DTA (Dopaminergic Therapy for Anhedonia) Study

Phase 4

Completed

Conditions: Depression
Anhedonia

Interventions: Drug: Carbidopa Levodopa
Drug: Placebo

Registration Number: NCT04723147

Lead Sponsor: Emory University

Brief Summary: The purpose of this 6-week, double-blind, placebo-controlled, crossover study is to explore new treatment options for people with depression who have high inflammation and anhedonia. Thirty-five male and female participants with depression, between the ages of 25-55 years of age, will be randomized to two study tracks (A and B) to receive both placebo and three doses of L-DOPA, given in different orders. Increases or decreases in each dose will occur gradually over 6 weeks of the study. Participants will complete lab tests, medical and psychiatric assessments, neurocognitive testing and functional MRI (fMRI) scans as part of the study. The total length of participation is about 2 months.

Detailed Description: Depression is a widespread disorder (lifetime prevalence \>20%). Current antidepressant medications are effective for many patients; however, more than 30% fail to respond. Of the patients that do respond to treatment, some continue to suffer with primary symptoms of depression like an inability to experience pleasure, called anhedonia. In this regard, one biological pathway that may contribute to symptoms of depression and particularly anhedonia is inflammation.

The purpose of this 6-week, double-blind, placebo-controlled, crossover study is to explore new treatment options for people with depression who have high inflammation and anhedonia. Despite evidence of low dopamine function in patients with depression, the ability of existing dopaminergic therapies, like L-DOPA, to affect brain circuits in depression has yet to be explored. This study will help determine the best dose of an FDA-approved medication, Sinemet (L-DOPA) that might be used in the future to treat sub-groups of depressed individuals.

Forty male and female participants with depression, between the ages of 25-55 years of age, will be randomized to two study tracks (A and B) to receive both placebo and three doses of L-DOPA, given in different orders. Increases or decreases in each dose will occur gradually over 6 weeks of the study. Participants will complete lab tests, medical and psychiatric assessments, neurocognitive testing and functional MRI (fMRI) scans as part of the study. The total length of participation is about 2 months.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 19

Inclusion Criteria

willing and able to give written informed consent;
men or women, 25-55 years of age
a primary diagnosis of DSM-V MD, current, as diagnosed by the SCID-I;
score >10 on the Patient Health Questionnaire [PHQ]-9
off all antidepressant or other psychotropic therapy (e.g. mood stabilizers, antipsychotics, anxiolytics, and sedative hypnotics) for at least 4 weeks prior to baseline visit (8 weeks for fluoxetine)
CRP ≥2 mg/L
Score >/=2 on the anhedonia question of Patient Health Questionnaire [PHQ]-9

Exclusion Criteria

history or evidence (clinical or laboratory) of an autoimmune disorder ;
history or evidence (clinical or laboratory) of hepatitis B or C infection or human immunodeficiency virus infection; - history of any type of cancer requiring treatment with more than minor surgery;
unstable cardiovascular, endocrinologic, hematologic, hepatic, renal, or neurologic disease (as determined by physical examination, EKG and laboratory testing);
history of any (non-mood-related) psychotic disorder; active psychotic symptoms of any type; history or current bipolar disorder; history or current gambling disorder; substance abuse/dependence within 6 months of study entry (as determined by SCID);
active suicidal plan as determined by a score >3 on item #3 on the HAM-D; g. an active eating disorder (except for patients with binge eating disorder in whom binging is clearly associated with worsening of mood symptoms) ;
a history of a cognitive disorder
pregnancy or lactation;
chronic use of non-steroidal anti-inflammatory agents (NSAIDS) (excluding 81mg of aspirin), glucocorticoid containing medications or statins;
use of NSAIDS, glucocorticoids, or statins at any time during the study;
urine toxicology screen is positive for drugs of abuse,
any contraindication for MRI scanning; n. intolerance, sensitivity or contraindication to carbidopa-levodopa (including history of narrow-angle glaucoma, melanoma, gastric and/or duodenal ulcers, bleeding disorders, or frequent migraines).

