This is an international, multicenter, randomized controlled trial of an internet-based CBT intervention for depression (Deprexis) conducted in five MS centers in the US and Germany. The trial consists of a three-arm primary trial phase and an extension phase targeted at maintenance.

Depression is highly common in MS with a lifetime risk for major depressive disorder (MDD) as high as 25-50% and a 12-month prevalence of up to 25%, particularly in younger patients. Depression in MS has been linked to biological as well as psychological factors and substantially impacts psychosocial function. Importantly, depressive symptoms correlate with decreased quality of life, absence from work, and lower social support and are among the strongest predictors for suicidal ideation in MS patients.

Despite its immediate clinical relevance, depression in MS remains underdiagnosed and often untreated and evidence for the efficacy of pharmacological or non-pharmacological interventions for MS-associated depression is scarce. For example, guidelines recently published by the AAN concluded that evidence for pharmacotherapy and individual or group therapies for MS-depression was insufficient but recommended cognitive behavioral therapy (CBT) delivered by phone with weak level of evidence. Such approaches, however, still require availability of a trained psychotherapist.

Given the mobility problems, cognitive impairment, and fatigue typically associated with MS as well as the limited availability of psychotherapists, self-guided, automated, internet-based interventions may help to overcome treatment barriers often encountered by patients with MS. In a recent phase II randomized controlled trial (RCT) in Germany, the investigators found one such internet-based CBT program, Deprexis, to significantly reduce depressive symptoms in MS (Fischer et al., Lancet Psychiatry 2015). Despite these encouraging results, large, definitive trials of the most promising therapeutic approaches for MS-associated depression that could inform clinical practice are completely lacking.

Here, the investigators conduct a large, international, multicenter RCT of the Deprexis program to treat depression in MS patients. Patients will be recruited in five specialized MS centers in Germany (Charité Berlin and University Medical Center Hamburg) and the US (Cedars Sinai Los Angeles, University of Missouri - Kansas City, and Penn State University). The investigators plan to enroll n=400 patients who will be randomly assigned to two different versions of Deprexis (either Deprexis alone or Deprexis plus regular Email support, DeprexisPlus) for 3 months or a waitlist control group and undergo clinical assessments at baseline and month 3. In addition, the investigators will conduct long-term online follow up at month 6 and month 12.

The trial will address the following three main aims:

Aim 1: To definitively test the effectiveness of Deprexis for reducing depressive symptoms in MS at the end of treatment.

Aim 2: To determine the added value of email support for Deprexis (DeprexisPlus) in MS.

Aim 3: To explore the long-term stability of therapeutic effects (12 months) and the potential of a booster session to enhance maintenance.

Inclusion criteria

• age > 18
• neurologist-confirmed diagnosis of MS (all forms)
• self-reported depressive symptoms (BDI-Fastscreen > 4)
• fluent in German or English (depending on study site),
• willingness to engage in self-administration of an iCBT intervention for 3 months and complete follow-up
• ability to travel to the outpatient center for two clinical assessments (baseline and month 3)
• internet access at home

Exclusion criteria:

• unwilling or unable to consent,
• diagnosis of bipolar or psychosis (as determined by M.I.N.I structured interview),
• substantial neurocognitive impairments such as dementia or autism
• moderate or high risk of suicide (according to MINI module C) or by clinical impression
• very severe depression that would interfere with the ability to participate in the study (based on clinical judgment by the physician at the recruitment site).
• current psychotherapy/behavioral treatments for depression
• started pharmacotherapy for depression within the last 2 months
• MS relapse or steroid treatment in the last 4 weeks
• concurrent participation in another clinical trial that includes an intervention
• refusal to saving, processing and forwarding of pseudonymized data

Anonymized individual data on the primary endpoint will be published alongside the trial report in a peer reviewed journal.