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Neurosci Biobehav Rev. 2014 Nov;47:336-58. doi: 10.1016/j.neubiorev.2014.08.017. Epub 2014 Sep 16.

The role of NMDA receptors in the pathophysiology and treatment of mood disorders.

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Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Neurology, University of Massachusetts Medical School, Worcester, MA, USA. Electronic address:
Department of Physical Therapy, Arkansas State University, Jonesboro, AR, USA.
Department of Psychiatry, Washington University, St. Louis, MO, USA.
Department of Biological Sciences, Stanford University, Stanford, CA, USA.
VA Palo Alto Health Care System, Palo Alto, CA, USA; Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA.


Mood disorders such as major depressive disorder and bipolar disorder are chronic and recurrent illnesses that cause significant disability and affect approximately 350 million people worldwide. Currently available biogenic amine treatments provide relief for many and yet fail to ameliorate symptoms for others, highlighting the need to diversify the search for new therapeutic strategies. Here we present recent evidence implicating the role of N-methyl-D-aspartate receptor (NMDAR) signaling in the pathophysiology of mood disorders. The possible role of NMDARs in mood disorders has been supported by evidence demonstrating that: (i) both BPD and MDD are characterized by altered levels of central excitatory neurotransmitters; (ii) NMDAR expression, distribution, and function are atypical in patients with mood disorders; (iii) NMDAR modulators show positive therapeutic effects in BPD and MDD patients; and (iv) conventional antidepressants/mood stabilizers can modulate NMDAR function. Taken together, this evidence suggests the NMDAR system holds considerable promise as a therapeutic target for developing next generation drugs that may provide more rapid onset relief of symptoms. Identifying the subcircuits involved in mood and elucidating the role of NMDARs subtypes in specific brain circuits would constitute an important step toward the development of more effective therapies with fewer side effects.


Bipolar disorder; Glutamatergic system; Ketamine; Major depressive disorder; Mood disorders; NMDA receptor antagonists; NMDA receptors

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