Skip to main content
SpringerLink
Log in

Outcome definitions and clinical predictors influence pharmacogenetic associations between HTR3A gene polymorphisms and response to clozapine in patients with schizophrenia

Psychopharmacology Aims and scope Submit manuscript

Abstract

Rationale

Pharmacogenetics of schizophrenia has not yet delivered anticipated clinical dividends. Clinical heterogeneity of schizophrenia contributes to the poor replication of the findings of pharmacogenetic association studies. Functionally important HTR3A gene single-nucleotide polymorphisms (SNPs) were reported to be associated with response to clozapine.

Objective

The aim of this study was to investigate how the association between HTR3A gene SNP and response to clozapine is influenced by various clinical predictors and by differing outcome definitions in patients with treatment-resistant schizophrenia (TRS).

Methods

We recruited 101 consecutive patients with TRS, on stable doses of clozapine, and evaluated their HTR3A gene SNP (rs1062613 and rs2276302), psychopathology, and serum clozapine levels. We assessed their socio-demographic and clinical profiles, premorbid adjustment, traumatic events, cognition, and disability using standard assessment schedules. We evaluated their response to clozapine, by employing six differing outcome definitions. We employed appropriate multivariate statistics to calculate allelic and genotypic association, accounting for the effects of various clinical variables.

Results

T allele of rs1062613 and G allele of rs2276302 were significantly associated with good clinical response to clozapine (p = 0.02). However, varying outcome definitions make these associations inconsistent. rs1062613 and rs2276302 could explain only 13.8 % variability in the responses to clozapine, while combined clinical predictors and HTR3A pharmacogenetic association model could explain 38 % variability.

Conclusions

We demonstrated that the results of pharmacogenetic studies in schizophrenia depend heavily on their outcome definitions and that combined clinical and pharmacogenetic models have better predictive values. Future pharmacogenetic studies should employ multiple outcome definitions and should evaluate associated clinical variables.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price includes VAT (France)

Instant access to the full article PDF.

Institutional subscriptions

References

  • Andreasen NC, Carpenter WT Jr, Kane JM, Lasser RA, Marder SR, Weinberger DR (2005) Remission in schizophrenia: proposed criteria and rationale for consensus. Am J Psychiatry 162:441–449

    Article  PubMed  Google Scholar 

  • APA (2000) Diagnostic and statistical manual of mental disorders—fourth edition text revision (DSM-IV-TR). American Psychiatric Association, Washington, DC

  • Arranz MJ, Kapur S (2008) Pharmacogenetics in psychiatry: are we ready for widespread clinical use? Schizophr Bull 34:1130–1144

    Article  PubMed  Google Scholar 

  • Arranz MJ, Munro J, Birkett J, Bolonna A, Mancama D, Sodhi M, Lesch KP, Meyer JF, Sham P, Collier DA, Murray RM, Kerwin RW (2000) Pharmacogenetic prediction of clozapine response. Lancet 355:1615–1616

    Article  PubMed  CAS  Google Scholar 

  • Basile VS, Masellis M, Potkin SG, Kennedy JL (2002) Pharmacogenomics in schizophrenia: the quest for individualized therapy. Hum Mol Genet 11:2517–2530

    Article  PubMed  CAS  Google Scholar 

  • Briskin JK, Curtis JL (1997) Augmentation of clozapine therapy with ondansetron. Am J Psychiatry 154:1171

    PubMed  CAS  Google Scholar 

  • Buckley P, Miller A, Olsen J, Garver D, Miller DD, Csernansky J (2001) When symptoms persist: clozapine augmentation strategies. Schizophr Bull 27:615–628

    Article  PubMed  CAS  Google Scholar 

  • Burns T (2007) Evolution of outcome measures in schizophrenia. Br J Psychiatry Suppl 50:s1–s6

