Modulation of NMDA receptor function as a treatment for schizophrenia

Cioffi, Christopher

doi:10.1016/j.bmcl.2013.07.019

Cited by 30 publications

(18 citation statements)

References 184 publications

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“…If NMDAR hypofunction is involved in the pathophysiology of schizophrenia, then a possible treatment target is the glycine system (Coyle and Tsai, 2004). Oral glycine administration improves negative symptoms in schizophrenia (Javitt et al, 1994; Heresco-Levy et al, 1996; Heresco-Levy et al, 1999; Heresco-Levy and Javitt, 2004) and has been explored as a possible drug target (Hashimoto, 2011; Cioffi, 2013). While a recent meta-analysis found no observable differences in serum glycine levels between healthy controls and adults with schizophrenia (Brouwer et al, 2013), a recent 1 H-MRS study, in which healthy adult males were given two weeks of high dose oral glycine, showed elevated levels of Gly/Cr in 10 out of 11 participants in the occipital cortex (Kaufman et al, 2009).…”

Section: 0 1h-mrs In Schizophreniamentioning

confidence: 99%

In vivo assessment of neurotransmitters and modulators with magnetic resonance spectroscopy: Application to schizophrenia

Wijtenburg

Yang

Fischer

et al. 2015

Neuroscience & Biobehavioral Reviews

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In vivo measurement of neurotransmitters and modulators is now feasible with advanced proton magnetic resonance spectroscopy (1H-MRS) techniques. This review provides a basic tutorial of MRS, describes the methods available to measure brain glutamate, glutamine, γ-aminobutyric acid, glutathione, N-acetylaspartylglutamate, glycine, and serine at magnetic field strengths of 3Tesla or higher, and summarizes the neurochemical findings in schizophrenia. Overall, 1H-MRS holds great promise for producing biomarkers that can serve as treatment targets, prediction of disease onset, or illness exacerbation in schizophrenia and other brain diseases.

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Section: 0 1h-mrs In Schizophreniamentioning

confidence: 99%

In vivo assessment of neurotransmitters and modulators with magnetic resonance spectroscopy: Application to schizophrenia

Wijtenburg

Yang

Fischer

et al. 2015

Neuroscience & Biobehavioral Reviews

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“…Autopsy studies also revealed reduced expression of NMDAR in patients’ brain compared with age-matched controls [7]. These observations lead to an attempt to compensate the reduced NMDAR with positive modulators to treat schizophrenia [8]. …”

Section: Introductionmentioning

confidence: 99%

A Naturally Occurring Null Variant of the NMDA Type Glutamate Receptor NR3B Subunit Is a Risk Factor of Schizophrenia

et al. 2015

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Hypofunction of the N-methyl-D-aspartate type glutamate receptor (NMDAR) has been implicated in the pathogenesis of schizophrenia. Here, we investigated the significance of a common human genetic variation of the NMDAR NR3B subunit that inserts 4 bases within the coding region (insCGTT) in the pathogenesis of schizophrenia. The cDNA carrying this polymorphism generates a truncated protein, which is electrophysiologically non-functional in heterologous expression systems. Among 586 schizophrenia patients and 754 healthy controls, insCGTT was significantly overrepresented in patients compared to controls (odds ratio = 1.37, p = 0.035). Among 121 schizophrenia patients and 372 healthy controls, genetic analyses of normal individuals revealed that those carrying insCGTT have a predisposition to schizotypal personality traits (F1,356 = 4.69, p = 0.031). Furthermore, pre-pulse inhibition, a neurobiological trait disturbed in patients with schizophrenia, was significantly impaired in patients carrying insCGTT compared with those with the major allele (F1,116 = 5.72, p = 0.018, F1,238 = 4.46, p = 0.036, respectively). These results indicate that a naturally occurring null variant in NR3B could be a risk factor of schizophrenia.

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“…Dysfunction of dopaminergic neurotransmission contributes to the genesis of positive symptoms, but other evidence highlights widespread and variable involvement of other brain areas and circuits. Disturbances of synaptic function might underlie abnormalities of neuronal connectivity, but the precise nature, location and timing of these events are uncertain 17,18. The first clearly effective antipsychotic drugs, chlorpromazine and reserpine, were structurally different from each other, but they shared antidopaminergic properties.…”

Section: Resultsmentioning

confidence: 99%

“…Thus, other neurotransmitters, such as norepinephrine, serotonin and gamma-aminobutyric acid (GABA), are involved. Some studies focused on the N -methyl- d -aspartate (NMDA) subclass of glutamate receptors, since its antagonism can lead to psychotic symptoms 17–20. Some neuroimaging studies show differences in some areas between the brains of those with schizophrenia and those without the disease (eg, decrease of volume of temporal and hippocampus areas; abnormalities in neocortical and limbic regions) 21–23.…”

Section: Resultsmentioning

confidence: 99%

Iloperidone in the treatment of schizophrenia: an evidence-based review of its place in therapy

Tonin¹,

Wiens²,

Fernández-Llimós³

et al. 2016

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IntroductionSchizophrenia is a chronic and debilitating mental disorder that affects the patient’s and their family’s quality of life, as well as financial costs and health care settings. Despite the variety of available antipsychotics, optimal treatment outcomes are not always achieved. Novel drugs, such as iloperidone, can provide more effective, tolerable and safer strategies.AimTo review the evidence for the clinical impact of iloperidone on the treatment of patients with schizophrenia.Evidence reviewClinical trials, observational studies and meta-analyses reached a common consensus that iloperidone is as effective as haloperidol, risperidone and ziprasidone in reducing schizophrenia symptoms. Similar amounts of adverse events and discontinuations were observed with iloperidone compared to placebo and active treatments. Common adverse events are mild and include dizziness, hypotension, dry mouth and weight gain. Iloperidone can induce extension of QTc interval, and clinicians should be aware of its contraindications. In long-term trials, iloperidone also showed promising safety and tolerability profiles. The low propensity to cause akathisia, extrapyramidal symptoms (EPS), increased prolactin levels or changes to metabolic laboratory parameters support its use in practice. Results showed that iloperidone prevents relapse in stabilized patients, with a time to relapse superior to placebo and similar to haloperidol. Patients using a prior antipsychotic (eg, risperidone and aripiprazole) can easily switch to iloperidone with no serious impact on safety or efficacy. However, the acquisition costs of iloperidone may hamper its use. Further evidence comparing iloperidone with other antipsychotics, and pharmacoeconomic studies would be welcome.Place in therapyConsidering just the clinical profile of iloperidone, it represents a promising drug for treating schizophrenia, particularly in patients who are intolerant to previous antipsychotics, as well as being suitable as first-line therapy. Cost-effectiveness comparisons are needed to justify its use in clinical practice.

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Modulation of NMDA receptor function as a treatment for schizophrenia

Cited by 30 publications

References 184 publications

In vivo assessment of neurotransmitters and modulators with magnetic resonance spectroscopy: Application to schizophrenia

In vivo assessment of neurotransmitters and modulators with magnetic resonance spectroscopy: Application to schizophrenia

A Naturally Occurring Null Variant of the NMDA Type Glutamate Receptor NR3B Subunit Is a Risk Factor of Schizophrenia

Iloperidone in the treatment of schizophrenia: an evidence-based review of its place in therapy

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