Accepted Manuscript Effectiveness and cost-effectiveness of individually tailored Internet-delivered cognitive behavior therapy for anxiety disorders in a primary care population: A randomized controlled trial Lise Bergman Nordgren , Erik Hedman , Julie Etienne , Jessica Bodin , Åsa Kadowaki , Stina Eriksson , Emelie Lindkvist , Gerhard Andersson , Per Carlbring PII:

S0005-7967(14)00076-X

DOI:

10.1016/j.brat.2014.05.007

Reference:

BRT 2718

To appear in:

Behaviour Research and Therapy

Received Date: 25 June 2013 Revised Date:

19 April 2014

Accepted Date: 21 May 2014

Please cite this article as: Nordgren, L.B., Hedman, E., Etienne, J., Bodin, J., Kadowaki, Å., Eriksson, S., Lindkvist, E., Andersson, G., Carlbring, P., Effectiveness and cost-effectiveness of individually tailored Internet-delivered cognitive behavior therapy for anxiety disorders in a primary care population: A randomized controlled trial, Behaviour Research and Therapy (2014), doi: 10.1016/j.brat.2014.05.007. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT Effectiveness and cost-effectiveness of individually tailored Internet-delivered cognitive behavior therapy for anxiety disorders in a primary care population: A randomized controlled trial Lise Bergman Nordgren,1 Erik Hedman,2,3 Julie Etienne,1 Jessica Bodin,1 Åsa Kadowaki,4

1

RI PT

Stina Eriksson,5 Emelie Lindkvist,5 Gerhard Andersson,1,2 Per Carlbring6

Department of Behavioural Sciences and Learning, Linköping University,

2

SC

581 83 Linköping, Sweden

Department of Clinical Neuroscience, Psychiatry Section, Karolinska Institutet,

3

M AN U

171 77 Stockholm, Sweden

Department of Clinical Neuroscience, Osher Center for Integrative Medicine, Karolinska Institutet, 171 77 Stockholm, Sweden

County council of Östergötland, 581 91 Linköping, Sweden

5

Department of Psychology, Umeå University, 901 87 Umeå, Sweden

6

Department of Psychology, Stockholm University, 106 91 Stockholm, Sweden

Corresponding author:

EP

Lise Bergman Nordgren

TE D

4

Department of Behavioural Sciences and Learning, Linköping University, SE-581 83

AC C

Linköping, Sweden.

Telephone: +46 13 28 20 37 E-mail: [email protected]

ACCEPTED MANUSCRIPT Abstract A significant proportion of the general population suffers from anxiety disorders, often with comorbid psychiatric conditions. Internet-delivered cognitive behavior therapy (ICBT) has

RI PT

been found to be a potent treatment for patients with specific psychiatric conditions. The aim of this trial was to investigate the effectiveness and cost-effectiveness of ICBT when tailoring the treatment to address comorbidities and preferences for primary-care patients with a

principal anxiety disorder. One hundred participants were recruited through their primary-care

SC

contact and randomized to either treatment or an active control group. The treatment consisted

M AN U

of 7–10 weekly individually assigned modules guided by online therapists. At post-treatment, 46% of the treatment group had achieved clinically significant improvement on the primary outcome measure (CORE-OM) and between-group effect sizes ranged from d = 0.20 to 0.86, with a mean effect of d = 0.59. At one-year follow-up, within-group effect sizes varied between d = 0.53 to 1.00. Cost analysis showed significant reduction of total costs for the

TE D

ICBT group, the results were maintained at one-year follow-up and the incremental costeffectiveness ratio favored ICBT compared to control group. Individually tailored ICBT is an

EP

effective and cost-effective treatment for primary-care patients with anxiety disorders with or without comorbidities.

