Drugs

, Volume 67, Issue 1, pp 27–56 | Cite as

Serotonergic Drugs

Effects on Appetite Expression and Use for the Treatment of Obesity
  • Jason C. G. Halford
  • Joanne A. Harrold
  • Emma J. Boyland
  • Clare L. Lawton
  • John E. Blundell
Review Article

Abstract

Over 35 years of research suggests that endogenous hypothalamic serotonin (5-hydroxytryptamine) plays an important part in within-meal satiation and post-meal satiety processes. Thus, the serotonin system has provided a viable target for weight control, critical to the action of at least two effective anti-obesity treatments, both producing clinically significant weight loss over a year or more. Numerous serotonin receptor subtypes have been identified; of these, serotonin 5-HT1B and 5-HT2C receptors have been specifically recognised as mediators of serotonin-induced satiety.

A number of serotonergic drugs, including selective serotonin reuptake inhibitors (SSRIs), dexfenfluramine and 5-HT2C receptor agonists, have been shown to significantly attenuate rodent bodyweight gain. This effect is strongly associated with marked hypophagia and is probably mediated by the hypothalamic melanocortin system. Additionally, sibutramine, dexfenfluramine, fluoxetine and the 5-HT2C receptor agonist chlorophenylpiperazine (mCPP) have all been shown to modify appetite in both lean and obese humans, resulting in reduced caloric intake. Clinical studies demonstrate serotonergic drugs specifically reduce appetite prior to and following the consumption of fixed caloric loads, and cause a reduction in pre-meal appetite and caloric intake at ad libitum meals. Weight loss in the obese has also been produced by treatment with both the serotonin precursor 5-hydroxytryptophan and the preferential 5-HT2C receptor agonist mCPP.

A new generation of 5-HT2C receptor selective agonists have been developed and at least one, lorcaserin (APD356), is currently undergoing clinical trials. In addition, 5-HT6 receptor antagonists such as PRX-07034 and BVT74316 have been shown to potently reduce food intake and bodyweight gain in rodent models and have recently entered clinical trials. However, the role of the 5-HT6 receptor in the expression of appetite remains to be determined. The hope is that these drugs will not only be free of their predecessors’ adverse effect profiles, but will also be equally or more effective at regulating appetite and controlling bodyweight.

Notes

Acknowledgements

The authors would like to thank Miss Lisa D.M. Richards for her help in preparing this manuscript and Dr Steve Vickers (RenaSci Consultancy Ltd) for providing much useful material for inclusion within this review. The authors would like in particular to thank Lora Heisler (University of Cambridge), Joel Elmquist (Harvard Medical School) and Michael Cowley (Oregon Health Sciences University) for providing updates on their most recent research and allowing us to reproduce their figure. The website for the Kissileff Laboratory is http://www.liv.ac.uk/Psychology/kissilefflab/Home.html.

The laboratory would like to thank corporate donors GlaxoSmithKline, NJ, USA, for providing funds for postgraduate training. Drs Harrold and Halford have received research funding from Predix Pharmaceuticals. Professor Blundell and Dr Halford have received research funding from Sanofi-Aventis.

