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10 AUTHORS, INCLUDING:
Tracie Shea
Paul A Pilkonis
Brown University
University of Pittsburgh
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Joseph Collins
Department of Veterans Affairs, Perry Point V
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Regular
and
Articles
Patient
Predictors
of Response
to Psychotherapy
Pharmacotherapy:
Findings
in the NIMH
Treatment
of Depression
Collaborative
Research
Program
Stuart
M. Sotsky,
M.D., M.P.H.,
David R. Glass, Ph.D., M. Tracie Shea, Ph.D.,
Paul A. Pilkonis,
Ph.D., Joseph F. Collins,
Sc.D., Irene Elkin, Ph.D.,
John T. Watkins,
Ph.D., Stanley D. Imber, Ph.D., William
R. Leber, Ph.D.,
Janet Moyer,
M.S., and Mary Ellen Oliveri,
Ph.D.
Objective:
The authors
investigated
patient
characteristics
predictive
of treatment
response
in the National
Institute
of Mental
Health
(NIMH)
Treatment
of Depression
Collaborative
Research
Program.
Method:
Two hundred
thirty-nine
outpatients
with major
depressive
disorder
according
to the Research
Diagnostic
Criteria
entered
a 1 6-week
multicenter clinical
trial and were randomly
assigned
to interpersonal
psychotherapy,
cognitivebehavior
therapy,
imipramine
with clinical
management,
or placebo
with clinical
management.
Pretreatment
sociodemographic
features,
diagnosis,
course
of illness,
function,
personality,
and symptoms
were studied
to identify
patient
predictors
of depression
severity
(measured
with the Hamilton
Rating Scale for Depression)
and complete
response
(measured
with the Hamilton
scale and the Beck Depression
Inventory).
Results:
One hundred
sixtytwo patients
completed
the entire 1 6-week
trial. Six patient
characteristics,
in addition
to
depression
severity
previously
reported,
predicted
outcome
across all treatments:
social dysf unction,
cognitive
dysfunction,
expectation
of improvement,
endogenous
depression,
double depression,
and duration
of current
episode.
Significant
patient
predictors
of differential
treatment
outcome
were identified.
1) Low social dysfunction
predicted
superior
response
to
interpersonal
psychotherapy.
2) Low cognitive
dysfunction
predicted
superior
response
to
cognitive-behavior
therapy
and to irniprarnine.
3) High work dysfunction
predicted
superior
response
to irnipramine.
4) High depression
severity
and impairment
of function
predicted
superior
response
to imipramine
and to interpersonal
psychotherapy.
Conclusions:
The resuits demonstrate
the relevance
of patient
characteristics,
including
social,
cognitive,
and
work function,
for prediction
of the outcome
of major depressive
disorder.
They provide
indirect
evidence
of treatment
specificity
by identifying
characteristics
responsive
to different
modalities,
which may be of value in the selection
of patients
for alternative
treatments.
(Am J Psychiatry
1991;
148:997-1008)
Presented
in part at the 139th annual
meeting
of the American
Psychiatric
Association,
Washington,
D.C., May 10-16,
1986. Received Aug. 13, 1990; revision
received
Feb. 20, 1991; accepted
March 20, 1991. From the Department
of Psychiatry
and Behavioral
Sciences, George Washington
University
Medical
Center;
the Mood,
Anxiety
and Personality
Disorders
Research
Branch,
NIMH,
Rockville, Md.; Western
Psychiatric
Institute
and Clinics, Pittsburgh,
Pa.;
the VA Medical
Center,
Perry Point, Md.; the University
of Chicago
School of Social Service Administration;
and the Department
of Psy-
Am
J Psychiatry
1 48:8,
August
1991
997
PATIENT
PREDICTORS
OF RESPONSE
by indicating
patient
characteristics
that
are
especially
responsive
to it, such as functional
and relational
capacities
or type of depression.
This may be
especially
important
because
only limited
evidence
about differential
treatment
effects on measures
of outcome hypothesized
to be specific to each modality
has
emerged
from this study (1, 2). Although
we chose to
consider
patient
characteristics
initially,
since there is
some indication
from the literature
(3, 4) that they
have greater
influence
on outcome,
we plan to address
therapist,
relationship,
and process
variables
in future
analyses.
Comprehensive
reviews
of general
predictors
of response to psychotherapy
(5, 6) and to tricyclic
antidepressants
(7-9) reveal that the literature
is characterized by lack of consensus
about or replication
of many
findings.
The general
predictors
of response
to psychotherapy
that have emerged
have been derived
from
many studies
based on various
psychotherapies,
often
in small and heterogeneous
samples
of patients
with
diverse
disorders.
Other
major
reasons
for the inconsistent
findings
among
studies
include
lack of specification
of the treatment,
variability
of inclusion
and
diagnostic
criteria,
lack of standardization
of outcome
measures,
variability
of criteria
for improvement,
and
differences
in selection
of patient
variables
and measures investigated.
The purpose
of this article
is to report
the patient
characteristics
that predicted
treatment
response
in the
National
Institute
of Mental
Health
(NIMH)
Treatment of Depression
Collaborative
Research
Program
(10), which was the first multicenter,
comparative
dinical treatment
trial in the field of psychotherapy
research
initiated
by NIMH.
This study compared
the
efficacy
of interpersonal
psychotherapy,
cognitive-behavior
therapy,
imipramine
with clinical
management
(as a standard
reference
condition),
and placebo
with
clinical
management
(as a control
condition)
for out-
998
patients
with nonbipolar,
nonpsychotic
major
depressive disorder.
Several
features
of the Collaborative
Research
Program
clinical
trial
design
were
considered
advantageous
for the study
of the relation
of patient
predictors
to treatment
outcome.
First,
the
multisite,
common
protocol
design
permitted
study
of a larger
sample
than do most single-site
studies,
but with uniformity
of
diagnosis
and severity
of depression
across
sites. Second,
the extraordinary
standardization
of the thera-
pies-with
treatment
manuals,
therapist
training,
and
monitoring
of the quality
of performance-would
enhance
the prediction
of response
to specific
treatments
by reducing
the variability
of the treatments
themselves.
