Pharmacogenetics in schizophrenia: a review of clozapine studies

Fabiana Barzotti Kohlrausch About the author

Abstract

Objectives:

Clozapine is quite effective to treat schizophrenia, but its use is complicated by several factors. Although many patients respond to antipsychotic therapy, about 50% of them exhibit inadequate response, and ineffective medication trials may entail weeks of unremitted illness, potential adverse drug reactions, and treatment nonadherence. This review of the literature sought to describe the main pharmacogenetic studies of clozapine and the genes that potentially influence response to treatment with this medication in schizophrenics.

Methods:

We searched the PubMed database for studies published in English in the last 20 years using keywords related to the topic.

Results and Conclusions:

Our search yielded 145 studies that met the search and selection criteria. Of these, 21 review articles were excluded. The 124 studies included for analysis showed controversial results. Therefore, efforts to identify key gene mechanisms that will be useful in predicting clozapine response and side effects have not been fully successful. Further studies with new analysis approaches and larger sample sizes are still required.

Schizophrenia; clozapine; polymorphisms; pharmacogenetics; adverse effects


Introduction

Schizophrenia is an oft-devastating neuropsychiatric illness with a lifetime prevalence of 0.8%.11. Saha S, Chant D, Welham J, McGrath J. A systematic review of the prevalence of schizophrenia. PLoS Med. 2005;2:e141. Its clinical manifestations usually arise in late adolescence and early adulthood. Schizophrenia is a complex and highly heritable disorder with a significant impact on public health. In Brazil, patients with schizophrenia occupy 30% of psychiatric hospital beds, or about 100,000 beds/day. In addition, 14% of first outpatient psychiatric visits are provided for schizophrenic patients, and schizophrenia is the fifth most common illness leading people to apply for social security disability benefits.22. Pádua AC, Gama CS, Lobato MI, Belmonte-de-Abreu OS. Esquizofrenia: diretrizes e algoritmo para o tratamento farmacológico. In: Cordioli AV, editor. Psicofármacos: consulta rápida. 3rd ed. Porto Alegre: Artmed; 2005. p. 343.

Clozapine is an antipsychotic drug widely used in the treatment of schizophrenia. It is more effective than traditional antipsychotics for patients with poor response or resistance to treatment.33. Malhotra AK. Pharmacogenomics and schizophrenia: clinical implications. Pharmacogenomics J. 2001;1:109-14. The antipsychotic effect of clozapine has been attributed in part to its ability to block stimulation of the serotonin 2A receptor (5-HT2A), particularly when associated with weak dopamine D2 receptor blockade (DRD2).44. Miyamoto S, Duncan GE, Marx CE, Lieberman JA. Treatments for schizophrenia: a critical review of pharmacology and mechanisms of action of antipsychotic drugs. Mol Psychiatry. 2005;10:79-104. The action of this agent is not limited to 5-HT2 receptors (in particular 5-HT2A and 5-HT2C) and, to a lesser extent, to D2 receptors; it also acts on other dopaminergic (D1, D3, D4), histaminergic, adrenergic and cholinergic receptors.55. Ereshefsky L. Pharmacologic and pharmacokinetic considerations in choosing an antipsychotic. J Clin Psychiatry. 1999;60:20-30.

The variability of response to clozapine treatment in schizophrenia patients has a marked impact on clinical practice. Approximately 50% of patients who do not respond to typical antipsychotics benefit from clozapine.66. Reynolds GP. The pharmacogenetics of symptom response to antipsychotic drugs. Psychiatry Investig. 2012;9:1-7. Additionally, clozapine is associated with side effects, including sedation, drowsiness, dizziness, hypersalivation, headache, constipation, generalized seizures, anticholinergic effects, orthostatic hypotension, weight gain, and agranulocytosis.77. Haddad PM, Sharma SG. Adverse effects of atypical antipsychotics : differential risk and clinical implications. CNS Drugs. 2007;21:911-36.

The effect of psychopharmacological treatment depends on many factors that influence response. The heterogeneity of response is partly attributable to physiological and environmental factors affecting individuals, including age, sex, ethnicity, liver and kidney function, diet, co-medication, severity and type of illness, and alcohol and tobacco use.88. Goldstein DB, Need AC, Singh R, Sisodiya SM. Potential genetic causes of heterogeneity of treatment effects. Am J Med. 2007;120:S21-5. In some cases, however, response heterogeneity cannot be explained only by these factors, and genetic aspects should be considered as a potential source of variability.

In a study of monozygotic twins, Vojvoda et al.99. Vojvoda D, Grimmell K, Sernyak M, Mazure CM. Monozygotic twins concordant for response to clozapine. Lancet. 1996;347:61. showed the importance of genetic factors in predicting the response to clozapine. Symptom improvement following clozapine treatment showed strong concordance in monozygotic twin pairs. Similarly, the contribution of genetics to antipsychotic-induced weight gain was addressed in studies of monozygotic twins and sib pairs,10. Theisen FM, Gebhardt S, Haberhausen M, Heinzel-Gutenbrunner M, Wehmeier PM, Krieg JC, et al. Clozapine-induced weight gain: a study in monozygotic twins and same-sex sib pairs. Psychiatr Gen. 2005;15:285-9. 11. Wehmeier PM, Gebhardt S, Schmidtke J, Remschmidt H, Hebebrand J, Theisen FM. Clozapine: weight gain in a pair of monozygotic twins concordant for schizophrenia and mild mental retardation. Psychiatry research. 2005;133:273-6. 10-1212. Gebhardt S, Theisen FM, Haberhausen M, Heinzel-Gutenbrunner M, Wehmeier PM, Krieg JC, et al. Body weight gain induced by atypical antipsychotics: an extension of the monozygotic twin and sib pair study. J Clin Pharm Ther. 2010;35:207-11. suggesting a genetic contribution of 60-80%. Two case reports of agranulocytosis induced by clozapine in monozygotic twins with schizophrenia provided evidence for a genetic basis of this adverse event.1313. Horáèek J, Libiger J, Höschl C, Borzova K, Hendrychová I. Clozapine-induced concordant agranulocytosis in monozygotic twins. Int J Psychiatry Clin Pract. 2001;5:71-3.,1414. Anil Yagcioglu AE, Ilhan BC, Goktas MT, Babaoglu MO, Uz E, Yazici MK. Agranulocytosis related to clozapine in monozygotic twins and association with allelic variants of multidrug resistance gene MDR1. J Clin Psychopharmacology. 2011;31:247-9.

Pharmacogenetics is the study of the influence of genetic variants on response to medications and adverse effects, as well as the consequent understanding of how genes interact to determine individual variability in this response. The goal of pharmacogenetics is to find polymorphisms in genes encoding proteins and enzymes involved in the transport, metabolism, and action of drugs, enabling knowledge of the applicability of a particular drug and increasing its effectiveness.1515. Poolsup N, Li Wan Po A, Knight TL. Pharmacogenetics and psychopharmacotherapy. J Clin Pharm Ther. 2000;25:197-220. Pharmacogenomic studies consider the genome as a whole and do not rely on prior knowledge of candidate genes or specific hypotheses.1616. Arranz MJ, Rivera M, Munro JC. Pharmacogenetics of response to antipsychotics in patients with schizophrenia. CNS Drugs. 2011;25:933-69.

The detection of individual genetic differences in the response to clozapine may provide new strategies for the treatment of major psychoses such as schizophrenia. The application of pharmacogenetic data has been analyzed in several studies investigating the impact of genetic polymorphisms on adverse effects and response to treatment with clozapine. The objective of the present literature review was to discuss the main results of these studies.

Methods

We searched the PubMed database for scientific articles published in English in the last 20 years about the use of clozapine to treat schizophrenia. The last search was performed on October 11, 2012. The following keywords were used in the search: antipsychotic or clozapine combined with polymorphism or genetics. Combinations of these keywords with schizophrenia, pharmacogenetic, pharmacogenomic, side effects, adverse effects, genotype, and allele were also used. Further searches were conducted based on the list of references of the selected articles and included in this review when relevant.

The articles were selected according to the following criteria: studies evaluating the impact of genetic polymorphisms on 1) treatment response and/or side effects, and 2) clozapine-treated patients or treatment with no more than three antipsychotics, when clozapine was the main prescribed drug (since findings from studies exploring mixed antipsychotics provided unclear and often contradictory results). Studies containing no information about the type of antipsychotics were not included.

Results

One hundred and forty-five articles met the search and selection criteria. Of these, 21 review articles were excluded. To supplement the data of the 124 remaining studies, six meta-analyses were also assessed.

The articles were divided according to their focus: studies investigating the effect of genetic and pharmacokinetic variation and studies investigating the effect of pharmacodynamic and genetic variability on treatment response and adverse effects. Table 1 summarizes significant results regarding response to treatment. Table 2 shows findings related to adverse effects. Nevertheless, these results are uncertain and should be considered cautiously, since several studies did not report the same associations.

Table 1
Reported associations between genetic polymorphisms and clozapine response*
Table 2
Reported associations between genetic polymorphisms and clozapine side effects*

Genetic variants in metabolizing enzymes and response to treatment

Most drugs used in clinical practice that act on the central nervous system (CNS) are extensively metabolized in the liver by enzymes of the cytochrome P450 (CYP) system.1616. Arranz MJ, Rivera M, Munro JC. Pharmacogenetics of response to antipsychotics in patients with schizophrenia. CNS Drugs. 2011;25:933-69.,8585. Kawanishi Y, Tachikawa H, Suzuki T. Pharmacogenomics and schizophrenia. Eur J Pharmacol. 2000;410:227-41.,8686. Ozaki N. Pharmacogenetics of antipsychoatics. Nagoya J Med Sci. 2004;67:1-7. Pharmacogenetic studies report that phenotypes generated by the activity of cytochrome P450 isoenzymes strongly influence the sensitivity or response to medication because of different elimination, concentration, and biotransformation rates.8585. Kawanishi Y, Tachikawa H, Suzuki T. Pharmacogenomics and schizophrenia. Eur J Pharmacol. 2000;410:227-41. These phenotypes are genetically determined and show great variation between different individuals. Variations in genes coding for CYP enzymes can result in absent, deficient, or increased activity.8787. Human Cytochrome P450 (CYP) Allele Nomenclature Committee [Internet]. The Human Cytochrome P450 (CYP) Allele Nomenclature Database. [cited 2013 July 1]. http://www.cypalleles.ki.se/
http://www.cypalleles.ki.se/...

