Efficacy and safety of pramipexole extended-release in Parkinson’s disease: a review based on meta-analysis of randomized controlled trials. Eur J Neurol. 2017;24(6):835–43. https://doi.org/10.1111/ene.13303.CrossRefPubMed

20.

Leentjens AFG, Koester J, Fruh B, Shephard DTS, Barone P, Houben JJG. The effect of pramipexole on mood and motivational symptoms in Parkinson’s disease: a meta-analysis of placebo-controlled studies. Clin Ther. 2009;31(1):89–98. https://doi.org/10.1016/j.clinthera.2009.01.012.CrossRefPubMed

21.

Barone P, Poewe W, Albrecht S, Debieuvre C, Massey D, Rascol O, et al. Pramipexole for the treatment of depressive symptoms in patients with Parkinson’s disease: a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2010;9(6):573–80. https://doi.org/10.1016/S1474-4422(10)70106-X.CrossRefPubMed

22.

Ashok AH, Marques TR, Jauhar S, Nour MM, Goodwin GM, Young AH, et al. The dopamine hypothesis of bipolar affective disorder: the state of the art and implications for treatment. Mol Psychiatry. 2017;22(5):666–79. https://doi.org/10.1038/mp.2017.16.CrossRefPubMedPubMedCentral

23.

Sporn J, Ghaemi SN, Sambur MR, Rankin MA, Recht J, Sachs GS, et al. Pramipexole augmentation in the treatment of unipolar and bipolar depression: a retrospective chart review. Ann Clin Psychiatry Off J Am Acad Clin Psychiatr. 2000;12(3):137–40. https://doi.org/10.3109/10401230009147102.CrossRef

24.

Fawcett J, Rush AJ, Vukelich J, Diaz SH, Dunklee L, Romo P, et al. Clinical experience with high-dosage Pramipexole in patients with treatment-resistant depressive episodes in unipolar and bipolar depression. Am J Psychiatry. 2016;173(2):107–11. https://doi.org/10.1176/appi.ajp.2015.15060788.CrossRefPubMed

25.

Perugi G, Toni C, Ruffolo G, Frare F, Akiskal H. Adjunctive dopamine agonists in treatment-resistant bipolar II depression: an open case series. Pharmacopsychiatry. 2001;34(4):137–41. https://doi.org/10.1055/s-2001-15872.CrossRefPubMed

26.

Lattanzi L, Dell’Osso L, Cassano P, Pini S, Rucci P, Houck PR, et al. Pramipexole in treatment-resistant depression: a 16-week naturalistic study. Bipolar Disord. 2002;4(5):307–14. https://doi.org/10.1034/j.1399-5618.2002.01171.x.CrossRefPubMed

27.

El-Mallakh RS, Penagaluri P, Kantamneni A, Gao Y, Roberts RJ. Long-term use of pramipexole in bipolar depression: a naturalistic retrospective chart review. Psychiatr Q. 2010;81(3):207–13. https://doi.org/10.1007/s11126-010-9130-6.CrossRefPubMed

28.

Hori H, Kunugi H. The efficacy of pramipexole, a dopamine receptor agonist, as an adjunctive treatment in treatment-resistant depression: an open-label trial. ScientificWorldJournal. 2012;2012:372474.CrossRefPubMedPubMedCentral

29.

Dell’osso B, Timtim S, Hooshmand F, Miller S, Wang PW, Hill SJ, et al. Superior chronic tolerability of adjunctive modafinil compared to pramipexole in treatment-resistant bipolar disorder. J Affect Disord. 2013;150(1):130–5. https://doi.org/10.1016/j.jad.2012.11.030.CrossRefPubMed

30.

Goldberg JF, Burdick KE, Endick CJ. Preliminary randomized, double-blind, placebo-controlled trial of pramipexole added to mood stabilizers for treatment-resistant bipolar depression. Am J Psychiatry. 2004;161(3):564–6. https://doi.org/10.1176/appi.ajp.161.3.564.CrossRefPubMed

31.

