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Faustman WO, Elliot PJ, Ringo DL, Fauli KF (1993): CSF 5 HIAA and atmospheric pressure: Failure to replicate. Biol Psychiatry 33:61-62. Gordon E, Perlow M, Oliver J, Ebert M, Kopin I (1975): Origins of catecholamine metabolites in monkey cerebrospinal fluid. J Neurochem 25:347-349. Heilig M, M~nsson JE, Blennow K (1996): Cerebrospinal fluid monoamine metabolites and atmospheric pressure. Biol Psychiatry 39:299-301. Nordin C, Swedin A, Zachau A (1992): CSF 5 HIAA and atmospheric pressure. Biol Psychiatry 31:644-645. Sj~strtm R, Ekstedt J, ,~ngg~rd E (1975): Concentration gradients of monoamine metabolites in human cerebrospinal fluid. J Neurol Neurosurg Psychiatry 38:666-668. Wehrens J (1981): Sammanhange mellem selvmordshyppighed og luftryksforhold. Ugeskr Laeger 143:2293-2296.

Glycine Therapy of Schizophrenia To the editor: In his recent editorial, Dr. Waziri (1996) discusses some caveats concerning long-term glycine treatment of schizophrenia, in particular the concept that glycine may induce excitotoxic effects at high doses. Although it is always reasonable to be concerned about the long-term risks of any drug treatment, or even of food additives such as aspartame (Olney 1984), potential benefits of treatment must also be considered. In the case of glycine, there are reasons to believe that the risks of treatment discussed in the editorial may be overstated. Further, the risks of not treating must also be considered. The articles cited in the editorial derive largely from studies of artificial stroke in rodents. Brain conditions that prevail during artificial stroke, however, are dramatically different from those encountered normally. For example, in one study (Globus et al 1991) glutamate levels during stroke were 25-fold higher than preischemic levels. Under such circumstances, elevation of brain glycine levels may exacerbate the toxic effects of glutamate. In schizophrenia, however, glutamate levels are, if anything, reduced (Tsai et al 1995). No study has yet demonstrated neurotoxic effects of glycine in the presence of physiological glutamate levels. Furthermore, studies that have specifically addressed the effects of glycine in the absence of increased glutamate have concluded that "exposure of cortical neurons to glycine or D-serine had very little effect on cell survival when added alone" (Patel et al 1990). It should also be noted that there are data addressing the effects of chronic large doses of glycine. The best data derive from studies of the glycine prodrug milacemide (CP 1552 S, 2-n-pentylaminoacetomide). Milacemide is an N-substituted glycineamide derivative that is metabolized in brain to glycine. Administration of 0.1 g/kg milacemide in rodents induces elevations in brain glycine levels that are similar to those induced by 0.45 g/kg glycine (Christophe et al 1983; Chapman and Hart 1988). Moreover, the elevations in cerebrospinal fluid (CSF) glycine levels induced by milacemide persist far longer than the comparable elevations induced by glycine (Semba et al 1993). Thus, if elevation of glycine levels were associated with long-

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term neuropathological changes, such changes would be far more apparent following milacemide, than following glycine, treatment. Milacemide has been extensively studied in humans as a potential antiepileptic and cognition enhancer. It has been shown to be capable of reversing discriminative stimulus effects of phencyclidine and of enhancing cognition in various animal (Handelmann et al 1989; Quartermain et al 1990; Finkelstein et al 1994) and human (Schwartz et al 1991) models, consistent with its ability to potentiate N-methyl-D-aspartate (NMDA) receptor neurotransmission via metabolism to glycine. Before the drug was made available for clinical use, it was subjected to a full range of subacute, subchronic, and chronic toxicity studies (up to 2 years) at doses of up to 400 mg/kg. No gross or histopathological brain abnormalities were found during mandatory preclinical testing preceding its Food and Drug Administration approval. Further, many hundreds of patients were exposed to milacemide in various clinical trials without evidence of neurotoxicity, although the drug was eventually withdrawn due to hepatoxocity unrelated to central nervous system (CNS) glycine elevations. Counterbalancing the potential, and as yet unproven, risk of glycine-induced excitotoxicity is the potential risk that schizophrenia is associated with ongoing NMDA hypofunction-induced neurotoxicity. Animals given NMDA antagonists may develop widespread neuronal degeneration. It has been proposed that this process may be ongoing in schizophrenia and may lead to progressive deterioration (Olney and Farber 1995). Lesions similar to those observed following NMDA antagonist administration have not yet been demonstrated in postmortem brain tissue from schizophrenic subjects. Nevertheless, the caveat must be raised that the risks of failing to address potential NMDA receptor dysfunction in schizophrenia may be as great or greater than the risks of treatment. Finally, and perhaps most importantly, the caveat must be raised that large-scale, long-term application of glycine treatment in schizophrenia will only become a reality if appropriate placebo-controlled, double-blind studies are conducted. It has now been almost a decade since potentially beneficial effects of glycine were first observed in schizophrenia (Waziri 1988), yet it remains unresolved whether glycine treatment is, in fact, effective. Of the five studies cited by Dr. Waziri, only one (Javitt et al 1994) was conducted under double-blind conditions, and that study included a total of only 14 patients. It is superficially attractive to suggest that the "neurotoxic effects of glycine have to be ruled out"; however, on the one hand, glycine has been found to be free of acute CNS toxicity even following administration of quite large doses (e.g., 3 g/kg) (Page and Gingras 1946, 1947; Daly and Aprison 1983), and there is little reason to suspect that its chronic effects would differ from its acute effects. On the other hand, it is impossible to entirely rule out neurotoxic effects of any CNS active agent. As with neuroleptics and tardive dyskinesia, long-term side effects may emerge that cannot be predicted a priori from preclinical toxicology. The best defense is close clinical vigilance during investigational trials, and rapid drug discontinuation should unanticipated side effects emerge. Meanwhile, perhaps the greatest risk to schizophrenic subjects is

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not that too much will be done in terms of medication development, but too little.

rats by repetitive withdrawal of blood and cerebrospinal fluid: Milacemide. Br J Pharmacol 108:1117-1124.

