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Double-blind Switch Study of Imipramine or Sertraline Treatment of Antidepressant-Resistant Chronic Depression
Michael E. Thase, MD;
A. John Rush, MD;
Robert H. Howland, MD;
Susan G. Kornstein, MD;
James H. Kocsis, MD;
Alan J. Gelenberg, MD;
Alan F. Schatzberg, MD;
Lorrin M. Koran, MD;
Martin B. Keller, MD;
James M. Russell, MD;
Robert M. A. Hirschfeld, MD;
Lisa M. LaVange, PhD;
Daniel N. Klein, PhD;
Jan Fawcett, MD;
Wilma Harrison, MD
Arch Gen Psychiatry. 2002;59:233-239.
ABSTRACT
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Background Although various strategies have been proposed to treat antidepressant
nonresponders, little controlled research has been published that examines
prospectively the use of switching to an alternate antidepressant.
Methods This was a multisite study in which outpatients with chronic major depression
(with or without concurrent dysthymia), who failed to respond to 12 weeks
of double-blind treatment with either sertraline hydrochloride (n = 117) or
imipramine hydrochloride (n = 51), were crossed over or switched to 12 additional
weeks of double-blind treatment with the alternate medication. Outcome measures
included the 24-item Hamilton Rating Scale for Depression and the Clinical
Global Impressions–Severity and Improvement scales.
Results The switch from sertraline to imipramine (mean dosage, 221 mg/d) and
from imipramine to sertraline (mean dosage, 163 mg/d) resulted in clinically
and statistically significant improvements. The switch to sertraline treatment
was associated with fewer adverse effect complaints and significantly less
attrition owing to adverse effects. Although sertraline treatment also resulted
in significantly higher response rates in the intent-to-treat samples (60%
in the sertraline group and 44% in the imipramine group), neither the intent-to-treat
remission rates nor the response and remission rates among study completers
differed significantly. Moreover, after considering the effect of attrition,
there were no significant treatment effects on the more comprehensive generalized
estimating equation analyses of the continuous dependent measures.
Conclusions More than 50% of chronically depressed antidepressant nonresponders
benefited from a switch from imipramine to sertraline, or vice versa, despite
a high degree of chronicity. As in the initial trial, sertraline was generally
better tolerated than imipramine. Switching to a standard antidepressant of
a different class is a useful treatment strategy for antidepressant nonresponders
and could be considered a standard of comparison for future studies of novel
alternate strategies.
INTRODUCTION
AT LEAST 40% of patients treated for depression do not respond to the
initial trial of antidepressant medication.1
Thase and Rush2-3 characterized
this as stage I antidepressant resistance, the first of a sequence of 5 stages
defined by treatment history. Numerous treatment options are available for
such individuals, including switching between or within classes of medications,
as well as various augmentation strategies. In fact, the major issue facing
clinicians is trying to decide which "next step" strategy to choose.3-4 Some clinicians favor augmentation strategies
because of ease of implementation (eg, no tapering is needed), whereas others
view switching to a different antidepressant, especially one from a different
class, as a more prudent option.3 In an era
in which selective serotonin reuptake inhibitors and tricyclic antidepressants
are the most widely prescribed antidepressants,5-7
it is important to document the efficacy of each medication class, in sequence,
when the other has failed.
Despite the public health importance of antidepressant nonresponse,
surprisingly few switch studies2-3
have been conducted. Only a handful have confirmed prospectively the adequacy
of the ineffective medication trial or have used controlled, double-blind
methods. We report herein the results of a large, double-blind study of patients
with chronic forms of major depression who, after failing to respond to 12
weeks of double-blind treatment with sertraline hydrochloride or imipramine
hydrochloride, were crossed over or switched to the alternate compound.
