“…a placebo controlled clinical trial by Hallak et al. has reported that has for the first time demonstrated a safe, rapid (within hours), and long-lasting (several weeks) improvement of positive, negative, anxiety, and depressive symptoms in patients with schizophrenia after a single intravenous injection of sodium nitroprusside at a randomized, placebo-controlled trial
Sodium nitroprusside is an antihypertensive drug that has vasodilatation-effects. It owes its principal activity to being a NO donor, so that it raises NO synthesis. When administered to schizophrenic patients via infusion, NO production escalates, so the tissue levels increase directly, without mediation by NMDA receptors in brain. It is a prominent finding that a single dose administration of nitroprusside in schizophrenia patients provides amelioration in symptoms that lasts up to 2 weeks. It is highly likely that a single dose sodium nitroprusside infusion given to treatment resistant schizophrenia patients yielded a rapid and weeks long improvement just like ketamine, an NMDA receptor antagonist, provided in treatment resistant depression. The effects of nitroprusside on schizophrenia symptoms could be explained by an increase in cerebral perfusion due to vasodilatation. Studies have proven that the blood stream in frontal and temporal cortex, which are concluded to be related to the negative symptoms of schizophrenia, decay in schizophrenia patients when compared to healthy controls” 
“Sodium nitroprusside (SNP) alone produced no changes in any of the behaviors evaluated. Ketamine produced hyperlocomotion and stereotypies. However, pretreatment with SNP for up to 1 week before ketamine administration significantly prevented the emergence of hyperactivity induced by ketamine, and pretreatment with SNP for up to 1 day before ketamine administration significantly prevented the emergence of stereotypies induced by ketamine.
The precise mechanism by which the SNP shows antipsychotic effects after its application is finished is not completely understood. A plausible explanation would be the ability of SNP, as a NO donor, to modulate protein kinases, transcription factors and other gene production factors through cGMP enhancement, making its cascading effects last even when SNP itself is no longer acting directly. As an up-regulation on NOS-expressing neurons in the rat hippocampus has been observed after ketamine administration (Keilhoff et al., 2004), another possible explanation to our findings might be related to SNP’s capacity to promote a feedback inhibition of NOS, correcting the up-regulation reported above. Indeed, SNP has been shown to inhibit the enhancement of NOS activity induced in rat neutrophils by treatment with lipopolysaccharide (LPS), an endotoxin. This SNP capacity could be explained through both an inhibition of NOS expression in the neutrophils caused by the nitrosonium ion (NO +) derived from SNP and an increase in NO that could be released directly from SNP (Mariotto et al., 1995).
SNP can also interfere directly with the capacity of NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells), a protein complex that controls transcription of DNA, to translocate into the nucleus. SNP inactivates NF-κB by nitration of the p65 subunit at Tyr-66 and Tyr-152, suppressing iNOS mRNA expression and preventing the activation of NF-κB target genes by TNFα (Tumor necrosis factor alpha), a cytokine involved in systemic inflammation which stimulates the acute phase reaction (Godínez-Rubí et al., 2013).
There is also evidence that SNP acts directly on NMDA receptors, which could correct the NMDA receptor dysfunction observed in schizophrenia (Oliveira et al., 2008 and Dhami et al., 2013), and that NO exerts a tonic inhibitory effect on dopamine transporters, which could correct a reduced activity of dopamine in the prefrontal cortex and, through feedback cascades, correct dopaminergic hyperactivity in accumbens and striatum, both findings reported in schizophrenia patients (Pycock et al., 1980).
Acute SNP effects in both glutamatergic and dopaminergic pharmacological models of psychosis had already been suggested by other pre-clinical studies. In 2000, Bujas-Bobanovic et al. found that SNP was able to abolish the psychotic behavior and brain c-fos expression induced in rats by PCP, a NMDA antagonist drug (Bujas-Bobanovic et al., 2000). Recently, it was demonstrated that treatment with SNP attenuated the schizophrenia-like changes on prepulse inhibition (PPI) induced in rats by amphetamine, a dopaminergic agonist drug (Issy et al., 2014), and that SNP administration produced a break in the pattern of the sleep–wake cycle similar to that found in animals depleted of dopamine in mice treated with ketamine, another NMDA antagonist drug (Maia-de-Oliveira et al., 2014a).
Interactions between NO and the dopaminergic system also have been reported in some clinical studies. Lee and Kim (2008) found decreased serum NO in schizophrenic patients compared with a control group, and reported that six-week treatment with the antipsychotic risperidone increased NO levels and that this increase was associated with symptom improvement. Among the patients who improved clinically (≥ 30% improvement in PANSS score), NO levels significantly increased after risperidone. However, no significant changes in NO levels were found in the non-responders (Lee and Kim, 2008). A recent meta-analysis described that patients taking antipsychotic medications have higher NO serum levels than those of controls (effect size g = 0.663, 95%CI = 0.365 to 0.961, p < 0.001) (Maia-de-Oliveira et al., 2012), and some interesting research reported enhanced cGMP concentrations in the plasma of patients with schizophrenia after the use of antipsychotic drugs (as mentioned before, NO stimulates cGMP synthesis) (Ebstein et al., 1976, Smith et al., 1976 and Ziimmer et al., 1980).
Furthermore, our group recently observed an improvement of positive and negative symptoms after 4 h of SNP infusion, at a dose of 0.5 μg/kg per minute, in 2 well-documented patients with clozapine-refractory schizophrenia”
To our knowledge, the results described here indicate for the first time that SNP, an NO donor, may present preventive antipsychotic effects. With regard to translation to the clinic, these findings with rats, which have an even faster metabolic rate than humans, suggest that SNP on its own could be responsible for the therapeutic effects up to 4 weeks found in our previous clinical study. If these preventive antipsychotic effects of SNP are replicated in further studies, SNP could be a significant agent for improving patient care outcomes in the near future. We believe that one of the next steps should be the investigation of the effects of SNP in patients at clinical high risk for psychosis. 
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