L-arginine add-on Therapy in Patients With Schizophrenia

L-Arginine add-on Treatment for Schizophrenia: A Randomized, Double Blind, Placebo Controlled, Cross Over Study

This study evaluates the addition of L-Arginine to the usual regimen in the treatment of schizophrenia in adults. As a requisite of crossover design, half of the participants started with L-Arginine and the other half with placebo and switched over after a three weeks use and one week of a washout period.

Study Overview

• Status: Completed
• Conditions: Schizophrenia; Schizoaffective Disorder
• Intervention / Treatment: Dietary supplement: L-Arginine; Other: Placebo

Detailed Description

L-arginine is the precursor of nitric oxide (NO), a neuromodulator of dopamine, gamma-aminobutyrate (GABA) and glutamate systems. Nitric oxide donors which increase NO levels at the cellular level could improve N-methyl-D-aspartate (NMDA) receptor dysfunction. Using L-arginine could bypass the blocked NMDA receptors and improve the therapeutic efficacy by reversing the dysfunction.

The investigators proposed that using L-Arginine, a dietary supplement in most cultures, might constitute a safe option as an add-on treatment which may display beneficial effects on positive, negative, cognitive and affective symptoms associated with schizophrenia.

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Turkey
  • Ankara, Turkey, 06100
    • Hacettepe University Faculty of Medicine Department of Psychiatry

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Schizophrenia-Schizoaffective Disorder
• Clinical Global Impression >4
• Able to take oral medication and likely to comply the required evaluations
• On stable medication regimen for 8 weeks
• Competent and willing to give informed consent

Exclusion Criteria:

• Uncontrolled medical illness (renal disease, hepatic, cardiac diseases, gout, asthma, diabetes, sickle cell anemia, low-high blood pressure)
• History of Myocardial Infarction (MI)
• History of genital herpes infections/ receiving lysine containing treatments
• Pregnancy/ lactation
• Substance related and Addictive Disorders
• Drugs that might induce hypotension
• Intolerance to L-arginine and ingredients of placebo or L-arginine capsule

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: L-Arginine-First; For the first three weeks, L-Arginine 3 g bid (500mg capsules 6 x 2), one week wash-out, then for the next three weeks placebo capsules (6 x 2)	Dietary supplement: L-Arginine; Experimental supplement; Other: Placebo; Placebo capsules in the same color and shape with the experimental supplement
Experimental: Placebo-First; For the first three weeks, placebo capsules (6 x 2), one week wash-out, then for the next three weeks L-Arginine 3 g bid (500 mg capsules 6 x 2)	Dietary supplement: L-Arginine; Experimental supplement; Other: Placebo; Placebo capsules in the same color and shape with the experimental supplement

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from baseline in Positive and Negative Syndrome Scale	Evaluating change in Positive and Negative Syndrome Scale between baseline and Week 3, comparing subjects treated with L-Arginine for 3 weeks to subjects treated with placebo for 3 weeks.	baseline and week 3

