Medication (Nefazodone) or psychotherapy (CBASP) is effective when the other is not

Article (PDF Available)inArchives of General Psychiatry 62(5):513-20 · June 2005with171 Reads
DOI: 10.1001/archpsyc.62.5.513 · Source: PubMed
Abstract
Although various strategies are available to manage nonresponders to an initial treatment for depression, no controlled trials address the utility of switching from an antidepressant medication to psychotherapy or vice versa. To compare the responses of chronically depressed nonresponders to 12 weeks of treatment with either nefazodone or cognitive behavioral analysis system of psychotherapy (CBASP) who were crossed over to the alternate treatment (nefazodone, n = 79; CBASP, n = 61). Crossover trial. Twelve academic outpatient psychiatric centers. There were 140 outpatients with chronic major depressive disorder; 92 (65.7%) were female, 126 (90.0%) were white, and the mean age was 43.1 years. Thirty participants dropped out of the study prematurely, 22 in the nefazodone group and 8 in the CBASP group. Treatment lasted 12 weeks. The dosage of nefazodone was 100 to 600 mg/d; CBASP was provided twice weekly during weeks 1 through 4 and weekly thereafter. The 24-item Hamilton Rating Scale for Depression, administered by raters blinded to treatment, the Clinician Global Impressions-Severity scale, and the 30-item Inventory for Depressive Symptomatology-Self-Report. Analysis of the intent-to-treat sample revealed that both the switch from nefazodone to CBASP and the switch from from CBASP to nefazodone resulted in clinically and statistically significant improvements in symptoms. Neither the rates of response nor the rates of remission were significantly different when the groups of completers were compared. However, the switch to CBASP following nefazodone therapy was associated with significantly less attrition due to adverse events, which may explain the higher intent-to-treat response rate among those crossed over to CBASP (57% vs 42%). Among chronically depressed individuals, CBASP appears to be efficacious for nonresponders to nefazodone, and nefazodone appears to be effective for CBASP nonresponders. A switch from an antidepressant medication to psychotherapy or vice versa appears to be useful for nonresponders to the initial treatment.
3 Figures
ORIGINAL ARTICLE
Chronic Depression
Medication (Nefazodone) or Psychotherapy (CBASP) Is Effective
When the Other Is Not
Alan F. Schatzberg, MD; A. John Rush, MD; Bruce A. Arnow, PhD; Phillip L. C. Banks, MS; Janice A. Blalock, PhD;
Frances E. Borian, RN; Robert Howland, MD; Daniel N. Klein, PhD; James H. Kocsis, MD; Susan G. Kornstein, MD;
Rachel Manber, PhD; John C. Markowitz, MD; Ivan Miller, PhD; Philip T. Ninan, MD; Barbara O. Rothbaum, PhD;
Michael E. Thase, MD; Madhukar H. Trivedi, MD; Martin B. Keller, MD
Context: Although various strategies are available to man-
age nonresponders to an initial treatment for depres-
sion, no controlled trials address the utility of switching
from an antidepressant medication to psychotherapy or
vice versa.
Objective: To compare the responses of chronically de-
pressed nonresponders to 12 weeks of treatment with
either nefazodone or cognitive behavioral analysis sys-
tem of psychotherapy (CBASP) who were crossed over
to the alternate treatment (nefazodone, n=79; CBASP,
n=61).
Design: Crossover trial.
Setting: Twelve academic outpatient psychiatric centers.
Patients: There were 140 outpatients with chronic ma-
jor depressive disorder; 92 (65.7%) were female, 126
(90.0%) were white, and the mean age was 43.1 years.
Thirty participants dropped out of the study prema-
turely, 22 in the nefazodone group and 8 in the CBASP
group.
Interventions: Treatment lasted 12 weeks. The dos-
age of nefazodone was 100 to 600 mg/d; CBASP was pro-
vided twice weekly during weeks 1 through 4 and weekly
thereafter.
Main Outcome Measures: The 24-item Hamilton Rat-
ing Scale for Depression, administered by raters blinded
to treatment, the Clinician Global Impressions–Severity
scale, and the 30-item Inventory for Depressive Symp-
tomatology–Self-Report.
Results: Analysis of the intent-to-treat sample revealed
that both the switch from nefazodone to CBASP and the
switch from from CBASP to nefazodone resulted in clini-
cally and statistically significant improvements in symp-
toms. Neither the rates of response nor the rates of re-
mission were significantly different when the groups of
completers were compared. However, the switch to CBASP
following nefazodone therapy was associated with sig-
nificantly less attrition due to adverse events, which may
explain the higher intent-to-treat response rate among
those crossed over to CBASP (57% vs 42%).
Conclusions: Among chronically depressed individu-
als, CBASP appears to be efficacious for nonresponders
to nefazodone, and nefazodone appears to be effective
for CBASP nonresponders. A switch from an antidepres-
sant medication to psychotherapy or vice versa appears
to be useful for nonresponders to the initial treatment.
Arch Gen Psychiatry. 2005;62:513-520
A
SUBSTANTIAL PROPORTION
of patients treated for de-
pression do not respond to
the initial trial of either an
antidepressant medica-
tion or depression-targeted psycho-
therapy.
1
This so-called stage I antidepres-
sant resistance
2,3
is one of several degrees
of resistance defined by prior treatment his-
tory. Numerous treatment options are avail-
able in such situations, including switch-
ing medication type or class, augmenting
or combining medications, and switching
to or augmenting with psychotherapy.
There are few controlled data to guide cli-
nicians as to the preferable next step.
3-5
Im-
portantly, many depressed patients ini-
tially receive psychotherapy alone.
Surprisingly few studies
6
have evaluated the
role of medication following nonresponse
to psychotherapy.
7
None has evaluated the
efficacy of psychotherapy following non-
response to medication. Surprisingly few
controlled switch studies are available even
for medication-to-medication switches.
7,8
This report provides the first prospective
controlled trial evidence, using blinded rater
methodology, to examine switching from
nefazodone therapy to psychotherapy (spe-
cifically, cognitive behavioral analysis sys-
Author Affiliations are listed at
the end of this article.
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tem of psychotherapy [CBASP])
9
or switching from CBASP
to nefazodone therapy following completion with nonre-
sponse to a 12-week trial of the alternative treatment.
