Abstract
The underlying mechanisms of antipsychotic (AP)-induced weight gain are unknown, but both central and peripheral AP target receptors could potentially be involved. This study used radioligand binding assays to compare the binding affinities of clozapine, olanzapine and haloperidol for candidate receptors potentially involved in AP-induced weight gain. Selected candidates derived from known pathways involved in body weight regulation included receptors classified as anorexigenic (bombesin receptor subtype 3, calcitonin gene-related peptide receptor, cholecystokinin receptor, melanocortin-4 receptor, neurotensin receptor 1) or orexigenic (cannabinoid receptor 1, galanin 1 receptor, melanin-concentrating hormone receptor (MCHR), neuropeptide Y1 receptor) as well as receptors involved in physiological actions related to digestion and fluid homeostasis (angiotensin II type 1 receptor, bradykinin B2 receptor, endothelin receptor, neurokinin 1 receptor, vasoactive intestinal polypeptide receptor 1). Clozapine, olanzapine and haloperidol exhibited negligible affinities to all of these receptors except for the MCHR (Ki=501 nM; haloperidol). With respect to other candidates from (neuro)transmitter systems already suggested to be involved in AP-induced weight gain, the binding profile of olanzapine resembled that of clozapine, with high affinity (Ki<10 nM) for serotonin (5-HT) 5-HT2A, 5-HT2C and 5-HT6, muscarinic M1 and histamine H1 receptors. In contrast, the binding profile of haloperidol was substantially different (high affinity only for the dopamine D1 receptor). In conclusion, we have not identified a novel binding site of the two investigated atypical AP that could contribute to the induced weight gain.
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References
Baptista T . Body weight gain induced by antipsychotic drugs: mechanisms and management. Acta Psychiatr Scand 1999; 100: 3–16.
Allison DB, Mentore JL, Heo M, Chandler LP, Cappelleri JC, Infante MC et al. Antipsychotic-induced weight gain: a comprehensive research synthesis. Am J Psychiatry 1999; 156: 1686–1696.
Wirshing DA, Wirshing WC, Kysar L, Berisford MA, Goldstein D, Pashdag J et al. Novel antipsychotics: comparison of weight gain liabilities. J Clin Psychiatry 1999; 60: 358–363.
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 Genet 2005; 15: 285–289.
Leadbetter R, Shutty M, Pavalonis D, Vieweg V, Higgins P, Downs M . Clozapine-induced weight gain: prevalence and clinical relevance. Am J Psychiatry 1992; 149: 68–72.
Bromel T, Blum W F, Ziegler A, Schulz E, Bender M, Fleischhaker C et al. Serum leptin levels increase rapidly after initiation of clozapine therapy. Mol Psychiatry 1998; 3: 76–80.
Theisen FM, Cichon S, Linden A, Martin M, Remschmidt H, Hebebrand J . Clozapine and weight gain. Am J Psychiatry 2001; 158: 816.
Theisen FM, Linden A, Konig IR, Martin M, Remschmidt H, Hebebrand J . Spectrum of binge eating symptomatology in patients treated with clozapine and olanzapine. J Neural Transm 2003; 110: 111–121.
Gothelf D, Falk B, Singer P, Kairi M, Phillip M, Zigel L et al. Weight gain associated with increased food intake and low habitual activity levels in male adolescent schizophrenic inpatients treated with olanzapine. Am J Psychiatry 2002; 159: 1055–1057.
Graham KA, Perkins DO, Edwards LJ, Barrier Jr RC, Lieberman JA, Harp JB . Effect of olanzapine on body composition and energy expenditure in adults with first-episode psychosis. Am J Psychiatry 2005; 162: 118–123.
Procyshyn RM, Chau A, Tse G . Clozapine's effects on body weight and resting metabolic rate: a case series. Schizophr Res 2004; 66: 159–162.
Seeman P . Atypical antipsychotics: mechanism of action. Can J Psychiatry 2002; 47: 27–38.
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 (Suppl 23): 45–66.
Basile VS, Masellis M, De-Luca V, Meltzer HY, Kennedy JL . 759C/T genetic variation of 5HT(2C) receptor and clozapine-induced weight gain. Lancet 2002; 360: 1790–1791.
Correll CU, Malhotra AK . Pharmacogenetics of antipsychotic-induced weight gain. Psychopharmacology (Berl) 2004; 174: 477–489.
Muller DJ, Muglia P, Fortune T, Kennedy JL . Pharmacogenetics of antipsychotic-induced weight gain. Pharmacol Res 2004; 49: 309–329.
Reynolds GP, Zhang ZJ, Zhang XB . Association of antipsychotic drug-induced weight gain with a 5-HT2C receptor gene polymorphism. Lancet 2002; 359: 2086–2087.
Reynolds GP, Zhang ZJ, Zhang XB . Polymorphism of the promoter region of the serotonin 5-HT(2C) receptor gene and clozapine-induced weight gain. Am J Psychiatry 2003; 160: 677–679.
