Clinical trial NCT00718510: L-arginine in Treatment as Usual in Schizophrenia
Official title: A Randomised, Double-blind, Cross-over, Placebo Controlled, Adjunctive-treatment of L-arginine Added to Treatment-as-usual (TAU) in Schizophrenia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Schizophrenia
Lead sponsor: University of Alberta
Sponsor class: OTHER
Collaborators: name: Alberta Health services
First posted: 2008-07-18
Enrollment: 13
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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.

Eligibility criteria: 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 exclusion criteria.

  1. 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.
  2. Patients receiving active treatments for Herpes virus as L-arginine may counteract the benefits of lysine to treat herpes virus
  3. Patients who are currently receiving NSAIDs or other drugs that can cause significant stomach an gastrointestinal side-effects
  4. Drugs that alter potassium levels in the body, such as ACE inhibitors and potassium sparing diuretics
  5. Patients who are pregnant or plan to become pregnant while using this amino acid
  6. Patients who are breastfeeding
  7. Prior history of intolerance to L-arginine
  8. Any significant change of psychotropic medications done within the previous 4 weeks
  9. Diagnosis of substance abuse (except nicotine or caffeine) or dependence within the last three months according to DSM-IV criteria

Primary outcomes:
measure: Change From Baseline in Mean Positive and Negative Syndrome Scale (PANSS) Total and Positive, Negative and General Psychopathology Subscale Scores at 3 Weeks
timeFrame: Baseline and 3 Weeks
Secondary outcomes:
measure: Change From Baseline in Mean Clinical Global Impression (CGI) Scale at 3 Weeks
timeFrame: Baseline and 3 Weeks
measure: Change From Baseline in Mean Calgary Depression Scale for Schizophrenia (CDSS) at 3 Weeks
timeFrame: Baseline and 3 Weeks
Other outcomes:
Locations:
city: Edmonton
country: Canada
facility: Alberta Hospital Edmonton
state: Alberta
Study officials:
affiliation: University of Alberta
name: Serdar Dursun, M.D., Ph.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Alberta
name: Glen Baker, Ph.D., D.Sc.
role: PRINCIPAL_INVESTIGATOR
affiliation: Alberta Hospital Edmonton
name: John C. Lind, Ph.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Alberta
name: Phil Tibbo, F.R.C.P.C.
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Alberta
name: Mee-Sook Song, Ph.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: Alberta Hospital Edmonton
name: Pierre Flor-Henry, F.R.C.P.C.
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Alberta
name: Diane Cox, Ph.D.
role: PRINCIPAL_INVESTIGATOR
References: