Cognitive deficits in schizophrenia are critically important predictors of long-term psychosocial and occupational outcome and are not significantly ameliorated by currently available medications. Cognitive remediation training can alleviate cognitive deficits associated with schizophrenia, but the impact and practicality of this approach has been limited, largely, by effect sizes and/or the time requirements needed to achieve clinically significant improvement. The proposed project is testing a novel strategy aiming at pharmacological enhancement of cognitive remediation training. Thus, rather than seeking agents capable of improving cognitive functions per se, this project is seeking to redirect efforts toward agents capable of enhancing the beneficial effects of training challenges. The prototypical nicotinic agonist nicotine facilitates sensory processing, alertness, attention, and learning and memory and thus displays an ideal effects profile for promoting training benefits. Thus, intermittent nicotine exposure during cognitive training sessions is expected to accelerate and enhance the training effects, thereby providing the proof of principle to guide the search for other, more selective compounds. Fifty people with schizophrenia will be enrolled into a 10-week, 5 days/week, computerized auditory and visual cognitive training regimen and randomized into one of two treatment groups. Every Monday and Thursday, participants in the nicotine group will receive a nicotine polacrilex lozenge (2 or 4 mg, depending on smoking status) prior to the training and participants in the placebo group a placebo lozenge. Outcome measures are neurocognitive functions assessed by the MATRICS consensus cognitive battery, level of everyday-life functioning, quality of life, and psychiatric symptoms. These measures are taken on a no-lozenge day (Wednesday) in week 0 (baseline), 4, 7, 10 and 16 (4 weeks after the intervention ends). Nicotine is expected to potentiate training-induced enhancements in these measures and to shorten the training duration necessary to induce clinically significant improvement. These results would provide proof of concept for an intervention that can markedly improve some of the most debilitating symptoms of schizophrenia. The results would also form the basis for studies of the critical training components and neuronal changes modulated by nicotine;of success rates in different patient subgroups, with different medication backgrounds, smoking status and other variables;and of more selective nicotinic agonists specifically targeted at potentiating cognitive training outcome.

Public Health Relevance

Schizophrenia is marked by problems in attention, memory and problem solving. These deficits predict long- term functional outcome such as the ability to live independently and maintain employment, but they are not ameliorated by currently available medications. Cognitive training improves these functions to some degree, but this approach is very time- and resource-intensive. The current project aims at enhancing and accelerating the benefits that people with schizophrenia derive from cognitive training by administering nicotine during some of the training sessions. This would provide the proof of principle for a treatment intervention that can markedly improve some of the most debilitating symptoms of schizophrenia.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Exploratory/Developmental Grants (R21)
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Interventions Committee for Adult Disorders (ITVA)
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Kozak, Michael J
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University of Maryland Baltimore
Schools of Medicine
United States
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