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The Challenges of Psychopharmacogenetics

1999; Elsevier BV; Volume: 65; Issue: 3 Linguagem: Inglês

10.1086/302559

1537-6605

Marco Catalano,

Pharmacogenetics and Drug Metabolism

Residing at the intersection of two relatively young fields—psychopharmacology and pharmacogenetics— psychopharmacogenetics is only now becoming recognized as a biomedical discipline in its own right. The introduction of chlorpromazine, in 1952, for the treatment of psychotic disorders, may be considered to mark the birth of psychopharmacology. Since that time, a wide array of psychotropic drugs have been applied to the treatment of various psychiatric conditions, including anxiety disorders and such mood disorders as depression and mania. Clinical experience quickly accumulated, indicating that these drugs are of variable usefulness. Stark interindividual differences in outcome and side effects are distressingly common for this group of therapeutic drugs. Early on, and continuing to this day, psychiatrists have relied on clinical experience and, not infrequently, guesswork to predict the outcome of prescribing a standard dosage of a psychotropic drug. Increasingly, however, evidence—which is often anecdotal but which is sometimes based on the results of family and twin studies—has suggested that genetic factors underlie (1) the observed interindividual and interethnic or racial differences in psychopharmacological response (Smith and Mendoza Smith and Mendoza, 1996Smith MW Mendoza RP Ethnicity and pharmacogenetics.Mt Sinai J Med. 1996; 63: 285-290PubMed Google Scholar; Frackiewicz et al. Frackiewicz et al., 1997Frackiewicz EJ Sramek JJ Herrera JM Kurtz NM Cutler NR Ethnicity and antipsychotic response.Ann Pharmacother. 1997; 31: 1360-1369PubMed Google Scholar; Varner et al. Varner et al., 1998Varner RV Ruiz P Small DR Black and white patients response to antidepressant treatment for major depression.Psychiatr Q. 1998; 69: 117-125Crossref PubMed Scopus (26) Google Scholar) and (2) the concordant responses, among relatives, to antidepressant therapy (Franchini et al. Franchini et al., 1998Franchini L Serretti A Gasperini M Smeraldi E Familial concordance of fluvoxamine response as a tool for differentiating mood disorder pedigrees.J Psychiatr Res. 1998; 32: 255-259Abstract Full Text PDF PubMed Scopus (138) Google Scholar). Thus, perhaps to their own surprise, psychiatrists have found themselves concerned about familial patterns of drug kinetics and about polymorphisms in genes for receptors or enzymes, although both of these issues have traditionally been the province of pharmacogeneticists. As originally defined by Vogel (Vogel, 1959Vogel F Moderne probleme der humagenetik.Ergeb Inn Med Kinderheilkd. 1959; 12: 52-125Crossref Google Scholar), pharmacogenetics is the study of the heritable differences in the metabolism and activity of exogenous agents such as drugs or environmental toxins. In recent years, researchers in pharmacogenetics have focused on evaluating structural and regulatory polymorphisms both in genes coding for drug-metabolizing enzymes and in genes coding for other enzymes or receptors. Here, I wish to argue that psychiatry should not overuse psychopharmacogenetics as a tool to solve its own uncertainties, nor should psychopharmacogenetics be viewed as a special facetof pharmacogenetics. Instead, psychopharmacogenetics should be seen as a separate field of inquiry with a specific set of challenges. Mental disorders are intrinsically heterogeneous and can seldom be defined or diagnosed by the same rigorous methods applied to other conditions of interest to medical geneticists. In addition, the interactions between genetic and environmental factors that make psychiatric phenotypes difficult to study may render equally difficult the pursuit of optimal individual treatments for these diseases. Nevertheless, there is reason for optimism, since, in this era of molecular biology, psychopharmacogenetics now has appropriate tools at its disposal for addressing these challenges. Before the advent of molecular tools, researchers in psychopharmacogenetics were restricted to examination of questions about the kinetics and dynamics of psychoactive drugs. Animal models, which were a staple of such work, have proved to be poor predictors of the range of drug responses in humans. The ability to work at the DNA level