Repetitive Transcranial Magnetic Stimulation as Treatment for Acute Suicidality in Adult Patients (rTMS)

Suicide was responsible for almost 40,000 deaths in 2011 in America. It is still singularly difficult to predict who is going to commit suicide and how to establish adequate interventions. Growing evidence supports the view that suicide is associated with poor decision making. Suicide is hypothesized to be triggered by stressful situations that create overwhelming psychological pain in an individual who chooses to terminate his/her own life, disregarding all future consequences. We have previously demonstrated rewarding impulsive choice common to both recent suicide attempters and suicidal depressed patients (1). Consistent with these findings, we hypothesize that high frequency repetitive transcranial magnetic stimulation (rTMS) of the left prefrontal cortex will improve impulsive response tendencies as measured by the delay discounting procedure, and this in turn will be associated with a faster resolution of suicidal ideation. To these effects we will be using a randomized control trial of rTMS in adult inpatients at the Psychiatric Research Institute (PRI) hospitalized for acute suicidality. At the conclusion of these studies, we will have tested the value of decision making in the development of suicide ideation and behavior, as well as piloted the use of rTMS in the treatment of these patients.

The proposed study seeks to improve the prevention of suicide by advancing our understanding of the neurobiology of suicide by using a randomized control trial of repetitive transcranial magnetic stimulation (rTMS) as a hypothesis driven intervention for acute suicidality. In 2010 suicide was responsible for more than 38,364 deaths in the United States and 447 in the state of Arkansas (CDC, 2012). Suicide represents the 10th leading cause of death in this country, and claims more deaths than chronic liver disease, hypertension, Parkinson's disease or homicide. Furthermore, suicide consequences extend beyond the termination of an individual's life to impact those that are left behind. These statistics are far more alarming because they are believed to be underestimates, with substantial numbers of suicides and suicide attempts undetected or misclassified. The high and rising prevalence of suicide is complicated by the clinical challenge of identifying those patients at highest risk for suicide. A variety of biological, psychological and social risk factors for suicide have been identified. However, we currently lack reliable predictors of suicide risk and must rely heavily upon self-report and clinical judgment. Thus, it remains singularly difficult to predict who is going to commit suicide. Therefore, there is an urgent unmet need to develop effective early detection methods and treatments for high-risk populations. Suicide has been described as "a permanent solution to a temporary problem" (Buchwald, 2006), reflecting the view that suicide is the result of poor decision making. The strongest biological finding in suicide research is the association with reduced serotonergic neurotransmission, particularly within the ventromedial prefrontal cortex (VMPFC) (Mann, 2003). This deficit in serotonergic neurotransmission is thought to impair cognition, predisposing patients to become more impulsive, rigid in their thinking, and poorer decision makers. Decisions during depressed states are tainted by negative affect and distorted negative cognitions (Martin-Soelch, 2009). However, suicide has been associated with cognitive impairments that go beyond those of depression. Asymptomatic patients with a history of suicide attempts exhibit significant cognitive deficits suggestive of generalized prefrontal cortex (PFC) dysfunction (Raust et al, 2007; Westheide et al, 2008), and corollary disruptions in risk assessment (Martino et al, 2010). Poor inhibition is found in suicide attempters when compared with patients with only suicidal ideation (Burton et al, 2011), and greater cognitive impairments are found in depressed patients with suicidal ideation compared to those without it (Dombrovski et al, 2010). It is possible that cognitive deficits may be specific to suicidal behavior rather than to any comorbid or specific psychiatric diagnosis because this observation holds true for suicidal patients with depression, bipolar disorder, and even temporal lobe epilepsy. However, most of these studies were performed in symptom-free patients, often months or years after the presence of suicidal ideation or behavior. In a previous report (Cáceda et al, 2014) we demonstrated that inability to delay gratification (choosing smaller immediate rewards over larger delayed rewards) is shared by both recent suicide attempters and depressed patients with suicidal ideation. On a follow up assessment, 5-10 days after the suicide attempt, reduction of suicidal ideation and intent was correlated with decreased symptoms of depression and recovery of delayed gratification impairments (Cáceda et al, 2014). These data are congruent with the hypothesis that stressful situations in combination with a biological and psychological predisposition may create a critical climate of overwhelming psychological pain in an individual who chooses an impulsive escapist strategy to terminate his/her own life discounting all future outcomes (Vohs et al, 2002). However, the underlying neural mechanisms remain unknown and therefore not amenable to therapeutic interventions. TMS is a noninvasive method to cause depolarization or hyperpolarization in the neurons in the brain using electromagnetic induction to induce weak electric currents using a rapidly changing magnetic field. TMS is a novel intervention developed in the field of neurology that has been used in the treatment of patients suffering from migraine, stroke, Parkinson's disease, tinnitus and depression. In healthy subjects, high frequency rTMS over the left DLPFC has been shown to alter impulsive choice behavior (to decrease delay discounting) in healthy individuals and in smokers (Sheffer et al, 2013). On the other hand, a trial of TMS by one of the leaders in the field has shown it to be safe and well tolerated in recent suicide attempters suffering from depression with comorbid post-traumatic stress disorder and traumatic brain injury (George et al, 2014). Dr. Mennemeier, the director of the Transcranial Magnetic Stimulation Laboratory in the Center for Translational Neuroscience has been using repetitive transcranial magnetic stimulation (rTMS) to understand and treat phantom sound perception in subjects with tinnitus and to examine risky choices and impulsive behaviors using delay discounting in smokers. We propose to replicate a randomized controlled trial of rTMS over 3 days in a sample of well characterized acutely suicidal inpatients. Our overall hypothesis is that 10 Hertz rTMS of the left dorsolateral prefrontal cortex (DLPFC) will correct impulsive choice behavior deficits found in acutely suicidal patients that in turn will translate into faster resolution of acute suicidal ideation. The current proposal will expand our understanding of the neurobiology of suicidal behavior by examining a potential neurocognitive mechanism of acute suicidality and test the value of rTMS as intervention for acute suicidal behavior. The current proposal will utilize behavioral assessments and rTMS in a randomized controlled trial in a group of adult patients hospitalized: a) following a recent suicide attempt with persistent suicidal ideation, or b) for severe suicidal ideation (n=20). Specifically, we propose: Specific Aim 1. Determine the safety of repetitive transcranial magnetic stimulation (rTMS) in depressed patients with severe suicidal ideation. Hypothesis 1: Given studies of rTMS for clinical depression, the investigators predict that rTMS in patients with severe suicidal ideation will be well tolerated and not associated with significant side effects. Specific Aim 2. Determine the effect of rTMS on delay discounting on depressed patients with severe suicidal ideation. Hypothesis 2: In depressed patients with severe suicidal ideation the rTMS active will reduce impulsive choice behavior (measured as delay discounting) compared with the non-treatment group. Specific Aim 3. Determine the effect of rTMS on suicidal ideation on depressed patients with severe suicidal ideation. Hypothesis 3.1: In depressed patients who had recently attempt suicide the rTMS active group will reduce suicidal ideation severity (measured by the Beck Scale for Suicidal Ideation) compared with the non-treatment group. Hypothesis 3.2: Suicidal ideation in depressed patients who recently attempt suicide will vary in function of delay discounting. Specific Aim 4. Identification of biomarkers of positive response to rTMS in depressed patients with severe suicidal ideation. Hypothesis 4: A composite of serum hormonal and inflammatory markers will predict positive response to rTMS in depressed patients with severe suicidal ideation

