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  • Growing evidence suggests that the glycine site seems


    Growing evidence suggests that the glycine site seems to play a pivotal role in NMDAR-related function. For example, it adiponectin receptor has been demonstrated in a hippocampal slice study that the glycine site sub-serves the spatiotemporal detection of synaptic activity (Li et al., 2009). Moreover, mice with point mutations at the glycine site show severe deficits in learning related tasks such as in the Morris water maze (MWM), and this deficit could be enhanced by the administration of NMDAR glycine site agonist (Ballard et al., 2002; Kew et al., 2000). Additionally, the activation of the glycine site of the NMDA receptors has shown minimal adverse effects in animal and human studies, making it an attractive target for drug development. Notably, hyperactivation of NMDARs can result in adverse outcomes, such as epilepsy (Croucher et al., 1982), neuronal cell death (Simon et al., 1984) and hyperalgesia (Davies and Lodge, 1987). As a result, hyperactivation of the NMDAR is not desired; the main goal is to modulate NMDARs without aggravating pathological consequences (Collingridge et al., 2013).
    Agents targeting the glycine site of the NMDAR Preclinical and clinical studies examining the cognitive and antidepressant effects of NMDAR glycine site modulators were identified for six specific agents: d-serine, D-cycloserine, sarcosine, D-alanine, glycine and rapastinel. Herein we review the preclinical and clinical studies for each agent as well as an overview on their pharmacology, therapeutic dose and side effects. A summary of clinical trials reviewed can be found in Table 1, Table 2, Table 3, Table 4.
    Discussion Among the modulators reviewed, DCS had the greatest amount of clinical evidence supporting pro-cognitive (from schizophrenia and Alzheimer's disease studies) and antidepressant effects (from MDD studies). Preliminary studies have shown the effectiveness of DCS in reducing depressive symptoms in MDD with high doses of 1000 mg/day (Heresco-Levy et al., 2013). In addition, DCS administration improved negative symptoms of schizophrenia with a dose of 50 mg/day (Buchanan et al., 2007; Duncan et al., 2004; Goff et al., 1999b). Concomitantly, the studies that showed the memory-boosting effect by DCS in Alzheimer's disease reported two doses of 15 (Fakouhi et al., 1995; Randolph et al., 1994) and 100 mg/day (Tsai et al., 1999a). The inconsistent results observed in the cognition-related clinical studies of DCS can be explained through various rationale. First, the fact that DCS functions as a partial agonist in lower doses whereas in higher dosages it behaves as an antagonist (Lanthorn, 1994). This behaviour might help to explain the observed discrepancies. Another given explanations refer to the desensitization that occurs with chronic administration of DCS (Herting, 1991; Quartermain et al., 1994) as well as hypothesis that glycine receptors might be involved in endocytosis mechanism (Nong et al., 2003). Moreover, the mechanism of action of DCS as a cognitive enhancer might change or reverse under stressful conditions such as sleep deprivation, due to changes in other neurotransmitter concentrations (Silvestri and Root, 2008). Other studies have shown that previous exposure to antidepressants such as citalopram and imipramine (Werner-Seidler and Richardson, 2007) or antipsychotics such as olanzapine and clozapine (Van Berckel et al., 1999), might reduce or prevent the positive effects of DCS. Additionally, DSR, glycine and sarcosine show promising clinical and preclinical results suggestive of potential antidepressant and pro-cognitive effects. Particularly, sarcosine has had positive results in improving cognitive symptoms in numerous RCTs. Rapastinel, with its partial agonism function, facilitates normal synaptic transmission without the risk of hyperactivation of NMDA receptors (Moskal et al., 2005). In addition, its rapid antidepressant effects, without the psychotomimetic side effects associated with ketamine, makes rapastinel a unique agent, showing promise to potentially be translated into clinical practice if additional larger RCTs confirm its antidepressant and pro-cognitive effects (Preskorn et al., 2015).