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Cognitive Therapy vs Medications in the Treatment of Moderate to Severe Depression

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There is substantial evidence that antidepressant medications treat moderate to severe depression effectively, but there is less data on cognitive therapy's effects in this population. To compare the efficacy in moderate to severe depression of antidepressant medications with cognitive therapy in a placebo-controlled trial. Random assignment to one of the following: 16 weeks of medications (n = 120), 16 weeks of cognitive therapy (n = 60), or 8 weeks of pill placebo (n = 60). Research clinics at the University of Pennsylvania, Philadelphia, and Vanderbilt University, Nashville, Tenn. Two hundred forty outpatients, aged 18 to 70 years, with moderate to severe major depressive disorder. Some study subjects received paroxetine, up to 50 mg daily, augmented by lithium carbonate or desipramine hydrochloride if necessary; others received individual cognitive therapy. The Hamilton Depression Rating Scale provided continuous severity scores and allowed for designations of response and remission. At 8 weeks, response rates in medications (50%) and cognitive therapy (43%) groups were both superior to the placebo (25%) group. Analyses based on continuous scores at 8 weeks indicated an advantage for each of the active treatments over placebo, each with a medium effect size. The advantage was significant for medication relative to placebo, and at the level of a nonsignificant trend for cognitive therapy relative to placebo. At 16 weeks, response rates were 58% in each of the active conditions; remission rates were 46% for medication, 40% for cognitive therapy. Follow-up tests of a site x treatment interaction indicated a significant difference only at Vanderbilt University, where medications were superior to cognitive therapy. Site differences in patient characteristics and in the relative experience levels of the cognitive therapists each appear to have contributed to this interaction. Cognitive therapy can be as effective as medications for the initial treatment of moderate to severe major depression, but this degree of effectiveness may depend on a high level of therapist experience or expertise.
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ORIGINAL ARTICLE
Cognitive Therapy vs Medications in the Treatment
of Moderate to Severe Depression
Robert J. DeRubeis, PhD; Steven D. Hollon, PhD; Jay D. Amsterdam, MD; Richard C. Shelton, MD; Paula R. Young, PhD;
Ronald M. Salomon, MD; John P. O’Reardon, MD; Margaret L. Lovett, MEd; Madeline M. Gladis, PhD;
Laurel L. Brown, PhD; Robert Gallop, PhD
Background: There is substantial evidence that anti-
depressant medications treat moderate to severe depres-
sion effectively, but there is less data on cognitive thera-
py’s effects in this population.
Objective: To compare the efficacy in moderate to se-
vere depression of antidepressant medications with cog-
nitive therapy in a placebo-controlled trial.
Design: Random assignment to one of the following: 16
weeks of medications (n=120), 16 weeks of cognitive
therapy (n= 60), or 8 weeks of pill placebo (n=60).
Setting: Research clinics at the University of Pennsyl-
vania, Philadelphia, and Vanderbilt University, Nash-
ville, Tenn.
Patients: Two hundred forty outpatients, aged 18 to 70
years, with moderate to severe major depressive disor-
der.
Interventions: Some study subjects received parox-
etine, up to 50 mg daily, augmented by lithium carbon-
ate or desipramine hydrochloride if necessary; others re-
ceived individual cognitive therapy.
Main Outcome Measure: The Hamilton Depression
Rating Scale provided continuous severity scores and al-
lowed for designations of response and remission.
Results: At 8 weeks, response rates in medications (50%)
and cognitive therapy (43%) groups were both superior
to the placebo (25%) group. Analyses based on continu-
ous scores at 8 weeks indicated an advantage for each of
the active treatments over placebo, each with a medium
effect size. The advantage was significant for medica-
tion relative to placebo, and at the level of a nonsignifi-
cant trend for cognitive therapy relative to placebo. At
16 weeks, response rates were 58% in each of the active
conditions; remission rates were 46% for medication, 40%
for cognitive therapy. Follow-up tests of a site treatment
interaction indicated a significant difference only at
Vanderbilt University, where medications were supe-
rior to cognitive therapy. Site differences in patient char-
acteristics and in the relative experience levels of the cog-
nitive therapists each appear to have contributed to this
interaction.
Conclusion: Cognitive therapy can be as effective as medi-
cations for the initial treatment of moderate to severe ma-
jor depression, but this degree of effectiveness may de-
pend on a high level of therapist experience or expertise.
Arch Gen Psychiatry. 2005;62:409-416
A
NTIDEPRESSANT MEDICA-
tions (ADMs) are the most
widely used treatment for
major depressive disorder
(MDD) in the United
States.
1
Evidence from numerous random-
ized placebo-controlled trials has sup-
ported the efficacy of ADMs, particularly
among more severely depressed patients.
2
Cognitive therapy (CT), a type of cog-
nitive behavioral therapy pioneered by
Beck et al,
3
has also shown promise in the
treatment of MDD.
4
Rush et al
5
initially re-
ported that CT was more effective than
ADM in a randomized, comparative trial.
However, their ADM dosages were low and
the medications were tapered 2 weeks be-
fore the final outcome assessment. De-
spite these shortcomings, these findings
generated enthusiasm for CT as an alter-
native to ADM for the treatment of de-
pression.
The Treatment of Depression Collabo-
rative Research Program (TDCRP),
6
ini-
tiated by the National Institute of Mental
Health, compared CT, ADM, pill pla-
cebo, and interpersonal psychotherapy
treatments in depressed outpatients. No
differences in outcome were observed be-
tween CT and ADM among all patients.
See also page 417
Author Affiliations:
Departments of Psychology
(Dr DeRubeis), and Psychiatry
(Drs Amsterdam, Young,
O’Reardon, and Gladis),
University of Pennsylvania,
Philadelphia ; Departments of
Psychology (Dr Hollon), and
Psychiatry (Drs Shelton,
Salomon, Lovett, and Brown),
Vanderbilt University, Nashville,
Tenn; Department of
Mathematics and Applied
Statistics, West Chester
University, West Chester, Pa
(Dr Gallop).
