TMS for Exposure Therapy Resistant OCD

Rationale:

Obsessive-compulsive disorder (OCD) is a serious and disabling mental disorder, characterized by obsessions and compulsions and associated with substantial comorbidity and morbidity (Stein et al. 2019). Approximately 50% of patients treated with standard treatments (exposure therapy with response prevention (ERP) with/without medication) fail to respond fully, resulting in chronicity and poor participation in social and educational/occupational domains. We propose to fill the gap between the standard treatments (exposure therapy with/without medication) on the one side and invasive end-stage strategies (brain surgery) on the other side, using a non-invasive alternative: repetitive transcranial magnetic stimulation (rTMS). Despite proven efficacy (Zhou et al. 2017; Rehn et al. 2018; Fitzsimmons et al. 2022), rTMS for OCD is not yet covered by the Dutch insurance system while rTMS for treatment resistant depression is. This multi-center randomized controlled trial, supported by the 'veelbelovende zorg' grant of Zorg Instituut Nederland (ZIN), aims to establish the added value of rTMS applied over the pre-supplementary motor area (preSMA) when combined with ERP in OCD patients, who show no/insufficient response to ERP (alone or combined with medication). In case of proven cost-effectiveness it will lead to the addition of rTMS as insured health care for patients with OCD.

Objective: assess the (cost-)effectiveness of 1Hz rTMS to the pre-SMA as adjuvant treatment to ERP in OCD patients who show no/insufficient response to ERP (alone or combined with medication)

Study design: multi-center placebo-controlled double-blind randomized controlled trial with an intervention phase of 5-7 weeks and a follow-up phase of 12 months

Study population: 250 adult (18 years and older) OCD patients who show no/insufficient response to ERP

Intervention (if applicable): Low frequency (1 Hz) rTMS to the pre-SMA (compared to sham rTMS to the pre-SMA) as adjuvant treatment to ERP, 4 times/week for at least 5 weeks (20 sessions), with optional extension phase of 1 or 2 weeks (maximum of 28 sessions in total)

Main study parameters/endpoints: OCD severity at post-treatment, as measured by the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS, v1). The primary endpoint is the difference between the active and sham intervention groups in post-treatment severity of OCD, estimated using an ANCOVA model that adjusts for pre-treatment severity of OCD. The intervention effect will also be reported as a standardized mean difference.

Secondary outcomes - Clinical

* Response (=35% reduction on Y-BOCS v1) * Remission (Y-BOCS v1 \<12) * The severity of OCD, as measured using the newer version of the Yale-Brown Obsessive-Compulsive Scale - Y-BOCS v2. A combined version of the Y-BOCS v1 and v2 is administered pre-treatment and post-treatment. Additionally, Y-BOCS-v2 severity scores are collected weekly during treatment and at all follow-up sessions, enabling comparison between the two versions and potentially supporting further implementation of the newer Y-BOCS v2. * The Clinical Global Impression (CGI) severity scale * Comorbid depression symptoms, measured using the Beck Depression Inventory (BDI) at baseline, post-treatment and follow-up. In addition we administer a VAS for depression at these same time points, plus every week during treatment, to monitor treatment response on mood. The simultaneous administration of VAS and BDI at baseline and post-treatment will allow us to scale and validate the VAS relative to the BDI, while offering a much quicker and simpler assessment for the participants * Anxiety, measured using the Beck Anxiety Inventory (BAI) and a VAS; following the same procedure and rationale as for depression. * For participants with comorbid tics, as identified using the Yale Global Tic Severity Scale (YGTSS), tic severity will be assessed using the same scale.

Tolerability of the treatment and side effects, using an in-house questionnaire developed as part of our previous TIPICCO trial.

Secondary outcomes - Cost-effectiveness

* Societal costs will be measured using the iMTA Productivity Cost Questionnaire (iPCQ) and the iMTA Medical Consumption Questionnaire (iMCQ). * Quality of life (EQ-5D-5L). Quality-Adjusted Life-Years (QALYs) are the most important outcome measure for healthcare decision makers when deciding about the reimbursement of healthcare interventions.

