Tolerance and efficacy of D-cycloserine in drug-free schizophrenic patients

Berckel, Bart N.M. van; Hijman, Ron; Linden, J.A. van der; Westenberg, H. G. M.; Ree, Jan M. van; Kahn, R.S.

doi:10.1016/0920-9964(96)85448-x

Cited by 20 publications

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“…The second study reported that 250 mg D-cycloserine daily in addition to conventional antipsychotics aggravated psychotic symptoms in four of seven patients with chronic schizophrenia (Cascella et al 1994). Comparison of this study with our previous report (van Berckel et al 1996) and the only other report currently available in which beneficial effects of D-cycloserine on the negative symptoms of schizophrenia were described (Goff et al 1996) is hampered by differences in design (increasing dosages versus fixed dose), treatment regime (drug-free patients versus patients treated with neuroleptics), and inclusion criteria. In the previous study, we reported a decrease in the score on the negative subscale of the PANSS after a 4-day treatment with 100 mg of D-cycloserine, following 4-day treatment periods with 15 mg, 25 mg, and 50 mg of D-cycloserine, respectively.…”

Section: Discussionsupporting

confidence: 61%

“…Both studies reported a selective reduction in negative symptoms, most prominent at dosages of 50 mg (Goff et al 1996) or 100 mg (van Berckel et al 1996). D-cycloserine (10 and 30 mg), when added to the typical antipsychotic molindole (Rosse et al 1996) did not induce symptomatic changes.…”

mentioning

confidence: 95%

“…This suggests that the glycine recognition site of the NMDA receptor is probably not saturated in vivo in healthy subjects and that low dosages of D-cycloserine can indeed be used, as in animals, to stimulate human NMDA receptor activity. Thus, low dosages of D-cycloserine may be expected to be effective in the treatment of schizophrenia.Two open, uncontrolled, dose-findings studies with D-cycloserine have been performed in patients with schizophrenia, either added to typical antipsychotics, using 5 mg, 15 mg, 50 mg, and 250 mg D-cycloserine daily consecutively for 2 weeks (Goff et al 1995) or in drug-free patients using 15 mg, 25 mg, 50 mg, 100 mg, and 250 mg daily consecutively for 4 days (van Berckel et al 1996). Both studies reported a selective reduction in negative symptoms, most prominent at dosages of 50 mg (Goff et al 1996) or 100 mg (van Berckel et al 1996).…”

mentioning

confidence: 99%

“…Two open, uncontrolled, dose-findings studies with D-cycloserine have been performed in patients with schizophrenia, either added to typical antipsychotics, using 5 mg, 15 mg, 50 mg, and 250 mg D-cycloserine daily consecutively for 2 weeks (Goff et al 1995) or in drug-free patients using 15 mg, 25 mg, 50 mg, 100 mg, and 250 mg daily consecutively for 4 days (van Berckel et al 1996). Both studies reported a selective reduction in negative symptoms, most prominent at dosages of 50 mg (Goff et al 1996) or 100 mg (van Berckel et al 1996).…”

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confidence: 99%

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D-Cycloserine Increases Positive Symptoms in Chronic Schizophrenic Patients When Administered in Addition to Antipsychotics A Double-Blind, Parallel, Placebo-Controlled Study

