Haukeland University Hospital, Bergen
National Hospital, Oslo, Norway
Ulleråker University Hospital, Uppsala, Sweden
Ullevål University Hospital, Norway
Huddinge University Hospital, Sweden
Elverum Medical Center, Elverum
Innherred Hospital, Levanger, Norway
Correspondence: Tone Tangen Haug, Haukeland University Hospital, 0021 Bergen, Norway
Declaration of interest Funding was provided by Pfizer, Inc.
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ABSTRACT |
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Aims To examine the effect of exposure therapy and sertraline 28 weeks after cessation of medical treatment.
Method In this study 375 patients with social phobia were randomised to treatment with sertraline or placebo for 24 weeks, with or without the addition of exposure therapy. Fifty-two weeks after inclusion, 328 patients were evaluated by the same psychometric tests as at baseline and the end of treatment (24 weeks).
Results The exposure therapy group and the placebo group had a further improvement in scores on social phobia during follow-up: mean change in the Clinical Global Impression Social Phobia overall severity score was 0.45 (95% CI 0.16-0.65, P < 0.01) for the exposure group, and 0.25 (95% CI 0.00-0.48, P < 0.05) for the placebo group. At week 52 the sertraline plus exposure group and the sertraline-alone group had a significant deterioration on the 36-item Short Form Health Survey compared with exposure alone.
Conclusions Exposure therapy alone yielded a further improvement during follow-up, whereas exposure therapy combined with sertraline and sertraline alone showed a tendency towards deterioration after the completion of treatment.
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INTRODUCTION |
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In this study we examine the effect on generalised social phobia of 24 weeks of treatment with sertraline, with or without the addition of exposure therapy, 1 year after the start of treatment.
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METHOD |
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All patients were scheduled for nine meetings with the investigator during
the first 16 weeks of treatment and a final efficacy assessment after 24
weeks. The patients were randomised to four treatment groups and treated by
general practitioners for 24 weeks with sertraline or a pill placebo, combined
with 12 weeks of exposure therapy or of only general medical care. Exposure
therapy was given in eight sessions for the first 12 weeks of treatment. Each
of the sessions had an estimated duration of 15-20 min. In the first sessions,
main problem areas were identified and agreement was reached about homework
assignments. In the remaining sessions, the patients were instructed to
gradually expose themselves to feared situations, and to keep exposure
homework diaries. Details of the exposure therapy have been published
elsewhere (Haug et al,
2000). At week 24, patients treated with sertraline were
significantly more improved than those who did not receive sertraline
(2=12.53, P < 0.001; OR=0.534, 95% CI
0.347-0.835). No significant difference was observed between those who
received exposure therapy and those who did not (
2=2.18,
P=0.140; OR=0.732, 95% CI 0.475-1.134). In the pairwise comparisons,
combined sertraline and exposure (
2=12.32, P <
0.001) and sertraline alone (
2=10.13, P=0.002) were
significantly superior to placebo. Trends towards increased efficacy of
exposure alone compared with placebo (P=0.083) and combined
sertraline and exposure compared with exposure alone (P=0.059) were
also observed. More-detailed results have been presented in an earlier paper
(Blomhoff et al,
2001). One year after inclusion, all patients were asked to
participate in a follow-up assessment (week 52). Those who had not improved
satisfactorily at the end of week 24 could be offered further treatment during
the follow-up period either psychological treatment or medication, as
decided by the clinical judgement of the general practitioner. At week 52 the
participants attended an interview and filled in the same questionnaires used
for assessment at base-line and at the completion of therapy (24 weeks).
Instruments
The Mini International Neuropsychiatric Interview (MINIR;
Sheehan et al, 1994)
was used to assess DSMIV psychiatric diagnoses. The Clinical Global
Impression Severity Scale (CGISP; Liebowitz, 1992) the Social Phobia
Scale (SPS; Mattick & Clark, 1998), the Fear of Negative Evaluation (FNE)
scale (Watson & Friend,
1969) and the Marks Fear Questionnaire (MFQ,
Marks & Matthews, 1979)
assessed the degree of social phobia. The Sheehan Disability Inventory (SDI;
Leon et al, 1992) and
the mental health sub-scale of the MOS 36-item Short Form Health Survey
(SF36; McHorney et al,
1993) assessed daily functioning. The
MontgomeryÅsberg Depression Rating Scale (MADRS;
Montgomery & Åsberg,
1979) assessed degree of depression. Patients were also asked
about their employment, sick leave and medical symptoms during the preceding
year.