now allows researchers to identify and score polymorphisms with ease. It also allows them to tap into the insights of molecular neuroscientists, who are concerned with the physiological and developmental roles of genes that have come to our attention because of their possible pathological roles. Pharmacogenetics has often been used to solve the problem of the biological heterogeneity of psychiatric diseases. However, both the use of markers, such as human leukocyte antigens, that have a questionable relevance to the disease process and the lack of reliable diagnoses have led to inconclusive and contradictory findings about the nosology of schizophrenia and affective (mood) disorders. Differences in response to treatment do indeed provide potentially important clues to these problems, primarily because they suggest different etiopathogenetic hypotheses, but they absolutely cannot take the place of the reliable diagnostic criteria that we are still obliged to seek. In its molecular form, however, psychopharmacogenetics could help refine diagnoses and provide a tool for independent genetic testing of a given drug-responsive phenotype. The earliest applications of molecular data in psychiatric treatment did little to address the familiar methodological difficulties that arise from working with poorly defined clinical entities. Unfortunately, psychiatric nosology has not seemed to have kept up with progress in neurobiology and molecular biology (van Praag van Praag, 1997van Praag HM Over the mainstream: diagnostic requirements for biological psychiatric research.Psychiatry Res. 1997; 72: 201-212Abstract Full Text PDF PubMed Scopus (82) Google Scholar; Smoller and Tsuang Smoller and Tsuang, 1998Smoller JW Tsuang MT Panic and phobic anxiety: defining phenotypes for genetic studies.Am J Psychiatry. 1998; 155: 1152-1162Crossref PubMed Scopus (125) Google Scholar), and the etiologic factors of major psychiatric disorders are still unknown, despite considerable efforts and methodological advances (Peroutka Peroutka, 1997Peroutka SJ The medical utility of genomics data in neuropsychiatry: mutational genetics versus association genetics.Curr Opin Biotechnol. 1997; 8: 688-691Crossref PubMed Scopus (6) Google Scholar). This may reflect, in part, an overly simplistic focus on individual receptor molecules, despite the fact that most psychotropic drugs target multiple signaling pathways. Although much of the variability in psychotropic drug action is linked to genetic factors, the results of studies of drug-metabolizing enzymes (DMEs) and receptor variants have proved, on the whole, to be confusing and inconsistent. Thus, polymorphisms within the CYP2D6 gene, which encodes a cytochrome P450 DME, have been extensively screened in psychiatric patients, although there have been no conclusive results (Andreassen et al. Andreassen et al., 1997Andreassen OA MacEwan T Gulbrandsen AK McCreadie RG Steen VM Non-functional CYP2D6 alleles and risk for neuroleptic-induced movement disorders in schizophrenic patients.Psychopharmacology (Berl). 1997; 131: 174-179Crossref PubMed Scopus (102) Google Scholar; Armstrong et al. Armstrong et al., 1997Armstrong M Daly AK Blennerhassett R Ferrier N Idle JR Antipsychotic drug-induced movement disorders in schizophrenics in relation to CYP2D6 genotype.Br J Psychiatry. 1997; 170: 23-26Crossref PubMed Scopus (89) Google Scholar; Kawanishi et al. Kawanishi et al., 1997Kawanishi C Hanihara T Maruyama Y Matsumura T Onishi H Inoue K Sugiyama N et al.Neuroleptic malignant syndrome and hydroxylase gene mutations: no association with CYP2D6A or CYP2D6B.Psychiatr Genet. 1997; 7: 127-129Crossref PubMed Scopus (12) Google Scholar; Mihara et al. Mihara et al., 1997aMihara K Otani K Suzuki A Yasui N Nakano H Meng X Ohkubo T et al.Relationship between the CYP2D6 genotype and the steady-state plasma concentrations of trazodone and its active metabolite m-chlorophenylpiperazine.Psychopharmacology (Berl). 1997; 133: 95-98Crossref PubMed Scopus (35) Google Scholara,Mihara et al., 1997bMihara K Otani K Tybring G Dahl ML Bertilsson L Kaneko S The CYP2D6 genotype and plasma concentrations of mianserin enantiomers in relation to therapeutic response to mianserin in depressed Japanese patients.J Clin Psychopharmacol. 1997; 17: 467-471Crossref PubMed Scopus (42) Google Scholarb; de Leon et al. de Leon et al., 1998de Leon J Barnhill J Rogers T Boyle J Chou WH Wedlund PJ Pilot study of the cytochrome P450-2D6 genotype in a psychiatric state hospital.Am J Psychiatry. 