Department of Psychosomatic and Behavioural Medicine, National Hospital, Oslo, Norway
Department of Psychiatry, Haukeland University Hospital, Bergen, Norway
Department of Neuroscience and Psychiatry, Ulleraaker University Hospital, Uppsala, Sweden
Life Insurance Companies Institute for Medical Statistics, Ullevaal University Hospital, Oslo, Norway
Department of Psychiatry, Huddinge University Hospital, Huddinge, Sweden
Elverum Medical Center, Elverum, Norway
Department of Child and Adolescent Psychiatry, Innherred Hospital, Levanger, Norway
Correspondence: Svein Blomhoff, Department of Psychosomatic and Behavioural Medicine, National Hospital, N-0027 Oslo, Norway
Declaration of interest Funding was obtained from Pfizer Inc.
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ABSTRACT |
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Aims To examine the efficacy of sertraline or exposure therapy, administered alone or in combination in this setting.
Method Study was of a randomised, double-blind design. Patients (n = 387) received sertraline 50-150 mg or placebo for 24 weeks. Patients were additionally randomised to exposure therapy or general medical care.
Results Sertraline-treated patients were significantly more improved
than non-sertraline-treated patients (2=12.53,
P<0.001; odds ratio=0.534; 95% Cl 0.347-0.835). No significant
difference was observed between exposure- and non-exposure-treated patients
(
2=2.18, P=0.140; odds ratio=0.732; 95% Cl
0.475-1.134). In the pairwise comparisons, combined sertraline and exposure
(
2=12.32; P<0.001) and sertraline
(
2=10.13; P=0.002) were significantly superior to
placebo.
Conclusions Sertraline is an effective treatment for generalised social phobia. Combined treatment with sertraline and exposure therapy, conducted by the general practitioner, may enhance the treatment efficacy in primary care.
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INTRODUCTION |
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METHOD |
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Training of investigators
Fifty physicians were included in a 30-hour training programme over three
weekends. All participants were trained in DSMIV criteria and
MINIR interviewing to identify GSP and comorbid disorders through
lectures, videotapes and group supervision. The training is described in more
detail elsewhere (Haug et al,
2000). Exposure therapy training, a videotape demonstrating an
eight-session exposure therapy programme and a manual were given to all
investigators. Additionally, exposure therapy supervision was offered in local
groups throughout the study.
The physicians were trained in rating of the CGISP severity scale. Consensus ratings between five trained psychiatrists/ psychologists and one general practitioner of five videotaped patient interviews were defined as the gold-standard severity rating. Based on a minimum of 12 videotaped patient interviews, the intraclass correlation (ICC 1,1) as a measure of interrater reliability of at least 0.70 compared with the gold standard on the CGISP overall severity sub-scale was required (Friis & Sundsvold, 1987). Forty-five physicians (mean ICC 1,1=0.78, range 0.70-0.91) met this requirement. After repeated training two physicians treating a total of 12 patients did not reach the goal (ICC 1,1=0.62 and 0.65, respectively). However, since their patients already were randomised they were included in the intent-to-treat population. Three physicians withdrew during the training period.
The group of investigators constituted 12 females and 35 men with a median age of 49 (range 32-64) years. All had private clinical practice as their main occupation, with a median of 16 (range 3-33) years in this position. Two were private practising psychiatrists, 28 specialists in family medicine, the others non-specialist primary care physicians. The median time in clinical work was 40 (range 10-60) hours/week, and physicians treated a median of 93 (range 15-200) patients weekly. The physicians were not informed of the exposure therapy component in the study design during the process to recruit investigators, but learned about this additional element prior to entering the training programme.
Recruitment and assignment
Patients were consecutively recruited from subjects seeking medical
consultations with one of the 47 participating physicians located at 41
different private primary care centres in Norway or Sweden. To recruit
potential patients for the study, a form listing DSMIV criteria for
generalised social phobia and informing about the ongoing trial was
distributed in the waiting room of all investigators. Based on the response to
the form and the symptoms presented in the consultation, 289 primary care
patients were included in the screening process (see
Fig. 1). Eighteen investigators
additionally screened 159 patients recruited through newspaper or other media
advertisements.
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Three hundred and eighty-seven patients were randomly assigned by a computer to receive double-blind sertraline or placebo in blocks of eight subjects so that four patients in each block were randomised to each of the treatments. No other stratification factors were used. Each block was assigned to a specific general practitioner. In both the sertraline and placebo groups half of the patients were randomly allocated to exposure or general medical care. A separate randomisation list was made for exposure or non-exposure treatment. Sealed envelopes of allocations from this list were kept by the investigators and opened after the inclusion of the patient into the study. During this procedure equal numbers of subjects were assigned to each treatment option in each block. Tablets were packaged and numbered by the sponsor and personally delivered to each investigator.
Patient characteristics
Two hundred and thirty-four females and 153 males (mean age of 40.4 years
(s.d.=10.4)) comprised the study population. Two hundred and fifty-eight (67%)
were married or living with a partner. The median age at symptom onset was 13
years (range 3-48 years), duration of illness 23.6 years (s.d.=12.2). A
comorbid psychiatric disorder was diagnosed in 135 (35%) patients: 101 (26%)
phobic anxiety disorder, six (2%) panic disorder, six (2%) dysthymia and 13
(3%) other diagnoses.
The mean physician-rated CGISP disease severity was 5.0 (s.d.=0.9)
on the subscale for anxiety attacks, 4.9 (s.d.=0.9) for avoidance, 4.8
(s.d.=0.8) for performance anxiety, 4.7 (s.d.=0.8) for disability and 4.7
(s.d.=0.7) for overall severity. The mean patient-rated severity as assessed
by the Social Phobia Scale (SPS, range 20-100;
Mattick & Clarke, 1998)
was 54.0 (s.d.=16.2). The mean level of depression at baseline as rated with
the Montgomersberg Depression Rating
Scale (MADRS, range 0-60; Montgomery &
sberg, 1979) was 7.3
(s.d.=4.9).
Design and medication
All patients were scheduled for nine visits with the investigator during
the first 16 weeks of treatment and a final efficacy visit after 24 weeks. For
ethical reasons, all patients rated as not improved (CGISP overall
improvement 4) according to the protocol criteria at the Week 16 visit
completed the final study assessment at this time and were withdrawn from the
study. All patients received general medical care according to the National
Institute of Mental Health (NIMH) study guidelines for clinical management of
mood disorders (Fawcett et al,
1987). These guidelines recommend the physician to give general
therapeutic support, reassurance and encouragement. The physician should give
information and simple advice and permit the patient to ventilate fears and
doubts. Specific behavioural instructions or psychological interpretations are
not allowed.
Following a 1-week single-blind placebo period to identify fast placebo
responders all subjects received either one tablet of sertraline 50 mg or
placebo once daily. If the CGISP overall improvement score was not
rated at least minimally improved (3) after 4 weeks of treatment, the dose
was increased to two tablets of sertraline (100 mg daily) or placebo. Further
dose escalations were allowed after 8 and 12 weeks to a maximum dose of 150
mg. In the absence of tolerability problems requiring dose reduction, the dose
level achieved after 12 weeks of treatment was maintained for the remainder of
the study. Adherence to treatment was assessed by returned-tablet counts and
serum level assessments of sertraline and its metabolite
desmethylsertraline.
Exposure therapy
Instructions for exposure therapy were given in eight sessions during the
first 12 weeks of treatment, each with an estimated duration of 15-20 minutes.
Further encouragement and advice were given at the Week 16 visit. A
description of the exposure therapy is published in more detail elsewhere
(Haug et al, 2000).
Briefly, in the first session patients were informed of the rationale for
treatment and the main problem areas were identified. In the next session
agreement was made about homework assignments, and the use of a
symptommonitoring diary during exposure training was explained. In the
remaining sessions, the patients were instructed to gradually expose
themselves to feared situations, and thus learn new coping strategies. They
were told to stay as long as they could in the phobic situation, ideally until
the anxiety decreased. All patients received homework between the sessions and
brought a report of the training with them to the next session. The patients
were told to continue the exposure therapy according to the individually
designed treatment programme in the last 12 weeks of the study. The physician
helped the patients to identify goals and new coping strategies and supported
them in the self-exposure training.
Primary efficacy measures
The patients were defined as responders, partial responders or
non-responders based on assessments on the investigator-rated CGISP and
the patient-rated SPS. Investigators made intermediate efficacy ratings after
4, 8, 12 and 16 weeks, and final efficacy assessment after 24 weeks of
treatment.
Response was defined as a reduction of at least 50% on SPS-assessed symptom
burden compared with baseline, a CGISP overall severity score at the
final visit in the no mental illness to mild
severity range (3), and a CGISP overall improvement score of
very much or much improved (
2). Non-response was defined as less than 25%
reduction on SPS compared with baseline, or CGISP overall improvement
rating of no change or worse (
4). Partial response was defined as all
responses between the criteria for response and non-response.
