Dr. Rundell is professor of psychiatry and Dr. Shinozaki has a collaborative research appointment, both in the Department of Psychiatry and Psychology at the Mayo Clinic in Rochester, Minnesota. Dr. Shinozaki is also a psychiatrist at the Sioux Falls Veterans’ Administration Medical Center in South Dakota.
Disclosure: The authors report no affiliation with or financial interest in any organization that may pose a conflict of interest.
Objective: This article identifies situations wherein an evidence base exists for informing the use of pharmacogenomic testing in treating comorbid medical and psychiatric disorders.
Method: A review of literature was conducted to identify medical conditions with frequent psychiatric comorbidity that had level 1 evidence or meta-analytic studies related to pharmacogenomic factors as they relate to safety, tolerability, efficacy, or cost.
Results: Three situations met inclusion criteria: tamoxifen clinical response, warfarin clinical management, and opioid pain management. Each of these situations is associated with elevated risk of mood or anxiety disorders. For tamoxifen, cancer recurrence risk is the primary indicator for the need for testing. For warfarin, patient safety is paramount. For opioid management, efficacy and tolerability are primary indications for pharmacogenomic testing.
Conclusion: Available clinical data and cost effectiveness data suggest that for tamoxifen patients, pharmacogenomic testing should be routine. In patients treated with warfarin, testing is supported by current safety and clinical evidence in patients who are unable to obtain a stable international normalized ratio level. Testing of analgesic patients is indicated if there is demonstrated treatment non-response or unexpected tolerability. Additional clinical applications of pharmacogenomic testing of patients with comorbid medical-psychiatric illness will be justified by the outcomes of future studies examining effects such as clinical outcome, patient safety, efficacy, and cost.
• Patients with comorbid medical and psychiatric problems often have polypharmacy.
• Polypharmacy increases drug interaction possibilities.
• Specific disease-drug and drug-drug interactions increase morbidity.
• Pharmacogenomic testing can optimize pharmacotherapy in comorbid disorder patients.
Pharmacogenomic testing is increasingly available to physicians to assist with clinical decision making and is probably most useful in cases that involve medication treatment resistance, intolerable adverse effects, or the potential for problematic drug-drug or drug-disease interactions.1-8 Though relatively well studied in psychiatry practice,5,9 the use of pharmacogenomic testing has not been as systematically investigated in patients who are treated for comorbid medical and psychiatric disorders.10 In these patients, additional challenges of medical comorbidities and polypharmacy are more prominent than in general psychiatry or routine primary care practice.11-16 Psychiatric medication polypharmacy is increasing despite concerns regarding multiple medication prescriptions. The percentage of patients being treated with >3 psychiatric medications simultaneously has increased more than 10-fold in the past 30 years.17
Personalized medicine, defined as the implementation of genetic variation to guide prescribing tailored to the individual, is considered to be an inevitable consequence of completion of the Human Genome Project. This is not a new concept, given that genetic factors have been recognized to influence individual responses to medications for >50 years.18 However, many conditions which were mysterious in terms of who was afflicted (eg, malignant hyperthermia) are now demystified because of pharmacogenomic studies.19 A striking failure of modern medical practice is the high morbidity and mortality associated with adverse drug reactions. These reactions are now one of the leading causes of death and illness in the United States. It is estimated that 100,000–200,000 deaths annually are the consequence of an adverse drug reaction.20-22 Adverse drug reactions are reported to account for 7% of all hospital admissions, but this estimate is believed to be low as a consequence of underreporting.20,23 Genetic variations in cytochrome P450 (CYP) enzymes explain some of the variation in patient tolerability and therapeutic response.9,24 However, catastrophic deaths have been the consequence of non-functional enzymes.25
Development of specific applications for the use of pharmacogenomic testing has been rapid in cancer chemotherapy, where associations between specific genetic markers and chemotherapy outcome are well documented.26,27 Similarly, metabolic enzyme genotype variability has been linked with tamoxifen outcome which has resulted in specific recommendations for clinically important genotyping.28 However, for most currently available medications, variability in drug response has been presumed to be the result of a complex interaction of multiple factors. It is relevant to consider the opioid individual response, variations in absorption and distribution, opioid receptor pharmacodynamics, and whether a medication is a prodrug.29 This article identifies clinical situations for which a well-developed evidence base exists to inform the use of pharmacogenomic testing in clinical practice settings which treat patients who are comorbid for medical and psychiatric disorders.
