Psychosomatics 47:75-85, February 2006
doi: 10.1176/appi.psy.47.1.75
© 2006 Academy of Psychosomatic Medicine
Clinical Guidelines for Psychiatrists for the Use of Pharmacogenetic Testing for CYP450 2D6 and CYP450 2C19
Jose de Leon, M.D.,
Scott C. Armstrong, M.D., and
Kelly L. Cozza, M.D.
From the University of Kentucky Mental Health Research Center at Eastern State Hospital. Dr. Armstrong is the Medical Director, Center for Geriatric Psychiatry, Tuality Forest Grove Hospital, Forest Grove, OR, and Associate Clinical Professor of Psychiatry, OR Health Sciences University, Portland, OR. Dr. Cozza is the staff psychiatrist for the Infectious Disease Service, Department of Medicine, Walter Reed Army Medical Center, Washington, DC, and Assistant Professor of Psychiatry, Uniformed Services University of Health Sciences, Bethesda, MD. Drs. Armstrong and Cozza are co-authors, along with Dr. Jessica R. Oesterheld, of the Concise Guide to Drug Interaction Principles for Medical Practice: Cytochrome P450s, UGTs, P-glycoproteins, 2nd Edition. (American Psychiatric Publishing, Inc., 2003). Address correspondence and reprint requests to Dr. de Leon, Mental Health Research Center at Eastern State Hospital, 627 West 4th St., Lexington, KY 40508. e-mail: jdeleon{at}uky.edu
The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Army or the Department of Defense.
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ABSTRACT
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Pharmacogenetics has arrived in clinical psychiatric practice with the FDA approval of the AmpliChip CYP450 Test that genotypes for two cytochrome P450 2D6 (CYP2D6) and 2C19 (CYP2C19) genes. Other pharmacogenetic tests, including those focused on pharmacodynamic genes, are far from ready for clinical application. CYP2D6 is important for the metabolism of many antidepressants and antipsychotics, and CY2C19 is important for some antidepressant metabolism. Poor metabolizers (PMs), lacking the enzyme, account for up to 7% of Caucasians for CYP2D6 and up to 25% of East Asians for CYP2C19. Patients having three or more active CYP2D6 alleles (up to 29% in North Africa and the Middle East), are called CYP2D6 ultra-rapid metabolizers (UMs). CYP2D6 phenotypes (particularly PMs) are probably important in patients taking tricyclic antidepressants (TCAs), venlafaxine, typical antipsychotics, and risperidone. The CYP2C19 PM phenotype is probably important in patients taking TCAs and perhaps citalopram, escitalopram, and sertraline. On the basis of the literature and the authors’ clinical experience, the authors provide provisional recommendations for identifying and treating CYP2D6 PMs, CYP2C19 PMs, and CYP2D6 UMs. The next few years will determine whether CYP2D6 genotyping is beneficial for patients taking the new drugs aripiprazole, duloxetine, and atomoxetine. Practical recommendations for dealing with laboratories offering CYP2D6 and CYP2C29 genotyping are provided.
