Folate Supplementation in Schizophrenia

• Sponsor: Massachusetts General Hospital (Other)
• Overall Status: Completed
• CT.gov ID: NCT00249288
• Collaborator: National Alliance for Research on Schizophrenia and Depression (Other)
• Enrollment: 46
• Location: 1
• Arms: 2
• Duration (Months): 54
• Patients Per Site Per Month: 0.9

Study Details

Study Description

Brief Summary

This study aims to examine factors potentially contributing to differences in blood folate, homocysteine or B12 levels between schizophrenia patients, to test the hypothesis that low folate is associated with negative symptoms, and to examine the efficacy of folate supplementation for reducing negative symptoms.

Condition or Disease	Intervention/Treatment	Phase
Schizophrenia	Drug: Folate; Drug: Placebo	Phase 4

Detailed Description

This study is a three-month, placebo-controlled trial of folate 2mg/d in 50 schizophrenia patients who score at least a 3 (moderate or greater severity) on at least one of the SANS global assessment subscales, with the exception of the attention global assessment subscale.

The specific aims of this study are:

• To examine factors potentially contributing to differences in blood folate, homocysteine or B12 levels between patients at baseline, including dietary intake and cigarette smoking.

• To test the hypothesis that low folate is associated with negative symptoms by examining correlations between red blood cell folate concentrations and clinical ratings of negative symptoms and by comparing folate concentrations in deficit syndrome versus non-deficit syndrome patients. We will also control for dietary intake cigarettes smoking, gender, and age.

• To examine the efficacy of folate supplementation for reducing negative symptoms

Study Design

• Study Type: Interventional
• Actual Enrollment: 46 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Folate Supplementation in Schizophrenia
• Study Start Date: Dec 1, 2003
• Actual Primary Completion Date: Jun 1, 2008
• Actual Study Completion Date: Jun 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Folate Participants will receive a 2 mg/ day dose of folate, for 12 weeks	Drug: Folate; Folic acid taken as 2, 1mg capsule daily for 12 weeks; Other Names: Folate or folic acid
Placebo Comparator: Placebo Participants will receive a 2 mg/ day dose of placebo, for 12 weeks	Drug: Placebo; Placebo taken as 2, 1mg capsule daily for 12 weeks

Outcome Measures

Primary Outcome Measures

1. Correlation Between Baseline Blood Folate and Smoking Status [Baseline]

   Baseline blood folate lab levels are reported by smoking status.

2. Correlation Between Baseline Blood Folate and MTHFR Genotype [Baseline]

   Baseline blood folate lab levels are reported by MTHFR genotype.

3. Correlation Between Baseline Blood Folate Levels and Dietary Intake [Baseline]

   Baseline blood folate lab levels and dietary intake levels are reported.

4. Efficacy of Folate Supplementation for Reducing Negative Symptoms as Measured by the SANS Modified Total [Baseline score vs. week 12 score]

   The change from baseline to week 12 on the scale for the assessment of negative symptoms (SANS) modified total score. Total SANS scores range from 0-100. The SANS is comprised of 5 sub-scales: Affective Flattening or Blunting (score range 0-35), Alogia (score range 0-20), Avolition-Apathy (score range 0-15), Anhedonia-Asociality (score range 0-20), and Attention (0-10). For each sub-scale, the higher the score the more prominent the negative symptoms were. The total score was computed by adding all the sub-scale total scores. To compute change in scores, baseline scores were subtracted from week 12 scores, resulting in a change score. Lower values signify greater improvement (i.e. week 12 score was lower than baseline score). The SANS modified total score is the SANS total score minus the Attention subscale.

5. Correlation Between Baseline Serum B12 Levels and Smoking Status [Baseline]

   Baseline serum B12 lab levels are reported by smoking status.

6. Correlation Between Baseline Homocysteine Levels and Smoking Status [Baseline]

   Baseline blood homocysteine lab levels are reported by smoking status.

7. Correlation Between Baseline Blood B12 Levels and MTHFR Genotype [Baseline]

   Baseline blood B12 lab levels are reported by MTHFR genotype.

8. Correlation Between Baseline Blood Homocysteine Levels and MTHFR Genotype [Baseline]

   Baseline blood homocysteine lab levels are reported by MTHFR genotype.

9. Correlation Between Baseline Serum B12 Levels and Dietary Intake [Baseline]

   Baseline serum B12 lab levels and dietary intake levels are reported.

10. Correlation Between Baseline Blood Homocysteine Levels and Dietary Intake [Baseline]

    Baseline blood homocysteine lab levels and dietary intake levels are reported.

