Anhedonia, Depression, Bipolar, Depression, Unipolar, Dysthymia
Conditions
Brief summary
The heterogeneity of depression suggests that 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 an endophenotype within the depression spectrum, with a distinct pathophysiology of 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. In this proof-of-concept pilot study the investigators test the anti-anhedonic and antidepressant effects of add-on pramipexole using an enriched population study design including only depressed patients with significant anhedonia. To understand the neurobiology of anhedonia in depression and to identify treatment predictors, the investigators also do assessments of anhedonia-related neurocircuitry using (f)MRI and blood biomarkers.
Interventions
DRUGPramipexole Pill
Add-on pramipexole
Sponsors
Lund University
Region Skane
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1. Age ≥18 and ≤75. 2. Diagnosis of unipolar depression; bipolar disorder in depressive phase or dysthymia. 3. Symptoms of depression; Total-score ≥ 18, measured by Montgomery-Åsberg Depression Rating Scale (MADRS). 4. Symptoms of anhedonia; Total-score \< 27, measured by Dimensional Anhedonia Rating Scale (DARS). 5. Ongoing treatment with at least one antidepressant drug ≥ 4 weeks without major changes in dosage. Patients with bipolar disorder must have a mood-stabilizing drug treatment. 6. Must sign an informed consent. -
Exclusion criteria
1. Ongoing pregnancy, breastfeeding or planning for pregnancy. 2. High suicidality assessed by the researcher with medical degree. 3. Ongoing substance use disorder (last 12 month). 4. Diagnosis of psychosis. 5. Ongoing involuntary psychiatric treatment. 6. History of Impulse-control disorder or current ADHD diagnosis. 7. Diagnosis of Intellectual disability, dementia, or other circumstances leading to difficulties to understand the implications of participating in the study and to give informed consent. 8. Diagnosis of renal failure (eGFR \< 50 ml/min/1,73 m2 ) or severe cardiovascular disease (defined as symptoms of heart failure NYHA class 2). 9. Recently committed to psychotherapy (during the last 6 weeks) or planning for psychotherapy during the participation of the study. 10. Ongoing ECT-treatment. 11. Other diseases, disorders or medical treatments that according to the researchers might influence the results of the study or increases the risks of the study. Such as Parkinson's disorder, liver failure, cancer not in remission (for at least over a year). 12. Confirmed or suspected allergy to the active substance or excipients of the drug used in this study. 13. Committed to other trials 14. Other reasons that according to the researcher might prevent the subject to fulfill the obligations of the study. For example insufficient drug compliance. -
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dimensional Anhedonia Rating Scale (DARS) Score | baseline to week 10 | Change in anhedonia symptoms (total score on the DARS). The range is 0-68, lower score indicating more severe anhedonia. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Montgomery Åsberg Depression Rating Scale (MADRS) Score | baseline to week 10 | Change in depression symptoms (total score on the MADRS). The range is 0-60, lower score indicating less general depressive symptoms. |
| Snaith-Hamilton Anhedonia Pleasure Scale | baseline to week 10 | Change in anhedonia symptoms (total score on the Snaith-Hamilton Anhedonia Pleasure Scale) score 0-1-2-3. Range 0-32. Higher score indicating more intense anhedonic symptoms. |
| Generalized Anxiety Disorder-7 | baseline to week 10 | Change in anxiety symptoms (total score on the the Generalized Anxiety Disorder-7 scale = GAD-7). Range 0-21. Higher score indicating more anxiety. |
| Insomnia Severity Index | baseline to week 10 | Change in insomnia symptoms (total score on the the Insomnia Severity Index scale = ISI). Range 0-28. Higher score indicating more insomnia symptoms. |
| Response | baseline to week 10 | Montgomery Åsberg Depression Rating Scale (MADRS). The range is 0-60, lower score indicating less general depressive symptoms. Response definition: reduction of at least 50% Remission definition: MADRS total score equal to or below 10 |
| The Apathy Evaluation Scale | baseline to week 10 | Change in apathy symptoms (total score on the the The Apathy Evaluation Scale = AES). Range 0-54. Higher score indicating more severe apathy. |
| Change in Inflammatory Biomarkers | baseline to week 10 | The investigators will measure blood levels of Interleukin-6 (IL-6), C-reactive protein (CRP), Tumor Necrosis Factor Alpha (TNF), and White Blood Cell count (WBC) at baseline and at study completion. The investigators will test if baseline levels and treatment-associated change in inflammatory markers can predict treatment response |
| Participation in fMRI With MID-task | baseline to week 10 (and baseline data as potential predictor) | fMRI = functional magnetic resonance tomography. Structural imaging, followed by resting-state functional imaging, diffusion tensor imaging and thereafter the MID (monetary incentive delay) task. |
| Fatigue Severity Scale | baseline to week 10 | Change in fatigue symptoms (total score on the the Fatigue Severity scale = FSS). Range 9-63. Higher score indicating more fatigue. |
Countries
Sweden
Participant flow
Recruitment details
Patients were recruited from outpatient clinics in Lund, Sweden. All study visits were conducted via the adult psychiatric clinic in Lund, Baravägen 1, 221 85, Lund during the period 4 Oct 2019 - 18 Mar 2021.
