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A placebo-controlled crossover trial of d -cycloserine added to clozapine in patients with schizophrenia
A Placebo-Controlled Crossover Trial of D-Cycloserine Added to Clozapine in Patients with Schizophrenia Donald C. Goff, David C. Henderson, A. Eden Evins, and Edward Amico Background: D-Cycloserine, a partial agonist at the glycine recognition site of the NMDA receptor, has previously been shown to improve negative symptoms when added to conventional antipsychotics and, in one preliminary dose-finding study, worsened negative symptoms when added to clozapine. Methods: Seventeen schizophrenia outpatients treated with clozapine were assigned in random order to 6-week trials of D-cycloserine 50 mg/day and placebo in a crossover design separated by a 1 week placebo washout. Results: Eleven patients competed the 13-week study. D-Cycloserine significantly worsened ratings of negative symptoms compared to placebo but did not significantly affect ratings of psychotic symptoms. Conclusions: The differing effects of D-cycloserine on negative symptoms when added to clozapine compared to conventional antipsychotics suggests that activation of the glycine recognition site may play a role in clozapine’s efficacy for negative symptoms. Biol Psychiatry 1999;45: 512–514 © 1999 Society of Biological Psychiatry Key Words: D-cycloserine, glycine, schizophrenia, clozapine, negative symptoms, glutamate
Introduction Dysregulation of the glutamatergic N-methyl-D-aspartate (NMDA) receptor has been linked to negative symptoms of schizophrenia by several lines of evidence (Goff and Wine 1997) including the demonstration that ketamine, an antagonist at this receptor complex, produces negative symptoms in normal subjects (Krystal et al 1994). DCycloserine, a partial agonist at the glycine recognition site of the NMDA receptor, significantly improved negative symptoms when added to conventional antipsychotic agents at a dose of 50 mg daily in a preliminary dose finding trial (Goff et al 1995) and in a fixed-dose, From the Psychotic Disorders Program of the Massachusetts General Hospital and the Consolidated Department of Psychiatry, Harvard Medical School, Boston, MA. Address reprint requests to Dr. Goff, Freedom Trail Clinic, 25 Staniford Street, Boston MA 02114. Received September 22, 1998; revised November 9, 1998; accepted November 18, 1998.
© 1999 Society of Biological Psychiatry
placebo-controlled trial involving 46 patients with schizophrenia (Goff et al, in press). Several investigators have also reported efficacy for negative symptoms with highdose glycine augmentation (Heresco-Levy et al 1996). In contrast, negative symptoms worsened when D-cycloserine 50 mg/day was added to clozapine in a similar dose finding trial (Goff et al 1996). If replicated, these findings suggest that clozapine differs from conventional agents in its activation of the glycine recognition site of the NMDA receptor, which may contribute to clozapine’s efficacy for negative symptoms. For this reason, we set out to test in a placebo-controlled crossover trial our previous preliminary finding that D-cycloserine 50 mg/day worsens negative symptoms when added to clozapine.
Methods and Materials Patients meeting DSM-IV criteria for schizophrenia and demonstrating prominent negative symptoms (SANS total .30) despite treatment with an optimal dose of clozapine for at least 6 months, were recruited from an outpatient clinic of an urban community mental health center. Patients were excluded if they had any significant medical illness or were actively abusing alcohol or illicit drugs. After obtaining written informed consent, patients entered a double-blind crossover trial consisting of 6-week trials of Dcycloserine 50 mg/day and matching placebo in random order separated by a 1 week single-blind placebo washout. Patients were assessed at baseline and after weeks 2, 4, and 6 of each trial using the Positive and Negative Syndrome Scale (PANSS), Scale for Assessment of Negative Symptoms (SANS), Global Assessment Scale (GAS), Hamilton Depression Scale (HAM), Abnormal Involuntary Movement Scale (AIMS), Simpson Angus Scale for assessment of extrapyramidal symptoms (SAS), and the Barnes Akathisia Scale (BAS). Patients were asked about side effects in an unstructured interview at each assessment. Changes in clinical ratings were compared between the two treatment conditions in patients who completed both trials using repeated measures analyses of variance. All comparisons were made with two-tailed tests and results are reported as means and standard deviations.
