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Sodium Nitroprusside Rapidly Quells Schizophrenia Symptoms

10 May 2013. A shot in the arm may bring some rapid, not to mention long-lasting, relief to people with schizophrenia, according to a small study published May 8 in JAMA Psychiatry. A team of researchers, led by Serdar Dursun of the University of Alberta, Edmonton, Canada, conducted a randomized, double-blind, placebo-controlled trial of sodium nitroprusside, a vasodilator used to combat high blood pressure. They found that a low dose of the drug delivered intravenously reduced positive and negative symptoms of psychosis, as well as other psychiatric symptoms. These improvements emerged quickly—some as early as two hours after the infusion began—and persisted for at least four weeks afterwards.

The study suggests a new, and sorely needed, avenue for schizophrenia treatment. Sodium nitroprusside raises levels of nitric oxide (NO), a gaseous signaling molecule within cells. Though NO-related irregularities have been found in schizophrenia (Bernstein et al., 2011), the molecule is also associated with the disorder by way of the N-methyl-D-aspartate (NMDA) receptor. Normally, NMDA receptor activation triggers a chain of events that includes NO production. Because NMDA receptors seem underactive in schizophrenia (see SRF Webinar), the production of NO by sodium nitroprusside might make up for a shortfall resulting from sluggish NMDA receptor action upstream.

Consistent with this idea, a previous study found that sodium nitroprusside abolished behavioral and brain changes in rats given the NMDA receptor blocker phencyclidine (PCP) to model psychosis (Bujas-Bobanovic et al., 2000). The mechanism of action in this study, however, is far from clear, and the authors advise caution in interpreting findings from their small study, as does Joseph Coyle of Harvard University, Boston, Massachusetts, in an accompanying editorial. “It is true that the field is littered with small trials with robust outcomes that ultimately are not replicated,” Coyle writes.

A new vein for treatment?
First author Jaime Hallak and colleagues studied 20 people with schizophrenia in Brazil who had come to the hospital because of a new bout of psychosis. Ten were randomly assigned to the sodium nitroprusside group, and 10 to the placebo group, which received an intravenous glucose solution. The two groups did not differ significantly in their demographics or clinical features of their illness (e.g., length of illness and number of hospitalizations), and everyone was taking antipsychotic medication. The infusion lasted four hours, and the study participants stayed in the hospital for four weeks.

At two hours after the infusion began, symptom scores in the sodium nitroprusside group improved. Using the Brief Psychiatric Rating Scale (BPRS), the researchers measured a 10-point reduction in the nitroprusside group’s scores relative to the stable scores of the placebo group at this timepoint; this difference remained after the infusion was finished, and lasted up to four weeks. Each person in the sodium nitroprusside group showed some improvement relative to baseline, whereas the placebo recipients did not. Looking at the BPRS scores from subcategories of related symptoms (thought disorder, anxiety-depression, withdrawal-retardation, activation), the researchers found largely similar patterns of improvement during and after sodium nitroprusside infusion.

Similar improvements emerged when researchers assessed symptoms with the negative subscale of the Positive and Negative Syndrome Scale (PANSS). By 12 hours post-infusion, the sodium nitroprusside group score had improved by about 10 points relative to the placebo group, and this lasted for up to four weeks.

The fine print
The researchers did not find any adverse effects of sodium nitroprusside, and various physiological measures like blood pressure and heart rate did not differ between the two groups. Although this might seem odd for a vasodilator, it is consistent with the low dose of sodium nitroprusside used. It also suggests that a mere increase in blood flow to the brain does not explain the improvements.

The treatment was not a panacea, however. Seven days after the infusions, patients were allowed to change their antipsychotic medication, if needed. Seven people in the sodium nitroprusside group made changes, compared to 10 in the placebo group. Still, this suggests that symptoms were not satisfactorily reduced after sodium nitroprusside infusion. This switching also clouds the interpretation of any improvements found after seven days. In fact, patients were allowed to change their supplemental medications (e.g., benzodiazepines and analgesics) already 48 hours after the infusion. Overall symptom scores were fairly stable post-infusion, but these medication changes make it hard to attribute improvements to sodium nitroprusside alone.