1998; 155: 1278-1280PubMed Google Scholar; Kapitany et al. Kapitany et al., 1998Kapitany T Meszaros K Lenzinger E Schindler SD Barnas C Fuchs K Sieghart W et al.Genetic polymorphisms for drug metabolism (CYP2D6) and tardive dyskinesia in schizophrenia.Schizophr Res. 1998; 32: 101-106Abstract Full Text PDF PubMed Scopus (120) Google Scholar). No clear-cut explanation for interindividual differences in drug plasma levels has emerged from this research. Drug efficacy and side-effect patterns cannot be predicted by genotyping at this locus, although there are some consistent data regarding the variable risk of extrapyramidal side effects, including such movement disorders as tardive dyskinesia (Armstrong et al. Armstrong et al., 1997Armstrong M Daly AK Blennerhassett R Ferrier N Idle JR Antipsychotic drug-induced movement disorders in schizophrenics in relation to CYP2D6 genotype.Br J Psychiatry. 1997; 170: 23-26Crossref PubMed Scopus (89) Google Scholar; Kapitany et al. Kapitany et al., 1998Kapitany T Meszaros K Lenzinger E Schindler SD Barnas C Fuchs K Sieghart W et al.Genetic polymorphisms for drug metabolism (CYP2D6) and tardive dyskinesia in schizophrenia.Schizophr Res. 1998; 32: 101-106Abstract Full Text PDF PubMed Scopus (120) Google Scholar). The dopamine D4 receptor (DRD4) gene, which exhibits considerable genetic variability both within and between populations, was initially studied as a candidate risk factor for major psychiatric disorders; however, no convincing associations have emerged. The pharmacology of this receptor suggests that it might still be related to variability in clinical response. DRD4 binds to the antipsychotic drug clozapine, and several study groups (Rietschel et al. Rietschel et al., 1996Rietschel M Naber D Oberlander H Holzbach R Fimmers R Eggermann K Moller HJ et al.Efficacy and side-effects of clozapine: testing for association with allelic variation in the dopamine D4 receptor gene.Neuropsychopharmacology. 1996; 15: 491-496Crossref PubMed Scopus (85) Google Scholar; Hwu et al. Hwu et al., 1998Hwu HG Hong CJ Lee YL Lee PC Lee SF Dopamine D4 receptor gene polymorphisms and neuroleptic response in schizophrenia.Biol Psychiatry. 1998; 44: 483-487Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar) have obtained conflicting results on how sequence variants effect responsiveness to this drug. An in vitro study on an expressed variant of DRD4 failed to show significant variation either in the receptor's affinity for clozapine or for other drugs or neurotransmitters or in its functional properties (Zenner et al. Zenner et al., 1998Zenner MT Nobile M Henningsen R Smeraldi E Civelli O Hartman DS Catalano M Expression and characterization of a dopamine D4R variant associated with delusional disorder.FEBS Lett. 1998; 422: 146-150Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar). However, clozapine also interacts with the serotonin receptors 5HT2C and 5HT2A (Meltzer Meltzer, 1990Meltzer HY An overview of the mechanism of action of clozapine.J Clin Psychiatry. 1990; 55: 47-52Google Scholar; Kuoppamaki et al. Kuoppamaki et al., 1995Kuoppamaki M Palvimaki EP Hietala J Syvalahti E Differential regulation of rat 5-HT2A and 5-HT2C receptors after chronic treatment with clozapine, chlorpromazine and three putative atypical antipsychotics drugs.Neuropsychopharmacology. 1995; 13: 139-150Crossref PubMed Scopus (79) Google Scholar), which raises the question of whether variation at the corresponding loci affects the efficacy of this drug. Indeed, although some of the study groups (Sodhi et al. Sodhi et al., 1995Sodhi MS Arranz MJ Curtis D Ball DM Sham P Roberts GW Price J et al.Association between clozapine response and allelic variation in the 5-HT2C receptor gene.Neuroreport. 1995; 7: 169-172Crossref PubMed Scopus (167) Google Scholar; Malhotra et al. Malhotra et al., 1996Malhotra AK Goldman D Ozaki N Breier A Buchanan R Pickar D Lack of association between polymorphisms in the 5-HT2A receptor gene and the antipsychotic response to clozapine.Am J Psychiatry. 1996; 153: 1092-1094Crossref PubMed Scopus (103) Google Scholar; Chen et al. Chen et al., 1997Chen CH Lee YR Wei FC Koong FJ Hwu HG Hsiao KJ Lack of allelic association between 102T/C polymorphism of serotonin receptor type 2A gene and schizophrenia in Chinese.Psychiatr Genet. 