METHODS
SUBJECTS
This protocol was part of a multiphase collaborative research pro-
gram studying chronic depressive disorders (see Keller et al
10
for
a full description of study design, rationale, and methods). The
institutional review boards at all 12 sites approved the study.
Briefly, outpatients 18 to 75 years of age who were in a current
major depressive episode were eligible to enroll at one of 12 cen-
ters if they met the DSM-IV criteria for chronic major depres-
sive disorder (ie, current major depressive episode 2 years in
duration), “double depression” (ie, a current major depressive
episode superimposed on antecedent dysthymic disorder), or re-
current major depressive disorder with incomplete interepi-
sode recovery. Additionally, patients had to have a score of 20
or higher on the 24-item Hamilton Rating Scale for Depression
(HRS-D
24
) both at screening and following a 2-week drug-free
period at baseline prior to treatment initiation.
The Structured Clinical Interview for DSM-IV Axis I Disor-
ders
11
and an abbreviated version of the Structured Clinical In-
terview for DSM-IV Personality Disorders
12
were used to estab-
lish the intake diagnoses. Patients with organic mental syndromes;
bipolar disorder or cyclothymia; schizophrenia or other psy-
chotic disorders; obsessive-compulsive disorder; or schizotypal,
antisocial, or severe borderline personality disorder were ex-
cluded, as were those with principal current diagnoses of panic,
generalized anxiety, or posttraumatic stress disorders. Patients were
not eligible if they had abused alcohol or drugs within the last 6
months or suffered from bulimia or anorexia nervosa within 1
year of intake. Patients considered to be at immediate risk of sui-
cide, to have medical contraindications to antidepressant therapy,
or to have significant, unstable general medical disorders were
also excluded. Patients who had not responded previously to a
minimally adequate trial of nefazodone (ie, at least 4 weeks at 300
mg/d) were not eligible. Patients could not have been treated with
benzodiazepines within 2 weeks, fluoxetine or monoamine oxi-
dase inhibitors within 4 weeks, electroconvulsive therapy within
6 months, or depot neuroleptics within 6 months. No psycho-
therapy outside the study protocol was permitted.
INITIAL ACUTE-PHASE TREATMENT TRIAL
Participants were recruited via advertisements in newspapers,
radio, and printed flyers as well as through physician refer-
rals. After providing written informed consent, subjects un-
derwent a complete medical history interview, physical exami-
nation, electrocardiogram, and laboratory screening test battery
to confirm medical eligibility. No nonprotocol psychotropic
medications were allowed during the study, including anxio-
lytics and sedative hypnotics. Patients agreed to randomiza-
tion to CBASP, nefazodone, or the combination for this 12-
week acute-phase trial (
Figure 1).
Patients randomized to nefazodone monotherapy or com-
bined nefazodone therapy and CBASP received open-label treat-
ment with oral nefazodone. Those patients receiving nefaz-
odone, either with or without CBASP, received an initial daily
dose of 200 mg (100 mg twice a day), which was increased to
300 mg/d during the second week. Thereafter, when indi-
cated, the dose was increased in increments of 100 mg/d to a
maximum of 600 mg/d. To remain in the study, patients were
required to take a minimum of 300 mg/d by week 3. Patients
noncompliant with prescribed dosing were dropped from the
study. At the end of the initial acute-phase trial, the overall fi-
nal average daily dosage of nefazodone was 461.0 mg/d (SD,
143.3 mg/d). Psychopharmacology visits were conducted ac-
cording to a manual
13
for clinical management (eg, review of
symptoms, adverse events, illnesses, and concomitant medi-
cations) and were limited to 15 to 20 minutes.
Cognitive behavioral analysis system of psychotherapy, which
was developed to address the specific challenges of treating in-
dividuals with chronic depression, incorporates both cogni-
tive behavioral and interpersonal features.
9
Treatment was con-
ducted according to a manual
14
specifying sessions twice weekly
during weeks 1 through 4 and weekly thereafter until week 12.
Sessions could be held twice weekly during weeks 5 through 8
if the patient was having trouble mastering situational analy-
sis, the core procedure in CBASP.
9
Patients who attended fewer
than 13 sessions or missed 3 consecutive sessions were dropped
from the study. The overall mean number of total CBASP ses-
sions for the intent-to-treat acute-phase sample was 16 (SD, 5.4).
Psychotherapists had either (1) an MD or PhD degree along
with at least 2 years of post-training experience or (2) an MSW
degree along with at least 5 years of post-degree experience.
All psychotherapists attended a 2-day training workshop and
met the criteria for mastery of CBASP treatment procedures on
2 pilot training cases, as assessed by videotape-based adher-
ence rating, before they were allowed to see study patients. Ad-
herence monitoring to the CBASP protocol took place through-
out the study. All study CBASP sessions were videotaped. The
CBASP supervisors at each site conducted weekly adherence
monitoring by videotape review using a standardized adher-
ence rating scale. Site supervisor adherence was similarly moni-
tored by a CBASP coordinator.
ASSESSMENT OF RESPONSE
Vital signs and adverse events (volunteered or observed) were
assessed at each visit. The primary outcome measure was the
HRS-D
24
,
15-17
which was completed once weekly through week
Declined
Crossover
(n
=
12)
Declined
Crossover
(n
=
4)
Entered CBASP
(Intention-to-
Treat Sample)
(n
=
61)
Entered
Nefazodone
(Intention-to-
Treat Sample)
(n
=
79)
Nonresponders
(n
=
73)
Nonresponders
(n
=
83)
Combination
(n
=
227)
Randomized
(n
=
681)
Not Randomized (n
=
354)
Did Not Meet Inclusion
Criteria (n
=
235)
Withdrew Consent
(n
=
47)
Other Reasons (n
=
72)
Dropped
Out
(n
=
8)
Dropped
Out
(n
=
22)
Completers
(n
=
53)
Completers
(n
=
57)
Nefazodone
(n
=
226)
Assessed for Eligibility
(N
=
1035)
CBASP
(n
=
228)
Figure 1. Randomization and disposition.
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4 and biweekly thereafter. Secondary outcomes included the
Clinical Global Impressions–Severity scale (CGI-S),
18
the 30-
item Inventory for Depressive Symptomatology–Self-Report
(IDS-SR
30
),
19,20
and the Hamilton Rating Scale for Anxiety Psy-
chic Anxiety factor score (HAM-A
PA
). All clinical ratings were
completed by an independent evaluator without knowledge of
the treatment received.