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INTRODUCTION
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The genetic revolution has been the result of two interwoven processes: human genome sequencing and the development of new technologies permitting genetic testing in an automated and efficient way. Although the development of genomic medicine and genetic testing has helped in diagnosing some relatively rare and unusual disorders, this progress has had limited impact in medicine.1 Pharmacogenetics is usually defined as the study of variability in drug response due to heredity.2 More recently, the term "pharmacogenomics" is being used, a broader term encompassing all genes in the genome that may determine drug response. The distinction is arbitrary, given that the terms are often used interchangeably.2
The FDA completed the approval of the first pharmacogenetic test, the AmpliChip CYP450 Test, in January 2005.3,4 This test performs massive parallel genotyping, using one of the major technological advances in genetic testing, the so-called DNA microarray, DNA chip, or GeneChip. The latter name was given by Fodor,5 the Affymetrix CEO who first developed this technology for massive parallel genotyping based on the hybridization process (the patient’s DNA strand recognizes the uniquely complementary sequence in a computer chip through base pairing). The AmpliChip CYP450 Test assesses two polymorphic genes, the Cytochrome P450 2D6 (CYP2D6) and the Cytochrome P450 2C19 (CYP2C19).3
In 1997, the journal Science6 described "personalized prescription" or "tailoring drugs to a patient’s genetic make-up" in their "six research horizons for 1998" and predicted that it will "soon" reach clinical practice. More precise estimations for the generalized used of personalized prescription have been provided: the year 2015, according to the lay journal Time7 and 2020, by JAMA.8 Because CYP2D6 metabolizes many of the psychiatric drugs, psychiatry has become the first area of medicine for the practical clinical use of pharmacogenetic testing. A recent article9 in a mainstream economic journal focused on "personalized medicine," presenting an example of a bipolar patient who had a complicated pharmacological treatment history. Although many psychiatrists may not be ready for "personalized prescription," their patients may be reading this article9 or listening to government officials promoting "personalized prescription" in the media.10
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PHARMACOGENETIC APPROACHES IN PSYCHIATRY
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To appreciate the context of these initial and limited practical pharmacogenetic recommendations for clinicians, one has to understand the different ways that pharmacogenetics may be used in the future in psychiatry. The first and most obvious distinction is between using single-gene and multiple-gene testing (Table 1). 11–13 Single-gene testing can include pharmacodynamic genes, such as the serotonin transporter or the dopamine receptors,11 but these gene tests are not ready for clinical use (Table 1) and may require many years until they are useful and available. As an example, the dopamine2 receptor (DRD2) gene14 appears a reasonable choice to explore for antipsychotic response, but many of its known single-nucleotide polymorphisms (SNPs) have no functional influence; there are a couple of SNPs believed to be functional, but the studies on association with treatment response have not been encouraging. The DRD2 gene-status research can be compared with more than 30 years of CYP2D6 knowledge that has allowed the identification of more than 50 SNPs that have functional consequences relatively well established.
The two pharmacokinetic genes, CYP2D6 and CYP2C19, have reached clinical practice by means of the FDA’s approval of the AmpliChip CYP450 Test. No other technology using massive parallel CYP genetic testing has yet been completely developed or approved by the FDA. The authors are aware15 that other companies developing CYP testing, include General Electric Health Care (CodeLinkTM P450 SNP Bioarray); Tm Bioscience (Tag-ItTM Mutation Detection Kit), which uses the microsphere-based universal array genotyping platform developed by Luminex; Third Wave Molecular Diagnostics (Invader® Technology); and Jurilab Ltd (DrugMetTM Genotyping Test). Finally, the authors know that two U.S. academic laboratories and several commercial pharmacogenetic companies offer physicians the opportunity to genotype their patients for CYP genes (costs for an individual sample range from $250 to $500, depending on the number of genes tested).
Current genetic microarray systems could easily test hundreds of SNPs from many genes to identify a complex pattern predicting drug response.16,17 However, considering how difficult taking a well-understood polymorphic gene such as CYP2D6 to the clinical environment has been, it is unlikely that such an approach, using multiple SNPs of multiple genes, may reach the market in the next 5 to 10 years. The currently available technology simply helps clinicians and selected patients to decide if they should "not take that drug" or "take this low or high dose," an application called "safety pharmacogenetics."18 The future may lead to recommendations that would determine the best drug for a particular patient, which determination is called "efficacy pharmacogenetics."18
Testing for a limited number of genetic variations of multiple pharmacokinetic genes (Table 1) can be done easily, from a technical point of view. Several commercial laboratories provide batteries of genotype testing that include pharmacokinetic genes besides CYP2D6 and CYP2C19. The tested genes vary from laboratory to laboratory and include other CYP and other Phase I enzymes, but most of these genetic variations have little relevance for psychiatric patients; therefore there are no clear reasons to consider genotyping other genes besides CYP2D6 and CYP2C19 in a typical psychiatric patient at this time.