References

  1. 1.
    Haiford JCG, Blundell JE. Separate systems for serotonin and leptin in appetite control. Ann Med 2000; 32: 222–32CrossRefGoogle Scholar
  2. 2.
    Vickers SP, Dourish CT. Serotonin receptor ligands and the treatment of obesity. Curr Opin Invest Drugs 2004; 5: 377–88Google Scholar
  3. 3.
    Bentley JM, Adams DR, Bebbington D. Indoline derivatives as 5-HT2C receptor agonists. Bioorg Med Chem Let 2004; 14: 2367–70CrossRefGoogle Scholar
  4. 4.
    Bray GA, York DA. Studies on food intake of genetically obese rats. Am J Physiol 1972; 233: 176–9Google Scholar
  5. 5.
    Jesperson S, Scheel-Kruger J. Evidence for a difference in mechanism of action between fenfluramine- and amphetamine-induced anorexia. J Pharm Pharmacol 1973; 22: 637–8CrossRefGoogle Scholar
  6. 6.
    Barrett AM, McSherry L. Inhibition of drug-induced anorexia in rats by methysergide. J Pharm Pharmacol 1975; 27: 889–95PubMedCrossRefGoogle Scholar
  7. 7.
    Pinder BM, Brogden RN, Sawyer PR, et al. Fenfluramine: a review of its pharmacological properties and therapeutic efficacy in obesity. Drugs 1975; 10: 241–323PubMedCrossRefGoogle Scholar
  8. 8.
    Garattini S, Samanin R. Anorectic drugs and brain neurotransmitters. In: Silverstone T, editor. Food intake and appetite. Berlin: Dahlem Konferenzen, 1976: 82–208Google Scholar
  9. 9.
    MacKenzie RG, Hoebel BG, Ducret RP, et al. Hyperphagia following intraventricular p-chlorophenylalanine-, leucine- or tryptophan-methyl esters: lack of correlation with whole brain serotonin levels. Pharmacol Biochem Behav 1979; 10: 951–5PubMedCrossRefGoogle Scholar
  10. 10.
    Blundell JE. Is there a role for serotonin (5-hydroxytryptamine) in feeding? Int J Obesity 1977; 1: 15–42Google Scholar
  11. 11.
    Hoyer D, Martin G. 5-HT receptor classification and nomenclature: towards a harmonization with the human genome. Neuropharmacology 1997; 36: 419–28PubMedCrossRefGoogle Scholar
  12. 12.
    Blundell JE, Halford JCG. Serotonin and appetite regulation: implications for the treatment of obesity. CNS Drugs 1998; 9: 473–95CrossRefGoogle Scholar
  13. 13.
    Rogers P, McKibbin PE, Williams G. Acute fenfluramine administration reduces neuropeptide Y concentrations in specific hypothalamic regions of the rat: possible implications for the anorectic effect of fenfluramine. Peptides 1991; 12: 251–5PubMedCrossRefGoogle Scholar
  14. 14.
    Brown CM, Coscina DV. Ineffectiveness of hypothalamic serotonin to block neuropeptide Y-induced feeding. Pharmacol Biochem Behav 1995; 51: 641–6PubMedCrossRefGoogle Scholar
  15. 15.
    Compan V, Dusticier N, Nieoullon A, et al. Opposite changes in striatal neuropeptide Y immunoreactivity after partial and complete serotonergic depletion in the rat. Synapse 1996; 24: 87–96PubMedCrossRefGoogle Scholar
  16. 16.
    Currie PJ. Integration of hypothalamic feeding and metabolic signals: focus on neuropeptide Y. Appetite 2003; 41: 335–7PubMedCrossRefGoogle Scholar
  17. 17.
    Heisler LK, Cowley MA, Tecott LH, et al. Activation of central melanocortin pathways by fenfluramine. Science 2002; 297: 609–11PubMedCrossRefGoogle Scholar
  18. 18.
    Heisler LK, Cowley MA, Kishi T, et al. Central serotonin and melanocortin pathways regulating energy homeostasis. N Y Acad Sci 2003; 994: 169–74CrossRefGoogle Scholar
  19. 19.
    Heisler LK, Jobst EE, Sutton GM, et al. Serotonin reciprocally regulated melanocortin neurons to modulate food intake. Neuron 2006; 51: 239–49PubMedCrossRefGoogle Scholar
  20. 20.
    Nambu T, Sakurai T, Mizukami K, et al. Distribution of orexin neurons in the adult rat brain. Brain Res 1999; 827: 243–60PubMedCrossRefGoogle Scholar
  21. 21.
    Hervieu GJ, Cluderay JE, Harrison DC, et al. Gene expression and protein distribution of the orexin-1 receptor in the rat brain and spinal cord. Neuroscience 2001; 103: 777–97PubMedCrossRefGoogle Scholar
  22. 22.
    Marcus JN, Aschkenasim CJ, Lee CE, et al. Differential expression of orexin receptors 1 and 2 in the rat brain. J Comp Neurol 2001; 435: 6–25PubMedCrossRefGoogle Scholar
  23. 23.
    Brown RE, Sergeeva OA, Eriksson KS, et al. Convergent excitation of dorsal raphe serotonin neurons by multiple arousal systems (orexin/hypocretin, histamine and noradrenaline). J Neurosci 2002; 22: 8850–9PubMedGoogle Scholar
  24. 24.
