Abstract
Clozapine is the gold standard medication for treatment refractory schizophrenia, but unfortunately, its use is also associated with many adverse metabolic side effects. There may be a strong genetic component to the development of these adverse effects. We undertook a systematic review to examine the evidence for genetic variation being associated with secondary metabolic outcomes in patients with schizophrenia on clozapine, under both longitudinal and cross-sectional study designs. We limited studies to those examining patients definitely taking clozapine, unlike prior reviews that have examined metabolic effects of patients taking a range of antipsychotic medications. We found associations with outcomes such as increases in BMI and metabolic syndrome for variants in genes such as LEP and HTR2C. Meta-analysis of rs381328 in HTR2C revealed that the presence of the T allele led to a 0.63 kg/m2 (95% CI − 1.06 to − 0.19; p = 0.005) decrease in BMI compared to the C allele. Study and population heterogeneity and lack of statistical power among reviewed articles mean that evidence is lacking to warrant prophylactic genotyping of patients commencing clozapine to predict those at increased risk of developing adverse metabolic effects. Further efforts to establish collaborative consortia, consensus around study design and replication studies in independent populations should be encouraged.
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References
Agid O, Arenovich T, Sajeev G, Zipursky RB, Kapur S, Foussias G, Remington G (2011) An algorithm-based approach to first-episode schizophrenia: response rates over 3 prospective antipsychotic trials with a retrospective data analysis. J Clin Psychiatry 72:1439–1444. https://doi.org/10.4088/JCP.09m05785yel
Brandl EJ et al (2012) Association study of polymorphisms in leptin and leptin receptor genes with antipsychotic-induced body weight gain. Prog Neuropsychopharmacol Biol Psychiatry 38:134–141. https://doi.org/10.1016/j.pnpbp.2012.03.001
Chen PY et al (2015) The relationships of obesity-related genetic variants with metabolic profiles and response to metformin in clozapine-treated patients with schizophrenia. J Clin Psychopharmacol 35:574–578. https://doi.org/10.1097/jcp.0000000000000386
Chowdhury NI et al (2013) Genetic association study between antipsychotic-induced weight gain and the melanocortin-4 receptor gene. Pharmacogenomics J 13:272–279. https://doi.org/10.1038/tpj.2011.66
Dong E, Tueting P, Matrisciano F, Grayson DR, Guidotti A (2016) Behavioral and molecular neuroepigenetic alterations in prenatally stressed mice: relevance for the study of chromatin remodeling properties of antipsychotic drugs. Transl Psychiatry 6:e711. https://doi.org/10.1038/tp.2015.191
Donovan MH, Tecott LH (2013) Serotonin and the regulation of mammalian energy balance. Front Neurosci 7:36. https://doi.org/10.3389/fnins.2013.00036
Ellingrod VL, Grove TB, Burghardt KJ, Taylor SF, Dalack G (2015) The effect of folate supplementation and genotype on cardiovascular and epigenetic measures in schizophrenia subjects. NPJ Schizophr 1:15046. https://doi.org/10.1038/npjschz.2015.46
Fall T, Ingelsson E (2014) Genome-wide association studies of obesity and metabolic syndrome. Mol Cell Endocrinol 382:740–757. https://doi.org/10.1016/j.mce.2012.08.018
Fernandez E et al (2010) Polymorphisms of the LEP- and LEPR genes, metabolic profile after prolonged clozapine administration and response to the antidiabetic metformin. Schizophr Res 121:213–217. https://doi.org/10.1016/j.schres.2010.06.001
