Combined transcranial magnetic stimulation and brief cognitive behavioral therapy for suicide: study protocol for a randomized controlled trial in veterans

Participants will be veterans aged 18–70, any gender, and receiving care at the VA. They must be able to comply with all study-related procedures and visits and be capable of independently reading and understanding study materials and providing informed consent. Participants recruited from the inpatient unit must have been admitted due to suicide ideation with a suicide plan, or a suicide attempt in the prior 2 weeks. Participants recruited from outpatient settings must have attempted suicide or reported a plan to commit suicide in the prior 2 weeks.

Participants will be excluded if they meet diagnostic criteria for a primary psychotic (e.g., schizophrenia, schizoaffective disorder) or bipolar I disorder, or past month active moderate-to-severe substance use disorder (with the exception of dependencies on nicotine or caffeine). Medical exclusionary criteria specific to TMS include current significant cognitive impairment (e.g., dementia), current unstable medical condition, prior moderate-to-severe traumatic brain injury, current (or past, if appropriate) significant neurological disorder, or a lifetime history of seizures (except febrile seizures of infancy), central nervous system tumors, stroke, or cerebral aneurysm. Moreover, participants with certain medical conditions that may render TMS administration unsafe, such as having a cardiac pacemaker, or implanted device or metal in the brain, cervical spinal cord, or upper thoracic spinal cord, will be excluded from the study. Female veterans who are pregnant or planning to become pregnant during the study or are of childbearing potential and do not agree to a consistent use of a measure of birth control during the TMS portion of the study will also be excluded from participation.

This study will build on recruitment and retention strategies used by the investigative team across clinical trials of TMS in veterans [47] and cognitive therapy for severely depressed and suicidal inpatients [48‐51]. In our prior TMS research in veterans, more than 90% of participants completed the intensive daily TMS treatment protocol [47]. In our suicide prevention study (Veterans Coping Long Term with Active Suicide Program), we recruited and retained over 100 high-risk veterans throughout the course of treatment, with most returning for multiple follow-up assessments (80% at 3 months). These data support the feasibility and acceptability of our treatment protocol for patients.

Participants will be randomized to condition via an urn randomization strategy [52, 53]. Urn randomization is a biased coin technique, which randomly assigns veterans of a given subgroup to treatment conditions while systematically biasing randomization to balance treatment conditions on select variables. Here, randomization will be stratified along the following variables related to suicidal behavior or intervention response: admission for suicide attempt vs. suicide ideation, number of previous suicide attempts (none vs. single vs. multiple), and gender (male vs. female). The data analyst for this study will generate a reference document containing the number of participants to be randomized into the treatment conditions in these strata. This reference document will be input to the randomization feature in Red Cap which will ensure that the correct number of participants by strata is randomized per condition.

Participants will be randomized prior to the start of treatment. Each participant will be randomly assigned to one of the treatment groups via the Red Cap computer program by inputting strata features for each patient into Red Cap. Only study team members responsible for ensuring the integrity of the TMS condition (e.g., staff who switch the TMS active and sham coils and do not administer assessments or treatment) will be un-blinded. Each participant’s resulting treatment condition will be recorded in a participant randomization key stored on a secured computer folder accessible only by un-blinded treatment staff.

Following randomization, participants will complete a 12-week course of BCBT in conjunction with 30 sessions of daily (active or sham) TMS. Prior to each BCBT session, participants will complete the Beck Scale for Suicide Ideation (SSI) [39] to obtain weekly ratings of suicide risk. Symptoms of depression and post-traumatic stress disorder will be measured every 5 sessions of TMS. After completing TMS treatment, participants will finish the remaining BCBT sessions. The intervention will be administered in addition to treatment-as-usual (e.g., pharmacotherapy).

Participants will receive a standard course of BCBT [7] (12 weekly individual therapy sessions; the first session is 90 min and the remaining eleven sessions are 60 min in duration) provided by a VA mental health counselor. The therapist will have experience and training in cognitive behavioral therapy principles and be trained and supervised weekly by the creator of the BCBT treatment to meet fidelity standards set forth in the BCBT treatment manual. Therapy is divided into three phases: orientation, skill focus, and relapse prevention. Phase one (orientation) includes creating a model of how suicide functions for the patient, developing a safety plan, enhancing treatment motivation, and developing basic emotion regulation skills. Phase two (skills focus) centers on the consolidation of emotional regulation, problem-solving, mindfulness, and cognitive appraisal skills. Phase three (relapse prevention) continues with skills learned in phase two but with a focus on skill generalization and maintenance. Participants will be asked to complete weekly homework tasks to practice skills learned in each therapy session. Therapists will follow the structure and format outlined in the brief cognitive behavioral therapy manual [54] and attend weekly supervision and clinical consultation with one of the therapy developers. Sessions will be audio recorded for subsequent ratings of treatment fidelity. Study therapists will be blind to the treatment condition of each participant.

