Pharmacogenetics of leptin in antipsychotic-associated weight gain and obesity-related complications

Papers of special note have been highlighted as: ▪ of interest ▪▪ of considerable interest

Bibliography

• 1  Allison DB, Mentore JL, Heo M et al. Antipsychotic-induced weight gain: a comprehensive research synthesis. Am. J. Psychiatry156(11),1686–1696 (1999).
  Medline CASGoogle Scholar
• 2  American Diabetes Association, American Psychiatric Association, American Association of Clinical Endocrinologists, North American Association for the Study of Obesity. Consensus development conference on antipsychotic drugs and obesity and diabetes. Diabetes Care27(2),596–601 (2004).
  MedlineGoogle Scholar
• 3  Parsons B, Allison DB, Loebel A et al. Weight effects associated with antipsychotics: a comprehensive database analysis. Schizophr. Res.110(1–3),103–110 (2009).
  MedlineGoogle Scholar
• 4  Arranz MJ, De Leon J. Pharmacogenetics and pharmacogenomics of schizophrenia: a review of last decade of research. Mol. Psychiatry12(8),707–747 (2007).
  Medline CASGoogle Scholar
• 5  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.10(5),697–704 (2007).
  Medline CASGoogle Scholar
• 6  Sicard MN, Zai CC, Tiwari AK et al. Polymorphisms of the HTR2C gene and antipsychotic-induced weight gain: an update and meta-analysis. Pharmacogenomics11(11),1561–1571 (2010).
  CASGoogle Scholar
• 7  Flegal KM, Carroll MD, Ogden CL, Curtin LR. Prevalence and trends in obesity among US adults, 1999–2008. JAMA303(3),235–241 (2010).
  Medline CASGoogle Scholar
• 8  National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third report of the national cholesterol education program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel III) final report. Circulation106(25),3143–3421 (2002).
  MedlineGoogle Scholar
• 9  Mottillo S, Filion KB, Genest J et al. The metabolic syndrome and cardiovascular risk a systematic review and meta-analysis. J. Am. Coll. Cardiol.56(14),1113–1132 (2010).
  MedlineGoogle Scholar
• 10  Citrome L, Blonde L, Damatarca C. Metabolic issues in patients with severe mental illness. South Med. J.98(7),714–720 (2005).
  MedlineGoogle Scholar
• 11  Holt RI, Peveler RC. Obesity, serious mental illness and antipsychotic drugs. Diabetes. Obes. Metab.11(7),665–679 (2009).
  MedlineGoogle Scholar
• 12  Newcomer JW. Metabolic considerations in the use of antipsychotic medications: a review of recent evidence. J. Clin. Psychiatry68(Suppl. 1),20–27 (2007).
  Medline CASGoogle Scholar
• 13  Brown S, Birtwistle J, Roe L, Thompson C. The unhealthy lifestyle of people with schizophrenia. Psychol. Med.29(3),697–701 (1999).
  Medline CASGoogle Scholar
• 14  Jin H, Meyer JM, Mudaliar S, Jeste DV. Impact of atypical antipsychotic therapy on leptin, ghrelin, and adiponectin. Schizophr. Res.100(1–3),70–85 (2008).
  MedlineGoogle Scholar
• 15  Kinon BJ, Basson BR, Gilmore JA, Tollefson GD. Long-term olanzapine treatment: weight change and weight-related health factors in schizophrenia. J. Clin. Psychiatry62(2),92–100 (2001).
  Medline CASGoogle Scholar
• 16  Gentile S. Contributing factors to weight gain during long-term treatment with second-generation antipsychotics. A systematic appraisal and clinical implications. Obes. Rev.10(5),527–542 (2009).
  Medline CASGoogle Scholar
• 17  Leucht S, Corves C, Arbter D, Engel RR, Li C, Davis JM. Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis. Lancet373(9657),31–41 (2009).
  Medline CASGoogle Scholar
• 18  Leucht S, Komossa K, Rummel-Kluge C et al. A meta-analysis of head-to-head comparisons of second-generation antipsychotics in the treatment of schizophrenia. Am. J. Psychiatry166(2),152–163 (2009).