    Cai XJ, Liu XH, Evans M, et al. Orexins and feeding: special occasions or everyday occurrence? Reg Peptides 2002; 104: 1–9CrossRefGoogle Scholar
  25. 25.
    Orlando G, Brunetti Ll, Di Nisio C, et al. Effects of cocaine- and amphetamine-regulated transcript peptide, leptin and orexins on hypothalamic serotonin release. Eur J Pharmacol 2001; 430: 269–72PubMedCrossRefGoogle Scholar
  26. 26.
    Matsuzaki I, Sakurai T, Kunii K, et al. Involvement of the serotonergic system in orexin-induced behavioral alterations in rats. Reg Peptides 2002; 104: 119–23CrossRefGoogle Scholar
  27. 27.
    Brown RE, Sergeeva O, Eriksson KS, et al. Orexin A excites serotonergic neurons in the dorsal raphe nucleus of the rat. Neuropharmacology 2001; 40: 457–9PubMedCrossRefGoogle Scholar
  28. 28.
    Simansky KJ. Serotoninergic control of the organisation of feeding and satiety. Behav Brain Res 1996; 73: 37–42PubMedCrossRefGoogle Scholar
  29. 29.
    Hewitt KN, Lee MD, Dourish CT, et al. Serotonin 2C receptor agonists and the behavioural satiety sequence in mice. Pharmacol Biochem Behav 2002; 71: 691–700PubMedCrossRefGoogle Scholar
  30. 30.
    Collin M, Backberg M, Onnestam K, et al. 5-HT1A receptor immunoreactivity in hypothalamic neurons involved in body weight control. Neuroreport 2002; 13: 945–51PubMedCrossRefGoogle Scholar
  31. 31.
    Muraki Y, Yamanaka A, Tsujino N, et al. Serotonergic regulation of the orexin/hypocretin neurons through the 5-HT1A receptor. J Neurosci 2004; 24: 7159–66PubMedCrossRefGoogle Scholar
  32. 32.
    Barrafan-Majia MG, Castilla-Serna L, Calderon-Guzman D, et al. Effect of nutritional status and ozone exposure on rat brain serotonin. Arch Med Res 2002; 33: 15–9CrossRefGoogle Scholar
  33. 33.
    Xie QW. Experimental studies on changes of neuroendocrine functions during starvation and refeeding. Neuroendocrinology 1991; 53: 52–9PubMedCrossRefGoogle Scholar
  34. 34.
    Nishimura F, Nishihara M, Torii K, et al. Changes in responsiveness to serotonin on rat ventromedial hypothalamic neurons after food deprivation. Physiol Behav 1996; 60: 7–12PubMedCrossRefGoogle Scholar
  35. 35.
    Wolfe BW, Metzger ED, Stollar C. The effects of dieting on plasma tryptophan concentration and food intake in healthy women. Physiol Behav 1997; 61: 537–41PubMedCrossRefGoogle Scholar
  36. 36.
    Cowen PJ, Clifford EM, Walsh AES, et al. Moderate dieting causes 5-HT2C supersensitization. Psychol Med 1996; 26: 1156–9CrossRefGoogle Scholar
  37. 37.
    Varma M, Torelli GF, Meguid MM, et al. Potential strategies for ameliorating early cancer anorexia. J Surg Res 1998; 81: 69–76CrossRefGoogle Scholar
  38. 38.
    Yang ZJ, Blaha V, Meguid MM, et al. Interleukin-1α injection into ventromedial hypothalamic nucleus of normal rats depresses food intake and increases release of dopamine and serotonin. Pharmacol Biochem Behav 1999; 62: 61–5PubMedCrossRefGoogle Scholar
  39. 39.
    Cangiano C, Laviano A, Muscaritoli M, et al. Cancer anorexia: new pathogenic and therapeutic insights. Nutrition 1996; 12: S48–51PubMedGoogle Scholar
  40. 40.
    Cangiano C, Testa U, Muscaritoli M, et al. Cytokines, tryptophan and anorexia in cancer patients before and after surgical tumor ablation. Anticancer Res 1994; 14: 1451–5PubMedGoogle Scholar
  41. 41.
    Meguid MM, Fetissov SO, Blaha V, et al. Dopamine and serotonin VMN release is related to feeding status in obese and lean Zucker rats. Neuroreport 2000; 11: 2069–72PubMedCrossRefGoogle Scholar
  42. 42.
    Svec F, Thompson H, Porter J. Levels of hypothalamic neurotransmitters in lean and obese Zucker rats. Nutr Neurosci 2002; 5: 321–6PubMedCrossRefGoogle Scholar
  43. 43.
    Harrold JA, Widdowson PS, Clapham JC, et al. Individual severity of dietary obesity in unselected Wistar rats: relationship with hyperphagia. Am J Physiol 2000; 279: E340–7Google Scholar
  44. 44.
    Hassanain M, Levin BE. Dysregulation of hypothalamic serotonin turnover in diet-induced obese rats. Brain Res 2002; 929: 175–80PubMedCrossRefGoogle Scholar
  45. 45.
    Breum L, Rasmussen MH, Hilsted J. Twenty-four-hour plasma tryptophan concentrations and ratios are below normal in obese subjects and are not normalized by substantial weight reduction. Am J Clin Nutr 2003; 77: 1112–8PubMedGoogle Scholar
  46. 46.
    Clifton PG. The neuropharmacology of meal patterning. In: Cooper SJ, editor. Ethology and psychopharmacology. Chichester: Wiley, 1994: 313–28Google Scholar
