The Effect of Serum Psychotropic Drug Levels and Drug Metabolizer Status on Delirium Duration and Long-term Cognition - PROJECT SUMMARY Delirium occurs in about 50% of older hospitalized patients. This form of acute brain failure is associated with accelerated cognitive decline, leading to incident or worsening Alzheimer's disease and related dementias (ADRD). Psychotropic medications cause delirium in up to 42% of cases and represent an opportunity for intervention. However, deprescribing, which is stopping or reducing the dose of a medication, has not been shown to be effective in the treatment of delirium. This is because deprescribing relies on medication lists, which do not take into account drug toxicity. Novel approaches are needed to identify new medications for deprescribing to increase its efficacy. Incorporating serum psychotropic medication measurements using liquid- chromatography-mass spectroscopy (LC-MS) may identify new targets for deprescribing by uncovering supratherapeutic psychotropic drug levels (SPDLs) that usually go unrecognized. In our preliminary study of 158 older hospitalized patients, we found that 10% had SPDLs, and they were associated with longer delirium duration. The majority of SPDLs were selective serotonin and serotonin-norepinephrine reuptake inhibitors (SSRI/SNRIs) antidepressants, which are one of the most commonly prescribed psychotropic medications in older adults. Higher SSRI/SNRI levels were associated with prolonged delirium duration, particularly in patients with pre-existing ADRD. Because these were secondary analyses, we must confirm these findings. Assessing the patient's ability to metabolize a drug based on cytochrome P450 (CYP) genotypes may also identify additional deprescribing targets. Intermediate or poor metabolizers can have higher serum psychotropic drug levels, leading to delirium and accelerated cognitive decline. Medications that inhibit CYP (CYP-inhibitors) may also need to be deprescribed because they may cause genotype-phenotype conversion. This drug-drug interaction causes a genotype-predicted normal metabolizer into a phenotypic poor metabolizer, leading to higher serum psychotropic drug levels. Prior to incorporating these precision medicine tools into a deprescribing intervention, we must evaluate their clinical utility. Therefore, we propose this prospective cohort study of 600 older hospitalized patients with the following specific aims: Determine if serum concentrations of SSRI/SNRIs and other serum psychotropic medication classes measured at enrollment, 12-24 hours, and 48- 72 hours are associated with delirium duration (Aim #1) and 12-month global cognition (Aim #2) in older hospitalized adults. Evaluate how specific CYP polymorphisms affect serum concentrations of SSRI/SNRIs and other psychotropic medications (Aim #3). Explore how drug-drug interactions leading to poorer metabolizer genotype-phenotype conversion are associated with increased serum SSRI/SNRI concentrations (Aim #4). While SSRI/SNRIs are the focus, we will evaluate all psychotropic medication classes for Aims #1-3. This R01 will help develop a novel deprescribing intervention incorporating serum psychotropic drug measurements, CYP-genotyping, and CYP-inhibitor identification to be tested in a future randomized trial.