Results Seventeen patients (fifteen men and two women, all Caucasian) entered and six (35%) did not complete the 0006-3223/99/$19.00 PII S0006-3223(98)00367-9
D-Cycloserine
Added to Clozapine
BIOL PSYCHIATRY 1999;45:512–514
513
anhedonia, attention, and avolition (p . .1). The change in SANS total score between baseline and week 6 during treatment with D-cycloserine did not correlate significantly (p . .05) with changes in ratings of psychosis (r 5 .08), depression (r 5 .56), or parkinsonism (r 5 .19); and the change in SANS total score did not correlate significantly with age (r 5 .001), duration of illness (r 5 0.13), clozapine dose (r 5 2.31), or baseline score on the SANS total (r 5 .13).
Discussion Figure 1. Response of negative symptoms in eleven patients who completed trials of D-cycloserine 50 mg/day and placebo added to clozapine in a crossover design.
13-week study. Five of the six dropouts occurred during the placebo condition (p . .1 by Fisher’s exact test) and four of the dropouts occurred during the first treatment condition. The only dropout during treatment with Dcycloserine occurred in the third week and was due to a worsening of psychosis. Completers scored significantly higher than dropouts on the SAS (df 5 15, t 5 2.5, p 5 .02) but did not differ from dropouts in age, gender, clozapine dose, or any other rating scale at baseline. The eleven completers consisted of nine men and two women, had a mean age of 36.6 6 9.6 years, a duration of illness of 14.8 6 8.4 years, and were receiving a mean clozapine dose of 490.9 6 141.1 mg/day. Among the five completers who received D-cycloserine during weeks 1 to 6, mean scores at baseline and at week 7, following the placebo washout, did not differ for the SANS total (40.6 6 1.7 vs 40.3 6 2.9) or for the negative symptom subscale of the PANSS (18.4 6 1.82 vs 18.6 6 2.8), indicating the absence of a carry-over effect of D-cycloserine between trials. D-Cycloserine 50 mg was associated with an increase of 13.5% in mean SANS total scores and an increase of 10.0% in the negative symptom subscale of the PANSS from baseline to week 6 compared to a decrease of 3.7% in mean SANS total scores and a decrease of 4.3% in the negative symptom subscale of the PANSS during the placebo condition (Figure 1). The interaction between medication condition and time was significant for both the SANS total (df 5 3,60; F 5 5.1; p 5 .003) and the PANSS negative symptom subscale (df 5 3,60; F 5 3.4, p 5 .02) but was not significant for any other clinical rating (p . .1). Analysis of subscales of the SANS revealed significant interactions between medication treatment and time for flat affect (df 5 3,60; F 5 4.8; p 5 .005) and alogia (df 5 3,60; F 5 4.2; p 5 .009). Interactions were not significant for the SANS subscales,
This study replicates the result from our previous dosefinding trial that D-cycloserine 50 mg/day selectively worsens negative symptoms of schizophrenia when added to clozapine. Although serum concentrations of clozapine were not measured in this study, D-cycloserine did not affect clozapine levels in a previous study (Goff et al 1996). When added to clozapine, only flat affect and alogia subscales of the SANS were significantly affected by D-cycloserine, whereas in a previous trial (Goff et al, in press), addition of D-cycloserine 50 mg/day to conventional agents resulted in a significant improvement in scores on the flat affect subscale only. The crossover design allowed us to determine that worsening of negative symptoms with D-cycloserine did not persist, since scores on the SANS returned to baseline by the end of the 1-week placebo washout phase. The worsening of negative symptoms, while statistically significant, was quite modest and was not associated with a significant change in global clinical ratings. Surprisingly, dropouts occurred less frequently during the D-cycloserine treatment condition than during the placebo condition, suggesting that the worsening of negative symptoms was not particularly distressing to patients or clinicians. Clozapine, and possibly other atypical agents, have been shown to differ from conventional agents in their activity on glutamatergic systems. Compared to conventional dopamine D2 antagonists, treatment with clozapine results in different patterns of glutamate release (Yamamoto and Cooperman 1994) and reuptake (Schneider et al 1998), potentiation of NMDA-mediated neurotransmission (Arvanov et al 1997), reversal of phencyclidine-induced isolative behavior (Corbett et al 1995) and deficits in senorimotor gating (Bakshi et al 1994), and alterations in the subunit composition of glutamatergic receptors (Fitzgerald et al 1995). Reversal of phencyclidine-induced isolative behavior was also produced by olanzapine (Corbett et al 1995), suggesting that other atypical agents may share glutamatergic properties in common with clozapine. In one small study, switching patients from conventional agents to clozapine was associated with significant elevation of serum concentrations
514
BIOL PSYCHIATRY 1999;45:512–514
of glutamate and aspartate (Evins et al 1997). Baseline serum concentrations of glycine inversely correlated with response of negative symptoms. The observation that D-cycloserine worsens negative symptoms when added to clozapine and improves them when added to conventional agents points to activity at the glycine modulatory site of the NMDA-receptor complex as a possible mechanism contributing to clozapine’s efficacy for negative symptoms. D-Cycloserine is a partial agonist, producing approximately 60% activity compared to the full agonist, glycine, and so acts like an agonist in the presence of low concentrations of glycine and as an antagonist in the presence of high concentrations (Emmett et al 1991). Recent studies have demonstrated that both haloperidol and clozapine act like partial agonists at the glycine site at concentrations approximating therapeutic levels (Banerjee et al 1995; Fletcher and MacDonald 1993). McCoy and Richfield (1996) also found that chronic administration of conventional and atypical agents produced a desensitization of the augmenting effect of glycine. Differences in the magnitude of concentrationdependent partial agonist activity at the glycine modulatory site acutely, and of desensitization of glycine receptor sites with chronic treatment, could account for differing responses to D-cycloserine when added to clozapine or conventional agents, although this explanation remains quite speculative pending further clarification of mechanisms responsible for antipsychotic activity, direct or indirect, at the NMDA-receptor complex.
