Six-year outcome of cognitive behavior therapy for prevention of recurrent depression.

Abstract

A paucity of studies use nonpharmacological strategies for preventing recurrence in depression. Cognitive behavior treatment of residual symptoms was found to yield a significantly lower relapse rate than clinical management in recurrent depression at a 2-year follow-up. The objective of this investigation was to provide a 6-year follow-up of cognitive behavior treatment versus clinical management.
Forty patients with recurrent major depression who had been successfully treated with antidepressant drugs were randomly assigned to either cognitive behavior treatment of residual symptoms (supplemented by lifestyle modification and well-being therapy) or clinical management. In both groups, antidepressant drugs were tapered and discontinued. A 6-year follow-up was undertaken. During this period, no antidepressant drugs were used unless a relapse ensued.
Cognitive behavior treatment resulted in a significantly lower relapse rate (40%) at a 6-year follow-up than did clinical management (90%). When multiple recurrences were considered, the group that received cognitive behavior treatment had a significantly lower number of relapses in comparison with the clinical management group.
The results suggest that the sequential use of cognitive behavior treatment after pharmacotherapy may improve the long-term outcome in recurrent depression. A significant proportion of patients with recurrent depression might be able to withdraw from medication successfully and to stay well for at least 6 years with a focused course of psychotherapy.

Full text

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Article
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Am J Psychiatry 161:10, October 2004http://ajp.psychiatryonline.org
Six-Year Outcome of Cognitive Behavior Therapy
for Prevention of Recurrent Depression
Giovanni A. Fava, M.D.
Chiara Ruini, Ph.D.
Chiara Rafanelli, M.D., Ph.D.
Livio Finos, Ph.D.
Sandra Conti, M.D.
Silvana Grandi, M.D.
Objective: A paucity of studies use non-
pharmacological strategies for preventing
recurrence in depression. Cognitive behav-
ior treatment of residual symptoms was
found to yield a significantly lower relapse
rate than clinical management in recur-
rent depression at a 2-year follow-up. The
objective of this investigation was to pro-
vide a 6-year follow-up of cognitive behav-
ior treatment versus clinical management.
Method: Forty patients with recurrent
major depression who had been success-
fully treated with antidepressant drugs
were randomly assigned to either cogni-
tive behavior treatment of residual symp-
toms (supplemented by lifestyle modifica-
tion and well-being therapy) or clinical
management. In both groups, antidepres-
sant drugs were tapered and discontinued.
A 6-year follow-up was undertaken. During
this period, no antidepressant drugs were
used unless a relapse ensued.
Results: Cognitive behavior treatment re-
sulted in a significantly lower relapse rate
(40%) at a 6-year follow-up than did clinical
management (90%). When multiple recur-
rences were considered, the group that re-
ceived cognitive behavior treatment had a
significantly lower number of relapses in
comparison with the clinical management
group.
Conclusions: The results suggest that the
sequential use of cognitive behavior treat-
ment after pharmacotherapy may im-
prove the long-term outcome in recurrent
depression. A significant proportion of pa-
tients with recurrent depression might be
able to withdraw from medication success-
fully and to stay well for at least 6 years
with a focused course of psychotherapy.
