N-Methyl-d-aspartate receptors as a target for improved antipsychotic agents: novel insights and clinical perspectives

Abstract

Reduced activity at NMDA receptors is implicated in the aetiology of schizophrenia. Correspondingly, drugs that (directly or indirectly) increase activity at Glycine(B) sites may be of use as adjuncts to other classes of antipsychotic agent. However, there is an urgent need for broader clinical evaluation of this possibility, and, to date, there is no evidence that stimulation of Glycine(B) sites alone improves psychotic states.

Phenotypic characterization of spatial cognition and social behavior in mice with ‘knockout’ of the schizophrenia risk gene neuregulin 1

“…[NMDA] hypofunction is a contemporary hypothesis for schizophrenia (Coyle and Tsai, 2004;Millan, 2005). Reduction in forebrain NMDA receptors has been reported in TM-NRG1 mutants (Stefansson et al, 2002) and abnormalities in social behaviour have been reported in hypomorphic NMDA mutants (Mohn et al, 1999;Duncan et al, 2004); however, these studies did not resolve sociability vs social novelty.…”

Differential Effects of Antipsychotic and Glutamatergic Agents on the phMRI Response to Phencyclidine

“…These compounds have also been shown to exacerbate positive symptoms of patients with schizophrenia (Lahti et al, 2001;Malhotra et al, 1997b). Moreover, both clinical and experimental evidence suggest that the expression and functionality of NMDAR might be dysregulated in schizophrenia (Kristiansen et al, 2007;Millan, 2005). These findings have led to the hypothesis that a decreased NMDAR function may be a predisposing or even causative factor for this disabling disease (Farber, 2003;Greene, 2001).…”

Dual- and Triple-Acting Agents for Treating Core and Co-morbid Symptoms of Major Depression: Novel Concepts, New Drugs

“…Supporting interest in mixed NMDA agents/SRIs, the open channel blocker ketamine exerts rapid antidepressant properties in patients. [153][154][155] Although the risk of cognitive impairment and psychosis tempers interest in channel blockers as a therapeutic strategy, 34,146,156 the anti-Alzheimer agent memantine has only a low risk of psychosis, because of its marked voltage-dependency and rapid kinetics 156 -158 ; its potential antidepressant actions are under investigation, although clinical data are as yet ambivalent. 159 -161 In fact, memantine interacts with several other sites 156 (Table 2), supporting the notion that NMDA receptor blockers could serve as a template for generating well-tolerated multitarget antidepressants of accelerated onset of action.…”

“…Multitarget drugs could also be constructed around structures specifically blocking NR2B NMDA receptor subunits or the colocalized glycine B sites, which should have a reduced risk of psychosis and other adverse effects. 146 One theory of the antidepressant actions of NMDA antagonists suggests that they indirectly favor transmission at AMPA versus NMDA sites. 155 Correspondingly, positive allosteric modulators (ampakines) at AMPA receptors exert antidepressant properties, induce neurogenesis, and favor cognitive performance, both singly and in association with SSRIs.…”

“…Other intracellular modulators controlling mood could also be cited, such as 1) neuronal nitric oxide, which is recruited by NMDA receptors and interacts with 5-HT transporters, 3,146,233,234 or 2) 1 sites, which also interact with NMDA receptors and modulate intracellular Ca 2ϩ availability. 3,[235][236][237] To reiterate, multitarget approaches appear more promising than selective agents for manipulation of intracellular proteins-not least, because they can help vector drug actions to cerebral areas involved in the induction and control of depression.…”