Atypical antipsychotic drugs (AADs) are the standard treatment for both the acute and long-term management of schizophrenia and an augmentation to mood stabilizers for bipolar disorder (BD). Yet many individuals who take AADs do not fully respond to them, while others experience side effects that include weight gain and metabolic disorder. This in vitro pharmacogenetic study examined whether allelic variants in the 5-hydroxytryptamine (HT)2A receptor alter the in vitro pharmacology of six AADs (clozapine, olanzapine, risperidone, quetiapine, ziprasidone, and aripiprazole). We selected 4 functional single-nucleotide polymorphisms (SNPs) for investigation (Thr25Asn, Ile197Val, Ala447Val, and His452Tyr), conducted site-directed mutagenesis studies to induce variants into human HEK-293 cell lines, and screened allelic variants for their effects on 5-HT 2A receptors in the cell lines. We conducted numerous binding assays and fluorescence-based assay system (FLEX station) experiments using the six AADs. Our results indicated that three polymorphic 5-HT2A receptors (Ile197Val, Ala447Val, and His452Tyr) exhibited statistically significant, though modest, changes in atypical antipsychotic affinity. In addition, three polymorphic receptors (Thr25Asn, Ile197Val, and His452Try) altered AAD potency. Our findings support in vivo evidence that functional SNPs in genes encoding neuroreceptor drug targets could explain interindividual differences in AAD drug response and tolerability. We suggest that more in vivo pharmacogenetic studies of well-characterized patients who are prescribed AADs be indicated. Future pharmacogenetic studies of well-characterized patients will likely involve tagging SNPs and the use of haplotypes related to other genes encoding neuroreceptor drug targets.
Arranz, M.J., Munro, J., Birkett, J., Bolonna, A., Mancama, D., Sodhi, M., et al. (2000). Pharmacogenetic prediction of clozapine response. Lancet, 355, 1615-1616.
2.
Arranz, M.J., Munro, J., Owen, M.J., Spurlock, G., Sham, P.C., Zhao, J., et al. (1998). Evidence for association between polymorphisms in the promoter and coding regions of the 5-HT2A receptor gene and response to clozapine. Molecular Psychiatry, 3, 61-66.
3.
Baker, R.A., Pikalov, A., Tran, Q.V., Kremenets, T., Arani, R.B., & Doraiswamy, P.M. (2009). Atypical antipsychotic drugs and diabetes mellitus in the US Food and Drug Administration Adverse Event Database: A systematic Bayesian signal detection analysis. Psychopharmacological Bulletin, 42, 11-31.
4.
Bhana, N., & Perry, C.M. ( 2001). Olanzapine: A review of its use in the treatment of bipolar I disorder. CNS Drugs, 15, 871-904.
5.
Bitter, I., Dossenbach, M.R., Brook, S., Feldman, P.D., Metcalfe, S., Gagiano, C.A., et al. (2004). Olanzapine versus clozapine in treatment-resistant or treatment-intolerant schizophrenia. Progress in Neuropsychopharmacoly and Biological Psychiatry, 28, 173-180.
6.
Burris, K.D., Molski, T.F., Xu, C., Ryan, E., Tottori, K., Kikuchi, T., et al. (2002). Aripiprazole, a novel antipsychotic, is a high-affinity partial agonist at human dopamine D2 receptors. Journal of Pharmacology and Experimental Therapeutics, 302, 381-389.
7.
Chang, J.S., Ha, K.S., Young Lee, K., Sik Kim, Y., & Min Ahn, Y. (2006). The effects of long-term clozapine add-on therapy on the rehospitalization rate and the mood polarity patterns in bipolar disorders. Journal of Clinical Psychiatry , 67, 461-467.
8.
Cheer, S.M., & Wagstaff, A.J. (2004). Quetiapine. A review of its use in the management of schizophrenia. CNS Drugs, 18, 173-199.
9.
Chiu, C.C., Chen, K.P., Liu, H.C., & Lu, M.L. ( 2006). The early effect of olanzapine and risperidone on insulin secretion in atypical-naive schizophrenic patients. Journal of Clinical Psychopharmacology, 26, 504-507.
10.
Corallo, C.E., & Ernest, D. ( 2007). Atypical neuroleptic malignant syndrome with long-term clozapine. Critical Care Resuscitation, 9, 338-340.
11.
Correll, C.U., Frederickson, A.M., Kane, J.M., & Manu, P. ( 2008). Equally increased risk for metabolic syndrome in patients with bipolar disorder and schizophrenia treated with second-generation antipsychotics . Bipolar Disorder, 10, 788-797.
