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


IMPORTANCE 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, Oct 02, 2015
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    • "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.
    Neurotoxicity Research 09/2015; DOI:10.1007/s12640-015-9562-8 · 3.54 Impact Factor
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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.
    European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology 06/2015; DOI:10.1016/j.euroneuro.2015.06.012 · 4.37 Impact Factor
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    • "The precise antipsychotic mechanism of action of SNP is still unclear. Perhaps its antipsychotic effects could start faster than the usual antipsychotic medications because of SNP's capacity to modulate the NMDA–NO–cGMP pathway (Hallak et al., 2013). If the effects of SNP on dopamine are confirmed by future and better designed studies, this may represent an exciting link between glutamate and dopamine, the two transmitters most widely investigated in schizophrenia (Coyle, 2012; Seeman, 2013), and yield important clues for the development of more effective antipsychotic drugs. "
    Schizophrenia Research 11/2014; 159(2-3). DOI:10.1016/j.schres.2014.08.020 · 3.92 Impact Factor
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