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However, in a secondary analysis of more severely de-
pressed patients (intake Hamilton Depression Rating Scale
[HDRS] scores of 20 or above), ADM outcomes were su-
perior to both placebo and CT, and the outcomes of CT
were not significantly superior to placebo.
7
Because of
the size and methodological sophistication of the TDCRP,
these findings have had a major impact on the field. For
example, the American Psychiatric Association’s Prac-
tice Guidelines for Major Depressive Disorder in Adults
4
rec-
ommended the use of ADM, and not CT, as first-line
therapy for patients with moderate to severe MDD.
Concerns have been raised about the quality of the
CT provided in the TDCRP, leading some to question
whether these findings should supersede those of other
randomized comparisons of ADM and CT in MDD.
8
Neither Murphy et al
9
nor Hollon et al
10
reported differ-
ences in efficacy between ADM and CT in their random-
ized trials, although both studies, like that of Rush et al,
5
included patients with MDD with a broad range of
depression severity. A mega-analysis that focused on the
more severely depressed patients from the 4 studies
mentioned earlier yielded a finding that did not favor
ADM over CT.
11
To date, no comparison of ADM and CT has con-
tained a large sample of patients with moderate to se-
vere MDD, and only the TDCRP study included a pla-
cebo control group. We therefore conducted a large 2-site,
placebo-controlled, randomized trial to test the relative
efficacy of ADM and CT in outpatients with more se-
vere MDD. We made special efforts to ensure that the pro-
vision of both ADM and CT was consistent with “best
practices” in the respective treatment modalities.
METHODS
The protocol was approved by the respective institutional
review boards at the University of Pennsylvania, Philadelphia,
and Vanderbilt University, Nashville, Tenn. All participants
provided written informed consent prior to any research activ-
ity. Subjects were recruited from referrals and from media
announcements that described the respective research clinics.
Evaluations were conducted blind to treatment condition by
interviewers who were trained and supervised by one of the
authors (M.M.G.), who herself trained with the Biometrics
Research Department (New York State Psychiatric Institute,
New York). The Structured Clinical Interviews for DSM-IV
Diagnosis (Axis I and Axis II) were used to determine diagnos-
tic eligibility for the study.
12,13
In addition, the first 17 items of
the 24-item HDRS
14,15
were used to determine whether the
depressive symptoms of the subjects were severe enough for
inclusion in the trial. There are numerous versions of the
HDRS, but most investigators report the standard 17-item ver-
sion. Selected items were modified to allow patients to be
scored for either typical or atypical presentations of symptoms
associated with sleep, appetite, and change in weight.
16
The
remaining 7 HDRS items, including 3 that emphasize cognitive
symptoms, were obtained in the interviews but were not
employed in the primary analyses reported in this article. Sec-
ondary analyses including these additional items did not alter
the basic pattern of the results. Interviewers at both sites (4 at
Pennsylvania and 3 at Vanderbilt) rated a subset of these tapes.
An intraclass correlation coefficient of 0.96 was obtained for
the 17-item total HDRS score (n=24). Assessment of the reli-
ability of the major depressive episode designation yielded a
coefficient of 0.80 (n=12).
17
Diagnoses were confirmed by an
experienced research psychiatrist.
Inclusion criteria were: diagnosis of MDD according to DSM-
IV
18
criteria, age 18 to 70 years, English speaking, and willing-
ness and ability to give informed consent. Consistent with the
TDCRP’s definition of “more severely depressed,” all included
patients had scores of 20 or higher on the modified 17-item
HDRS at the screen and baseline visits, separated by at least 7
days.
A total of 437 patients were evaluated for the study, 96 of
whom either did not meet diagnostic criteria for MDD or did
not achieve HDRS scores of 20 or higher at both the screen and
baseline study visits. Another 101 patients met the following
exclusion criteria: (1) history of bipolar I disorder (n=25); (2)
substance abuse or dependence judged to require treatment
(n=26); (3) current or past psychosis (n=10); (4) another
DSM-IV Axis I disorder judged to require treatment in prefer-
ence to the depression (anxiety disorders, n=5; eating disor-
ders, n=2); (5) 1 of the 3 excluded DSM-IV Axis II disorders
deemed to be poorly suited to the treatments under investiga-
tion (antisocial, n=3; borderline, n=8; schizotypal, n=1); (6)
suicide risk requiring immediate hospitalization (n= 4); (7) medi-
cal condition that contraindicated study medications (n=13);
or (8) nonresponse to an adequate trial of paroxetine in the pre-
ceding year (n=4).
The 240 patients who met entry criteria were randomly as-
signed to 1 of 3 treatment conditions: ADM (n=120), pill pla-
cebo (n=60), or CT (n =60). The ADM cell was designed to
have twice as many patients as the CT and pill placebo cells
because responders to ADM at study week 16 were to be ran-
domized a second time for a companion study of subsequent
relapse prevention.
19
Antidepressant medication and CT were
each provided for 16 weeks. For ethical reasons, the pill pla-
cebo condition was terminated after 8 weeks; this duration was
sufficient to reveal differences in drug vs placebo.
20
Random-
ization was implemented after stratifying on sex and the num-
ber of prior episodes.
TREATMENT PROCEDURES
Pharmacotherapy and Placebo
Patients in the pharmacotherapy cells were treated for 8 weeks
with paroxetine or placebo. All 5 pharmacotherapists (3 at Penn-
sylvania, 2 at Vanderbilt) were male, board-certified psychia-
trists with extensive experience (9-23 years) treating MDD phar-
macologically. Patients in pharmacotherapy received weekly
treatment sessions for the first 4 weeks, and every other week
thereafter. Initial sessions typically lasted 30 to 45 minutes; sub-
sequent sessions lasted about 20 minutes. During the first 8
weeks, patients and pharmacotherapists remained blind as to
whether the pills contained paroxetine.
Pharmacotherapy sessions were conducted in accordance
with the manual used in the TDCRP.
21
Jan Fawcett, MD, the
author of the manual, provided training and consultation in
clinical management throughout the study. Pharmacotherapy
sessions focused on the following: (1) medication manage-
ment, which involved education about medications, adjust-
ment of dosage and dosage schedules, and discussions of ad-
verse effects; and (2) clinical management, which involved a
review of the patient’s functioning in major life spheres, brief
supportive counseling, and limited advice giving. Techniques
and strategies specific to CT were prohibited.