Secondary outcomes - Neuroplasticity

* Blood sampling at baseline, directly post-treatment and at 3 months follow-up is performed to establish markers of treatment-induced neuroplasticity and predictors of treatment response. * Pre- and post-treatment MRI scans to analyse ERP and rTMS-induced effects on multiple levels in the brain, using innovative multi-modal neuroimaging. * Pre-treatment structural and functional MRI scans to assess brain structure and network activation and connectivity to predict treatment response.

Exploratory variables:

* Patient adherence to treatment protocol, as measured using the Patient Exposure and Response Prevention Adherence Scale (PEAS) and its relationship to treatment outcome. This scale is carried out by the therapists as part of usual treatment. * Difference between responders and non-responders on circadian rhythm and other sleep disorders at baseline as defined by the Holland Sleep Disorders Questionnaire (HSDQ), as a possible prognostic marker for response. * The relationship of demographic and clinical variables (gender, age, medication status) and pre-existing comorbidities (i.e. comorbid tics, depression, anxiety, autism) to the treatment outcome. A simplified Dutch version of the Mini-International Neuropsychiatric Interview (M.I.N.I.) for DSM-5-diagnoses is used to confirm OCD diagnosis and establish current comorbidity. To specifically evaluate symptoms of comorbid autism spectrum disorder, the Dutch version of the Autism Spectrum Questionnaire (AQ-NL) is administered. * The Y-BOCS symptom checklist is used to categorize symptom dimensions and examine treatment effects and underlying mechanisms in different OCD subgroups. * Measuring the exact stimulation location as ascertained and recorded by neuronavigation on three separate sessions (session 1, 10 and 20) will allow us to map the variation in achieved location in relation to treatment outcome. * Variation in treatment expectancy (7-items credibility and expectancy questionnaire) and blinding success (1-item question 'in which condition do you think you were?') in relation to treatment outcome

• response and remission [Срок оценки: baseline (T0) versus directly post-treatment (5, 6 or 7 weeks post-baseline, dependent on duration of treatment) + 3, 6 and 12 months follow-up]
• Standard Mean Difference (SMD) on the Clinical Global Impression (CGI) severity scale [Срок оценки: baseline (T0) versus directly post-treatment (5, 6 or 7 weeks post-baseline, dependent on duration of treatment) + 3, 6 and 12 months follow-up]
• Clinical Global Impression (CGI) improvement scale [Срок оценки: baseline (T0) versus directly post-treatment (5, 6 or 7 weeks post-baseline, dependent on duration of treatment) + 3, 6 and 12 months follow-up]
• Quality of life (EQ-5D-5L) [Срок оценки: baseline (T0) versus directly post-treatment (5, 6 or 7 weeks post-baseline, dependent on duration of treatment) + 3, 6 and 12 months follow-up]
• Societal costs, measured through the iMTA Productivity Cost Questionnaire (iPCQ) [Срок оценки: baseline (T0) versus directly post-treatment (5, 6 or 7 weeks post-baseline, dependent on duration of treatment) + 6 and 12 months follow-up]
• Societal costs, measured through the iMTA Medical Consumption Questionnaire (iMCQ) [Срок оценки: baseline (T0) versus directly post-treatment (5, 6 or 7 weeks post-baseline, dependent on duration of treatment) + 6 and 12 months follow-up]
• depression, measured through the Beck Depression Inventory [Срок оценки: baseline (T0) versus directly post-treatment (5, 6 or 7 weeks post-baseline, dependent on duration of treatment) + 3, 6 and 12 months follow-up]
• anxiety, measured through the Beck Anxiety Inventory [Срок оценки: baseline (T0) versus directly post-treatment (5, 6 or 7 weeks post-baseline, dependent on duration of treatment) + 3, 6 and 12 months follow-up]
• Tolerability of the treatment and side effects, using an in-house questionnaire [Срок оценки: after 1st and last week of treatment]