  47. 47.
    Neill JC, Cooper SJ. Evidence that d-fenfluramine anorexia is mediated by 5-HT1 receptors. Psychopharmacology 1989; 97: 213–8PubMedCrossRefGoogle Scholar
  48. 48.
    Samanin R, Mennini T, Bendotti C, et al. Evidence that central 5-HT2C receptors do not play an important role in anorectic activity of d-fenfluramine in the rat. Neuropharmacology 1989; 28: 465–9PubMedCrossRefGoogle Scholar
  49. 49.
    Neill JC, Bendotti C, Samanin R. Studies on the role of 5-HT receptors in satiation and the effect of d-fenfluramine in the runway test. Eur J Pharmacol 1990; 190: 105–12PubMedCrossRefGoogle Scholar
  50. 50.
    Simansky JJ, Nicklous DM. Parabrachial infusion of — fenfluramine reduces food intake: blockade by the 5-HT1B antagonist SB-216641. Pharmacol Biochem Behav 2002; 71: 681–90PubMedCrossRefGoogle Scholar
  51. 51.
    Vickers SP, Dourish CT, Kennett GA. Evidence that hypophagia induced by d-fenfluramine and d-norfenfluramine in the rat is mediated by 5-HT2C receptors. Neuropharmacology 2001; 41: 200–9PubMedCrossRefGoogle Scholar
  52. 52.
    Wong DT, Reid LR, Threlkeld PG. Suppression of food intake in rats by fluoxetine: comparison of enantiomers and effects of serotonin antagonists. Pharmacol Biochem Behav 1988; 31: 475–9PubMedCrossRefGoogle Scholar
  53. 53.
    Grignaschi G, Samanin R. Role of serotonin and catecholamines in brain in feeding suppressant effects of fluoxetine. Neuropharmacology 1992; 31: 445–9PubMedCrossRefGoogle Scholar
  54. 54.
    Lightowler S, Wood M, Brown T, et al. An investigation of the mechanism responsible for fluoxetine-induced hypophagia in rats. Eur J Pharmacol 1996; 296: 137–43PubMedCrossRefGoogle Scholar
  55. 55.
    Lee MD, Clifton PG. Partial reversal of fluoxetine anorexia by the 5-HT antagonist metergoline. Psychopharmacology 1992; 107: 359–64PubMedCrossRefGoogle Scholar
  56. 56.
    Halford JCG, Blundell JE. Metergoline antagonizes fluoxetine induced suppression of food intake but not changes in the behavioural satiety sequence. Pharmacol Biochem Behav 1996; 54: 745–51PubMedCrossRefGoogle Scholar
  57. 57.
    Koe BK, Weissman A, Welch WM, et al. Sertraline, 1S,4S-N-methyl-4(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphathylamine, a new uptake inhibitor with selectivity for serotonin. J Pharmacol Exp Ther 1983; 266: 686–700Google Scholar
  58. 58.
    Lucki I, Kreider MS, Simansky KJ. Reduction of feeding behaviour by the serotonin uptake inhibitor sertraline. Psychopharmacology 1988; 96: 289–95PubMedCrossRefGoogle Scholar
  59. 59.
    Kennett GA, Curzon G. Evidence that the hypophagia induced by mCPP and TFMPP requires 5-HT1C and 5-HT1B receptors; hypophagia induced by RU-24969 only requires 5-HT1B receptors. Psychopharmacology 1988; 96: 93–100PubMedCrossRefGoogle Scholar
  60. 60.
    Kennett GA, Curzon G. Evidence that mCPP may have behavioural effects mediated by central 5-HT1C receptors. Br J Pharmacol 1988; 94: 137–47PubMedCrossRefGoogle Scholar
  61. 61.
    Kennett GA, Curzon G. Potencies of antagonists indicate that 5-HT1C receptors mediate 1–3(chlorophenyl)piperazine-induced hypophagia. BrJ Pharmacol 1991; 10: 2016–20CrossRefGoogle Scholar
  62. 62.
    Halford JCG, Blundell JE. The 5-HT1B receptor agonist CP-94,253 reduces food intake and preserves the behavioural satiety sequence. Physiol Behav 1996; 60: 933–9PubMedGoogle Scholar
  63. 63.
    Lee MD, Simansky KJ. CP-94,253: a selective serotoninlB (5-HT1B) agonist that promotes satiety. Psychopharmacology 1997; 131: 264–70PubMedCrossRefGoogle Scholar
  64. 64.
    Schreiber R, Selbach K, Asmussen M, et al. Effects of serotonin1/2 receptor agonists on dark-phase food and water intake in rats. Pharmacol Biochem Behav 2000; 67: 291–305PubMedCrossRefGoogle Scholar
  65. 65.
    Clifton PG, Lee MD, Dourish CT. Similarities in the action of Ro 60-0175, a 5-HT2C receptor agonist, and d-fenfluramine on feeding patterns in the rat. Psychopharmacology 2000; 152: 256–67PubMedCrossRefGoogle Scholar
  66. 66.
    Lee MD, Kennett GA, Dourish CT, et al. 5-HT1B receptors modulate components of satiety in the rat: behavioural and pharmacological analyses of the selective serotonin1B agonist CP-94,253. Psychopharmacology 2002; 164: 49–60PubMedCrossRefGoogle Scholar
  67. 67.
