Transcranial Magnetic Stimulation (TMS) Maintenance as a Substitute for Maintenance Electroconvulsive Therapy (ECT) - A Case Series

Abstract

Background

TMS is an efficacious, well–tolerated, non-invasive brain stimulation treatment for major depressive disorder. ECT is an effective maintenance treatment for depression but is not tolerated by some patients and declined by others.

Objective

We evaluated the effectiveness of TMS as a substitution strategy for successful maintenance ECT.

Methods

A consecutive clinical case series (n=6) of maintenance ECT patients were transitioned to maintenance TMS due to side effects from ECT or because of specific patient request and preference. Patients were in either full remission or had clinical response to ECT at the time of transition. Primary outcome was the change in the Beck Depression Inventory (BDI) score from initiation of TMS maintenance sessions to the last observation time point.

Relapse of depressive symptoms was also documented.

Results

Mean age of patient was 64 years and most were female (n=5). The majority (5 out of 6) were diagnosed with major depressive disorder (MDD). Reasons for transition from ECT to TMS were in order of frequency: cognitive side effects, fear of general anesthesia, time burden, lack of remission with ECT, and stigma associated with ECT. The mean frequency of TMS sessions was 1 every 3.5 weeks . Based on BDI scores, all patients maintained or improved their clinical status achieved with ECT at 3 and 6 months of TMS treatment. At last observation (Range: 7 to 23 months) 4 patients maintained or improved their clinical status (total BDI score remained constant or decreased by 1–8 points). Two patients relapsed after 8 and 9 months. Stimulation was well tolerated with side effects limited to headache and scalp discomfort.

Discussion

In this case series TMS was effective and safe when used as a substitution strategy for successful maintenance ECT.

INTRODUCTION

Electroconvulsive therapy (ECT) is an effective maintenance treatment for depression, but it is not tolerated by some patients and declined by others. It is not infrequent that patients choose to not undergo maintenance ECT even after responding to an acute course or decide to discontinue maintenance ECT due to poor tolerability, logistic difficulties, or stigma associated to ECT.

Transcranial Magnetic Stimulation (TMS) is a noninvasive neuromodulation procedure approved by the Food and Drug Administration (FDA) for the treatment of patients with major depression who have failed one adequate antidepressant trial in the current episode.¹ TMS offers a generally more favorable side effect profile than ECT or antidepressant medications.² Nonetheless, improvement of depressive symptoms after completion of a TMS course tends to dissipate over time as reflected by Janickak PG et al. in patients with MDD that responded to TMS (~ 6 weeks) and transitioned to antidepressant monotherapy (n=99). After 6 months 38.4% of patients reported worsening symptoms and 10% relapsed. ³ Long term efficacy or TMS in depression was also studied by Mantovani et al. who reported a 3 month relapse rate of 13.5% among patients that achieved remission with TMS.⁴ Dissipation of antidepressant benefit from TMS after discontinuation was also reported by Cohen et al. In their 204 patient sample, 60% of patients remained in sustain remission 3 months after completion of a TMS course. This proportion decreased to 22.6% after 6 months. ⁵ Available evidence supporting TMS use as a maintenance treatment for mood disorders is limited to case reports, case series, small prospective studies ^6–10 and its role as an alternative to ECT in the maintenance treatment of major depression has not been studied.. TMS for recurrent depression as a substitute for maintenance ECT may be valuable for patients that are unable to continue ECT due to side effects or lack of sustained benefit. In this case series we evaluated the effectiveness of TMS as a substitution strategy for successful maintenance ECT.

METHODS

Data were collected prospectively in a consecutive case series (n=6) of maintenance ECT patients who transitioned to maintenance TMS due to side effects from ECT or because of specific patient request and preference. Patients underwent ECT (i.e., index course followed by continuation and maintenance treatment) for major depression and were in either full remission (total Beck Depression Inventory [BDI] score ≤9 not meeting DSM criteria for major depressive episode) (n=1) or had clinical response (improvement greater than 50%) to ECT (n=5) at the time of transition. Improvement were sustained over time with maintenance ECT. Frequency of ECT sessions ranged from once a month to once every two months before the transition to TMS. Previous to transitioning to TMS and during the transition period, 2 patients received ECT with unilateral electrode placement (i.e., D’Elia). Another 2 patient received bilateral stimulation. The remaining 2 patients received ECT in an outside hospital and information on electrode placement is not available to us at this juncture. Medications were held fixed, as clinically feasible, during the transition and post transition observation period. Of note 1 subject (subject # 2) was on a stable dose of Lamotrigine and a total of 2 subjects (subject #3 and #5) were on fixed dose of benzodiazepines pre TMS and during transition period. The MagPro R30 (Magventure, Inc., Copenhagen, Denmark) and the Magstim model Rapid2 (Magstim Ltd, Whitland, UK) devices with a figure 8 coil were used to deliver TMS on an off-label basis at the neuromodulation treatment program of the University of Pennsylvania. All patients had an evaluation with an attending psychiatrist with expertise in TMS. Safety measures consistent with TMS consensus guidelines ¹¹ were applied, including hearing protection and availability of oxygen and anticonvulsant medications.

Primary outcome was the change in the BDI score from initiation of TMS maintenance sessions (baseline) to last observation time point. Relapse of depressive symptoms was documented and defined, in this study as a BDI score higher than the one at initial observation (baseline – prior to first TMS session)Outcomes were assessed generally every 2 weeks and analyzed at 3 months, 6 months, and at last observation after transition to TMS.

