Guest Writer: David Durham, M.D., MPH
Psychiatry remains the most subjective field in medicine. This has probably been the greatest barrier to improve accuracy of diagnosis, quantifiably reduce adverse drug events, and substantially improve treatment outcomes. The utilization of pharmacogenetic technology in psychiatry is the first clinical modality of its kind to increase both accuracy and precision of prescribing psychotropic medications while simultaneously reducing adverse drug events.
The Centers for Medicaid and Medicare Services estimate that Adverse Drug Events (ADEs) in the U.S. cost about $289 billion, a figure that does not consider data from numerous private insurance companies. Over 770,000 people are injured or die each year in hospitals from ADEs. Adverse drug reactions are estimated to be responsible for an estimated 100,000 deaths every year and range from the 4th to the 6th leading cause of death in the U.S. Studies of geriatric outpatients have found the percentage of potential clinically significant adverse drug reactions to range from 6 percent to 25 percent. An estimated 17 percent of the top 200 prescribed drugs in 2012 have an FDA pharmacogenetic warning in the package insert. These numbers grow larger each year.
Pharmacogenetics is rooted in the Cytochrome P450 system. Cytochromes (CYPs) are the metabolic factories in the liver and mucosal surface of the intestinal tract. They can be likened to the body’s waste management system for drugs, toxins, and cellular waste products. Scientists have also related them to cellular highways for drugs. CYPS can be conceptualized as a combination of both.
There are four CYPs that metabolize almost all hepatic drugs. They are CYP2D6, CYP2C9, CYP2C19, and CYP3A4/5. Important for psychiatric pharmacogenetics, the first three of these – CYP2D6, CYP2C9, and CYP2C19 – metabolize approximately 70 percent of all psychotropic medications. Genetic variations in Cytochromes impact more patients than common genetic disorders. These include Trisomy 21, aka Down Syndrome, which occurs in 1 out of about 700 US births; Cystic Fibrosis, which occurs in about 1 in 31 people or 1000 babies born each year; and familial breast cancer BRCA 1 and 2, which occurs in about 1 in 8 women. Data from the Mayo Clinic, Genelex Corporation, and the National Institute of Health’s Clinical Pharmacogenetics Implementation Consortium (“CPIC”) estimate that 70 percent of people have variation in at least one of the principal CYP enzymes and do not metabolize medication normally . This individual variability is what contributes to adverse drug reactions.
There is mounting evidence showing a reduction in adverse drug reactions directly attributable to pharmacogenetic testing in clinical practice. All of the studies to date have shown, quite conclusively, improved clinical outcomes with this technology. The evidence also demonstrates reduced cost with the technology’s appropriate utilization. The genetic evolution of psychiatry holds the most promise for both.
The New Mexico Pharmacogenetics Cohort Study was a study I completed in June of 2013. It involved out-patient adult and adolescent (age > 15 y/o) psychiatric patients primarily of Caucasian, Hispanic, and mixed-racial ethnicity. Using Genelex Corporation’s proprietary risk analysis software, YouScript, as our database, patients were pre-screened for appropriateness of testing. The pre-screen criteria consisted of the aforementioned epidemiology and clinical utility of CYP450 2D6, 2C9, and 2C19 genotypes. Additionally, pre-screening criteria included patients with a history of several failed antidepressant/antipsychotic/psychotropic medication trials or a history of experiencing numerous side effects from these same classes of medications. Out of 348 patients, 296 were determined to meet criteria for pharmacogenetic testing. The results were impressive. Testing the 296 patients revealed 101 previously unknown significant interaction risks (drug-drug/drug-gene interactions) in 82 (27.2 percent) of the patients.
Based on the results of pharmacogenetic testing, a major change in management occurred in 112 of the patients (38 percent). Utilizing the YouScript software to retrospectively analyze the potential for drug-drug/drug-gene interactions in the 296 patients, the power of predicting adverse interactions was shown to have significantly improved when compared to the trained clinician alone (p < 0.005). The software’s proprietary software assigns one star as a mild-to-moderate risk of drug-drug/drug-gene interactions, two stars for a moderate risk of such interactions, and three stars for a high risk of drug-drug/drug-gene interactions. Of the 296 patients, 26 received a one-star risk, 117 received a two-star risk and 152 received a three-star risk. Utilization of the software, in addition to an experienced clinician, was noted to provide the greatest clinical utility. The combination of both was shown to be much more sensitive and specific (p < 0.004) in pre-screen patients for pharmacogenetic testing. Thus, using a ‘trained eye,’ in addition to drug-drug/drug-gene interaction prediction software, was conclusively superior in reducing the risk of adverse drug reactions and improving treatment outcomes for patients than using either alone.
