Neurocognitive Effects of Ziprasidone: Relationship to Working Memory and Dopamine Blockade

Typical neuroleptics (i.e., haloperidol, chlorpromazine) are effective at ameliorating the positive psychotic symptoms of schizophrenia but are less efficacious in the treatment of negative symptoms, and there is limited evidence to support their ability to attenuate the cognitive dysfunction observed in schizophrenia (Meltzer et al. 1999). The primary mechanism through which typical neuroleptics achieve their effect is through dopamine (DA) blockade, but recent data suggest that DA blockade may be associated with diminished cognitive improvement despite effective clinical treatment. For example, in a recent molecular genetics study we have shown that subjects with greater DA availability display better cognitive performance on a task of executive functioning (Malhotra et al. in press). Thus, DA blockade may interfere with potential cognitive improvements associated with antipsychotic drug treatment.

Atypical antipsychotics have a higher 5-hydroxytryptamine-2 (5-HT2) to D2 receptor binding ratio than typical agents, and therefore may be more effective in the treatment of cognitive impairments.Unfortunately, there is limited data on the cognitive properties of the new atypical agent, ziprasidone. In addition to having a high 5-HT2 to D2 receptor binding ratio, like the other atypicals, ziprasidone also has weak anticholinergic effects and minimal activity at muscarinic (M1), histaminergic (H1) and alpha1-adrenergic receptors (Casey, 2001) which may also beneficially influence cognitive performance (Byerly et al., 2001). Therefore, ziprasidone may have a unique ability to improve the cognitive performance of patients with schizophrenia.

Evidence from neuropsychology (Gold, Carpenter, Randolph, Goldberg, & Weinberger, 1997), brain imaging (Buchsbaum et al., 1992) and electrophysiology (Shelley et al., 1996) all converge to implicate impaired working memory (WM) function in schizophrenia. As such, the neural substrates that subsume WM, the temporal course of information flow through this system, and importantly whether ziprasidone intervention can aid in normalization of function, are critical issues in schizophrenia research. In the present study, we propose to integrate:

1. A novel cognitive electrophysiological assessment specifically designed to detect subtle differences in the stages of information processing where WM deficits become manifest.
2. A state of the art computerized neuropsychological battery that assesses WM and other cognitive domains.
3. Positron emission tomography (PET) of dopamine D2 receptor occupancy.

These methods will provide a means to specifically characterize the effects of ziprasidone on cognitive performance and dopamine blockade in patients with schizophrenia. The primary hypotheses to be tested are 1) that ziprasidone treatment will be associated with improvements in WM and, 2) WM performance will be associated with D2 occupancy in ziprasidone treated patients.