Third,
the use of a control
condition,
placebo
with
clinical
management,
would
help
differentiate
predictors
of response
to specific
treatments
from predictors
of general
response
or response
to nonspecific
treatment.
Fourth,
the use of standard
outcome
measures and response
criteria
would
permit
better
comparison
with the results
of other
studies.
We examined
predictors
in two groups
of patients:
1) those
who
completed
the course
of treatment,
in order
to search
for predictors
of outcome
sure to the
all of those
specific
ingredients
who entered
the
those
who
search
for
withdrew
of the
was
full expo-
therapies,
trial,
completion,
full
range
and 2)
including
in order
to
of outcomes.
single-site
comparative
treatment
studies
psychotherapy
and cognitive-behavior
therapy
whose
results
would
those
of the NIMH
Treatment
orative
there
of the
treatment
before
predictors
In previous
of interpersonal
when
Research
Program,
be
most
comparable
to
of Depression
Collab-
some
patient
predictors
of
response
to psychotherapy
and
tricyclic
antidepressants
were
reported.
Among
the six studies
that
reported
patient
predictors
of response
to cognitive-behavior
therapy,
one
(1 1) found
that
pretreatment
symptom
severity
was
significantly
associated
with
negative
outcome
at termination,
while
another
(12)
reported
an association
with positive
outcome.
Inconsistent
findings
were reported
for endogenous
depression (13, 14). Learned
resourcefulness,
assessed
by the
Self-Control
itive
ured
poor
Schedule,
,
by the
response
havior
Dysfunctional
at termination
therapy
follow-up,
(16)
though
and
not
cognitive-behavior
Among
was
found
to be related
to posdysfunction,
as measAttitude
Scale, predicted
for group
cognitive-be-
( 1 1 1 5). Cognitive
outcome
negative
therapy
studies
of patient
interpersonal
psychotherapy,
on the Social
Adjustment
outcome
at termination,
Am
1-year
individual
(17).
predictors
initial
Scale
of outcome
social
and
interpersonal
(19).
J Psychiatry
of emo-
predicted
not depreswas associpsychotreatment
with favor-
psychotherapy
148:8,
in
adjustment
an index
tional
freedom,
education,
and occupation
positive
outcome
in social
adjustment
but
sion severity
(4). Endogenous
depression
ated with
poorer
outcome
for interpersonal
therapy
than
for tricyclic
or combination
(18). Situational
depression
was associated
able response
to either
a tricyclic
antidepressant
at
for
August
or
1991
SOTSKY,
Among
these
studies,
there
were
several
patient
characteristics
that predicted
response
to tricyclic
antidepressants.
Endogenous
depression
was associated
with
favorable
outcome
with an antidepressant
alone
or in combination
with
interpersonal
psychotherapy
(18), as well as good
outcome
for patients
who completed
treatment,
but poor
outcome
for those
who
dropped
out (14).
Depression
severity
was related
to
negative
outcome
( 1 1 ), and
learned
resourcefulness
was related
to poor
response
(15).
METHOD
A common
protocol
was
conducted
at three
clinical
research
sites with a prospective,
random-assignment,
placebo-controlled
design,
double-blind
for pharmacotherapy
and with
independent,
blind
clinical
evaluation. A detailed
description
of the background
and design of the main treatment
study
and the pilot training
study
has been previously
published
(10).
The subjects
were
male and female
outpatients
between
the ages of 21 and 60 years
who met the Research
Diagnostic
Criteria
(RDC)
for a current,
definite episode
of major
depressive
disorder
on the basis
of the Schedule
for Affective
Disorders
and Schizophrenia
(SADS)
(20) structured
interview
and who had
a score
of 14 or more
on the 17-item
modified
version
of the Hamilton
Rating
Scale for Depression
(2 1) for at
least 2 weeks
before
initial
screening
and again
at rescreening
after
a 1- to 2-week
wait or drug washout
period.
Exclusion
criteria
consisted
of other
specific
psychiatric
disorders,
medical
contraindications
for
the use of imipramine,
concurrent
psychiatric
treatment,
current
active
suicide
potential,
and need
for
immediate
treatment.
Patients
were clinically
referred,
voluntary
research
subjects
who gave written
informed
consent
to participate.
All 28 therapists
were
experienced
psychiatrists
and
psychologists
who
had received
further
clinical
training by independent
expert
trainers
and had met competence
criteria
in order
to participate.
Their
performance
was monitored
throughout
the study
(10, 2224). Treatments
were conducted
in accord
with detailed
manuals
that specified
the theoretical
rationale,
strategies, techniques,
and boundaries
of each modality
(2527). All treatments
were
planned
to be 16 weeks
in
duration
and to consist
of 16-20
sessions.
The pharmacotherapy
dosage
schedule
was flexible,
with a goal
of 200 mg
management
and
a maximum
component
for
conditions
provided
not only guidelines
for medication
monitoring
and management
but also support,
encouragement,
and
advice
as necessary,
although
specific
psychotherapy
interventions
were proscribed.
The total
who actually
sample
entered
(N=239)
treatment
comprised
all patients
from among
the 250
patients
assigned.
criteria
sample
and were
comprised
patients
who
at least
12 sessions
Am
J Psychiatry
completed
148:8,
August
1991
randomly
only
the
and
15
GLASS,
SHEA,
ET AL.
weeks
of treatment
and had clinical
evaluations
at termination.
Clinical
evaluations
were available
for 155
patients
on the Hamilton
depression
scale for analyses
of depression
severity
and for 156 patients
for analyses
of complete
response
(because
of the inclusion
of an
additional
patient
for whom
the Beck inventory
score
only
was
available).
There
were
no statistically
significant
differences
between
treatments
in overall
attrition,
treatment-related
attrition,
or symptomatic
failure.
