Study of 6(S)-5-MTHF Among Selective Serotonin Reuptake Inhibitor-Resistant Outpatients With Major Depressive Disorder (TRD-2)

• ClinicalTrials.gov Identifier: NCT00955955
• Recruitment Status: Completed
• First Posted: August 10, 2009
• Results First Posted: January 18, 2013
• Last Update Posted: April 28, 2017
• Sponsor: George I. Papakostas
• Collaborator: Pamlab, L.L.C.
• Information provided by (Responsible Party): George I. Papakostas, Massachusetts General Hospital

Study Description

Brief Summary:

The purpose of the study is to test whether oral 6(S)-5-MTHF (Deplin) is safe and effective in relieving depression when it is added to standard kinds of antidepressants called serotonin reuptake inhibitors (SSRIs).

Condition or disease	Intervention/treatment	Phase
Depression	Other: 6(S)-5-MTHF(Deplin); Other: Placebo	Phase 4

Detailed Description:

The study consists of two phases, each lasting a total of four weeks (8 weeks total), with visits at the DCRP every 10 days. If the subject is eligible, they will be asked to return two weeks later for a baseline visit, when they will be randomly assigned, like a flip of a coin, to one of three treatment groups: a) drug/drug, b) placebo/drug, c) placebo/placebo (a placebo is a pill that looks like a study drug but contains no active medication). They will have a greater than 50% chance of receiving active medication (Deplin) at some point in the 8 week study.

Neither the subject nor the research staff will know which group the subject is in.

All subjects will be asked to take the study medication in the morning, in addition to their ongoing SSRI treatment.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 75 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: TRD - 2: A Double-Blind, Placebo Controlled Study of 6(S)-5-MTHF Among SSRI-Resistant Outpatients With Major Depressive Disorder (MDD)
• Study Start Date: July 2009
• Actual Primary Completion Date: April 2011
• Actual Study Completion Date: April 2011

Arms and Interventions

Arm	Intervention/treatment
Experimental: 6(S)-5-MTHF(Deplin); Participants will receive 15 mg/day of Deplin, a medical food, for 8 weeks. The SPCD approach, is modified and conducted as follows: The phase II dataset of interest is limited to patients treated with placebo during phase I who completed phase I, who did not experience a clinical response according to the HDRS-17 during phase I and entered phase II. Drug is compared to placebo in phase II for this patient subset alone. The ITT/LOCF data comparing drug and placebo during phase I is combined with the data comparing drug and placebo according to the SPCD model for phase II (see steps 2 and 3 above), and analyzed using the statistical model as described in Fava et al, 2003	Other: 6(S)-5-MTHF(Deplin); Deplin is a medical food. Patients will take 15 mg/day of deplin.
Experimental: Placebo/Deplin; Participants will receive placebo for the first 4 weeks, and then 15 mg/day of Deplin (6(S)-5-MTHF) for the next 4 weeks. The SPCD approach, is modified and conducted as follows: The phase II dataset of interest is limited to patients treated with placebo during phase I who completed phase I, who did not experience a clinical response according to the HDRS-17 during phase I and entered phase II. Drug is compared to placebo in phase II for this patient subset alone. The ITT/LOCF data comparing drug and placebo during phase I is combined with the data comparing drug and placebo according to the SPCD model for phase II (see steps 2 and 3 above), and analyzed using the statistical model as described in Fava et al, 2003	Other: 6(S)-5-MTHF(Deplin); Deplin is a medical food. Patients will take 15 mg/day of deplin.; Other: Placebo; Inactive substance
Experimental: Placebo/Placebo; Participants will receive placebo for both phases of the study. The SPCD approach, is modified and conducted as follows: The phase II dataset of interest is limited to patients treated with placebo during phase I who completed phase I, who did not experience a clinical response according to the HDRS-17 during phase I and entered phase II. Drug is compared to placebo in phase II for this patient subset alone. The ITT/LOCF data comparing drug and placebo during phase I is combined with the data comparing drug and placebo according to the SPCD model for phase II (see steps 2 and 3 above), and analyzed using the statistical model as described in Fava et al, 2003	Other: Placebo; Inactive substance

Outcome Measures

Primary Outcome Measures :

1. The 17-item Hamilton Depression Scale (HAM-D-17) [ Time Frame: Baseline and Day 60 ]

   The HAM-D-17 is a multiple choice questionnaire that clinicians may use to rate the severity of a patient's major depression. Items are scored on a scale of zero to four and higher scores indicate greater impairment. This scale is scored by summing the scores on each item and scores can range from 0-68.