Eap et al.,2121. Eap CB, Bender S, Jaquenoud Sirot E, Cucchia G, Jonzier-Perey M, Baumann P, et al. Nonresponse to clozapine and ultrarapid CYP1A2 activity: clinical data and analysis of CYP1A2 gene. J Clin Psychopharmacol. 2004;24:214-9. evaluating cytochrome P450, family 1, subfamily A, polypeptide 2 (CYP1A2) and plasma levels of clozapine, found that treatment non-responders had low levels of the drug and the *1F/*1F genotype, suggesting that this variation is associated with resistance to treatment. However, van der Weide et al.8888. van der Weide J, Steijns LS, van Weelden MJ. The effect of smoking and cytochrome P450 CYP1A2 genetic polymorphism on clozapine clearance and dose requirement. Pharmacogenetics. 2003;13:169-72. observed that mean clozapine ratios and daily doses did not vary significantly between patients with different CYP1A2 genotypes, neither among smokers nor nonsmokers.

The cytochrome P450, family 2, subfamily D, polypeptide 6 gene (CYP2D6) is highly polymorphic, and more than 90 allelic variants and subvariants have been described.8787. Human Cytochrome P450 (CYP) Allele Nomenclature Committee [Internet]. The Human Cytochrome P450 (CYP) Allele Nomenclature Database. [cited 2013 July 1]. http://www.cypalleles.ki.se/
http://www.cypalleles.ki.se/...
Three studies (one conducted in Brazil) evaluating polymorphisms in CYP2D6 were unable to find a significant association between CYP2D6 alleles and response to clozapine.1717. Jaquenoud Sirot E, Knezevic B, Morena GP, Harenberg S, Oneda B, Crettol S, et al. ABCB1 and cytochrome P450 polymorphisms: clinical pharmacogenetics of clozapine. J Clin Psychopharmacol. 2009;29:319-26.,8989. Arranz MJ, Dawson E, Shaikh S, Sham P, Sharma T, Aitchison K, et al. Cytochrome P4502D6 genotype does not determine response to clozapine. Br J Clin Pharmacol. 1995;39:417-20.,9090. Kohlrausch FB, Gama CS, Lobato MI, Belmonte-de-Abreu P, Gesteira A, Barros F, et al. Molecular diversity at the CYP2D6 locus in healthy and schizophrenic southern Brazilians. Pharmacogenomics. 2009;10:1457-66. Dahl et al.9191. Dahl ML, Llerena A, Bondesson U, Lindstrom L, Bertilsson L. Disposition of clozapine in man: lack of association with debrisoquine and S-mephenytoin hydroxylation polymorphisms. Br J Clin Pharmacol. 1994;37:71-4. evaluated the importance of genetic factors for the metabolism of clozapine and did not find significant differences in the plasma concentrations or any of the pharmacokinetic parameters of clozapine between poor and extensive metabolizers of debrisoquine. Since clozapine is metabolized minimally by this enzyme,9292. Arranz MJ, Collier D, Kerwin RW. Pharmacogenetics for the individualization of psychiatric treatment. Am J Pharmacogenomics. 2001;1:3-10. more studies on clozapine metabolism would be helpful.

However, variations in metabolizing enzymes cannot be fully responsible for the heterogeneity observed in the response of an individual to treatment. The pharmacological effects of the medication are not typically monogenic traits; moreover, they are determined by the interposition of several genes encoding proteins involved in multiple pathways that determine the disposition and effects of drugs in addition to their metabolism.8585. Kawanishi Y, Tachikawa H, Suzuki T. Pharmacogenomics and schizophrenia. Eur J Pharmacol. 2000;410:227-41.

Genetic variants in drug target proteins and response to treatment

Since clozapine is a high-affinity antagonist of dopamine receptors, initial studies focused on the relationship between the dopamine D4 receptor gene (DRD4) and the response to clozapine. Zhao et al.2929. Zhao AL, Zhao JP, Zhang YH, Xue ZM, Chen JD, Chen XG. Dopamine D4 receptor gene exon III polymorphism and interindividual variation in response to clozapine. The Int J Neurosci. 2005;115:1539-47. and Hwang et al.3030. Hwang R, Tiwari AK, Zai CC, Felsky D, Remington E, Wallace T, et al. Dopamine D4 and D5 receptor gene variant effects on clozapine response in schizophrenia: replication and exploration. Prog Neuropsychopharmacol Biol Psychiatry. 2012;37:62-75. found significant associations between polymorphisms in DRD4 and response to clozapine. However, most studies were unable to detect this significant association.93. Kerwin RW, Pilowsky L, Munro J, Shaikh S, Gill M, Collier D. Functional neuroimaging and pharmacogenetic studies of clozapine's action at dopamine receptors. J Clin Psychiatry. 1994;55:57-62. 94. Rao PA, Pickar D, Gejman PV, Ram A, Gershon ES, Gelernter J. Allelic variation in the D4 dopamine receptor (DRD4) gene does not predict response to clozapine. Arch Gen Psychiatry. 1994;51:912-7. 95. Shaikh S, Collier DA, Sham P, Pilowsky L, Sharma T, Lin LK, et al. Analysis of clozapine response and polymorphisms of the dopamine D4 receptor gene (DRD4) in schizophrenic patients. Am J Med Genet. 1995;60:541-5. 96. Rietschel M, Naber D, Oberlander H, Holzbach R, Fimmers R, Eggermann K, et al. Efficacy and side-effects of clozapine: testing for association with allelic variation in the dopamine D4 receptor gene. Neuropsychopharmacology. 1996;15:491-6. 97. Kohn Y, Ebstein RP, Heresco-Levy U, Shapira B, Nemanov L, Gritsenko I, et al. Dopamine D4 receptor gene polymorphisms: relation to ethnicity, no association with schizophrenia and response to clozapine in Israeli subjects. Eur Neuropsychopharmacol. 1997;7:39-43. 93-9898. Kaiser R, Konneker M, Henneken M, Dettling M, Muller-Oerlinghausen B, Roots I, et al. Dopamine D4 receptor 48-bp repeat polymorphism: no association with response to antipsychotic treatment, but association with catatonic schizophrenia. Mol Psychiatry. 2000;5:418-24.

The dopamine D3 receptor gene (DRD3) is important because antipsychotics show high affinity for this receptor, especially in the mesolimbic system.9999. Kerwin R, Owen M. Genetics of novel therapeutic targets in schizophrenia. Br J Psychiatry Suppl. 1999:1-4. Two studies analyzed the Ser9Gly polymorphism in DRD3, and the Ser/Ser genotype was found to be more frequent among non-responders to clozapine,2727. Shaikh S, Collier DA, Sham PC, Ball D, Aitchison K, Vallada H, et al. Allelic association between a Ser-9-Gly polymorphism in the dopamine D3 receptor gene and schizophrenia. Hum Genet. 1996;97:714-9.,2828. Scharfetter J, Chaudhry HR, Hornik K, Fuchs K, Sieghart W, Kasper S, et al. Dopamine D3 receptor gene polymorphism and response to clozapine in schizophrenic Pakastani patients. Eur Neuropsychopharmacol. 1999;10:17-20. but other studies failed to replicate these findings.100. Gaitonde EJ, Morris A, Sivagnanasundaram S, McKenna PJ, Hunt DM, Mollon JD. Assessment of association of D3 dopamine receptor MscI polymorphism with schizophrenia: analysis of symptom ratings, family history, age at onset, and movement disorders. Am J Med Genet. 1996;67:455-8. 101. Malhotra AK, Goldman D, Buchanan RW, Rooney W, Clifton A, Kosmidis MH, et al. The dopamine D3 receptor (DRD3) Ser9Gly polymorphism and schizophrenia: a haplotype relative risk study and association with clozapine response. Mol Psychiatry. 1998;3:72-5. 102. Arranz MJ, Munro J, Birkett J, Bolonna A, Mancama D, Sodhi M, et al. Pharmacogenetic prediction of clozapine response. Lancet. 2000;355:1615-6. 103. Staddon S, Arranz MJ, Mancama D, Mata I, Kerwin RW. Clinical applications of pharmacogenetics in psychiatry. Psychopharmacology (Berl). 2002;162:18-23. 104. Barlas IO, Cetin M, Erdal ME, Semiz UB, Basoglu C, Ay ME, et al. Lack of association between DRD3 gene polymorphism and response to clozapine in Turkish schizoprenia patients. Am J Med Genet B Neuropsychiatr Genet. 2009;150B:56-60. 105. Hwang R, Zai C, Tiwari A, Muller DJ, Arranz MJ, Morris AG, et al. Effect of dopamine D3 receptor gene polymorphisms and clozapine treatment response: exploratory analysis of nine polymorphisms and meta-analysis of the Ser9Gly variant. Pharmacogenomics J. 2010;10:200-18. 100-106106. Hwang R, Souza RP, Tiwari AK, Zai CC, Muller DJ, Potkin SG, et al. Gene-gene interaction analyses between NMDA receptor subunit and dopamine receptor gene variants and clozapine response. Pharmacogenomics. 2011;12:277-91. The importance of Ser9Gly was confirmed in a meta-analysis, where significant differences were found when the DRD3 Ser9 allele or the Ser/Ser genotype were compared between responders and non-responders to clozapine in a sample of 233 schizophrenia patients.107107. Jonsson EG, Flyckt L, Burgert E, Crocq MA, Forslund K, Mattila-Evenden M, et al. Dopamine D3 receptor gene Ser9Gly variant and schizophrenia: association study and meta-analysis. Psychiatr Genet. 2003;13:1-12. However, a more recent meta-analysis with a much larger sample size (n=758) reported a negative but consistent trend for the DRD3 Ser9 allele and poor clozapine response.108108. Hwang R, Zai C, Tiwari A, Muller DJ, Arranz MJ, Morris AG, et al. Effect of dopamine D3 receptor gene polymorphisms and clozapine treatment response: exploratory analysis of nine polymorphisms and meta-analysis of the Ser9Gly variant. Pharmacogenomics J. 2010;10:200-18.

