Intermittent Explosive DisorderPhase 2LPSSNCT06665074
Inflammatory Challenge in Human Aggression.
A Phase 2 study testing Endotoxin (E. coli O:113, Reference Endotoxin) in people with Intermittent Explosive Disorder, run by Ohio State University at 1 site in United States.
Trial summary
The goal of this clinical trial is to explore the differences in behavioral and cytokine response to a low dose infusion of endotoxin (vs. placebo) in individuals with histories of frequent, problematic, impulsive aggression ("aggressives") compared to similar individuals without this history ("controls"). Read more about this study
- Who is it for?
- Ages 21 to 55 yearsHealthy volunteers can take part
- Conditions the study is for
- Intermittent Explosive Disorder
- What is being tested?
- Endotoxin (E. coli O:113, Reference Endotoxin)
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 112 participants
- Where
- 1 siteUnited States
- Study dates
- 16 Feb 2026to Jan 2030
- Phase
- Phase 2
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 21 to 55 years
- All sexes
- Healthy volunteers accepted
- Adult
Who may be able to join
- "Aggressive Subjects" will have a current DSM-5 diagnosis of Intermittent Explosive Disorder (IED) and have a Life History of Aggression (LHA) > 12.
- "Control Subjects" will not have current or past history of IED and will have LHA scores < 11 ("Control Subjects" may have a past, but not current, history of Major Depression (MD), Generalized Anxiety Disorder (GAD), Panic Disorder (PDx), or Post-Traumatic Stress (PTSD) Disorder.
- Participant is between 21 and 55 years of age and is able to give informed consent.
- Participant is physically healthy as confirmed by medical history, physical evaluation, and (in females) a negative pregnancy test.
Who cannot join
- Participants with a current clinically significant medical condition.
- Participants current co-morbid Major Depression (MD), Generalized Anxiety Disorder (GAD), Panic Disorder (PDx), or Post-Traumatic Stress (PTSD) Disorder.
- Participants currently taking prescribed medications for an active medical or psychiatric condition.
- Participants not free of prescribed medications for four weeks.
- Participants with Grade 2 or higher abnormalities on clinical laboratory examination (e.g., CBC with Differential, Metabolic Panel, and PT/INR/PTTa).
- Participants with Bradycardia (i.e., heart rate < 50 beats/minute) or other Grade 2 or higher ECG abnormality.
Show all 23Show fewer
- Participants with autoimmune conditions (e.g., asthma, psoriasis, etc.)
- Participants who are immunocompromised.
- Participants taking immunomodulatory, or anti-inflammatory, agents.
- Participants that are pregnant, breastfeeding, or plan to become pregnant within nine months of enrollment in the study.
- Female study participants of childbearing potential must remain abstinent or agree to use a highly effective form of contraception (e.g., an intrauterine device). Childbearing potential is defined as, study participants who have reached menarche and have not undergone a documented sterilization procedure (i.e., hysterectomy, bilateral oophorectomy, or salpingotomy), and have not reached menopause.
- Life history of bipolar disorder / schizophrenia / organic mental syndrome, or intellectual disability.
- Current alcohol / drug use disorder of greater than mild severity.
- Current suicidal ideation.
- History of a suicide attempt in the past year prior to study entry.
- Life history of > 3 or more suicide attempts of any type.
- Life history of any moderately severe suicide attempt.
- Current or life history of homicidal ideation.
- Current or life history of felony assault and/or battery.
- Currently on parole for aggressive behavior.
- Allergy, or contraindication, to receiving endotoxin.
- Current treatment with opiates or any agents that affect pain threshold (exclusionary for the TAP).
- Unwilling/unable to sign informed consent document.
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
Julian Roberts, RN contact
United States1 site, 1 recruiting
- Recruiting
The Ohio State University Medical Center
Columbus, Ohio, 43210
Emil Coccaro, MD, 773-852-1338, emil.coccaro@osumc.edu
Julian Roberts, RN, julian.roberts@osumc.edu
About this study
The goal of this clinical trial is to explore the differences in behavioral and cytokine response to a low dose infusion of endotoxin (vs. placebo) in individuals with histories of frequent, problematic, impulsive aggression ("aggressives") compared to similar individuals without this history ("controls"). Endotoxin is a substance that produces a reliable inflammation response in human subjects. The main questions it aims to answer are:
- Do aggressive individuals have greater self-rated anger responses to low-dose endotoxin compared with controls?
