Managing Patients After Transcranial Magnetic Stimulation
How to Best Maintain Response and Remission
In this chapter, we review how to best manage patients who respond to transcranial magnetic stimulation (TMS) therapy. We focus on managing patients who receive TMS for major depression, but we also highlight key clinical points that can be applied to the management of bipolar disorder. Pivotal long-term studies with outcomes at 6 and 12 months post-TMS will be reviewed. We make recommendations for clinical practice, keeping in mind the limitations of the existing database.
Difficulty of Achieving Sustained Remission With Treatment-Resistant Depression
Phases in the management of a depressive episode involve acute, continuation, and maintenance treatments (Frank et al. 1991). This perspective is important when using antidepressant pharmacotherapy and psychotherapy for individuals presenting for initial treatment or for chronic depression. The usual time frame allocated for acute treatment is 6–12 weeks to achieve a response or remission of symptoms. Research studies demonstrate that continuation treatment with pharmacotherapy and/or psychotherapy for an additional several months (4–12 months) reduces the likelihood of relapse (Dobson et al. 2008; Dunner 2001; Gelenberg et al. 2003; Keller et al. 2000, 2007a, 2007b; Klein et al. 2004; Kocsis et al. 2003; Paykel et al. 1995). Maintenance treatment is the next step (i.e., beyond 4–12 months), and evidence supports the efficacy of maintenance treatment for individuals with recurrent and chronic forms of depression (Frank et al. 1990; Keller et al. 2007a; Klein et al. 2004).
Research studies demonstrate that individuals with chronic forms of depression are more difficult to treat than individuals with acute depressive episodes (Dunner 2001). Furthermore, the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study showed a decrease in the rate of antidepressant response with repeated treatment failures (Gaynes et al. 2009; Rush et al. 2006). For example, individuals who experience three failed treatment trials have a low (about 15%) rate of remission in the subsequent trial. These data are similar to the results of a 2-year study of “treatment as usual” for individuals who had experienced multiple failed antidepressant treatments (Dunner et al. 2006; George et al. 2005).
Although most depressed patients respond well to treatment with psychotherapy and/or antidepressant pharmacotherapy, those who do not respond can be considered to have treatment-resistant depression (TRD). Sustained remission for patients with TRD is difficult to achieve with currently available options. A patient who attains remission after one prior antidepressant treatment failure has a 40% chance of relapse over the next year, whereas a patient who has attained remission after three prior antidepressant treatment failures has a 65% chance of relapse (Warden et al. 2007). Table 6–1 displays data from the STAR*D study and shows how increasing treatment resistance predicts an increasing chance of relapse. When patients do not respond to multiple medications, their prognosis for long-term remission decreases. One might say the “durability of response” to antidepressant medications decreases with more failed trials.
Acute-phase remission rate (%)
Continuation-phase relapse rate (%)
Note. Level1=initial treatment; Level 2=failure to remit with Level 1 treatment; Level 3=failure to remit with Level 2 treatment; Level 4=failure to remit with Level 3 treatment.
Source. Data from Warden et al. 2007.
Studies indicate that electroconvulsive therapy (ECT) is the most effective acute antidepressant treatment; however, in community settings it is difficult to achieve sustained remission with ECT. In a prospective, naturalistic study involving 347 patients at seven hospitals, clinical outcomes immediately after ECT and over a 24-week follow-up period were examined in relation to patient characteristics and treatment variables (Prudic et al. 2004). Remission rates during the acute phase were documented in the range of 30%–45%, in contrast to the 70% rates observed in research studies. Likewise, the probability of relapse during the continuation phase was as high as 64%. Patients who did not achieve remission during the acute phase had a poorer prognosis; however, the chance of relapse was high for all patients.
A 53-year-old man with a 4-year history of major depression presented for follow-up with his general psychiatrist after completing 6 weeks of acute TMS therapy 1 month earlier. The patient reported that he was sleeping well and had returned to work. His 9-item Patient Health Questionnaire (PHQ-9) score was 6 (mild). The treatment report from the TMS center indicated that his PHQ-9 score was 18 (severe) at baseline and 4 (remission) at the end of the TMS taper. He was currently taking the medications fluoxetine and L-methylfolate and fish oil. His psychiatrist discontinued the patient’s previously prescribed quetiapine used as an augmentation agent and encouraged close mood monitoring, with the PHQ-9 to be completed every 2 weeks. He also encouraged the patient to initiate a healthy balance of leisure and productive activities and prescribed cognitive restructuring homework from a free online tool, MoodGYM (moodgym.com.au). The patient’s follow-up appointment was set for 6 weeks later, but he was encouraged to call sooner if his symptoms worsened on the PHQ-9.
