In 2013, a small preliminary study suggested that sodium nitroprusside, generally an antihypertensive drug, could result in startlingly positive improvements in schizophrenia symptoms, within hours of a single infusion. Unfortunately, a new, more extensive study has failed to replicate this finding. It’s the third such study to show no effect.
The current study was led by Hannah E. Brown at Massachusetts General Hospital, Harvard Medical School, and Boston University. The primary investigators listed on clinicaltrials.gov were Maurizio Fava and Roy Perlis, both also at Massachusetts General Hospital.
The study included 60 participants; they were randomly assigned to three groups. One group received the drug, one group received the placebo, and one received the placebo and then the drug. This served as a placebo wash-out period, which meant that people who improved on placebo were removed from the analysis.
Theoretically, this should have made the study even more likely to detect an effect of the drug. However, the researchers found that there was no effect—no difference between any of the groups. Studies from 2016 and 2018 found similar results.
Shitij Kapur and Marcus Munafò are researchers at the University of Melbourne, Australia, and the University of Bristol, UK, respectively. They wrote an accompanying editorial, also in JAMA Psychiatry. In their editorial, they argue that (in light of these three failures to replicate) the only explanation for the positive findings of the 2013 trial is that a single trial with a small sample size can render almost any outcome possible. They suggest that we should re-evaluate the way small preliminary studies are reported, as they are too likely to find false positive effects.
The authors of the original 2013 study suggested that “This discovery will be an important advance in the pharmacologic treatment of this devastating disorder.” After three failed replications, however, it now appears unlikely to be such an advance.
Brown, H. E., Freudenreich, O., Fan, X., Heard, S. O., Goff, D., Petrides, G. . . . Perlis, R. H. (2019). Efficacy and tolerability of adjunctive intravenous sodium nitroprusside treatment for outpatients with schizophrenia: A randomized clinical trial. JAMA Psychiatry. Published online March 27, 2019. doi:10.1001/jamapsychiatry.2019.0151 (Link)