SUBJECTS AND METHODS
SUBJECTS
This protocol was part of a multiphase, collaborative research program
studying chronic depressive disorders. A full description of the study design,
rationale, and methods has been previously published.8
Briefly, outpatients aged 21 to 65 years were eligible to enroll at 1 of 12
centers if they met DSM-III-R criteria for chronic
major depressive disorder (ie, current major depressive episode of  2 years
in duration) or "double depression" (ie, a current major depressive episode
superimposed on an antecedent dysthymic disorder). The findings of the main
study9-11 have been
described elsewhere.
Intake diagnoses were based on interviews using the Structured Clinical
Interview for DSM-III-R12
and Structured Clinicial Interview for DSM-III-R
Personality Disorders.13 Patients were excluded
if they had organic mental syndromes, bipolar disorder or cyclothymia, schizophrenia
or other psychotic disorder, obsessive compulsive disorder, or schizotypal,
antisocial, or severe borderline personality disorder. Those with principal
current diagnoses of panic, generalized anxiety, or posttraumatic stress disorders
were also excluded. Patients were not eligible if they had abused alcohol
or other drugs within 6 months or had experienced bulimia or anorexia nervosa
within 1 year of intake. Patients considered to be an immediate suicide risk,
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 minimally adequate trials of sertraline or imipramine
(ie, at least 4 weeks of 50 mg of sertraline or 150 mg of imipramine
daily) were ineligible. Patients could not have been treated with anxiolytic
or other antidepressant medication within 2 weeks, monoamine oxidase inhibitors
within 3 weeks, fluoxetine hydrochloride within 1 month, electroconvulsive
therapy within 3 months, or depot neuroleptics within 6 months. Psychotherapy
was permitted during the study only if it had been ongoing for at least 3
months before intake.
INITIAL TREATMENT TRIAL
After providing written informed consent, a complete medical history,
physical examination, electrocardiography, and laboratory screening battery
were completed to confirm medical eligibility. Patients began a 1-week, single-blind
placebo lead-in, during which the only psychotropic medications permitted
were chloral hydrate or temazepam, used sparingly for severe insomnia. Patients
whose Clinical Global Impressions–Improvement (CGI-I)14
score was 3 or higher and whose score on the 24-item Hamilton Rating Scale
for Depression (HAM-D)15 was 18 or higher at
the end of the lead-in period were randomized to double-blind treatment with
either sertraline (n = 426) or imipramine (n = 209). This 2:1 proportion was
used because responders to sertraline, but not imipramine, could subsequently
participate in a placebo-controlled maintenance-phase trial.11
All patients were seen initially for 6 weekly visits, followed by visits
every other week for the balance of the 12-week trial. Imipramine was started
at 50 mg/d and titrated by 50 mg/d per week, as tolerated, up to a maximum
of 300 mg/d. Sertraline was also initiated at 50 mg/d, but a dosage increase
was not permitted until the end of week 3. Thereafter, weekly increases of
50 mg/d were possible, if indicated and tolerated, up to a maximum of 200
mg/d. Therefore, maximum dosages of either study drug could be reached by
week 6. Patients who could not tolerate at least 50 mg/d of either study medication
were withdrawn from the trial. Mean ± SD dosages of 141 ± 59
mg/d of sertraline and 200 ± 82 mg/d of imipramine were achieved at
the end point of the initial acute-phase trial.
ASSESSMENT OF RESPONSE
Vital signs and adverse events (volunteered or observed) were assessed
at each visit. The principal dependent measures, the CGI-I (Improvement) and
the 24-item HAM-D, were obtained at each visit. Secondary measures included
the CGI-S (Severity), Montgomery-Åsberg Depression Rating Scale,16 Cornell Dysthymia Scale,17
and self-report 21-item Beck Depression Inventory.18
All clinical ratings were completed by a blinded, independent evaluator. A
satisfactory therapeutic response (hereafter referred to as response) was noted if the final CGI-I score was 1 or 2, there was
at least a 50% reduction in total HAM-D score to a final score of 15 or lower,
and the CGI-S score was 3 or lower (ie, the patient was no more than mildly
ill). Patients not meeting these criteria were considered nonresponders. A
full remission was defined as a final HAM-D score of 7 or lower and a CGI-I
score of 2 or lower.