Statistical procedures
The program SAS version 6.12 for Windows
(SAS Institute, 1997) was
employed in all analyses. All efficacy analyses were on the intention-to-treat
patient population: this population was defined as those who received at least
one dose of medication and at least one efficacy evaluation post-baseline. All
statistical tests were two-tailed with =0.05. Sample size calculation
was based on an estimated 20% difference between active drug and placebo. This
required a sample size of at least 340 patients to detect a significant
difference if ß=0.10 and the drop-out rate is 35%. This procedure made
the study primarily powered for analyses of sertraline v.
non-sertraline and exposure v. non-exposure, but allowed also
pairwise comparisons between the treatment groups. In the latter analyses,
however, the power was reduced and the risk of false-negative results
increased. Repeated-measures analysis of covariance for each scale measurement
at 24 weeks and 52 weeks was done to test differences between treatment groups
globally, adjusted for baseline values at week 0. Multiple ordinal logistic
regression was also used to identify any statistical interaction between
treatment groups on response. Pairwise comparisons for changes from week 24 to
week 52, adjusted for baseline, were made between each of the three
active-treatment groups and the placebo-only group. At each time point (24
weeks and 52 weeks) in the time point analyses all groups were compared
pairwise, with Bonferroni P-value adjustments for each scale
analysed.
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RESULTS |
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Changes in psychometric scores from baseline to week 52
All four study groups had a significant reduction in scores on CGISP
(all sub-scales), SPS, Brief Social Phobia Scale (all sub-scales;
Davidson et al, 1991),
MFQ and FNE (P<0.001) from baseline to week 52. There were also
significant reductions in MADRS score and in scores on the SDI and
SF36.
Changes in psychometric scores from week 24 to week 52
Participants who had been treated with exposure alone had a significant
improvement in scores on the CGISP overall severity sub-scale (mean
change 0.45, 95% CI 0.16-0.65, P<0.01) and disability sub-scale
(mean change 0.32, 95% CI 0.06-0.52, P<0.01), and on the SPS (mean
change 3.86, 95% CI 1.27-5.64, P<0.01) during follow-up. The
placebo-only group also had a significant improvement on the CGISP
overall severity sub-scale (mean change 0.25, 95% CI 0.00-0.48,
P<0.05), disability sub-scale (mean change 0.32, 95% CI 0.08-0.53,
P<0.01) and performance sub-scales (mean change 0.36, 95% CI
0.05-0.56, P<0.05). For the sertraline plus exposure and the
sertraline-alone groups there was a slight deterioration in scores on most of
the CGI sub-scales and on SPS, but the changes were not significant
(Table 1,
Fig. 2).
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The exposure-alone group had also a significant improvement on the fear and avoidance sub-scales of the Brief Social Phobia Scale (mean changes 1.01, 95% CI 0.06-1.96, P<0.05, and 1.07, 95% CI 0.01-2.14, P<0.05, respectively), MFQ (mean change 3.46, 95% CI 1.27-5.64, P<0.01), FNE (mean change 2.36, 95% CI 0.97-3.77, P<0.01) and SF36 (mean change 1.34, 95% CI 0.89-1.85, P<0.01) between week 24 and week 52. The placebo-only group had a significant improvement on the Brief Social Phobia Scale fear sub-scale (mean change 1.01, 95% CI 0.03-2.00, P<0.05), MFQ (mean change 3.48, 95% CI 1.12-5.83, P<0.01), FNE (mean change 1.29, 95% CI 0.92-2.65, P<0.05), SDI work sub-scale (mean change 1.07, 95% CI 0.44-1.69, P<0.01), SDI social sub-scale (mean change 0.91, 95% CI 0.27-1.54, P<0.05) and the SF36 (mean change 1.51, 95% CI 1.01-2.45, P<0.01). For the sertraline plus exposure and the sertraline-alone groups there was a deterioration in scores on SF36 between week 24 and week 52 (mean change -0.89, 95% CI -1.35 to 1.34, P<0.05; -1.40, 95% CI -1.90 to 1.92, P<0.01, respectively). Other changes were not significant (Table 2, Figs 3 and 4).
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Compared with the placebo group, the sertraline-alone group were found to have a significant deterioration on the CGISP performance anxiety sub-scale (mean difference in change 0.54, 95% CI 0.13-0.96, P=0.05), MFQ (mean difference in change 4.84, 95% CI 0.95-8.74, P=0.01), FNE (mean difference in change 2.34, 95% CI 0.15-4.54, P=0.03) and SF36 (mean difference in change -2.92, 95% CI -4.67 to -1.17, P<0.01). There was also a significant deterioration in sertraline compared with exposure on MFQ (mean difference in change 4.10, 95% CI 0.17-8.03, P=0.03), FNE (mean difference in change 3.00, 95% CI 0.78-5.22, P<0.01) and SF36 (mean difference in change -2.74, 95% CI -4.51 to -0.97, P<0.01). The sertraline plus exposure group had a significant deterioration in SF36 compared with both exposure-alone and placebo (mean difference in change -2.22, 95% CI -4.02 to -0.43, P=0.01, and -2.40, 95% CI -4.17 to -0.63, P<0.01, respectively). Changes in sertraline plus exposure compared with sertraline alone and in exposure alone compared with placebo were non-significant (Tables 3 and 4, Figs 3 and 4).
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The sertraline plus exposure group had a significant deterioration in MADRS score (P<0.01) between week 24 and week 52. The changes in the other treatment groups were not significant.
