Cognitive effects of adjunctive <i>N</i>-acetyl cysteine in psychosis

Rapado-Castro, Marta; Dodd, Seetal; Bush, Ashley I.; Malhi, Gin S; Skvarc, David; On, Zhi Xiang; Berk, Michael; Dean, Olivia

doi:10.1017/s0033291716002932

Cited by 86 publications

(58 citation statements)

References 94 publications

(151 reference statements)

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“…The import of cystine through Sxc produces glutathione as a precursor, and exported glutamate plays important roles in extra‐synaptic transmission . Several clinical studies show that NAC ameliorates cognitive dysfunctions in patients with early stage Alzheimer's disease, severe schizophrenia, and bipolar disorder . Preclinical studies also demonstrate that behavioral deficits in rat phencyclidine models are addressed by NAC treatments .…”

Section: Discussionmentioning

confidence: 99%

Memantine protects thalamocortical hyper‐glutamatergic transmission induced by NMDA receptor antagonism via activation of system xc⁻

Okada

Fukuyama

Kawano

et al. 2019

Pharmacology Res & Perspec

119

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Deficiencies in N‐methyl‐d‐aspartate (NMDA)/glutamate receptor (NMDAR) signaling have been considered central to the cognitive impairments of schizophrenia; however, an NMDAR antagonist memantine (MEM) improves cognitive impairments of Alzheimer's disease and schizophrenia. These mechanisms of paradoxical clinical effects of NMDAR antagonists remain unclear. To explore the mechanisms by which MK801 and MEM affect thalamocortical transmission, we determined interactions between local administrations of MK801, MEM, system xc− (Sxc), and metabotropic glutamate receptors (mGluRs) on extracellular glutamate and GABA levels in the mediodorsal thalamic nucleus (MDTN) and medial prefrontal cortex (mPFC) using dual‐probe microdialysis with ultra‐high‐pressure liquid chromatography. Effects of MK801 and MEM on Sxc activity were also determined using primary cultured astrocytes. Sxc activity was enhanced by MEM, but was unaffected by MK801. MK801 enhanced thalamocortical glutamatergic transmission by GABAergic disinhibition in the MDTN. In the MDTN and the mPFC, MEM weakly increased glutamate release by activating Sxc, whereas MEM inhibited thalamocortical glutamatergic transmission. Paradoxical effects of MEM were induced following secondary activation of inhibitory II‐mGluR and III‐mGluR by exporting glutamate from astroglial Sxc. The present results suggest that the effects of therapeutically relevant concentrations of MEM on thalamocortical glutamatergic transmission are predominantly caused by activation of Sxc rather than inhibition of NMDAR. These demonstrations suggest that the combination between reduced NMDAR and activated Sxc contribute to the neuroprotective effects of MEM. Furthermore, activation of Sxc may compensate for the cognitive impairments that are induced by hyperactivation of thalamocortical glutamatergic transmission following activation of Sxc/II‐mGluR in the MDTN and Sxc/II‐mGluR/III‐mGluR in the mPFC.

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Section: Discussionmentioning

confidence: 99%

Memantine protects thalamocortical hyper‐glutamatergic transmission induced by NMDA receptor antagonism via activation of system xc⁻

Okada

Fukuyama

Kawano

et al. 2019

Pharmacology Res & Perspec

119

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“…Because of its anti-oxidative and anti-inflammatory properties NAC has been successfully applied to different models of schizophrenia (Lutgen et al, 2013; Cabungcal et al, 2014). In a small number of studies NAC has been used as an add-on treatment in schizophrenic patients where it improved negative symptoms, working memory and global functioning (Berk et al, 2008; Lavoie et al, 2008; Farokhnia et al, 2013; Rapado-Castro et al, 2017). The protracted progression to psychosis represents both a window of vulnerability and opportunity for therapeutic intervention (Do et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Antioxidant Treatment with N-acetyl Cysteine Prevents the Development of Cognitive and Social Behavioral Deficits that Result from Perinatal Ketamine Treatment

Phensy

Duzdabanian

Brewer

et al. 2017

Front. Behav. Neurosci.

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Alterations of the normal redox state can be found in all stages of schizophrenia, suggesting a key role for oxidative stress in the etiology and maintenance of the disease. Pharmacological blockade of N-methyl-D-aspartic acid (NMDA) receptors can disrupt natural antioxidant defense systems and induce schizophrenia-like behaviors in animals and healthy human subjects. Perinatal administration of the NMDA receptor (NMDAR) antagonist ketamine produces persistent behavioral deficits in adult mice which mimic a range of positive, negative, and cognitive symptoms that characterize schizophrenia. Here we tested whether antioxidant treatment with the glutathione (GSH) precursor N-acetyl-cysteine (NAC) can prevent the development of these behavioral deficits. On postnatal days (PND) 7, 9 and 11, we treated mice with subanesthetic doses (30 mg/kg) of ketamine or saline. Two groups (either ketamine or saline treated) also received NAC throughout development. In adult animals (PND 70–120) we then assessed behavioral alterations in a battery of cognitive and psychomotor tasks. Ketamine-treated animals showed deficits in a task of cognitive flexibility, abnormal patterns of spontaneous alternation, deficits in novel-object recognition, as well as social interaction. Developmental ketamine treatment also induced behavioral stereotypy in response to an acute amphetamine challenge, and it impaired sensorimotor gating, measured as reduced prepulse inhibition (PPI) of the startle response. All of these behavioral abnormalities were either prevented or strongly ameliorated by NAC co-treatment. These results suggest that oxidative stress is a major factor for the development of the ketamine-induced behavioral dysfunctions, and that restoring oxidative balance during the prodromal stage of schizophrenia might be able to ameliorate the development of several major symptoms of the disease.

