The development of new, more effective antipsychotics with fewer adverse effects (eg, extrapyramidal symptoms, tardive dyskinesia, metabolic syndrome) is paramount. In most patients with schizophrenia, the disease is resistant or only partially responsive to treatment with available antipsychotics. In addition, the adverse effects of both typical and atypical antipsychotics add to the difficulty of obtaining a satisfactory treatment response.
Given that the neurobiology of schizophrenia is poorly understood, the development of new treatments is primarily based on current pharmacological models of schizophrenia, such as dopaminergic and serotoninergic models. In addition to these models of neurotransmission, glutamatergic neurotransmission has been implicated in the pathophysiology of schizophrenia.1,2 Because the N-methyl d-aspartic acid (NMDA) receptor, a subtype of the ionotropic glutamate receptor, plays an important role in neurodevelopment and cognition, deficits in NMDA neurotransmission can potentially account for developmental risk factors and cognitive impairments in schizophrenia.
The involvement of the NMDA system in schizophrenia is further evidenced by the effects of the psychotomimetic drug phencyclidine and the dissociative anesthetic, ketamine, both of which are NMDA-receptor antagonists. The psychotic symptoms induced by these NMDA antagonists involve not only positive symptoms, as seen with dopaminergic agonists, but negative symptoms and cognitive deficits as well.3 These findings support the possibility that symptoms observed in patients with schizophrenia could arise through attenuated NMDA receptor-mediated neurotransmission. It can be further postulated that the psychotomimetic effects may not be limited to noncompetitive antagonists but could result from any dysfunctional attenuation of the NMDA receptor-mediated neurotransmission.
NMDA involvement in schizophrenia
Two lines of study support the pharmacological model of NMDA hypofunction as being involved in schizophrenia. The first line of evidence comes from findings of clinical studies that indicate that new NMDA-enhancing agents are beneficial in the treatment of schizophrenia symptoms. These agents serve as coagonists at the NMDA receptor, which bind to the glycine (and/or d-serine) binding site concurrently with separate occupancy of the glutamate binding site (Figure). Occupancy of both glutamate and “glycine” sites is essential for the activation of the NMDA receptor. Amino acids acting on either site are coagonists; just as d-serine or glycine cannot activate the NMDA receptor, neither aspartate nor glutamate alone can activate the NMDA receptor without the co-occupancy of the glycine “modulatory” site.
Considering that agonists of the NMDA recognition site are excitotoxic, molecules that act on the obligatory NMDA-glycine site are promising therapeutic candidates. Several agents that directly or indirectly enhance the NMDA function via the activation of the NMDA-glycine site have been tested to determine their effectiveness in the treatment of schizophrenia. The Table summarizes the mechanisms of action of these agents. These agonists of the NMDA-glycine site include the simple amino acids glycine, d-serine, d-alanine, and the partial agonist d-cycloserine.4-7 Most of the double-blind placebo-controlled studies of the NMDA-enhancing agents showed significant improvement in multiple symptom domains of schizophrenia, including positive, negative, cognitive, and depressive symptoms. In addition, the effect of d-cycloserine is limited to negative symptoms and the effect is at times negative.6
Because glycine transporter 1 (GlyT1) plays a pivotal role in maintaining the concentration of glycine within NMDA synapses at a subsaturating level, and the anatomical distribution of GlyT1 is parallel to that of the NMDA receptor, another approach to enhance NMDA neurotransmission is by blocking the reuptake of glycine through GlyT1. This is analogous to the rationale behind using a serotonin reuptake inhibitor to enhance serotonergic neurotransmission. In support of the critical role that GlyT1 plays in NMDA neurotransmission, the GlyT1 inhibitor, a sarcosine (N-methylglycine) analogue, N[3-(49-fluorophenyl)3-(49 phenylphenoxy)propyl] sarcosine, and the GlyT1 knockdown mutation have been shown to enhance NMDA neurotransmission.8 Sarcosine, which is an endogenous inhibitor of GlyT1, has shown clinical efficacy when added to typical and atypical antipsychotics, and it has also shown efficacy when administered alone, thereby supporting its NMDA-enhancing and antipsychotic function.9
The second line of inquiry comes from a series of genetic linkage and association studies that support hypofunction of NMDA neurotransmission in schizophrenia, a common defect at glutamatergic and other synapses, including the NMDA synapse.10 NMDA neurotransmission is influenced to varying degrees by most, if not all, of the putative susceptibility genes including the proline dehydrogenase gene, the dysbindin gene, the neuregulin gene 1, the disrupted-in-schizophrenia gene 1, the V-akt murine thymoma viral oncogene homolog gene 1, the regulator of G-protein signaling gene 4, and the metabotropic glutamate receptor gene 3. These risk genes include the enzyme that catabolizes d-serine and d-alanine, d-amino acid oxidase (DAAO), and its primate-specific activator G72; they are directly involved in NMDA neurotransmission (Figure). DAAO appears to be the critical determinant of d-serine levels, since its activity correlates inversely with d-serine levels both regionally and developmentally. Facilitation of G72 function up-regulates DAAO activity, enhances metabolism of d-serine and d-alanine, and attenuates NMDA neurotransmission.