Another obvious candidate for pharmacogenetic studies is DRD2, because clozapine has an affinity for this receptor.109109. Seeman P. Dopamine receptor sequences. Therapeutic levels of neuroleptics occupy D2 receptors, clozapine occupies D4. Neuropsychopharmacology. 1992;7:261-84. Studies with DRD2 polymorphisms produced contradictory results. Positive results were found by Malhotra et al.2424. Malhotra AK, Buchanan RW, Kim S, Kestler L, Breier A, Pickar D, et al. Allelic variation in the promoter region of the dopamine D2 receptor gene and clozapine response. Schizophr Res. 1999;36:92-3. and Hwang et al.,2525. Hwang R, Shinkai T, De Luca V, Muller DJ, Ni X, Macciardi F, et al. Association study of 12 polymorphisms spanning the dopamine D(2) receptor gene and clozapine treatment response in two treatment refractory/intolerant populations. Psychopharmacology (Berl). 2005;181:179-87.,2626. Hwang R, Shinkai T, Deluca V, Macciardi F, Potkin S, Meltzer HY, et al. Dopamine D2 receptor gene variants and quantitative measures of positive and negative symptom response following clozapine treatment. Eur Neuropsychopharmacol. 2006;16:248-59. not corroborated by Arranz et al.,110110. Arranz MJ, Li T, Munro J, Liu X, Murray R, Collier DA, et al. Lack of association between a polymorphism in the promoter region of the dopamine-2 receptor gene and clozapine response. Pharmacogenetics. 1998;8:481-4. Reynolds et al.,111111. Reynolds GP, Yao Z, Zhang X, Sun J, Zhang Z. Pharmacogenetics of treatment in first-episode schizophrenia: D3 and 5-HT2C receptor polymorphisms separately associate with positive and negative symptom response. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology. 2005;15:143-51. and Hwang et al.106106. Hwang R, Souza RP, Tiwari AK, Zai CC, Muller DJ, Potkin SG, et al. Gene-gene interaction analyses between NMDA receptor subunit and dopamine receptor gene variants and clozapine response. Pharmacogenomics. 2011;12:277-91. In a meta-analysis including 889 individuals, Zhang et al.112112. Zhang JP, Lencz T, Malhotra AK. D2 receptor genetic variation and clinical response to antipsychotic drug treatment: a meta-analysis. Am J Psychiatry. 2010;167:763-72. concluded that single-nucleotide polymorphisms (SNPs) in the DRD2 promoter region, such as -141C Ins/Del, may be particularly important in predicting clinical response to various antipsychotic drugs.

Recently, Xu et al.4646. Xu M, Xing Q, Li S, Zheng Y, Wu S, Gao R, et al. Pharacogenetic effects of dopamine transporter gene polymorphisms on response to chlorpromazine and clozapine and on extrapyramidal syndrome in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 2010;34:1026-32. found a haplotype combination of genetic variants in the dopamine transporter gene (DAT or SLC6A3) significantly associated with response to clozapine, but in a previous study this association was not observed.113113. Szekeres G, Keri S, Juhasz A, Rimanoczy A, Szendi I, Czimmer C, et al. Role of dopamine D3 receptor (DRD3) and dopamine transporter (DAT) polymorphism in cognitive dysfunctions and therapeutic response to atypical antipsychotics in patients with schizophrenia. Am J Med Genet B Neuropsychiatr Genet. 2004;124B:1-5. Two studies analyzed DRD1 and found a significant association with clozapine response in African Americans2222. Hwang R, Shinkai T, De Luca V, Ni X, Potkin SG, Lieberman JA, et al. Association study of four dopamine D1 receptor gene polymorphisms and clozapine treatment response. J Psychopharmacol. 2007;21:718-27. and Caucasians,2323. Potkin SG, Basile VS, Jin Y, Masellis M, Badri F, Keator D, et al. D1 receptor alleles predict PET metabolic correlates of clinical response to clozapine. Mol Psychiatry. 2003;8:109-13. but another study was unable to replicate this association.106106. Hwang R, Souza RP, Tiwari AK, Zai CC, Muller DJ, Potkin SG, et al. Gene-gene interaction analyses between NMDA receptor subunit and dopamine receptor gene variants and clozapine response. Pharmacogenomics. 2011;12:277-91. Hwang et al.3030. Hwang R, Tiwari AK, Zai CC, Felsky D, Remington E, Wallace T, et al. Dopamine D4 and D5 receptor gene variant effects on clozapine response in schizophrenia: replication and exploration. Prog Neuropsychopharmacol Biol Psychiatry. 2012;37:62-75. evaluated the importance of DRD5 and found no significant association with clozapine response.

Of the seven subtypes of serotonin receptors (5-HT1-7), 5-HT2 subtypes are the strongest targets of atypical antipsychotic drugs.114114. Arranz MJ, Kerwin RW. Neurotransmitter-related genes and antipsychotic response: pharmacogenetics meets psychiatric treatment. Ann Med. 2000;32:128-33. The 102T>C polymorphism in HTR2A was studied by Arranz et al.3535. Arranz M, Collier D, Sodhi M, Ball D, Roberts G, Price J, et al. Association between clozapine response and allelic variation in 5-HT2A receptor gene. Lancet. 1995;346:281-2. They found a significant association between the 102C allele and failure to respond to clozapine in schizophrenic patients treated with the drug. These results were subsequently replicated by Yu et al.,3636. Yu YW, Tsai SJ, Yang KH, Lin CH, Chen MC, Hong CJ. Evidence for an association between polymorphism in the serotonin-2A receptor variant (102T/C) and increment of N100 amplitude in schizophrenics treated with clozapine. Neuropsychobiology. 2001;43:79-82. but several other studies did not achieve similarly significant results.3737. Masellis M, Basile V, Meltzer HY, Lieberman JA, Sevy S, Macciardi FM, et al. Serotonin subtype 2 receptor genes and clinical response to clozapine in schizophrenia patients. Neuropsychopharmacology. 1998;19:123-32.,) Another less common polymorphism is HTR2A (His452Tyr), which seems to produce functional effects in vitro, providing both positive3737. Masellis M, Basile V, Meltzer HY, Lieberman JA, Sevy S, Macciardi FM, et al. Serotonin subtype 2 receptor genes and clinical response to clozapine in schizophrenia patients. Neuropsychopharmacology. 1998;19:123-32.,3838. Arranz MJ, Collier DA, Munro J, Sham P, Kirov G, Sodhi M, et al. Analysis of a structural polymorphism in the 5-HT2A receptor and clinical response to clozapine. Neurosci Lett. 1996;217:177-8. and negative results.116116. Nothen MM, Rietschel M, Erdmann J, Oberlander H, Moller HJ, Nober D, et al. Genetic variation of the 5-HT2A receptor and response to clozapine. Lancet. 1995;346:908-9.,117117. Masellis M, Paterson AD, Badri F, Lieberman JA, Meltzer HY, Cavazzoni P, et al. Genetic variation of 5-HT2A receptor and response to clozapine. Lancet. 1995;346:1108.,118118. Malhotra 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;153:1092-4. The -1438A>G polymorphism was significantly associated with clozapine response in one study,3939. Arranz MJ, Munro J, Owen MJ, Spurlock G, Sham PC, Zhao J, 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;3:61-6. whereas another study failed to detect this association.120120. Hamdani N, Bonniere M, Ades J, Hamon M, Boni C, Gorwood P. Negative symptoms of schizophrenia could explain discrepant data on the association between the 5-HT2A receptor gene and response to antipsychotics. Neurosci Lett. 2005;377:69-74. A meta-analysis of association studies on the 102T>C and His452Tyr polymorphisms in 733 clozapine-treated patients found an association between these two polymorphisms and poor response to medication.121121. Arranz MJ, Munro J, Sham P, Kirov G, Murray RM, Collier DA, et al. Meta-analysis of studies on genetic variation in 5-HT2A receptors and clozapine response. Schizophr Res. 1998;32:93-9.