AC C

Key words: Primary care, anxiety, depression, comorbidity, Internet-administered cognitive behaviour therapy, cognitive behavior therapy, cost-effectiveness Trial registration: Clinicaltrials.gov: NCT01390168

1

ACCEPTED MANUSCRIPT Background In Europe, anxiety disorders have an estimated 12-month prevalence of nearly 14 percent (Alonso et al., 2004b; Wittchen et al., 2011). Comorbidity across different anxiety and mood

RI PT

disorders is high in the general population (Alonso et al., 2004a) and the occurrence of an additional Axis-I diagnosis is even higher in individuals seeking treatment for their anxiety in primary care centers for treatment of stress, anxiety and related disorders (Brown, Campbell, Lehman, Grisham, & Mancill, 2001). The most common comorbid disorder for individuals

SC

with one anxiety disorder is a mood disorder or another anxiety disorder. All of these

M AN U

conditions are associated with reduced quality of life (Mendlowicz & Stein, 2000; Olatunji, Cisler, & Tolin, 2007), an increased risk of developing somatic disorders (Denollet, Maas, Knottnerus, Keyzer, & Pop, 2009), and high societal costs (Smit, Cuijpers, et al., 2006). Despite these high numbers of individuals suffering from anxiety disorders, only a small proportion receive adequate treatment (Weisberg, Dyck, Culpepper, & Keller, 2007;

TE D

Wittchen & Jacobi, 2005). Primary care facilities often lack resources to meet the need for psychological treatments in general and evidence-based treatments in particular. One way of

EP

increasing access to evidence-based psychological treatments in primary care could be to use guided Internet-administered cognitive behavior therapy (ICBT) (Andersson, 2009; Carlbring

AC C

& Andersson, 2006). Guided ICBT has been shown to be effective for a variety of anxiety and mood disorders (Andrews, Cuijpers, Craske, McEvoy, & Titov, 2010; Spek et al., 2007), and has also been found to be cost-effective when compared to no treatment or to conventional cognitive behavior therapy (Hedman, Andersson, Ljótsson, et al., 2011; Hedman, Ljótsson, & Lindefors, 2012). There is some evidence for the long-term effects of ICBT for anxiety disorders (Carlbring et al., 2011; Carlbring, Nordgren, Furmark, & Andersson, 2009; Hedman, Furmark, et al., 2011; Paxling et al., 2011), and the evidence base for the clinical effectiveness of ICBT is growing, showing promising results (Bell, Colhoun, Carter, & 2

ACCEPTED MANUSCRIPT Frampton, 2012; Hedman, Ljótsson, et al., 2013; Hoifodt, Strom, Kolstrup, Eisemann, & Waterloo, 2011; Mewton, Wong, & Andrews, 2012; Roy-Byrne et al., 2010; Ruwaard, Lange, Schrieken, Dolan, & Emmelkamp, 2012). One potential problem when disseminating guided ICBT in primary care is that many randomized controlled trials (RCTs) on guided ICBT make

RI PT

use of strict single diagnosis protocols and suffer from high exclusion rates. One example is a study by Carlbring et al. (2005), where over 80% of the individuals applying for the study were excluded, the lion´s share because panic disorder was not their primary problem. The

SC

impact of existing co-morbidity on these protocols is largely unknown. In the field of guided ICBT, there is some evidence that comorbidity is reduced following ICBT for social anxiety

M AN U

disorder (Titov et al., 2009). Overall, however, it is reasonable to assume that patients with comorbidities present with more deficits in their functioning and that treatments that focus on only one aspect of the problem may run the risk of going against patient preferences, which potentially can affect outcome. In CBT, different approaches have been developed to deal

TE D

with comorbidity and high exclusion rates. One such approach is the unified transdiagnostic treatment protocol (Barlow, Allen, & Choate, 2004), in which common shared characteristics across treatments for specific conditions are assumed to serve as active ingredients across

EP

disorders. But still there is not much evidence that a unified treatment approach is more effective than conventional CBT (Craske, 2012).

