, Volume 72, Issue 10, pp 1313–1333 | Cite as

Targeting the Glutamatergic System to Treat Major Depressive Disorder

Rationale and Progress to Date
  • Daniel C. Mathews
  • Ioline D. Henter
  • Carlos A. ZarateJr
Leading Article


Major depressive disorder (MDD) is a severe, debilitating medical illness that affects millions of individuals worldwide. The young age of onset and chronicity of the disorder has a significant impact on the long-term disability that affected individuals face. Most existing treatments have focused on the ‘monoamine hypothesis’ for rational design of compounds. However, patients continue to experience low remission rates, residual subsyndromal symptoms, relapses and overall functional impairment.

In this context, growing evidence suggests that the glutamatergic system is uniquely central to the neurobiology and treatment of MDD. Here, we review data supporting the involvement of the glutamatergic system in the pathophysiology of MDD, and discuss the efficacy of glutamatergic agents as novel therapeutics. Preliminary clinical evidence has been promising, particularly with regard to the N-methyl-D-aspartate (NMDA) antagonist ketamine as a ‘proof-of-concept’ agent. The review also highlights potential molecular and inflammatory mechanisms that may contribute to the rapid antidepressant response seen with ketamine.

Because existing pharmacological treatments for MDD are often insufficient for many patients, the next generation of treatments needs to be more effective, rapid acting and better tolerated than currently available medications. There is extant evidence that the glutamatergic system holds considerable promise for developing the next generation of novel and mechanistically distinct agents for the treatment of MDD.


Ketamine Major Depressive Disorder Memantine AMPA Receptor Antidepressant Effect 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



The authors gratefully acknowledge the support of the Intramural Research Program of the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH; Bethesda, MD, USA), and thank the 7SE Research Unit of the NIMH-NIH for their support.

Role of funding source: This review was supported by the IRP-NIMH-NIH. The NIMH had no further role in the writing of this review, or in the decision to submit the paper for publication.

Financial disclosures: The authors gratefully acknowledge the support of the IRP-NIMH-NIH, and the NARSAD Independent Investigator Award and Brain and Behavior Foundation Bipolar Research Award (Dr Zarate). Dr Mathews and Ioline Henter have no conflict of interest to disclose, financial or otherwise. Dr Zarate is listed as a co-inventor on a patent application for the use of ketamine and its metabolites in major depression. Dr Zarate has assigned his rights in the patent to the US Government but will share a percentage of any royalties that may be received by the Government.


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Copyright information

© Springer International Publishing AG 2012

Authors and Affiliations

  • Daniel C. Mathews
    • 1
  • Ioline D. Henter
    • 2
  • Carlos A. ZarateJr
    • 1
  1. 1.Experimental Therapeutics and Pathophysiology Branch, Intramural Research ProgramNational Institute of Mental Health, National Institutes of HealthBethesdaUSA
  2. 2.Molecular Imaging BranchNational Institute of Mental Health, National Institutes of HealthBethesdaUSA

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