Repetitive Transcranial Magnetic Stimulation (rTMS) will be delivered to the left PFC, defined as a location 6 cm (cm) anterior to the right hand motor thumb area. A research nurse will deliver the treatments. rTMS will be delivered with a figure-eight coil at 120% motor threshold, 10 Hertz (Hz), 5 s (s) train duration, 20 s intertrain interval for 50 min (6000 pulses) 3 times daily for 3 days (total 9 sessions, 54,000 stimuli).

Parameters for sham Repetitive Transcranial Magnetic Stimulation (rTMS) are identical to those for active stimulation except that aluminum plate blocks the propagation of a magnetic field. The sound and physical sensation is the same as with the active coil while been biologically inactive.

A Neurostar TMS Therapy System and Neurostar XPLOR coil system (Neuronetics, Malvern, Pennsylvania) will be used to deliver stimulation.

Inclusion Criteria: Age 18-60 years, of all races and ethnicities; Admitted voluntarily to the adult psychiatric inpatient at PRI; Suffering from a current depressive episode Reason for hospitalization should be a recent suicide attempt or suicidal ideation Current severe suicidal ideation defined by a score >7 on the Beck Scale for Suicidal Ideation Ability to read, write and speak English. Exclusion Criteria: History of dementia, neurovascular or neurodegenerative conditions Physical disabilities that prohibit task performance (such as blindness or deafness) Choosing to opt out of the research study. Additional exclusion criteria for TMS include the following: a personal history or 1st degree relative with history of epilepsy; a personal history of head injury, aneurysm, stroke, previous cranial neurosurgery, neurological, or migraines; recent use of cocaine or alcohol; ferromagnetic metal implants in the head or neck, active or inactive implants(including device leads), deep brain stimulators, cochlear implants or vagus nerve stimulators; a pacemaker; pregnancy (or the possibility of pregnancy); Medications that lower seizure threshold (bupropion or tricyclic antidepressants, such as thorazine, clozapine, amitriptyline, amoxapine, Norpramin, Sinequan, Tofranil, Pamelor, Vivactil, or Surmontil). Other antidepressant and antipsychotic medications have been deemed exhibit a relatively low seizurogenic potential (Pisani et al. 2002). Patients taking a medication for weight loss and depression called bupropion (Wellbutrin) they will be excluded because it may increase the likelihood of experiencing a seizure.

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