Original Papers
`
`The 5-HT2C receptor and antipsychotic-
`induced weight gain – mechanisms and
`genetics
`
`JPsychopharm
`
`Journal of Psychopharmacology
`20(4) Supplement (2006) 15–18
`© 2006 British Association
`for Psychopharmacology
`ISSN 1359-7868
`SAGE Publications Ltd,
`London, Thousand Oaks,
`CA and New Delhi
`10.1177/1359786806066040
`
`Gavin P. Reynolds Division of Psychiatry and Neuroscience, Queen’s University Belfast, Belfast, UK.
`Matthew J. Hill Division of Psychiatry and Neuroscience, Queen’s University Belfast, Belfast, UK.
`Shona L. Kirk Division of Psychiatry and Neuroscience, Queen’s University Belfast, Belfast, UK.
`
`Abstract
`
`The mechanisms underlying weight gain resulting from antipsychotic
`drugs are not fully understood, although antagonism of the 5-HT2C
`receptor is likely to contribute. Animal studies indicate that the drugs
`most likely to cause weight gain, clozapine and olanzapine, have direct
`effects on the NPY-containing neurons of the hypothalamus; these
`neurons mediate the effects of the circulating anorexigenic hormone
`leptin on the control of food intake.
`The substantial differences between individuals in the extent of
`antipsychotic-induced weight gain suggest that genetic factors may be
`important. We have been studying pharmacogenetic correlates and find
`that a common 5-HT2C receptor promoter region polymorphisms
`demonstrates strong associations with weight gain in two first episode
`psychotic samples. In both series, we have found further association of
`antipsychotic drug-induced weight gain with a common and functional
`polymorphism of the gene for leptin. Along with initial BMI, these two
`pharmacogenetic factors account for almost 30% of the variance in drug-
`
`induced weight gain. Interestingly, the 5-HT2C polymorphism appears to
`determine levels of circulating leptin, providing a potential mechanism
`underlying the genetic association of the 5-HT2C receptor with weight
`gain. We have undertaken functional studies of haplotypes of the 5-HT2C
`promoter region and find the allele associated with protection from
`weight gain results in reduced promoter activity.
`These findings demonstrate the value of pharmacogenetics in
`determining liability to a major side effect of antipsychotic treatment,
`and indicate both the molecular and physiological mechanisms
`underlying this side effect.
`
`Keywords
`
`antipsychotic drugs, pharmacogenetics, weight gain, 5-HT2C receptor,
`side effects
`
`Introduction – pharmacological mechanisms
`of antipsychotic-induced weight gain
`
`The extrapyramidal side effects have in the past been considered
`to be the most troublesome consequences of antipsychotic drug
`treatment. However, with the introduction of newer ‘atypical’
`drugs that may minimize these problems, other side effects have
`become more apparent. One of these, weight gain, will not only
`influence compliance with drug treatment but is inevitably associ-
`ated with substantial morbidity. This includes diabetes, hyperten-
`sion and cardiovascular disease, consequences of obesity that
`make up the metabolic syndrome.
`The mechanism of antipsychotic-induced weight gain is
`unclear at present, however drugs which produce weight gain have
`high affinities at several receptors such as the 5-HT2C, 5-HT1A,
`dopamine D2 and histamine H1 receptors. Certainly, 5-HT
`
`systems are important in food and body weight regulation: 5-HT is
`a potent satiety signal; administration of 5-HT to rodents
`decreases food intake (Blundell and Leshem, 1975). Agonists at
`the 5-HT1A and 5-HT2C receptors have opposing effects on food
`intake with 5-HT1A agonists increasing food intake (Dourish et al.,
`1985) and 5-HT2C agonists decreasing food intake (Vickers et al.,
`2000). 5-HT2C antagonists have been shown to increase food
`intake (Bonhaus et al., 1997) and also attenuate the decrease in
`food intake which is produced by 5-HT2C agonists (Jackson et al.,
`1997; Clifton et al., 2000; Hayashi et al., 2005) or sibutramine, a
`5-HT and noradrenaline reuptake inhibitor (Hayashi et al., 2004).
`Knock-out of the 5-HT2C receptor in mice can result in obesity and
`increased feeding (Tecott et al., 1995). The antipsychotics causing
`the greatest weight gain are clozapine and olanzapine (Allison et
`al., 1999); they are also high-affinity 5-HT2C antagonists.
