Rapid Improvement of Acute Schizophrenia Symptoms After Intravenous Sodium Nitroprusside A Randomized, Double-blind, Placebo-Controlled Trial

JAMA Psychiatry (Impact Factor: 12.01). 05/2013; 70(7):1-9. DOI: 10.1001/jamapsychiatry.2013.1292
Source: PubMed


The treatment of schizophrenia remains a challenge, and the currently available antipsychotic drugs are slow acting and produce a number of adverse effects.Objective
To examine the effectiveness and safety of a single intravenous administration of sodium nitroprusside (0.5 μg/kg/min for 4 hours) on the positive, negative, anxiety, and depressive symptoms in patients with schizophrenia.Design
Single-center, randomized, double-blind, placebo-controlled trial performed from March 9, 2007, to March 12, 2009.Setting
University teaching hospital in São Paulo, Brazil.Participants
Twenty inpatients aged 19 to 40 years with a diagnosis of schizophrenia who were in the first 5 years of the disease who are taking antipsychotics.Intervention
Sodium nitroprusside administration.Main Outcome Measures
The 18-item Brief Psychiatric Rating Scale and the negative subscale of the Positive and Negative Syndrome Scale.Results
After the infusion of sodium nitroprusside, a rapid (within 4 hours) improvement of symptoms was observed. The placebo and experimental groups had significant differences in the 18-item Brief Psychiatric Rating Scale total score and subscale scores, which persisted for 4 weeks after infusion.Conclusions
The results clearly show a therapeutic effect of sodium nitroprusside. If this drug is approved for routine clinical use in patients with schizophrenia, this discovery will be an important advance in the pharmacologic treatment of this devastating disorder.Trial Registration Identifier: NCT01548612

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Available from: Paulo Belmonte-de-Abreu
    • "The adjunctive administration of sodium nitroprusside (SNP), an agent shown to have a rapid acting antipsychotic effect (Hallak et al. 2013), has also been evaluated in preclinical models, showing that SNP pretreatment may reduce ketamine-induced psychosis-like behavior in rats (Maia-de-Oliveira et al. 2015). The results of the study suggest that administering SNP one week before and again one day before ketamine treatment prevents psychotic behavior as no hyperactivity or stereotypes in the rates were observed. "
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    ABSTRACT: OBJECTIVES: Replicated evidence has demonstrated that ketamine exerts rapid-acting and potent antidepressant effects. Notwithstanding, its promise to mitigate depressive symptoms and suicidality in antidepressant-resistant populations, several limitations and safety concerns accompany ketamine including, but not limited to, the potential for abuse and psychotomimetic/dissociative experiences. The focus of the current narrative review is to synthesize available evidence of strategies that may mitigate and fully prevent treatment emergent psychotomimetic and dissociative effects associated with ketamine administration. METHODS: PubMed, Google Scholar and were searched for relevant articles. RESULTS: Potential avenues investigated to minimize psychotomimetic effects associated with ketamine administration include the following: 1) altering dosing and infusion rates; 2) route of administration; 3) enantiomer choice; 4) co-administration with mood stabilizers of antipsychotics; and 5) use of alternative NMDA modulating agents. Emerging evidence indicates that dissociative experiences can be significantly mitigated by using an intranasal route of administration, lower dosages, or use of alternative NMDA modulating agents, namely lanicemine (AZD6765) and GLYX-13. CONCLUSIONS: Currently, intranasal administration presents as the most promising strategy to mitigate dissociative and psychotomimetic effects; however, studies of strategies to mitigate the adverse events of ketamine are limited in number and quality and thus further investigation is still needed.
    No preview · Article · Jan 2016 · The World Journal of Biological Psychiatry
    • "The mechanisms of this effect have not been entirely understood. Instead, a recent clinical trial with the NO donor SNP showed improvement of symptoms in schizophrenic patients (Hallak et al. 2013). Therefore, the involvement of NO on DA system and on these diseases has not been completely elucidated. "
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    ABSTRACT: Previous research has shown that nitric oxide (NO) synthase inhibitors prevent rodents' sensorimotor gating impairments induced by dopamine releasing drugs, such as amphetamine (Amph) and methylphenidate. The mechanisms of this effect have not been entirely understood. In the present work, we investigated some possible mechanisms by which the NO donor, NOC-12 (3-ethyl-3-(ethylaminoethyl)-1-hydroxy-2-oxo-1-triazene), influence spontaneous and Amph-induced dopamine release, using rat mesencephalic primary cultured neurons preparations. Our results showed that NOC-12 increased dopamine release in a concentration-dependent manner and potentiated the Amph-induced one. Dopamine release induced by NOC-12 was disrupted by N-acetyl-L-cystein (NAC-a free radical scavenger) and MK-801, a NMDA (N-methyl-D-aspartate) non-competitive antagonist, and was concentration dependently affected by oxadiazolo[4,3]quinoxalin-1-one, an inhibitor of the soluble guanylate cyclase (sGC). In contrast, dopamine released by Amph was facilitated by NAC and by MK-801 and not affected by nifedipine (a L-type-Ca(+2) channel blocker), which enhanced NOC-12-induced dopamine release. The present work demonstrates that DA release induced by NOC-12 is partially dependent on sGC and on NMDA activation, and is modulated by L-type Ca(+2) channel and the antioxidant NAC. This mechanism differs from the Amph-induced one, which appears not to depend on L-type Ca(+2) channel and seems to be facilitated by NMDA channel blocking and by NAC. These results suggest that Amph and NOC-12 induce dopamine release through complementary pathways, which may explain the potentiation of Amph-induced dopamine release by NOC-12. These findings contribute to understand the involvement of NO in dopamine-related neuropsychiatric and neurodegenerative diseases.
    No preview · Article · Sep 2015 · Neurotoxicity Research
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    • "The NO donor SNP blocks in rats schizophrenia-like abnormalities induced by ketamine (Maia-de-Oliveira et al., 2015) and another NMDAR antagonist, phencyclidine (PCP) (Bujas- Bobanovic et al., 2000). Recent clinical studies reported significant antipsychotic action of a single dose of SNP in humans with schizophrenia (Hallak et al., 2013), an effect that was long-lasting over weeks comparable with the antidepressant effect of ketamine. These results suggest a role of nitrinergic pathways in the psychotomimetic effects of NMDAR antagonists and possibly in schizophrenia. "
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    ABSTRACT: Ketamine may represent an efficient alternative antidepressant with rapid therapeutic onset; however, the clinical use of ketamine is hampered by psychosis-like side-effects. Recent studies suggest that the nitric oxide (NO) donor sodium nitroprusside (SNP) prevents psychosis-like abnormalities triggered by ketamine or another NMDA receptor (NMDAR) antagonist, phencyclidine (PCP) in rats. SNP was shown to elicit antipsychotic effects also in humans. Considering the tight interrelation between NMDAR activation and neuronal NO synthesis, we evaluated the effect of pre-treatment with SNP on the antidepressant action of ketamine. We found that SNP (0.5-1mg/kg, i.p.) did not alter the antidepressant effect of ketamine (30mg/kg) in the Porsolt Forced Swim Test (FST) in mice. Additionally, SNP by itself produced no effect in the FST or in the openfield. This suggests indirectly a differential involvement of the nitrinergic system in the antidepressant vs. psychotomimetic effect of ketamine, although an influence of species-specific differences cannot be excluded in this interpretation. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.
    Full-text · Article · Jun 2015 · European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology
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