Effectiveness of Vitamin Supplementation in Treating People With Residual Symptoms of Schizophrenia

• Sponsor: Massachusetts General Hospital (Other)
• Overall Status: Completed
• CT.gov ID: NCT00611806
• Collaborator: National Institute of Mental Health (NIMH) (NIH)
• Enrollment: 140
• Locations: 3
• Arms: 2
• Duration (Months): 36
• Patients Per Site: 46.7
• Patients Per Site Per Month: 1.3

Study Details

Study Description

Brief Summary

This study will evaluate the effectiveness of folate and B12 supplementation in reducing negative symptoms in people with schizophrenia.

Condition or Disease	Intervention/Treatment	Phase
Schizophrenia	Dietary Supplement: Folic Acid; Dietary Supplement: B12; Other: Placebo	Phase 4

Detailed Description

About 30% of people with schizophrenia suffer from treatment-resistant psychotic symptoms, which may include social withdrawal, apathy, and depression. These negative symptoms can produce substantial distress for those affected, often disrupting social and occupational functioning and resulting in hospitalization. Although atypical antipsychotic medications have demonstrated some success in treating negative symptoms, the degree to which many negative symptoms respond is unclear. Depression and poor response to antidepressant medication have been linked to deficiency in the vitamins folate and B12. It is believed that vitamin supplementation with folate and B12 may offer a safe and inexpensive approach to improve outcomes for people with schizophrenia who have residual negative symptoms and have exhibited poor treatment response. This study will compare the effectiveness of folate and B12 versus placebo in reducing negative symptoms in people with schizophrenia.

Participation in this double-blind study will last 19 weeks. Potential participants will undergo initial screening, which will include a medical and psychiatric evaluation, physical exam, blood draw, urine sampling, and questionnaires. Participants will also be asked for permission to use a portion of the blood sample for genetic analysis. Eligible participants will be randomly assigned to take folate with B12 or placebo. Participants will first complete a 2-week stabilization phase, followed by the 16-week treatment study. Medication visits, occurring every 2 weeks during treatment, will include questions about medication side effects and the distribution of study medication. During specified medication visits, participants will complete various assessments, which will include questionnaires about schizophrenia, tests of learning and memory, repeat blood tests, and pregnancy tests. The medication visits will last between 15 minutes and 4 hours, depending on the scheduled assessments for that visit.

Study Design

• Study Type: Interventional
• Actual Enrollment: 140 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Placebo-Controlled Trial of Folate With B12 in Schizophrenia Patients With Residual Symptoms
• Study Start Date: Dec 1, 2007
• Actual Primary Completion Date: Aug 1, 2010
• Actual Study Completion Date: Dec 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Folate with B12 Participants will take folic acid plus B12 for 18 weeks.	Dietary Supplement: Folic Acid; Folic acid 2mg po daily; Dietary Supplement: B12; B12 400 micrograms po daily; Other Names: cobalamin
Placebo Comparator: Placebo Participants will take placebo for 18 weeks.	Other: Placebo; 1 capsule po daily

Outcome Measures

Primary Outcome Measures

1. Positive and Negative Syndrome Scale (PANSS) [Baseline vs. Week 16]

   The change from baseline on the Positive and Negative Syndrome Scale (PANSS).The PANNS has three subscales: positive (score range 7-49), negative (score range 7-49), and general psychopathology (score range 16-112). The PANSS positive symptom sub-scale is comprised of 7 items rated on a scale of 1-7, representing positive symptoms of schizophrenia. The PANSS negative symptom subscale is comprised of 7 items rated on a scale of 1-7 representing the negative symptoms of schizophrenia, and the general psychopathology subscale is comprised of 16 items rated on a scale of 1-7 representing symptoms of general psychopathology in mental illness. The total score was computed by adding all the items on the sub-scale together. Scores reported are change in symptoms per week, relative to baseline. A negative score represents a decrease in total PANSS score per week, whereas a positive score represents an increase in total PANSS score per week.

