The role of phosphodiesterases in schizophrenia : therapeutic implications.

Recent studies have suggested that currently available antipsychotic medications, while useful in treating some aspects of schizophrenia, still possess considerable limitations. Improving the treatment of negative symptoms and cognitive dysfunction, and decreasing adverse effects remain significant challenges. Many new drug strategies have been proposed in recent years and increasing evidence suggests that members of the phosphodiesterase (PDE) gene family may play a role in the aetiology or treatment of schizophrenia. PDEs are key enzymes responsible for the degradation of the second messengers cAMP (3',5'-cyclic adenosine monophosphate) and cGMP (3',5'-cyclic guanosine monophosphate). Mammalian PDEs are composed of 21 genes and are categorized into 11 families based on sequence homology, enzymatic properties and sensitivity to pharmacological inhibitors. Representatives from most families have been identified in the brain by the presence of protein or RNA, and numerous studies suggest that PDEs play an important role in the regulation of intracellular signalling downstream of receptor activation in neurons. Insights into the multiple brain processes to which PDEs contribute are emerging from the phenotype of genetically engineered mice that lack activity of specific PDEs (knockout mice), as well as from in vitro and in vivo studies with PDE inhibitors.This article provides a brief overview of recent studies implicating PDE inhibition, focusing on PDE4 and PDE10, as targets for treating the positive, negative or cognitive symptoms associated with schizophrenia.