Zarate CA, Payne JL, Singh J, Quiroz JA, Luckenbaugh DA, Denicoff KD, et al. Pramipexole for bipolar II depression: a placebo-controlled proof of concept study. Biol Psychiatry. 2004;56(1):54–60. https://doi.org/10.1016/j.biopsych.2004.03.013.CrossRefPubMed

32.

Geddes JR, Gardiner A, Rendell J, Voysey M, Tunbridge E, Hinds C, et al. Comparative evaluation of quetiapine plus lamotrigine combination versus quetiapine monotherapy (and folic acid versus placebo) in bipolar depression (CEQUEL): a 2 × 2 factorial randomised trial. Lancet Psychiatry. 2016;3(1):31–9. https://doi.org/10.1016/S2215-0366(15)00450-2.CrossRefPubMed

33.

Rush AJ, Trivedi MH, Ibrahim HM, Carmody TJ, Arnow B, Klein DN, et al. The 16-item quick inventory of depressive symptomatology (QIDS), clinician rating (QIDS-C), and self-report (QIDS-SR): a psychometric evaluation in patients with chronic major depression. Biol Psychiatry. 2003;54(5):573–83. https://doi.org/10.1016/S0006-3223(02)01866-8.CrossRefPubMed

34.

Altman EG, Hedeker D, Peterson JL, Davis JM. The Altman self-rating mania scale. Biol Psychiatry. 1997;42(10):948–55. https://doi.org/10.1016/S0006-3223(96)00548-3.CrossRefPubMed

35.

Spitzer RL, Kroenke K, Williams JBW, Löwe B. A brief measure for assessing generalized anxiety disorder: the GAD-7. Arch Intern Med. 2006;166(10):1092–7. https://doi.org/10.1001/archinte.166.10.1092.CrossRefPubMed

36.

Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry J Ment Sci. 1979;134(4):382–9. https://doi.org/10.1192/bjp.134.4.382.CrossRef

37.

Young RC, Biggs JT, Ziegler VE, Meyer DA. A rating scale for mania: reliability, validity and sensitivity. Br J Psychiatry J Ment Sci. 1978;133(5):429–35. https://doi.org/10.1192/bjp.133.5.429.CrossRef

38.

Snaith RP, Hamilton M, Morley S, Humayan A, Hargreaves D, Trigwell P. A scale for the assessment of hedonic tone the Snaith-Hamilton pleasure scale. Br J Psychiatry J Ment Sci. 1995;167(1):99–103. https://doi.org/10.1192/bjp.167.1.99.CrossRef

39.

Mundt JC, Marks IM, Shear MK, Greist JH. The work and social adjustment scale: a simple measure of impairment in functioning. Br J Psychiatry J Ment Sci. 2002;180(5):461–4. https://doi.org/10.1192/bjp.180.5.461.CrossRef

40.

Weintraub D, Mamikonyan E, Papay K, Shea JA, Xie SX, Siderowf A. Questionnaire for impulsive-compulsive disorders in Parkinson’s disease-rating scale. Mov Disord Off J Mov Disord Soc. 2012;27(2):242–7. https://doi.org/10.1002/mds.24023.CrossRef

41.

Atkinson MJ, Sinha A, Hass SL, Colman SS, Kumar RN, Brod M, et al. Validation of a general measure of treatment satisfaction, the treatment satisfaction questionnaire for medication (TSQM), using a national panel study of chronic disease. Health Qual Life Outcomes. 2004;2(1):12. https://doi.org/10.1186/1477-7525-2-12.CrossRefPubMedPubMedCentral

42.

Herdman M, Gudex C, Lloyd A, Janssen M, Kind P, Parkin D, et al. Development and preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L). Qual Life Res Int J Qual Life Asp Treat Care Rehabil. 2011;20(10):1727–36. https://doi.org/10.1007/s11136-011-9903-x.CrossRef

43.