    Google Scholar 

  • Conley RR, Carpenter WT Jr, Tamminga CA (1997) Time to clozapine response in a standardized trial. Am J Psychiatry 154:1243–1247

    PubMed  CAS  Google Scholar 

  • Davies PA, Pistis M, Hanna MC, Peters JA, Lambert JJ, Hales TG, Kirkness EF (1999) The 5-HT3B subunit is a major determinant of serotonin-receptor function. Nature 397:359–363

    Article  PubMed  CAS  Google Scholar 

  • de Leon J, Arranz MJ, Ruano G (2008) Pharmacogenetic testing in psychiatry: a review of features and clinical realities. Clin Lab Med 28:599–617

    Article  PubMed  Google Scholar 

  • Dratcu L, Grandison A, McKay G, Bamidele A, Vasudevan V (2007) Clozapine-resistant psychosis, smoking, and caffeine: managing the neglected effects of substances that our patients consume every day. Am J Ther 14:314–318

    Article  PubMed  Google Scholar 

  • Endicott J, Spitzer RL, Fleiss JL, Cohen J (1976) The global assessment scale. A procedure for measuring overall severity of psychiatric disturbance. Arch Gen Psychiatry 33:766–771

    Article  PubMed  CAS  Google Scholar 

  • Estellat C, Torgerson DJ, Ravaud P (2009) How to perform a critical analysis of a randomised controlled trial. Best Pract Res Clin Rheumatol 23:291–303

    Article  PubMed  Google Scholar 

  • Feise RJ (2002) Do multiple outcome measures require p-value adjustment? BMC Med Res Methodol 2:8

    Article  PubMed  Google Scholar 

  • Foster A, Miller DD, Buckley PF (2007) Pharmacogenetics and schizophrenia. Psychiatr Clin North Am 30:417–435

    Article  PubMed  Google Scholar 

  • Gauderman WJ (2002) Sample size requirements for association studies of gene-gene interaction. Am J Epidemiol 155:478–484

    Article  PubMed  Google Scholar 

  • Gutierrez B, Arranz MJ, Huezo-Diaz P, Dempster D, Matthiasson P, Travis M, Munro J, Osborne S, Kerwin RW (2002) Novel mutations in 5-HT3A and 5-HT3B receptor genes not associated with clozapine response. Schizophr Res 58:93–97

    Article  PubMed  Google Scholar 

  • Henderson DC, Cagliero E, Gray C, Nasrallah RA, Hayden DL, Schoenfeld DA, Goff DC (2000) Clozapine, diabetes mellitus, weight gain, and lipid abnormalities: A five-year naturalistic study. Am J Psychiatry 157:975–981

    Article  PubMed  CAS  Google Scholar 

  • Horacek J, Bubenikova-Valesova V, Kopecek M, Palenicek T, Dockery C, Mohr P, Hoschl C (2006) Mechanism of action of atypical antipsychotic drugs and the neurobiology of schizophrenia. CNS Drugs 20:389–409

    Article  PubMed  CAS  Google Scholar 

  • Hwang R, Shinkai T, De Luca V, Muller DJ, Ni X, Macciardi F, Potkin S, Lieberman JA, Meltzer HY, Kennedy JL (2005) Association study of 12 polymorphisms spanning the dopamine D(2) receptor gene and clozapine treatment response in two treatment refractory/intolerant populations. Psychopharmacology (Berl) 181:179–187

    Article  CAS  Google Scholar 

  • Iidaka T, Ozaki N, Matsumoto A, Nogawa J, Kinoshita Y, Suzuki T, Iwata N, Yamamoto Y, Okada T, Sadato N (2005) A variant C178T in the regulatory region of the serotonin receptor gene HTR3A modulates neural activation in the human amygdala. J Neurosci 25:6460–6466

    Article  PubMed  CAS  Google Scholar 

  • Ioannidis JP, Trikalinos TA, Khoury MJ (2006) Implications of small effect sizes of individual genetic variants on the design and interpretation of genetic association studies of complex diseases. Am J Epidemiol 164:609–614

