BRIEF REPORTS

Six-Year Outcome for Cognitive Behavioral Treatment

of Residual Symptoms in Major Depression

Giovanni A. Fava, M.D., Chiara Rafanelli, M.D., Silvana Grandi, M.D.,

Renzo Canestrari, M.D., and Murray A. Morphy, M.D.

Objective: The authors goal was to determine whether cognitive behavioral treatment
of residual symptoms of depression might have a significant effect on relapse rate. Method:
A 6-year follow-up assessment was conducted of 40 patients with primary major depres-
sive disorder who had been successfully treated with antidepressants and were randomly
assigned to either cognitive behavioral treatment of residual symptoms or standard clinical
management. Results: Ten of the patients (50%) in the cognitive behavioral treatment
group and 15 (75%) in the standard clinical management group relapsed. The difference
did not attain statistical significance. When multiple relapses were considered, patients in
the cognitive behavioral treatment group had a significantly lower number of depressive ep-
isodes than those in the standard clinical management group. Patients responded to the
same antidepressant drug used in the index episode; in two cases (4%), resistance oc-
curred. Conclusions: The protective effects of cognitive behavioral treatment that were ev-
ident at 4-year follow-up faded afterward. Cognitive behavioral treatment of residual symp-
toms, however, improved the long-term outcome of major depression in terms of total
number of episodes during the follow-up period.
(Am J Psychiatry 1998; 155:14431445)

T here is increasing awareness of the recurrent na-

ture of major depressive disorders (1). In a previous
METHOD

study (2), 40 patients with primary major depressive
disorder who had been successfully treated with anti-
depressant drugs were randomly assigned to either
cognitive behavioral treatment of residual symptoms
or standard clinical management. Cognitive behavioral
treatment resulted in a significantly lower rate of re-
lapse at 4-year follow-up than did clinical management
(35% versus 70%) (3).
The purpose of this study was to extend the follow-
up to 6 years, comparing the two groups also as to to-
tal number of episodes of major depression during the
follow-up period.
Received Oct. 17, 1997; revision received April 14, 1998; accepted
May 15, 1998. From the Department of Psychiatry, State Univer-
sity of New York at Buffalo; the VA Medical Center, Buffalo, N.Y.;
and the Affective Disorders Program and the Laboratory of Experi-
mental Psychotherapy, Department of Psychology, University of
Bologna. Address reprint requests to Dr. Fava, Department of Psy-
chology, University of Bologna, Viale Berti Pichat 5, 40127 Bolo-
gna, Italy.
Supported in part by a grant from the Mental Health Project, Isti-
tuto Superiore di Sanit, Rome.
Maria Zielezny, Ph.D., performed the statistical analysis.
The original protocol from which this study group was drawn
was detailed in our previous report (2). Forty consecutive depressed
outpatients who met the Research Diagnostic Criteria (RDC) (4) for
a primary major depressive disorder were treated for at least 3
months with full doses of antidepressant drugs. They were randomly
assigned to cognitive behavioral treatment of residual symptoms
(primarily anxiety and irritability) or clinical management. Anti-
depressant drugs were tapered and discontinued.
A clinical psychologist, who was blind to treatment assignment,
reassessed the 40 patients (20 in each group) every 6 months up to
72 months. Further treatment (psychotherapy, antidepressants, or
both) was not allowed during follow-up unless a relapse occurred.
Follow-up evaluations consisted of a brief update of clinical and
medical status, including any treatment contacts or use of medica-
tions. Relapse was defined as the occurrence of an RDC-defined ep-
isode of major depression. Written informed consent was obtained
after the procedures had been explained fully to the patients.
Patients were instructed to call during the follow-up period if any
depressive symptoms occurred. Since prodromal symptoms of re-
lapse often mirror those of the initial episode (5), patients were also
warned to look specifically for those symptoms. If patients presented
in a state of substantial clinical worsening, they were observed and
evaluated within a 7-day period by both the independent clinical
evaluator (C.R.) and the treating clinician (G.A.F.). Once a relapse
was ascertained by the consensus of both, patients were prescribed
the same antidepressant drug at the same dose as in the index epi-
sode. No patient received further cognitive behavioral treatment. All
patients who relapsed were treated for at least 3 months with full
doses of antidepressant drugs according to a standardized protocol
(6). Antidepressant drugs were again tapered, at the rate of 25 mg of

