Schizophrenia
Conditions
Brief summary
STUDY OBJECTIVES: To determine whether the addition of L-arginine to treatment as usual (TAU) in schizophrenia further improves and enhances therapeutic efficacy (positive, negative and depressive symptoms) and effectiveness of antipsychotic treatment STUDY POPULATION: Patients diagnosed (DSM-IV criteria) with schizophrenia or schizoaffective disorder Total expected number of patients: 14 INVESTIGATIONAL COMPOUND: L-arginine capsules, 3 grams of L-arginine given twice a day (total daily dose of 6 grams/day) DURATION OF ACTIVE TREATMENT: 3 weeks followed by wash-out phase of 5 days and 3 weeks of second treatment phase (cross-over design) EVALUATION CRITERIA: Primary (efficacy) outcomes: PANSS scores. Secondary outcomes: Calgary Depression Scale for schizophrenia, CGI; AIMS, UKU-assessment of side-effects ASSESSMENT SCHEDULE: Treatment arm 1: Baseline, weeks: 1,2,3, wash-out phase; week 4, cross-over phase: treatment phase-2; weeks 5,6,7 STATISTICAL CONSIDERATIONS: Analysis of variance of outcome measures with treatment as the between-subject factor and pre- and post-treatment scores as within- subjects factors. DURATION OF STUDY PERIOD: Patient recruitment to be completed in 12 months, study full completion 18 months.
Detailed description
In the current study, our goals were to examine the clinical benefits of the nitric oxide (NO) donor and main precursor of NO, L-arginine, to further improve the symptoms of schizophrenia with minimum or no additional side-effects. L-Arginine is classified as a semi-essential or conditionally essential amino acid depending on the developmental stage and health status of the individual. Glutamate N-methyl-D-aspartate (NMDA) receptors have functional connections to the NO system in the brain. Dysfunction of connectivity of the neuroregulators glutamate and NO have been implicated in mechanisms of psychosis. Therefore, any downstream effects of NMDA dysfunction in schizophrenia may be ultimately mediated by the NO system at a cellular level. As an augmenting treatment to antipsychotic therapy, we examined the ability of L-arginine to further improve residual symptoms in the illness.
Interventions
DRUGL-Arginine
3 grams, twice daily, oral administration
Sponsors
Alberta Health services
University of Alberta
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
1. Aged 18-65 years 2. Diagnoses of schizophrenia or schizoaffective disorder using the Diagnostic and Statistical Manual-IV (DSM-IV) criteria 3. Competent and willing to give informed consent 4. Able to take oral medication and likely to complete the required evaluations. 5. Medication remained stable 4 weeks prior to baseline. 6. Female participants of child bearing capability must be willing to use adequate contraceptives (4.6.1a) for the duration of the study, and, willing to have a pregnancy test pretreatment and during the study. Adequate contraception is defined as use of contraceptive double barrier system (i.e. condom and spermicide) or contraceptive implant, oral contraceptive or injected depot contraceptive plus other form of contraceptive, i.e. condom. Females will be considered incapable of child bearing if they are one year postmenopausal or irreversibly surgically sterilised.