RESULTS

Mean age of patient in the series was 64 years (Range: 41–79). Most were female (5 out of 6) and recurrent unipolar depression was the most common diagnosis [MDD (n=5); Bipolar-I (n=1)]. All of the patients had psychiatric comorbidities with generalized anxiety disorder (GAD) being the most prevalent (n=4). Reasons for discontinuation of ECT were, in order of frequency: cognitive side effects (5/6), fear of general anesthesia (5/6), perceived time burden of ECT (5/6), lack of remission with ECT (2/6), and perceived stigma associated with ECT (1/6).

The majority of patients received left dorsolateral prefrontal cortex stimulation (DLPFC) as the initial TMS placement of choice. One subject was started on bilateral stimulation due to significant residual symptoms of depression. A ratio of 1:2 relative frequency of ECT to TMS sessions was used during the transition period (during which patients received both treatments i.e. 1 ECT sessions and 2 TMS sessions per month for 2–3 months). One patient was switched directly from one ECT session per month to 2 TMS sessions per month. (i.e. 1:2 ratio without overlapping).

Settings for stimulation of left DLPFC consisted of 80 trains of 5 seconds each at 10 Hz with a 15 seconds inter-train interval, 110–120% motor threshold (MT), 4000 pulses per session. Stimulation over the right DLPFC consisted of 300–600 pulses at 1 Hz for 300–600 at 110–120% of MT per session. A total of 4 patients required further optimization of stimulation parameters: increase in number of pulses per session (n=4) up to maximum of 6600 pulses per session, crossover to bilateral TMS (n=2), or increased frequency of sessions (n=2).

The mean frequency of TMS sessions at the last observation time point was 1 every 3.5 weeks (range:1/week to 1/8weeks). The cohort received a grand cumulative total of over half a million pulses (627,600) with only transient and mild intra-session side effects (i.e. headache (n=1) and scalp discomfort (n=1)). No serious adverse events were reported.

Change in BDI scores from initial observation (baseline – prior to first TMS session) to 3 months, 6 months, and last observation with TMS are presented in figure 1. All patients maintained or improved the clinical status achieved with ECT at 3 and 6 months of TMS treatment. At last observation time point (Range: 7 to 23 months. i.e., 20 months for patient #1, 7 months for patient #2, 16 months for patient #3, 23 months for patient #4, 9 months for patient #5, and 8 months for patient #6) 4 patients maintained or improved clinical status achieved with ECT (total BDI score remained constant or decreased by 1–8 points) and 2 patients (patient #5 and #6 in figure 1) were classified as relapsed [BDI total score higher than BDI at initial observation (baseline – prior to first TMS session)] Subject #5 responded to ECT but managed to achieve remission status with TMS (a BDI score of 9 or less) which was sustained for 6 months followed by relapse at 9 months. Subject #6, also an ECT responder, achieved remission with TMS but relapsed at 8 months and is currently receiving acute treatment. One patient (subject #2) elected to transfer back to ECT after 7 months, despite maintaining responder clinical status with TMS (a total BDI score of 13 at time of transition back to ECT).

Figure 1.

DISCUSSION

In our case series TMS was effective and safe when used as a substitution strategy for successful maintenance ECT for prolongation of remission/response status. Two patients worsened after 8 and 9 months of maintenance TMS despite improvement at 6 months when compared to their baseline clinical status upon transition from ECT. Thus 4 patients did well following TMS substitution and 2 relapsed, a better result than might have been expected. More over, these patients had severe symptoms with a treatment resistant course of illness, and were mostly females which are factors associated with faster relapse after an a acute course of ECT.¹² The relapse rate in our case series (2 out of 6 patients) at last observation (Range:7–23 months) is lower when compared to that of continuation ECT (37.1% at 6 months) in unipolar major depression.¹³

There is a paucity of research on substitution of ECT by TMS. Pridmore et al.¹⁴ randomized 22 depressed patients in a study examining right unilateral ECT alone at a standard frequency of 3 sessions per week versus the combination of TMS with ECT (with ECT frequency reduced to one per week with a TMS session on the other 4 days) for a total of 2 weeks of treatment. In this small underpowered study the antidepressant effect of ECT alone was not superior to that of the combination treatment. Combined TMS and ECT treatment exhibited a more benign side effect profile. The authors concluded that TMS sessions could be used in lieu of ECT sessions in an acute course without loss of antidepressant effect and with the advantage of minimizing the side effects relate to ECT. Based on their findings, the authors speculated that a 1:2 relation between ECT and TMS may be effective (i.e., one unilateral ECT session may be equivalent to 2 TMS sessions).¹⁴

Of note, the maintenance schedule used in our series was rather liberal when compared to schedules used in maintenance ECT considering a potential 1:2 ECT to TMS ratio. Perhaps, as it is the case with ECT, a shorter interval between sessions and a more gradual taper of session frequency can improve outcomes.

Although this case series has multiple limitations including small sample size, open label design, concomitant use of medication, it is of importance given the sparse literature on maintenance TMS. To our knowledge this is the first reported experience on complete substitution of maintenance ECT by maintenance TMS for major depression. Further research to identify the optimal protocol for ECT to TMS conversion and maintenance TMS is needed.