Background
Among persons with epilepsy (PwE), depression is exceedingly common and is associated with intense personal suffering and dramatic reductions in quality of life [
1]. According to a recent systematic review, 23.1% of PwE are affected by depression within the past year [
2], compared to 6.6% in the general population [
3]. Lifetime depression prevalence is estimated at 30 to 35 percent among PwE [
4], compared to 16.2% in the general population [
3].
Even though their frequent co-occurrence has been observed repeatedly, questions remain regarding the causal mechanisms underlying the relationship between epilepsy and depression. The conventional view has long held that depression arises as a consequence of having epilepsy, but evidence is not consistent with such unidirectional causation [
4‐
7]. Indeed, experiencing depression before seizure onset may increase risk for the subsequent development of epilepsy and, vice versa, having epilepsy may increase subsequent depression risk [
5]. Research suggests that multiple pathogenic mechanisms might explain the common co-occurrence of epilepsy with depression and related syndromes, such as anxiety [
4]. These include common neurobiological pathways, including neurotransmitter disturbances, brain-structural or neuropathological abnormalities, and psychosocial pathways, such as inadequate social support, stigma or maladaptive coping [
1,
4,
6,
8]. Additionally, iatrogenic pathways must also be considered, as some antiepileptic drugs facilitate depression and anxiety symptoms [
6].
Research has attempted to identify sociodemographic and disease-related risk factors for depression and anxiety among PwE, albeit with limited success [
9]. According to a recent systematic review, age and gender are not associated consistently with depression, whereas seizure frequency and recency appear to increase depression risk [
9]. Different seizure types, however, are not linked differentially with depression or anxiety. Overall, it remains difficult to predict the course of psychiatric symptoms among PwE from known patient characteristics, even though an increased general risk has been established, compared to healthy comparison populations.
Several pharmacological and psychosocial depression and anxiety treatments have been shown to be effective among PwE. A recent systematic review reported that cognitive behavioral therapy (CBT) might help alleviate depression among PwE, although it appears to be less effective for seizure control, and more high-quality studies are needed before definitive conclusions can be drawn [
10]. Even though CBT and perhaps other forms of psychotherapy are promising treatments for anxiety or depression among PwE, they require the availability of trained therapists, ideally with experience in treating PwE, which is often unrealistic in many treatment settings. According to an international expert consensus statement, CBT as well as psychotropic medication (particularly selective serotonin reuptake inhibitors) are recommended for the treatment of depression and anxiety in PwE [
11]. Unfortunately, though, the vast majority of depressed PwE typically do not receive any depression-related treatment; in a recent study, depression remained untreated in 70% of depressed PwE [
12].
Even though treatments with some degree of effectiveness exist, then, depression and anxiety often remain undetected and undertreated among PwE, for at least two reasons: (1) Epilepsy symptoms can overlap with or mask psychiatric symptomatology, making detection difficult and ambiguous (e.g., fatigue can be a symptom of epilepsy, depression, or both), and (2) physicians are often reluctant to prescribe antidepressants because of concerns over side effects, drug interactions, or lowered seizure thresholds [
13]. Additionally, other barriers may prevent depressed individuals from seeking or accessing depression treatment, including stigma concerns, time constraints, lack of motivation, skepticism regarding psychotherapy, disease-related restrictions (e.g., inability to drive), and perceived lack of necessity [
14]. It is important, though, to identify depression, overcome potential barriers, and initiate treatment, as untreated depression in PwE may increase risk for work absenteeism, increased health care system utilization, and direct medical costs [
15].
To improve access and extend the range of available depression treatment options, Internet-based treatments could play a key role [
16,
17]. Indeed, several Internet-based interventions have been developed and tested over the past decade and are making a considerable impact upon the field of mental health care delivery [
18,
19]. As early as 2002, expert panels have recommended exploiting the Internet to deliver evidence-based psychological treatments to underserved populations [
20], and recent systematic reviews and meta-analyses have confirmed that some such interventions, most of which are based on CBT-principles, are effective for a range of psychiatric symptoms and conditions, including depression and anxiety disorders [
21‐
23]. However, this body of research has also been criticized: many trials are conducted solely online, without establishing contact with participants to verify identity and diagnoses, and they suffer from various methodological problems such as excessive attrition and lack of follow-up data [
24]. Nevertheless, at least in some countries, including Sweden, the Netherlands, Australia, and the United Kingdom, Internet-based psychological interventions with robust evidence are finding their ways into national treatment guidelines and are increasingly integrated in routine care services for patients suffering from depression, anxiety, and other psychiatric conditions [
18,
25,
26]. Despite the considerable promise and success of some Internet-based psychological interventions, though, they have rarely been applied to the treatment of depression and anxiety among PwE.