12.
Davies, M.A., Chang, C., & Roth, B.L. ( 2006). Polymorphic and posttranscriptional modifications of 5-HT receptor structure. In B. L. Roth (Ed.), The serotonic receptors: From molecular pharmacology to human therapeutics (pp. 59-90). New Jersey: Humana Press.
13.
Davies, M.A., Setola, V., Strachan, R.T., Sheffler, D.J., Salay, E., Hufeisen, S.J., et al. (2006). Pharmacologic analysis of non-synonymous coding h5-HT2A SNPs reveals alterations in atypical antipsychotic and agonist efficacies. Pharmacogenomics Journal, 6, 42-51.
14.
de Leon, J., Susce, M.T., & Murray-Carmichael, E. (2006). The AmpliChip CYP450 genotyping test: Integrating a new clinical tool. Molecular Diagnosis & Therapy, 10, 135-151.
15.
Duggan, L., Fenton, M., Rathbone, J., Dardennes, R., El-Dosoky, A., & Indran, S. ( 2005). Olanzapine for schizophrenia. Cochrane Database of Systematic Review, 2, , CD001359.
16.
Dunner, D.L. ( 2005). Safety and tolerability of emerging pharmacological treatments for bipolar disorder. Bipolar Disorder, 7, 307-325.
17.
Fenton, C., & Scott, L.J. ( 2005). Risperidone: A review of its use in the treatment of bipolar mania. CNS Drugs, 19, 429-444.
18.
Forutan, F., Estalji, S., Beu, M., Nikolaus, S., Hamacher, K., Coenen, H.H., et al. (2002). Distribution of 5HT2A receptors in the human brain: Comparison of data in vivo and post mortem. Nuklearmedizin, 41, 197-201.
19.
Gray, J.A., Compton-Toth, B.A., & Roth, B.L. ( 2003). Identification of two serine residues essential for agonist-induced 5-HT@A receptor desensitization. Biochemistry, 42, 10853-10862.
20.
Gunes, A., Melkersson, K.I., Scordo, M.G., & Dahl, M.L. ( 2009). Association between HTR2C and HTR2A polymorphisms and metabolic abnormalities in patients treated with olanzapine or clozapine. Journal of Clinical Psychopharmacoly, 29, 65-68.
21.
Haiman, C.A., & Stram, D.O. ( 2008). Utilizing HapMap and tagging SNPs. Methods in Molecular Medicine, 141, 37-54.
22.
Hardoy, M.C., Garofalo, A., Carpiniello, B., Calabrese, J.R., & Carta, M.G. ( 2005). Combination quetiapine therapy in the long-term treatment of patients with bipolar I disorder. Clinical Practice and Epidemiology in Mental Health, 1, 7.
23.
Hardoy, M.C., Garofalo, A., Mellino, G., Tuligi, F., Cadeddu, M., & Carta, M.G. ( 2007). Quetiapine as add-on treatment for bipolar I disorder: efficacy in preventing relapse of depressive episodes. Clinical Practice and Epidemiology in Mental Health, 3, 17.
24.
Henderson, D.C., Nguyen, D.D., Copeland, P.M., Hayden, D.L., Borba, C.P., Louie, P.M., et al. (2005). Clozapine, diabetes mellitus, hyperlipidemia, and cardiovascular risks and mortality: Results of a 10-year naturalistic study. Journal of Clinical Psychiatry, 66, 1116-1121.
25.
Hennen, J., Perlis, R.H., Sachs, G., Tohen, M., & Baldessarini, R.J. (2004). Weight gain during treatment of bipolar I patients with olanzapine. Journal of Clinical Psychiatry, 65, 1679-1687.
26.
Himei, A., & Okamura, T. ( 2005). Evaluation of the clinical efficacy of risperidone for untreated and treated cases of schizophrenia from various aspects. Psychiatry and Clinical Neurosciences, 59, 556-562.
27.
International HapMap Consortium. (2005). A haplotype map of the human genome. Nature, 437, 1299-1320.
28.
Kane, J.M., Carson, W.H., Saha, A.R., McQuade, R.D., Ingenito, G.G., Zimbroff, D.L., et al. (2002). Efficacy and safety of aripiprazole and haloperidol versus placebo in patients with schizophrenia and schizoaffective disorder. Journal of Clinical Psychiatry, 63, 763-771.
29.
