NIMH Addresses Critical Need for Rapid-Acting Interventions for Severe Suicide Risk

April 15, 2021 • Research Highlight

Suicide rates have been steadily rising in the U.S. for the past two decades. While recent progress has been made in bending the curve in this trajectory, much work remains to be done to save lives. The National Institute of Mental Health (NIMH) has been working to meet the urgent need for rapid-acting suicide prevention interventions by supporting research  investigating the feasibility and safety of treatment protocols that have the potential to quickly reduce severe suicide risk in youth and adults.

Research shows that up to 80% of people who die by suicide visit health care settings in the year before their death, and about a fifth of people who die by suicide are seen in a health care setting within the week of their death . Despite advances in psychiatric treatments and psychosocial interventions that reduce repeat suicide attempts, there remain few evidence-based interventions that rapidly reduce suicide risk within healthcare settings. The lack of such interventions often means that people at high risk for suicide must be treated in resource-intensive health care settings, such as the emergency department or inpatient settings. Identifying and developing rapid-acting treatments can reduce or eliminate the need for hospitalization and help “jumpstart” the recovery trajectory.

NIMH is supporting eight new research projects that focus on testing the safety, efficacy, and feasibility of ketamine and esketamine (medications known to rapidly reduce depressive symptoms in hours or days) or transcranial magnetic stimulation (which uses magnets to activate specific parts of the brain), to rapidly reduce suicidal thoughts and behaviors in youth and adults. These projects include:

• Effectiveness of a Synergistic, Neuroplasticity-Based Intervention for Rapid and Durable Suicide Risk Reduction 
  In this project, Rebecca Price, Ph.D. , of the University of Pittsburgh, investigates ketamine treatment in medical inpatient unit patients between the ages of 18 and 65 following a suicide attempt. Specifically, the researchers seek to understand whether pre-treatment with a single ketamine infusion followed by standard inpatient care is more effective at reducing suicidal thoughts and behaviors than standard care alone, both acutely and over a 12-month follow-up. In addition, the researchers aim to understand whether active cognitive training (employing a series of fully automated, computer-based games to encourage self-positive conditioned associations over 2-4 days immediately following ketamine infusion) extends the beneficial effects of ketamine by promoting new, protective learning.
• Intramuscular (IM) Ketamine for Rapid Reduction of Suicidal Thoughts in High-Risk Emergency Room Patients: A Midazolam-Controlled Trial 
  Michael Grunebaum, M.D. , of the Columbia University Medical Center and the New York State Psychiatric Institute, is leading a study examining the feasibility, safety, and effectiveness of IM ketamine to reduce suicidal thoughts within 24 hours in people who present to emergency departments with severe suicidal ideation or behavior requiring psychiatric hospitalization. If successful, the project will provide support for IM ketamine as a scalable intervention that could be implemented within emergency departments.
• Double-Blind Randomized Controlled Trial of Acute-Course of Ketamine Versus Midazolam for Recurrence of Suicidality in Adolescents 
  In this project, led by Madhukar Trivedi, M.D. , of the University of Texas Southwestern Medical Center, researchers are conducting a randomized, controlled trial of ketamine in youth with recent suicidal behaviors. While ketamine has been shown to be safe and effective in adults, its safety, effectiveness, and potential role in the treatment of adolescents at risk for suicide is less well understood. This study will examine four active or control infusions given with usual therapy in the context of an intensive outpatient program to determine the effects of ketamine on suicidal thoughts and behaviors in adolescents.
• Ketamine Treatment of Youth Suicide Attempters for Fast Reduction of Severe Suicide Risk and Facilitation of Long-term Collaborative Clinical Engagement: A Randomized Placebo-Controlled Trial 
  Tatiana Falcone, M.D. , and Amit Anand, M.D., of the Cleveland Clinic Lerner College of Medicine, lead a study testing the effectiveness of pairing a series of infusions of ketamine with weekly sessions of a therapy called Collaborative Assessment for the Management of Suicidality for reducing suicide risk in hospitalized 15- to 24-year-olds who have previously attempted suicide. The researchers hope that ketamine will help facilitate a rapid decrease in suicidality, allowing participants to be more engaged and successful in their therapy, which will continue on an outpatient basis.
• Reducing Adolescent Suicide Risk: Safety, Efficacy, and Connectome Phenotypes of Intravenous Ketamine 
  Jennifer Dwyer, M.D., Ph.D. , of the Yale Child Study Center, leads a team of researchers who will investigate whether intravenous ketamine (four doses over two weeks) rapidly reduces suicidal ideation in teenagers with treatment-resistant depression and suicidal thinking compared to an active control. All participants will be followed over four months while receiving standard medication management and eight weeks of cognitive behavioral therapy. The study will track the trajectory of suicidal thinking, depressive symptoms, and participants’ use of mental health resources over this four-month period. A unique feature of this clinical trial is the use of functional magnetic resonance imaging (fMRI) and connectome predictive modeling to test if brain-based measures can predict who will respond to ketamine treatment and to identify possible mechanisms of ketamine’s therapeutic effect in pediatric patients.
• A Feasibility Trial of Esketamine Plus Cognitive Behavioral Therapy for Patients With Major Depressive Disorder Who Are Hospitalized for Suicidal Ideation 
  Samuel Wilkinson, M.D. , of Yale University, leads a study investigating the ability of cognitive behavioral therapy (CBT) to extend the anti-suicidality effects of intranasal esketamine  in people with major depressive disorder who are hospitalized for suicidal thoughts or a suicide attempt. Participants will receive a course of computer-assisted CBT and treatment with esketamine or esketamine plus usual treatment only. The researchers hypothesize that ketamine will enhance the ability of CBT to improve longer-term treatment outcomes.
• A Randomized Controlled Trial of Sequential Bilateral Accelerated Theta Burst Stimulation in Adolescents with Suicidal Ideation Associated with Major Depressive Disorder 
  Paul Croarkin, D.O. , of the Mayo Clinic, leads a study examining the safety, feasibility, and clinical effects of sequential bilateral accelerated theta burst stimulation to the prefrontal cortex of adolescents with major depressive disorder. Preliminary evidence suggests that TMS applied to the prefrontal cortex of adolescents may reduce clinical symptoms of depression. The researchers hope this treatment will show TMS is effective at reducing suicidal thoughts in participants.
• The Effects of Stanford Accelerated Intelligent Neuromodulation Therapy on Explicit and Implicit Suicidal Cognition 
  Nolan Williams, M.D. , of Stanford University Medical Center, leads a study testing the efficacy and safety of a personalized repetitive TMS method called the Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT) for reducing suicidal thoughts in patients hospitalized in psychiatric units. The researchers propose SAINT, which includes an accelerated course of TMS doses, will regulate the neural circuitry that underlies suicidal thoughts, along with factors such as hopelessness, anhedonia, and depression that contribute to them.

Although more research is needed to identify and develop fast-acting treatments for suicidal thoughts and behaviors, these studies are an important step toward making this type of treatment a reality.

Grants

MH125214 , MH125181 , MH125203 , MH125155 , MH124983 , MH125205 , MH124655 , MH125160