Once-weekly d-cycloserine effects on negative symptoms and cognition in schizophrenia: An exploratory study
Introduction
Converging lines of evidence have implicated dysregulation of N-methyl d-aspartate (NMDA) receptors as a factor contributing to clinical and cognitive features of schizophrenia (Goff and Coyle, 2001). The observation that NMDA channel blockers produce positive, negative, and cognitive symptoms characteristic of schizophrenia in healthy subjects (Krystal et al., 1994) led to clinical trials of agents that activate this receptor complex. A meta-analysis of clinical trials in schizophrenia found that glycine, a full agonist at the glycine modulatory site of the NMDA receptor, significantly improved negative symptoms (Tuominen et al., 2005). The glycine site partial agonist, d-cycloserine, was effective for negative symptoms in one placebo-controlled trial in 47 schizophrenia patients (Goff et al., 1999b), whereas several studies were negative (Duncan et al., 2004, Goff et al., 2005, van Berckel et al., 1999) and d-cycloserine did not achieve significant efficacy in the meta-analysis (Tuominen et al., 2005). More recently, the Cognitive and Negative Symptoms in Schizophrenia Trial (CONSIST) failed to find efficacy with either glycine or d-cycloserine compared to placebo for negative symptoms or cognitive deficits in 171 schizophrenia patients, although significant differences in outcomes between sites complicate interpretation of this negative finding (Buchanan et al., 2007).
In contrast to the inconsistent findings in clinical trials with d-cycloserine, facilitation of learning and memory has been well-established in rodents and nonhuman primates with single-dose administration of d-cycloserine. Cognitive impairments produced by anticholinergic agents (Andersen et al., 2002), hippocampal lesions (Andersen et al., 2002), early social deprivation (Stromme and Myhrer, 2002), and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (Schneider et al., 2000) have been reversed by d-cycloserine in single-dose experiments. In healthy animals, d-cycloserine significantly enhanced avoidance learning (Flood et al., 1992), extinction of conditioned fear (Parnas et al., 2005), performance on maze tasks (Quartermain et al., 1994), and visual recognition memory (Matsuoka and Aigner, 1996). Memory effects of d-cycloserine do not become evident until 24 h after learning, a delay that is believed to reflect NMDA receptor modification of memory consolidation (Santini et al., 2001). Whereas single-dose administration of d-cycloserine consistently produced positive effects on memory and learning, several studies have demonstrated tachyphylaxis with repeated administration. For example, pre-treatment with d-cycloserine for 15 days attenuated facilitation in mice of a maze learning task (Quartermain et al., 1994). Increasing the d-cycloserine dose from 3 mg/kg to 20 mg/kg did not counter the tolerance produced by 15 days of pre-treatment. Similarly, five daily doses of d-cycloserine administered over a 10-day period completely attenuated the facilitation of extinction of conditioned fear in rats (Parnas et al., 2005). Recent evidence suggests that elevated concentrations of glycine or d-serine at the glycine recognition site “prime” the NMDA receptor for removal from the cell surface to the intracellular compartment (Nong et al., 2003). This process of “internalization” is believed to represent a mechanism for desensitization of NMDA receptors.
In anxiety disorders, intermittent treatment with d-cycloserine combined with cognitive behavioral therapy has produced persistent therapeutic effects (Davis et al., 2006). Ressler and colleagues (Ressler et al., 2004) treated 28 acrophobia patients with d-cycloserine 50 mg, 500 mg, or placebo prior to two sessions of desensitization using virtual reality exposure. Treatments were separated by 1–2 weeks. Outcomes for the two d-cycloserine treatment groups did not differ significantly and were combined. d-cycloserine pre-treatment was associated with significantly greater improvements in acrophobia symptoms, physiological measures of anxiety, and behavioral ratings 1 week and 3 months after treatment. Similarly, Hoffman and colleagues (Hofmann et al., 2006) treated 27 patients with social anxiety disorder with d-cycloserine 50 mg or placebo 1 h before each of 4 weekly cognitive behavioral exposure sessions for public speaking anxiety and found that d-cycloserine significantly improved all outcome measures following completion of treatment and at one-week follow-up.
d-cycloserine is a relatively selective partial agonist at the glycine site with approximately 35%–68% activity compared to glycine for NMDA receptors containing NR2A or NR2B subunits and 192% activity for receptors containing the NR2C subunit (Sheinin et al., 2001). d-cycloserine readily crosses the blood–brain barrier and is cleared by the kidneys unmetabolized with a serum half-life estimated between 7–15 h (Hanngren et al., 1961). In an oral single-dose challenge study in 16 healthy subjects, d-cycloserine 15, 50 and 150 mg achieved maximal plasma levels beginning 30–60 min after administration; plasma levels remained stable over the four-hour period of monitoring (van Berckel et al., 1997). d-cycloserine was originally developed as an antibiotic; it is administered at doses up to 2 g for treatment-refractory tuberculosis.
