The heterogeneity of depression suggests that several different neurocircuits and pathophysiological mechanisms are involved. Anhedonia - the inability to experience pleasure from, or the lack of motivation to carry out, usually enjoyable activities - is a promising endophenotype within the depression spectrum, with a distinct pathophysiology involving dopaminergic mesolimbic projections. Anhedonia is common in depression and associated with treatment resistance. Pramipexole, an agonist to the dopamine -receptor 3, is an established treatment of Parkinson's disease. Based on its mechanism of action, pramipexole might be efficacious in a subtype of depression characterized by anhedonia and lack of motivation - symptoms linked to dopaminergic hypofunction. This is supported by animal data, clinical experience, and recent pilot study data, but randomized controlled trials (RCTs) are lacking. In this double-blind placebo-controlled RCT the anti-anhedonic and antidepressant effects of add-on pramipexole will be tested, using an "enriched population study design" including only depressed patients with significant anhedonia. To better understand the neurobiology of anhedonia in depression and to identify treatment predictors, simultaneous assessments of anhedonia-related neurocircuitry using (f)MRI will be done, and anhedonia-related biomarkers in blood and cerebrospinal fluid analyzed. The aim of the study is to confirm the efficacy of pramipexole in this depression subtype, which would be an important step towards personalized medicine in psychiatry.

This is a randomized, double-blind drug trial in which 80 patients are included and treated with adjuvant pramipexole or placebo for 9 weeks. The treatment trial will be supplemented by two sub-trials with fMRI examination and lumbar puncture in research subjects who wish to participate (not mandatory for participation in the main trial).

The aim of the project is to administer pramipexole as an adjuvant to ongoing antidepressant treatment of patients with affective disorders with a symptom profile characterized by anhedonia. This trial may fill an important knowledge gap through i) the inclusion of depressive patients with significant anhedonia symptoms regardless of baseline diagnosis, ii) the use anhedonia symptoms as the primary outcome measure, iii) the use higher doses of pramipexole compared to previous studies and iv) the use of fMRI and biomarkers to predict treatment response in the future. In order to achieve a higher dosage and sufficient treatment effect compared to previously, and avoid intolerable adverse reactions, a flexible dosing schedule will be used. According to the literature, this should be an average dose of about 1.75 mg base/day but is expected to vary between individuals. In a pilot study, the mean dose of pramipexole among participants was 2.51 mg base/day (equivalent to 3.59 mg salt/day). For example, D3 receptors are known to vary with age (fewer at older ages) and thus older individuals tolerate and require higher doses to achieve treatment efficacy. Blood and cerebrospinal fluid (CSF) samples are taken for analysis of dopamine and inflammatory markers and for genetic analysis linked to these systems to investigate any association between inflammation and anhedonia symptoms, brain reward-system dysfunction and treatment response to pramipexole. In addition, an fMRI study (Monetary Incentive Delay task: reward-system test) is planned to be performed before and after treatment with pramipexole, which can be used in future follow-up studies to investigate reward-system dysfunction in anhedonia and for predictive analyses of the treatment effect of pramipexole.

Prior to the baseline visit, fMRI screening is performed for the research subjects participating in the fMRI sub-trial. Before the research subject starts treatment with pramipexole or placebo, blood samples (and CSF if the research subject is participating in the CSF sub-trial) will be taken for storage in a biobank. Study participants are assessed with Snaith-Hamilton Pleasure Scale, Hamilton Depression 6-item rating scale and self-assessed with Dimensional Anhedonia Rating Scale, Montgomery-Åsberg Depression Rating Scale, Apathy Evaluation Scale, Insomnia Severity Scale, Generalized Anxiety Disorder 7-item rating scale and Brunnsviken Brief Quality of Life scale. Trial drugs are dispensed by trial staff and the study participant begins treatment according to a titration schedule. A dosing diary is distributed and the research subject is instructed to bring this completed diary to the next visit. Activity measurement results between screening and baseline are noted and activity measurement continues while treatment with pramipexole is given. Before starting pramipexole treatment, an fMRI examination and lumbar puncture will be performed for the research subjects participating in the sub-trial(s).