Conclusions This study replicates a previous finding that patients treated with clozapine differ from patients treated with conventional agents in the response of negative symptoms to D-cycloserine. In light of animal studies, which suggest that antipsychotic agents modulate activity at the glycine recognition site of the NMDA receptor, additional work is needed to establish whether activity at this site contributes to clozapine’s efficacy for negative symptoms.
D.C. Goff et al
Bakshi VP, Swerdlow NR, Geyer MA (1997): Clozapine antagonizes phencyclidine-induced deficits in sensorimotor gating of the startle response. J Pharmacol Exp Ther 271:787–794. Banerjee SP, Zuck LG, Yablonsky-Alter E, Lidsky TI (1995): Glutamate agonist activity: Implications for antipsychotic drug action and schizophrenia. Neuroreport 6:2500 –2504. Corbett R, Camacho R, Woods AT, et al (1995): Antipsychotic agents antagonize non-competitive N-methyl-D-aspartate antagonist-induced behaviors. Psychopharmacology 120:67–74. Emmett M, Mick S, Cler J (1991): Actions of D-cycloserine at the N-methyl-D-aspartate-associated glycine receptor site in vivo. Neuropharmacology 30:1167–1171. Evins A, Amico E, Shih V, Goff D (1997): Clozapine treatment increases serum glutamate and aspartate compared to conventional neuroleptics. J Neural Transm 104:761–766. Fitzgerald LW, Deutch AY, Gasic G, Heinemann SF, Nestler EJ (1995): Regulation of cortical and subcortical glutamate receptor subunit expression by antipsychotic drugs. J Neurosci 15:2453–2461. Fletcher EJ, MacDonald JF (1993): Haloperidol interacts with the strychnine-insensitive glycine site at the NMDA receptor in cultured mouse hippocampal neurones. Eur J Pharmacol 235:291–295. Goff D, Tsai G, Levitt J, et al (1999): A placebo-controlled trial of D-cycloserine added to conventional neuroleptics in patients with schizophrenia. Arch Gen Psychiatry 1999 56:21– 27. Goff DC, Tsai G, Manoach DS, Coyle JT (1995): Dose-finding trial of D-cycloserine added to neuroleptics for negative symptoms in schizophrenia. Am J Psychiatry 152:1213–1215. Goff DC, Tsai G, Manoach DS, Flood J, Darby DG, Coyle JT (1996): D-cycloserine added to clozapine for patients with schizophrenia. Am J Psychiatry 153:1628 –1630. Goff D, Wine L (1997): Glutamate in schizophrenia: Clinical and research implications. Schizophr Res 27:157–168. Heresco-Levy U, Silipo G, Javitt DC (1996): Glycinergic augmentation of NMDA receptor-mediated neurotransmission in the treatment of schizophrenia. Psychopharmacol Bull 32: 731–740. Krystal JH, Karper LP, Seibyl JP, et al (1994): Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans: Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry 51:199 –214.
Supported by PHS grants RO1MH54245 & RO1MH57708.
McCoy L, Richfield EK (1996): Chronic antipsychotic treatment alters glycine-stimulated NMDA receptor binding in rat brain. Neurosci Lett 213:137–141.