Seven
patients
did not have termination
evaluations
(1). The findings
on comparative
treatment
efficacy with regard
to depressive
symptoms
and general
functioning,
modality-specific
measures
of change,
and
the temporal
course
of treatment
effect
have been reported
elsewhere
(1, 2, and manuscript
by J.T. Watkins et al., submitted
for publication).
A comprehensive
review
of the literature
was
under-
taken
to identify
patient
predictors
of response
to cognitive-behavior
therapy,
interpersonal
psychotherapy,
and psychotherapy
in general,
as well as to tricyclic
antidepressants
and imipramine
in particular.
Among
the predictor
variables
for which
there was evidence
of
stability
and replication,
a limited
set of independent
variables
for the multivariate
analyses
was selected
on
the basis of the distribution,
intercorrelation,
reliability, and face validity
of the relevant
measures.
Personality disorders
were added
on the basis of experience
in
the pilot study.
Because
of the potential
importance
of
a cognitive
function
predictor
for cognitive-behavior
therapy,
the Dysfunctional
Attitude
Scale
total
score
was selected
on an exploratory
basis.
Two subsequent
reports
suggesting
its relationship
to outcome
(see the
beginning
of this article)
confirmed
that decision.
The 26 independent
variables
were grouped
within
three
domains:
1) sociodemographic
variables-age,
sex,
marital
status,
social
class;
2)
diagnostic
and
course
variables-endogenous,
recurrent,
primary,
situational,
and double
depression,
melancholia,
family
history
of affective
disorder,
age at onset
of first episode, duration
of current
episode,
acuteness
of onset
of
current
episode,
and number
of previous
episodes;
and
3) function,
personality,
and symptom
variables-social dysfunction,
work
dysfunction,
cognitive
dysfunction,
social
satisfaction,
expectation
of improvement,
number
of personality
disorders,
dramatic
personality
disorder,
odd personality
disorder,
anxiety,
somatization/hypochondriasis,
and interpersonal
sensitivity.
The dependent
measures
of depression
outcome
at
termination
were 1) complete
response,
a stringent
categorical
measure
based
on the combination
of a 17item Hamilton
depression
scale score less than or equal
to 6 and a Beck Depression
Inventory
(28) score
less
than or equal
to 9, and 2) depression
severity,
a continuous
measure
based
on the 23-item
Hamilton
depression
scale
score,
which
included
cognitive
and
atypical
vegetative
symptom
items.
Two
dependent
variables
were selected
to examine
predictors
of complete response
or remission
and change
in the severity
of depression,
which
would
reflect
partial
response
as
well. One measure
was based
solely
on clinical
evalu-
999
OF RESPONSE
PREDICTORS
PATIENT
ator ratings,
while the other also incorporated
patient
self-reports.
Scores were based on ratings
at termination of treatment
for completers
and on the last rating
obtained
for patients
who were withdrawn
or dropped
out (generally,
at either
interim
or early termination
evaluation,
but for 20 early dropouts,
at rescreening
evaluation).
The interrater
reliability,
as assessed
by
intraclass
correlation
coefficients,
for the Hamilton
17item scale score ranged
from 0.92 to 0.96 across sites
and from 0.90 to 0.98 within
sites; for the Hamilton
23-item
scale score it ranged
from 0.93 to 0.96 across
sites and from 0.89 to 0.98 within
sites. The Beck
inventory
total
score
showed
good
internal
consistency,
with an alpha coefficient
equal to 0.78. The percentages
of patients
achieving
complete
response
were
43.6%
(N=68)
and 31.4%
(N=7S)
in the completer
and total samples,
respectively.
The meanSD
depression severity
scores
at termination
were 9.43 7.33
and 13.9210.19
in the completer
and total samples,
respectively.
Data
Analysis
To reduce
further
the number
of independent
pa-
tient variables
from the initial set of 26 for the main
predictor
analyses
across treatments,
preliminary
multiple regression
analyses
were conducted
within
each
individual
treatment
condition,
and only the most consistent
predictors
of outcome
within
individual
treatments were selected
for the main analyses.
In both the
total sample
and the completer
sample,
initial analyses
were conducted
the three
single
of predictor
for independent
domains,
variables
and
within
variables
then
in each of
the best
each domain
subsets
were corn-
bined,
with
the pretreatment
Hamilton
depression
score included,
in final analyses
conducted
for each
outcome
measure.
For these preliminary
analyses
we
used the method
of all possible
subsets regression
(29),
which examines
all possible
models
containing
the independent
variables
and selects the best
subsets
on
the basis of an algorithm
that uses the criterion
of
minimal
Mallows
C (30) to select
the regression
model
which
minimizes
the relative
however,
importance
variable,
since
the
model.
We
recognize
that,
given
the
number
of
initial patient
variables
and the size of the groups in the
individual
treatment
conditions,
there is an increased
risk of chance
findings
because
of the inherent
limita-
1000
of the regression
analytic
approach.
We therefore
consider
these
analyses
exploratory
in nature.
While
certain
predictor
relationships
replicated
earlier
findings, other
predictors
will require
further
attempts
to
replicate.
regression
having
been
analyses
within
predictors
individual
in at least
treatments,
two
(Treatment
by
Predictor
by
Response)
were
performed,
and the best fit models
were examined
for predictor
main effects as well as Predictor
by Treatment interactions.
A significance
level of p<O.lO
was
chosen
for the overall
difference
among
treatments.
The Bonferroni
correction
for multiple
comparisons
was used, so for any individual
treatment
comparison
the obtained
probability
level had to be <0.017
to be
considered
significant
at an adjusted
alpha
level of
<0.10.
RESULTS
error
emphasized,
tions
Preliminary
Predictors
Within
Individual
Treatments
Cognitive-behavior
therapy.
The most
consistent
predictor
findings
indicated
that patients
were relatively more responsive
to cognitive-behavior
therapy
if
there was lower
initial
cognitive
dysfunction,
briefer
duration
of the current
episode
of depression,
absence
of a family
history
of affective
disorder,
later age at
onset, and a history
of more previous
episodes
of depression.
