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The University of Michigan Depression Center Colloquium Series The Colloquium Series is made possible by an educational grant from GlaxoSmithKline.
The University of Michigan Depression Center Colloquium
Series
The Colloquium Series is made possible by an educational grant from GlaxoSmithKline.
10/06
Eating Disorders and Mood Regulation
Walter Kaye, MDUniversity of Pittsburgh
University of California San Diego
Funding:MH046001, MH042984, MH066122; MH001894; Price Foundation
10/06
The New Neurobiology of ED
• Genetic risk - temperament
• Identification of brain circuits
• How is behavior encoded in the brain
• Develop more effective treatments
10/06
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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.
10/06
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
10/06
BEHAVIORAL TRAITS
10/06
Subtypes of Eating Disorders
DSM-IV AN AN-BN BN
% prevalence 0.25 0.25 1-3
% women 95 95 90
Weight Low Low Normal
Eating Restrict Restrict,binge
Restrict,binge
Mood/impulse control
Overcontrol
Over/under control
Over/under control
AN-BN=anorexia nervosa, binge-eating/purging subtype.APA. DSM-IV-TR; 2000.
10/06
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
10/06
Symptoms in Ill AN Patients Compared to Healthy Control Women (CW) p
< .001
Perfectionism (MPS)
0
50
100
150
ControlWomen
Ill AN Women
Drive for Thinness (EDI)
0
510
15
20
ControlWomen
Ill AN Women
Obsessions Compulsions (Y-BOCS)
0
5
10
15
ControlWomen
Ill AN Women
Speilberger Trait Anxiety
0102030405060
ControlWomen
Ill AN Women
Y-BOCS = Yale-Brown Obsessive Compulsive Scale; MPS = Multidimensional Perfectionism Index;EDI = Eating Disorder Index
10/06
Rates of Major Depressive Disorder
Probands Relatives
AN 43%-83% 6%-25%
BN 30%-80% 11%-50%
Winokur 1980, Gershon 1983; Hudson 1983, 1987; Rivinus 1984; Piran1985; Bulik, 1987; Logue 1989; Kassett 1989; Strober 1990; Fornari 1992; Herzog 1992; Kennedy 1994; Bushnell 1994; Boumann & Yates, 1994; Deep 1995; Brewerton1995; Garfinkel1995; Lilenfeld 1998
10/06
Childhood Onset of Major Depressive Disorder (MDD)
Price Foundation Genetic Collaborative Study RAN BAN BN ED
Number 468 377 167 1012
Lifetime MDD 86% 92% 98% 90%
% Childhood MDD* 29% 32% 32% 30%
*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
10/06
Childhood Symptoms of Obsessive-Compulsive Personality Traits: Percentage of Individuals
With Traits
0
20
40
60
80
100
Perfectionistic Inflexible Rule Bound
AN (n=26) AN-BN (n=18) BN (n=28)
% o
f Pat
ient
s
Anderluh MB, et al. Am J Psychiatry. 2003;160(2):242-247.
10/06
Lifetime Rates Anxiety Disorders (AD)Price Foundation Studies
group difference *p<.05
AD AN BAN BN TOTAL
n 97 293 282 672
1+ AD 55% 62% 68% 64%
OCD 34% 44% 40% 41%
Social Phobia 22% 23% 16% 20%
Specific Phobia 14% 18% 12% 15%
GAD 13% 10% 8% 10%
PTSD 5% 15% 13% 13%
Panic Disorder 9% 11% 11% 11%
Agoraphobia 3% 4% 2% 3%
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Anxiety Disorders (AD)Lifetime and Premorbid Rates
Study ED n Lifetime AD AD before ED
Deep 95 AN 24 68% 58%
Bulik 97 AN 68 60% 54%
Bulik 97 BN 116 57% 54%
Godart 00 AN 29 83% 62%
Godart 00 BN 34 71% 62%
10/06
Anxiety Disorders: Childhood / Premorbid Rates
Price Foundation Studies% AD onset before
ED onset% of entire sample
with childhood onsetRate in
community
1+ AD 61% 43% 4.7-17.7%
OCD 62% 23% 2-3%
Social Phobia 74% 13% 0.6-5.1%
Specific Phobia 83% 10% 0.3-9.1%
GAD 65% 5% 2.6-10.8%
PTSD 41% 4%
Panic Disorder 29% 3% 0-1.1%
Agoraphobia 47% 1% 0-2.2%
10/06
Speilberger Trait Anxiety InventoryED group vs CW *p<.05
ILL AN ILL AN-BN REC AN REC AN-BN REC BN CW
Sp
eilb
erg
er
Tra
it A
nxie
ty In
ve
nto
ry
20
30
40
50
60
70
80
**
*
**
10/06
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?