All patients in the pharmacotherapy conditions began treat-
ment with paroxetine or placebo (10-20 mg daily). This dose
was raised in 10- to 20-mg increments as tolerated based on
response and the occurrence of dose-limiting adverse effects,
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to a maximum of 50 mg daily by week 6 of treatment, or until
a significant reduction in symptoms was seen. The minimum
acceptable dose was 20 mg/d; 10 mg/d if 20 mg was not toler-
ated.
After 8 weeks of pharmacotherapy, the double-blind con-
dition was broken for the patient and pharmacotherapist (but
not for the interviewer). Patients who had been given placebo
were offered treatment without cost. Those in the ADM cell con-
tinued receiving their established paroxetine dose. For pa-
tients who did not meet the established response criteria (dis-
cussed later) by week 8 of treatment, augmentation with lithium
carbonate or desipramine hydrochloride was initiated, unless
there was an overriding clinical consideration, such as intol-
erance of paroxetine, in which case the pharmacotherapist was
free to prescribe another ADM.
Cognitive Therapy
Cognitive therapy was provided by 6 therapists, 3 at each site.
One therapist at each site was female. Five therapists were li-
censed psychologists with PhD degrees; 1 at Vanderbilt was a
psychiatric nurse practitioner. Their experience with psycho-
therapy ranged from 5 to 21 years at the beginning of the trial.
All 3 Pennsylvania therapists and 1 of the Vanderbilt thera-
pists had extensive experience conducting CT (7-21 years). The
other 2 Vanderbilt therapists each began the trial with 2 years
of CT experience. These 2 therapists received training through
the Beck Institute for Cognitive Therapy (Bala Cynwyd, Pa) dur-
ing the trial and were judged to have met criteria for compe-
tence as a result of this supplemental training.
All therapists followed the procedures outlined in stan-
dard texts of cognitive therapy for depression
3,22
and for co-
morbid personality disorders.
23
Guidelines called for 50-
minute sessions to be held twice weekly for the first 4 weeks
of treatment, once or twice weekly for the middle 8 weeks, and
once weekly for the final 4 weeks. At each site, cognitive thera-
pists met together weekly for 90 minutes to review ongoing cases.
OUTCOME MEASURES
The modified 17-item HDRS was used as the primary outcome
measure.
14-16
All evaluations were videotaped. We will report
on categorical indexes that use the HDRS at 8 weeks, when all
3 conditions were compared, and at 16 weeks, when only the
2 active treatments were compared. We employed a response
criterion based on absolute levels of symptoms, rather than per-
centage reduction, to ensure that no patient was classified as a
responder who exhibited a high level of symptomatology. At 8
weeks, the criterion for response was an HDRS score of 12 or
lower, with the last observation carried forward in the case of
study dropouts.
24
Response criteria for the 16-week comparison were also based
on an HDRS score of 12 or less, but they were designed to pre-
vent a transient exacerbation of depressive symptoms from keep-
ing a patient from meeting response criteria. The criteria were:
completion of the 16-week treatment phase and one of the fol-
lowing: (1) 16-week HDRS score of 12 or lower and either a
14-week score of 14 or lower or a 10- and 12-week score of 12
or lower; or (2) a 12-, 14-, and an 18-week HDRS score of 12
or lower. The 16-week response designation was also used to
determine which patients would be invited to participate in the
succeeding phase of the study, an investigation of relapse pre-
vention among responders to acute ADM or CT.
19
All of these
response criteria were also applied to determine full remis-
sion, with the additional requirement of the final HDRS score
having been 7 or less during the acute phase, consistent with
the MacArthur recommendation.
25
STATISTICAL ANALYSES
Based on numerous placebo-controlled randomized clinical
trials, we estimated that the drug-placebo comparison would
yield an effect size of a one-half standard deviation on the HDRS
(estimated mean difference =3.5, estimated SD = 7). Based on
these estimates, a cell size of at least 60 was required to achieve
a power of 0.8 or more to detect a difference at the 0.05 level,
2-tailed.
Treatment differences in response categories at 8 and 16
weeks were examined using the Cochran Q test.
26
The Co-
chran Q test approach extends the
2
test of association for con-
tingency tables to sets of contingency tables. Within-site com-
parisons and tests of sitetreatment interactions were assessed
using logistic regression models based on the Wald
2
.
27
At 8
weeks, the association for 2 sets of 3 2 tables was assessed.
(Note that the 2 sets correspond to the 2 sites of the study, 3
corresponds to the 3 treatments, and the second 2 corre-
sponds to response/nonresponse.) Under the null hypothesis,
there is no difference in response classification for the 3 levels
of treatment adjusting for site.
28
Similarly, the 16-week con-
trasts consisted of assessing the association for the 2 sets of 2 2
tables. (Note that only 2 treatments are involved in tests of the
16-week data.)
For continuous data, the analytical method was a multi-
level model adjusting for the repeated measures with nested
random effects. This analysis falls under the heading of ran-
dom coefficient models, hierarchical linear models (HLM), and
multilevel linear models.
29,30
In this approach, each subject’s
growth curve is characterized by a set of person-specific pa-
rameters. The standard HLM involves 2 levels: within-subject
(level 1) and between-subject (level 2). At level 1, the out-
come varies within subjects over time as a function of a person-
specific growth curve. At level 2, the person-specific change
parameters are viewed as varying randomly across subjects, as
a function of the subject’s treatment. The combination of the
level 1 and level 2 models results in a mixed linear model with
fixed and random coefficients. The person-specific param-
eters correspond to a random intercept and a random slope for
each subject. The random terms are assumed to follow a bi-
variate normal distribution, which allows the random terms to
be correlated. This is commonly referred to as an unstruc-
tured covariance structure. Analyses that fall under the head-
ing of HLM provide accurate statistical inferences for data that
have a nested or hierarchical structure by modeling the within-
subject correlation by the inclusion of random effects.
