Economic evaluation of a guided and unguided internet-based CBT intervention for major depression: Results from a multi-center, three-armed randomized controlled trial conducted in primary care

Depression is one of the most common mental disorders and will become one of the leading causes of disability in the world. Internet-based CBT programs for depression have been classified as “well established” following the American Psychological Association criteria for empirically supported treatments. The aim of this study is to analyze the cost effectiveness at 12-month follow-up of the Internet-based CBT program “Smiling is fun” with (LITG) and without psychotherapist support (TSG) compared to usual care. The perspective used in our analysis is societal. A sample of 296 depressed patients (mean age of 43.04 years; 76% female; BDI-II mean score = 22.37) from primary care services in four Spanish regions were randomized in the RCT. The complete case and intention-to-treat (ITT) perspectives were used for the analyses. The results demonstrated that both Internet-based CBT interventions exhibited cost utility and cost effectiveness compared with a control group. The complete case analyses revealed an incremental cost-effectiveness ratio (ICER) of €-169.50 and an incremental cost-utility ratio (ICUR) of €-11389.66 for the TSG group and an ICER of €-104.63 and an ICUR of €-6380.86 for the LITG group. The ITT analyses found an ICER of €-98.37 and an ICUR of €-5160.40 for the TSG group and an ICER of €-9.91 and an ICUR of €496.72 for the LITG group. In summary, the results of this study indicate that the two Internet-based CBT interventions are appropriate from both economic and clinical perspectives for depressed patients in the Spanish primary care system. These interventions not only help patients to improve clinically but also generate societal savings. Trial Registration: clinicaltrials.gov NCT01611818


BACKGROUND
Major depression will become the second most important cause of disability in 2020 according to World Health Organization reports [1]. Computerized cognitive-behavior therapy could be an efficacious and cost-effective option for its treatment, particularly in patients with mild or moderate depression. In fact, several studies support the efficacy of these type of interventions in patients with mild and moderate depression [2]. The expansion of the interventions based on computerized cognitive-behavior therapy has been motivated, among other reasons, in its costeffectiveness [3]. However, no studies on cost-effectiveness of low intensity vs self-guided psychotherapy have been carried out in a Spanish sample.

Objectives:
1) To develop a computerized cognitive-behavior therapy program for the treatment of depression adapted to Spanish culture, language and population.
2) To evaluate the effectiveness of a computer-based psychotherapy program in Spanish for the treatment of depression in primary care.
3) To evaluate the cost-effectiveness and cost-utility of the computer-based psychotherapy program in Spanish for the treatment of depression

Hypotheses:
1) It is feasible to develop a computerized cognitive-behavior therapy program for the treatment of depression adapted to Spanish culture, language and population.
2) Computerized cognitive-behavior therapy for mild and moderate depression in primary care is effective in Spanish population.
3) Computerized cognitive-behavior therapy for mild and moderate depression in primary care is cost-effective in Spanish population.

STUDY DESIGN:
Phases: Phase 1: Development of a computer-based psychotherapy program in Spanish for the treatment of depression: 1) Analysis of the programs for the treatment of depression developed in other contexts, such as "Beating the blues", "Blues Begone", "Living Life to the Full" or "Moodgym welcome". Randomized controlled trial, three-armed, with parallel assignment, double-blind study.

Arms AssignedInterventions
Low intensity Internet-delivered psychotherapy + improved treatment as usual by GP. Beck-II score of 29 or higher) who will be advised to consult their GP Receiving pharmacological treatment with antidepressants is not an exclusion criterion meanwhile, during the study period, treatment will not be modified or increased (decrease of pharmacological treatment is accepted).

Procedure and randomization
The recruitment process will begin with the selection of the patients by the general practitioner (GP) as suitable for the study. The GP will give brief information about the program to each patient. If the patient is interested, the GP will ask for permission in order to collect personal information and to check the inclusion and exclusion criteria. The GP will inform about the candidate to the evaluator, who will set an appointment with the patient. In this appointment, the independent evaluator will give structured information to the patient about the study. If the patient agrees to participate, he/she will sign the informed consent form and the evaluator will assess the patient using the booklet of instrument. After the appointment, the evaluator will contact with an independent statistician who will assign the patient to one of the three arms of the study (randomization by blocks). After that, the statistician will get in touch with the patient to inform him about the assignment to one of the arms. After the baseline assessment, an independent evaluator, blind to the assignment, will assess the patients at the end of the treatment (three months after the baseline), and also at two follow-ups (3-months and 12months). 7

Control intervention
All the patients of the study will receive improved usual care provided by their GPs. The general practitioners will receive a training course to improve their knowledge about mild and moderate depression.

Computerized CBT interventions
Two separate computerized cognitive-behavior therapy interventions will be provided. In the first one (Self-guided Internet-delivered psychotherapy), access to de platform will be provided to the patients allocated in this arm. Only technical support will be provided to the patients who need it.
In the second intervention (Low intensity Internet-delivered psychotherapy), besides access to the platform, the patients will have the possibility to get in touch with a trained psychotherapist via email, and ask for individualized advice.

Measures:
Primary Outcome Measures:  Severity of depressive symptomatology measured by Beck Depression Inventory II.
This is one of the most widely questionnaires used to evaluate severity of depression in pharmacological and psychotherapy trials. This questionnaire has been used because it is recommended to assess depression in primary care patients in which comorbidity with medical disorders is frequent. The Spanish validated version of the questionnaire will be used.

Secondary Measures:
 Socio-demographic variables. The following socio-demographic data will be collected: gender, age, marital status (single, married/relationship, separated/divorced, and widowed), education (years of education), occupation, economical level. impacts (such as time off work due to illness). The variant used in this study was designed to collect retrospective data on service utilization during the previous months after the last assessment. Data on baseline assess the previous three months before inclusion.

Schedule:
The patients will be assessed using the booklet by blinded evaluators at baseline, posttreatment (3 months after the first assessment), at 3-months follow-up and at 12-months followup.
The estimated time for the recruitment of the whole sample is one year, two years and a half including the 12-months follow-up.

STATISTICAL METHODS
The statistical analyses will follow the recommendations of the CONSORT statement. An intention-to-treat approach will be followed. First, a between group comparison of the main clinical and sociodemographic variables at baseline will be carried out in order to state the comparability of the groups. A mixed ANOVA 3x4 (three groups and four time points) with the main clinical measure (BDI-II) will be carried out in order to find group, time and mixed effects.
Post-hoc analyses will be performed to detect specific differences between groups and time points. The same analyses will be performed with the secondary measures.
The economic evaluation will be estimated from a societal perspective during the 12 months before the baseline and during the 12-months of follow-up. Direct health care costs will be calculated by adding the costs derived from medication consumption, medical tests, use of health-related services, and cost of the staff running the CBT intervention.

Sample size
Based on previous studies, a clinically significant difference in the main clinical measure used in this project (BDI-II) is 5 points. Assuming a statistical power of 90%, and apha of 0.05 and two tails, the sample size needed is 100 patients. Given that an attrition rate of 70% is expectable, 150 patients per group (three groups), 450 in total, is estimated an appropriate sample size.