Investigating leucine's effects on midlife depression

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

This study is testing whether taking leucine supplements can help people with midlife depression feel better by looking at changes in their brain and mood over six weeks.

Quick facts

• Phase: PHASE2
• Study type: Interventional
• Enrollment: 75 (estimated)
• Ages: 35 Years to 65 Years
• Sex: All
• Sponsor: Emory University (other)
• Locations: 1 site (Atlanta, Georgia)
• Trial ID: NCT06580145 on ClinicalTrials.gov

What this trial studies

This study aims to explore the impact of a 6-week leucine challenge on brain chemistry, connectivity, and behavior in individuals suffering from midlife depression. Participants will be divided into two groups, with one receiving leucine supplements and the other receiving an active comparator, lysine. The research focuses on the relationship between inflammation and depression, particularly through the kynurenine pathway, which may produce toxic substances affecting brain function. Brain scans and symptom assessments will be utilized to evaluate the effectiveness of leucine in improving mental health outcomes.

Who should consider this trial

Good fit: Ideal candidates include middle-aged adults diagnosed with major depression and exhibiting signs of inflammation.

Not a fit: Patients with contraindications to MRI or those who do not meet the inclusion criteria for depression severity may not benefit from this study.

Why it matters

Potential benefit: If successful, this research could lead to new treatment options for midlife depression, particularly for those with inflammation-related symptoms.

How similar studies have performed: While animal studies have shown promise for leucine's effects on depression, this approach in humans is novel and has not been extensively tested.

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

Where this trial is running

Atlanta, Georgia

• Emory University Hospital — Atlanta, Georgia, United States (RECRUITING)

Study contacts

• Principal investigator: Ebrahim Haroon, MD — Emory University
• Study coordinator: Ebrahim Haroon, MD

Conditions: Major Depression, Kynurenine pathway, Leucine in Midlife Depression, inflammation