Dopaminergic Therapy for Depression with Anhedonia

(DTA-2 Trial)

Overseen By Jennifer Felger, PhD

Age: 18 - 65

Sex: Any

Trial Phase: Phase 4

Sponsor: Emory University

Must not be taking: Antidepressants, Psychotropics, NSAIDs, others

Disqualifiers: Autoimmune, Cancer, Cardiovascular, Psychotic, others

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 8 weeks

70 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

The purpose of this 8-week, double-blind, placebo-controlled, study is to explore new treatment options for people with depression who have high inflammation and anhedonia. Seventy male and female participants with depression, between 25-55 years of age, with higher levels of inflammation and anhedonia will be randomized to receive L-DOPA or matched placebo over 8 weeks. Participants will complete lab tests, medical and psychiatric assessments, motivation and motor tasks, and MRI scans as part of the study. The total length of participation is approximately 10 to 12 weeks.

Will I have to stop taking my current medications?

Yes, you will need to stop taking all antidepressant or other psychotropic medications (like mood stabilizers, antipsychotics, and sedatives) for at least 4 weeks before the study starts (8 weeks for fluoxetine). You also cannot use NSAIDs, glucocorticoids, or statins during the study.

Is dopaminergic therapy with Carbidopa Levodopa safe for humans?

Research on Carbidopa Levodopa, often used for Parkinson's disease, shows it is generally safe for humans, with most side effects related to the method of administration rather than the drug itself. ^{1 2 3 4 5}

How does the drug Carbidopa Levodopa differ from other treatments for depression with anhedonia?

Carbidopa Levodopa is unique because it targets dopamine levels in the brain, which is a different approach compared to typical antidepressants that often focus on serotonin. This drug is traditionally used for Parkinson's disease to manage dopamine deficiency, and its use for depression with anhedonia is novel, as it may help address dopamine-related symptoms. ^{3 5 6 7 8}

What data supports the effectiveness of the drug Carbidopa Levodopa for depression with anhedonia?

Research shows that Carbidopa Levodopa is effective in treating Parkinson's disease by improving symptoms and quality of life. Although not directly related to depression, its ability to enhance dopamine levels might suggest potential benefits for conditions like depression with anhedonia, which involves a lack of pleasure. ^{1 3 9 10 11}

Who Is on the Research Team?

Jennifer Felger, PhD

Principal Investigator

Emory University

Are You a Good Fit for This Trial?

This trial is for men and women aged 25-55 with depression, specifically those who experience a lack of pleasure (anhedonia) and have high inflammation levels. Participants must not be on antidepressants or other psychotropic drugs for at least 4 weeks, have a CRP level ≥2 mg/L, and score highly on specific depression scales. Pregnant individuals, those with certain medical conditions or medication intolerances, substance abuse issues, or positive drug tests are excluded.

Inclusion Criteria

You have a score of 2 or more on the anhedonia section of the PHQ-9 questionnaire.

Your CRP level is 2 mg/L or higher.

I haven't taken any antidepressants or similar medications for at least 4 weeks.

Exclusion Criteria

You have tested positive for illegal drugs in a urine test.

I have had a cognitive disorder or a head injury that caused me to lose consciousness.

I am currently on hormone therapy for gender affirmation.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants are randomized to receive L-DOPA or placebo for 8 weeks, with assessments including lab tests, medical and psychiatric evaluations, motivation and motor tasks, and MRI scans.

8 weeks

Weekly visits for assessments

Follow-up

Participants are monitored for safety and effectiveness after treatment

2-4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Carbidopa Levodopa
• Placebo

Trial Overview The DTA-2 study is testing the effectiveness of Carbidopa Levodopa (L-DOPA), a dopaminergic therapy against a placebo in treating anhedonia in depressed individuals over an 8-week period. The study involves random assignment to either the medication or placebo group and includes lab tests, assessments, tasks related to motivation and movement control as well as MRI scans.

How Is the Trial Designed?

Group I: Carbidopa Levodopa Group Experimental Treatment 1 Intervention

Patients randomized to the Carbidopa Levodopa Group will receive one tablet per day of L-DOPA (150 mg levodopa administered with 37.5 mg carbidopa) for 4 weeks. Patients that respond after the initial 4 weeks will continue on the same dose for an additional 4 weeks to determine whether clinical response at the 150 mg dose is sustained over time compared to placebo. Patients that do not exhibit a clinical response (50% reduction in HAM-D scores from baseline) after 4-weeks on the 150 mg dose will escalate to 450 mg L-DOPA (three tablets per day of 150 mg levodopa administered with 37.5 mg carbidopa) and studied over an additional 4 weeks (8 weeks total in the study).

