Reviewing the ketamine model for schizophrenia

Frohlich, Joel; Horn, John D. Van

doi:10.1177/0269881113512909

Cited by 266 publications

(184 citation statements)

References 206 publications

(311 reference statements)

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“…Taking advantage of this important validation, preclinical studies often employ a short-term disruption in NMDA neurotransmission to mimic a psychosis-like state (Adell et al, 2012;Frohlich and Van Horn, 2014;Gunduz-Bruce, 2009). Several groups have used this approach to understand the role of NMDA receptors in the 40 Hz ASSR (Sivarao et al, 2013;Sullivan et al, 2015;Vohs et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

40 Hz Auditory Steady-State Response Is a Pharmacodynamic Biomarker for Cortical NMDA Receptors

Sivarao

Chen

Senapati

et al. 2016

Neuropsychopharmacol

108

106

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Schizophrenia patients exhibit dysfunctional gamma oscillations in response to simple auditory stimuli or more complex cognitive tasks, a phenomenon explained by reduced NMDA transmission within inhibitory/excitatory cortical networks. Indeed, a simple steady-state auditory click stimulation paradigm at gamma frequency (~40 Hz) has been reproducibly shown to reduce entrainment as measured by electroencephalography (EEG) in patients. However, some investigators have reported increased phase locking factor (PLF) and power in response to 40 Hz auditory stimulus in patients. Interestingly, preclinical literature also reflects this contradiction. We investigated whether a graded deficiency in NMDA transmission can account for such disparate findings by administering subanesthetic ketamine (1-30 mg/kg, i.v.) or vehicle to conscious rats (n = 12) and testing their EEG entrainment to 40 Hz click stimuli at various time points (~7-62 min after treatment). In separate cohorts, we examined in vivo NMDA channel occupancy and tissue exposure to contextualize ketamine effects. We report a robust inverse relationship between PLF and NMDA occupancy 7 min after dosing. Moreover, ketamine could produce inhibition or disinhibition of the 40 Hz response in a temporally dynamic manner. These results provide for the first time empirical data to understand how cortical NMDA transmission deficit may lead to opposite modulation of the auditory steady-state response (ASSR). Importantly, our findings posit that 40 Hz ASSR is a pharmacodynamic biomarker for cortical NMDA function that is also robustly translatable. Besides schizophrenia, such a functional biomarker may be of value to neuropsychiatric disorders like bipolar and autism spectrum where 40 Hz ASSR deficits have been documented.

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Section: Introductionmentioning

confidence: 99%

40 Hz Auditory Steady-State Response Is a Pharmacodynamic Biomarker for Cortical NMDA Receptors

Sivarao

Chen

Senapati

et al. 2016

Neuropsychopharmacol

108

106

View full text Add to dashboard Cite

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“…Non-competitive NMDA-R antagonists such as PCP, ketamine and dizolcipine (MK-801) have been very effective in triggering schizophrenia-like positive symptoms, negative symptoms and cognitive deficits in rodents (Bondi et al 2012;Frohlich and Van Horn 2014;. However, behavioral manifestations induced by NMDA-R antagonists seem particularly dependent on pharmacological and procedural features, which difficult the clarification of their neural underlying mechanisms.…”

Section: Introductionmentioning

confidence: 99%

PCP-based mice models of schizophrenia: differential behavioral, neurochemical and cellular effects of acute and subchronic treatments

2015

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“…In rodents, curcumin pretreatment at 20 mg/kg and 50 mg/kg for 2 weeks blocked the hyperactivity and oxidant stress in the ketamine mania model [40]. In the forced swimming test of rodent "depression-hopelessness", curcumin behaves as an antidepressant whose anti-depressant property is mediated through NMDA-NR2 [41]. Blockade of NMDA-NR2 by the specific antagonist, CPP reversed curcumin's behavioral effects.…”

Section: Nmda-glutamate Signaling and Curcuminmentioning

confidence: 97%

Targeting Epigenetics Signaling with Curcumin: A Transformative Drug Lead in Treatment of Schizophrenia?

Chiu¹,

Woodbury-Fariña²,

Terpstra³

et al. 2017

J Clin Epigenet

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While pharmacotherapy of second generation of atypical antipsychotics: clozapine, olanzapine, risperidol, quetiapine, ziprasidone, aripiprazole bring about significant improvement in the positive symptoms of schizophrenia [1], overall psychosocial outcomes in schizophrenia remain modest. Significant functional impairment related to negative symptoms (lack of volition, apathy, sociality, poverty of speech and affective flattening), active positive symptoms (delusions, hallucinations and bizarre behavioral disturbances) and neuro-cognition deficits, persists in 20-30% of patients with schizophrenia refractory to AbstractDespite advances in pharmacotherapy, schizophrenia continues to carry a high societal disease burden related to positive and negative symptoms, and neurocognitive deficits and severe functional impairment. Findings from epigenetics have yet to translate the epigenetics targets to efficacious drug therapy. We review the repertoire of CNS pharmacology of curcumin derived from Curcuma Longa, commonly known as "turmeric": the well-known curry extract. We highlight the body of evidence in support of the emerging role of curcumin as a panhistone deacetylase (HDAC) inhibitor regulating the expression of genes involved in inflammation and NMDA N-methyl-aspartic acid (NMDA)-glutamate systems, as related to schizophrenia. Based on the findings from translational studies of curcumin extracts, curcumin C-3 complex formulation (Supercurcumin TM ) and patented liposome-based curcumin (Lipocurc TM ), we propose that intravenous infusion of Lipocurc TM holds promise as the novel drug lead and preferred targeted brain delivery mode in reprogramming faculty epigenetics network and in remodeling restrictive chromatin configuration in schizophrenia. Phase II/Phase III epigenetics-biomarker-based randomized placebo-controlled trials in treatment resistant schizophrenia are warranted. Our approach of intravenous infusion of Lipocurc TM behaving as pan HDAC inhibitor represents a new paradigm of drug development in combining targeting epigenetics footprints with brain-specific drug delivery system in schizophrenia. Lipocurc TM can open the Pandora box in unexplored therapeutics vistas in modifying the phenotype of treatment resistant schizophrenia. [2]. Major breakthroughs in schizophrenia therapeutics are yet forthcoming. It becomes imperative to design molecular genetics and epigenetic tools to predict treatment responses, and to translate novel CNS drug targets for accelerating the development of new therapeutics for treatment refractory schizophrenia. Drug platforms require refinement of translational models of schizophrenia to catalyze clinical trials and to predict treatment responses. In the post-genomic era, deciphering the epigenetic code of the human genomes represents a major challenge in CNS disorders. A growing body of evidence supports dysregulation of epigenetics signaling: DNA methylation, histone modifications and microRNA, plays a significant role in schizophrenia [3][4][5]. Findings from studies of p...

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Reviewing the ketamine model for schizophrenia

Cited by 266 publications

References 206 publications

40 Hz Auditory Steady-State Response Is a Pharmacodynamic Biomarker for Cortical NMDA Receptors

40 Hz Auditory Steady-State Response Is a Pharmacodynamic Biomarker for Cortical NMDA Receptors

PCP-based mice models of schizophrenia: differential behavioral, neurochemical and cellular effects of acute and subchronic treatments

Targeting Epigenetics Signaling with Curcumin: A Transformative Drug Lead in Treatment of Schizophrenia?

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