Leucine for Depression

Overseen By Diana Beltran, BS

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Emory University

Must not be taking: Psychotropics, Sedatives, Benzodiazepines, others

Disqualifiers: Psychotic disorders, Mania, Substance use, 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

Compensation: Varies

Number of Visits: Unknown

Duration: 6 weeks

75 Participants Needed

Trial Summary

What is the purpose of this trial?

The study aims to investigate the effects of a 6-week leucine challenge on brain chemistry, connectivity, and behavior in people with midlife depression. The researchers will compare the leucine and an active comparator arm (lysine) for 6 weeks.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications, such as immune-active medications, antibiotics, steroids, supplements affecting the immune system, and psychotropic medications, before participating. Stabilized medications for general medical conditions are allowed if the dose remains the same during the trial.

What evidence supports the effectiveness of the treatment L-leucine and L-lysine for depression?

The study on 'Add-On'-therapy with amino acids showed that adding amino acids to antidepressants improved depression symptoms and had no side effects, suggesting that amino acids like L-leucine and L-lysine might help when used with other depression treatments. ^{1 2 3 4 5}

How does the drug L-leucine differ from other treatments for depression?

L-leucine is unique because it works by blocking the entry of kynurenine, a compound linked to depression, into the brain, which is different from traditional antidepressants that often target serotonin levels. This mechanism may help reduce inflammation-induced depression-like behavior. ^{2 3 6 7 8}

Research Team

Ebrahim Haroon, MD

Principal Investigator

Emory University

Eligibility Criteria

This trial is for adults with midlife depression who can consent, have a certain level of inflammation (CRP >1 mg/L), and are diagnosed with major depression. They must experience moderate to severe symptoms, be within a specific weight range (BMI 20-35), and have no issues that prevent MRI scans. Participants need support for post-procedure transport and should not have significant EKG findings.

Inclusion Criteria

I have been diagnosed with major depression.

Able and willing to provide informed consent

SHAPS score >30 on the 0-56 scale

Exclusion Criteria

I haven't taken immune-affecting drugs, steroids, certain supplements, or specific psychiatric meds recently.

My medications for other conditions are stable and won't change during the trial.

Cognitive: Cognitive impairment (MMSE score <28)

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either leucine or lysine supplements for 6 weeks to assess changes in brain chemistry and behavior

6 weeks

Weekly visits for assessments

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• L-leucine
• L-lysine

Trial Overview The study examines the impact of leucine on brain function and mood in people with midlife depression over six weeks, comparing it against lysine as an active comparator. It aims to understand how leucine affects brain chemistry, connectivity, and depressive behavior.

Participant Groups

Group I: L-leucine Experimental Treatment 1 Intervention

Group II: L-lysine Active Control 1 Intervention

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+

Findings from Research

In a 4-week study involving about 40 in-patients, adding a tailored amino acid mixture to the antidepressant Remeron significantly improved depression symptoms compared to a placebo.

The amino acid treatment showed no side effects, which may enhance patient compliance and improve the overall benefit/risk ratio of the therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

"Add-On"-therapy with an individualized preparation consisting of free amino acids for patients with a major depression. Ille, R., Spona, J., Zickl, M., et al.[2018]

Women with a history of major depression showed impaired regulation of brain serotonin (5-HT) function when subjected to dieting-induced tryptophan depletion, indicating a potential vulnerability during dietary changes.

While dieting lowered plasma tryptophan levels in both groups, only women without a history of depression exhibited an increased prolactin response to tryptophan, suggesting that their serotonin regulation is more intact compared to those with a history of depression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impaired regulation of brain serotonin function during dieting in women recovered from depression. Smith, KA., Williams, C., Cowen, PJ.[2019]

In a study of 58 patients with major depressive disorder, those receiving L-Carnosine in addition to citalopram showed significantly greater improvements in depression symptoms compared to the placebo group over six weeks, as measured by the Hamilton Depression Rating Scale.

L-Carnosine not only improved overall depression scores but also resulted in higher response and remission rates without increasing side effects, suggesting it is a safe and effective adjunct therapy for MDD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

L-Carnosine combination therapy for major depressive disorder: A randomized, double-blind, placebo-controlled trial. Araminia, B., Shalbafan, M., Mortezaei, A., et al.[2021]

A systematic review and meta-analysis of various nutritional supplements as adjuncts to antidepressants found that omega-3 polyunsaturated fatty acids (n-3 PUFAs) and zinc showed significant efficacy in improving depression symptoms, based on multiple studies.

In contrast, the evidence for folic acid was not supportive of its efficacy, and while some positive results were noted for vitamin D, vitamin B12, and S-adenosyl-L-methionine (SAMe), the overall data for most supplements remains inconclusive or insufficient.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of adding nutritional supplements in unipolar depression: A systematic review and meta-analysis. Schefft, C., Kilarski, LL., Bschor, T., et al.[2022]

In a double-blind placebo-controlled study involving hospitalized depressed patients, large doses of amino acid precursors levodopa and L-tryptophan did not lead to significant clinical improvement, as patients were unable to leave the hospital.

The study highlights the inconsistency in previous research regarding the effectiveness of amino acid precursors in treating depression, suggesting that these compounds may not be reliable treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Amine precursors and depression. Mendels, J., Stinnett, JL., Burns, D., et al.[2019]

Leucine administration in mice effectively blocked the entry of kynurenine into the brain, which is linked to inflammation-induced depression, demonstrating its potential as an antidepressant.

In experiments, leucine not only reduced brain kynurenine levels but also prevented depression-like behaviors induced by inflammation, suggesting a novel mechanism for its antidepressant effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Leucine competes with kynurenine for blood-to-brain transport and prevents lipopolysaccharide-induced depression-like behavior in mice. Walker, AK., Wing, EE., Banks, WA., et al.[2022]

In a double-blind study involving 16 depressive patients, L-tryptophan showed some antidepressant efficacy, with responses noted in 1 out of 10 unipolar patients and 3 out of 6 bipolar patients.

The study suggests that L-tryptophan, a precursor to serotonin, may interact with electrolyte systems, which could play a role in the development of mood disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

L-tryptophan in depression. Farkas, T., Dunner, DL., Fieve, RR.[2013]

L-tryptophan, as a precursor to serotonin, may be beneficial in treating mild depression and bipolar disorder that does not respond to standard treatments, based on its biochemical role and clinical trial evidence.

It has potential as a natural hypnotic and may improve mood in Parkinson's patients, while also enhancing the effects of certain antidepressants like monoamine oxidase inhibitors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

L-tryptophan: a rational anti-depressant and a natural hypnotic? Boman, B.[2017]

References

1. Germany pubmed.ncbi.nlm.nih.gov

"Add-On"-therapy with an individualized preparation consisting of free amino acids for patients with a major depression. [2018]

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

Impaired regulation of brain serotonin function during dieting in women recovered from depression. [2019]

3. Netherlands pubmed.ncbi.nlm.nih.gov

L-Carnosine combination therapy for major depressive disorder: A randomized, double-blind, placebo-controlled trial. [2021]

4. Netherlands pubmed.ncbi.nlm.nih.gov

Efficacy of adding nutritional supplements in unipolar depression: A systematic review and meta-analysis. [2022]

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

Amine precursors and depression. [2019]

6. England pubmed.ncbi.nlm.nih.gov

Leucine competes with kynurenine for blood-to-brain transport and prevents lipopolysaccharide-induced depression-like behavior in mice. [2022]

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

L-tryptophan in depression. [2013]

8. England pubmed.ncbi.nlm.nih.gov

L-tryptophan: a rational anti-depressant and a natural hypnotic? [2017]