Pramipexole treatment and substance use disorder risk in unipolar and bipolar depression: a Swedish nationwide register study.

Background: 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. Aims: To examine the association between cumulative pramipexole exposure and incident substance use disorder among individuals with unipolar depression or bipolar disorder. Methods: 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. Results: 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 1.02-2.23), 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 1.25-5.16). No significant association was observed among individuals with unipolar depression. Conclusions: 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.