    Article  PubMed  Google Scholar 

  • Jacob KS (1994) The quest for the etiology of mental disorders. J Clin Epidemiol 47:97–99

    Article  PubMed  CAS  Google Scholar 

  • Ji X, Takahashi N, Saito S, Ishihara R, Maeno N, Inada T, Ozaki N (2008) Relationship between three serotonin receptor subtypes (HTR3A, HTR2A and HTR4) and treatment-resistant schizophrenia in the Japanese population. Neurosci Lett 435:95–98

    Article  PubMed  CAS  Google Scholar 

  • Kane J, Honigfeld G, Singer J, Meltzer H (1988) Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine. Arch Gen Psychiatry 45:789–796

    Article  PubMed  CAS  Google Scholar 

  • Kendler KS (2005) Toward a philosophical structure for psychiatry. Am J Psychiatry 162:433–440

    Article  PubMed  Google Scholar 

  • Kilpatrick LA, Labus JS, Coveleskie K, Hammer C, Rappold G, Tillisch K, Bueller JA, Suyenobu B, Jarcho JM, McRoberts JA, Niesler B, Mayer EA (2011) The HTR3A polymorphism c. -42C>T is associated with amygdala responsiveness in patients with irritable bowel syndrome. Gastroenterology 140:1943–1951

    Article  PubMed  CAS  Google Scholar 

  • Leucht S, Davis JM, Engel RR, Kane JM, Wagenpfeil S (2007) Defining ‘response’ in antipsychotic drug trials: recommendations for the use of scale-derived cutoffs. Neuropsychopharmacology 32:1903–1910

    Article  PubMed  CAS  Google Scholar 

  • Lieberman JA, Safferman AZ, Pollack S, Szymanski S, Johns C, Howard A, Kronig M, Bookstein P, Kane JM (1994) Clinical effects of clozapine in chronic schizophrenia: response to treatment and predictors of outcome. Am J Psychiatry 151:1744–1752

    PubMed  CAS  Google Scholar 

  • Mancama D, Arranz MJ, Kerwin RW (2002) Genetic predictors of therapeutic response to clozapine: current status of research. CNS Drugs 16:317–324

    Article  PubMed  CAS  Google Scholar 

  • Melke J, Westberg L, Nilsson S, Landen M, Soderstrom H, Baghaei F, Rosmond R, Holm G, Bjorntorp P, Nilsson LG, Adolfsson R, Eriksson E (2003) A polymorphism in the serotonin receptor 3A (HTR3A) gene and its association with harm avoidance in women. Arch Gen Psychiatry 60:1017–1023

    Article  PubMed  CAS  Google Scholar 

  • Meltzer HY, Alphs L, Green AI, Altamura AC, Anand R, Bertoldi A, Bourgeois M, Chouinard G, Islam MZ, Kane J, Krishnan R, Lindenmayer JP, Potkin S (2003) Clozapine treatment for suicidality in schizophrenia: International Suicide Prevention Trial (InterSePT). Arch Gen Psychiatry 60:82–91

    Article  PubMed  CAS  Google Scholar 

  • Mioshi E, Dawson K, Mitchell J, Arnold R, Hodges JR (2006) The Addenbrooke’s Cognitive Examination Revised (ACE-R): a brief cognitive test battery for dementia screening. Int J Geriatr Psychiatry 21:1078–1085

    Article  PubMed  Google Scholar 

  • NCBI-SNP (2011) Reference SNP cluster report: rs1062613 [Online]. National Library of Medicine (US). Available: http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=1062613. Accessed 28 Nov 2011

  • Niesler B, Flohr T, Nothen MM, Fischer C, Rietschel M, Franzek E, Albus M, Propping P, Rappold GA (2001) Association between the 5′ UTR variant C178T of the serotonin receptor gene HTR3A and bipolar affective disorder. Pharmacogenetics 11:471–475