    Blundell JE, Latham CJ. Pharmacological manipulation of feeding behaviour: possible influences of serotonin and dopamine on food intake. In: Garattini S, Samanin R, editors. Central mechanisms of anorectic drugs. New York (NY): Raven Press, 1978: 83–109Google Scholar
  68. 68.
    Halford JCG, Wanninayake SCD, Blundell JE. Behavioural satiety sequence (BSS) for the diagnosis of drug action on food intake. Pharmacol Biochem Behav 1998; 61: 159–68PubMedCrossRefGoogle Scholar
  69. 69.
    Blundell JE, Latham CJ. Characteristic adjustments to the structure of feeding behaviour following pharmacological treatments: effects of amphetamine and fenfluramine and the antagonism by pimozide and metergoline. Pharmacol Biochem Behav 1980; 12: 717–22PubMedCrossRefGoogle Scholar
  70. 70.
    Blundell JE, McArthur RA. Behavioural flux and feeding: continuous monitoring of food intake and food selection, and the video-recording of appetitive and satiety sequences for the analysis of drug action. In: Samanin R, Garattini S, editors. Anorectic agents: mechanisms of action and tolerance. New York (NY): Raven Press, 1981: 19–43Google Scholar
  71. 71.
    Halford JCG, Blundell JE. 5-Hydroxytryptaminergic drugs compared on the behavioural sequence associated with satiety. Br J Pharmacol 1993; 100: 95Google Scholar
  72. 72.
    Clifton PG, Barnfield AMC, Philcox L. A behavioural profile of fluoxetine induced anorexia. Psychopharmacology 1989; 97: 89–95PubMedCrossRefGoogle Scholar
  73. 73.
    Simansky KJ, Viadya AH. Behavioural mechanisms for the anorectic actions of the serotonin (5-HT) uptake inhibitor sertraline in rats: comparison with directly acting agonists. Brain Res Bull 1990; 25: 953–60PubMedCrossRefGoogle Scholar
  74. 74.
    McGuirk J, Muscat R, Willner P. Effects of the 5-HT uptake inhibitors femoxetine and parpexetine, and the 5-HT1A agonist cltoprazine, on the behavioural satiety sequence. Pharmacol Biochem Behav 1992; 41: 801–5PubMedCrossRefGoogle Scholar
  75. 75.
    Kitchener SJ, Dourish CT. An examination of the behavioural specificity of hypophagia induced by 5-HT1B, 5-HT1C and 5-HT2 receptor agonists using the post-prandial sequence in rats. Psychopharmacology 1994; 113: 368–77CrossRefGoogle Scholar
  76. 76.
    Tecott LH, Sun LM, Akanna SF, et al. Eating disorder and epilepsy in mice lacking 5-HT2C serotonin receptors. Nature 1995; 374: 542–6PubMedCrossRefGoogle Scholar
  77. 77.
    Nonogaki K, Abdullah L, Goulding EH, et al. Hyperactivity and reduced energy cost of physical activity in serotonin 5-HT2C receptor mutant mice. Diabetes 2003; 52: 315–20PubMedCrossRefGoogle Scholar
  78. 78.
    Vickers SP, Clifton PG, Dourish CT, et al. Reduced satiating effect of d-fenfluramine in serotonin 5-HT2C receptor mutant mice. Psychopharmacology 1999; 143: 309–14PubMedCrossRefGoogle Scholar
  79. 79.
    Bouwknecht JA, van der Guten J, Hijsenm TH, et al. Male and female 5-HT1B receptor knockout mice have higher body weights than wildtypes. Physiol Behav 2001; 74: 507–16PubMedCrossRefGoogle Scholar
  80. 80.
    Silverstone T, Goodall E. The clinical pharmacology of appetite suppressant drugs. Int J Obes 1984; 8 (1): 23–33PubMedGoogle Scholar
  81. 81.
    Cangiano C, Ceci F, Casinco A, et al. Eating behaviour and adherence to dietary prescription in obese adult subjects treated with 5-hydroxytryptophan. Am J Clin Nutr 1992; 56: 863–7PubMedGoogle Scholar
  82. 82.
    Rogers PJ, Blundell JE. Effect of anorexic drugs on food intake and the micro-structure of eating in human subjects. Psychopharmacology 1979; 66: 159–65PubMedCrossRefGoogle Scholar
  83. 83.
    Hill AJ, Blundell JE. Sensitivity of the appetite control system in obese subjects to nutritional and serotoninergic challenges. Int J Obesity 1990; 14: 219–33Google Scholar
  84. 84.
    Wurtman JJ, Wurtman RJ, Growdon JH, et al. Carbohydrate craving in obese people: suppression by treatments affecting serotonergic transmission. Int J Eat Disord 1982; 1: 2–15CrossRefGoogle Scholar
  85. 85.
    Wurtman JJ, Wurtman RJ, Mark S, et al. d-Fenfluramine selectively suppresses carbohydrate snacking in obese subjects. Int J Eat Disord 1985; 4: 89–99PubMedCrossRefGoogle Scholar
  86. 86.
    Goodall E, Silverstone T. Differential effect of d-fenfluramine and metergoline on food intake in human subjects. Appetite 1988; 11: 215–88PubMedCrossRefGoogle Scholar
  87. 87.