Exclusion criteria
* Relevant medical illness \[serious renal, diabetes, hepatic, cardiac, low- or high-blood-pressure or other illnesses\] in the opinion of the investigators. In particular, history of past or recent cardiac illness, MI and abnormal ECG and current treatments for cardiac illness. The results of the Laboratory Investigations (LFT, TFT, RFT, WBC, ECG, platelets, blood chemistry, lipids, weight/BMI) will be taken into account in determining the
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Mean Positive and Negative Syndrome Scale (PANSS) Total and Positive, Negative and General Psychopathology Subscale Scores at 3 Weeks | Baseline and 3 Weeks | The primary outcome measure was the Positive and Negative Syndrome Scale (PANSS) total score and PANSS positive, negative and general psychopathology subscale scores. The PANSS is a 30-item scale used to evaluate the symptoms of schizophrenia. For each PANSS item, symptom severity was rated on a 7-point scale, from 1=absent to 7=extreme. The PANSS total score (30 items) ranges from 30 to 210 with a higher score indicating a greater severity of symptoms. The PANSS positive symptom subscale score (7 items) ranges from 7=absent to 49=extreme; the PANSS negative subscale score (7 items) ranges from 7=absent to 49=extreme; and the PANSS general psychopathology subscare score (16 items) ranges from 16=absent to 112=extreme. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Mean Clinical Global Impression (CGI) Scale at 3 Weeks | Baseline and 3 Weeks | The Secondary Outcome Measure was the Clinical Global Impression (CGI) scale. The CGI is a 3-item scale that rates treatment response and monitors the clinical course of all psychiatric illnesses including schizophrenia. Within the CGI, the Severity of Illness was rated on a 7-point scale, 0=not assessed to 7=among the most severely ill patients. For Global Improvement, the total improvement following treatment as compared to at baseline of the trial was rated on a 7-point scale, 0=not assessed to 7=very much worse. |
| Change From Baseline in Mean Calgary Depression Scale for Schizophrenia (CDSS) at 3 Weeks | Baseline and 3 Weeks | The Secondary Outcome Measure was the Calgary Depression Scale for Schizophenia (CDSS). The CDSS is a 9-item scale that is used to rate the depressive symptoms in patients with schizophrenia. For each CDSS item, symptom severity was rated on a 3-point scale, from 0=absent to 3=severe. The CDSS total score ranges from 0 to 27 with a higher score indicating a greater severity of symptoms. |
Countries
Canada
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| L-arginine Treatment First, Placebo Treatment Second The trial participants received 6 g p.o. (3 g twice per day at 0800h and 2000h) of L-arginine 500mg capsules for 3 weeks in addition to their antipsychotic treatment as usual. After a 5 day washout period, they then received placebo capsules (matching L-arginine 500mg) 6g p.o. (3 g twice per day at 0800h and 2000h) for 3 weeks in addition to their antipsychotic treatment as usual. | 6 |
| Placebo Treatment First, L-arginine Treatment Second The trial participants received the placebo capsules (matching L-arginine 500mg) 6 g p.o. (3 g twice per day at 0800h and 2000h) for 3 weeks in addition to their antipsychotic treatment as usual. After a 5 day washout period, they then received L-arginine (500mg capsules) 6g p.o. (3 g twice per day at 0800h and 2000h) for 3 weeks in addition to their antipsychotic treatment as usual. | 7 |
| Total | 13 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| First Intervention (3 Weeks) | Withdrawal by Subject | 0 | 1 |
| Second Intervention (3 Weeks) | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | L-arginine Treatment First, Placebo Treatment Second | Placebo Treatment First, L-arginine Treatment Second | Total |
|---|---|---|---|
| Age, Continuous | 33.8 years STANDARD_DEVIATION 15.1 | 37.8 years STANDARD_DEVIATION 8.1 | 36 years STANDARD_DEVIATION 11.5 |
| Sex: Female, Male Female | 1 Participants | 0 Participants | 1 Participants |
| Sex: Female, Male Male | 5 Participants | 7 Participants | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 13 | 0 / 13 |
| other Total, other adverse events | 0 / 13 | 0 / 13 |
| serious Total, serious adverse events | 0 / 13 | 0 / 13 |
Outcome results
Primary
Change From Baseline in Mean Positive and Negative Syndrome Scale (PANSS) Total and Positive, Negative and General Psychopathology Subscale Scores at 3 Weeks
The primary outcome measure was the Positive and Negative Syndrome Scale (PANSS) total score and PANSS positive, negative and general psychopathology subscale scores. The PANSS is a 30-item scale used to evaluate the symptoms of schizophrenia. For each PANSS item, symptom severity was rated on a 7-point scale, from 1=absent to 7=extreme. The PANSS total score (30 items) ranges from 30 to 210 with a higher score indicating a greater severity of symptoms. The PANSS positive symptom subscale score (7 items) ranges from 7=absent to 49=extreme; the PANSS negative subscale score (7 items) ranges from 7=absent to 49=extreme; and the PANSS general psychopathology subscare score (16 items) ranges from 16=absent to 112=extreme.