A remission was defined as a final HRS-D
24
score of 8 or lower
at both weeks 10 and 12. A response without remission was
declared if there was a reduction of 50% or greater in the total
HRS-D
24
score and there was a total score of 15 or lower at both
weeks 10 and 12 but remission was not achieved. In addition,
a single overall response/remission rate was calculated that com-
bined those in the remission group with those who demon-
strated response without remission. All other patients were con-
sidered nonresponders.
ACUTE-PHASE OUTCOME
A total of 454 patients were randomized either to CBASP mono-
therapy (n=228) or to nefazodone monotherapy (n =226). Of
these, 173 in the CBASP group (75.9%) and 167 in the nefaz-
odone group (73.9%) completed the 12-week acute-phase trial.
Among completers, 33.5% (56/167) of those in the nefaz-
odone group and 28.3% (49/173) of those in the CBASP group
had response without remission. These response rates did not
significantly differ from one another (
2
1
=1.08, P=.30). Remis-
sion rates for completers were 21.6% (36/167) for nefazodone
and 23.7% (41/173) for CBASP; again, these remission rates were
not significantly different (
2
1
=0.22, P=.64).
Among the patients randomized at study baseline to either
CBASP monotherapy or nefazodone monotherapy, 216 in the
CBASP group and 220 in the nefazodone group constituted the
intent-to-treat sample. For this sample, response and remis-
sion rates were determined based on the last available obser-
vation. The response rates without remission were 18.6%
(41/220) in the nefazodone group and 14.4% (31/216) in the
CBASP group. These response rates were not significantly dif-
ferent (
2
1
=1.45, P =.23). Remission rates were 29.1% (64/
220) for nefazodone therapy and 33.3% (72/216) for CBASP;
these remission rates were not significantly different (
2
1
=0.91,
P=.34).
Altogether, 156 nonresponders randomized to nefazodone
alone or CBASP alone completed the acute-phase trial (73 who
started in the nefazodone group and 83 who started in the CBASP
group). The 73 nonresponders in the nefazodone group re-
ceived a mean final daily dosage of 491.1 mg/d (SD, 125.4 mg/d;
range, 100-600 mg/d). Responders to nefazodone received a non-
significantly higher final daily dosage (520.1 mg/d; F
1,163
=2.73,
P=.10). The 83 nonresponders in the CBASP group attended
a total of 17.7 therapy sessions (SD, 1.9; range, 13-22). Re-
sponders to CBASP attended a slightly greater number of ses-
sions than nonresponders (18.2; F
1,171
=3.75, P =.054).
SWITCH PROTOCOL
There was no washout period for the switch (crossover) phase.
Nonresponders to nefazodone simply stopped taking the medi-
cation and began CBASP treatment if they met the criteria to
enter the crossover phase. Conversely, CBASP nonresponders
stopped psychotherapy and began nefazodone treatment. All
those who agreed to this crossover phase signed a new written
informed consent. Visits, assessments, medication dosing, CBASP
procedures, visit and session frequency, and outcome defini-
tions during the new (crossover) treatment were identical to
the methods used in the initial acute-phase trial.
STATISTICAL ANALYSES
The analyses performed included the analysis of baseline and
demographic characteristics to assess comparability of the two
crossover-phase treatment groups as well as comparisons of ef-
ficacy parameters and incidence of adverse events. Time to re-
sponse and likelihood of response (50% reduction in HRS-
D
24
score) were tested with Kaplan-Meier survival analysis. The
time to a reduction of 50% or greater in HRS-D
24
score was de-
fined as the number of days from randomization to the cross-
over treatment until the first postrandomization observation
of a decrease of 50% or greater in HRS-D
24
total score. If a
decrease of 50% or greater was not observed, the time was right-
censored using the visit date of the last usable postrandomiza-
tion HRS-D
24
score from the entire 24-week period. Kaplan-
Meier plots for the survival distribution for time to a reduction
of 50% or greater in HRS-D
24
score were generated and com-
parisons were made using the log-rank test statistic (
Figure 2).
To further explore response, we performed categorical analy-
ses (eg, response and remission rates, attrition rates, and rates
of adverse events) using the Fisher exact probability test,
McNemar test (for within-subject comparisons), or Cochran-
Mantel-Haenszel
2
test (stratified by study site) as appropri-
ate. Changes in continuously distributed efficacy variables (HRS-
D
24
, CGI-S, IDS-SR
30
, and HAM-A
PA
) were analyzed using analysis
of covariance at the endpoint visit with the crossover-phase base-
line value as the covariate and fixed effects for treatment and
site. These analyses were performed separately for the com-
pleter sample and the intent-to-treat sample. For the intent-
to-treat sample, response status was determined based on the
last available observation and the endpoint symptom severity
used in the analyses on continuous variables. An exploratory
analysis examined the correlation between the percentage change
in HRS-D
24
score from entry to exit in the acute phase and the
percentage change in HRS-D
24
score from entry to exit in the
crossover phase (overall and by treatment group).
A piecewise mixed-effects random regression model was used
to assess whether there were differences between nefazodone
and CBASP in the rate (linear slope) of improvement in symp-
toms, with change in HRS-D
24
scores from baseline to week 4
as one variable and from week 4 to week 12 (or the last visit)
as a second variable. The model included a random intercept
and a random slope. We hypothesized that patients receiving
nefazodone in the crossover phase (ie, patients who were
switched from CBASP to nefazodone) would exhibit a more rapid
rate of improvement in symptoms during the first 4 weeks than
patients who were switched from nefazodone to CBASP, just
as observed in the acute phase. This analysis examined the lin-
ear slopes between weeks 0 to 4 and weeks 4 to 12 in the cross-
over phase.
All statistical tests used 2-tailed probability values with un-
adjusted significance levels of P.05.
RESULTS
Of the 156 monotherapy nonresponders who com-
pleted the initial acute-phase trial, 140 (89.7%) con-
sented to begin the alternate treatment. There were no
significant differences in sociodemographic and clinical
measures between those who agreed and those who de-
clined to participate in the crossover trial. Twelve (16%)
of the 73 patients initially treated with nefazodone de-
clined the crossover treatment, while 4 (5%) of the 83
patients who initially received CBASP declined to pro-
ceed with crossover to nefazodone (
2
1
=5.7, P=.02).