    Blundell JE, Hill AJ. On the mechanism of action of dexfenfluramine: effect on alliesthesia and appetite motivation in lean and obese subjects. Clin Neuropharmacol 1988; 11 Suppl. 1: 121–34SGoogle Scholar
  88. 88.
    Goodall EM, Cowen PJ, Franklin M, et al. Ritanserin attenuates anorectic endocrine and thermic responses to d-fenfluramine in human volunteers. Psychopharmacology 1993; 112: 461–6PubMedCrossRefGoogle Scholar
  89. 89.
    McGuirk J, Silverstone T. The effect of 5-HT re-uptake inhibitor fluoxetine on food intake and body weight in healthy male subjects. Int J Obesity 1990; 14: 361–72Google Scholar
  90. 90.
    Lawton CL, Wales JK, Hill AJ, et al. Serotoninergic manipulation, meal-induced satiety and eating patterns: effects of fluoxetine in obese female subjects. Obes Res 1995; 3: 345–56PubMedCrossRefGoogle Scholar
  91. 91.
    Wadden TA, Bartlet SJ, Foster GD, et al. Sertraline and relapse prevention following treatment by a very low calorie diet: a controlled clinical trial. Obes Res 1995; 3: 549–57PubMedCrossRefGoogle Scholar
  92. 92.
    Walsh AE, Smith KA, Oldman AD. m-Chlorophenylpiperazine decreases food intake in a test meal. Psychopharmacology 1994; 116: 120–2PubMedCrossRefGoogle Scholar
  93. 93.
    Sargent PA, Sharpley AL, Williams C, et al. 5-HT2C receptor activation decreases appetite and body weight in obese subjects. Psychopharmacology 1997; 133: 309–12PubMedCrossRefGoogle Scholar
  94. 94.
    Boeles S, Williams C, Campling GM, et al. Sumatriptan decreases food intake and increases plasma growth hormone in healthy women. Psychopharmacology 1997; 129 (Pt 2): 179–82PubMedCrossRefGoogle Scholar
  95. 95.
    Rolls BJ, Shide DJ, Thorward ML, et al. Sibutramine reduces food intake in non-dieting women with obesity. Obes Res 1998; 6: 1–11PubMedCrossRefGoogle Scholar
  96. 96.
    Cangiano C, Laviano A, Del Ben M, et al. Effects of oral 5-hydroxy-tryptophan on energy intake and macronutrient selection in non-insulin dependent diabetic patients. Int J Obesity 1988; 22: 648–54CrossRefGoogle Scholar
  97. 97.
    Foltin RW, Haney M, Comer S, et al. Effect of fenfluramine on food intake, mood, and performance of humans living in a residential laboratory. Physiol Behav 1996a; 59: 295–305CrossRefGoogle Scholar
  98. 98.
    Drent ML, Zelissen PMJ, Kopperchaar HPF, et al. The effect of dexfenfluramine on eating habits in a Dutch ambulatory android overweight population with an overconsumption of snacks. Int J Obesity 1995; 19: 299–304Google Scholar
  99. 99.
    Pijl H, Koppeschaar HPF, Willekens FLA, et al. Effect of serotonin re-uptake inhibition by fluoxetine on body weight and spontaneous food choice in obesity. Int J Obesity 1991; 15: 237–42Google Scholar
  100. 100.
    Ward AS, Comer SD, Haney M, et al. Fluoxetine-maintained obese humans: effect on food intake and body weight. Physiol Behav 1999; 66: 815–21PubMedCrossRefGoogle Scholar
  101. 101.
    Chapelot D, Mamonier C, Thomas F, et al. Modalities of the food intake-reducing effect of sibutramine in humans. Physiol Behav 2000; 68: 299–308PubMedCrossRefGoogle Scholar
  102. 102.
    Hansen DL, Toubro S, Stock MJ, et al. Thermogenic effects of sibutramine in humans. Am J Clin Nutr 1998; 68: 1180–6PubMedGoogle Scholar
  103. 103.
    Hansen DL, Toubro S, Stock MJ, et al. The effect of sibutramine on energy expenditure and appetite during chronic treatment without dietary restriction. Int J Obesity 1999; 23: 1016–24CrossRefGoogle Scholar
  104. 104.
    Barkeling B, Elfhag K, Rooth P, et al. Short-term effects of sibutramine (Reductil™) on appetite and eating behaviour and the long-term therapeutic outcome. Int J Obesity 2003; 27: 693–700CrossRefGoogle Scholar
  105. 105.
    Cowen PJ, Sargent PA, Williams C, et al. Hypophagic, endocrine and subjective responses to m-chlorophenylpiperazine in healthy men and women. Hum Psychopharmacol 1995; 10: 385–91CrossRefGoogle Scholar
  106. 106.
    Ghaziuddin N, Welch K, Greden J. Central serotonergic effects of m-chlorophenylpiperazine (mCPP) among normal control adolescents. Neuropsychopharmacology 2003; 28: 133–9PubMedCrossRefGoogle Scholar
  107. 107.
    Fisler JS, Undernerger SJ, York DA, et al. d-Fenfluramine in a rat model of dietary fat-induced obesity. Pharmacol Biochem Behav 1993; 45: 487–93PubMedCrossRefGoogle Scholar
  108. 108.