Furthermore,
among
completers,
married
patients were relatively
more responsive
to this therapy.
Interpersonal
psychotherapy.
Less
social
dysfunction was associated
with complete
response
in both
samples,
accounting
for 12%-13%
of the outcome
variance,
and was also associated
with good outcome
on depression
severity
in the total sample.
The most
consistent
predictor
findings
Am
J Psychiatry
demonstrated
148:8,
that
August
pa-
1991
SOTSKY,
1. Patient
TABLE
Variables
Studied
for Their
Effect
on Outcome
of a Trial of Psychotherapy
GLASS,
or Pharmacotherapy
SHEA,
ET AL.
in a Sample
of De-
pressed Patients
Variable
Patients Who
Completed
Therapy Trial
(N l62)
Instrument
Age (years)
Mean
SD
Sex (female)
N
Sociodemographic
form
Sociodemographic
f0
Sociodemognaphic
Single
N
0/
_-
depression
Research
Diagnostic
depressionc
Research
Diagnostic
history
of affective
disorder
Family
psychiatric
0/
of current
episode
>6 months
Research
Diagnostic
I0
of onset
(<3
months)
Schedule
for Affective
Disorders
dysfunction
scone
Dysfunctional
Attitude
58
35.8
80
33.5
64
39.5
91
38.1
43
26.7
71
29.8
40
24.8
68
28.6
Social dysfunction
Mean
score
Social
Adjustment
Social
Schedule
Attitudes
141
59.0
68
42.2
100
42.0
141.6
35.6
139.3
34.9
2.9
0.8
2.9
0.7
2.7
0.8
2.7
0.8
12.0
4.6
12.4
4.7
Scaler
SD
Work dysfunction
score
Mean
SD
Anxiety score
Mean
SD
Patient expectation
of improvement
(much or completely
better)
N
97
59.9
Scalee
SD
Adjustment
for Affective
and expectations
Disorders
and
Schizophrenia
form
115
71.0
0/
f0
alncludes
bPercents
cDefined
63
26.4
and Schizophrenia
0/
Cognitive
Mean
37
22.8
Criteria
0/
Acuteness
N
96
40.2
historyd
N
Duration
N
67
41.4
Criteria
0/
Famil;
168
70.3
Criteria
0/
Double
N
109
67.3
...
Endogenous
N
35.0
8.5
form
0/
Separa
N
35.3
8.2
form
0/
Marital
status
Married
N
Total Group
of Patients
(N=239)L
seven patients
who completed
the trial but did not have termination
evaluations.
are based on slightly varying Ns because of missing data in some instances.
as major depressive
disorder plus chronic minor depression
on intermittent
depressive
162
68.1
disorder.
Presence
of family history indicated
by confirmed
diagnosis
of depression
or mania in the patients parents, siblings, or children.
Total scale score, where a low score indicates
the absence of dysfunctional
attitudes
(range=0-280).
tMean for 1 1 items in social and leisure activities
subscale,
where a low score indicates
the absence of impairment
(range
1-5).
for applicable
items in the work outside the house, work at home, and student
subscales,
where a low score indicates
the absence
impairment
(range=
1-5).
FSum of five subscale
items including
panic and psychic and somatic
anxiety symptoms
(range=4-30).
Patients
global response
regarding
his on her expectation
of improvement
with treatment.
tients,
particularly
males,
who had a lower pretreatment level of social dysfunction,
who were separated
or divorced,
and who had higher
interpersonal
sensitivity and overall
higher
satisfaction
with social relationships
were more responsive
to interpersonal
psy-
Am
J Psychiatry
1 48:8,
August
1991
of
chotherapy.
In addition,
there was some evidence
that
patients
with more acute onset
and endogenous
depressive
episodes
but not double depression
responded
more favorably
to this psychotherapy.
Imipramine
with clinical management
(imipramine-
1001
PREDICTORS
PATIENT
TABLE
PatIent
2.
OF RESPONSE
Predictor
Main
of Outcome
in Depressed
Patients
Who Completed
a Trial of Psychotherapy
or
Pharmacotherapy
Outcome
Dc pression
Predictor
Variable
Patients With
Scores Below
Median or
Depression
Subtype
Absent
Patients With
Scores Above
Median or
Depression
Subtype
Present
Adjusted
Mean
SE
Adjusted
Mean
SE
8.5
0.8
10.7
0.8
11.4
1.1
8.8
10.5
8.6
9.8
8.7
0.8
0.7
0.9
0.9
8.1
11.5
9.6
10.3
Cognitive
dysfunction
Patient expectation
of
improvement
Endogenous
depression
Double depression
Social dysfunction
Age
adfl,
Severity
(N
0/,o
3.6
0.06
43/79
0.7
4.3
0.04
0.9
1.1
0.8
0.8
3.9
4#{149}9a
0.0
1.7
0.02
0.04
n.s.
n.s.
(N=156)
Log Linear
Analysis
144)
x2
(dfl)
54
25/77
32
8.0
0.005
53/111
48
15/45
33
2.6
0.11
37/94
52/115
39/76
40/76
39
45
51
53
31/62
16/40
29/80
28/80
SO
40
36
35
2.0
0.2
2.8
4.5
n.s.
n.s.
0.09
0.03
143.
or
had
a low
expectation
of
improvement
Predictors
of Response
Across
Treatments
The 13 variables
most consistently
predictive
of outcome within
treatments,
which were selected
for examination
of potential
prediction
of outcome
across all
treatments
or of differential
outcome
among
treatments,
were age, sex, marital
status, endogenous
depression,
double
depression,
family history
of affective
disorder,
duration
of current episode,
acuteness
of onset, cognitive
dysfunction,
social dysfunction,
work
dysfunction,
anxiety,
and patient
expectation
of improvement.
