CM E

Pharmacogenetics of

Major Depressive Disorder

CM E
EDUCATIONAL OBJECTIVES

1. Demonstrate that genetic differences can inuence drug absorption, distribution, metabolism, and excretion (pharmacokinetics), as well as mechanism of action (pharmacodynamics). 2. Explain that the nature of genetic variation in drug metabolism for antidepressants involves multiple P450 enzymes, each of which may vary in DNA sequence, with resultant alteration in enzyme activity. 3. Discuss that no specic genetic variation has a large effect on antidepressant response to make that variation clinically meaningful. Falk W. Lohoff, MD, is Assistant Professor of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, and the Center for Neurobiology and Behavior, Translational Research Laboratories, Philadelphia. Address correspondence to: Falk W. Lohoff, MD, 125 South 31st Street, Room 2213, Philadelphia, PA 19104; fax 215573-2041; lohoff@mail.med.upenn.edu. Dr. Lohoff has disclosed no relevant nancial relationships.

Falk W. Lohoff, MD
ajor depressive disorder (MDD) is a common psychiatric illness with high levels of morbidity and mortality. It is estimated that 10% to 15% of the general population will experience clinical depression during their lifetime, and 5% of men and 9% of women will experience a depressive disorder in a given year.1 Although there are

a variety of pharmacological treatments available, response and tolerability to medication are highly variable with some patients responding to one treatment but not another. In general, only one-third of treated MDD patients respond to pharmacological treatment and reach remission of symptoms.2,3 There are several potential explanations for these poor drug response rates, including clinical heterogeneity and diagnostic uncertainty, envi-

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ronmental and social factors, and genetics factors. This article will focus on the recent developments in the eld of pharmacogenetics in MDD. Pharmacogenetics is the term used to describe the phenomenon that genes inuence drug response and side effects. Drug response and tolerability are inuenced by two main processes referred to as pharmacokinetics and pharmacodynamics. Pharmacokinetics involves the absorption, metabolism, and excretion of a drug, while pharmacodynamics refers to the effects of the compound on receptors, transporters, and downstream targets. Both of these systems are inuenced by heritable variation in genes. The complex interaction of multiple genes involved in pharmacokinetic and dynamic processes in the context of environmental inuences essentially comprises the action of a drug. By identifying genetic components implicated in drug response and side effects, the hope is to precisely match a medication to the patients genetic makeup and thus maximize treatment response and minimize potential adverse events. Although the environment of a patient will always remain unique and personal, advances in genomic medicine will soon enable a more comprehensive personalized pharmacotherapy. GENETICS OF PHARMACOKINETICS IN MDD The introduction of tricyclic antidepressants (TCA) in the 1950s represented a great advance in the treatment of depression; however, it soon became clear that serious side effects and toxicity limited their use and also varied substantially between patients. This variation in toxicity and tolerability is caused partially by differences in the metabolic activity in the cyptochrome P450 (CYP450) enzymes by which these antidepressants get metabolized. CYP450 enzymes are drug-metabolizing hemoproteins present in multiple tissues with predominance in the liver.

More than 50 enzymes have been described, which are encoded by more than 63 CYP450 genes. The main P450 enzymes involved in antidepressant drug metabolism are CYP2D6, CYP2C19, CYP3A4, and CYP1A2.4 The CYP2D6 system has been studied extensively and is so far the best characterized.5 Early experiments with debrisoquin and nortriptyline documented that patients fall into different categories, including poor, intermediate, extensive, and ultra-rapid metabolizers. Cloning and characterization of the CYP2D6 gene led to the

Although there are a variety of pharmacological treatments available, response and tolerability to medication are highly variable with some patients responding to one treatment but not another.
identication of more than 75 CYP2D6 alleles, which determine metabolizer status. For example, some individuals carry alleles that encode for an inactive or no enzyme at all, while others have gene duplications resulting in ultra rapid metabolism of CYP2D6 substrates. Metabolizer status is also inuenced by ethnicity, with 7% of whites being poor metabolizers compared with 1% in the Asian population. Certain African populations have higher proportions of ultrarapid metabolizers resulting from multiple copies of the CYP2D6 gene. Such individuals can have an inadequate therapeutic response to standard doses of the drugs metabolized by CYP2D6. In fact, plasma levels of the TCA nortriptyline and imipramine were closely related to the number of functional CYP2D6 gene copies.6,7 Bertilsson et al showed that