Durability of Antidepressant Response After Acute TMS
Once a patient responds to TMS, how long will the benefit last? Most patients pose this question during the consent process because they have experienced the disappointment of initially benefiting from an antidepressant treatment only to have their symptoms recur in the ensuing months. To investigate the mean remission time and the predictors associated with the treatment’s duration, Cohen et al. (2009) performed a large retrospective, naturalistic study with 204 patients who underwent TMS therapy. Patients were followed for up to 6 months after acute treatment, and about 80% took psychotropic medications. The rate of event-free remission, with the end point defined as relapse (i.e., Hamilton Depression Rating Scale [HDRS] scores higher than 8), was 75.3% at 2 months, 60.0% at 3 months, 42.7% at 4 months, and 22.6% at 6 months. The mean duration of remission was approximately 4 months (119 days), with younger age and greater number of TMS sessions predicting greater durability of benefit.
Janicak et al. (2010) studied the durability of TMS in a population of 99 patients with major depressive disorder who had at least partially responded to acute TMS treatment while medication free. The patients then received antidepressant monotherapy for 24 weeks. If patients met predefined criteria for symptom worsening, they could receive TMS reintroduction (i.e., two sessions/week for 2 weeks and, if needed, five sessions/week for 4 additional weeks). Thirty-eight patients (38%) had symptom worsening and received TMS reintroduction. Thirty-two of the 38 patients (84%) benefited, with the mean time to reintroduction of TMS being 109 days and the mean number of TMS reintroduction sessions being 14.3. Fifteen patients needed more than one course of TMS, and five patients needed up to three courses. Ten patients relapsed despite access to flexible reintroduction of TMS. TMS was found to be a durable and safe treatment when patients were allowed “flexible reintroduction of TMS” combined with antidepressant monotherapy, and those who initially achieved remission had a better prognosis.
Dunner et al. (2014) reported the 1-year outcome in 257 patients with major depressive disorder treated with TMS. The acute treatment response was reported by Carpenter et al. (2012). Because this was an observational study conducted across 42 clinical practices in the United States, all patients were permitted clinician-directed treatment as usual (i.e., patients were not limited to a predefined single antidepressant as in the Janicak et al.  study). Most were treated with antidepressant medications, and many received other medications (e.g., second-generation antipsychotic augmentation) during the acute and follow-up periods. Patients were allowed TMS reintroduction after acute treatment if deemed appropriate and prescribed by their physician. Other treatments such as psychotherapy were not reported. Over 60% of patients who had responded to or achieved remission during acute treatment with TMS sustained their response for 1 year. Ninety-three patients were treated with TMS during the ensuing 12 months of follow-up; the mean number of TMS sessions for this group was 16.2. Of the 45 subjects who did not maintain their remission or response status, 31 relapsed within 6 months. No safety or tolerability issues were noted during reintroduction of TMS.
These studies indicate that acute TMS therapy is beneficial for most patients with more chronic forms of depression for up to 4 months. Although research studies of TMS involved antidepressant medication–free patients, in clinical practice most patients continue medication after the acute phase and do not reduce their medication loads (Carpenter et al. 2012; Dunner et al. 2014). Having access to flexible doses of TMS to treat recurrent symptoms during the continuation phase improves durability, and most patients with such access require fewer TMS sessions to maintain their remission or response status. Continuing medication and reintroducing TMS is effective, but more research is needed to determine whether it is the optimal strategy for keeping patients well. For example, head-to-head studies comparing different protocols are needed, and researchers need to clarify whether participants are allowed to simultaneously receive other treatments with TMS.
Following TMS treatment, patients should be closely monitored, and their symptoms should be measured with a validated depression questionnaire. Research is needed to try to determine which patients are at most risk for relapse. Perhaps certain clinical or demographic variables predict relapse after TMS therapy. Several candidate variables were examined in the studies described in this section, but the results are inconsistent. Overall, patients who achieve remission with acute TMS have the best prognosis for maintaining response.
