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Adjunctive IV sodium nitroprusside not effective for treatment-resistant schizophrenia

Adding IV sodium nitroprusside did not improve psychotic symptoms or cognition in antipsychotic-treated patients with schizophrenia who had a history of treatment resistance, according to a randomized clinical trial.

Findings from a previous study indicated the efficacy of adjunctive IV sodium nitroprusside (SNP) in the treatment of patients with schizophrenia; however, a second study showed no benefit, Hannah E. Brown, MD, from the department of psychiatry, Boston Medical Center, and colleagues wrote in JAMA Psychiatry.

“Clarifying the potential therapeutic effect of SNP has both clinical and mechanistic importance: if efficacy could be confirmed, it might point the way to a new class of interventions, as with ketamine hydrochloride in major depressive disorder,” they wrote.

In their multicenter, randomized, double-blind acute treatment study, the researchers examined the efficacy and tolerability of IV sodium nitroprusside in treating the positive, negative and cognitive symptoms of schizophrenia.

SNP was infused at 0.5 g/kg/min for 4 hours in 52 adults with schizophrenia who took antipsychotic medication for at least 8 weeks and had at least one failed trial of an antipsychotic within the last year.

The trial included two, 2-week phases. Participants were randomized to a treatment sequence: SNP and SNP, placebo and SNP, or placebo and placebo. The double SNP group received SNP in both phases, but the phase 2 data were not included in the results. The placebo and SNP group received placebo in phase 1 and SNP in phase 2; data from phase 2 were included in analyses only when there was no response to placebo in phase 1. The double placebo group received placebo in both phases; data from phase 2 were included in analyses only when there was no response to placebo in phase 1.

There were no significant differences between the sodium nitroprusside and placebo groups at baseline, according to the findings. Brown and colleagues also observed no significant differences between the sodium nitroprusside and placebo groups for change in Positive and Negative Syndrome Scale (PANSS)-total (weighted beta = –1.04; P = .57), PANSS-positive (weighted beta = –0.62; P = .35) or PANSS-negative (weighted beta = –0.12; P = .85) scores from baseline.

In addition, they found no significant differences in cognition improvement scores between the groups (weighted = 1.11; P = .34). However, sodium nitroprusside was well-tolerated overall, according to the results. The researchers found no significant differences in safety or tolerability between groups, and there were no serious adverse events.

“As with any treatment, particular subgroups may respond differently; if further studies of [nitric oxide] donors are pursued, they might focus on a younger, nonsmoking population earlier in the course of illness, with alternate dosing and duration of drug delivery,” Brown and colleagues wrote.

This study — along with two others — failed to replicate the original finding, possibly because the original finding was based on a small patient sample, Shitij Kapur, PhD, from the University of Melbourne, Australia, and Marcus Munafò, PhD, from the University of Bristol, England, wrote in a related comment.

“Ultimately, studies should be large enough to give a sufficiently precise estimate, but not so large as to be wasteful,” they wrote. “However, calculation of sample size is not a perfect science and requires an estimation of the expected outcomes in the drug and placebo groups and an estimation of the expected variance. Getting these estimates right and realistic is at the heart of the matter.” – by Savannah Demko

Disclosures: Brown reports support from Acadia Pharmaceuticals, Janssen Pharmaceuticals, and the Stanley Medical Research Institute. Please see the study for all other authors’ relevant financial disclosures. Kapur reports coauthoring one of the previously published studies that failed to replicate the sodium nitroprusside effect.