Current and Emergent Treatments for Symptoms and Neurocognitive Impairment in Schizophrenia

Javitt, Daniel C.

doi:10.1007/s40501-014-0010-9

Cited by 20 publications

(16 citation statements)

References 94 publications

(107 reference statements)

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“…Indeed, the α7nAChR is the target of several therapeutics that have been taken into clinical trials to improve cognitive deficits associated with schizophrenia (Freedman, 2013; Beinat et al, 2015; Javitt, 2015). Yet, the mechanism underlying their beneficial effect is ill-defined.…”

Section: Resultsmentioning

confidence: 99%

“…Multiple human mutations associated with schizophrenia point to a compromised function of the NMDAR co-agonist binding site, and this has become a leading hypothesis for the etiology and treatment of this disorder (Javitt, 2015; Moghaddam and Javitt, 2011; Ripke et al, 2014). This includes mutations that impair the synthesis, availability, or binding of D-serine such as mutations associated with srr , DAO and Grin1 , respectively coding for D-serine synthesizing enzyme serine racemase (SR), D-serine degrading enzyme D-amino acid oxidase (DAAO), and NMDAR GluN1 subunit that arbors the co-agonist binding site (Labrie et al, 2012; Ma et al, 2012; Ripke et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

“…In line with this genetic evidence, clinical studies reported decreased D-serine levels in the plasma of schizophrenic patients (Hashimoto et al, 2003; Bendikov et al, 2007) and administration of D-serine improves negative, positive and general symptoms of schizophrenia (Kantrowitz et al, 2010). In parallel, the dysregulation of the cholinergic system has historically been a hallmark of schizophrenia (Javitt, 2015) and clinical attention is particularly focused on the α7nAChR. Indeed, α7nAChR modulators seem to significantly improve the cognitive deficits associated with schizophrenia in clinical trials (Beinat et al, 2015; Freedman, 2013; Javitt, 2015) even though no mechanisms have been proposed to explain such beneficial effects.…”

Section: Discussionmentioning

confidence: 99%

“…D-serine levels are lowered in the plasma of schizophrenic patients (Hashimoto et al, 2003; Bendikov et al, 2007) and many human mutations associated with schizophrenia result in a hypofunction of NMDAR co-agonist binding site by decreasing its affinity or by directly impairing D-serine availability (Labrie et al, 2012; Ma et al, 2012; Ripke et al, 2014). In parallel, a dysregulation of the cholinergic system is a hallmark of schizophrenia (Freedman, 2013; Javitt, 2015), and recent clinical trials aimed at improving cognitive symptoms of schizophrenic patients with cholinergic modulators (Javitt, 2015). …”

Section: Introductionmentioning

confidence: 99%

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Septal Cholinergic Neuromodulation Tunes the Astrocyte-Dependent Gating of Hippocampal NMDA Receptors to Wakefulness

Papouin

Dunphy

Tolman

et al. 2017

Neuron

205

222

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Summary The activation of the N-methyl D-aspartate receptor (NMDAR) is controlled by a glutamate-binding site and a distinct, independently regulated, co-agonist-binding site. In most brain regions, the NMDAR co-agonist is the astrocyte-derived gliotransmitter D-serine. We found that D-serine levels oscillate in mouse hippocampus as a function of wakefulness, in vitro and in vivo. This causes a full saturation of the NMDAR co-agonist site in the dark (active)-phase that dissipates to sub-saturating levels during the light (sleep)-phase, and influences learning performance throughout the day. We demonstrate that hippocampal astrocytes sense the wakefulness-dependent activity of septal cholinergic fibers through the α7-nicotinic acetylcholine receptor (α7nAChR), whose activation drives D-serine release. We conclude that astrocytes tune the gating of synaptic NMDARs to the vigilance state and demonstrate that this is directly relevant to schizophrenia, a disorder characterized by NMDAR and cholinergic hypofunctions. Indeed, bypassing cholinergic activity with a clinically-tested α7nAChR agonist successfully enhances NMDARs activation.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Septal Cholinergic Neuromodulation Tunes the Astrocyte-Dependent Gating of Hippocampal NMDA Receptors to Wakefulness

Papouin

Dunphy

Tolman

et al. 2017

Neuron

205

222

View full text Add to dashboard Cite

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“…Other approaches seek to modulate glycine and/or D-serine levels indirectly by affecting regulatory mechanisms (14). For example, glycine (GlyT1) transport inhibitors prevent removal of glycine from the synapse (15).…”

