An open-label feasibility study of repetitive transcranial magnetic stimulation (rTMS) for treatment-resistant depression in the New Zealand healthcare context

Major depressive disorder (MDD), as described in the DSM 5, is the most prevalent mental health disorder in New Zealand. It affects at least 5.3 % of the population and consequently poses a substantial health, social and economic burden.1 A particularly concerning subpopulation of MDD is the treatment-resistant (TR) class, defined as those patients who are unresponsive to at least two adequate courses of different antidepressant treatments. This group makes up approximately 30% of the population with MDD.2,3

Current treatment options for the TR population in New Zealand are further medication trials or non-pharmacological treatments such as cognitive behavioural therapy or electroconvulsive therapy (ECT). Remission rates in TR patients have been found to drop with each failed course of antidepressant medications, therefore further medication trials generally have poor response rates.4 ECT is an alternative to further medication trials offered in New Zealand and has a higher success rate with TR populations.5 However, there are disadvantages associated with ECT such as the risk of cognitive side effects, the need for general anaesthetic and the stigma associated with use of ECT for mental health conditions.

Over the past two decades, numerous randomised and sham-controlled trials summarised in multiple meta-analyses have established the efficacy of repetitive transcranial magnetic stimulation (rTMS) for the treatment of MDD.6–8 In addition to being a viable alternative for those that cannot tolerate or are unresponsive to pharmacological treatments, rTMS also has the advantage of not having adverse effects upon metabolic and sexual functions as do many pharmacological antidepressants.2 rTMS has a good tolerability profile for patients receiving treatment. The most frequent side effects are focal pain, headache, neck-ache and scalp discomfort, all of which are generally mild and very responsive to analgesics.9–11 The patient remains awake during the therapy, and afterwards may immediately continue with their daily activities, without needing time to recover from treatment sessions. rTMS is an FDA-approved treatment for depression in the US,12 and the Royal Australian and New Zealand College of Psychiatrists recommends that rTMS should be available in public and private mental health services for the treatment of MDD.13,14

New Zealand is currently behind in the uptake and availability of rTMS as a treatment for MDD, when compared to countries in the EU, Australia, Canada and the US. At the time of writing, aside from this study, only one psychiatrist has offered rTMS on a fee for service basis in New Zealand. Therefore, the majority of the large New Zealand TR population does not have access to rTMS. This limited access is not surprising given that the majority of funding for mental health care is publicly funded through locally unique pathways that prioritise emergency care over longer-term mental health conditions. Additionally, these services often do not provide newer treatments due to perceived cost burden.

For these reasons, the feasibility of offering a rTMS service for patients who might be referred in a New Zealand context requires evaluation. This study piloted the use of rTMS for participants referred from secondary and tertiary healthcare services and evaluated the real-world efficacy and acceptability of rTMS.

Methods

Participants

This open-label clinical study was approved by a Health and Disability Ethics Committee, and participants were recruited from the Auckland District Health Board and Waitematā District Health Board catchment areas. Written informed consent was obtained from all participants. Recruitment was primarily from Community Mental Health Centres in the central Auckland region. Recruitment and treatments ran from April 2016 to September 2019.

In order to be included in the study, participants were aged over 18 years and had a primary diagnosis of unipolar major depressive disorder (MDD) or bipolar affective disorder (BPD). Current depressive episode was a minimum of three months in duration, and at least moderate severity, determined by a MADRS score of ≥20. Additionally, they must have had an insufficient response to at least two adequate courses of antidepressant treatments. The adequacy of each treatment course was assessed using the Antidepressant Treatment Response Questionnaire,15 and medical records when available.