Mitchell PM, Al-Janabi H, Byford S, Kuyken W, Richardson J, Iezzi A, et al. Assessing the validity of the ICECAP-A capability measure for adults with depression. BMC Psychiatry. 2017;17(1):46. https://doi.org/10.1186/s12888-017-1211-8.CrossRefPubMedPubMedCentral

44.

Vergunst F, Jenkinson C, Burns T, Anand P, Gray A, Rugkåsa J, et al. Psychometric validation of a multi-dimensional capability instrument for outcome measurement in mental health research (OxCAP-MH). Health Qual Life Outcomes. 2017;15(1):250. https://doi.org/10.1186/s12955-017-0825-3.CrossRefPubMedPubMedCentral

45.

Simon J, Mayer S. HEQ (Health Economics Questionnaire) Version v5.0 (08–09-2016); 2016. https://doi.org/10.5281/zenodo.4559790.CrossRef

46.

BALANCE investigators and collaborators, Geddes JR, Goodwin GM, Rendell J, Azorin J-M, Cipriani A, et al. Lithium plus valproate combination therapy versus monotherapy for relapse prevention in bipolar I disorder (BALANCE): a randomised open-label trial. Lancet Lond Engl. 2010;375:385–95.CrossRef

47.

Goodwin GM, Haddad PM, Ferrier IN, Aronson JK, Barnes T, Cipriani A, et al. Evidence-based guidelines for treating bipolar disorder: revised third edition recommendations from the British Association for Psychopharmacology. J Psychopharmacol Oxf Engl. 2016;30(6):495–553. https://doi.org/10.1177/0269881116636545.CrossRef

48.

Deutschländer A, la Fougère C, Boetzel K, Albert NL, Gildehaus F-J, Bartenstein P, et al. Occupancy of pramipexole (Sifrol) at cerebral dopamine D2/3 receptors in Parkinson’s disease patients. NeuroImage Clin. 2016;12:41–6. https://doi.org/10.1016/j.nicl.2016.06.007.CrossRefPubMedPubMedCentral

49.

Moraga-Amaro R, Gonzalez H, Pacheco R, Stehberg J. Dopamine receptor D3 deficiency results in chronic depression and anxiety. Behav Brain Res. 2014;274:186–93. https://doi.org/10.1016/j.bbr.2014.07.055.CrossRefPubMed

50.

Jordan CJ, Humburg B, Rice M, Bi G-H, You Z-B, Shaik AB, et al. The highly selective dopamine D3R antagonist, R-VK4-40 attenuates oxycodone reward and augments analgesia in rodents. Neuropharmacology. 2019;158:107597. https://doi.org/10.1016/j.neuropharm.2019.04.003.CrossRefPubMedPubMedCentral

51.

Groman SM, Hillmer AT, Liu H, Fowles K, Holden D, Morris ED, et al. Midbrain D3 receptor availability predicts escalation in cocaine self-administration. Biol Psychiatry. 2020;88(10):767–76. https://doi.org/10.1016/j.biopsych.2020.02.017.CrossRefPubMedPubMedCentral

52.

Caravaggio F, Fervaha G, Browne CJ, Gerretsen P, Remington G, Graff-Guerrero A. Reward motivation in humans and its relationship to dopamine D2/3 receptor availability: a pilot study with dual [11C]-raclopride and [11C]-(+)-PHNO imaging. J Psychopharmacol Oxf Engl. 2018;32(3):357–66. https://doi.org/10.1177/0269881118756059.CrossRef

53.

Wang J, Jia Y, Li G, Wang B, Zhou T, Zhu L, et al. The dopamine receptor D3 regulates lipopolysaccharide-induced depressive-like behavior in mice. Int J Neuropsychopharmacol. 2018;21(5):448–60. https://doi.org/10.1093/ijnp/pyy005.CrossRefPubMedPubMedCentral

54.