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Carbidopa Levodopa followed by Placebo	Placebo	Participants will receive first Carbidopa Levodopa at doses ranging from 150 to 450 mg administered at a ratio of 1 mg carbidopa for every 4 mg L-DOPA with a starting dose of 150 mg/day with dose escalation 150 mg/day per week to a final dose of 450 mg/day; and then placebo.
Placebo followed by Carbidopa Levodopa	Placebo	Participants will receive first placebo, and then Carbidopa Levodopa (L-DOPA) at doses ranging from 150 to 450 mg administered at a ratio of 1 mg carbidopa for every 4 mg L-DOPA with a starting dose of 150 mg/day with dose escalation 150 mg/day per week to a final dose of 450 mg/day.
Carbidopa Levodopa followed by Placebo	Carbidopa Levodopa	Participants will receive first Carbidopa Levodopa at doses ranging from 150 to 450 mg administered at a ratio of 1 mg carbidopa for every 4 mg L-DOPA with a starting dose of 150 mg/day with dose escalation 150 mg/day per week to a final dose of 450 mg/day; and then placebo.
Placebo followed by Carbidopa Levodopa	Carbidopa Levodopa	Participants will receive first placebo, and then Carbidopa Levodopa (L-DOPA) at doses ranging from 150 to 450 mg administered at a ratio of 1 mg carbidopa for every 4 mg L-DOPA with a starting dose of 150 mg/day with dose escalation 150 mg/day per week to a final dose of 450 mg/day.

Primary Outcome Measures

Name	Time	Method
Targeted Ventral Striatum to Ventromedial Prefrontal Cortex (VS-vmPFC) Connectivity	Baseline, 1-week of placebo, and 1-week at each dose of L-DOPA (150 mg/day, 300 mg/day and 450 mg/day)	Patients will undergo resting-state and task-based functional magnetic resonance imaging (fMRI) to calculate functional connectivity (FC) between the ventral striatum (VS) and ventromedial prefrontal cortex (vmPFC). FC is measured as continuous Z scores reflecting the correlation of activity between the brain regions using Fisher's Z transformation {Z(R)=0.5ln\[(1+R)/(1-R)\]}. This is a standard method for calculating fMRI FC whereby higher FC Z scores reflect stronger connectivity.

Secondary Outcome Measures

Name	Time	Method
Effort-Expenditure for Rewards Task (EEfRT)	Baseline, 1-week of placebo, and 1-week at each dose of L-DOPA (150 mg/day, 300 mg/day and 450 mg/day)	The EEfRT is 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. EEfRT will be used as an objective measure of motivation and will be administered following MRI scans during the study. The EEfRT is reported as the percent of high effort trials selected. A higher percentage reflects higher motivation for effort expenditure.
Inventory of Depressive Symptomatology- Self-Report (IDS-SR) Anhedonia Scale	Baseline, 1-week of placebo, and 1-week at each dose of L-DOPA (150 mg/day, 300 mg/day and 450 mg/day)	Anhedonia symptoms experienced over the past 7 days will be assessed from a subscale of the Inventory of Depressive Symptomatology- Self-Report (IDS-SR), a widely used self-report for measuring depression severity. The anhedonia subscale score is created by summing responses to items #8 (responsiveness of mood to good or desired events), #19 (general interest), and #21 (capacity for pleasure). Total anhedonia subscale scores range from 0-9 with higher scores reflecting greater anhedonia.
Hedonic Capacity as Measured by the Snaith Hamilton Pleasure Clinician Scale (SHAPS-C )	Baseline, 1-week of placebo, and 1-week at each dose of L-DOPA (150 mg/day, 300 mg/day and 450 mg/day)	The Snaith-Hamilton Pleasure Scale-Clinician (SHAPS-C) is a clinician-administered version of a validated tool for assessing hedonic tone. The SHAPS-C uses 14 questions. If "Strongly disagree" or "disagree" is chosen as the answer, item receives a score of 1 per question. If "Strongly agree" or "agree" is chosen, item receives a score of 0; then sum the scores. Total possible score ranges from 0 to 14, with higher scores reflecting greater pathology (worse study outcome).
Motivation and Pleasure-Self-Report (MAP-SR)	Baseline, 1-week of placebo, and 1-week at each dose of L-DOPA (150 mg/day, 300 mg/day and 450 mg/day)	The Motivation and Pleasure-Self-Report (MAP-SR) will be used to capture self-reported aspects of anhedonia and reduced motivation. The scale uses 18 question each rated on a Likert scale of 0-4. Total possible score ranges from 18 to 72, with higher scores reflecting worse outcome.
Hamilton Depression Rating Scale (HAM-D) Anhedonia and Motivation Item	Baseline, 1-week of placebo, and 1-week at each dose of L-DOPA (150 mg/day, 300 mg/day and 450 mg/day)	The anhedonia and motivation-related item from the clinician administered Hamilton Depression Rating Scale (HAM-D) (item #7: work and activities) will be used to measure anhedonia. This item is rated on a scale of 0-4 with higher scores reflecting worse outcome.