Group II: Placebo Group Placebo Group 1 Intervention

Participants will receive placebo tablet. Placebo-treated non-responders at 4 weeks will remain on placebo but with the same instructions to increase daily pill intake.

Carbidopa Levodopa is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Levodopa for:

• Parkinson's disease
• Dopamine-responsive dystonia
• Restless legs syndrome

Approved in United States as Levodopa for:

• Parkinson's disease
• Dopamine-responsive dystonia
• Restless legs syndrome

Approved in Canada as Levodopa for:

• Parkinson's disease
• Dopamine-responsive dystonia
• Restless legs syndrome

Approved in Japan as Levodopa for:

• Parkinson's disease
• Dopamine-responsive dystonia
• Restless legs syndrome

Who Is Running the Clinical Trial?

Emory University

Lead Sponsor

Trials

1,735

Recruited

2,605,000+

National Institute of Mental Health (NIMH)

Collaborator

Trials

3,007

Recruited

2,852,000+

Published Research Related to This Trial

Levodopa, particularly in the form of levodopa-carbidopa intestinal gel, is crucial for providing continuous dopaminergic stimulation, which is essential in the treatment of Parkinson's disease.

Studies highlight the efficacy and safety of this treatment, showing improvements in the quality of life for patients undergoing long-term therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Levodopa: the story continues]. Titova, NV., Katunina, EA.[2016]

Levodopa/carbidopa gel (Duodopa®) has been shown to significantly improve motor symptoms in advanced Parkinson's disease, with 10 out of 11 studies reporting improvements that met clinically important differences on the Unified Parkinson's Disease Rating Scale (UPDRS) III.

The treatment also enhances quality of life, as all studies assessing this aspect reported improvements that met clinically important differences, although most adverse events were related to the infusion system rather than the drug itself.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Duodopa® treatment for advanced Parkinson's disease: a review of efficacy and safety. Nyholm, D.[2013]

A study involving 20 patients with Parkinson's disease confirmed that the combination of L-dopa with a peripheral aromatic amino acid decarboxylase inhibitor (benserazide or carbidopa) is the most effective treatment available, allowing for an 80% reduction in L-dopa dosage.

Switching between the two formulations, Madopar and Sinemet, can help maintain efficacy and prevent loss of effectiveness during long-term treatment, as both achieve similar plasma levels of L-dopa.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[The combined treatment of Parkinson's disease with L-dopa plus decarboxylase inhibitors (carbidopa, benserazide) (author's transl)]. Podiwinsky, F., Mentasti, M., Riederer, P., et al.[2013]

In a study of 34 patients with advanced Parkinson's disease who were intolerant to L-DOPA, a higher proportion of carbidopa (25%) was preferred by most patients and helped reduce gastrointestinal and psychiatric side effects associated with L-DOPA.

While increasing carbidopa improved side effects, the overall improvement in disability was modest, indicating that while the combination may enhance tolerability, it does not significantly enhance the effectiveness of L-DOPA in treating Parkinson's symptoms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Carbidopa dosage modifies L-dopa induced side effects and blood levels of L-dopa and other amino acids in advanced parkinsonism. Bermejo Pareja, F., Martinez-Martin, P., Muradas, V., et al.[2019]

In a double-blind study involving 28 patients with chronic schizophrenia, L-dopa treatment (up to 1250 mg daily) showed significant improvement in symptoms according to nurse assessments, despite psychiatrist and psychologist ratings indicating only minor changes.

The study lasted six weeks and all participants continued their regular neuroleptic medication, suggesting that L-dopa may enhance treatment outcomes in schizophrenia when combined with standard therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Double blind trial of L-dopa in chronic schizophrenia. Buchanan, FH., Parton, RV., Warren, JW., et al.[2017]

In a study involving 29 patients with Parkinson's disease, Sinemet-CR demonstrated a high effectiveness rate of 80%, particularly improving symptoms like rigidity, hypokinesia, and tremor over a treatment duration of 3 months.