Secondary Outcome Measures

1. Cognitive Deficits, as Measured by the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Cognitive Battery Composite Score [Measured at Week 16]

2. Positive Sub Scale of the Positive and Negative Syndrome Scale (PANSS) [Baseline vs. Week 16]

   The change from baseline on the positive symptom sub-scale of the Positive and Negative Syndrome Scale (PANSS). Total PANSS positive symptom sub-scale scores range from 7-49. The PANSS positive symptom sub-scale is comprised of 7 items rated on a scale of 1-7: delusions, conceptual disorganization, hallucinatory behavior, excitement, grandiosity, suspiciousness/persecution, and hostility. A score of one on each item 1 absent, 2 is minimal, 3 is mild, 4 is moderate, 5 is moderately severe, 6 is severe, and 7 is extreme. The total score was computed by adding all the items on the sub-scale together. Scores reported are change in symptoms per week, relative to baseline. A negative score represents a decrease in total PANSS score per week, whereas a positive score represents an increase in total PANSS score per week.

3. Scale for Assessment of Negative Symptoms (SANS) [Baseline vs. Week 16]

   The change from baseline on the scale for the assessment of negative symptoms (SANS) total score. Total SANS scores range from 0-100. The SANS is comprised of 5 subscores: 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 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. Scores reported are change in symptoms per week, relative to baseline. A negative score represents a decrease in total SANS score per week, whereas a positive score represents an increase in total SANS score per week.

4. Positive and Negative Syndrome Scale (PANSS) and FOLH1, MTHRF, MTR, and COMT Genotype [Baseline vs. Week 16]

   The change from baseline on the Positive and Negative Syndrome Scale (PANSS) (including FOLH1, MTHRF, MTR, and COMT genotype simultaneously into a linear mixed model).The PANNS has three sub-scales: positive (score range 7-49), negative (score range 7-49), and general psychopathology (score range 16-112). The PANSS negative and positive symptom sub-scale is comprised of 7 items rated on a scale of 1-7 representing the negative and positive symptoms of schizophrenia, respectively, and the general psychopathology sub-scale is comprised of 16 items rated on a scale of 1-7 representing symptoms of general psychopathology in mental illness. The total score was computed by adding all the items on the sub-scale together. Scores reported are change in symptoms per week, relative to baseline. A negative score represents a decrease in total PANSS score per week, whereas a positive score represents an increase in total PANSS score per week.

5. Relationship Between Response of Negative and Positive Symptoms and the Change in RBC Folate, Serum Folate, Serum B12, and Plasma Homocysteine Concentrations [Measured at Week 16]

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Diagnosis of schizophrenia, any subtype

• Treated with an antipsychotic medication for at least 6 months at a stable dose for at least 6 weeks before study entry

• PANSS total score of at least 60, with a score of at least 3 (moderate) on one negative symptom item or on one positive symptom item

• Simpson Angus Scale (SAS) for Extrapyramidal Syndrome (EPS) total score of 12 or less

• A score of 2 (mild) or less on all items of the Calgary Depression Scale (CDS)

• Speaks English adequately enough to complete cognitive testing

Exclusion Criteria:

• Serum B12 concentration less than 300 ug/L

• Complete blood count results consistent with megaloblastic anemia

• Serum creatinine concentration greater than 1.4

• Current use of folate or B12 supplementation

• Current use of any of the following medications: phenobarbital, phenytoin, carbamazepine, valproic acid, fosphenytoin, primidone, or pyrimethamine

• Alcohol or other substance abuse within 3 months before study entry (nicotine allowed)

• Positive baseline urine toxic screen

• Unstable medical illness

• Unstable psychiatric illness

• Seizure disorder

• Pregnant or breastfeeding

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Massachusetts General Hospital Schizophrenia Program - Freedom Trail Clinic	Boston	Massachusetts	United States	02114
2	Touchstone innovare	Grand Rapids	Michigan	United States	49503
3	URMC Severe Mental Disorders Program	Rochester	New York	United States	14623

Sponsors and Collaborators

• Massachusetts General Hospital
• National Institute of Mental Health (NIMH)

