Increasing NMDA Glutamate Receptor Instead of Blocking It Produces Antidepressant-Like Effects

Results from animal models of depression and a human clinical trial show that enhancing, instead of blocking, the NMDA glutamate receptor can cause antidepressant-like effects.

Studies have shown that ketamine works to produce antidepressant effects in depressed patients who had not responded to past treatments. It does this by blocking one of the targets for the brain neurotransmitter glutamate, the N-methyl-D-aspartate (NMDA) glutamate receptor. However, a new study concludes that enhancing, as opposed to blocking, the NMDA glutamate receptor can also cause antidepressant-like effects. The study was published in the November 15, 2013 issue of Biological Psychiatry.

Researchers from China Medical University Hospital in Taiwan worked in collaboration with scientists from University of California in Los Angeles to study sarcosine in an animal model of depression and, in another clinical trial, 40 patients with depression. Hsien-Yuan Lane, MD, Ph.D., the author of the article, noted in a press release, “We found that enhancing NMDA function can improve depression-like behaviors in rodent models and in human depression.”

For the six-week clinical trial, 40 patients were randomly assigned to receive sarcosine or citalopram (Celexa), an antidepressant already on the market that was used as the control. Neither the patients nor their doctors knew which drug they were receiving during the study. When compared to citalopram, patients who received sarcosine reported significantly improved mood scores, experienced relief of their depression symptoms, and were more likely to continue in the study. Neither group experienced any major side effects; however, the citalopram group reported more relatively minor side effects. Sarcosine improved scores of the Hamilton Depression Rating Scale, Clinical Global Impression, and Global Assessment of Function tests more than the citalopram treatment, the study noted.

Test rats were used to investigate the effects of sarcosine on NMDA glutamate receptor. The researchers conducted forced swim tests, tail suspension tests, elevated plus maze tests, novelty-suppressed feeding tests, and chronic unpredictable stress tests. Sarcosine decreased immobility in both the forced swim test and the tail suspension test. It reduced the latency to feed in the novelty-suppression feeding test and reversed behavioral deficits caused by the chronic unpredictable stress test. These effects are characteristic of an antidepressant.