AC C

There have been some promising results from the ICBT format for the delivery

of transdiagnostic treatment (Dear et al., 2011; Titov, Andrews, Johnston, Robinson, & Spence, 2010; Titov et al., 2011). Another way of dealing with comorbidities is by addressing them directly, using individually tailored treatments. When tailoring the treatment both the patient and the therapist are allowed to influence the protocol. A similar tailored program used in this study has been shown to be effective previously in a heterogeneous self-recruited sample, both directly at post-treatment and at a

3

ACCEPTED MANUSCRIPT long-term follow-up (Carlbring et al., 2011). In another study, the same protocol approach was tested for young adults and adults with panic symptoms (Silfvernagel et al., 2012). Moreover, tailored ICBT was found to be more effective for more severely depressed patients compared to moderately depressed patients in a controlled trial comparing standard ICBT

RI PT

versus tailored ICBT for depression (Johansson et al., 2012). All of these previous studies were efficacy trials and tailored ICBT has not been tested in any published effectiveness

study. The current study, designed to be clinically representative (Shadish, Matt, Navarro, &

SC

Phillips, 2000), aims to investigate whether this approach could be beneficial for a sample recruited through their primary-care contact and to explore if it is a cost-effective alternative.

M AN U

We expected, on the basis of previous efficacy trials, that the treatment would be moderately effective, both at post-treatment and at a one-year follow-up. We also expected that the

TE D

treatment would be cost-effective.

Method

Ethics statement

EP

The study was approved by the regional Ethical Board and has been registered in

AC C

clinicaltrials.gov (NCT01390168). Written informed consent was collected from all participants by surface post. Study design

The present study was an effectiveness study examining the effects of ten weeks of ICBT with scheduled e-mail guidance compared against an active waiting list control group who had access to health care and can be viewed as equivalent to care-as-usual when comparing pre- to post-treatment and pre-to-one-year follow-up results. For the full study design, we refer to the published study protocol (Nordgren, Andersson, Kadowaki, & Carlbring, 2012). We made 4

ACCEPTED MANUSCRIPT two changes to the protocol in the present study by not using ANCOVA for data analysis, but instead using a linear mixed model because of the large amount of missing data in the followup measurements (Gueorguieva & Krystal, 2004). Moreover, we managed to include only 100 participants, instead of the 128 outlined in the protocol. This change was made because of

RI PT

time limits of the project and funding. Inclusion took place in 18 different primary care settings, in ten different cities, between January 2010 and April 2011. A new power

calculation based on 100 participants revealed a power of 84%, given an alpha-level of .05

SC

and an effect size of d=0.6.

A total of 100 patients were recruited through their primary care contact (e.g.,

M AN U

physician) and were randomly assigned by an online true random-number service independent of the investigators and therapists to either immediate treatment or control. The control group received treatment after ten weeks, leaving no control group for the follow-up measurements. Inclusion and exclusion criteria

TE D

To be included in the study, participants had to fulfill the DSM-IV (American Psychiatric Association, 2000) criteria for any anxiety disorder as a primary diagnosis. Hence, all

EP

participants had a clinically significant impairment because of at least one anxiety disorder with or without comorbid problems. Participants had to be at least 18 years old, have Internet

AC C

access, not be participating in any ongoing psychological treatment, and if taking any medication for anxiety or depression, this had to be at an unchanged dosage for at least 12 weeks pre-treatment. Participants with a suicidal risk, defined as scoring > 3 on item 9 of the Montgomery Åsberg Depression Rating Scale (MADRS-S; Svanborg & Åsberg, 1994), were further interviewed using the SAD PERSONS scale (Patterson, Dohn, Bird, & Patterson, 1983) during a telephone-administered diagnostic interview and were excluded if their risk of suicide was confirmed (they then were referred back to their original primary care setting).