1997; 7: 35-38Crossref PubMed Scopus (45) Google Scholar; Rietschel et al. Rietschel et al., 1997Rietschel M Naber D Fimmers R Moller HJ Propping P Nothen MM Efficacy and side-effects of clozapine not associated with variation in the 5-HT2C receptor.Neuroreport. 1997; 8: 1999-2003Crossref PubMed Scopus (106) Google Scholar; Arranz et al. Arranz et al., 1998aArranz MJ Munro J Owen MJ Spurlock G Sham PC Zhao J Kirov G et al.Evidence for association between polymorphisms in the promoter and coding regions of the 5-HT2A receptor gene and response to clozapine.Mol Psychiatry. 1998; 3: 61-66Crossref PubMed Scopus (190) Google Scholara; Masellis et al. Masellis et al., 1998Masellis M Basile V Meltzer HY Lieberman JA Sevy S Macciardi FM Cola P et al.Serotonin subtype 2 receptor genes and clinical response to clozapine in schizophrenia patients.Neuropsychopharmacology. 1998; 19: 123-132Crossref PubMed Scopus (211) Google Scholar) that have examined this question have reported equivocal results, Arranz et al. (Arranz et al., 1998bArranz MJ Munro J Sham P Kirov G Murray RM Collier DA Kerwin RW Meta-analysis of studies on genetic variation in 5-HT2A receptors and clozapine response.Schizophr Res. 1998; 32: 93-99Abstract Full Text Full Text PDF PubMed Scopus (229) Google Scholarb) have shown, by meta-analysis, that 5HT2A variants do appear to influence the response to clozapine. Psychopharmacogenetics clearly has not succeeded in its pursuit of the DME polymorphisms that are at the heart of much of pharmacogenetics, nor has it succeeded in borrowing candidate genes from psychiatric genetic studies. It remains possible that these approaches will prove useful in the tailoring of individualized therapies. However, if the goal is to identify effective drug therapies for individuals with specific genetic backgrounds, then it seems that research should be guided, as far as possible, by a molecular description of the relevant disease processes and by the presence of functional polymorphisms in candidate genes. I would like to suggest that our experience with two psychiatric conditions—delusional depression and panic disorder—points the way toward a more sophisticated use of genetic data in psychiatric therapy. Depression with psychotic features is a particularly severe form of mood disorder, associated with high recurrence rates, great long-term morbidity, and a low response rate to either placebos or tricyclic antidepressants. Therefore, delusional depression seems to represent a syndrome that is biologically more homogeneous than other mood disorders. Evidence from studies in biochemistry, neuroendocrinology, and pharmacology suggests that dysfunctions in serotonergic pathways could play a pivotal, albeit nonexclusive, role in mood disorders. Patients with delusional depression are commonly treated with the selective serotonin-reuptake inhibitor (SSRI) fluvoxamine, but SSRI nonresponders are not uncommon. The addition of pindolol (a mixed β-adrenergic receptor [βAR] and 5-HT1A antagonist) has been proposed as augmentation therapy for SSRI nonresponders or partial responders, but reliable predictive criteria are needed. The serotonin transporter 5-HTT plays a critical role in the termination of 5-HT neurotransmission and represents the prime target for SSRIs, a finding that suggests the 5-HTT gene as a candidate for pharmacogenetic studies. Heils et al. (Heils et al., 1996Heils A Teufel A Petri S Stöber G Riederer P Bengel D Lesch KP Allelic variation of human serotonin transporter gene expression.J Neurochem. 1996; 66: 2621-2624Crossref PubMed Scopus (1907) Google Scholar) first identified an allele of 5-HTT with a 44-bp insertion in the promoter region. Studies of transfected cells in culture show that the long and short variants exhibit different transcriptional properties (Lesch et al. Lesch et al., 1996Lesch KP Bengel D Heils A Sabol SZ Greenberg BD Petri S Benjamin J et al.Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region.Science. 1996; 274: 1527-1531Crossref PubMed Scopus (4220) Google Scholar). The basal transcriptional activity of the long variant is more than twice that of the short variant, and choriocarcinoma cells containing the short variant produce concentrations of 5-HTT mRNA that are 30%–40% lower than those produced by the long variant. Significantly, these differences in 5-HTT mRNA synthesis result in different 5-HTT expression and 5-HT cellular uptake (Lesch et al. Lesch et al., 1996Lesch KP Bengel D Heils A Sabol SZ Greenberg BD Petri S Benjamin J et al.Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region.Science. 1996; 274: 1527-1531Crossref PubMed Scopus (4220) Google Scholar), which raises the possibility that individual differences in antidepressant response, in the face of comparable SSRI bioavailability, could result from differential expression of 5-HTT. The presence of a functional polymorphism within the promoter region of 5-HTT made the gene a good candidate and prompted my team and me to test whether this sequence variability affects response to the use of fluvoxamine, either alone or supplemented with pindolol, in cases of delusional depression. In a recent study (Smeraldi et al. Smeraldi et al., 1998Smeraldi E Zanardi R Benedetti F Di Bella D Perez J Catalano M Polymorphism within the promoter of the serotonin transporter gene and antidepressant efficacy of fluvoxamine.Mol Psychiatry. 1998; 3: 508-511Crossref PubMed Scopus (569) Google Scholar), we reported that, in patients with delusional depression, the promoter polymorphism correlates with the clinical response to fluvoxamine. To avoid extreme differences in the bioavailability of the drug, we excluded from the study those patients whose steady-state fluvoxamine plasma levels were >1.96 SD outside the mean value of the sample. Individuals who were homozygous for the long variant of the 5-HTT promoter showed a better response to treatment with fluvoxamine alone than did those who were either heterozygous or homozygous for the short variant. Hence, the antidepressant efficacy of fluvoxamine seems to be related to allelic variation within this regulatory sequence. Moreover, this correlation appears to apply more broadly to other depressive conditions for which SSRIs are used. We obtained similar results when we used the SSRI paroxetine in a sample of individuals with nondelusional depression (Zanardi et al., Zanardi et al., in pressZanardi R, Benedetti F, Di Bella D, Catalano M, Smeraldi E. Efficacy of paroxetine in depression is influenced by a functional polymorphism within the promoter of the serotonin transporter gene. J Clin Psychopharmacol (in press)Google Scholar). Genotyping of the 5-HTT promoter appears to represent a promising approach to individualization of the treatment of depression, since it identifies a subset of patients—those who are homozygous for the short variant in the promoter—who may require pindolol augmentation therapy. Given the well-known and frustrating latency of antidepressant response, the ability to identify such patients in advance could represent a significant advance in the care of depression. Because pindolol causes substantial side effects, primarily as a result of its antagonism to βAR, genotyping of the 5-HTT–linked polymorphic region could spare a large number of patients the risk of harm from unnecessary drug treatment. However, our results should be regarded cautiously, since data on independent replication in other samples and in other ethnic groups are still lacking. The monoamine oxidase A (MAOA; see Shih and Thompson Shih and Thompson, 1999Shih JC Thompson RF Monoamine oxidase in neuropsychiatry and behavior.Am J Hum Genet. 1999; 65 (in this issue): 593-598Abstract Full Text Full Text PDF PubMed Scopus (186) Google Scholar [in this issue]) gene provides another example of the use of genetics to tailor psychotropic-drug administration to individual cases. Because MAOA inhibitors are effective in the treatment of panic disorder, the X-linked MAOA gene might be expected to underlie the disease or to affect the efficacy of these drugs in its treatment. Therefore, we investigated a novel repeat polymorphism in the MAOA promoter, to determine its association with panic disorder. This polymorphism consists of a 30-bp motif that repeats two to five times. One variant, termed “3a,” carries three full repeats and one partial repeat of this sequence. We found that these polymorphisms affect MAOA-promoter function. Alleles with longer repeats—3a, 4, and 5—are consistently more active in transfected cells than is the shorter, three-repeat allele. We have not tested allele 2, which is very rare in the populations that we have studied. Furthermore, the more actively expressed alleles are found at a significantly greater frequency among affected females than among control females. Curiously, no significant differences were observed between male patients and male controls (Deckert et al. Deckert et al., 1999Deckert J Catalano M Syagailo YV Bosi M Okladnova O Di Bella D Nothen MM et al.Excess of high activity monoamine oxidase A gene promoter alleles in female patients with panic disorder.Hum Mol Genet. 