In spite of the obstacles that psychiatric pharmacogenetics may overcome in becoming standard clinical practice, it is encouraging that a recent paper indicated that current antipsychotics may be the ideal place for implementing pharmacogenetic techniques, since they are efficacious in only 30% of patients and tend to have a narrow therapeutic window. The report stressed that the cost-effectiveness of pharmacogenetics may be influenced by the therapeutic window and interindividual variability.19
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BRIEF REVIEW OF CYP2D6 AND CYP2C19 GENOTYPING
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CYP2D6 is a metabolic liver-enzyme that biotransforms approximately 25% of known drugs metabolized by CYPs.20 Many of these drugs are antipsychotic or antidepressant drugs, making it an important metabolic enzyme for psychiatry. The gene encoding this enzyme is located on Chromosome 22. The CYP2D6 enzyme is expressed constitutively in several tissues, in particular, the liver.
The activity of the CYP2D6 enzyme is extremely variable because of more than 50 genetic variations, and it can be expressed as having four main levels of activity (phenotypes).21 In the traditional view, the ultra-rapid metabolizer (UM) has three or more copies of the active CYP2D6 gene and exhibits extremely high CYP2D6 activity. There is increasing data that only some UMs have additional copies.22 A recent study has suggested that current genotyping methods only identified approximately 20% of CYP2D6 UMs; therefore, approximately 80% are currently missed by genetic testing.23 Currently, we do not know which other polymorphic variations may be associated with unusually high activity in individuals without known allele duplication or multiplication. In summary, psychiatrists need to be very aware that our current status of knowledge does not allow us to identify many of the CYP2D6 UMs.
The normal subject, or extensive metabolizer (EM), has one or two functional copies of the CYP2D6 gene and displays typical CYP2D6 activity. The term "intermediate metabolizer" (IM) usually refers to a subject with one nonfunctional CYP2D6 allele and an allele that is expressed as an enzyme with low activity. Other groups consider subjects with one functional copy of CYP2D6 as IM instead of EM.11 In reality, with our current limited knowledge, this distinction between IMs and EMs is more important for researchers than for clinicians, since the clinical relevance of the terms needs to be demonstrated. Without doubt, the most important phenotype is the "poor metabolizer" (PM). PMs are subjects with two nonfunctional CYP2D6 alleles and no CYP2D6 in their liver. Table 2 provides a summary of the CYP2D6 phenotypes in different racial groups.24–27 Quinidine, paroxetine, bupropion, and fluoxetine are powerful CYP2D6 inhibitors, and the use of potent inhibitors can render a patient that is a CYP2D6 EM (a normal individual with one or twp functional alleles) into a phenotypic PM. CYP2D6 induction is controversial, but appears likely not to be clinically relevant.
The CYP2C19 phenotypes include some PMs and a majority of normal (EM) subjects.28 Table 2 provides the estimated frequency, by race, for subjects who may lack both enzymes CYP2D6 and CYP2C19. These subjects may be rather rare, and the first author has found only 1 case among 1,500 patients genotyped in an ongoing study that will genotype up to 4,000 patients.
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CLINICAL GUIDELINES FOR USING CYP2D6 AND CYP2C19 GENOTYPING IN ANTIDEPRESSANT THERAPY
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Appendix 111,29–39 and Appendix 211,40–50 provide guidelines for the use of genetic testing with antidepressants and antipsychotics, respectively. We hope to explain that CYP2D6 and CYP2C19 testing may help some patients taking some antidepressants, and CYP2D6 testing may help some patients taking some antipsychotics. Extensive footnotes are included in case additional readings are needed. Extreme CYP2D6 and/or CYP2C19 genetic profiles should encourage clinicians to explore different treatment options. It is crucial to have a detailed pharmacological history. Clinical diagnosis is a Bayesian process of progressive accumulation of data, in which each piece makes the diagnosis "somewhat more or less suggestive."51 Therapeutic drug monitoring (TDM) of drug levels may be particularly helpful when one suspects unusual genetic profiles of CYP2D6 and CYP2C19.