5

ACCEPTED MANUSCRIPT Scoring above 30 on the MADRS-S or below 9 on the Beck Anxiety Inventory (BAI; Beck, Epstein, Brown, & Steer, 1988) also served as reasons for exclusion. Recruitment and participants

RI PT

Participants were recruited from a clinical population, typically by their general practitioner or nurse, when seeking help at their primary care setting. Prescribing clinicians were informed about the intervention and the inclusion criteria in order to decide for whom this might be adequate, regardless if the patient presented themselves with anxiety as their primary

SC

complaint. Based on the clinical judgement of the clinician eligible participants were given an

M AN U

information folder containing brief information about the trial and a link to the study website. On the website they found further information about the treatment, an informed consent form, a link to the questionnaires serving as screening, and the application form for participation. Initial selection took place through computerized screening consisting of the Clinical Outcomes in Routine Evaluation—Outcome Measure (CORE-OM; Barkham et al.,

TE D

2001), the self-rated version of the Montgomery Åsberg Depression Rating Scale (MADRSS; Svanborg & Åsberg, 1994), the Beck Anxiety Inventory (BAI; Beck et al., 1988), the

EP

Quality of Life Inventory (QOLI; Frisch, Cornell, Villanueva, & Retzlaff, 1992), and ten additional questions regarding demographics and current and past treatments. These results

AC C

were used as the pre-treatment assessment. The outcome measures all show good psychometric properties even when administered online (Carlbring et al., 2007; Hedman et al., 2010).

Participants who fulfilled the initial inclusion criteria according to the

computerized screening were contacted to take part in a telephone interview where they were interviewed using the Structured Clinical Interview for DSM-IV—Axis I Disorders (SCID-I; First, Gibbon, Spitzer, & Williams, 1997). Seven MSc clinical psychology students in the latter part of their clinical training conducted the interviews. All received training, including 6

ACCEPTED MANUSCRIPT role-playing and coding of videotapes, and supervision in using the interview. Telephone administration of the SCID-I interview has been found to be equally valid as a face-to-face administration of the SCID-I (Rohde, Lewinsohn, & Seeley, 1997). A psychiatrist and a licensed clinical psychologist together with the interviewers assessed the SCID protocols, and

RI PT

together they tailored the treatment according to each participant’s unique set of problems and, to some extent, preferences. Both the psychiatrist and clinical psychologist had

experience of working in primary care facilities, and the assessments and judgements were

SC

aimed to mirror how this procedure could be made in usual care. In summary, participants were first judged by their general practitioner to suffer from anxiety and after online screening

M AN U

were diagnosed thoroughly by the research team using SCID-I.

Of the 152 individuals who initially applied to participate in the study, 100 were included after a telephone-administrated diagnostic interview and randomised by an online true random-number service independent of the investigators and therapists. The reasons for

TE D

exclusion are specified in the CONSORT flowchart (Figure 1).

EP

FIGURE 1 ABOUT HERE

The mean age was 35.4 years, and 63 percent were female (63/100). Thirty six percent

AC C

(36/100) reported their marital status as married or living together, with children in the household. Sixty four per cent had a history of previous psychological treatment, and 26 per cent (26/100) were using antianxiety or antidepressant medication, while 31 percent reported a history of medical treatment for their condition. Demographic data on the included participants are presented in detail in Table 1.

TABLE 1 ABOUT HERE

7

ACCEPTED MANUSCRIPT

All included participants had an anxiety disorder as their principal diagnosis. A majority (58/100) had one (n = 39) or more comorbid Axis-I disorder. For 43 participants, a comorbid mood disorder (major depressive disorder or dysthymia) was present. There were no

RI PT

difference between the treatment and control group regarding patients presenting

comorbidities (n=30 in the treatment condition and n=28 in the control condition).