    Article  PubMed  CAS  Google Scholar 

  • Overall JE, Gorham DR (1962) The brief psychiatric rating scale. Psychol Rep 10:799–812

    Article  Google Scholar 

  • Pennebaker JW, Susman JR (1988) Disclosure of traumas and psychosomatic processes. Soc Sci Med 26:327–332

    Article  PubMed  CAS  Google Scholar 

  • Prasad S, Semwal P, Deshpande S, Bhatia T, Nimgaonkar VL, Thelma BK (2002) Molecular genetics of schizophrenia: past, present and future. J Biosci 27:35–52

    Article  PubMed  CAS  Google Scholar 

  • Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, Maller J, Sklar P, de Bakker PI, Daly MJ, Sham PC (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81:559–575

    Article  PubMed  CAS  Google Scholar 

  • Rabinowitz J, Levine SZ, Brill N, Bromet EJ (2007) The premorbid adjustment scale structured interview (PAS-SI): preliminary findings. Schizophr Res 90:255–257

    Article  PubMed  Google Scholar 

  • Rajkumar AP, Chitra C, Bhuvaneshwari S, Poonkuzhali B, Kuruvilla A, Jacob KS (2012) Clinical predictors of response to clozapine in patients with Treatment Resistant Schizophrenia. Psychopharmacol Bull 44 (in press)

  • Rammes G, Hosp C, Eisensamer B, Tanasic S, Nothdurfter C, Zieglgansberger W, Rupprecht R (2009) Identification of a domain which affects kinetics and antagonistic potency of clozapine at 5-HT3 receptors. PLoS One 4:e6715

    Article  PubMed  Google Scholar 

  • Remington G, Saha A, Chong SA, Shammi C (2005) Augmentation strategies in clozapine-resistant schizophrenia. CNS Drugs 19:843–872

    Article  PubMed  CAS  Google Scholar 

  • Schuhmacher A, Mossner R, Quednow BB, Kuhn KU, Wagner M, Cvetanovska G, Rujescu D, Zill P, Moller HJ, Rietschel M, Franke P, Wolwer W, Gaebel W, Maier W (2009) Influence of 5-HT3 receptor subunit genes HTR3A, HTR3B, HTR3C, HTR3D and HTR3E on treatment response to antipsychotics in schizophrenia. Pharmacogenet Genomics 19:843–851

    Article  PubMed  CAS  Google Scholar 

  • Schulte PF (2006) Risk of clozapine-associated agranulocytosis and mandatory white blood cell monitoring. Ann Pharmacother 40:683–688

    Article  PubMed  CAS  Google Scholar 

  • Solanki RK, Singh P, Munshi D (2009) Current perspectives in the treatment of resistant schizophrenia. Indian J Psychiatry 51:254–260

    Article  PubMed  CAS  Google Scholar 

  • Souza RP, de Luca V, Meltzer HY, Lieberman JA, Kennedy JL (2010) Influence of serotonin 3A and 3B receptor genes on clozapine treatment response in schizophrenia. Pharmacogenet Genomics 20:274–276