29,30
Ig-
noring this within-subject correlation for nested data may re-
sult in underestimation of the variance in the model, which
would result in significance levels closer to 0. Therefore, more
powerful HLMs were used to answer our primary questions that
concern continuous outcomes. The HLM analysis examined dif-
ferences in linear rates of change between ADM, CT, and pill
placebo groups in HDRS scores over the course of the first 8
weeks. Similarly, a second HLM examined the difference in lin-
ear rates of change between ADM and CT in HDRS scores over
the 16-week acute phase. For these models all available data
were used, making the HLM application a full intent-to-treat
analysis. For dropouts, all and only those data gathered prior
to the date of attrition were used in these models. The effects
of site and of initial baseline HDRS total score were covaried.
Because we collected a second baseline score (at least 1 week
after the initial one) on each of the 240 patients, we were able
to conduct a full intent-to-treat analysis on these data, even when
including the initial baseline as a covariate. The model (per-
formed using SAS version 8.0, PROC MIXED; SAS Institute Inc,
Cary, NC) estimated fixed effects for treatment and for site.
Population-averaged estimates for the linear trend over time
and linear trend over time per treatment are produced by this
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model. The model tests the linear slope difference between
the groups. Differential rates of change per treatment between
sites were assessed by the site time treatment interaction.
If nonsignificant, this interaction term was removed from the
model.
RESULTS
BASELINE CHARACTERISTICS
A total of 240 patients were randomized to treatments,
120 at each site. Baseline HDRS score means did not dif-
fer between conditions or between sites (overall mean ±
SD=23.4±2.9; range=20-35). Other important baseline
variables are presented in the
Table along with results
of t tests for continuous variables and
2
tests for binary
variables. The modal patient in the sample was middle-
aged, white, with partial college education and modest
income. One third of the sample was married or cohabi-
tating. The Pennsylvania sample, relative to the Vander-
bilt sample, was more likely to be male and ethnically
and racially diverse.
Overall, but especially at Vanderbilt, the sample was
highly chronic or recurrent, with early onsets and a sub-
stantial rate of prior hospitalizations. Comorbidity rates
were high at Pennsylvania, and even higher at Vander-
bilt. Nearly three quarters of the patients met criteria for
an Axis I comorbidity, the most common of which were
the anxiety disorders. Nearly half the patients met cri-
teria for at least 1 Axis II disorder.
Of all the variables listed in the Table, the rates of sub-
stance abuse, Axis I comorbidity, melancholic depres-
sion, and atypical depression differed significantly as a
function of treatment condition. Because none of these
variables predicted response across the treatments, no con-
founds were identified that would compromise the tests
of comparative efficacy. Secondary analyses with these
variables as covariates yielded the same pattern of re-
sults as those without these covariates. Thus, these vari-
ables were not included as covariates in the analyses re-
ported in this article.
ATTRITION
During the first 8-week treatment period, the overall
attrition rate in the sample was 13%. Attrition was 11%
in the ADM cell (8 at Pennsylvania, 5 at Vanderbilt);
15% in the CT cell (6 at Pennsylvania, 3 at Vanderbilt);
and 13% in the pill placebo cell (4 at each site). One
patient in the ADM cell and 2 patients in the pill placebo
cell withdrew consent immediately following random-
ization, while 9 others withdrew consent during treat-
ment without stating a specific reason (5 in the ADM
cell and 5 in the CT cell). Only 6 patients dropped out
Table. Baseline Characteristics
Variable
Whole Sample
(n = 240)
University of Pennsylvania
(n = 120)
Vanderbilt University
(n = 120)
HDRS score, mean ± SD 23.4 ± 2.9 23.4 ± 2.9 23.4 ± 2.8
Female, %* 59 52 65
White, % 82 75 88
Age, mean ± SD, y 40 ± 12 39 ± 12 42 ± 11
Education, mean ± SD, y 15 ± 2 15 ± 3 15 ± 2
Income, mean ± SD, (in thousands of US $) 34 ± 33 32 ± 33 36 ± 34
Married/cohabitating, % 33 33 33
Employed, % 82 82 82
Chronic or recurrent MDD, % 90 84 95
Age of onset, mean ± SD, y* 22 ± 12 25 ± 11.7 20 ± 12
No. of prior episodes, mean ± SD 2.4 ± 2.6 2.3 ± 3.0 2.6 ± 2.2
Duration of current episode, mean ± SD, mo 46 ± 75 46 ± 88 46 ± 61
Dysthymia, %* 25 9 41
History of prior ADM therapy, %* 60 47 74
History of psychiatric hospitalization, % 12 8 15
Met DSM-IV specifiers for melancholia, % 30 33 28
Met DSM-IV specifiers for atypical features, %* 22 15 28
Axis I or Axis II comorbidity, % 83 76 91
Any Axis I comorbidity, %* 72 63 82
Comorbid anxiety disorders, %* 53 41 65
Comorbid PTSD, %* 17 5 28
Comorbid eating disorders, %* 17 9 24
Comorbid substance abuse or dependence, % (primarily by history) 35 34 36
Any Axis II comorbidity, %* 48 38 57
Cluster A personality disorder, % 3 3 3
Cluster B personality disorder, % 3 2 5
Cluster C personality disorder, %* 28 19 38
Personality disorder NOS, % 17 19 14
Abbreviations: ADM, antidepressant medication; HDRS, Hamilton Depression Rating Scale; MDD, major depressive disorder; NOS, not otherwise specified;
PTSD, posttraumatic stress disorder.
*Indicates significant site difference (P.05).
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owing to adverse effects: 4 (3%) in the ADM cell, and 2
(3%) in the pill placebo cell. Four (7%) patients in the
CT cell and 4 (7%) patients in the pill placebo cell
dropped out because of dissatisfaction with treatment.
Two patients (2%) were withdrawn from ADM treat-
ment owing to worsening of symptoms. One patient in
the ADM cell committed suicide during the second week
of treatment.
