Abstract
Background
Pharmacogenomics (PGX) is the science of how genetic variations affect the body’s response to medications. 1 Somatic PGX is the study of acquired mutations in cancers and is used to guide cancer therapy. In contrast, germline PGX focuses on inherited genetic mutations linked to idiosyncratic reactions and differences in drug absorption, transportation, metabolism, and interactions with receptors.2–8 Germline PGX is a relatively new clinical field with the potential to provide more cost-effective therapy.8–10 Its benefits have been proven in drug development, in cancer care, and in reducing adverse drug reactions related to the metabolism of specific medications linked to discrete genetic polymorphisms. Depression is common in serious illness, and germline PGX testing is an emerging tool that has been applied most to guide the management of refractory depression that does not respond to standard treatment. While PGX testing as it relates to antidepressants (AD) is mostly utilized by mental health specialists, all clinicians who care for seriously ill patients should be aware of it, as they may encounter questions from patients and families. This Fast Fact will focus on the role of germline PGX in AD management.
Basics and Cytochrome P450 (CYP) System
While comorbidities, sex, age, drug interactions, and organ function play contributory roles, genetic variations are crucial to understanding why standard effective doses of ADs for some patients are ineffective or harmful in others.8,9,11 Most of the data for ADs focuses on genetic variations in the cytochrome P450 system.
The CYP enzyme system accounts for most phase 1 hepatic metabolism, specifically enzymes known as 2C9, 2C19, 2D6, and 3A4. 9 Each of these enzymes is made up of multiple alleles. Polymorphisms, or variations in the number of inherited functional alleles, are responsible for marked variation in enzyme activity in the human population. 2 More active alleles result in more enzyme function and increased medication metabolism. 2 These enzymatic polymorphisms are divided into several phenotypic categories linked to expected clinical response. Categories range from ultra-rapid (UM) to rapid, to extensive or expected metabolism, to intermediate (IM), and finally poor metabolizers (PM).8,10–12 Due to faster metabolism of the active drug to an inactive metabolite, patients categorized as UM phenotypes may experience reduced clinical effects for medications metabolized by the affected CYP system. Conversely, impaired degradation and excretion of active compounds in poor metabolizers can increase the risk of adverse reactions.8,12 For prodrugs requiring CYP metabolism to convert a nonactive starting agent to the physiologically active compound, the opposite is true.8,12 Coadministration of drugs that either induce or inhibit the CYP system can further alter metabolism.
Antidepressant PGX Test-Related Information
Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are first-line drugs for anxiety and depressive disorders. However, initial SSRI therapy fails in 50% of patients due to a lack of efficacy or intolerable side effects.11,12 Both side effect profiles and poor therapeutic responses for SSRI/SNRIs have been linked to CYP polymorphisms, particularly CYP2D6 and CYP2C19.11–16 PGX testing for specific alleles in the CYP system can identify whether a patient has a UM or PM phenotype for AD medications. Mental health specialists can then use this information to guide medication selection or dosing in patients not responding to usual therapy.11,12
Outcomes
While overall data are mixed, more recent meta-analyses and systemic reviews show that most well-designed studies support the effectiveness of PGX in improving AD treatment response, clinical remission rates, and reducing AD-related side effects in patients who have not responded to at least two ADs.17–22 In addition, PGX testing has been shown to be cost-effective for treating severe depression in those who have failed multiple previous treatment regimens. 10
Controversies
The lack of testing standardization, concern from patients about data privacy, and direct-to-patient testing remain important controversies in PGX testing. 22 Although the cost of testing has decreased significantly in recent years due to Medicare and Medicaid local coverage determinations, individual costs for PGX testing still present a substantial barrier. 10 Despite data supporting cost-effectiveness, patients often face out-of-pocket expenses amounting to hundreds of dollars.
Practical Information
Germline PGX testing is obtained using serum or cheek swab samples and is available through multiple national companies. For patients receiving somatic PGX testing for targeted cancer treatment, germline PGX testing can also be added to these specimens. Clinician pharmacists and mental health specialists can be helpful in interpreting and applying the results.
Conclusion
PGX testing seems to be cost-effective and improves clinical outcomes in patients with depression that has not responded to at least two ADs. Clinical evidence does not support using PGX testing for all patients considering AD therapy.