patients with no or only one functional copy of the gene reach therapeutic plasma levels with starting doses for nortriptyline and would easily reach potentially toxic plasma levels with high-normal doses. Patients with two to four copies, on the other hand, would require highnormal doses to even reach therapeutic plasma levels.8 Similar CYP2D6-allele/plasma level concentration correlations have been reported for selective serotonin reuptake inhibitors (SSRI)9 and serotonin norepinephrine reuptake inhibitors (SNRI).10,11 Although a clear dose-response curve of antidepressant efcacy has been described for TCA,12 it is less apparent for SSRIs and SNRIs; however, high plasma levels have been correlated with higher side effects for all antidepressants.13 Knowledge of the genetic metabolizer status of a patient is thus helpful to the clinician in order to potentially avoid side effects and might further help to reach therapeutic levels faster; however, the overall effects on improved efcacy are still unclear and need to be established. The idealistic vision of predicting side effects based on genotypes gets complicated by the reality of environmental factors and gene-environment interactions. For example, dietary factors (grapefruit juice, caffeine, nicotine) have known inuences on drug metabolism;14 however, perhaps the most common inuencing factor is taking another medication. A drug that strongly inhibits CYP2D6 may make an individual who is otherwise a normal metabolizer appear like a poor metabolizer with increased side effects. Future studies will be necessary to dissect the complicated interaction between clinical presentation, environmental factors, and CYP450 genotype. GENETICS OF PHARMACODYNAMICS IN MDD The term pharmacodynamics is used to describe the effects of a drug on the body. Pharmacodynamic aspects

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therefore include interactions of a drug with receptors, transporters, and downstream targets. Although the primary mechanism of action is known for most antidepressants and thought to involve predominantly monoaminergic neurotransmitter systems, the exact mechanisms by which antidepressants work remain elusive. Most pharmacogenetic studies in MDD so far have focused on candidate genes involved in monoaminergic neurotransmission. Some of the most obvious targets studied include genes encoding the serotonin transporter and receptors, norepinephrine transporter, dopamine receptors, monoamine oxidase A, tryptophan hydroxylase, and cathechol-O methyl transferase.15 It should be noted that candidate gene studies in pharmacogenetics face similar conceptional issues as psychiatric genetic studies in general. Many studies have been limited by small sample sizes, clinical and diagnostic heterogeneity, incomplete clinical data, differences in denition of treatment response, genetic complexity, unknown functional relevance of single nucleotide polymorphisms (SNPs), and limited biological evidence for candidate gene selection. Despite these obstacles, several candidate genes are worth mentioning as they have been repeatedly suggested to be implicated in treatment response to antidepressants. One of the most widely studied genes in pharmacogenetic studies of depression is the serotonin transporter gene (SLC6A4). This gene is located on chromosome 17q, and several polymorphisms have been reported. One polymorphism in the promoter region of the gene (5-HT transporter gene linked polymorphic region: 5-HTTLPR) consists of an insertion or deletion of a repetitive sequence, producing a short allele (S) or a long (L) allele.16 Although the 5-HTTLPR was originally described as bi-allelic, rare very-long and extralong alleles have been described in Japanese and blacks.17 The long version of

The idealistic vision of predicting side effects based on genotypes gets complicated by the reality of environmental factors and gene-environment interactions.
5-HTTLPR has been shown to affect transporter function, resulting in higher serotonin reuptake by the transporter. Based on this observation, several pharmacogenetic studies have investigated this polymorphism with regards to antidepressant response.18 Results have been mixed, with some studies showing an effect of the L-version while others failed to demonstrate an effect. A recent meta-analysis of 15 published studies, however, indicated that there was a signicant association between the L-allele and better treatment response to SSRIs.19 Interestingly, response within 4 weeks was the most robust nding in this metaanalysis, suggesting that the 5-HTTLPR might also predict the time course of response and remission. Although several other genes have been investigated as candidates for antidepressant response, the results are ambiguous, and no clear replicated relationship