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: 139–142.
Tsai SJ, Hong CJ, Yu W, Lin CH . 759C/T genetic variation of 5HT(2C) receptor and clozapine-induced weight gain. Lancet 2002; 360: 1790.
Miller del D, 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; 133: 97–100.
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 Genomics 2005; 15: 195–200.
Ellingrod VL, Perry PJ, Ringold JC, Lund BC, Bever-Stille K, Fleming F et al. Weight gain associated with the −759C/T polymorphism of the 5HT2C receptor and olanzapine. Am J Med Genet B Neuropsychiatr Genet 2005; 134: 76–78.
Kraus T, Haack M, Schuld A, Hinze-Selch D, Kuhn M, Uhr M et al. Body weight and leptin plasma levels during treatment with antipsychotic drugs. Am J Psychiatry 1999; 156: 312–314.
Baptista T, Beaulieu S . Are leptin and cytokines involved in body weight gain during treatment with antipsychotic drugs? Can J Psychiatry 2002; 47: 742–749.
Hosojima H, Togo T, Odawara T, Hasegawa K, Miura S, Kato Y et al. Early effects of olanzapine on serum levels of ghrelin, adiponectin and leptin in patients with schizophrenia. J Psychopharmacol 2006; 20: 75–79.
Albaugh VL, Henry CR, Bello NT, Hajnal A, Lynch SL, Halle B et al. Hormonal and metabolic effects of olanzapine and clozapine related to body weight in rodents. Obes Res 2006; 14: 36–51.
Theisen FM, Gebhardt S, Bromel T, Otto B, Heldwein W, Heinzel-Gutenbrunner M et al. A prospective study of serum ghrelin levels in patients treated with clozapine. J Neural Transm 2005; 112: 1411–1416.
Hauner H, Rohrig K, Hebebrand J, Skurk T . No evidence for a direct effect of clozapine on fat-cell formation and production of leptin and other fat-cell-derived factors. Mol Psychiatry 2003; 8: 258–259.
Pollmacher T, Hinze-Selch D, Mullington J . Effects of clozapine on plasma cytokine and soluble cytokine receptor levels. J Clin Psychopharmacol 1996; 16: 403–409.
Beck B . KO's and organisation of peptidergic feeding behavior mechanisms. Neurosci Biobehav Rev 2001; 25: 143–158.
Sawada H, Yamaguchi H, Shimbara T, Toshinai K, Mondal MS, Date Y et al. Central effects of calcitonin receptor-stimulating peptide-1 on energy homeostasis in rats. Endocrinology 2006; 147: 2043–2050.
Vickers SP, Kennett GA . Cannabinoids and the regulation of ingestive behaviour. Curr Drug Targets 2005; 6: 215–223.
Fallo F, Mulatero P, Vettor R, Scarda A, Della Mea P, Morello F et al. Bradykinin B2 receptor gene C-58T polymorphism and insulin resistance. A study on obese patients. Horm Metab Res 2004; 36: 243–246.
Ewert S, Johansson B, Holm M, Helander HF, Fandriks L . The bradykinin BK2 receptor mediates angiotensin II receptor type 2 stimulated rat duodenal mucosal alkaline secretion. BMC Physiol 2003; 3: 1.
Said SA, Ammar el SM, Suddek GM . Effect of bosentan (ETA/ETB receptor antagonist) on metabolic changes during stress and diabetes. Pharmacol Res 2005; 51: 107–115.
Grundy D, Al-Chaer ED, Aziz Q, Collins SM, Ke M, Tache Y et al. Fundamentals of neurogastroenterology: basic science. Gastroenterology 2006; 130: 1391–1411.
Ulrich II CD, Holtmann M, Miller LJ . Secretin and vasoactive intestinal peptide receptors: members of a unique family of G protein-coupled receptors. Gastroenterology 1998; 114: 382–397.
Cheng Y, Prusoff WH . Relationship between the inhibition constant (K1) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reaction. Biochem Pharmacol 1973; 22: 3099–3108.
Kathmann M, Schlicker E, Gothert M . Intermediate affinity and potency of clozapine and low affinity of other neuroleptics and of antidepressants at H3 receptors. Psychopharmacology (Berl) 1994; 116: 464–468.
Bymaster FP, Calligaro DO, Falcone JF, Marsh RD, Moore NA, Tye NC et al. Radioreceptor binding profile of the atypical antipsychotic olanzapine. Neuropsychopharmacology 1996; 14: 87–96.
Bymaster FP, Perry KW, Nelson DL, Wong DT, Rasmussen K, Moore NA et al. Olanzapine: a basic science update. Br J Psychiatry Suppl 1999; 37: 36–40.
Bymaster FP, Felder CC, Tzavara E, Nomikos GG, Calligaro DO, Mckinzie DL . Muscarinic mechanisms of antipsychotic atypicality. Prog Neuropsychopharmacol Biol Psychiatry 2003; 27: 1125–1143.
