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A Placebo-Controlled Study of Physiologic Effects of L-methylfolate in Schizophrenia Patients

Primary Purpose

Schizophrenia

Status

Completed

Phase

Not Applicable

Locations

United States

Study Type

Interventional

Intervention

Placebo

L-methylfolate

About this trial

This is an interventional supportive care trial for Schizophrenia focused on measuring L-methylfolate, Deplin, schizophrenia, folate, folic acid, homocysteine, methionine, MTHFR genotype, C677T mutation, vitamin B6, vitamin B12, psychotic symptoms, MTHFR C677T Polymorphism

Eligibility Criteria

18 Years - 68 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Diagnosis of schizophrenia, any subtype
Male of female
Age 18-68 years
Treated with an antipsychotic for at least 6 months at a stable dose for at least 6 weeks
PANSS total score of at least 60, with at least 3 (moderate) on one negative symptom item or on one positive symptom item
Simpson Angus Scale (SAS) for the EPS total score of 12 or less and
A score of 2 (mild) or less on all items of the Calgary Depression Rating Scale (CDRS)
Comprehension of English adequate to complete cognitive testing

Exclusion Criteria:

Unable to provide informed consent
CBC results consistent with megaloblastic anemia
Serum creatinine concentration greater than 1.4
Current use of folate supplementation > 400mcg folate
Alcohol or other substance abuse within 3 months (nicotine allowed)
Current use of any of the following medications: phenobarbital, phenytoin, carbamazepine, valproic acid, fosphenytoin, primidone or pyrimethamine
Positive baseline urine toxic screen, (positive test for PCP, barbiturates, cannabinoids, amphetamines, benzodiazepines, opiates, or cocaine)
Unstable medical illness (exclusionary lab values are listed in Appendix A)
Unstable psychiatric illness
Seizure disorder
Pregnant or nursing, or planning/trying to get pregnant within the next 6 months, and
DSM-IV diagnosis of major depressive disorder

Sites / Locations

Massachusetts General Hospital (MGH) Schizophrenia Program at Freedom Trail Clinic

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

L-methylfolate

Placebo

Arm Description

L-methylfolate 15mg (a medical food)

Placebo

Outcomes

Primary Outcome Measures

Examine the change in plasma L-methylfolate concentrations following a three-month trial of L-methylfolate 15 mg/d compared to placebo.

Secondary Outcome Measures

Examine the change in brain activation in patients receiving L-methylfolate 15 mg/d versus placebo as measured by fMRI using Sternberg's Iterm Recognition Paradigm, as well as changes in cortical thickness and connectivity.

Examine the relationship between MTHFR genotype, change in plasma homocysteine, and methionine concentration, and change in DLPC activation in subjects receiving L-methylfolate

Examine the change in negative symptoms (SANS total score) after three months compared to placebo

Examine the change in negative symptoms (SANS total score) in relation to change in plasma L-methylfolate levels

Examine the change in MATRICS cognitive battery composite score after three months compared to placebo

Examine the change in MATRICS cognitive battery composite score after three months in relation to change in plasma L-methylfolate concentration.

Examine the change in psychotic symptoms as measured by the PANSS total and subscale scores after three months compared to placebo

Examine the change in psychotic symptoms (PANSS score) in relation to change in plasma L-methylfolate concentration.

Examine the change in plasma homocysteine and methionine concentrations following a three-month trial of L-methylfolate 15 mg/d compared to placebo.

Full Information

NCT ID

NCT01091506

First Posted

March 22, 2010

Last Updated

August 2, 2016

Sponsor

Pamlab, Inc.

Collaborators

Massachusetts General Hospital

1. Study Identification

Unique Protocol Identification Number

NCT01091506

Brief Title

A Placebo-Controlled Study of Physiologic Effects of L-methylfolate in Schizophrenia Patients

Official Title

A Placebo-Controlled Study of Physiologic Effects of L-methylfolate in Schizophrenia Patients

Study Type

Interventional

2. Study Status

Record Verification Date

January 2015

Overall Recruitment Status

Completed

Study Start Date

March 2010 (undefined)

Primary Completion Date

March 2014 (Actual)

Study Completion Date

June 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Pamlab, Inc.

Collaborators

Massachusetts General Hospital

4. Oversight

Data Monitoring Committee

5. Study Description

Brief Summary

This study is a 12-week, double-blind, placebo-controlled trial of L-methylfolate 15 mg/d supplementation in schizophrenia patients with mild or greater negative symptoms. L-methylfolate, a prescription medical food, is the activated form of folate required for conversion of homocysteine to methionine and hence is the optimal form of folate for supplementation, since it eliminates the need for activation by MTHFR. The purpose of this study is to examine the change in plasma L-methylfolate concentrations following a three-month trial of L-methylfolate 15 mg/d compared to placebo.

