Rapid Antidepressant Effects of Leucine

• ClinicalTrials.gov Identifier: NCT03079297
• Recruitment Status: Terminated
• First Posted: March 14, 2017
• Results First Posted: January 26, 2023
• Last Update Posted: January 26, 2023
• Sponsor: University of Texas Southwestern Medical Center
• Information provided by (Responsible Party): Madhukar H. Trivedi, MD, University of Texas Southwestern Medical Center

Study Description

Brief Summary:

This randomized double-blind placebo-controlled crossover study seeks to evaluate the antidepressant effect of L-leucine, an essential amino acid, in patients with Major Depressive Disorder (MDD).

Condition or disease	Intervention/treatment	Phase
Major Depressive Disorder	Drug: L-Leucine; Other: Maltodextrin	Phase 2

Detailed Description:

This is a pilot phase II clinical trial of L-leucine to test its efficacy in reducing depressive symptoms in MDD patients, especially those who exhibit increased inflammation. The determination of increased inflammation will be done post-hoc. During the screening visit, all study participants will provide demographic information and complete self-report assessments and clinician evaluations and examinations. Blood and urine tests will also be performed. All participants who meet eligibility criteria and are willing to proceed with the study will enter this 6-week study after being randomized to two-week course of either L-leucine or placebo. In this cross-over study, participants will be crossed over to the second treatment after 2 weeks of washout. The study period will last 42 days (6 weeks) from the baseline visit. Both L-leucine and placebo will be provided as an effervescent mixture powder. Investigators hypothesize that MDD subjects will have greater reduction in depression severity on leucine as compared to placebo.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 16 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Pilot Double-Blind Randomized Placebo-Controlled Crossover Study to Investigate Rapid Antidepressant Effects of Leucine
• Actual Study Start Date: March 9, 2017
• Actual Primary Completion Date: October 4, 2021
• Actual Study Completion Date: October 4, 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: L-leucine; 4 gm L-leucine by mouth twice daily for two weeks	Drug: L-Leucine; L-leucine is an essential amino acid which will be provided as an effervescent powder mixture to participants.; Other Name: Leucine
Placebo Comparator: Maltodextrin; 4 gm maltodextrin by mouth twice daily for two weeks	Other: Maltodextrin; Maltodextrin is a nonsweet carbohydrate which will be provided as an effervescent powder mixture similar in taste and appearance to the L-leucine containing effervescent powder mixture; Other Name: Placebo

Outcome Measures

Primary Outcome Measures :

1. Change in QIDS-SR From Baseline at 14 Days [ Time Frame: Baseline to 14 days ]
   The Quick Inventory of Depressive Symptomatology, self-report (QIDS-SR), self-report is a 16-item measure of depression severity that includes the 9 criterion symptoms for MDD. Items are scored on a 4-point Likert scale, ranging from 0 to 3 (total score range, 0-27). Totals scores of ≤ 5 indicate no depression; 6-10 indicates mild depression; 11-15 indicates moderate depression; 16-20 indicates severe depression; and ≥ 21 indicates very severe depression. For purposes of this report, severe and very severe categories were combined as "severe to very severe" depression (≥ 16). The QIDS-A self-report has demonstrated acceptable psychometric properties.

Secondary Outcome Measures :

1. Percentage of MDD Patients With 50% or Greater Reduction in Depression Severity After 14 Days of LEU and PBO Treatments. [ Time Frame: Baseline to 14 days ]

   Response criteria defined based on QIDS-SR score at baseline and 14 days after treatment initiation.

   The Quick Inventory of Depressive Symptomatology, self-report (QIDS-SR), self-report is a 16-item measure of depression severity that includes the 9 criterion symptoms for MDD. Items are scored on a 4-point Likert scale, ranging from 0 to 3 (total score range, 0-27). Totals scores of ≤ 5 indicate no depression; 6-10 indicates mild depression; 11-15 indicates moderate depression; 16-20 indicates severe depression; and ≥ 21 indicates very severe depression. For purposes of this report, severe and very severe categories were combined as "severe to very severe" depression (≥ 16). The QIDS-A self-report has demonstrated acceptable psychometric properties.

2. Percentage of MDD Patients With QIDS-SR Score Less Than or Equal to 5 at 14 Days of LEU and PBO Treatments. [ Time Frame: 14 days ]

   Remission operationalized as QIDS-SR <=5.

