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Original Investigation
March 27, 2019

Efficacy and Tolerability of Adjunctive Intravenous Sodium Nitroprusside Treatment for Outpatients With Schizophrenia: A Randomized Clinical Trial

Author Affiliations
  • 1Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston
  • 2Department of Psychiatry, Boston Medical Center, Boston University School of Medicine, Boston, Massachusetts
  • 3Department of Psychiatry, UMass Memorial Health Care and UMass Medical School, Worcester, Massachusetts
  • 4Department of Anesthesiology and Perioperative Medicine, UMass Memorial Health Care and UMass Medical School, Worcester, Massachusetts
  • 5Department of Psychiatry, NYU Langone Medical Center, New York, New York
  • 6Department of Psychiatry, The Zucker Hillside Hospital, Glen Oaks, New York
  • 7Center for Psychiatric Neuroscience, Feinstein Institute for Medical Research, Manhasset, New York
  • 8Department of Psychiatry, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York
  • 9Department of Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York
JAMA Psychiatry. 2019;76(7):691-699. doi:10.1001/jamapsychiatry.2019.0151
Key Points

Question  Is adjunctive intravenous sodium nitroprusside an efficacious and safe treatment for individuals with schizophrenia who have some degree of treatment resistance?

Findings  In this multicenter, randomized double-blind clinical trial of 52 adults with chronic schizophrenia treated with antipsychotic medication, no improvement was seen in positive, negative, or cognitive symptoms after a 4-hour sodium nitroprusside infusion at 0.5 μg/kg/min; furthermore, there were no differences in response when stratified by clozapine treatment status. Overall, the treatment was well tolerated.

Meaning  Results of this well-powered clinical trial suggest that adding intravenous sodium nitroprusside infused at 0.5 μg/kg/min is not an efficacious treatment for individuals with schizophrenia with some history of treatment resistance.

Abstract

Importance  Antipsychotic medications for the treatment of schizophrenia have limitations, and new treatments are needed. A prior pilot investigation suggested that adjunctive sodium nitroprusside (SNP) administered intravenously had rapid efficacy in the treatment of patients with schizophrenia.

Objective  To determine the efficacy and tolerability of intravenous SNP infused at a rate of 0.5 μg/kg/min for 4 hours in patients with schizophrenia with some degree of treatment resistance.

Design, Setting, and Participants  Multicenter, randomized, double-blind acute treatment study using a sequential parallel comparison design conducted in two 2-week phases at 4 academic medical centers beginning May 20, 2015, and ending March 31, 2017. Participants were adults 18 to 65 years of age with a diagnosis of schizophrenia as confirmed by the Structured Clinical Interview for DSM-IV, taking antipsychotic medication for at least 8 weeks, and had at least 1 failed trial of an antipsychotic medication within the past year. A total of 90 participants consented, 60 participants enrolled, and 52 participants were included in the analyses. A modified intent-to-treat analysis was used.

Interventions  Participants were randomized in a 1:1:1 ratio to 1 of 3 treatment sequences: SNP and SNP, placebo and SNP, and placebo and placebo. The SNP and SNP group received SNP in phase 1 and SNP in phase 2 for the purpose of blinding, but the data from phase 2 were not included in the results. The placebo and SNP group received placebo in phase 1 and SNP in phase 2. If there was no response to placebo in phase 1, data from phase 2 were included in the analyses. The placebo and placebo group received placebo in both phases; if there was no response to placebo in phase 1, data from phase 2 were included in the analyses.

Main Outcomes and Measures  Effectiveness of SNP compared with placebo in improving Positive and Negative Syndrome Scale (PANSS) total, positive, and negative scores across each 2-week phase.

Results  Fifty-two participants (12 women and 40 men) were included in the study. In the SNP and SNP group, the mean (SD) age was 47.1 (10.5) years. In the placebo and SNP group, the mean (SD) age was 45.9 (12.3) years. In the placebo and placebo group, the mean (SD) age was 40.4 (11.0) years. There were no significant differences between the SNP and placebo groups at baseline or in change from baseline for PANSS-total (weighted β = –1.04; z = –0.59; P = .57), PANSS-positive (weighted β = –0.62; z = –0.93; P = .35), or PANSS-negative (weighted β = –0.12; z = –0.19; P = .85) scores. No significant differences in safety or tolerability measures were identified.

Conclusions and Relevance  Although intravenous SNP is well tolerated, it was not an efficacious adjunctive treatment of positive or negative symptoms of psychosis among outpatients with schizophrenia with prior history of treatment resistance.

Trial Registration  ClinicalTrials.gov identifier: NCT02164981

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