A MEDLINE review of literature was conducted to examine clinical situations in primary care and general medicine where pharmacogenomic clinical data have empirically demonstrated to be of relevance to clinical outcome. Search terms included pharmacogenomic testing, medication safety, medication tolerability, treatment-resistant depression, depressive disorder, drug-induced, treatment resistance, antidepressant treatment, medical-psychiatric comorbidity, antipsychotic treatment, and antipsychotic adverse effects. Meta-analyses and papers with level 1 evidence were included when there was available data about comorbid medical and psychiatric pharmacologic treatments. Over 400 papers were identified in the review; 65 papers meeting these inclusion criteria were reviewed to identify illustrative conditions that inform safety, tolerability, efficacy, or cost.
Three illustrative situations were identified that met the goals of this review and had sufficient scientific evidence to meet the study inclusion criteria. One is a situation where pharmacogenomic insights play a pre-eminent role in determining the outcome of tamoxifen clinical response. The clinical management of patients receiving warfarin and opioid pain management are additional treatments that have become more effective with testing. Treatment of all three situations is often complicated by the need to treat comorbid psychiatric disorders. For example, rates of mood and anxiety disorders are elevated among patients with breast cancer, cardiovascular disease, stroke, and chronic pain.30
Tamoxifen Clinical Response
Tamoxifen is a standard endocrine therapy for the prevention and treatment of estrogen receptor-positive breast cancer. It is a classic pro-drug, requiring metabolic activation to elicit pharmacologic activity. The CYP2D6 enzyme and other CYP isoenzymes catalyze the conversion of tamoxifen into metabolites with significantly greater affinity for the estrogen receptor and greater ability to inhibit cell proliferation than the parent drug.26 For example, 4-hydroxytamoxifen is 30- to 100-fold more potent than tamoxifen in suppressing estrogen-dependent cell proliferation.31
Major tamoxifen metabolites include N-desmethyltamoxifen, 4-hydroxytamoxifen, tamoxifen-N-oxide, a-hydroxytamoxifen, and N-didesmethyltamoxifen, all created by oxidation by CYP isoenzymes.26,32 These tamoxifen metabolites may then undergo secondary metabolism and further biotransformation. This is clinically important because the products of secondary metabolism may have concentrations several times higher than products of primary metabolism.31 One primary tamoxifen metabolite, N-desmethyltamoxifen, is biotransformed to at least four additional secondary metabolites, one of which is 4-hydroxy-N-desmethyl-tamoxifen (endoxifen). Endoxifen may be present in concentrations up to 10-fold higher than the primary metabolite. The transformation of N-desmethyltamoxifen to endoxifen is catalyzed exclusively by CYP2D6.