  MedlineGoogle Scholar
• 19  Lieberman JA, Stroup TS, Mcevoy JP et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N. Engl. J. Med.353(12),1209–1223 (2005).
  Medline CASGoogle Scholar
• 20  Gebhardt S, Haberhausen M, Heinzel-Gutenbrunner M et al. Antipsychotic-induced body weight gain: predictors and a systematic categorization of the long-term weight course. J. Psychiatr. Res.43(6),620–626 (2009).
  MedlineGoogle Scholar
• 21  Aichhorn W, Whitworth AB, Weiss EM, Marksteiner J. Second-generation antipsychotics: is there evidence for sex differences in pharmacokinetic and adverse effect profiles? Drug Saf.29(7),587–598 (2006).
  Medline CASGoogle Scholar
• 22  Basson BR, Kinon BJ, Taylor CC, Szymanski KA, Gilmore JA, Tollefson GD. Factors influencing acute weight change in patients with schizophrenia treated with olanzapine, haloperidol, or risperidone. J. Clin. Psychiatry62(4),231–238 (2001).
  Medline CASGoogle Scholar
• 23  Kinon BJ, Kaiser CJ, Ahmed S, Rotelli MD, Kollack-Walker S. Association between early and rapid weight gain and change in weight over one year of olanzapine therapy in patients with schizophrenia and related disorders. J. Clin. Psychopharmacol.25(3),255–258 (2005).
  Medline CASGoogle Scholar
• 24  Safer DJ. A comparison of risperidone-induced weight gain across the age span. J. Clin. Psychopharmacol.24(4),429–436 (2004).
  Medline CASGoogle Scholar
• 25  Strassnig M, Miewald J, Keshavan M, Ganguli R. Weight gain in newly diagnosed first-episode psychosis patients and healthy comparisons: one-year analysis. Schizophr. Res.93(1–3),90–98 (2007).
  MedlineGoogle Scholar
• 26  Saddichha S, Ameen S, Akhtar S. Predictors of antipsychotic-induced weight gain in first-episode psychosis: conclusions from a randomized, double-blind, controlled prospective study of olanzapine, risperidone, and haloperidol. J. Clin. Psychopharmacol.28(1),27–31 (2008).
  Medline CASGoogle Scholar
• 27  Ascher-Svanum H, Stensland MD, Kinon BJ, Tollefson GD. Weight gain as a prognostic indicator of therapeutic improvement during acute treatment of schizophrenia with placebo or active antipsychotic. J. Psychopharmacol.19(Suppl. 6),110–117 (2005).
  MedlineGoogle Scholar
• 28  Theisen FM, Gebhardt S, Haberhausen M et al. Clozapine-induced weight gain: a study in monozygotic twins and same-sex sib pairs. Psychiatr. Genet.15(4),285–289 (2005).
  MedlineGoogle Scholar
• 29  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 Res.133(2–3),273–276 (2005).
  Medline CASGoogle Scholar
• 30  Zhang XY, Zhou DF, Wu GY et al. BDNF levels and genotype are associated with antipsychotic-induced weight gain in patients with chronic schizophrenia. Neuropsychopharmacology33(9),2200–2205 (2008).
  Medline CASGoogle Scholar
• 31  Lane HY, Liu YC, Huang CL et al. Risperidone-related weight gain: genetic and nongenetic predictors. J. Clin. Psychopharmacol.26(2),128–134 (2006).
  Medline CASGoogle Scholar
• 32  Reynolds GP, Zhang ZJ, Zhang XB. Association of antipsychotic drug-induced weight gain with a 5-HT2C receptor gene polymorphism. Lancet359(9323),2086–2087 (2002).
  Medline CASGoogle Scholar
• 33  Lencz T, Robinson DG, Napolitano B et al.DRD2 promoter region variation predicts antipsychotic-induced weight gain in first episode schizophrenia. Pharmacogenet. Genomics20(9),569–572 (2010).
  Medline CASGoogle Scholar
• 34  Sickert L, Muller DJ, Tiwari AK et al. Association of the α 2A adrenergic receptor -1291C/G polymorphism and antipsychotic-induced weight gain in European–Americans. Pharmacogenomics10(7),1169–1176 (2009).