   When assessing changes in HAMD score, negative changes indicate improvement (i.e. the score has decreased) and positive scores indicate a worsening of symptoms (i.e. scores have increased).

Secondary Outcome Measures :

1. The Quick Inventory of Depressive Symptomatology - Self Report (QIDS-SR) [ Time Frame: Baseline and Day 60 ]

   This measure is a 16 item self report questionnaire assessing symptoms of depression. For each item, scores range from 0 to 3 with higher scores indicating greater impairment. To score this measure:

   1. Enter the highest score from questions 1-4 (sleep items): ______
   2. Enter score on item 5 ____
   3. Enter the highest score from questions 6-9 (appetite/weight): ______
   4. Enter score on item 10 ____
   5. Enter score on item 11 ____
   6. Enter score on item 12 ____
   7. Enter score on item 13 ____
   8. Enter score on item 14 ____
   9. Enter the highest score from questions 15-16 (psychomotor items): ______

   Total score range 0-27: ______

   When assessing changes in this measure over time, negative means indicate an improvement (i.e. the scores decreased over time) and positive means indicate worsening in functioning.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 65 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• 18-65 years old
• Meet criteria for current Major Depressive Disorder
• Currently taking an SSRI

Exclusion Criteria:

• Pregnant women
• Unstable medical illness including cardiovascular, hepatic, renal, respiratory, endocrine, neurological, or hematological disease
• Prior course of MTHF augmentation, or intolerance to MTHF at any dose
• Substance use disorders active within the last six months, any bipolar disorder (current or past), any psychotic disorder (current or past)
• Have failed more than 2 adequate antidepressant trials during the current Major Depressive Episode

Contacts and Locations

Locations

United States, California

University of California San Diego School of Medicine

San Diego, California, United States, 92093

United States, Illinois

Rush University Medical Center, Psychiatric Medicine Associates, LLC

Chicago, Illinois, United States, 60612

United States, Massachusetts

Massachusetts General Hospital

Boston, Massachusetts, United States, 02114

United States, Ohio

University of Cincinnati, College of Medicine

Cincinnati, Ohio, United States, 45221

United States, Pennsylvania

University of Pennsylvania

Philadelphia, Pennsylvania, United States, 19104

United States, Tennessee

Vanderbilt University Medical Center

Nashville, Tennessee, United States, 37232

Sponsors and Collaborators

George I. Papakostas

Pamlab, L.L.C.

Investigators

• Principal Investigator: George I. Papakostas, MD; Massachusetts General Hospital

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Shelton RC, Pencina MJ, Barrentine LW, Ruiz JA, Fava M, Zajecka JM, Papakostas GI. Association of obesity and inflammatory marker levels on treatment outcome: results from a double-blind, randomized study of adjunctive L-methylfolate calcium in patients with MDD who are inadequate responders to SSRIs. J Clin Psychiatry. 2015 Dec;76(12):1635-41. doi: 10.4088/JCP.14m09587.

Papakostas GI, Shelton RC, Zajecka JM, Bottiglieri T, Roffman J, Cassiello C, Stahl SM, Fava M. Effect of adjunctive L-methylfolate 15 mg among inadequate responders to SSRIs in depressed patients who were stratified by biomarker levels and genotype: results from a randomized clinical trial. J Clin Psychiatry. 2014 Aug;75(8):855-63. doi: 10.4088/JCP.13m08947.

Papakostas GI, Shelton RC, Zajecka JM, Etemad B, Rickels K, Clain A, Baer L, Dalton ED, Sacco GR, Schoenfeld D, Pencina M, Meisner A, Bottiglieri T, Nelson E, Mischoulon D, Alpert JE, Barbee JG, Zisook S, Fava M. L-methylfolate as adjunctive therapy for SSRI-resistant major depression: results of two randomized, double-blind, parallel-sequential trials. Am J Psychiatry. 2012 Dec;169(12):1267-74. doi: 10.1176/appi.ajp.2012.11071114.

• Responsible Party: George I. Papakostas, Director of Treatment Resistant Depression Studies-DCRP, Massachusetts General Hospital
• ClinicalTrials.gov Identifier: NCT00955955
• Other Study ID Numbers: 2006P000604 (2)
• First Posted: August 10, 2009
• Results First Posted: January 18, 2013
• Last Update Posted: April 28, 2017
• Last Verified: March 2017

Keywords provided by George I. Papakostas, Massachusetts General Hospital:

Depression; Medical food

Additional relevant MeSH terms:

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