Schizophrenia Research Forum - A Catalyst for Creative Thinking

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