1999; 8: 621-624Crossref PubMed Scopus (509) Google Scholar), although, given the linkage of MAOA to the X chromosome, males would be expected to be more, not less, sensitive to differences in genotype at this locus, as has been seen in studies of aggression (Shih and Thompson Shih and Thompson, 1999Shih JC Thompson RF Monoamine oxidase in neuropsychiatry and behavior.Am J Hum Genet. 1999; 65 (in this issue): 593-598Abstract Full Text Full Text PDF PubMed Scopus (186) Google Scholar [in this issue]). These findings may indicate that, in panic disorder, the etiopathogenetic pathways that are important are different in males versus females; this possibility is supported by other psychopharmacogenetic data. A nearly concomitant clinical study, which used artificial neural networks to model the efficacy of treatments for this condition, appears to confirm the sex difference that we observe and to suggest that, to control the symptoms of panic disorder, different therapies be applied in males versus females. Politi et al. (Politi et al., in pressPoliti E, Balduzzi C, Bussi R, Bellodi L. Artificial neural networks: a study in clinical psychopharmacology. J Psychiatr Res (in press)Google Scholar) have shown that moclobemide, a reversible MAOA inhibitor, works better in women with prominent anxiety symptoms than in men with similar symptoms. This difference seems to be specific to this class of drugs; no significant difference in responsiveness to SSRI treatment, which is commonly used in patients with panic and anxiety disorder, can be found between sexes. These results, along with our association data, may suggest that MAOA inhibitors are a good choice in the treatment of females with panic disorder. Recent trends justify some measured optimism about the prospects for psychopharmacogenetics. It now seems clear that psychiatrists and pharmacologists should not regard each other's fields merely as tools to solve their own problems but, rather, should note that an interesting set of questions is developing as a result of interactions between these disciplines. Both the development of more sophisticated molecular approaches and the growing interest in regulatory-sequence polymorphisms may finally make the pharmacogenetic approach useful in the psychiatric clinic. Genetic analysis of responses to psychoactive drugs clearly has much to offer, but large and small challenges remain. The goal of applying well-tailored individual therapies to relieve or even prevent the onset of symptoms will require us to make precise psychiatric diagnoses and to develop selective drugs. At present, establishing a diagnosis still seems to present intractable problems, and patterns of drug responsiveness are of limited help in this regard. Response to the same drug does not always mean that there are identical pathogenetic pathways: SSRIs are advantageous in the treatment of both depression and obsessive-compulsive disorder, but the effects of the 5-HTT–promoter polymorphism on SSRI response seem to be restricted to the former condition (Billet et al. Billett et al., 1997Billett EA Richter MA King N Heils A Lesch KP Kennedy JL Obsessive compulsive disorder, response to serotonin reuptake inhibitors and the serotonin transporter gene.Mol Psychiatry. 1997; 2: 403-406Crossref PubMed Scopus (135) Google Scholar). Conversely, lack of responsiveness to a given drug does not always mean a misdiagnosis, since refractory patients are an unfortunate reality. Molecular geneticists will likely concentrate their efforts either on genes with relatively large effects on pathogenesis or on those genes whose products represent direct targets of specific drugs. It is worth recalling, however, that psychiatric disorders are multifactorial and multigenic and that genes that are associated with a minor risk of disease could play a significant role in determining the response to treatment. I gratefully thank John Ashkenas for valuable discussion and friendly advice, Klaus-Peter Lesch and Jürgen Deckert for friendship and confidence, and my team for faithful support.