title: Intracellular signaling and approaches to the treatment of schizophrenia and associated cognitive impairment.
abstract: Schizophrenia is a pervasive neuropsychiatric disorder affecting over 1% of the world's population. Dopamine system dysfunction is strongly implicated in the etiology of schizophrenia. Data support the long-standing concept of schizophrenia as a disease characterized by hyperactivity within midbrain (striatal D2) dopamine systems. In addition, there is now considerable evidence that glutamate neurotransmission, mediated through NMDA-type receptors, is deficient in schizophrenic patients and that hypoactivity in cortical dopamine and glutamate pathways is a key feature of the schizophrenic brain. While current antipsychotic medications-typically dopamine D2 antagonists-adequately address positive symptoms of the disease, such as the acute hallucinations and delusions, they fail to substantially improve negative features, such as social isolation, and can further compromise poor cognitive function in schizophrenic patients. In fact, cognitive impairment is a core feature of schizophrenia. The treatment of cognitive impairment and other residual symptoms associated with schizophrenia, therefore, remains a significant unmet medical need. With current cell-surface receptor-based pharmacology falling short of addressing these core symptoms associated with schizophrenia, more recent approaches to treatment development have focused on processes within the cell. In this review, we discuss the importance of a number of intracellular targets, including cyclic nucleotide phosphodiestereases, and non-phosphodiesterase approaches such as ITI-007, which have been proposed to regulate hyperdopaminergic function, hypoglutamatergic function and/or the delicate balance of the two associated with cognitive deficits in schizophrenia. We also discuss the challenge facing those developing drugs to target specific pathways involved in psychopathology without involving other systems that produce concomitant side effects.
authors.forename: Gretchen L
authors.initials: GL
authors.lastname: Snyder
authors.affiliation: Intra-Cellular Therapies Inc, 3960 Broadway, New York, NY 10032. gsnyder@intracellulartherapies.com.
authors.forename: Kimberly E
authors.initials: KE
authors.lastname: Vanover
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D003072:Cognition Disorders / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D058990:Molecular Targeted Therapy / Q000379:methods; D018697:Nootropic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D009712:Nucleotides, Cyclic / Q000378:metabolism; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D012559:Schizophrenia / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism*; D012565:Schizophrenic Psychology; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D014150:Antipsychotic Agents; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D018697:Nootropic Agents; D009712:Nucleotides, Cyclic; C497928:PPP1R1B protein, human; D018698:Glutamic Acid; D010727:Phosphoric Diester Hydrolases; D004298:Dopamine