    Vickers SP, Benwell KR, Porter RH, et al. 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 2000; 130: 1305–14PubMedCrossRefGoogle Scholar
  109. 109.
    Vickers SP, Easton N, Webster LJ, et al. Oral administration of the 5-HT2C receptor agonist, mCPP, reduces body weight gain in rats over 28 days as a result of maintained hypophagia. Psychopharmacology 2003; 167: 274–80PubMedGoogle Scholar
  110. 110.
    Yen TT, Wong DT, Bemis KG. Reduction of food consumption and body weight of normal and obese mice by chronic treatment with fluoxetine: a serotonin reuptake inhibitor. Drug Dev Res 1987; 10: 37–45CrossRefGoogle Scholar
  111. 111.
    Fuller RW, Wong DT. Fluoxetine: a serotonergic appetite suppressant drug. Drug Dev Res 1989; 17: 1–15CrossRefGoogle Scholar
  112. 112.
    Nielsen JA, Chapin DS, Johson JL, et al. Sertraline, a serotonin-uptake inhibitor, reduces food intake and body weight in lean rats and genetically obese mice. Am J Clin Nutr 1992; 55: 185–8sGoogle Scholar
  113. 113.
    Wieczorek I, Schulz C, Jarry H, et al. The effects of the selective serotonin reuptake-inhibitor fluvoxamine on body weight in Zucker rats are mediated by corticotropin-releasing hormone. Int J Obesity 2001; 25: 1566–9CrossRefGoogle Scholar
  114. 114.
    Konkle ATM, Sreter KB, Bajer SL, et al. Chronic paroxetine infusion influences macronutrient selection in male Sprague-Dawley rats. Pharmacol Biochem Behav 2003; 74: 883–90PubMedCrossRefGoogle Scholar
  115. 115.
    Kennett GA, Wood MD, Bright F, et al. SB 242084, a selective and brain potent 5-HT2C receptor. Neuropharmacology 1997; 36: 609–20PubMedCrossRefGoogle Scholar
  116. 116.
    Hayashi A, Sonoda R, Kimura Y, et al. Antiobesity effect of YM348, a novel 5-HT2C receptor agonist, in Zucker rats. Brain Res 2004; 1011: 221–7PubMedCrossRefGoogle Scholar
  117. 117.
    Bjenning C, Williams J, Whelan K, et al. Chronic oral administration of APD356 significantly reduces body weight and fat mass in obesity-prone (DIO) male and female rats. Int J Obesity 2004; 28 (1 Suppl.): 214sGoogle Scholar
  118. 118.
    Haddock CK, Poston WSC, Dill PL, et al. Pharmacotherapy for obesity: a quantitative analysis of four decades of published randomized clinical trials. Int J Obesity 2002; 26: 262–73CrossRefGoogle Scholar
  119. 119.
    Pinder RM, Brogden RN, Sawyer PR, et al. Fenfluramine: a review of the pharmacological properties and therapeutic efficacy in obesity. Drugs 1975; 10: 241–323PubMedCrossRefGoogle Scholar
  120. 120.
    Guy-Grand B, Apfelbaum M, Creoaldi C, et al. International trial of long-term dexfenfluramine in obesity. Lancet 1989; Nov 11: 1142–5CrossRefGoogle Scholar
  121. 121.
    Guy-Grand B. Clinical studies with d-fenfluramine. Am J Clin Nutr 1992; 55: 173–6sGoogle Scholar
  122. 122.
    Finer N, Finer S, Naoumova RP. Drug therapy after very-low-calorie-diets. Am J Clin Nutr 1992; 56: 195–8sGoogle Scholar
  123. 123.
    James WPT, Astrup A, Finer N, et al. Effect of sibutramine on weight maintenance after weight loss: a randomised trial. Lancet 2000; 356: 2119–25PubMedCrossRefGoogle Scholar
  124. 124.
    McMahon FG, Fujioka K, Singh BN, et al. Efficacy and safety of sibutramine in obese white and African American patients with hypertension: a 1-year, double-blind, placebo-controlled, multicenter trial. Arch Intern Med 2000; 160: 2185–91PubMedCrossRefGoogle Scholar
  125. 125.
    Smith IG, Goulder MA. Randomized placebo-controlled trial of long-term treatment with sibutramine in mild to moderate obesity. J Fam Pract 2001; 50: 505–12PubMedGoogle Scholar
  126. 126.
    McNulty SJ, Ur E, Williams G. A randomized trial of sibutramine in the management of obese type 2 diabetic patients treated with metformin. Diabetes Care 2003; 26: 125–33PubMedCrossRefGoogle Scholar
  127. 127.
    Poston WSC, Reeves RS, Haddock CK, et al. Weight loss in obese Mexican Americans treated for 1-year with orlistat and lifestyle modification. Int J Obesity 2003; 27: 1486–93CrossRefGoogle Scholar
  128. 128.
    Arterburn DE, Crane PK, Veenstra DL. The efficacy and safety of sibutramine for weight loss: a systematic review. Arch Intern Med 2004; 164: 994–1003PubMedCrossRefGoogle Scholar
  129. 129.
    Padwal R, Li SK, Lau DCW. Long-term pharmacotherapy for overweight and obesity: a systematic review and meta-analysis of randomized controlled trials. Int J Obesity 2003; 27: 1437–46CrossRefGoogle Scholar