Secondary efficacy measures
The Brief Social Phobia Scale (BSPS;
Davidson et al, 1991),
the social phobia sub-scale of the Marks Fear Questionnaire
(Marks & Mathews, 1997),
Fear of Negative Evaluation Scale (Watson
& Friend, 1969), Sheehan Disability Inventory
(Leon et al, 1992),
and the mental health subscale of the MOS 36 Short-Form Health Survey
(SF36; McHorney et al,
1993) were employed as secondary efficacy measures.
Statistical procedures
The SAS version 6.12 (SAS Institute,
1997) was employed in all analyses. All efficacy analyses were on
the intent-to-treat patient population. This population was defined as those
who received at least one dose of medication and with at least one
post-baseline efficacy evaluation. 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 at least 340 patients to detect
a significant difference, if ß=0.10 and the drop-out rate 35%. This
procedure made the study primarily powered for the sertraline v.
non-sertraline and exposure v. non-exposure analyses, but it also
allowed pairwise comparisons between the specific groups. In these analyses,
however, the power was reduced and the risk of false-negative results
consequently increased. Data are reported as mean values, and 95% CIs are
reported when appropriate. Ordinal logistic regression analyses were employed
in the response analyses.
Multiple ordinal logistic regressions were also used to identify any statistical interactions between treatment groups on response. This was done by comparing models with and without interaction terms (drug treatment x exposure therapy) by like-lihood ratio tests. To fully utilise the power of the 2 x 2 factorial design, the specified strategy of analysis required that in case of no such interaction the main effects of sertraline should be tested by pooling exposed and non-exposed patients, and vice versa, with respect to the main effects of exposure therapy. Significant differences were followed up with pairwise comparisons.
In the time-point analyses the groups were compared with respect to response at each point in time. Differences in change from baseline scores on the continuous efficacy scales between all four groups were examined by parametric analyses of variance. Baseline scores and country were used as covariates.
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RESULTS |
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Analysis of response
In individual analyses, no interaction was observed between response and
each of the variables gender, age, country, recruitment method, medication or
exposure therapy. There was no indication of better outcome in patients
treated by the psychiatrists than by the other participating physicians.
Significantly more sertraline-treated patients than non-sertraline-treated patients (P=0.001) responded (Table 1). No significant difference between exposure- and non-exposure-treated patients was observed (P=0.140). Combined sertraline and exposure (40/88 response, 21/88 partial response; P<0.001) and sertraline alone (35/87 response, 25/87 partial response; P=0.002) were significantly superior to placebo (21/88 response, 18/88 partial response). Trends towards increased efficacy of exposure alone compared with placebo (30/91 response, 22/91 partial response; P=0.083) and combined sertraline and exposure compared with exposure alone (P=0.059) were additionally observed.
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Although the MADRS score at baseline was in the normal range in the sample as a whole (7.3, s.d.=4.9), a significant reduction (mean change 2.9, 95% CI 2.4-3.5) was observed during treatment. No significant interaction between MADRS-assessed level of depression and response was observed (P=0.67).
Time-point analysis
Significantly more patients in the combined sertraline and exposure group
fulfilled the response criteria compared with placebo from Week 12 and in all
further assessments (see Fig.
2). Sertraline alone was significantly superior to placebo at the
final visit in this analysis.
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Patients in all active treatment groups were significantly more improved (partial response or response) than placebo-treated patients at the Week 12 visit (see Fig. 3). However, only the sertraline groups remained significantly superior to placebo at the Week 16 and Week 24 visits. No significant difference between the active treatment groups appeared in any of the analyses.
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Psychometric scales
On the primary efficacy variables, subjects in the combined sertraline and
exposure group were significantly more improved than placebo-treated subjects
on all CGISP sub-scales, with the exception of CGISP
severity-assessed performance anxiety (see
Table 2). None of the
treatments was significantly better than placebo on this subscale. In those
receiving sertraline alone, borderline significances were observed on
CGISP severity-assessed anxiety attacks and overall severity, as well
as on CGISP improvement-assessed avoidance and SPS total score. No
significant differences between exposure alone and placebo were found on any
of the primary efficacy variables.
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In the Bonferroni-adjusted analyses of the adjusted secondary efficacy scales, combined sertraline and exposure treatment was significantly superior to placebo on five out of nine assessments, sertraline alone on four assessments and exposure alone on two assessments (see Table 3).
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Adverse experiences
Nausea (61/196 v. 27/191; 2=9.75,
P=0.002), malaise (37/196 v. 17/191;
2=5.26,
P=0.022) and sexual dysfunctions (14/196 v. 1/191;
2=9.78, P=0.002) were observed significantly more
frequently in sertraline than non-sertraline treatment groups. The nausea and
malaise were generally mild and occurred most frequently during the first
weeks of treatment. No unusual adverse experiences were reported.