ACUTE-PHASE OUTCOME
Among the 635 randomized patients, 302 completed the 12-week acute-phase
trial as responders (205 for sertraline and 97 for imipramine). Two hundred
seven completed the study as nonresponders. One hundred twenty-six patients
discontinued the study prematurely (76 in the sertraline-treated group and
50 in the imipramine-treated group), of whom 22 patients were responders at
the time of study discontinuation (15 in the sertraline-treated group and
7 in the imipramine-treated group) and of whom 12 patients discontinued before
the first evaluation after randomization (5 in the sertraline-treated group
and 7 in the imipramine-treated group). There was no difference in response
rates between treatments in the intent-to-treat samples (52% in the sertraline
group and 51% in the imipramine group).10 Of
the 311 nonresponders, attrition was significantly greater from imipramine
(41% [43/105]) than sertraline (30% [61/206]) ( 21
= 4.02, P = .045).
SWITCH PROTOCOL
Two hundred seven nonresponders completed the initial trial. The 62
imipramine nonresponders received a mean ± SD final dosage of 235 ±
66 mg/d (range, 100-300 mg/d). The 145 sertraline nonresponders received a
mean ± SD final dosage of 158 ± 57 mg/d (range, 50-200 mg/d).
In both cases, nonresponders received significantly higher mean ± SD
dosages than responders (205 sertraline responders: 144 ± 55 mg/d,
F1,348 = 6.23, P = .01; 97 imipramine
responders: 218 ± 72 mg/d, F1,157 = 4.30, P = .04).
Nonresponders were tapered off study medication over 1 to 2 weeks, with
the double blind maintained. After at least 1 week of not taking any study
medications, patients who continued to meet nonresponse criteria and who gave
renewed written informed consent were crossed over to the alternate medication.
Visits, assessments, medication dosaging, and outcome definitions for the
switch study followed the same protocol as that used in the initial acute-phase
trial.
STATISTICAL ANALYSES
Categorical analyses (eg, adverse effects, attrition, and response rates)
were performed using Fisher exact probability test, simple 2
tests, McNemar test (for within-subject comparisons), or Cochran-Mantel-Haenszel 2 test, as appropriate. The latter test was stratified by study site
and depression subtype. All statistical tests used 2-tailed probability values,
with unadjusted significance levels of P .05.
Response and remission rates are reported at the end point for the intent-to-treat
sample and for study completers.
The original data analysis plan called for analyses of covariance of
the continuous dependent measures for the intent-to-treat sample, using the
last observation carried forward method, and the completers sample. The availability
of more sophisticated statistical methods, coupled with a significant, nonrandom
difference in study completion rates, led us to pursue a different analytic
strategy.Tabulated results of the more conventional analyses of covariance
are available from one of us (M.E.T.).
To combine information for continuous outcome measures from all patient
visits in a single analysis, repeated-measures models were fit using generalized
estimating equation (GEE) methods.19-20
An independent correlation model was assumed for the analyses reported herein.
Separate GEE models were fit for each dependent measure, using data from all
available visits and including main effects for medication group and week
of treatment. Because missing data were not randomly dispersed (eg, virtually
all missing data were the result of premature attrition, which was associated
with poorer outcomes), we also included completion status as a main effect
in the GEE analyses. Although repeated-measures analysis of such data could
lead to biased results (ie, informative censoring), adjustment for completion
status may partially reduce this risk.21 z Score statistics based on GEE empirical SEs were used
to quantify main effects and interaction terms (in the context of repeated-measures
models), controlling for baseline severity, study site, and type of depression.
