Sodium Nitroprusside in Early Course Schizophrenia

Proof of Mechanism Study Using a Retinal Biomarker to Predict Treatment Response With Intravenous Sodium Nitroprusside in Symptomatic Early Course Schizophrenia

Peripheral inflammation and microvascular dysfunction are central to the pathophysiology of schizophrenia (SZ). Retinal imaging allows for the accurate quantitative assessment of the condition of retinal microvessels, and early studies implicate microvascular dysfunction in SZ, but the specific pathophysiological mechanisms underlying greater length, density, capillary network and diameter are not yet entirely understood. Anti-inflammatory drug trials in SZ suggest that Early Course Schizophrenia (ECS) individuals with elevated peripheral inflammation show the greatest benefit to adjunctive anti inflammatory treatments. Also, there is a growing interest in the use of Sodium Nitroprusside (SNP) in SZ but further studies are needed as results are inconsistent. This study will determine the effectiveness of SNP on psychosis symptoms, cognition, and retinal measures in symptomatic ECS.

The microvascular environment is the major interface of systemic factors affecting the brain, it is a logical focus for understanding the neurobiology of schizophrenia (SZ). However, our understanding of the immunological underpinnings of SZ and improved methodologies to detect microvascular disorder have led to increased research in this area. We have shown that inflammatory subtypes are found in psychosis and an increased pattern of peripheral inflammation (including C-Reactive Protein, CRP) is related with worse overall cognition. Retinal and cerebral microvessels are embryological related and can be utilized to measure the state of cerebral microvessels. Advances in retinal imaging, such as swept source optical coherence tomography angiography (SS-OCTA), provide greater microvascular clarity to visualize the retina non-invasively, in a more detailed, quicker and cost-effective manner. In a pilot study using SS-OCTA, we identified microvascular dysfunction associated with early-stages SZ. The pathophysiological mechanisms underlying these retinal microvascular changes are not entirely understood, but they have been associated with inflammation (including CRP), endothelial dysfunction, reactive oxygen species and hypoxia/ ischemia, which have also been consistently observed in SZ. Nitric oxide (NO) signaling is a potential mechanism for protecting the microvasculature against oxidative stress, inflammation and endothelial dysfunction and treatment with NOD have been shown to reduce oxidative stress/inflammation and to increase cerebral blood flow in cerebrovascular disorders. Anti-inflammatory drug trials in SZ suggest that Early Course Schizophrenia (ECS) individuals with elevated peripheral inflammation show the greatest benefit to adjunctive anti inflammatory treatments. In line with that there is a growing interest in the use of SNP in SZ. Preclinical and clinical evidence have shown that SNP may have an antipsychotic profile. Hallak et al (2013) demonstrated that a single infusion of SNP in patients with ECS was both safe and associated with immediate and longer-term clinical outcome. While three other studies demonstrated that SNP was well-tolerated in patient with multi-episode SZ, they were not able to replicate Hallak's finding, which was likely due to the disease heterogeneity, the inclusion of an older population with a longer duration or multi-episodes of illness, and the lack of treatment biomarkers. Further work is needed to determine whether the effect of SNP treatment is dependent on a patient's illness duration and whether a retinal biomarker for microvascular dysfunction/inflammation can predict treatment response to SNP. Thus, the principal goal in the field of SZ is to identify biomarker-based targets for early intervention, evidence of engaging this target by selective interventions and assessing therapeutic efficacy.

Inclusion Criteria: Having a DSM-V diagnosis of Schizophrenia or schizoaffective disorder with <5 years from the onset of psychosis Having up to 2 years of lifetime exposure to antipsychotics Having total score of >65 on the Positive and Negative Syndrome Scale (PANSS) with a score of >4 on 1 or more PANSS items (delusions, conceptual disorganization, hallucinatory behavior, suspiciousness, or unusual thought content) Having English proficiency Being competent and willing to give informed consent Exclusion Criteria: Having substance dependence or abuse within the past 6 months Having history of retinal disease; myopia >4.0 diopters; symptomatic orthostatic hypotension Any change of psychotropic medications within the previous 4 weeks Currently taking clozapine Having prior history of intolerance to Sodium Nitroprusside Having treatment with medications that may interfere with the metabolism or excretion or effects of Sodium Nitroprusside Being pregnancy/breast feeding Having unstable major medical (renal, hepatic, or cardiac) or neurologic illness Having significant inflammatory or immune conditions Having treatment with anti-inflammatory drugs, hormones or immunosuppressant agents in the 6 months before study entry.