The first investigational clinical trial of NO in schizophrenia was conducted at the University Teaching Hospital in Ribeirao Preto, Sao Paulo, Brazil. In this clinical trial, an intravenous infusion of SNP in patients who were already on antipsychotics produced rapid improvement of symptoms (within 4 h of a single infusion) as compared to those patients who received a placebo infusion (138, 192). Symptom improvement continued for 4 weeks following the infusion (although antipsychotic medication adjustments were permitted 7 days following the infusion). The lasting benefits are thought to be related to cGMP's ability to stimulate early gene products and subsequent modulatory effects on the NMDA receptor itself. Sodium nitroprusside has been beneficial in both early stage schizophrenia and in a few case reports of ultra-resistant schizophrenia and did improve a wide spectrum of symptom domains, including the positive, negative, and anxiety symptoms of the illness (138, 192, 193). The results were not replicated in a subsequent trial testing SNP in a population of long-term chronically ill patients (195), which may suggest that SNP-based therapies may be most effective when used within the earlier stages of the illness in those patients experiencing acute symptoms.