  CASGoogle Scholar
• 35  Wang YC, Bai YM, Chen JY, Lin CC, Lai IC, Liou YJ. Polymorphism of the adrenergic receptor α 2A -1291C>G genetic variation and clozapine-induced weight gain. J. Neural Transm.112(11),1463–1468 (2005).
  Medline CASGoogle Scholar
• 36  Kroeze WK, Hufeisen SJ, Popadak BA et al. H1-histamine receptor affinity predicts short-term weight gain for typical and atypical antipsychotic drugs. Neuropsychopharmacology28(3),519–526 (2003).
  Medline CASGoogle Scholar
• 37  Nasrallah HA. Atypical antipsychotic-induced metabolic side effects: insights from receptor-binding profiles. Mol. Psychiatry13(1),27–35 (2008).
  Medline CASGoogle Scholar
• 38  Nonogaki K, Strack AM, Dallman MF, Tecott LH. Leptin-independent hyperphagia and type 2 diabetes in mice with a mutated serotonin 5-HT2C receptor gene. Nat. Med.4(10),1152–1156 (1998).
  Medline CASGoogle Scholar
• 39  Tecott LH, Sun LM, Akana SF et al. Eating disorder and epilepsy in mice lacking 5-HT2C serotonin receptors. Nature374(6522),542–546 (1995).
  Medline CASGoogle Scholar
• 40  Meltzer HY, Matsubara S, Lee JC. Classification of typical and atypical antipsychotic drugs on the basis of dopamine D-1, D-2 and serotonin2 pKi values. J. Pharmacol. Exp. Ther.251(1),238–246 (1989).
  Medline CASGoogle Scholar
• 41  Roth BL, Sheffler DJ, Kroeze WK. Magic shotguns versus magic bullets: selectively non-selective drugs for mood disorders and schizophrenia. Nat. Rev. Drug Discov.3(4),353–359 (2004).
  Medline CASGoogle Scholar
• 42  Blum K, Braverman ER, Holder JM et al. Reward deficiency syndrome: a biogenetic model for the diagnosis and treatment of impulsive, addictive, and compulsive behaviors. J. Psychoactive Drugs32(Suppl. i–iv),1–112 (2000).
  Google Scholar
• 43  Wang GJ, Volkow ND, Logan J et al. Brain dopamine and obesity. Lancet357(9253),354–357 (2001).
  Medline CASGoogle Scholar
• 44  Elman I, Borsook D, Lukas SE. Food intake and reward mechanisms in patients with schizophrenia: implications for metabolic disturbances and treatment with second-generation antipsychotic agents. Neuropsychopharmacology31(10),2091–2120 (2006).
  Medline CASGoogle Scholar
• 45  Le Foll B, Gallo A, Le Strat Y, Lu L, Gorwood P. Genetics of dopamine receptors and drug addiction: a comprehensive review. Behav. Pharmacol.20(1),1–17 (2009).
  Medline CASGoogle Scholar
• 46  Jorgensen EA, Knigge U, Warberg J, Kjaer A. Histamine and the regulation of body weight. Neuroendocrinology86(3),210–214 (2007).
  Medline CASGoogle Scholar
• 47  Ookuma K, Sakata T, Fukagawa K et al. Neuronal histamine in the hypothalamus suppresses food intake in rats. Brain Res.628(1–2),235–242 (1993).
  Medline CASGoogle Scholar
• 48  Lecklin A, Tuomisto L. The blockade of H1 receptors attenuates the suppression of feeding and diuresis induced by inhibition of histamine catabolism. Pharmacol. Biochem. Behav.59(3),753–758 (1998).
  Medline CASGoogle Scholar
• 49  Han M, Deng C, Burne TH, Newell KA, Huang XF. Short- and long-term effects of antipsychotic drug treatment on weight gain and H1 receptor expression. Psychoneuroendocrinology33(5),569–580 (2008).
  Medline CASGoogle Scholar
• 50  Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature372(6505),425–432 (1994).
  Medline CASGoogle Scholar
• 51  Isse N, Ogawa Y, Tamura N et al. Structural organization and chromosomal assignment of the human obese gene. J. Biol. Chem.270(46),27728–27733 (1995).
