Etkin et al, Cognitive and Emotional Predictors of Antidepressant Outcome
SUPPLEMENTARY APPENDIX
Table of Contents:
Supplemental Methods........................................................................................................................2
Supplemental Figure 1 ........................................................................................................................3
Supplemental Figure 2 ........................................................................................................................4
Supplemental Figure 3 ........................................................................................................................5
Supplemental Table 1 .........................................................................................................................6
References for Supplemental Table 1 ...............................................................................................10
Supplemental Table 2 .......................................................................................................................18
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Etkin et al, Cognitive and Emotional Predictors of Antidepressant Outcome
SUPPLEMENTAL METHODS
Participant Recruitment
The study enrolled adults (aged 18-65 years) with a diagnosis of current
nonpsychotic MDD. Supplemental Figure 2 outlines the inclusion and exclusion criteria
used to recruit participants who would typically receive an ADM in clinical practice.
Patients over age 65 were excluded because concomitant medical conditions or
medications could interact with protocol medications. Adolescents/children were
excluded because the efficacy and safety of most study ADMs have not been established
for this age group.
Participants were recruited through the study management sites or from
community general practice clinics and university general health centers for which study
recruitment and participation was overseen by the local study management site
(Supplemental Figure 1).
Inclusion was based on the MINI-Plus to establish a diagnosis of MDD, the
HRSD17 to assess depressive symptom severity (score ≥16 for inclusion), a negative urine
toxicology (to provide data on illicit drug use and rule out other prescription medications)
and a pregnancy screen. The initial pre-screen for exclusion and inclusion criteria was
made by telephone.
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Etkin et al, Cognitive and Emotional Predictors of Antidepressant Outcome
Supplemental Figure 1: CONSORT diagram.
Recruitment
Participants were recruited from physician
referrals at participating sites or responded
to advertisements (including individuals who
had already presented to a physician plus
those who had not).
Phone screen completed by site staff to assess
eligibility (n= 6,693)
Enrolment
Baseline Visit – Assessed for eligibility (n=1,315)
N=5,378 Excluded for:
Practical reasons (n=1,086): Travel or
Scheduling difficulties, Cost of doctor
visit, or Staff discretion
Not meeting eligibility Criteria
(n=2,931): Age n=37, Bipolar/Manic
Episodes n=690, Psychosis n=86, Eating
Disorder n=50, Personality Disorder
n=32, Alcohol & Drug Dependence
n=171, Suicidality n=121, Sub-Clinical
MDD n=348, Primary Anxiety Disorder
n=183, On Treatment n=443, Previous
Contraindications to ADM n=206,
Medical n=223, Neurological n=125,
Receiving Therapy n=42, ADHD
treatment n=37, Autism n=1,
Pregnancy/breastfeeding n=23, Other
n=113, plus 147 missing specific
reasons)
Refused to participate (n=844): Did not
wish to take medication or time
commitment.
No Show (n=370)
N= 307 Excluded for:
Exclusionary criteria (n=296):
Comorbidity (Bipolar, PTSD,
Drug use), Suicidality,
HRSD17<16
Randomized (n=1008)
Refused to participate (n=7)
Investigator’s discretion (n=5)
Allocation
Txt Group 1
Txt Group 2
Txt Group 3
Allocation to
Escitalopram (n=336)
Allocation to Sertraline
(n=336)
Allocation to
Venlafaxine-XR (n=336)
Assessed at
Wk 8 n=244
Dropped out N=92
for: 2 Investigator’s
Discretion, 28 Lost to
follow-up, 6 Protocol
Violation, 13
Safety/efficacy, 28
Never Dosed, 15
Withdrew
Assessed at
Wk 8 n=298
Dropped out N=83
for: 2 Investigator’s
Discretion, 34 Lost to
follow-up, 2 Protocol
Violation, 10
Safety/efficacy, 17
Never Dosed, 18
Withdrew
Assessed at
Wk 8 n=240
Dropped out N=96 for:
1 Investigator’s
Discretion, 35 Lost to
follow-up, 4 Protocol
Violation, 11
Safety/efficacy, 30
Never Dosed, 13
Withdrew, 2 Not
specified
3
Abbreviations: ADHD: Attention Deficit Hyperactivity Disorder, ADM: antidepressant medication, HRSD17,
17-item Hamilton Rating Scale for Depression; MDD: Major Depressive Disorder; PTSD, Post-Traumatic
Stress Disorder
Etkin et al, Cognitive and Emotional Predictors of Antidepressant Outcome
Supplemental Figure 2: Inclusion and exclusion criteria.