(Am J Psychiatry 2004; 161:1872–1876)
A number of controlled trials have suggested that cog-
nitive behavior strategies may decrease the risk of relapse in
major depressive disorders (1–5). The risk of relapse in de-
pression is strongly related to the number of depressive ep-
isodes and to the amount of residual symptoms (6). Frank
et al. (7) conducted a randomized 3-year maintenance pro-
gram in 128 patients with recurrent depression who had re-
sponded to combined short-term and continuation treat-
ment with imipramine and interpersonal psychotherapy. A
five-cell design was used to determine whether imipra-
mine, placebo, and interpersonal psychotherapy could play
a role in the prevention of recurrence. The use of imipra-
mine at an average dose of 200 mg/day provided the stron-
gest prophylactic effect, whereas monthly interpersonal
psychotherapy displayed a modest protective effect, al-
though the latter was superior to placebo (7). The clinical
consequence of this investigation is that patients with re-
current depression merit continued antidepressant drug
prophylaxis. A sequential approach (based on the use of
pharmacotherapy in the acute phase of depression and
cognitive behavioral therapy in its residual phase) was
applied to 40 patients with recurrent major depression,
who had been successfully treated with antidepressant
drugs by using the same criteria that had been outlined by
Frank et al. (7). Those were three or more episodes of unipo-
lar depression (with the immediately preceding episode be-
ing no more than 2.5 years before the onset of the present
episode). Patients were randomly assigned to either cogni-
tive behavior treatment of residual symptoms—supple-
mented by lifestyle modification and well-being therapy
(8)—or clinical management. In both groups, antidepres-
sant drugs were tapered and discontinued. At the 2-year
follow-up, cognitive behavior treatment resulted in a sig-
nificantly lower relapse rate (25%) than did clinical man-
agement (80%) (3). The differential relapse rate was found
to be significantly related to the abatement of residual
symptoms (9).
The aims of this investigation were to extend the follow-
up to 6 years and to further explore therapeutic tools when,
regardless of previous treatment (cognitive behavior or
clinical management), relapse ensued.
Method
Patients
Forty-five consecutive outpatients satisfying the criteria to be
described, who had been referred to and treated in the Affective
Disorders Program of the University of Bologna, were enrolled in
this study. The patients’ diagnoses were established by the con-
sensus of a psychiatrist (G.A.F.) and a clinical psychologist (C.R.),
independently using the Schedule for Affective Disorders and
Schizophrenia (10). Subjects had to meet the following criteria:

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1) Having a current diagnosis of major depressive disorder ac-
cording to the Research Diagnostic Criteria (RDC) (11)
2) Having their third or subsequent episode of depression, with
the immediately preceding episode being no more than 2.5
years before the onset of the present episode
3) Reporting a minimum 10-week remission according to the RDC
(no more than two symptoms present to no more than a mild
degree with an absence of functional impairment) between the
index episode and the immediately preceding episode (7)
4) Having a minimum global severity score of 7 for the current
episode of depression (12)
5) Having no history of manic, hypomanic, or cyclothymic features
6) Having no history of active drug or alcohol abuse, depen-
dence, or personality disorder, according to DSM-IV criteria
7) Having no history of antecedent dysthymia
8) Having no active medical illness
9) Having a successful response to antidepressant drugs admin-
istered by two psychiatrists (S.G. and S.C.), according to stan-
dardized protocol (13).
This protocol involved the use of tricyclic antidepressants, with
gradual increase in dose. Patients who could not tolerate tri-
cyclics were switched to selective serotonin reuptake inhibitors
(SSRIs) (3).
After drug treatment, all patients were assessed by the same
psychologist who had evaluated them at intake but who did not
take part in the treatment. Only the patients rated as “better” or
“much better” according to a global scale of improvement (12)
and as in full remission (14) were enrolled in the study. The sub-
jects also had to show no evidence of depressed mood after treat-
ment, according to a modified version of Paykel’s Clinical Inter-
view for Depression (15).
All patients were treated for at least 3 but no more than 5 months
with full doses of antidepressant drugs (3), after which the modi-
fied version of Paykel’s Clinical Interview for Depression (15) was
administered by the clinical psychologist. This interview covered
19 symptom areas, as described in detail elsewhere (10). After com-
plete description of the study to the subjects, written informed
consent was obtained.
Treatment
After assessment with the Clinical Interview for Depression,
the 45 patients were randomly assigned to one of two treatment
groups: 1) pharmacotherapy and cognitive behavior treatment or
2) pharmacotherapy and clinical management. In both cases,
treatment consisted of 10 30-minute sessions once every other
week.
