Pharmacologic strategies for augmenting cognitive performance in schizophrenia.

There is recognition that the cognitive symptoms of schizophrenia have the most substantial impact on illness outcome. Domains of cognition reported to be significantly affected include serial learning, executive function, vigilance, and distractibility, to name a few. Dopamine activity at D1 receptors mediates many cognitive processes subserved by the prefrontal cortex (PFC), particularly working memory. The number of D1 receptors in the PFC is decreased in schizophrenics and is unaffected by chronic administration of typical neuroleptics. Therefore, medications that increase dopamine in the PFC, such as atypical neuroleptics, or that directly activate the D1 receptor may prove useful in the remediation of prefrontal-dependent cognitive deficits in schizophrenia. Decreased levels of cortical norepinephrine (NE) are associated with impaired learning and working memory in animal models, and can be reversed by drugs that restore NE activity. More specifically, alpha-2 adrenergic receptor agonists have been particularly effective in improving delayed response performance in young monkeys with localized 6-hydroxydopamine lesions in the PFC. Furthermore, human postmortem studies have demonstrated decreased NE in the frontal cortex of demented schizophrenic patients. Therefore, alpha-2 receptor agonists hold promise as drugs to improve cognitive performance on tasks dependent upon PFC function in schizophrenics. Finally, the finding that cortical choline acetyl transferase activity correlates with Clinical Dementia Rating scores in schizophrenic patients and that cholinomimetic drugs enhance cognition in healthy subjects suggests that cholinergic drugs may also treat cognitive symptoms in schizophrenia. Two potential types of cholinomimetics for use in schizophrenics are the acetylcholinesterase inhibitors and M1/M4 muscarinic agonists, both of which increase cortical cholinergic activity.