Sodium Nitroprusside in Early Course Schizophrenia

• ClinicalTrials.gov Identifier: NCT04986072
• Recruitment Status: Recruiting
• First Posted: August 2, 2021
• Last Update Posted: April 14, 2022
• Sponsor: Beth Israel Deaconess Medical Center
• Information provided by (Responsible Party): Paulo Lizano, Beth Israel Deaconess Medical Center

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Schizophrenia; Schizoaffective Disorder	Drug: Sodium Nitroprusside; Drug: 5% Dextrose solution	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 32 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Proof of Mechanism Study Using a Retinal Biomarker to Predict Treatment Response With Intravenous Sodium Nitroprusside in Symptomatic Early Course Schizophrenia
• Actual Study Start Date: March 14, 2022
• Estimated Primary Completion Date: July 31, 2023
• Estimated Study Completion Date: August 31, 2023

Arms and Interventions

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.
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.

Outcome Measures

Primary Outcome Measures :

1. Positive and Negative Syndrome Scale (PANSS) [ Time Frame: Measured at hour 2 ]
   Comparing total, positive, and negative scores between SNP and Placebo
2. Positive and Negative Syndrome Scale (PANSS) [ Time Frame: Measured at hour 5 ]
   Comparing total, positive, and negative scores between SNP and Placebo
3. Positive and Negative Syndrome Scale (PANSS) [ Time Frame: Measured at week 1 ]
   Comparing total, positive, and negative scores between SNP and Placebo
4. Positive and Negative Syndrome Scale (PANSS) [ Time Frame: Measured at week 2 ]
   Comparing total, positive, and negative scores between SNP and Placebo
5. Positive and Negative Syndrome Scale (PANSS) [ Time Frame: Measured at week 4 ]
   Comparing total, positive, and negative scores between SNP and Placebo

Secondary Outcome Measures :

1. Brief Assessment of Cognition in Schizophrenia (BACS) [ Time Frame: Measured at hour 2 ]
   Comparing cognitive function score between SNP and Placebo
2. Brief Assessment of Cognition in Schizophrenia (BACS) [ Time Frame: Measured at week 1 ]
   Comparing cognitive function score between SNP and Placebo
3. Brief Assessment of Cognition in Schizophrenia (BACS) [ Time Frame: Measured at week 2 ]
   Comparing cognitive function score between SNP and Placebo
4. Brief Assessment of Cognition in Schizophrenia (BACS) [ Time Frame: Measured at week 4 ]
   Comparing cognitive function score between SNP and Placebo
5. SS-OCTA Retinal Imaging [ Time Frame: Measured at hour 2 ]
   Comparing retinal microvascular measures between SNP and Placebo
6. SS-OCTA Retinal Imaging [ Time Frame: Measured at hour 5 ]
   Comparing retinal microvascular measures between SNP and Placebo
7. Inflammatory Markers [ Time Frame: Measured at Baseline Visit (before the infusion) ]
   Comparing inflammatory markers in blood samples between SNP and Placebo
8. Inflammatory Markers [ Time Frame: Measured at week 2 ]
   Comparing inflammatory markers in blood samples between SNP and Placebo
9. Inflammatory Markers [ Time Frame: Measured at week 4 ]
   Comparing inflammatory markers in blood samples between SNP and Placebo

Eligibility Criteria

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

Criteria

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.

Contacts and Locations

Contacts

Contact: Yusuf Sendil, MD; 617 899 6668; yasendil@bidmc.harvard.edu

Locations

United States, Massachusetts

Beth Israel Deaconess Medical Center; Recruiting

Boston, Massachusetts, United States, 02215

Contact: Yusuf Sendil, MD 617-899-6668 yasendil@bidmc.harvard.edu

Contact: MD PhD

Principal Investigator: Paulo Lizano, MD PhD

Sponsors and Collaborators

Beth Israel Deaconess Medical Center

Investigators

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

More Information

• Responsible Party: Paulo Lizano, Assistant Professor, Beth Israel Deaconess Medical Center
• ClinicalTrials.gov Identifier: NCT04986072
• Other Study ID Numbers: ALK3831-A309
• First Posted: August 2, 2021
• Last Update Posted: April 14, 2022
• Last Verified: April 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• 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

Additional relevant MeSH terms:

Schizophrenia; Psychotic Disorders; Schizophrenia Spectrum and Other Psychotic Disorders; Mental Disorders; Nitroprusside; Antihypertensive Agents; Vasodilator Agents; Nitric Oxide Donors; Molecular Mechanisms of Pharmacological Action