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SAMPLE CHARACTERISTICS
A total of 61 patients were switched from nefazodone to
CBASP, and 79 CBASP nonresponders were switched to
nefazodone. With the exception of the percentage of pa-
tients with a lifetime history of anxiety disorders, base-
line characteristics did not differ significantly between
the two groups (
Table 1). The mean dosage of nefaz-
odone at the endpoint of the crossover phase was 419.0
mg/d (SD, 154.7 mg/d). The mean number of psycho-
therapy sessions attended during the crossover phase was
16.5 (SD, 4.4). Patients receiving nefazodone were sched-
uled to see a pharmacotherapist at each of 9 scheduled
study visits during the crossover phase. The mean num-
ber of study visits attended during crossover for those
in the nefazodone condition was 7.8 (SD, 1.8, n=61).
ATTRITION AND TOLERABILITY
During the crossover phase, 30 patients dropped out, 22
(28%) in the nefazodone group and 8 (13%) in the CBASP
group (
2
1
=4.61, P=.03). This difference was probably
caused by the fact that more patients receiving nefaz-
odone dropped out because of adverse events (18% vs
3%;
2
1
=6.79, P=.009).
RESPONSE AND REMISSION
Response and remission rates are presented in
Table 2
for both the intent-to-treat and completer samples. In the
intent-to-treat sample, overall response rates were sig-
nificantly higher for patients who crossed over to CBASP
from nefazodone (57% [35/61]) than for patients who
crossed over to nefazodone from CBASP (42% [33/79];
2
=5.03, P=.03). There was no significant difference in
rates of remission or response without remission be-
tween the two groups. In the completer sample, there were
no significant between-group differences in the rates of
response without remission, remission, or overall re-
sponse.
Table 3 presents the observed values for HRS-D
24
,
CGI-S, IDS-SR
30
, and HAM-A
PA
at the baseline of the cross-
over phase and at the endpoint. The change from base-
line to endpoint and the adjusted means of the change
in each measure are also presented. The results of the
analysis of covariance for all 4 parameters indicated that
patients in both groups improved over time. In the intent-
to-treat sample, the group switched from nefazodone to
CBASP had a significantly greater improvement in HRS-
D
24
and HAM-A
PA
scores than the group switched from
CBASP to nefazodone. However, there were no signifi-
cant differences in outcome on these 4 measures when
completers were compared.
A piecewise random regression analysis comparing the
rates of symptomatic improvement (linear slope) based
on the HRS-D
24
score (Figure 3) revealed no signifi-
cant difference between the two groups during the first
4 weeks of the crossover phase (F
1,138
=0.16, P=.69). How-
ever, a significantly greater rate of symptomatic improve-
ment was evident for weeks 4 to 12 among the patients
who were switched from nefazodone to CBASP
(F
1,138
=10.38, P=.002).
COMMENT
Results of this controlled, rater-blinded switch study in-
dicate that a switch strategy for nonresponders provides
1.0
0.3
0.4
0.2
0.1
0.7
0.8
0.9
0.6
0.5
0 20406080
100 120 140 160 180 200
Time to 50% Reduction in HRS-D
24
Score, d
Survival Distribution
CBASP Followed by Nefazodone
Nefazodone Followed by CBASP
Figure 2. Kaplan-Meier plot of the time to a 50% reduction in the HRS-D
24
(24-item Hamilton Rating Scale for Depression) score from the baseline of the acute
phase. CBASP indicates cognitive behavioral analysis system of psychotherapy.
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substantial benefit for chronically depressed patients.
Treatment with nefazodone following nonresponse to
CBASP and treatment with CBASP following nonre-
sponse to nefazodone were equally effective for patients
who completed 12 weeks of treatment, with a response
rate of approximately 50%. As in the initial trial,
10
CBASP
was associated with significantly less attrition due to ad-
verse events than nefazodone, which is in keeping with
the fact that patients were not blind to their treatment
and the fact that psychotherapy has few adverse events.
Table 1. Demographic and Clinical Characteristics of the Crossover Phase Patients
Variable
Total
(n = 140)
Nefazodone CBASP
(n = 61)
CBASP Nefazodone
(n = 79) Statistics*
Female, No. (%) 92 (65.7) 44 (72) 48 (61)
2
1
= 2.70, P = .10
Age, y† 43.1 ± 11 42.3 ± 12.0 43.7 ± 10.4 F
1,127
= 0.56, P = .46
White, No. (%) 126 (90.0) 55 (90) 71 (90)
2
1
= 0.03, P = .87
Marital status, No. (%)‡
2
3
= 2.12, P = .55
Currently married or cohabiting 63 (45.0) 29 (48) 34 (43)
Single 40 (28.6) 14 (23) 26 (33)
Widowed 3 (2.1) 2 (3) 1 (1)
Divorced/separated 34 (24.3) 16 (26) 18 (23)
Employment status, No. (%)‡
2
4
= 2.15, P = .71
Work for pay 96 (68.6) 42 (69) 54 (68)
Housewife 17 (12.1) 8 (13) 9 (11)
Student 4 (2.9) 3 (5) 1 (1)
Retired 4 (2.9) 1 (2) 3 (4)
Unemployed 18 (12.9) 6 (10) 12 (15)
Data missing 1 (0.7) 1 (2) 0 (0)
Depression diagnosis, No. (%)‡
2
2
= 2.19, P = .34
Chronic major depression 56 (40.0) 27 (44) 29 (37)
Double depression 53 (37.9) 24 (39) 29 (37)
Recurrent depression, incomplete interepisode recovery 31 (22.1) 10 (16) 21 (27)
Age at onset of initial episode of MDD, y† 26.4 ± 12.4 25.7 ± 12.0 26.9 ± 12.8 F
1,114
= 2.32, P = .13
Duration of current MDD, y† 8.0 ± 9.28 7.5 ± 9.1 8.3 ± 9.45 F
1,127
= 0.19, P = .66
Age at onset of dysthymia, y† 21.6 ± 14.87 20.8 ± 13.1 22.3 ± 16.4 F
1,41
= 0.46, P = .50
Duration of current dysthymia, y† 20.2 ± 15.59 20.6 ± 16.26 19.8 ± 15.3 F
1,36
= 0.66, P = .42
History of alcohol abuse/dependence, No. (%) 43 (30.7) 17 (28) 27 (34)
2
1
= 2.42, P = .12
Lifetime comorbid anxiety disorder, No. (%) 41 (29.3) 24 (39) 17 (22)
2
1
= 3.84, P = .05
Previous treatment with psychotherapy, No. (%) 94 (67.1) 40 (66) 54 (68)
2
1
= 0.45, P = .50
Previous treatment with antidepressant, No. (%) 95 (67.9) 41 (67) 54 (68)
2
1
= 0.00, P = .98
Abbreviations: CBASP, cognitive behavioral analysis system of psychotherapy; MDD, major depressive disorder.
