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Studies Explore Glutamate Receptors as Target for Schizophrenia Monotherapy

2 September 2007. Two recent studies show that focusing on glutamate neurotransmission may lead to new treatments for schizophrenia. The first comes from a multinational team of scientists that includes Ferenc Martenyi of Lilly Medical Center in Vienna, James A. Monn of Eli Lilly and Company in Indianapolis, and first author Sandeep T. Patil, formerly of Eli Lilly but now at Merck and Company in North Wales, Pennsylvania. Published online today in Nature Medicine, the paper reported a randomized, controlled trial that found that an agonist of metabotropic glutamate receptors relieves schizophrenia symptoms (preliminary results were reported by SRF from the ICOSR 2007 meeting).

In a paper published online at Biological Psychiatry on July 20, Guochuan E. Tsai of Harbor-UCLA Medical Center, lead author Hsien-Yuan Lane of China Medical University and Hospital in Taichung, and others in Taiwan describe a small, double-blind study of sarcosine, a molecule that enhances glutamate neurotransmission via NMDA receptors. The researchers report evidence suggesting that drug-naïve subjects with symptomatic schizophrenia had significant reductions in psychopathology with sarcosine.

Activating glutamate receptors

Today, antipsychotic drugs that act on dopamine receptors comprise the mainstay of the schizophrenia treatment arsenal, but their side effects and other shortcomings have spurred a search for alternatives. The glutamate hypothesis of schizophrenia, which puts poorly functioning NMDA receptors at the heart of the disease (see SRF Current Hypothesis by Bita Moghaddam), points to drugs that affect glutamate neurotransmission.

The Nature Medicine paper details work previously presented at several recent meetings (see SRF ICOSR 2007 meeting report). It builds on animal studies indicating that a substance called LY404039 may exert antipsychotic effects. This amino acid analog acts selectively as an agonist on metabotropic glutamate 2/3 receptors. Unlike ionotropic receptors, metabotropic receptors produce their effects through second-messenger chemicals. Since humans cannot absorb LY404039 well after taking it orally, the study instead used a substance called LY2140023, which breaks down to form LY404039.

The study recruited 196 hospital patients, ages 18 to 65 years old, who showed what the researchers called “considerable pathology of schizophrenia.” It excluded women of childbearing potential.

In the double-blind study, subjects received 4 weeks of treatment with placebo, LY2140023, or olanzapine, an atypical antipsychotic. Those in the LY2140023 and olanzapine groups not only showed significantly higher rates of completing treatment, but also larger reductions in both positive and negative symptoms of schizophrenia than placebo-treated patients.

The apparent benefits of taking LY2140023 came without elevated prolactin levels or extrapyramidal symptoms. Patients who were assigned the drug even lost weight. However, compared to those on placebo, their moods fluctuated more.

According to the Lilly team, the study “provides strong new evidence for the role of glutamate modulation in treating psychosis.” Additionally, they conclude that the results support the safety and efficacy of LY2140023 as a potential monotherapy for a variety of schizophrenia symptoms. At the same time, they acknowledge the need for longer-term studies.

Blocking glycine reuptake

The second study randomly assigned subjects to receive either 1 or 2 grams of sarcosine daily for 6 weeks. (There were no arms of the trial with placebo or other antipsychotic treatment.) Sarcosine, also known as N-methylglycine, seems to improve NMDA neurotransmission by blocking reuptake of endogenous glycine.

Lane and colleagues note that prior studies support sarcosine’s efficacy for treating schizophrenia when used with other antipsychotics (Lane et al., 2005; Tsai et al., 2004). They wondered if it would work as the sole antipsychotic.

The study recruited Taiwanese hospital patients, ages 18-60 years old, who were experiencing acute schizophrenia flare-ups. Of the 20 who started the study, three in the low-dose group and one in the high-dose group left due to poor response.

The study found no statistically significant differences between the groups on symptom or quality of life measures. However, Lane and colleagues write, “There were more patients showing a clinically significant response in the 2-g group.” In fact, 45 percent of patients in that group showed a response, defined as a 20 percent or more decrease in total scores on the Positive and Negative Syndrome Scale. No one in the 1-g group responded.

A closer look revealed that the response occurred only in the five subjects who had never taken antipsychotic drugs. The researchers suggest that impaired NMDA receptors might play an important role early in the disease process, when treatment with NMDA enhancers might prove most fruitful.

The authors deemed both doses “well-tolerated.” They saw no extrapyramidal effects. Insomnia was the most frequent adverse event, but the groups showed no significant difference in the mean dose of lorazepam they needed to counter insomnia or agitation. In contrast to the study of LY2140023, two subjects on the high dose and one on the low dose gained 1 to 2 kilograms of body weight.

Of course, the study’s small size, short duration, and lack of a placebo arm make drawing definitive conclusions from it difficult. Still, together with the mGlu2/3 agonist study, it may offer clues to researchers who are eyeing the glutamate system for potential remedies.—Victoria L. Wilcox.

Lane H-Y, Liu Y-C, Huang C-L, Chang Y-C, Liau C-H, Perng C-H, Tsai GE. Sarcosine (N-methylglycine) treatment for acute schizophrenia: A randomized, double-blind study. Biological Psychiatry. July 20, 2007. Abstract

Patil ST, Zhang L, Martenyi F, Lowe SL, Jackson KA, Andreev BV, Avedisova AS, Bardenstein LM, Gurovich IY, Morozova MA, Mosolov SN, Neznanov NG, Reznik AM, Smulevich AB, Tochilov VA, Johnson BG, Monn JA, Schoepp DD. Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: A randomized Phase 2 clinical trial. Nature Medicine. Sept 2, 2007. Abstract

Comments on News and Primary Papers
Comment by:  Dan Javitt, SRF Advisor
Submitted 3 September 2007 Posted 3 September 2007

A toast to success, or new wine in an old...  Read more

View all comments by Dan Javitt

Comment by:  Gulraj Grewal
Submitted 4 September 2007 Posted 4 September 2007
  I recommend the Primary Papers

Comment by:  Shoreh Ershadi
Submitted 8 June 2008 Posted 9 June 2008
  I recommend the Primary Papers
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