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The University of Michigan Depression Center Colloquium Series

The University of Michigan Depression Center Colloquium Series. The Colloquium Series is made possible by an educational grant from GlaxoSmithKline. Eating Disorders and Mood Regulation. Walter Kaye, MD University of Pittsburgh University of California San Diego Funding:

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The University of Michigan Depression Center Colloquium Series

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  1. The University of Michigan Depression Center Colloquium Series The Colloquium Series is made possible by an educational grant from GlaxoSmithKline.

  2. Eating Disorders and Mood Regulation Walter Kaye, MD University of Pittsburgh University of California San Diego Funding: MH046001, MH042984, MH066122; MH001894; Price Foundation

  3. The New Neurobiology of ED • Genetic risk - temperament • Identification of brain circuits • How is behavior encoded in the brain • Develop more effective treatments

  4. Nervous Consumption” (Morton, 1689) Mrs. Duke’s daughter, in the eighteenth year of her age, fell into a total suppression of her monthly courses from a multitude of cares and passions of her mind...from which time her appetite began to abate. She thus neglected herself for two full years. Never did I see one conversant with the living, so much wasted, yet there was no fever, no distemper of the lungs, or signs of preternatural expence of the nutritious juices. Only her appetite was diminished.

  5. Anorexia Nervosa • Many women diet in our culture • Relatively few develop anorexia nervosa • Are there susceptibility factors that make some women vulnerable to dieting, weight loss? • Most homogenous psychiatric disorders • 90-95% female • Onset teenage years – puberty • Monotonous symptoms • Highest mortality rate

  6. BEHAVIORAL TRAITS

  7. Subtypes of Eating Disorders AN-BN=anorexia nervosa, binge-eating/purging subtype.APA. DSM-IV-TR; 2000.

  8. Potential AN, BN TraitsStrober 1980; Casper 1990; O’Dwyer 1996; Ward 1998; Johnson-Sabine 1992; Collings & King 1994; Sullivan 1998; Srinivasagam 1995; Fallon 1991; Norring 1993; Keller 1992; Kaye 1998; Deep 1995; Bulik 1996;7; Fairburn 1997;9; Steiger 2000, 2001; Godart 2000 • Premorbid • “Best little girl in the world” • Majority have childhood anxiety disorder that precedes onset AN, BN • Childhood negative self-evaluation, perfectionism , obsessive personality • Persistent Symptoms After Recovery • Obsessions - body image, weight, food • Obsessions - perfectionism, symmetry, exactness • Anxiety, harm avoidance • Differences Between AN and BN • Novelty seeking BN > AN, BN extremes of over- and under-control • Behaviors are exaggerated by malnutrition

  9. Symptoms in Ill AN Patients Compared to Healthy Control Women (CW) p < .001 Obsessions Speilberger Trait Anxiety Compulsions (Y-BOCS) 60 50 15 40 30 10 20 5 10 0 0 Control Ill AN Women Control Ill AN Women Women Women Drive for Thinness (EDI) Perfectionism (MPS) 20 150 15 100 10 50 5 0 0 Control Ill AN Women Control Ill AN Women Women Women Y-BOCS = Yale-Brown Obsessive Compulsive Scale; MPS = Multidimensional Perfectionism Index; EDI = Eating Disorder Index

  10. Rates of Major Depressive Disorder

  11. Childhood Onset of Major Depressive Disorder (MDD) Price Foundation Genetic Collaborative Study *the percent of individuals who had the onset of MDD in childhood before the onset of the eating disorder, In comparison to all the individuals with an eating disorder

  12. Childhood Symptoms of Obsessive-Compulsive Personality Traits: Percentage of Individuals With Traits % of Patients Anderluh MB, et al. Am J Psychiatry. 2003;160(2):242-247.