between genetic variants and antidepressant treatment outcome has been demonstrated so far.15,20,21 Recently, results from the Sequential Treatment Alternatives to Relieve Depression (STAR*D) trial became available. This multi-center trial included 3,671 patients with MDD who were treated with the SSRI citalopram as a rst-line agent for 12 weeks.22 Main outcome measures were categorical response, remission, tolerance, and adverse effect burden. Analyses of the rst phase of the trial showed that only 30% of treated patients reached remission after adequate citalopram treatment.2 As part of the trial, 1,953 patients gave blood for pharmacogenetic testing. Several groups have investigated whether genetic factors might predict clinical outcome in the STAR*D sample. McMahon et al investigated 68 candidate genes and genotyped 768 SNPs in this sample. They detected an association between the serotonin receptor gene HTR2A and treatment outcome.23 Although citalopram does not bind directly to 5-HT2A receptors, citalopram downregulates 5-HT2A receptors in animal models,24,25 which could play a role in differences in treatment response. Other candidate genes implicated in antidepressant efcacy in the STAR*D trial are FKBP5 and GRIK4;26,27 however, all these ndings require replication. Given the fact that response and remission are complex and inuenced by multiple factors, perhaps focusing on the side-effect prole of antidepressants might reveal a closer link to genetics. For example, while an effect of the 5HTTLPR on primary efcacy could not be established in the STAR*D sample,28 this polymorphism seems to be associated with side effects.29 In addition, several recent studies have suggested an association between genetic markers and treatment emergent suicidal ideation using the STAR*D sample.30,31 All of these studies using the STAR*D sample were candidate gene studies.

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Genes and polymorphisms were selected based on the current understanding of the neurobiology of mood disorders. With the advance of technology, it is now possible to investigate several hundred thousand SNPs in an individual at the same time without pre-selection based on biological plausibility. These studies are called whole genome association (WGA) studies. WGA studies of the STAR*D and other samples are currently underway, and results are expected to be available in the near future. Even though these promising new approaches to investigate genetic variants at a large scale are intriguing, caution should be use with the interpretation of potential ndings. Although the STAR*D sample has advantages of being relatively large and all patients received citalopram, it is important to note that the STAR*D trial was not designed to answer pharmacogenetic questions. There are several concerns regarding this sample from a pharmacogenetic perspective, including heterogeneity in the severity of depression, multi-center design, inclusion of different ethnic populations, and no available drug levels. In order for pharmacogenetic studies in MDD to succeed, there is a clear need for well designed, large, prospective trials, with focus on the genetic component.32 One such attempt is currently being undertaken by the European consortium project Genome-Based Therapeutic Drugs for Depression (GENDEP). This is the rst, large-scale, multicenter human pharmacogenomics study focused on the prediction of therapeutic response to antidepressants and adverse effects.33 WGA studies are currently underway for this sample. Finally, genetic studies can only suggest an association between a polymorphism and treatment. Currently, very little is known about the biological relevance of these polymorphisms and how genetic variation inuences treatment response on the cellular level. Soon-to-be-identied SNPs associated with antidepressant

treatment response might lead into promising new drug development but also need to undergo extensive validation and neurobiological investigations. PHARMACOGENETICS OF MDD IN CLINICAL PRACTICE AND CONCLUSIONS The eld of psychiatric pharmacogenetics is rapidly developing, and genetic patient information will likely inuence clinical practice in the immediate future. Currently, there is only one commercial pharmacogenetic test available (Roche Diagnostic, AmpliChip CYP450), which can be ordered through a few commercial and academic laboratories. This test was approved by the Food and Drug Administration in 2005 and provides genotypes for the two cytochrome P450 genes, CYP2D6 and CYP2C19. Theoretically, by genotyping patients for variation in these genes, the clinician should be able to predict metabolizer status of a patient, which might inuence medication choice and dosing. There are currently no universal guidelines regarding who should get tested, but several suggestions have been published.34,35 Limitations of the AmpliChip test include false-positive and false-negative results every laboratory test faces, but more importantly, the test does not identify all poor or ultra-rapid metabolizers. In addition, cost effectiveness and long-term benets for patients taking antidepressants have yet to be established. A recent publication by the Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group (http://www.egappreviews.org) discourages use of CYP450 testing for patients beginning SSRI treatment until further clinical trials are completed. Although pharmacogenetics in clinical practice is currently limited to side effects and metabolism, comprehensive pharmacogenetic proling is already a reality in many pharmaceutical companies. Many phase 2 and phase 3