Over the past 5 years, more than 10 studies have demonstrated the association of G72 with schizophrenia or bipolar disorder.11 This is an intriguing association, given recent findings that serum and cerebrospinal fluid levels of d-serine are reduced in patients with schizophrenia.12
Drugs Referenced in this article
Ketamine (Ketanest, others)
1. Tsai G, Coyle JT. Glutamatergic mechanisms in schizophrenia. Annu Rev Pharmacol Toxicol. 2001;42: 165-179.
2. Lindsley CW, Shipe WD, Wolkenberg SE, et al. Progress towards validating the NMDA receptor hypofunction hypothesis of schizophrenia. Curr Top Med Chem. 2006;6:771-785.
3. 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;51:199-214
4. Javitt DC, Silipo G, Cienfuegos A, et al. Adjunctive high-dose glycine in the treatment of schizophrenia. Int J Neuropsychopharmacol. 2001;4:385-391.
5. Tsai G, Yang P, Chung LC, et al. D-Serine added to antipsychotics for the treatment of schizophrenia. Biol Psychiatry. 1998;44:1081-1089.
6. Tsai GE, Yang P, Chang YC, Chong MY. D-Alanine added to antipsychotics for the treatment of schizophrenia. Biol Psychiatry. 2006;59:230-234.
7. Goff DC, Tsai G, Levitt J, et al. A placebo-controlled trial of D-cycloserine added to conventional neuroleptics in patients with schizophrenia. Arch Gen Psychiatry. 1999;56:21-27.
8. Tsai G, Ralph-Williams RJ, Martina M, et al. Gene knockout of glycine transporter 1: characterization of the behavioral phenotype. Proc Natl Acad Sci U S A. 2004;101:8485-8890.
9. Tsai G, Lane HY, Yang P, et al. Glycine transporter I inhibitor, N-methylglycine (sarcosine) added to antipsychotics for the treatment of schizophrenia. Biol Psychiatry. 2004;55:452-456.
10. Harrison PJ,Weinberger DR. Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence. Mol Psychiatry. 2005;10:40-68.
11. Chumakov I, Blumenfeld M, Guerassimenko O, et al. Genetic and physiological data implicating the new human gene G72 and the gene for D-amino acid oxidase in schizophrenia. Proc Natl Acad Sci U S A. 2002; 99:13675-13680.
12. Hashimoto K, Engberg G, Shimizu E, et al. Reduced D-serine to total serine ratio in the cerebrospinal fluid of drug naive schizophrenic patients. Prog Neuropsychopharmacol Bio Psychiatry. 2005;29:767- 769.
13. Altamura AC, Bobo WV, Meltzer HY. Factors affecting outcome in schizophrenia and their relevance for psychopharmacological treatment. Int Clin Psychopharmacol. 2007;22:249-267.
14. Lane HY, Liu YC, Huang CL, et al. Sarcosine (N-methylglycine) treatment for acute schizophrenia: a randomized, double-blind study. Biol Psychiatry. 2008;63:9-12.
15. Green MF.What are the functional consequences of neurocognitive deficits in schizophrenia? Am J Psychiatry. 1996;153:321-330.
16. Lechner SM. Glutamate-based therapeutic approaches: inhibitors of glycine transport. Curr Opin Pharmacol. 2006;6:75-81.
17. Lane HY, Huang CL, Wu PL, et al. Glycine transporter I inhibitor, N-methylglycine (sarcosine), added to clozapine for the treatment of schizophrenia. Biol Psychiatry. 2006;60:645-649.
18. Lane HY, Liu YC, Huang CL, et al. Double blind comparison of sarcosine (N-methylglycine), D-serine and placebo treatments for chronic schizophrenia. Presented at: Annual Meeting of American College of Neuropsychopharmacology; December 9-13, 2007; Boca Raton, FL.
19. Lane HY, Chang YC, Liu YC, et al. Sarcosine or D-serine add-on treatment for acute exacerbation of schizophrenia: a randomized, double-blind, placebocontrolled study. Arch Gen Psychiatry. 2005;62:1196- 1204.
20. Goff DC,Tsai G, Manoach DS, Coyle JT. Dose-finding trial of D-cycloserine added to neuroleptics for negative symptoms in schizophrenia. Am J Psychiatry. 1995;152:1213-1215.
21. Heresco-Levy U, Javitt DC, Ebstein R, et al. D-Serine efficacy as add-on pharmacotherapy to risperidone and olanzapine for treatment-refractory schizophrenia. Biol Psychiatry. 2005;57:577-585.
22. Tsai G, Falk W, Gunther G, Coyle JT. D-Cycloserine improves cognition of Alzheimer’s disease. Am J Psychiatry. 1999;156:467-469.
23. Heresco-Levy U, Kremer I, Javitt DC, et al. Pilotcontrolled trial of D-cycloserine for the treatment of post-traumatic stress disorder. Int J Neuropsychopharmacol. 2002;5:301-307.
24. Posey DJ, Kem DL, Swiezy NB, et al. A pilot study of D-cycloserine in subjects with autistic disorder.Am J Psychiatry. 2004;161:2115-2117.
25. Ressler KJ, Rothbaum BO, Tannenbaum L, et al. Cognitive enhancers as adjuncts to psychotherapy: use of D-cycloserine in phobic individuals to facilitate extinction of fear. Arch Gen Psychiatry. 2004;61:1136- 1144.