Levodopa for Depression

(LLDOPA Trial)

Overseen By Nicholas J Ainsworth, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of British Columbia

Must be taking: Psychotropic medications

Must not be taking: Dopamine antagonists, Benzodiazepines

Disqualifiers: Neurocognitive disorder, Psychosis, Unstable illness, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

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

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

50 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether Levodopa, a drug commonly used for Parkinson's disease, can improve symptoms of depression and slow thinking in older adults with major depression. The study targets adults aged 60 and over who experience moderate to severe depression. Participants will take Levodopa for two weeks, and researchers will assess changes in mood and mental processing. Ideal candidates have been experiencing major depression and are currently on stable doses of psychiatric medication. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to important findings.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you must be on stable doses of any psychotropic medications, including antidepressants, for at least 4 weeks before joining. If you recently started or changed the dose of such medications, you may not be eligible.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research shows that Levodopa, often used with Carbidopa, is usually well-tolerated for treating conditions like Parkinson’s disease. This combination helps replace dopamine in the brain. However, some side effects can occur, such as nausea and dizziness. In some cases, individuals might experience confusion, hallucinations, or mood changes.

Levodopa has been used for a long time and is approved by the FDA for treating Parkinson's disease, indicating its safety for long-term use in that context. While it is being tested here for a new purpose—helping with depression in older adults—its safety record from past use provides some confidence in its tolerability.

Prospective trial participants should know that their health will be closely monitored, and any side effects will be managed to ensure comfort. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about using levodopa-carbidopa for depression because it taps into a different mechanism than most current antidepressants. While standard treatments like SSRIs and SNRIs primarily focus on serotonin and norepinephrine, levodopa-carbidopa targets dopamine pathways, which could offer relief for patients who don't respond well to conventional options. Additionally, this treatment might show faster effects, potentially improving symptoms in just a couple of weeks compared to the typical several weeks required by traditional antidepressants.

What evidence suggests that Levodopa might be an effective treatment for late-life depression?

Research shows that Levodopa, a medication that increases dopamine in the brain, might help treat depression. Studies have found that it can boost motivation and reduce depression symptoms in some people. Specifically, Levodopa has improved motivation related to effort and decreased feelings of anhedonia and the severity of depression. In a small group of patients with Parkinson’s disease, Levodopa treatment lowered depression scores. While results can differ, these findings suggest that Levodopa may offer benefits for those with depression, especially when it involves slowed movement and thinking. Participants in this trial will undergo an L-DOPA Challenge to assess its effects on psychomotor speed and depression symptoms. ^{6 7 8 9 10}

Are You a Good Fit for This Trial?

This trial is for adults over 60 with moderate to severe major depression, known as late-life depression (LLD). They must be able to visit the research site daily and tolerate L-DOPA's side effects. The study excludes those who cannot commit to the schedule or have conditions that may worsen with L-DOPA.

Inclusion Criteria

MINI International Neuropsychiatric Interview diagnosis of major depressive disorder, based on DSM-5 criteria

MADRS score of ≥15 (moderate/severe depression)

Able to adhere to the intervention schedule

Exclusion Criteria

History of allergy or other hypersensitivity to levodopa, carbidopa, or to any other ingredient in the formulation of Levocarb

Current active psychosis

Have a non-correctable clinically significant sensory impairment (i.e., cannot hear or see well enough to complete the neuropsychological tests)

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

L-DOPA Challenge

Participants undergo a 2-week L-DOPA challenge with daily dosing to assess psychomotor response

2 weeks

Daily visits (in-person)

Antidepressant Treatment

Participants receive an antidepressant for 12 weeks if moderate or severe depression persists after the L-DOPA challenge

12 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Apo-levocarb

Trial Overview The trial tests if Levodopa (L-DOPA) can improve psychomotor function in people with LLD by giving them a dose once daily for one week, then twice daily for another week. It also looks at whether this treatment affects depressive symptoms, processing speed, and working memory.

How Is the Trial Designed?

Group I: L-DOPA Challenge Experimental Treatment 1 Intervention

Participants will be administered a levodopa-carbidopa challenge, at a dosage of 150mg/37.5mg once daily for one week, followed by twice daily for one week. Psychomotor speed will be assessed before and after the challenge.

Apo-levocarb is already approved in European Union, United States, Canada for the following indications:

Approved in European Union as Levodopa for:

• Parkinson's disease
• Postencephalitic parkinsonism
• Symptomatic parkinsonism due to carbon monoxide intoxication

Approved in United States as Levodopa for:

• Parkinson's disease
• Postencephalitic parkinsonism
• Symptomatic parkinsonism due to carbon monoxide intoxication
• Restless leg syndrome
• Periodic limb movement in sleep (PLMS)

Approved in Canada as Levodopa for:

• Parkinson's disease
• Postencephalitic parkinsonism
• Symptomatic parkinsonism due to carbon monoxide intoxication

Who Is Running the Clinical Trial?

University of British Columbia

Lead Sponsor

Trials

1,506

Recruited

2,528,000+

Providence Health & Services

Collaborator

Trials

131

Recruited

827,000+

Published Research Related to This Trial

In a three-year open-label trial with 18 patients, Sinemet CR (carbidopa/levodopa) showed no significant change in daily dosing frequency, indicating stable long-term management of Parkinson's symptoms.

While patients experienced stable 'on' time, there was an increase in 'on with dyskinesias' over the study period, but no serious side effects or adverse laboratory results were linked to the medication.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term evaluation of Sinemet CR in parkinsonian patients with motor fluctuations. Hutton, JT., Morris, JL.[2019]

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 a study involving 18 healthy volunteers, controlled-release formulations of levodopa (Madopar HBS and Sinemet CR) showed a significant reduction in peak concentration (Cmax) and an increase in minimum concentration (Cmin) compared to conventional Madopar capsules, indicating a more stable release profile.