  Medline CASGoogle Scholar
• 52  Sinha MK, Opentanova I, Ohannesian JP et al. Evidence of free and bound leptin in human circulation. Studies in lean and obese subjects and during short-term fasting. J. Clin. Invest.98(6),1277–1282 (1996).
  Medline CASGoogle Scholar
• 53  Licinio J, Mantzoros C, Negrao Ab et al. Human leptin levels are pulsatile and inversely related to pituitary-adrenal function. Nat. Med.3(5),575–579 (1997).
  Medline CASGoogle Scholar
• 54  Sinha MK, Ohannesian JP, Heiman ML et al. Nocturnal rise of leptin in lean, obese, and non-insulin-dependent diabetes mellitus subjects. J. Clin. Invest.97(5),1344–1347 (1996).
  Medline CASGoogle Scholar
• 55  Baumann H, Morella KK, White DW et al. The full-length leptin receptor has signaling capabilities of interleukin 6-type cytokine receptors. Proc. Natl Acad. Sci. USA93(16),8374–8378 (1996).
  Medline CASGoogle Scholar
• 56  Thompson DB, Ravussin E, Bennett PH, Bogardus C. Structure and sequence variation at the human leptin receptor gene in lean and obese Pima Indians. Hum. Mol. Genet.6(5),675–679 (1997).
  Medline CASGoogle Scholar
• 57  Lee GH, Proenca R, Montez JM et al. Abnormal splicing of the leptin receptor in diabetic mice. Nature379(6566),632–635 (1996).
  Medline CASGoogle Scholar
• 58  Morris DL, Rui L. Recent advances in understanding leptin signaling and leptin resistance. Am. J. Physiol. Endocrinol. Metab.297(6),E1247–1259 (2009).▪ Comprehensive review of leptin molecular signaling as well as proposed mechanism of leptin resistance as it relates to weight gain/appetite regulation.
  Medline CASGoogle Scholar
• 59  Zhang F, Chen Y, Heiman M, Dimarchi R. Leptin: structure, function and biology. Vitam. Horm.71,345–372 (2005).
  Medline CASGoogle Scholar
• 60  Lammert A, Kiess W, Bottner A, Glasow A, Kratzsch J. Soluble leptin receptor represents the main leptin binding activity in human blood. Biochem. Biophys. Res. Commun.283(4),982–988 (2001).
  Medline CASGoogle Scholar
• 61  Kloek C, Haq AK, Dunn SL, Lavery HJ, Banks AS, Myers MG Jr. Regulation of Jak kinases by intracellular leptin receptor sequences. J. Biol. Chem.277(44),41547–41555 (2002).
  Medline CASGoogle Scholar
• 62  Gong Y, Ishida-Takahashi R, Villanueva EC, Fingar DC, Munzberg H, Myers MG Jr. The long form of the leptin receptor regulates STAT5 and ribosomal protein S6 via alternate mechanisms. J. Biol. Chem.282(42),31019–31027 (2007).
  Medline CASGoogle Scholar
• 63  Vaisse C, Halaas JL, Horvath CM, Darnell JE Jr, Stoffel M, Friedman JM. Leptin activation of Stat3 in the hypothalamus of wild-type and ob/ob mice but not db/db mice. Nat. Genet.14(1),95–97 (1996).
  Medline CASGoogle Scholar
• 64  Robertson SA, Leinninger GM, Myers MG Jr. Molecular and neural mediators of leptin action. Physiol. Behav.94(5),637–642 (2008).
  Medline CASGoogle Scholar
• 65  Schwartz MW, Woods SC, Porte D Jr, Seeley RJ, Baskin DG. Central nervous system control of food intake. Nature404(6778),661–671 (2000).
  Medline CASGoogle Scholar
• 66  Margetic S, Gazzola C, Pegg GG, Hill RA. Leptin: a review of its peripheral actions and interactions. Int. J. Obes. Relat. Metab. Disord.26(11),1407–1433 (2002).
