Leucine for Depression Study (L-DEP)

June 6, 2023 updated by: Joshua Hyong-Jin Cho, University of California, Los Angeles

An Experimental Treatment Approach for Inflammation-Induced Depression

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.

Study Overview

Study Type

Interventional

Enrollment (Actual)

59

Phase

  • Early Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

    • California
      • Los Angeles, California, United States, 90095
        • UCLA Cousins Center for Psychoneuroimmunology

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years to 63 years (Adult, Older Adult)

Accepts Healthy Volunteers

Yes

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Basic Science
  • Allocation: Randomized
  • Interventional Model: Factorial Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / 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
amino acid leucine in powder
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
purified bacterial wall component as an inflammatory challenge
maltodextrin
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
amino acid leucine in powder
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
maltodextrin
0.9% saline

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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
Depression Subscale of the Short Form of the Profile of Mood States (POMS-SF): total score ranges from 0 to 32; higher values represent worse outcome, i.e., more severe depressed mood; the absolute values at each time point are presented here rather than change of values between time points; zero (0) in mean and standard deviation reflect measured data and not placeholder values.
At baseline and then at 1, 1.5, 2, 3, 4, 5, and 6 hours after LPS (or saline) administration

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in Depressive Symptoms From Baseline
Time Frame: At baseline and then at 2 and 4 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.
At baseline and then at 2 and 4 hours after LPS (or saline) administration
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.
At baseline and then at 1, 1.5, 2, 3, 4, 5, and 6 hours after LPS (or saline) administration
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
Fatigue Subscale of the Short Form of the Profile of Mood States (POMS-SF): total score ranges from 0 to 20; higher values represent worse outcome, i.e., more severe fatigue; the absolute values at each time point are presented here rather than change of values between time points.
At baseline and then at 1, 1.5, 2, 3, 4, 5, and 6 hours after LPS (or saline) administration
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
Confusion Subscale of the Short Form of the Profile of Mood States (POMS-SF): total score ranges from 0 to 20; higher values represent worse outcome, i.e., more severe confusion; the absolute values at each time point are presented here rather than change of values between time points; zero (0) in mean and standard deviation reflect measured data and not placeholder values.
At baseline and then at 1, 1.5, 2, 3, 4, 5, and 6 hours after LPS (or saline) administration
Change in Memory Domains of Cognitive Function From Baseline
Time Frame: At baseline and then 3 hours after LPS (or saline) administration
Memory domains of cognitive function were measured using the computerized tests from CNS Vital Signs™: verbal memory using "Verbal Memory Test" (total scores ranging from 0 to 60; higher scores mean a better outcome); and visual memory using "Visual Memory Test" (total scores ranging from 0 to 60; higher scores mean a better outcome). The absolute values at each time point are presented.
At baseline and then 3 hours after LPS (or saline) administration
Change in Non-memory Domains of Cognitive Function From Baseline
Time Frame: At baseline and then 3 hours after LPS (or saline) administration
Non-memory domains of cognitive function were measured using the computerized tests from CNS Vital Signs™: executive function using "Stroop Test" (average reaction time in milliseconds thus ranging from 0 to infinite; shorter reaction time means a better outcome); and attention using "Shifting Attention Test" (average reaction time for correct responses in milliseconds thus ranging from 0 to infinite; shorter reaction time means a better outcome) and "Continuous Performance Test" (average reaction time for correct responses in milliseconds thus ranging from 0 to infinite; shorter reaction time means a better outcome). The absolute values at each time point are presented.
At baseline and then 3 hours after LPS (or saline) administration

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
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 hours after LPS (or saline) administration
Subjective Sensitivity to Social Rejection
Time Frame: 2 hours after LPS (or saline) administration
Using the Cyberball Social Exclusion Task, feelings of social distress to social rejection are evaluated based on a scale with the total score ranging from 0 to 48; higher values represent worse outcome, i.e., more severe social distress. The Overall Number of Participants Analyzed is different from numbers of participants reported in the Participant Flow module because some participants declined to complete this task.
2 hours after LPS (or saline) administration
Negative Bias in Facial Emotion Recognition
Time Frame: 2 hours after LPS (or saline) administration
Emotional Face Recognition Task consists in showing participants a series of black and white photographs (Ekman Pictures of facial affect), in which the facial expression is morphed from neutral to either Sad, Angry, or Happy. For each image, participants will be asked to make a forced choice about the emotion expressed, and rate their certainty.
2 hours after LPS (or saline) administration
Subjective Sensitivity to Social Acceptance
Time Frame: 2 hours after drug administration
Prior to the experimental session, participants are asked to complete a survey that contains several personality questionnaires and are video-recorded for 2-5 minutes as they discuss what they like about themselves. Participants are told that 8 people will form impressions of them by selecting personality traits to describe them. Participants then see a photograph of themselves along with a descriptive word underneath (supposedly provided by the evaluators), which is pre-rated based on desirability, and are asked to rate subjective happiness when each of the feedback items is presented. The total score of the scale ranges from 0 to 105; higher values represent better outcome, i.e., higher social reward. The Overall Number of Participants Analyzed is different from numbers of participants reported in the Participant Flow module because some participants declined to complete this task.
2 hours after drug administration
Reward
Time Frame: 2 hours after LPS (or saline) administration
Reward Learning Task (a laboratory based probabilistic reward task that objectively measures participants' ability to modulate behavior as a function of reward)
2 hours after LPS (or saline) administration
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)
At baseline and then at 1, 1.5, 2, 3, 4, 5, and 6 hours after LPS (or saline) administration
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
At baseline and then at 1, 1.5, 2, 3, 4, 5, and 6 hours after LPS (or saline) administration
Change in Gene Expression From Baseline
Time Frame: At baseline and 30 minutes after LPS (or saline) administration
Genome-wide transcriptional profiling conducted using Illumina HT-12 BeadArrays
At baseline and 30 minutes after LPS (or saline) administration

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Investigators

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

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

September 1, 2018

Primary Completion (Actual)

July 31, 2021

Study Completion (Actual)

July 31, 2021

Study Registration Dates

First Submitted

June 5, 2018

First Submitted That Met QC Criteria

June 5, 2018

First Posted (Actual)

June 15, 2018

Study Record Updates

Last Update Posted (Actual)

June 8, 2023

Last Update Submitted That Met QC Criteria

June 6, 2023

Last Verified

June 1, 2023

More Information

Terms related to this study

Other Study ID Numbers

  • R21MH113915 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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