Table 1 shows
their distribution
in both
1002
Response
Patients With
Scores Above
Median or
Depression
Subtype
Present
F
(df=1,
with treatment
responded
more poorly.
Placebo
with
clinical
management
(placebo-CM).
Among
the more
consistent
predictors,
patients
of
younger
age and with higher
expectation
of improvement appeared
to respond
more favorably
to placeboCM. Patients
with higher levels of initial anxiety
and
depression
severity
responded
less favorably,
as did
patients
with double
depression,
who had a lower likelihood
of complete
response.
Low cognitive
dysfunction and dramatic
personality
disorder
were associated
with worse outcome
on depression
severity in the total
sample
only, suggesting
a possible
relation
to attrition
in this condition.
Main
Complete
Patients With
Scores Below
Median on
Depression
Subtype
Absent
ANCOVA
CM). Higher
work
dysfunction
was the most robust
predictor
of good outcome
with imipramine-CM
in the
completer
sample
for both complete
response
and depression
severity.
The most consistent
predictor
findings indicated
that, overall,
the patients
who showed
the most work dysfunction
responded
best to the effects of imipramine-CM,
as did those with highest
depression
severity
and endogenous
or primary
depression,
but those
with
dramatic
personality
disorder
responded
poorly.
In the total sample,
patients
who
were not married,
had a high level of cognitive
dysfunction,
Measure
155)
samples,
the
instruments
with
which
they
were
as-
conditions
were
identified
from
the
main
effects
in the ANCOVAs
and log linear analyses
in the completer
sample
(table
2), and another
predictor
was
identified
in the total sample
only.
Lower
cognitive
dysfunction
and
provement
were
greater
likelihood
level of depression
main
effects
for
higher
patient
expectation
significantly
associated
of complete
response
severity
at termination.
expectation
of
im-
with both a
and a lower
Significant
of improvement
were
also
present
in the total sample
for both measures,
and a
trend effect was present
for cognitive
dysfunction
on
complete
response.
Although
not evident
in the cornpleter sample,
shorter
duration
of the current
episode
was significantly
associated
with both
complete
response
(2=2.9,
df=1,
p=O.O9)
and lower depression
severity
(F=S.43,
df=1,
228,
p=O.O2)
in
the
total
sample,
suggesting
that the influence
of length of episode on recovery
was more notable
among
patients
who discontinued
treatment,
particularly
in the placebo condition.
Endogenous
depression
was significantly
associated
with lower depression
severity,
whereas
double depression was associated
with higher depression
severity,
in
both the completer
and total samples.
However,
neither variable
predicted
complete
response,
suggesting
a
relation
to residual
depressive
symptoms
but not remission
per
se across
all conditions.
Lower
social
dys-
function
was significantly
associated
with a greater
likelihood
of complete
response
in both samples
but
was not related
to level of residual
depressive
symptoms. There was one significant
main effect of age on
complete
response
in the completer
sample
only, with
older patients
less responsive,
particularly
in the pharmacotherapy
conditions.
Am
J Psychiatry
148:8,
August
1991
SOTSKY,
FIGURE
1. Social Dysfunction
as a Predictor of Differential
Response
to Treatment
in the Total Sample of Depressed Patients
FIGURE
2. Cognitive
(N=239)
(N=239)a
GLASS,
SHEA,
ET AL.
sponse to Treatment
20
20
-15
E15
c
I
a)
10
>
0)
C,)
C
C,)
10
U)
U)
a)
ci)
I.-
a0)
a.
a)
0
CBT
IPT
Ml
CBT
PLA
therapy;
PT
High Social
IPT=intenpersonal
apy; IMI=imipramine;
PLA=placebo.
b1p- significantly
less than PLA (t=3.6,
df=6S,
Ml
CBT
PLA
Dysfunction
psychothen-
p=O.000S).
Am J Psychiatry
148:8,
August
1991
Ml
Low Cognitive
aCBT
CBT
PtA
DySfUflCtiO&
cognitive-behavior
therapy;
less than
IPT
PLA (t=2.7,
that group
and the lowest
dysfunction
group.
Thus,
most differentiated
treatment
PT
Ml
High Cognitive
df=S9,
df=S6,
PLA
Dysfunction
interpersonal
apy; IMI=imipramine;
PLA=placebo.
bIMI significantly
less than PLA (t=3.8,
significantly
Differential
predictor
effects. In the ANCOVAs,
two
of the variables,
social dysfunction
and cognitive
dysfunction,
demonstrated
significant
differential
treatment effects on depression
severity
as outcome
in the
total sample.
Because
of considerable
heterogeneity
of
regression
with regard
to pretreatment
depression
Severity, these analyses
included
only marital
status as a
covariate.
For social dysfunction
(figure
1), as measured by the score on the social and leisure
activities
subscale
of the Social Adjustment
Scale, there was a
significant
overall
Treatment
by Predictor
interaction
(F=2.84,
df=3,
229, p=O.O4).
When the sample
was
divided
at the median
score into high and low social
dysfunction,
the significant
treatment
effect appeared
only in the group with low social dysfunction
(F=4.37,
df=3, 116, p=O.OO6),
such that interpersonal
psychotherapy
patients
had the lowest
mean depression
severity scores
at termination,
significantly
superior
to
scores in the placebo-CM
group.
Although
there were
no significant
differences
among
treatments
in the
group
with
high social
dysfunction
(F= 1.44,
df=
3, 1 1 1, n.s.), it should
be noted
that interpersonal
psychotherapy
patients
had the highest
mean severity
in
IPT
psychother-
pO.0003);
CBT
p=O.0O9).
severity
in the low social
level of social
functioning
response
among
patients
who received
interpersonal
For cognitive
dysfunction
psychotherapy.
(figure 2), as measured
by
the total
score
on the Dysfunctional
Attitude
Scale,
there
was a significant
overall
Treatment
by Predictor
interaction
(F4.27,
df3,
229, pO.OO6)
in the total
sample.