Given the compelling evidence of enhanced learning with single-dose d-cycloserine administration in animal models and impressive therapeutic effects in recent clinical trials in anxiety disorders, we questioned whether tachyphylaxis with daily dosing may have attenuated d-cycloserine effects in previous schizophrenia trials. We adopted the approach of a one-week interval between doses of d-cycloserine 50 mg from successful trials in anxiety disorders to see if efficacy for cognitive deficits and negative symptoms of schizophrenia could be enhanced in an eight-week add-on trial. In addition, as an exploratory analysis, we examined whether the first dose of d-cycloserine affected memory consolidation by measuring delayed recall.
Section snippets
Methods
Subjects were stable adult outpatients at an urban community mental health center, ages 18–65 years, with a diagnosis of schizophrenia, treated with any antipsychotic except clozapine. Subjects had been taking a stable dose of antipsychotic medication for at least 4 weeks, did not have an unstable medical condition, seizure disorder, renal insufficiency or dementia, did not have a lifetime history of ketamine or phencyclidine abuse, and denied using alcohol or illicit substances within 3 months
Statistical analysis
All demographic and clinical variables were compared between treatment groups at baseline using t-tests and chi-square tests. The primary endpoints were the change from baseline to week 8 in negative symptoms as defined by the modified SANS total score (SANS minus the Attention subscale), and in the composite cognitive score. Both analyses were performed using ANCOVA controlling for baseline. The treatment effect on negative symptoms was secondarily analyzed by comparing response rates, with
Results
Fifty subjects were enrolled; 38 completed screening and were randomized (Fig. 1). Baseline and week 1 assessments were completed by 37 subjects (97%); 33 subjects (87%) completed week 8. Placebo and d-cycloserine groups did not differ significantly on any demographic or clinical variable at baseline (Table 1), nor did they differ in dropout rates (Fig. 1). Dropouts did not differ from completers on any demographic or clinical variable at baseline.
The modified SANS total score significantly
Side effects
d-cycloserine was generally well-tolerated (Table 3). No dropouts were directly attributed to d-cycloserine side effects, although one subject in the d-cycloserine group dropped out with worsening of psychosis after discontinuing her antipsychotic medication ( Table 4).
Discussion
Our results suggest that once-weekly dosing with d-cycloserine for 8 weeks may be sufficient to produce improvement compared to placebo in negative symptoms. Furthermore, because the SANS rating at week 8 was performed prior to the weekly d-cycloserine dose, this finding indicates that intermittent dosing with d-cycloserine may produce persistent alterations in excitatory synapses involved in expression of negative symptoms. Whether the magnitude of the effect is of clinical significance is
Conclusion
d-cycloserine 50 mg administered once-weekly for 8 weeks significantly improved negative symptoms compared to placebo in schizophrenia patients treated with a variety of antipsychotic agents. Once-weekly d-cycloserine did not improve cognitive functioning after 8 weeks. However, an exploratory test of verbal memory following a delay in recall of 7 days significantly improved after the first dose of d-cycloserine. This finding is consistent with animal studies in which d-cycloserine facilitates
Role of the funding source
The funding source was in no way involved in the collection, analysis and interpretation of the data, in writing the report or the decision to submit this manuscript for publication.
Contributors
Dr. Goff designed the study, authored the protocol, and functioned as research psychiatrist. Drs. Cather and Gottlieb supervised administration of the neuropsychological battery and collection of cognitive data, and assisted with analysis and reporting of results. Dr. Evins contributed to the design of the protocol and the preparation of the manuscript. Drs. Green and Otto consulted on the development and application of the neuropsychological battery, formulation of a composite cognitive score,
Conflict of interest
Dr. Goff has received grant support from: Janssen Pharmaceuticals, Pfizer, Inc., Cephalon, Bristol-Myers-Squibb, NARSAD, NIMH, and the Sidney Baer Foundation; Dr. Goff has received compensation or honoraria from: AstraZenca, Eli Lilly, Glaxo Smith Kline, Merck, Organon, Solvay, Wyeth, XenoPort, Vox, DiMedix, SG Cowen, Advanced Health Media, Pfizer, Inc., American Psychiatric Association, Primedia, Behavioral Options, Axio, Verusmed, the Nelson Group, Letters and Science, Centron, Imedex,
Acknowledgements
This study was funded by NIMH 2 K24 MH002025-06 (D. Goff) and NIMH 2 P50 MH0060450-08A1 (J. Coyle). Dr. Goff had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
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