Investigators

• Principal Investigator: Donald Goff, MD, Massachusetts General Hospital

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Donald C. Goff, MD, Director of the Schizophrenia Clinical and Research Program, Massachusetts General Hospital
• ClinicalTrials.gov Identifier: NCT00611806
• Other Study ID Numbers: R01MH070831; R01MH070831; DATR A5-ETPD
• First Posted: Feb 11, 2008
• Last Update Posted: Aug 19, 2014
• Last Verified: Jul 1, 2014

• Keywords provided by Donald C. Goff, MD, Director of the Schizophrenia Clinical and Research Program, Massachusetts General Hospital: Cognition; Folic Acid; B12
• Additional relevant MeSH terms: Schizophrenia; Folic Acid; Vitamin B 12

Study Results

Participant Flow

Pre-assignment Detail	189 Participants were screened for enrollment, but 49 were excluded. 40 were ineligible, 2 withdrew consent, 1 terminated because of an adverse event, and 6 were terminated because of study visit noncompliance.

Arm/Group Title	Folate With B12	Placebo
Arm/Group Description	Participants will take folic acid plus B12 for 18 weeks. Folic Acid: Folic acid 2mg po daily B12: B12 400 micrograms po daily	Participants will take placebo for 18 weeks. Placebo: 1 capsule po daily
Period Title: Overall Study
STARTED	94	46
COMPLETED	78	43
NOT COMPLETED	16	3

Baseline Characteristics

Arm/Group Title	Folate With B12	Placebo	Total
Arm/Group Description	Participants will take folic acid plus B12 for 18 weeks. Folic Acid: Folic acid 2mg po daily B12: B12 400 micrograms po daily	Participants will take placebo for 18 weeks. Placebo: 1 capsule po daily	Total of all reporting groups
Overall Participants	94	46	140
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	45.3 (1.1)	45.9 (1.6)	45.6 (1.35)
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	94 100%	46 100%	140 100%
>=65 years	0 0%	0 0%	0 0%
Sex: Female, Male (Count of Participants)
Female	28 29.8%	32 69.6%	60 42.9%
Male	66 70.2%	14 30.4%	80 57.1%
Region of Enrollment (participants) [Number]
United States	94 100%	46 100%	140 100%

Outcome Measures

1. Primary Outcome

Title	Positive and Negative Syndrome Scale (PANSS)
Description	The change from baseline on the Positive and Negative Syndrome Scale (PANSS).The PANNS has three subscales: positive (score range 7-49), negative (score range 7-49), and general psychopathology (score range 16-112). The PANSS positive symptom sub-scale is comprised of 7 items rated on a scale of 1-7, representing positive symptoms of schizophrenia. The PANSS negative symptom subscale is comprised of 7 items rated on a scale of 1-7 representing the negative symptoms of schizophrenia, and the general psychopathology subscale is comprised of 16 items rated on a scale of 1-7 representing symptoms of general psychopathology in mental illness. The total score was computed by adding all the items on the sub-scale together. Scores reported are change in symptoms per week, relative to baseline. A negative score represents a decrease in total PANSS score per week, whereas a positive score represents an increase in total PANSS score per week.
Time Frame	Baseline vs. Week 16

Outcome Measure Data

Analysis Population Description

Participants analyzed were those who completed at least 1 post-baseline visit or more (n = 135). 120 participants completed the study to the week 16 endpoint; however, 15 participants did not complete the entire 16 weeks, but completed at least one post-baseline study visit where the PANSS assessment was performed.

Arm/Group Title	Folate With B12	Placebo
Arm/Group Description	Participants will take folic acid plus B12 for 18 weeks. Folic Acid: Folic acid 2mg po daily B12: B12 400 micrograms po daily	Participants will take placebo for 18 weeks. Placebo: 1 capsule po daily
Measure Participants	89	46
Mean (95% Confidence Interval) [units on a scale]	-.21	-.22

2. Secondary Outcome

Title	Cognitive Deficits, as Measured by the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Cognitive Battery Composite Score
Time Frame	Measured at Week 16