  Medline CASGoogle Scholar
• 67  Sentissi O, Grouselle D, Viala A et al. Ghrelin and leptin levels in schizophrenic patients treated with antipsychotic monotherapy. J. Clin. Psychopharmacol.29(3),304–306 (2009).
  MedlineGoogle Scholar
• 68  Wang HC, Yang YK, Chen PS, Lee IH, Yeh TL, Lu RB. Increased plasma leptin in antipsychotic-naive females with schizophrenia, but not in males. Neuropsychobiology56(4),213–215 (2007).
  Medline CASGoogle Scholar
• 69  Dieudonne MN, Pecquery R, Boumediene A, Leneveu MC, Giudicelli Y. Androgen receptors in human preadipocytes and adipocytes: regional specificities and regulation by sex steroids. Am. J. Physiol.274(6 Pt 1),C1645–C1652 (1998).
  Medline CASGoogle Scholar
• 70  Mizutani T, Nishikawa Y, Adachi H et al. Identification of estrogen receptor in human adipose tissue and adipocytes. J. Clin. Endocrinol. Metab.78(4),950–954 (1994).
  Medline CASGoogle Scholar
• 71  O’Brien SN, Welter BH, Mantzke KA, Price TM. Identification of progesterone receptor in human subcutaneous adipose tissue. J. Clin. Endocrinol. Metab.83(2),509–513 (1998).
  MedlineGoogle Scholar
• 72  Elbers JM, Asscheman H, Seidell JC, Frolich M, Meinders AE, Gooren LJ. Reversal of the sex difference in serum leptin levels upon cross-sex hormone administration in transsexuals. J. Clin. Endocrinol. Metab.82(10),3267–3270 (1997).
  Medline CASGoogle Scholar
• 73  Machinal F, Dieudonne MN, Leneveu MC, Pecquery R, Giudicelli Y. In vivo and in vitro ob gene expression and leptin secretion in rat adipocytes: evidence for a regional specific regulation by sex steroid hormones. Endocrinology140(4),1567–1574 (1999).
  Medline CASGoogle Scholar
• 74  Considine RV, Sinha MK, Heiman ML et al. Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N. Engl. J. Med.334(5),292–295 (1996).
  Medline CASGoogle Scholar
• 75  Sentissi O, Epelbaum J, Olie JP, Poirier MF. Leptin and ghrelin levels in patients with schizophrenia during different antipsychotics treatment: a review. Schizophr. Bull.34(6),1189–1199 (2008).
  MedlineGoogle Scholar
• 76  Ribeiro R, Vasconcelos A, Costa S et al. Overexpressing leptin genetic polymorphism (-2548 G/A) is associated with susceptibility to prostate cancer and risk of advanced disease. Prostate59(3),268–274 (2004).
  Medline CASGoogle Scholar
• 77  Ma D, Feitosa MF, Wilk JB et al. Leptin is associated with blood pressure and hypertension in women from the national heart, lung, and blood institute family heart study. Hypertension53(3),473–479 (2009).
  Medline CASGoogle Scholar
• 78  Hoffstedt J, Eriksson P, Mottagui-Tabar S, Arner P. A polymorphism in the leptin promoter region (-2548 G/A) influences gene expression and adipose tissue secretion of leptin. Horm. Metab. Res.34(7),355–359 (2002).
  Medline CASGoogle Scholar
• 79  Hager J, Clement K, Francke S et al. A polymorphism in the 5´ untranslated region of the human ob gene is associated with low leptin levels. Int. J. Obes. Relat. Metab. Disord.22(3),200–205 (1998).
  Medline CASGoogle Scholar
• 80  Dahlman I, Arner P. Obesity and polymorphisms in genes regulating human adipose tissue. Int. J. Obes. (Lond.)31(11),1629–1641 (2007).
  CASGoogle Scholar
• 81  Rosmond R. Association studies of genetic polymorphisms in central obesity: a critical review. Int. J. Obes. Relat. Metab. Disord.27(10),1141–1151 (2003).
  Medline CASGoogle Scholar
• 82  Stratigopoulos G, Leduc CA, Matsuoka N et al. Functional consequences of the human leptin receptor (LEPR) Q223R transversion. Obesity (Silver Spring)17(1),126–135 (2009).