RESULTS
Of the 207 nonresponders who completed the acute-phase trial, 168 (81%)
began the alternate antidepressant. There were no significant differences
in sociodemographic or clinical measures between those who did or did not
participate in the second treatment trial. Reasons for not enrolling in the
switch phase were not recorded systematically. However, several patients improved
significantly during the washout period, and 1 patient experienced a significant
clinical worsening necessitating emergency hospitalization.
SAMPLE CHARACTERISTICS
Fifty-one patients were switched from imipramine to sertraline, and
117 sertraline nonresponders were switched to imipramine. These groups did
not differ significantly on any relevant characteristic (Table 1). There was, however, a trend for women to be overrepresented
in the group switched from imipramine to sertraline (78% vs 62%; 21 = 3.50, P = .06). The mean ±
SD dosages of imipramine and sertraline received at the end point of the second
trial were 221 ± 84 mg/d and 163 ± 48 mg/d, respectively.
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Table 1. Demographic and Clinical Characteristics of Study Group*
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ATTRITION AND TOLERABILITY
Thirty-four patients dropped out, including 10% (5/51) of those switched
to sertraline treatment and 25% (29/117) of those switched to imipramine treatment
(21 = 4.94, P = .03).
This difference was largely the result of a significantly greater number of
patients discontinuing imipramine because of intolerable adverse effects (9%
vs 0%; Fisher exact test, P = .04).
Adverse effects reported during the first and second antidepressant
trials are summarized in Table 2.
Anticholinergic adverse effects, including dry mouth, constipation, and urinary
complaints, were significantly more common in the group that switched to imipramine.
There were also significantly more complaints of sweating, dizziness, and
somnolence in the imipramine group. Diarrhea and insomnia were significantly
more common among the group that switched to sertraline therapy. Other common
adverse effects, including headache, nausea, fatigue, and sexual dysfunction,
were comparable in both groups.
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Table 2. Most Common Treatment-Related Adverse Events During Acute-Phase
and Switch-Phase Treatment*
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Comparing adverse effect reports between the 2 treatment phases revealed
that patients who switched from sertraline to imipramine experienced significant
reductions in 3 adverse effects, but significant increases in 8 adverse effects
(columns 2 through 4 of Table 2).
In contrast, the switch from imipramine to sertraline resulted in statistically
significant reductions in 7 adverse effects, but no significant increase in
any adverse effect columns 5 through 7 of Table 2).
RESPONSE AND REMISSION RATES
Response status could not be determined for 1 patient. The sertraline
intent-to-treat response rate was 60% (30/50), while the imipramine intent-to-treat
response rate was 44% (52/117) (21 = 4.90, P = .03). Remission rates were 32% for sertraline and 23%
for imipramine (21 = 2.28, P = .13). Among the 134 completers, response rates were 63% in the sertraline
group and 55% in the imipramine group (21 = 1.96, P = .16). Remission rates also did not differ significantly
among completers (35% for sertraline and 30% for imipramine; 21 = 0.94, P = .33).
ANALYSES OF CONTINUOUS MEASURES
Mean scores at baseline and end point and mean change scores for continuous
clinical outcome measures are presented in Table 3. Results of the repeated-measures GEE analyses indicated
that the patients in both treatment groups improved significantly across time,
and completers improved significantly more than noncompleters on all measures.
After averaging across the study weeks and adjusting for completion status,
baseline value, site, and depression type, there were no significant differences
between the medication groups for each outcome. In addition, when the effect
of attrition was considered, there were no significant week-by-medication
group interactions, indicating that the groups did not differ in their pattern
of symptomatic improvement over time.
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Table 3. Mean Scores on Continuous Dependent Measures at Baseline and
End Point and Results of Repeated-Measures Analyses Using a Generalized Estimating
Equation (GEE) Model Method*
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COMMENT
This double-blind switch study provides further evidence that chronic
depressions are responsive to antidepressant monotherapy after nonresponse
to a vigorous 12-week initial trial. Overall, more than 50% of the patients
who began treatment with a second antidepressant responded. These results
are particularly noteworthy as the patients had a mean duration of more than
6 years of continuous major depressive disorder.