Daniel C. Javitt

Tsai G, Passani LA, Slucher BS, et al (1995): Abnormal excitatory neurotransmitter metabolism in schizophrenic brains. Arch Gen Psychiatry 52:829-836.

Department of Psychiatry New York University Medical Center/ Nathan Kline Institute for Psychiatric Research Orangeburg, NY 10962 PII S0006-3223

Waziri R (1988): Glycine therapy of schizophrenia [letter]. Biol Psychiatry 23:210-211. Waziri R (1996): Glycine therapy of schizophrenia: Some caveats. Biol Psychiatry 39:155-156.

PII S0006-3223(96)00269-7

References Chapman AG, Hart GP (1988): Anticonvulsant drug action and regional neurotransmitter amino acid changes. J Neural Transm 72:201-212. Christophe J, Kutzner T, Nguyen-Bui ND, Damien C, Chatelain P, Gillet L (1983): Conversion of orally administered 2-npentylaminoacetamideinto glycinamide and glycine in the rat brain. Life Sci 33:533-541. Daly EC, Aprison MH (1983): Glycine. In: Lajtha A (ed), Handbook of Neurochemistry, Vol. 3. New York: Plenum Press. Finkelstein JE, Hengemihle JM, Ingrain DK, Petri HL (1994): Milacemide treatment in mice enhances acquistion of a Morris-type water maze task. Pharmacol Biochem Behav 49:707-710. Globus MYT, Ginsberg MD, Busto R (1991): Excitotoxic index--A biochemical marker of selective vulnerability.Neurosci Lett 127:39-42. Handelmann GE, Nevins ME, Mueller LL, Arnolde SM, Cordi AA (1989): Milacemide, a glycine prodrug, enhances performance of learning tasks in normal and amnestic rodents. Pharmacol Biochem Behav 34:823-828. Javitt DC, Zylberman I, Zukin SR, et al (1994): Amelioration of negative symptoms in schizophrenia by glycine. Am J Psychiatry 151:1234-1236. Olney JW (1984): Excitotoxic food additives--Relevance of animal studies to human safety. Neurobehav Tox Teratol 6:455-462. Olney JW, Farber NB (1995): Glutamate receptor dysfunction and schizophrenia. Arch Gen Psychiatry 52:998-1007. Page E, Gingras R (1946): Glycine toxicity and pyridoxine requirements in the white rat. Trans R Soc Can 41:119-122. Page E, Gingras R (1947): Toxic effects of glycocoll in the rat: Leucopenia and creatinuria. Rev Can Biol 6:802. Patel J, Zinkand WC, Thompson C, Keith R, Salama A (1990): Role of glycine in N-methyl-D-asparate-mediated neuronal cytotoxicity. J Neurochem 54:849-854. Quartermain D, Nuygen T, Sheu J, Herting RL (1990): Milacemide enhances memory storage and alleviates spontaneous forgetting in mice. Pharmacol Biochem Behav 39:31-35. Schwartz BL, Hashtroudi S, Herting RL, Handerson H, Deutsch SI (1991): Glycine prodrug facilitates memory retrieval in humans. Neurology 41:1341-1343. Semba J, Curzon G, Patsalos PN (1993): Antiepileptic drug pharmacokinetics and neuropharmacolokinetics in individual

Response To the Editor In his letter commenting on my editorial (Waziri 1996), Dr. Javitt makes several points that I would like to discuss further. First I applaud him and his coworkers on the excellent, wellcontrolled observations they have made in their studies of glycine treatment of schizophrenics. I agree with him that in such novel approaches to the treatment of schizophrenics, the possible risks should be weighed against the benefits, especially in patients who have not responded to conventional treatments. I also agree with him that careful, continuous observation of patients receiving novel treatments is quite important. The concerns I expressed were based on my reading of the literature on the effects of glycine on NMDA receptors. Dr. Javitt feels that these concerns are overstated. Commenting on the work of Globus et al (1991), which I had cited, he suggests that the neurotoxic effects of glycine are seen only when very high levels of glutamate are present, and such events are unlikely in schizophrenics, because there is evidence for decreased glutamatergic neurotransmission on autopsied brains of schizophrenics. By necessity, all such studies, by using bulk tissues for measurements, provide incomplete information, where distinction between damaged (or dead) and functioning neurons cannot be made. Let us consider the following plausible scenario. During various periods of neurodevelopment, some noxious agents damage and/or destroy a critical percentage of pre- and postsynaptic glutamatergic neurons that are necessary for the prevention of brain disturbances that lead to the symptoms of schizophrenia. According to the studies available, these destructive events can be continuous or discontinuous. Because of the loss of a crucial percentage of the glutamatergic neurons in a discrete system, the activity of the remaining presynaptic glutamatergic neurons is increased as a compensatory mechanism. As long as these compensatory mechanisms are not overwhelmed by further damage or various stressors, the emergence of schizophrenic symptoms will be held in abeyance. With the increased activity, the release of glutamate in the synaptic units of the remaining neurons will also increase, resulting in high glutamate levels. Such levels combined with high concentrations of the coagonist glycine will make these remaining neurons vulnerable to damage and death. The increases in activity may involve both glutamate and glutamate-gammaaminobutyric acid (GABA) connection. In this context, it should be noted that glycine plays not only a permissive role (Patel et al 1990), but also an enhancing role at the NMDA receptor, because it increases the affinity of this receptor to glutamate (Fadda et al