Dosage
In the sertraline groups the mean dose level at Week 16, before the
non-responders were excluded from the study, was 98.6 (87.5, 109.7) mg daily
in the response group, 131.6 (121.2, 142.0) mg in the partial responder group
and 140.2 (131.4, 149.0) mg in the non-responder group. In the placebo group,
the mean dose was 2.5 (0.0, 3.9) tablets daily.
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DISCUSSION |
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The high response we found in the placebo group is probably in part explained by the study design. General medical care is not equivalent to no treatment, particularly in a 24-week study comprising 10 sessions with a physician. It is also possible that the physicians, all freshly trained in exposure therapy, may have included some information and encouragement with respect to self-exposure in their general medical care.
Exposure therapy in primary care
This study is the first to assess the efficacy of a behavioural treatment
intervention performed by primary care physicians for an anxiety disorder. The
exposure therapy proved easy to learn and appeared suitable for use in general
practice. The behavioural intervention seemed to be comparable in efficacy
with that seen in exposure therapy studies in specialist settings
(van Dyck, 1996). A trend
towards significance between exposure alone and placebo was observed in the
final efficacy evaluation. Time-point improvement analyses (see
Fig. 3) revealed that exposure
was superior to placebo at the end of the physician-assisted exposure training
(i.e. after 12 weeks) and that most exposure therapy patients that were
improved (i.e. partial response or response) at the final visit also were
improved at the Week 12 assessment. Only marginal symptom improvement was seen
during the self-training period in non-responders at the Week 12 assessment,
but the number of patients that fulfilled the criteria for response increased.
The study design presupposed that the patients would learn the principles of
graded exposure and continue the training on their own. Although patients were
encouraged to continue to practise and were given an additional exposure
session at the Week 16 visit, we do not know that the exposure patients
actually performed the training. It is thus possible that if
physician-administered exposure therapy had been continued throughout the
study, the statistical efficacy of exposure therapy at the final efficacy
evaluation might have been enhanced.
Sertraline in the primary care treatment of GSP
This study demonstrated that sertraline, both alone and combined with
exposure therapy, is effective and well tolerated in the treatment of
generalised social phobia carried out in primary care. Other pharmacological
treatments, such as irreversible monoamine oxidase inhibitors (MAOI)
(Liebowitz et al,
1992; Heimberg et al,
1998) and benzodiazepines
(Davidson et al, 1993)
have primarily shown efficacy in GSP treatment in psychiatric out-patients.
However, tolerability and safety problems such as dietary restrictions and
dependence limit the use of these drugs. It is possible that sertraline
(van Ameringen et al,
1994), as well as other selective serotonin reuptake inhibitors
that have shown efficacy in GSP treatment
(Baldwin et al, 1999;
Stein et al, 1999)
may be more acceptable drugs in primary care settings, owing to their milder
side-effect profiles.
What treatment should be used in primary care?
The study suggested an enhanced efficacy of combined sertraline and
exposure treatment, primarily through increasing the number of patients who
achieved response. Since we did not find any statistical interaction between
sertraline and exposure therapy, the finding most probably must be interpreted
as the result of additive treatment effects, as also suggested in treatment
studies in anxiety disorders performed in other health care settings
(Gelder, 1998;
Lader & Bond, 1998;
O'Connor et al,
1999). If our findings are confirmed in further research, it may
be argued that good primary care treatment should include a brief structured
behavioural intervention such as exposure therapy as an adjuvant to drug
treatment.
Some primary care physicians might argue that even this brief behavioural intervention is too time-consuming to be acceptable in their practice. However, patients with GSP are long-term patients requiring considerable use of time in primary care. A combined treatment programme that includes eight sessions of 15-20 minutes' duration may be acceptable with respect to the use of time. A trial of exposure therapy may be relevant in patients not suited to pharmacological treatment, or who do not fully respond to drug treatment. The combination of sertraline and exposure therapy seems to be particularly effective, mainly by increasing the number of patients reaching response, and may constitute the treatment of choice in primary care.
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Clinical Implications and Limitations |
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LIMITATIONS
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ACKNOWLEDGMENTS |
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We thank F. Bendiksen, K. A. Moe, K. Lagermalm, M. Groensleth, T. Smedsrud, A. Sjoeberg, W. L. Andersen, T. Stamnes at Pfizer, Norway and Sweden for giving practical and administrative support. We also thank U. F. Malt for giving scientific advice.
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Received for publication July 3, 2000. Revision received February 5, 2001. Accepted for publication February 8, 2001.