Future studies will have to confirm these findings and explore whether these improvements translate into gains in the real world. Still, the study offers a rare proof of concept for a different approach to treating schizophrenia, and suggests that, like the rapid, depression-alleviating effect of a ketamine injection (Zarate et al., 2006), schizophrenia could someday have its own single-dose treatment of acute psychosis.—Michele Solis.

Hallak JE, Maia-de-Oliveira JP, Abrao J, Evora PR, Zuardi AW, Crippa JA, Belmonte-de-Abreu P, Baker GB, Dursun SM. Rapid Improvement of Acute Schizophrenia Symptoms After Intravenous Sodium Nitroprusside: A Randomized, Double-blind, Placebo-Controlled Trial. JAMA Psychiatry. 2013 Jul 1; 70(7):668-76. Abstract

Coyle JT. Nitric oxide and symptom reduction in schizophrenia. JAMA Psychiatry . 2013 Jul 1 ; 70(7):664-5. Abstract

Comments on News and Primary Papers
Comment by:  Philip Seeman (Disclosure)
Submitted 15 May 2013
Posted 15 May 2013

Hopefully, this apparent antipsychotic action of nitroprusside can be replicated. In the meantime, it should be noted that their background work on animals found that nitroprusside inhibited the action of phencyclidine, thought to act on NMDA receptors. Phencyclidine, however, has a higher affinity for the dopamine D2 receptor (with dissociation constant of 4 nM at the D2High receptor) compared to the ionotropic glutamate receptor (with dissociation constant of between 100 nM and 2,000 nM) (Seeman and Guan, 2008).

More importantly, Giannini et al. (1984, 1984-1985) showed that phencyclidine was selectively blocked in emergency room subjects by haloperidol, which has selective D2 blocking action but no action on NMDA transmission. Therefore, should nitroprusside and related drugs (amyl nitrate, nitroglycerin) have antipsychotic action, the potencies of these drugs on dopamine transmission will need to be examined.


Giannini AJ, Eighan MS, Loiselle RH, Giannini MC. 1984. Comparison of haloperidol and chlorpromazine in the treatment of phencyclidine psychosis. J Clin Pharmacol 24:202-204. Abstract

Giannini AJ, Nageotte C, Loiselle RH, Malone DA, Price WA. 1984-85. Comparison of chlorpromazine, haloperidol and pimozide in the treatment of phencyclidine psychosis: DA-2 receptor specificity. Clin Tox 22(6):573-579. Abstract

Seeman P, Guan H-C. Phencyclidine and glutamate agonist LY379268 stimulate dopamine D2High receptors: D2 basis for schizophrenia. Synapse 62: 819-828 (2008). Abstract

View all comments by Philip SeemanComment by:  Leslie Citrome
Submitted 10 June 2013
Posted 10 June 2013

The authors report on a double-blind, randomized, placebo-controlled study of 20 persons with schizophrenia early on in their disease course. After a single infusion of sodium nitroprusside, a rapid improvement of symptoms was observed, with evidence suggesting a persistence of effect for four weeks after drug administration. This treatment was adjunctive to antipsychotics, mostly dosed in the low range, but there were subjects receiving relatively high doses, suggesting they were not easy to treat. Patients on clozapine were excluded. The use of lithium, antidepressants, or anticonvulsant medications was not described, nor was the use of PRN medication for sleep, anxiety, or agitation.

The authors do acknowledge that further studies are required. The accompanying editorial by Dr. Coyle notes "the field is littered with small trials with robust outcomes that ultimately are not replicated." In addition to supporting a claim for efficacy, larger trials are required to establish safety.

Although the use of intravenous agents to quell the symptoms of schizophrenia is not a new idea (recall the experiments with the peptide secretin), their use in early-episode schizophrenia is intriguing, as we usually reserve more heroic interventions for those who have been treatment resistant. Mainstream use of parenteral administration of medications can ultimately de-stigmatize these types of therapeutic interventions, opening the door to novel approaches for an illness that begs for more effective treatments.

View all comments by Leslie Citrome