11. Correlation Between Baseline Blood Folate or B12 Levels and Dietary Intake [Baseline]

    Baseline blood folate and B12 lab levels and dietary intake levels are reported.

Secondary Outcome Measures

1. Correlations Between Baseline Blood Folate and Clinical Ratings of Negative Symptoms by Comparing Lab Levels in Deficit Syndrome Versus Non-deficit Syndrome Patients [Baseline]

   Baseline blood folate lab levels are reported by deficit syndrome status.

2. Correlations Between Baseline Blood B12 Levels and Clinical Ratings of Negative Symptoms by Comparing Lab Levels in Deficit Syndrome Versus Non-deficit Syndrome Patients [Baseline]

   Baseline blood B12 lab levels are reported by deficit syndrome status.

3. Correlations Between Baseline Blood Homocysteine Levels and Clinical Ratings of Negative Symptoms by Comparing Lab Levels in Deficit Syndrome Versus Non-deficit Syndrome Patients [Baseline]

   Baseline blood homocysteine lab levels are reported by deficit syndrome status.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 68 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Schizophrenia, any subtype

2. Ages 18-68

3. Male or female

4. A score at least a 3 (moderate or greater severity) on at least one of the SANS global assessment subscales, with the exception of the attention global assessment subscale

5. Stable antipsychotic dose for > 6 weeks

6. Capable of providing informed consent

Exclusion Criteria:

1. Unstable medical illness

2. Substance abuse

3. Megaloblastic anemia

4. Non-english speaking

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Massachusetts General Hospital	Boston	Massachusetts	United States	02114

Sponsors and Collaborators

• Massachusetts General Hospital
• National Alliance for Research on Schizophrenia and Depression

Investigators

• Principal Investigator: Donald C. Goff, M.D., Massachusetts General Hospital

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Related Info

Publications

None provided.

• Responsible Party: Donald C. Goff, MD, Director of the Schizophrenia Clinical and Research Program, Massachusetts General Hospital
• ClinicalTrials.gov Identifier: NCT00249288
• Other Study ID Numbers: 2004P-000495
• First Posted: Nov 7, 2005
• Last Update Posted: Apr 5, 2018
• Last Verified: Mar 1, 2018

• Keywords provided by Donald C. Goff, MD, Director of the Schizophrenia Clinical and Research Program, Massachusetts General Hospital: Schizophrenia; Negative Symptoms; Folate
• Additional relevant MeSH terms: Schizophrenia; Folic Acid; Vitamin B Complex

Study Results

Participant Flow

Recruitment Details	Forty six participants were enrolled; 38 completed screening and 32 received study drug.

Arm/Group Title	Folate	Placebo
Arm/Group Description	Participants receiving 2 mg/daily of folate, for 12 weeks
Period Title: Overall Study
STARTED	19	19
Initiated Treatment	17	15
COMPLETED	14	14
NOT COMPLETED	5	5

Baseline Characteristics

Arm/Group Title	Placebo	Folate	Total
Arm/Group Description	Participants received 2 mg/daily of placebo, for 12 weeks	Patients underwent a 12 week trial of folate 2 mg/d	Total of all reporting groups
Overall Participants	15	17	32
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	15 100%	17 100%	32 100%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	46.5 (11.3)	45.5 (9.6)	46 (10.3)
Sex: Female, Male (Count of Participants)
Female	2 13.3%	4 23.5%	6 18.8%
Male	13 86.7%	13 76.5%	26 81.3%
Region of Enrollment (participants) [Number]
United States	15 100%	17 100%	32 100%

Outcome Measures

1. Primary Outcome

Title	Correlation Between Baseline Blood Folate and Smoking Status
Description	Baseline blood folate lab levels are reported by smoking status.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

1 past smoker and 1 never smoker are missing RBC folate values. For the present analysis, as opposed to a comparison of treatment groups, folate levels are compared across smoking status.

Arm/Group Title	Current Smoker	Past Smoker	Never Smoker
Arm/Group Description	Study participants with current smoker status	Participants with past smoker status	Participants with never smoker status
Measure Participants	17	8	7
Serum folate, ng/ml	14.6 (3.3)	14.6 (5.2)	14.2 (4.1)
RBC folate, ng/ml	614 (142)	542 (122)	475 (161)

2. Primary Outcome

Title	Correlation Between Baseline Blood Folate and MTHFR Genotype
Description	Baseline blood folate lab levels are reported by MTHFR genotype.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

One participant with CC genotype is missing RBC folate value. For the present analysis, as opposed to a comparison of treatment groups, folate levels are compared across MTHFR genotype.