Pre-assignment details
12 patients with unipolar or bipolar, moderate-to-severe, depression were assigned to active open-label treatment with pramipexole. The sample was enriched for significant anhedonia symptoms, enrolling only patients with a score of \<27 on the Dimensional Anhedonia Rating Scale (DARS, inverse scale). 1 dropout pre-assignment/pre-treatment.
Participants by arm
| Arm | Count |
|---|---|
| Pramipexole 12 patients | 12 |
| Total | 12 |
Baseline characteristics
| Characteristic | Pramipexole |
|---|---|
| Age, Continuous | 45 Years STANDARD_DEVIATION 16 |
| Anxiety comorbidity | 6 Participants |
| Concurrent pharmacological treatment Antipsychotics users | 0 Participants |
| Concurrent pharmacological treatment Mood stabilizers users | 2 Participants |
| Concurrent pharmacological treatment NDRI users | 2 Participants |
| Concurrent pharmacological treatment SNRI users | 6 Participants |
| Concurrent pharmacological treatment SSRI users | 5 Participants |
| ECT | 4 Participants |
| hsCRP | 3.8 mg/L STANDARD_DEVIATION 4.7 |
| Number of previous antidepressants | 5 Number of different antidepressants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 12 Participants |
| Region of Enrollment Sweden | 12 Participants |
| Sex: Female, Male Female | 8 Participants |
| Sex: Female, Male Male | 4 Participants |
| Tobacco users | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 12 |
| other Total, other adverse events | 12 / 12 |
| serious Total, serious adverse events | 0 / 12 |
Outcome results
Primary
Dimensional Anhedonia Rating Scale (DARS) Score
Change in anhedonia symptoms (total score on the DARS). The range is 0-68, lower score indicating more severe anhedonia.
Time frame: baseline to week 10
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pramipexole | Dimensional Anhedonia Rating Scale (DARS) Score | DARS total score baseline | 15.75 score on a scale | Standard Deviation 6.44 |
| Pramipexole | Dimensional Anhedonia Rating Scale (DARS) Score | DARS total score week 10 | 33.08 score on a scale | Standard Deviation 11.782 |
Secondary
Change in Inflammatory Biomarkers
The investigators will measure blood levels of Interleukin-6 (IL-6), C-reactive protein (CRP), Tumor Necrosis Factor Alpha (TNF), and White Blood Cell count (WBC) at baseline and at study completion. The investigators will test if baseline levels and treatment-associated change in inflammatory markers can predict treatment response
Time frame: baseline to week 10
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pramipexole | Change in Inflammatory Biomarkers | CRP at baseline | 3.8 mg/L | Standard Deviation 4.7 |
| Pramipexole | Change in Inflammatory Biomarkers | CRP at week 10 | 2.6 mg/L | Standard Deviation 3.5 |
Secondary
Fatigue Severity Scale
Change in fatigue symptoms (total score on the the Fatigue Severity scale = FSS). Range 9-63. Higher score indicating more fatigue.