SC

Outcome Measures Primary outcome measure

M AN U

The CORE-OM (Barkham et al., 2001) served as the primary outcome measure. This is a 34item scale covering four subscales of generic psychological well-being (Barkham et al., 2001). The subscales are subjective well-being, symptoms (anxiety, depression, physical problems, trauma), functioning (general functioning, close relationships, social relationships),

TE D

and risk (to self and others). Items are scored from 0–4 and relate to the preceding week. CORE-OM clinical scores can range from 0–40, with higher scores indicating greater severity. Internal consistency has been reported as α = .94 (Barkham et al., 2001), with a cut-

EP

off score between a clinical and non-clinical population of 12 for men and 12.6 for women on

AC C

the composite scale (Elfstrom et al., 2012). Secondary outcome measures As secondary outcome measures, the BAI (Beck et al., 1988), the MADRS-S (Svanborg & Åsberg, 1994), and the QOLI (Frisch et al., 1992) were used. BAI measures anxiety symptoms and contains 21 short questions. Total scores range between 0 and 63, with a score of 30 or higher indicating severe anxiety symptoms. Internal consistency is high (Beck et al., 1988), with Cronbach’s alpha ranging from .90 to .94, and test-retest reliability at r = .75. 8

ACCEPTED MANUSCRIPT The MADRS-S (Svanborg & Åsberg, 1994) measures depressive symptoms over the past three days and consists of nine items rated on a seven-grade scale. Total scores range between 0 and 54, with scores above 35 (Snaith, Harrop, Newby, & Teale, 1986)

.83 (Mattila-Evenden, Svanborg, Gustavsson, & Åsberg, 1996).

RI PT

considered severe. Concurrent validity is shown to be good with a test-retest reliability of r =

The QOLI (Frisch et al., 1992) assesses the subjective degree of satisfaction in 16 different areas of life (e.g., health and work). The scale shows high internal consistency (α

SC

= .77–.89), and a test-retest reliability from r = .80 to .91 (Frisch et al., 1992; Lindner,

M AN U

Andersson, Öst, & Carlbring, in press).

Cost assessment

We used the Trimbos and Institute of Medical Technology Assessment Cost Questionnaire for Psychiatry (TIC-P; Hakkaart-Van Roijen, Van Straten, & Donker, 2002) to obtain health

TE D

economic cost data. The TIC-P measures monthly direct medical costs, that is, health care consumption (e.g., primary care visits) as well as nondirect medical costs, that is, costs of

EP

other health-related services not directly associated with health care (e.g., time spent in selfhelp groups). Nonmedical costs, which are costs pertaining to work and domestic productivity

AC C

loss, were also measured with the TIC-P. The costs of ICBT and the control condition was represented mainly by the costs

of therapists, and we used the tariff of visits to licensed clinical psychologists when estimating costs for both conditions. This tariff was multiplied with time spent treating patients. Health Related Quality of Life The EuroQol (EQ-5D) was used to assess quality of life from a health perspective (EuroQolGroup, 1990). The EQ-5D measures five health domains related to quality of life: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression (Rabin & Charro, 2001). 9

ACCEPTED MANUSCRIPT The measure has demonstrated good psychometrics properties, including acceptable test-retest reliability (intraclass coefficient =.82–.83) and acceptable convergent validity (RavensSieberer et al., 2010).

RI PT

Intervention

The ICBT treatment were a form of text-based guided self-help treatment with therapist

support via the internet that consisted of seven-to-ten treatment modules, or chapters, per

SC

participant covering a period of ten weeks. The modules have been shown to be effective previously when used on specific diagnosed samples (i.e., panic disorder; Carlbring et al.,

M AN U

2006), social phobia (Andersson et al., 2006), generalized anxiety disorder (Paxling et al., 2011), and depression (Vernmark et al., 2010) and were adapted to be able to be presented together in the tailored format by being slightly rewritten (e.g., words relating to specific conditions were removed). Tailoring included both the order of treatment modules, the

TE D

amount of text presented to the participant and how many modules to include in the ten week treatment protocol. The same seven MSc students who conducted the SCID-interviews served as Internet therapists. The therapists had access to supervision by a licensed clinical

EP

psychologist both regarding the format and client-specific questions throughout the study period. All communication between participants and therapists was made through the internet,

AC C

using a messenger system within the treatment platform similar to e-mail, and the main nature of the feedback was to answer any questions regarding the module and homework assignments.

