Schizophrenia Clinical Trial
Official title:
NMDA and Cognitive Remediation in Schizophrenia
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.
Status | Unknown status |
Enrollment | 16 |
Est. completion date | June 2013 |
Est. primary completion date | June 2013 |
Accepts healthy volunteers | No |
Gender | All |
Age group | 18 Years to 64 Years |
Eligibility |
Inclusion Criteria: - 18 to 64 years old, IQ=85 and estimated Glomerular Filtration Rate (GFR) < or =60. All oral and depot antipsychotics (with the exception of clozapine) are allowable. - Patients must be on their antipsychotic medication for 1 month and stable on dose of antipsychotic and adjunctive medications for 2 weeks prior to study entry. Exclusion Criteria: - Include a history of neurological visual or hearing impairment, active suicidal ideation on the Calgary Depression Scale (CDS), current alcohol or drug abuse (<1 month) or substance dependence (<4 months). - All women of child-bearing potential must have a negative serum pregnancy test at the baseline visit. - We require an IQ of greater or equal to 85 to ensure that subjects will have a capacity to learn. - In our cross-sectional studies, we have observed an IQ greater than 85 in over 90% of candidates, suggesting that this is not an overly restrictive criterion. |
Country | Name | City | State |
---|---|---|---|
United States | Nathan Kline Insitute for Psychiatric Research | Orangeburg | New York |
Lead Sponsor | Collaborator |
---|---|
Nathan Kline Institute for Psychiatric Research | Columbia University |
United States,
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Primary | Tone Matching threshold | Three 80-tone pair blocks will be used per session (~1 hour with breaks). To minimize practice effects, we will use a different base tone for each treatment day (e.g. 500, 1000, and 2000 Hz), also in a randomized counter-balanced order. To assess the improvement over a treatment day, we will record the ratio of the frequencies in all tone pairs. To correct this non-normal distribution we take the natural log of each of these ratios to determine the tone matching threshold. | 3 weeks | |
Primary | Mismatch Negativity (MMN) | MMN will be obtained independently to pitch stimuli utilizing the same base frequencies as the SBR, (e.g. 500, 1000, and 2000 Hz). Two sessions will be held each day, both before and after study drug/SBR intervention. MMN will be generated using previously published methods. MMN is maximal at frontocentral electrodes (Fz, Cz). For all measures, peak amplitude at frontocentral electrodes within predefined latency range will be primary outcome measure. We primarily evaluate effect of study drug. | 3 weeks | |
Secondary | Tone Matching | This task consists of pairs of 100-ms tones in series, with 500-ms intertone interval. Within each pair, tones are either identical or differed in frequency by specified amounts in each block (2.5%, 5%, 10%, 20%, or 50%). In each block, 12 of the tones are identical and 14 are dissimilar. Tones are derived from 3 reference frequencies (500, 1000, and 2000 Hz) to avoid learning effects. | 3 weeks | |
Secondary | Auditory Emotion Recognition Task | The sentences will be scored based on the speaker's intended emotion (happy, sad, angry, fear or neutral). The sentences are semantically neutral and consisted of both statements and questions (i.e., ''It is eleven o'clock'', ''Is it eleven o'clock?''). | 3 weeks | |
Secondary | Positive and Negative Symptom Scale (PANSS | Assesses severity of positive, negative and cognitive symptoms in SZ | 3 weeks | |
Secondary | Medical Symptom Inventory (aka Side Effect Checklist) | designed to assess vital signs and commonly occurring antipsychotic side effects. | 3 weeks | |
Secondary | MATRICS consensus cognitive battery, | Improvement is particularly expected in visual and auditory-based measures (verbal memory) as well as composite score. | 3 weeks | |
Secondary | Contrast sensitivity | Contrast sensitivity: stimuli consist of sine wave gratings shown side-by-side with a solid gray panel. Contrast is reduced until subjects can no longer tell the grating from the solid gray panel. | 3 weeks | |
Secondary | The Perceptual Organization Index (POI): | a component of the WAIS Performance IQ construct and consists of 3 tests: Picture Completion, Matrix Reasoning, and Block Design. | Baseline-final | |
Secondary | Emotion in motion | This is a computerized task that includes videos of faces expressing 4 basic emotions - happiness, sadness, anger, or fear - and neutral expressions. | 3 weeks |
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