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

3. Secondary Outcome

Title	Positive Sub Scale of the Positive and Negative Syndrome Scale (PANSS)
Description	The change from baseline on the positive symptom sub-scale of the Positive and Negative Syndrome Scale (PANSS). Total PANSS positive symptom sub-scale scores range from 7-49. The PANSS positive symptom sub-scale is comprised of 7 items rated on a scale of 1-7: delusions, conceptual disorganization, hallucinatory behavior, excitement, grandiosity, suspiciousness/persecution, and hostility. A score of one on each item 1 absent, 2 is minimal, 3 is mild, 4 is moderate, 5 is moderately severe, 6 is severe, and 7 is extreme. The total score was computed by adding all the items on the sub-scale together. Scores reported are change in symptoms per week, relative to baseline. A negative score represents a decrease in total PANSS score per week, whereas a positive score represents an increase in total PANSS score per week.
Time Frame	Baseline vs. Week 16

Outcome Measure Data

Analysis Population Description

Participants analyzed were those who completed at least 1 post-baseline visit or more (n = 135). 120 participants completed the study to the week 16 endpoint; however, 15 participants did not complete the entire 16 weeks, but completed at least one post-baseline study visit where the PANSS assessment was performed.

Arm/Group Title	Folate With B12	Placebo
Arm/Group Description	Participants will take folic acid plus B12 for 18 weeks. Folic Acid: Folic acid 2mg po daily B12: B12 400 micrograms po daily	Participants will take placebo for 18 weeks. Placebo: 1 capsule po daily
Measure Participants	89	46
Mean (95% Confidence Interval) [units on a scale]	-.06	-.04

4. Secondary Outcome

Title	Scale for Assessment of Negative Symptoms (SANS)
Description	The change from baseline on the scale for the assessment of negative symptoms (SANS) total score. Total SANS scores range from 0-100. The SANS is comprised of 5 subscores: 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 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. Scores reported are change in symptoms per week, relative to baseline. A negative score represents a decrease in total SANS score per week, whereas a positive score represents an increase in total SANS score per week.
Time Frame	Baseline vs. Week 16

Outcome Measure Data

Analysis Population Description

Participants analyzed were those who completed at least 1 post-baseline visit or more (n = 135). 120 participants completed the study to the week 16 endpoint; however, 15 participants did not complete the entire 16 weeks, but completed at least one post-baseline study visit where the SANS assessment was performed.

Arm/Group Title	Folate With B12	Placebo
Arm/Group Description	Participants will take folic acid plus B12 for 18 weeks. Folic Acid: Folic acid 2mg po daily B12: B12 400 micrograms po daily	Participants will take placebo for 18 weeks. Placebo: 1 capsule po daily
Measure Participants	89	46
Mean (95% Confidence Interval) [units on a scale]	-.19	.02

5. Secondary Outcome

Title	Positive and Negative Syndrome Scale (PANSS) and FOLH1, MTHRF, MTR, and COMT Genotype
Description	The change from baseline on the Positive and Negative Syndrome Scale (PANSS) (including FOLH1, MTHRF, MTR, and COMT genotype simultaneously into a linear mixed model).The PANNS has three sub-scales: positive (score range 7-49), negative (score range 7-49), and general psychopathology (score range 16-112). The PANSS negative and positive symptom sub-scale is comprised of 7 items rated on a scale of 1-7 representing the negative and positive symptoms of schizophrenia, respectively, and the general psychopathology sub-scale is comprised of 16 items rated on a scale of 1-7 representing symptoms of general psychopathology in mental illness. The total score was computed by adding all the items on the sub-scale together. Scores reported are change in symptoms per week, relative to baseline. A negative score represents a decrease in total PANSS score per week, whereas a positive score represents an increase in total PANSS score per week.
Time Frame	Baseline vs. Week 16

Outcome Measure Data

Analysis Population Description

Participants analyzed were those who completed at least 1 post-baseline visit or more (n = 135) and agreed to the DNA blood draw (n = 120).

