This application for a FIRST Award is a continuation and enhancement of the research program begun under the applicant's Clinical Mental Health Academic Award (KO7 MHO1O4O). The overarching goal of this research is to improve acute pharmacotherapy for severe behavioral disturbances requiring hospitalization, in patients diagnosed with Dementia of the Alzheimer's Type (DAT). The behavioral complications of DAT are among the most distressing problems confronting elderly patients and their families. A five-year double-blind, placebo-controlled trial of the most selective and highly potent serotonin reuptake inhibitor (citalopram) and standard neuroleptic pharmacotherapy (perphenazine) will be conducted in 112 DAT inpatients. It is believed that both medications will have efficacy in the acute treatment of severe behavioral disturbances. Nonetheless, it is anticipated that the use of perphenazine, a dopamine receptor blocking agent, in a population that already has significantly reduced dopaminergic function, might lead to more adverse consequences than the use of citalopram. This protocol will also examine drug metabolic covariates of treatment tolerance and platelet serotonergic correlates of response. Phenotyping for debrisoquine hydroxylase (P450 2D6) and S-mephenytoin hydroxylase (P450 2C19) will be employed to identify those at risk of adverse medication side effects. These enzymes are constitutionally deficient in as many as 20% of the population. They are also subject to variable and largely unquantified degrees of inhibition in older patients taking multiple medications. The relationship between neuroreceptor indices of serotonergic function and neurochemically specific pharmacotherapy for behavioral disturbances in DAT-afflicted patients will be examined through assessment of platelet serotonin transporters and serotonin-2 receptors. It is postulated that patients, with lower pretreatment serotonin transporter binding values, will respond preferentially to citalopram and that these patients will show a reduction in the density of their serotonin-2 receptors in response to medication. In contrast, peripheral serotonin indices will not be associated with treatment response to perphenazine. The research conducted under this proposal will lay the basis for new therapeutic approaches, such as the identification of patients who might respond preferentially to a serotonergic drug or the recognition, prior to treatment, that a patient with poor drug metabolic capacity will have diminished tolerance to standard doses of psychotropic medication. Improved treatment of behavioral complications would reduce excess disability in DAT patients, allowing them to be maintained in the community for greater periods of time.