As in the initial trial,10 sertraline
was significantly better tolerated than imipramine. The better tolerability
of sertraline was reflected by a significantly lower attrition rate owing
to adverse effects and a greater reduction in adverse effect burden following
the switch to the alternate antidepressant. The difference in tolerability
also helped to explain a significantly higher intent-to-treat response rate
in the sertraline group, although a smaller difference in intent-to-treat
remission rates was not statistically significant.
Overall, we observed response rates that were similar to those in earlier
published studies2, 22-25
of switching across antidepressant classes. Response to the second medication
was maximized in the present study by providing 12 weeks of pharmacotherapy
(rather than the customary 4-6 weeks) and by permitting imipramine and sertraline
dosages to be increased gradually, if tolerated, to the highest levels permitted
within the manufacturers' therapeutic indications.
Compared with augmentation strategies for antidepressant nonresponders,
switching antidepressant classes has the advantages of simplicity and parsimony
(eg, lower cost and little risk of drug-drug interactions). Given the tolerability
problems observed in the group that switched from sertraline to imipramine,
it may be more useful to switch within the selective serotonin reuptake inhibitors
class26-27 or to a dissimilar newer
antidepressant (eg, bupropion hydrochloride, mirtazapine, nefazodone hydrochloride,
reboxetine, or venlafaxine hydrochloride).3
Augmenting the initial antidepressant with lithium salts,28-29
thyroid hormone,29 pindolol,30
or buspirone hydrochloride31 is also an option.
Although it is unlikely that the augmentation strategies would have produced
better outcomes than those observed in the present study, some clinicians
favor them because of quicker implementation. Combining antidepressants (eg,
adding sertraline to imipramine, or vice versa) is another widely used approach,
although there is the potential for drug-drug interactions and there are no
large, well-controlled, prospective studies of this strategy.32
Despite a favorable antidepressant response rate observed following
the switch of antidepressants, low percentages of patients who began the second
treatment trial (32% in the sertraline group and 23% in the imipramine group)
achieved full remission. In other words, about one half of the responders
had significant residual symptoms after 12 weeks of pharmacotherapy. Such
patients are unlikely to have robust social recoveries,33
and they are at high risk for subsequent relapse.34-35
It is likely that patients with chronic depression warrant longer acute-phase
trials. Indeed, 42% of the patients who responded but did not remit during
the initial trial converted to full remission during continuation therapy.35 Evidence from another recent study36
of chronic depression suggests that the combination of psychotherapy and pharmacotherapy
also increases the likelihood of remission.
Our study has several methodological limitations that affect interpretation
of the results. The first limitation is the lack of a placebo control group,
which precludes more definitive assessment of the true magnitude of the treatment
effects. We decided against using a placebo-controlled design because of concerns
about withholding active treatment from chronically depressed antidepressant
nonresponders. Most investigators studying treatment-resistant depression
have made the same choice.3 However, placebo
has been used in several studies29-31
of augmentation strategies, and nonspecific response rates of 10% to 20% are
typically observed. Kocsis and colleagues37
similarly found a placebo response rate of only 13% in their study of imipramine
as the initial treatment of chronic depression. If it is assumed that 20%
of our patients would have responded to placebo, the effects of sertraline
and imipramine would have been statistically significant.
A second methodological problem is that switching the antidepressants
of only the nonresponders is not representative of a true crossover design,
which would require that responders also switch medications. Because the nonresponders
are no longer necessarily representative of the initial randomized samples,
we cannot rule out that the 2 switch groups differed in some meaningful way.
Confidence in the validity of comparing these groups is strengthened by the
lack of significant differences in the sociodemographic and clinical characteristics,
as well as a virtual lack of predictors of differential response in the main
trial.38 Nevertheless, without rerandomization
of nonresponders to alternate treatments, our comparative results should be
viewed as tentative.