Participants were also screened for a variety of exclusion criteria during a screening risk assessment conducted by a consultant psychiatrist. Participants with a history of psychosis, any unstable medical or neurologic condition, or imminent risk of suicide as determined by the Columbia-Suicide Severity Rating Scale (CSSRS) and a clinical interview were excluded from the study. Additionally, participants were excluded if they had planned or probable major changes to psychotropic medication, planned use of ECT, any substance abuse or dependence in the previous six months, or contraindications to rTMS assessed using the University of Auckland safety checklist (eg, history of epilepsy, metallic head implants). Prior to starting treatment, participants were not withdrawn from any current medications, but the dose was required to remain stable for four weeks prior to treatment, and for the duration of the four weeks of treatment. Each participant completed a drug urine test and a pregnancy test when appropriate.

TMS

TMS was delivered via a figure of eight coil using a Magstim Rapid stimulator (MagStim Company, Dyfed, UK) for the first seven participants, and a Neurosoft Neuro-MS/D stimulator (Neurosoft, Russia) for the remainder of the participants. Resting motor threshold (RMT) was measured during the screening process, before each participant was confirmed to receive treatment. Surface electromyography (EMG) was recorded from the right first dorsal interossei (FDI). The coil was positioned over the left motor cortex, at the optimal site for eliciting responses in the FDI muscle. RMT was determined using established methods,16 as the minimum intensity sufficient to produce a response in the target muscle 50% of the time. Participants with a RMT >80% maximum stimulator output (MSO) were withdrawn from the study due to safety and discomfort of treatment at higher intensities.

rTMS treatment

Participants received daily treatment of rTMS for four weeks. A standard course of rTMS in clinical practice is four to six weeks of daily treatment.12 For treatment, the figure of eight coil was positioned over the left dorsolateral prefrontal cortex (DLPFC) using the Beam F3 method.17 rTMS was administered at 120% of RMT, intermittent 10Hz bursts, for 4,000 stimuli per day. RMT was re-measured weekly using methods detailed above to check treatment was administered at a safe intensity for the individual. If threshold changed by more than 5% MSO from when last measured, the treatment session was postponed until the patient was reviewed by a medical practitioner.

This initial daily treatment was then followed by an optional three-month maintenance period. Maintenance treatment is not currently standard in clinical practice, however, it was offered as an option to the participants aiming to prolong response and evaluate potential feasibility in the New Zealand context. Methods and results of maintenance treatment can be found in the Appendix.

Clinical evaluation

Depressive symptomology assessed by the Montgomery–Åsberg Depression Rating Scale (MADRS).18 The MADRS was administered at baseline, halfway through treatment (at the end of week 2), and at completion of treatment (at the end of week 4). Primary endpoint was extent of clinical response, stratified into three categories based on difference in MADRS score between baseline and end of treatment; responders, partial responders and non-responders. As reduction in MADRS score indicates improvement in depressive symptomology, responders were defined as those who demonstrated a ≥50% reduction, partial responders as those with a 25–49% reduction and non-responders as those with <25% reduction. Remission was also evaluated as a secondary endpoint, classified as a MADRS score of ≤10/50.

Results

A total of 39 participants were recruited, and 30 completed the rTMS treatment (16 female, mean age 46.7y, age range 19–77y, five left-handed). Mean baseline MADRS score was 32.0 (range 21–48), and mean RMT was 43.4% MSO (range 29–68%). Of the eight participants who did not complete treatment, two participants were not eligible as they had RMTs above 80%. Four participants withdrew prior to beginning treatment, two due to the time commitment required, one was postponed to reach medication stability but reached remission on new medications, and one failed to respond to invitation to participate following screening. Two participants withdrew during the treatment, one due to onset of an unrelated mental health crisis requiring acute care, and the other because of time commitment and reduced accessibility due to change in employment. Demographic information for the 30 participants who completed treatment is presented in Table 1.

Table 1: Participant demographics.

Abbreviations: ADHD, attention deficit hyperactivity disorder; BPD, bipolar disorder; CMHC, community mental health centre; CNS, central nervous system; F, female; GAD, generalised anxiety disorder; GP, General Practitioner; ID, patient identification number; M, male; MDD, major depressive disorder; MMH, Māori mental health; NZ, New Zealand; OAIPU, old age inpatient psychiatric unit; PP, private psychiatrist/psychologist; PS, previous study; X, transgender.

