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PDE Inhibitors for the Treatment of Schizophrenia

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Part of the Advances in Neurobiology book series (NEUROBIOL, volume 17)

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 patients with schizophrenia and that hypoactivity in cortical dopamine and glutamate pathways is a key feature of this serious mental disorder. While current antipsychotic medications—with a common mechanism involving dopamine D2 receptor antagonism or pre-synaptic partial agonism—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 associated with schizophrenia. 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 cognitive symptoms, more recent approaches to treatment development have focused on processes within the cell. In this review, we discuss the importance of cyclic nucleotide (cNT) phosphodiestereases (PDEs)—intracellular enzymes that control the activity of key second messenger signaling pathways in the brain—which have been proposed as targets for new schizophrenia therapies. We also discuss the challenge facing those developing drugs to target specific PDE enzymes involved in psychopathology without involving other systems that produce concomitant side effects.

Keywords

Antipsychotic Dopamine Glutamate Prefrontal cortex Cognition 
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Notes

Financial Disclosure

Gretchen Snyder and Kimberly Vanover are full-time employees of Intra-Cellular Therapies Inc. (ITI).

Conflict of Interest

The authors declare that they have no conflicts of interest.

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Authors and Affiliations

  1. 1.Molecular NeuropharmacologyIntra-Cellular Therapies Inc (ITI)New YorkUSA
  2. 2.Clinical DevelopmentIntra-Cellular Therapies Inc (ITI)New YorkUSA

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