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a peak or minimum response that occurred between 650 750mg/dayCPZeq. Measures of startle prepulseinhibition deficits (PPI: second-order polynomial fit, p <0.05), evoked potential latency (p<0.02), sustained attention (p<0.10), smooth pursuit eye movement saccades (p < 0.10) and alpha EEG power (p<0.10) had peaks near 700mg/day, while negative symptoms (p < 0.05), anergia symptoms (p < 0.001 ), and delta EEG power (p<0.10) had minima near this dose. When patient maintenance doses were modified, PPI responses changed dramatically, but still fell along the bimodal curve. Neuroleptic-induced depolarization block of forebrain DA systems provides an appealing explanation for these observa- tions. Low chronic doses of neuroleptics might stimulate DAergic activity in the nucleus accumbens (NAcc) without inducing generalized depolarization block. In rodent models, elevated NAcc DAergic activity disrupts PPI. With high doses, depolarization block and strong postsynaptic receptor blockade could reverse NAcc PPI effects. Whatever the mechanism, the biphasic responses appear to be robust since several relatively independent, cross-disciplinary outcomes are similarly affected. These results represent the strongest clinical evidence to date for the phenomenon of neuroleptic-induced depolarization block.

N M D A R E C E P T O R A U G M E N T A T I O N

T H E R A P Y I N S C H I Z O P H R E N I A

I. Zylberman*, D.C. Javitt, S.R. Zukin

Departments of Psychiatry and Neuroscience, Albert Einstein College of Medicine of Yeshiva University and Research Unit, Bronx Psychiatric Center, Bronx, N Y 10461, USA

Stimulation of dopaminergic neurotransmission by amphet- amine reproduces positive symptoms of schizophrenia in neuro- leptic-reversible fashion, but fails to mimic negative symptoms or cognitive dysfunction. By contrast, blockade of N-methyl- D-aspartate (NMDA) receptors by single low doses of phency- clidine (PCP) mimics cognitive dysfunction and negative symp-

toms of schizophrenia in normal volunteers, and exacerbates illness*specific symptoms in schizophrenic subjects. Neuroleptic blockade of dopamine receptors ameliorates positive symptoms but has much less effect upon negative symptoms, and little or no effect upon cognitive impairment, suggesting that while positive symptoms may be governed mainly by dopaminergic mechanisms, negative and cognitive symptoms are in part determined by nondopaminergic mechanisms. If negative and cognitive symptoms can be provoked or exacerbated by NMDA receptor blockade, pharmacological augmentation of NMDA receptor-mediated neurotransmission may ameliorate these symptoms. The degree of NMDA receptor activation by a given concentration of L-glutamate is regulated by the local concentration of glycine, acting at a site on the NMDA receptor complex. Animal studies have shown that orally-administered glycine increases brain glycine levels and can reverse PCP- induced behavioral changes. In a double-blind study utilizing 0.4 g/kg/day of oral glycine, neuroleptic-treated chronic schizo- phrenic subjects demonstrated significant, moderate improve- ment in negative symptom ratings, without change in positive symptom or EPS ratings. (Javitt et al., Am. J. Psychiatry, 151, 1234 36, 1994). Glycine is not actively transported across the blood-brain barrier. In order to obtain higher brain glycine levels, we shall conduct a new study in which DSM-IV schizo- phrenic subjects, symptomatic despite optimal neuroleptic treat- ment, will receive oral glycine (0.8 g/kg/day) in a randomized double-blind crossover design utilizing a matched placebo as control. Subjects will receive fixed doses of haloperidol and benztropine. Serum haloperidol and glycine levels will be monitored. The Positive and Negative Symptom Scale will be administered at baseline and at two-week intervals during the study. Cognitive dysfunction will be measured by neuropsychi- atric testing. Results will determine whether higher-dose glycine therapy can benefit neuroleptic-nonresponsive negative symp- toms and cognitive dysfunction of schizophrenia more robustly. Augmentation of NMDA receptor-mediated neurotransmission is a novel approach to treatment of neuroleptic-nonresponsive symptoms of schizophrenia. Drug discovery efforts should be aimed at development of synthetic compounds directly or indirectly stimulating the glycine site of the NMDA receptor which can cross the blood-brain barrier more readily than glycine.