Over the second 8 weeks of the trial, 6 patients in the
ADM cell (4 at Pennsylvania and 2 at Vanderbilt; 5% over-
all) dropped out because of adverse effects (n=4) or be-
cause they were no longer interested in treatment (n=2),
whereas no patient in the CT cell dropped out during this
period. Thus, over the 16-week treatment course, attri-
tion rate was 16% for the ADM cell and 15% for CT. At-
trition did not differ significantly between sites or across
conditions after 8 weeks or after 16 weeks.
MEDICATION DOSAGES
The mean (±SD) daily paroxetine dose during the first
week of treatment was 14.0±4.9 mg (Pennsylva-
nia=12.4±4.3; Vanderbilt=15.5 ±5.0; P.001). The mean
daily dosage was increased to 31.6±11.2 by the fourth
week (Pennsylvania=30.4 ±12.4; Vanderbilt=32.8±9.9;
P =.26), and to 38.8±11.0 at week 8 (Pennsylva-
nia=38.3±11.9; Vanderbilt=39.3±10.2; P=.66).
Mean daily paroxetine dosage over the second 8-week
treatment period was 37.3±12.4 mg (Pennsylva-
nia=33.5±14.2; Vanderbilt=40.8 ±9.4; P=.003). One pa-
tient was switched to buproprion and another to sertra-
line owing to intolerance of paroxetine; the dosages of
these patients were excluded from the calculations of
means. The difference in average dosage between sites
was primarily due to differential prescribing in the pa-
tients with augmented treatment (47 of the 101 pa-
tients). Patients with nonaugmented treatments (21 at
Pennsylvania, 33 at Vanderbilt) received similar dos-
ages at the 2 sites (Pennsylvania= 36.0±12.6; Vander-
bilt=39.5±8.2; P=.28). However, among the patients with
augmented treatments (Pennsylvania n=27, Vanderbilt
n=20), mean paroxetine dosages were lower at Pennsyl-
vania than at Vanderbilt (Pennsylvania=31.8 ±15.2;
Vanderbilt=42.9±10.8; P=.004). This difference is in con-
trast to the mean paroxetine dosages of patients with aug-
mented treatment at the end of 8 weeks of treatment,
which were similar between sites (Pennsylva-
nia=40.4±10.7, Vanderbilt=44.3±8.7; P=.16). The dif-
ference in prescribing patterns between Pennsylvania and
Vanderbilt among the patients with augmented treat-
ment was not planned or addressed by the protocol. In
the absence of specific guidelines, Pennsylvania psychia-
trists followed conventional practice more closely in this
regard, whereas Vanderbilt psychiatrists followed a more
aggressive strategy than is typically practiced. Examina-
tion of the data did not suggest that the site differences
in outcome in the ADM cell could be explained by this
difference in practices between the sites.
Of the 47 patients who received augmentation treat-
ment, 32 (64%) were prescribed lithium, 28 (56%) were
prescribed desipramine, and 1 (2%) was treated with ven-
lafaxine. (Percentages add to greater than 100% because
some patient treatments were augmented with more than
1 drug, either in combination or in sequence.)
OUTCOME AT 8 WEEKS
(PLACEBO-CONTROLLED)
Categorical Analyses at 8 Weeks
Rates of response at 8 weeks (12 on the HDRS, with
last observation carried forward for dropouts) were 50%
in the ADM cell (95% confidence interval (CI), 41%-
59%), 43% in the CT cell (95% CI, 31%-56%), and 25%
in the pill placebo cell (95% CI, 16%-38%). A Cochran
Q test controlling for site indicated a difference in re-
sponse across the 3 treatments (
2
2
=10.22, P=.006). Pair-
wise comparisons indicated a significant difference in fa-
vor of ADM compared with pill placebo (
2
1
=10.17,
P=.001), and a significant difference in favor of CT com-
pared with pill placebo (
2
1
=4.44, P=.04). The pairwise
comparison of ADM with CT was nonsignificant (
2
1
=0.71,
P=.40). A logistic regression model indicated that re-
sponse rates across treatment conditions were not dif-
ferential between the sites (Wald
2
2
=1.59, P=.45).
Continuous Analyses at 8 Weeks
Across the first 8 weeks of treatment, the test of a
sitetreatment interaction was not significant (F
2,228
=1.65,
P=.19). As displayed in
Figure 1, there was improve-
ment during the first 8 weeks across treatments
(F
1,231
=395.9, P.001). The term in the model that tests
for differential change on the HDRS as a function of treat-
ment over time was significant (F
2,231
=3.81, P=.02). Pair-
wise contrasts revealed a significant advantage of ADM
compared with pill placebo (F
1,231
=7.60 P=.006) and a non-
significant trend in favor of CT compared with pill pla-
cebo (F
1,231
=2.96, P=.09). Effect sizes, derived from the
subject-specific slopes of the HLM model,
31
were 0.60 for
ADM compared with pill placebo, and 0.44 for CT rela-
tive to pill placebo. The difference between ADM and CT
was not significant (F
1,231
=0.56; P=.46); the associated effect
size estimate was 0.16, in favor of ADM. Effect sizes be-
tween 0.5 and 0.8 can be considered “medium” in mag-
nitude, and effect sizes between 0.2 and 0.5 “small.”
32
24
20
16
22
18
14
12
10
8
6
4
2
0
Intake
2468
Weeks
HDRS Score
P-P
CT
ADM
Figure 1. Biweekly Hamilton Depression Rating Scale (HDRS) scores during
the first 8 weeks of acute treatment. ADM indicates antidepressant medication
therapy (n =120); CT, cognitive therapy (n=60); and P-P, pill placebo (n=60).
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OUTCOME AT 16 WEEKS
(ACTIVE TREATMENTS ONLY)
Categorical Analyses at 16 Weeks
As displayed in
Figure 2, 58% of the patients treated
with ADM (95% CI, 48%-66%) and 58% of the patients
in the CT cell (95% CI, 45%-70%) met the response cri-
teria at 16 weeks. This difference was not significant
(
2
1
=0.01, P =.92). The test of a site treatment interac-
tion yielded a nonsignificant trend (Wald
2
1
=3.31, P=.07).
The difference in response rates was not significant at
either Pennsylvania (Wald 2
1
=1.83, P= .18) or Vander-
bilt (Wald
2
1
=1.50, P=.22).