Section: Introductionmentioning

confidence: 99%

Modulating NMDA Receptor Function with d-Amino Acid Oxidase Inhibitors: Understanding Functional Activity in PCP-Treated Mouse Model

et al. 2016

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Deficits in N-methyl-D-aspartate receptor (NMDAR) function are increasingly linked to persistent negative symptoms and cognitive deficits in schizophrenia. Accordingly, clinical studies have been targeting the modulatory site of the NMDA receptor, based on the decreased function of NMDA receptor, to see whether increasing NMDA function can potentially help treat the negative and cognitive deficits seen in the disease. Glycine and D-serine are endogenous ligands to the NMDA modulatory site, but since high doses are needed to affect brain levels, related compounds are being developed, for example glycine transport (GlyT) inhibitors to potentially elevate brain glycine or targeting enzymes, such as D-amino acid oxidase (DAAO) to slow the breakdown and increase the brain level of D-serine. In the present study we further evaluated the effect of DAAO inhibitors 5-chloro-benzo[d]isoxazol-3-ol (CBIO) and sodium benzoate (NaB) in a phencyclidine (PCP) rodent mouse model to see if the inhibitors affect PCP-induced locomotor activity, alter brain D-serine level, and thereby potentially enhance D-serine responses. D-Serine dose-dependently reduced the PCP-induced locomotor activity at doses above 1000 mg/kg. Acute CBIO (30 mg/kg) did not affect PCP-induced locomotor activity, but appeared to reduce locomotor activity when given with D-serine (600 mg/kg); a dose that by itself did not have an effect. However, the effect was also present when the vehicle (Trappsol®) was tested with D-serine, suggesting that the reduction in locomotor activity was not related to DAAO inhibition, but possibly reflected enhanced bioavailability of D-serine across the blood brain barrier related to the vehicle. With this acute dose of CBIO, D-serine level in brain and plasma were not increased. Another weaker DAAO inhibitor sodium benzoate (NaB) (400 mg/kg), and NaB plus D-serine also significantly reduced PCP-induced locomotor activity, but without affecting plasma or brain D-serine level, arguing against a DAAO-mediated effect. However, NaB reduced plasma L-serine and based on reports that NaB also elevates various plasma metabolites, for example aminoisobutyric acid (AIB), a potential effect via the System A amino acid carrier may be involved in the regulation of synaptic glycine level to modulate NMDAR function needs to be investigated. Acute ascorbic acid (300 mg/kg) also inhibited PCP-induced locomotor activity, which was further attenuated in the presence of D-serine (600 mg/kg). Ascorbic acid may have an action at the dopamine membrane carrier and/or altering redox mechanisms that modulate NMDARs, but this needs to be further investigated. The findings support an effect of D-serine on PCP-induced hyperactivity. They also offer suggestions on an interaction of NaB via an unknown mechanism, other than DAAO inhibition, perhaps through metabolomic changes, and find unexpected synergy between D-serine and ascorbic acid that supports combined NMDA glycine- and redox-site intervention. Although mechanisms of these specific agents need to be det...

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The current conceptualization of negative symptoms in schizophrenia

Marder¹,

2017

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Negative symptoms have long been conceptualized as a core aspect of schizophrenia. They play a key role in the functional outcome of the disorder, and their management represents a significant unmet need. Improvements in definition, characterization, assessment instruments and experimental models are needed in order to foster research aimed at developing effective interventions. A consensus has recently been reached on the following aspects: a) five constructs should be considered as negative symptoms, i.e. blunted affect, alogia, anhedonia, asociality and avolition; b) for each construct, symptoms due to identifiable factors, such as medication effects, psychotic symptoms or depression, should be distinguished from those regarded as primary; c) the five constructs cluster in two factors, one including blunted affect and alogia and the other consisting of anhedonia, avolition and asociality. In this paper, for each construct, we report the current definition; highlight differences among the main assessment instruments; illustrate quantitative measures, if available, and their relationship with the evaluations based on rating scales; and describe correlates as well as experimental models. We conclude that: a) the assessment of the negative symptom dimension has recently improved, but even current expert consensus-based instruments diverge on several aspects; b) the use of objective measures might contribute to overcome uncertainties about the reliability of rating scales, but these measures require further investigation and validation; c) the boundaries with other illness components, in particular neurocognition and social cognition, are not well defined; and d) without further reducing the heterogeneity within the negative symptom dimension, attempts to develop successful interventions are likely to lead to great efforts paid back by small rewards.

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Current and Emergent Treatments for Symptoms and Neurocognitive Impairment in Schizophrenia

Cited by 20 publications

References 94 publications

Septal Cholinergic Neuromodulation Tunes the Astrocyte-Dependent Gating of Hippocampal NMDA Receptors to Wakefulness

Septal Cholinergic Neuromodulation Tunes the Astrocyte-Dependent Gating of Hippocampal NMDA Receptors to Wakefulness

Modulating NMDA Receptor Function with d-Amino Acid Oxidase Inhibitors: Understanding Functional Activity in PCP-Treated Mouse Model

The current conceptualization of negative symptoms in schizophrenia

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