Arm/Group Title	Folate With B12	Placebo
Arm/Group Description	Participants will take folic acid plus B12 for 18 weeks. Folic Acid: Folic acid 2mg po daily B12: B12 400 micrograms po daily	Participants will take placebo for 18 weeks. Placebo: 1 capsule po daily
Measure Participants	79	41
Mean (95% Confidence Interval) [units on a scale]	-.21	-.1

6. Secondary Outcome

Title	Relationship Between Response of Negative and Positive Symptoms and the Change in RBC Folate, Serum Folate, Serum B12, and Plasma Homocysteine Concentrations
Time Frame	Measured at Week 16

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Arm/Group Title	Folate With B12		Placebo
Arm/Group Description	Participants will take folic acid plus B12 for 18 weeks. Folic Acid: Folic acid 2mg po daily B12: B12 400 micrograms po daily		Participants will take placebo for 18 weeks. Placebo: 1 capsule po daily
All Cause Mortality
	Folate With B12		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Folate With B12		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/94 (4.3%)		4/46 (8.7%)
Eye disorders
Vision Decreased	0/94 (0%)	0	1/46 (2.2%)	1
Gastrointestinal disorders
Cholelithiasis	1/94 (1.1%)	1	0/46 (0%)	0
Nervous system disorders
Body Numbness	0/94 (0%)	0	1/46 (2.2%)	1
Brain Tumor	0/94 (0%)	0	1/46 (2.2%)	1
Psychiatric disorders
Hospitalization due to worsening psychosis	1/94 (1.1%)	2	1/46 (2.2%)	2
Suicidal Tendency	1/94 (1.1%)	1	0/46 (0%)	0
Skin and subcutaneous tissue disorders
Irritation of Skin	1/94 (1.1%)	1	0/46 (0%)	0
Other (Not Including Serious) Adverse Events
	Folate With B12		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	21/94 (22.3%)		16/46 (34.8%)
Cardiac disorders
Tachycardia	1/94 (1.1%)	1	0/46 (0%)	0
Endocrine disorders
Hypoglycemia	1/94 (1.1%)	1	0/46 (0%)	0
Eye disorders
Eye Blood Shot	0/94 (0%)	0	1/46 (2.2%)	1
Vision Decreased	0/94 (0%)	0	1/46 (2.2%)	1
Gastrointestinal disorders
Cholelithiasis	1/94 (1.1%)	2	0/46 (0%)	0
Dirrhea	1/94 (1.1%)	1	0/46 (0%)	0
Dry Mouth	1/94 (1.1%)	1	0/46 (0%)	0
Nausea	0/94 (0%)	0	1/46 (2.2%)	1
Vomiting	0/94 (0%)	0	1/46 (2.2%)	1
General disorders
Back Pain	0/94 (0%)	0	1/46 (2.2%)	1
Chest Pain	0/94 (0%)	0	1/46 (2.2%)	1
Malaise	1/94 (1.1%)	1	0/46 (0%)	0
Laboratory Test Abnormality	1/94 (1.1%)	1	0/46 (0%)	0
Infections and infestations
Infection	1/94 (1.1%)	1	0/46 (0%)	0
Nervous system disorders
Constipation	2/94 (2.1%)	2	0/46 (0%)	0
Numbness	0/94 (0%)	0	1/46 (2.2%)	1
Dizziness	0/94 (0%)	0	1/46 (2.2%)	1
Injury	0/94 (0%)	0	1/46 (2.2%)	1
Insomnia	1/94 (1.1%)	1	0/46 (0%)	0
Muscle Spasm	1/94 (1.1%)	1	0/46 (0%)	0
Somnolence	1/94 (1.1%)	1	1/46 (2.2%)	1
Brain Tumor	0/94 (0%)	0	1/46 (2.2%)	1
Psychiatric disorders
Delusions	0/94 (0%)	0	1/46 (2.2%)	2
Manic Psychosis	1/94 (1.1%)	1	0/46 (0%)	0
Psychosis	3/94 (3.2%)	3	1/46 (2.2%)	1
Suicidal Tendency	1/94 (1.1%)	1	0/46 (0%)	0
Renal and urinary disorders
Enuresis	1/94 (1.1%)	1	0/46 (0%)	0
Respiratory, thoracic and mediastinal disorders
Asthema	0/94 (0%)	0	1/46 (2.2%)	1
Skin and subcutaneous tissue disorders
Irritation of Skin	1/94 (1.1%)	1	0/46 (0%)	0
Rash	1/94 (1.1%)	1	0/46 (0%)	0
Urticaria	0/94 (0%)	0	2/46 (4.3%)	2

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.