March 29, 2017
Over the past decade, precision medicine — care designed to optimize therapeutic effect for individual patients — has made significant strides in medical specialties such as oncology. Less progress has occurred in psychiatry, as the neuroscience of specific psychiatric illnesses is generally less defined than the genetics of particular cancers.
Mayo Clinic is committed to applying precision medicine to psychiatry. Antidepressants are among the most commonly prescribed medications in the United States, and it is increasingly recognized that genetic variations in patients may contribute to the variability in effectiveness and adverse-effect toxicity profile of these drugs.
Researchers at Mayo Clinic's campus in Rochester, Minnesota, have proposed pharmacokinetic and pharmacogenetic prescribing guidelines for antidepressants, as a template for psychiatric precision medicine. In a literature-review study published in Mayo Clinic Proceedings in 2016, the researchers note that providing more-precise pharmacotherapeutic recommendations for individual patients — beyond the evidence base of large-scale clinical trials — can potentially improve treatment.
"We are learning how complex the interaction is between genes and the environment and how those interactions can lead to psychiatric illness," says Malik M. Nassan, M.B.B.S., a psychiatrist in the Depression Center at Mayo Clinic's campus in Minnesota. "Currently there is actionable data on the pharmacokinetics of antidepressants. Based on a patient's genetic code for relevant metabolic enzymes, it is possible to select the antidepressant that can provide the needed efficacy with the least side effects for that particular patient."
CYP2D6 and CYP2C19 pharmacogenetic test algorithm
CYP2D6 and CYP2C19 pharmacogenetic test algorithm. Image reprinted with permission from Mayo Clinic Proceedings.
The researchers focused on cytochrome P450 (CYP) genetic variation, which is known to influence the way in which selective serotonin reuptake inhibitors are metabolized. Specifically, the researchers analyzed the approximately 140 major genetic allelic variants encoding for two CYP-metabolizing enzymes, CYP2D6 and CYP2C19. Fluoxetine, paroxetine, and the serotonin and norepinephrine reuptake inhibitor venlafaxine are largely metabolized by CYP2D6. Citalopram and escitalopram are primarily metabolized by CYP2C19.
The genetic variations were categorized into four main metabolizer phenotypes:
Ultrarapid metabolizers potentially have lower bioavailability of the medication and thus possibly lower efficacy. Poor metabolizers' inability to produce a functional enzyme leads to an increased drug plasma level with a potentially increased rate of adverse effects.
"We know the side effects emerging from different antidepressants. These side effects can affect compliance and also possibly endanger patients," Dr. Nassan says.
For example, citalopram has been associated with a dose-dependent QTc interval increase. The Food and Drug Administration (FDA) initially approved dosing of no greater than 40 milligrams (mg) a day, later revising that dosage to no greater than 20 mg a day. The FDA also identified CYP2C19 poor metabolizers as being a risk factor for QTc prolongation.
The Mayo Clinic study cites the report of a 34-year-old patient with major depressive disorder who was taking venlafaxine at the time of death; the report's authors concluded that the cause of death was likely cardiac arrest due to a high blood concentration of venlafaxine attributed to CYP2D6 poor metabolizer phenotype.
"Having pharmacokinetic information prior to prescribing an antidepressant can help in prescribing a safer medication for the patients, and possibly adjusting the dose based on the genetic structure," Dr. Nassan says.
At Mayo Clinic, pharmacokinetic and pharmacogenetic data are incorporated into clinical decision support systems. For patients who have had genotype testing, test results are included in their electronic health records. If a patient is at risk of a drug-gene interaction, a warning appears when the clinician enters the prescribed medication into the patient's electronic record.
"At this point and based on the current data, the alert will suggest changing to another medication that's metabolized differently, which likely has a similar efficacy but lower rate for side effects," Dr. Nassan says.
Mayo Clinic doesn't routinely conduct genetic testing for all patients, due partially to insurance coverage issues. "However, if the genetic information is in the record, then using it to make a more informed decision on which antidepressant to select is just common sense," Dr. Nassan says. That genetic information will increasingly be available, as many Mayo Clinic patients participating in clinical trials undergo genetic sequencing.
"This is where medicine is moving forward," Dr. Nassan says. "In the near future, with the constant decrease of genetic testing cost, better insurance coverage and the expansion of a body of evidence further supporting the clinical significance, genotyping will become a routine test prior to prescribing relevant antidepressants and, by extension, other psychotropics to all patients.
"We need more translational research that links advances in clinical neuroscience and genetics research to the clinical practice of psychiatry, in order to make evidence-based personalized psychiatry practice a reality," he adds.
For more information
Nassan M, et al. Pharmacokinetic pharmacogenetic prescribing guidelines for antidepressants: A template for psychiatric precision medicine. Mayo Clinic Proceedings. 2016;91:897.