This candidate for a Scientist Development Award for Clinicians plans to develop his investigative skills in Geriatric Psychopharmacology. The elderly, particularly the very old and those with dementia, undergo age and disease related changes in drug disposition and dynamics which leave them at risk for drug toxicity and altered therapeutic response. Pharmacodynamic assessment techniques can be used to delineate the relationships between drug concentration and clinical response or toxicity, optimizing the use of drug treatments. As a vehicle for the development of expertise in the clinical pharmacologic skills needed in the pharmacodynamic assessment of psychotropic agents in late life, the candidate proposes to study the pharmacodynamics of the neuroleptics perphenazine (PZ) and melperone (MEL) in patients diagnosed with dementia of the Alzheimer's type (DAT) complicated by psychotic symptoms or behavioral disturbance and in patients diagnosed with Psychotic Major Depression (PMD). Pharmacokinetic-pharmacodynamic techniques will be used to determine the characteristics of the pharmacodynamic curves for PZ and MEL using instrumental measurement of rigidity and tremor, and plasma level of prolactin (PRL) and homovanillic acid (pHVA) as effect measures. The following questions will be addressed: (i) What is the nature of the pharmacodynamic curve for PZ and MEL in causing altered PRL, pHVA, rigidity or tremor in patients with DAT and PMD, eg linear, sigmoidal (first or higher orders), anticlockwise hysteresis?; (ii) What are the relative contributions of the concentrations of the parent compounds (PZ and MEL) versus that of their metabolites in inducing alterations in dopaminergic function, and to a lesser extent muscarinic effects, at steady state conditions?; (iii) What is the nature of the relationship between the measured changes in dopaminergic function and ex vivo determination of antagonism, by the treated patient's plasma dialysates, at cloned human Dl, D2, D3, D4, and MI receptors expressed in cell membrane suspensions from cells transfected with individual receptor subtypes? The above research, building on the candidate's work in the clinical characterization of neuroleptic-induced movement disorders in the elderly, will be accomplished in conjunction with a career development plan focusing on developing a blend of skills in clinical and laboratory pharmacologic methods of investigation. This will allow the candidate to make a unique contribution to the clinical pharmacology of aging, with the goals of elucidating the pharmacodynamics of dopamine receptors and of psychopharmacologic agents acting on dopamine systems. The candidate's work will be directed towards both the rational development of currently available agents for use in the elderly and towards leads to successful new drug discoveries.
