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

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.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Brown reported receiving research support from Janssen Pharmaceutica, Acadia Pharmaceuticals, and the Stanley Medical Research Institute. Dr Freudenreich reported serving on advisory boards or serving as a consultant to Alkermes, Neurocrine, Janssen, Novartis, and Roche; receiving research grants from Avanir, Otsuka, and Saladax; serving as a content developer for Global Medical Education; and receiving royalties from Wolters-Kluwer and UpToDate. Dr Fan reported receiving research support or honoraria from Alkermes, Neurocrine, Avanir, Allergen, Otsuka, Lundbeck, Boehringer Ingelheim, and Janssen. Dr Goff reported receiving research support from the National Institutes of Health, the Stanley Medical Research Institute, and Avanir Pharmaceuticals. Dr Petrides reported receiving research support from the National Institute of Mental Health, National Institute on Aging, and Janssen. Dr Kane reported serving as a consultant for or receiving honoraria from Alkermes, Eli Lilly, EnVivo Pharmaceuticals (Forum), Forest (Allergan), Genentech, Lundbeck, Intra-Cellular Therapies, Janssen Pharmaceutica, Johnson & Johnson, LB Pharmaceuticals, Merck, Minerva, Neurocrine, Otsuka, Pierre Fabre, Reviva, Roche, Sunovion, Takeda, and Teva; and receiving grant support from Otsuka, Lundbeck, and Janssen. Dr Kane reported serving on advisory boards for Alkermes, Intra-Cellular Therapies, Lundbeck, Neurocrine, Otsuka, Pierre Fabre, Takeda, and Teva; and being a shareholder in Vanguard Research Group and LB Pharmaceuticals. Dr Fava reported receiving research support from Alkermes, Johnson & Johnson, Axsome, Acadia Pharmaceuticals, Cerecor, Lundbeck, Neuralstem, Otsuka, Taisho, Marinus Pharmaceuticals, BioHaven, Takeda, Vistagen, Relmada Therapeutics, Stanley Medical Research Institute, National Institute of Drug Abuse, National Institute of Mental Health, and PCORI; having equity holdings in Compellis and PsyBrain; and holding patents for Sequential Parallel Comparison Design (licensed by Massachusetts General Hospital to Pharmaceutical Product Development, LLC), a patent application for a combination of ketamine plus scopolamine in major depressive disorder (licensed by Massachusetts General Hospital to Biohaven), and patents for pharmacogenomics of depression treatment with folate. Dr Perlis reported holding equity in Psy Therapeutics and Outermost Therapeutics and serving on advisory boards or providing consulting to Genomind, Psy Therapeutics, RIDVentures, and Takeda. No other disclosures were reported.

Figures

Figure 1.. CONSORT Flow Diagram

SNP indicates sodium nitroprusside; and SPCD, sequential parallel comparison design.

Figure 2.. Change in Positive and Negative Syndrome Scale (PANSS) Scores for Phases 1 and 2

A, Mean change scores for the PANSS total score. B, Mean change scores for the PANSS positive subscale. C, Mean change scores for the PANSS negative subscale. For phase 1, change scores are scores at day 14 minus scores at day 0; for phase 2, day 28 minus day 14. Error bars represent 1 SD. SNP indicates sodium nitroprusside.

Figure 3.. Mean Blood Pressure and Heart Rate per Treatment Group for Each Infusion

A, Mean systolic blood pressure for infusion 1. B, Mean systolic blood pressure for infusion 2. C, Mean diastolic blood pressure for infusion 1. D, Mean diastolic blood pressure for infusion 2. E, Mean heart rate for infusion 1. F, Mean heart rate for infusion 2. During phase 1 (ie, infusion 1), 18 patients received sodium nitroprusside (SNP) and 34 received placebo. During phase 2 (ie, infusion 2), 14 patients received SNP and 18 received placebo. Reference lines denote start and end of infusion.