Remission rates were 46% in the ADM cell (95% CI,
37%-55%) vs 40% in the CT cell (95% CI, 28%-53%).
The test of site treatment interaction was significant
(Wald
2
1
=4.15, P=.04). At Pennsylvania, the remission
rates were not significantly different (Wald
2
1
=0.81,
P=.37), whereas at Vanderbilt, the remission rate in ADM
was higher than the remission rate in CT at the level of
a nonsignificant trend (Wald
2
1
=3.80, P=.05).
Continuous Analyses at 16 Weeks
After 16 weeks, there was no significant main effect for
treatment in the HLM analysis, but there was a signifi-
cant sitetreatment interaction (F
1,173
=5.51, P=.02; effect
size=0.36). As a result, we report analyses separately for
each site (
Figure 3). At Pennsylvania the difference be-
tween the groups was not significant (F
1,173
=1.67, P=.2,
effect size=0.37), whereas at Vanderbilt, change in the
ADM cell was significantly greater than change in the CT
cell (F
1,173
=4.19, P=.04, effect size=0.57).
To explore differences between the populations at the
2 sites that might explain the sitetreatment interac-
tion, we first identified pretreatment variables that pre-
dicted responses within the respective treatments (at
P.10, using the subject-specific slopes as estimated
through the HLM model).
In the ADM cell, patients with Axis I comorbidity
fared better than patients without Axis I comorbidity
(ES=0.17, P= .07). Of the patients with Axis I comorbid-
ity, presence of generalized anxiety disorder met this cri-
terion (ES=0.30, P=.02). Also in the ADM cell, patients
fared worse if they had chronic depression (ES=-0.24,
P=.004) or were unemployed (ES =-0.25, P=.04). Of the
4 variables that predicted response in the ADM cell, only
Axis I comorbidity was differentially prevalent in the
ADM conditions at the 2 sites (Pennsylvania=52%,
Vanderbilt 87%;
2
=17.23, P.001). Patients with Axis I
comorbidity fared as well in the ADM cell at Pennsylva-
nia as they did at Vanderbilt (slope estimate at
Pennsylvania=-0.82, SE = 0.08; slope estimate at
Vanderbilt=-0.82, SE= 0.06). Thus, the higher rate of
Axis I comorbidity at Vanderbilt contributed to the
superior performance of patients in the ADM cell at
Vanderbilt, relative to Pennsylvania.
In the CT cells, patients fared better if they met cri-
teria for the melancholic subtype of MDD (ES=0.40,
P=.02); they fared worse if they were comorbid for so-
cial phobia (ES=-0.26, P =.06). Neither of these vari-
ables was associated with differential prevalence in the
CT conditions at the 2 sites.
COMMENT
Both pharmacotherapy and CT treatments outper-
formed placebo in moderately to severely depressed out-
patients. The finding of superiority of an established medi-
cation relative to placebo is often regarded as essential
in any comparison between the established treatment and
a newer treatment.
33
Comparisons between the 2 active treatments in this
trial must take into account a site treatment interac-
tion. Such interactions reflect either differences in pa-
tients sampled or differences in treatment procedures.
There is evidence of a contribution from each of these
kinds of factors in the present study.
With respect to differences in the samples, Axis I co-
morbidity was differentially prevalent in the ADM con-
ditions at the 2 sites. Patients with Axis I comorbidity,
who were primarily comorbid with anxiety disorders, fared
particularly well on ADM, perhaps because paroxetine,
the primary medication in this study, has anxiolytic ef-
fects. These patients with comorbidity responded as well
at Pennsylvania as they did at Vanderbilt, but the higher
prevalence of these patients at Vanderbilt led to a better
overall response to ADM at Vanderbilt.
With respect to differences in the treatments at the 2
sites, the superior performance of CT at Pennsylvania,
relative to Vanderbilt, was likely related to therapist ex-
perience. The more experienced cognitive therapists at
Pennsylvania produced outcomes at least comparable to
those produced by ADM, whereas Vanderbilt’s less ex-
perienced cognitive therapists produced outcomes that
were inferior to those produced by ADM at that site. This
calls to mind the site differences observed in the TDCRP.
7
Among their more severely depressed patients, differ-
ences favoring ADM relative to CT were large at the 2
sites that had less experience with CT, and were negli-
gible at the one site that had greater experience with CT.
34
On the whole, these findings do not support the cur-
rent American Psychiatric Association guideline,
4
based
80
100
60
40
20
0
ADM CT ADM CT ADM CT
Overall University of
Pennsylvania
Vanderbilt
University
Response and Remission Rates, %
ADM Response Only
ADM Remission
CT Response Only
CT Remission
58 58
40
46
48
63
50
40
67
53
30
52
Figure 2. Response and remission rates at 16 weeks for antidepressant
medication therapy (ADM) (n=120, 60 per site) and cognitive therapy (CT)
(n=60, 30 per site).
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414
©2005 American Medical Association. All rights reserved.
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on the TDCRP,
7
that “most (moderately and severely de-
pressed) patients will require medications.” It appears that
cognitive therapy can be as effective as medications, even
among more severely depressed outpatients, at least when
provided by experienced cognitive therapists.
Submitted for Publication: August 12, 2003; final revi-
sion received August 12, 2004; accepted September 9, 2004.
Correspondence: Robert J. DeRubeis, PhD, Depart-
ment of Psychology, University of Pennsylvania, Phila-
delphia, PA 19104-6196 (derubeis@psych.upenn.edu).
Funding/Support: This study was supported by grants
MH50129 (R10) (Dr DeRubeis) and MH55875 (R10) and
MH01697 (K02) (Dr Hollon) from the National Insti-
tute of Mental Health, Bethesda, Md. GlaxoSmithKline,
Brentford, Middlesex, United Kingdom, provided medi-
cations and pill placebos for the trial.
Previous Presentation: Presented at the 155th Annual
Convention of the American Psychiatric Association, May
23, 2002; Philadelphia, Pa.
