A Two-site Pilot Randomized 3 Day Trial of High Dose Left Prefrontal Repetitive Transcranial Magnetic Stimulation (rTMS) for Suicidal Inpatients

Abstract

Background

Suicide attempts and completed suicides are common, yet there are no proven acute medication or device treatments for treating a suicidal crisis. Repeated daily left prefrontal repetitive transcranial magnetic stimulation (rTMS) for 4–6 weeks is a new FDA-approved treatment for acute depression. Some open-label rTMS studies have found rapid reductions in suicidality.

Design

This study tests whether a high dose of rTMS to suicidal inpatients is feasible and safe, and also whether this higher dosing might rapidly improve suicidal thinking. This prospective, 2-site, randomized, active sham-controlled (1:1 randomization) design incorporated 9 sessions of rTMS over 3 days as adjunctive to usual inpatient suicidality treatment. The setting was two inpatient military hospital wards (one VA, the other DOD).

Patients

Research staff screened approximately 377 inpatients, yielding 41 adults admitted for suicidal crisis. Because of the funding source, all patients also had either post-traumatic stress disorder, mild traumatic brain injury, or both.

TMS methods

Repetitive TMS (rTMS) was delivered to the left prefrontal cortex with a figure-eight solid core coil at 120% motor threshold, 10 Hertz (Hz), 5 second (s) train duration, 10 s intertrain interval for 30 minutes (6000 pulses) 3 times daily for 3 days (total 9 sessions; 54,000 stimuli). Sham rTMS used a similar coil that contained a metal insert blocking the magnetic field and utilized electrodes on the scalp, which delivered a matched somatosensory sensation.

Main outcome measure

Primary outcomes were the daily change in severity of suicidal thinking as measured by the Beck Scale of Suicidal Ideation (SSI) administered at baseline and then daily, as well as subjective visual analog scale measures before and after each TMS session. Mixed model repeated measures (MMRM) analysis was performed on modified intent to treat (mITT) and completer populations.

Results

This intense schedule of rTMS with suicidal inpatients was feasible and safe. Minimal side effects occurred, none differing by arm, and the 3-day retention rate was 88%. No one died of suicide within the 6 month followup. From the mITT analyses, SSI scores declined rapidly over the 3 days for both groups (sham change −15.3 points, active change −15.4 points), with a trend for more rapid decline on the first day with active rTMS (sham change −6.4 points, active −10.7 points, P = 0.12). This decline was more pronounced in the completers subgroup [sham change −5.9 (95% CI: −10.1, −1.7), active −13 points (95% CI: −18.7, −7.4); P = 0.054]. Subjective ratings of ‘being bothered by thoughts of suicide’ declined non-significantly more with active rTMS than with sham at the end of 9 sessions of treatment in the mITT analysis [sham change −31.9 (95% CI: −41.7, −22.0), active change −42.5 (95% CI: −53.8, −31.2); P = 0.17]. There was a significant decrease in the completers sample [sham change −24.9 (95% CI: −34.4, −15.3), active change −43.8 (95% CI: −57.2, −30.3); P = 0.028].

Conclusions

Delivering high doses of left prefrontal rTMS over three days (54,000 stimuli) to suicidal inpatients is possible and safe, with few side effects and no worsening of suicidal thinking. The suggestions of a rapid anti-suicide effect (day 1 SSI data, Visual Analogue Scale data over the 3 days) need to be tested for replication in a larger sample.

Trial registration

ClinicalTrials.gov Identifier: NCT01212848, TMS for suicidal ideation.

Introduction

Suicide is the 10th leading cause of death for Americans of all ages and is the number two killer of US young adults [1], [17], [23], [27], [37]. More Americans now die from suicide than die from car accidents [2], [3]. Someone in the US dies by suicide every 13 min [3]. Suicide is a major problem in the military [4]. For the past several years more soldiers have died by suicide than were killed in combat [5], [6]. Eighteen US veterans die each day by suicide [7].

Despite these grim statistics, clinicians have no truly effective treatment for acute suicidal crisis. Much of the research in the area of suicide has focused on understanding risk factors and trends, while perhaps undertaking large initiatives to reduce overall rates. Much less attention has been paid to developing new treatments for patients who are actively struggling with thoughts of suicide or who have recently tried to kill themselves. Recently there is renewed interest in acute treatments that have anti-suicide effects such as electroconvulsive therapy (ECT) [8], clozapine, lithium [9], [10], [11] and ketamine [12]. While suicide is common, it remains relatively rare, requiring large samples with extended followup to show an effect [13]. However studying enriched samples – patients who have recently attempted suicide – is particularly difficult, and these patients are often deemed too sick to study [14]. Thus, there have been relatively few controlled studies of interventions in the acute setting of a recent suicide attempt; what we refer to in this manuscript as a ‘suicidal crisis.’ Patients attempting suicide and those at high risk are routinely hospitalized in order to keep them from killing themselves and to remove them from the stresses in their lives that may be aggravating the situation. Hospital admission, with its structure and counseling, does result in reductions in suicidality [15], [16]. Commonly medications are adjusted or changed; however, the effect of antidepressant medications requires several weeks and thus is unlikely to quickly treat the suicidal crisis [17].

Repeated daily left prefrontal rTMS is a non-invasive approach to treating depression, differing from medications and electroconvulsive therapy (ECT) [18], [19]. The FDA has now cleared two devices for treating depression. Recent studies suggest that stimulating the prefrontal cortex non-invasively with transcranial magnetic stimulation (TMS) might rapidly reduce suicidal thinking [20]. Other open-label studies have demonstrated the feasibility of delivering higher doses of TMS in a short timeframe [21].

Daily prefrontal TMS is thought to treat depression by improving cortical-limbic regulatory control over emotional drive [18]. Some researchers have conceptualized suicidal crisis as a dysfunctional brain event (like a stroke). Although patients are not routinely psychotic, there is clear evidence that the governing prefrontal cortex is unable to do its job of regulating emotional drive, put problems in context, and plan for the future [22].

We therefore conducted this study to test the safety, feasibility, and potential efficacy of delivering high doses of rTMS to suicidal inpatients. As mentioned above, studying these patients is difficult, for both regulatory and administrative reasons. We sought inpatients either who recently attempted to kill themselves or who were hospitalized because their thoughts of suicide were so intense that they were not safe. Because no prior data existed about the safety of using TMS in this setting, or of this high dose of TMS to a vulnerable population such as patients in suicidal crisis, we could only conduct this first study in an inpatient setting. Moreover, as there were no efficacy data for treating suicidality with rTMS, and because patients were in a critical, life-threatening condition, we were ethically compelled to conduct this study in an adjunctive fashion such that subjects also received their prescribed anti-suicidal treatments, which allowed subjects to get the full benefits of hospitalization, medication changes and counseling.