N-methyl-D-aspartic Acid (NMDA) and Cognitive Remediation in Schizophrenia
Status:
Unknown status
Trial end date:
2013-06-01
Target enrollment:
Participant gender:
Summary
Persistent neurocognitive deficits are a major cause of severe disability and impaired
long-term psychosocial outcome in schizophrenia (SZ). In particular, within the auditory
system, early deficits such as the behavioral and neurophysiological ability to match tones
that vary in pitch correlate with impairments in auditory emotion recognition (affective
prosody) and general functioning, suggesting that interventions aimed at remediating
sensory-level dysfunction may lead to significant improvement in higher order
cognitive/emotion processes. Efforts to ameliorate cognitive deficits in schizophrenia
utilize either pharmacological agents or behavioral treatments such as cognitive remediation,
which generally focus on higher order processes, and not on the early sensory processing
which may be key to functioning.
Numerous pharmacological agents have been proposed, but accumulating evidence suggests that
dysfunction of the N-methyl-D-aspartic acid (NMDA) receptor may be one of the root causes of
schizophrenia, including sensory and cognitive impairments, suggesting that an NMDA based
treatment may be efficacious in reversing these deficits. D-Cycloserine, a synthetic partial
NMDA agonist has been used in anxiety disorders to augment learning in cognitive remediation.
Because of a tendency to act as an NMDA antagonist at higher doses D-cycloserine is not
effective in schizophrenia. In contrast, D-serine (DSR), is a full agonist, and is therefore
more ideal for enhancing NMDA function and cognitive remediation. While previous use of DSR
was limited by safety concerns in rodents,the investigators have shown that it can safely be
used at doses of 60 mg/kg and, moreover, demonstrates converging improvement in symptomatic,
cognitive and sensory-based measures in schizophrenia. Evidence also suggests that NMDA
receptor dysfunction in schizophrenia may be relative, rather than absolute, suggesting that
the enhanced practice of a cognitive remediation paradigm might be able to overcome reduced
plasticity and treat cognitive dysfunction.
This project will be the first to combine the NMDA based and sensory-based cognitive
remediation (SBR) approaches, and will utilize not only DSR, but also a tone matching SBR
paradigm has been shown to enhance learning in healthy controls, as well as a paradigm
designed to augment visual motion detection. This study will pilot these interventions in a
double-blind, placebo-controlled, randomized crossover design that will use neurophysiology
together with cognitive tests to explore the effects on brain activity and cognitive function
in 16 patients with schizophrenia or schizoaffective disorder. The investigators hypothesize
that DSR+SBR will lead to improvement. Subjects will have an initial visit to establish
baseline performance on cognitive tasks before returning for 3 visits when they will receive
blinded study medication [60 mg/kg of DSR (2 days) or placebo (1 day)] in a randomized order.
The procedures on the treatment days will include the SBR paradigm and pre/post
neurophysiological measurements. Primary outcomes are improvements in neurophysiologic and
behavioral sensory processing. The main goal is to establish the preliminary efficacy to use
in a follow-up multi-dose study utilizing a multiple session SBR R01 application.