Antidepressant drugs were tapered at the rate of 25 mg of ami-
triptyline or its equivalent every other week, and then they were
withdrawn completely (in all cases, in the two last sessions, the
patients were drug free). This was not feasible for five patients
(three in the cognitive behavior treatment and two in the clinical
management groups), who were therefore excluded from the
study at that point. The same psychiatrist (G.A.F.) performed all
treatments in both groups.
Cognitive behavior treatment consisted of the following three
main ingredients: cognitive behavior treatment of residual symp-
toms of major depression, lifestyle modification, and well-being
therapy, as described in our previous article (3).
The 40 subjects were reassessed with the Clinical Interview for
Depression, after treatment and while drug free, by the same clin-
ical psychologist who had performed the previous evaluations
and who was blind as to treatment assignment. The patients were
then assessed 3, 6, 9, 12, 15, 18, 21, 24, 30, 36, 42, 48, 54, 60, 66, and
72 months after treatment. They were instructed to call immedi-
ately if any new symptoms appeared and were guaranteed a re-
newed course of antidepressant drug therapy only in the event of
relapse. Follow-up evaluation consisted of an update of clinical
and medical status, including any treatment contacts or use of
medications. Relapse was defined as the occurrence of an RDC-
defined episode of major depression. During follow-up (unless a
relapse occurred), no patient received additional antidepressant
drug treatment or psychotherapeutic intervention.
When a first relapse ensued, patients were treated with the
same antidepressant drug that had been used in the previous
episode, for the same duration, and with the same modalities.
Clonazepam (0.5 mg b.i.d.) was added to the treatment regimen
and continued when the antidepressant drug was stopped. If a
second relapse during the 6-year follow-up occurred, clonaze-
pam was discontinued, and the patients were treated again with
the same antidepressant drug, which, however, was then main-
tained throughout the study period at the same dose, which yielded
remission. Remission was defined according to the same criteria
already specified for enrollment.
Statistical Methods
Fisher’s exact test and two-tailed t tests were used to compare
the two groups. Survival analysis (16) was used for time until re-
lapse into major depression. Six factors were investigated as possi-
ble predictors of outcome: assignment to cognitive behavior treat-
ment or clinical management, age, sex, duration of the depressive
episode, number of previous depressive episodes, and number of
residual symptoms regardless of, and before, treatment assign-
ment. The Kaplan-Meier method was used for estimating survival
curves. Since relapse was the event of interest, survival referred to
relapse-free status. Each factor was dichotomized, with a cutoff
point around the median for measurement-type factors. The log-
rank test and Cox proportional hazards model were used to com-
pare any survival distributions for each of the six factors con-
sidered. For all tests performed, the significance level was set at
0.05, two-tailed. Results are expressed as means and standard
deviations.
Results
All 40 patients (20 in each group) completed the 6-year
follow-up. During this period, eight (40%) of the patients
in the cognitive behavior treatment group and 18 (90%) in
the clinical management group relapsed at least once. The
difference was significant (p=0.001, Fisher’s exact test).
The mean survival time was 235.0 weeks (SD=111.7) for
the cognitive behavior treatment and 95.5 weeks (SD=
93.3) for the clinical management group (t=4.29, df=38,
p<0.001). Of the six variables selected for survival analysis,
only treatment assignment (Figure 1) attained statistical
significance (χ2=13.82, df=1, p<0.001, log-rank test). When
we used the Cox proportional hazards model, cognitive
behavior treatment had a significant effect in delaying re-
currence (p<0.001, Fisher’s exact test).
Four of the eight patients who had a first relapse in the
cognitive behavior treatment group and were adminis-
tered clonazepam had a second relapse. This occurred in
11 of the 18 patients of the clinical management group.