Known polymorphisms in other CYPs may have less relevance in psychiatry. CYP1A2 genetic variations associated with PM or UM profiles appear to be very rare.52 More frequent CYP1A2 polymorphisms may influence the response to CYP1A2-inducers such as smoking.52
In general, CYP2D6 PMs are likely to have poor tolerance of tricyclic antidepressants (TCAs) and perhaps of venlafaxine, with average tolerance of the majority of other antidepressants. TCA levels will surely help to identify CYP2D6 PMs and may be less costly than genetic testing. In spite of our limited knowledge and the lack of studies supporting this strategy, it appears safer to recommend prescribing antidepressants not dependent on CYP2D6, such as bupropion, citalopram, escitalopram, mirtazapine, or sertraline to CYP2D6 PMs. (The "BCEMS" mnemonic may be helpful.) CYP2D6 UMs are likely to have low plasma levels of TCAs and perhaps of venlafaxine. Although not all CYP2D6 UMs may be identified by current genotyping, it appears safer to recommend prescribing antidepressants not dependent on CYP2D6 (BCEMS) to patients identified as CYP2D6 UMs. Other more complex alternatives37–39 are described in Appendix 1.
CYP2C19 PMs are likely to have poor tolerance of several TCAs that are demethylated by CYP2C19 and may also have poor tolerance to citalopram, escitalopram, and sertraline ("CES"). In spite of our limited knowledge and the lack of studies supporting this strategy, it appears safer to recommend prescribing CYP2C19 PMs antidepressants not dependent on CYP2C19, such as bupropion, fluvoxamine, mirtazapine, or paroxetine ("BFMP"). TCA levels may help to identify PMs of 2C19 and may be less costly.
PMs for both CYP2D6 and CYP2C19 are rare, but recommending antidepressants not dependent on CYP2D6 or CYP2C19, such as bupropion or mirtazapine, would seem prudent.
The tables do not have any reference to duloxetine, since we do not have enough information and cannot easily predict its profile. According to the marketer, duloxetine is metabolized by CYP2D6 and CYP1A2.53 Thus, it is likely that CYP2D6 phenotypes may influence duloxetine response.
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CLINICAL GUIDELINES FOR USING CYP2D6 GENOTYPING IN ANTIPSYCHOTIC THERAPY
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Appendix 2 summarizes our current limited knowledge of metabolism of antipsychotics.11,40–50 CYP2D6 PMs are likely to have poor tolerance of many typical antipsychotics and risperidone, with average tolerance for other antipsychotics. TDM of drug levels may be particularly helpful when one suspects unusual CYP2D6 genetic profiles.
In spite of our limited knowledge and the limited studies supporting this strategy, it appears safer to recommend prescribing CYP2D6 PMs antipsychotics not dependent on CYP2D6, such as clozapine, olanzapine, quetiapine, or ziprasidone ("COQZ"), or, at least, very low doses of CYP2D6-dependent antipsychotics. CYP2D6 UMs are likely not to respond to usual doses of typical antipsychotics and risperidone, although they may respond normally to other antipsychotics. In spite of our limited knowledge and the lack of studies supporting this strategy, it appears safer to recommend prescribing CYP2D6 UMs antipsychotics not dependent on CYP2D6 ("COQZ").
According to its marketer, aripiprazole (not included in Appendix 2) is metabolized, like risperidone, by CYP2D6 and CYP3A; thus it may behave very similarly to risperidone, although it may have a wider therapeutic window.52 The company studies are very limited,54 and independent studies are needed.
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CASE EXAMPLES FOR USING PHARMACOGENETIC TESTING
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Pharmacogenetic testing may be a new addition to psychiatric treatment, but, to use it properly, one needs to take into account basic pharmacological knowledge and common sense. Drug response is controlled by pharmacokinetic and pharmacodynamic factors,55 which can be both genetic and environmental. Thus, CYP2D6 and CYP2C19 testing provides information only on one aspect: genetic pharmacokinetic factors. To understand and use these data, clinicians may want to read recent reviews on antipsychotic52 and antidepressant56,57 metabolism, psychiatric pharmacogenetics,11 and the AmpliChip CYP 450 Test.4 Because many psychiatric patients undergo polypharmacy and are at risk for drug–drug interactions (DDIs), clinicians need to be very familiar with the basic concepts of DDI, such as inhibition and induction.58 Pharmacogenetic testing of CYP2D6 and CYP2C19 adds a new level of complexity in assessing drug efficacy and/or adverse drug reactions (ADRs). Even with this new technology, the principle of Occam’s Razor still holds true. For example, the most likely cause of very-low or nondetectable plasma drug levels would be nonadherence to a drug regimen, and not a polymorphic UM at CYP2D6.
