Glutamatergic agents for schizophrenia: current evidence and perspectives

Abstract

Suboptimal outcomes in schizophrenia are a consequence of lacking insight into the etiology, biomarkers and treatment-relevant subgroups, the therapeutic restriction to dopaminergic-modulating antipsychotics that fail to significantly improve negative and cognitive symptoms, non-adherence, and, in the case of treatment-resistance, the underutilization of clozapine. Evidence suggests additional, extra-dopaminergic abnormalities in amino acid neurotransmission, particularly the glutamatergic system. Antidopaminergic antipsychotics modulate this system on several levels, as do mood stabilizers, including lamotrigine, topiramate and pregabaline. Recently, agonists at metabotropic glutamate receptors and glycine uptake inhibitors failed in large placebo-controlled trials for schizophrenia. Problems to overcome for successfully leveraging glutamatergic agents for schizophrenia are patient selection, focus on positive symptoms and late disease stages, and dose-response relationships. Because glutamate guides processes of brain development and maturation, clinical research should focus on the at-risk mental state or first-episode psychosis, address cognition and negative symptoms and use monotherapy designs in parallel to augmentation strategies.

Effects of acute memantine administration on MATRICS Consensus Cognitive Battery performance in psychosis: Testing an experimental medicine strategy

“…While antipsychotics (APs) can blunt the most severe acute psychotic symptoms, any salubrious effects of APs on neurocognitive deficits are generally of small effect sizes (Keefe et al 2007). Several studies investigating pro-cognitive interventions for SZ have targeted specific neurotransmitter systems including nicotine (AhnAllen et al 2008; Barr et al 2008) and glutamate (Heresco-Levy et al 2004, 2005; Buchanan et al 2007; Patil et al 2007; Zink and Correll 2015), based on their hypothesized role in the pathophysiology of neurocognitive deficits, but to date no clear functional benefits from pro-cognitive agents have been demonstrated in SZ patients.…”

Drugs, games, and devices for enhancing cognition: implications for work and society

“…However, among others, a couple of recent meta-analyses showed no significant effect of drugs that positively modify glutamatergic signaling or act as agonists or coactivators on glutamatergic receptors. 188,[194][195][196] Similarly, the use of antidepressants aimed at manipulating the serotonergic system to improve cognition in schizophrenia was not successful in improving cognition, but did improve depressive symptoms (e.g., see Ref. 197).…”

Cognitive remediation in schizophrenia—now it is really getting personal

“…Basic studies conducted on animals and healthy volunteers have linked RL and cognitive training with brain neuroplastic changes and alteration in dopaminergic action [19,20]. More recent animal models and pilot clinical trials also suggest that glutamatergic and GABAergic systems may be relevant targets to improve cognition in people with schizophrenia and may be associated with RL processes [21,22]. However, evidence in this area is scarce and mostly based on animal studies.…”