The mean survival time was 266.5 weeks (SD=69.0) after
the first relapse for the cognitive behavior treatment
group and 217.3 weeks (SD=83.5) for the clinical manage-
ment group. The difference was not significant. None of
the six variables selected for survival analysis in the 26 pa-
tients who had a first relapse (using the second relapse as

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the event of interest) attained statistical significance. Pa-
tients who had a first relapse, regardless of treatment as-
signment, and who were given clonazepam (N=26) had a
survival time of 232.5 weeks (SD=81.3). Such time was
significantly longer (t=–9.84, df=25, p<0.001) compared to
the survival time until first relapse in the same patients
(mean=86.3, SD=73.0). After being given maintenance
antidepressant treatment after the second relapse, four of
the 11 patients in the clinical management group and
none of the four in the cognitive behavior treatment
group had a further relapse. One patient had four relapses
during the 6-year follow-up.
The cognitive behavior treatment group had a total of
12 depressive episodes during the follow-up compared
with 34 of the clinical management group (t=3.73, df=38,
p<0.001).
Four patients of the 26 who had at least one relapse
(15%) did not respond to the same antidepressant drug
that was used in the first episode. This occurred in three
patients taking desipramine (successfully switched to am-
itriptyline in one case, fluoxetine in another, and fluvox-
amine in the third) and in one taking imipramine (the pa-
tient responded to fluvoxamine).
Discussion
This study has obvious limitations because of its prelim-
inary nature. First, it involved a small number of patients
in the evaluation of long-term effects. Second, it had a
seminaturalistic design, since patients were treated with
different types of antidepressant drugs and there was no
placebo-controlled withdrawal of medication. Finally,
treatment was provided by only one psychiatrist with
extensive experience in affective disorders and cognitive
behavior psychotherapy. The results might have been dif-
ferent with multiple, less experienced therapists. None-
theless, the study provides new, important clinical insight
regarding the treatment of recurrent, unipolar, major de-
pressive disorder because of the long follow-up and its
closeness to clinical practice.
Short-term cognitive behavior treatment after success-
ful antidepressant therapy had a substantial effect on the
rate of relapse after discontinuation of antidepressant
drugs. Patients who received such treatment reported a
substantially lower rate of relapse (40%) during the 6-year
follow-up than the patients assigned to clinical manage-
ment (90%). Such difference was significant, both in terms
of comparison of mean survival time and survival analysis.
This high relapse rate in the clinical management group is
in line with the findings of Frank et al. (7). Indeed, the abil-
ity of 10 sessions of psychotherapy to yield long-term ben-
efits (more than half of the patients had no relapse during
a 6-year period while being drug free) is impressive. Fur-
ther, the group treated with cognitive behavior treatment
had a significantly lower number of recurrences, when
multiple relapses were taken into account.
Cognitive behavior treatment was found to be effective
in decreasing the residual symptoms of depression (3, 9).
By deferring the psychotherapeutic intervention until af-
ter pharmacotherapy, we were able to provide a less in-
tense course of therapy than is customary (e.g., 16–20 ses-
sions) because psychotherapy could concentrate only on
the symptoms that did not abate after pharmacotherapy.
The fact that most of the residual symptoms of depression
are also prodromal and that prodromal symptoms of re-
lapse tend to mirror those of the initial episode provides
explanation for the protective effect of this targeted treat-
ment. Cognitive behavior treatment may act on those
residual symptoms of major depression that progress to
become prodromal symptoms of relapse (17). This may
particularly apply to anxiety and irritability, which are
prominent in the prodromal phase of depression, may be
covered by mood disturbances but are still present in the
acute phase, and are again a prominent feature of its resid-
ual phase (6). Indeed, substantial comorbidity concerned
with anxiety disorders was found in both groups (3). This
led us to explore the feasibility of clonazepam administra-
tion after the first relapse and to continue treatment with
it after the antidepressant drug was discontinued. The
mean survival time after introduction of clonazepam was
significantly longer than the one before the first relapse.
However, the noncontrolled nature of the intervention
hinders any conclusion.
This issue, however, is worthy of further research in view
of three lines of evidence. First, long-term treatment with
antidepressant drugs is not exempt from considerable
problems (18), in particular, the loss of clinical effect (19).
