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

Abstract

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)...

Glutamate as a therapeutic target in psychiatric disorders

“…With Dcycloserine, doses in excess of 100 mg cause symptom exacerbation due to emergent NMDAR antagonist effects, producing a narrow therapeutic window. 96 Results of clinical trials conducted with NMDAR agonists have been consistent across studies (Table 1). All studies have demonstrated large effect-size (0.9-2.1 SD units) improvement in negative and cognitive symptoms when these agents are added to typical antipsychotics, or newer atypicals.…”

Glutamate-N-methyl-D-aspartate receptor modulation and minocycline for the treatment of patients with schizophrenia: an update

“…Seven of them (6,12,31-34,47) did not find any significant change in positive symptoms and two (with higher dosages, namely 100 and 250 mg/day) reported worsening of positive symptoms (36,46).…”

“…Ten trials evaluated the addition of D-cycloserine to typical antipsychotics (6,12,(31)(32)(33)(34)36,37,46,47). Seven of them (6,12,31-34,47) did not find any significant change in positive symptoms and two (with higher dosages, namely 100 and 250 mg/day) reported worsening of positive symptoms (36,46).…”

Building a Better Antipsychotic: Receptor Targets for the Treatment of Multiple Symptom Dimensions of Schizophrenia

“…Of the four agents, D-cycloserine has been the least promising, possibly due to its partial agonism and the fact that it acts as an antagonist at high (100 mg) doses. 51 Another proposed approach to rectifying NMDA hypoactivity via glycine allosterism involves the glial glycine transporter GLYT1, which is a reuptake pump that terminates the synaptic action of glycine by shuttling glycine back into glial cells; inhibition of this transporter should theoretically increase the synaptic availability of glycine, thus enhancing NMDA neurotransmission. 52 In this manner, GLYT1 inhibitors are analogous to drugs that inhibit reuptake of other neurotransmitters, such as serotonin selective reuptake inhibitors.…”