   The Quick Inventory of Depressive Symptomatology, self-report (QIDS-SR), self-report is a 16-item measure of depression severity that includes the 9 criterion symptoms for MDD. Items are scored on a 4-point Likert scale, ranging from 0 to 3 (total score range, 0-27). Totals scores of ≤ 5 indicate no depression; 6-10 indicates mild depression; 11-15 indicates moderate depression; 16-20 indicates severe depression; and ≥ 21 indicates very severe depression. For purposes of this report, severe and very severe categories were combined as "severe to very severe" depression (≥ 16). The QIDS-A self-report has demonstrated acceptable psychometric properties.

3. Rates of Adverse Effects After 3 Days, 7 Days and 14 Days of LEU and PBO Treatments. [ Time Frame: Baseline to 3 days, 7 days, and 14 days ]

   Adverse effect burden will be measured with Frequency Intensity and Burden of Side-effect rating scale (FIBSER).

   The Frequency, Intensity, Burden of Side Effects Rating (FIBSER) scale was designed by Dr. Stephen Wisniewski for use in the U.S. STAR*D effectiveness study. It is a 3-item scale to assess side effects from antidepressant treatment. To use the FIBSER in measurement-based care, clinicians should consider item 3 (Burden). If the score is 0 to 2 (None to Mild interference with activities), no change in medication is needed. If the score is 3-4 (Moderate to Marked interference with activites), the side effects need to be addressed (i.e., change in dose, side effect antidote, etc). If the score is 5-6 (Severe interference with activities or Unable to Function), the dose needs to be decreased or the medication needs to be switched.

4. Change in Fatigue Symptoms From Baseline After 3, 7, and 14 Days of LEU and PBO Treatments Measured With Multidimensional Fatigue Inventory. [ Time Frame: Baseline to 3 days, 7 days, and 14 days ]

   Fatigue will be measured with Multidimensional fatigue inventory

   The Multidimensional Fatigue Inventory (MFI) is a 20-item self-report instrument designed to measure fatigue. It contains five scales: general fatigue (items 1, 5, 12, 16), mental fatigue (items 7, 11, 13, 19), physical fatigue (items 2, 8, 14, 20), reduced motivation (items 4, 9, 15, 18) and reduced activity (items 3, 6, 10, 17). Items are scored on a 5-point scale on which the participant expressed the degree to which the statement applied to him or her (from agreement "yes, that is true" to disagreement "no, that is not true") in the previous days. Item scores are summed to create a sum score for each scale, ranging between 4 (best condition) and 20 (worst condition). Higher scores indicate more fatigue.

5. Change in Psychosocial Function From Baseline After 3, 7, and 14 Days of LEU and PBO Treatments Measured Using Work and Social Adjustment Scale. [ Time Frame: Baseline to 3 days, 7 days, and 14 days ]

   Psychosocial function will be measured using Work and Social Adjustment Scale

   The Work and Social Adjustment Scale ("WSAS") is a 5-item measure for impairment in functioning. Items are scored on an 8-point scale on how much participants' problems impaired their ability to carry out the activity (from "Not at all" to "Very severely"). Item scores are summed to create a sum score. The maximum score of the WSAS is 40, lower scores are better. A WSAS score above 20 appears to suggest moderately severe or worse psychopathology. Scores between 10 and 20 are associated with significant functional impairment but less severe clinical symptomatology. Scores below 10 appear to be associated with subclinical populations.

6. Change in Anhedonia From Baseline After 3, 7, and 14 Days of LEU and PBO Treatments Measured Using Snaith-Hamilton Pleasure Scale (SHAPS) [ Time Frame: Baseline to 3 days, 7 days, and 14 days ]

   Anhedonia will be measured using Snaith-Hamilton Pleasure Scale (SHAPS).

   The Snaith-Hamilton Pleasure Scale (SHAPS) is a 14-item scale that measures anhedonia, the inability to experience pleasure. The items cover the domains of: social interaction, food and drink, sensory experience, and interest/pastimes. A score of 2 or less constitutes a "normal" score, while an "abnormal" score is defined as 3 or more. Each item has four possible responses: strongly disagree, disagree, agree, or strongly agree. Either of the "disagree" responses score one point, and either of the "agree" responses score 0 points. Thus, the final score ranges from 0 to 14.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 64 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Current primary diagnosis of nonpsychotic major depressive disorder.
• Stable antidepressant dose of no more than one antidepressant medication for 4 weeks and no anticipated changes during the study period.
• Stable doses of all concomitant medications for over 6 weeks.
• No more than two failed antidepressant trials of adequate dose and duration, as defined by ATRQ, in the current episode.