Treatment during the follow-up period
Sixty-six patients (20.5%) were treated with selective serotonin reuptake
inhibitors (SSRIs): 13 (15.5%) in the combined sertraline plus exposure group,
18 (21.6%) in the sertraline-alone group, 14 (19.2%) in the exposure group and
21 (19.5%) in the placebo group. Twenty-seven patients (7.6%) were offered
exposure therapy by their general practitioner during the follow-up period,
and 26 patients (7.0%) had been referred to a psychologist or
psychiatrist.
Psychiatric diagnoses at week 52
A total of 19 patients (5.7%) had a major depression according to
DSMIV at week 52. Ten of these patients were in the group who had
received the combined sertraline and exposure therapy, 2 had received
sertraline alone, 4 had received exposure alone and 3 were in the placebo
group.
Employment records
At the week 52 assessment 223 patients were employed and 33 were students.
About a third (32%) of the patients were on sick leave the year preceding
baseline; less than a quarter (23%) were on sick leave the year preceding
follow-up. There was also a slight reduction in mean days of sick leave: 15.8
days in the year preceding baseline and 13.0 days in the year preceding
follow-up.
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DISCUSSION |
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Maintenance of treatment effect
All four treatment groups had a significant improvement from baseline to
week 52 on all the psychometric assessments. Patients who had been given
exposure therapy or placebo had a further improvement in social phobia after
the end of the treatment period, whereas patients who had been treated with
sertraline either alone or in combination with exposure therapy
had no further improvement during the follow-up period and there was a
tendency towards deterioration. However, the deterioration was significant
only for the score on SF-36 (Table
2). At week 52 the participants in both the sertraline-alone and
the combined sertraline plus exposure groups had a significant deterioration
compared with patients in the exposure-alone and placebo groups. These results
are in accordance with the study by Liebowitz et al
(1999), who concluded that
cognitivebehavioural group therapy and phenelzine differed in their
long-term effects, with a more favourable outcome for the group therapy. They
also accord with the findings by Marks et al
(1993), in a multi-centre
study of alprazolam and exposure therapy in panic disorder, that gains after
alprazolam were lost during follow-up, whereas gains after exposure were
maintained. Combining alprazolam with exposure marginally enhanced gains
during treatment, but impaired improvement thereafter. Barlow et al
(2000), in a study of
imipramine and cognitivebehavioural therapy in the treatment of panic,
reported similar results. From this we can conclude that exposure techniques
applied in situations with low levels of anxiety achieved by medication may
have less impact than exposure therapy applied in situations with a higher
level of anxiety, and may lead to a higher degree of relapse after end of
treatment. During the follow-up period about a fifth of the patients were
treated with SSRIs, 25 (7.5%) were given exposure therapy by their general
practitioner and 23 (7.0%) were referred to psychiatrists or psychologists.
The treatment was initiated at the discretion of the general practitioners, so
we lack information about whether the treatment was given because of
insufficient improvement at week 24 or because of relapse. However, this
additional treatment might have contributed to the maintenance of treatment
effect during the follow-up period.
General effects
A substantial proportion of the patients improved regardless of the
treatment given, and even in the placebo-alone group only about a fifth of the
patients were in need of additional treatment during the follow-up period. The
fact that social phobia was focused on as a problem, combined with regular
contact with a general practitioner in a total of 11 sessions over 24 weeks,
seemed to be sufficient treatment for many patients.
Methodological considerations
The general practitioners evaluated their own patients at both week 24 and
week 52. This lack of masking may represent a potential bias. Since many of
these doctors worked in single-handed practices, it was difficult to obtain
masked efficacy measures. However, scores on social phobia were achieved both
on investigator-rated CGISP overall severity and on patient-rated
SPS.
To evaluate the specific effects of exposure therapy and sertraline, a waiting-list control group could have been useful. In addition, this study does not inform us of follow-up periods longer than 28 weeks. There was no systematic registration of relapses during follow-up and the physicians initiated additional treatment based on their own clinical judgement. This limits our possibility to draw firm conclusions about maintenance therapy and relapse prevention. However, the study was naturalistic and was conducted in general practice, where most patients with social phobia will have their treatment. The study also had a large sample size, which strengthens the statistical power.
Which treatment should be chosen for social phobia?
Exposure therapy, sertraline and the combination of sertraline and exposure
therapy are all effective treatments for social phobia. Sertraline and the
combination of sertraline and exposure seemed to have a short-term advantage,
but gains were reduced during follow-up. For exposure therapy alone there
seemed to be a further improvement after the end of active treatment, and
there are indications that exposure therapy alone is more effective in the
long term than exposure in combination with sertraline treatment. For some
patients, just being in regular contact with a general practitioner focusing
on social phobia as a problem is effective.
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Clinical Implications and Limitations |
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LIMITATIONS
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Received for publication April 24, 2002. Revision received August 15, 2002. Accepted for publication October 23, 2002.
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