UMMS Affiliation

Department of Psychiatry; Implementation Science and Practice Advances Research Center; Department of Anesthesiology and Perioperative Medicine

Publication Date


Document Type



Anesthesia and Analgesia | Mental and Social Health | Mental Disorders | Psychiatry


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 mug/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 beta = -1.04; z = -0.59; P = .57), PANSS-positive (weighted beta = -0.62; z = -0.93; P = .35), or PANSS-negative (weighted beta = -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: identifier: NCT02164981.


schizophrenia, antipsychotic medications, adjunctive sodium nitroprusside, therapy

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© 2019 American Medical Association. Publisher PDF posted after 12 months as allowed by the publisher's author rights policy at

DOI of Published Version



JAMA Psychiatry. 2019 Jul 1;76(7):691-699. doi: 10.1001/jamapsychiatry.2019.0151. Link to article on publisher's site

Journal/Book/Conference Title

JAMA psychiatry

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Link to Article in PubMed

PubMed ID


Available for download on Wednesday, July 01, 2020