trials now have genetic components, and the FDA has recently issued the rst genotype-based indications for medications. This new paradigm shift offers great opportunities in identifying particular subgroups for which a compound works especially well or causes severe side effects. On the other hand, pharmaceutical companies might limit their phase 2 and 3 trials to certain genetic populations in order to document safety and efcacy, leaving patients with complicated risk genetics out of trials and drug development. It is therefore important to develop comprehensive pharmacogenetic policies and regulations in order to avoid misuse of genetic information.36 Although psychiatry has entered the new area of pharmacogenetics, it is important to remember that this new technology will only provide additional information on one aspect of the complex and personal history of psychiatric patients. It is the sum of inside and outside factors that contribute and inuence mental pathology and well being. REFERENCES
1. Kessler RC, Chiu WT, Demler O, Merikangas KR, Walters EE. Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2005;62(6):617-627. 2. Trivedi MH, Rush AJ, Wisniewski SR, et al; STAR*D Study Team. Evaluation of Outcomes With Citalopram for Depression Using Measurement-Based Care in STAR*D: Implications for Clinical Practice. Am J Psychiatry. 2006;163(1):28-40. 3. Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163(11):1905-1917. 4. Staddon S, Arranz MJ, Mancama D, Mata I, Kerwin RW. Clinical applications of pharmacogenetics in psychiatry. Psychopharmacology (Berl). 2002;162(1):18-23. 5. Weinshilboum RM, Wang L. Pharmacogenetics and pharmacogenomics: development, science, and translation. Annu Rev Genomics Hum Genet. 2006;7:223-245 6. Daln P, Dahl ML, Bernal Ruiz ML, Nordin J, Bertillson L. 10-Hydroxylation of nortriptyline in white persons with 0, 1, 2, 3, and 13 functional CYP2D6 genes. Clin Pharmacol Ther. 1998;63(4):444-452

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7. Schenk PW, van Fessem MA, VerploeghVan Rij S, et al. Association of graded allele-specic changes in CYP2D6 function with imipramine dose requirement in a large group of depressed patients. Mol Psychiatry. 2008;13(6):597-605. 8. Bertilsson L, Dahl ML, Daln P, Al-Shurbaji A. Molecular genetics of CYP2D6: clinical relevance with focus on psychotropic drugs. Br J Clin Pharmacol. 2002;53(2):111-122. 9. Charlier C, Broly F, Lhermitte M, Pinto E, Ansseau M, Plomteax G. Polymorphisms in the CYP 2D6 gene: association with plasma concentrations of uoxetine and paroxetine. Ther Drug Monit. 2003;25(6):738-742. 10. Veefkind AH, Haffmans PM, Hoencamp E. Venlafaxine serum levels and CYP2D6 genotype. Ther Drug Monit. 2000;22(2):202-208. 11. Shams ME, Arneth B, Hiemke C, et al. CYP2D6 polymorphism and clinical effect of the antidepressant venlafaxine. J Clin Pharm Ther. 2006;31(5):493-502. 12. Perry PJ, Zeilmann C, Arndt S. Tricyclic antidepressant concentrations in plasma: an estimate of their sensitivity and specicity as a predictor of response. J Clin Psychopharmacol. 1994;14(4):230-240. 13. Murphy GM, Kremer C, Rodrigues HE, Schatzberg AF. Pharmacogenetics of antidepressant medication intolerance. Am J Psychiatry. 2003;160(1):1830-1835. 14. Alvares AP, Pantuck EJ, Anderson KE, Kappas A, Conney AH. Regulation of drug metabolism in man by environmental factors. Drug Metab Rev. 1979;9(2):185-205. 15. Serretti A, Artioli P. From molecular biology to pharmacogenetics: a review of the literature on antidepressant treatment and suggestions of possible candidate genes. Psychopharmacology (Berl). 2004;174(4):490-503. 16. Lesch KP, Bengel D, Heils A, et al. Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science. 1996;274(5292):1527-1531. 17. Gelernter J, Cubells JF, Kidd JR, et al. Popu-

18.