- Do aggressive individuals have greater analog aggressive responses (in the Taylor Aggression Paradigm) to low-dose endotoxin compared with controls?
- Do aggressive individuals have greater hostile attributional and negative emotional responses (in the V-SEIP) to low-dose endotoxin compared with controls?
- Do aggressive individuals have greater plasma pro-inflammatory responses to low-dose endotoxin compared with controls?
- Do aggressive individuals display a greater activation of brain responses to anger-related picture during an MRI scan during low-dose endotoxin compared with controls? Researchers will compare endotoxin to a placebo (a look-alike substance that contains no drug) explore the differences in behavioral and cytokine response to a low dose infusion of endotoxin (vs. placebo) in individuals with histories of frequent, problematic, impulsive aggression ("aggressives") compared to similar individuals without this history ("controls").
Read more
Participants will:
- Receive a low-dose of endotoxin and placebo on two (2) separate days. The study drugs will be given through a plastic tube inserted in a forearm vein.
- Visit the laboratory on at least two (2) separate days to receive the endotoxin and placebo.
- Complete rating forms, behavioral testing, and an MRI on each of the two (2) laboratory days.
Read the detailed description
While elevations of circulating pro-inflammatory modulators correlate directly with variables of aggression, and direct application of cytokines to specific cortico- limbic regions in animals elicit aggressive responding, no studies have tested the hypothesis that acute increases in pro-inflammatory modulators can/will increase aggressive behavior in humans. The investigators aim to demonstrate a causal relationship between pro-inflammatory cytokines and aggression in human subjects by showing that an acute pro-inflammatory state, via endotoxin challenge, will increase aggressive responding, anger ratings, and hostile social cognition, to a greater degree in "aggressive" (n = 45), compared with "non-aggressive" (n = 45), individuals with mood/anxiety/ stress-related and/or personality disorders. The proposed study is a double-blind comparison of endotoxin/placebo challenge in the same individuals (within-subject) as a function of aggression status. Aggressive individuals will have high lifetime aggression (> 12 on Life History of Aggression: LHA) and be positive for an average of two anger attacks per week and/or three anger attacks per year that include physical assault of another person and/or or non-trivial destruction of property. "Non-Aggressive" individuals will be similar diagnostically but will have low lifetime aggression. "Aggressive responding" will be assessed using the Taylor Aggression Paradigm (TAP), "Anger" will be assessed by self-reported assessments (Profile of Mood States: POMS), and "Hostile Social Cognition" will be assessed by the Video-Social and Emotional Information Processing (V-SEIP) paradigm. The primary plasma pro-inflammatory outcome measures will be a composite of CRP, IL-6, IL-8, and TNF-α (as in the investigators' previous studies). MRI scans will including task-based scans involving "explicit" and "ambiguous" social threat. The investigators hypothesize that aggressive responding, anger ratings, and hostile social cognition (Primary Outcomes) and Composite Plasma Pro-Inflammatory Marker levels (Secondary Outcome), will be greater after endotoxin, compared with placebo, and will be greater in "aggressive" than "non- aggressive" study participants. The Investigators also hypothesize that these variables will correlate with dimensional measures of aggression. In addition, the investigators hypothesize that amygdala responses to explicit social threat (anger faces) will be enhanced (greater BOLD fMRI signal response) after Endotoxin, and that cortico-limbic responses to ambiguous social threat (V-SEIP) will be reduced (i.e., lesser BOLD fMRI signal response) in all study participants but reduced to a greater extent in "aggressive", compared with "non- aggressive", study participants. Finally, the investigators hypothesize that the pro-inflammatory effects of the endotoxin challenge will result in reduced connectivity between the functional edges supporting higher aggressive behavior and that endotoxin challenge will facilitate stronger connections among nodes associated with low aggressive behavior. If supported, this study will provide a strong rationale for clinical trials of anti-inflammatory agents in impulsive aggressive individuals.
