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Effect of Adjunctive Pramipexole on Anhedonia in Adults with Bipolar Depression – Randomized, Double‑Blind, Placebo‑Controlled Phase III Trial

Registered drugNo placebo

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What is this trial about?

A plain-language summary of the goals, design and what participants do

Bipolar disorder is a mental health condition that can cause periods of high mood (mania) and periods of low mood (depression). In this study the focus is on people who are currently experiencing a depressive episode with a loss of pleasure or interest, known as anhedonia. The medication being tested is a high‑dose form of pramipexole, taken as a once‑daily tablet, and it is compared with identical looking placebo tablets that contain no active drug.

The purpose of the trial is to find out whether adding pramipexole to the usual treatment can reduce anhedonia more effectively than placebo over a period of six weeks. Participants will be randomly assigned to receive either the active medication or the placebo, and neither the participants nor the study staff will know which is which (this is called a double‑blind design). Throughout the study, participants will visit the clinic several times for brief checks, and they will keep taking the tablets every day.

After the initial six‑week period, participants may be offered an open‑label follow‑up where everyone receives the active medication for up to 15 additional weeks. During the trial, simple tools such as questionnaires about mood and activity levels will be used, and some participants may undergo brain imaging with fMRI to explore how the drug affects brain activity. Safety will be monitored by asking about side effects and checking for any signs of mood changes.

The research process

The trial runs in 6 steps – from screening to follow-up. Each step says what happens and what the team monitors.

Step 1
Baseline assessment
On the first day after joining the study, you will attend a baseline visit. during this visit you will complete questionnaires that measure pleasure (the shaps), depression severity (the madrs), and overall health. you will also have a brief physical exam, blood sample taken, and be asked to wear a small movement sensor that records activity and sleep.
The purpose of these assessments is to record your condition before any study medication is started, so that later changes can be measured.
Step 2
Receive study medication
After the baseline assessments, you will be given a bottle of tablets. the tablets contain either pramipexole or a matching placebo. the study is double-blind, meaning neither you nor the study staff will know which type you received.
The tablets are available in four strengths: 0.26 mg, 0.52 mg, 1.05 mg, and 2.1 mg. the specific strength you receive is chosen at random by the study system.
Step 3
Daily medication intake (weeks 0‑6)
You will take one tablet by mouth each morning with water. the tablet is taken once daily for a total of six weeks.
If you are assigned to the pramipexole group, the tablet contains the active drug; if you are assigned to the placebo group, the tablet contains no active ingredient but looks the same.
Step 4
Weekly follow‑up visits (weeks 1‑6)
Each week you will return to the clinic for a short visit. at these visits you will be asked about any side effects, have your blood pressure and heart rate checked, and complete the same questionnaires used at baseline.
The movement sensor will be collected and re‑issued each visit to continue recording activity and sleep patterns.
Step 5
Final assessment at week 6
At the end of week 6 you will undergo a final assessment. this includes the shaps questionnaire, the madrs rating, and the other scales listed in the study protocol. a final blood sample and movement‑sensor data will also be collected.
The results of these assessments will be used to determine whether the study medication reduced anhedonia compared with the placebo.
Step 6
Optional open‑label extension (up to week 15)
After the six‑week double‑blind phase, you may be offered an open‑label extension. in this phase, all participants receive the active drug, pramipexole, for up to an additional fifteen weeks.
The same assessments (questionnaires, blood tests, and movement monitoring) will be performed at regular intervals during the extension, allowing further observation of safety and effectiveness.

Who can join the trial?

11 criteria

Written consent: you must sign a form agreeing to join the study.
Contraception and pregnancy test for women who could become pregnant: you need to use reliable birth control and have a negative pregnancy test.
Age: you must be at least 18 years old and not older than 80 years.
Bipolar disorder type I or II diagnosed according to the ICD-11 classification system.
Current depressive state that has lasted at least 2 weeks but no more than 18 months, as defined by the ICD-11.
Significant anhedonia (loss of pleasure) measured by scoring 3 or 4 points on three or more items of the SHAPS questionnaire.
MADRS score of 20 or higher on the clinician‑rated depression scale (MADRS).
Ongoing mood stabilizing medication with enough antimanic protection, meaning you are already taking a drug that helps keep mood steady and prevents manic episodes.
If you are taking lithium, a blood test must show a level between 0.4 and 0.9, measured within the past month.
If you are taking a mood‑stabilizing anticonvulsant or antipsychotic, the dose must not have been changed in the 4 weeks before the study start, and any recent changes must be reported.
If you are taking an antidepressant, the dose must have been stable for at least 4 weeks before joining the study.