*For categorical variables, the
2
values were determined using the Cochran-Mantel-Haenszel test stratified by site. Analysis of variance F-test values were
determined for continuous variables.
†Values are mean ± SD.
‡Percentages may not add to 100% because of rounding.
Table 2. Response* and Remission† Rates at the End of the Crossover Phase
No. (%)‡
2
§ P ValueNefazodone CBASP CBASP Nefazodone
Completers (n = 110)
No. of subjects 53 57
Response without remission 21 (40) 14 (25) 2.73 .10
Remission 13 (25) 16 (28) 0.01 .92
Overall response/remission 34 (64) 30 (53) 2.86 .09
Intent-to-Treat Sample (n = 140)
No. of subjects 61 79
Response without remission 13 (21) 12 (15) 0.95 .33
Remission 22 (36) 21 (27) 2.63 .11
Overall response/remission 35 (57) 33 (42) 5.03 .03
Abbreviations: CBASP, cognitive behavioral analysis system of psychotherapy; HRS-D
24
, 24-item Hamilton Rating Scale for Depression.
*Response was defined as a reduction of 50% or greater in the HRS-D
24
score and a total score of 15 or lower.
†Remission was defined as a final HRS-D
24
score of 8 or lower.
‡Percentages may not add to overall values because of rounding.
§The
2
values were determined using the Cochran-Mantel-Haenszel test; df = 1 for all
2
values.
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Although there was a significant difference in the over-
all response rate between the two crossover groups in the
intent-to-treat sample (57% response for those who
crossed over to CBASP vs 42% for those who crossed over
to nefazodone), this was likely due to the higher overall
attrition rate among those receiving nefazodone than
among those receiving CBASP. A slower titration of nefaz-
odone might have resulted in a lower number of pa-
tients dropping out of the crossover trial because of ad-
verse events, potentially increasing the response and
remission rates.
The finding of differential attrition was unexpected.
In the acute-phase trial, although the reasons for prema-
ture termination were different in the CBASP and nefaz-
odone groups, overall dropout rates were almost iden-
tical. Specifically, greater attrition due to adverse events
in the nefazodone group was essentially matched by at-
trition due to dissatisfaction with treatment in the CBASP
group. Across the sequential trials, attrition was compa-
rable in the nefazodone groups whether it was the first
or second treatment received, whereas a significantly
smaller proportion of patients dropped out while receiv-
ing CBASP when it was the second treatment in the se-
quence. It appears that the experience of an unsuccess-
ful initial trial of pharmacotherapy may have strengthened
the motivation of patients to participate in an adequate
trial of psychotherapy, whereas nonresponse to CBASP
did not improve patients’ ability to tolerate unpleasant
adverse effects of medication.
Interestingly, the overall response and remission rates
observed in the intent-to-treat crossover sample were simi-
lar to those observed in the acute phase of this study
10
as
well as to those observed by our collaborative research
group
8
in another sample of chronically depressed pa-
tients who were crossed over to sertraline or imipra-
mine following nonresponse to one of these two antide-
pressant medications. These results underscore how
important it is that clinicians not be discouraged—
though their chronically depressed patients may be—by
initial treatment resistance.
Few data are available to guide the clinician about the
best way to treat depressed patients who have not re-
sponded to an initial adequate course of treatment. The
present study provides support for a switch from medi-
cation to psychotherapy and vice versa. Other strategies
include switching within treatment (eg, switch to an-
other antidepressant medication) or augmentation either
with another treatment of the same modality or with a
treatment of a different modality (ie, combined treat-
ments). Compared with medication augmentation strat-
egies for nonresponders to an antidepressant medica-
tion, switching antidepressant classes has the advantages
of simplicity and parsimony (eg, lower cost and lower
risk of drug-drug interactions). However, further stud-
ies are required to test the relative short- and long-term
effectiveness of the different strategies as well as their rela-
tive acceptability. In the present study, a larger propor-
Table 3. Mean Scores for Continuous Efficacy Outcomes During the Crossover Phase*
Outcome
Measure
Nefazodone CBASP
CBASP Nefazodone
Statistics‡Baseline Endpoint Change
Adjusted
Change† Baseline Endpoint Change
Adjusted
Change†
Intention-to-Treat Sample
HRS-D
24
24.1 (6.5) 13.4 (8.4) −10.7 (9.1) −11.1 (1.1) 23.2 (6.5) 15.4 (9.1) −7.8 (10.2) −8.1 (1.0) F
1,126
= 4.12, P = .045
CGI-S 4.2 (0.8) 3.1 (1.1) −0.9 (1.0) −0.9 (0.2) 4.0 (0.6) 3.0 (1.3) −1.1 (1.4) −1.1 (0.1) F
1,98
= 0.27, P = .60
IDS-SR
30
33.9 (10.2) 20.4 (12.3) −13.7 (11.8) −14.6 (1.6) 33.4 (9.6) 22.2 (13.8) −11.2 (14.0) −11.3 (1.4) F
1,124
= 2.34, P = .13
HAM-A
PA
1.5 (0.6) 0.8 (0.6) −0.6 (0.6) −0.7 (0.1) 1.5 (0.5) 1.0 (0.7) −0.4 (0.8) −0.4 (0.1) F
1,125
= 4.21, P = .04
Completers
HRS-D
24
24.1 (6.6) 11.9 (7.7) −12.2 (8.3) −12.6 (1.1) 23.6 (6.5) 13.3 (8.3) −10.2 (10.2) −10.2 (1.1) F
1,96
= 2.26, P = .14
CGI-S 4.3 (0.9) 2.9 (1.1) −1.2 (1.0) −1.1 (0.2) 4.1 (0.6) 2.6 (1.3) −1.4 (1.4) −1.4 (0.2) F
1,70
= 1.25, P = .27
IDS-SR
30
34.0 (10.7) 18.5 (11.8) −15.2 (11.0) −15.9 (1.6) 34.2 (9.7) 19.3 (12.6) −15.0 (13.5) −14.5 (1.6) F
1,95
= 0.36, P = .55
HAM-A
PA
1.4 (0.6) 0.7 (0.6) −0.7 (0.6) −0.6 (0.1) 1.5 (0.6) 0.9 (0.6) −0.6 (0.8) −0.6 (0.1) F
1,96
= 1.51, P = .22
Abbreviations: CBASP, cognitive behavioral analysis system of psychotherapy; CGI-S, Clinical Global Impressions–Severity scale; HAM-A
PA
, Hamilton Rating
Scale for Anxiety Psychic Anxiety factor subscale; HRS-D
24
, 24-item Hamilton Rating Scale for Depression; IDS-SR
30
, 30-item Inventory for Depressive
Symptomatology–Self-Report.