FIGURE 1. Proportion of Depressed Patients in Remission 6
Years After Cognitive Behavior Therapy (N=20) or Clinical
Management (N=20)
0 12 24 36 48 6072
Time From Baseline (months)
Proportion Still in Remission
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
Patients in clinical management
Patients in cognitive behavior therapy
0.9
1.0

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Indeed, also in our sample, there were instances of relapse
despite antidepressant drug continuation after the second
recurrence. The second line of evidence is based on the
fact that in anxiety disorders, treatment of phobic distur-
bances was found to entail beneficial effects on the inci-
dence of depression during long-term follow-up (20, 21).
Finally, coadministration of clonazepam and an SSRI was
found to significantly improve short-term outcome in ma-
jor depression (22, 23), and clonazepam alone has mood-
stabilizing effects (24). Intermittent use of antidepressant
medication, as endorsed by the protocol of this investiga-
tion, also presents some disadvantages (25), such as resis-
tance (when a patient, after a drug-free period, fails to re-
spond to an antidepressant drug that yielded remission in
a previous episode) (26), as was found to occur also in this
study.
Cognitive behavior treatment was not targeted to de-
creasing residual symptoms only. Two additional ingredi-
ents were added, in view of the clinical challenge repre-
sented by a patient population with recurrent depression.
One was defined as lifestyle modification. Clinical experi-
ence has suggested in fact that recovered depressed pa-
tients are often unaware of the long-term consequences of
a maladaptive lifestyle, which does not take chronic, mi-
nor life stress, interpersonal friction, excessive work (par-
ticularly in male professionals in their 40s) and inade-
quate rest into proper account. We postulated that both
the presence of subsyndromal psychiatric symptoms (6)
and chronic stress exposure may cause an allostatic load,
i.e., fluctuating and heightened neural or endocrine re-
sponses resulting from environmental challenge (27). Fur-
ther, it should also be noted that interventions that bring
the person out of negative functioning are one form of
success, but facilitating progression toward restoration of
the positive is quite another (28). Ryff and Singer (28) sug-
gested that the absence of well-being creates conditions of
vulnerability to possible future adversities. A specific well-
being-enhancing psychotherapeutic strategy (8) was the
third main ingredient of the cognitive behavior approach.
The study by Frank and colleagues (7, 29) alerted the cli-
nician to the need of providing maintenance therapies in
recurrent depression. Long-term, high-dose, antidepres-
sant drugs appeared to be the treatment of choice. This
preliminary investigation, using a similar patient popula-
tion and a comparable follow-up, and other similar investi-
gations (1, 2, 4, 5) would challenge such stance while con-
firming the unfavorable long-term outcome of patients not
receiving pharmacotherapy or psychotherapy. Long-term
maintenance drug treatment (7, 29) or psychotherapy (30)
may be necessary in several patients. However, a two-stage
(cognitive behavior treatment after pharmacotherapy), se-
quential intensive approach may considerably affect the
long-term outcome of patients with recurrent depression.
The cognitive behavior intervention provided in this report
was quite brief. It is conceivable, even though it has yet to
be tested, that even better results might have been ob-
tained with longer courses of cognitive behavior treat-
ment and if patients beginning to experience signs and
symptoms of relapse had received additional booster ses-
sions of therapy.
Received Jan. 22, 2003; revision received June 27, 2003; accepted
Nov. 23, 2003. From the Affective Disorders Program and Laboratory
of Experimental Psychotherapy, Department of Psychology, University
of Bologna; the Department of Psychiatry, State University of New
York at Buffalo, Buffalo, N.Y.; and the Department of Statistical Sci-
ences, University of Padova, Padova, Italy. Address reprint requests to
Dr. Fava, Department of Psychology, University of Bologna, viale Berti
Pichat 5, 40127 Bologna, Italy; giovanniandrea.fava@unibo.it (e-
mail).
Supported in part by grants from the Mental Health Evaluation
Project (Istituto Superiore di Sanità) and the Ministero dell’Università
e della Ricerca Scientifica e Tecnologica to Dr. Fava.
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