References
Schneider J, Wade T, Lidsky T (1998): Chronic neuroleptic treatment alters expression of glial glutamate transporter GLT-1 mRNA in the striatum. Neuroreport 9:133–136.
Arvanov V, Liang X, Schwartz J, et al (1997): Clozapine and haloperidol modulate N-methyl-D-aspartate and non-N-methyl-D-aspartate receptor-mediated neurotransmission in rat prefrontal cortical neurons in vitro. J Pharmacol Exp Ther 283:226 –234.
Yamamoto BK, Cooperman MA (1994): Differential effects of chronic antipsychotic drug treatment on extracellular glutamate and dopamine concentrations. J Neurosci 14:4159 – 4166.
Introduction Dysregulation of the glutamatergic N-methyl-D-aspartate (NMDA) receptor has been linked to negative symptoms of schizophrenia by several lines of evidence (Goff and Wine 1997) including the demonstration that ketamine, an antagonist at this receptor complex, produces negative symptoms in normal subjects (Krystal et al 1994). DCycloserine, a partial agonist at the glycine recognition site of the NMDA receptor, significantly improved negative symptoms when added to conventional antipsychotic agents at a dose of 50 mg daily in a preliminary dose finding trial (Goff et al 1995) and in a fixed-dose, From the Psychotic Disorders Program of the Massachusetts General Hospital and the Consolidated Department of Psychiatry, Harvard Medical School, Boston, MA. Address reprint requests to Dr. Goff, Freedom Trail Clinic, 25 Staniford Street, Boston MA 02114. Received September 22, 1998; revised November 9, 1998; accepted November 18, 1998.
© 1999 Society of Biological Psychiatry
placebo-controlled trial involving 46 patients with schizophrenia (Goff et al, in press). Several investigators have also reported efficacy for negative symptoms with highdose glycine augmentation (Heresco-Levy et al 1996). In contrast, negative symptoms worsened when D-cycloserine 50 mg/day was added to clozapine in a similar dose finding trial (Goff et al 1996). If replicated, these findings suggest that clozapine differs from conventional agents in its activation of the glycine recognition site of the NMDA receptor, which may contribute to clozapine’s efficacy for negative symptoms. For this reason, we set out to test in a placebo-controlled crossover trial our previous preliminary finding that D-cycloserine 50 mg/day worsens negative symptoms when added to clozapine.
Methods and Materials Patients meeting DSM-IV criteria for schizophrenia and demonstrating prominent negative symptoms (SANS total .30) despite treatment with an optimal dose of clozapine for at least 6 months, were recruited from an outpatient clinic of an urban community mental health center. Patients were excluded if they had any significant medical illness or were actively abusing alcohol or illicit drugs. After obtaining written informed consent, patients entered a double-blind crossover trial consisting of 6-week trials of Dcycloserine 50 mg/day and matching placebo in random order separated by a 1 week single-blind placebo washout. Patients were assessed at baseline and after weeks 2, 4, and 6 of each trial using the Positive and Negative Syndrome Scale (PANSS), Scale for Assessment of Negative Symptoms (SANS), Global Assessment Scale (GAS), Hamilton Depression Scale (HAM), Abnormal Involuntary Movement Scale (AIMS), Simpson Angus Scale for assessment of extrapyramidal symptoms (SAS), and the Barnes Akathisia Scale (BAS). Patients were asked about side effects in an unstructured interview at each assessment. Changes in clinical ratings were compared between the two treatment conditions in patients who completed both trials using repeated measures analyses of variance. All comparisons were made with two-tailed tests and results are reported as means and standard deviations.
Results Seventeen patients (fifteen men and two women, all Caucasian) entered and six (35%) did not complete the 0006-3223/99/$19.00 PII S0006-3223(98)00367-9
D-Cycloserine
Added to Clozapine
BIOL PSYCHIATRY 1999;45:512–514
513
anhedonia, attention, and avolition (p . .1). The change in SANS total score between baseline and week 6 during treatment with D-cycloserine did not correlate significantly (p . .05) with changes in ratings of psychosis (r 5 .08), depression (r 5 .56), or parkinsonism (r 5 .19); and the change in SANS total score did not correlate significantly with age (r 5 .001), duration of illness (r 5 0.13), clozapine dose (r 5 2.31), or baseline score on the SANS total (r 5 .13).
Discussion Figure 1. Response of negative symptoms in eleven patients who completed trials of D-cycloserine 50 mg/day and placebo added to clozapine in a crossover design.