`However, ziprasidone, another antipsychotic which also has an
`
`Corresponding author: G.P. Reynolds, Division of Psychiatry and Neuroscience, Queen’s University Belfast, Whitla Medical Building, 97 Lisburn Rd, Belfast BT9 7BL, UK. Email:
`g.reynolds@qub.ac.uk
`
`1
`
`Exhibit 2039
`Slayback v. Sumitomo
`IPR2020-01053
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`16 5-HT2C receptor and weight gain
`
`affinity for 5-HT2C receptors, does not produce increased body
`weight. One explanation may be that ziprasidone acts as a partial
`agonist/antagonist at 5-HT1A receptors and this may provide a pro-
`tective mechanism against increases in body weight and/or food
`intake. Our finding that co-administration of ziprasidone and olan-
`zapine to rats prevents the hyperphagic effect produced by olanza-
`pine alone
`is certainly consistent with such a protective
`mechanism (Kirk et al., 2004).
`Histamine H1 receptors are also implicated in antipsychotic-
`induced weight gain. The mechanism by which histamine H1
`receptor blockade may induce weight gain is unknown; however
`activation of central histamine H1 receptors decreases food intake
`in rats and histamine H1 antagonists attenuate the reduction in
`food intake produced by histamine (Lecklin et al., 1998). Hista-
`mine H1 antagonists have also been shown to dose-dependently
`induce feeding in rats (Sakata et al., 1988).
`
`Drug-induced weight gain – leptin and
`hypothalamic processes
`
`The effects of weight-inducing antipsychotic drugs may be medi-
`ated through the hypothalamus; this is an important area of the
`brain which is involved in food intake and body weight regulation.
`A number of hormones provide satiety signals to the central
`nervous system; one of these hormones is leptin. Leptin is a circu-
`lating hormone that is released by adipocytes in response to
`increased fat deposition to regulate body weight. Serotonergic and
`catecholamineric neurons that have inputs to the hypothalamus
`often contain leptin receptors (Hay-Schmidt et al., 2001). Several
`neuropeptides act in the hypothalamus to influence food intake
`and related processes; these include neuropeptide Y (NPY),
`agouti-related peptide (AGRP), pro-opiomelanocortin (POMC),
`ghrelin and orexin. NPY is one of the most abundant neuropep-
`tides in the brain with high levels in several brain areas including
`the arcuate nucleus (ARC) and the paraventricular nucleus (PVN)
`of the hypothalamus (Adrian et al., 1983) where it plays a major
`role in the stimulation of food intake (Levine and Morley, 1984).
`These neuropeptides respond to changes in leptin levels to ulti-
`mately maintain body weight. Central leptin administration in rats
`decreases NPY levels in the rat hypothalamus (Wang et al., 1997).
`It is believed that leptin acts directly on NPY neurons within the
`arcuate nucleus of the hypothalamus as a subset of these neurons
`express leptin receptors (Hakansson et al., 1996; Baskin et al.,
`1999). The normal inhibitory effect of leptin on NPY is inter-
`rupted in genetic models of obesity leading to increased NPY
`expression (Wilding et al., 1993). NPY is also regulated by sero-
`tonin; the 5-HT1B/2C agonist mCPP produced decreases in food
`intake and NPY levels in the PVN (Dryden et al., 1996).
`The rat hypothalamus contains 5-HT2C receptors (Abramowski
`et al., 1995; Clemett et al., 2000). Furthermore, there is evidence
`suggesting an interaction between 5-HT2C and leptin; 5-HT2C
`antagonists attenuate the reduction in food intake produced by
`leptin thus suggesting that the 5-HT2C receptors are involved in the
`mechanism of leptin-induced anorexia (von Meyenburg et al.,
`2003). The orexins are present in high levels in the lateral hypo-
`
`thalamus and the perifornical area (de Lecea et al., 1998; Sakurai
`et al., 1998); these peptides stimulate food intake (Edwards et al.,
`1999). Drugs which produce weight gain clinically also produce
`an increase in the activation of hypothalamic orexin neurons
`(Fadel et al., 2002).
`Work carried out in our laboratory suggests that NPY is also
`involved in antipsychotic-induced weight gain. Chronic adminis-
`tration of clozapine, but not haloperidol, produced an increase in
`NPY-immunoreactive cell density in the rat arcuate nucleus (Kirk
`et al., 2005). Furthermore, we also found that acute olanzapine
`also produced an increase in NPY (Kirk and Reynolds, 2005).