When
separate
ANCOVAs
were
performed
for the high and low cognitive
dysfunction
groups
divided
at the median,
the significant
treatment
effect
appeared
only in the low cognitive
dysfunction
group
(F=4.97,
df=3,
112,
p=O.OO3),
such
that
patients
who
ceived
received
imipramine-CM
and
cognitive-behavior
lower
depression
patients
who
imipramine-CM
severity
received
yielded
therapy
patients
had
who
re-
significantly
scores
at termination
than
placebo-CM.
Treatment
with
the
lowest
mean
depression
severity
score.
Among
the high cognitive
dysfunction
group,
there
were
no significant
differences
between
any of the active
treatments
and placebo-CM
treatment
(F= 1.56, df3,
1 iS, n.s).
It is important
to note
that neither
predictor
directly
distinguished
differential
1003
PATIENT
FIGURE
to
PREDICTORS
OF RESPONSE
3. Work Dysfunction
15O
as a Predictor
Sample
of Differential
of Depressed
Response
Patients
(N=
response
than
did
ratio4.6;
if they
were
treated
with
imipramine-CM
those
with
high cognitive
dysfunction
(odds
X25.8,
df=1,
p<O.OS).
There
was a further
dysfunction
(2=6.7,
the significant
treatment
mine-CM,
indicating
significant
interaction
for work
df=3,
p=O.O8)
(figure
3), and
effect
was again
for imipra-
that
patients
with
high
work
dys-
function
in the completer
sample
who were treated
with
imipramine-CM
had a significantly
greater
chance
of
complete
response
than those
with low work
dysfunction (odds
ratio=S.0;
2=3.7,
df=1,
p=O.O6).
DISCUSSION
The results
of this collaborative
clinical
treatment
trial
comparing
the efficacy
of two specific
forms
of
psychotherapy
with active
and placebo
pharmacotherapy demonstrate
the relevance
of patient
characteristics for the prediction
of outcome
from
an episode
of
major
depressive
disorder.
Several
characteristics
of
the depressive
episode
and
patient
functioning
and
cognition
were indicators
of overall
prognosis
without
regard
to the specific
treatment
received.
These
six patient predictors
of depression
severity
or complete
response
were social
dysfunction,
cognitive
dysfunction,
patient
expectation
of improvement,
endogenous
depression,
double
depression,
and duration
of current
episode.
The
results
of these
analyses
also
provide
evidence
for a limited
number
of characteristics
of patient
function that significantly
predicted
differential
response
to
psychotherapy
or pharmacotherapy
with
imipramine
compared
to placebo.
There
were
no significant
predictors
of differential
response
among
the three
active
treatments.
Among
patients
with
better
initial
social
adjustment
(e.g.,
low social
dysfunction),
those
who
received
interpersonal
psychotherapy
became
significantly
less depressed
than
those
who
received
place-
bo-CM
and
had
a higher
rate
of complete
response
than
those
with
high
social
dysfunction.
Among
patients
with
less perfectionistic
and socially
dependent
attitudes
(e.g., low cognitive
dysfunction),
those
who
received
treatment
with imipramine-CM
or cognitivebehavior
therapy
became
significantly
less depressed
than
those
who
received
placebo-CM,
and
those
treated
with imipramine-CM
also had a higher
rate of
complete
response
than those
with high cognitive
dysfunction.
Among
patients
with
more
impairment
of
function
at work,
school,
or home
(e.g.,
high
work
dysfunction),
those
who received
imipramine-CM
had
response
differential
than those
predictor
with low
effects of
social
and cognitive
dysfunction
were observed
in the
total sample
only, which
may have been because
of 1)
the larger
size of the total
sample,
2) the comparison
with
all placebo-treated
patients
rather
than
placebo
completers
only, or 3) the inclusion
of the full range
of
outcomes,
including
attrition,
thereby
reflecting
differential
acceptability
of the treatments,
an important
1004
Am
J Psychiatry
148:8,
August
1991
SOTSKY,
These
patient
pre-
ET AL.
ent limitations
of the multiple
regression
analytic
approach.
Nevertheless,
where the interesting
patterns of
predictors
of response
within
individual
treatment
conditions
are consistent
with the results of the main
analyses,
we include
them, with appropriate
statistical
caution,
in the discussion.
Given the historical
difficulty of replicating
predictors
across studies,
we have
emphasized
in our interpretation
the consistent
pattern
of findings
across
samples
and measures
of outcome.
We believe that the main results may be of both theoretical and clinical
interest,
particularly
because
of the
uncommon
effort to compare
predictors
of differential
outcome
with a placebo
control.
Our finding that social dysfunction
was a significant
predictor
of differential
response
to interpersonal
psychotherapy
is consistent
with the finding
from the individual
treatment
analyses
that greater
impairment
in
social function
was associated
with poorer
response
to
interpersonal
psychotherapy
greater
and recovery
from
differential
SHEA,
social support,
social satisfaction,
and the ability
to
develop
a good relationship
have been associated
with
favorable
response
to psychotherapy
(31, 34-38).
However,
this specific
relation
with pretreatment
social adjustment
was neither
observed
nor previously
reported
for patients
treated with cognitive-behavior
therapy,
the other psychotherapy
in our study. Thus,
while the study shows that low social dysfunction
predicts favorable
general
prognosis
for outcome
from
depression,
it also provides
evidence
of a specific
responsiveness
to interpersonal
psychotherapy
among
those patients.
Less impairment
in cognitive
function
as measured
by the Dysfunctional
Attitude
Scale appears
to be a
general
predictor
of good prognosis
as well as a specific predictor
of good response
to cognitive-behavior
therapy
(on depression
severity)
and imipramine-CM
(on both outcome
measures).