19.

20.

21.

22.

23.

24.

25.

26.

lation studies of polymorphisms of the serotonin transporter protein gene. Am J Med Genet. 1999;88(1):61-66. Serretti A, Benedetti F, Zanardi R, Smeraldi E. The inuence of Serotonin Transporter Promoter Polymorphism (SERTPR) and other polymorphisms of the serotonin pathway on the efcacy of antidepressant treatments. Prog Neuropsychopharmacol Biol Psychiatry. 2005;29(6):1074-1084. Serretti A, Kato M, De Ronchi D, Kinoshita T. Meta-analysis of serotonin transporter gene promoter polymorphism (5-HTTLPR) association with selective serotonin reuptake inhibitor efcacy in depressed patients. Mol Psychiatry. 2007;12(3):247-257. Perlis RH. Pharmacogenetic studies of antidepressant response: how far from the clinic? Psychiatr Clin North Am. 2007;30(1):125-138. Binder EB, Holsboer F. Pharmacogenomics and antidepressant drugs. Ann Med. 2006;38(2):82-94. Rush AJ, Fava M, Wisniewski SR, et al. Sequenced treatment alternatives to relieve depression (STAR*D): rationale and design. Control Clin Trials. 2004;25(1):119-142. McMahon FJ, Buervenich S, Charney D, et al. Variation in the gene encoding the serotonin 2A receptor is associated with outcome of antidepressant treatment. Am J Hum Genet. 2006;78(5):804-814. Strome EM, Clark CM, Zis AP, Doudet DJ. Electroconvulsive shock decreases binding to 5-HT2 receptors in nonhuman primates: an in vivo positron emission tomography study with [18F]setoperone. Biol Psychiatry. 2005;57(9):1004-1010. Manji HK, Drevets WC, Charney DS. The cellular neurobiology of depression. Nat Med. 2001;7(5):541-547. Lekman M, Laje G, Charney D, et al. The FKBP5-Gene in Depression and Treatment Response-an Association Study in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D). Cohort Biol Psychia-

try. Jan 10, 2008. 27. Paddock S, Laje G, Charney D, et al. Association of GRIK4 with outcome of antidepressant treatment in the STAR*D cohort. Am J Psychiatry. 2007;164(8):1181-1188. 28. Kraft JB, Peters EJ, Slager SL, et al. Analysis of association between the serotonin transporter and antidepressant response in a large clinical sample. Biol Psychiatry. 2007;61(6):734-742. 29. Hu XZ, Rush AJ, Charney D, et al. Association between a functional serotonin transporter promoter polymorphism and citalopram treatment in adult outpatients with major depression. Arch Gen Psychiatry. 2007;64(7):783-792. 30. Laje G, Paddock S, Manji H, et al. Genetic markers of suicidal ideation emerging during citalopram treatment of major depression. Am J Psychiatry. 2007;164(10):1530-1538. 31. Perlis RH, Purcell S, Fava M, et al. Association between treatment-emergent suicidal ideation with citalopram and polymorphisms near cyclic adenosine monophosphate response element binding protein in the STAR*D study. Arch Gen Psychiatry. 2007;64(6):689-697. 32. Serretti A, Kato M, Kennedy JL. Pharmacogenetic studies in depression: a proposal for methodologic guidelines. Pharmacogenomics J. 2008;8(2):90-100. 33. Uher R, Farmer A, Maier W, et al. Measuring depression: comparison and integration of three scales in the GENDEP study. Psychol. Med. 2008;38(2):289-300. 34. de Leon J, Armstrong SC, Cozza KL. Clinical guidelines for psychiatrists for the use of pharmacogenetic testing for CYP450 2D6 and CYP450 2C19. Psychosomatics. 2006;47(1):75-85. 35. Mrazek DA. Incorporating pharmacogenetics into clinical practice: reality of a new tool in psychiatry. The context of genetic testing in clinical psychiatric practice. CNS Spectr. 2006;11(3 Suppl 3):3-4. 36. Katsanis SH, Javitt G, Hudson K. Public health. A case study of personalized medicine. Science. 2008;320(5872):53-54.

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