Current Psychiatry Reports

, Volume 14, Issue 4, pp 398–405

Antipsychotic Agents in the Treatment of Anorexia Nervosa: Neuropsychopharmacologic Rationale and Evidence from Controlled Trials

Eating Disorders (E Attia, Section Editor)

Abstract

The search for an effective psychopharmacologic strategy in the treatment of anorexia nervosa (AN) has been elusive for decades and has run the gamut from reserpine to typical antipsychotics, to lithium, to tetrahydrocannabinol, to growth hormone, to anticonvulsants, to antidepressants, to atypical antipsychotics. Only recently has there arisen a potential “diamond in the rough” in the form of the atypical antipsychotic agent, olanzapine, which, in four randomized clinical trials, has shown superiority to placebo (two studies), chlorpromazine (one study), and aripiprazole (one study) in terms of weight gain and/or reduction in obsessional symptoms. The pharmacologic profile of olanzapine and other antipsychotic medications is discussed in light of the known pathophysiology of AN involving serotonin and dopamine systems, as well as brain-derived neurotrophic factor.

Keywords

Anorexia nervosa AN Eating disorders Antipsychotics Olanzapine Risperidone Aripiprazole Quetiapine Chlorpromazine Pimozide Sulpiride Serotonin 5-HT receptors Dopamine DA receptors Neuropsychopharmacology Neurophysiology Genetics Delusions Cognitive behavioral therapy Behavior therapy Treatment 

