Elsevier

Biological Psychiatry

Volume 44, Issue 11, 1 December 1998, Pages 1081-1089
Biological Psychiatry

Priority Communications
D-serine added to antipsychotics for the treatment of schizophrenia

https://doi.org/10.1016/S0006-3223(98)00279-0Get rights and content

Abstract

Background: Hypofunction of N-methyl-D-aspartate (NMDA) subtype glutamate receptor has been implicated in the pathophysiology of schizophrenia. D-serine is a full agonist of the glycine site of NMDA receptor, an endogenous cotransmitter enriched in corticolimbic regions and distributed in parallel with NMDA receptor. Supplementation of D-serine may improve the symptoms of schizophrenia.

Methods: Thirty-one Taiwanese schizophrenic patients enrolled in a 6-week double-blind, placebo-controlled trial of D-serine (30 mg/kg/day), which was added to their stable antipsychotic regimens. Of these, 28 completed the trial. Measures of clinical efficacy, side effects, and serum levels of amino acids and D-serine were determined every other week. Wisconsin Card Sorting Test (WCST) was performed at the beginning and end of the trial.

Results: Patients who received D-serine treatment revealed significant improvements in their positive, negative, and cognitive symptoms as well as some performance in WCST. D-serine levels at week 4 and 6 significantly predicted the improvements. D-serine was well tolerated and no significant side effects were noted.

Conclusions: The significant improvement with the D-serine further supports the hypothesis of NMDA receptor hypofunction in schizophrenia. Given the effects of D-serine on positive symptoms, a trial of D-serine alone in schizophrenia should be considered.

Introduction

Schizophrenia is a devastating mental disorder with high morbidity and mortality, affecting about 1% of the population worldwide. The etiology of schizophrenia remains elusive. Although neuroleptic drugs that act by blocking dopamine D2 receptors have been the mainstay of treatment for over 40 years, their efficacy, especially with regard to negative symptoms and cognitive dysfunction, is limited (Carpenter and Buchanan 1994). In addition, conventional antipsychotics produce significant side effects and consequently result in poor compliance. Although new antipsychotics targeting both D2 and serotonin (5-HT)2 receptors have more favorable side effect profiles when compared to the conventional antipsychotics, they are also limited by their clinical efficacy Marder and Meibach 1994, Small et al 1997, Tollefson et al 1997, Zimbroff et al 1997. In addition, of all the atypical agents, only clozapine has been found superior to conventional antipsychotics in rigorously defined refractory schizophrenic patients (Kane 1992). Thus, there is a great need to develop new therapeutic agents, providing additional benefits for the substantial portion of schizophrenic patients who are only partially responsive or resistant to the available antipsychotics.

In addition to dopaminergic neurotransmission, glutamatergic neurotransmission has been implicated in the pathophysiology of schizophrenia Coyle 1996, Javitt and Zukin 1991, Olney and Farber 1995. Glutamate, aspartate, and related excitatory amino acids (EAAs), are the primary neurotransmitters mediating fast excitatory neurotransmission in the central nervous system (CNS) via ligand-gated cation channels (Cotman and Monaghan 1987). Furthermore, the N-methyl-D-aspartate (NMDA) receptor, a subtype of ionotropic glutamate receptor, plays an important role in neurocognition and neurotoxicity. Glycine serves as a coagonist at the NMDA receptor with activation of both the glutamate and glycine sites required for channel opening (Thomson et al 1989).

The most compelling link between the NMDA system and schizophrenia concerns the mechanism of action of phencyclidine (PCP); for reviews, see: Coyle 1996, Deutsch et al 1989, Halberstadt 1995, Javitt and Zukin 1991. The psychotomimetic PCP, and its analogues MK-801 and ketamine, bind to a site within the channel and act as noncompetitive antagonists. Acute and chronic abuse of PCP can produce a psychotic condition with compelling similarities to schizophrenic psychosis (Javitt and Zukin 1991). Ketamine and MK-801 also elicit similar symptoms as PCP Grotta 1994, Herrling 1994, Kristensen et al 1992, Krystal et al 1994.

In fact, NMDA antagonist-induced psychosis models certain aspects of schizophrenia more closely than the amphetamine/dopamine agonist model (Krystal et al 1994). The psychosis induced by NMDA antagonists not only causes positive symptoms similar to the action of dopaminergic agonists but also negative symptoms and cognitive deficits associated with schizophrenia. Therefore, it was suggested that dysfunction or dysregulation of NMDA receptor-mediated neurotransmission might be a primary deficit in schizophrenia Coyle 1996, Javitt and Zukin 1991, Olney and Farber 1995.

