{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T06:28:01Z","timestamp":1786343281630,"version":"build-2736575974"},"reference-count":32,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T00:00:00Z","timestamp":1786320000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Psychiatry"],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Over the past decades, evidence supporting the antidepressant efficacy of the dopamine agonist pramipexole as an augmentation strategy in mood disorders has accumulated. While dopaminergic treatments have been associated with behavioural adverse effects, the relationship between pramipexole treatment and incident substance use disorder in psychiatric populations remains poorly understood.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>To examine the association between cumulative pramipexole exposure and incident substance use disorder among individuals with unipolar depression or bipolar disorder.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We utilised data from Swedish national registries to conduct a nationwide cohort study including individuals with unipolar depression or bipolar disorder treated in specialised mental health care (n = 3105) who were prescribed pramipexole. Cumulative pramipexole exposure was modelled longitudinally and analysed as a time-varying variable. The primary outcome was incident substance use disorder identified in specialised healthcare registers. Associations were examined using Cox proportional hazards models, with analyses separated by diagnostic subgroup.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>High cumulative exposure to pramipexole was associated with an increased risk of incident substance use disorder in the overall cohort (aHR 1.51, 95% CI 1.02\u20132.23), whereas intermediate exposure was not associated with elevated risk. In stratified analyses, the association was particularly pronounced among individuals with bipolar disorder, where high cumulative exposure was associated with more than a twofold increased risk (aHR 2.54, 95% CI 1.25\u20135.16). No significant association was observed among individuals with unipolar depression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>High cumulative exposure to pramipexole was associated with increased risk of incident substance use disorder in individuals with mood disorders, with the strongest associations observed in bipolar disorder. Although no causal inference can be made due to the observational design, these findings raise the possibility that prolonged pramipexole exposure may be associated with increased risk of substance use disorder in some psychiatric populations, particularly among individuals with bipolar disorder.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fpsyt.2026.1919633","type":"journal-article","created":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T05:31:15Z","timestamp":1786339875000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Pramipexole treatment and substance use disorder risk in unipolar and bipolar depression: a Swedish nationwide register study"],"prefix":"10.3389","volume":"17","author":[{"given":"Sara","family":"Lindstr\u00f6m","sequence":"first","affiliation":[{"name":"Department of Clinical Sciences, Lund, Psychiatry, Lund University","place":["Lund, Sweden"]},{"name":"Department of Psychiatry, Lund, Sk\u00e5ne University Hospital","place":["Lund, Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mirjam","family":"Wolfschlag","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences, Lund, Psychiatry, Lund University","place":["Lund, Sweden"]},{"name":"Department of Psychiatry, Lund, Sk\u00e5ne University Hospital","place":["Lund, Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anders","family":"H\u00e5kansson","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences, Lund, Psychiatry, Lund University","place":["Lund, Sweden"]},{"name":"Department of Psychiatry, Malm\u00f6, Sk\u00e5ne University Hospital","place":["Malm\u00f6, Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonas","family":"Berge","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences, Lund, Psychiatry, Lund University","place":["Lund, Sweden"]},{"name":"Department of Psychiatry, Malm\u00f6, Sk\u00e5ne University Hospital","place":["Malm\u00f6, Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,10]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1002\/wps.20128","article-title":"Risks of all-cause and suicide mortality in mental disorders: a meta-review","volume":"13","author":"Chesney","year":"2014","journal-title":"World Psychiatry"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jad.2016.07.011","article-title":"Prevalence of comorbid bipolar and substance use disorders in clinical settings 1990-2015: Systematic review and meta-analysis","volume":"206","author":"Hunt","year":"2016","journal-title":"J Affect Disord"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.jad.2016.06.051","article-title":"Comorbidity of bipolar and substance use disorders in national surveys of general populations 1990--2015: Systematic review and meta-analysis","volume":"206","author":"Hunt","year":"2016","journal-title":"J Affect Disord"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1511480","article-title":"Neurobiologic advances from the brain disease model of addiction","volume":"374","author":"Volkow","year":"2016","journal-title":"N Engl J Med"},{"key":"B5","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1111\/ejn.13390","article-title":"The dopamine D3 receptor, a quarter century later","volume":"45","author":"Sokoloff","year":"2017","journal-title":"Eur J Neurosci"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1176\/appi.ajp.161.3.564","article-title":"Preliminary randomized, double-blind, placebo-controlled trial of pramipexole added to mood stabilizers for treatment-resistant bipolar depression","volume":"161","author":"Goldberg","year":"2004","journal-title":"Am J Psychiatry"},{"key":"B7","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1016\/j.biopsych.2004.03.013","article-title":"Pramipexole for bipolar II depression: a placebo-controlled proof of concept study","volume":"56","author":"Zarate","year":"2004","journal-title":"Biol Psychiatry"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.4088\/JCP.12m08093","article-title":"A randomized, double-blind, placebo-controlled trial of pramipexole augmentation in treatment-resistant major depressive disorder","volume":"74","author":"Cusin","year":"2013","journal-title":"J Clin Psychiatry"},{"key":"B9","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1176\/appi.ajp.2015.15060788","article-title":"Clinical experience with high-dosage pramipexole in patients with treatment-resistant depressive episodes in unipolar and bipolar