In the two previous
studies that examined
the relation
of dysfunctional
attitudes to treatment
response,
high cognitive
dysfunction was also associated
with poor outcome
at the
termination
of group cognitive-behavior
therapy
(16)
and poor outcome
at 1-year follow-up
after individual
cognitive-behavior
therapy (17). Although
in our study
cognitive-behavior
therapy
appeared
specifically
to improve dysfunctional
attitudes
concerning
the need for
social approval
(2), there was a less favorable
antidepressant
response
to cognitive-behavior
therapy
in patients with greater
cognitive
dysfunction.
This pattern
of findings
suggests
that there may be an important
distinction
between
the empirical
effects of cognitive
techniques
in changing
dysfunctional
attitudes
and a
theory
that links the presence
of dysfunctional
attitudes
in depression
to a preferential
response
to cognitive therapy.
To our knowledge,
the relation
of dysfunctional
attitudes
to outcome
with
other
psychotherapies
or
pharmacotherapy
has not been reported.
The finding
that in the total sample,
low cognitive
dysfunction
predicted
greater
likelihood
of complete
response
and
aspect
dictors
ificity
of effectiveness.
GLASS,
indirect
evidence
of the specby identifying
characteristics
most responsive
to those modalities.
We consider
the findings
that emerged
from both
the main analyses
across
treatments
and the preliminary
multiple
regression
analyses
within
individual
treatment
conditions
exploratory
in nature
and in
need of further
replication.
The main data analyses
(ANCOVAs
and log linear analyses)
were based on 13
independent
variables
and S2 analyses
(two dependent
variables
and
two
samples);
with
an
alpha
level
of
0.10,
would
approximately
one predictor
and five analyses
be expected
to be significant
by chance alone.
Although
eight variables
were identified
as significant
predictors
and there were 16 significant
main effects
and five interactions
among
the analyses,
some findings (i.e., for age) may have been chance
effects and
may not be replicable.
With the number
of initial patient variables
and the size of the samples
within
the
preliminary
individual
treatment
analyses,
there is a
greater
risk
of chance
interpersonal
initial
findings,
on
depression.
termination
adjustment
for
depressed
the
measures
One
psychotherapy
social
considering
(4)
reported
predicted
good
patients,
of
previous
but
inher-
severity
study
that
of
good
outcome
only
on
at
meas-
relationship,
higher
satisfaction
with
social
re-
lationships
in general,
and heightened
interpersonal
sensitivity
seems consistent
with reports
in the general
psychotherapy
literature
that various
indicators
of social competence
or achievement
are associated
with
good psychotherapy
response,
whereas
social impairment is not. Poor social skills and poor interpersonal
relationships
have been reported
to be related to poor
outcome
of psychotherapy
(32, 33), while perceived
AmJPsychiatry
148:8,
August
1991
improvement
in depression
severity
for patients
100s
PATIENT
PREDICTORS
OF
RESPONSE
ably to interpersonal
psychotherapy.
One possible
explanation
for these results is that each psychotherapy
relies on specific
and different
learning
techniques
to
alleviate
depression,
and thus each may depend on an
adequate
capacity
in the corresponding
sphere of patient function
to produce
recovery
with the use of that
approach.
Therefore,
patients
with good social function may be better able to take advantage
of interpersonal strategies
to recover
from depression,
while patients
without
severe
dysfunctional
attitudes
may
better utilize cognitive
techniques
to restore
mood and
behavior.
Patients
with more impairment
in social or
cognitive
function
might be further overwhelmed
and
demoralized
by a treatment
approach
that requires reliance
on those
capacities
to achieve
improvement.
Such patients
might respond
better to an alternative
psychotherapy
or combination
treatment
or require
longer-term
psychotherapeutic
intervention.
Work dysfunction
is a major aspect of overall social
adjustment
in depression,
measuring
impaired
perfor-
mance,
subjective
distress,
and interpersonal
function.
Among
patients
who completed
treatment
with irnipramine-CM,
impairment
of work function
was a significant
differential
predictor
of recovery,
and the resuits on both outcome
measures
within
the individual
treatment
analyses were consistent.
On the contrary,
in
the few previous
studies,
social impairment,
work disability,
and poor employment
history
have been related to poor outcome
with antidepressant
medication
(39, 43). However,
in our study imipramine-CM
was
previously
reported
(1) to show consistent,
significant
superiority
over placebo-CM
on measures
of recovery
and symptomatic
improvement
among
the more severely impaired
and depressed
patients,
as defined by
the Global
Assessment
Scale. Furthermore,
we observed
(manuscript
by J.T.
Watkins
et al.,
submitted
for publication)
that imipramine-CM
had a significant
early advantage
for improvement
in global social adjustment
at 4 weeks and 12 weeks of treatment
among
the more severely
depressed
patients.
To the extent
that impaired
work function
in depression
may result
from diminished
interest,
energy,
initiative,
and concentration,
psychomotor
retardation,
and social withdrawal,
preferential
improvement
with imipramine
would be consistent
with the recognized
clinical effects
of tricyclic
antidepressants
on these symptoms.
This
pattern
of findings
suggests
that more severe depression, impairment,
and work
dysfunction
are patient
characteristics
which are especially
responsive
to pharmacotherapy
with imipramine
and which may be of
value in the selection
of patients
for this modality.
In this study endogenous
depression
was an overall
predictor
of lower depression
severity
at termination
across all conditions.
Previous
studies,
though,
have
reported
that endogenous
depression
is a negative
indicator
of response
to psychotherapy,
both
interpersonal
psychotherapy
(18) and cognitive-behavior
therapy
(13).
However,
Kovacs
et al. (14) found
endogenous
depression
to be a positive
predictor
of
outcome
for patients
who completed
treatment
with
1006
either a tricyclic
antidepressant
or cognitive-behavior
therapy,
while Blackburn
et al. (44) found no effect of
endogenous
features
on response
to either treatment.
In our individual
treatment
analyses
for interpersonal
psychotherapy,
endogenous
depression
predicted
reduction
of depression
severity.
This relationship
was
not observed
for cognitive-behavior
therapy.