`This increase could, at least in part, be due to antagonism of the
`5-HT2C receptor resulting in disinhibition of the NPY neurons.
`
`Pharmacogenetic associations with drug-
`induced weight gain
`
`That the 5-HT2C receptor is directly involved in antipsychotic-
`induced weight gain is also demonstrated by pharmacogenetic obser-
`vations. Yuan et al. (2000) identified several haplotypes of the
`promoter region of the 5-HT2C receptor gene – involving three single
`nucleotide polymorphisms (SNPs) and a variable length GT repeat
`sequence, all in linkage dysequilibrium – which are associated with
`obesity and diabetes. This finding prompted us to determine whether
`one 5-HT2C promoter polymorphism, -759 C/T, might be associated
`with weight gain in a sample of initially drug-naive Chinese patients.
`We found that this was indeed the case; the 22% of subjects carrying
`the -759T allele had substantially lower weight gain following 10
`weeks of treatment with antipsychotic drugs (Reynolds et al., 2002).
`We have recently replicated this in a group of Caucasian first-
`episode patients, finding that the genetic association remains after
`long-term (9 months) treatment (Templeman et al., 2005). In this
`study we also observed an effect of the 5-HT2C receptor genotype on
`blood leptin prior to drug treatment, in which the protective -759T
`allele is associated with higher concentrations of leptin.
`The link with leptin is also apparent from pharmacogenetic studies
`of the leptin gene. We find circulating leptin increases substantially in
`patients receiving antipsychotic drugs (Zhang et al., 2004), indicating
`that the normal control this hormone imparts on food intake is awry in
`such patients. Recent reports show that genetic variants in the leptin
`gene promoter region are associated with obesity and influence leptin
`function (Mammès et al., 2000). We hypothesized that this may also
`affect drug-induced weight gain and found an association of the -
`2548A/G polymorphism with weight gain (Templeman et al., 2005).
`We find that the 5-HT2C and leptin promoter polymorphisms, together
`with age and body mass index, account for almost 30% of the vari-
`ance in short-term drug-induced weight gain.
`
`5-HT2C receptor pharmacogenetics – molecular
`mechanisms
`
`To understand fully the mechanism(s) underlying the association
`of the 5-HT2C receptor polymorphism with drug-induced weight
`gain, it is necessary to understand the effect of the polymorphism
`
`2
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`

`5-HT2C receptor and weight gain 17
`
`on receptor expression. There have been several gene-reporter
`studies investigating the effects of the 5-HT2C receptor gene pro-
`moter polymorphisms on levels of transcription. First, it has been
`reported that haplotypes containing either the -759T or -697C
`genotype show increased promoter activity when expressed in a
`mouse embryonal carcinoma cell line (Yuan et al., 2000). Investi-
`gations again using non-neuronal cell lines support the increased
`activity of the -759T genotype and also report functionality at the
`-997 site (Buckland et al., 2005). In addition they demonstrate that
`the length of the GT repeat and the previously untested -1165G/A
`polymorphism have no discernable effects on transcription levels.
`Data contrary to these findings are also evident in the literature.
`McCarthy et al. (2005) applied the mouse cell model to an
`extended region of the promoter that incorporated six promoter
`polymorphisms. Despite the apparent similarities to the published
`methodology of Yuan et al. (2000) there was no reported dif-
`ference in activity between the two most common haplotypes.
`However, a reduction in activity was observed in haplotypes con-
`taining the -697C genotype, which only reached significance in the
`haplotype containing -759C and -997G genotypes.
`It is therefore unclear whether the resistance to antipsychotic-
`induced weight gain, conferred to carriers of haplotypes contain-
`ing the -759T genotype, is a result of increased expression of the
`receptor. We undertook an investigation into the relative activities
`of the two most abundant haplotypes. That most strongly associ-
`ated with antipsychotic-induced weight gain, -997G, -759C,
`-697G (haplotype A) and the haplotype associated with resistance
`to weight gain, -997A, -759T, -697C (haplotype B) were assessed
`in SH-SY5Y human neuroblastoma cells, a more physiological
`relevant cell line. We have reported that haplotype B shows
`reduced activity, 41% that of haplotype A. A similar reduction,
`66% compared to haplotype A, was still apparent after differenti-
`ating the cells to produce a more neuronal, post-mitotic, pheno-
`type (Hill and Reynolds, 2005). The apparent contradiction in
`effect compared to previous findings using non-neuronal cells can
`be understood in terms of differences in the transcription factor
`complement between cell types.