The precise mechanisms by which NMDA neurotransmission dysfunction might occur in schizophrenia remain to be determined. We have previously demonstrated alterations in brain metabolism of glutamatergic neurotransmission in postmortem brains of schizophrenia (Tsai et al 1995). Others have reported differences in glutamate receptor expression in cortex and hippocampus in postmortem studies in schizophrenia Ulas and Cotman 1993, D’souza et al 1995. Accordingly, potentiation of NMDA receptor-mediated neurotransmission has been proposed as a treatment of schizophrenia Deutsch et al 1989, Javitt and Zukin 1991.

It is plausible that EAAs can be used for the potentiation of NMDA neurotransmission in the treatment of schizophrenia; however, EAAs are a double-edged sword. EAAs can cause neuronal damage when there is persistent or excessive stimulation of their receptors, a phenomenon known as “excitotoxicity” (Olney 1990). This has led to the speculation that they would not be good candidates to potentiate the NMDA neurotransmission. Augmentation through the NMDA-glycine site appears to be a safer way to enhance the NMDA neurotransmission, with a more benign side effect profile (Leeson and Iversen 1994). The glycine site of the NMDA receptor (NMDA-glycine site) is likely not saturated (for a review: Hashimoto and Oka 1997). The results of some glycine Heresco-Levy et al 1996b, Javitt et al 1994 and D-cycloserine, a partial agonist of the NMDA-glycine site, trials with patients on stable doses of typical neuroleptics Goff et al 1995, van Berckel et al 1996 support this hypothesis, but their effects are mainly for the improvement of negative symptoms. In addition, several reports of glycine and D-cycloserine trials did not support their clinical efficacy (for a review: D’souza et al 1995). Therefore, it is important to test other NMDA-glycine site agents.

D-serine is a selective and potent agonist at the NMDA-glycine site (for a review: Hashimoto and Oka 1997). There is no other known neurotransmitter system affected by D-serine, including the strychnine-sensitive inhibitory glycine receptor. D-serine is selectively enriched in forebrain Kumashiro et al 1995, Schell et al 1997 with regional distribution and the postnatal changes closely paralleling the NMDA receptors (Hashimoto et al 1993b). Immunocytochemical studies reveal that D-serine is located close to the NMDA receptor on dendritic spines (Schell et al 1997), suggesting D-serine may be an important endogenous ligand for the NMDA-glycine site. In addition to its action as a coagonist, D-serine prevents the desensitization of NMDA current (Mayer et al 1989). Supporting the hypo-NMDA hypothesis of schizophrenia, D-serine selectively blocks the PCP-induced hyperactivity and stereotypy behavior Contreras 1990, Tanii et al 1991, Tanii et al 1994.

For the present study, we hypothesized that D-serine can be a therapeutic agent for schizophrenia due to its activity as an endogenous full agonist on the NMDA-glycine site. In addition, glycine and D-cycloserine trials had been reported mainly in Caucasian populations Goff et al 1995, Heresco-Levy et al 1996b, Javitt et al 1994, van Berckel et al 1996. It is important to test this approach in other ethnic populations. We hence performed a double-blind placebo-controlled study of D-serine added to antipsychotics in a group of Taiwanese schizophrenic patients.

Section snippets

Subjects

Patients were recruited from the affiliated day program and inpatient unit of the Tsyr-Huey Mental Hospital, Kaohsiung Medical School, which is one of the major medical centers in Taiwan. The research protocol was approved by the institutional review board. After a description of the study to the patients, written informed consent was obtained. Thirty-one Taiwanese schizophrenic patients enrolled and 28 completed the double-blind, placebo-controlled study. Three patients withdrew consent and

Results

Characteristics of the schizophrenic illness were similar in the two groups (Table 1). Both groups had similar ratios of paranoid vs. nonparanoid subtypes of schizophrenia; however, the D-serine group had higher positive symptoms at baseline (t = 2.5, p = .02) despite randomization (Table 2). Since the patients were on different antipsychotics and the placebo group received higher, but statistically insignificant, chlorpromazine dosage, the chlorpromazine equivalent dose was also included in

Discussion

Our findings strongly indicate that D-serine, acting as a full agonist on the NMDA-glycine site, can improve positive, negative, and cognitive symptoms. Since there is no other known signal transduction site at which D-serine acts except the NMDA-glycine site, the effect of D-serine is likely due to its specific action on the NMDA receptor. Although the results of glycine and D-cycloserine treatments were mixed (D’souza et al 1995), together with the positive findings of glycine (Heresco-Levy

Acknowledgements

Supported in part by NARSAD Young Investigator Award, Stanley Foundation Research Award, and the Peter and Elizabeth C. Tower Foundation (GT).

The authors thanks Drs. Mian-Yoon Chong and Chien-Te Lee for their generous support and Dr. Cheng-Sheng Chen, Hsiu-Yueh Wu, and Chih-Ping Song for their participation in the study.

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