Acknowledgment: Gratitude is expressed to our col-
leagues for contributing to this research. Robert J. DeRu-
beis, PhD, and Steven D. Hollon, PhD, were the princi-
pal investigators and oversaw the implementation of
cognitive therapy at the respective sites. Jay D. Amster-
dam, MD, and Richard C. Shelton, MD, were the co-
principal investigators and supervised the implementa-
tion of medication treatment. Edward Schweizer, MD,
provided important consultation about study design and
implementation, especially early in the trial. Paula R.
Young, PhD, and Margaret L. Lovett, MEd, served as the
study coordinators. John P. O’Reardon, MD, Ronald M.
Salomon, MD, and the late Martin Szuba, MD, served as
study pharmacotherapists (along with Drs Amsterdam
and Shelton). Cory P. Newman, PhD, Karl N. Jannasch,
PhD, Frances Shusman, PhD, and Sandra Seidel, MSN,
served as the cognitive therapists (along with Drs DeRu-
beis and Hollon). Jan Fawcett, MD, provided consulta-
tion with regard to the implementation of clinical man-
agement pharmacotherapy. Aaron T. Beck, MD, Judith
Beck, PhD, Christine Johnson, PhD, and Leslie Sokol,
PhD, provided consultation with respect to the imple-
mentation of cognitive therapy. Madeline M. Gladis,
PhD, and Kirsten L. Haman, PhD, oversaw the training
of the clinical interviewers, and David Appelbaum,
PsyD, Laurel L. Brown, PhD, Richard C. Carson, PhD,
Barrie Franklin, PhD, Nana A. Landenberger, PhD, Jes-
sica Londa-Jacobs, PhD, Julie L. Pickholtz, PhD, Pamela
Fawcett-Pressman, MEd, Sabine Schmid, MA, Ellen D.
Stoddard, PhD, Michael Suminski, PhD, and Dorothy
Tucker, PhD, served as project interviewers. Robert
Gallop, PhD, and Andrew J. Tomarken, PhD, provided
statistical consultation. Joyce L. Bell, BA, Brent B. Free-
man, BA, Cara C. Grugan, BA, Nathaniel R. Herr, BA,
Mary B. Hooper, MS, Miriam Hundert, BSN, Veni Linos,
MSc, and Tynya Patton, MA, provided research support.
Kelly Bemis Vitousek, PhD, provided helpful comments
on an earlier draft of the manuscript.
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Research Proposal
Full-text available
Hopelessness (negative expectations of the future) and entity theories of emotion (beliefs that one’s emotions are fixed) are associated with depressive symptoms. These constructs, however, are yet to be targeted by interventions that are delivered via mental health applications. Hence, this study proposes digital mood-tracking as a potential intervention for reducing entity theories of emotion and hopelessness. This intervention is based on (a) objectivity of mood-tracking, which may influence hopelessness via its link to negative memory bias, and (b) increased emotional awareness as a result of mood-tracking, which may have implications for entity theories of emotion. Accordingly, the hypotheses are that digital mood-tracking reduces hopelessness and entity theories of emotion in individuals with depressive symptoms. This research, therefore, will make use of a randomized controlled trial to evaluate effects of digital mood-tracking on hopelessness and entity theories of emotion in individuals with depressive symptoms. Keywords: Hopelessness, implicit theories, entity theories of emotion, mood-tracking
Chapter
This is a book of psychiatry at its most practical level. It aims to answer the sorts of questions psychiatrists ask on a daily basis. What treatments are available for the condition that I think this patient has? What is the relative value of each of these treatments? Are there any other treatments that I should be considering if a first approach has failed? Is there any value in combinations of treatment? And, can I be sure that the evidence and recommendations I read are free from bias? The content is organised into three sections covering disease classification, the major treatment modalities and the application of these treatments to the wide range of psychiatric diagnoses. All professionals in mental health want to give the best treatments for their patients. This book provides clinicians with the knowledge and guidance to achieve this aim.
Chapter
Depression caused by either genetic factors or environmental stimulates such as chronic psychological or physiological stress, traumatic or sports-related brain injuries, neurodegenerative diseases, and/or substance abuse and drug dependence leads to serious neurological manifestation and affects mortality and morbidity since ages. Stress is one of the powerful stimulants to induce disruption of the blood-brain barrier (BBB). In all the above cases breakdown of the BBB occurs resulting in abnormal neuronal functions and precipitating brain pathology. Disruption of BBB could be one of the leading factors affecting thought processes and mental health leading to depression. Accordingly, depressive episodes often lead to suicide that is estimated to be around 40 k individuals per year in the USA. About 10–15% of these individuals were on antidepressant therapy at that time. These antidepressants adversely affect the BBB breakdown. Thus, although our knowledge on depression expanded in recent years, the biological mechanisms of depression and suitable treatment strategies are still obscure. In depressive episodes alterations in the metabolism of biogenic amines in the brain formed the basis of treatment with amine precursors in clinic. However, these treatments are only helping up to some extent in clinics, indicating the involvement of further agents beyond the amine mechanisms in depression. It appears that today’s view on depression is not only genetics and environmental but rather an integrative etiopathogenetic and biopsychological phenomena. In this review the potential role of amine precursors in depression is discussed in the light of recent development in relation to the new developing clinical strategies and mechanisms to treat depression.
Chapter
This is a book of psychiatry at its most practical level. It aims to answer the sorts of questions psychiatrists ask on a daily basis. What treatments are available for the condition that I think this patient has? What is the relative value of each of these treatments? Are there any other treatments that I should be considering if a first approach has failed? Is there any value in combinations of treatment? And, can I be sure that the evidence and recommendations I read are free from bias? The content is organised into three sections covering disease classification, the major treatment modalities and the application of these treatments to the wide range of psychiatric diagnoses. All professionals in mental health want to give the best treatments for their patients. This book provides clinicians with the knowledge and guidance to achieve this aim.
Chapter
This is a book of psychiatry at its most practical level. It aims to answer the sorts of questions psychiatrists ask on a daily basis. What treatments are available for the condition that I think this patient has? What is the relative value of each of these treatments? Are there any other treatments that I should be considering if a first approach has failed? Is there any value in combinations of treatment? And, can I be sure that the evidence and recommendations I read are free from bias? The content is organised into three sections covering disease classification, the major treatment modalities and the application of these treatments to the wide range of psychiatric diagnoses. All professionals in mental health want to give the best treatments for their patients. This book provides clinicians with the knowledge and guidance to achieve this aim.
