The improved treatment of cognitive disorders in schizophrenia has become a priority for the National Institute of Mental Health, because of the evidence that cognitive dysfunction is the chief cause of chronic disability from the illness. Currently available antipsychotic drugs do not effectively address this dysfunction. One promising lead comes from studies of nicotinic acetylcholine receptors. For the alpha7-receptor there is genetic and neurobiological evidence of involvement in schizophrenia. Nicotine has some neurocognitive effects, but they are not clinically significant and there is considerable health risk associated with nicotine in any form. alpha7-agonists have the promise of safer, more targeted effects and may not have nicotine's considerable tachyphylaxis. In the previous funding period, we completed a Phase 1 study of 3-2,4 dimethoxybenzylidene anabaseine (DMXB-A), a partial agonist at alpha7-nicotinic receptors, in schizophrenia. A positive neurocognitive effect was found. The proposed continuation of this project will test the drug's effectiveness using the newly available MATRICS Battery, developed by NIMH to assess neurocognitive effects of new drugs potentially useful in schizophrenia. We will also determine the time course of drug effect, with the intent of developing administration paradigms that prolong drug action throughout the day. We will also determine if the drug interacts with nicotine for schizophrenics who smoke. In a final experiment, we will determine if clinically useful of DMXB-A are sustained during periods of administration of one moYrth or longer. Persons with schizophrenia have difficulty with many aspects of their thinking, including their attention and their ability to learn. The drugs that they currently take are not entirely helpful, and many of them turn to smoking. We are studying a new, nicotine-like drug, that does not have the harmful effects of tobacco, but may help persons with schizophrenia to think better. ? ? ?
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