Dopamine Modulation of Motivation and Motor Function in Major Depression & Inflammation

Study Overview
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Brief Summary
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A large body of evidence on depression heterogeneity point to an immunometabolic subtype characterized by the clustering of immunometabolic dysregulations with atypical behavioral symptoms related to energy homeostasis. Motivational and motor impairments reflected by symptoms of anhedonia and psychomotor retardation in major depression are closely related to alterations in energy homeostasis, are associated with increased inflammation, and may be a direct consequence of the impact of inflammatory cytokines on the dopamine system in the brain. In the proposed project, the investigators will examine the effect of dopamine stimulation on motivation and motor function in patients with major depression and healthy controls and the role of inflammation using a double-blind, randomized, placebo-controlled, cross-over design. If successful, this study would provide crucial evidence that pharmacologic strategies that increase dopamine may effectively treat inflammation-related symptoms of anhedonia and psychomotor retardation in major depression.

Official Title
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Effects of Pharmacological Dopamine Modulation on Motivation and Motor Function in Major Depression Characterized by Low-grade Inflammation.

Conditions
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Depressive Disorder, Major

Intervention / Treatment
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* Drug: L-dopa/Carbidopa
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: For patients with major depressive disorder: diagnosis of major depressive disorder according to DSM-5 C-reactive protein (CRP): > 3 mg/l or ≤ 1 mg/l free of antidepressant medication For healthy participants: C-reactive protein (CRP): ≤ 1 mg/l free of antidepressant medication free of any current psychiatric disorder Exclusion Criteria: diagnosis of schizophrenia, schizoaffective disorder, bipolar disorder, dementia, and current/past alcohol or drug dependence central nervous system diseases neurological diseases suspicious undiagnosed skin lesions or a history of melanoma narrow-angle or wide-angle glaucoma bronchial asthma history of peptic ulcer disease history of seizures any severe somatic disease current infections or chronic inflammatory diseases (e.g., rheumatic diseases, inflammatory bowel disease) pregnancy / breast-feeding class 3 obesity (body mass index of 40 or higher) Use of medication containing reserpine (certain antihypertensive agents), tricyclic antidepressants, bon-selective monoamine oxidase (MAO) inhibitors, antiparkinsonian drugs, sympathomimetic drugs, tetrabenazine.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: L-dopa/Carbidopa followed by placebo<br>Participants will receive first L-dopa/Carbidopa (100/25 mg), and then placebo. | Drug: L-dopa/Carbidopa<br>* Patients and healthy controls will receive one time administration of L-dopa/Carbidopa (100/25 mg).<br>Drug: Placebo<br>* Patients and healthy controls will receive one time administration of Placebo.<br>|
| Experimental: Placebo followed by L-dopa/Carbidopa<br>Participants will receive first placebo, and then L-dopa/Carbidopa (100/25 mg). | Drug: L-dopa/Carbidopa<br>* Patients and healthy controls will receive one time administration of L-dopa/Carbidopa (100/25 mg).<br>Drug: Placebo<br>* Patients and healthy controls will receive one time administration of Placebo.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The change in response bias (logb) after L-dopa/Carbidopa compared to placebo in the Probabilistic Reward Task (PRT). | The PRT, which uses a signal detection paradigm, will be used to measure response bias, the propensity to select the more rewarded response (rich). | All participants will be tested on two separate experimental sessions separated by an interval of 48 hours, after L-dopa/Carbidopa or placebo. | 
| The change in mean gait speed [m/s] after L-dopa/Carbidopa compared to placebo in the dual task. | The dual task mean gait speed will be measured with six wearable inertial measurement units. In this dual task, participants walk at their usual speed while naming as many animals as possible. | All participants will be tested on two separate experimental sessions separated by an interval of 48 hours, after L-dopa/Carbidopa or placebo. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The change in choice of the hard task after L-dopa/Carbidopa compared to placebo in the Effort Expenditure for Rewards Task (EEfRT). | The EEfRT, a widely used, multi-trial task in which participants are given an opportunity on each trial to choose between two different task difficulty levels in order to obtain monetary rewards, will be used as an objective measure of reward motivation. The EEfRT is reported as the percent of high effort (hard) trials selected. A higher percentage reflects higher motivation for effort expenditure. | All participants will be tested on two separate experimental sessions separated by an interval of 48 hours, after L-dopa/Carbidopa or placebo. | 
| The change in movement time [ms] after L-dopa/Carbidopa compared to placebo in the Reaction Time Task (RTI). | The RTI from the Cambridge Neuropsychological Test Automated Battery (CANTAB) will be used to assess movement time, which is the time taken to touch the stimulus on the computer screen after the press pad had been released. | All participants will be tested on two separate experimental sessions separated by an interval of 48 hours, after L-dopa/Carbidopa or placebo. | 
| The change in risk propensity after L-dopa/Carbidopa compared to placebo in the Risky Decision-Making Task. | In the Risky Decision-Making Task, participants have to make choices between a risky option and a safe alternative. Risk Propensity, the proportion of risk-taking trials, will be a secondary outcome. | All participants will be tested on two separate experimental sessions separated by an interval of 48 hours, after L-dopa/Carbidopa or placebo. | 
| Response bias (logb) in the PRT |  | After administration of placebo on Day 2 or Day 3. | 
| Mean gait speed [m/s] in the dual task |  | After administration of placebo on Day 2 or Day 3. | 
| Choice of the hard task in the EEfRT |  | After administration of placebo on Day 2 or Day 3. | 
| Movement time [ms] in the RTI |  | After administration of placebo on Day 2 or Day 3. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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depression, inflammation, anhedonia, psychomotor retardation