  13. Lifetime Rates Anxiety Disorders (AD)Price Foundation Studies group difference *p<.05

  14. Anxiety Disorders (AD)Lifetime and Premorbid Rates

  15. Anxiety Disorders: Childhood / Premorbid RatesPrice Foundation Studies

  16. Speilberger Trait Anxiety InventoryED group vs CW *p<.05 * * * * *

  17. Depression and Anxiety(and perfectionism, obsessionality, etc) • Common comorbid symptoms in AN, BN • Exaggerated by malnutrition • Onset often in childhood before development of an ED • Tends to persist after remission of ED symptoms • Are these vulnerabilities that put people at risk for developing an ED? • Are they heritable? • How are they encoded in the brain?

  18. VULNERABILITIESPOSITIVE ASPECTS • Many traits are positive • Precise, attention to detail, achievement oriented • Advantage in engineering, medicine, academics, etc • Perhaps illness caused by • Excessive load of traits (overwhelms compensatory mechanisms) • Female gonadal steroids and/or age-related • Environment influences: stress, culture, dieting • Treatment strategies • ? Constructive utilization of traits

  19. GENETICS Funding: MH046001, MH042984, MH066122; MH001894; Price Foundation

  20. Familial Transmission of AN and BN Strober 2000 Am J Psych (504 probands and 1831 relatives); *< .05 vs. relatives of CW

  21. Heritability EstimatesTreasure & Holland 1990; Fichter & Noegel 1990; Holland 1984, 1988; Hsu 1990; Kendler 1991, 1995; Walters & Kendler 1995; Bulik 1998, 2003; Klump et al, 2001; Wade 1999; 2000; Ben-Dor 2002; Rowe 2002

  22. Price Foundation International Multicenter Genetic Study Kaye 2003, 2004; Bulik et al, 2005, 2004; Devlin et al, 2003, 2005 • 600 families with AN, BN • Found heritable traits • Obsessionality • Composite Anxiety measure • Concern over mistakes • Food-related obsessions • These and other behaviors strongly associated with regions of chromosomes • Actual genes remain to be discovered LOD scores for ch 1 showing suggestive linkage for AN for those with obsessionality and EDI drive for thinness occurring in their family

  23. Genetic Study of Anorexia Nervosa In FamiliesNational Institute of Health Collaborative Study • 10 clinical sites N America, Europe • 400 families with 2 or more members • with AN • Repository owned by the public • for investigation of genes and behavior • www.angenetics.org (info, contact form) • 1 888 895 3886 • EDResearch@msx.upmc.edu

  24. NeurobiologyBrain Imaging

  25. Puzzling AN SymptomsTreatment Targets • Feeding • Restrictive eating • Obsessive interest in diet, recipes, cooking for others • Odd food choices and combinations • Body image distortions • Feeling fat • Increased exercise • Stereotypic, fidgety, relentless • Increased drive • Achievement oriented, goal directed • Lack of insight (when ill) • Ego syntonic symptoms • Failure to learn from experience (or think logically) • ? Alterations of reward, hedonics • Ascetic, anhedonic personality • Lack of response to normally rewarding stimuli • Anxious, obsessive, perfectionistic temperament

  26. Brain and Behavior • Unlikely to be a center in the brain causing “AN” • Behavior combination of multiple “traits” • Gene differences can alter temperament “traits” and brain chemistry • How do we figure out what is a trait? • Do they occur before someone gets AN, BN? • Do they persist after recovery from AN, BN? • Do they run in families? • How does temperament become an illness?

  27. HOW DOES THE BRAIN CODE BEHAVIOR? • OLD: Syndromes – collection of symptoms • AN, BN, depression, anxiety • NEW: Behavioral Economics • Assess stimuli • Compare to past memories • Choose appropriate response, consider short and long term consequences • Action • Assess effect of action • Learn from experience

  28. hippocampus PLAN ACTION LEARN MEMORY OPTIMAL STIMULI RESPONSE GOAL DIRECTED BEHAVIOR AFFECT amygdala

  29. Brain Dopamine (DA)Optimal Response to Stimuli • DA cell fires in response to salient environmental stimuli (rewarding, aversive, novel) • DA encodes motivation and appropriate choices • Part of apparatus that makes value judgments and makes “correct” decision in response to a stimuli • Disturbances of brain DA - altered activity, reward, motivation • Parkinson’s Disorder • Drug abuse