Chapter
This is a book of psychiatry at its most practical level. It aims to answer the sorts of questions psychiatrists ask on a daily basis. What treatments are available for the condition that I think this patient has? What is the relative value of each of these treatments? Are there any other treatments that I should be considering if a first approach has failed? Is there any value in combinations of treatment? And, can I be sure that the evidence and recommendations I read are free from bias? The content is organised into three sections covering disease classification, the major treatment modalities and the application of these treatments to the wide range of psychiatric diagnoses. All professionals in mental health want to give the best treatments for their patients. This book provides clinicians with the knowledge and guidance to achieve this aim.
Chapter
This is a book of psychiatry at its most practical level. It aims to answer the sorts of questions psychiatrists ask on a daily basis. What treatments are available for the condition that I think this patient has? What is the relative value of each of these treatments? Are there any other treatments that I should be considering if a first approach has failed? Is there any value in combinations of treatment? And, can I be sure that the evidence and recommendations I read are free from bias? The content is organised into three sections covering disease classification, the major treatment modalities and the application of these treatments to the wide range of psychiatric diagnoses. All professionals in mental health want to give the best treatments for their patients. This book provides clinicians with the knowledge and guidance to achieve this aim.
Chapter
This is a book of psychiatry at its most practical level. It aims to answer the sorts of questions psychiatrists ask on a daily basis. What treatments are available for the condition that I think this patient has? What is the relative value of each of these treatments? Are there any other treatments that I should be considering if a first approach has failed? Is there any value in combinations of treatment? And, can I be sure that the evidence and recommendations I read are free from bias? The content is organised into three sections covering disease classification, the major treatment modalities and the application of these treatments to the wide range of psychiatric diagnoses. All professionals in mental health want to give the best treatments for their patients. This book provides clinicians with the knowledge and guidance to achieve this aim.
Article
This article reviews recent developments in the pharmacotherapy of mood disorders. Pharmacotherapy is the best studied and most widely validated approach for acute phase treatment and prevention of relapse-recurrence for patients with major depression, dysthymia, and bipolar affective disorder. Antidepressants are also the mainstay of inpatient treatment and, when considered together with electroconvulsive therapy, represent the first line of treatment for the most severe and incapacitating forms of depression. Similarly, pharmacotherapy with mood stabilizers is the first line of treatment for bipolar depression and mania. Despite such efficacy, problems associated with pharmacotherapy include acceptability, tolerability, adherence, incomplete remission, and high rates of recurrence after drug discontinuation. Moreover, a small subset of patients do not respond to multiple medication trials.
Article
In these concluding comments to the exchange among N. S. Jacobson and S. D. Hollon (1996), D. F. Klein (1996), I. Elkin, R. D. Gibbons,M. T. Shea, and B. F. Shaw(1996), and R. J. McNally (1996) issues of continuing controversy are highlighted: the best ways to control for the allegiance effect, the complexities of assessing competence, and the role of pill placebos in comparisons between cognitive-behavior therapy (CBT) and pharmacotherapy. It is concluded that controlling for allegiance within site is the optimal strategy, that measures of competence must take context into account, and that pill placebo controls are optimal but not essential to comparisons between CBT and pharmacotherapy.
Article
Recent reanalyses suggest that pharmacotherapy was superior to cognitive-behavior therapy in the acute treatment of more severely depressed outpatients in the National Institute of Mental Health Treatment of Depression Collaborative Research Program (TDCRP). At the same time, this finding was neither robust across sites within the TDCRP nor consistent with findings from other studies. D. F. Klein has argued that those other studies were inherently flawed because they did not include pill-placebo controls, an argument that he extended to drug-psychotherapy comparisons in the treatment of panic as well. It is agreed that the inclusion of such controls would have facilitated the interpretation of the findings, but it is not agreed that their omission rendered those studies uninterpretable. Cognitive-behavior therapy remains a viable alternative to pharmacotherapy in the treatment of depression and a particularly promising intervention in the treatment of panic disorder.
Chapter
In the last several years, there has been a growing interest in the study and understanding of personality disorders. Patients with personality disorders have been part of the clinician’s case load since the beginning of the recorded history of psychotherapy; the general psycho­therapeutic literature on the treatment of personality disorders, however, has emerged more recently and is growing quickly. The main theoretical orientation in the present literature is psychoanalytic (Abend, Porder, & Willick, 1983; Chatham, 1985; Goldstein, 1985; Gunder­son, 1984; Horowitz, 1977; Kernberg, 1975, 1984; Lion, 1981; Masterson, 1978, 1980, 1985; Reid, 1981; Saul & Warner, 1982). Millon (1981) is one of the few volumes in the area of personality disorders that offers a behavioral focus, and the volume by Beck, Freeman and associates (1989) will be the first to offer a specific cognitive-behavioral focus. This is of interest, in that leading cognitive therapists have been, and remain, interested in “personality disorder” and “personality change” (Hartman & Blankenstein, 1986). When Beck (1963a,b) and Ellis (1957a, 1958) first introduced cognitive approaches, they drew upon the ideas of “ego analysts,” derived from Adler’s critiques of early Freudian psychoanalysis. Though their therapeutic innovations were seen as radical, their earliest cognitive therapies were, in many ways, “insight therapies” in that the therapy was assumed to change a patient’s overt “personality,” whether or not the therapy changed some hypothesized underlying personality. Although Beck and Ellis were among the first to use a wide array of behavioral treatment techniques, including structured in vivo homework, they have consistently emphasized the therapeutic impact of these techniques on cognitive schemata and have argued in favor of the integration of behavioral techniques into therapy within a broad framework that has some roots in prior analytic practice (Beck, 1976; Ellis & Bernard, 1985); they and their associates have emphasized the impact of treatment for particular types, or styles, of cognitive errors on dysfunctional self-concepts, as well as on presenting focal problems (Beck & Freeman, 1989; Ellis, 1985; Freeman, 1987).