Schizophrenia
Conditions
Keywords
Cognition, Folic Acid, B12
Brief summary
This study will evaluate the effectiveness of folate and B12 supplementation in reducing negative symptoms in people with schizophrenia.
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.
Interventions
DIETARY_SUPPLEMENTFolic Acid
Folic acid 2mg po daily
DIETARY_SUPPLEMENTB12
B12 400 micrograms po daily
OTHERPlacebo
1 capsule po daily
Sponsors
National Institute of Mental Health (NIMH)
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
* 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| Cognitive Deficits, as Measured by the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Cognitive Battery Composite Score | Measured at Week 16 | — |
| 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. |
| 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. |
| 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. |
| 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 | — |
Countries
United States
Participant flow
Pre-assignment details
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.
Participants by arm
| Arm | Count |
|---|---|
| Folate With B12 Participants will take folic acid plus B12 for 18 weeks.
Folic Acid: Folic acid 2mg po daily
B12: B12 400 micrograms po daily | 94 |
| Placebo Participants will take placebo for 18 weeks.
Placebo: 1 capsule po daily | 46 |
| Total | 140 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 1 |
| Overall Study | Lost to Follow-up | 6 | 0 |
| Overall Study | Withdrawal by Subject | 8 | 2 |
Baseline characteristics
| Characteristic | Folate With B12 | 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 | 94 Participants | 46 Participants | 140 Participants |
| Age, Continuous | 45.3 Years STANDARD_DEVIATION 1.1 | 45.9 Years STANDARD_DEVIATION 1.6 | 45.6 Years STANDARD_DEVIATION 1.35 |
| Region of Enrollment United States | 94 participants | 46 participants | 140 participants |
| Sex: Female, Male Female | 28 Participants | 32 Participants | 60 Participants |
| Sex: Female, Male Male | 66 Participants | 14 Participants | 80 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 21 / 94 | 16 / 46 |
| serious Total, serious adverse events | 4 / 94 | 4 / 46 |
Outcome results
Primary
Positive and Negative Syndrome Scale (PANSS)
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
Population: 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 | Measure | Value (MEAN) |
|---|---|---|
| Folate With B12 | Positive and Negative Syndrome Scale (PANSS) | -.21 units on a scale |
| Placebo | Positive and Negative Syndrome Scale (PANSS) | -.22 units on a scale |
Secondary
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
Secondary
Positive and Negative Syndrome Scale (PANSS) and FOLH1, MTHRF, MTR, and COMT Genotype
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
Population: 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 | Measure | Value (MEAN) |
|---|---|---|
| Folate With B12 | Positive and Negative Syndrome Scale (PANSS) and FOLH1, MTHRF, MTR, and COMT Genotype | -.21 units on a scale |
| Placebo | Positive and Negative Syndrome Scale (PANSS) and FOLH1, MTHRF, MTR, and COMT Genotype | -.1 units on a scale |
Secondary
Positive Sub Scale of the Positive and Negative Syndrome Scale (PANSS)
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
Population: 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 | Measure | Value (MEAN) |
|---|---|---|
| Folate With B12 | Positive Sub Scale of the Positive and Negative Syndrome Scale (PANSS) | -.06 units on a scale |
| Placebo | Positive Sub Scale of the Positive and Negative Syndrome Scale (PANSS) | -.04 units on a scale |
Secondary
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
Secondary
Scale for Assessment of Negative Symptoms (SANS)
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
Population: 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 | Measure | Value (MEAN) |
|---|---|---|
| Folate With B12 | Scale for Assessment of Negative Symptoms (SANS) | -.19 units on a scale |
| Placebo | Scale for Assessment of Negative Symptoms (SANS) | .02 units on a scale |