Four real-world examples regarding CYP2D6 and CYP2C19 testing are described here to demonstrate a common-sense approach.
1. A fellow-psychiatrist calls the psychiatric consultant, describing one of her complex patients with bipolar disorder. The patient’s history is long and complicated. In brief, he did not respond to mood stabilizers, antidepressants, or antipsychotics. This led the treating psychiatrist to believe that the patient must be a UM, and she wanted to know how he could be tested.
It was important to note with the consultee that mood stabilizers are not metabolized by CYP2D6 or CYP2C19. Also, several of the antipsychotics and antidepressants that were presented were also not dependent on these enzymes. The cause for this patient’s lack of response to medications cannot be explained by his being a UM for CYP2D6; therefore, testing would probably be unproductive.
2. A 72-year-old female patient with long-lasting panic disorder calls the psychiatric consultant and explains that she cannot tolerate any antidepressant. The patient believes she must be "a universal PM" for antidepressants. She has tried seven or eight antidepressants and had problems with all of them. She has been genotyped in an academic lab. She reads the report that describes her as an IM and explains that she has one normal allele. The consultant explains to her that she has CYP2D6 in her liver and is "relatively normal." The patient tells the consultant that the academic lab’s report lists 30–40 medications that she cannot take. The consultant explains that several of the antidepressants that she has tried are not metabolized by CYP2D6 and/or CYP2C19 and that there are likely other reasons for the lack of tolerance she has with antidepressants. Also, the lab’s list of medications was one for PMs, and was overstated in her case. She is not a CYP2D6 PM. She is an IM, essentially the same as a normal EM.
3. A mother calls the psychiatric consultant, asking how she can get her daughter genotyped, because medications do not help her, and she may be a "universal UM." Her daughter has seizures and does not respond to any anticonvulsants. The consultant explains that anticonvulsants are not metabolized by CYP2D6, and, thus, testing would not likely be helpful. Phenytoin is only metabolized in part by CYP2C19. Further history reveals that the daughter is autistic; she has gained significant weight when on risperidone and has been tried on paroxetine. Nothing clinically appears to suggest that her daughter is a CYP2D6 PM, CYP2D6 UM, or a CYP2C19 PM. However, the mother appears overwhelmed by the complexity of her daughter’s clinical situation. The psychiatrist helps the mother to contact a laboratory and recommends she discuss the need for testing with her daughter’s psychiatrists, since she appears to feel that she needs to try all possible alternatives in helping her daughter.
4. A 23-year-old patient with borderline intelligence and borderline personality traits was admitted to the hospital. After we spoke with the patient’s brother, it was obvious that, since his father died 3 years ago, the patient has had a pattern of utilizing multiple emergency rooms, with false allegations of symptoms. Problems have included use of drugs or alcohol, psychotic symptoms, and suicidal and homicidal ideation. During this admission, he complained of "voices," was treated with perphenazine, 4 mg/day, and developed a severe case of stiffness. More worrisome, several years ago he received a high dose of parenteral haloperidol and developed a serious case of neuroleptic malignant syndrome, from which he almost died. There are also some indications that the patient may have developed priapism on trazadone, but complete ADR documentation was lacking. His genotyping revealed that he was a CYP2D6 PM. All medications were stopped, and the psychiatrist explained to the patient and the family the high risk of serious ADRs on some antidepressants and antipsychotics (a list was provided), since his psychiatrists appeared particularly prone to using high doses of medications to control some of his acting out.
These first three cases suggest that CYP2D6 and CYP2C19 cannot and will not resolve all psychopharmacologically difficult cases. In other instances, such as the fourth case, genotyping provides very helpful information that may be even life-saving.