*Values are mean (SD).
†Least squares adjusted means.
P values are comparing adjusted mean change from baseline to end point.
30
15
25
20
10
5
0
Baseline Week 1 Week 2 Week 3 Week 4 Week 6 Week 8 Week 10 Week 12
Visit
HRS-D
24
Score
CBASP Followed by Nefazodone
Nefazodone Followed by CBASP
Figure 3. Mean HRS-D
24
(24-item Hamilton Rating Scale for Depression)
scores in the crossover phase. CBASP indicates cognitive behavioral analysis
system of psychotherapy.
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tion of participants were willing to cross over to medi-
cation after nonresponse to psychotherapy than the
reverse.
Although significant improvement was observed in ap-
proximately 50% of patients who completed the cross-
over treatment, only about 1 in 4 patients (28% [16/57]
for nefazodone and 25% [13/53] for CBASP) achieved full
remission; that is, about half of the responders still had
significant residual symptoms at the end of the cross-
over phase. Responders without remission have less ro-
bust social recoveries than those who achieve full remis-
sion
21,22
and are at higher risk for subsequent relapse.
23
Chronically depressed patients might benefit from the
combination of both CBASP and nefazodone or from
longer courses of treatment. Consistent with this, roughly
40% of chronically depressed patients who had a re-
sponse but not a remission after 12 weeks of acute-
phase treatment with either imipramine or sertraline con-
verted to full remission during continuation therapy with
the same agent.
24
Several methodological limitations affect interpreta-
tion of these results. First, in the absence of a placebo
condition, it is difficult to determine whether the effects
that are observed are due to treatment. We did not use a
placebo-controlled design in the crossover phase be-
cause of concerns about withholding active treatment from
chronically depressed patients who had already not re-
sponded to initial treatment with nefazodone or CBASP.
Absence of a placebo control group is less critical in the
study of populations in which low placebo response rates
have been documented. Such populations include those
with treatment-resistant depression (placebo response
rates of 10%-20%)
25-27
and those with a chronic depres-
sive illness (double depression; placebo response rate,
13%).
28
Second, switching treatments only for nonre-
sponders who were able to complete the acute trial lim-
its the generalizability of findings to such acute study com-
pleters. If we had switched treatments at the point where
nonresponse was evident rather than at a specific pre-
determined time point, we might have observed higher
(or lower) response or remission rates during the cross-
over trial. Similarly, we cannot determine how well the
switch strategy would have worked for those who de-
cided to drop out prior to completing the acute phase of
treatment. Third, although patients with a number of co-
morbid conditions were allowed to participate in this
study, the exclusion of patients with greater levels of co-
morbidity further limits generalizability of our findings.
We do not know whether such excluded patients would
have responded preferentially to one or the other cross-
over treatment.
Fourth, nonresponders in the two groups who en-
tered the crossover phase may not have been compa-
rable since they were not rerandomized at initiation of
the switch. However, our confidence in the validity of
comparing these groups is strengthened by the absence
of significant differences in sociodemographic and clini-
cal characteristics in the main trial
10
and in the cross-
over trial. In fact, minimal improvement during the ini-
tial treatment trial was predictive of success (albeit weakly)
with both crossover strategies. Nevertheless, without re-
randomization of nonresponders to alternate treat-
ments, interpretation of these comparative results re-
mains tentative. On the other hand, these results have
high applicability to routine practice, where treatment
would never be chosen by randomization.
This is the first prospective, comparative random-
ized study of switching depressed outpatients from medi-
cation to psychotherapy and vice versa in the context of
nonresponse to but completion of the first treatment.
Given the magnitude of the problem of nonresponse to
antidepressant medication, randomized controlled stud-
ies of switch strategies as well as augmentation strate-
gies are desperately needed. The only other large con-
trolled crossover trial found that roughly 50% of
imipramine nonresponders responded to sertraline and
vice versa; this study was conducted among chronically
depressed outpatients who completed 12 weeks of acute
treatment with either of these two medications.
8
It is essential to know more about the range of effi-
cacy of other second-step treatments. For example, we
do not know whether nonresponders to either nefaz-
odone or CBASP, given a different medication as a switch
strategy, would have achieved equivalent or even greater
success. The recently initiated Sequenced Treatment Al-
ternatives to Relieve Depression (STAR*D) (www.star-d
.org) randomized controlled trial is comparing 4 differ-
ent switch treatments (sustained-release bupropion,
cognitive therapy, sertraline, or extended-release venla-
faxine) in outpatients who do not respond to a selective
serotonin reuptake inhibitor (citalopram) as the first treat-
ment. The STAR*D trial will determine whether a switch
within the class of selective serotonin reuptake inhibi-
tors, an out-of-class switch, a switch to a dual-action agent,
or a switch to cognitive therapy is most effective.
The findings of the present study provide the first evi-
dence from a controlled trial of the value of switching to
an antidepressant medication or to psychotherapy after
the failure of the alternative treatment in an initial trial.
