A Portable, Low-Cost, Pont-of-care Microfluidic System for Rapid Pharmacogenomic Screening of Patients with Major Depressive Disorder

University Of Virginia, Charlottesville VA

Investigators

Abstract

Project Summary/Abstract The current approaches to prescribing medication to patients with major depressive disorder (MDD) involve a ‘trial and error’ approach to prescribing selective serotonin reuptake inhibitors (SSRIs) based on patient interview and physician insight. Unfortunately, a high percentage of trials fail on the first try and after two or more ‘failed’ drug treatments, patients are considered “treatment resistant.” Relevant research has elucidated that liver cytochrome P450 (CYPs) enzymes are responsible for carrying out a series of oxidations that metabolize drugs as part of a pathway to excretion. As such, the expression of the 57 CYP enzymes coded for by the CYP genes determines how rapid an individual metabolizes a particular drug and, not surprisingly, this varies dramatically from one patient to another. This is important because ‘rapid metabolizers’ often DO NOT hit the critical systemic thresholds needed of the drug to be effective, while ‘slow metabolizers’ tend to accumulate drug and, hence, reach levels that are often toxic and riddled with side effects, including suicide. In fact, clinical responses to the same dose of a drug can vary among individuals based on single nucleotide variants (SNVs) in CYP genes, especially CYP2D6 which metabolizes up to >25% of all drugs prescribed today in medical practice and plays an important role in targeted drug selection, optimization of dose, and prevention of toxicity. CYP2C19 is another candidate enzyme, whose genetic variations are known to control the metabolism of many phototropic medications. Despite a considerable public database containing genome-to-phenome information on these enzymes, the only current method to interrogating those SNPs and their effect on the ‘metabolizer status’ of a patient, is sequencing the patient sample in a clinical testing lab, which is costly and slow (1-2 weeks), and during that time, if the prescribed treatment plan is ineffective, there can be serious consequences for the patient. Hence, we propose to use these CYP alleles to define patient ‘metabolizer status’ as fast, moderate or slow, at the point of patient care and avoid the ‘trial and error’ approach. We will develop a point-of-care (POC) rapid assay for the pharmacogenetic screening of MDD patients. This microdevice will require minimal physician intervention beyond collection of a patient buccal swab and placement of the swab into the system for swab-to-genotype analysis. In less than 1 hour, physicians will be endowed with actionable data with regard to MDD therapy, including an SSRI therapeutic recommendation and dosing suggestion.