Evidence-Based Reviews

Glutamate: New hope for schizophrenia treatment

Current Psychiatry. 2011 April;10(4):68-74

References

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5. Egan MF, Goldberg TE, Kolachana BS, et al. Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia. Proc Natl Acad Sci U S A. 2001;98:6917-6922.

6. Kantrowitz JT, Javitt DC. Glutamatergic approaches to the conceptualization and treatment of schizophrenia. In: Kantrowitz JT Javitt DC, eds. Handbook of neurochemistry and molecular neurobiology: schizophrenia. 3rd ed. New York, NY: Springer; 2009.

7. Krystal JH, Karper LP, Seibyl JP, et al. Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry. 1994;51(3):199-214.

8. Krystal J, D’Souza DC, Mathalon D, et al. NMDA receptor antagonist effects, cortical glutamatergic function, and schizophrenia: toward a paradigm shift in medication development. Psychopharmacology. 2003;169(3-4):215-233.

9. Malhotra AK, Pinals DA, Adler CM, et al. Ketamine-induced exacerbation of psychotic symptoms and cognitive impairment in neuroleptic-free schizophrenics. Neuropsychopharmacology. 1997;17(3):141-150.

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16. Javitt DC, Balla A, Burch S, et al. Reversal of phencyclidine-induced dopaminergic dysregulation by N-methyl-D-aspartate receptor/glycine-site agonists. Neuropsychopharmacology. 2004;29(2):300-307.

17. Kantrowitz JT, Malhotra AK, Cornblatt B, et al. High dose D-serine in the treatment of schizophrenia. Schizophr Res. 2010;121(1-3):125-130.

18. Tsai GE, Lin PY. Strategies to enhance N-methyl-D-aspartate receptor-mediated neurotransmission in schizophrenia a critical review and meta-analysis. Curr Pharm Des. 2010;16(5):522-537.

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28. A multi-center, inpatient, phase 2, double-blind, placebo-controlled dose ranging study of LY2140023 in patients with DSM-IV schizophrenia. ClinicalTrials.gov identifier NCT00520923. Available at: http://clinicaltrials.gov/ct2/show/NCT00520923?intr=LY2140023&rank=1. Accessed February 23 2011.

Glycine transport inhibitors. A potential indirect approach to raising glycine levels in the brain is using GlyT1-type glycine transport inhibitors (GTIs). GlyT1 transporters are co-localized in brain with NMDARs and modulate local glycine levels. Rather than binding directly to the NMDAR glycine binding site, GTIs increase glycine levels in the synapse by preventing its removal by GlyT1 transporters. Their function is analogous to using selective serotonin reuptake inhibitors to increase serotonin levels in patients with depression.⁶

Sarcosine (N-methylglycine) is a naturally occurring GlyT1 inhibitor that has been used in early clinical trials in Taiwan. Initial studies with sarcosine showed efficacy similar to—and in some cases better than—that of direct glycine/D-serine site agonists when added to first-generation or non-clozapine second-generation antipsychotics.¹⁸ Sarcosine also has been found to be effective for acute treatment of schizophrenia.²⁰ At present, however, sarcosine is not available for experimental use in the United States because of toxicity considerations.

Using high-affinity GTIs for schizophrenia was first proposed in the mid-1990s,⁶ but such compounds are only now entering clinical efficacy studies. Most recently, phase II results were presented for RG1678, a compound developed by Hoffman LaRoche.²¹ The study targeted persistent negative symptoms in patients receiving chronic antipsychotic treatment. Adding RG1678, 10 mg and 30 mg, to antipsychotics led to significant improvement in persistent negative symptoms vs placebo. These promising results are being followed up in phase III studies.

Other glutamatergic options. Few compounds are available to modulate NMDARs at sites other than the glycine/D-serine site. One study administered N-acetylcysteine, a glutathione precursor, as a potential treatment for persistent negative symptoms.²² Encouraging clinical results were observed in this double-blind study, along with improvement in electrophysiologic measures, negative symptoms, and overall functioning, but the study was limited by relatively high rates of noncompletion. Preclinical studies have combined D-serine with an inhibitor of D-amino acid oxidase to prevent D-serine breakdown.²³ In rodents, this approach produces a 30-fold increase in D-serine potency.

Tetrahydrobiopterin (BH₄) is a cofactor for enzymes responsible for the synthesis of dopamine and other monoamines, and presynaptic release of dopamine and glutamate. Reductions in BH₄ levels have been reported in schizophrenia, which suggests that this compound may be etiologically important.²⁴ Researchers have initiated a study of this compound in schizophrenia.

Other schizophrenia models propose that the crucial issue is not NMDA blockade but subsequent dysregulation of presynaptic glutamate release. Type 2/3 metabotropic glutamate receptors (mGluR2/3) are located on presynaptic glutamate terminals and inhibit presynaptic glutamate release. mGluR2/3 agonists have been shown to reverse ketamine’s effects in humans and in animal models,^25,26 which suggests a potential role in schizophrenia treatment.

Clinical Point

A meta-analysis suggests that glycine/D-serine site antagonists can significantly improve negative symptoms

The first mGluR2/3 agonist entered into monotherapy clinical efficacy trials for schizophrenia was LY-2140023. In an initial trial, this compound showed significant efficacy in improving positive and negative symptoms, comparable to that of olanzapine.²⁷ However, a follow-up study failed because of a large placebo effect,²⁸ which leaves the efficacy question unresolved.

In contrast to mGluR2/3, type 5 metabotropic receptors (mGluR5) are co-localized with NMDA receptors and potentiate activation. Thus, mGluR5 agonists also may be effective for treating schizophrenia. These compounds remain in preclinical development. Other approaches, such as stimulating specific types of GABA receptors to overcome glutamatergic deficits, remain promising but have not been tested in definitive clinical trials.

Clinical Point

GlyT1 -type transport inhibitors increase glycine levels by preventing glycine’s removal by GlyT1 transporters

Related Resources

Kantrowitz JT, Javitt DC. N-methyl-D-aspartate (NMDA) receptor dysfunction or dysregulation: the final common pathway on the road to schizophrenia? Brain Res Bull. 2010; 83(3-4): 108-121.
Kantrowitz JT, Javitt DC. Glutamatergic approaches to the conceptualization and treatment of schizophrenia. In: Kantrowitz JT, Javitt DC, eds. Handbook of neurochemistry and molecular neurobiology: schizophrenia. 3rd ed. New York, NY: Springer; 2009.

Drug Brand Names

Chlorpromazine • Thorazine
Clozapine • Clozaril
Ketamine • Ketalar
Olanzapine • Zyprexa

Disclosures

Dr. Javitt receives grant/research support from Jazz Pharmaceuticals, Pfizer Inc., and Roche and is a consultant to AstraZeneca, Cypress, Eli Lilly and Company, NPS Pharmaceuticals, Sepracor, Solvay, Sunovion, and Takeda. He holds intellectual property rights for use of glycine, D-serine, and glycine transport inhibitors in treatment of schizophrenia and related disorders.

Dr. Kantrowitz receives grant/research support from Eli Lilly and Company, Jazz Pharmaceuticals, Pfizer Inc., Roche, and Sepracor.

Preparation of this manuscript was supported in part by National Institute of Health grants R01 DA03383, R37 MH49334, and P50 MH086385.