Fernandez E, Carrizo E, Connell L, Baptista T (2012) Pro12Ala polymorphism of the PPAR-gamma2 gene, metabolic syndrome and response to metformin in clozapine-treated patients. Schizophr Res 137:262–263. https://doi.org/10.1016/j.schres.2012.02.005
Gregoor JG, van der Weide J, Mulder H, Cohen D, van Megen HJ, Egberts AC, Heerdink ER (2009) Polymorphisms of the LEP- and LEPR gene and obesity in patients using antipsychotic medication. J Clin Psychopharmacol 29:21–25. https://doi.org/10.1097/JCP.0b013e31819359be
Gregoor JG, van der Weide J, Loovers HM, van Megen HJ, Egberts TC, Heerdink ER (2011) Polymorphisms of the LEP, LEPR and HTR2C gene: obesity and BMI change in patients using antipsychotic medication in a naturalistic setting. Pharmacogenomics 12:919–923. https://doi.org/10.2217/pgs.11.40
Hong CJ, Lin CH, Yu YW, Yang KH, Tsai SJ (2001) Genetic variants of the serotonin system and weight change during clozapine treatment. Pharmacogenetics 11:265–268 https://www.ncbi.nlm.nih.gov/pubmed/11337942
Hong CJ, Lin CH, Yu YW, Chang SC, Wang SY, Tsai SJ (2002) Genetic variant of the histamine-1 receptor (glu349asp) and body weight change during clozapine treatment. Psychiatr Genet 12:169–171
Janssens AC, Ioannidis JP, van Duijn CM, Little J, Khoury MJ, Group G (2011) Strengthening the reporting of genetic risk prediction studies: the GRIPS statement. BMJ 342:d631. https://doi.org/10.1136/bmj.d631
Jassim G et al (2011) Association study of energy homeostasis genes and antipsychotic-induced weight gain in patients with schizophrenia. Pharmacopsychiatry 44:15–20. https://doi.org/10.1055/s-0030-1263174
Jorde LB, Wooding SP (2004) Genetic variation, classification and ‘race’. Nat Genet 36:S28–S33. https://doi.org/10.1038/ng1435
Kang SH, Lee JI, Chang AK, Joo YH, Kim CY, Kim SY (2011) Genetic polymorphisms in the HTR2C and peroxisome proliferator-activated receptors are not associated with metabolic syndrome in patients with schizophrenia taking clozapine. Psychiatry Invest 8:262–268. https://doi.org/10.4306/pi.2011.8.3.262
Kang SH, Lee JI, Han HR, Soh M, Hong JP (2014) Polymorphisms of the leptin and HTR2C genes and clozapine-induced weight change and baseline BMI in patients with chronic schizophrenia. Psychiatr Genet 24:249–256. https://doi.org/10.1097/ypg.0000000000000053
Kao AC, Muller DJ (2013) Genetics of antipsychotic-induced weight gain: update and current perspectives. Pharmacogenomics 14:2067–2083. https://doi.org/10.2217/pgs.13.207
Klemettila JP et al (2015) Association study of the HTR2C, leptin and adiponectin genes and serum marker analyses in clozapine treated long-term patients with schizophrenia. Eur Psychiatry 30:296–302. https://doi.org/10.1016/j.eurpsy.2014.08.006
Klemettila JP et al (2016) Association study of arcuate nucleus neuropeptide Y neuron receptor gene variation and serum NPY levels in clozapine treated patients with schizophrenia. Eur Psychiatry 40:13–19. https://doi.org/10.1016/j.eurpsy.2016.07.004
Kohen D (2004) Diabetes mellitus and schizophrenia: historical perspective. Br J Psychiatry Suppl 47:S64–S66 https://www.ncbi.nlm.nih.gov/pubmed/15056595
Komossa K et al (2010) Olanzapine versus other atypical antipsychotics for schizophrenia. Cochrane Database Syst Rev. https://doi.org/10.1002/14651858.CD006654.pub2:CD006654
Koskinen S et al (2016) INSIG2 polymorphism and weight gain, dyslipidemia and serum adiponectin in Finnish patients with schizophrenia treated with clozapine. Pharmacogenomics 17:1987–1997. https://doi.org/10.2217/pgs-2016-0117
Krashes MJ, Lowell BB, Garfield AS (2016) Melanocortin-4 receptor-regulated energy homeostasis. Nat Neurosci 19:206–219. https://doi.org/10.1038/nn.4202