Since CYP2D6 is a highly polymorphic gene, CYP2D6 genotype can have a marked impact on clinical outcomes when there is exclusive catalysis, as with biotransformation to endoxifen from tamoxifen.28 Women homozygous for the most common allele associated with the CYP2D6 poor metabolizer phenotype (ie, CYP2D6 *4) tend to have worse relapse-free time (hazard ratio, 1.85; P=.176) and disease-free survival time (hazard ratio, 1.86; P=.089) than other tamoxifen patients, even after accounting for lymph node status and tumor size.33 As many as 10% of Caucasian women are CYP2D6 poor metabolizers.9 The relative decrement in biotransformation to endoxifen among women with this genotype was further demonstrated by the finding that none of the women with the poor metabolizer genotype experienced moderate or severe hot flashes, a characteristic tamoxifen adverse effect, compared with 20% of the women with more adequate production of the CYP2D6 enzyme. Most strikingly, for patients with either poor 2D6 metabolism or medication inhibition of CYP2D6, there was significantly higher risk for cancer relapse (hazard ration, 3.12; P=.007), shorter time to cancer recurrence (hazard ratio, 1.91; P=.034), and worse relapse-free survival (hazard ratio, 1.74; P=.017).34
Women with breast cancer often take antidepressants because of the elevated incidence and prevalence of depression.30 Selective serotonin reuptake inhibitors such as paroxetine and fluoxetine, which are strong CYP2D6 inhibitors, reduce plasma endoxifen concentrations.26,31,35 Other antidepressants exhibit varying degrees of CYP2D6 inhibition; until more is known, it may be best to prescribe antidepressants which appear to have little or no capacity for CYP2D6 inhibition. Examples of antidepressants which may avoid CYP2D6 inhibition are escitalopram, fluvoxamine, and desvenlafaxine. The combination of an intermediate CYP2D6 genotype status and CYP2D6 inhibition with medications can cause additive negative impact on survival and recurrence in tamoxifen-treated patients.28 CYP2D6 genotyping is now integrated into many breast cancer clinics and is recommended by expert panels as important in the management of estrogen receptor-positive breast cancer patients.28 The Food and Drug Administration is considering updating the product labeling for tamoxifen with recommendations regarding CYP2D6 genotyping.
Warfarin Clinical Management
Warfarin is a vitamin K antagonist used for >50 years as the most commonly prescribed antithrombotic medication in the US.36 Warfarin therapy presents numerous challenges in clinical practice.37 There are significant risks associated with over- and under-coagulation. Genetic variations account for some of the differences in achieving stable international normalized ratio (INR) levels. Fully 33% of the time the INR in patients receiving warfarin is outside of the target range,38 with 50% of the values being subtherapeutic and 50% being supratherapeutic. Researchers have focused on pharmacogenomic testing to individualize warfarin dosing and improve the safety, efficacy, and cost-effectiveness of warfarin therapy. Testing may be particularly helpful when patients are taking other concurrent medications, including psychotropic medications, which can affect how warfarin is utilized.
Genetic testing has focused on the genes that code for vitamin K epoxide reductase complex subunit 1 (VKORC1) and CYP2C9, which are enzymes involved in the mechanism of action of warfarin and the metabolism of S-warfarin, respectively. VKORC1 is responsible for the conversion of vitamin K epoxide to vitamin K, and is the rate-limiting step in the physiologic process of Vitamin K recycling.39 The CYP2C9 enzyme is largely responsible for metabolism of warfarin. The contribution of VKORC1 polymorphisms to warfarin dose variability has been estimated to be between 15% and 30%.40-42 A single CYP2C9 nucleotide polymorphism accounts for 6% to 18% of the difference in warfarin dose requirements among patients.40-42
Patients who are CYP2C9 intermediate or poor metabolizers have been found to have a lower warfarin dose requirement.40,41 CYP2C9 inhibitors, such as sertraline and fluvoxamine, can prolong bleeding time.43 The combination of being an intermediate metabolizer and taking a medication which inhibits CYP2C9 could potentially have catastrophic consequences. VKORC1 genetic variation is generally felt to have a more significant impact on early response to warfarin anticoagulation, and CYP2C9 a greater impact on achieving steady-state concentrations of warfarin,37,44 because of the different roles these enzymes play in warfarin effects.
Though a great deal of effort is going into the study of how genotyping of VKORC1 and CYP2C9 contribute to safer and more effective warfarin management algorithms,37 there is no single agreed upon recommendation. Numerous factors contribute to the complexity of creating a clinical algorithm.45 First, the interactions between effects of polymorphisms of VKORC1 and CYP2C9 have been difficult to quantify. Second, patients with different ancestry have different frequencies of polymorphisms.46 Third, cost-effective use of genotyping has not yet been demonstrated in terms of time to anticoagulation and improved out-of-range INRs. Fourth, there is some controversy regarding which variants should be included in a testing panel.47 Last, there are non-genetic factors that contribute ~20% to variance in warfarin dose, including age, sex, adherence, and weight.39
Despite the complexities related to pharmacogenomic testing and warfarin therapy, there are advocates who make the case that clinicians should not wait until there is an algorithm that covers all the permutations possible in decision making, or until there is profitability or cost neutrality, to start obtaining pharmacogenomic data when instituting warfarin therapy or when there is a patient on warfarin with unstable INRs.48 Because of the considerable medical risks of under- or over-coagulation, pharmacogenomic testing may make positive individual contributions to safety and efficacy, especially when warfarin is initiated or when medications known to affect CYP2C9 functioning are initiated in a patient receiving warfarin.
