Leucine for Depression Study (L-DEP)

• ClinicalTrials.gov Identifier: NCT03557684
• Recruitment Status: Terminated
• First Posted: June 15, 2018
• Last Update Posted: November 9, 2021
• Sponsor: University of California, Los Angeles
• Collaborator: National Institute of Mental Health (NIMH)
• Information provided by (Responsible Party): Hyong Jin Cho, University of California, Los Angeles

Study Description

Brief Summary:

Depression is very common and poses a huge disease burden. About 20% of the US population suffers from depression at lease once in their lifetime. Inflammations that are hidden inside our body as a result of aging, obesity, chronic diseases, or certain treatments (e.g., interferon for hepatitis C) appear to cause depressive symptoms and even clinical depression. Individuals with such inflammations are more likely to suffer from depression and are less likely to respond to currently available antidepressant medications. This study will test leucine, an amino acid, as a new way to mitigate depressive symptoms in response to such inflammations. This study begins with a 90-minute screening session to determine whether participants are eligible to join the main study. Those who meet the eligibility criteria will then join the main study, which will consist of taking leucine or maltodextrin (i.e., oral placebo) for 2 weeks at home and an 8-hour session at the UCLA Medical Center. A brief telephone follow-up every 3 months for 2 years with questions on mood is also planned. Approximately 90 healthy adults will be recruited for participation in the study. During the course of the study, participants will take leucine or maltodextrin for 2 weeks at home and then will be injected either lipopolysaccharide (LPS) or saline (i.e., intravenous placebo) at the UCLA Medical Center. LPS is a bacterial substance that can initiate chemical reactions that are similar to those seen in individuals with mild sickness symptoms, such as a slight increase in body temperature, muscle aches, or tiredness. It is a safe way of investigating the body's response to inflammation and how these changes may alter cognitive, emotional, or neural function. It has been given thousands of times to healthy volunteers - both younger and older adults - without any serious side effects.

Condition or disease	Intervention/treatment	Phase
Depression	Dietary Supplement: leucine; Other: PO placebo; Biological: lipopolysaccharide (LPS); Other: IV placebo	Early Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 64 participants
• Allocation: Randomized
• Intervention Model: Factorial Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Basic Science
• Official Title: An Experimental Treatment Approach for Inflammation-Induced Depression
• Actual Study Start Date: September 1, 2018
• Actual Primary Completion Date: July 31, 2021
• Actual Study Completion Date: July 31, 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: PO leucine & IV LPS; Oral (PO) leucine 6 g twice a day for 2 weeks followed by a single intravenous (IV) bolus of lipopolysaccharide (LPS) 0.8 ng/kg of body weight	Dietary Supplement: leucine; amino acid leucine in powder; Biological: lipopolysaccharide (LPS); purified bacterial wall component as an inflammatory challenge
Experimental: PO placebo & IV LPS; PO maltodextrin (placebo) twice a day for 2 weeks followed by a single IV bolus of LPS 0.8 ng/kg of body weight	Other: PO placebo; maltodextrin; Biological: lipopolysaccharide (LPS); purified bacterial wall component as an inflammatory challenge
Experimental: PO leucine & IV placebo; PO leucine 6 g twice a day for 2 weeks followed by a single IV bolus of 0.9% saline	Dietary Supplement: leucine; amino acid leucine in powder; Other: IV placebo; 0.9% saline
Placebo Comparator: PO placebo & IV placebo; PO maltodextrin (placebo) twice a day for 2 weeks followed by a single IV bolus of 0.9% saline	Other: PO placebo; maltodextrin; Other: IV placebo; 0.9% saline

Outcome Measures

Primary Outcome Measures :

1. Change in depressed mood from baseline [ Time Frame: At baseline and then at 1, 1.5, 2, 3, 4, 5, and 6 hours after LPS (or saline) administration ]
   Short Form of the Profile of Mood States (POMS-SF)

Secondary Outcome Measures :

1. Change in depressive symptoms from baseline [ Time Frame: At baseline and then at 2, 4, and 6 hours after LPS (or saline) administration ]
   Montgomery-Asberg Depression Rating Scale (MADRS): a clinician-rated questionnaire of depressive symptoms with scores ranging from 0 to 60, with higher scores indicating more severe depressive symptoms.
2. Change in feelings of social disconnection from baseline [ Time Frame: At baseline and then at 1, 1.5, 2, 3, 4, 5, and 6 hours after LPS (or saline) administration ]
   Feelings of Social Disconnection Scale: a self-report questionnaire of feelings of social disconnection with scores ranging from 0 to 28, with higher scores indicating more severe feelings of social disconnection.
3. Change in fatigue from baseline [ Time Frame: At baseline and then at 1, 1.5, 2, 3, 4, 5, and 6 hours after LPS (or saline) administration ]
   Short Form of the Profile of Mood States (POMS-SF)
4. Change in confusion from baseline [ Time Frame: At baseline and then at 1, 1.5, 2, 3, 4, 5, and 6 hours after LPS (or saline) administration ]
   Profile of Mood States (POMS) Confusion subscale
5. Change in cognitive function from baseline [ Time Frame: At baseline and then 3 hours after LPS (or saline) administration ]
   Verbal memory, visual memory, executive function, and attention measured using computerized tests from CNS Vital Signs™ including Verbal Memory Test, Visual Memory Test, Stroop Test, Shifting Attention Test, and Continuous Performance Test