- Conditions
- Intermittent Explosive Disorder
- Being tested
- Endotoxin (E. coli O:113, Reference Endotoxin), Saline (Placebo)
- Keywords
- IED, Inflammation, Cytokines, Aggression
- Medical subject headings
- Disruptive, Impulse Control, and Conduct Disorders, Inflammation, Aggression
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Endotoxin (E. coli O:113, Reference Endotoxin)Biological
Dosage of endotoxin is 0.8 ng/Kg body Weight
Saline (Placebo)Other
Volume of saline to be the same as volume of endotoxin
| Study group | Role | What they receive |
|---|---|---|
| Aggressive Subjects | Experimental | Subjects with Intermittent Explosive Disorder (IED) Receives: Biological: Endotoxin (E. coli O:113, Reference Endotoxin); Other: Saline (Placebo) |
| Non-Aggressive Subjects | Other | Subjects without IED Receives: Biological: Endotoxin (E. coli O:113, Reference Endotoxin); Other: Saline (Placebo) |
What is being measured
The primary outcome is the main question the study is designed to answer.
Profile of Mood States (POMS) - Anger
Self-report questionnaire of "anger". Scale goes form 0-48 with higher scores meaning greater anger.
Measured: Before and during the Endotoxin/Placebo Infusion for up to six hours only on ach of the two study days..
Secondary outcomes (4)
Taylor Aggression Paradigm (TAP)
An analog assessment of aggression widely used in human studies of aggression. This is the number of times that a selection of higher and very-high shock was set by the subject against the "confederate".
Measured: Done once during the endotoxin (and placebo) infusion only. The TAP takes about 30 minutes.
Video-Social Emotional Information Processing (V-SEIP)
A computer-delivered task that assesses hostile attributional bias and negative emotional response to ambiguous social threat. The scores range from 0-3 with the higher numbers mean the more hostile attribution and negative emotional response.
Measured: Done one during the endotoxin (and placebo) infusion only. The V-SEIP takes about 30 minutes on each of the two study days..
Pro-Inflammatory Cystokines (IL-6, THN-Alpha)
These are pro-inflammatory cytokines that are stimulated for release by endotoxin. These values range from 0 to > 100 with the higher values representing greater inflammation.
Measured: Prior to and after infusion of endotoxin and placebo for up to six hours only on each of the two study days.
Functional MRI
BOLD Signal Response to Explicit (Anger Faces), and to Ambiguous, Social Threat.
Measured: Once during the Endotoxin Infusion and once during the Salin Infusion only. The MRI scan takes 90 minutes on each of the two study days.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted30 Oct 2024
- Study start16 Feb 2026
- Primary completionJul 2029 (estimated)
- Study completionJan 2030 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Intermittent Explosive DisorderStudies of the same condition, open and under way.
- More trials run by Ohio State UniversityThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind
- Who is masked
- Participant, Investigator, Outcomes assessor
- Enrolment
- 112 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Ohio State University
- Sponsor type
- University, hospital or other
- Collaborators
- National Institute of Mental Health (NIMH)
- Responsible party
- Principal investigator, Emil Coccaro, Ohio State University
- Investigators
- Emil F. Coccaro, MD, Principal investigator, The Ohio State University College of Medicine
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06665074
- Sponsor's protocol ID
- 2023H0217
- Other IDs
- R01MH133925-01A1
- Acronym
- LPSS
- Status last verified
- Mar 2026
- First submitted
- 21 Oct 2024
- Last updated
- 27 Mar 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: Only de-identifed data will be shared.
Study at a glance
From the registry record, last updated by the sponsor on 27 Mar 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Inflammatory Challenge in Human Aggression.
- ClinicalTrials.gov ID
- NCT06665074
- Acronym / sponsor ID
- LPSS / 2023H0217
- Conditions
- Intermittent Explosive Disorder
- Keywords
- IED, Inflammation, Cytokines, Aggression
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 112 participants (estimated)
- Lead sponsor
- Ohio State UniversityUniversity, hospital or other
- Collaborators
- National Institute of Mental Health (NIMH)
- Study start
- 16 Feb 2026 (actual)
- Primary completion
- Jul 2029 (estimated)
- Study completion
- Jan 2030 (estimated)
- First posted
- 30 Oct 2024 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The goal of this clinical trial is to explore the differences in behavioral and cytokine response to a low dose infusion of endotoxin (vs. placebo) in individuals with histories of frequent, problematic, impulsive aggression ("aggressives") compared to similar individuals without this history ("controls"). Endotoxin is a substance that produces a reliable inflammation response in human subjects. The main questions it aims to answer are:
- Do aggressive individuals have greater self-rated anger responses to low-dose endotoxin compared with controls?