Sertraline has an evidence base supporting its use in cardiology patients, making its co-administration with warfarin a clinical event with considerable frequency. Though there is no clear consensus about whether to always order pharmacogenomic testing in a patient on both warfarin and sertraline, it is recommended by some experts, and would be important when there is difficulty with unstable INRs. Other antidepressants that are at least partly metabolized by CYP2C9 inhibition potential include fluoxetine and bupropion. Examples of antidepressants that largely avoid potential problems with CYP2C9 inhibition are citalopram, paroxetine, escitalopram, venlafaxine, and desvenlafaxine. Unfortunately, there are no current guidelines or algorithms that suggest how frequently an INR should be measured in a patient on a medication partly or largely metabolized by CYP2C9; there are too many patient-specific determinants of clinical effect apart from presence or absence of a single medication.
Opioid Pain Management
Many factors influence individual response to opioids. These include individual variations in absorption and distribution, opioid receptor pharmacodynamics, and drug metabolism.29 All these factors may be affected by the co-administration of another medication. Studies of genetic influences on the pharmacodynamic effects of variations in the μ-opioid receptor have been conducted. Factors which influence neurotransmitter pathways include variations in the catechol-O-methyltransferase (COMT) gene and drug transporter proteins.
Genetic polymorphisms that change mu-opioid receptor function result in variability in inter-patient opioid effects.29 COMT gene mutations can affect the perception of pain, as reduced COMT activity results in the up-regulation of opioid receptors.49 Clinical studies of COMT polymorphisms suggest that patients with low COMT activity who have the Met/Met genotype of the Val158Met polymorphism require smaller opioid doses.49 Drug transporter proteins facilitate passage of opioid drugs across biologic membranes such as the liver, kidneys, and intestines, as well as at the blood-brain barrier. Genetic variation in the production of these proteins affects both the efflux and uptake of opiod drugs and contributes to inter-patient variability in response to these drugs.29
Opioid metabolism by CYP enzymes and enzymes that regulate glucuronidation to active metabolites also influence drug concentrations and clinical efficacy. Psychotropic medications are metabolized by many of the same CYP enzymes that metabolize opioid analgesics and their metabolites. The higher incidence and prevalence of mood and anxiety disorders among patients with chronic pain30 creates pharmacologic scenarios that complicate the management of these patients.
The clinical effects of the weaker opioids codeine, hydrocodeine, tramadol, oxycodone, and hydrocodone rely upon formation of their more potent metabolites (eg, morphine, dihydromorphone, and oxymorphone) by a metabolic pathway mediated by CYP2D6.50 A number of in vivo retrospective or case studies51-53 of patients receiving codeine have demonstrated significant differences in plasma morphine concentrations between extensive and poor CYP2D6 metabolizers. Approximately 10% of patients of European ancestry are poor metabolizers and unlikely to gain full benefit from codeine administration, but are just as likely to suffer codeine-related side effects. These findings can be exacerbated when a patient is also on a CYP2D6 inhibitor, including many antidepressants, such as fluoxetine and paroxetine. However, ultrarapid CYP2D6 metabolism is associated with codeine intoxication.54 This phenomenon may extend to breastfeeding neonates of codeine-prescribed mothers who are ultra-rapid metabolizers.55
Tramadol exerts analgesia via the opioid agonist metabolite O-demethyl tramadol and via modulation of noradrenergic and serotonergic monoamine pathways. O-demethylation of tramadol to the opioid agonist O-demethyl tramadol is mediated by CYP2D6; there is lower plasma concentrations in poor metabolizers compared to extensive metabolizers, and there are reduced analgesic effects.56,57 Though the prevalence of CYP2D6 polymorphisms in the population undergoing pain management does not appear to be different from the general population,58 patient care may be improved by genotyping and following therapeutic drug concentrations when there is treatment resistance or poor tolerability.
