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.

Study Overview

• Status: Terminated
• Conditions: Schizophrenia; Schizoaffective Disorder
• Intervention / Treatment: Drug: Sodium Nitroprusside; Drug: 5% Dextrose solution

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 1
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 40 years (Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Sodium Nitroprusside Arm; Sodium Nitroprusside (0.5 μg/kg/min) for 4 hours	Drug: Sodium Nitroprusside; Half of participants will receive Intravenous Sodium Nitroprusside (0.5 μg/kg/min) for 4 hours.; Other Names: Active
Placebo Comparator: Placebo Arm; 5% Dextrose (0.5 μg/kg/min) for 4 hours	Drug: 5% Dextrose solution; Half of participants will receive intravenous 5% Dextrose solution for 4 hours.; Other Names: Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Positive and Negative Syndrome Scale (PANSS)	Comparing total, positive, and negative scores between SNP and Placebo	Measured at hour 2

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Brief Assessment of Cognition in Schizophrenia (BACS)	Comparing cognitive function score between SNP and Placebo	Measured at hour 2
Brief Assessment of Cognition in Schizophrenia (BACS)	Comparing cognitive function score between SNP and Placebo	Measured at week 1
Brief Assessment of Cognition in Schizophrenia (BACS)	Comparing cognitive function score between SNP and Placebo	Measured at week 2
Brief Assessment of Cognition in Schizophrenia (BACS)	Comparing cognitive function score between SNP and Placebo	Measured at week 4
SS-OCTA Retinal Imaging	Comparing retinal microvascular measures between SNP and Placebo	Measured at hour 2
SS-OCTA Retinal Imaging	Comparing retinal microvascular measures between SNP and Placebo	Measured at hour 5
Inflammatory Markers	Comparing inflammatory markers in blood samples between SNP and Placebo	Measured at Baseline Visit (before the infusion)
Inflammatory Markers	Comparing inflammatory markers in blood samples between SNP and Placebo	Measured at week 2
Inflammatory Markers	Comparing inflammatory markers in blood samples between SNP and Placebo	Measured at week 4

Collaborators and Investigators

• Sponsor: Beth Israel Deaconess Medical Center
• Investigators: Principal Investigator: Paulo Lizano, MD, PhD, Beth Israel Deaconess Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): March 14, 2022
• Primary Completion (Actual): June 1, 2024
• Study Completion (Actual): July 1, 2024

Study Registration Dates

• First Submitted: July 23, 2021
• First Submitted That Met QC Criteria: July 23, 2021
• First Posted (Actual): August 2, 2021

Study Record Updates

• Last Update Posted (Actual): December 30, 2025
• Last Update Submitted That Met QC Criteria: December 9, 2025
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Schizophrenia Spectrum and Other Psychotic Disorders; Mental Disorders; Schizophrenia; Psychotic Disorders; Motor Activity; Movement; Musculoskeletal Physiological Phenomena; Musculoskeletal and Neural Physiological Phenomena; Inorganic Chemicals; Nitrogen Compounds; Anions; Ions; Electrolytes; Ferric Compounds; Iron Compounds; Ferricyanides; Cyanides; Hydrogen Cyanide; Nitroprusside; Exercise
• Other Study ID Numbers: ALK3831-A309

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No