There is a consensus that current treatments of schizophrenia do not offer satisfactory efficacy for negative and cognitive symptoms. Recently, the dopaminergic hyperfunction hypothesis of schizophrenia has been enriched by the addition of the glutamatergic hypofunction concept. Accordingly, agents enhancing glutamatergic transmission should provide benefit in psychosis. In fact, some preclinical studies suggest that positive modulators of alpha-amino-3-hydroxy-5-methyl-4 isoxazolepropionic acid (AMPA) receptors, previously developed mainly for dementia, may fulfill such expectations. These agents attenuate various biochemical or behavioral effects produced by amphetamine or methamphetamine and enhance the action of antipsychotics. More importantly, preliminary clinical studies with the most advanced member of this class, CX-516(Cortex Pharmaceuticals Inc), indicate beneficial action on negative and cognitive symptoms as an add-on treatment t o clozapine. If these observations are confirmed in a larger scale clinical trial, this approach could be a major improvement in the treatment of schizophrenia.