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
Comments on News and Primary Papers
Comment by: Philip Seeman
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