10/06
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
10/06
GENETICS
Funding:
MH046001, MH042984, MH066122; MH001894; Price Foundation
10/06
Familial Transmission of AN and BN Strober 2000 Am J Psych
(504 probands and 1831 relatives); *< .05 vs. relatives of CW
% of Relatives with Diagnosis
Proband Diagnosis
AN BN Total ED
AN 3.5* 3.8* 7.2*
BN 3.7* 4.0* 7.7*
CW 0.3 0.9 1.3
10/06
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
Disorder Heritability Autism .8 - 1 Schizophrenia .5 - .9 Bipolar .3 - .8 AN, BN .5 - .8 Early MDD .5 - .75 OCD .5 - .7 Obesity .4 - .7
10/06
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
10/06
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
10/06
Neurobiology
Brain Imaging
10/06
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
10/06
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?
10/06
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
10/06
OPTIMAL STIMULI
RESPONSE
amygdala
hippocampus
MEMORY
AFFECT
GOALDIRECTEDBEHAVIOR
PLANACTIONLEARN
10/06
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
10/06
Brain Imaging Studies
Dopamine D2/D3 Receptors in Striatum
10/06
Increase in DA in nucleus accumbens induced by food and by amphetamines as assessed by
microdialysis in rodents Volkow and Wise 2005
10/06
Brain Reward Center - Dopamine D2 Receptors are Lower in Addiction Volkow et al
DA
D2
Rec
epto
r A
vaila
bili
ty
control addicted
Cocaine
Heroin
Alcohol
DA
DA
DA
DA DA DA
DA
Reward Circuits
DA DA DA DA
DA
Reward Circuits
DA
DA
DA
DA DA
DA
Drug Abuser
Non-Drug Abuser
10/06
Clinical Characteristics“Recovered” ED Subjects
CW REC RAN REC BAN pnumber 14 16 11Age (years) 27.6 ± 7 25.6 ± 7 27.3 ± 7 nsBody Mass Index 22.6 ± 2 20.5 ± 2 23.5 ± 2 0.01Length of Recovery (months) 37 ± 40 83 ± 98 nsHarm Avoidance (TCI) 8.9 ± 4 17.9 ± 9 15.1 ± 10 0.02
10/06
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
ControlWomen
RecoveredRAN
1.4
1.6
1.8
2.0
2.2
2.4
2.6
2.8
3.0
[11C
]rac
lop
ride
bind
ing
pot
entia
l (B
P)
RecoveredBAN
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Reward Circuits Reward CircuitsReward Circuits
“Normal” Anorexia NervosaAddictive State
DA
DA D2
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Reward Circuits Reward Circuits
“Normal” Anorexia NervosaAddictive State
DA
DA D2
Amphetamines
Reward Circuits
10/06
Reward Circuits Reward Circuits
“Normal” Anorexia NervosaAddictive State
DA
DA D2
Amphetamines
Reward Circuits
Food
Small amount food
causes exaggerated
effect?
10/06
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
10/06
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
10/06
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.
10/06
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)
-0.15
-0.1
-0.05
0
0.05
0.1
0.15
0.2
1 2 3 4 5 6 7
Time
% c
han
ge
fro
m t
ime
1
CW Win
CW Loss
AN Win
AN Loss
10/06
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
10/06
BRAIN IMAGING AND OTHER AN SYMPTOMS
SYMPTOMS BRAIN REGION
Body image distortions
Left parietal lobe
Anxiety DA “uncertainty” circuits in cognitive brain pathways
Impulse control Frontal lobe serotonin pathways
10/06
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
10/06
Guido Frank
Julie PriceJulie Price
CarolynCarolyn MeltzerMeltzer
Chet MathisChet Mathis
Jennifer FigurskiHoward Aizenstein Guido FrankGuido Frank
Ursula BailerUrsula Bailer
Angela Wagner
Kathy PlotnicovKathy PlotnicovSharon BarnesSharon Barnes
Claire McConahaClaire McConahaEva GerardiEva Gerardi Frank MolchenFrank Molchen
Michael HimesMichael Himes
Victoria VogelVictoria Vogel
Lorie FischerLorie Fischer
BartBart ConardConard
Not picturedLaura Mazurkewicz
Shannon HenryChris May
Nicole BarbarichCarl BeckerJessica HogeScott ZiolkoWinshu Li