  130. 130.
    Wise SD. Clinical studies with fluoxetine in obesity. Am J Clin Nutr 1992; 55: 181–4sGoogle Scholar
  131. 131.
    Goldstein DJ, Rampey AH, Roback PJ, et al. Efficacy and safety of long-term fluoxetine treatment of obesity-maximising success. Obes Res 1995; 3 Suppl. 4: 481–90sGoogle Scholar
  132. 132.
    Darga LL, Carroll-Michals C, Botsford SJ, et al. Fluoxetine’s effect on weight loss in obese subjects. Am J Clin Nutr 1991; 54: 315–21Google Scholar
  133. 133.
    Goldstein DJ, Rampey AH, Enas GG, et al. Fluoxetine: a randomized clinical trial in the treatment of obesity. Int J Obesity 1994; 18: 129–35Google Scholar
  134. 134.
    Simpson RJ, Lawton DJ, Watt MH, et al. Effect of zimelidine, a new antidepressant, on appetite and body weight. Br J Clin Pharmacol 1981; 11: 96–8PubMedCrossRefGoogle Scholar
  135. 135.
    Van Baak M, Lentjes M, Mujakovic S, et al. Behavior modification and societal change in the prevention of obesity. Obes Res 2003; 11 (1 Suppl.): A111Google Scholar
  136. 136.
    Halford JCG. Serotonin (5-HT) drugs: effects on appetite expression and use for the treatment of obesity. Curr Drug Targets 2004; 5: 637–46PubMedCrossRefGoogle Scholar
  137. 137.
    Abeniam L, Moride Y, Brenot F, et al. Appetite suppressant drugs and the risk of primary pulmonary hypertension. N Engl J Med 1996; 335: 609–16CrossRefGoogle Scholar
  138. 138.
    Greenway FL, Caruso MK. Safety of obesity drugs. Expert Opin Drug Saf. In pressGoogle Scholar
  139. 139.
    Bays HE, Dujovene CA. Anti-obesity drug development. Expert Opin Invest Drugs 2002; 11: 1189–204CrossRefGoogle Scholar
  140. 140.
    Bays HE. Current and investigational antiobesity agents and obesity therapeutic treatment targets. Obes Res 2004; 12: 1197–211PubMedCrossRefGoogle Scholar
  141. 141.
    Smith BM, Smith JM, Tsai JH, et al. Discovery and SAR of new benzazapines and potent and selective 5-HT2C receptor agonist for the treatment of obesity. Bioorgan Med Chem Lett 2005; 12: 1467–70CrossRefGoogle Scholar
  142. 142.
    Smith S, Anderson J, Frank A, et al. The effects of APD356, a selective 5-HT2C agonist, on weight loss in a 4 week study in healthy obese patients [Abstract]. Obes Res 2005; 13 Suppl.: 101–RCrossRefGoogle Scholar
  143. 143.
    Halford JCG, Cooper GD, Dovey TM, et al. Pharmacological approaches to obesity treatment; current medical chemistry. CNS Agents 2003; 3: 283–310Google Scholar
  144. 144.
    Van Gaal LF, Rissanen AM, Scheen AJ, et al. Effects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1-year experience from the RIO-Europe study. Lancet 2005; 365: 1389–97PubMedCrossRefGoogle Scholar
  145. 145.
    Woolley ML, Marsden CA, Fone KC. 5-HT6 receptors. Current drug targets: CNS Neurol Disord 2004; 3: 59–79CrossRefGoogle Scholar
  146. 146.
    Vickers SP, Dourish CT. Serotonin receptor ligands and the treatment of obesity. Curr Opin Invest Drugs 2004; 5: 377–88Google Scholar
  147. 147.
    Shacham S, Marantz Y, Senderowitz H, et al. Novel 5-HT6 receptor antagonists for the treatment of obesity. Obes Res 2005; 13: A192CrossRefGoogle Scholar
  148. 148.
    EPIX Pharmaceuticals. EPIX Pharmaceuticals announces findings from obesity and cognitive impairment studies at Society for Neuroscience Meeting [online]. Available from URL: http://investor.epixpharma.com/phoenix.zhtml?c=91717&p=irol-newsArticle&ID=917339&highlight [Accessed 2006 Nov13]
  149. 149.
    Biovitrum’s project portfolio within obesity advances [online]. Available from URL: http://www.stockholmbioregion.com/templates/page___517.aspx [Accessed 2006 Nov 13]
  150. 150.
    Halford JCG. Obesity drugs in clinical development. Curr Opin Invest Drugs 2006; 7: 312–8Google Scholar

Copyright information

© Adis Data Information BV 2007

Authors and Affiliations

  • Jason C. G. Halford
    • 1
    • 2
  • Joanne A. Harrold
    • 1
    • 3
  • Emma J. Boyland
    • 1
  • Clare L. Lawton
    • 2
  • John E. Blundell
    • 2
  1. 1.Kissileff Laboratory for the Study of Human Ingestive Behaviour, School of PsychologyUniversity of LiverpoolLiverpoolUK
  2. 2.Institute of PsychologyUniversity of LeedsLeedsUK
  3. 3.Department of Medicine, Diabetes and Endocrinology Research GroupUniversity of LiverpoolLiverpoolUK

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