The treatment was found to be safe, with only 6 cases reporting negative side effects, supporting its recommendation for broader use in managing Parkinson's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[The use of the Sinemet-CR preparation in treating Parkinson's disease]. Artem'ev, DV., Damulin, IV., Iakhno, NN.[2016]

In 1984, the average use of L-dopa-containing drugs in Sweden was 1.46 defined daily doses per 1,000 inhabitants, indicating a strong correlation with the prevalence of Parkinson's disease, the primary condition treated with these medications.

The county of Gävleborg showed an exceptionally high usage rate of 2.34 DDD per 1,000 inhabitants, prompting further investigation into local factors that may influence this increased utilization.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Swedish county with unexpectedly high utilization of anti-parkinsonian drugs. Aquilonius, SM., Hartvig, P.[2019]

In a study of 60 Parkinsonism patients, the combination of levodopa with G31,406 showed potential benefits due to its anticataleptic effects, likely linked to its anticholinergic and dopaminergic actions.

The study aimed to assess not only the efficacy of these drug combinations but also the side effects and their impact on depression commonly experienced by Parkinson's patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The L-dopa sparing effect of G 31,406 in the treatment of parkinson's disease. Couto, B., Oliveira, C., Mattos, JP., et al.[2013]

Carbidopa (CD) significantly accumulates in the rat hypothalamus and striatum after administration, with peak levels observed one hour post-injection, indicating its ability to penetrate the brain and potentially influence dopamine metabolism.

At higher doses, carbidopa can inhibit dopamine formation in the brain, particularly in the hypothalamus, while also affecting the levels of other metabolites, suggesting a complex interaction between carbidopa and levodopa in the treatment of conditions like Parkinson's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of systemic carbidopa on dopamine synthesis in rat hypothalamus and striatum. Kaakkola, S., Tuomainen, P., Wurtman, RJ., et al.[2019]

Levodopa therapy revolutionized the treatment of Parkinson's disease (PD) after its effectiveness was confirmed in 1967, despite initial inconsistent results, but it also introduced significant side effects like dyskinesias and motor fluctuations.

The addition of dopa decarboxylase inhibitors, such as carbidopa, in the 1970s improved symptom control and reduced side effects, leading to more effective long-term management of PD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

History of levodopa and dopamine agonists in Parkinson's disease treatment. Tolosa, E., Martí, MJ., Valldeoriola, F., et al.[2019]

Levodopa is the primary treatment for Parkinson's disease, working by restoring dopamine release from damaged brain cells, which helps alleviate symptoms.

While effective, levodopa can cause side effects like dyskinesia due to its action on brain receptors, and using peripheral decarboxylase inhibitors can help reduce nausea associated with its use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A review of some aspects of the pharmacology of levodopa. Morris, JG.[2014]

Citations

1. Russia (Federation) pubmed.ncbi.nlm.nih.gov

[Levodopa: the story continues]. [2016]

2. England pubmed.ncbi.nlm.nih.gov

Duodopa® treatment for advanced Parkinson's disease: a review of efficacy and safety. [2013]

3. Austria pubmed.ncbi.nlm.nih.gov

[The combined treatment of Parkinson's disease with L-dopa plus decarboxylase inhibitors (carbidopa, benserazide) (author's transl)]. [2013]

4. Denmark pubmed.ncbi.nlm.nih.gov

Carbidopa dosage modifies L-dopa induced side effects and blood levels of L-dopa and other amino acids in advanced parkinsonism. [2019]

5. England pubmed.ncbi.nlm.nih.gov

Double blind trial of L-dopa in chronic schizophrenia. [2017]

6. Russia (Federation) pubmed.ncbi.nlm.nih.gov

[The use of the Sinemet-CR preparation in treating Parkinson's disease]. [2016]

7. Denmark pubmed.ncbi.nlm.nih.gov

A Swedish county with unexpectedly high utilization of anti-parkinsonian drugs. [2019]

8. Mexico pubmed.ncbi.nlm.nih.gov

The L-dopa sparing effect of G 31,406 in the treatment of parkinson's disease. [2013]

9. Austria pubmed.ncbi.nlm.nih.gov

Effects of systemic carbidopa on dopamine synthesis in rat hypothalamus and striatum. [2019]

10. United States pubmed.ncbi.nlm.nih.gov

History of levodopa and dopamine agonists in Parkinson's disease treatment. [2019]

11. Australia pubmed.ncbi.nlm.nih.gov

A review of some aspects of the pharmacology of levodopa. [2014]