Would an 'anti-ketamine' also treat depression?

November 18, 2013

Philadelphia, PA, November 18, 2013 - Thirteen years ago, an article in this journal first reported that the anesthetic medication, ketamine, showed evidence of producing rapid antidepressant effects in depressed patients who had not responded to prior treatments. Ketamine works by blocking one of the targets for the neurotransmitter glutamate in the brain, the N-methyl-D-aspartate (NMDA) glutamate receptor.

Now, a new study in Biological Psychiatry reports that enhancing, instead of blocking, that same target - the NMDA glutamate receptor - also causes antidepressant-like effects.

Scientists theorize that NMDA receptor activity plays an important role in the pathophysiology of depression, and that normalizing its functioning can, potentially, restore mood to normal levels.

Prior studies have already shown that the underlying biology is quite complex, indicating that both hyperfunction and hypofunction of the NMDA receptor is somehow involved. But, most studies have focused on antagonizing, or blocking, the receptor, and until now, studies investigating NMDA enhancement have been in the early phases.

Sarcosine is one such compound that acts by enhancing NMDA function. Collaborators from China Medical University Hospital in Taiwan and the University of California in Los Angeles studied sarcosine in an animal model of depression and, separately, in a clinical trial of depressed patients.

"We found that enhancing NMDA function can improve depression-like behaviors in rodent models and in human depression," said Dr. Hsien-Yuan Lane, the corresponding author on the article.

In the clinical portion of the study, they conducted a 6-week trial where 40 depressed patients were randomly assigned to receive sarcosine or citalopram (Celexa), an antidepressant already on the market that was used as a comparison drug. Neither the patients nor their doctors knew which one they were receiving.

Compared to citalopram, patients receiving sarcosine reported significantly improved mood scores, were more likely to experience relief of their depression symptoms, and were more likely to continue in the study. There were no major side effects in either group, but patients receiving citalopram reported more relatively minor side effects than the patients being treated with sarcosine.

"It will be important to understand how sarcosine, which enhances NMDA receptor function, produces the interesting effects reported in this study. There are ways that its effects, paradoxically, might converge with those of ketamine, a drug that blocks NMDA receptors," commented Dr. John Krystal, Editor of Biological Psychiatry. "For example, both compounds may enhance neuroplasticity, the capacity to remodel brain networks through experience. Also, both potentially attenuate signaling through NMDA receptors, ketamine with single doses and sarcosine, with long-term administration, by evoking an adaptive down regulation of NMDA receptors."

Better understanding the reported findings may help to advance the development of medication treatments for patients who do not respond to available treatments. This is an important goal, with estimates indicating that as many as half of all patients do not experience complete relief of their depression.
-end-
The article is "Inhibition of Glycine Transporter-I as a Novel Mechanism for the Treatment of Depression" by Chih-Chia Huang, I-Hua Wei, Chieh-Liang Huang, Kuang-Ti Chen, Mang-Hung Tsai, Priscilla Tsai, Rene Tun, Kuo-Hao Huang, Yue-Cune Chang, Hsien-Yuan Lane, and Guochuan Emil Tsai (doi: 10.1016/j.biopsych.2013.02.020). The article appears in Biological Psychiatry, Volume 74, Issue 10 (November 15, 2013), published by Elsevier.

Notes for editors

Full text of the article is available to credentialed journalists upon request; contact Rhiannon Bugno at +1 214 648 0880 or Biol.Psych@utsouthwestern.edu. Journalists wishing to interview the authors may contact Dr. Hsien-Yuan Lane at +88 692 106 7260 or hylane@gmail.com.

The authors' affiliations, and disclosures of financial and conflicts of interests are available in the article.

John H. Krystal, M.D., is Chairman of the Department of Psychiatry at the Yale University School of Medicine, Chief of Psychiatry at Yale-New Haven Hospital, and a research psychiatrist at the VA Connecticut Healthcare System. His disclosures of financial and conflicts of interests are available here.

About Biological Psychiatry

Biological Psychiatry is the official journal of the Society of Biological Psychiatry, whose purpose is to promote excellence in scientific research and education in fields that investigate the nature, causes, mechanisms and treatments of disorders of thought, emotion, or behavior. In accord with this mission, this peer-reviewed, rapid-publication, international journal publishes both basic and clinical contributions from all disciplines and research areas relevant to the pathophysiology and treatment of major psychiatric disorders.

The journal publishes novel results of original research which represent an important new lead or significant impact on the field, particularly those addressing genetic and environmental risk factors, neural circuitry and neurochemistry, and important new therapeutic approaches. Reviews and commentaries that focus on topics of current research and interest are also encouraged.

Biological Psychiatry is one of the most selective and highly cited journals in the field of psychiatric neuroscience. It is ranked 4th out of 135 Psychiatry titles and 13th out of 251 Neurosciences titles in the Journal Citations Reports® published by Thomson Reuters. The 2012 Impact Factor score for Biological Psychiatry is 9.247.ABOUT ELSEVIER

Elsevier is a world-leading provider of scientific, technical and medical information products and services. The company works in partnership with the global science and health communities to publish more than 2,000 journals, including The Lancet and Cell, and close to 20,000 book titles, including major reference works from Mosby and Saunders. Elsevier's online solutions include ScienceDirect, Scopus, Reaxys, ClinicalKey and Mosby's Nursing Suite, which enhance the productivity of science and health professionals, and the SciVal suite and MEDai's Pinpoint Review, which help research and health care institutions deliver better outcomes more cost-effectively.

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