Adjunctive Pramipexole in Bipolar Depression with Anhedonia: Phase III Double‑Blind Randomized Controlled Trial

Primary objective: to assess the efficacy of adjunctive pramipexole compared with placebo in reducing anhedonia over a 6‑week period in participants with bipolar disorder experiencing a depressive episode, reflecting the clinical need to ameliorate this core affective deficit. Secondary objectives include evaluation of overall depressive symptoms, quantification of 24‑hour movement behaviours using wearable accelerometers, investigation of improvement in specific depressive features such as apathy, assessment of impact on quality of life, and comprehensive monitoring of safety and tolerability with emphasis on emergence of manic and impulse control symptoms. Additional aims comprise analysis of longer‑term efficacy and tolerability, comparison of response between bipolar I and II subtypes, examination of performance on the Probabilistic Reward Task and broader cognitive function, demonstration of target engagement of the reward circuitry by fMRI, exploration of associations with peripheral and central biomarkers, evaluation of sleep parameters via accelerometry, characterization of the relationship between administered dose, steady‑state serum concentrations, clinical response and adverse events, and qualitative assessment of the lived experience of treatment.

The trial enrolled adult individuals aged 18 to 80 years, inclusive of both female and male participants, who met diagnostic criteria for bipolar disorder type I or II and were experiencing a current depressive episode with significant anhedonia. Eligibility required written informed consent, a confirmed diagnosis according to ICD‑11, a depressive state lasting at least two weeks but not exceeding 18 months, a SHAPS score of 3–4 on three or more items, and a MADRS score of 20 or higher. Participants were required to be on stable mood‑stabilising therapy, with lithium levels within the therapeutic range or stable doses of anticonvulsants, antipsychotics, or antidepressants for at least four weeks prior to enrollment. Women of childbearing potential needed to use adequate contraception and provide a negative pregnancy test. The sponsor did not provide information on the total number of participants enrolled.

The study is a phase III, double‑blind, randomized, placebo‑controlled trial evaluating adjunctive pramipexole for the treatment of bipolar disorder depressive episodes; participants are randomized in a 1:1 ratio to receive either pramipexole prolonged‑release tablets (0.26 mg, 0.52 mg, 1.05 mg or 2.1 mg) or matching placebo, with dosing titrated over the first two weeks and maintained through week 6, the primary efficacy interval, after which an optional open‑label extension continues for up to 15 weeks. The trial schedule includes a screening visit to confirm eligibility, obtain written consent, and perform baseline laboratory assessments; a baseline/randomization visit where the study medication is initiated; follow‑up visits at weeks 2, 4 and 6 to collect efficacy data (SHAPS, MADRS, CGI‑S, EQ‑5D‑5L, accelerometry, safety assessments, and adverse‑event monitoring, including YMRS for (hypo)manic symptoms); and a final end‑of‑study visit at week 6 for the double‑blind phase (or week 15 for participants entering the extension). Overall participant involvement therefore spans approximately 6 weeks for the core trial, with the possibility of an additional 15 weeks for those who continue into the extension. Early termination may occur if a participant withdraws consent, experiences a serious adverse event, develops a manic or mixed episode, requires prohibited concomitant medication, or violates key protocol criteria such as dose stability of background mood‑stabilizing agents.

The investigational product is pramipexole administered as prolonged‑release tablets for oral use. Four tablet strengths are supplied (0.26 mg, 0.52 mg, 1.05 mg, and 2.10 mg) to permit dose titration to a target total daily dose of 3.15 mg. Tablets are taken by mouth once daily, with the specific combination of strengths determined by the titration algorithm to reach the target dose.

The control arm receives matching placebo tablets that are identical in size, shape, and appearance to the active tablets of each strength (0.26 mg, 0.52 mg, 1.05 mg, and 2.10 mg). Placebo tablets are administered orally once daily using the same titration schedule as the active product.

Dosing is adjusted in a stepwise manner during the first two weeks to achieve the 3.15 mg daily target, after which the dose is maintained for the remaining treatment period. Participant adherence is monitored by pill count at each study visit and by review of dosing diaries completed by the participant.

Primary efficacy is assessed by the change from baseline to week 6 on the SHAPS self‑rating scale, which quantifies anhedonia. Secondary efficacy endpoints include the change in the Montgomery‑Åsberg Depression Rating Scale (MADRS) from baseline to week 6, changes in the Dimensional Anhedonia Rating Scale (DARS) and Apathy Evaluation Scale (AES) over the same period, and changes in the Clinical Global Impression‑Severity (CGI‑S) and health‑related quality of life measured by the EQ‑5D‑5L (EQ‑5D‑5L) between baseline and week 6. All clinical scales are administered by trained raters or completed by participants according to validated procedures at baseline and week 6.

Objective efficacy assessments comprise continuous monitoring of 24‑hour movement behaviour using wearable accelerometers, with data on sedentary behaviour, low‑intensity physical activity, moderate‑to‑vigorous physical activity, total sleep time, wake after sleep onset and number of awakenings collected at baseline and at each post‑baseline visit. Neurocognitive performance is evaluated with a digital test battery that includes the Trail Making Test, Rey Auditory Verbal Learning Test, Click Reaction Time, Victoria Stroop Test, Digital Corsi Block‑Tapping Test, Symbol Digit Processing Test, and Verbal Fluency Test, administered at baseline and week 6. Functional magnetic resonance imaging (fMRI) using the monetary incentive delay task measures reward‑system activity at baseline and week 6. Blood and cerebrospinal fluid samples are analysed for predefined biomarkers, and serum pramipexole concentrations are measured at baseline, week 6, and week 15. All efficacy outcomes will be analyzed with stratification by bipolar subtype in exploratory analyses.