- Do aggressive individuals have greater analog aggressive responses (in the Taylor Aggression Paradigm) to low-dose endotoxin compared with controls?
- Do aggressive individuals have greater hostile attributional and negative emotional responses (in the V-SEIP) to low-dose endotoxin compared with controls?
- Do aggressive individuals have greater plasma pro-inflammatory responses to low-dose endotoxin compared with controls?
- Do aggressive individuals display a greater activation of brain responses to anger-related picture during an MRI scan during low-dose endotoxin compared with controls? Researchers will compare endotoxin to a placebo (a look-alike substance that contains no drug) explore the differences in behavioral and cytokine response to a low dose infusion of endotoxin (vs. placebo) in individuals with histories of frequent, problematic, impulsive aggression ("aggressives") compared to similar individuals without this history ("controls").
Participants will:
- Receive a low-dose of endotoxin and placebo on two (2) separate days. The study drugs will be given through a plastic tube inserted in a forearm vein.
- Visit the laboratory on at least two (2) separate days to receive the endotoxin and placebo.
- Complete rating forms, behavioral testing, and an MRI on each of the two (2) laboratory days.
Detailed description
While elevations of circulating pro-inflammatory modulators correlate directly with variables of aggression, and direct application of cytokines to specific cortico- limbic regions in animals elicit aggressive responding, no studies have tested the hypothesis that acute increases in pro-inflammatory modulators can/will increase aggressive behavior in humans. The investigators aim to demonstrate a causal relationship between pro-inflammatory cytokines and aggression in human subjects by showing that an acute pro-inflammatory state, via endotoxin challenge, will increase aggressive responding, anger ratings, and hostile social cognition, to a greater degree in "aggressive" (n = 45), compared with "non-aggressive" (n = 45), individuals with mood/anxiety/ stress-related and/or personality disorders. The proposed study is a double-blind comparison of endotoxin/placebo challenge in the same individuals (within-subject) as a function of aggression status. Aggressive individuals will have high lifetime aggression (> 12 on Life History of Aggression: LHA) and be positive for an average of two anger attacks per week and/or three anger attacks per year that include physical assault of another person and/or or non-trivial destruction of property. "Non-Aggressive" individuals will be similar diagnostically but will have low lifetime aggression. "Aggressive responding" will be assessed using the Taylor Aggression Paradigm (TAP), "Anger" will be assessed by self-reported assessments (Profile of Mood States: POMS), and "Hostile Social Cognition" will be assessed by the Video-Social and Emotional Information Processing (V-SEIP) paradigm. The primary plasma pro-inflammatory outcome measures will be a composite of CRP, IL-6, IL-8, and TNF-α (as in the investigators' previous studies). MRI scans will including task-based scans involving "explicit" and "ambiguous" social threat. The investigators hypothesize that aggressive responding, anger ratings, and hostile social cognition (Primary Outcomes) and Composite Plasma Pro-Inflammatory Marker levels (Secondary Outcome), will be greater after endotoxin, compared with placebo, and will be greater in "aggressive" than "non- aggressive" study participants. The Investigators also hypothesize that these variables will correlate with dimensional measures of aggression. In addition, the investigators hypothesize that amygdala responses to explicit social threat (anger faces) will be enhanced (greater BOLD fMRI signal response) after Endotoxin, and that cortico-limbic responses to ambiguous social threat (V-SEIP) will be reduced (i.e., lesser BOLD fMRI signal response) in all study participants but reduced to a greater extent in "aggressive", compared with "non- aggressive", study participants. Finally, the investigators hypothesize that the pro-inflammatory effects of the endotoxin challenge will result in reduced connectivity between the functional edges supporting higher aggressive behavior and that endotoxin challenge will facilitate stronger connections among nodes associated with low aggressive behavior. If supported, this study will provide a strong rationale for clinical trials of anti-inflammatory agents in impulsive aggressive individuals.
