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.

Keywords:

• amino acid neurotransmission
• antipsychotic
• cognition
• glutamate
• psychosis
• schizophrenia

Financial & competing interests disclosure

M Zink has received unrestricted scientific grants of ERAB (European Research Advisory Board), German Research Foundation (DFG), Servier, Pfizer Pharma GmbH, Bristol-Myers Squibb GmbH & CoKGaA, further speaker and travel support from Pfizer Pharma GmbH, Bristol-Myers Squibb, Otsuka, Astra Zeneca, Eli-Lilly, Janssen Cilag, Servier, Trommsdorff and Roche. C Correll has been a consultant and/or advisor to, or has received honoraria from: Actavis, AbbVie, Alkermes, Bristol-Myers Squibb, Eli Lilly, Genentech, Gerson Lehrman Group, IntraCellular Therapies, Janssen/J&J, Lundbeck, MedAvante, Medscape, Otsuka, Pfizer, ProPhase, Reviva, Roche, Sunovion, Supernus, and Takeda. He has received grant support from BMS, Otsuka, and Takeda. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• At present, negative and cognitive symptoms of schizophrenia are insufficiently addressed by currently available antipsychotics. Incomplete recovery is the rule and not the exception in patients with schizophrenia.

• Multifold reasons cause suboptimal outcomes of schizophrenia treatment, in particular the lack of modulators of additional neurotransmitter systems, such as the glutamatergic system.

• First-generation antipsychotics, second-generation antipsychotics and mood stabilizers modulate glutamatergic properties.

• More specifically, agonists at metabotropic glutamate receptors and enhancers of NR function aim at improving glutamatergic functions, but results of clinical trials did not withstand scrutiny for regulatory approval.

• Glutamatergic interventions should target early phase patients (at-risk mental state, first episode patients) with primary endpoints in cognitive dysfunction and the transition to psychosis. All clinical endpoints should be investigated together with a search for biomarkers of their efficacy and tolerability.

• Besides in monotherapy, glutamatergic modulators should also be tested in augmentation strategies together with cognitive behavioral therapy and second-generation antipsychotics.

• Close attention to the appropriate selection and characterization of patients and outcome targets, trial conduct issues, means to minimize the placebo response, and glutamatergic drug dosing will be essential.