The HTR2C Cys23Ser polymorphism was associated with response to clozapine by Sodhi et al.,4040. Sodhi MS, Arranz MJ, Curtis D, Ball DM, Sham P, Roberts GW, et al. Association between clozapine response and allelic variation in the 5-HT2C receptor gene. Neuroreport. 1995;7:169-72. but other studies did not replicate these results.3737. Masellis M, Basile V, Meltzer HY, Lieberman JA, Sevy S, Macciardi FM, et al. Serotonin subtype 2 receptor genes and clinical response to clozapine in schizophrenia patients. Neuropsychopharmacology. 1998;19:123-32.,122122. Malhotra AK, Goldman D, Ozaki N, Rooney W, Clifton A, Buchanan RW, et al. Clozapine response and the 5HT2C Cys23Ser polymorphism. Neuroreport. 1996;7:2100-2.,123123. Rietschel 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;8:1999-2003. The serotonin receptor type 6 gene (HTR6) was analyzed in two studies; the first study observed a significant association between the HTR6 and the 267T>C polymorphism,4343. Yu YW, Tsai SJ, Lin CH, Hsu CP, Yang KH, Hong CJ. Serotonin-6 receptor variant (C267T) and clinical response to clozapine. Neuroreport. 1999;10:1231-3. whereas the second study was unable to replicate this result.124124. Masellis M, Basile VS, Meltzer HY, Lieberman JA, Sevy S, Goldman DA, et al. Lack of association between the T-->C 267 serotonin 5-HT6 receptor gene (HTR6) polymorphism and prediction of response to clozapine in schizophrenia. Schizophr Res. 2001;47:49-58. Individual studies evaluated the influence of HTR5A125125. Birkett JT, Arranz MJ, Munro J, Osbourn S, Kerwin RW, Collier DA. Association analysis of the 5-HT5A gene in depression, psychosis and antipsychotic response. Neuroreport. 2000;11:2017-20. and HTR3B,126126. Gutierrez B, Arranz MJ, Huezo-Diaz P, Dempster D, Matthiasson P, Travis M, et al. Novel mutations in 5-HT3A and 5-HT3B receptor genes not associated with clozapine response. Schizophr Res. 2002;58:93-7. and no significant results were found. Unclear results were observed for HTR3A.4141. Rajkumar AP, Poonkuzhali B, Kuruvilla A, Srivastava A, Jacob M, Jacob KS. Outcome definitions and clinical predictors influence pharmacogenetic associations between HTR3A gene polymorphisms and response to clozapine in patients with schizophrenia. Psychopharmacology (Berl). 2012;224:441-9.,4242. Souza RP, de Luca V, Meltzer HY, Lieberman JA, Kennedy JL. Influence of serotonin 3A and 3B receptor genes on clozapine treatment response in schizophrenia. Pharmacogenet Genomics. 2010;20:274-6.,126126. Gutierrez B, Arranz MJ, Huezo-Diaz P, Dempster D, Matthiasson P, Travis M, et al. Novel mutations in 5-HT3A and 5-HT3B receptor genes not associated with clozapine response. Schizophr Res. 2002;58:93-7.

The serotonin transporter gene (HTT or SLC6A4) has also been studied. Arranz et al.4747. Arranz MJ, Bolonna AA, Munro J, Curtis CJ, Collier DA, Kerwin RW. The serotonin transporter and clozapine response. Mol Psychiatry. 2000;5:124-5. observed an association between response to clozapine and the HTTLPR (HTT repeat promoter length) polymorphism in the promoter region of the gene. They found that individuals homozygous for the short allele tended to show a poor response to treatment with clozapine. Kohlrausch et al.4848. Kohlrausch FB, Salatino-Oliveira A, Gama CS, Lobato MI, Belmonte-de-Abreu P, Hutz MH. Influence of serotonin transporter gene polymorphisms on clozapine response in Brazilian schizophrenics. J Psychiatric Res. 2010;44:1158-62. observed a significant association between the presence of short allele and failure to respond to clozapine in Brazilian schizophrenia patients. Two previous studies did not find a significant relationship.127127. Tsai SJ, Hong CJ, Yu YW, Lin CH, Song HL, Lai HC, et al. Association study of a functional serotonin transporter gene polymorphism with schizophrenia, psychopathology and clozapine response. Schizophr Res. 2000;44:177-81.,128128. Kaiser R, Tremblay PB, Schmider J, Henneken M, Dettling M, Muller-Oerlinghausen B, et al. Serotonin transporter polymorphisms: no association with response to antipsychotic treatment, but associations with the schizoparanoid and residual subtypes of schizophrenia. Mol Psychiatry. 2001;6:179-85.

Arranz et al.,102102. Arranz MJ, Munro J, Birkett J, Bolonna A, Mancama D, Sodhi M, et al. Pharmacogenetic prediction of clozapine response. Lancet. 2000;355:1615-6. analyzing different polymorphisms, found a combination of six polymorphisms in neurotransmitter receptor-related genes predicting clozapine response (HTR2A 102T>C and His452Tyr, HTR2C -330-GT/244-CT repeat and Cys23Ser, 5HTTLPR, HRH2 -1018G>A). This finding constituted a great potential for pharmacogenetic studies as a key for future improvement and individualization of clinical treatment of patients with schizophrenia. However, these results have not been replicated with the same approach so far, and the pharmacogenetic test designed for use in clinical practice is no longer available on the market.66. Reynolds GP. The pharmacogenetics of symptom response to antipsychotic drugs. Psychiatry Investig. 2012;9:1-7.

Genetic variants in other classes of proteins and response to treatment

Since catecholamine receptors are G-protein-coupled (GPCRs) and antipsychotics exert their effects by competitive antagonism of postsynaptic GPCRs, this protein may have an important influence on the function of dopaminergic and serotoninergic systems. Müller et al.3333. Muller DJ, De Luca V, Sicard T, King N, Hwang R, Volavka J, et al. Suggestive association between the C825T polymorphism of the G-protein beta3 subunit gene (GNB3) and clinical improvement with antipsychotics in schizophrenia. Eur Neuropsychopharmacol. 2005;15:525-31. found the 825C>T polymorphism in the gene encoding the small Beta-subunit 3 of G proteins (GNB3) to be associated with response to clozapine in patients with schizophrenia. This result was corroborated by the study conducted by Kohlrausch et al.3434. Kohlrausch FB, Salatino-Oliveira A, Gama CS, Lobato MI, Belmonte-de-Abreu P, Hutz MH. G-protein gene 825C>T polymorphism is associated with response to clozapine in Brazilian schizophrenics. Pharmacogenomics. 2008;9:1429-36. in Brazilians, where homozygosity for the 825T allele was more frequent among non-responders to treatment with clozapine.

Studies involving other genes with significant associations include variants in the following genes: ATP-binding cassette sub-family B member 1 (ABCB1),17. Jaquenoud Sirot E, Knezevic B, Morena GP, Harenberg S, Oneda B, Crettol S, et al. ABCB1 and cytochrome P450 polymorphisms: clinical pharmacogenetics of clozapine. J Clin Psychopharmacol. 2009;29:319-26. 18. Consoli G, Lastella M, Ciapparelli A, Catena Dell'Osso M, Ciofi L, Guidotti E, et al. ABCB1 polymorphisms are associated with clozapine plasma levels in psychotic patients. Pharmacogenomics. 2009;10:1267-76. 17-1919. Lee ST, Ryu S, Kim SR, Kim MJ, Kim S, Kim JW, et al. Association study of 27 annotated genes for clozapine pharmacogenetics: validation of preexisting studies and identification of a new candidate gene, ABCB1, for treatment response. J Clin Psychopharmacol. 2012;32:441-8. catechol-O-methyltransferase (COMT),2020. Woodward ND, Jayathilake K, Meltzer HY. COMT val108/158met genotype, cognitive function, and cognitive improvement with clozapine in schizophrenia. Schizophr Res. 2007;90:86-96. dystrobrevin binding protein 1 (DTNBP1),3131. Zuo L, Luo X, Krystal JH, Cramer J, Charney DS, Gelernter J. The efficacies of clozapine and haloperidol in refractory schizophrenia are related to DTNBP1 variation. Pharmacogenet Genomics. 2009;19:437-46. GDNF family receptor alpha 2 (GFRA2),3232. Souza RP, Romano-Silva MA, Lieberman JA, Meltzer HY, MacNeil LT, Culotti JG, et al. Genetic association of the GDNF alpha-receptor genes with schizophrenia and clozapine response. J Psychiatr Res. 2010;44:700-6. neurexin 1 (NRXN1),4444. Lett TA, Tiwari AK, Meltzer HY, Lieberman JA, Potkin SG, Voineskos AN, et al. The putative functional rs1045881 marker of neurexin-1 in schizophrenia and clozapine response. Schizophr Res. 2011;132:121-4. and oxytocin prepropeptide (OXT).4545. Souza RP, de Luca V, Meltzer HY, Lieberman JA, Kennedy JL. Schizophrenia severity and clozapine treatment outcome association with oxytocinergic genes. Int J Neuropsychopharmacol. 2010;13:793-8. In contrast, the adrenoreceptor alpha 2A (ADRA2A),129129. Bolonna AA, Arranz MJ, Munro J, Osborne S, Petouni M, Martinez M, et al. No influence of adrenergic receptor polymorphisms on schizophrenia and antipsychotic response. Neurosci Lett. 2000;280:65-8.,130130. Tsai SJ, Wang YC, Yu Younger WY, Lin CH, Yang KH, Hong CJ. Association analysis of polymorphism in the promoter region of the alpha2a-adrenoceptor gene with schizophrenia and clozapine response. Schizophr Res. 2001;49:53-8. brain-derived neurotrophic factor (BDNF),131131. Hong CJ, Yu YW, Lin CH, Tsai SJ. An association study of a brain-derived neurotrophic factor Val66Met polymorphism and clozapine response of schizophrenic patients. Neurosci Lett. 2003;349:206-8. human glutathione peroxidase (GPX1),132132. Souza RP, Tampakeras M, Basile V, Shinkai T, Rosa DV, Potkin S, et al. Lack of association of GPX1 and MnSOD genes with symptom severity and response to clozapine treatment in schizophrenia subjects. Human Psychopharmacol. 2009;24:676-9. glutamate receptor ionotropic N-methyl D-aspartate 1 (GRIN1),106106. Hwang R, Souza RP, Tiwari AK, Zai CC, Muller DJ, Potkin SG, et al. Gene-gene interaction analyses between NMDA receptor subunit and dopamine receptor gene variants and clozapine response. Pharmacogenomics. 2011;12:277-91. 2A (GRIN2A)106106. Hwang R, Souza RP, Tiwari AK, Zai CC, Muller DJ, Potkin SG, et al. Gene-gene interaction analyses between NMDA receptor subunit and dopamine receptor gene variants and clozapine response. Pharmacogenomics. 2011;12:277-91. and 2B (GRIN2B),106106. Hwang R, Souza RP, Tiwari AK, Zai CC, Muller DJ, Potkin SG, et al. Gene-gene interaction analyses between NMDA receptor subunit and dopamine receptor gene variants and clozapine response. Pharmacogenomics. 2011;12:277-91.,133133. Hong CJ, Yu YW, Lin CH, Cheng CY, Tsai SJ. Association analysis for NMDA receptor subunit 2B (GRIN2B) genetic variants and psychopathology and clozapine response in schizophrenia. Psychiatr Genet. 2001;11:219-22. histamine receptor H1 (HRH1),134134. Mancama D, Arranz MJ, Munro J, Osborne S, Makoff A, Collier D, et al. Investigation of promoter variants of the histamine 1 and 2 receptors in schizophrenia and clozapine response. Neurosci Lett. 2002;333:207-11. histamine receptor H2 (HRH2),134134. Mancama D, Arranz MJ, Munro J, Osborne S, Makoff A, Collier D, et al. Investigation of promoter variants of the histamine 1 and 2 receptors in schizophrenia and clozapine response. Neurosci Lett. 2002;333:207-11. and superoxide dismutase 2 mitochondrial (MNSOD)132132. Souza RP, Tampakeras M, Basile V, Shinkai T, Rosa DV, Potkin S, et al. Lack of association of GPX1 and MnSOD genes with symptom severity and response to clozapine treatment in schizophrenia subjects. Human Psychopharmacol. 2009;24:676-9. were investigated and no significant associations were observed. The tumor necrosis factor gene (TNF) showed significant4949. Zai G, Muller DJ, Volavka J, Czobor P, Lieberman JA, Meltzer HY, et al. Family and case-control association study of the tumor necrosis factor-alpha (TNF-alpha) gene with schizophrenia and response to antipsychotic medication. Psychopharmacology (Berl). 2006;188:171-82. and nonsignificant135135. Tsai SJ, Hong CJ, Yu YW, Lin CH, Liu LL. No association of tumor necrosis factor alpha gene polymorphisms with schizophrenia or response to clozapine. Schizophr Res. 2003;65:27-32. results. As these studies are mostly unique, confirmation of the results is necessary.