depression","volume":"173","author":"Fawcett","year":"2016","journal-title":"Am J Psychiatry"},{"key":"B10","doi-asserted-by":"publisher","first-page":"1043","DOI":"10.3390\/life13041043","article-title":"Pramipexole augmentation for treatment-resistant unipolar and bipolar depression in the real world: A systematic review and meta-analysis","volume":"13","author":"Tundo","year":"2023","journal-title":"Life (Basel)"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/S2215-0366(25)00194-4","article-title":"Pramipexole augmentation for the acute phase of treatment-resistant, unipolar depression: a placebo-controlled, double-blind, randomised trial in the UK","volume":"12","author":"Browning","year":"2025","journal-title":"Lancet Psychiatry"},{"key":"B12","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3310\/HBFC1953","article-title":"Pramipexole in addition to mood stabilisers for treatment-resistant bipolar depression: the PAX-BD randomised double-blind placebo-controlled trial","volume":"29","author":"McAllister-Williams","year":"2025","journal-title":"Health Technol Assess"},{"key":"B13","doi-asserted-by":"publisher","first-page":"2570","DOI":"10.1038\/s41591-026-04465-9","article-title":"Efficacy and target engagement of dopamine agonist pramipexole for anhedonic depression: a randomized placebo-controlled trial","volume":"32","author":"Ventorp","year":"2026","journal-title":"Nat Med"},{"key":"B14","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1007\/s40264-017-0590-6","article-title":"Dopamine agonists and impulse control disorders: A complex association","volume":"41","author":"Grall-Bronnec","year":"2018","journal-title":"Drug Saf"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1007\/s10072-023-07254-1","article-title":"Impulse control disorders in parkinson's disease patients treated with pramipexole and ropinirole: a systematic review and meta-analysis","volume":"45","author":"Soileau","year":"2024","journal-title":"Neurol Sci"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1016\/j.parkreldis.2025.108147","article-title":"Impulse control disorders and dopamine receptor agonism in parkinson's disease patients: Clinical implications","volume":"143","author":"Tangedal","year":"2026","journal-title":"Parkinsonism Related Disord"},{"key":"B17","doi-asserted-by":"crossref","first-page":"25","DOI":"10.4324\/9781003032762-5","article-title":"Neurobiologic advances from the brain disease model of addiction","volume-title":"Evaluating the Brain Disease Model of Addiction","author":"Volkow","year":"2022"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1136\/bmjopen-2022-070744","article-title":"Indications of alcohol or drug use disorders in five different national registers in Sweden: a cross-sectional population-based study","volume":"13","author":"Lundin","year":"2023","journal-title":"BMJ Open"},{"key":"B19","doi-asserted-by":"publisher","first-page":"450","DOI":"10.1186\/1471-2458-11-450","article-title":"External review and validation of the swedish national inpatient register","volume":"11","author":"Ludvigsson","year":"2011","journal-title":"BMC Public Health"},{"key":"B20","unstructured":"Production and the Quality of the Patient Register\n          \n          2023"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1007\/s10654-017-0316-1","article-title":"The swedish cause of death register [artikel","volume":"32","author":"Brooke","year":"2017","journal-title":"Eur J Epidemiol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.7326\/m16-2607","article-title":"Sensitivity analysis in observational research: Introducing the E-value","volume":"167","author":"VanderWeele","year":"2017","journal-title":"Ann Intern Med"},{"key":"B23","volume-title":"R: A language and environment for statistical computing","year":"2024"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2018.01041","article-title":"Impulse control disorders and dopamine-related creativity: Pathogenesis and mechanism, short review, and hypothesis [mini review","author":"Garcia-Ruiz","year":"2018","journal-title":"Front Neurol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.2174\/1570159X23666241023115252","article-title":"Oral and long-acting injectable aripiprazole in severe mental illness and substance use disorder comorbidity: An updated systematic review","volume":"23","author":"Mario","year":"2025","journal-title":"Curr Neuropharmacol"},{"key":"B26","doi-asserted-by":"publisher","first-page":"109942","DOI":"10.1016\/j.pnpbp.2020.109942","article-title":"The role of dopamine pharmacotherapy and addiction-like behaviors in parkinson\u2019s disease","volume":"102","author":"Napier","year":"2020","journal-title":"Prog Neuro-Psychopharmacol Biol Psychiatry"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1038\/nrn.2017.62","article-title":"Non-motor features of parkinson disease","volume":"18","author":"Schapira","year":"2017","journal-title":"Nat Rev Neurosci"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.7759\/cureus.86363","article-title":"Comprehensive review on association of bipolar disorder and substance abuse: Dual diagnosis and treatment approaches","volume":"17","author":"Bonner-Reid","year":"2025","journal-title":"Cureus"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.3389\/fpsyt.2023.1115357","article-title":"Editorial: Comorbidity in bipolar disorder, volume II [editorial","author":"De Berardis","year":"2023","journal-title":"Front Psychiatry"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-clinpsy-080822-041621","article-title":"Reward processing in mood disorders and schizophrenia: A neurodevelopmental framework","volume":"21","author":"Nusslock","year":"2025","journal-title":"Annu Rev Clin Psychol"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1016\/s2215-0366(16)00104-8","article-title":"Neurobiology of addiction: a neurocircuitry analysis","volume":"3","author":"Koob","year":"2016","journal-title":"Lancet Psychiatry"},{"key":"B32","doi-asserted-by":"publisher","first-page":"2446","DOI":"10.1001\/jama.2022.21383","article-title":"Target trial emulation: A framework for causal inference from observational data","volume":"328","author":"Hern\u00e1n","year":"2022","journal-title":"JAMA"}],"container-title":["Frontiers in Psychiatry"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fpsyt.2026.1919633\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T05:31:16Z","timestamp":1786339876000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fpsyt.2026.1919633\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,10]]},"references-count":32,"alternative-id":["10.3389\/fpsyt.2026.1919633"],"URL":"https:\/\/doi.org\/10.3389\/fpsyt.2026.1919633","relation":{},"ISSN":["1664-0640"],"issn-type":[{"value":"1664-0640","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,10]]},"article-number":"1919633"}}