A third limitation is the exclusion of more complicated and comorbid
patients from the main trial. Because such patients tend to be overrepresented
among antidepressant nonresponders,1-2
the generalizability of our findings is somewhat attenuated. However, there
is no reason to assume that excluded patients would have responded preferentially
to one or the other of the study medications.
Finally, it could be argued that the slower dose-titration schedule
of imipramine during the first weeks of the protocol, while necessary, might
have biased the results in favor of sertraline. However, because rapidity
of response did not differ between the treatments and because all imipramine-treated
patients received up to 6 weeks of therapy at maximal dosage, it is unlikely
that speed of titration affected the final results. Faster titration of imipramine
also may have exaggerated the tolerability problems observed with this medication.
To our knowledge, this is the largest double-blind study of switching
antidepressants conducted to date. Given the magnitude of the problem of antidepressant
nonresponse and the large number of controlled studies of antidepressants
under way at any given time, it is puzzling that switch designs are not used
more widely. There is an impression that these studies are too difficult to
conduct, because of perceived problems such as subject refusal, attrition,
and inability to maintain the double blind. We experienced no such difficulties
(eg, more than 80% of patients consented to the switch study), and our patients'
outcomes were as good as those observed in the initial trial. Furthermore,
the costs of a switch study are small compared with those of the parent trial.
The public health importance of treatment-resistant depression provides a
strong justification for broader use of the switch designs, which would facilitate
the study of promising strategies for antidepressant nonresponders.
The findings of this study illustrate the value of switching to an antidepressant
of a different class after the failure of first-line pharmacotherapy. Switching
nonresponders to an alternate antidepressant monotherapy is a straightforward
strategy that could be considered an ethical standard of comparison for future
studies of treatment-resistant depression.
AUTHOR INFORMATION
Submitted for publication November 3, 1998; final revision received
October 19, 2001; accepted October 24, 2001.
This multicenter research project was supported in part by a series
of grants from Pfizer Inc.
Corresponding author and reprints: Michael E. Thase, MD, Department
of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric
Institute and Clinic, 3811 O'Hara St, Pittsburgh, PA 15213 (e-mail: thaseme{at}msx.upmc.edu).
From the Departments of Psychiatry, University of Pittsburgh School
of Medicine, and Western Psychiatric Institute and Clinic, Pittsburgh, Pa
(Drs Thase and Howland), The University of Texas Southwestern Medical Center
at Dallas (Dr Rush), Medical College of Virginia, Virginia Commonwealth University,
Richmond (Dr Kornstein), Cornell University School of Medicine, New York,
NY (Dr Kocsis), University of Arizona, Tucson (Dr Gelenberg), Stanford University
School of Medicine, Stanford, Calif (Drs Schatzberg and Koran), Butler Hospital,
Brown University, Providence, RI (Dr Keller), and The University of Texas
Medical Branch at Galveston (Drs Russell and Hirschfeld); Quintiles, Inc,
Research Triangle Park, North Carolina (Dr LaVange); Departments of Psychiatry,
State University of New York at Stony Brook (Dr Klein), and Rush-Presbyterian-St
Luke's Medical Center, Chicago, Ill (Dr Fawcett); Pfizer Inc and Department
of Psychiatry, College of Physicians and Surgeons, Columbia University, New
York (Dr Harrison). The following authors have served as paid consultants
to these companies: Pfizer Inc (Drs Thase, Rush, Kornstein, Kocsis, Gelenberg,
Schatzberg, Koran, Keller, Russell, Hirschfeld, LaVange, and Fawcett) and
Abbott Laboratories, North Chicago, Ill (Drs Hirschfeld and Fawcett). Drs
Kocsis, Gelenberg, and Harrison own stock in Pfizer Inc.
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