Exploring the Relationship
Among Co-Morbidities,
Cognitive Process, and
Treatment Moderation in
Adolescent Anorexia Nervosa
and Bulimia Nervosa
James Lock, MD, PhD
Professor of Psychiatry and Pediatrics
Stanford University
Overview
• What do we know about types and rates of co-morbidity from
published RCTs of FBT for adolescent AN and BN?
• What do we know about co-morbidity and treatment predictors and
moderators from RCTs of adolescent AN and BN?
• What do we know about treatment response of co-morbid conditions
from RCTs of adolescent AN and BN?
• Is there a relationship between co-morbid symptoms and cognitive
process?
• What does this mean for treatment and future studies?
What do we know about types and rates of comorbidity from published RCTs of FBT for
adolescent AN and BN?
Rates of Psychiatric Co-Morbidity
Anxiety
Disorders
STUDY
Depression Anxiety
OCD
PTSD
Other
FBT vs AFT
17% (20)
7% (8)
4% (5)
2% (2)
FBT vs
SFT
CRT vs
CBT
FBT short vs long
26% (20)
14% (11) 10% (8)
35% (15)
11% (5)
24% (21)
14% (12)
Hospital short vs
long
31% (9)
35% (10) 14% (4)
PFT vs FBT
24% (23)
24% (23) 6% (6)
9% (4)
11% (5)
Total
5% (6)
Medication
use
15% (9)
7% (7)
17.9% (14)
29%
7% (3)
37% (17)
48%
5% (4)
14% (12)
43%
17% (5)
33%
12% (13)
8% (8)
58%
9% (10)
67%
9% (7)
32% (26)
60%
7% (6)
Substance
Abuse
34% (29)
48%
BN FBT vs CBT
BN FBT vs
Support
BN FBT vs CBT GSH
48% (38)
41% (35)
4% (3)
27%
For adolescent AN long term follow-up: No effect
of treatment type on co-morbidities (Le Grange et
al 2015)
Long-term follow-up
Adolescent
Family-Based
Focused
Full Sample
Treatment
Treatment
(n=79)
(n=36)
(n=43)
Percent (%), or Mean (Standard Deviation)
Test statistic
Age
19.54 (1.82)
19.83 (1.36)
19.70 (1.59)
t = -0.80, p = .43
YBC-ED
3.31 (5.88)
5.54 (7.40)
4.51 (6.79)
t = -1.43, p = .15
BDI
6.11 (8.00)
7.75 (7.59)
6.99 (7.77)
t = -0.91, p = .37
RSES
29.11 (7.56)
28.70 (7.11)
28.89 (7.28)
t = 0.24, p = .81
41.70%
34.90%
38.00%
Medication
φ = -0.07, p = .54
Summary of Co-morbidity in Treatment Trials
• Depression in adolescent AN to range from 17-35%, with a mean rate of
17%;
• Anxiety disorders in AN excluding OCD ranged from 7-35%, with a mean
rate of 9%;
• OCD rates in AN ranged from 4-14%, with a mean rate of 4%;
• PTSD rates in AN ranged from 2-17%, with a mean rate of 3%;
• Other diagnoses (e.g., ADHD, phobias, Tics, Substance abuse) ranged from
5-7%, with a mean rate of 5%.
• The overall co-morbidity rate in AN was 37% (181/485)
• For adolescent BN we find a mean overall co-morbidity rate of 59%
(162/274), with a range of 48-67%, with depression being the most
common co-morbid diagnosis.
What do we know about co-morbidity and
treatment predictors and moderators from RCTs of
adolescent AN and BN?
Predictors and Moderators
• Predictors are baseline characteristics that interact with treatment in
a non-specific way that either improves or diminishes response.
• Moderators are baseline variables that interact with treatment type
and therefore help match specific treatments to the clinical needs of
a specific patient or patient group.
• Co-morbidity might be expected to be a predictor or moderator of
treatment, because presumably the clinical needs related to these
additional diagnoses could complicate treatment, lowering response
rates, or requiring more or additional treatment.