Of the 30 participants who completed treatment 12 were classified as responders. This demonstrates a response rate of 40%. Another six were classified as partial responders, and 12 as non-responders. Proportional improvement in MADRS scores for individual participants demonstrating responder status can be seen in Figure 1.

Figure 1: Percent MADRS score change for individual participants from baseline to end of week 4. A ≥50% improvement classified as response, indicated by dashed line.

*Participant reached remission.

Remission rates were also evaluated during treatment. Nine participants reached remission over the duration of this study. One participant (#01) was in remission halfway through treatment (week 2), with the other eight in remission at the end of treatment (week 4). Individual MADRS scores are presented in Figure 2 with remission indicated as a score ≤10.

Figure 2: Individual MADRS scores for non-responders, partial responders, and responders to rTMS at baseline, week 2, week 4 (at the completion of treatment).

Dashed line indicates remission (MADRS score ≤10).

No serious adverse events were reported. The treatment was tolerable throughout every session for 26 of the 30 participants. The remaining four participants reported intolerable discomfort upon starting the treatment and were unable to complete their first session at the treatment intensity of 120% of RMT. All four reported pain at the site of stimulation, and one additionally reported intolerable jaw movement due to facial nerve activation. Stimulation intensity was then lowered and incrementally increased to maximum tolerability within the session, and across treatment days until an intensity of 100% RMT or higher was tolerable. In three cases (#04, #09, and #19), within two weeks 120% RMT was tolerable and remained so for the remainder of the treatment. In one case (#17), a maximum tolerability of 105% RMT was reached and therefore was treated at this intensity for the duration. Treatment sessions administered below 100% RMT were not counted, therefore as required additional sessions were added to reach 20 sessions at ≥100% RMT. Headache immediately after treatment was infrequently reported and was not a significant burden to the participants. Treatment with paracetamol if necessary was advised.

Discussion

This pilot study demonstrated that rTMS is both an acceptable and efficacious treatment option that could be more widely used in New Zealand. A limitation of the current study when evaluating efficacy is the lack of a sham control group. As the study was open-label the clinical response data will contain a mixture of clinical response to the rTMS treatment regimen, placebo effect, environmental effects from coming to daily treatment sessions, and regression to the mean. However, the clinical efficacy of rTMS is well established in multiple meta-analyses,6–8 and our data reflect the real-world effects clinicians might expect to see in practice.

In general, the response rate of 40% was perhaps slightly lower than has been previously reported. For example, in a recent multicentre analysis of a population of 130 Australian patients a response rate of 55 % was reported.19 This may reflect the relatively small sample size, or the naturalistic sample that had many failed treatments with a number of psychiatric co-morbidities often with multiple concomitant CNS medications (see Table 1). In particular, because the treatment was locally novel many of the referrals received were from clinicians for their most TR patients. Like response to further medication trials, it has been demonstrated that the success rate of rTMS therapy declines with the number of failed pharmacological treatments,20 and response rates are higher in less treatment-resistant patients.21 However there is some evidence that this decline is less in rTMS when compared to further medication trials.22 This study also included participants with BPD in a depressed state (note the four patients with BPD were non-responders). Nevertheless, the fact that acceptability of the treatment was so high with such a complex TR sample that has been difficult to successfully treat is encouraging for its use as a patient service. We note that two patients who were actually treated from an inpatient ward were able to be discharged from the inpatient setting during the treatment. This indicates that some patients can have large functional improvements that meaningfully transform their lives with large economic benefit. We also note that another limitation of our study is that being a pilot trial with a fixed treatment protocol we were limited to offering four weeks of treatment. However, partial responders who were improving but not yet responders at week four may have benefitted from a six week treatment protocol, and in clinical practice extending for an additional two weeks may be practical.