Time frame: Baseline and 3 Weeks
Population: All participants who received all doses of each intervention and completed all study visits were included in the efficacy analysis
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| L-arginine | Change From Baseline in Mean Positive and Negative Syndrome Scale (PANSS) Total and Positive, Negative and General Psychopathology Subscale Scores at 3 Weeks | PANSS Total Score at Baseline | 71.6 units on a scale | Standard Deviation 7.2 |
| L-arginine | Change From Baseline in Mean Positive and Negative Syndrome Scale (PANSS) Total and Positive, Negative and General Psychopathology Subscale Scores at 3 Weeks | PANSS Total Score at 3 Weeks | 68.0 units on a scale | Standard Deviation 7.2 |
| L-arginine | Change From Baseline in Mean Positive and Negative Syndrome Scale (PANSS) Total and Positive, Negative and General Psychopathology Subscale Scores at 3 Weeks | PANSS Positive Scale at Baseline | 14.6 units on a scale | Standard Deviation 4.4 |
| L-arginine | Change From Baseline in Mean Positive and Negative Syndrome Scale (PANSS) Total and Positive, Negative and General Psychopathology Subscale Scores at 3 Weeks | PANSS Positive Scale at 3 Weeks | 14.5 units on a scale | Standard Deviation 4.6 |
| L-arginine | Change From Baseline in Mean Positive and Negative Syndrome Scale (PANSS) Total and Positive, Negative and General Psychopathology Subscale Scores at 3 Weeks | PANSS Negative Scale at Baseline | 22.8 units on a scale | Standard Deviation 5 |
| L-arginine | Change From Baseline in Mean Positive and Negative Syndrome Scale (PANSS) Total and Positive, Negative and General Psychopathology Subscale Scores at 3 Weeks | PANSS Negative Scale at 3 Weeks | 21.9 units on a scale | Standard Deviation 5.2 |
| L-arginine | Change From Baseline in Mean Positive and Negative Syndrome Scale (PANSS) Total and Positive, Negative and General Psychopathology Subscale Scores at 3 Weeks | PANSS General Psychopathology Score at Baseline | 33.4 units on a scale | Standard Deviation 4.4 |
| L-arginine | Change From Baseline in Mean Positive and Negative Syndrome Scale (PANSS) Total and Positive, Negative and General Psychopathology Subscale Scores at 3 Weeks | PANSS General Psychopathology Score at 3 Weeks | 31.2 units on a scale | Standard Deviation 3.9 |
| Placebo | Change From Baseline in Mean Positive and Negative Syndrome Scale (PANSS) Total and Positive, Negative and General Psychopathology Subscale Scores at 3 Weeks | PANSS General Psychopathology Score at 3 Weeks | 33.6 units on a scale | Standard Deviation 3.7 |
| Placebo | Change From Baseline in Mean Positive and Negative Syndrome Scale (PANSS) Total and Positive, Negative and General Psychopathology Subscale Scores at 3 Weeks | PANSS Total Score at Baseline | 72.2 units on a scale | Standard Deviation 5.7 |
| Placebo | Change From Baseline in Mean Positive and Negative Syndrome Scale (PANSS) Total and Positive, Negative and General Psychopathology Subscale Scores at 3 Weeks | PANSS Negative Scale at Baseline | 22.6 units on a scale | Standard Deviation 4.3 |
| Placebo | Change From Baseline in Mean Positive and Negative Syndrome Scale (PANSS) Total and Positive, Negative and General Psychopathology Subscale Scores at 3 Weeks | PANSS Total Score at 3 Weeks | 70.2 units on a scale | Standard Deviation 7 |
| Placebo | Change From Baseline in Mean Positive and Negative Syndrome Scale (PANSS) Total and Positive, Negative and General Psychopathology Subscale Scores at 3 Weeks | PANSS General Psychopathology Score at Baseline | 34.4 units on a scale | Standard Deviation 2.7 |
| Placebo | Change From Baseline in Mean Positive and Negative Syndrome Scale (PANSS) Total and Positive, Negative and General Psychopathology Subscale Scores at 3 Weeks | PANSS Positive Scale at Baseline | 14.3 units on a scale | Standard Deviation 4.5 |
| Placebo | Change From Baseline in Mean Positive and Negative Syndrome Scale (PANSS) Total and Positive, Negative and General Psychopathology Subscale Scores at 3 Weeks | PANSS Negative Scale at 3 Weeks | 22.2 units on a scale | Standard Deviation 5.2 |
| Placebo | Change From Baseline in Mean Positive and Negative Syndrome Scale (PANSS) Total and Positive, Negative and General Psychopathology Subscale Scores at 3 Weeks | PANSS Positive Scale at 3 Weeks | 13.6 units on a scale | Standard Deviation 4 |
Comparison: Null hypothesis is that there was no difference in change of PANSS between L-arginine and Placebo. A two-factor ANOVA was used across all subjects with the within-subject factor being the treatment phase (L-arginine first/Placebo second or Placebo first/L-arginine second) and the between-subject factor being the day of treatment (time). A sample size of 14 patients was needed to give 90% power to detect a 4 point difference on the PANSS. This included a drop-out rate of about 10%.p-value: <0.05ANOVA
Secondary
Change From Baseline in Mean Calgary Depression Scale for Schizophrenia (CDSS) at 3 Weeks
The Secondary Outcome Measure was the Calgary Depression Scale for Schizophenia (CDSS). The CDSS is a 9-item scale that is used to rate the depressive symptoms in patients with schizophrenia. For each CDSS item, symptom severity was rated on a 3-point scale, from 0=absent to 3=severe. The CDSS total score ranges from 0 to 27 with a higher score indicating a greater severity of symptoms.
