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.