Clinical and preclinical studies suggest that dysfunction of the glutamatergic system is implicated in mood disorders such as major depressive disorder and bipolar depression. In clinical studies of individuals with major depressive disorder and bipolar depression, rapid reductions in depressive symptoms have been observed in response to subanesthetic-dose ketamine, an agent whose mechanism of action involves the modulation of glutamatergic signaling. The findings from these studies have prompted the repurposing and/or development of other glutamatergic modulators for antidepressant efficacy, both as monotherapy or as an adjunct to conventional monoaminergic antidepressants. This review highlights the evidence supporting the antidepressant effects of subanesthetic-dose ketamine as well as other glutamatergic modulators, such as d-cycloserine, riluzole, CP-101,606, CERC-301 (previously known as MK-0657), basimglurant, JNJ-40411813, dextromethorphan, nitrous oxide, GLYX-13, and esketamine.
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The authors thank the 7SE research unit and staff for their support. We also thank Ioline Henter (National Institute of Mental Health) for providing invaluable editorial assistance.
Funding for this work was supported by the Intramural Research Program at the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH; ZIA-MH002857), by a NARSAD Independent Investigator to Dr. Zarate, and by a Brain and Behavior Mood Disorders Research Award to Dr. Zarate.
Conflict of interest
Dr. Zarate is listed as a co-inventor on a patent for the use of (2R,6R)-hydroxynorketamine, (S)-dehydronorketamine, and other stereoisomeric dehydro and hydroxylated metabolites of (R,S)-ketamine metabolites in the treatment of depression and neuropathic pain. Dr. Zarate is listed as a co-inventor on a patent application for the use of (2R,6R)-hydroxynorketamine and (2S,6S)-hydroxynorketamine in the treatment of depression, anxiety, anhedonia, suicidal ideation, and post-traumatic stress disorders. Dr. Zarate has assigned his patent rights to the US Government but will share a percentage of any royalties received by the government. Drs. Lener and Kadriu have no conflict of interest to disclose, financial or otherwise.
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Lener, M.S., Kadriu, B. & Zarate, C.A. Ketamine and Beyond: Investigations into the Potential of Glutamatergic Agents to Treat Depression. Drugs 77, 381–401 (2017). https://doi.org/10.1007/s40265-017-0702-8
- Depressive Symptom
- Major Depressive Disorder
- Antidepressant Effect