Exclusion Criteria:

• Psychiatric co-morbidity posing safety risk.
• Pregnant or breastfeeding or plan to become pregnant over the ensuing 2 months following study entry or are sexually active and not using adequate contraception
• Exclusionary psychiatric conditions (such as substance dependence in the last 6 months, substance abuse in the last 2 months, or lifetime history of psychotic disorders.
• Unstable or terminal general medical condition (GMC).
• Concomitant medications that interact with L-leucine (e.g. sildenafil).
• Vagus nerve stimulation, ECT, or rTMS, or other somatic antidepressant treatment during current episode
• Inadequately controlled hypothyroidism.
• Therapy that is depression specific, such as CBT or Interpersonal Psychotherapy of Depression.
• Hypersensitivity to L-leucine
• Have Maple Syrup Urine Disease.

Contacts and Locations

Locations

United States, Texas

University of Texas Southwestern Medical Center

Dallas, Texas, United States, 75390

Sponsors and Collaborators

University of Texas Southwestern Medical Center

Investigators

• Principal Investigator: Madhukar H Trivedi, M.D.; UT Southwestern Medical Center

  Study Documents (Full-Text)

Documents provided by Madhukar H. Trivedi, MD, University of Texas Southwestern Medical Center:

Study Protocol and Statistical Analysis Plan  [PDF] August 16, 2016

More Information

Publications:

Dantzer R, O'Connor JC, Freund GG, Johnson RW, Kelley KW. From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci. 2008 Jan;9(1):46-56. doi: 10.1038/nrn2297.

Jha MK, Minhajuddin A, Gadad BS, Greer T, Grannemann B, Soyombo A, Mayes TL, Rush AJ, Trivedi MH. Can C-reactive protein inform antidepressant medication selection in depressed outpatients? Findings from the CO-MED trial. Psychoneuroendocrinology. 2017 Apr;78:105-113. doi: 10.1016/j.psyneuen.2017.01.023. Epub 2017 Jan 24.

Rush AJ, Wisniewski SR, Warden D, Luther JF, Davis LL, Fava M, Nierenberg AA, Trivedi MH. Selecting among second-step antidepressant medication monotherapies: predictive value of clinical, demographic, or first-step treatment features. Arch Gen Psychiatry. 2008 Aug;65(8):870-80. doi: 10.1001/archpsyc.65.8.870.

Rush AJ, Trivedi MH, Wisniewski SR, Stewart JW, Nierenberg AA, Thase ME, Ritz L, Biggs MM, Warden D, Luther JF, Shores-Wilson K, Niederehe G, Fava M; STAR*D Study Team. Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression. N Engl J Med. 2006 Mar 23;354(12):1231-42. doi: 10.1056/NEJMoa052963.

Trivedi MH, Fava M, Wisniewski SR, Thase ME, Quitkin F, Warden D, Ritz L, Nierenberg AA, Lebowitz BD, Biggs MM, Luther JF, Shores-Wilson K, Rush AJ; STAR*D Study Team. Medication augmentation after the failure of SSRIs for depression. N Engl J Med. 2006 Mar 23;354(12):1243-52. doi: 10.1056/NEJMoa052964.

• Responsible Party: Madhukar H. Trivedi, MD, MD, University of Texas Southwestern Medical Center
• ClinicalTrials.gov Identifier: NCT03079297
• Other Study ID Numbers: STU 082016-037
• First Posted: March 14, 2017
• Results First Posted: January 26, 2023
• Last Update Posted: January 26, 2023
• Last Verified: December 2022

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
• Product Manufactured in and Exported from the U.S.: No

Keywords provided by Madhukar H. Trivedi, MD, University of Texas Southwestern Medical Center:

Antidepressant; Inflammation; Biomarker; Depression; Treatment Resistant Depression; Leucine

Additional relevant MeSH terms:

Depressive Disorder; Depressive Disorder, Major; Mood Disorders; Mental Disorders