Who cannot join the trial?

17 criteria

Pregnancy, breastfeeding, or planning to become pregnant (for women) prevents participation.
A diagnosis of intellectual disability, dementia, cognitive impairment, or any condition that makes it hard to understand the study and give consent.
Severe kidney problems (measured as eGFR < 50 ml/min/1.73 m²) or serious heart disease (symptomatic heart failure worse than Class II NYHA, a scale that describes how much heart failure limits activity).
Started psychotherapy within the last 6 weeks or planning to start it during the trial (standard psycho‑educational treatment is allowed).
Currently receiving electroconvulsive therapy (ECT), ketamine, or repetitive transcranial magnetic stimulation (rTMS).
Other medical problems or treatments that could affect the study or raise risk, such as Parkinson’s disease, serious liver disease, or active cancer that has not been in remission for at least one year.
Known or suspected allergy to any ingredient in the study medication.
Participation in another treatment study at the same time.
Any other reason the investigator believes the participant cannot complete the trial, such as likely non‑compliance.
Having a mixed episode according to ICD‑11 (the international system used to classify diseases).
High suicide risk as judged by the research doctor.
Ongoing substance abuse (use of alcohol or drugs) within the past 6 months.
Current psychotic symptoms (such as hearing voices or strong false beliefs).
Previous diagnosis of schizophrenia or schizoaffective disorder.
When the main problem is a personality disorder rather than bipolar depression.
Being under compulsory psychiatric care (LPT), which means treatment ordered by a court or authority.
History of, or strong suspicion of, an impulse control disorder (e.g., binge‑eating disorder). A diagnosis of ADHD alone does not exclude participation unless impulse‑control symptoms dominate.

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Investigated drugs

pramipexole is a medication taken by mouth in a tablet that releases the drug slowly over time. In this study it is added to the patients’ regular bipolar disorder medicines to see if it can help lessen the feeling of not being able to enjoy things (anhedonia) during a depressive episode. The drug works by stimulating certain brain pathways that use dopamine, a chemical that influences mood and pleasure.

Pramipexole

What is already known about the treatment

Pramipexol AL 0.26 mg Retardtabletten
This medication is taken by mouth as a prolonged‑release tablet. It is an approved drug for Parkinson’s disease and restless‑leg syndrome and is well described in medical literature, while its use for depression is still being studied. The main approved uses are to improve movement problems in Parkinson’s and to reduce leg sensations in restless‑leg syndrome; in this trial it is tested for anhedonic depression in bipolar disorder. Pramipexole works by stimulating dopamine D2/D3 receptors in the brain, and it belongs to the class of dopamine agonists.
Pramipexol AL 0.52 mg Retardtabletten
This medication is taken orally as a prolonged‑release tablet. It is a recognized treatment for Parkinson’s disease and restless‑leg syndrome and is documented in many studies, though its role in mood disorders is still under investigation. It is mainly used to control motor symptoms of Parkinson’s and leg discomfort in restless‑leg syndrome, and here it is being examined as an add‑on for anhedonic depression in bipolar patients. Pramipexole activates dopamine D2/D3 receptors, classifying it as a dopamine agonist.
Pramipexol AL 1.05 mg Retardtabletten
This drug is administered by mouth in a prolonged‑release tablet form. It is an established therapy for Parkinson’s disease and restless‑leg syndrome, with extensive clinical data, while its effectiveness for depressive symptoms is still experimental. Its primary indications are to improve movement in Parkinson’s and relieve restless‑leg sensations; in this study it is used to try to lessen anhedonia in bipolar depression. Pramipexole’s action is to bind to dopamine D2/D3 receptors, placing it in the dopamine agonist class.
Pramipexol AL 2.1 mg Retardtabletten
This medication is taken orally as a prolonged‑release tablet. It is approved for Parkinson’s disease and restless‑leg syndrome and is well covered in the literature, with ongoing research into its potential for treating depressive symptoms. The drug is chiefly prescribed to manage Parkinsonian motor problems and restless‑leg symptoms, and in this trial it serves as an adjunct to reduce anhedonia in bipolar depression. It works by stimulating dopamine D2/D3 receptors, making it a dopamine agonist.

Investigated diseases

Bipolar disorder - Bipolar disorder is a mood condition that causes alternating periods of unusually high energy and mood (mania) and periods of low mood and energy (depression). The length and intensity of these episodes can differ widely between individuals and may change over time. As the disorder progresses, episodes can become more frequent or last longer, and the pattern of mood changes may shift. It commonly starts in early adulthood and can affect daily activities, relationships, and work performance.