Schizophrenia
Conditions
Keywords
Schizophrenia, Negative Symptoms, Folate
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.
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
Interventions
DRUGFolate
Folic acid taken as 2, 1mg capsule daily for 12 weeks
DRUGPlacebo
Placebo taken as 2, 1mg capsule daily for 12 weeks
Sponsors
National Alliance for Research on Schizophrenia and Depression
Massachusetts General Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 68 Years
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| Correlation Between Baseline Blood Homocysteine Levels and MTHFR Genotype | Baseline | Baseline blood homocysteine lab levels are reported by MTHFR genotype. |
| Correlation Between Baseline Serum B12 Levels and Dietary Intake | Baseline | Baseline serum B12 lab levels and dietary intake levels are reported. |
| Correlation Between Baseline Blood Homocysteine Levels and Dietary Intake | Baseline | Baseline blood homocysteine lab levels and dietary intake levels are reported. |
| Correlation Between Baseline Blood Folate and Smoking Status | Baseline | Baseline blood folate lab levels are reported by smoking status. |
| Correlation Between Baseline Blood Folate and MTHFR Genotype | Baseline | Baseline blood folate lab levels are reported by MTHFR genotype. |
| Correlation Between Baseline Blood Folate Levels and Dietary Intake | Baseline | Baseline blood folate lab levels and dietary intake levels are reported. |
| 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. |
| Correlation Between Baseline Serum B12 Levels and Smoking Status | Baseline | Baseline serum B12 lab levels are reported by smoking status. |
| Correlation Between Baseline Homocysteine Levels and Smoking Status | Baseline | Baseline blood homocysteine lab levels are reported by smoking status. |
| Correlation Between Baseline Blood B12 Levels and MTHFR Genotype | Baseline | Baseline blood B12 lab levels are reported by MTHFR genotype. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
Countries
United States
Participant flow
Recruitment details
Forty six participants were enrolled; 38 completed screening and 32 received study drug.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received 2 mg/daily of placebo, for 12 weeks | 15 |
| Folate Patients underwent a 12 week trial of folate 2 mg/d | 17 |
| Total | 32 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 3 | 3 |
| Overall Study | Withdrawal by Subject | 2 | 2 |
Baseline characteristics
| Characteristic | Folate | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 17 Participants | 15 Participants | 32 Participants |
| Age, Continuous | 45.5 years STANDARD_DEVIATION 9.6 | 46.5 years STANDARD_DEVIATION 11.3 | 46 years STANDARD_DEVIATION 10.3 |
| Region of Enrollment United States | 17 participants | 15 participants | 32 participants |
| Sex: Female, Male Female | 4 Participants | 2 Participants | 6 Participants |
| Sex: Female, Male Male | 13 Participants | 13 Participants | 26 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 19 | 0 / 19 |
| serious Total, serious adverse events | 0 / 19 | 0 / 19 |
Outcome results
Primary
Correlation Between Baseline Blood B12 Levels and MTHFR Genotype
Baseline blood B12 lab levels are reported by MTHFR genotype.
Time frame: Baseline
Population: For the present analysis, as opposed to a comparison of treatment groups, B12 levels are compared across MTHFR genotype.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Current Smoker | Correlation Between Baseline Blood B12 Levels and MTHFR Genotype | 605.5 picograms per milliliter | Standard Deviation 312.9 |
| Past Smoker | Correlation Between Baseline Blood B12 Levels and MTHFR Genotype | 557.1 picograms per milliliter | Standard Deviation 170.1 |
Primary
Correlation Between Baseline Blood Folate and MTHFR Genotype
Baseline blood folate lab levels are reported by MTHFR genotype.
Time frame: Baseline
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Current Smoker | Correlation Between Baseline Blood Folate and MTHFR Genotype | Serum folate, ng/ml | 13.3 nanograms/mL | Standard Deviation 3.3 |
| Current Smoker | Correlation Between Baseline Blood Folate and MTHFR Genotype | RBC folate, ng/ml | 624.8 nanograms/mL | Standard Deviation 143 |
| Past Smoker | Correlation Between Baseline Blood Folate and MTHFR Genotype | Serum folate, ng/ml | 15.2 nanograms/mL | Standard Deviation 4.1 |
| Past Smoker | Correlation Between Baseline Blood Folate and MTHFR Genotype | RBC folate, ng/ml | 542.8 nanograms/mL | Standard Deviation 150.6 |
Primary
Correlation Between Baseline Blood Folate and Smoking Status
Baseline blood folate lab levels are reported by smoking status.