Each module consisted of text and illustrations (9–39 A4 pages) presenting a specific symptom and exercises and were to be completed by three-to-eight essay questions to be worked through during a period of one week. Some of the modules (i.e., relaxation and mindfulness) had audio files attached to them for the participants to listen to. The homework

10

ACCEPTED MANUSCRIPT questions were intended to encourage learning and to help the Internet therapist assess whether the participants had assimilated the material or not. Participants were asked to answer the questions and provide worksheets and report on outcomes of different exercises to their therapist once a week. Following submission of the report, they were given individual

RI PT

feedback, most often within 24 hours. When the therapist received a homework assignment showing that the participant has assimilated the material, the next module was made

accessible through an encrypted message exchange system. The therapists were instructed not

SC

to spend more than 15 minutes per participant per week in reading and communicating feedback.

M AN U

Prescribed modules were available for download in PDF format, and participants were advised to print out or to download the self-help material to have the material readily available.

The first module (introduction) and the last (relapse prevention) were fixed,

TE D

which gave the possibility to tailor the treatment by adding any of the following: cognitive restructuring (2 modules), social anxiety (2 modules), generalized anxiety (3 modules), panic disorder (2 modules), agoraphobia, behavioral activation (2 modules), applied relaxation,

EP

mindfulness, assertiveness, problem solving, stress management, and sleep. All modules, except for cognitive restructuring, applied relaxation, assertiveness, problem solving and

AC C

stress management, were disorder specific in that they targeted core symptoms of each of the diagnoses.

Attention control group

Participants in the control condition were asked questions about their well-being on a weekly basis by their therapist. Each participant e-mailed his or her answers to the therapist once a week in order to track possible deterioration, but was generally not given any specific feedback on the answers unless the therapist judged the answer to warrant further action. 11

ACCEPTED MANUSCRIPT

Statistical analysis Treatment effects

RI PT

In order to handle missing data and be able to use the full sample, we used intention-to-treat (ITT) analysis. This method accounts for missing data without assuming that the last

measurement was stable (as is assumed when using the last observation carried forward;

Salim, Mackinnon, Christensen, & Griffiths, 2008) and is appropriate for designs with few

SC

time points. For pre- to post- changes, the sample size was all 100 participants; for the

M AN U

calculation of pre- to one-year follow-up effects, sample size was set to 92 participants, excluding the patients withdrawing their application during their time on the waiting list (n = 8). For both treatment effects and cost-effectiveness, SPSS 20.0 (SPSS Inc., Chicago) was used, and for further calculations of costs and cost-effectiveness, STATA IC/11.0 (Stata Corp) was used.

TE D

Treatment effects were calculated using a linear mixed model with restricted maximum-likelihood estimation (REML) and an unstructured (UN) covariance structure.

EP

Analyses of post-treatment effects were made using the treatment—control group design. And for the analyses for effects at one-year follow-up, we used the treatment and control group as

AC C

one. Measure points were individual, using each participant’s baseline as time one and then assessing post and twelve month follow-up measures using this time as starting point. This resulted in that data were collected from first inclusions in January 2010 until the spring of 2013 for the last follow-up measures. Effect sizes (Cohen’s d) were calculated by dividing the differences between means by the pooled standard deviation. Standard deviations were calculated from the standard errors by using the formula SD= SE*√N. An effect size of 0.20 was considered to be small, of 0.50 to be moderate, and 0.80 and above to be large (Cohen, 1988). 12

ACCEPTED MANUSCRIPT To define responders on the main outcome measure, we used the criteria for clinically significant improvement proposed by Jacobson and Truax (1991). The reliable change index was calculated using the test-retest reliability coefficient of 0.85 and then using the cut-off scores for the nonclinical sample (Elfstrom et al., 2012) to decide whether or not

RI PT

the changes were clinically significant. Costs and cost-effectiveness

Costs were assessed at baseline, post-treatment, and at 12-month follow-up.