`These data demonstrate that the 5-HT2C receptor genotype con-
`ferring resistance to antipsychotic-induced weight gain is likely to
`reflect diminished neuronal expression of the receptor. It is there-
`fore hypothesized that underactivity of the 5-HT2C receptor associ-
`ated with haplotype B results in adaptive changes in other systems
`regulating weight and food intake resulting in resistance to weight
`gain. We have observed possible adaptive changes in the leptin
`system where carriers of the -759T genotype, (i.e. primarily haplo-
`type B) have increased basal levels of circulating leptin (Temple-
`man et al., 2005). Although the mechanisms by which 5-HT2C
`receptor signalling regulates leptin levels is unknown it is possible
`that increased circulating leptin levels act on hypothalamic NPY
`neurones to decrease NPY release resulting in reduced feeding.
`
`Conclusions
`
`The 5-HT2C receptor is closely involved in the weight gain that
`occurs following treatment with many antipsychotic drugs. It is
`
`likely to contribute directly, via the 5-HT2C antagonist effects of
`these drugs, to the pharmacological mechanisms leading to
`increased food intake, although effects of the drugs at other recep-
`tors may also be important as additional, or modulatory, mechan-
`isms. The receptor effects of the antipsychotics are likely to be
`mediated by neuronal systems in the hypothalamus and involve
`disruption of the normal response to leptin and possibly other hor-
`mones controlling food intake and body weight. Additional to the
`antagonist effect of the antipsychotic drugs at the 5-HT2C receptor,
`functional variants of the promoter region of the receptor gene
`also determine the severity of antipsychotic-induced weight gain.
`The underlying mechanisms are likely to involve effects of pro-
`moter region polymorphisms on receptor expression, with conse-
`quent effects that may include an influence on levels of circulating
`leptin.
`
`References
`Abramowski D, Rigo M, Duc D, Hoyer D, Staufenbiel M (1995) Localiza-
`tion of the 5-hydroxytryptamine2C receptor protein in human and rat
`brain using specific antisera. Neuropharmacology 34: 1635–1645
`Adrian T E, Allen J M, Bloom S R, Ghatei M A, Rossor M N, Roberts G
`W, Crow T J, Tatemoto K, Polak J M (1983) Neuropeptide Y distribu-
`tion in human brain. Nature 306: 584–586
`Allison D B, Mentore J L, Heo M, Chandler L P, Cappelleri J C, Infante M
`C, Weiden P J (1999) Antipsychotic-induced weight gain: a compre-
`hensive research synthesis. Am J Psychiatry 156: 1686–1696
`Baskin D G, Schwartz M W, Seeley R J, Woods S C, Porte D Jr,
`Breininger J F, Jonak Z, Schaefer J, Krouse M, Burghardt C, Camp-
`field L A, Burn P, Kochan J P (1999) Leptin receptor long-form splice-
`variant protein expression in neuron cell bodies of the brain and
`co-localization with neuropeptide Y mRNA in the arcuate nucleus. J
`Histochem Cytochem 47: 353–362
`Blundell J E, Leshem M B (1975) The effect of 5-hydroxytryptophan on
`food intake and on the anorexic action of amphetamine and fenflu-
`ramine. J Pharm Pharmacol 27: 31–37
`Bonhaus D W, Weinhardt K K, Taylor M, DeSouza A, McNeeley P M,
`Szczepanski K, Fontana D J, Trinh J, Rocha C L, Dawson M W,
`Flippin L A, Eglen R M (1997) RS-102221: a novel high affinity and
`selective, 5-HT2C
`receptor antagonist. Neuropharmacology 36:
`621–629
`Buckland P R, Hoogendoorn B, Guy C A, Smith S K, Coleman S L,