Arm/Group Title	CC Genotype	T- Genotype
Arm/Group Description	Study participants with MTHFR genotype CC	Participants with MTHFR genotype T (T allele carrier)
Measure Participants	13	15
Serum folate, ng/ml	13.3 (3.3)	15.2 (4.1)
RBC folate, ng/ml	624.8 (143.0)	542.8 (150.6)

3. Primary Outcome

Title	Correlation Between Baseline Blood Folate Levels and Dietary Intake
Description	Baseline blood folate lab levels and dietary intake levels are reported.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

All study participants at baseline. For the present analysis, as opposed to a comparison of treatment groups, folate levels are described for all participants at baseline.

Arm/Group Title	Overall
Arm/Group Description	All study participants at baseline
Measure Participants	32
Serum folate, ng/ml	14.5 (3.9)
RBC folate, ng/ml	569.3 (148.1)

4. Primary Outcome

Title	Efficacy of Folate Supplementation for Reducing Negative Symptoms as Measured by the SANS Modified Total
Description	The change from baseline to week 12 on the scale for the assessment of negative symptoms (SANS) modified total score. Total SANS scores range from 0-100. The SANS is comprised of 5 sub-scales: Affective Flattening or Blunting (score range 0-35), Alogia (score range 0-20), Avolition-Apathy (score range 0-15), Anhedonia-Asociality (score range 0-20), and Attention (0-10). For each sub-scale, the higher the score the more prominent the negative symptoms were. The total score was computed by adding all the sub-scale total scores. To compute change in scores, baseline scores were subtracted from week 12 scores, resulting in a change score. Lower values signify greater improvement (i.e. week 12 score was lower than baseline score). The SANS modified total score is the SANS total score minus the Attention subscale.
Time Frame	Baseline score vs. week 12 score

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Folate	Placebo
Arm/Group Description	Participants will receive a 2 mg/ day dose of folate, for 12 weeks Folate: Folic acid taken as 2, 1mg capsule daily for 12 weeks	Participants will receive a 2 mg/ day dose of placebo, for 12 weeks Placebo: Placebo taken by mouth daily as 2, 1mg capsule daily for 12 weeks
Measure Participants	14	14
Mean (Standard Deviation) [Units on a scale]	-8.5 (7.6)	-9.7 (8.5)

5. Primary Outcome

Title	Correlation Between Baseline Serum B12 Levels and Smoking Status
Description	Baseline serum B12 lab levels are reported by smoking status.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

For the present analysis, as opposed to a comparison of treatment groups, B12 levels are compared across smoking status.

Arm/Group Title	Current Smoker	Past Smoker	Never Smoker
Arm/Group Description	Study participants with current smoker status	Participants with past smoker status	Participants with never smoker status
Measure Participants	17	8	7
Mean (Standard Deviation) [picograms per milliliter]	625 (273)	436 (130)	574 (160)

6. Primary Outcome

Title	Correlation Between Baseline Homocysteine Levels and Smoking Status
Description	Baseline blood homocysteine lab levels are reported by smoking status.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

1 participant who have never smoker status is missing plasma homocysteine values. For the present analysis, as opposed to a comparison of treatment groups, homocysteine levels are compared across smoking status.

Arm/Group Title	Current Smoker	Past Smoker	Never Smoker
Arm/Group Description	Study participants with current smoker status	Participants with past smoker status	Participants with never smoker status
Measure Participants	17	8	6
Mean (Standard Deviation) [micromoles per liter]	9.1 (2.6)	10.8 (1.6)	9 (2.5)

7. Primary Outcome

Title	Correlation Between Baseline Blood B12 Levels and MTHFR Genotype
Description	Baseline blood B12 lab levels are reported by MTHFR genotype.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

For the present analysis, as opposed to a comparison of treatment groups, B12 levels are compared across MTHFR genotype.

Arm/Group Title	CC Genotype	T- Genotype
Arm/Group Description	Study participants with MTHFR genotype CC	Participants with MTHFR genotype T (T allele carrier)
Measure Participants	13	15
Mean (Standard Deviation) [picograms per milliliter]	605.5 (312.9)	557.1 (170.1)

8. Primary Outcome

Title	Correlation Between Baseline Blood Homocysteine Levels and MTHFR Genotype
Description	Baseline blood homocysteine lab levels are reported by MTHFR genotype.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

For the present analysis, as opposed to a comparison of treatment groups, homocystein levels are compared across MTHFR genotype.