SC

Because the control condition was crossed over to treatment after post-treatment, betweengroup comparisons were made only for the post-treatment data and not at 12-month follow-

M AN U

up. In this analysis, missing data from baseline to post-treatment were imputed using the last observation carried forward (LOCF), which has been shown to produce the same costeffectiveness outcomes as imputation based on linear methods when applied on cost data assessed with the TIC-P (Andersson, E. et al.,, 2011, Hedman, Andersson, Ljótsson et al.,

TE D

2011) , but does not rely on assumption of linearity of cost data. However, considering the long period between post-treatment and 1-year follow-up LOCF was not used at the latter assessment point. Instead, 1-year follow-up estimates are based only on participants who

EP

provided data. The statistical analysis was conducted in four steps.

AC C

Incremental cost effectiveness ratio (ICER), which was the primary health economic outcome, was estimated using the following formula: (∆

C1

– ∆C2) / (∆E1 – ∆E2),

where C1–C2 is the difference in costs between ICBT and the control condition, and E1–E2 refers to the difference of the average effectiveness of the two conditions (Drummond et al., 2005). The costs, from all cost domains, of the participants in the ICBT condition were subtracted from the costs of the participants in the control condition. This difference was then divided by the subtracted effects, i.e. improvement of the CORE-OM scores. This procedure was bootstrapped 5000 times, generating an estimated figure of the treatment groups’ 13

ACCEPTED MANUSCRIPT incremental costs in relation to their incremental health benefit. Bootstrap analysis was used because it is considered to generate reliable cost distribution estimates (Efron & Tibshirani, 1993). A cost-utility analysis was also conducted, which is identical to the cost-

RI PT

effectiveness analysis with the exception that the cost of an additional quality-adjusted life year (QALY; Bravo Vergel & Sculpher, 2008) is calculated instead of an additional unit of the CORE-OM. The analysis was performed applying the population-based index weights

SC

proposed by the EuroQol Group (Dolan, 1997). A QALY of 1 is equivalent to one year of full health and score of 0 equals death, which means that five years lived with a quality of life of

M AN U

0.20 yields a QALY of 1 (Bravo Vergel & Sculpher, 2008).

Two sensitivity analyses were performed to test the robustness of the results. The main objective in these analyses was to investigate how sensitive the ICERs would be to changes of cost estimates within a reasonable uncertainty range. In a first step, we repeated

TE D

the analysis but increased the estimated intervention cost of ICBT with $200. In a second step, we performed an analysis where $600 was added to the cost of ICBT, corresponding to the cost of ICBT during the first year of providing the service and thus including developmental

EP

costs and costs of establishing the treatment unit. These costs were expected to decrease rapidly after establishing the treatment unit as they are one-time costs. In addition to analysis

AC C

of ICERs, repeated measures ANOVA and t-tests were used to test cost changes for each cost domain.

Results Adherence and attrition Adherence was measured by using the percentage of completed prescribed modules for the treatment group. Completion was defined as when the participant had sent in his or her 14

ACCEPTED MANUSCRIPT homework assignment to the therapist for the prescribed module. All prescribed modules were completed by 32 per cent (16/50) of the treatment group. One participant (2%) did not complete any of the prescribed modules, while the mean completion rate was 53.5 percent of the prescribed modules.

RI PT

In the treatment group three persons dropped out, and two were excluded (for details, see Figure 1), leaving 45 participants remaining in the treatment group at the end of the ten-week treatment period. In the control group, eight persons withdrew their application

SC

before starting the treatment. During the treatment of the control group, three participants

M AN U

dropped out, and two were excluded.

Treatment effects Pre to post changes.

