Double-blind, placebo-controlled, crossover trial of D-cycloserine adjuvant therapy for treatment-resistant schizophrenia

Abstract

Dysfunction of N-methyl-D-aspartate (NMDA) receptor-mediated glutamatergic neurotransmission may be relevant to the pathogenesis of negative symptoms in schizophrenia. The tuberculostatic compound D-cycloserine (DCS) acts as a partial agonist at the strychnine-insensitive glycine regulatory site on the NMDA receptor complex. Dose-finding trials suggest that DCS doses of 50-100 mg/d may be beneficial in the treatment of negative symptoms in schizophrenia. Nine treatment-resistant chronic schizophrenic patients participated in a double-blind, placebo-controlled, adjuvant treatment trial with 50 mg/d DCS. Between treatment-groups differences in symptom changes were not significant. However, a significant (p<0.05) reduction in negative symptoms was registered during treatment with DCS but not placebo. Greater reductions were registered in patients with lower baseline serum glycine levels (p<0.008). No side effects were registered. These preliminary findings indicate a potential role of DCS in the treatment of negative symptoms in schizophrenia. However, the degree of symptom reduction may be modest, at least among treatment-resistant inpatients.

Modulation of Striatal Dopamine Release by Glycine Transport Inhibitors

“…More recent theories have suggested alternative use of drugs targeted at the NMDA receptor (Javitt, 2001;Javitt and Zukin, 1991). 'First-generation' agents that have been used in clinical studies include both glycine (Heresco-Levy et al, 2004;Heresco-Levy et al, 1999;Javitt et al, 2001;Javitt et al, 1994) and D-serine (Tsai et al, 1998), which are endogenous agonists, as well as the synthetic glycine/D-serine derivative D-cycloserine, which is a partial agonist (Goff et al, 1999;Heresco-Levy et al, 1998). Development of high-affinity glycine-site agonists, however, is limited by the small molecular size of the target (McBain et al, 1989).…”

Inhibitory Action of Clozapine on Rat Ventral Tegmental Area Dopamine Neurons Following Increased Levels of Endogenous Kynurenic Acid

“…An interaction between clozapine and the a7* nicotinic receptor is supported by the demonstration of a clozapine-induced release of acetylcholine in the prefrontal cortex (Ichikawa et al, 2002). In favor of an interaction by clozapine with glutamatergic mechanisms, treatment augmentation studies with agents acting at the glycine-site of the NMDA receptor have shown that glycine and Dcycloserine improve negative symptoms when added to conventional antipsychotic drugs, but not when added to clozapine (Evins et al, 2002;Goff et al, 1999, Heresco-Levy et al, 1998Javitt et al, 1994;Tsai et al, 1998). This indicates that clozapine may be an agonist or partial agonist at the glycine-site of the NMDA receptor or an inhibitor of the glycine transporter and such actions may contribute to its unique clinical efficacy.…”

Neurochemical, Electrophysiological and Pharmacological Profiles of the Selective Inhibitor of the Glycine Transporter-1 SSR504734, a Potential New Type of Antipsychotic

“…For example, recent studies, some of them double blind and placebo-controlled, have shown that d-cycloserine, glycine, and d-serine improve some aspects of negative symptomatology and cognitive dysfunction, do not interfere with the beneficial effects of antipsychotics on the positive symptomatology and are also well tolerated (Goff et al, 1995(Goff et al, , 1999Tsai et al, 1998;Heresco-Levy et al, 1998, 2002Javitt et al, 2001;Evins et al, 2002). Beneficial effects on negative symptomatology and cognitive dysfunction are of interest, as current antipsychotics are marginally effective against these two aspects of the pathology.…”