Kane, J.M., Honigfeld, G., Singer, J., & Meltzer, H. ( 1988). Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine. Archives of General Psychiatry, 45, 789-796.
30.
Kane, J.M., Meltzer, H.Y., Carson, W.H. Jr., McQuade, R.D., Marcus, R.N., & Sanchez, R. ( 2007). Aripiprazole for treatment-resistant schizophrenia: Results of a multicenter, randomized, double-blind, comparison study versus perphenazine . Journal of Clinical Psychiatry, 68, 213-223.
31.
Keck, P.E. Jr. ( 2005). Bipolar depression: A new role for atypical antipsychotics ? Bipolar Disorder, 7, 34-40.
32.
Keks, N.A., & Culhane, C. ( 1999). Risperidone (Risperdal): Clinical experience with a new antipsychosis drug. Expert Opinion on Investigational Drugs , 8, 443-452.
33.
Keltner, N.L. ( 2005). Genomic influences on schizophrenia-related neurotransmitter systems. Journal of Nursing Scholarship, 37, 322-328.
34.
Kozuki, Y., & Schepp, K.G. ( 2005). Adherence and nonadherence to antipsychotic medications . Issues in Mental Health Nursing, 26, 379-396.
35.
Lambert, B.L., Cunningham, F.E., Miller, D.R., Dalack, G.W., & Hur, K. ( 2006). Diabetes risk associated with use of olanzapine, quetiapine, and risperidone in veterans health administration patients with schizophrenia . American Journal of Epidemiology, 164, 672-681.
36.
Landegren, U., Nilsson, M., & Kwok, P.Y. ( 1998). Reading bits of genetic information: Methods for single-nucleotide polymorphism analysis. Genome Research, 8, 769-776.
37.
Larmo, I., Nayer, A.D., Windhager, E., Lindenbauer, B., Rittmannsberger, H., Platz, T., et al. (2005). Efficacy and tolerability of quetiapine in patients with schizophrenia who switched from haloperidol, olanzapine or risperidone. Human Psychopharmacology, 20, 573-581.
38.
Leslie, D.L., & Rosenheck, R.A. (2004). Adherence of schizophrenia pharmacotherapy to published treatment recommendations: patient, facility, and provider predictors. Schizophrenia Bulletin, 30, 649-658.
39.
Lieberman, J.A., Stroup, T.S., McEvoy, J.P., Swartz, M.S., Rosenheck, R.A., Perkins, D.O., et al. (2005). Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. New England Journal of Medicine, 353, 1209-1223.
40.
Lund, B.C., & Perry, P.J. ( 2000). Olanzapine: An atypical antipsychotic for schizophrenia . Expert Opinion on Pharmacotherapy, 1, 305-323.
41.
Malhotra, A.K., Goldman, D., Buchanan, R., Breier, A., & Pickar, D. ( 1996). 5HT 2a receptor T102C polymorphism and schizophrenia . Lancet, 347, 1830-1831.
42.
Mancinelli, L., Cronin, M., & Sadee, W. ( 2000). Pharmacogenomics: The promise of personalized medicine . AAPS PharmSci, 2, E4.
43.
Marnellos, G. ( 2003). High-throughput SNP analysis for genetic association studies. Current Opinion in Drug Discovery & Development , 6, 317-321.
44.
Masellis, M., Basile, V., Meltzer, H.Y., Lieberman, J.A., Sevy, S., Macciardi, F.M., et al. (1998). Serotonin subtype 2 receptor genes and clinical response to clozapine in schizophrenia patients. Neuropsychopharmacology, 19, 123-132.
45.
McCormack, P.L., & Wiseman, L.R. ( 2004). Olanzapine: A review of its use in the management of bipolar I disorder. Drugs, 64, 2709-2726.
46.
McCormack, P.L., & Wiseman, L.R. ( 2005). Spotlight on olanzapine in bipolar I disorder. CNS Drugs, 19, 553-555.
47.
Moller, H.J. ( 2005). Risperidone: A review. Expert Opinion on Pharmacotherapy, 6, 803-818.
48.
Nemeroff, C.B., Masand, P.S., Lieberman, J.A., Weiden, P.J., Harvey, P.D., Newcomer, J.W., et al. (2005). From clinical research to clinical practice: A 4-year review of ziprasidone. CNS Spectrum, 10, 1-19.
49.
Norris, B., Angeles, V., Eisenstein, R., & Seale, J.P. ( 2006). Neuroleptic malignant syndrome with delayed onset of fever following risperidone administration. Annals of Pharmacotherapy , 40, 2260-2264.