The evidence specifically pertains to nefazodone and
CBASP. The general principle may hold for other anti-
depressant medications, as suggested by the findings of
Thase et al
8
with imipramine and sertraline. It remains
to be determined whether other forms of depressed-
focused psychotherapies would yield similar benefits to
CBASP. It would be of interest, for example, to deter-
mine whether therapies with a more interpersonal or psy-
chodynamic focus are useful when a cognitive behav-
ioral strategy is not.
For patients with chronic depression, the present re-
sults provide a strong basis for switching to CBASP after
a medication does not produce a response and, con-
versely, for switching to medication after patients do not
respond to an adequate trial of psychotherapy.
Submitted for Publication: November 17, 2003; final re-
vision received October 8, 2004; accepted November 16,
2004.
Author Affiliations: Department of Psychiatry and Be-
havioral Sciences, Stanford University School of Medi-
cine, Stanford, Calif (Drs Schatzberg, Arnow, and Man-
ber); Department of Psychiatry, University of Texas
Southwestern Medical Center at Dallas (Drs Rush and
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©2005 American Medical Association. All rights reserved.
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Trivedi); i3STATPROBE Inc, Dublin, Ohio (Mr Banks);
Behavioral Science Department, University of Texas MD
Anderson Cancer Center, Houston (Dr Blalock); Bristol-
Myers Squibb Co, Plainsboro, NJ (Ms Borian); Depart-
ment of Psychiatry, University of Pittsburgh School of
Medicine (Drs Howland and Thase), Pittsburgh, Pa; De-
partment of Psychology, State University of New York
at Stony Brook (Dr Klein); Department of Psychiatry, Cor-
nell University Medical College, New York, NY (Drs Koc-
sis and Markowitz); Department of Psychiatry, Virginia
Commonwealth University, Richmond (Dr Kornstein);
Department of Psychiatry and Human Behavior, Brown
Medical School, Providence, RI (Drs Miller and Keller);
and Department of Psychiatry, Emory University School
of Medicine, Atlanta, Ga (Drs Ninan and Rothbaum).
Correspondence: Alan F. Schatzberg, MD, Department
of Psychiatry and Behavioral Sciences, Stanford Univer-
sity School of Medicine, 401 Quarry Rd, Stanford, CA
94305-5717 (afschatz@stanford.edu).
Funding/Support: This multicenter project was sup-
ported in part by a series of grants from Bristol-Myers
Squibb Co, New York, NY.
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    • Truly individualised therapy could be enhanced by assessment of the range of SPF aspects plus the division of overall CASI-D scores into these three factors. As mentioned above, depression is not a unitary disorder and the relatively low rate of efficacy for first-line treatments (i.e., about 40–50 %: Rush et al. (2006)) may reflect the mismatching of generalised anti-depressant therapies with different profiles of depressive symptoms that require more specific treatment approaches (Schatzberg et al. 2005). This variability may be particularly relevant in children with an ASD simply because of their differences in sensory sensitivity compared to non- ASD children.
    [Show abstract] [Hide abstract] ABSTRACT: The association between Sensory Features (SF) and seven anxiety disorders was investigated using self-reports and parental reports about 140 young males with an Autism Spectrum Disorder (ASD). Although there were significant correlations between SF and self- and parent-ratings of some of the seven anxiety disorders, overall, SF was found to have an inconsistent association across the seven anxiety disorders and this was also found for the 8 symptoms of Generalised Anxiety Disorder. These data challenge the practice of assessing SF and anxiety via global measures and argue for individualized disorder-specific assessments to develop more effective diagnoses and treatments for the effects of SF.
    Full-text · Article · Mar 2016
    • One reason why patients do not receive CBT may be that some clinicians consider antidepressants to be superior. Five papers suggested that CBT was as good as antidepressants.11–15 Two trials have been undertaken to see the full benefits of CBT and the benefits of combination treatment.16,17
    [Show abstract] [Hide abstract] ABSTRACT: National Institute for Clinical Excellence (NICE) guidelines recommend a combination of cognitive behavioral therapy (CBT) and antidepressants to treat chronic depression. The Cognitive Behavioral Analysis System of Psychotherapy (CBASP) is the only therapy model specifically designed for the treatment of chronic depression. To determine the clinical response to the CBASP of patients in a specialist clinical service for affective disorder and to ascertain their views on the value of the CBASP for their condition. Qualitative data from interviews including a questionnaire and objective data from Becks Depression Inventory II symptom rating scales were used to monitor the progress of a small case series of five patients with chronic, treatment refractory depression as they received the CBASP over a 10-month period. Common themes from patient interviews show very positive engagement and attitudes to the CBASP from the questionnaire. Rating scales from Becks Depression Inventory II pre- and posttreatment showed very little change for three patients with improvements between 2 and 7 points but deterioration in symptoms of 2 points for the fourth patient. The CBASP is a well-liked and positive therapy that helps patients manage their lives and deal with personal relationships, although objective data indicate little change in symptom severity.
    Article · Oct 2012
    • This near-doubling of rTMS efficacy over the last 4 years represents a significant advance towards the viability of rTMS as a firstline treatment for refractory depression. In this population, rTMS remission rates now match or exceed the 23e33% remission rates seen for an open-label second medication trial or cognitive therapy in patients failing a first medication trial in the STAR*D study [22], or the 35% response and 22% remission rates seen for patients switching to psychotherapy after failing an antidepressant medication [23]. At the same time, these advances also suggest that rTMS still has substantial scope for optimization, and that clinically meaningful improvements in rTMS efficacy may accrue with further refinements in technique.
    [Show abstract] [Hide abstract] ABSTRACT: Although rTMS is moving steadily into the mainstream as a treatment for medically refractory depression, its efficacy continues to lag behind that of more invasive neuromodulation treatments such as ECT or DBS. Here we review evidence to suggest that a fruitful, but neglected, strategy for improving rTMS efficacy may be to explore alternatives to the conventional stimulation target in the dorsolateral prefrontal cortex (DLPFC). The convergent evidence of lesion, stimulation, connectivity, and correlative neuroimaging studies suggests that the DLPFC may have a relatively peripheral role in mood regulation, at least compared to several alternative areas within the prefrontal cortex. In particular, we consider the evidence base in support of four new potential targets for rTMS in depression: dorsomedial prefrontal cortex (DMPFC), frontopolar cortex (FPC), ventromedial prefrontal cortex (VMPFC), and ventrolateral prefrontal cortex (VLPFC). Each of these regions enjoys broader support, from a more diverse evidence base, than the DLPFC in terms of its role in emotion regulation in major depression. We discuss the relative merits of each of these novel targets, including potential obstacles to stimulation using currently available technologies, and potential strategies for overcoming these obstacles. It is hoped that this detailed review will spur a more vigorous exploration of new targets for rTMS in depression. The use of new targets may help to propel rTMS across the threshold of efficacy required of a first-line treatment, to assume a more widespread role in the treatment of depressed mood.