Maintenance TMS Sessions to Prevent Relapse or Recurrence
Because maintenance antidepressants and psychotherapy are effective in delaying a relapse or recurrence of depression, it would seem logical that providing TMS in some ongoing manner after response would also provide protection against relapse or recurrence. Table 6–2 summarizes several published TMS maintenance studies. Before 2015, the studies were retrospective or prospective observational studies without a comparison group, or they were case reports (Chatterjee et al. 2012; Demirtas-Tatlidede et al. 2008). Most defined maintenance TMS as scheduled sessions delivered weekly (e.g., 1–2 sessions/week) with a taper to a frequency of monthly (e.g., 1 session/month) delivered during the continuation phase. TMS delivered in this fashion preserves the response and remission rates obtained in the acute phase of treatment, or at least delays the decrement in the antidepressant effect achieved after the acute phase.
Two of the more recent studies used deep TMS (dTMS), which is a TMS device with an H1 coil rather than a figure-eight coil. These studies indicate that continuing TMS after acute response or remission can benefit patients. In the Harel et al. (2014) study, subjects participated in three distinct phases: 1) an acute phase for 4 weeks in which daily dTMS sessions were conducted five times per week, for a total of 20 sessions; 2) a first continuation treatment phase for 8 weeks, in which dTMS sessions were conducted twice a week for a total of 16 sessions; and 3) a second continuation treatment phase for 10 weeks, during which dTMS sessions were conducted once a week. Patients also continued their antidepressant medications. A significant decrease from baseline in HDRS score was found at the end of the acute phase (P<0.0001) and maintained throughout the 18-week study. Furthermore, the probability of response and remission increased over the course of the study, almost doubling for those who received continuation treatment.
The study by Levkovitz et al. (2015) also included a continuation treatment phase. The investigators randomly assigned 212 patients with TRD to monotherapy with dTMS or sham dTMS. Patients received daily sessions for 4 weeks, and 159 patients were available to continue twice-weekly sessions for 18 weeks. Response and remission rates were higher in the dTMS group than in the sham group (P=0.013 response; P=0.005 remission), and these benefits were preserved during the next 3 months with maintenance dTMS.
Research indicates that the benefits from TMS can be preserved with scheduled TMS sessions or with monitoring and then reintroducing TMS when symptoms recur. A relevant concern is how to proceed clinically when patients are finishing their acute course. In a pilot study, Philip et al. (2016) attempted to address this issue by comparing outcomes in patients who received either scheduled TMS or observation after a 6-week course of TMS therapy. Forty-nine patients who met response criteria at the end of the acute phase were randomly assigned to one treatment monthly or to a monthly visit without TMS treatment during 12 months of follow-up. Patients in both groups who relapsed could receive reintroduction TMS. Importantly, subjects remained medication free during the acute and follow-up periods. Over 80% of subjects in both groups met criteria for remission at the end of acute treatment, defined as a score of 7 or less on the 17-item HDRS. Subsequently, there was no between-group difference in the number of patients who did not require TMS reintroduction (the primary outcome variable). However, TMS-treated patients had a slightly longer duration to first relapse (91 vs. 77 days); were slightly less likely to require retreatment with TMS (39% vs. 35%); required fewer retreatments in case of relapse (14.3 vs. 16.9); and showed a slightly higher percentage of response to retreatment (78% vs. 63%). In summary, in this study, which had a small sample size (i.e., 49), both approaches were comparable based on the primary and secondary outcomes.
Frequency of TMS
6 months to 6 years
3 patients maintained response
Tapered to 1 session/month
62% maintained response
Clustered 5 treatments over 2 days monthly
Delay in relapse
Tapered to 1 session/month
38% relapsed with maintenance, whereas 68% relapsed without maintenance
Twice-weekly sessions for 8 weeks, then weekly
50% remission rate at end of study
Prospective, sham controlled
Active treatment superior to sham
No significant differences between groups
Note. N=number of subjects.
Pharmacotherapy After Acute TMS Treatment to Prevent Relapse or Recurrence
Providers may choose to use antidepressant medication instead of TMS maintenance or reintroduction to prevent relapse. Schüle et al. (2003) reported a study of 26 medication-free patients with major depression who were treated with TMS, to which 39% responded after 2 weeks. Patients then received mirtazapine alone for 4 weeks, and then 13 of the patients had additional lithium, carbamazepine, or antipsychotic medication for the last 2 weeks. After 6 weeks, 77% achieved response. Although the authors suggested that pharmacotherapy after TMS could improve response rates, the sample size was small and the study duration was brief (i.e., within the time usually allocated for acute treatment).