To limit heterogeneity of therapy administration, participants will be asked to temporarily refrain from other individual psychotherapy, particularly psychotherapy that is CBT-based, while receiving BCBT. However, they will be instructed to continue with all other usual mental health care (i.e., continue prescribed mental health medications and working with their mental health providers).

Participants will receive 6 weeks of daily TMS (i.e., active or sham). Prior to receiving TMS, participants will complete a motor threshold determination to determine the neurostimulation threshold to be used during treatment. The motor threshold is defined as the amount of energy administered via a coil that is required to induce movement in the contralateral hand in at least 50% of stimulations. A separate coil system is used for motor thresholds to reduce accidental unblinding. After the motor threshold is determined, each participant will begin the TMS treatment protocol.

TMS stimulation will use a triple-blind stimulation procedure as implemented in prior randomized controlled trials [47]. Prior to each TMS session, an unblinded study member will assure the setup of either an active or a sham coil according to the participants’ randomization code. Blinded study staff will administer stimulation treatment under the supervision of a blinded attending physician, and participants will not know whether they are receiving active or sham TMS. The sham stimulation coil for this study was selected because it administers sensations to the scalp that are indistinguishable from those experienced during active stimulation (e.g., [50]). To assess the integrity of the blind, participants will be asked which treatment condition they believe they were in at the end of the TMS treatment protocol. TMS treatment (both active and sham) will be delivered using a 70-mm cooled coil via a MagStim Super Rapid 2 + 1 system. Intermittent theta burst TMS will be used for this study; this option was selected because a) it is cleared by the US Food and Drug Administration for pharmacoresistant major depression, and b) each session takes approximately 3 min, thus easing the combination of stimulation and therapy. The (active or sham) coil will be positioned over the left dorsolateral prefrontal cortex using individual scalp landmarks (i.e., Beam/F3 method) [55]. We will use the coil to deliver intermittent theta burst stimulation to the treatment site for 600 pulses at 120% of motor threshold; if participants are unable to tolerate this intensity, we will utilize theta burst delivered at 80% for 1800 pulses (following guidelines from other research in this area [47]).

Several procedures are in place to monitor participants’ safety throughout the intervention period. Prior to each TMS session, study staff will verify patients’ medication adherence, assess for any substance use, and query about potential side effects, to ensure ongoing medical safety for TMS. As veterans in our sample are high-risk for suicide, consistent with good clinical practice guidelines in the VA system, participants will be screened for imminent suicide risk at the beginning of each TMS and BCBT session. When clinically indicated, the attending psychiatrist or a licensed therapist will meet individually with the participant to assess risk and identify emergency services if needed. Any adverse events will be reported immediately to the Providence VA IRB and included in the annual IRB report.

Participants will be discontinued from treatment if they choose to withdraw from the study, experience serious symptoms that may be related to the treatment (e.g., seizure, manic episode), and/or cease to be eligible for treatment (e.g., initiate or increase substance use in ways that contraindicate TMS administration). Given the high-risk nature of this patient population, when discontinued from the study, participants will meet with a member of the study staff to discuss alternative treatment options and potential referrals. Research staff will also contact other members of the participant’s treatment team at the VA system to notify them that the participant is no longer receiving care from the study, to facilitate continuity of care. No other information about the participant’s involvement in the study will be disclosed. Unexpected serious adverse events may require unblinding if the information is needed to make informed decisions about the study continuation or patient care. We will report expected and unexpected adverse events in the publication of the results of the trial.

Study staff will manually extract electronic health record data from participants’ VA medical charts. Data will be extracted to cover the period from baseline through 1 year from the start of the intervention. Study staff will extract information pertaining to health services utilization, medication management and changes, and mental health diagnoses to be used in data analyses. Death by suicide will be captured by review of medical records and death records.

