Long-term repetitive transcranial magnetic stimulation for treatment-resistant depression: Report of two cases

Dear Editor, Repetitive transcranial magnetic stimulation (rTMS) has emerged as a promising non-invasive brain stimulation (NIBS) treatment for treatment-resistant depression (TRD).[1] Most acute rTMS protocols typically require 20–30 sessions to achieve a meaningful improvement in depressive symptoms, with response and remission rates ranging from 40–50% and 25–30%, respectively.[2] A meta-analysis found that 66.5% of the initial responders maintained their response at the third month, decreasing to 46.2% by the end of one year.[3] Notably, individuals who received maintenance TMS demonstrated higher response rates during follow-ups.[3] Increasing evidence suggests that a subgroup of patients may require more than 30 sessions to achieve improvement and attain response and remission through treatment extension.[2] A recent systematic review of maintenance rTMS in depression reported beneficial effects in maintaining response and remission, as well as in preventing relapse.[4] However, there is currently no structured protocol or treatment regimen for maintenance rTMS. This report presents two cases in which we administered maintenance rTMS, resulting in sustained remission at one year and eight months, respectively. CASE REPORTS Patient 1, a 56-year-old gentleman, has a nine-year history of recurrent depressive disorder and presented to us in his ninth episode. Despite undergoing adequate trials of paroxetine, desvenlafaxine, sertraline, and augmentation with lithium in the past, he failed to respond to these treatments. Additionally, he has multiple medical comorbidities [refer to Table 1] and received a permanent dual-chamber demand pacemaker installation four years ago due to sick sinus syndrome. While electroconvulsive therapy (ECT) was recommended as the primary treatment option, given his previous positive response to ECT, the patient expressed a preference to try rTMS instead. Refer to Table 1 for his symptom severity scores and current medication details.Table 1: Patient demographics, comorbidities, medication details, illness severity, and the rTMS protocol usedPatient 2, a 40-year-old gentleman, diagnosed with bipolar type 2 disorder twenty years ago, was referred to our center for rTMS treatment for a depressive episode that has been unresponsive to medications. Apart from drug-induced psoriasis, he does not have any other medical comorbidities. Despite undergoing adequate trials of escitalopram, sertraline, mirtazapine, fluoxetine, bupropion, and venlafaxine, he showed a poor response to these treatments. Additionally, he received six modified bifrontal ECT sessions with inadequate response. Refer to Table 1 for his symptom severity scores and current medication details. Maintenance rTMS treatment protocol Written informed consent was obtained from both participants for acute phase rTMS and again before maintenance rTMS. Both patients received 10 Hz rTMS at 120% of the resting motor threshold (RMT) over the left dorsolateral prefrontal cortex (3000 pulses per session), five sessions per week, for acute treatment, as detailed in Table 1. RMT was estimated from the right first dorsal interossei muscle using the Rossini-Rothwell method, observing visible finger twitch.[5] The RMT was estimated weekly until the treatment frequency was reduced to once a week. Thereafter, the RMT was assessed before each maintenance TMS session, and the treatment doses were adjusted accordingly. Both patients achieved remission of depressive symptoms after 15 daily sessions. Patient 1 received 15 daily sessions, while patient 2 received 20 sessions in the acute phase. We used the TMS adult safety screen (TASS) to ensure the safety of undergoing TMS, and adverse effects after each session were monitored using a TMS adverse effect questionnaire.[6,7] Given that patient 1 had multiple medical comorbidities, including a pacemaker, we conducted a pre-treatment cardiac evaluation and closely monitored the patient during each session in the acute phase.[8] Due to their excellent response and patient preference, we planned to give continuation and maintenance TMS by gradually tapering the number of sessions, as previously suggested.[9] Session frequency was reduced to thrice a week for two weeks, then twice a week for another two weeks, followed by once-a-week sessions for four weeks, fortnightly sessions for eight weeks, and finally monthly sessions. Figure 1 illustrates the session frequency of both patients over time and changes in their depression severity. Four months into the once-a-month rTMS, patient 1 experienced a relapse (Hamilton Depression Rating Scale [HDRS] score of 15); hence, we increased the session frequency to once a week and continued treatment. There was a two-month break in the sessions for both patients due to machine-related issues, during which symptoms worsened. We resumed both patients' maintenance sessions after the break, adjusting session frequency based on improvement and patient-reported well-being. Patient 1 completed 60 sessions over 70 weeks and currently receives once-a-week maintenance rTMS, remaining in remission. Patient 2 also remains in remission; he underwent 66 sessions over 44 weeks and is currently on twice-a-week maintenance rTMS. Both patients tolerated the treatment well, reporting only mild scalp pain and self-limited eyebrow twitches. They both consider this period the most improved phase of their lives since the onset of their illness.Figure 1: Maintenance rTMS in both patients (HDRS scores and session frequency/week over time)DISCUSSION There is no definitive schedule for maintenance rTMS, and the session frequency is often tailored based on the individual patient response. Research suggests that a session frequency of at least once every two weeks is necessary to sustain the improvement.[4] We implemented a tapering schedule suggested by Chang et al.,[9] and one of our patients relapsed when we reduced the session frequency to once a month. For the second patient, we could not reduce the frequency below once a week as the patient reported subjective worsening whenever we attempted to reduce the frequency further. Our patient's medication doses were stable, except for the period of rTMS break, suggesting that the beneficial effects can be attributed to maintenance rTMS. Thus, a tapering schedule during the continuation phase followed by at least weekly sessions may be necessary for the maintenance of rTMS after acute treatment response. Our first patient experienced relapse after 42 weeks, aligning with findings from follow-up studies on rTMS in depression, which observed an average time to relapse of ten months.[10] Notably, we were able to use TMS as a rescue treatment during the relapse, underscoring its versatility. These findings contribute to the evidence supporting maintenance rTMS in TRD, demonstrating its feasibility even in patients with multiple medical comorbidities, including cardiac pacemakers. Furthermore, our report highlights the safety and tolerability of long-term rTMS use, significantly improving the quality of life for patients with longstanding TRD. Nevertheless, extensive clinical trials are warranted to establish an optimal maintenance regimen for rTMS in depression. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.