Kedzior et al. (2015) performed a meta-analysis of 16 double-blind, parallel-design, randomized controlled trials utilizing acute TMS and reported the results of available follow-up data. Maintenance TMS was not provided in any of these trials, but medication after acute TMS treatment was allowed. Subjects received high-frequency TMS over the left dorsolateral prefrontal cortex for 2–3 weeks (i.e., 10–15 treatment sessions). Most of the studies had brief follow-up data (i.e., 1–4 weeks after the last TMS session); only one study reported more than 3 months of follow-up. The authors noted that the durability of the antidepressant effect of TMS was “small but stable” and that posttreatment antidepressant pharmacotherapy tended to enhance the antidepressant effect. The analysis was limited, however, because of the relatively short courses of TMS therapy used in the 16 trials. By contrast, most patients today receive up to 6 weeks of treatment (30 sessions) during the acute course.
Typical coverage policies
Major plans will cover, but some conditions may apply. Most plans require at least a 50% improvement in depressive symptoms with TMS in a prior episode. Some plans require a 3- to 6-month waiting period.
Repeated courses of TMS treatment
Most plans will cover. Most require either a 50% improvement or remission in the previous course. Some plans require a 3- to 6-month waiting period.
Typically, most plans do not cover “maintenance TMS.” However, some plans may approve, on a case-by-case basis, time-limited scheduled TMS—that is, “extended taper”—with a plan to decrease utilization.
In clinical practice, providers advise patients to monitor their symptoms closely and continue with psychotherapy and pharmacotherapy after TMS. It is rare for insurance policies to include coverage of TMS during the continuation or maintenance phases (Table 6–3). We recommend that patients who have responded to TMS in the past restart TMS if they relapse, and most major insurance policies will cover “reintroduction treatment” on a limited basis. In certain communities and in specific clinical circumstances, however, patients are prescribed scheduled TMS treatments (McClintock et al. 2017; Perera et al. 2016). Patients with multiple relapses who continue to benefit from reintroduction may benefit from a more frequent schedule of TMS therapy (e.g., once a week) with a longer taper over many months, as is often the practice with ECT treatment (Sackeim 2016).
Psychotherapy After Acute TMS Treatment to Prevent Relapse or Recurrence
There is no research indicating that psychotherapy improves the durability of TMS. However, certain psychotherapies are effective for residual depressive symptoms and relapse prophylaxis (Dobson et al. 2008; Frank et al. 1991). For example, mindfulness-based cognitive therapy is effective for patients with TRD, especially those who have a history of childhood trauma (Williams et al. 2014), unstable pharmacotherapy remitters (Segal et al. 2010), and those who have experienced three or more depressive episodes (Piet and Hougaard 2011). Many TMS practitioners will refer patients to psychotherapy as the patients’ depressive symptoms are decreasing and they are responding to TMS. Many patients report increased or new benefits from psychotherapy, and restarting psychotherapy can be an opportunity to work on recovery and correct maladaptive patterns that may have developed during their depressive illness. Other important lifestyle changes can be effective as the patient responds (e.g., dietary changes, weight loss, improved sleep hygiene, exercise) (see Chapter 5, “Transcranial Magnetic Stimulation and Psychotherapy”).
The patient is a 27-year-old woman with a 3-year history of major depression. After 6 weeks of TMS therapy, her PHQ-9 score decreased from a baseline of 21 (severe) to a posttreatment of 9 (mild). During her TMS taper, she started duloxetine and began interpersonal psychotherapy. At her 1-month post-TMS visit, her PHQ-9 score was 12, so duloxetine was increased from 30 to 60 mg/day. She presented to her general psychiatrist for her second follow-up visit with a PHQ-9 score of 17 and reported worsening depressive symptoms since tapering TMS 3 months earlier, as well as sexual side effects from her antidepressant. Her general psychiatrist referred her for reintroduction TMS therapy, which the patient began with two sessions/week for 2 weeks, at which point her PHQ-9 score was 9. She then received one session/week for 3 weeks followed by one session every other week for 4 weeks (i.e., a total of nine sessions over 9 weeks). One month later at her next visit, her PHQ-9 score was 5.