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.