RecruitingPhase 2NCT06580145

Leucine in Midlife Depression

Leucine as a Probe of Kynurenine-Induced Glutamate and Neural Circuit Dysfunction in Midlife Depression

Sponsor

Emory University

Enrollment

75 participants

Start Date

Feb 1, 2025

Study Type

INTERVENTIONAL

Conditions

Major Depression

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.

Eligibility

Min Age: 35 YearsMax Age: 65 Years

Inclusion Criteria15

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 Criteria48

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

Interventions

DRUGL-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.

DRUGL-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