Antischizophrenic activity independent of dopamine D2 blockade

Currently, the drug therapy of schizophrenia consists of blockade of central dopamine D2 receptors. There is, however, an urgent medical need for alternative, more effective treatments. Clinical and preclinical literature suggests that stimulation of AMPA-type glutamate receptors may be involved in positive symptoms of schizophrenia, whereas hypofunctionality of NMDA-type glutamate receptors may be involved in negative symptoms and cognitive deficits. Several pharmacological approaches are conceivable to prevent stimulation of AMPA receptors (AMPA receptor blockade, metabotropic glutamate receptors (mGlu(2) receptor) stimulation or lamotrigine-like Na(+)/Ca(2+) channel blockade). Similarly, several pharmacological principles are conceivable to enhance neurotransmission at NMDA receptors (catechol-o-methyl transferase inhibition, glycine uptake blockade, glutathione suppletion and others). In this review, the possible pharmacological approaches and their respective advantages and disadvantages are discussed.