Kuo PH, Kao CF, Chen PY, Chen CH, Tsai YS, Lu ML, Huang MC (2011) Polymorphisms of INSIG2, MC4R, and LEP are associated with obesity- and metabolic-related traits in schizophrenic patients. J Clin Psychopharmacol 31:705–711. https://doi.org/10.1097/JCP.0b013e318234ee84
Lawrence D, Hancock KJ, Kisely S (2013) The gap in life expectancy from preventable physical illness in psychiatric patients in Western Australia: retrospective analysis of population based registers. BMJ 346:f2539. https://doi.org/10.1136/bmj.f2539
Le Hellard S et al (2009) 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 Psychiatr 14:308–317. https://doi.org/10.1038/sj.mp.4002133
Lett TA, Wallace TJ, Chowdhury NI, Tiwari AK, Kennedy JL, Muller DJ (2012) Pharmacogenetics of antipsychotic-induced weight gain: review and clinical implications. Mol Psychiatry 17:242–266. https://doi.org/10.1038/mp.2011.109
Locke AE et al (2015) Genetic studies of body mass index yield new insights for obesity biology. Nature 518:197–206. https://doi.org/10.1038/nature14177
Malhotra AK et al (2012) Association between common variants near the melanocortin 4 receptor gene and severe antipsychotic drug-induced weight gain. Arch Gen Psychiatry 69:904–912. https://doi.org/10.1001/archgenpsychiatry.2012.191
Mayfield K, Siskind D, Winckel K, Russell AW, Kisely S, Smith G, Hollingworth S (2016) Glucagon-like peptide-1 agonists combating clozapine-associated obesity and diabetes. J Psychopharmacol 30:227–236. https://doi.org/10.1177/0269881115625496
Melkersson KI, Scordo MG, Gunes A, Dahl ML (2007) Impact of CYP1A2 and CYO2D6 polymorphisms on drug metabolism and on insulin and lipid elevations and insulin resistance in clozapine-treated patients. J Clin Psychiatry 68:697–704
Miller DD, Ellingrod VL, Holman TL, Buckley PF, Arndt S (2005) Clozapine-induced weight gain associated with the 5HT2C receptor -759C/T polymorphism. Am J Med GenetB Neuropsychiatr Genet 133:97–100. https://doi.org/10.1002/ajmg.b.30115
Mitchell AJ, Vancampfort D, Sweers K, van Winkel R, Yu W, De Hert M (2013) Prevalence of metabolic syndrome and metabolic abnormalities in schizophrenia and related disorders—a systematic review and meta-analysis. Schizophr Bull 39:306–318. https://doi.org/10.1093/schbul/sbr148
Moher D, Liberati A, Tetzlaff J, Altman DG, Group P (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 6:e1000097. https://doi.org/10.1371/journal.pmed.1000097
Olsson E, Edman G, Bertilsson L, Hukic DS, Lavebratt C, Eriksson SV, Osby U (2015) Genetic and clinical factors affecting plasma clozapine concentration. Prim Care Companion CNS Disord 17 doi:https://doi.org/10.4088/PCC.14m01704
Opgen-Rhein C, Brandl EJ, Muller DJ, Neuhaus AH, Tiwari AK, Sander T, Dettling M (2010) Association of HTR2C, but not LEP or INSIG2, genes with antipsychotic-induced weight gain in a German sample. Pharmacogenomics 11:773–780. https://doi.org/10.2217/pgs.10.50
Ozdemir V et al (2001) CYP1A2 activity as measured by a caffeine test predicts clozapine and active metabolite steady-state concentrationin patients with schizophrenia. J Clin Psychopharmacol 21:398–407. https://www.ncbi.nlm.nih.gov/pubmed/11476124
Pillinger T, Beck K, Gobjila C, Donocik JG, Jauhar S, Howes OD (2017) Impaired glucose homeostasis in first-episode schizophrenia: a systematic review and meta-analysis. JAMA Psychiatry 74:261–269. https://doi.org/10.1001/jamapsychiatry.2016.3803
Reynolds GP, Zhang ZJ, Zhang XB (2003) Polymorphism of the promoter region of the serotonin 5-HT2C receptor gene and clozapine-induced weight gain. Am J Psychiat 160:677–679. https://doi.org/10.1176/appi.ajp.160.4.677