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CLINICAL GUIDELINES FOR SELECTING A LABORATORY
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Appendix 33,22,23,28,59 presents information on how to select a laboratory and how to interpret AmpliChip CYP 450 Test results. Current available information and testing reliability appears reasonable for CYP2D6 PMs and CYP2C19 PMs. A CYP2D6 PM or a CYP2C19 PM genotype needs to be taken seriously in order to avoid side effects. It is more difficult to be sure about other genotypes. Remember that normal alleles are frequently diagnosed by defect, so the fewer alleles that the laboratory tests, the more likely it is to classify subjects as EMs. It is much more likely that the lab reports a false negative in the case of an EM with one active copy than in an EM with two copies. If the pharmacological profile strongly suggests a PM, and the test result is an EM, you may need to discuss with them their estimations of their false negatives for CYP2D6 PMs. For example, if a patient has repeated high nortriptyline levels after a low dose, and a lab labels him a CYP2D6 EM, clinicians definitively need to discuss with the lab the possibility of rechecking the genotyping and considering the possibility of a false negative.
Assuming that the laboratory classifies the subject as a CYP2D6 PM, what is the clinical relevance? According to the first author’s experience, CYP2D6 PM explains only 10%–20% of risperidone ADRs or discontinuations because of ADRs (public health perspective),7 but CYP2D6 PMs (individual perspective)4 have 3–6 times more risk of having risperidone ADRs or discontinuations because of ADRs. In the context of predicting risperidone ADRs, the CYP2D6 PM genotype has low sensitivity (10%–20%), but very high specificity (>90%). Risperidone TDM had a little higher sensitivity (25%), but, clearly, lower specificity (72%) of predicting risperidone ADRs.4
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CONCLUSION
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"Personalized medicine" has reached psychiatry with FDA approval of the first pharmacogenetic test, the AmpliChip CYP450. CYP2D6 and CYP2C19 testing may help patients with a history of excessive difficulties with antidepressants; CYP2D6 testing may help patients with a history of problems with antipsychotics. Current available information and testing reliability appears reasonable for CYP2D6 PMs and CYP2C19 PMs. Other CYP2D6 phenotypes, such as UMs, may be important, but both the literature and our ability to detect them are quite deficient. CYP2D6 phenotypes (particularly PM) are probably important for patients taking TCAs, venlafaxine, typical antipsychotics, and risperidone. The CYP2C19 PM phenotype is probably important for patients taking TCAs and, perhaps, citalopram, escitalopram, and sertraline. The next few years will determine whether CYP2D6 genotyping is beneficial for patients taking the new drugs aripiprazole, duloxetine, and atomoxetine.60,61 The availability of laboratories offering CYP2D6 and CYP2C19 genotyping is currently limited but will expand significantly in the next several years. Time and clinical experience will be required to develop appropriate and practical laboratory guidelines for pharmacogenetic testing.
Finally, the recently published CATIE study62 suggests that the first antipsychotic a psychiatrist prescribes to a patient may not be the best choice for an individual patient. Therefore, the future of "personalized medicine," with better pharmacokinetic and pharmacodynamic genetic testing, could ultimately lead to better clinical outcomes. Studies such as CATIE may help clinical researchers to change their focus from simply trying to find the best antipsychotic or antidepressant for the average patient. The "average" patient may, indeed, be uncommon.
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ACKNOWLEDGMENTS
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Roche Molecular Systems, Inc. markets the Amplichip CYP450 Test detecting the CYP2D6 and CYP2C19 gene variations. Jose de Leon, M.D., has received support for his laboratory and research-initiated grants from Roche-Molecular Systems, Inc. and has lectured once supported by Roche-Molecular Systems, Inc., but he has not received any consultant payments. He has no other financial arrangements with Roche Molecular Systems, Inc. He has no stocks in Roche, Affymetrix, or any other companies developing pharmacogenetic tests. In the past 2 years, Dr. de Leon has 1) been on the advisory board of Bristol-Myers Squibb; 2) received researcher-initiated grants from Eli Lilly; and 3) delivered a lecture supported by Eli Lilly (once).
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