REVIEW ARTICLES Pharmacologic Strategies for Augmenting Cognitive Performance in Schizophrenia Joseph I. Friedman, Humberto Temporini, and Kenneth L. Davis There is recognition that the cognitive symptoms of schizo- phrenia have the most substantial impact on illness out- come. Domains of cognition reported to be significantly affected include serial learning, executive function, vigi- lance, and distractibility, to name a few. Dopamine activity at D1 receptors mediates many cognitive pro- cesses subserved by the prefrontal cortex (PFC), particu- larly 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 prefron- tal-dependent cognitive deficits in schizophrenia. De- creased levels of cortical norepinephrine (NE) are asso- ciated with impaired learning and working memory in animal models, and can be reversed by drugs that restore NE activity. More specifically, -2 adrenergic receptor agonists have been particularly effective in improving delayed response performance in young monkeys with localized 6-hydroxydopamine lesions in the PFC. Further- more, human postmortem studies have demonstrated de- creased NE in the frontal cortex of demented schizo- phrenic patients. Therefore, -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 cho- linergic drugs may also treat cognitive symptoms in schizophrenia. Two potential types of cholinomimetics for use in schizophrenics are the acetylcholinesterase inhibi- tors and M1/M4 muscarinic agonists, both of which increase cortical cholinergic activity. Biol Psychiatry 1999;45:1–16 © 1999 Society of Biological Psychiatry Key Words: Cognitive, remediation, schizophrenia, do- pamine, norepinephrine, acetylcholine Introduction T he last few years have seen a recognition that cogni- tive symptoms have the most substantial impact upon illness outcome in schizophrenia, more so than either positive or negative symptoms (Breier et al 1991; Green 1996; Harvey and Keefe 1997). There are cognitive deficits that prevent a patient from retaining or relearning skills that are necessary for community functioning and reintegration that can be regarded as “rate limiting cogni- tive factors.” Improvement of these deficits is hypothe- sized to lead to improved illness outcome. Although typical neuroleptics are most effective in the management of positive symptoms, they do not remediate cognitive dysfunction (Verdoux et al 1995; Seidman et al 1993; Cleghorn et al 1990). Most patients experience cognitive deficits despite having achieved remission of positive symptom (Bilder et al 1992; Nuechterlein and Dawson 1984), which refutes the notion that cognitive dysfunction derives from positive symptoms. Therefore, cognitive symptoms have emerged as an independent feature of schizophrenia that needs to be targeted for remediation independent of positive symptoms. There is a great deal of evidence implicating the prefrontal cortex (PFC) in cognitive functions relevant to schizophrenia (Goldman-Rakic 1987). The PFC has rich catecholaminergic innervation (Lewis 1992) so that dys- function of this brain region could likely involve disrup- tion of normal catecholaminergic functioning including dopaminergic (DA) and noradrenergic (NE) functioning. Therefore, pharmacologic remediation of cognitive symp- toms through manipulations of these neurotransmitter systems merits investigation. In addition, evidence impli- cating the involvement of acetylcholine (ACh) in cogni- tive processes relevant to schizophrenia provides potential for remediation strategies by manipulations of acetylcho- line as well. This review will be limited in scope to the DA, NE, and ACh neurotransmitter systems for a few reasons. First, animal models demonstrate that enhancement of these neurotransmitter systems improves cognitive function, especially those relevant to schizophrenia. Second, there is direct evidence from human studies that dysfunction of these neurotransmitter systems correlates with the cogni- tive dysfunction in schizophrenia. Lastly, drugs targeting From the Department of Psychiatry, Mount Sinai School of Medicine, One Gustave Levy Place, New York, New York. Address reprint requests to Joseph I. Friedman, MD, Mount Sinai School of Medicine, Department of Psychiatry, Box 1230, One Gustave Levy Place, New York, NY 10029. Received April 8, 1998; revised August 4, 1998; accepted August 7, 1998. © 1999 Society of Biological Psychiatry 0006-3223/99/$19.00 PII S0006-3223(98)00287-X