    Full-text · Article · Sep 2012
    • Patients achieving less than full remission were randomized into phase 2. Full remission was defined by concomitantly meeting the following three conditions: a) ≥ 60% reduction in Hamilton Scale for Depression [HAM-D] score, b) a 24- item HAM-D total score less than 8, and c) no longer meeting DSM-IV criteria for MDD for 2 consecutive visits during weeks 6 through 12. Phase 2 participants all received the nextstep treatment in the pharmacotherapy algorithm and were randomly assigned to one of three treatment cells in a 2:2:1 ratio: to have CBASP or BSP added to their pharmacotherapy or to receive medication alone. The 12-week duration for phase 2 mirrored the length of treatment in a previous chronic depression study by our group (Keller et al., 2000; Schatzberg et al., 2005) and the STAR*D study (Thase et al., 2007).
    [Show abstract] [Hide abstract] ABSTRACT: Depression is associated with poor social problem solving, and psychotherapies that focus on problem-solving skills are efficacious in treating depression. We examined the associations between treatment, social problem solving, and depression in a randomized clinical trial testing the efficacy of psychotherapy augmentation for chronically depressed patients who failed to fully respond to an initial trial of pharmacotherapy (Kocsis et al., 2009). Participants with chronic depression (n = 491) received cognitive-behavioral analysis system of psychotherapy (CBASP; McCullough, 2000), which emphasizes interpersonal problem solving, plus medication; brief supportive psychotherapy (BSP) plus medication; or medication alone for 12 weeks. CBASP plus pharmacotherapy was associated with significantly greater improvement in social problem solving than BSP plus pharmacotherapy, and a trend for greater improvement in problem solving than pharmacotherapy alone. In addition, change in social problem solving predicted subsequent change in depressive symptoms over time. However, the magnitude of the associations between changes in social problem solving and subsequent depressive symptoms did not differ across treatment conditions. It does not appear that improved social problem solving is a mechanism that uniquely distinguishes CBASP from other treatment approaches.
    Full-text · Article · Jun 2011
    • Fourth, in the current staging models effective psychotherapies (interpersonal, cognitive and behavioral) are absent , despite recommendation in guidelines (Lam et al., 2009; NICE, 2007). The literature lacks adequate numbers of randomized controlled trials investigating the effectiveness of psychotherapy in patients with TRD (McPherson et al., 2005), although some studies investigated the effect of cognitive behavioral analysis system of psychotherapy (CBASP) (Keller et al., 2000; Kocsis et al., 2009; Schatzberg et al., 2005; Wiersma et al., 2008) and interpersonal psychotherapy (IPT) (Schramm et al., 2008) in chronic depression. In addition, STAR*D only investigated a switch/ augmentation with CBT after nonresponse to a first antidepressant (Thase et al., 2007).
    [Show abstract] [Hide abstract] ABSTRACT: Treatment resistant depressant (TRD) is classified in different staging models, but these are not used routinely. We aimed to identify staging models for TRD and compare them regarding predictive utility and reliability. Systematic review of Pubmed, Embase and PsycINFO (1985-January 2010) without language limits, plus articles identified from reference lists of previous reviews. We excluded articles focusing on TRD treatment. We qualitatively summarized characteristics of the identified staging models, describing strengths and limitations for each model. If available, we reported results of validation studies. From 950 retrieved articles five staging models were found; the Antidepressant Treatment History Form, Thase and Rush Model, European Staging Model, Massachusetts General Hospital Staging model and the Maudsley Staging Model (MSM). Six studies investigated the predictive utility (of four models). We observed an evolution from single antidepressant adequacy ratings, towards a multidimensional and more continuous scored staging model which also introduced TRD characteristics (severity and duration). The operationalization criteria improved; the scoring of different treatment strategies (between/within class switching and augmentation/combination) changed according to the existing evidence. Over time, efforts to validate models improved. The predictive utility was assessed best for the MSM. Few staging models existed; their reliability was hardly assessed. Despite validation of the MSM, further investigation of the reliability and predictive utility of TRD staging models and additional disease characteristics is required. Correct staging of TRD might improve generalizability of results from clinical studies and improve delivery of care to TRD patients. We propose methods to validate staging models in TRD.
    Full-text · Article · Mar 2011
    • This process underlies many successful psychological treatments[e.g., 16, 17-22], and is characterised by a focus upon the purpose or outcome of behaviour for the organism exhibiting it[21], information that is acquired by examining the antecedents and consequences of a particular behaviour and determining the links between these two aspects. As well as being successful with mild to moderate depression, there are also data which support the use of some of these functional analytic approaches with Major Depressive Disorder (MDD)[23], indicating that this form of psychotherapy may be at least as effective as antidepressant medication for reducing the symptoms of acute depression[24][25][26]. This process of analysing the antecedents and consequences of overt behaviours as causal vectors for depression is the central theme of Behavioural Functional Analysis, and may reveal the outcomes of depressive behaviour for the individual exhibiting it[27,28].
    [Show abstract] [Hide abstract] ABSTRACT: Depression is one of the major contributors to the Total Disease Burden and afflicts about one-sixth of Western populations. One of the most effective treatments for depression focuses upon analysis of causal chains in overt behaviour, but does not include brain-related phenomena as steps along these causal pathways. Recent research findings regarding the neurobiological concomitants of depressive behaviour suggest a sequence of structural and functional alterations to the brain which may also produce a beneficial outcome for the depressed individual--that of adaptive withdrawal from uncontrollable aversive stressors. Linking these brain-based explanations to models of observable contingencies for depressive behaviour can provide a comprehensive explanation of how depressive behaviour occurs and why it persists in many patients.
    Full-text · Article · Dec 2010
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