`O’Donovan M C (2005) Low gene expression conferred by association
`of an allele of the 5-HT2C receptor gene with antipsychotic-induced
`weight gain. Am J Psychiatry 162: 613–615
`Clemett D A, Punhani T, Duxon M S, Blackburn T P, Fone K C (2000)
`Immunohistochemical localisation of the 5-HT2C receptor protein in the
`rat CNS. Neuropharmacology 39: 123–132
`Clifton P G, Lee M D, Dourish C T (2000) Similarities in the action of Ro
`60-0175, a 5-HT2C receptor agonist and d-fenfluramine on feeding pat-
`terns in the rat. Psychopharmacology (Berl) 152: 256–267
`de Lecea L, Kilduff T S, Peyron C, Gao X, Foye P E, Danielson P E,
`Fukuhara C, Battenberg E L, Gautvik V T, Bartlett F S, Frankel W N,
`van den Pol A N, Bloom F E, Gautvik K M, Sutcliffe J G (1998) The
`hypocretins: hypothalamus-specific peptides with neuroexcitatory
`activity. Proc Natl Acad Sci U S A 95: 322–327
`Dourish C T, Hutson P H, Curzon G (1985) Low doses of the putative
`serotonin agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-
`DPAT) elicit feeding in the rat. Psychopharmacology (Berl) 86:
`197–204
`Dryden S, Wang Q, Frankish H M, Williams G (1996) Differential effects
`
`3
`
`

`

`18 5-HT2C receptor and weight gain
`
`of the 5-HT 1B/2C receptor agonist mCPP and the 5-HT1A agonist
`flesinoxan on hypothalamic neuropeptide Y in the rat: evidence that
`NPY may mediate serotonin’s effects on food intake. Peptides 17:
`943–949
`Edwards C M, Abusnana S, Sunter D, Murphy K G, Ghatei M A, Bloom S
`R (1999) The effect of the orexins on food intake: comparison with
`neuropeptide Y, melanin-concentrating hormone and galanin. J
`Endocrinol 160: R7–12
`Fadel J, Bubser M, Deutch A Y (2002) Differential activation of orexin
`neurons by antipsychotic drugs associated with weight gain. J Neurosci
`22: 6742–6746
`Hakansson M L, Hulting A L, Meister B (1996) Expression of leptin
`receptor mRNA in the hypothalamic arcuate nucleus – relationship
`with NPY neurones. Neuroreport 7: 3087–3092
`Hay-Schmidt A, Helboe L, Larsen P J (2001) Leptin receptor immunoreac-
`tivity is present in ascending serotonergic and catecholaminergic
`neurons of the rat. Neuroendocrinology 73: 215–226
`Hayashi A, Suzuki M, Sasamata M, Miyata K (2005) Agonist diversity in
`5-HT(2C) receptor-mediated weight control in rats. Psychopharmacol-
`ogy (Berl) 178: 241–249
`Hayashi A, Sonoda R, Kimura Y, Takasu T, Suzuki M, Sasamata M,
`Miyata K (2004) Antiobesity effect of YM348, a novel 5-HT2C recep-
`tor agonist, in Zucker rats. Brain Res 1011: 221–227
`Hill M J, Reynolds G P (2005) Activity of the 5-HT2C receptor gene pro-
`moter is influenced by haplotype in a neuroblastoma cell line. J Psy-
`chopharmacology 19 (suppl.): A36
`Jackson H C, Bearham M C, Hutchins L J, Mazurkiewicz S E, Needham
`A M, Heal D J (1997) Investigation of the mechanisms underlying the
`hypophagic effects of the 5-HT and noradrenaline reuptake inhibitor,
`sibutramine, in the rat. Br J Pharmacol 121: 1613–1618
`Kirk S L, Reynolds G P (2005) Acute olanzapine increases NPY-contain-
`ing cells in the rat hypothalamus. J Psychopharm 19(suppl.): A33
`Kirk S L, Cahir M, Reynolds G P (2006) Clozapine, but not haloperidol,
`increases neuropeptide Y neuronal expression in the rat hypothalamus.
`J Psychopharmacol (in press)
`Kirk S L, Neill J C, Jones D N, Reynolds G P (2004) Ziprasidone sup-
`presses olanzapine-induced increases in ingestive behaviour in the rat.