  30. Brain Imaging Studies Dopamine D2/D3 Receptors in Striatum

  31. Increase in DA in nucleus accumbens induced by food and by amphetamines as assessed by microdialysis in rodents Volkow and Wise 2005

  32. Cocaine DA D2 Receptor Availability Alcohol Heroin control addicted Brain Reward Center - Dopamine D2 Receptors are Lower in AddictionVolkow et al DA DA DA DA DA DA DA DA DA DA DA DA Reward Circuits Non-Drug Abuser DA DA DA DA DA DA Reward Circuits Drug Abuser

  33. Clinical Characteristics“Recovered” ED Subjects

  34. Higher AVS Dopamine D2/D3 receptors in recovered RAN compared to recovered BAN or control women (CW) p = .03 PET [11C] Raclopride Binding Potential (Frank et al 2005; submitted) Recovered RAN Control Woman

  35. Addictive State Anorexia Nervosa “Normal” DA DA D2 Reward Circuits Reward Circuits Reward Circuits

  36. Addictive State Anorexia Nervosa “Normal” Amphetamines DA DA D2 Reward Circuits Reward Circuits Reward Circuits

  37. Addictive State Anorexia Nervosa “Normal” Amphetamines Food DA DA D2 Small amount food causes exaggerated effect? Reward Circuits Reward Circuits Reward Circuits

  38. AN have increased dopamine activity in the “reward” center • Do AN have an exaggerated stimuli response to a small amounts of food? • Are small amounts of food (or the thought of food) sufficient or even aversive (e.g. anxiety producing) stimuli? • Food restriction may be coping strategy to reduce DA activation • Similarly, exaggerated response to other stimuli may explain why AN restrict stimuli, and thus are anhedonic and ascetic. • This may account for sustained self denial of food, as well as most comforts and pleasures in life

  39. How Do People with AN Respond to Reward? • ‘Guessing-game’ task to see how the brain responds to positive (WIN) and negative (LOSS) feedback • Functional magnetic resonance brain imaging (fMRI) used to look at reward center in the brain • Signal related to activity of reward center Delgado et al, 2000, 2003, 2004; Tricomi et al, 2004; May et al 2004

  40. The Guessing Game • Participants guess whether the value of a hidden card is greater or less than ‘5’. • Participants are given $5.00 at the start. • Correct guess: WIN $2.00 • Incorrect guess: LOSE $1.00 • No response: lose $0.50 • Outcomes are determined before each guess and are randomly distributed but equal count.

  41. Brain AVS: Response to Wins and LossesWagner submitted. CW Wins vs Losses (F=5.76(6,72) p<0.0001); AN Wins vs Losses (F=2.03(6,72) ns); Group x condition x time (F=2.85(6,144) p=0.012)

  42. Altered AVS Response • CW distinguished between wins and losses • AN have similar response to wins and losses • AN may have increased DA receptor binding in the AVS • Perhaps overactive DA response to both Wins and Losses • Difficulty discriminating positive and negative stimuli? • Clinical implications • AN may be unable to discriminate pleasurable and aversive stimuli • May be very oversensitive to stimuli • Cannot learn easily learn from experience • May explain why it is difficult to use reward to motivate people with AN

  43. BRAIN IMAGING AND OTHER AN SYMPTOMS

  44. Implications • New insights into weight regulation, exercise, and achievement (“natural” amphetamine) • Development of new AN treatments targeted at unique symptoms, biology • Benefit of just understanding temperament traits • Remedial therapy – is it possible to train people to be able to more precisely modulation appropriate feelings and thoughts

  45. Not pictured Laura Mazurkewicz Shannon Henry Chris May Nicole Barbarich Carl Becker Jessica Hoge Scott Ziolko Winshu Li Frank Molchen Michael Himes Eva Gerardi Claire McConaha Lorie Fischer Sharon Barnes Victoria Vogel BartConard Kathy Plotnicov Angela Wagner Ursula Bailer Chet Mathis Julie Price Jennifer Figurski Guido Frank CarolynMeltzer Howard Aizenstein Guido Frank

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