Predictors
Moderators
FBT
Dose
Age, co-morbidity; family conflicts
YBC-ED
Family Structure (longer treatment)
FBT vs
AFT
Age, duration of illness, prior hospitalization
YBC-ED
Purging
EDE Score
Age, duration of illness; family status (intact); no purging YBOCS (SFT)
FBT vs
SFT
Hospital EDE and RSE (on hospital days)
Dose
=FBT
PFT vs
Expressed Emotion; Duration of Illness;
FBT
FBT vs
SPT (BN)
FBT vs
CBT for
BN
CHOI (on hospital days)
YBC-ED (FBT); Duration of Illness (PFT); expectation of
treatment success high (PFT)
EDE, depression, and binge purge episodes
EDE (Low) (FBT)
males, individuals with lower YBC Total, higher FES
cohesion, intellectual-cultural orientation, activerecreational orientation, and organization all showed
higher abstinence at EOT.
FES Conflict (less conflict did better in FBT)
YBC-ED
EDE Score
Binge-Purge sub-type
Moderators of FBT vs SyFT
14
Change in % ideal body weight
14
12
CYBOCS<8
10
CYBOCS>8
8
6
4
2
0
FBT
SFT
Change in BMI by Treatment and YBC TOTAL
3.5
3
Change in BMI
2.5
2
1.5
1
Long term Low YBC n=21
Long term High YBC n=19
0.5
Short term Low YBC n=15
Short term High YBC n=24
0
0
6
Months of treatment
12
Change in BMI by Treatment and YBC TOTAL
3.5
3
Change in BMI
2.5
2
1.5
1
Long term Low YBC n=21
Long term High YBC n=19
0.5
Short term Low YBC n=15
Short term High YBC n=24
0
0
6
Months of treatment
12
Early weight gain in FBT and outcome
• Weight gain >4 lbs. by wk 4 correctly characterized:
• 79% of responders [AUC = .814 (p<.001)]
• 71% of non-responders [AUC = .811 (p<.001)]
• Doyle, Le Grange, Celio-Doyle, Loeb & Crosby, IJED, 2009; Le Grange,
Accurso, Lock, Agras & Bryson, IJED, 2013. Madden et al, IJED, 2015
Adaptive Intensive Parental Coaching (IPC)
%IBW
100
98
96
%IBW
94
FBT+IPC
92
n=12
90
88
%IBW FBT
n= 33
86
84
82
80
BL
Ses4
EOT
FU6
FU12
Summary
• For AN, we can say that obsessiveness, especially around food and
eating likely contributes to poor treatment response
• For BN, it appears that ED symptom severity (EDE score) and
depression contribute to both specific and overall treatment
response.
• Treatment response can likely be changed by adding additional
treatments not addressing co-morbidity (adaptive study).
What do we know about treatment response of
co-morbid conditions from RCTs of adolescent AN
and BN?
Clinical response to Co-Morbid conditions in
Adolescent BN
• In a post hoc examination of the CBT vs FBT, there were large and
significant improvements in self-esteem and depression regardless of
treatment type
Clinical Correlates of Treatment Moderators
in AN
• Stepwise regression was utilized and variables relevant to ED comorbidity and symptomatology
were included in the models.
• In study 1, 164 adolescents with AN (mean age=14.8, 89% females) completed standardized
interviews and self report assessments. Results indicated that global Eating Disorder Examination.
(EDE) score was the strongest predictor of YBC-EDS (adjR squared=55%), whereas Beck
Depression Inventory (BDI) and CYBOCS were significant predictors, but added only 3% to the
model
• In study 2, we attempted to replicate these findings in a sample of 45 adolescents with AN
(age=14.6, 89% females). EDE global score was the strongest predictor of YBC-EDS (adjR
squared=68%), followed by the CYBOCS (which attributed an additional 4%). However, the BDI did
not emerge as a significant predictor in this sample.
• These findings suggest that illness severity is related to elevated YBC scores. Therefore, although
the EDE, BDI, and CYBOCS appear to contribute to illness severity and may be important
indicators for treatment selection.
• In clinical settings, even in the absence of data on ED-related obsessions and compulsions,
measures of ED severity could serve as a reasonable proxy for treatment selection
Is there a relationship between co-morbid
symptoms and cognitive process?
What is the relationship between comorbidity and cognitive process (RDoC)?
Neurobiology and Co-Morbidity in Child
Psychiatric Disorders
• Some recent studies suggest that there may be similar underlying
neurobiology among some neurodevelopmental disorders that are
highly co-morbid (Rogers, JAACAP 2016: 55: 832; Ameis et al, AJP
2016)
• Could shared neurobiology explain some of the moderating
influences and treatment response of adolescent EDs?
What is the relationship between co-morbidity
and eating disordered cognitive processes?