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“…Further analysis of the literature suggests NAC could have a positive impact on human cognition, though further research is required (Skvarc et al, ). A preliminary study of patients with psychosis (n = 58) found an association between NAC treatment and improved working memory after 24 weeks (Rapado‐Castro et al, ).…”

Section: Resultsmentioning

confidence: 99%

“…Lithium has received more clinical assessment of its neuroprotective capacity than any other agent, most notably in bipolar disorder. Crosssectional studies of bipolar patients have associated lithium treatment with: (a) attenuation of cortical grey matter loss and (b) maintained white matter integrity (Table 1) (Giakoumatos et al, 2015;Gildengers et al, 2015;Hajek et al, 2012Hajek et al, , 2014Hartberg et al, 2015;Pfennig et al, 2014;Poletti, Locatelli, Radaelli, Colombo, & Benedetti, 2014;Simonetti et al, 2016;van Erp et al, 2012;Zung et al, 2016), though few have correlated lithium's structural benefits with a similar improvement in brain function.…”

Section: Lithiummentioning

confidence: 99%

“…In these studies, lithium treatment was associated with ameliorated bipolar disorderassociated cortical atrophy, restoring the volume of the hippocampus and other affected regions to the level of healthy controls. Furthermore, chronicity of lithium treatment is positively associated with the maintenance of cortical thickness (Giakoumatos et al, 2015;Hajek et al, 2014;Hartberg et al, 2015;Poletti et al, 2014;Simonetti et al, 2016;van Erp et al, 2012;Zung et al, 2016). This occurs without global increase in cortical thickness, suggesting lithium's neuroprotective qualities may be targeted at disease affected areas only.…”

Section: Lithiummentioning

confidence: 99%

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Putative neuroprotective pharmacotherapies to target the staged progression of mental illness

Robertson

Coronado

Sethi

et al. 2019

Early Intervention Psych

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Aim: Neuropsychiatric disorders including depression, bipolar and schizophrenia frequently exhibit a neuroprogressive course from prodrome to chronicity. There are a range of agents exhibiting capacity to attenuate biological mechanisms associated with neuroprogression. This review will update the evidence for putative neuroprotective agents including clinical efficacy, mechanisms of action and limitations in current assessment tools, and identify novel agents with neuroprotective potential.Method: Data for this review were sourced from online databases PUBMED, Embase and Web of Science. Only data published since 2012 were included in this review, no data were excluded based on language or publication origin.Results: Each of the agents reviewed inhibit one or multiple pathways of neuroprogression including: inflammatory gene expression and cytokine release, oxidative and nitrosative stress, mitochondrial dysfunction, neurotrophin dysregulation and apoptotic signalling. Some demonstrate clinical efficacy in preventing neural damage or loss, relapse or cognitive/functional decline. Agents include: the psychotropic medications lithium, second generation antipsychotics and antidepressants; other pharmacological agents such as minocycline, aspirin, cyclooxygenase-2 inhibitors, statins, ketamine and alpha-2-delta ligands; and others such as erythropoietin, oestrogen, leptin, N-acetylcysteine, curcumin, melatonin and ebselen.Conclusions: Signals of evidence of clinical neuroprotection are evident for a number of candidate agents. Adjunctive use of multiple agents may present a viable avenue to clinical realization of neuroprotection. Definitive prospective studies of neuroprotection with multimodal assessment tools are required.

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Cognitive effects of adjunctive N-acetyl cysteine in psychosis

Cited by 86 publications

References 94 publications

Memantine protects thalamocortical hyper‐glutamatergic transmission induced by NMDA receptor antagonism via activation of system xc⁻

Memantine protects thalamocortical hyper‐glutamatergic transmission induced by NMDA receptor antagonism via activation of system xc⁻

Antioxidant Treatment with N-acetyl Cysteine Prevents the Development of Cognitive and Social Behavioral Deficits that Result from Perinatal Ketamine Treatment

Putative neuroprotective pharmacotherapies to target the staged progression of mental illness

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Cognitive effects of adjunctive N-acetyl cysteine in psychosis

Cited by 86 publications

References 94 publications

Memantine protects thalamocortical hyper‐glutamatergic transmission induced by NMDA receptor antagonism via activation of system xc−

Memantine protects thalamocortical hyper‐glutamatergic transmission induced by NMDA receptor antagonism via activation of system xc−

Antioxidant Treatment with N-acetyl Cysteine Prevents the Development of Cognitive and Social Behavioral Deficits that Result from Perinatal Ketamine Treatment

Putative neuroprotective pharmacotherapies to target the staged progression of mental illness

Contact Info

Product

Resources

About

Memantine protects thalamocortical hyper‐glutamatergic transmission induced by NMDA receptor antagonism via activation of system xc⁻

Memantine protects thalamocortical hyper‐glutamatergic transmission induced by NMDA receptor antagonism via activation of system xc⁻