Studies assessing the adverse effects of clozapine

There is strong evidence that the serotonergic (5-HT) system plays a role in the regulation of feeding behavior; thus, clozapine-induced weight gain could be explained by dysfunction of this neurotransmitter.1616. Arranz MJ, Rivera M, Munro JC. Pharmacogenetics of response to antipsychotics in patients with schizophrenia. CNS Drugs. 2011;25:933-69. Several studies linking HTR2C (Cys23Ser and -759C>T) polymorphisms to weight gain have been conducted, with significant57. Gunes A, Melkersson KI, Scordo MG, Dahl ML. Association between HTR2C and HTR2A polymorphisms and metabolic abnormalities in patients treated with olanzapine or clozapine. J Clin Psychopharmacol. 2009;29:65-8. 58. Reynolds GP, Zhang Z, Zhang X. Polymorphism of the promoter region of the serotonin 5-HT(2C) receptor gene and clozapine-induced weight gain. Am J Psychiatry. 2003;160:677-9. 59. Miller DD, Ellingrod VL, Holman TL, Buckley PF, Arndt S. Clozapine-induced weight gain associated with the 5HT2C receptor -759C/T polymorphism. Am J Med Genet B Neuropsychiatr Genet. 2005;133B:97-100. 57-6060. Opgen-Rhein C, Brandl EJ, Muller DJ, Neuhaus AH, Tiwari AK, Sander T, et al. Association of HTR2C, but not LEP or INSIG2, genes with antipsychotic-induced weight gain in a German sample. Pharmacogenomics. 2010;11:773-80. and nonsignificant136. Hong CJ, Lin CH, Yu YW, Yang KH, Tsai SJ. Genetic variants of the serotonin system and weight change during clozapine treatment. Pharmacogenetics. 2001;11:265-8. 137. Basile VS, Masellis M, McIntyre RS, Meltzer HY, Lieberman JA, Kennedy JL. Genetic dissection of atypical antipsychotic-induced weight gain: novel preliminary data on the pharmacogenetic puzzle. J Clin Psychiatry. 2001;62:45-66. 138. Tsai SJ, Hong CJ, Yu YW, Lin CH. -759C/T genetic variation of 5HT(2C) receptor and clozapine-induced weight gain. Lancet. 2002;360:1790. 139. Theisen FM, Hinney A, Bromel T, Heinzel-Gutenbrunner M, Martin M, Krieg JC, et al. Lack of association between the -759C/T polymorphism of the 5-HT2C receptor gene and clozapine-induced weight gain among German schizophrenic individuals. Psychiatr Genet. 2004;14:139-42. 136-140140. De Luca V, Mueller DJ, de Bartolomeis A, Kennedy JL. Association of the HTR2C gene and antipsychotic induced weight gain: a meta-analysis. Int J Neuropsychopharmacol. 2007;10:697-704. results. A recent meta-analysis of 522 schizophrenia individuals suggested that the -759C allele is associated with weight gain.141141. Sicard MN, Zai CC, Tiwari AK, Souza RP, Meltzer HY, Lieberman JA, et al. Polymorphisms of the HTR2C gene and antipsychotic-induced weight gain: an update and meta-analysis. Pharmacogenomics. 2010;11:1561-71. However, this study detected a relevant publication bias, suggesting preferential publication of significant findings over nonsignificant observations. A previous meta-analysis of 588 subjects reporting data on -759C>T supported the existence of an association between this individual marker and the side effect only under a fixed model.142142. De Luca V, Mueller DJ, de Bartolomeis A, Kennedy JL. Association of the HTR2C gene and antipsychotic induced weight gain: a meta-analysis. Int J Neuropsychopharmacol. 2007;10:697-704. Both analyses included studies with mixed antipsychotics. Recently, Hill & Reynolds143143. Hill MJ, Reynolds GP. Functional consequences of two HTR2C polymorphisms associated with antipsychotic-induced weight gain. Pharmacogenomics. 2011;12:727-34. established -759C>T as a functional polymorphism and suggested disruption of DNA-protein interactions as a mechanism whereby HTR2C expression is perturbed, leading to an influence on antipsychotic-induced weight gain.