Detailed Description

Blood levels of L-methylfolate and biological activity will be evaluated by examining changes in plasma homocysteine concentrations, serum methionine concentrations and changes in brain activation as measured by fMRI.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Schizophrenia

Keywords

L-methylfolate, Deplin, schizophrenia, folate, folic acid, homocysteine, methionine, MTHFR genotype, C677T mutation, vitamin B6, vitamin B12, psychotic symptoms, MTHFR C677T Polymorphism

7. Study Design

Primary Purpose

Supportive Care

Study Phase

Not Applicable

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

55 (Actual)

8. Arms, Groups, and Interventions

Arm Title

L-methylfolate

Arm Type

Experimental

Arm Description

L-methylfolate 15mg (a medical food)

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

Placebo

Intervention Type

Other

Intervention Name(s)

Placebo

Intervention Description

Placebo once a day for 12 weeks

Intervention Type

Other

Intervention Name(s)

L-methylfolate

Other Intervention Name(s)

Deplin

Intervention Description

L-methylfolate 15mg once a day for 12 weeks

Primary Outcome Measure Information:

Title

Examine the change in plasma L-methylfolate concentrations following a three-month trial of L-methylfolate 15 mg/d compared to placebo.

Time Frame

Weeks 2, 8, and 12

Secondary Outcome Measure Information:

Title

Time Frame

Week 12

Title

Examine the relationship between MTHFR genotype, change in plasma homocysteine, and methionine concentration, and change in DLPC activation in subjects receiving L-methylfolate

Time Frame

Weeks 2, 8, and 12

Title

Examine the change in negative symptoms (SANS total score) after three months compared to placebo

Time Frame

Weeks 2, 8, and 12

Title

Examine the change in negative symptoms (SANS total score) in relation to change in plasma L-methylfolate levels

Time Frame

Weeks 2, 8, and 12

Title

Examine the change in MATRICS cognitive battery composite score after three months compared to placebo

Time Frame

Weeks 2, 8, and 12

Title

Examine the change in MATRICS cognitive battery composite score after three months in relation to change in plasma L-methylfolate concentration.

Time Frame

Weeks 2, 8, and 12

Title

Examine the change in psychotic symptoms as measured by the PANSS total and subscale scores after three months compared to placebo

Time Frame

Weeks 2, 8, and 12

Title

Examine the change in psychotic symptoms (PANSS score) in relation to change in plasma L-methylfolate concentration.

Time Frame

Weeks 2, 8, and 12

Title

Examine the change in plasma homocysteine and methionine concentrations following a three-month trial of L-methylfolate 15 mg/d compared to placebo.

Time Frame

Weeks 2, 8, and 12

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

68 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Diagnosis of schizophrenia, any subtype Male of female Age 18-68 years Treated with an antipsychotic for at least 6 months at a stable dose for at least 6 weeks PANSS total score of at least 60, with at least 3 (moderate) on one negative symptom item or on one positive symptom item Simpson Angus Scale (SAS) for the EPS total score of 12 or less and A score of 2 (mild) or less on all items of the Calgary Depression Rating Scale (CDRS) Comprehension of English adequate to complete cognitive testing Exclusion Criteria: Unable to provide informed consent CBC results consistent with megaloblastic anemia Serum creatinine concentration greater than 1.4 Current use of folate supplementation > 400mcg folate Alcohol or other substance abuse within 3 months (nicotine allowed) Current use of any of the following medications: phenobarbital, phenytoin, carbamazepine, valproic acid, fosphenytoin, primidone or pyrimethamine Positive baseline urine toxic screen, (positive test for PCP, barbiturates, cannabinoids, amphetamines, benzodiazepines, opiates, or cocaine) Unstable medical illness (exclusionary lab values are listed in Appendix A) Unstable psychiatric illness Seizure disorder Pregnant or nursing, or planning/trying to get pregnant within the next 6 months, and DSM-IV diagnosis of major depressive disorder

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Joshua Roffman, MD

Organizational Affiliation

Massachusetts General Hospital Schizophrenia Program at Freedom Trail Clinic

Official's Role

Principal Investigator

Facility Information:

Facility Name

Massachusetts General Hospital (MGH) Schizophrenia Program at Freedom Trail Clinic

City

Boston

State/Province

Massachusetts

Country

United States

12. IPD Sharing Statement

Citations:

PubMed Identifier

28289280

Citation

Roffman JL, Petruzzi LJ, Tanner AS, Brown HE, Eryilmaz H, Ho NF, Giegold M, Silverstein NJ, Bottiglieri T, Manoach DS, Smoller JW, Henderson DC, Goff DC. Biochemical, physiological and clinical effects of l-methylfolate in schizophrenia: a randomized controlled trial. Mol Psychiatry. 2018 Feb;23(2):316-322. doi: 10.1038/mp.2017.41. Epub 2017 Mar 14.

Results Reference

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A Placebo-Controlled Study of Physiologic Effects of L-methylfolate in Schizophrenia Patients

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