Reynolds GP, Hill MJ, Kirk SL (2006) The 5-HT2C receptor and antipsychoticinduced weight gain—mechanisms and genetics. J Psychopharmacol 20:15–18. https://doi.org/10.1177/1359786806066040
Rietschel M, Naber D, Fimmers R, Moller HJ, Propping P, Nothen MM (1997) Efficacy and side-effects of clozapine not associated with variation in the 5-HT2C receptor. Neuroreport 8:1999–2003
Rosenberg NA, Huang L, Jewett EM, Szpiech ZA, Jankovic I, Boehnke M (2010) Genome-wide association studies in diverse populations. Nat Rev Genet 11:356–366. https://doi.org/10.1038/nrg2760
Rouillon F, Sorbara F (2005) Schizophrenia and diabetes: epidemiological data. Eur Psychiatry 20(Suppl 4):S345–S348 https://www.ncbi.nlm.nih.gov/pubmed/16459249
Ryan MC, Collins P, Thakore JH (2003) Impaired fasting glucose tolerance in first-episode, drug-naive patients with schizophrenia. Am J Psychiatry 160:284–289. https://doi.org/10.1176/appi.ajp.160.2.284
Saha S, Chant D, McGrath J (2007) A systematic review of mortality in schizophrenia: is the differential mortality gap worsening over time? Arch Gen Psychiatry 64:1123-1131. https://doi.org/10.1001/archpsyc.64.10.1123
Saha S, Chant D, Welham J, McGrath J (2005) A systematic review of the prevalence of schizophrenia. PLoS Med 2:e141. https://doi.org/10.1371/journal.pmed.0020141
Schizophrenia Working Group of the Psychiatric Genomics C (2014) Biological insights from 108 schizophrenia-associated genetic loci. Nature 511:421–427. https://doi.org/10.1038/nature13595
Siskind DJ, Leung J, Russell AW, Wysoczanski D, Kisely S (2016a) Metformin for clozapine associated obesity: a systematic Review and meta-analysis. PloS one 11:e0156208. https://doi.org/10.1371/journal.pone.0156208
Siskind D, McCartney L, Goldschlager R, Kisely S (2016b) Clozapine v. first- and second-generation antipsychotics in treatment-refractory schizophrenia: systematic review and meta-analysis. Br J Psychiatry 209:385–392. https://doi.org/10.1192/bjp.bp.115.177261
Spelman LM, Walsh PI, Sharifi N, Collins P, Thakore JH (2007) Impaired glucose tolerance in first-episode drug-naive patients with schizophrenia. Diabet Med 24:481–485. https://doi.org/10.1111/j.1464-5491.2007.02092.x
Staeker J, Leucht S, Steimer W (2012) Peroxisome proliferator-activated receptor gamma (PPARG) Pro12Ala: lack of association with weight gain in psychiatric inpatients treated with olanzapine or clozapine. Mol Diagn Ther 16:93–98. https://www.ncbi.nlm.nih.gov/pubmed/22413765
Swathy B, Saradalekshmi KR, Nair IV, Nair C, Banerjee M (2017) Pharmacoepigenomic responses of antipsychotic drugs on pharmacogenes are likely to be modulated by miRNAs. Epigenomics. https://doi.org/10.2217/epi-2016-0181
Theisen FM et al (2004) Lack of association between the -759C/T polymorphism of the 5-HT 2C receptor gene and clozapine-induced weight gain among German schizophrenic individuals. Psychiatr Genet 14:139–142. https://doi.org/10.1097/00041444–200409000-00003
Tsai SJ, Hong CJ, Yu YW, Lin CH, Liu LL (2003) No association of tumor necrosis factor alpha gene polymorphisms with schizophrenia or response to clozapine. Schizophr Res 65:27–32
Tsai SJ, Yu YW, Lin CH, Wang YC, Chen JY, Hong CJ (2004) Association study of adrenergic beta3 receptor (Trp64Arg) and G-protein beta3 subunit gene (C825T) polymorphisms and weight change during clozapine treatment. Neuropsychobiology 50:37–40. https://doi.org/10.1159/000077939
Vancampfort D, Wampers M, Mitchell AJ, Correll CU, De Herdt A, Probst M, De Hert M (2013) A meta-analysis of cardio-metabolic abnormalities in drug naïve, first-episode and multi-episode patients with schizophrenia versus general population controls. World Psychiatry 12:240–250. https://doi.org/10.1002/wps.20069
