PRIME-PRAXOL: Pramipexole for Anhedonic Depression

Sponsor

Region Skane (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05355337

Collaborator

Lund University (Other)

Enrollment

Location

Arms

51.9

Anticipated Duration (Months)

1.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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 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.

Condition or Disease	Intervention/Treatment	Phase
Psychiatric Disorders Mood Anhedonia Depression Fatigue Syndrome, Chronic	Drug: Pramipexole Drug: Placebo	Phase 3

Study Design

Study Type:

Interventional

Anticipated Enrollment :

60 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Randomized placebo-controlled with two armsRandomized placebo-controlled with two arms

Masking:

Double (Participant, Investigator)

Primary Purpose:

Treatment

Official Title:

Adjunctive Treatment With Pramipexole for Anhedonic Depression Symptoms in Depression - PRIME-PRAXOL

Anticipated Study Start Date :

Nov 1, 2022

Anticipated Primary Completion Date :

Dec 1, 2026

Anticipated Study Completion Date :

Mar 1, 2027

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Pramipexole Pramipexole prolonged-release tablet, 0.26 mg base to 3.15 mg base / day for 9 weeks (individually varying dose titrating during these weeks).	Drug: Pramipexole 9 weeks of treatment with Pramipexole
Placebo Comparator: Placebo Tablets in appearance identical to the active comparator tablets, but without the the active substance (pramipexole).	Drug: Placebo 9 weeks of treatment with Placebo

Arm

Intervention/Treatment

Active Comparator: Pramipexole

Pramipexole prolonged-release tablet, 0.26 mg base to 3.15 mg base / day for 9 weeks (individually varying dose titrating during these weeks).

Drug: Pramipexole

9 weeks of treatment with Pramipexole

Placebo Comparator: Placebo

Tablets in appearance identical to the active comparator tablets, but without the the active substance (pramipexole).

Drug: Placebo

9 weeks of treatment with Placebo

Outcome Measures

Primary Outcome Measures

Effect on anhedonia [9 weeks]
Change in Snaith-Hamilton Pleasure Scale (SHAPS-C) total score from baseline to week 9