Abbreviations: CNS, Central nervous system; EEG, Electroencephalogram;
HRSD17, 17-item Hamilton Rating Scale for Depression; MDD, Major
depressive disorder; MINI, Mini-International Neuropsychiatric Interview; XR,
Extended release
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Etkin et al, Cognitive and Emotional Predictors of Antidepressant Outcome
Supplemental Figure 3: Outline of the classification algorithm used to predict
treatment outcome.
training subset
(for each of 1000 subsamplings)
test
subset
Discriminant function: LDA
•
•
•
second eigenvariate
Maximize distance between means of each group
Minimize within-group variance
Determine generalization accuracy of each model
first eigenvariate
X 1000 subsamplings
Cross-valida on: apply models to le out subjects and
majority vote on ensemble of retained classifiers
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Etkin et al, Cognitive and Emotional Predictors of Antidepressant Outcome
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Etkin et al, Cognitive and Emotional Predictors of Antidepressant Outcome
Supplemental Table 1: Prior findings using cognitive and emotional function tests in depression and with antidepressant medications.
COGNITION
Studies of mechanisms of drug effects on behavioural cognition probes
MDD itself
Acute (Controls)
Finger Tapping with Paroxetine
Motor coordination
Finger tapping
1-3↓Finger
Tapping
4, 5,6-8↓Simple Reaction Task
9↓Single line drawings
10↑
Attention
Continuous Performance
(n-back)
13, 14↓Rapid
24↓Sustained
Processing
15↓Vigil Continuous Performance Test
(↑errors)
3, 16-20↓Continuous Performance (RT,
20Errors, 3unmasked)
21-23↓n-back (1,2,3 back)
Dothiepin
24↓Sustained Attention Test with
Fluoxetine
25↓Mackworth Clock with
Venlafaxine
25↓Mackworth Clock with Mianserin
26↓Mackworth Clock with
Escitalopram & Ketanserin
27↓Mackworth Clock with Citalopram
Decision speed
Choice Reaction time
7, 30↓Choice
32↓Choice
Information Processing
Speed
Switching of Attention
(Trails A,B)
33-38↓Digit
Symbol (WAIS-R) (35, 36%)
A
22, 34, 37, 38, 40-44↓Trailmaking (A & B)
7, 35, 45, 46↓Trailmaking B
47↓Inspection Task
21↓ Visual Elevator
17↓Shifting Attention testˉ
32↓Digit
Verbal Memory
Verbal Memory and
Learning Test
1, 14, 39, 8, 34, 51, 52↓Rey
55↓Visual
7, 31↓Choice
Visual Information
Reaction time
Reaction time (7&31¢ )
Attention Test with
Treatment Prediction
13ˆ,14↑Rapid
Visual Information
Processing with Escitalopram and
Duloxetine
28↑Continuity of Attention with
Reboxetineˇ
19↑Continuous Performance (RT) with
Imipramine & Fluvoxamine©
12↑ Continuous Performance test with
Venlafaxine & Fluoxetine
22↑ n-back with Mirtazapine
29↑n-back
28↑Combined
50↑Digit
at baseline
predicted SSRI response at 3
months* - using HRSD17
Reaction Time with
Amitriptyline
Symbol with Amitriptyline
18, 39↓Trailmaking
Auditory Verbal
Learning
53↓Hopkins Verbal Learning Test (53