13-week study. Five of the six dropouts occurred during the placebo condition (p . .1 by Fisher’s exact test) and four of the dropouts occurred during the first treatment condition. The only dropout during treatment with Dcycloserine occurred in the third week and was due to a worsening of psychosis. Completers scored significantly higher than dropouts on the SAS (df 5 15, t 5 2.5, p 5 .02) but did not differ from dropouts in age, gender, clozapine dose, or any other rating scale at baseline. The eleven completers consisted of nine men and two women, had a mean age of 36.6 6 9.6 years, a duration of illness of 14.8 6 8.4 years, and were receiving a mean clozapine dose of 490.9 6 141.1 mg/day. Among the five completers who received D-cycloserine during weeks 1 to 6, mean scores at baseline and at week 7, following the placebo washout, did not differ for the SANS total (40.6 6 1.7 vs 40.3 6 2.9) or for the negative symptom subscale of the PANSS (18.4 6 1.82 vs 18.6 6 2.8), indicating the absence of a carry-over effect of D-cycloserine between trials. D-Cycloserine 50 mg was associated with an increase of 13.5% in mean SANS total scores and an increase of 10.0% in the negative symptom subscale of the PANSS from baseline to week 6 compared to a decrease of 3.7% in mean SANS total scores and a decrease of 4.3% in the negative symptom subscale of the PANSS during the placebo condition (Figure 1). The interaction between medication condition and time was significant for both the SANS total (df 5 3,60; F 5 5.1; p 5 .003) and the PANSS negative symptom subscale (df 5 3,60; F 5 3.4, p 5 .02) but was not significant for any other clinical rating (p . .1). Analysis of subscales of the SANS revealed significant interactions between medication treatment and time for flat affect (df 5 3,60; F 5 4.8; p 5 .005) and alogia (df 5 3,60; F 5 4.2; p 5 .009). Interactions were not significant for the SANS subscales,
This study replicates the result from our previous dosefinding trial that D-cycloserine 50 mg/day selectively worsens negative symptoms of schizophrenia when added to clozapine. Although serum concentrations of clozapine were not measured in this study, D-cycloserine did not affect clozapine levels in a previous study (Goff et al 1996). When added to clozapine, only flat affect and alogia subscales of the SANS were significantly affected by D-cycloserine, whereas in a previous trial (Goff et al, in press), addition of D-cycloserine 50 mg/day to conventional agents resulted in a significant improvement in scores on the flat affect subscale only. The crossover design allowed us to determine that worsening of negative symptoms with D-cycloserine did not persist, since scores on the SANS returned to baseline by the end of the 1-week placebo washout phase. The worsening of negative symptoms, while statistically significant, was quite modest and was not associated with a significant change in global clinical ratings. Surprisingly, dropouts occurred less frequently during the D-cycloserine treatment condition than during the placebo condition, suggesting that the worsening of negative symptoms was not particularly distressing to patients or clinicians. Clozapine, and possibly other atypical agents, have been shown to differ from conventional agents in their activity on glutamatergic systems. Compared to conventional dopamine D2 antagonists, treatment with clozapine results in different patterns of glutamate release (Yamamoto and Cooperman 1994) and reuptake (Schneider et al 1998), potentiation of NMDA-mediated neurotransmission (Arvanov et al 1997), reversal of phencyclidine-induced isolative behavior (Corbett et al 1995) and deficits in senorimotor gating (Bakshi et al 1994), and alterations in the subunit composition of glutamatergic receptors (Fitzgerald et al 1995). Reversal of phencyclidine-induced isolative behavior was also produced by olanzapine (Corbett et al 1995), suggesting that other atypical agents may share glutamatergic properties in common with clozapine. In one small study, switching patients from conventional agents to clozapine was associated with significant elevation of serum concentrations
514
BIOL PSYCHIATRY 1999;45:512–514
of glutamate and aspartate (Evins et al 1997). Baseline serum concentrations of glycine inversely correlated with response of negative symptoms. The observation that D-cycloserine worsens negative symptoms when added to clozapine and improves them when added to conventional agents points to activity at the glycine modulatory site of the NMDA-receptor complex as a possible mechanism contributing to clozapine’s efficacy for negative symptoms. D-Cycloserine is a partial agonist, producing approximately 60% activity compared to the full agonist, glycine, and so acts like an agonist in the presence of low concentrations of glycine and as an antagonist in the presence of high concentrations (Emmett et al 1991). Recent studies have demonstrated that both haloperidol and clozapine act like partial agonists at the glycine site at concentrations approximating therapeutic levels (Banerjee et al 1995; Fletcher and MacDonald 1993). McCoy and Richfield (1996) also found that chronic administration of conventional and atypical agents produced a desensitization of the augmenting effect of glycine. Differences in the magnitude of concentrationdependent partial agonist activity at the glycine modulatory site acutely, and of desensitization of glycine receptor sites with chronic treatment, could account for differing responses to D-cycloserine when added to clozapine or conventional agents, although this explanation remains quite speculative pending further clarification of mechanisms responsible for antipsychotic activity, direct or indirect, at the NMDA-receptor complex.
