The Effects of Sodium Nitroprusside Treatment on Cognitive Deficits in Schizophrenia

Maia‐de‐Oliveira, João Paulo; Abrão, João; Évora, Paulo Roberto Barbosa; Zuardi, Antônio Waldo; Crippa, José Alexandre S; Belmonte-de-Abreu, Paulo; Baker, Glen B.; Dursun, Serdar; Hallak, Jaime Eduardo Cecílio

doi:10.1097/jcp.0000000000000258

Cited by 25 publications

(36 citation statements)

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“…In the present study, SNP neither prevented (Fig 4; 5.0 mg/kg; 3 h and 35 min prior to MK-801) nor rescued (Fig 3; 2.0 mg/kg; 5 min prior to MK-801) MK-801-induced impairments in the TUNL task. Our findings fail to replicate previous reports of reduced cognitive impairments in patients (Maia-de-Oliveira et al 2015a) and ketamine-treated rats (Trevlopoulou et al 2016) following SNP, suggesting that acute MK-801 administration in the TUNL task may not be an appropriate paradigm to study the effects SNP in schizophrenia.…”

Section: Snp Did Not Block Mk-801-induced Impairments But Improved Pacontrasting

confidence: 57%

“…The lack of a positive control has limited the assessment of predictive validity in rodent models of schizophrenia, impeding the translatable development and evaluation of treatments for these symptoms (Markou et al 2009). However, when SNP was administered as an adjunct treatment to patients with schizophrenia, it reduced working memory impairments on the n-back task (Maia-de-Oliveira et al 2015a). Previous rodent studies have mirrored these findings as SNP reduces ketamine-induced cognitive deficits (Trevlopoulou et al 2016).…”

Section: Snp Did Not Block Mk-801-induced Impairments But Improved Pamentioning

confidence: 59%

“…Recently, SNP has demonstrated promise as an adjunct treatment to reduce these symptoms, specifically reducing working memory impairments (Maia-de-Oliveira et al 2015a). In the current experiments, we examined the effects of SNP in (Adell et al 2012;Coyle 2012).…”

Section: Discussionmentioning

confidence: 99%

“…Recently, human clinical trials have reduce positive, negative and some cognitive symptoms in schizophrenia following the administration of SNP (Hallak et al 2013;Maia-de-Oliveira et al 2015a). Importantly, one of the assessed cognitive domains was working memory (Maia-de-Oliveira et al 2015a).…”

Section: Rationale and Hypothesesmentioning

confidence: 99%

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MK-801-induced impairments on the trial-unique, delayed nonmatching-to-location task in rats: effects of acute sodium nitroprusside

et al. 2016

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The cognitive symptoms observed in schizophrenia are highly prevalent and predictive of patient functional outcome but are not usually alleviated by conventional antipsychotics. In a recent pilot study, sodium nitroprusside (SNP), a nitric oxide donor, was identified as a promising adjunct treatment to reduce the working memory impairments experienced by schizophrenia patients.Adjunctive SNP has also been reported to decrease the positive and negative symptoms experienced by patients for weeks following a single administration. The mechanisms underlying these changes and the areas of cognition affected remain largely unknown.Therefore, it is of interest to examine the effects of SNP using a rodent model of schizophrenia that has demonstrated predictive validity. The aim of the present experiment was to explore the effects of SNP on the acute MK-801 rodent model of schizophrenia using a highly translatable task in order to establish its validity. Working memory and pattern separation were measured using the trial-unique, delayed nonmatching-to-location (TUNL) task in touchscreen-equipped operant conditioning chambers. Acute MK-801 administration 25 minutes prior to task initiation impaired both areas of cognition. When SNP and MK-801 were administered within 5 minutes of each other, no interaction was observed. Interestingly, SNP improved performance on trials with difficult to discriminate patterns (p=0.058). Previous rodent studies using the ketamine model of schizophrenia and the novel object preference task observed a preventative effect of SNP administration. When we administered SNP nearly 4 hours prior to MK-801, no cognitive improvements were observed. Our results suggest that SNP may have intrinsic cognitive enhancing properties but is not capable of reducing MK-801-induced working memory and pattern separation impairments in the TUNL task. This study failed to mirror the results of the human pilot study that observed improved working memory following SNP administration.iii Further, it did not replicate previous animal studies using ketamine. Ultimately, the findings suggest that the effects of MK-801 in the TUNL task may not hold the predictive validity needed for its use in the study of SNP. In order to advance the understanding of SNP, future studies should investigate other translatable paradigms to establish validity. iv ACKNOWLDGEMENTSFirst and foremost, I would like to thank my supervisor Dr. John Howland, for his guidance and encouragement over the past three years. He believed in my abilities before I had proven them to myself and pushed me to be the best scientist and student I could be. John has provided me with countless opportunities to grow as a researcher and selflessly helped me make decisions about my future. I would not be where I am today without him and will always be grateful to have had such an incredible mentor in my life.I would like to thank my committee members, Dr.