To our knowledge, only one randomized controlled trial to date has examined whether an Internet-administered intervention can reduce depression among PwE [
27]. In this study, Schröder et al. randomized 78 PwE either to a care-as-usual (CAU) control or to an intervention condition, in which participants received CAU plus access to a depression-focused Internet intervention termed Deprexis, which has been tested in non-epilepsy samples in seven additional studies [
28‐
34]. In the Schröder et al. trial, participants in the intervention group experienced significantly greater depression reduction than those in the control group over the course of nine weeks, with a small to moderate post-treatment between-groups effect size (Cohen’s
d = .43). The study suffered from some methodological limitations, though, including lack of long-term follow-up data and structured diagnostic interviews. Perhaps most importantly, the intervention was not tailored to address the unique needs of PwE, as noted by the authors: “In their subjective appraisal … most participants found that the program should be adapted to the special needs of PwEs with respect to involving more epilepsy-related topics, [which] … could increase the acceptability as well as the effectiveness of the intervention in this particular patient group” [
27]. The Deprexis program also does not target anxiety, which is a common comorbid condition among PwE and correlates as highly as
r = .75 with depression [
1,
6,
35], justifying the development of interventions for both syndromes rather than just one.
The goal of the present randomized controlled trial (RCT) is to test the efficacy of a novel CBT-based, depression-focused Internet intervention that specifically addresses the needs of PwE. This new program was developed by the same group of therapists and researchers that developed Deprexis, the above-mentioned intervention that was shown to be effective in the treatment of depression among PwE. The novel intervention has been developed and is operated by Gaia, an e-Health company with more than ten years of experience in the development of e-Health interventions, located in Hamburg, Germany. The content and technical design of this intervention are described in the methods section below.
The goal of this parallel-groups, pragmatic RCT is to evaluate the extent to which a novel Internet intervention, used adjunctively to CAU, can contribute to improving symptoms of depression and anxiety, social-occupational functioning, physical health (epilepsy symptoms), medication adherence, and health-related quality of life, among PwE. Furthermore, the trial aims to evaluate the extent to which patients with epilepsy regard this intervention as a helpful and valuable tool. The primary focus of the software-based intervention is on facilitating depression reduction; hence, this is the target identified in the primary hypothesis.
It is hypothesized that, between baseline and three months, patients randomized to the intervention group will report greater reductions in depression, as measured by the Patient Health Questionnaire (PHQ-9), a well validated depression measure [
36,
37], compared to patients randomized to the control condition. The goal of this pragmatic RCT [
38] is to test the effectiveness of a novel Internet intervention on depression reduction among PwE over a period of three months, in comparison to a CAU/waitlist (CAU/WL) control group, which only receives access to the intervention after three months. Data will also be collected at six and nine months, which will allow us to examine the stability of intervention effects over time.
Secondary measures are administered to examine effects of the intervention on anxiety symptoms, stress symptoms, and depression-related psychosocial impairment, and it is hypothesized that participants assigned to the intervention group will show greater improvements in these respective measures over three months, compared to control group participants. Exploratory analyses will be conducted to examine potential negative effects of the intervention, effects on epilepsy symptom severity and seizure frequency, health-related quality of life, epilepsy self-management, and medication adherence. The subjective usefulness of the intervention will also be examined, and we expect that users will rate the intervention favorably, given that it was developed to address several of their epilepsy-specific needs and concerns.
Discussion
This protocol describes a methodological rigorous, statistically adequately powered trial of a novel Internet-based psychological treatment for depression and anxiety among PwE. There is an urgent need for innovate and low-threshold interventions in this area, given that depression and anxiety are exceedingly common in epilepsy, complicate treatment response and prognosis, dramatically reduce quality of life, and yet often remain undetected and are treated inadequately. The personal suffering and societal burden associated with depression among PwE could potentially be reduced by Internet-based interventions such as the one evaluated in this trial.
Although the allegedly low costs of Internet-based interventions are often emphasized, developing and maintaining effective, technologically adequate and secure Internet interventions incurs considerable expenses. In this project, a research-focused e-Health company is driving the development of a novel Internet intervention and investing considerable resources to enable the conduct of a methodologically rigorous, independent scientific investigation, whose results will be published regardless of whether they are consistent with the research hypothesis, and the hopes or expectations of the program developers. Several collaborating investigators with no conflicts of interest will ensure the scientific integrity and independence of this project. In our view, this type of collaborative arrangement seems ethically responsible and scientifically viable. Along with others [
19,
97,
98], we feel confident that evidence-based Internet interventions will increasingly be regarded as legitimate, valuable additions to the armamentarium of professional medical care, particularly if their value can be demonstrated repeatedly in rigorously designed trials.
First and foremost, this trial seeks to make a scientific contribution to the field of depression and anxiety treatment among PwE. This will be the first trial in which an Internet-based intervention is evaluated that has been designed specifically to address the unique needs of PwE. It is also one of the few such trials in which diagnoses are established by a structured, validated interview. Several additional methodological strengths are noteworthy, including follow-up assessments and the inclusion of an array of validated measures for the primary outcome of depression and secondary outcomes such as anxiety, quality of life, epilepsy disease status, and potential negative effects of treatment, which are highly relevant for the quality and safety management of novel Internet interventions. As in most studies, these strengths are balanced by some methodological limitations, including the lack of clinician outcome-ratings, laboratory tests, or brain imaging measures. Studies utilizing such methods are desirable but costly, and it is hoped that future investigations, including health-economic studies, will further explore the effects and utility of the novel, Internet-based intervention described and tested in this trial.
Trial status
Recruitment is ongoing. It is anticipated that the trial will be completed (T3) by October 2017.
Acknowledgments
We acknowledge the contributions of the multidisciplinary development team at Gaia, who designed and produced the Internet intervention examined in this study, as well as the contributions of the patients, relatives of patients, and treatment providers who provided feedback and valuable suggestions in the intervention development process.