title: Schizophrenia drug discovery and development in an evolving era: are new drug targets fulfilling expectations?
abstract: Current therapeutics for schizophrenia, the typical and atypical antipsychotic class of drugs, derive their therapeutic benefit predominantly by antagonism of the dopamine D2 receptor subtype and have robust clinical benefit on positive symptoms of the disease with limited to no impact on negative symptoms and cognitive impairment. Driven by these therapeutic limitations of current treatments and the recognition that transmitter systems beyond the dopaminergic system in particular glutamatergic transmission contribute to the etiology of schizophrenia significant recent efforts have focused on the discovery and development of novel treatments for schizophrenia with mechanisms of action that are distinct from current drugs. Specifically, compounds selectively targeting the metabotropic glutamate receptor 2/3 subtype, phosphodiesterase subtype 10, glycine transporter subtype 1 and the alpha7 nicotinic acetylcholine receptor have been the subject of intense drug discovery and development efforts. Here we review recent clinical experience with the most advanced drug candidates targeting each of these novel mechanisms and discuss whether these new agents are living up to expectations.
authors.affiliation: AstraZeneca Neuroscience iMed, Cambridge, MA, USA john.dunlop@azneuro.com.
authors.forename: John
authors.initials: J
authors.lastname: Dunlop
authors.affiliation: AstraZeneca Neuroscience iMed, Cambridge, MA, USA.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Brandon
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D016503:Drug Delivery Systems / Q000379:methods; D055808:Drug Discovery / Q000379:methods; D050487:Glycine Plasma Membrane Transport Proteins / Q000378:metabolism; D006801:Humans; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D017470:Receptors, Glutamate / Q000378:metabolism; D012559:Schizophrenia / Q000188:drug therapy* / Q000378:metabolism; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000378:metabolism
chemical_list: D014150:Antipsychotic Agents; D050487:Glycine Plasma Membrane Transport Proteins; D017470:Receptors, Glutamate; D064569:alpha7 Nicotinic Acetylcholine Receptor; D010727:Phosphoric Diester Hydrolases
keywords: Schizophrenia; drug discovery; new targets