    PubMed  CAS  Google Scholar 

  • Stefansson H, Ophoff RA, Steinberg S, Andreassen OA, Cichon S, Rujescu D, Werge T, Pietilainen OP, Mors O, Mortensen PB, Sigurdsson E, Gustafsson O, Nyegaard M, Tuulio-Henriksson A, Ingason A, Hansen T, Suvisaari J, Lonnqvist J, Paunio T, Borglum AD, Hartmann A, Fink-Jensen A, Nordentoft M, Hougaard D, Norgaard-Pedersen B, Bottcher Y, Olesen J, Breuer R, Moller HJ, Giegling I, Rasmussen HB, Timm S, Mattheisen M, Bitter I, Rethelyi JM, Magnusdottir BB, Sigmundsson T, Olason P, Masson G, Gulcher JR, Haraldsson M, Fossdal R, Thorgeirsson TE, Thorsteinsdottir U, Ruggeri M, Tosato S, Franke B, Strengman E, Kiemeney LA, Melle I, Djurovic S, Abramova L, Kaleda V, Sanjuan J, de Frutos R, Bramon E, Vassos E, Fraser G, Ettinger U, Picchioni M, Walker N, Toulopoulou T, Need AC, Ge D, Yoon JL, Shianna KV, Freimer NB, Cantor RM, Murray R, Kong A, Golimbet V, Carracedo A, Arango C, Costas J, Jonsson EG, Terenius L, Agartz I, Petursson H, Nothen MM, Rietschel M, Matthews PM, Muglia P, Peltonen L, St Clair D, Goldstein DB, Stefansson K, Collier DA (2009) Common variants conferring risk of schizophrenia. Nature 460:744–747

    PubMed  CAS  Google Scholar 

  • Tandon R, Fleischhacker WW (2005) Comparative efficacy of antipsychotics in the treatment of schizophrenia: a critical assessment. Schizophr Res 79:145–155

    Article  PubMed  Google Scholar 

  • WHO (2001) WHODAS II Disability Assessment Schedule: 12-item interviewer administered version. World Health Organization, Geneva

    Google Scholar 

  • Wongsinsup C, Taesotikul W, Kaewvichit S, Sangsrijan S, Sangsrija S (2010) Determination of clozapine in human plasma by high-performance liquid chromatography with UV-Vis detector. CMU J Nat Sci 9:29–37

    Google Scholar 

  • Zhao AL, Zhao JP, Zhang YH, Xue ZM, Chen JD, Chen XG (2005) Dopamine D4 receptor gene exon III polymorphism and interindividual variation in response to clozapine. Int J Neurosci 115:1539–1547

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This study was funded by a fluid research grant (22 X 356) by the Christian Medical College, Vellore, India. The funding source had no further role in study design in the collection, analysis and interpretation of data, in the writing of the report, and in the decision to submit the paper for publication. We are grateful to Dr. S. Bhuvaneshwari, Ms. C. Chitra, Dr. P. Thangadurai, Ms. Vaidegi, Ms. Senthamizh selvi, Dr. S.D. Manoranjitham, Dr. Binu Susan Mathew, Mr. K. Saravanakumar, and Mrs. S. Velvizhi, Christian Medical College, Vellore, for their help and support. We thank all participants and their families.

Conflict of interests

This study was funded by a fluid research grant (22 X 356) by the Christian Medical College, Vellore, India. None of the authors have any competing interests to declare.

Author information

Authors and Affiliations

  1. Department of Psychiatry, Christian Medical College, Vellore, 632002, India

    A. P. Rajkumar, A. Kuruvilla & K. S. Jacob

  2. Center for Psychiatric Research, Aarhus University Hospital, Risskov, 8240, Denmark

    A. P. Rajkumar

  3. Department of Biomedicine, Aarhus University, Aarhus, 8000, Denmark

    A. P. Rajkumar

  4. Department of Haematology, Christian Medical College, Vellore, 632002, India

    B. Poonkuzhali & A. Srivastava

  5. Department of Biochemistry, Christian Medical College, Vellore, 632002, India

    M. Jacob

Authors
  1. A. P. Rajkumar
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. B. Poonkuzhali
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A. Kuruvilla
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A. Srivastava
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M. Jacob
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. K. S. Jacob
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to K. S. Jacob.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rajkumar, A.P., Poonkuzhali, B., Kuruvilla, A. et al. Outcome definitions and clinical predictors influence pharmacogenetic associations between HTR3A gene polymorphisms and response to clozapine in patients with schizophrenia. Psychopharmacology 224, 441–449 (2012). https://doi.org/10.1007/s00213-012-2773-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-012-2773-2

Keywords

Search

Navigation