The primary outcome (see Table 2) is suicidal events (a composite of all actual, interrupted, and aborted suicide attempts measured by the Columbia Suicide Severity Ratings Scale and Longitudinal Interval Follow-Up Evaluation interviews; CSSRS) at treatment endpoint. Secondarily to this primary outcome, we will examine effects of treatment condition on suicidal ideation severity, number of weeks of active suicidal ideation, suicide attempts, and time to first suicide event after discharge (measured by the Columbia Suicide Severity Ratings Scale and Longitudinal Interval Follow-Up Evaluation interviews; CSSRS). Subsequent time points are considered secondary outcomes.

Besides the primary outcomes, this study will examine multiple secondary outcomes (see Table 2). We will examine improvements in psychosocial functioning (measured by the World Health Organization Disability Assessment Schedule 2.0; WHODAS) and the number of crisis visits and psychiatric hospitalizations (measured by the Treatment History Interview (THI) and record review) measured at treatment endpoint and follow-up assessments.

We will also examine whether improvement in particular processes explains the impacts of treatment conditions on our outcomes of interest. In particular, we will examine changes in suicide risk factors (e.g., hopelessness, global functioning) and associated psychiatric symptoms (e.g., depressive symptoms). These variables will be measured using the self-report questionnaires and interviews collected during the endpoint and follow-up assessments, as noted in Table 1.

During data collection, several processes will be employed to improve data quality and completeness. Protocols will be developed to describe the procedures that should be completed at each study visit. Research staff will document the completion of each aspect of visit procedures and data collected on case report forms that will be developed by the investigative team. Before the end of each visit, the study staff will review all self-report and interview forms for completeness and ask participants to answer any remaining questions.

To protect participants’ confidentiality, participant data will be labeled using a unique participant identification code that contains no personal identifiers. Paper data will be stored securely in locked file cabinets, and electronic data on VA secure servers accessible only by study staff. Access to participant-identifiable information and data will be limited to researchers included in this study protocol.

Study staff will employ several strategies to promote data quality, including double data entry, and range checks for data values during study analyses. Interview assessments will be audio-recorded and double-rated for inter-rater reliability purposes and to resolve discrepancies in coding. BCBT sessions will be audio recorded for subsequent ratings of the fidelity of sessions to the BCBT manual. Fidelity ratings will be conducted for 25% of therapy sessions (with sessions randomly selected) by an independent rater based on fidelity checklists provided in the BCBT manual and regularly conducted throughout the course of the clinical trial. Where appropriate, providers not meeting fidelity standards will be supported through further training and additional case supervision time to meet fidelity standards.

A Data Safety Monitoring Board (DSMB) will be responsible for making recommendations to the Principal Investigators regarding changes to the risks and benefits of the study, including recommendations to discontinue new patient enrollments or discontinue the study. The DSMB will be independent from the sponsor and competing interests. The DSMB members will include the study investigators, a suicide prevention expert, a medical expert in TMS, and an expert in statistical analysis. Investigator members will have a reputation for objectivity, absence of conflict of interest (and appearance of the same), and knowledge of clinical study methodology. The DSMB will meet every 6 months to review study progress and any concerns. Participants will be contacted and notified/re-consented in the event that there are important protocol modifications made that impact their participation in the study after being enrolled. All data will be stored for a minimum of 6 years following the end of the trial, in accordance with VA policy.

Approximately 130 veterans will be recruited for this study (65 per treatment group). According to Lehr’s equation [60], this sample size powers this study to detect a medium-sized difference (Cohen’s d = 0.5) on our primary outcome (a composite of suicidal events) between treatment groups. This effect size magnitude was selected because it is likely to describe effects of minimal clinical significance or practical importance while being robust to expected attrition (< 10% of attrition among Veterans in our prior intensive TMS studies). This effect size is informed by prior stimulation studies reporting effect sizes of d = 0.5 on reductions in depressive symptoms [47]. We note that other studies have found even larger (d = 0.9) effect sizes of TMS used with medications [63]. We selected improvement in depressive symptoms as a reference for our power analyses because reductions in depressive symptoms and suicide ideation were highly correlated in our pilot work [27]. We used simulations to estimate the minimum detectible differences on our secondary outcomes (i.e., suicide attempts, suicidal ideation severity, weeks of active suicidal ideation, time to first suicide event). Assuming that 21% of the sample will experience a suicide attempt over 12 months follow-up, if the cumulative risk of suicide attempt is 4.5% over 12 months in the TMS + BCBT group (hazard ratio = 0.19), we will have 81.1% power to detect such an effect using a type-I error rate of 5% in a Cox proportional hazards model framework.