Precision Phenotyping of Behavioral Risk and Response to Electromagnetic and Psychedelic Therapies (PRE-EMPT)

PRE-EMPT will assemble a study group of 150 civilian and Veteran participants from three populations (low risk, intermediate risk, and high risk for self-harm). The investigators will obtain clinical assessments, MRI, and blood levels for circular RNA (circRNA). The teams will then administer three interventions (neurofeedback, transcranial magnetic stimulation, and psilocybin assisted therapy), and repeat the tests above. A team with expertise in artificial intelligence will then use our data to try to find patterns that identify who is at high risk versus low risk with a high degree of accuracy.

Study Overview

• Status: Withdrawn
• Conditions: Suicidal Ideation
• Intervention / Treatment: Behavioral: fMRI Neurofeedback; Device: Accelerated theta burst stimulation; Drug: Psilocybin assisted therapy

Detailed Description

For U.S. Service Members, deployment and combat exposure can result in significant mental strain, with high rates of disability and suicide. Unfortunately our ability to predict and treat those at high risk of intentional self-harm is limited. PRE-EMPT (Precision Phenotyping of Behavioral Risk and Response to Electromagnetic and Psychedelic Therapies) seeks to transform the assessment and treatment of the spectrum of depression, posttraumatic stress, and self-harm. PRE-EMPT will utilize multimodal neuroimaging, blood-based biomarkers, and predictive analytics to devise highly accurate models of behavioral risk, and to characterize response to three neuroplasticity-enhancing interventions.

Background: Rates of suicide have increased 37% since the year 2000 despite concerted governmental and institutional programs to address root causes such as stigma and lack of access. Suicide was the number one cause of active-duty fatality from 2014 to 2019, highlighting the vulnerability of Service Members and Veterans. Suicide is a highly multifactorial event and may be conceptualized as a state in which individuals cannot come up with any other option to endure difficult circumstances or intense feelings, representing failures of cognitive control (CC) and emotion regulation (ER). Similarly, the heritability of suicide risk is well known, and transcriptomics, or the study of transcript molecules such as RNA that regulate gene expression, has potential to reveal mechanisms of risk not fully explained by DNA analysis. Better methods of classifying suicide risk according to objective and measurable factors are needed to proactively identify persons at risk and provide interventions tailored to risk.

Research Plan: PRE-EMPT will assemble a cohort of 150 civilian and Veteran participants from three populations (low risk, intermediate risk, and high risk for self-harm). The investigators will obtain baseline clinical assessments, structural and functional MRI utilizing tasks pioneered by our team to assess cognitive control (CC) and emotion regulation (ER), and peripheral circular RNA (circRNA) levels to characterize the molecular brain states associated with behavioral risk. In parallel, investigators will mine publicly available databases to identify network nodes and use deep learning techniques on multivariate patterns of brain activation, structural topography, and functional connectivity. The clinical, imaging, and transcriptomic data will be fused and jointly analyzed to increase the accuracy of risk prediction models. PRE-EMPT in three separate arms will then prospectively assess three promising and innovative interventions for their potential to reduce suicidal ideation and alter activity in key neural networks: 1) neurofeedback (NF) using real-time fMRI with simultaneous electroencephalography (EEG), 2) accelerated intermittent theta burst stimulation (aiTBS) with dose optimization through electric field modeling; and 3) psilocybin assisted therapy (PSI), with flexible dosing plan to maximize the depth of psychedelic experience. Assessments will be repeated at post-treatment and at 1, 3, and 6 months after intervention. These therapies were chosen based on our team's prior work in all three interventions demonstrating rapid action and large effects. Each clinical arm will contribute independent insights into mediators of efficacy for the specific interventions and risk groups, while pooling data to identify predictors across the risk spectrum.

Specific Aim 1: To construct a neurobehavioral model from structural and functional MRI, clinical, and transcriptomic data that accurately predicts behavioral risk.

Specific Aim 2: To test three potential rapid-acting therapies for suicidal ideation and identify mechanistic mediators of response.

• Study Type: Interventional
• Phase: Phase 2

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. 18-69 years old
2. Have been on a stable psychiatric medication regimen for at least four weeks prior to study participation.

Exclusion Criteria:

1. A prior history of other central nervous system disease or any history of seizures;
2. history of psychotic disorders (e.g., schizophrenia, schizoaffective disorder, bipolar disorder type I);
3. history of current or recent (within two years) substance/alcohol use disorder, with the exception of tobacco use disorder;
4. meet criteria for Very High risk of suicide, or require inpatient hospital-level care for psychiatric reasons at time of consent, to reduce exacerbation of risk of harm to self during study;
5. presence of any implanted metal or electrical device (e.g. pacemaker);
6. recent medical hospitalization (within three weeks);
7. any condition that would prevent the participant from completing the protocol, such as significant agitation;
8. appointment of a legal representative or treatment guardian;
9. any ongoing litigation related to a health condition;
10. any other contraindication to exposure to strong magnetic fields or MRI, such as severe claustrophobia;
11. pregnancy or lactation;
12. a family history of schizophrenia or schizoaffective disorder (first or second degree relatives), or bipolar disorder type 1 (first degree relatives), to reduce risk of exacerbation of an undiagnosed psychotic condition;
13. other medical conditions that would preclude safe participation in the trial (e.g., decompensated heart failure);
14. starting or planning to start psychotherapy or changing the frequency or intensity of existing psychotherapy during the trial (current psychotherapy can be continued provided the frequency and intensity has been stable for ≥2 months prior to screening);
15. membership in a vulnerable population (minors, prisoners);
16. any contraindication for blood draws.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: fMRI Neurofeedback; Participants undergo two sessions of fMRI neurofeedback, during which they attempt to modulate a visual display of amygdala activity during fMRI.	Behavioral: fMRI Neurofeedback; Participants undergo two sessions of fMRI neurofeedback, during which they attempt to modulate a visual display of amygdala activity during fMRI.
Experimental: Accelerated theta burst stimulation; Participants undergo 50 sessions of theta burst stimulation, delivered to the dorsolateral prefrontal cortex.	Device: Accelerated theta burst stimulation; Participants undergo 50 sessions of theta burst stimulation, delivered to the dorsolateral prefrontal cortex.
Experimental: Psilocybin assisted therapy; Participants undergo three sessions of preparation, two psilocybin administration sessions, and two integration sessions.	Drug: Psilocybin assisted therapy; Participants undergo three sessions of preparation, two psilocybin administration sessions, and two integration sessions.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Scale of Suicidal Ideation	The SSI is a 19-item, interviewer-administered rating scale that measures the current intensity of specific attitudes, behaviors, and plans to commit suicide.	Baseline (Day 1) to Post-Treatment Visit (Month 6)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Beck Depression Inventory-II	The Beck Depression Inventory-II (BDI-II) is a 21-item self-report questionnaire widely used by mental health professionals to measure the severity of depression in adults and adolescents aged 13 and older.	Baseline (Day 1) to Post-Treatment Visit (Month 6)
PTSD Checklist-for DSM 5	The PCL-5 is the Posttraumatic Stress Disorder (PTSD) Checklist for DSM-5, a 20-item self-report measure used by healthcare professionals to screen for, monitor, and provisionally diagnose PTSD symptoms in adults.	Baseline (Day 1) to Post Treatment Visit (Month 6)
Columbia Suicide Severity Rating Scale	The Columbia Suicide Severity Rating Scale (C-SSRS) is a comprehensive clinical interview tool designed to assess the full history and current severity of suicidal ideation and behavior.	Baseline (Day 1) to Post Treatment Visit (Month 6)
Generalized Anxiety Disorder-7	The GAD-7 (Generalized Anxiety Disorder 7-item scale) is a self-administered screening tool designed to measure the severity of generalized anxiety disorder (GAD).	Baseline (Day 1) to Post Treatment Visit (Month 6)
WHODAS 2.0	The World Health Organization Disability Assessment Schedule 2.0 is a self-report tool for measuring general health and disability across various conditions, including mental and neurological disorders.	Baseline (Day 1) to Post Treatment Visit (Month 6)
Patient Global Impression of Change	The Patient Global Impression of Change (PGIC) is a 7-point self-report scale to measure a patient's subjective assessment of their improvement following treatment.	Baseline (Day 1) to Post Treatment Visit (Month 6)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
BOLD Signal Change	Blood oxygen level dependent (BOLD) signal level during fMRI tasks	Baseline (Day 1) to Post Treatment Visit (Month 6)

Collaborators and Investigators

• Sponsor: University of New Mexico
• Collaborators: Washington University School of Medicine; The Mind Research Network; Georgia State University; New Mexico VA Healthcare System

Study record dates

Study Major Dates

• Study Start (Estimated): May 1, 2026
• Primary Completion (Estimated): August 31, 2029
• Study Completion (Estimated): August 31, 2029

Study Registration Dates

• First Submitted: February 12, 2026
• First Submitted That Met QC Criteria: March 16, 2026
• First Posted (Actual): March 20, 2026

Study Record Updates

• Last Update Posted (Actual): March 20, 2026
• Last Update Submitted That Met QC Criteria: March 16, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: neurofeedback; depression; artificial intelligence; suicidal ideation; psilocybin; transcranial magnetic stimulation; posttraumatic stress disorder; predictive modeling
• Additional Relevant MeSH Terms: Trauma and Stressor Related Disorders; Mental Disorders; Behavioral Symptoms; Self-Injurious Behavior; Suicide; Stress Disorders, Traumatic; Behavior; Suicidal Ideation; Depression; Stress Disorders, Post-Traumatic
• Other Study ID Numbers: HRRC# 25-535; HT9425-25-1-0954 (Other Grant/Funding Number: Department of Defense)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Behavioral (primary and secondary outcome measures) and imaging data will be shared via the NIMH Data Archive
• IPD Sharing Time Frame: 2 years after conclusion of study (8/31/2031) for as long as NDA remains available (end date).
• IPD Sharing Access Criteria: Users of NIMH Data Archive will be able to access the de-identified IPD through the NDA website.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: Yes