Time frame: Baseline
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Current Smoker | Correlation Between Baseline Blood Folate and Smoking Status | Serum folate, ng/ml | 14.6 nanograms per milliliter | Standard Deviation 3.3 |
| Current Smoker | Correlation Between Baseline Blood Folate and Smoking Status | RBC folate, ng/ml | 614 nanograms per milliliter | Standard Deviation 142 |
| Past Smoker | Correlation Between Baseline Blood Folate and Smoking Status | Serum folate, ng/ml | 14.6 nanograms per milliliter | Standard Deviation 5.2 |
| Past Smoker | Correlation Between Baseline Blood Folate and Smoking Status | RBC folate, ng/ml | 542 nanograms per milliliter | Standard Deviation 122 |
| Never Smoker | Correlation Between Baseline Blood Folate and Smoking Status | Serum folate, ng/ml | 14.2 nanograms per milliliter | Standard Deviation 4.1 |
| Never Smoker | Correlation Between Baseline Blood Folate and Smoking Status | RBC folate, ng/ml | 475 nanograms per milliliter | Standard Deviation 161 |
Primary
Correlation Between Baseline Blood Folate Levels and Dietary Intake
Baseline blood folate lab levels and dietary intake levels are reported.
Time frame: Baseline
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Current Smoker | Correlation Between Baseline Blood Folate Levels and Dietary Intake | Serum folate, ng/ml | 14.5 nanograms/mL | Standard Deviation 3.9 |
| Current Smoker | Correlation Between Baseline Blood Folate Levels and Dietary Intake | RBC folate, ng/ml | 569.3 nanograms/mL | Standard Deviation 148.1 |
Primary
Correlation Between Baseline Blood Folate or B12 Levels and Dietary Intake
Baseline blood folate and B12 lab levels and dietary intake levels are reported.
Time frame: Baseline
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Current Smoker | Correlation Between Baseline Blood Folate or B12 Levels and Dietary Intake | Total folate, mcg | 531.3 micrograms | Standard Deviation 386.5 |
| Current Smoker | Correlation Between Baseline Blood Folate or B12 Levels and Dietary Intake | Dietary folate, mcg | 765.7 micrograms | Standard Deviation 637.7 |
| Current Smoker | Correlation Between Baseline Blood Folate or B12 Levels and Dietary Intake | Natural folate, mcg | 198.8 micrograms | Standard Deviation 73.3 |
| Current Smoker | Correlation Between Baseline Blood Folate or B12 Levels and Dietary Intake | Synthetic folate, mcg | 333.4 micrograms | Standard Deviation 362.9 |
| Current Smoker | Correlation Between Baseline Blood Folate or B12 Levels and Dietary Intake | Total B12, mcg | 7.5 micrograms | Standard Deviation 7.3 |
Primary
Correlation Between Baseline Blood Homocysteine Levels and Dietary Intake
Baseline blood homocysteine lab levels and dietary intake levels are reported.
Time frame: Baseline
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Current Smoker | Correlation Between Baseline Blood Homocysteine Levels and Dietary Intake | 9.6 micromoles/liter | Standard Deviation 2.4 |
Primary
Correlation Between Baseline Blood Homocysteine Levels and MTHFR Genotype
Baseline blood homocysteine lab levels are reported by MTHFR genotype.
Time frame: Baseline
Population: For the present analysis, as opposed to a comparison of treatment groups, homocystein levels are compared across MTHFR genotype.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Current Smoker | Correlation Between Baseline Blood Homocysteine Levels and MTHFR Genotype | 9.4 micromoles/liter | Standard Deviation 2.9 |
| Past Smoker | Correlation Between Baseline Blood Homocysteine Levels and MTHFR Genotype | 9.6 micromoles/liter | Standard Deviation 2.3 |
Primary
Correlation Between Baseline Homocysteine Levels and Smoking Status
Baseline blood homocysteine lab levels are reported by smoking status.
Time frame: Baseline
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Current Smoker | Correlation Between Baseline Homocysteine Levels and Smoking Status | 9.1 micromoles per liter | Standard Deviation 2.6 |
| Past Smoker | Correlation Between Baseline Homocysteine Levels and Smoking Status | 10.8 micromoles per liter | Standard Deviation 1.6 |
| Never Smoker | Correlation Between Baseline Homocysteine Levels and Smoking Status | 9 micromoles per liter | Standard Deviation 2.5 |
Primary
Correlation Between Baseline Serum B12 Levels and Dietary Intake
Baseline serum B12 lab levels and dietary intake levels are reported.