Other Outcome Measures:

1. Anhedonia [ Time Frame: 2 hours after LPS (or saline) administration ]
   Facial expressions and skin conductance in response to funny film clips using the iMotions®Attention Tool (iMotions Inc., Cambridge, MA) which performs automatic analysis of facial expressions from video and integrates simultaneous measurement of skin conductance
2. Subjective Sensitivity to Social Rejection [ Time Frame: 2 hours after LPS (or saline) administration ]
   Cyberball Social Exclusion Task
3. Negative Bias in Facial Emotion Recognition [ Time Frame: 2 hours after LPS (or saline) administration ]
   Emotional Face Recognition Task
4. Subjective Sensitivity to Social Acceptance [ Time Frame: 2 hours after drug administration ]
   Positive Social Feedback Task
5. Reward [ Time Frame: 2 hours after LPS (or saline) administration ]
   Reward Learning Task
6. Change in proinflammatory cytokines from baseline [ Time Frame: At baseline and then at 1, 1.5, 2, 3, 4, 5, and 6 hours after LPS (or saline) administration ]
   Plasma proinflammatory cytokines (interleukin-1 receptor antagonist, interleukin-6, tumor necrosis factor-α, and soluble tumor necrosis factor receptor)
7. Change in kynurenine Metabolites from baseline [ Time Frame: At baseline and then at 1, 1.5, 2, 3, 4, 5, and 6 hours after LPS (or saline) administration ]
   Plasma tryptophan, kynurenine, quinolinic acid, and kynurenic acid
8. Change in gene expression from baseline [ Time Frame: At baseline and 30 minutes after LPS (or saline) administration ]
   Genome-wide transcriptional profiling

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 65 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

Inclusion Criteria:

Participants will be required to be in good general health (as evaluated during the phone and in-person screening sessions) and aged 18 to 65 years.

Exclusion Criteria:

Following a structured telephone interview, prospective participants with the following conditions will not advance to the in-person screening session: presence of chronic mental or physical illness, history of allergies, autoimmune, liver, or other severe chronic diseases, current use of prescription medications such as steroids, NSAIDs, immune modifying drugs, opioid analgesics, and psychotropics, or previous history of fainting during blood draws. These inclusion and exclusion criteria will be examined in detail and confirmed in the in-person screening session by the study physician. Furthermore, any participant who has any of the following conditions will be ineligible for the study. Medical Conditions: (1) presence of co-morbid medical conditions not limited to but including maple syrup urine disease (a contraindication to leucine treatment), cardiovascular (e.g., history of acute coronary event, stroke) and neurological diseases (e.g., Parkinson's disease), as well as pain disorders; (2) presence of co-morbid inflammatory disorders such as rheumatoid arthritis or other autoimmune disorders; (3) presence of an uncontrolled medical condition that is deemed by the investigators to interfere with the proposed study procedures, or to put the study participant at undue risk; (4) presence of chronic infection, which may elevate proinflammatory cytokines; (5) presence of an acute infectious illness in the two weeks prior to the screening session. Psychiatric Disorders: (6) an Axis I psychiatric disorder as determined by the Research Version of the Structured Clinical Interview for DSM-5 (SCID-5-RV) including a current major depressive disorder (a prior history of depression is not an exclusion criterion, which will be considered for a pre-planned sensitivity analysis); (7) lifetime history of suicide attempt or inpatient psychiatric admission; (8) current suicidal ideation assessed by the Columbia Suicide Severity Rating Scale (C-SSRS); (9) current depressive symptoms assessed by the PHQ-9 (≥ 5)). Medication and Substance Use: (10) current and/or past regular use of hormone-containing medications including steroids; (11) current and/or past regular use of non-steroid anti-inflammatory drugs; (12) current and/or past regular use of immune modifying drugs that target specific immune responses such as TNF antagonists; (13) current and/or past regular use of analgesics such as opioids; (14) current and/or past regular use of psychotropic medications, including antidepressants, anxiolytics, antipsychotics, hypnotics, sedatives, and barbiturates; (15) current and/or past regular use of cardiovascular medications, including antihypertensive, antiarrhythmic, antianginal, and anticoagulant drugs; (16) current smoking or excessive caffeine use (>600 mg/day) because of the known effects on proinflammatory cytokine levels; (17) evidence of recreational drug use from urine test. Health Factors: (18) BMI > 35 because of the effects of obesity on proinflammatory cytokine activity and also on risk for sleep disordered breathing; or (19) any abnormalities on screening laboratory tests.

Contacts and Locations

Locations

United States, California

UCLA Cousins Center for Psychoneuroimmunology

Los Angeles, California, United States, 90095

Sponsors and Collaborators

University of California, Los Angeles

National Institute of Mental Health (NIMH)

Investigators

• Principal Investigator: Joshua H Cho, MD, PhD; University of California Los Angeles David Geffen School of Medicine

More Information

• Responsible Party: Hyong Jin Cho, Principal Investigator, University of California, Los Angeles
• ClinicalTrials.gov Identifier: NCT03557684
• Other Study ID Numbers: R21MH113915 ( U.S. NIH Grant/Contract ); R21MH113915 ( U.S. NIH Grant/Contract )
• First Posted: June 15, 2018
• Last Update Posted: November 9, 2021
• Last Verified: November 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Depression; Depressive Disorder; Behavioral Symptoms; Mood Disorders; Mental Disorders