A moderate association between the GNB3 825C>T polymorphism and weight gain5656. Wang YC, Bai YM, Chen JY, Lin CC, Lai IC, Liou YJ. C825T polymorphism in the human G protein beta3 subunit gene is associated with long-term clozapine treatment-induced body weight change in the Chinese population. Pharmacogene Genomics. 2005;15:743-8. was not observed in a previous study.144144. Tsai SJ, Yu YW, Lin CH, Wang YC, Chen JY, Hong CJ. Association study of adrenergic beta3 receptor (Trp64Arg) and G-protein beta3 subunit gene (C825T) polymorphisms and weight change during clozapine treatment. Neuropsychobiology. 2004;50:37-40. Other genes with significant associations include ADRA2A,5151. Wang YC, Bai YM, Chen JY, Lin CC, Lai IC, Liou YJ. Polymorphism of the adrenergic receptor alpha 2a -1291C>G genetic variation and clozapine-induced weight gain. J Neural Transm. 2005;112:1463-8.,5252. Sickert L, Muller DJ, Tiwari AK, Shaikh S, Zai C, De Souza R, et al. Association of the alpha 2A adrenergic receptor -1291C/G polymorphism and antipsychotic-induced weight gain in European-Americans. Pharmacogenomics. 2009;10:1169-76. BDNF,5353. Tsai A, Liou YJ, Hong CJ, Wu CL, Tsai SJ, Bai YM. Association study of brain-derived neurotrophic factor gene polymorphisms and body weight change in schizophrenic patients under long-term atypical antipsychotic treatment. Neuromolecular Med. 2011;13:328-33. DRD2,5454. Hong CJ, Liou YJ, Bai YM, Chen TT, Wang YC, Tsai SJ. Dopamine receptor D2 gene is associated with weight gain in schizophrenic patients under long-term atypical antipsychotic treatment. Pharmacogenet Genomics. 2010;20:359-66.,5555. Muller DJ, Zai CC, Sicard M, Remington E, Souza RP, Tiwari AK, et al. Systematic analysis of dopamine receptor genes (DRD1-DRD5) in antipsychotic-induced weight gain. Pharmacogenomics J. 2012;12:156-64. adiponectin, C1Q and collagen domain containing (ADIPOQ),5050. Jassim G, Ferno J, Theisen FM, Haberhausen M, Christoforou A, Havik B, et al. Association study of energy homeostasis genes and antipsychotic-induced weight gain in patients with schizophrenia. Pharmacopsychiatry. 2011;44:15-20. melanocortin 4 receptor (MC4R),6363. Chowdhury NI, Tiwari AK, Souza RP, Zai CC, Shaikh SA, Chen S, et al. Genetic association study between antipsychotic-induced weight gain and the melanocortin-4 receptor gene. Pharmacogenomics. 2013;13:272-9. protein kinase beta 2 non-catalytic subunit (PRKAB2),6565. Souza RP, Tiwari AK, Chowdhury NI, Ceddia RB, Lieberman JA, Meltzer HY, et al. Association study between variants of AMP-activated protein kinase catalytic and regulatory subunit genes with antipsychotic-induced weight gain. J Psychiatr Res. 2012;46:462-8. protein kinase gamma 2 non-catalytic subunit (PRKAG2),5050. Jassim G, Ferno J, Theisen FM, Haberhausen M, Christoforou A, Havik B, et al. Association study of energy homeostasis genes and antipsychotic-induced weight gain in patients with schizophrenia. Pharmacopsychiatry. 2011;44:15-20. and roundabout axon guidance receptor homolog 1 (ROBO1).6666. Vehof J, Al Hadithy AF, Burger H, Snieder H, Risselada AJ, Wilffert B, et al. Association between the ROBO1 gene and body mass index in patients using antipsychotics. Psychiatr Genet. 2011;21:202-7. Controversial results were observed for HTR2A 5757. Gunes A, Melkersson KI, Scordo MG, Dahl ML. Association between HTR2C and HTR2A polymorphisms and metabolic abnormalities in patients treated with olanzapine or clozapine. J Clin Psychopharmacol. 2009;29:65-8.,136136. Hong CJ, Lin CH, Yu YW, Yang KH, Tsai SJ. Genetic variants of the serotonin system and weight change during clozapine treatment. Pharmacogenetics. 2001;11:265-8. (positive and negative results, respectively), insulin induced gene 2 (INSIG2)6060. Opgen-Rhein C, Brandl EJ, Muller DJ, Neuhaus AH, Tiwari AK, Sander T, et al. Association of HTR2C, but not LEP or INSIG2, genes with antipsychotic-induced weight gain in a German sample. Pharmacogenomics. 2010;11:773-80.,6161. Le Hellard S, Theisen FM, Haberhausen M, Raeder MB, Ferno J, Gebhardt S, et al. Association between the insulin-induced gene 2 (INSIG2) and weight gain in a German sample of antipsychotic-treated schizophrenic patients: perturbation of SREBP-controlled lipogenesis in drug-related metabolic adverse effects? Mol Psychiatry. 2009;14:308-17.,145145. Tiwari AK, Zai CC, Meltzer HY, Lieberman JA, Muller DJ, Kennedy JL. Association study of polymorphisms in insulin induced gene 2 (INSIG2) with antipsychotic-induced weight gain in European and African-American schizophrenia patients. Hum Psychopharmacol. 2010;25:253-9. (positive results only in the second study), leptin (LEP)6060. Opgen-Rhein C, Brandl EJ, Muller DJ, Neuhaus AH, Tiwari AK, Sander T, et al. Association of HTR2C, but not LEP or INSIG2, genes with antipsychotic-induced weight gain in a German sample. Pharmacogenomics. 2010;11:773-80.,6262. Zhang XY, Tan YL, Zhou DF, Haile CN, Cao LY, Xu Q, et al. Association of clozapine-induced weight gain with a polymorphism in the leptin promoter region in patients with chronic schizophrenia in a Chinese population. J Clin Psychopharmacol. 2007;27:246-51. (negative and positive results, respectively), protein kinase alpha 2 catalytic subunit (PRKAA2)5050. Jassim G, Ferno J, Theisen FM, Haberhausen M, Christoforou A, Havik B, et al. Association study of energy homeostasis genes and antipsychotic-induced weight gain in patients with schizophrenia. Pharmacopsychiatry. 2011;44:15-20.,6565. Souza RP, Tiwari AK, Chowdhury NI, Ceddia RB, Lieberman JA, Meltzer HY, et al. Association study between variants of AMP-activated protein kinase catalytic and regulatory subunit genes with antipsychotic-induced weight gain. J Psychiatr Res. 2012;46:462-8. (negative and positive results, respectively), and TNF6767. Wang YC, Bai YM, Chen JY, Lin CC, Lai IC, Liou YJ. Genetic association between TNF-alpha -308 G>A polymorphism and longitudinal weight change during clozapine treatment. Hum Psychopharmacol. 2010;25:303-9.,137137. Basile VS, Masellis M, McIntyre RS, Meltzer HY, Lieberman JA, Kennedy JL. Genetic dissection of atypical antipsychotic-induced weight gain: novel preliminary data on the pharmacogenetic puzzle. J Clin Psychiatry. 2001;62:45-66.,146146. Huang HH, Wang YC, Wu CL, Hong CJ, Bai YM, Tsai SJ, et al. TNF-alpha -308 G>A polymorphism and weight gain in patients with schizophrenia under long-term clozapine, risperidone or olanzapine treatment. Neurosci Lett. 2011;504:277-80. (positive results only in the second study). No correlation was observed for adrenoreceptor beta 3 (ADRB3),144144. Tsai SJ, Yu YW, Lin CH, Wang YC, Chen JY, Hong CJ. Association study of adrenergic beta3 receptor (Trp64Arg) and G-protein beta3 subunit gene (C825T) polymorphisms and weight change during clozapine treatment. Neuropsychobiology. 2004;50:37-40. cholecystokinin (CCK),147147. Tiwari AK, Rodgers JB, Sicard M, Zai CC, Likhodi O, Freeman N, et al. Association study of polymorphisms in cholecystokinin gene and its receptors with antipsychotic induced weight gain in schizophrenia patients. Prog Neuropsychopharmacol Biol Psychiatry. 2010;34:1484-90. cannabinoid receptor 1 (CNR1),148148. Tiwari AK, Zai CC, Likhodi O, Lisker A, Singh D, Souza RP, et al. A common polymorphism in the cannabinoid receptor 1 (CNR1) gene is associated with antipsychotic-induced weight gain in Schizophrenia. Neuropsychopharmacology. 2010;35:1315-24. fatty acid binding protein 3 (FABP3),5050. Jassim G, Ferno J, Theisen FM, Haberhausen M, Christoforou A, Havik B, et al. Association study of energy homeostasis genes and antipsychotic-induced weight gain in patients with schizophrenia. Pharmacopsychiatry. 2011;44:15-20. fat mass and obesity associated (FTO),5050. Jassim G, Ferno J, Theisen FM, Haberhausen M, Christoforou A, Havik B, et al. Association study of energy homeostasis genes and antipsychotic-induced weight gain in patients with schizophrenia. Pharmacopsychiatry. 2011;44:15-20. peroxisome proliferator-activated receptor gamma (PPARG),149149. Staeker J, Leucht S, Steimer W. Peroxisome proliferator-activated receptor gamma (PPARG) Pro12Ala: lack of association with weight gain in psychiatric inpatients treated with olanzapine or clozapine. Mol Diagn Ther. 2012;16:93-8. protein kinase alpha 1 catalytic subunit (PRKAA1),5050. Jassim G, Ferno J, Theisen FM, Haberhausen M, Christoforou A, Havik B, et al. Association study of energy homeostasis genes and antipsychotic-induced weight gain in patients with schizophrenia. Pharmacopsychiatry. 2011;44:15-20. protein kinase gamma 1 non-catalytic subunit (PRKAG1),5050. Jassim G, Ferno J, Theisen FM, Haberhausen M, Christoforou A, Havik B, et al. Association study of energy homeostasis genes and antipsychotic-induced weight gain in patients with schizophrenia. Pharmacopsychiatry. 2011;44:15-20. protein kinase gamma 3 non-catalytic subunit (PRKAG3),5050. Jassim G, Ferno J, Theisen FM, Haberhausen M, Christoforou A, Havik B, et al. Association study of energy homeostasis genes and antipsychotic-induced weight gain in patients with schizophrenia. Pharmacopsychiatry. 2011;44:15-20. DRD1,5555. Muller DJ, Zai CC, Sicard M, Remington E, Souza RP, Tiwari AK, et al. Systematic analysis of dopamine receptor genes (DRD1-DRD5) in antipsychotic-induced weight gain. Pharmacogenomics J. 2012;12:156-64. DRD3,5555. Muller DJ, Zai CC, Sicard M, Remington E, Souza RP, Tiwari AK, et al. Systematic analysis of dopamine receptor genes (DRD1-DRD5) in antipsychotic-induced weight gain. Pharmacogenomics J. 2012;12:156-64. DRD4,5555. Muller DJ, Zai CC, Sicard M, Remington E, Souza RP, Tiwari AK, et al. Systematic analysis of dopamine receptor genes (DRD1-DRD5) in antipsychotic-induced weight gain. Pharmacogenomics J. 2012;12:156-64.,150150. Rietschel M, Naber D, Oberlander H, Holzbach R, Fimmers R, Eggermann K, et al. Efficacy and side-effects of clozapine: testing for association with allelic variation in the dopamine D4 receptor gene. Neuropsychopharmacology. 1996;15:491-6. DRD5,5555. Muller DJ, Zai CC, Sicard M, Remington E, Souza RP, Tiwari AK, et al. Systematic analysis of dopamine receptor genes (DRD1-DRD5) in antipsychotic-induced weight gain. Pharmacogenomics J. 2012;12:156-64. HRH1,151151. Hong CJ, Lin CH, Yu YW, Chang SC, Wang SY, Tsai SJ. Genetic variant of the histamine-1 receptor (glu349asp) and body weight change during clozapine treatment. Psychiatr Genet. 2002;12:169-71. HTR6,136136. Hong CJ, Lin CH, Yu YW, Yang KH, Tsai SJ. Genetic variants of the serotonin system and weight change during clozapine treatment. Pharmacogenetics. 2001;11:265-8. and SLC6A4.136136. Hong CJ, Lin CH, Yu YW, Yang KH, Tsai SJ. Genetic variants of the serotonin system and weight change during clozapine treatment. Pharmacogenetics. 2001;11:265-8. Confirmation of these results by other studies is also needed.