Am J Psychiatry 155:10, October 1998 1443

BRIEF REPORTS
FIGURE 1. Proportions of Depressed Patients Who Remained
in Remission 6 Years After Cognitive Behavioral Therapy or
Clinical Management for Residual Symptoms
amitriptyline or its equivalent every other week, and then were with-
drawn completely. Drug discontinuation was not feasible for one pa-
tient in the standard clinical management group. The patients rated
as better or much better according to Kellners global rating
scale of improvement (7) and those rated as in full remission (8) were
defined as responders.
Survival analysis (9) was used for time until relapse into major de-
pression. Six factors were investigated as possible predictors of out-
come: assignment to cognitive behavioral treatment or standard clin-
ical management, age, sex, duration of depressive episode, past
history of depression, and the number of residual symptoms regard-
less of treatment assignment after completion of the study. The Ka-
plan-Meier method was used for estimating survival curves. The log-
rank test was employed to compare any two survival distributions
for each of the six factors considered (9).
In addition, t test for independent data was used to compare the
number of depressive episodes during follow-up in the two treat-
ment groups. For all tests performed, the significance level was set at
0.05, two-tailed.
RESULTS
During the 6-year follow-up, 10 of the patients
(50%) in the cognitive behavioral treatment group and
15 (75%) in the standard clinical management group
relapsed. None of the risk factors examined attained
statistical significance by survival analysis. Only treat-
ment assignment (figure 1) was close to significance
(log-rank test, 2=3.45, df=1, p=0.06).
Of the 25 patients who relapsed, 16 did so more
than once during the 6-year follow-up. This included
the patient for whom discontinuation of antidepres-
sant drugs was not feasible. This 64-year-old woman,
who belonged to the standard clinical management
group, relapsed while on a regimen of desipramine,
150 mg/day. Increase of the dose to 250 mg (the high-
est she could tolerate) was unsuccessful. However, she
responded to fluoxetine, 40 mg/day, which she contin-
ued throughout the study with no further relapse. Pa-
tients in the cognitive behavioral treatment group had
a significantly lower number of new depressive epi-
sodes (mean=0.80; SD=0.95) than those in the stan-
dard clinical management group (mean=1.70, SD=
1444
1.30) (t=2.50, df=38, p<0.05); that is, multiple re-
lapses during follow-up were less frequent.
Excluding the patient who received continuation
treatment for part of the study period, there were 47
new occurrences of depression. In 45 of the cases, pa-
tients responded to the same treatment used in the in-
dex episode; in two cases (4%)both involving desip-
raminethis did not occur, despite further increases in
dose. For these two female patients (ages 48 and 44),
response occurred when they were switched to fluoxe-
tine (one patient) or amitriptyline (one patient). The
phenomena concerned with resistance that occurred in
these two patients did not take place in three other pa-
tients who relapsed and were treated again with desip-
ramine or in 12 patients rechallenged with amitrip-
tyline, in four with imipramine, and in three with
mianserin.
DISCUSSION
The 4-year follow-up disclosed that cognitive behav-
ioral treatment of residual symptoms of depression has
a substantial effect on relapse rate (3). Such a protec-
tive effect for the occurrence of a new depressive epi-
sode faded at 6-year follow-up. However, when multi-
ple relapses during the 6-year period were taken into
account, patients in the cognitive behavioral treatment
group had significantly fewer new episodes of depres-
sion than those in the clinical management group. The
results thus suggest that treatment of residual symp-
toms entails a significantly lower risk of relapse within
4 years from the index episode and is associated with
an overall more favorable course. The results provide
further support to the stage-oriented (10) model of
psychotherapy of depression (2). According to this
model, the psychotherapeutic intervention, which is
considerably different from commonly used ap-
proaches (2), is deferred until after pharmacotherapy.
The fact that most of the residual symptoms of depres-
sion are also prodromal (2) and that prodromal symp-
toms of relapse tend to mirror those of the initial epi-
sode (5) provides an explanation for the protective
effect of this targeted treatment. Cognitive behavioral
treatment may act on those residual symptoms of ma-
jor depression that progress to become prodromal
symptoms of relapse (11). The methodological limita-
tions of this preliminary investigation, such as the fact
that all treatment was carried out by one experienced
clinician and our patient group was carefully selected,
have been discussed in detail (2, 3).
Two treatment strategies (maintenance drug treat-
ment and intermittent use of medication with frequent
follow-ups and attention to prodromal symptoms)
have been outlined in recurrent depression (11). A po-
tential negative aspect of the latter strategy is con-
cerned with the issue of resistance: the possibility of
the patients illness becoming refractory to a previ-
ously effective treatment by its intermittent use (12,
13), as reported with lithium prophylaxis (12). Our re-
Am J Psychiatry 155:10, October 1998

sults indicate that resistance after rechallenge with a
drug that was previously successful also occurs with
antidepressant drugs, although only in a small percent-
age of instances (4%). Further, the possibility cannot
be excluded that the two patients in whom resistance
occurred were initially placebo responders (14) and
that after they experienced a relapse, their expectations
for a second medication trial might not have been as
high as for the initial treatment. Fading or tolerance to
ongoing antidepressant treatment, however, may also
occur (13) and indeed took place in one patient. The
large majority of patients displayed a satisfactory re-
sponse to drug therapy when a new episode of depres-
sion ensued. This confirms the advantages of early
treatment of a depressive episode and the value of edu-
cating patients to watch for prodromal symptoms of
relapse (11).
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Am J Psychiatry 155:10, October 1998
BRIEF REPORTS
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