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Section: Snp Did Not Block Mk-801-induced Impairments But Improved Pacontrasting

confidence: 57%

Section: Snp Did Not Block Mk-801-induced Impairments But Improved Pamentioning

confidence: 59%

Section: Discussionmentioning

confidence: 99%

Section: Rationale and Hypothesesmentioning

confidence: 99%

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MK-801-induced impairments on the trial-unique, delayed nonmatching-to-location task in rats: effects of acute sodium nitroprusside

et al. 2016

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“…Hallak et al 6 and Maia-de-Oliveira et al 7,8 described rapid improvements in psychotic symptoms and cognitive measures after a single, acute infusion of SNP. Using the same design as Hallak et al 6 , Stone et al 9 failed to find the same improvements, explaining that the divergent findings could result from differences in the clinical characteristics of the two samples, mainly length of illness and symptom exacerbation.…”

Section: Introductionmentioning

confidence: 99%

Effects of sodium nitroprusside in the prevention of schizophrenia-like symptoms induced by ketamine – A translational double-blind study

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Maia‐de‐Oliveira

Kandratavicius

et al. 2017

Arch. Clin. Psychiatry (São Paulo)

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Background: Recent evidence has shown improvements in schizophrenia symptoms after the infusion of sodium nitroprusside (SNP), a nitric oxide (NO) donor. In the rat model of schizophrenia using ketamine injection, pretreatment with SNP seems to prevent behavioral changes associated with positive symptoms for up to one week. Objective: We investigated whether SNP would have preventative effects on psychogenic symptoms induced by ketamine in healthy subjects. Methods: Healthy subjects (N = 38) were assigned to distinct groups that received SNP in different doses (0.15, 0.25, and 0.5 mcg/kg/min). First, participants received an infusion of SNP or placebo over 75 minutes. After 10 minutes, they were injected for 1 minute with a bolus of 0.26 mg/kg of ketamine and a maintenance dose was started 5 minutes later, with 0.25 mg/kg/h of ketamine for 50 minutes. Results: Ketamine-induced psychopathological alterations induced were reduced by SNP, as assessed with the Brief Psychological Rating Scale. Scores in the objective subscale of the Clinician-Administered Dissociative States Scale were also lower in SNP sessions compared to placebo. SNP had protective effects against deterioration in facial emotion and identity recognition tasks induced by ketamine. Discussion: Our findings support the view that SNP has preventative properties against psychotic manifestations.

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Efficacy and Tolerability of Adjunctive Intravenous Sodium Nitroprusside Treatment for Outpatients With Schizophrenia

et al. 2019

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IMPORTANCE Antipsychotic medications for the treatment of schizophrenia have limitations, and new treatments are needed. A prior pilot investigation suggested that adjunctive sodium nitroprusside (SNP) administered intravenously had rapid efficacy in the treatment of patients with schizophrenia.OBJECTIVE To determine the efficacy and tolerability of intravenous SNP infused at a rate of 0.5 μg/kg/min for 4 hours in patients with schizophrenia with some degree of treatment resistance.DESIGN, SETTING, AND PARTICIPANTS Multicenter, randomized, double-blind acute treatment study using a sequential parallel comparison design conducted in two 2-week phases at 4 academic medical centers beginning May 20, 2015, and ending March 31, 2017. Participants were adults 18 to 65 years of age with a diagnosis of schizophrenia as confirmed by the Structured Clinical Interview for DSM-IV, taking antipsychotic medication for at least 8 weeks, and had at least 1 failed trial of an antipsychotic medication within the past year. A total of 90 participants consented, 60 participants enrolled, and 52 participants were included in the analyses. A modified intent-to-treat analysis was used.INTERVENTIONS Participants were randomized in a 1:1:1 ratio to 1 of 3 treatment sequences: SNP and SNP, placebo and SNP, and placebo and placebo. The SNP and SNP group received SNP in phase 1 and SNP in phase 2 for the purpose of blinding, but the data from phase 2 were not included in the results. The placebo and SNP group received placebo in phase 1 and SNP in phase 2. If there was no response to placebo in phase 1, data from phase 2 were included in the analyses. The placebo and placebo group received placebo in both phases; if there was no response to placebo in phase 1, data from phase 2 were included in the analyses. MAIN OUTCOMES AND MEASURES Effectiveness of SNP compared with placebo in improvingPositive and Negative Syndrome Scale (PANSS) total, positive, and negative scores across each 2-week phase.RESULTS Fifty-two participants (12 women and 40 men) were included in the study. In the SNP and SNP group, the mean (SD) age was 47.1 (10.5) years. In the placebo and SNP group, the mean (SD) age was 45.9 (12.3) years. In the placebo and placebo group, the mean (SD) age was 40.4 (11.0) years. There were no significant differences between the SNP and placebo groups at baseline or in change from baseline for PANSS-total (weighted β = -1.04; z = -0.59; P = .57), PANSS-positive (weighted β = -0.62; z = -0.93; P = .35), or PANSS-negative (weighted β = -0.12; z = -0.19; P = .85) scores. No significant differences in safety or tolerability measures were identified. CONCLUSIONS AND RELEVANCEAlthough intravenous SNP is well tolerated, it was not an efficacious adjunctive treatment of positive or negative symptoms of psychosis among outpatients with schizophrenia with prior history of treatment resistance.

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The Effects of Sodium Nitroprusside Treatment on Cognitive Deficits in Schizophrenia

Cited by 25 publications

References 12 publications

MK-801-induced impairments on the trial-unique, delayed nonmatching-to-location task in rats: effects of acute sodium nitroprusside

MK-801-induced impairments on the trial-unique, delayed nonmatching-to-location task in rats: effects of acute sodium nitroprusside

Effects of sodium nitroprusside in the prevention of schizophrenia-like symptoms induced by ketamine – A translational double-blind study

Efficacy and Tolerability of Adjunctive Intravenous Sodium Nitroprusside Treatment for Outpatients With Schizophrenia

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