Dunlap et al 2016, Frontiers in Neuroscience
Does cognitive process change with ED
treatment?
Prefrontal Cortex—Executive Functioning
en.wikipedia.org/wiki/File:Prefrontal_cortex.png
Neuropsychology and
Eating Disorders
• The frontal lobe is generally implicated
• Dorsolateral Prefrontal Cortex (dlPFC)
• Mental flexibility, organization, planning and
concept formation
• Medial Prefrontal Cortex (mPFC)
• Initiating and maintenance of behavior
• Orbitofrontal Cortex (OFC)
• Behavioral inhibition, learning from reinforcement
Neurocognitive Features of
Eating Disorders
•
Studies have suggested two broad domains of
neurocognitive inefficiencies in eating disorders
• Weak central coherence
• Difficulties in set-shifting
Illusions
Cognitive Flexibility
• Set shifting difficulties
•
•
•
•
Clinical observations of rigidity, conforming, and obsessional style
Adults with AN take longer to set shift than normals with similar IQs
Set-shifting inefficiencies persist after recovery
Set-shifting inefficiencies in siblings
Central Coherence
• AN subjects excel on Embedded Figure Task (finding detail)
• AN subjects superior in Matching Figures Task
• AN subjects display a piece-meal approach to Rey-O demonstrating
difficulty in seeing the gestalt— weak coherence leads to poor recall,
due to overemphasis of details
Examples of Rey-O
Low weight AN subject
Low weight medical subject
Central Coherence Findings
• Weak central coherence leads individuals with AN to
adopt a “piecemeal” approach to complex information
• This impairs performance on tasks requiring integration of
many details
• On Rey-O
• Accuracy remains relatively intact
• Elements of the figure are generally represented
• Weak Central Coherence
• Order - how they construct a figure
• Style - degree of continuity or segmentation
NAVON TASK
Figure 1. Stimuli used in the current task. a. in the congruent condition the large and small arrows point in the
same direction. b. In the incongruent condition the large and small arrows point in opposite directions. c.
example of a typical experimental trial.
Central Coherence in Adolescent AN (Weinbach et
al under review)
• Direct assessment of global/local processing using the Navon task.
• When attending the bigger picture, adolescents with AN have greater
difficulty to ignore the details.
• When attending the details, adolescents with AN demonstrate greater
ability to ignore the bigger picture.
Interference effect in ms
120
HC
*
AN
100
80
*
60
40
20
0
Local interference
Global interference
38
Expanding the Developmental
Range of CRT for AN
• Our research suggests that adolescents demonstrate
similar neurocognitive inefficiencies to adults
• Largely relative weaknesses
• Utilizing neuropsychological assessments normed across the lifespan
• Correlated with similar cognitive and behavioral challenges
• Excessive detail orientation
• Rigid, inflexible thinking and information processing styles
Set-Shifting Difficulties
• Wisconsin Card Sort Task
• Performance impaired relative to norm group
• Performance significantly impaired relative to IQ testing
• Deficits specific to perseverative response style
• Total errors and non-perseverative errors within normal limits
• Perseverative errors elevated
• Group mean T-score 66.1 (89.6%)
• Perseverative response style score is highly elevated for an intact
population
• Group mean T-score 66.25 (89.3%)
Cognitive Style and Anorexia Nervosa
• Cognitive rigidity supports the rule-bound approach
to dieting, exercise, and performance metrics
common in AN; this contrasts with the impulsive style
of BN subjects
• Over focus on detail supports cognitive rigidity
through obsessive review and analysis
• Weak central coherence supports denial of major
global problems that result from AN (medical, work
and social problems)
CBT vs CRT for adolescent/adult AN: impacts
on set shifting and central coherence
What does this mean for treatment and future
studies?
Ideas and speculations
• Medication to address co-morbidities may not be needed….until the
eating disorder is treated and symptoms remain?
• Can reassure clinicians and families that treating the eating disorder
likely will have a major impact on other co-morbid symptoms and
disorders—may not need separate psychological treatments
Current studies
• Adding CRT to FBT at baseline to adolescents with AN with evidence
of obsessive compulsive features vs art therapy with FBT (nearing
completion)
• Family aggregation studies of neurocognitive features in adolescents
with AN (sibs in same age cohort; family members), neural correlates
using fMRI (nearing completion)
• Neuroimaging studies examining the relationship between emotion
regulation and executive function (cognitive inhibition) in adolescents
with binge eating (just beginning)