After the screening visit and randomization, an unblinded staff member places the correct packs of either placebo or active treatment in different concentrations to be distributed during the study in a box unique to each research subject. A logbook is kept of the packages placed in each box. Study participants are given oral and written information on how to take the tablets. Every third week during the study, the research subject will be called for a physical visit to discuss symptom assessment, titration plan and adverse reactions (using rating scales): New estimates including SHAPS and HDRS-6 are performed. Monitoring of adverse reactions, such as the onset of mania and impulse control disorders such as gambling addiction, is carried out using a form based on the Young Ziegler Mania Rating Scale (YMRS), Problem Gambling Severity Index (PGSI) and Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease (QUIP). Compliance is assessed as sufficient for continued participation in the study. If intolerable adverse reactions develop, the research subject will be asked to contact the investigator and the strategy will be to return to the last tolerable dose and wait seven days before attempting a new dose increase. Activity meters will be checked at follow-up visits. At the time of the visit, the research subject receives investigational medicinal products until the next scheduled visit and information on how to take them. Unused medicines are collected for compliance checks. Dispensed and returned trial medicines are logged. Between visits, research subjects are contacted by telephone to check on their titration status and possible adverse reactions.

After nine weeks, a final visit is made. New blood samples for the biobank are taken at the time of the visit. New fMRI examination and lumbar puncture will be performed on the research subjects participating in the sub-trial. The maximum tolerable dose of pramipexole is noted and new psychometric estimates are performed. Activity meters are read and submitted. After completing the study, the research participant will see an unblinded doctor at the clinic. If the research subject is randomized to active treatment, they have a choice to either continue pramipexole (but outside of the trial) or to taper pramipexole according to the tapering schedule.

To be able to compare fMRI examination and biomarkers between depressed and healthy controls, 40 healthy controls will also be recruited. The healthy controls will undergo blood sampling, lumbar puncture and fMRI according to the same protocol as the depressed patients.

Inclusion Criteria:

• Age between 18 years and 75 years.
• Informed consent
• Diagnosis of unipolar depressive episode or bipolar disorder in depressive phase or dysthymia.
• Clinically significant anhedonia symptoms: SHAPS self-report score 3 or 4 on ≥ 3 items.
• Ongoing stable treatment with at least one antidepressant or mood stabilizing medication for at least 4 weeks. Has tried an antidepressant at a therapeutic dose but not achieved remission (refractory stage 1 depression)

Exclusion Criteria:

• Ongoing pregnancy, breastfeeding or planned pregnancy.
• High risk of suicide according to the overall clinical assessment of the research physician.
• Substance abuse within the last 6 months.
• Diagnosis of current psychotic disorder.
• Known diagnosis of Emotionally unstable personality disorder.
• Ongoing treatment under the Compulsory Psychiatric Care Act.
• Medical history or strong clinical suspicion of impulse control disorder (including current binge-eating disorder) or a current Attention Deficit Hyperactivity Disorder diagnosis with hyperactivity.
• Diagnosis of intellectual disability, dementia, or other circumstances that makes it difficult to understand the meaning of participating in the trial and provide informed consent.
• Diagnosis of renal failure (eGFR < 50 ml/min/1.73m2) or severe cardiovascular disease (specifically symptomatic heart failure New York Heart Association Class II or greater).
• Recently started psychotherapy (within 6 weeks) or planning to start such treatment during participation in the trial.
• Ongoing treatment with electroconvulsive therapy (ECT), ketamine or repetitive transcranial magnetic stimulation (rTMS), except maintenance ECT, ketamine or rTMS. (Maintenance treatment is defined as the use of ECT/ketamine/rTMS for a period exceeding 3 months after a series of ECT/ketamine/rTMS treatment in order to prevent the onset of a new episode.
• Other medical conditions or other concomitant drug treatment which, 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, obesity surgery affecting the absorption of extended-release tablets.
• Ongoing treatment with drugs that affect plasma levels of pramipexole or have similar or antagonistic mechanism of action as pramipexole are not allowed. Ongoing treatment with neuroleptics are not allowed except for low-dose quetiapine 27 (≤150 mg/day) since it has very low binding to dopamine receptors at such low doses.
• 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 subject's participation, such as the risk that the research subject is unable to complete the trial (non-compliance).