TE D

Effect sizes varied from d = 0.20 to 0.86 with a mean effect size of d = 0.59. In terms of treatment response, 46% (23/50) of the participants in the treatment group showed a clinically significant improvement on the CORE-OM, compared to 12% (6/50) in the control condition.

EP

Detailed data on the pre to post results are presented in Table 2. When taking a comorbid mood disorder into consideration, no interaction effects

AC C

of time and group and mood disorder were found on either the primary measure (F (1,90.026) = 1.666, p = .200) or on secondary measures (BAI; F (1,93.632) = 0.266, p =.608; MADRSS; F (1,89.482) = 0.280, p=.598; QOLI; F(1,89.318)=0.832, p=.364). Taken together, the results indicate that participants in the treatment group reported an improvement on all outcomes and the mean between-group effect was moderate. Comorbid depression did not moderate the outcome. INSERT TABLE 2 ABOUT HERE 15

ACCEPTED MANUSCRIPT

Pre to follow-up. Results from the follow up measures (see Table 3) revealed that results from post-treatment

RI PT

were sustained at a one-year follow-up with within-group effect-sizes ranging from d = 1.00 – 0.53, with a mean of d = 0.71, indicating that the treatment had sustained effects one year after completion. On the primary measure (CORE-OM), 33.3 % (25/75) showed a clinical significant improvement one year after completion. If non responding persons would be

SC

regarded as treatment failures, these figures would have changed to 27.2% (25/92).

M AN U

Further exploration of interaction effects of comorbid mood disorder revealed no moderating effect on the CORE-OM (F (1,77.974) = 2.353, p = .102) or on the BAI (F (1,75.120) = 1.301, p = .278) or the MADRS-S (F (1,71.172) = 2.492, p =.090). There was a significant interaction effect of time and mood disorder on the QOLI, however (F (1,67.021) = 3.969, p =.023). This indicates that patients with a comorbid mood disorder had a larger

TE D

gain in their quality-of-life assessments from pretreatment to one year follow-up.

EP

INSERT TABLE 3 ABOUT HERE

AC C

Psychological treatment and medication At the one-year follow-up, based on observed data (n = 75), 36 % (27/75) reported that they had started another psychological treatment for their condition, and 16% (12/75) reported increasing or starting anxiolytic or antidepressant medication. A majority 90.7% (68/75) reported no changes in medication, and 12% (9/75) reported lowering their dosage. In these data the persons not using anxiolytic or antidepressant medication at baseline were reported as “no changes in medication” if this had not changed. Divided into the original groups 31% (13/42) of the treatment group started an additional psychological treatment, 16.3% (7/42) 16

ACCEPTED MANUSCRIPT increased or started medication, 9.5% (4/42) decreased or stopped and 69.1% (29/42) reported unchanged medication. In the control group 39.4% (13/33) started an additional psychological treatment, 3% (1/33) increased or started medication, 6.1% (2/33) decreased and 51.5% (17/33) reported no changes in medication. No differences were found on altering medication

RI PT

(χ2(2)= .952, p=.621) or starting psychological treatment (χ2(1)= .319, p=.572) between the two groups.

SC

Costs

Table 4 presents the per capita costs at baseline, post-treatment, and at a 12-month follow-up.

M AN U

Analysis of change in gross total costs from baseline to post-treatment showed a significant interaction effect of time and group, indicating that the ICBT group made larger cost reductions than the control condition (F (1,95) = 7.80; p =.006). Analysis of subtype of the cost domain revealed that this effect was primarily driven by larger indirect cost reductions in

TE D

the ICBT group compared to the control condition (F (1,95) = 7.54); p=.007). There were no significant interaction effects of group and time in the other cost domains ((F (1,95)= 0.411.42); p=.24-53). Within-group tests showed that participants who received ICBT made

EP

significant gross total cost reductions from baseline to post-treatment (t(47) = 3.23; p =.002), and from baseline to the 12-month follow-up (t(40)=4.02; p