d-Cycloserine augmentation of cognitive remediation in schizophrenia

Abstract

D-cycloserine (DCS) has been shown to enhance memory and, in a previous trial, once-weekly DCS improved negative symptoms in schizophrenia subjects. We hypothesized that DCS combined with a cognitive remediation (CR) program would improve memory of a practiced auditory discrimination task and that gains would generalize to performance on unpracticed cognitive tasks. Stable, medicated adult schizophrenia outpatients participated in the Brain Fitness CR program 3–5 times per week for 8 weeks. Subjects were randomly assigned to once-weekly adjunctive treatment with DCS (50 mg) or placebo administered before the first session each week. Primary outcomes were performance on an auditory discrimination task, the MATRICS cognitive battery composite score and the Scale for the Assessment of Negative Symptoms (SANS) total score. 36 subjects received study drug and 32 completed the trial (average number of CR sessions = 26.1). Performance on the practiced auditory discrimination task significantly improved in the DCS group compared to the placebo group. DCS was also associated with significantly greater negative symptom improvement for subjects symptomatic at baseline (SANS score ≥20). However, improvement on the MATRICS battery was observed only in the placebo group. Considered with previous results, these findings suggest that DCS augments CR and alleviates negative symptoms in schizophrenia patients. However, further work is needed to evaluate whether CR gains achieved with DCS can generalize to other unpracticed cognitive tasks.

Augmenting NMDA receptor signaling boosts experience-dependent neuroplasticity in the adult human brain

“…This framework suggests that, given the minimum NMDAR activation necessary to produce transient, persistent firing, further NMDAR activation should have relatively limited effect on working memory performance. Our finding of similar working memory performance between DCS and Placebo participants is consistent with this theory and is in line with prior studies that failed to find effects of DCS on working memory in healthy volunteers or patient groups (27,(34)(35)(36). This dissociation of effects of DCS on experience-dependent learning versus working memory highlights the importance of considering the cellular mechanisms underlying distinct cognitive functions and demonstrates how investigating targeted hypotheses that capitalize on basic cognitive neuroscience can help reconcile discrepant effects of potential cognitive-enhancing drugs.…”

“…These findings suggest exciting possibilities for using NMDAR agonists to help ameliorate plasticity deficits in neurodegenerative and psychiatric disorders. Our results complement a growing literature that suggests that DCS can enhance new learning during CBT interventions (29,32) and cognitive training programs (33,34). The dissociation of effects of DCS on incremental learning versus working memory highlights the importance of capitalizing on progress in basic cognitive neuroscience to develop more specific hypotheses for targets of cognitive-enhancing drugs.…”

“…No drug or placebo was administered on the second day. Although the idea of using NMDAR agonists to enhance cognition is not new, past studies examining diverse cognitive domains have yielded mixed results (24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36). Difficulty reconciling divergent effects has limited our ability to harness NMDAR agonists as cognitive enhancers.…”

Effects of Augmenting N-Methyl-D-Aspartate Receptor Signaling on Working Memory and Experience-Dependent Plasticity in Schizophrenia: An Exploratory Study Using Acute d-cycloserine

“…One recent study found that DCS improved performance on an auditory discrimination task on which patients were trained over 8 weeks. 68 However, numerous studies found minimal effects of DCS on neuropsychological tests of short-term verbal or spatial learning in schizophrenia patients. [61][62][63]68 Given that we did not measure NMDAR signaling or synaptic changes directly in the current study, any mechanistic explanations for our negative findings of DCS on plasticity in schizophrenia are speculative.…”

“…68 However, numerous studies found minimal effects of DCS on neuropsychological tests of short-term verbal or spatial learning in schizophrenia patients. [61][62][63]68 Given that we did not measure NMDAR signaling or synaptic changes directly in the current study, any mechanistic explanations for our negative findings of DCS on plasticity in schizophrenia are speculative. However, the minimal effects of DCS on plasticity in the current study could reflect a breakdown in the translation of electrical signaling across the NMDAR into the signaling cascades and synaptic changes that underlie experience-dependent plasticity.…”