Arm/Group Title	CC Genotype	T- Genotype
Arm/Group Description	Study participants with MTHFR genotype CC	Participants with MTHFR genotype T (T allele carrier)
Measure Participants	13	15
Mean (Standard Deviation) [micromoles/liter]	9.4 (2.9)	9.6 (2.3)

9. Primary Outcome

Title	Correlation Between Baseline Serum B12 Levels and Dietary Intake
Description	Baseline serum B12 lab levels and dietary intake levels are reported.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

For the present analysis, as opposed to a comparison of treatment groups, B12 levels are described for all baseline participants.

Arm/Group Title	Overall
Arm/Group Description	All study participants at baseline
Measure Participants	32
Mean (Standard Deviation) [picograms/mL]	566.6 (231.5)

10. Primary Outcome

Title	Correlation Between Baseline Blood Homocysteine Levels and Dietary Intake
Description	Baseline blood homocysteine lab levels and dietary intake levels are reported.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

All study participants at baseline. For the present analysis, as opposed to a comparison of treatment groups, homocysteine levels are described for all baseline participants.

Arm/Group Title	Overall
Arm/Group Description	All study participants at baseline
Measure Participants	31
Mean (Standard Deviation) [micromoles/liter]	9.6 (2.4)

11. Primary Outcome

Title	Correlation Between Baseline Blood Folate or B12 Levels and Dietary Intake
Description	Baseline blood folate and B12 lab levels and dietary intake levels are reported.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

All participants at baseline. For the present analysis, as opposed to a comparison of treatment groups, folate and B12 levels are described for all baseline participants.

Arm/Group Title	Overall
Arm/Group Description	All study participants at baseline
Measure Participants	16
Total folate, mcg	531.3 (386.5)
Dietary folate, mcg	765.7 (637.7)
Natural folate, mcg	198.8 (73.3)
Synthetic folate, mcg	333.4 (362.9)
Total B12, mcg	7.5 (7.3)

12. Secondary Outcome

Title	Correlations Between Baseline Blood Folate and Clinical Ratings of Negative Symptoms by Comparing Lab Levels in Deficit Syndrome Versus Non-deficit Syndrome Patients
Description	Baseline blood folate lab levels are reported by deficit syndrome status.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

One deficit syndrome participant and one participant without deficit syndrome are missing RBC folate values. For the present analysis, as opposed to a comparison of treatment groups, folate levels are compared across deficit syndrome status.

Arm/Group Title	Deficit Syndrome	Not Deficit Syndrome
Arm/Group Description	Study participants with deficit syndrome	Participants without deficit syndrome
Measure Participants	17	14
Serum folate, ng/ml	14.9 (4.3)	14.0 (3.5)
RBC folate, ng/ml	585 (171)	546 (123)

13. Secondary Outcome

Title	Correlations Between Baseline Blood B12 Levels and Clinical Ratings of Negative Symptoms by Comparing Lab Levels in Deficit Syndrome Versus Non-deficit Syndrome Patients
Description	Baseline blood B12 lab levels are reported by deficit syndrome status.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

For the present analysis, as opposed to a comparison of treatment groups, B12 levels are compared across deficit syndrome status.

Arm/Group Title	Deficit Syndrome	Not Deficit Syndrome
Arm/Group Description	Study participants with deficit syndrome	Participants without deficit syndrome
Measure Participants	17	14
Mean (Standard Deviation) [picograms/mL]	603 (193)	513 (275)

14. Secondary Outcome

Title	Correlations Between Baseline Blood Homocysteine Levels and Clinical Ratings of Negative Symptoms by Comparing Lab Levels in Deficit Syndrome Versus Non-deficit Syndrome Patients
Description	Baseline blood homocysteine lab levels are reported by deficit syndrome status.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

One participant without deficit syndrome is missing homocysteine. For the present analysis, as opposed to a comparison of treatment groups, homocysteine levels are compared across deficit syndrome status.

Arm/Group Title	Deficit Syndrome	Not Deficit Syndrome
Arm/Group Description	Study participants with deficit syndrome	Participants without deficit syndrome
Measure Participants	17	13
Mean (Standard Deviation) [micromoles/liter]	9.4 (2.6)	9.7 (2.5)

Adverse Events

Arm/Group Title	Folate		Placebo
Arm/Group Description	Participants receiving 2 mg/daily of folate, for 12 weeks		Participants receiving 2mg/daily of placebo, for 12 weeks
All Cause Mortality
	Folate		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Folate		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/19 (0%)		0/19 (0%)
Other (Not Including Serious) Adverse Events
	Folate		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/19 (0%)		0/19 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.