50.
Nothen, M.M., Rietschel, M., Erdmann, J., Oberlander, H., Moller, H.J., Nober, D., et al. (1995). Genetic variation of the 5-HT2A receptor and response to clozapine. Lancet, 346, 908-909.
51.
Ozen, M.E., Yumru, M., Savas, H.A., Cansel, N., & Herken, H. ( 2007). Neuroleptic malignant syndrome induced by ziprasidone on the second day of treatment. World Journal of Biological Psychiatry, 8, 42-44.
52.
Potkin, S.G., Saha, A.R., Kujawa, M.J., Carson, W.H., Ali, M., Stock, E., et al. (2003). Aripiprazole, an antipsychotic with a novel mechanism of action, and risperidone vs placebo in patients with schizophrenia and schizoaffective disorder. Archives of General Psychiatry , 60, 681-690.
53.
Riedel, M., Muller, N., Strassnig, M., Spellmann, I., Engel, R.R., Musil, R., et al. (2005). Quetiapine has equivalent efficacy and superior tolerability to risperidone in the treatment of schizophrenia with predominantly negative symptoms. European Archives of Psychiatry and Clinical Neuroscience255, 432-437.
54.
Rodriguez, O.P., & Dowell, M.S. ( 2006). A case report of neuroleptic malignant syndrome without fever in a patient given aripiprazole. Journal of the Oklahoma State Medical Association, 99, 435-438.
55.
Roth, B.L., Sheffler, D.J., & Kroeze, W.K. ( 2004). Magic shotguns versus magic bullets: Selectively non-selective drugs for mood disorders and schizophrenia. Nature Reviews Drug Discovery, 3, 353-359.
56.
Sacchetti, E., Panariello, A., Regini, C., & Valsecchi, P. ( 2004). Quetiapine in hospitalized patients with schizophrenia refractory to treatment with first-generation antipsychotics: A 4-week, flexible-dose, single-blind, exploratory, pilot trial. Schizophrenia Research , 69, 325-331.
57.
Scherk, H., Pajonk, F.G., & Leucht, S. ( 2007). Second-generation antipsychotic agents in the treatment of acute mania: A systematic review and meta-analysis of randomized controlled trials. Archives of General Psychiatry, 64, 442-455.
58.
Small, J.G., Kolar, M.C., & Kellams, J.J. ( 2004). Quetiapine in schizophrenia: Onset of action within the first week of treatment. Current Medical Research and Opinion , 20, 1017-1023.
59.
Srisurapanont, M., Maneeton, B., & Maneeton, N. ( 2004). Quetiapine for schizophrenia. Cochrane Database of Systematic Reviews, 2, CD000967.
60.
Srivastava, A., Borkar, H.A., & Chandak, S. ( 2009). Olanzapine-induced neuroleptic malignant syndrome in a patient with paranoid schizophrenia. Psychiatry and Clinical Neurosciences, 63, 119-121. Stimmel, G.L., Gutierrez, M.A., & Lee, V. ( 2002). Ziprasidone: An atypical antipsychotic drug for the treatment of schizophrenia. Clinical Therapeutics, 24, 21-37.
61.
Tamminga, C.A., & Kane, J.M. ( 1997). Olanzapine (Zyprexa): Characteristics of a new antipsychotic . Expert Opinion on Investigational Drugs, 6, 1743-1752.
62.
Tandon, R., & Fleischhacker, W.W. (2005). Comparative efficacy of antipsychotics in the treatment of schizophrenia: A critical assessment . Schizophrenia Research, 79, 145-155.
63.
Tohen, M., Chengappa, K.N., Suppes, T., Baker, R.W., Zarate, C.A., Bowden, C.L., et al. (2004). Relapse prevention in bipolar I disorder: 18-month comparison of olanzapine plus mood stabiliser v. mood stabiliser alone. British Journal of Psychiatry, 184, 337-345.
64.
Tohen, M., Chengappa, K.N., Suppes, T., Zarate, C.A. Jr., Calabrese, J.R., Bowden, C.L., et al. (2002). Efficacy of olanzapine in combination with valproate or lithium in the treatment of mania in patients partially nonresponsive to valproate or lithium monotherapy. Archives of General Psychiatry , 59, 62-69.
65.
Zhang, W., Ratain, M.J., & Dolan, M.E. ( 2008). The HapMap resource is providing new insights into ourselves and its application to pharmacogenomics. Bioinformatics and Biology Insights, 2, 15-23.