In the individual
treatment
analyses
for irnipramine-CM,
our
finding
that endogenous
depression
was associated
with complete
response
and depression
severity
corroborates
the many previous
reports
that the endogenous subtype
of depression
is a major indicator
of response
to tricyclic
antidepressants
(7, 14, 18, 19, 45).
The lack of differential
predictive
effect for endogenous depression
may be a result of measuring
outcome
after 4 months,
since the differential
effect of imipramine-CM
on endogenous
symptoms
was most manifest at 8 and 12 weeks of treatment
(manuscript
by J.T.
Watkins
et a!., submitted
for publication).
The reports
of situational
depression
as a predictor
of negative
outcome for tricyclics
and positive
outcome
for psychotherapy were not replicated,
however.
The presence
of double depression
and the duration
of the depressive
episode
are important
aspects
of the
course
of illness that appear
to influence
response
to
treatment.
In a large naturalistic
study uncontrolled
for treatment,
double depression
was associated
with
favorable
outcome
from the major depressive
episode
only, but with poor outcome
if outcome
was defined as
full recovery
from the underlying
chronic
minor
depression
as well (46-48).
In our controlled
treatment
trial, double
depression
was predictive
of higher
depression
severity
at termination
but not of complete
response,
suggesting
a relation
to degree
of improvement but not remission
per se across all treatment
conditions.
Within
the individual
treatment
analyses,
double depression
predicted
lack of complete
response
from the episode
among
patients
treated
with placebo-CM
but not among those who received
one of the
three active treatments.
This may suggest
that with
active treatment,
recovery
from the major depressive
episode
is achieved
as readily
by patients
with double
depression
as by those without
chronic
illness, but that
more
residual
depressive
symptoms
persist
among
those with double
depression.
However,
patients
with
double
depression
treated
only by placebo-CM
do not
recover as readily. Results at follow-up
should be most
interesting,
since previous
studies have noted the greatest impact
of double
depression
on subsequent
course
after recovery
from the initial episode
(38, 48).
Longer
duration
of the current
episode
predicted
higher depression
severity
and a lower rate of complete
response
in the total sample
but not the completer
sample,
suggesting
that the influence
of chronicity
on
recovery was greater among patients who did not complete treatment,
most notably
in the placebo-CM
condition.
This finding
is consistent
with many previous
studies
that have reported
a negative
relation
between
duration
of illness and clinical
outcome
of psychotherapy
(49-52),
imipramine
and other tricyclic
anti-
Am
J Psychiatry
148:8,
August
1991
SOTSKY,
depressants
(34, 39, 53-55),
and placebo
(34, 56). Previous
reports
have
indicated
that
acute
onset
of
depression
is a positive
indicator
of response
to both
tricyclic
antidepressant
treatment
(7, 9, 45) and psychotherapy
(33). In our study acute onset was associated
with
complete
response
among
patients
tions.
Acute
dictor
onset
did
of differential
analyses.
We
not
emerge
treatment
therefore
consider
as a significant
outcome
this
to be only
evidence
supporting
earlier findings.
Last, patients
with higher
expectation
ment had a higher
likelihood
of recovery
level of depression
in both samples.
severity
across
Within
individual
in the
treatment
treatment
pre-
The National
Institute of Mental Health Treatment
of Depression
Collaborative
Research
Program
is a multisite
program
initiated
and
sponsored
by the Psychosocial
Treatments
Research
Branch,
Division of Extramural
Research
Programs
(now part of the Mood,
Anxiety
and Personality
Disorders
Research
Branch,
Division
of
Clinical Research),
NIMH.
The program
was funded by cooperative
agreements
with six participating
sites (George Washington
University, grant MH-33762;
University
of Pittsburgh,
MH-33753;
University
of Oklahoma,
MH-33760;
Yale University,
MH-33827;
Clarke Institute of Psychiatry,
MH-3823
I ; and Rush PresbyterianSt. Lukes Medical
Center,
MH-35017).
The principal
NIMH
collaborators
were Irene Elkin, Ph.D., Coordinator;
Tracie Shea, Ph.D.,
Associate
Coordinator;
John P. Docherty,
M.D.; and Morris B. Parloff, Ph.D. The principal
investigators
and project
coordinators
at
the three participating
research sites were George Washington
University:
Stuart M. Sotsky,
M.D., and David R. Glass, Ph.D.; University
of Pittsburgh:
Stanley D. Imber, Ph.D., and Paul A. Pilkonis,
Ph.D.;
and University
of Oklahoma:
John T. Watkins,
Ph.D., and
William
Leber, Ph.D. The principal
investigators
and project coondinators
at the three sites responsible
for training
therapists
were
Yale University:
Myrna Weissman,
Ph.D., Eve Chevron,
M.S., and
Bruce J. Rounsaville,
M.D.; Clarke Institute
of Psychiatry:
Brian F.
Shaw, Ph.D., and T. Michael Vallis, Ph.D.; and Rush Presbyterian-
148:8,
August
4.
S.
6.
7.
8.
9.
10.
1 1.
12.
13.
ACKNOWLEDGMENTS
J Psychiatry
2.
3.
the negative
influence
of lower expectation
of improvement appeared
to occur among
patients
who received
only placebo-CM
or an incomplete
course
of imipramine (in the total sample
only, not among
completers
of imipramine
treatment).
Low expectation
of response
to pharmacotherapy
has been previously
reported
to predict
attrition
but not clinical
outcome
(57). In the psychotherapy
literature,
the relation
of
patient
expectations
to outcome
has been generally
positive
(5, 6), consistent
with these results.
Other
components
of patient
expectations
and attitudes
regarding
treatment
and depression
remain
to be explored.
Since the pattern
of findings
for several patient
predictors
suggested
a relation
to outcome
among
patients who did not complete
treatment,
analyses
of predictors
of attrition
are planned.
Furthermore,
the identification
of potential
patient
predictors
of long-term
prognosis
after initial
treatment
response
will be of
considerable
clinical
interest.
Am
1. Elkin
limited
conditions
analyses,
1991
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