Time frame: Baseline
Population: For the present analysis, as opposed to a comparison of treatment groups, B12 levels are described for all baseline participants.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Current Smoker | Correlation Between Baseline Serum B12 Levels and Dietary Intake | 566.6 picograms/mL | Standard Deviation 231.5 |
Primary
Correlation Between Baseline Serum B12 Levels and Smoking Status
Baseline serum B12 lab levels are reported by smoking status.
Time frame: Baseline
Population: For the present analysis, as opposed to a comparison of treatment groups, B12 levels are compared across smoking status.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Current Smoker | Correlation Between Baseline Serum B12 Levels and Smoking Status | 625 picograms per milliliter | Standard Deviation 273 |
| Past Smoker | Correlation Between Baseline Serum B12 Levels and Smoking Status | 436 picograms per milliliter | Standard Deviation 130 |
| Never Smoker | Correlation Between Baseline Serum B12 Levels and Smoking Status | 574 picograms per milliliter | Standard Deviation 160 |
Primary
Efficacy of Folate Supplementation for Reducing Negative Symptoms as Measured by the SANS Modified Total
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
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Current Smoker | Efficacy of Folate Supplementation for Reducing Negative Symptoms as Measured by the SANS Modified Total | -8.5 Units on a scale | Standard Deviation 7.6 |
| Past Smoker | Efficacy of Folate Supplementation for Reducing Negative Symptoms as Measured by the SANS Modified Total | -9.7 Units on a scale | Standard Deviation 8.5 |
Secondary
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 blood B12 lab levels are reported by deficit syndrome status.
Time frame: Baseline
Population: For the present analysis, as opposed to a comparison of treatment groups, B12 levels are compared across deficit syndrome status.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Current Smoker | Correlations Between Baseline Blood B12 Levels and Clinical Ratings of Negative Symptoms by Comparing Lab Levels in Deficit Syndrome Versus Non-deficit Syndrome Patients | 603 picograms/mL | Standard Deviation 193 |
| Past Smoker | Correlations Between Baseline Blood B12 Levels and Clinical Ratings of Negative Symptoms by Comparing Lab Levels in Deficit Syndrome Versus Non-deficit Syndrome Patients | 513 picograms/mL | Standard Deviation 275 |
Secondary
Correlations Between Baseline Blood Folate and Clinical Ratings of Negative Symptoms by Comparing Lab Levels in Deficit Syndrome Versus Non-deficit Syndrome Patients
Baseline blood folate lab levels are reported by deficit syndrome status.
Time frame: Baseline
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Current Smoker | Correlations Between Baseline Blood Folate and Clinical Ratings of Negative Symptoms by Comparing Lab Levels in Deficit Syndrome Versus Non-deficit Syndrome Patients | Serum folate, ng/ml | 14.9 nanograms/mL | Standard Deviation 4.3 |
| Current Smoker | Correlations Between Baseline Blood Folate and Clinical Ratings of Negative Symptoms by Comparing Lab Levels in Deficit Syndrome Versus Non-deficit Syndrome Patients | RBC folate, ng/ml | 585 nanograms/mL | Standard Deviation 171 |
| Past Smoker | Correlations Between Baseline Blood Folate and Clinical Ratings of Negative Symptoms by Comparing Lab Levels in Deficit Syndrome Versus Non-deficit Syndrome Patients | Serum folate, ng/ml | 14.0 nanograms/mL | Standard Deviation 3.5 |
| Past Smoker | Correlations Between Baseline Blood Folate and Clinical Ratings of Negative Symptoms by Comparing Lab Levels in Deficit Syndrome Versus Non-deficit Syndrome Patients | RBC folate, ng/ml | 546 nanograms/mL | Standard Deviation 123 |
Secondary
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 blood homocysteine lab levels are reported by deficit syndrome status.
Time frame: Baseline
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Current Smoker | Correlations Between Baseline Blood Homocysteine Levels and Clinical Ratings of Negative Symptoms by Comparing Lab Levels in Deficit Syndrome Versus Non-deficit Syndrome Patients | 9.4 micromoles/liter | Standard Deviation 2.6 |
| Past Smoker | Correlations Between Baseline Blood Homocysteine Levels and Clinical Ratings of Negative Symptoms by Comparing Lab Levels in Deficit Syndrome Versus Non-deficit Syndrome Patients | 9.7 micromoles/liter | Standard Deviation 2.5 |