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

Trial Summary

What is the purpose of this trial?

Background Adults over the age of 60 with symptoms of major depressive disorder are said to have late-life depression (LLD), a condition that usually decreases a person's quality of life and is associated with other risks like physical frailty and dementia. A common feature of more severe LLD is psychomotor slowing, where a person's ability to think and move are impaired. For example, they might not be able to walk or process information as quickly, and they might have problems with their working memory. Psychomotor slowing in LLD might be the result of a problem with the way a person's body produces or responds to the neurotransmitter dopamine. The drug Levodopa (L-DOPA), which can replace missing dopamine in the brain, has been used to treat to treat Parkinson's disease for many decades, and it might also affect psychomotor slowing in LLD. Methods In this study, participants are adults aged 60 years or older with moderate to severe major depression. Participants undergo the "L-DOPA challenge"-a 2-week period where they receive a dose of L-DOPA once a day for the first week and a dose of L-DOPA twice a day for the second week. Before and after a participant completes the L-DOPA challenge, the study team assesses their depressive symptoms and psychomotor function. After the L-DOPA challenge, if a participant still shows signs of moderate or severe depression, they receive an antidepressant for 12 weeks. Aims The first aim of this study is to test the feasibility of the L-DOPA challenge-that is, whether most of the 50 participants recruited for this study will complete the L-DOPA challenge. For example, participants might have to withdraw if they can't make the daily visits to the research site to receive their L-DOPA medication, if they can't tolerate the medication's side effects, or if their depressive symptoms get significantly worse. Our hypothesis is that 80% of the participants will complete the L-DOPA challenge. The second aim of the study is to see if L-DOPA affects participants' depressive symptoms, processing speed, and working memory. Our hypothesis is that L-DOPA response, measured as an improvement in gait speed, is associated with a decrease in depressive symptoms and an increase in processing speed and working memory.

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 Levodopa generally safe for human use?

Levodopa, often combined with carbidopa, has been used safely in humans for conditions like Parkinson's disease. While it can cause side effects such as gastrointestinal issues and dyskinesia (involuntary movements), no unexpected side effects or adverse laboratory results have been reported in long-term studies. ^{1 2 3 4 5}

How is the drug Apo-levocarb unique for treating depression?

Apo-levocarb, which combines levodopa and carbidopa, is unique because it is primarily used for Parkinson's disease, where it helps manage symptoms by providing a steady release of dopamine. This controlled-release mechanism might offer a novel approach for depression by potentially stabilizing mood through similar dopamine regulation. ^{1 4 5 6 7}

Eligibility Criteria

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

I am at least 60 years old.

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

MADRS score of ≥15 (moderate/severe depression)

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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]

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]

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 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 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]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Comparative multiple-dose pharmacokinetics of controlled-release levodopa products. [2018]

2. England 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. [2019]

3. England pubmed.ncbi.nlm.nih.gov

Long-term evaluation of Sinemet CR in parkinsonian patients with motor fluctuations. [2019]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Pharmacokinetics of Rytary®, An Extended-Release Capsule Formulation of Carbidopa-Levodopa. [2022]

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

Sinemet (CR4): an open-label study in moderately severe Parkinson's disease. [2019]

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

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

7. Netherlands 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. [2019]