Leucine in Midlife Depression

NCT ID: NCT06580145

Last Updated: 2025-04-24

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 75 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2025-02-01
• Study Completion Date: 2029-06-30

Brief Summary

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.

Detailed Description

Major depression is a common and serious mental health condition that can severely impact a person's quality of life. Some symptoms, like loss of pleasure in activities and slowed movements, may be signs that the depression will be harder to treat. These symptoms are also linked to a higher risk of dementia later in life.

Scientists think that long-term, low-level inflammation in the body may contribute to depression, especially in middle-aged adults. This inflammation may affect areas of the brain involved in feeling good and controlling movement.

One way inflammation might lead to depression is through a process in the body called the kynurenine pathway. When activated by inflammation, this pathway can produce substances that are toxic to brain cells. These toxins can disrupt how brain cells communicate and function.

Leucine, a nutrient found in some foods, may help block these toxic substances from entering the brain. While animal studies have shown promise, we do yet know if leucine can help humans with depression.

To find out, researchers are planning a 6-week study in middle-aged adults with depression and signs of inflammation. Half the participants will take leucine supplements, while the other half will take a different supplement (lysine) for comparison. The study will use brain scans and symptom assessments to see if leucine improves brain function and reduces depression.

If successful, this research could point to new ways to treat depression, especially in cases that do not respond well to current treatments. It may also help reduce the risk of dementia in people with depression. This study is an important step in understanding how inflammation affects mental health and in developing new treatments to help people feel better.

Conditions

Major Depression

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

L-leucine

Group Type: EXPERIMENTAL

L-leucine

Intervention Type: DRUG

L-leucine is an essential amino acid used to competitively inhibit kynurenine uptake into the brain via the large neutral amino acid transporter (LAT1).

The proposed dose for L-leucine is 4.31 g/day, administered orally.

L-lysine

Group Type: ACTIVE_COMPARATOR

L-lysine

Intervention Type: DRUG

L-lysine monohydrochloride is also an essential amino acid. It serves as an active comparator to control for general effects on brain protein synthesis and enters the brain through separate cationic amino acid transporters.

The proposed dose for L-lysine is 6 g/day, administered orally

Interventions

L-leucine

L-leucine is an essential amino acid used to competitively inhibit kynurenine uptake into the brain via the large neutral amino acid transporter (LAT1).

The proposed dose for L-leucine is 4.31 g/day, administered orally.

Intervention Type: DRUG

L-lysine

L-lysine monohydrochloride is also an essential amino acid. It serves as an active comparator to control for general effects on brain protein synthesis and enters the brain through separate cationic amino acid transporters.

The proposed dose for L-lysine is 6 g/day, administered orally

Intervention Type: DRUG

Other Intervention Names

Leucine; Lysine

Eligibility Criteria

Inclusion Criteria

• Able and willing to provide informed consent
• Diagnosis of major depression per Structured Interview for DSM-V (SCID-V)
• Moderate to severe depression- Inventory of Depressive Symptoms - Self Reported (IDS-SR score >34).
• SHAPS score >30 on the 0-56 scale
• Body mass index (BMI) between 20-35 kg/m2
• Plasma CRP >1 mg/L
• No contraindications to MRI
• Availability of friends or family for transportation after lumbar puncture procedure
• Clinically significant findings on EKG
• Patient Health Questionnaire (PHQ-9) score greater than 10
• Willingness to adopt contraceptive measures. Persons exempt from contraception requirements are:

• Persons assigned male at birth
• Persons assigned female at birth who:

• have undergone a hysterectomy or bilateral oophorectomy; or
• have been naturally postmenopausal for at least 24 consecutive months (i.e., has NOT had menses at any time in the preceding 24 consecutive months)

Exclusion Criteria

• Leucine-Specific:

• History of maple syrup urine disease
• Risk of hypoglycemia (unstable diabetes)
• History of vitamin B6 deficiency, relative
• Lysine-Specific:

• On calcium supplements, relative
• History of renal/gall stones (could cleared by a primary care provider)
• Cognitive:

--Cognitive impairment (MMSE score <28)

• Psychiatric Disorders:

• Lifetime diagnosis of psychotic disorders.
• Current mania/hypomania.
• Substance use disorder in the last 6 months.
• Active suicidal ideation:
• Psychiatric hospitalization in the past year.
• Suicide attempts within the last five years.
• Scores >3 on the Columbia Suicide Severity Rating Scale (C-SSRS)
• Binge eating in the absence of mood symptoms increases.
• Primary diagnosis of severe DSM-V79 anxiety disorders.
• Primary diagnosis of DSM-V PTSD (if severity exceeds major depression).
• Primary diagnosis of DSM-V obsessive-compulsive disorders.
• Significant personality disorders with multiple hospitalizations or suicide attempts.
• Developmental disorders (e.g., ADHD).
• Concomitant medications:

• Immune-active medications (e.g., non-steroidal anti-inflammatory agents).
• Antibiotics and immunizations in the past 2 weeks.
• Topical or inhaled steroids within the past week.
• Oral/parenteral steroids in the last 6 months.
• Supplements that impact the immune system (e.g., omega-3, probiotics) within the past 2 weeks.
• Psychotropic medications within the last 4 weeks (8 weeks for fluoxetine).
• Daily use of sedative-hypnotics, benzodiazepines, and opiates.
• Medical Disorders:

• Unstable medical disorders (frequent provider or medication changes).
• Lifetime diagnosis/treatment of cancers (excluding basal cell carcinoma).
• Lifetime diagnosis/treatment of autoimmune disorders.
• Lifetime exposure to chemotherapeutic agents.
• MRI Considerations:

-- Location and quantity of metallic objects safe to MR

• Concomitant Treatment for Depression:

-- Treatments with antidepressant medications or those with antidepressant effects (dopamine supplements).

• Treatment for General Medical Conditions (GMCs):

• Stabilized medications are allowed if maintained at the same dose during the trial.
• Multiple recent changes in concomitant medications reviewed by the study PI
• Population

• Pregnant women.
• Children.
• Prisoners.
• Individuals unable to consent

• Minimum Eligible Age: 35 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Institute of Mental Health (NIMH)

NIH

Sponsor Role: collaborator

Emory University

OTHER

Sponsor Role: lead

Responsible Party

Ebrahim Haroon

Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Ebrahim Haroon, MD

Role: PRINCIPAL_INVESTIGATOR

Emory University

Locations

Emory University Hospital

Atlanta, Georgia, United States

Site Status: RECRUITING

Countries

United States

Central Contacts

Ebrahim Haroon, MD

Role: CONTACT

eharoon@emory.edu

(404) 727-8229

Diana Beltran, BS

Role: CONTACT

djbeltr@emory.edu

404-712-7686

Facility Contacts

Ebrahim Haroon, MD

Role: primary

eharoon@emory.edu

404-712-2890

Other Identifiers

R01MH132059

Identifier Type: NIH

Identifier Source: secondary_id

View Link

STUDY00006751

Identifier Type: -

Identifier Source: org_study_id