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Bruch H. Eating disorders: Obesity, anorexia nervosa, and the person within. Houston: Basic Books; 1973.Google Scholar
  2. 2.
    Steinglass JE, Eisen JL, Attia E, et al. Is anorexia nervosa a delusional disorder? An assessment of eating beliefs in anorexia nervosa. J Psychiatr Prac. 2007;13:65–71.CrossRefGoogle Scholar
  3. 3.
    American Psychiatric Association. Diagnostic and statistical manual of mental disorders (DSM-IV). 4th ed. Washington: American Psychiatric Association; 1994.Google Scholar
  4. 4.
    Maher AR, Maglione M, Bagley S, et al. Efficacy and comparative effectiveness of atypical antipsychotic medications for off-label uses in adults: a systematic review and meta-analysis. JAMA. 2011;306:1359–69.PubMedCrossRefGoogle Scholar
  5. 5.
    McElroy SL, Kotwal R, Keck Jr PE, Akiskal HS. Comorbidity of bipolar and eating disorders: distinct or related disorders with shared dysregulations? J Affect Dis. 2005;86:107–27.PubMedCrossRefGoogle Scholar
  6. 6.
    McElroy SL, Kotwal R, Keck Jr PE. Comorbidity of eating disorders with bipolar disorder and treatment implications. Bipolar Dis. 2006;8:686–95.CrossRefGoogle Scholar
  7. 7.
    Wildes JE, Marcus MD, Fagiolini A. Prevalence and correlates of eating disorder co-morbidity in patients with bipolar disorder. Psychiatry Res. 2008;161:51–8.PubMedCrossRefGoogle Scholar
  8. 8.
    Wang TS, Chou YH, Shiah IS. Combined treatment of olanzapine and mirtazapine in anorexia nervosa associated with major depression. Prog Neuro-Psychopharm Biol Psychiatry. 2006;30:306–9.CrossRefGoogle Scholar
  9. 9.
    Attia E, Mayer L, Killory E. Medication response in the treatment of patients with anorexia nervosa. J Psychiatr Pract. 2001;7:157–62.PubMedCrossRefGoogle Scholar
  10. 10.
    Walsh BT, Kaplan AS, Attia E, et al. Fluoxetine after weight restoration in anorexia nervosa: A randomized controlled trial. JAMA. 2006;295:2605–12.PubMedCrossRefGoogle Scholar
  11. 11.
    Brewerton TD. Drug therapy for patients with eating disorders. Psychiatric Times. 2004;21:59–68.Google Scholar
  12. 12.
    Brewerton TD. Toward a unified theory of serotonin dysregulation in eating and related disorders. Psychoneuroendocrinol. 1995;20:561–90.CrossRefGoogle Scholar
  13. 13.
    Brewerton TD. Transmitter systems in the eating disorders. In: D’aemon (ed) Textbook of biological psychiatry. 2002. Google Scholar
  14. 14.
    Brewerton TD, Steiger H. Neurotransmitter dysregulation in anorexia nervosa, bulimia nervosa and binge eating disorder. In: Brewerton TD, editor. Clinical handbook of eating disorders: An integrated approach. London: Marcel Dekker; 2004.Google Scholar
  15. 15.
    Brewerton TD, Frampton I, Lask B. The neurobiology of anorexia nervosa. US Psychiatry. 2009;2:57–64.Google Scholar
  16. 16.
    Kaye WH. Persistent alterations in behavior and serotonin activity after recovery from anorexia and bulimia nervosa. Ann N Y Acad Sci. 1997;817:162–78.PubMedCrossRefGoogle Scholar
  17. 17.
    Kaye WH, Gwirtsman HE, George DT, Ebert MH. Altered serotonin activity in anorexia nervosa after long-term weight restoration. Arch Gen Psychiatry. 1991;48:556–62.PubMedCrossRefGoogle Scholar
  18. 18.
    Kaye W, Strober M, Stein D, Gendall K. New directions in treatment research of anorexia and bulimia nervosa. Biol Psychiatry. 1999;45:1285–92.PubMedCrossRefGoogle Scholar
  19. 19.
    Kaye W. Neurobiology of anorexia and bulimia nervosa. Physiol Behav. 2008;94:121–35.PubMedCrossRefGoogle Scholar
  20. 20.
    Bailer UF, Price JC, Meltzer CC, et al. Altered 5-HT(2A) receptor binding after recovery from bulimia-type anorexia nervosa: relationships to harm avoidance and drive for thinness. Neuropsychopharmacol. 2004;29:1143–55.CrossRefGoogle Scholar
  21. 21.
    Bailer UF, Frank GK, Henry SE, Price JC, Meltzer CC, Mathis CA, Wagner A, Thornton L, Hoge J, Ziolko SK, Becker CR, McConaha CW, Kaye WH. Exaggerated 5-HT1A but normal 5-HT2A receptor activity in individuals ill with anorexia nervosa. Biol Psychiatry. 2007;61:1090–9.PubMedCrossRefGoogle Scholar
  22. 22.
    Galusca B, Costes N, Zito NG, et al. Organic background of restrictive-type anorexia nervosa suggested by increased serotonin 1A receptor binding in right frontotemporal cortex of both lean and recovered patients: [18 F]MPPF PET scan study. Biol Psychiatry. 2008;64:1009–13.PubMedCrossRefGoogle Scholar
  23. 23.
    Audenaert K, Van Laere K, Dumont F, et al. Decreased 5-HT2a receptor binding in patients with anorexia nervosa. J Nuclear Med. 2003;44:163–9.Google Scholar
  24. 24.
