Nitric oxide-based treatments
An alternative and novel approach that may improve glutamate NMDA receptor signaling and circuit connectivity in schizophrenia is to target the glutamate-NO-cyclic guanosine monophosphate (cGMP) signaling cascade. Nitric oxide is produced in the brain by a complex interaction with a functional glutamate NMDA receptor and there have been a number of clinical studies suggesting that signaling within the glutamate-NO-cGMP pathway may be disrupted in the illness (138, 181–187). As a gaseous signaling molecule, NO is classified as a neuromodulator or second messenger due to its ability to generate the production of cGMP. Nitric oxide-mediated signal transduction is an important driver for a variety of cellular processes throughout the body, including those critical for the establishment and maintenance of functional neuronal circuits and synaptogenesis (138, 188). In the cerebral cortex, neurons that produce NO are among the earliest differentiating cells that develop (138, 189). The presence of NO-producing neurons during critical developmental growth periods suggests that NO may be required for the formation and subsequent migration of neurons in the brain, and interruption of NO synthesis could lead to impairment in neuronal connectivity as is observed in schizophrenia.
Studies examining the effects of the NO donor drug sodium nitroprusside (SNP) in PCP-treated rats has contributed insight into the role of NO in psychosis (138, 190, 191). The results then stimulated the investigation of the therapeutic effects of SNP in schizophrenia (192, 193). Sodium nitroprusside is a nitrovasodilator drug traditionally used for hypertensive crisis (194). When SNP is administered, it reacts with oxyhemoglobin molecules that are within erythrocytes to form methemoglobin which causes the molecule to become unstable and immediately release NO (138, 194).
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.
In relation to these findings, Dr. Paul Morrison (King's College London) is currently testing the NO-based compound glyceryl trinitrate (GTN) for its ability to improve the cognitive symptom domain of patients experiencing acute psychosis and who are requiring hospitalization (Clinicaltrials.gov Identifier: NCT02906553). Glyceryl trinitrate is another nitrovasodilator drug that has been used to treat angina and other cardiac conditions including myocardial infarction and congestive heart failure. The biotransformation of GTN involves both enzymatic and nonenzymatic pathways that are linked to the pharmacokinetic and pharmacodynamics properties of the drug (138, 196). The metabolic conversion of GTN to NO may also improve downstream glutamate signaling. This clinical trial aims to assess the role of the NO system in cognition and will initiate a sublingual GTN spray 0.4 mg dose, once per day for 3 days or matching placebo formulation spray not containing GTN before the patients are initiated on antipsychotic medication. Glyceryl trinitrate in sublingual spray formulation is a much more convenient and less invasive approach to drug delivery than intravenous infusion of SNP in patients with schizophrenia and may be a promising approach to further improve treatment-resistant cognitive symptoms in the illness.