recall)
3, 18, 38, 54↓Weschler Memory Scale
(logical memory, 3verbal memory)
Chronic (MDD)
Tapping test with Clovoxamine &
Amitriptyline
12↑ Finger tapping with Venlafaxine &
Fluoxetine
11↑
Speed with Reboxetineˇ
A with Fluoxetine˜
49
↑Digit Symbol with Prozac &
Deprexan
11↑Digit Symbol with Clovoxamine &
Amitriptyline
22↑Trailmaking B normalized with
Mirtazapine
22↑ Trailmaking A with Mirtazapine
48↑Trailmaking
Verbal Learning Test with
Tryptophan depletion (long term
memory only)
56↓Visual Verbal Learning Test with
Paroxetine
57↓Visual Verbal Learning Test with
Mirtazapine
58↑Auditory Verbal Learning Test
Symbol task at
baseline predicted placebo
response 8 weeks later using HRSD17
14, 59̃↑Rey
Auditory Verbal Learning
with Duloxetine# > Escitalopram˚
60↑Auditory Verbal Learning Test with
Escitalopram and mineralocorticoid
receptor
18↑Weschler Memory Scale (Logical
Memory) with Fluoxetine
11↓Verbal Recognition Memory with
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Etkin et al, Cognitive and Emotional Predictors of Antidepressant Outcome
with Citalopram (long term memory)
Working Memory
Digit Span
Executive Function Maze
Cognitive Control Verbal
Interference (Stroop)
5, 13, 23, 38, 40, 42, 43, 54, 61, 62↓Digit
amitriptyline
Span
backwards
38, 43, 52, 54↓Digit span forwards
53↓Paced auditory serial addition test
63↓ BACS digit sequencing task¥
13↓Stockings Of Cambridge
6, 22, 23, 30, 35, 40, 42, 46↓Wisconsin Card
Sorting Task (40errors;35%)
64↓Iowa Gambling Task
8↓Groton Maze Learning Task
65, 66↓Tower of Londoñ
13↑Digit
Span Backwards with
Escitalopram and Duloxetineˆ
59↑Digit Span Backwards with
Duloxetine > Escitalopram˚
1, 2, 4-6, 8, 13, 17, 22, 23, 37, 38, 41, 42, 45, 46, 68-
13, 59˚↑Stroop
74↓Stroop(71¬
Duloxetineˆ
75↑Stroop with Sertraline
75↑Emotion stroop (words) with
Sertraline
22↑ Stroop with Mirtazapine
13↑Stockings
Of Cambridge with
Escitalopram & Duloxetineˆ
22↑ Wisconsin Card Sorting Task with
Mirtazapine
12↑ Wisconsin Card Sorting Task with
Venlafaxine & Fluoxetine
)
75↓ Emotion Stroop (words)
41, 76↓ Prose distraction task
77↓D-KEFS color-word interference task
44↓Color word Interference Test
31↓Spatial Stroop¢
EMOTION
78-85↓
Sad
86* 83, 88-90↓
overall
disgust*
87↓ angry
86↓
Card Sorting
Task at baseline predicted
treatment response at 9 weeks
with 20mg Fluoxetine* using HRSD17
67↑Stroop
(errors) at baseline
predicted treatment response
at 9 weeks with 20mg
Fluoxetine* - using HRSD17
121↑Stroop
word and color
reading at baseline predicted
treatment response at 12
weeks with Fluoxetine* using HRSD17
Studies of mechanisms of drug effects on behavioral emotion probes
Acute (Controls)
Acute (Controls)
Chronic (MDD)
Treatment Prediction
Single dose
>7 days
MDD itself
Identifying Emotions
Overall impairment
Threat-related (disgust, fear, anger)
with Escitalopram &
67↑Wisconsin
94↓
fear with high-dose antidepressant!
