Pharmacogenetic Decision Support IT System for Psychiatric Hospitalization: RCT

Over 1.4 million hospitalizations for mental health conditions occur annually in the United States (3.4% of all hospitalizations), and more than half are for major depressive disorder (MDD). Remarkably, of the 30 antidepressant and antipsychotic medications available to treat MDD, nearly 50% are primarily metabolized by the liver enzyme encoded by the CYP2D6 gene. The CYP2D6 gene is notable for common sequence and structural polymorphisms which markedly affect the enzyme's capacity, causing a decrease or increase in drug metabolism in 60% of patients, and creating challenges for therapeutic management. The metabolic alterations caused by CYP2D6 gene polymorphisms may require longer hospitalizations due to "trial-and-error" prescribing, which delays improvement in health status and consumes resources. Reliable genotype testing is now available to detect an array of 21 gene alterations. Prescribing psychotropics using knowledge of the patient's CYP2D6 gene status is potentially cost effective.

For this research, the Genetics Research Center performs the CYP2D6 genotyping, and the Institute of Living's Clinical Evaluation and Monitoring System (CEMS) transmits explicit alerts regarding prescription or proscription of specific psychotropics.

The RCT will compare outcomes in patients whose treatment is guided by CYP2D6 functional status and pharmacogenetic alerts versus standard-of-care treatment to test the hypothesis that the provision of clinically actionable prescription or proscription information can decrease hospitalization length of stay and reduce subsequent readmission.

Using funds from AHRQ R01 HS022304-01, the RCT will enroll patients admitted to IOL over the next 5 years with a diagnosis of MDD and who are receiving psychotropic therapy at the time of admission or who will receive psychotropic therapy during hospitalization. Patients will be assigned to standard-of-care pharmacotherapy (Group S), where CYP2D6 genotype is determined but not transmitted to the clinician and psychotropic therapy follows the institutional norm. Patients will be assigned to genetically-guided pharmacotherapy (Group G) where pharmacogenetic alerts based on CYP2D6 genotype are furnished via CEMS to the clinician within 48 hours of admission. Genotyping encompasses 19 common polymorphisms in CYP2D6 and their quantification into a drug metabolism reserve index to establish levels of sub-normal function (poor metabolizer) or supra-normal function (rapid metabolizer). For the estimated 40% of patients in Group G who are poor or rapid metabolizers, CEMS will proscribe medications which are major CYP2D6 substrates.

The PI is Dr. Gualberto Ruaño, Director of GRC, and the lead clinician and Co-I is Dr. John Goethe, retired Director of IOL's Burlingame Research Center. Drs. Ruaño and Goethe have previously collaborated for 15 years on the pharmacogenetics of CYP450 and psychotropics. Dr. Theodore Holford of Yale University serves as statistical consultant.

The expected benefits are quantitative understanding of CYP2D6 pharmacogenetic information on outcomes and associated costs of psychiatric hospitalization. Importantly, this Program will provide objective benchmarking data for the comparative effectiveness of CYP2D6 genotyping for guiding psychiatric inpatient prescription.

The Specific Aims are:

1. RCT RECRUITMENT: To recruit patients with Major Depressive Disorder admitted to the IOL and randomly assign to Group G (genetically guided) and to Group S (standard of care).
2. RCT INTERVENTION: To conduct CYP2D6 genotyping of null alleles (*3, *4, *4XN, *5, *6, *7, *8, *11, *12, *14, *15), deficient alleles (*9, *10, *17, *29, *41), functional variants (*1, *2), and rapid alleles (*1XN, *2XN, *2a, *35) for all patients. In Group G the genotyping result is communicated to the treating clinician with prescription and proscription alerts for CYP2D6 substrate drugs; in Group S, the genotype is withheld. CEMS furnished results for 826 patients.
3. PRIMARY ENDPOINT: To compare length of hospitalization for all patients in Groups G vs. S.
4. SECONDARY ENDPOINT: To compare the rates of 30-day psychiatric hospital readmission in Group G vs. S.
5. ANCILLARY STUDIES: To assess the impact of genetic stratification in Groups G vs. S. with regard to the primary and secondary endpoints and specific drug utilization (removals, additions, co-prescriptions).