L-arginine in Treatment as Usual in Schizophrenia

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Randomised, Double-blind, Cross-over, Placebo Controlled, Adjunctive-treatment of L-arginine Added to Treatment-as-usual (TAU) in Schizophrenia

Conditions
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Schizophrenia

Intervention / Treatment
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* Drug: L-Arginine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged 18-65 years Diagnoses of schizophrenia or schizoaffective disorder using the Diagnostic and Statistical Manual-IV (DSM-IV) criteria Competent and willing to give informed consent Able to take oral medication and likely to complete the required evaluations. Medication remained stable 4 weeks prior to baseline. 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 exclusion criteria. Relevant medical illness will be determined in the first instance by asking the patients mental health care team if the patient has any medical condition/problems. After consent has been obtained, the research nurse/research doctor will then have access to the patient's notes and if necessary communicate with his/her GP and will assess patient eligibility to take part in the clinical trial by scrutinising the patient's past medical history, most recent blood results, electrocardiograms, as well as any physical tests that have been performed on the patient. If there are any deviations from the 'norm' the investigators will assess the eligibility of the individual patient. Patients receiving active treatments for Herpes virus as L-arginine may counteract the benefits of lysine to treat herpes virus Patients who are currently receiving NSAIDs or other drugs that can cause significant stomach an gastrointestinal side-effects Drugs that alter potassium levels in the body, such as ACE inhibitors and potassium sparing diuretics Patients who are pregnant or plan to become pregnant while using this amino acid Patients who are breastfeeding Prior history of intolerance to L-arginine Any significant change of psychotropic medications done within the previous 4 weeks Diagnosis of substance abuse (except nicotine or caffeine) or dependence within the last three months according to DSM-IV criteria

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: L-arginine first/placebo second<br>Patients with diagnosis of schizophrenia will be randomised to receive L-arginine first/placebo second 3 grams bid (cross-over design) in addition to treatment as usual. The active treatment period will be 3 weeks, with a wash-out period of 5 days and re-commencing on the alternative arm of the randomization | Drug: L-Arginine<br>* 3 grams, twice daily, oral administration<br>* Other names: Placebo;|
| Placebo Comparator: Placebo first/L-arginine second<br>Patients with diagnosis of schizophrenia will be randomised to receive placebo first/L-arginine second 3 grams bid (cross-over design) in addition to treatment as usual. The active treatment period will be 3 weeks, with a wash-out period of 5 days and re-commencing on the alternative arm of the randomization | Drug: L-Arginine<br>* 3 grams, twice daily, oral administration<br>* Other names: Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline and 3 Weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline and 3 Weeks | 
| 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. | Baseline and 3 Weeks |