95↓ fear with Mirtazipine
96↑ fear with Tryptophan
97-99↑ fear with Citalopram
99↑ fear normalized with
Citalopram
100↑ disgust with Duolextine
103↓anger
& fear with
Citalopram/ Reboxetine
104↓fear with Citalopram
105↑
disgust with
Reboxetine & Citalopram
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Etkin et al, Cognitive and Emotional Predictors of Antidepressant Outcome
Happy
91*, 88, 89, 92↓
97
↑ with Citalopram
with Tryptophan
96↑
Neutral
86* 93↓
103↑with
Citalopram/
Reboxetine
102↓
with Tryptophan
depletion
105 ↑ with Reboxetine &
Citalopram
101↑
with Reboxetine
with Tryptophan
100 ↑ with Duolextine
102 ↑ with Tryptophan
depletion
96↑
Speed of identifying Emotion
Overall impairment
86, 93slower
Threat-related (disgust, fear ,anger)
8Responders>non-
responders;
106slower
Sad
106slower
Happy
107,108Happy
<
Fearful, 109
110Happy < Sad
Neutral
111slower
Biases in speed of identifying Emotion
Threat-related (disgust, fear ,anger)
112Angry
Sad
113Sad
>Neutral
> Neutral
(attentional
bias);114Sad >
Neutral (attentional
bias)
Happy
110Happy
>
Neutral; 114Happy <
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Etkin et al, Cognitive and Emotional Predictors of Antidepressant Outcome
Neutral (attentional
bias)
Emotional priming of face recognition
memory (delayed recognition)
Negative Priming (when target in probe task
was distracter in previous task)
Positive Priming (when target in probe was
target in previous task)
Response Inhibition
Go/No-Go
115
Sad > Happy
Sad > Control
condition (sad target
in non priming
condition)
115 Sad > Happy
116
117
No difference in
RT of delayed
recognition
(dysphoric and nondysphoric; happy,
sad, angry, neutral)
118-120↓Parametric
Go/No-Go
ˆResults were collapsed across Tx group
#Pts were washed out of medication and in remission at time of testing 13
ˇCombined Speed was a factor combined of Simple Reaction Task, Choice Reaction Time, Digit vigilance, numeric working memory, word recognition/Continuity of Attention was a factor
including Choice Reaction Time and digit vigilance – Paroxetine was also investigated – however did not show any sig results
ˉShifting Attention test is a sub task of the CNS Vital Signs cognitive battery
˚No control groups used
&Melancholic < Non-Melancholic on Choice Reaction time
*Responders < Non –responders
% Melancholic < Non-Meloncholic
©Omission errors were improved following treatment with fluvoxamine (not imipramine)
¥ MDD, Remitted MDD < Controls
¬ 71only for non-melancholic pts
¢ Melancholic < Controls
* facial emotion stimuli were presented with expressed rated as low intensity
!Remitted MDD patients
Abbreviations: ; BACS, Brief Assessment of Schizophrenia; CNS, Central Nervous System; D-KEFS, Delis-Kaplan Executive Function System; HRSD17, 17-item Hamilton Rating Scale for
Depression; MDD, Major Depressive Disorder; RT, Reaction Time; WAIS-R, Wechsler Adult Intelligence Scale (Revised).
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Etkin et al, Cognitive and Emotional Predictors of Antidepressant Outcome
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Supplemental Table 2: Classification results for the different outcomes, divided by medication arm, using only tests identified as
predicting treatment outcome in prior studies (see supplemental table 1; includes attention, cognitive flexibility, information
processing speed and maze navigation).
Performance
Outcome Criterion
Medication
Number
Accuracy
Sensitivity
Cluster
Intact
Uncorrected
Corrected
p-value
p-value
Specificity
ESC
152
52
52
52
0.355
n.s.
SER
175
42
71
15
0.993
n.s.
VEN
152
46
49
43
0.952
n.s.
ESC
65
57
68
49
0.200
n.s.
SER
59
56
35
69
0.183
n.s.
VEN
52
48
45
50
0.662
n.s.
ESC
152
52
58
42
0.363
n.s.
SER
175
63
85
8
0.006
n.s.
VEN
152
49
44
57
0.645
n.s.
ESC
65
58
68
44
0.132
n.s.
SER
59
54
53
56
0.298
n.s.
VEN
52
58
50
68
0.290
n.s.
ESC
152
51
52
50
0.450
n.s.
SER
175
45
85
20
0.833
n.s.
VEN
152
48
57
43
0.750
n.s.
ESC
65
58
57
60
0.175
n.s.
HRSD17 remission
Impaired
Intact
HRSD17 response
Impaired
Intact
QIDS-SR16 remission
Impaired
19
Etkin et al, Cognitive and Emotional Predictors of Antidepressant Outcome
Intact
SER
59
47
22
59
0.745
n.s.
VEN
52
50
31
56
0.584
n.s.
ESC
152
55
56
53
0.238
n.s.
SER
175
52
85
14
0.413
n.s.
VEN
152
50
55
45
0.529
n.s.
ESC
65
60
80
37
0.134
n.s.
SER
59
447
29
58
0.715
n.s.
VEN
52
62
42
73
0.104
n.s.
QIDS-SR16 response
Impaired
20