Trials designed to investigate the clinical utility of drugs for cognitive disorders are often quite expensive and time consuming. This is particularly true for drugs whose clinical benfits are to prevent the emergence of cognitive impairment in persons at high risk. This presentation will review some of the reasons why even real beneficial effects of drugs on human cognition are difficult to demonstrate and will offer some suggestions for speeding drug testing in this area. Data from trials of cholinesterase inhibitors in patients with dementia indicate that these drugs improve cognitive test performance over baseline. Clinician’s global ratings of drug efficacy do not reveal improvement over baseline; rather, drug benefit appears as greater stability relative to the clinical decline in placebo-treated patients. Thus, even real symptomatic drug effects on cognition are difficult to observe without specialized testing or long term observation. Studies on the predictive power of animal and normal human cognitive models of drug effects are reviewed; neither model is very predictive of the effects of drugs on patients with cognitive deficits. Data are presented to demonstrate that, even in patients with Alzheimer’s disease, the magnitude of drug effect is heavily dependent upon the extent of neuropathologic damage. These findings suggest that proof of concept studies for potential cognition enhancing drugs should be conducted in patients with the disorder to be treated. Measures and study designs specifically tailored to the disease, patient severity and drug class should be used to maximize the likelihood of detecting a drug effect. Psychometric and biological markers that might serve as pharmakodynamic measures in proof of concept studies will be described. The relationship of these measures to clinical outcomes, as used in ordinary clinical practice, will be described using data from cholinesterase inhibitor trials.
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