Other opioid analgesics such as methadone are metabolized by other enzymes, such as the CYP3A4 enzyme. Although genetic polymorphisms occur in the enzyme CYP3A4, unlike CPY2D6, this has not yet been correlated with particular clinical phenotypes.59
The three illustrative clinical management situations reviewed in this paper demonstrate the potential value and complexity of pharmacogenomic testing in the clinical situation where comorbid medical and psychiatric disorders exist. Because of increasing frequency of psychiatric polypharmacy,17 patients with comorbid psychiatric and medical illness represent a growing and unique group of patients where pharmacogenomic testing may improve safety and clinical outcomes. The considerations presented in the three patient categories discussed in this paper highlight how complex the interactive contributions of genetic and non-genetic factors are in determining patient responses.
Available clinical data suggest that for tamoxifen patients, pharmacogenomic testing should be routine. Testing also appears to be clinically indicated when there are difficulties obtaining stable INR levels in patients receiving warfarin and when patients receiving opiate analgesic medications demonstrate treatment non-response or severe tolerability problems. Additional studies of cost effectiveness and clinical utility may identify additional clinical populations who could benefit.27 Studies of cost effectiveness may draw different conclusions over time; the cost of testing varies across laboratories and is currently in a phase of rapid decline. In addition to cost, variability in coverage by insurance providers and turnaround time for results (typically several days) may limit more widespread utilization of pharmacogenomic testing; these factors are likely to change with time.
As the scientific literature identifies clinical situations where pharmacogenomic testing can add value to healthcare, other medical specialists will begin to use this emerging technology. For example, within the field of infectious diseases, the genomes of both the host and the pathogen are relevant to antibiotic efficacy and resistance.60 Examples of host-relevant genetic polymorphisms include genes of antigen recognition molecules, pro-inflammatory cytokines, anti-inflammatory cytokines, and effectors molecules. Genetic mutations for these different factors could define a genetic profile of a high-risk patient for whom a specific treatment should be added urgently. However, co-treatment of the infection and concurrent psychiatric disorders may complicate clinical outcomes and require modifications of treatment algorithms.
Special patient populations may benefit from pharmacogenomic testing. Children and adolescents in particular may have unique considerations related to genomic variations that will translate into childhood-specific genomic testing algorithms. Examples of reported conditions relevant to childhood that are influenced by pharmacogenomic considerations are azathioprine-induced myelosuppression, codeine-induced infant mortality, warfarin-associated anti-phospholipid syndrome, and adverse drug reactions that appear to occur disproportionately in children and adolescents.22 Children are at even greater risk for adverse drug reactions than adults. An estimated 15% of pediatric hospitalizations are a consequence of adverse drug reactions, and 28% of these adverse reactions are severe.61,62 More than 75% of pharmaceuticals licensed in North America have never been tested in pediatric populations and are used without adequate guidelines for safety or efficacy.63
Patient satisfaction surveys indicate that patients are gradually becoming more aware of pharmacogenenomic testing and are beginning to expect their providers to be knowledgeable about the indications for testing.64 Specifically, they expect their providers to be able to interpret test results, provide education about the benefits and limits of testing, and to provide up-front education about cost. As knowledge about benefits of pharmacogenomic testing emerges, an increasing number of situations will be identified where it will prove cost effective and clinically beneficial to employ pharmacogenomic testing early in the course of treatment. Evidence-based pharmacogenomic testing will guide patients and providers in their selection of specific medications, and in implementation of safe and effective dosing strategies.15,65,66 Future development of clinical application of pharmacogenomic testing, in general and in the special setting of comorbid medical-psychiatric illness, will depend on future study outcomes measuring effects of testing on clinical outcome, patient safety, efficacy, and cost. PP
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