Kohen R, Metcalf MA, Khan N, Druck T, Huebner K, Lachowicz JE et al. Cloning, characterization, and chromosomal localization of a human 5-HT6 serotonin receptor. J Neurochem 1996; 66: 47–56.
Schoemaker H, Claustre Y, Fage D, Rouquier L, Chergui K, Curet O et al. Neurochemical characteristics of amisulpride, an atypical dopamine D2/D3 receptor antagonist with both presynaptic and limbic selectivity. J Pharmacol Exp Ther 1997; 280: 83–97.
Arnt J, Skarsfeldt T . Do novel antipsychotics have similar pharmacological characteristics? A review of the evidence. Neuropsychopharmacology 1998; 18: 63–101.
Leysen JE, Janssen PFM, Heylen L, Gommeren W, Van Gompel P, Lesage AS et al. Receptor interactions of new antipsychotics: relation to pharmacodynamic and clinical effects. Int J Psychiat Clin 1998; 2 (Suppl 1): 3–17.
Millan MJ, Schreiber R, Dekeyne A, Rivet JM, Bervoets K, Mavridis M et al. S 16924 ((R)-2-[1-[2-(2,3-dihydro-benzo[1,4]dioxin-5-yloxy)-ethyl]-pyrrolidin-3yl]-1-(4-fluoro-phenyl)-ethanone), a novel, potential antipsychotic with marked serotonin (5-HT)1A agonist properties: II. Functional profile in comparison to clozapine and haloperidol. J Pharmacol Exp Ther 1998; 286: 1356–1373.
Morisset S, Sahm UG, Traiffort E, Tardivel-Lacombe J, Arrang JM, Schwartz JC . Atypical neuroleptics enhance histamine turnover in brain via 5-hydroxytryptamine2A receptor blockade. J Pharmacol Exp Ther 1999; 288: 590–596.
Branchek TA, Blackburn TP . 5-ht6 receptors as emerging targets for drug discovery. Annu Rev Pharmacol Toxicol 2000; 40: 319–334.
Remschmidt H, Hennighausen K, Clement HW, Heiser P, Schulz E . Atypical neuroleptics in child and adolescent psychiatry. Eur Child Adolesc Psychiatry 2000; 9 (Suppl 1): I9–19.
Richelson E, Souder T . Binding of antipsychotic drugs to human brain receptors focus on newer generation compounds. Life Sci 2000; 68: 29–39.
Campiani G, Butini S, Gemma S, Nacci V, Fattorusso C, Catalanotti B . Pyrrolo [1,3]benzothiazepine-based atypical antipsychotic agents. Synthesis, structure–activity relationship, molecular modeling, and biological studies. J Med Chem 2002; 45: 344–359.
http://www.emea.eu.int/humandocs/PDFs/EPAR/Zyprexa/H-115-PI-en.pdf.
Silvestre JS, Prous J . Research on adverse drug events. I. Muscarinic M3 receptor binding affinity could predict the risk of antipsychotics to induce type 2 diabetes. Methods Find Exp Clin Pharmacol 2005; 27: 289–304.
Kroeze WK, Hufeisen SJ, Popadak BA, Renock SM, Steinberg S, Ernsberger P et al. H1-histamine receptor affinity predicts short-term weight gain for typical and atypical antipsychotic drugs. Neuropsychopharmacology 2003; 28: 519–526.
Kalra SP, Dube MG, Pu S, Xu B, Horvath TL, Kalra PS . Interacting appetite-regulating pathways in the hypothalamic regulation of body weight. Endocr Rev 1999; 20: 68–100.
Stahl SM . Neuropharmacology of obesity: my receptors made me eat it. J Clin Psychiatry 1998; 59: 447–448.
Stahl SM . How to appease the appetite of psychotropic drugs. J Clin Psychiatry 1998; 59: 500–501.
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: 265–268.
Buckland PR, Hoogendoorn B, Guy CA, Smith SK, Coleman SL, O’Donovan MC . Low gene expression conferred by association of an allele of the 5-HT2C receptor gene with antipsychotic-induced weight gain. Am J Psychiatry 2005; 162: 613–615.
Acknowledgements
We acknowledge the contribution of Peter Eickelmann. This study was supported by the ‘Deutsche Forschungsgemeinschaft’ (DFG; Re 471/11-2; Th 707/1-1) and the ‘Bundesministerium für Bildung und Forschung’ (BMBF: National Genome Research Network 01GS0118 and NGFN2: 01GS0482).
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Theisen, F., Haberhausen, M., Firnges, M. et al. No evidence for binding of clozapine, olanzapine and/or haloperidol to selected receptors involved in body weight regulation. Pharmacogenomics J 7, 275–281 (2007). https://doi.org/10.1038/sj.tpj.6500418
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DOI: https://doi.org/10.1038/sj.tpj.6500418
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