Hypertension Drug Works for Schizophrenia

By Michael Smith, North American Correspondent, MedPage Today Published: May 09, 2013 Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner

Psychotic patients improved rapidly after a single infusion of sodium nitroprusside, researchers reported. In a small randomized trial, patients who got the antihypertensive agent saw most of their symptoms diminish within 4 hours, while those who got a matching placebo did not, according to Serdar Dursun, MD, PhD, of the University of Alberta in Edmonton, and colleagues. The improvements lasted up to 4 weeks without any apparent adverse effects, Dursun and colleagues reported online in JAMA Psychiatry. While the findings should be considered preliminary because of the size of the study -- just 20 patients -- the authors concluded the results "are exciting in terms of effectiveness of the drug." Sodium nitroprusside is a vasodilator used to treat severe hypertension, but there is pre-clinical evidence that it also modulates the activity of Nmethyl-D-aspartate (NMDA) glutamate receptors, Dursun and colleagues noted. Since blocking those receptors in animals leads to psychosis-like behavior, the researcher hypothesized that the drug might be beneficial in humans with schizophrenia. To test the idea, they enrolled 20 patients, in an acute phase of schizophrenia, who required inpatient care. The volunteers were 19 to 40 and were in the first 5 years since diagnosis. All were on stable antipsychotics at the time of the infusion. Ten participants got sodium nitroprusside at 0.5 micrograms per kilogram of body weight per minute for 4 hours -- the lowest recommended dose for humans. The remaining 10 patients got 5% glucose, also infused for 4 hours. During the infusions and for 4 weeks afterward, psychiatrists monitored schizophrenia symptoms using the 18-item Brief Psychiatric Rating Scale and the negative subscale of the Positive and Negative Syndrome Scale. They also measured safety and tolerability of the drug, both physiologically and psychologically. During the infusion, they found a beneficial effect on the brief rating scale that was apparent by the second hour and was significant at

P<0.001. The effect was seen in all patients getting the drug, but not in any placebo patient. A similar rapid effect, also significant at P<0.001, was observed on the positive-negative symptom scale. On both scales, the improvement persisted for at least 4 weeks, the researchers reported. Dursun and colleagues also reported that they found no significant difference between the groups on any physiological measurement -- including systolic and diastolic blood pressure, blood oxygen saturation level, and heart rate -- up to 240 minutes after the infusion. There were also no major psychiatric differences between groups, they reported. The findings are additional evidence that NMDA receptors are under-performing in schizophrenia, commented Joseph Coyle, MD, of Harvard Medical School. In an accompanying editorial, he noted that the results are consistent with other studies that involved the receptor. But, he concluded, the current study remains too small to justify changes in clinical practice. "Caution must be exercised until sufficiently powered clinical trials of nitroprusside are performed in patients with schizophrenia," Coyle wrote. Dursun and colleagues cautioned that participants were fairly early in their disease course. Future research, they argued, should test the drug in patients with long-term illness. They also noted that the study protocol allowed changes to supplemental medications (such as benzodiazepines and analgesics) 48 hours after the infusion and to antipsychotics after 7 days. For that reason, they cautioned, there is "uncertainty to the antipsychotic effects of sodium nitroprusside alone at later time points." Finally, they noted that follow-up in the study was short. The study had support from the Fundao de Amparo; Pesquisa do Estado de Paulo and CNPq in Brazil. The journal said the authors made no disclosures. The editorial author holds a patent on D-serine for the treatment of schizophrenia and related serious mental disorders.