Additionally, polymorphisms in the HTR2C68. Mulder H, Franke B, van der-Beek van der AA, Arends J, Wilmink FW, Scheffer H, et al. The association between HTR2C gene polymorphisms and the metabolic syndrome in patients with schizophrenia. J Clin Psychopharmacol. 2007;27:338-43. 69. Mulder H, Cohen D, Scheffer H, Gispen-de Wied C, Arends J, Wilmink FW, et al. HTR2C gene polymorphisms and the metabolic syndrome in patients with schizophrenia: a replication study. J Clin Psychopharmacol. 2009;29:16-20. 70. Risselada AJ, Vehof J, Bruggeman R, Wilffert B, Cohen D, Al Hadithy AF, et al. Association between HTR2C gene polymorphisms and the metabolic syndrome in patients using antipsychotics: a replication study. The Pharmacogenomics J. 2012;12:62-7. 68-7171. Bai YM, Chen TT, Liou YJ, Hong CJ, Tsai SJ. Association between HTR2C polymorphisms and metabolic syndrome in patients with schizophrenia treated with atypical antipsychotics. Schizophr Res. 2011;125:179-86. and methylenetetrahydrofolate reductase (MTHFR) genes7272. van Winkel R, Rutten BP, Peerbooms O, Peuskens J, van Os J, De Hert M. MTHFR and risk of metabolic syndrome in patients with schizophrenia. Schizophr Res. 2010;121:193-8.,7373. van Winkel R, Moons T, Peerbooms O, Rutten B, Peuskens J, Claes S, et al. MTHFR genotype and differential evolution of metabolic parameters after initiation of a second generation antipsychotic: an observational study. Int Clin Psychopharmacol. 2010;25:270-6. were associated with risk of metabolic syndrome induced by clozapine or risperidone/olanzapine. No significant association was found for ADRA2A.152152. Risselada AJ, Vehof J, Bruggeman R, Wilffert B, Cohen D, Al Hadithy AF, et al. Association between the 1291-C/G polymorphism in the adrenergic alpha-2a receptor and the metabolic syndrome. J Clin Psychopharmacol. 2010;30:667-71. Polymorphisms in the apolipoprotein A-V (APOA5) and C-III (APOC3) genes, but not in LEP, showed an influence on triglyceride and cholesterol levels in patients treated with clozapine or olanzapine.7474. Smith RC, Segman RH, Golcer-Dubner T, Pavlov V, Lerer B. Allelic variation in ApoC3, ApoA5 and LPL genes and first and second generation antipsychotic effects on serum lipids in patients with schizophrenia. Pharmacogenomics J. 2008;8:228-36.

Agranulocytosis is a serious adverse effect associated with clozapine. Some studies showed strong associations between polymorphisms in genes of the major histocompatibility complex (HLA) and the occurrence of this adverse effect.76. Corzo D, Yunis JJ, Yunis EJ, Howard A, Lieberman JA. HSP70-2 9.0 kb variant is in linkage disequilibrium with the HLA-B and DRB1* alleles associated with clozapine-induced agranulocytosis. J Clin Psychiatry. 1994;55:149-52. 77. Corzo D, Yunis JJ, Salazar M, Lieberman JA, Howard A, Awdeh Z, et al. The major histocompatibility complex region marked by HSP70-1 and HSP70-2 variants is associated with clozapine-induced agranulocytosis in two different ethnic groups. Blood. 1995;86:3835-40. 78. Amar A, Segman RH, Shtrussberg S, Sherman L, Safirman C, Lerer B, et al. An association between clozapine-induced agranulocytosis in schizophrenics and HLA-DQB1*0201. Int J Neuropsychopharmacol. 1998;1:41-4. 79. Valevski A, Klein T, Gazit E, Meged S, Stein D, Elizur A, et al. HLA-B38 and clozapine-induced agranulocytosis in Israeli Jewish schizophrenic patients. Eur J Immunogenet. 1998;25:11-3. 80. Dettling M, Schaub RT, Mueller-Oerlinghausen B, Roots I, Cascorbi I. Further evidence of human leukocyte antigen-encoded susceptibility to clozapine-induced agranulocytosis independent of ancestry. Pharmacogenetics. 2001;11:135-41. 76-8181. Athanasiou MC, Dettling M, Cascorbi I, Mosyagin I, Salisbury BA, Pierz KA, et al. Candidate gene analysis identifies a polymorphism in HLA-DQB1 associated with clozapine-induced agranulocytosis. J Clin Psychiatry. 2011;72:458-63. Significant associations were also found with the NAD(P)H dehydrogenase quinone 2 (NQO2)8282. Ostrousky O, Meged S, Loewenthal R, Valevski A, Weizman A, Carp H, et al. NQO2 gene is associated with clozapine-induced agranulocytosis. Tissue Antigens. 2003;62:483-91. and TNF genes.8383. Turbay D, Lieberman J, Alper CA, Delgado JC, Corzo D, Yunis JJ, et al. Tumor necrosis factor constellation polymorphism and clozapine-induced agranulocytosis in two different ethnic groups. Blood. 1997;89:4167-74. In other studies, no associations were observed with the cytochrome b-245 alpha polypeptide (CYBA),153153. Mosyagin I, Dettling M, Roots I, Mueller-Oerlinghausen B, Cascorbi I. Impact of myeloperoxidase and NADPH-oxidase polymorphisms in drug-induced agranulocytosis. J Clin Psychopharmacol. 2004;24:613-7. P450 family 2 subfamily D polypeptide 6 (CYP2D6),154154. Dettling M, Sachse C, Muller-Oerlinghausen B, Roots I, Brockmoller J, Rolfs A, et al. Clozapine-induced agranulocytosis and hereditary polymorphisms of clozapine metabolizing enzymes: no association with myeloperoxidase and cytochrome P4502D6. Pharmacopsychiatry. 2000;33:218-20. and myeloperoxidase (MPO).153153. Mosyagin I, Dettling M, Roots I, Mueller-Oerlinghausen B, Cascorbi I. Impact of myeloperoxidase and NADPH-oxidase polymorphisms in drug-induced agranulocytosis. J Clin Psychopharmacol. 2004;24:613-7.,154154. Dettling M, Sachse C, Muller-Oerlinghausen B, Roots I, Brockmoller J, Rolfs A, et al. Clozapine-induced agranulocytosis and hereditary polymorphisms of clozapine metabolizing enzymes: no association with myeloperoxidase and cytochrome P4502D6. Pharmacopsychiatry. 2000;33:218-20.

A study conducted with a Brazilian population sample evaluated the influence of GNB3 polymorphisms and the occurrence of tonic-clonic seizures due to clozapine treatment.3434. Kohlrausch FB, Salatino-Oliveira A, Gama CS, Lobato MI, Belmonte-de-Abreu P, Hutz MH. G-protein gene 825C>T polymorphism is associated with response to clozapine in Brazilian schizophrenics. Pharmacogenomics. 2008;9:1429-36. The 825T allele of the 825C>T polymorphism was significantly associated with an increased risk of developing seizures.

Ferrari et al.8484. Ferrari M, Bolla E, Bortolaso P, Callegari C, Poloni N, Lecchini S, et al. Association between CYP1A2 polymorphisms and clozapine-induced adverse reactions in patients with schizophrenia. Psychiatry Res. 2012;200:1014-7. studied the influence of CYP1A2 polymorphisms and clozapine-induced adverse effects (neurological, cardiovascular, gastroenterological, hematological, behavioral, and musculoskeletal adverse drug reactions, ADRs) and observed that the LA (low activity) phenotype was significantly more frequent in subjects with clozapine-induced ADRs than in those without ADRs.

From candidate genes to genome-wide association studies

Genome-wide association studies (GWASs), a powerful method for the large-scale analysis of genotype-phenotype relationships, are currently the method of choice for dissecting the genetic basis of complex traits.155155. Stranger BE, Stahl EA, Raj T. Progress and promise of genome-wide association studies for human complex trait genetics. Genetics. 2011;187:367-83. In GWASs, genetic variations associated with response to treatment are detected randomly throughout the genome. Few studies of antipsychotic response and adverse effects have been published, partly due to the need for large samples to achieve truly significant results.156156. Malhotra AK, Zhang JP, Lencz T. Pharmacogenetics in psychiatry: translating research into clinical practice. Mol Psychiatry. 2012;17:760-9. Although the few published studies have little statistical power because of insufficient sample size, they may identify new genes for investigation and assist in the elucidation of new metabolic pathways possibly related to efficacy and adverse effects of clozapine.1616. Arranz MJ, Rivera M, Munro JC. Pharmacogenetics of response to antipsychotics in patients with schizophrenia. CNS Drugs. 2011;25:933-69.

A few GWASs have been conducted using samples from the CATIE study (Clinical Antipsychotic Trials of Intervention Effectiveness, n=750),157157. Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med. 2005;353:1209-23. where treatment of patients was based on several classes of antipsychotics. One of these studies7575. Adkins DE, Aberg K, McClay JL, Bukszar J, Zhao Z, Jia P, et al. Genomewide pharmacogenomic study of metabolic side effects to antipsychotic drugs. Mol Psychiatry. 2011;16:321-32. examined 12 indicators of metabolic side effects of antipsychotics and found a polymorphism in the protein kinase type II beta gene (PRKAR2B) mediating effects of clozapine on triglyceride levels.

Malhotra et al.6464. Malhotra AK, Correll CU, Chowdhury NI, Muller DJ, Gregersen PK, Lee AT, et al. Association between common variants near the melanocortin 4 receptor gene and severe antipsychotic drug-induced weight gain. Arch Gen Psychiatry. 2012;69:904-12. conducted the first GWAS of weight gain in patients undergoing initial exposure to second-generation antipsychotics (SGAs) and also assessing three independent replication cohorts (one treated only with clozapine) to confirm the results. The authors found one polymorphism (rs489693) located approximately 190kb downstream from MC4R (previously identified as a candidate for weight-related phenotypes), implicating MC4R in extreme SGA-induced weight gain and related metabolic disturbances, including in the clozapine-treated sample.

More intriguing is that most candidate genes that were previously found to be associated with individual response to treatment, or adverse effects of clozapine (Tables 1 and 2), did not show statistical significance in these studies. As GWASs are exploratory, they should be replicated in independent samples.

Discussion

The study of pharmacogenetics in schizophrenia had its milestone in the work of Arranz et al.,102102. Arranz MJ, Munro J, Birkett J, Bolonna A, Mancama D, Sodhi M, et al. Pharmacogenetic prediction of clozapine response. Lancet. 2000;355:1615-6. conducted 12 years ago. This study had a great impact at the time because of its multigene approach and the observation of a strong association between a specific set of six polymorphisms and response to clozapine in schizophrenic patients, with a positive predictive value of 76%. Since then, few studies have been carried out with this approach. Studies with individual candidate genes have been more frequent in recent years, and GWASs are the real promise.155155. Stranger BE, Stahl EA, Raj T. Progress and promise of genome-wide association studies for human complex trait genetics. Genetics. 2011;187:367-83.