Conclusions This study replicates a previous finding that patients treated with clozapine differ from patients treated with conventional agents in the response of negative symptoms to D-cycloserine. In light of animal studies, which suggest that antipsychotic agents modulate activity at the glycine recognition site of the NMDA receptor, additional work is needed to establish whether activity at this site contributes to clozapine’s efficacy for negative symptoms.
D.C. Goff et al
Bakshi VP, Swerdlow NR, Geyer MA (1997): Clozapine antagonizes phencyclidine-induced deficits in sensorimotor gating of the startle response. J Pharmacol Exp Ther 271:787–794. Banerjee SP, Zuck LG, Yablonsky-Alter E, Lidsky TI (1995): Glutamate agonist activity: Implications for antipsychotic drug action and schizophrenia. Neuroreport 6:2500 –2504. Corbett R, Camacho R, Woods AT, et al (1995): Antipsychotic agents antagonize non-competitive N-methyl-D-aspartate antagonist-induced behaviors. Psychopharmacology 120:67–74. Emmett M, Mick S, Cler J (1991): Actions of D-cycloserine at the N-methyl-D-aspartate-associated glycine receptor site in vivo. Neuropharmacology 30:1167–1171. Evins A, Amico E, Shih V, Goff D (1997): Clozapine treatment increases serum glutamate and aspartate compared to conventional neuroleptics. J Neural Transm 104:761–766. Fitzgerald LW, Deutch AY, Gasic G, Heinemann SF, Nestler EJ (1995): Regulation of cortical and subcortical glutamate receptor subunit expression by antipsychotic drugs. J Neurosci 15:2453–2461. Fletcher EJ, MacDonald JF (1993): Haloperidol interacts with the strychnine-insensitive glycine site at the NMDA receptor in cultured mouse hippocampal neurones. Eur J Pharmacol 235:291–295. Goff D, Tsai G, Levitt J, et al (1999): A placebo-controlled trial of D-cycloserine added to conventional neuroleptics in patients with schizophrenia. Arch Gen Psychiatry 1999 56:21– 27. Goff DC, Tsai G, Manoach DS, Coyle JT (1995): Dose-finding trial of D-cycloserine added to neuroleptics for negative symptoms in schizophrenia. Am J Psychiatry 152:1213–1215. Goff DC, Tsai G, Manoach DS, Flood J, Darby DG, Coyle JT (1996): D-cycloserine added to clozapine for patients with schizophrenia. Am J Psychiatry 153:1628 –1630. Goff D, Wine L (1997): Glutamate in schizophrenia: Clinical and research implications. Schizophr Res 27:157–168. Heresco-Levy U, Silipo G, Javitt DC (1996): Glycinergic augmentation of NMDA receptor-mediated neurotransmission in the treatment of schizophrenia. Psychopharmacol Bull 32: 731–740. Krystal JH, Karper LP, Seibyl JP, et al (1994): Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans: Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry 51:199 –214.
Supported by PHS grants RO1MH54245 & RO1MH57708.
McCoy L, Richfield EK (1996): Chronic antipsychotic treatment alters glycine-stimulated NMDA receptor binding in rat brain. Neurosci Lett 213:137–141.
References
Schneider J, Wade T, Lidsky T (1998): Chronic neuroleptic treatment alters expression of glial glutamate transporter GLT-1 mRNA in the striatum. Neuroreport 9:133–136.
Arvanov V, Liang X, Schwartz J, et al (1997): Clozapine and haloperidol modulate N-methyl-D-aspartate and non-N-methyl-D-aspartate receptor-mediated neurotransmission in rat prefrontal cortical neurons in vitro. J Pharmacol Exp Ther 283:226 –234.
Yamamoto BK, Cooperman MA (1994): Differential effects of chronic antipsychotic drug treatment on extracellular glutamate and dopamine concentrations. J Neurosci 14:4159 – 4166.