Pramipexole vs Placebo Treatment in Bipolar Disorder With Anhedonic Depression

B-HAPPI: Bipolar Disorder and High-dose Adjunctive Pramipexole in Anhedonic Depression - a Phase III, Double-blind, Randomized Controlled Trial

Among psychiatric disorders, bipolar disorder stands out due to its alarmingly high suicide rates. This condition presents unique management challenges, especially during its depressive phase, which carries the highest risk of suicide. B-HAPPI is an academic randomized controlled trial to evaluate a new medication for bipolar depression. It will investigate the efficacy and safety of pramipexole, a potent dopamine agonist that has demonstrated significant effectiveness in bipolar disorder in preliminary studies, showing large effect sizes.

• Population: 126 patients with bipolar depression
• Intervention: Pramipexole added to ongoing treatment with mood stabilizer, flexible dosing - target dose 2.1 mg/day
• Control: Add-on identical placebo
• Outcomes: Primary outcome is change in anhedonia symptoms between baseline and 6 weeks of intervention. Key secondary outcomes include (for example) general depression symptoms and safety measures.

There will be a 15 weeks open label follow up. If shown to be effective and safe, this intervention could become a key treatment option for bipolar depression, reducing suffering and potentially lowering suicide risk.

Inclusion Criteria:

• The participant has given their written consent to participate in the trial.
• For WOCBP, adequate contraception should be used (see section 9.6) and a negative pregnancy test is (u-hCG) required. WOCBP: For the purpose of this protocol, a woman is considered of childbearing potential, i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause.
• Age ≥18 years ≤80 years.
• Diagnosis of bipolar disorder type I or II as verified by ICD-11.
• Ongoing depressive state according to ICD-11 (at least 2 weeks, maximum 18 months).
• Significant anhedonia, defined as 3 or 4 points on ≥3 items on the SHAPS self-rating scale
• Minimum score on the MADRS expert rating scale ≥ 20
• Ongoing treatment with at least one mood stabilising agent (with sufficient antimanic protection as determined by clinical judgment). If treatment with lithium is ongoing, serum levels must be within the reference range of 0.4-0.9. The latest concentration measurement should be within one month before treatment initiation. If treatment is ongoing with a mood stabilising anticonvulsant or an antipsychotic, any dose adjustments made within 4 weeks prior to study start must be reported. Mood-stabilising anticonvulsants and antipsychotics must not be newly initiated within 4 weeks prior to study start. If treatment with antidepressants is ongoing the dose must have been stable for at least 4 weeks.

Exclusion Criteria:

• Pregnancy, breastfeeding or planned pregnancy (if female). See also section 8.6 below for clarification.
• Meets criteria for a mixed episode according to ICD-11.
• High suicide risk according to the overall clinical assessment of the research physician.
• Ongoing substance abuse (within 6 months).
• Ongoing psychotic symptoms.
• Prior diagnosis of schizophrenia or schizoaffective disorder.
• Clinical presentation is primarily attributable to a personality disorder.
• Subject to compulsory psychiatric care (LPT).
• History of, or strong clinical suspicion of, impulse control disorder (including current binge-eating disorder). A diagnosis of ADHD is not, in itself, an exclusion criterion; however, participants will be excluded if the clinical presentation is primarily characterised by impulse control-related symptoms.
• Diagnosis of intellectual disability, dementia, cognitive impairment, or other conditions (including those related to the depressive disorder itself) that, in the judgment of the study physician, may substantially impair the participant's ability to understand the study and provide informed consent.
• Diagnosis of renal failure (eGFR <50 ml/min/1.73m2) or severe cardiovascular disease (specifically symptomatic heart failure >Class II New York Heart Association (NYHA)).
• Recently started psychotherapy (within 6 weeks) or planning to start such treatment during participation in the trial. Psychoeducational treatment, which is standard care at bipolar units, is not an exclusion criterion.
• Ongoing treatment with ECT, ketamine or rTMS.
• Other medical conditions, other ongoing interventions or other concomitant drug treatment (see section 7.3) that, in the opinion of the investigators, may affect the evaluability of the trial or conditions that increase trial risk. For example: Parkinson's disease, hepatic insufficiency, ongoing cancer not in remission for more than one year.
• Known or suspected allergy to any active substance or excipient in the medicinal product included in the trial.
• Participation in other treatment studies.
• Other reason, as assessed by the investigator, that prevents the research participant's participation, such as the risk that the research participant is unable to complete the trial (non-compliance).