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from baseline in Neuropsychological Test Battery	Evaluating change in Neuropsychological Test Battery between baseline and Week 3, comparing subjects treated with L-Arginine for 3 weeks to subjects treated with placebo for 3 weeks.	baseline and week 3
Change from baseline in the The Calgary Depression Scale for Schizophrenia	Evaluating change in The Calgary Depression Scale for Schizophrenia between baseline and Week 3, comparing subjects treated with L-Arginine for 3 weeks to subjects treated with placebo for 3 weeks.	baseline and week 3
Change from baseline in Clinical Global Impression - Severity	Evaluating change in Clinical Global Impression - Severity between baseline and Week 3, comparing subjects treated with L-Arginine for 3 weeks to subjects treated with placebo for 3 weeks.	baseline and week 3
Change from baseline in Abnormal Involuntary Movement Scale	Evaluating change in Abnormal Involuntary Movement Scale between baseline and Week 3, comparing subjects treated with L-Arginine for 3 weeks to subjects treated with placebo for 3 weeks.	baseline and week 3
Change from baseline in Uku Side Effects Rating Scale	Evaluating change in Uku Side Effects Rating Scale between baseline and Week 3, comparing subjects treated with L-Arginine for 3 weeks to subjects treated with placebo for 3 weeks.	baseline and week 3
Change from baseline in blood pressure		baseline and week 7
Change from baseline in heart rate		baseline and week 7
Change from baseline in temperature		baseline and week 7
Change from baseline in respiratory rate		baseline and week 7
Change from baseline in weight		baseline and week 7
Change from baseline in electrocardiogram		baseline and week 7
Change from baseline in complete blood count	Composed of different measures. Change in any measure indicates impairment in the composite measure	baseline and week 7
Change from baseline in alanine aminotransferase		baseline and week 7
Change from baseline in aspartate aminotransferase		baseline and week 7
Change from baseline in alkaline phosphatase		baseline and week 7
Change from baseline in urea		baseline and week 7
Change from baseline in creatinine		baseline and week 7
Change from baseline in sodium		baseline and week 7
Change from baseline in potassium		baseline and week 7
Change from baseline in chloride		baseline and week 7
Change from baseline in calcium		baseline and week 7
Change from baseline in thyroid-stimulating hormone		baseline and week 7
Change from baseline in free T4		baseline and week 7
Change from baseline in total cholesterol		baseline and week 7
Change from baseline in HDL		baseline and week 7
Change from baseline in LDL		baseline and week 7
Change from baseline in triglycerides		baseline and week 7
Change from baseline in human chorionic gonadotropin	Pregnancy test in women	baseline and week 7

Collaborators and Investigators

• Sponsor: Hacettepe University
• Investigators: Principal Investigator: Kazım M Yazıcı, MD, Hacettepe University Faculty of Medicine Department of Psychiatry

Publications and helpful links

General Publications

• Boger RH. The pharmacodynamics of L-arginine. J Nutr. 2007 Jun;137(6 Suppl 2):1650S-1655S. doi: 10.1093/jn/137.6.1650S.
• Maia-de-Oliveira JP, Trzesniak C, Oliveira IR, Kempton MJ, Rezende TM, Iego S, Baker GB, Dursun SM, Machado-de-Sousa JP, Hallak JE. Nitric oxide plasma/serum levels in patients with schizophrenia: a systematic review and meta-analysis. Braz J Psychiatry. 2012 Oct;34 Suppl 2:S149-55. doi: 10.1016/j.rbp.2012.07.001. English, Portuguese.
• Vayisoglu S, Anil Yagcioglu AE, Yagcioglu S, Karahan S, Karci O, Gurel SC, Yazici MK. Lamotrigine augmentation in patients with schizophrenia who show partial response to clozapine treatment. Schizophr Res. 2013 Jan;143(1):207-14. doi: 10.1016/j.schres.2012.11.006. Epub 2012 Dec 2.
• Kocyigit Y, Yoca G, Karahan S, Ayhan Y, Yazici MK. [L-Arginine Add-On Treatment for Schizophrenia: A Randomized,Double-Blind, Placebo-Controlled, Crossover Study]. Turk Psikiyatri Derg. 2018 Fall;29(3):147-153. Turkish.

Study record dates

Study Major Dates

• Study Start: June 1, 2011
• Primary Completion (Actual): December 1, 2012
• Study Completion (Actual): April 1, 2013

Study Registration Dates

• First Submitted: March 6, 2015
• First Submitted That Met QC Criteria: March 19, 2015
• First Posted (Estimate): March 25, 2015

Study Record Updates

• Last Update Posted (Estimate): March 25, 2015
• Last Update Submitted That Met QC Criteria: March 19, 2015
• Last Verified: March 1, 2015

More Information

Terms related to this study

• Keywords: schizophrenia; nitric oxide; L-Arginine; drug augmentation
• Additional Relevant MeSH Terms: Mental Disorders; Schizophrenia Spectrum and Other Psychotic Disorders; Schizophrenia; Psychotic Disorders
• Other Study ID Numbers: 011D01101013

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No