In 2011, The Mayo Clinic completed a retrospective study of 60 out-patient adult psychiatric patients at the Hamm Clinic in St. Paul, Minnesota. The results impressively showed a 31.2 percent reduction in depressive symptoms in those patients who received pharmacogenetic testing compared to only a 7.2 percent reduction in depressive symptoms in those who were not tested (P < 0.02). A larger follow-up replication study of 200 out-patient psychiatric patients by a Mayo Health System affiliate in La Cross, Wisconsin showed a 44.8 percent reduction in depressive symptoms with pharmacogenetic testing compared to a 26.4 percent reduction without testing. This study yielded a much greater power in its results, with p < 0.001.
A more recent study by a research group at the University of Illinois Department of Psychiatry completed in 2012 and published in 2013 employed a blinded retrospective method to follow 96 patients over one year. They utilized proprietary software by AssureRx to identify those patients at increased risk of adverse drug reactions, and found those who were slow-metabolizers in either the 2D6 or 2C19 enzymatic pathways had 69 percent more total health care visits, 67 percent more general medical visits, greater than three-fold more medical absence days, and greater than four-fold more disability claims.
One of the more elegant studies was by Chou, et. al.. His team studied 100 psychiatric inpatient adults at Eastern State Hospital in Lexington, Kentucky. All patients were genotyped for CYP2D6 and individually tracked for ADEs, hospital stays, and total costs over a one-year period. The research team observed three dramatic trends. The first was a trend toward greater numbers of ADEs from psychotropic medications as one moved from patients with Ultrarapid CYP2D6 activity (UMs) to patients with absent CYP2D6 activity – poor metabolizers (PMs). The second trend was the average cost of treating patients with extremes in CYP2D6 activity (UM and PM) , which was $4,000 to $6,000 per year greater than the cost of treating normal and intermediate metabolizers (IMs). The third trend was that CYP2D6 PMs had longer hospital stays. This study demonstrated that patients who are CYP2D6 poor metabolizers and CYP2D6 ultrarapid metabolizers have more adverse drug events, longer hospital stays, and simply more expensive to treat. The proper application of pharmacogenetic technology is both a simple and precise answer to help reduce ADEs, reduce cost, and better manage hospital stays.
Psychotropic medications are now the most prescribed drugs in medicine, despite a repository of data that clearly reveals they are far from benign and are likely over-prescribed. Just as compelling is the data showing that nearly half of people prescribed these medications do not respond well to treatment. Many of these non-responding patients often require complex psychotropic cocktails which dramatically compound the potential for adverse drug events. In conjunction, these facts provide the perfect opportunity to introduce psychiatric pharmacogenetic technology, not only to the broader psychiatric community, but also to the broader medical community in the United States. The time is now for us to tailor our methods of prescribing, using a technology to give the right medicine at the right dose at the right time.
Dr. David Durham is a consulting neuropsychiatrist at Sage Neuroscience Center in Albuquerque, New Mexico. He is a Clinical Assistant Professor of Psychiatry at the University of New Mexico, School of Medicine, the Chair of the Board of Governors of the American College of Neurocognitive Medicine, and a Senior Scientific Advisor to Genelex Corporation in Seattle, Washington.
[1} Classen DC, Pestotnik SL, Evans RS, et al. Adverse drug events in hospitalized patients. JAMA 1997;277(4):3016.
 Cullen DJ, Bates DW, Small SD, et al. The incident reporting system does not detect adverse drug events: A problem for quality
improvement. Journal on Quality Improvement 1995;21(10):5418.
 Ibid and Lazarou J, Pomeranz BH, Corey PN. Incidence of adverse drug reactions in hospitalized pateints: a metaanalysis of
prospective studies. JAMA. 1998;279(15): 12001205.
 Tulner LR, Frankfort SV, et. al. Drugdrug interactions in a geriatric outpatient cohort: prevalence and relevance.
Drugs Aging. 2008;25(4):343355.
 Relling, MV, Klein, TE. CPIC: Clinical Pharmacogenetics Implementation Consortium of the Pharmacogenomics Research
Network. Clinical Pharmacology and Therapeutics. Vol.89. No.3. March (2011).
 Mrazek, D. Psychiatric Pharmacogenomics. Oxford Un. Press, 2011.
 Durham, D. Efficayof pharmacogenetic technology in clinical psychiatry – data from the New Mexico cohort. 2013. Under
 Runde I, et. al., 2011, Translational Psychiatry.
 Mrazek, D. Clinical Implementation of Psychiatric Pharmacogenomic Testing: characterizing and displaying genetic
variants for clinical action. Mayo Clinic. December 2, 2011.
 HallFlavin DK, Winner JG, Allen JD, Jordan JJ, Nesheim RS, Snyder KA, et al. Using a pharmacogenomic algorithm to
guide the treatment of depression. Transl Psychiatry. 2012;2:e172.
 Winner, J, Allen JD, et. al. Psychiatric pharmacogenomics predicts health resource utilizaton of outpatients with anxiety
and depression. Transl Psychiatry. March: 3(3). 2013. Published online March 19, 2013.
 Chou, WH, Yan FX, et. al. Extension of a pilot study: impact from the cytochrome P450 2D6 polymorphism on outcome
and costs associated with severe mental illness. J Clin Psychopharmacol. 2000 April; 20(2):24651.