    Goethals I, Vervaet M, Audenaert K, et al. Differences of cortical 5-HT2A receptor binding index with SPECT in subtypes of anorexia nervosa: relationship with personality traits? J Psychiatr Res. 2007;41:455–8.PubMedCrossRefGoogle Scholar
  25. 25.
    Bailer UF, Frank GK, Henry SE, Price JC, Meltzer CC, Becker CR, Ziolko SK, Mathis CA, Wagner A, Barbarich-Marsteller NC, Putnam K, Kaye WH. Serotonin transporter binding after recovery from eating disorders. Psychopharmacol. 2007;195:315–24.CrossRefGoogle Scholar
  26. 26.
    Ehrlich S, Franke L, Schott R, et al. Platelet monoamine oxidase activity in under weight and weight-recovered females with anorexia nervosa. Pharmacopsychiatry. 2008;41:226–31.PubMedCrossRefGoogle Scholar
  27. 27.
    Gorwood P, Kipman A, Foulon C. The human genetics of anorexia nervosa. Eur J Pharmacol. 2003;480:163–70.PubMedCrossRefGoogle Scholar
  28. 28.
    Rybakowski F, Slopien A, Dmitrzak-Weglarz M, et al. The 5-HT2A–1438 A/G and 5-HTTLPR polymorphisms and personality dimensions in adolescent anorexia nervosa: association study. Neuropsychobiology. 2006;53:33–9.PubMedCrossRefGoogle Scholar
  29. 29.
    • Kiezebrink K, Mann ET, Bujac SR, Stubbins MJ, Campbell DA, Blundell JE. Evidence of complex involvement of serotonergic genes with restrictive and binge purge subtypes of anorexia nervosa. World J Biol Psychiatry. 2010;11:824–33. This recent genetic study showed a substantial and complex inter-relationship between several serotoninergic genes and AN. HTR2A was associated with both AN subtypes, while genes encoding HTR1D and HTR1B were associated with RAN and the gene encoding HTR2C was associated with BPAN. This study will help to guide future genetic research and also gives support for the use of atypical antipsychotics, such as olanzapine.PubMedCrossRefGoogle Scholar
  30. 30.
    Bergen AW, van den Bree MB, Yeager M, et al. Candidate genes for anorexia nervosa in the 1p33-36 linkage region: serotonin 1D and delta opioid receptor loci exhibit significant association to anorexia nervosa. Mol Psychiatry. 2003;8:397–406.PubMedCrossRefGoogle Scholar
  31. 31.
    Hu X, Giotakis O, Li T, et al. Association of the 5-HT2c gene with susceptibility and minimum body mass index in anorexia nervosa. Neuroreport. 2003;14:781–3.PubMedCrossRefGoogle Scholar
  32. 32.
    Hammer C, Kapeller J, Endele M, et al. Functional variants of the serotonin receptor type 3A and B gene are associated with eating disorders. Pharmacogenet Genom. 2009;19:790–9.CrossRefGoogle Scholar
  33. 33.
    Martaskova D, Slachtova L, Kemlink D, et al. Polymorphisms in serotonin-related genes in anorexia nervosa. The first study in Czech population and metaanalyses with previously performed studies. Folia Biol. 2009;55:192–7.Google Scholar
  34. 34.
    Brown KM, Bujac SR, Mann ET, et al. Further evidence of association of OPRD1 & HTR1D polymorphisms with susceptibility to anorexia nervosa. Biol Psychiatry. 2007;61:367–73.PubMedCrossRefGoogle Scholar
  35. 35.
    Hillebrand JJ, van Elburg AA, Kas MJ, van Engeland H, Adan RA. Olanzapine reduces physical activity in rats exposed to activity-based anorexia: possible implications for treatment of anorexia nervosa? Biol Psychiatry. 2005;58:651–7.PubMedCrossRefGoogle Scholar
  36. 36.
    Verhagen LA, Luijendijk MC, Hillebrand JJ, Adan RA. Dopamine antagonism inhibits anorectic behavior in an animal model for anorexia nervosa. Eur Neuropsychopharmacol. 2009;19:153–60.PubMedCrossRefGoogle Scholar
  37. 37.
    Wagner A, Aizenstein H, Venkatraman VK, et al. Altered reward processing in women recovered from anorexia nervosa. Am J Psychiatry. 2007;164:1842–9.PubMedCrossRefGoogle Scholar
  38. 38.
    Bachner-Melman R, Lerer E, Zohar AH, et al. Anorexia nervosa, perfectionism, and dopamine D4 receptor (DRD4). Am J Med Genetics. 2007;144B:748–56.CrossRefGoogle Scholar
  39. 39.
    Frank GK, Bailer UF, Henry SE, et al. Increased dopamine D2/D3 receptor binding after recovery from anorexia nervosa measured by positron emission tomography and [11c]raclopride. Biol Psychiatry. 2005;58:908–12.PubMedCrossRefGoogle Scholar
  40. 40.
    Frieling H, Romer KD, Scholz S, et al. Epigenetic dysregulation of dopaminergic genes in eating disorders. Int J Eat Disord. 2010;43:577–83.PubMedCrossRefGoogle Scholar
  41. 41.
    • Brandys MK, Kas MJ, van Elburg AA. A meta-analysis of circulating BDNF concentrations in anorexia nervosa. World J Biol Psychiatry. 2011;12:444–54. This study suggests that BDNF is not only an important indicator of illness and recovery but may also be a target for drug action in the treatment of AN. It is already known that atypical antipsychotics, especially olanzapine, increase BDNF levels..PubMedCrossRefGoogle Scholar