Madopar HBS demonstrated superior tolerability with fewer adverse events (only 2 reported) compared to conventional Madopar (18 events), suggesting it may be a safer option for patients, particularly in reducing initial nausea.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative multiple-dose pharmacokinetics of controlled-release levodopa products. Grahnén, A., Eckernäs, SA., Collin, C., et al.[2018]

In a study of 21 patients with Parkinson's disease, the combination of levodopa and carbidopa (Sinemet) led to an average improvement of 51.9% in clinical condition within just 2 weeks, compared to levodopa alone.

Using the combination therapy allowed for a significant reduction in the daily dosage of levodopa by 77%, while also reducing gastrointestinal side effects and avoiding arrhythmogenic effects, indicating a safer and more effective treatment approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A comparative clinical investigation of the therapeutic effect of levodopa alone and in combination with a decarboxylase inhibitor (carbidopa) in cases of Parkinson's disease. Wajsbort, J., Dorner, A., Wajsbort, E.[2019]

In a 1-year study of 20 patients with moderate to severe Parkinson's disease, Sinemet CR4 provided nocturnal benefits for all patients, indicating its potential for improving nighttime symptoms.

Despite some patients experiencing initial benefits, all required higher overall dosages of levodopa over time, and side effects remained prevalent, suggesting that while Sinemet CR4 may be a useful adjunct therapy, it cannot replace standard Sinemet.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sinemet (CR4): an open-label study in moderately severe Parkinson's disease. Ming, A., Temlett, JA., Fritz, VU.[2019]

In a six-month study involving 17 patients with severe Parkinson's disease, controlled-release levodopa-carbidopa (Sinemet CR-4) showed significant clinical benefits, including improved disability and reduced 'off' periods, compared to standard levodopa/carbidopa.

While the systemic bioavailability of CR-4 was higher, it had a delayed onset of action, leading to the need for additional standard levodopa in some patients to manage symptoms effectively.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical and pharmacokinetic evaluation of controlled-release levodopa/carbidopa (CR-4) in parkinsonian patients with severe motor fluctuations: a six month follow-up study. Deleu, D., Jacques, M., Michotte, Y., et al.[2019]

The new extended-release carbidopa-levodopa capsule (Rytary®/Numient®) provides both rapid initial absorption and stable plasma levels of levodopa, which helps reduce motor fluctuations and dyskinesia in Parkinson's disease patients.

Phase III studies demonstrated that this extended-release formulation significantly decreases 'off' time compared to immediate-release carbidopa-levodopa, indicating improved efficacy in managing Parkinson's disease symptoms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics of Rytary®, An Extended-Release Capsule Formulation of Carbidopa-Levodopa. Mittur, A., Gupta, S., Modi, NB.[2022]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4174860/

Influence of Depressive Symptoms on Dopaminergic ... Levodopa (l-DOPA) and dopaminergic agonists have been shown to reduce the depressive symptoms (21, 22), to have no effects (23, 24), or to worsen the ...

2. news.emory.edu news.emory.edu/stories/2025/03/hs_bhc_levodopa_depression/story.html

Levodopa may improve motivation in depression linked to ... A study from Emory University suggests that levodopa, a medication that increases dopamine levels in the brain, may help treat individuals with depression.

3. sciencedirect.com sciencedirect.com/science/article/pii/S0889159124007554

Sustained effects of repeated levodopa (L-DOPA) ... L-DOPA improved effort-based motivation, with preliminary effects on anhedonia and depression severity. 3.2.1. Primary behavioral outcome, objective-motivation.

4. clinicaltrials.gov clinicaltrials.gov/study/NCT04650217

Levodopa and Exercise for Older Adults With Depression ... A number of reports and meta-analytic reviews suggest that exercise is an effective non-pharmacologic treatment for depression, including depression in older ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC2987522/

Potential mechanisms underlying anxiety and depression in ... For example, acute L-DOPA treatment was shown to reduce scores on the Beck Depression Inventory (BDI) and apathy in a small group of PD patients (Witt et al., ...

6. mayoclinic.org mayoclinic.org/drugs-supplements/carbidopa-and-levodopa-oral-route/description/drg-20095211

Carbidopa and levodopa (oral route) - Side effects & dosage Other changes might be confusion, worsening of depression, visual hallucinations (seeing things that are not there), suicidal thoughts, and ...

7. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/books/NBK482140/

Levodopa (L-Dopa) - StatPearls - NCBI Bookshelf - NIH Levodopa can increase the risk of psychosis in patients already diagnosed with a major psychotic disorder. Per the Food and Drug Administration ...

8. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2020/017555s072lbl.pdf

SINEMET - accessdata.fda.gov At steady state, the bioavailability of carbidopa from SINEMET tablets is approximately 99% relative to the concomitant administration of carbidopa and levodopa ...

9. go.drugbank.com go.drugbank.com/drugs/DB01235

Levodopa: Uses, Interactions, Mechanism of Action The risk or severity of CNS depression can be increased when Levodopa is combined with Agomelatine. Aldesleukin, The risk or severity of hypotension and ...

10. medsafe.govt.nz medsafe.govt.nz/profs/datasheet/s/Sinemettab.pdf

SINEMET® 25/100 (25 mg/100 mg Tablets) Safety and effectiveness of SINEMET in infants and children have not been established, and its use in patients below the age of 18 years is not recommended. ...