MST for treatment-resistant depression

Introduction

Magnetic seizure therapy (MST), as the name implies, is a treatment that involves the induction of therapeutic seizures generated through magnetic fields. The impetus for developing this treatment was the goal of achieving comparable therapeutic effects to ECT, while minimizing its cognitive side effect profile. ECT is known to be a highly effective treatment for treatment-resistant depression (TRD) ( ), and this is reviewed in detail in this book in Chapter 19 . As highlighted in this chapter, ECT is the most effective treatment for depression with a remission rate of up to 75% in TRD ( ). Although it has impressive treatment effects, a significant proportion of patients do not tolerate the treatment due to troublesome side effects that include postictal confusion ( ), anterograde and retrograde memory loss ( ), and other cognitive sequelae ( ). In fact, difficulties forming new memories can last up to several months after completion of a treatment course of ECT ( ; ; ), and although rare, the loss of past memories, formed prior to a treatment course, remains as a serious adverse effect ( ).

ECT has been optimized and fine-tuned to improve its tolerability. For example, the development of right unilateral ultrabrief pulse width ECT demonstrated similar efficacy in treating depression, with fewer cognitive side effects in comparison to standard ECT techniques ( ; ). Evidence suggests that higher electrical field charge can predict cognitive outcomes for ECT, and that RUL ECT tends to have far fewer adverse cognitive effects than bilateral ECT ( ). This advancement in ECT delivery was made possible with knowledge of the neurophysiology of neuronal depolarization ( ; ). This supports the notion that rational approaches to improvements in convulsive therapy are warranted and may lead to additional advances in the future. Even with these advances in ECT practice, cognitive side effects and negative stigma still greatly limit its use and accessibility, as less than 1% of patients with TRD end up receiving this treatment ( ). Therefore, the development of MST brings the promise of a fresh approach with the hope for little to no cognitive side effects, presumably as a result of more focal stimulation and an altogether different method of stimulus ( ). Based on the concept of electrical shunting from impedance of the skull and cerebrospinal fluid, electrical fields produced through electromagnetic induction could in theory greatly improve targeting of brain structures and eliminate cognitive side effects. The hope for MST is that it will achieve similar efficacy to ECT, but with a superior cognitive side effect profile to reduce the morbidity for patients with severe psychiatric and treatment-resistant illness.

In this chapter, we first review the origins of MST and then explore recent advances in the use of MST in TRD and related conditions. We then focus on research exploring potential mechanisms of action of MST. This chapter includes a review of the safety, efficacy, and adverse effects of MST.

History and development

The initial development of MST emerged out of work in the mid-1980s on the magnetic stimulation of nerve and muscle tissue in healthy individuals and patients with neurological conditions. Barker was the first to report on subconvulsive magnetic stimulation in the human brain, and described its relative ease of use, limited adverse effects, and the great clinical potential of this technology, in comparison to pure electric stimulation ( ). Barker found significant ease in dealing with the high resistance structures of the skull in order to produce muscle contractions in the contralateral limb, which was previously seen with electric impulses ( ). This early work was with magnetic stimulators capable of frequencies only as high as 0.33 Hz, and so development of magnetic stimulators capable of much higher frequencies of stimulation would later be essential for the advancement of this field in psychiatry, and medicine in general ( ).

Soon after Barker’s work researchers using magnetic stimulators capable of repetitive transcranial magnetic stimulation (rTMS) showed that, while overall safe, rTMS had the capability to induce generalized tonic-clonic seizures in healthy individuals without epilepsy with frequencies as low as 10 Hz stimulation ( ). While unwanted in this particular study, this finding would later be the basis for purposefully induced therapeutic seizures with magnetic stimulation. In 1994, Sackeim commented on the potential of this technology and described how MST could drastically increase the specificity of brain areas targeted in convulsive type treatment, which could theoretically reduce or eliminate side effects seen with ECT treatment; brought about by discharge of deeper brain structures ( ). This then spurred the first investigations of magnetic seizure therapy in mammals and primates, and later in human subjects.

Lisanby et al. performed the seminal translational research and early troubleshooting that brought MST from the bench to the bedside, with the development of optimal treatment parameters and targeting of specific brain regions ( ). The first MST device could produce frequencies of 25 Hz, and would not induce seizures reliably in macaques ( ). Yet, they were able to demonstrate consistent seizures with a device capable of a treatment frequency of 40 Hz with a 6.3 s train duration and machine output of 90% intensity. With this device though the authors describe struggles with overheating coils, which would be a major limitation in later clinical trials ( ). A subsequent report demonstrated the first successful use of MST in a human, a case report of a young female patient diagnosed with TRD who received four MST treatments during a course of ECT ( ). In this case, 40 Hz stimulation was administered over the right prefrontal cortex for 4 s; the patient did experience modest clinical improvement ( ).

MST devices capable of 50 Hz frequency for 8 s train durations were developed next ( ), and in 2003, Kosel et al. published a case report on the first full MST treatment course for a patient with TRD with these treatment parameters ( ). This patient was in remission after 12 treatments, and importantly, there were minimal side effects, no memory issues, and a fast reorientation time after treatments, with overall improvement in verbal and nonverbal learning tasks ( ). Concurrent with the above human studies, a histological analysis in 12 macaques randomized to full courses of ECT, MST and sham demonstrated a clear absence of structural brain damage with MST treatment ( ). These early reports suggested both safety and efficacy of MST, and they set the stage for several case series and small pilot studies on the safety and feasibility of MST as a treatment for TRD.

In the first clinical trial to prospectively investigate the effects of MST in patients with TRD, Lisanby et al. studied the effect of MST in 10 inpatients in a within-subject comparison to ECT during an acute treatment course ( ). In this study, the authors treated these inpatients with two MST treatments, with a maximum output of 60 Hz treatment at 100% output for 6.6 s with successful tonic-clonic seizures in all 10 patients ( ). The authors experimented with three different coil arrangements and with different coil types as well in this study ( ). They found an overall more favorable cognitive side effect profile posttreatment with MST treatments when compared to ECT treatments on the same patients during the same treatment course ( ). This study, however, was not designed to compare the efficacy of MST to that of ECT. It is also important to note that the authors reasoned that the maximum treatment output was limited with the MST technology of that time, and they suggested that a direct comparison of efficacy and tolerability for equivalently dosed MST and ECT would be needed in the future. We review studies that address these specific issues below.

By this point, the High Dose MST device was developed to answer the issue of equivalent dosing for ECT and MST, as it was able to provide stimulation at 6 × the seizure threshold, identical to that used in right unilateral ECT. This MST device also provides 100 Hz frequency for a duration of 10 s ( ) and is currently used in major clinical trials of MST. Kirov et al. were the first to test this machine in a pilot, feasibility study in 11 patients with MDD or schizoaffective disorder ( ). They tested both frontal and vertex stimulation targets with more consistent seizures found with the vertex stimulation approach. No adverse effects were seen, and similar to that seen in the above studies, reorientation time after stimulation was much quicker with MST compared to ECT in these patients. Further technical advances in the delivery of MST would allow for more reliable seizure induction in the frontal cortex target, the main target in recent, large clinical trials described below.