We note here some pragmatic observations based on our experiences. Relevant to New Zealand, our study sample included six patients who self-identified as Māori and two identified with a Pacific Island ethnicity. Interviews with patients conducted after treatment suggested no cultural issues with the treatment but identification of the head as tapu is an important cultural consideration. Two participants who were unable to be treated due to high thresholds highlight the need for appropriate screening before guaranteeing the treatment as an option. First testing if RMT was below 80% of MSO reduced the burden of disappointment when treatment could no longer be offered. Finally, for rTMS provided in an outpatient setting, basic considerations such as availability of public transport, ease of parking and general physical accessibility for 20-plus daily sessions are important. These factors combined with robust screening, resulted in low dropout rates, with only one participant discontinuing treatment after beginning the initial phase.

No participants dropped out of the study due to intolerable side effects. If used as a proxy measure of acceptability, this indicates that the acceptability of the treatment was good. Additionally, the majority of patients (25/30) elected to receive the additional maintenance treatment sessions, four of whom did not demonstrate a clinical response to the initial or maintenance treatment, further indicating the acceptability and tolerability of the treatment sessions, even in the absence of clinically measured benefit. It is also worth noting, newer iterations of rTMS including theta burst TMS offer more efficient treatment with similar response rates in the TR population, which could improve the practicalities and patient tolerability of daily sessions.23

Cost is an important consideration for making rTMS more available in New Zealand. rTMS machines are relatively inexpensive at approximately ~$70,000NZD, but the ongoing operator and occupancy costs need to be considered. However, several studies have shown that after two treatment failures rTMS is less costly relative to further pharmacotherapy or ECT.24–26 Of course cost-effectiveness in the New Zealand context would require a New Zealand specific cost-analysis, which is beyond the scope of this work.

In summary, rTMS therapy has distinct need in light of the New Zealand Mental Health Inquiry and the potential for new patient services to be commissioned in mental health services. Providing an alternative to psychological and pharmacological treatments for those who are treatment resistant or unable to tolerate antidepressant medications will augment patient options and potentially improve outcomes for one of New Zealand’s leading disease burdens.1 There have already been developments in rTMS, which will likely improve the efficient delivery of rTMS for mental health conditions.

Appendix

Maintenance treatment

Methods

The initial 20 days of rTMS treatment was followed by an optional three-month maintenance period using the same treatment parameters. Frequency of treatment sessions however tapered off, with maintenance consisting of treatment once weekly for one month (weeks 5–8), then treatment once fortnightly for one month (weeks 8 and 12), and then a final session at the end of the third month (week 16). During maintenance RMT was measured at each session using methods detailed previously. Clinical symptomology was assessed using the MADRS upon the completion of maintenance treatment at week 16. Differences in depressive scores across time were compared using Wilcoxon signed ranks test. A p value of <0.05 was considered statistically significant.

Results

At the time of writing this manuscript, 15 participants had completed maintenance treatment, with another five in progress. Five participants elected not to receive maintenance treatment due to lack of clinical response. An additional five participants (two partial responders, two non-responders) who began maintenance elected to withdraw during the maintenance phase due to lack of noticeable further benefit. MADRS scores for the 15 patients who completed maintenance treatment are shown in Appendix Figure 1.

Appendix Figure 1: Individual MADRS scores for non-responders, partial responders, and responders to rTMS at baseline, week 2, week 4 (at the completion of treatment) and week 16 (at the completion of maintenance treatment. Dashed line indicates remission (MADRS score >10).

MADRS scores at end of maintenance were not significantly different from those at the end of initial treatment for the 16 participants who completed maintenance treatment (p>0.05). Tolerability was good with no reports of pain at the site of stimulation, or any other side effects. All sessions were able to be conducted at 120% RMT. Maintenance treatment was found to be tolerable and no additional practical considerations were found to those of initial daily treatment.

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