tms for exposure therapy resistant ocd

Conditions: 1 Hz Real rTMS to the Pre-SMA; 1 Hz Sham rTMS to the Pre-SMA

Summary: tetro is a 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 in 250 adult (18 years and older) ocd patients who show no/insufficient response to erp, aiming to establish the cost-effectiveness of low frequency (1 hz) rtms to the pre-sma (compared to sham rtms to the pre-sma) as adjuvant treatment to exposure with response prevention (erp). the treatment consists of 4 times/week rtms combined with erp for at least 5 weeks (20 sessions), with optional extension phase of 1 or 2 weeks (maximum of 28 sessions in total).

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: the pre-versus-post-treatment standardized mean difference (smd) in severity of ocd (yale-brown obsessive-compulsive scale - y-bocs), version 2. the post-treatment y-bocs score will be obtained at the end of treatment, i.e, after 20, 24 or 28 sessions. secondary study parameters/endpoints: * response (≥35% reduction on y-bocs-v2) and remission (y-bocs≤12) as established through international expert opinion * standard mean difference (smd) on the clinical global impression (cgi) severity scale * clinical global impression (cgi) improvement scale * quality of life (eq-5d-5l) * societal costs, measured through the imta productivity cost questionnaire (ipcq) and the imta medical consumption questionnaire (imcq) * depression, measured using the beck depression inventory (bdi) at baseline, post-treatment and follow-up. in addition we will administer a visual analogue scale (vas) for depression at these same time points, plus every week during treatment, to monitor the effects of treatment on severity of depressive symptoms. * anxiety, measured using the beck anxiety inventory (bai) and a vas; following the same procedure and rationale as for depression. * tolerability of the treatment and side effects, using an in-house questionnaire exploratory outcomes and/or influencing factors: * patient adherence to treatment protocol, as measured using the patient exposure and response prevention adherence scale (peas) * difference between responders and non-responders on circadian rhythm and sleep disorders at baseline as defined by the holland sleep disorders questionnaire (hsdq). * structural brain network characteristics (using t1 and diffusion weighted scans) to predict treatment response / relapse. * functional resting-state and task-based (during emotional processing) brain network characteristics (using echo-planar imaging) to predict treatment response / relapse. * variation in the exact stimulation location as ascertained and recorded by neuronavigation in relation to treatment outcome. * contribution of demographic and clinical variables (sex, age, medication status) and pre-existing comorbidities (i.e. comorbid tics, depression, anxiety, autism) to the variance in treatment outcome. * in ocd patients with comorbid tics: tic severity, measured using the yale global tic severity scale (y-gtss). * variation in treatment expectancy (7-items credibility and expectancy questionnaire (ceq)) and blinding success (1-item question 'in which condition do you think you were?') in relation to treatment outcome.

Eligibility criteria:
inclusion criteria: * ocd as current primary diagnosis * age 18 and older * yale-brown obsessive-compulsive scale (ybocs) score of 16 or higher. * insufficient response to state-of-the art exposure therapy with response prevention (erp) and/or drop-out from erp due to extreme anxiety/avoidance * the following comorbid disorders are allowed (as long as ocd is the current primary diagnosis): depression, other anxiety disorders, adhd, tic/tourette's disorder, eating disorders, personality disorders, autism spectrum disorder (when this does not dominate the clinical profile, i.e. is not main diagnosis). * commitment to actively undergo intensive exposure therapy (both supervised during erp sessions, as well as unsupervised at home) * unmedicated (for at least 8 weeks) or stable dosage of psychotropic medication (for at least 8 weeks), involving serotonergic antidepressants (ssri, snri, clomipramine). other psychotropic medication that is allowed (provided dosage is stably established for at least 8 weeks): methylphenidate, mood stabilizers, antipsychotic drugs * ability to participate in frequent treatment sessions (4 days/week, for 5 (or 6, or 7) weeks) at one of the 5 sites nearest to their home and/or work * ability to participate in pre-treatment mri session (for neuronavigation) at one of the 3 academic sites nearest to their home and/or work * capacity for providing informed consent exclusion criteria: * ocd patients with hoarding as main symptom dimension * the following comorbid disorders (current diagnosis) are not allowed: psychotic disorders, bipolar disorder, autism spectrum disorder (when this dominates the clinical profile, i.e. is diagnosed as main disorder), substance use disorder * active suicidal thoughts and intent to act on it * chronic use of benzodiazepines is not allowed * cochlear implant * (history of) epilepsy * pregnancy * extreme claustrophobia or metallic objects in or on the body, preventing from participation in mri session * space-occupying lesion on mri * previous rtms treatment (for blinding reasons)