L-arginine Study for Persistent Symptoms of Schizophrenia

Inclusion Criteria: 1. Males or Females aged 18-65 years inclusive. 2. English speaking. 3. Primary diagnosis of Schizophrenia established by a structured psychiatric evaluation (MINI) based on Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM-V) criteria. 4. Written informed consent in compliance with 21 CFR part 50 and in accordance with the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. 5. A Positive and Negative Syndrome Scale (PANSS) (Kay et al 1987) total score ≥ 70 with a score of \> 4 on two or more of the following PANSS items: delusions, conceptual disorganization, hallucinatory behavior, suspiciousness, and unusual thought content. 6. A score of ≥4 on the Clinical Global Impression-Severity (CGI-S) (Guy, 1976). 7. Must have ongoing antipsychotic treatment for at least 8 weeks, with a stable dose for at least 4 weeks. Antipsychotic medication will not be modified by the research team during the subject's enrollment or participation. 8. Subjects who have failed to achieve clinically-recognized symptom reduction to at least 1 marketed antipsychotic agent, given at a Physician Desk Reference (PDR)-defined therapeutic dose for ≥ 8 weeks during the past 12 months, will be eligible. 9. Women of childbearing potential must have a negative pregnancy test performed at screening visit prior to randomization. Women enrolled in this trial must use adequate birth control. 10. Understands and is able, willing, and (in the opinion of the investigator) likely to fully comply with the study procedures and restrictions. Exclusion Criteria: 1. Subjects with a history of renal insufficiency, congestive heart failure, cardiac arrhythmias or history of myocardial infarction, liver cirrhosis, guanidinoacetate methyltransferase deficiency, herpes. 2. Subjects who are non-English speaking. 3. Subjects with any clinically significant abnormalities as determined by medical history, physical exam, clinical and lab evaluation suggestive of an underlying disease state that may, in the opinion of the investigator, confound the results of study, increase risk to the subject, or lead to difficulty complying with the protocol. 4. Subjects with the lab values defined as exclusionary safety values in Table 1. 5. On medications known to inhibit folate metabolism (e.g., methotrexate). 6. On medications known to affect NO-mediated vaso-relaxation (e.g., PDE-5 inhibitors such as sildenafil, vardenafil, or tadalafil). 7. Subjects on nitrates. 8. Subjects on levodopa. 9. Subjects on antihypertensive medications (such as ACE inhibitors, angiotensin receptor blockers, isoproterenol, potassium-sparing diuretics). 10. Subjects on antidiabetes medications. 11. Subjects on anticoagulant/antiplatelet medications. 12. Subjects with a current (within the last 3 months) DSM-V diagnosis of alcohol or substance use disorder (excluding nicotine and caffeine) as established by the clinical assessment (MINI) at the screening visit will be excluded. 13. Tested positive for the urine drug screen. 14. Subjects at imminent risk of suicide or injury to self or others, as per the opinion of the investigator, or history of significant suicide attempt within the last 6 months as per the Columbia Suicide Severity Rating Scale (C-SSRS). 15. Subjects that have taken an investigational drug or taken part in a clinical trial within 30 days prior to screening. 16. Known history of phenylketonuria (PKU). 17. Known hypersensitivity reactions (such as anaphylaxis and rash) to L-arginine and/or BH4. 18. Any other reason that, in the opinion of the investigator, would compromise patient safety or integrity of the study.