Vancampfort D, Stubbs B, Mitchell AJ, De Hert M, Wampers M, Ward PB, Rosenbaum S, Correll CU (2015) Risk of metabolic syndrome and its components in people with schizophrenia and related psychotic disorders, bipolar disorder and major depressive disorder: a systematic review and meta-analysis. World Psychiatry 14:339–347. https://doi.org/10.1002/wps.20252
Vasudev K, Choi YH, Norman R, Kim RB, Schwarz UI (2017) Genetic determinants of clozapine-induced metabolic side effects. Can J Psychiatry Rev Can Psychiatr 62:138–149. https://doi.org/10.1177/0706743716670128
Wang YC, Bai YM, Chen JY, Lin CC, Lai IC, Liou YJ (2005a) 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. Pharmacogenet Genomics 15:743–748 https://www.scopus.com/inward/record.uri?eid=2-s2.0-25144497419&partnerID=40&md5=1b7fdb7d072642a1bac443d505496676
Wang YC, Bai YM, Chen JY, Lin CC, Lai IC, Liou YJ (2005b) Polymorphism of the adrenergic receptor alpha 2a -1291C>G genetic variation and clozapine-induced weight gain. J Neural Transm (Vienna, Austria : 1996) 112:1463–1468. https://doi.org/10.1007/s00702-005-0291-7
Wang YC, Bai YM, Chen JY, Lin CC, Lai IC, Liou YJ (2010) Genetic association between TNF-alpha-308 G>A polymorphism and longitudinal weight change during clozapine treatment. Hum Psychopharmacol-Clin Exp 25:303–309. https://doi.org/10.1002/hup.1122
Yang L et al (2014) Association between SREBF2 gene polymorphisms and metabolic syndrome in clozapine-treated patients with schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 56:136–141. https://doi.org/10.1016/j.pnpbp.2014.08.015
Yevtushenko OO, Cooper SJ, O'Neill R, Doherty JK, Woodside JV, Reynolds GP (2008) Influence of 5-HT2C receptor and leptin gene polymorphisms, smoking and drug treatment on metabolic disturbances in patients with schizophrenia. Br J Psychiatry 192:424–428. https://doi.org/10.1192/bjp.bp.107.041723
Zhang XY et al (2007) 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 27:246–251. https://doi.org/10.1097/jcp.0b013e3180582412
Zhang Y, Chen M, Wu Z, Chen J, Yu S, Fang Y, Zhang C (2013) Association study of Val66Met polymorphism in brain-derived neurotrophic factor gene with clozapine-induced metabolic syndrome: preliminary results. PloS one 8:e72652. https://doi.org/10.1371/journal.pone.0072652
Zhang Y, Chen M, Chen J, Wu Z, Yu S, Fang Y, Zhang C (2014) Metabolic syndrome in patients taking clozapine: prevalence and influence of catechol-O-methyltransferase genotype. Psychopharmacology 231:2211–2218. https://doi.org/10.1007/s00213-013-3410-4
Zhang C, Zhang Y, Cai J, Chen M, Song L (2015) Complement 3 and metabolic syndrome induced by clozapine: a cross-sectional study and retrospective cohort analysis. Pharmacogenomics J. https://doi.org/10.1038/tpj.2015.68
Zhang JP et al (2016) Pharmacogenetic associations of antipsychotic drug-related weight gain: a systematic review and meta-analysis. Schizophr Bull 42:1418–1437. https://doi.org/10.1093/schbul/sbw058
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DS is partially supported by an NHMRC ECF APP1111136.
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Suetani, R.J., Siskind, D., Reichhold, H. et al. Genetic variants impacting metabolic outcomes among people on clozapine: a systematic review and meta-analysis. Psychopharmacology 234, 2989–3008 (2017). https://doi.org/10.1007/s00213-017-4728-0
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DOI: https://doi.org/10.1007/s00213-017-4728-0