  42. 42.
    Ehrlich S, Salbach-Andrae H, Eckart S, et al. Serum brain-derived neurotrophic factor and peripheral indicators of the serotonin system in underweight and weight-recovered adolescent girls and women with anorexia nervosa. J Psych Neurosci. 2009;34:323–9.Google Scholar
  43. 43.
    Mercader JM, Fernandez-Aranda F, Gratacos M, et al. Blood levels of brain-derived neurotrophic factor correlate with several psychopathological symptoms in anorexia nervosa patients. Neuropsychobiology. 2007;56:185–90.PubMedCrossRefGoogle Scholar
  44. 44.
    Monteleone P, Maj M. Genetic susceptibility to eating disorders: associated polymorphisms and pharmacogenetic suggestions. Pharmacogenomics. 2008;9:1487–520.PubMedCrossRefGoogle Scholar
  45. 45.
    Stahl SM. Describing an atypical antipsychotic: Receptor binding and its role in pathophysiology. J Clin Psychiatry. 2003;5 Suppl 3:9–13.Google Scholar
  46. 46.
    Rizos EN, Papadopoulou A, Laskos E, et al. Reduced serum BDNF levels in patients with chronic schizophrenic disorder in relapse, who were treated with typical or atypical antipsychotics. World J Biol Psychiatry. 2010;11:251–5.PubMedCrossRefGoogle Scholar
  47. 47.
    Brambilla F, Garcia CS, Fassino S, et al. Olanzapine therapy in anorexia nervosa: psychological effects. Int Clin Psychopharmacol. 2007;22:197–204.PubMedCrossRefGoogle Scholar
  48. 48.
    •• Bissada H, Tasca GA, Barber AM, Bradwejn J. Olanzapine in the treatment of low body weight and obsessive thinking in women with anorexia nervosa: a randomized, double-blind, placebo-controlled trial. Am J Psychiatry. 2008;165:1281–8. This is a very important randomized, placebo-controlled study that demonstrated olanzapine’s ability to promote faster weight gain and alleviate obsessive symptoms in adult patients with AN who were receiving concurrent day treatment.PubMedCrossRefGoogle Scholar
  49. 49.
    •• Attia E, Kaplan AS, Walsh BT, et al. Olanzapine versus placebo for out-patients with anorexia nervosa. Psychol Med. 2011;41:2177–82. This is a recent breakthrough study which showed that olanzapine significantly facilitates weight recovery in adult outpatients with AN in comparison to placebo. This was despite the absence of any adjunctive psychotherapy or behavior therapy during the trial.PubMedCrossRefGoogle Scholar
  50. 50.
    Mondraty N, Birmingham CL, Touyz S, et al. Randomized controlled trial of olanzapine in the treatment of cognitions in anorexia nervosa. Australas Psychiatry. 2005;13:72–5.PubMedGoogle Scholar
  51. 51.
    Attia E, Kaplan AS, Schroeder L, Federici A. Atypical antipsychotic medication for patients with anorexia nervosa. Presented at the Annual Meeting of the Eating Disorders Research Society, Toronto, Canada, 2005.Google Scholar
  52. 52.
    Vandereycken W, Pierloot R. Pimozide combined with behavior therapy in the short-term treatment of anorexia nervosa. A double-blind placebo-controlled cross-over study. Acta Psychiatr Scand. 1982;66:445–50.PubMedCrossRefGoogle Scholar
  53. 53.
    Vandereycken W. Neuroleptics in the short-term treatment of anorexia nervosa. A double-blind placebo-controlled study with sulpiride. Br J Psychiatry. 1984;144:288–92.PubMedCrossRefGoogle Scholar
  54. 54.
    • Hagman J, Gralla J, Sigel E, et al. A double-blind, placebo-controlled study of risperidone for the treatment of adolescents and young adults with anorexia nervosa: a pilot study. J Am Acad Child Adol Psych. 2011;50:915–24. This is the only randomized, placebo-controlled study that has examined the role of risperidone in the treatment of AN—in this case, adolescent inpatients being treated in a specialized eating disorder service. Although there was no difference in weight gain, those receiving risperidone demonstrated significant improvements in interpersonal distrust compared with placebo.CrossRefGoogle Scholar
  55. 55.
    • Kafantaris V, Leigh E, Hertz S, et al. A placebo-controlled pilot study of adjunctive olanzapine for adolescents with anorexia nervosa. J Child Adol Psychopharmacol. 2011;21:207–12. This recent randomized, placebo-controlled study examined the role of olanzapine in a group of adolescents being treated in a specialty eating disorder service. There was no statistically significant benefit of olanzapine for weight or psychological symptoms. Again, we see that olanzapine seems to primarily benefit individuals who are not receiving concurrent intensive treatment.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Department of Psychiatry and Behavioral SciencesMedical University of South CarolinaCharlestonUSA
  2. 2.Mt. PleasantUSA

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