  Medline CASGoogle Scholar
• 83  Furusawa T, Naka I, Yamauchi T et al. The Q223R polymorphism in LEPR is associated with obesity in Pacific Islanders. Hum. Genet.127(3),287–294 (2010).
  Medline CASGoogle Scholar
• 84  Quinton ND, Lee AJ, Ross RJ, Eastell R, Blakemore AI. A single nucleotide polymorphism (SNP) in the leptin receptor is associated with BMI, fat mass and leptin levels in postmenopausal Caucasian women. Hum. Genet.108(3),233–236 (2001).
  Medline CASGoogle Scholar
• 85  Yiannakouris N, Yannakoulia M, Melistas L, Chan JL, Klimis-Zacas D, Mantzoros CS. The Q223R polymorphism of the leptin receptor gene is significantly associated with obesity and predicts a small percentage of body weight and body composition variability. J. Clin. Endocrinol. Metab.86(9),4434–4439 (2001).
  Medline CASGoogle Scholar
• 86  Mammes O, Aubert R, Betoulle D et al.LEPR gene polymorphisms: associations with overweight, fat mass and response to diet in women. Eur. J. Clin. Invest.31(5),398–404 (2001).
  Medline CASGoogle Scholar
• 87  Heo M, Leibel RL, Fontaine KR et al. A meta-analytic investigation of linkage and association of common leptin receptor (LEPR) polymorphisms with body mass index and waist circumference. Int. J. Obes. Relat. Metab. Disord.26(5),640–646 (2002).
  Medline CASGoogle Scholar
• 88  Paracchini V, Pedotti P, Taioli E. Genetics of leptin and obesity: a HuGE review. Am. J. Epidemiol.162(2),101–114 (2005).
  MedlineGoogle Scholar
• 89  Sun Q, Cornelis MC, Kraft P et al. Genome-wide association study identifies polymorphisms in LEPR as determinants of plasma soluble leptin receptor levels. Hum. Mol. Genet.19(9),1846–1855 (2010).
  Medline CASGoogle Scholar
• 90  Zhang ZJ, Yao ZJ, Mou XD et al. Association of -2548G/A functional polymorphism in the promoter region of leptin gene with antipsychotic agent-induced weight gain. Zhonghua Yi Xue Za Zhi83(24),2119–2123 (2003).
  Medline CASGoogle Scholar
• 91  Ruano G, Goethe JW, Caley C et al. Physiogenomic comparison of weight profiles of olanzapine- and risperidone-treated patients. Mol. Psychiatry12(5),474–482 (2007).
  Medline CASGoogle Scholar
• 92  Yevtushenko OO, Cooper SJ, O’Neill R, Doherty JK, Woodside JV, Reynolds GP. Influence of 5-HT2C receptor and leptin gene polymorphisms, smoking and drug treatment on metabolic disturbances in patients with schizophrenia. Br. J. Psychiatry192(6),424–428 (2008).
  MedlineGoogle Scholar
• 93  Gregoor JG, Van Der Weide J, Mulder H et al. Polymorphisms of the LEP- and LEPR gene and obesity in patients using antipsychotic medication. J. Clin. Psychopharmacol.29(1),21–25 (2009).
  Medline CASGoogle Scholar
• 94  Gregoor JG, Mulder H, Cohen D et al. Combined HTR2C-LEP genotype as a determinant of obesity in patients using antipsychotic medication. J. Clin. Psychopharmacol.30(6),702–705 (2010).
  Medline CASGoogle Scholar
• 95  Opgen-Rhein C, Brandl EJ, Muller DJ et al. Association of HTR2C, but not LEP or INSIG2, genes with antipsychotic-induced weight gain in a German sample. Pharmacogenomics11(6),773–780 (2010).
  CASGoogle Scholar
• 96  Fernandez E, Carrizo E, Fernandez V et al. Polymorphisms of the LEP- and LEPR genes, metabolic profile after prolonged clozapine administration and response to the antidiabetic metformin. Schizophr. Res.121(1–3),213–217 (2010).