`Eur J Pharmacol 505: 253–254
`Lecklin A, Etu-Seppala P, Stark H, Tuomisto L (1998) Effects of intrac-
`erebroventricularly infused histamine and selective H1, H2 and H3
`agonists on food and water intake and urine flow in Wistar rats. Brain
`Res 793: 279–288
`Levine A S, Morley J E (1984) Neuropeptide Y: a potent inducer of con-
`summatory behavior in rats. Peptides 5: 1025–1029
`McCarthy S, Mottagui-Tabar S, Mizuno Y, Sennblad B, Hoffstedt J, Arner
`P, Wahlestedt C, Andersson B (2005) Complex HTR2C linkage dise-
`quilibrium and promoter associations with body mass index and serum
`leptin. Hum Genet 109: 939–946
`Mammès O, Betoulle D, Aubert R, Herbeth B, Siest G, Fumeron F (2000)
`Association of the G-2548A polymorphism in the 5' region of the LEP
`gene with overweight. Ann Hum Genet 64: 391–394
`
`Reynolds G P, Zhang Z J, Zhang X B (2002) Association of antipsychotic
`drug-induced weight gain with a 5-HT2C receptor gene polymorphism.
`Lancet 359: 2086–2087
`Sakata T, Ookuma K, Fukagawa K, Fujimoto K, Yoshimatsu H, Shiraishi
`T, Wada H (1988) Blockade of the histamine H1-receptor in the rat
`ventromedial hypothalamus and feeding elicitation. Brain Res 441:
`403–407
`Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli R M, Tanaka H,
`Williams S C, Richardson J A, Kozlowski G P, Wilson S, Arch J R,
`Buckingham R E, Haynes A C, Carr S A, Annan R S, McNulty D E,
`Liu W S, Terrett J A, Elshourbagy N A, Bergsma D J, Yanagisawa M
`(1998) Orexins and orexin receptors: a family of hypothalamic neu-
`ropeptides and G protein-coupled receptors that regulate feeding
`behavior. Cell 92: 573–585
`Tecott L H, Sun L M, Akana S F, Strack A M, Lowenstein D H, Dallman
`M F, Julius D (1995) Eating disorder and epilepsy in mice lacking 5-
`HT2C serotonin receptors. Nature 374: 542–546
`Templeman L A, Reynolds G P, Arranz B, San L (2005) Polymorphisms
`of the 5-HT2C receptor and leptin genes are associated with antipsy-
`chotic drug-induced weight gain in Caucasian subjects with a first-
`episode psychosis. Pharmacogenet Genomics 15: 195–200
`Vickers S P, Benwell K R, Porter R H, Bickerdike M J, Kennett G A,
`Dourish C T (2000) Comparative effects of continuous infusion of
`mCPP, Ro 60-0175 and d-fenfluramine on food intake, water intake,
`body weight and locomotor activity in rats. Br J Pharmacol 130:
`1305–1314
`von Meyenburg C, Langhans W, Hrupka B J (2003) Evidence for a role of
`the 5-HT2C receptor in central lipopolysaccharide-, interleukin-1 beta-,
`and
`leptin-induced anorexia. Pharmacol Biochem Behav 74:
`1025–1031
`Wang Q, Bing C, Al Barazanji K, Mossakowaska D E, Wang X M,
`McBay D L, Neville W A, Taddayon M, Pickavance L, Dryden S,
`Thomas M E, McHale M T, Gloyer I S, Wilson S, Buckingham R,
`Arch J R, Trayhurn P, Williams G (1997) Interactions between leptin
`and hypothalamic neuropeptide Y neurons in the control of food intake
`and energy homeostasis in the rat. Diabetes 46: 335–341
`Wilding J P, Gilbey S G, Bailey C J, Batt R A, Williams G, Ghatei M A,
`Bloom S R (1993) Increased neuropeptide-Y messenger ribonucleic
`acid (mRNA) and decreased neurotensin mRNA in the hypothalamus
`of the obese (ob/ob) mouse. Endocrinology 132: 1939–1944
`Yuan X, Yamada K, Ishiyama-Shigemoto S, Koyama W, Nonaka K
`(2000) Identification of polymorphic loci in the promoter region of the
`serotonin 5-HT2C receptor gene and their association with obesity and
`type II diabetes. Diabetologia 43: 373–376
`Zhang Z J, Yao Z J, Liu W, Fang Q, Reynolds G P (2004) Effects of
`antipsychotics on fat deposition and changes in leptin and insulin
`levels. Magnetic resonance imaging study of previously untreated
`people with schizophrenia. Br J Psychiatry 184: 58–62
`
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