A drug on the market for almost a century to treat severe high blood pressure produces rapid and long-lasting improvement of schizophrenia’s positive and negative symptoms.
Once in a while, research findings published in medical journals seem too good to be true.
This is the case for results from a small proof-of-concept study published May 8 in JAMA Psychiatry. Scientists reported that a single infusion of the drug sodium nitroprusside into schizophrenia subjects led to a rapid and dramatic decline in both positive and negative symptoms—and the effects lasted for four weeks.
In an accompanying editorial, Joseph Coyle, M.D., a professor of psychiatry at Harvard Medical School and editor in chief of JAMA Psychiatry, described the results as “remarkable.” Nonetheless, “the field is littered with small trials with robust outcomes that ultimately are not replicated,” he cautioned.
Serdar Dursan, M.D., Ph.D.: While researchers hypothesized that sodium nitroprusside would ameliorate schizophrenia symptoms,
The research was conducted by Canadian and Brazilian scientists with an interest in the same areas of research. The scientist leading the Canadian team was Serdar Dursun, M.D., Ph.D., a professor of psychiatry and neuroscience at the University of Alberta; the scientist leading the Brazilian team was Jaime Hallak, M.D., Ph.D., of the University of Sao Paulo.
Sodium nitroprusside has been in clinical use since 1929 for severe high blood pressure and is commercially available for intravenous administration. Dursun, Hallak, and their colleagues found in animal experiments that blocking NMDA glutamate receptors induced psychosis-like behavior, but that giving the animals sodium nitroprusside abolished the behavior. These findings prompted them to believe that sodium nitroprusside might improve symptoms in people with schizophrenia, and they decided to conduct a small study to test the hypothesis.
They conducted the study in a university teaching hospital in Sao Paulo. It included 20 inpatients aged 19 to 40 with a diagnosis of schizophrenia who were in the first five years of the illness and being treated with antipsychotics. Half of the subjects received an infusion of sodium nitroprusside, and half received an infusion of a placebo (a glucose solution). They were evaluated with the 18-item Brief Psychiatric Rating Scale and the negative subscale of the Positive and Negative Syndrome Scale before, during, and after treatment.
Most of the subjects who had received the sodium nitroprusside experienced a rapid—within hours—and dramatic improvement in both their positive and negative symptoms—an improvement that lasted for four weeks. Subjects who had received a placebo experienced no improvement.
“The results clearly show a therapeutic effect of sodium nitroprusside,” the scientists concluded.
Furthermore, the sodium nitroprusside infusion was found to be safe in those who received it. As the researchers explained, “The dose used in this study was the minimum dose required for sodium nitroprusside to lower blood pressure in hypertensive patients, and it is well established that in normotensive individuals, much higher doses of sodium nitroprusside are needed to lower blood pressure than for hypertensive patients.”
Dursun told Psychiatric News that he was surprised by these findings. “Based on the very impressive preclinical data…, we did hypothesize that sodium nitroprusside would improve schizophrenia symptoms….However, we did not predict that the improvement would be as fast as observed and so dramatic.”
As for the clinical implications of the findings, he said, “There is a need for a rapid-onset antipsychotic medication with minimal side effects to use in acute care and emergency settings. Therefore we can only hope that sodium nitroprusside may prove to address this gap in helping patients with schizophrenia.” Moreover, “We are very keen to develop different easy-to-use formulations of sodium nitroprusside, such as transdermal patches or nasal sprays…and to investigate the effectiveness of these formulations in schizophrenia.”
Actually “such a persistent effect after a single-dose treatment is not unprecedented,” Coyle noted in his editorial. “Recent research has demonstrated that a single dose of the NMDA receptor antagonist ketamine when given to patients with drug-resistant depression can provide a rapid improvement in mood that persists for a week or more" (Psychiatric News, September 17, 2010).
When Dursun was asked whether he sees a parallel between sodium nitroprusside’s rapid and dramatic action against schizophrenia and ketamine’s rapid and dramatic action against depression, he noted that “there may be some overlapping similarities….The precise mechanism of action of sodium nitroprusside in schizophrenia remains unclear, but it seems likely that at least one mechanism is through the involvement of nitric oxide in modulating NMDA glutamate receptors.”
Furthermore, there is “an increasingly compelling body of evidence from drug challenges, postmortem analyses, and gene-association studies that hypofunction of the NMDA receptor, a glutamate receptor subtype that mediates neural plasticity, is a core feature of schizophrenia,” Coyle pointed out. “NMDA receptor hypofunction appears to be particularly relevant to negative symptoms and cognitive impairment in schizophrenia.”
The research was funded by Brazil’s Fundacao de Amparo a Pesquisa do Estado de Sao Paulo. ■
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