In this issue of the journal, Hallak et al1 report results from a placebo-controlled clinical trial showing that infusion of sodium nitroprusside causes a rapid and persistent reduction of symptoms in patients with schizophrenia who have been symptomatically stabilized with antipsychotic medications. The peer reviewers of the manuscript concurred that the study pointed to a potentially new avenue for pharmacologic intervention in schizophrenia, although they recognized that the small number of patients studied was a serious limitation. It is true that the field is littered with small trials with robust outcomes that ultimately are not replicated. However, the rationale for the study was tethered to an increasingly compelling body of evidence from drug challenges, postmortem analysis, and gene association studies that hypofunction of the N-methyl-d-aspartate (NMDA) receptor, a glutamate receptor subtype that mediates neural plasticity, is a core feature of schizophrenia.2 In particular, NMDA receptor hypofunction appears to be particularly relevant to negative symptoms and cognitive impairments in schizophrenia.
Coyle JT. Nitric Oxide and Symptom Reduction in Schizophrenia. JAMA Psychiatry. 2013;70(7):664-665. doi:10.1001/jamapsychiatry.2013.210