Accelerated deep transcranial magnetic stimulation using iTBS protocol for refractory obsessive-compulsive disorder

Obsessive-compulsive disorder (OCD) is a chronic debilitating condition with purported dysfunction in the fronto-striatal circuits [[1]Stein D.J. Costa D.L.C. Lochner C. Miguel E.C. Reddy Y.C.J. Shavitt R.G. et al.Obsessive-compulsive disorder.Nat Rev Dis Prim. 2019; 5: 52https://doi.org/10.1038/s41572-019-0102-3Crossref PubMed Scopus (152) Google Scholar]. Around half the patients have unsatisfactory response to first-line treatment strategies including serotonin reuptake inhibitors (SRIs) and cognitive-behaviour therapy (CBT) [[1]Stein D.J. Costa D.L.C. Lochner C. Miguel E.C. Reddy Y.C.J. Shavitt R.G. et al.Obsessive-compulsive disorder.Nat Rev Dis Prim. 2019; 5: 52https://doi.org/10.1038/s41572-019-0102-3Crossref PubMed Scopus (152) Google Scholar]. Non-invasive brain stimulation (NIBS) has proven to be a valuable add-on treatment, especially in non-responders to first-line treatments [[2]Shivakumar V. Dinakaran D. Narayanaswamy J. Venkatasubramanian G. Noninvasive brain stimulation in obsessive-compulsive disorder.Indian J Psychiatr. 2019; 61: S66-S76https://doi.org/10.4103/psychiatry.IndianJPsychiatry_522_18Crossref PubMed Scopus (17) Google Scholar]. Deep transcranial magnetic stimulation (dTMS) can stimulate deeper and broader cortical networks compared to standard rTMS coils. The efficacy of dTMS has been demonstrated in a multi-centre randomised controlled trial and is the only FDA approved NIBS intervention for OCD [[3]Carmi L. Tendler A. Bystritsky A. Hollander E. Blumberger D.M. Daskalakis J. et al.Efficacy and safety of deep transcranial magnetic stimulation for obsessive-compulsive disorder: a prospective multicenter randomized double-blind placebo-controlled trial.Am J Psychiatr. 2019; 176: 931-938https://doi.org/10.1176/appi.ajp.2019.18101180Crossref PubMed Scopus (150) Google Scholar]. It has been found to be helpful even in non-responders to multiple medications and CBT [[4]Roth Y. Barnea-Ygael N. Carmi L. Storch E.A. Tendler A. Zangen A. Deep transcranial magnetic stimulation for obsessive-compulsive disorder is efficacious even in patients who failed multiple medications and CBT.Psychiatr Res. 2020; 290113179https://doi.org/10.1016/J.PSYCHRES.2020.113179Crossref PubMed Google Scholar]. With the standard protocol (5 sessions per week), treatment response is observed around 32 days after treatment initiation [[5]Roth Y. Tendler A. Arikan M.K. Vidrine R. Kent D. Muir O. et al.Real-world efficacy of deep TMS for obsessive-compulsive disorder: post-marketing data collected from twenty-two clinical sites.J Psychiatr Res. 2020; https://doi.org/10.1016/j.jpsychires.2020.11.009Crossref Scopus (21) Google Scholar]. Accelerated protocols may hasten treatment response. For example, a recent open-labelled trial demonstrated the safety and feasibility of accelerated rTMS protocol targeting the left orbitofrontal cortex for resistant OCD, with response noted within 7 days of treatment [[6]Williams N.R. Sudheimer K.D. Cole E.J. Varias A.D. Goldstein-Piekarski A.N. Stetz P. et al.Accelerated neuromodulation therapy for obsessive-compulsive disorder.Brain Stimul. 2021; 14: 435-437https://doi.org/10.1016/j.brs.2021.02.013Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar]. In this trial, 10 sessions of continuous theta burst stimulation (cTBS) were administered per day for 5 days, each session consisting of 600 bursts (1800 pulses) amounting to a total of 90,000 pulses. In another study, 2 dTMS per day administered over 2–3 weeks has been found to be safe in patients with depressive disorder [[7]Bahun I. Ivezic E. Dogas V.V. Filipcic I.S. Filipcic I. A pilot study of accelerated deep transcranial magnetic stimulation effects on cognitive functioning in patients diagnosed with treatment resistant major depressive disorder.Psychiatr Res. 2022; 316114750https://doi.org/10.1016/J.PSYCHRES.2022.114750Crossref PubMed Google Scholar]. To the best of our knowledge, the safety and clinical utility of a truly accelerated dTMS protocol (with 5 or more sessions per day) has not been assessed previously. We describe our experience with accelerated dTMS in 2 subjects with treatment-resistant OCD which resulted in a rapid clinical improvement with a robust safety profile. Ms. S (S1), a 31-year-old female with schizotypal traits, presented with history of OCD since the age of 15 years. Her illness was characterised by contamination obsessions, sexual obsessions, obsessive need for symmetry, pathological doubts, and aggressive impulses along with washing compulsions, repeating compulsions, reassurance seeking and mental compulsions. She had a fair insight but avoided social interactions and other activities that triggered her OC symptoms leading to significant socio-occupational dysfunction. She had previously failed to respond to adequate trials of 4 different SRIs, augmentation with risperidone and aripiprazole, and to 26 sessions of low frequency rTMS to pre-supplementary motor area. She was diagnosed to have treatment-resistant OCD and was started on venlafaxine up to 225 mg 10 days before the initiation of the accelerated dTMS protocol. Mr. N (S2), a 24-year-old gentleman with anankastic personality disorder presented with history of OCD