Time frame: Baseline and 3 Weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| L-arginine | Change From Baseline in Mean Calgary Depression Scale for Schizophrenia (CDSS) at 3 Weeks | CDSS at Baseline | 4.5 units on a scale | Standard Deviation 3.4 |
| L-arginine | Change From Baseline in Mean Calgary Depression Scale for Schizophrenia (CDSS) at 3 Weeks | CDSS at 3 Weeks | 3.4 units on a scale | Standard Deviation 2.7 |
| Placebo | Change From Baseline in Mean Calgary Depression Scale for Schizophrenia (CDSS) at 3 Weeks | CDSS at Baseline | 4.5 units on a scale | Standard Deviation 2.8 |
| Placebo | Change From Baseline in Mean Calgary Depression Scale for Schizophrenia (CDSS) at 3 Weeks | CDSS at 3 Weeks | 3.8 units on a scale | Standard Deviation 2.1 |
Comparison: Null hypothesis is that there was no difference in change of CDSS ratings between L-arginine and Placebo. A two-factor ANOVA was used across all subjects with the within-subject factor being the treatment phase (L-arginine first/Placebo second or Placebo first/L-arginine second) and the between-subject factor being the day of treatment (time).p-value: 0.55ANOVA
Secondary
Change From Baseline in Mean Clinical Global Impression (CGI) Scale at 3 Weeks
The Secondary Outcome Measure was the Clinical Global Impression (CGI) scale. The CGI is a 3-item scale that rates treatment response and monitors the clinical course of all psychiatric illnesses including schizophrenia. Within the CGI, the Severity of Illness was rated on a 7-point scale, 0=not assessed to 7=among the most severely ill patients. For Global Improvement, the total improvement following treatment as compared to at baseline of the trial was rated on a 7-point scale, 0=not assessed to 7=very much worse.
Time frame: Baseline and 3 Weeks
Population: All participants who received all doses of each intervention and completed all study visits were included in the efficacy analysis
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| L-arginine | Change From Baseline in Mean Clinical Global Impression (CGI) Scale at 3 Weeks | CGI Score at Baseline | 4.0 units on a scale | Standard Deviation 0 |
| L-arginine | Change From Baseline in Mean Clinical Global Impression (CGI) Scale at 3 Weeks | CGI Score at 3 Weeks | 3.6 units on a scale | Standard Deviation 0.5 |
| Placebo | Change From Baseline in Mean Clinical Global Impression (CGI) Scale at 3 Weeks | CGI Score at Baseline | 4.0 units on a scale | Standard Deviation 0 |
| Placebo | Change From Baseline in Mean Clinical Global Impression (CGI) Scale at 3 Weeks | CGI Score at 3 Weeks | 3.7 units on a scale | Standard Deviation 0.4 |
Comparison: Null hypothesis is that there was no difference in change of CGI ratings between L-arginine and Placebo. A two-factor ANOVA was used across all subjects with the within-subject factor being the treatment phase (L-arginine first/Placebo second or Placebo first/L-arginine second) and the between-subject factor being the day of treatment (time).p-value: 0.46ANOVA