Berckel¹

1999

Neuropsychopharmacology

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A hypofunction of the glutamatergic system and NMDA receptors in schizophrenia has been hypothesized. Therefore, stimulation of these receptors could be of benefit to patients with schizophrenia. D-cycloserine has been used for this purpose. This study reports the effects of 100 mg D-cycloserine, when added to typical antipsychotics in chronic schizophrenic patients exhibiting prominent negative symptoms, using a placebo-controlled, double-blind, parallel, design. D-cycloserine (Paschen 1996) and schizophrenia (Javitt and Zukin 1991;Henn 1995;Olney and Farber 1995).In schizophrenia, a role for excitatory amino acids and NMDA receptors was suggested when NMDA receptor antagonists, such as phencyclidine (PCP) and ketamine, were found to induce symptoms resembling the positive and negative symptoms of schizophrenia in healthy subjects and exacerbate such symptoms in patients with schizophrenia (Luby et al. 1962;Javitt and Zukin 1991;Krystal et al. 1994;Lahti et al. 1995;Malhotra et al. 1997b). A hypofunction of the glutamatergic system and NMDA receptors has been hypothesized in schizophrenia (for review, see Olney and Farber 1995) and appears to be supported by post-mortem studies (Nishikawa et al. 1983;Toru et al. 1988;Ishimaru et al. 1994;Tsai et al. 1995). If schizophrenic symptoms are the result of the diminished functioning of NMDA receptors, stimulation of these receptors could be beneficial for patients with schizophrenia. Glycine and D-cycloserine stimulate the strychnine-insensitive glycine recognition site of the NMDA receptor and, by inference, may ameliorate schizophrenic symptoms. Some studies have used glycine for this purpose. In a double-blind, parallel, placebo-controlled study with seven patients in each group, glycine treatment during 8 weeks in a dose ‫ف‬ 30 grams daily, added to typical antipsychotics, selectively reduced the scores on the negative symptom subscale of the Positive and Negative Symptoms Scale (PANSS) (Javitt et al. 1994). A similar result has also been reported in 11 schizophrenic patients using glycine in dosages between 40 and 80 grams daily in a doubleblind crossover design with treatment periods of 6 weeks (Heresco-Levy et al. 1996). These two studies suggest that stimulation of the NMDA receptor may ameliorate the negative symptoms of schizophrenia.As a treatment of schizophrenic symptoms, glycine's major limitation is its limited access to the central nervous system (CNS). Contrary to glycine, the partial NMDA agonist D-cycloserine, an antibiotic used in the treatment of tuberculosis (Walker and Murdoch 1957), rapidly passes the blood-brain barrier and may therefore be more suitable for the treatment of patients with schizophrenia than glycine. However, D-cycloserine acts as a partial agonist of the NMDA receptor, with around 60%-90% of the agonistic efficacy of glycine (Chessell et al. 1991;Priestley et al. 1995) and with between 6 to 20 times less affinity for the glycine recognition site of the NMDA receptor than glycine (Ishimaru et al. 1994;Priestley et al. 1995)...

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Section: Discussionsupporting

confidence: 61%

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confidence: 95%

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confidence: 99%

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confidence: 99%

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D-Cycloserine Increases Positive Symptoms in Chronic Schizophrenic Patients When Administered in Addition to Antipsychotics A Double-Blind, Parallel, Placebo-Controlled Study

Berckel¹

1999

Neuropsychopharmacology

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“…[109][110][111] d-Cycloserine, a partial agonist at the glycine regulatory site on the NMDA receptor, has also been tested in schizophrenic patients. In a very narrow dose range, d-cycloserine was demonstrated to improve negative symptoms when administered alone 112 and when added to conventional neuroleptic treatment regimes. 113,114 However, when d-cycloserine was administered in conjunction with clozapine, the negative symptoms of the patients were worsened.…”

Section: Therapeutic Potential Of Agonists Of the Glycine Site On Thementioning

confidence: 99%

Mechanisms of typical and atypical antipsychotic drug action in relation to dopamine and NMDA receptor hypofunction hypotheses of schizophrenia