Secondary Outcome Measures

Effect on depression [9 weeks]
Change in Hamilton Rating Scale for Depression 6 items (HDRS-6) total score baseline to week 9
Effect on physical activity [9 weeks]
Change in relevant parameters (number of steps and distance travelled), using a digital activity monitor (bracelet), from baseline to week 9
Effect on physical sleep quality [9 weeks]
Change in relevant parameters (movement during sleep cycles), using a digital activity monitor (bracelet), from baseline to week 9
Effect on other anhedonic domains not measured by SHAPS-C [9 weeks]
Change in Dimensional Anhedonia Rating Scale (DARS) total score (inverse scale, lower points equals more anhedonia) from baseline to week 9
Effect on general depressive symptoms [9 weeks]
Change in Montgomery-Åsberg Depression Rating Scale (MADRS-S) total score from baseline to week 9
Effect on sleep and insomnia [9 weeks]
Change in Insomnia Severity Index (ISI) total score from baseline to week 9
Effect on apathy [9 weeks]
Change in Apathy Evaluation Scale (AES) total score from baseline to week 9
Effect on anxiety [9 weeks]
Change in Generalized Anxiety Disorder 7-item scale (GAD-7) total score from baseline to week 9
Effect on quality of life [9 weeks]
Change in Brunnsviken Brief Quality of life scale (BBQ) total score from baseline to week 9
Effect on reward system activation [9 weeks]
Functional magnetic resonance imaging (fMRI) with Monetary Incentive Delay (MID)-task measuring Blood-Oxygen Level Dependent (BOLD) imaging pre/post treatment: Change in BOLD signals in nucleus accumbens from baseline to week 9
L-DOPA, blood: biomarker of dopaminergic neurotransmission [9 weeks]
Change in levels of L-DOPA in blood sample from baseline to week 9
L-DOPA, CSF: biomarker of dopaminergic neurotransmission [9 weeks]
Change in levels of L-DOPA in cerebrospinal fluid sample from baseline to week 9
Homovanillic acid, blood: biomarker of dopaminergic neurotransmission [9 weeks]
Change in levels of homovanillic acid in blood sample from baseline to week 9
Homovanillic acid, CSF: biomarker of dopaminergic neurotransmission [9 weeks]
Change in levels of homovanillic acid in cerebrospinal fluid sample from baseline to week 9
BH4, blood: biomarker of dopaminergic neurotransmission [9 weeks]
Change in levels of tetrahydrobiopterin (BH4) in blood sample from baseline to week 9
BH4, CSF: biomarker of dopaminergic neurotransmission [9 weeks]
Change in levels of tetrahydrobiopterin (BH4) in cerebrospinal fluid sample from baseline to week 9
Tyrosine, blood: biomarker of dopaminergic neurotransmission [9 weeks]
Change in levels of tyrosine in blood sample from baseline to week 9
Tyrosine, CSF: biomarker of dopaminergic neurotransmission [9 weeks]
Change in levels of tyrosine in cerebrospinal fluid sample from baseline to week 9
Phenylalanine, blood: biomarker of dopaminergic neurotransmission [9 weeks]
Change in levels of phenylalanine in blood sample from baseline to week 9
Phenylalanine, CSF: biomarker of dopaminergic neurotransmission [9 weeks]
Change in levels of phenylalanine in cerebrospinal fluid sample from baseline to week 9
IL-6, blood: biomarker of inflammation [9 weeks]
Change in levels of interleukin-6 (IL-6) in blood sample from baseline to week 9
IL-6, CSF: biomarker of inflammation [9 weeks]
Change in levels of interleukin-6 (IL-6) in cerebrospinal fluid sample from baseline to week 9
IL-1b, blood: biomarker of inflammation [9 weeks]
Change in levels of interleukin-1b (IL-1b) in blood sample from baseline to week 9
IL-1b, CSF: biomarker of inflammation [9 weeks]
Change in levels of interleukin-1b (IL-1b) in cerebrospinal fluid sample from baseline to week 9
IFN-y, blood: biomarker of inflammation [9 weeks]
Change in levels of interferon gamma (IFN-y) in blood sample from baseline to week 9
IFN-y, CSF: fluid biomarker of inflammation [9 weeks]
Change in levels of interferon gamma (IFN-y) in cerebrospinal fluid sample from baseline to week 9
hs-CRP, blood: biomarker of inflammation [9 weeks]
Change in levels of high-sensitivity C-reactive peptide (hs-CRP) in blood sample from baseline to week 9
hs-CRP, CSF: biomarker of inflammation [9 weeks]
Change in levels of high-sensitivity C-reactive peptide (hs-CRP) in cerebrospinal fluid from baseline to week 9
TNF, blood: biomarker of inflammation [9 weeks]
Change in levels of tumor necrosis factor-alpha (TNF-alpha) in blood sample from baseline to week 9
TNF, CSF: biomarker of inflammation [9 weeks]
Change in levels of tumor necrosis factor-alpha (TNF-alpha) in cerebrospinal fluid from baseline to week 9

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Age between 18 years and 75 years.
Informed consent
Diagnosis of unipolar depressive episode, bipolar disorder in depressive phase, exhaustion disorder or dysthymia.
All patients should have clinically significant anhedonia symptoms (SHAPS score 3 or 4 on ≥ 3 items).
Subjects must have an ongoing stable treatment with at least one antidepressant / mood stabilizer for at least 4 weeks.

Exclusion Criteria:

Ongoing pregnancy, breastfeeding or planned pregnancy.
High risk of suicide.
Substance abuse.
Psychosis.
Borderline personality disorder.
Ongoing compulsory care.
History of impulse control disorder.
Diagnosis of moderate / severe kidney failure or severe cardiovascular disease.
Recently started psychotherapy.
Ongoing treatment with ECT, ketamine or TMS.
Concomitant medication or somatic disorder that would be a risk for the subject or making it difficult to evaluate efficacy of the intervention (e.g. Parkinson's disease, cancer not in remission, other drugs with similar mechanisms of action defined in protocol)
Allergic to pramipexole
Participation in other interventional studies
Other factors that in the investigators opinion could influence compliance