  MedlineGoogle Scholar
• 97  Moons T, Claes S, Martens GJ et al. Clock genes and body composition in patients with schizophrenia under treatment with antipsychotic drugs. Schizophr. Res.125(2–3),187–193 (2011).
  MedlineGoogle Scholar
• 98  Ellingrod Vl, Bishop JR, Moline J, Lin YC, Miller DD. Leptin and leptin receptor gene polymorphisms and increases in body mass index (BMI) from olanzapine treatment in persons with schizophrenia. Psychopharmacol. Bull.40(1),57–62 (2007).
  MedlineGoogle Scholar
• 99  Srivastava V, Deshpande SN, Nimgaonkar VL, Lerer B, Thelma B. Genetic correlates of olanzapine-induced weight gain in schizophrenia subjects from north India: role of metabolic pathway genes. Pharmacogenomics9(8),1055–1068 (2008).
  CASGoogle Scholar
• 100  Templeman LA, Reynolds GP, Arranz B, San L. Polymorphisms of the 5-HT2C receptor and leptin genes are associated with antipsychotic drug-induced weight gain in Caucasian subjects with a first-episode psychosis. Pharmacogenet. Genomics15(4),195–200 (2005).▪ First prospective pharmacogenetic study of weight gain and leptin polymorphisms in a primarily drug-naive population.
  Medline CASGoogle Scholar
• 101  Zhang XY, Tan YL, Zhou DF 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.27(3),246–251 (2007).
  MedlineGoogle Scholar
• 102  Kang SG, Lee HJ, Park YM et al. Possible association between the -2548A/G polymorphism of the leptin gene and olanzapine-induced weight gain. Prog. Neuropsychopharmacol. Biol. Psychiatry32(1),160–163 (2008).
  Medline CASGoogle Scholar
• 103  Perez-Iglesias R, Mata I, Amado JA et al. Effect of FTO, SH2B1, LEP, and LEPR polymorphisms on weight gain associated with antipsychotic treatment. J. Clin. Psychopharmacol.30(6),661–666 (2010).
  Medline CASGoogle Scholar
• 104  Calarge CA, Ellingrod VL, Zimmerman B, Acion L, Sivitz WI, Schlechte JA. Leptin gene -2548G/A variants predict risperidone-associated weight gain in children and adolescents. Psychiatr. Genet.19(6),320–327 (2009).▪ The first study of leptin polymorphisms and antipsychotic weight gain in a pediatric population.
  MedlineGoogle Scholar
• 105  Gregoor JG, van der Weide J, Loovers HM, van Megen HJ, Egberts TC, Heerdink ER. Association between LEP and LEPR gene polymorphisms and dyslipidemia in patients using atypical antipsychotic medication. Psychiatr. Genet.20(6),311–316 (2010).
  MedlineGoogle Scholar
• 106  Kluge M, Schuld A, Schacht A et al. Effects of clozapine and olanzapine on cytokine systems are closely linked to weight gain and drug-induced fever. Psychoneuroendocrinology34(1),118–128 (2009).▪ First randomized study comparing immunomodulatory effects of olanzapine and clozapine with discussion of how cytokines may influence weight gain.
  Medline CASGoogle Scholar
• 107  Vehof J, Risselada AJ, Al Hadithy AF et al. Association of genetic variants of the histamine H1 and muscarinic M3 receptors with BMI and HbA1c values in patients on antipsychotic medication. Psychopharmacology (Berl.)216(2),257–265 (2011).
  Medline CASGoogle Scholar
• 108  Newcomer JW. Second-generation (atypical) antipsychotics and metabolic effects: a comprehensive literature review. CNS Drugs19(Suppl. 1),1–93 (2005).▪▪ Comprehensive review of relationship of second-generation antipsychotics and metabolic complications.
  Medline CASGoogle Scholar
• 109  Thompson A, Lavedan C, Volpi S. Absence of weight gain association with the HTR2C -759C/T polymorphism in patients with schizophrenia treated with iloperidone. Psychiatry Res.175(3),271–273 (2010).
  Medline CASGoogle Scholar
• 110  Tartaglia LA. The leptin receptor. J. Biol. Chem.272(10),6093–6 (1997).
  Medline CASGoogle Scholar