Study limitations

Most of the reviewed articles were individual association studies. This approach has minimal practical value, since most antipsychotics have multiple targets, and it would be unlikely for only one of these targets to be responsible for all variability in treatment response.114114. Arranz MJ, Kerwin RW. Neurotransmitter-related genes and antipsychotic response: pharmacogenetics meets psychiatric treatment. Ann Med. 2000;32:128-33.

Association studies are the most appropriate strategy for pharmacogenetic research.158158. Risch NJ. Searching for genetic determinants in the new millennium. Nature. 2000;405:847-56. However, determining the practical relevance of pharmacogenetic variants is difficult, partly because of problems with the design and replication of such studies.159159. Arranz MJ, Munro J, Osborne S, Collier D, Kerwin RW. Difficulties in replication of results. Lancet. 2000;356:1359-60. The results of many studies of response to antipsychotics were not replicated in clinically similar populations, and the implication of the few studies that have been replicated still needs to be established. In addition to type I and II statistical errors, the difficulty lies mainly in the standardization of clinical samples in relation to an appropriate number of individuals and detailed clinical information about symptom improvement and development of adverse effects. The complexity of genetic factors implicated in psychiatric illness and response to medication is also a complicating factor.159159. Arranz MJ, Munro J, Osborne S, Collier D, Kerwin RW. Difficulties in replication of results. Lancet. 2000;356:1359-60. Polygenic involvement in the etiology of schizophrenia hinders the identification and characterization of many genes that would be relevant as therapeutic targets and how these components interact or combine in the process. Other difficulties include incomplete knowledge of the mechanisms of schizophrenia, the complexity of brain function, and the influence of nongenetic factors, including age, diet, environmental exposures and interactions, comorbidities, and drug interactions. The dynamics of epigenetic events can also be responsible for the variations observed in the clinical response to antipsychotics.160160. Flomen R, Knight J, Sham P, Kerwin R, Makoff A. Evidence that RNA editing modulates splice site selection in the 5-HT2C receptor gene. Nucleic Acids Res. 2004;32:2113-22.,161161. Abdolmaleky HM, Thiagalingam S, Wilcox M. Genetics and epigenetics in major psychiatric disorders: dilemmas, achievements, applications, and future scope. Am J Pharmacogenomics. 2005;5:149-60.

In most meta-analyses, the heterogeneity of the antipsychotic drugs used in the analyzed studies limits the possibility of examining the association of candidate genes with any specific drug. In the pharmacogenetics of schizophrenia, meta-analyses support the involvement of DRD2112112. Zhang JP, Lencz T, Malhotra AK. D2 receptor genetic variation and clinical response to antipsychotic drug treatment: a meta-analysis. Am J Psychiatry. 2010;167:763-72. and DRD3107107. Jonsson EG, Flyckt L, Burgert E, Crocq MA, Forslund K, Mattila-Evenden M, et al. Dopamine D3 receptor gene Ser9Gly variant and schizophrenia: association study and meta-analysis. Psychiatr Genet. 2003;13:1-12. in treatment response and HTR2C in weight gain141141. Sicard MN, Zai CC, Tiwari AK, Souza RP, Meltzer HY, Lieberman JA, et al. Polymorphisms of the HTR2C gene and antipsychotic-induced weight gain: an update and meta-analysis. Pharmacogenomics. 2010;11:1561-71.,142142. De Luca V, Mueller DJ, de Bartolomeis A, Kennedy JL. Association of the HTR2C gene and antipsychotic induced weight gain: a meta-analysis. Int J Neuropsychopharmacol. 2007;10:697-704. but simultaneously indicate that the establishment of pharmacogenetics associations in clinical psychiatry requires much larger sample sizes.

Population stratification in case-control studies causes most false-positive associations,162162. Pritchard JK, Rosenberg NA. Use of unlinked genetic markers to detect population stratification in association studies. Am J Hum Genet. 1999;65:220-8. because genetic differences between ethnic groups often lead to differences in treatment response. Additionally, non-publication of negative findings also generates a problem in terms of replication of results.159159. Arranz MJ, Munro J, Osborne S, Collier D, Kerwin RW. Difficulties in replication of results. Lancet. 2000;356:1359-60. For greater uniformity in studies, some characteristics should be assured, including: 1) large sample sizes, since most genes influencing response have little effect on the phenotype; 2) standardization of clinical data important for the outcome of the phenotype (such as dose, treatment duration, age at start of treatment)163163. Lerer B, Segman RH. Pharmacogenetics of antipsychotic therapy: pivotal research issues and the prospects for clinical implementation. Dialogues Clin Neurosci. 2006;8:85-94.; 3) presence of co-medication; 4) standardization of response criteria; 5) disease severity; and 6) prospective studies.

Despite continuous advances toward revealing the genetic basis of many complex traits using GWASs, a major proportion of genetic variance remains unexplained. A large number of disorders have been studied by GWASs, contributing to the detection of many previously undetected loci. For example, Franke et al.164164. Franke A, McGovern DP, Barrett JC, Wang K, Radford-Smith GL, Ahmad T, et al. Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci. Nat Genet. 2010;42:1118-25. conducted a meta-analysis of six Crohn's disease GWASs and 30 new susceptibility loci were identified at genome-wide significance. Jia et al.165165. Jia P, Wang L, Fanous AH, Pato CN, Edwards TL, Zhao Z. Network-assisted investigation of combined causal signals from genome-wide association studies in schizophrenia. PLoS Comput Biol. 2012;8:e1002587. examined multiple GWAS datasets in schizophrenia through meta-analysis of the related SNPs and identified 205 module genes significantly associated with schizophrenia, including well-studied candidate genes, such as GRIN2B, disrupted in schizophrenia 1 (DISC1), G protein-coupled receptor 17 (GPR17), guanine nucleotide binding protein alpha 12 (GNA12) and alpha 13 (GNA13), and alpha inhibiting activity polypeptide 1 (GNAI1). However, most GWASs have achieved limited success in explaining a considerable proportion of genetic variance of complex traits.166166. Clarke AJ, Cooper DN. GWAS: heritability missing in action? Eur J Hum Genet. 2010;18:859-61. The very large number of markers under investigation raises the issue of multiple testing, and the need for correction, which makes it even harder to detect a small association signal.167167. Cordell HJ. Detecting gene-gene interactions that underlie human diseases. Nat Ver Genet. 2009;10:392-404. Most of the susceptibility loci that have been discovered so far by GWASs are of small predisposing risk. In addition, detecting such contributions is difficult when the predisposing allele is rare or the sample size is not sufficiently large.168168. Risch NJ. Searching for genetic determinants in the new millennium. Nature. 2000;405:847-56. Additionally, these studies do not take into account existing biological knowledge about the trait, which could help narrow down datasets and guide the process of extracting biologically meaningful results in a more effective manner.169169. Moore JH, Asselbergs FW, Williams SM. Bioinformatics challenges for genome-wide association studies. Bioinformatics. 2010;26:445-55. In view of these limitations, new approaches to analyze complex traits would be helpful.

Clinical applications

The CATIE study157157. Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med. 2005;353:1209-23. and a double-blind study investigating dose of antipsychotics,170170. Stroup TS, McEvoy JP, Swartz MS, Byerly MJ, Glick ID, Canive JM, et al. The National Institute of Mental Health Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) project: schizophrenia trial design and protocol development. Schizophr Bull. 2003;29:15-31. controlled for confounding variables in clinical practice, indicated that variations in metabolizing enzymes play a small role in determining the clinical response to antipsychotics. However, combining assessment of these pharmacokinetic factors with analysis of pharmacodynamic markers, each conferring moderate effects, may be a more valid approach, possibly improving cost-effectiveness in clinical practice.

Substantial advances in knowledge of the gene-response connection have been made, and pharmacogenomics approaches have become increasingly popular. With advances in sequencing technologies and bioinformatics, new dimensions in the search for multiple genes and how their expression affects response to medication are being generated. However, clinical and pharmacogenomic knowledge has not advanced as rapidly as technology, and no application has been developed yet regarding the management of schizophrenia treatment and drug development.66. Reynolds GP. The pharmacogenetics of symptom response to antipsychotic drugs. Psychiatry Investig. 2012;9:1-7.

Conclusions

Despite several decades of research, no biological or clinical predictors of response to antipsychotic medication or development of side effects have been identified.66. Reynolds GP. The pharmacogenetics of symptom response to antipsychotic drugs. Psychiatry Investig. 2012;9:1-7. To date, efforts to identify key genes that may be useful in predicting response and adverse effects to clozapine treatment have not been fully successful, and additional studies are required. Meta-analysis results have confirmed one of the greatest difficulties of association studies: sample sizes are not large enough to detect positive associations. Therefore, further studies with much larger sample sizes are still needed to detect real associations. Great hope lies in the introduction of GWASs, as the hypothesis that a combination of genes contribute to the effect of the drug is a more likely explanation for the interindividual variability in treatment response.114114. Arranz MJ, Kerwin RW. Neurotransmitter-related genes and antipsychotic response: pharmacogenetics meets psychiatric treatment. Ann Med. 2000;32:128-33.

Pharmacogenetic-driven prescription focused on genotypes might enable optimal selection of medications and their doses in the future. However, in the treatment of multifactorial diseases, pharmacogenetics is only one of several approaches that should be analyzed, such as expression analysis and proteomics. Thus, as noted by Pirmohamed, pharmacogenetics “is coming along, but not for everything.”171171. Mayor S. Fitting the drug to the patient. BMJ. 2007;334:452-3. Only time will tell whether prediction of drug efficacy will reduce suffering and improve patient quality of life.

Acknowledgement

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Fundação Carlos Chagas Filho de Amparo è Pesquisa do Estado do Rio de Janeiro (FAPERJ), Pró-Reitoria de Pesquisa e Inovação/Universidade Federal Fluminense (PROPPI/UFF).

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Publication Dates

  • Publication in this collection
    Jul-Sep 2013

History

  • Received
    23 Aug 2012
  • Accepted
    19 Dec 2012
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