Study design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Aggressive Subjects | Experimental | Biological: Endotoxin (E. coli O:113, Reference Endotoxin), Other: Saline (Placebo)Subjects with Intermittent Explosive Disorder (IED) |
| Non-Aggressive Subjects | Other | Biological: Endotoxin (E. coli O:113, Reference Endotoxin), Other: Saline (Placebo)Subjects without IED |
Who may qualify
- Ages
- 21 to 55 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (4 listed)
- "Aggressive Subjects" will have a current DSM-5 diagnosis of Intermittent Explosive Disorder (IED) and have a Life History of Aggression (LHA) > 12.
- "Control Subjects" will not have current or past history of IED and will have LHA scores < 11 ("Control Subjects" may have a past, but not current, history of Major Depression (MD), Generalized Anxiety Disorder (GAD), Panic Disorder (PDx), or Post-Traumatic Stress (PTSD) Disorder.
- Participant is between 21 and 55 years of age and is able to give informed consent.
- Participant is physically healthy as confirmed by medical history, physical evaluation, and (in females) a negative pregnancy test.
Key exclusion criteria (23 listed)
- Participants with a current clinically significant medical condition.
- Participants current co-morbid Major Depression (MD), Generalized Anxiety Disorder (GAD), Panic Disorder (PDx), or Post-Traumatic Stress (PTSD) Disorder.
- Participants currently taking prescribed medications for an active medical or psychiatric condition.
- Participants not free of prescribed medications for four weeks.
- Participants with Grade 2 or higher abnormalities on clinical laboratory examination (e.g., CBC with Differential, Metabolic Panel, and PT/INR/PTTa).
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Endotoxin (E. coli O:113, Reference Endotoxin)Dosage of endotoxin is 0.8 ng/Kg body Weight | Biological | Aggressive Subjects, Non-Aggressive Subjects |
| Saline (Placebo)Volume of saline to be the same as volume of endotoxin | Other | Aggressive Subjects, Non-Aggressive Subjects |
Primary outcome
Profile of Mood States (POMS) - Anger
Time frame: Before and during the Endotoxin/Placebo Infusion for up to six hours only on ach of the two study days..
Self-report questionnaire of "anger". Scale goes form 0-48 with higher scores meaning greater anger.
4 secondary outcomes
Taylor Aggression Paradigm (TAP)
Time frame: Done once during the endotoxin (and placebo) infusion only. The TAP takes about 30 minutes.
Video-Social Emotional Information Processing (V-SEIP)
Time frame: Done one during the endotoxin (and placebo) infusion only. The V-SEIP takes about 30 minutes on each of the two study days..
Pro-Inflammatory Cystokines (IL-6, THN-Alpha)
Time frame: Prior to and after infusion of endotoxin and placebo for up to six hours only on each of the two study days.
Functional MRI
Time frame: Once during the Endotoxin Infusion and once during the Salin Infusion only. The MRI scan takes 90 minutes on each of the two study days.
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 27 Mar 2026.
- Individual participant dataSharing planned: Yes. Only de-identifed data will be shared.
Related trials for Intermittent Explosive Disorder
RecruitingObservational study
LHC-CIDI-5 in Hong Kong
Major Depressive Episode (MDE), Major Depressive Disorder (MDD)
RecruitingPhase 2
Effect of Nitrous Oxide on Aggression.
Intermittent Explosive Disorder
RecruitingPhase 2
Neural Correlates During Alcohol Intoxication
Alcohol Use Disorder, Intermittent Explosive Disorder
RecruitingPhase 2
Pimavanserin and Aggression and Social Cognition.
Intermittent Explosive Disorder
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Julian Roberts, RN contact
Emil F. Coccaro, MD principal investigator
The Ohio State University College of Medicine
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Endotoxin (E. coli O:113, Reference Endotoxin) in people with Intermittent Explosive Disorder, run by Ohio State University at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 23 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 27 Mar 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Emil F. Coccaro, MD (7738521338, emil.coccaro@osumc.edu), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Profile of Mood States (POMS) - Anger (time frame: Before and during the Endotoxin/Placebo Infusion for up to six hours only on ach of the two study days..). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 27 Mar 2026.