Therapeutic Potential of Ampakines in Schizophrenia

Johnson, Steven

Abstract

Current antipsychotic drugs produce many side effects, but treat only some of the symptoms. Modern theories of schizophrenia are expanding from the traditional dopamine hypothesis to include the concept of reduced glutamatergic function. A new pharmacology that increases AMPA-type glutamate receptor activity (AMPAKINE) has been developed. Ampakines facilitate several kinds of memory in rodents and humans and are currently being developed for the treatment of memory disorders. Ampakines are active in a common animal model for screening antipsychotic compounds (amphetamine hyperactivity) and synergistically enhance the activity of current antipsychotics, while lacking characteristics that cause most antipsychotics to induce treatment-limiting side-effects. Ampakines may be useful alone or as adjuncts in treating schizophrenia and other psychoses. Furthermore, Ampakines, as cognition enhancers, may alleviate the cognitive disturbances of schizophrenia, which are not addressed by available therapies. Current Ampakines exhibit short pharmacokinetic half-lives or low potency and cannot justify expensive clinical development. This research proposes to identify compounds that have better characteristics for clinical development. These new compounds should 1) enhance AMPA receptor function; 2) possess a potency and stability that predict suitability for once-a-day administration in patients and 3) be active in animal models predictive of antipsychotic efficacy.