1999

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Available evidence indicates that clozapine is the most effective antipsychotic currently used for the pharmacotherapy of schizophrenia. Unfortunately, clozapine can cause serious side effects that limit the use of the drug. The therapeutic mechanism of action of clozapine is poorly understood, and accordingly, it has been difficult to design new drugs with the advantageous therapeutic properties of clozapine. Based on hypotheses that dopaminergic and serotonergic receptor-blocking properties of clozapine account for its clinical efficacy, several novel antipsychotic drugs have been introduced recently. There is currently insufficient data to reach definitive conclusions regarding the efficacy of the newer 'atypical' antipsychotics in comparison to clozapine. However, most published studies, and general clinical impressions, suggest that none of the newer drugs are as effective as clozapine in treating patients resistant to typical antipsychotic drug therapy. The present paper briefly reviews the clinical experience with the newer 'atypical' antipsychotic drugs and then discusses clinical and preclinical data potentially relevant to mechanisms of action of clozapine in relation to the NMDA receptor hypofunction hypothesis of schizophrenia.Keywords: clozapine; olanzapine; risperidone; ziprasidone; quetiapine; antipsychotic; schizophrenia; dopamine; NMDA The introduction of clozapine for the pharmacotherapy of schizophrenia represented a significant advance in the treatment of this devastating mental illness. Clozapine is superior to typical neuroleptic drugs (eg haloperidol) in treating positive and negative symptoms, and is effective in many patients who are refractory to typical antipsychotics. [1][2][3] In addition, clozapine does not induce the extrapyramidal side effects (EPS) commonly caused by the typical agents. Because of these properties, clozapine was termed atypical and represents the prototype drug of this class. Although clozapine is the most efficacious antipsychotic currently available, serious side effects induced by the drug, including agranulocytosis, impose substantial limitations on its use. Concerted research and development efforts have been made to produce an antipsychotic drug with the therapeutic advantages of clozapine, without the properties contributing to its serious side effects. However, the specific pharmacological characteristics of clozapine that confer its therapeutic properties are poorly understood. Clozapine binds to a diverse number of neurotransmitter receptors (see Table 1) but it is unclear whether actions at specific serotonin, dopamine, or adrenergic receptors, alone or in combination, account for its clinical efficacy.A number of specific hypotheses concerning mechanisms of action of clozapine have directed drug discovery efforts and led to clinical trials of drugs with widely different receptor-binding characteristics. The clinical experience with drugs whose development was inspired by clozapine will be briefly reviewed and then actions of clozapine and other antip...

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A Placebo-Controlled Trial of D-Cycloserine Added to Conventional Neuroleptics in Patients With Schizophrenia

Goff

Tsai²,

Levitt³

et al. 1999

Arch Gen Psychiatry

401

203

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Background: In a preliminary dose-finding study, D-cycloserine, a partial agonist at the glycine modulatory site of the glutamatergic N-methyl-D-aspartate (NMDA) receptor,improvednegativesymptomsandcognitivefunctionwhen added to conventional neuroleptics at a dose of 50 mg/d. Methods:Forty-seven patients with schizophrenia meeting criteria for deficit syndrome were randomized to Dcycloserine, 50 mg/d (n=23) or placebo (n=24) added to their conventional neuroleptic for an 8-week, doubleblind trial. Clinical assessments were performed at baseline and at weeks 1, 2, 4, 6, and 8. Serum concentrations of D-cycloserine, relevant amino acids, and homovanillic acid were assayed at baseline and at weeks 4 and 8. A cognitive battery was performed at baseline and at week 8.Results: Thirty-nine patients completed the 8-week trial. Seven dropouts occurred in the D-cycloserine group and D -Cycloserine (D-4-amino-3isoxazolidone), an antituberculosis drug, is a relatively selective partial agonist at the

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Tolerance and efficacy of D-cycloserine in drug-free schizophrenic patients

Cited by 20 publications

References 0 publications

D-Cycloserine Increases Positive Symptoms in Chronic Schizophrenic Patients When Administered in Addition to Antipsychotics A Double-Blind, Parallel, Placebo-Controlled Study

D-Cycloserine Increases Positive Symptoms in Chronic Schizophrenic Patients When Administered in Addition to Antipsychotics A Double-Blind, Parallel, Placebo-Controlled Study

Mechanisms of typical and atypical antipsychotic drug action in relation to dopamine and NMDA receptor hypofunction hypotheses of schizophrenia

A Placebo-Controlled Trial of D-Cycloserine Added to Conventional Neuroleptics in Patients With Schizophrenia

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