American Psychiatric Association. Diagnostic and statistical manual of mental disorders (DSM-5®). Arlington: American Psychiatric Association; 2013. https://doi.org/10.1176/appi.books.9780890425596.CrossRef

55.

Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E, et al. The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry. 1998;59(Suppl 20):22–33 quiz 34–57.PubMed

56.

Curtis L, Burns A. Unit costs of health and social care 2017. Canterbury: University of Kent; 2017.

57.

Joint Formulary Committee. British National Formulary. 76th ed. London: BMJ Group and Pharmaceutical Press; 2018.

58.

Tarricone R. Cost-of-illness analysis. What room in health economics? Health Policy Amst Neth. 2006;77(1):51–63. https://doi.org/10.1016/j.healthpol.2005.07.016.CrossRef

59.

Drummond M, O’Brien B, Stoddard G, Torrance G. Methods for the economic evaluation of health care programmes. 2nd ed. Oxford: Oxford Medical Publications; 1997.

60.

NICE. Developing NICE guidelines: the manual 2014 (April 2017 update) - incorporating economic evaluation. National Institute for Health and Clinical Excellence; 2017.

61.

EuroQol Group. EuroQol--a new facility for the measurement of health-related quality of life. Health Policy Amst Neth. 1990;16:199–208.CrossRef

62.

Nederland Z. Guideline for economic evaluations in healthcare. 2016. https://english.zorginstituutnederland.nl/publications/reports/2016/06/16/guideline-for-economic-evaluations-in-healthcare.

63.

Flynn TN, Huynh E, Peters TJ, Al-Janabi H, Clemens S, Moody A, et al. Scoring the Icecap-a capability instrument. Estimation of a UK general population tariff. Health Econ. 2015;24(3):258–69. https://doi.org/10.1002/hec.3014.CrossRefPubMed

64.

Efron B, Tibshirani R. An introduction to the bootstrap. New York: CRC press; 1994.CrossRef

65.

Fenwick E, Byford S. A guide to cost-effectiveness acceptability curves. Br J Psychiatry J Ment Sci. 2005;187(2):106–8. https://doi.org/10.1192/bjp.187.2.106.CrossRef

66.

Stinnett AA, Mullahy J. Net health benefits: a new framework for the analysis of uncertainty in cost-effectiveness analysis. Med Decis Mak Int J Soc Med Decis Mak. 1998;18(2 Suppl):S68–80. https://doi.org/10.1177/0272989X98018002S09.CrossRef

67.

Northern Centre for Mood Disorders. 2019. Available from: http://www.mood-disorders.co.uk/. Accessed 22 May 2021.

68.

PAX-BD study. 2021. Available from: https://paxbd.org/. Accessed 22 May 2021.

Title: Study protocol for a randomised placebo-controlled trial of pramipexole in addition to mood stabilisers for patients with treatment resistant bipolar depression (the PAX-BD study)
Authors: Lumbini Azim
Paul Hindmarch
Georgiana Browne
Thomas Chadwick
Emily Clare
Paul Courtney
Lyndsey Dixon
Nichola Duffelen
Tony Fouweather
John R. Geddes
Nicola Goudie
Sandy Harvey
Timea Helter
Eva-Maria Holstein
Garry Martin
Phil Mawson
Jenny McCaffery
Richard Morriss
Judit Simon
Daniel Smith
Paul R. A. Stokes
Jenn Walker
Chris Weetman
Faye Wolstenhulme
Allan H. Young
Stuart Watson
R. Hamish McAllister-Williams
Publication date: 01-12-2021
Publisher: BioMed Central
Keywords: Mood Disorders
Affective Disorder
Pramipexole
Published in: BMC Psychiatry / Issue 1/2021
Electronic ISSN: 1471-244X
DOI: https://doi.org/10.1186/s12888-021-03322-y

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Study protocol for a randomised placebo-controlled trial of pramipexole in addition to mood stabilisers for patients with treatment resistant bipolar depression (the PAX-BD study)

Abstract

Background

Methods

Trial registration

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Trial registration

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