Time frame: baseline to week 10
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pramipexole | Fatigue Severity Scale | FSS total score baseline | 46.45 score on a scale | Standard Deviation 12.581 |
| Pramipexole | Fatigue Severity Scale | FSS total score week 10 | 38.45 score on a scale | Standard Deviation 15.807 |
Secondary
Generalized Anxiety Disorder-7
Change in anxiety symptoms (total score on the the Generalized Anxiety Disorder-7 scale = GAD-7). Range 0-21. Higher score indicating more anxiety.
Time frame: baseline to week 10
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pramipexole | Generalized Anxiety Disorder-7 | GAD-7 total score baseline | 9.64 score on a scale | Standard Deviation 6.087 |
| Pramipexole | Generalized Anxiety Disorder-7 | GAD-7 total score week 10 | 6.18 score on a scale | Standard Deviation 6.57 |
Secondary
Insomnia Severity Index
Change in insomnia symptoms (total score on the the Insomnia Severity Index scale = ISI). Range 0-28. Higher score indicating more insomnia symptoms.
Time frame: baseline to week 10
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pramipexole | Insomnia Severity Index | ISI total score baseline | 15.73 score on a scale | Standard Deviation 6.182 |
| Pramipexole | Insomnia Severity Index | ISI total score week 10 | 10.27 score on a scale | Standard Deviation 4.839 |
Secondary
Montgomery Åsberg Depression Rating Scale (MADRS) Score
Change in depression symptoms (total score on the MADRS). The range is 0-60, lower score indicating less general depressive symptoms.
Time frame: baseline to week 10
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pramipexole | Montgomery Åsberg Depression Rating Scale (MADRS) Score | MADRS total score baseline | 26.33 score on a scale | Standard Deviation 4.185 |
| Pramipexole | Montgomery Åsberg Depression Rating Scale (MADRS) Score | MADRS total score week 10 | 15.67 score on a scale | Standard Deviation 6.401 |
Secondary
Participation in fMRI With MID-task
fMRI = functional magnetic resonance tomography. Structural imaging, followed by resting-state functional imaging, diffusion tensor imaging and thereafter the MID (monetary incentive delay) task.
Time frame: baseline to week 10 (and baseline data as potential predictor)
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Pramipexole | Participation in fMRI With MID-task | Not participating in fMRI | 4 Participants |
| Pramipexole | Participation in fMRI With MID-task | Participating in fMRI | 8 Participants |
Secondary
Response
Montgomery Åsberg Depression Rating Scale (MADRS). The range is 0-60, lower score indicating less general depressive symptoms. Response definition: reduction of at least 50% Remission definition: MADRS total score equal to or below 10
Time frame: baseline to week 10
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Pramipexole | Response | Responders | 4 Participants |
| Pramipexole | Response | Non-responders | 8 Participants |
Secondary
Snaith-Hamilton Anhedonia Pleasure Scale
Change in anhedonia symptoms (total score on the Snaith-Hamilton Anhedonia Pleasure Scale) score 0-1-2-3. Range 0-32. Higher score indicating more intense anhedonic symptoms.
Time frame: baseline to week 10
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pramipexole | Snaith-Hamilton Anhedonia Pleasure Scale | SHAPS total score baseline | 30.00 score on a scale | Standard Deviation 5.592 |
| Pramipexole | Snaith-Hamilton Anhedonia Pleasure Scale | SHAPS total score week 10 | 17.50 score on a scale | Standard Deviation 6.389 |
Secondary
The Apathy Evaluation Scale
Change in apathy symptoms (total score on the the The Apathy Evaluation Scale = AES). Range 0-54. Higher score indicating more severe apathy.
Time frame: baseline to week 10
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pramipexole | The Apathy Evaluation Scale | AES total score baseline | 52.55 score on a scale | Standard Deviation 6.905 |
| Pramipexole | The Apathy Evaluation Scale | AES total score week 10 | 36.18 score on a scale | Standard Deviation 9.152 |