since the age of 14 years. His illness was characterized by obsessions of symmetry, just right phenomena, ordering and repeating rituals, ritualistic bathing, reassurance seeking, rereading, rewriting, avoidance and compulsions by proxy with significant socio-occupational dysfunction. He had excellent insight. The patient had previously failed to respond to adequate trials of 3 SRIs, clomipramine, venlafaxine, and to augmentation with risperidone. He had dropped out of CBT due to intolerance of anxiety associated with the treatment. He was also diagnosed to have treatment resistant OCD and was on treatment with Paroxetine 75mg, clonazepam 1 mg and propranolol 20mg with no significant improvement in symptoms. Both the patients were offered a trial of adjunctive accelerated dTMS for which they provided informed consent. dTMS sessions were administered using the Brainsway H7-coil. Five sessions of intermittent theta burst (iTBS) stimulation were delivered at 100% of foot resting motor threshold with 1 hour interval between the sessions for 5 continuous days (total 25 sessions). Each session consisted of 1200 magnetic pulses delivered in 40 trains with 8 second inter-train interval. Each train consists of 10 bursts of three biphasic pulses delivered at 50 Hz, bursts repeated at 5Hz. This would amount to 6000 pulses per day and a total of 30000 pulses over 5 days of treatment. A personalised symptom provocation paradigm was developed during the baseline assessment and was administered before each session to evoke a moderate level of distress. Both the subjects tolerated the entire protocol without any significant side effects. Symptoms were rated on Yale-Brown Obsessive Compulsive Scale (Y-BOCS) and Clinical Global Impression-Severity (CGI-S) scale at baseline, at the end of the treatment, at 1-, 2- and 4-week follow-ups. OCD-Visual Analogue Scale (OCD-VAS) [[8]Rodriguez C.I. Kegeles L.S. Levinson A. Feng T. Marcus S.M. Vermes D. et al.Randomized controlled crossover trial of ketamine in obsessive-compulsive disorder: proof-of-concept.Neuropsychopharmacology. 2013; 38: 2475-2483https://doi.org/10.1038/npp.2013.150Crossref PubMed Scopus (192) Google Scholar] was applied at the end of each treatment day to assess the rapid changes in OC symptoms. There was a 40% and 35% reduction in Y-BOCS score after 1 week of the treatment for S1 and S2 respectively with CGI-S score improving from 6 to 4 for both. Subjective severity as rated by OCD-VAS score also decreased (from 10,6 to 2,2 respectively) in both subjects 7 days after treatment initiation. S1 showed a worsening of symptoms post-treatment with YBOCS score increasing to 31 at 2-week follow-up, while S2 maintained improvement at 2- and 4-week follow-ups (see Fig. 1). These 2 cases demonstrate the safety and potential clinical utility of accelerated dTMS protocol as an adjunctive modality in the treatment of OCD. As opposed to the usual once-daily protocol, an accelerated protocol might lead to a faster clinical improvement. However, it has to be evaluated whether a higher number of sessions may be required for sustained response. The FDA-approved high frequency (HF) dTMS protocol for OCD consists of 50 trains of 2 seconds at 20Hz with 20 seconds inter-train interval and amounts to a total of 2000 pulses per session. This protocol takes 18 minutes to deliver each session. Like the HF protocol, the iTBS protocol is also an excitatory intervention [[9]Di Lazzaro V. Pilato F. Dileone M. Profice P. Oliviero A. Mazzone P. et al.The physiological basis of the effects of intermittent theta burst stimulation of the human motor cortex.J Physiol. 2008; 586: 3871-3879https://doi.org/10.1113/jphysiol.2008.152736Crossref PubMed Scopus (226) Google Scholar]. We used an iTBS protocol with 1200 pulses per session which takes only 6 minutes to deliver and maybe more tolerable. Though the improvement was modest, it was encouraging to observe rapid changes in treatment-refractory patients. However, S1 relapsed within a few weeks and S2 did not have adequate follow-up data. It has to be evaluated whether there is a need for optimisation of the protocol or maintenance sessions for sustainability of improvement. Overall, the experience with these 2 cases warrants more systematic studies to assess the efficacy and tolerability of accelerated dTMS in OCD. SSA, SR & VT conceptualized the study. SR, VT, and PKP were involved in clinical assessment and administration of dTMS sessions. SR and VT prepared the first draft. All authors reviewed and contributed to the final draft of the manuscript. The authors certify that they have obtained written informed consent from both the subjects including the consent for their clinical information to be reported in the journal. The subjects understand that their names and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed. This report is supported by the grants received from the Department of Biotechnology (DBT) – Wellcome Trust India Alliance (IA/CRC/19/1/610005 & IA/CPHI/18/1/50393). There are no potential conflicts of interest to report. SR is supported by Department of Biotechnology (DBT) - Wellcome Trust India Alliance (IA/CRC/19/1/610005). SSA acknowledges the support of the Department of Biotechnology (DBT) - Wellcome Trust India Alliance (IA/CRC/19/1/610005 & IA/CPHI/18/1/50393).