Exploratory fMRI Study on the Treatment for Impulsive Aggression in Children With ADHD

Exploratory Neuroimaging Study to Evaluate the Effect on Brain Activity of SPN-810 for Impulsive Aggression (IA) in Patients With Attention-Deficit/Hyperactivity Disorder (ADHD) in Conjunction With Standard ADHD Treatment

The purpose of this study was to evaluate the effect of 4-week SPN-810 treatment on brain functioning in patients aged 8-12 years with ADHD and associated feature of impulsive aggression (IA). This was achieved using functional magnetic resonance imaging (fMRI) in conjunction with the point subtraction aggression paradigm (PSAP) Task, a behavioral aggression paradigm in which subjects are provoked by having money indirectly taken from them by a fictitious opponent, simulating an aggression response.

Study Overview

• Status: Terminated
• Conditions: Attention Deficit Hyperactivity Disorder (ADHD); Impulsive Aggression
• Intervention / Treatment: Diagnostic test: Functional Magnetic Resonance Imaging (fMRI); Diagnostic test: Magnetic Resonance Spectroscopy (MRS); Behavioral: Point Subtraction Aggression Paradigm (PSAP) Task; Drug: Placebo; Drug: SPN-810

Detailed Description

Approximately 30 subjects aged 8-12 diagnosed with ADHD and associated feature of IA were recruited in this study. The PSAP is a behavioral aggression test used to evaluate behavioral response related to impulsive aggression. The task was combined with functional MRI to evaluate the change in brain activity measured as BOLD signal (blood oxygenation level-dependent) from baseline to the end of the treatment with SPN-810.

The level of neurotransmitters Glutamate and GABA were also measured using magnetic resonance spectroscopy (MRS).

Additionally, the improvement and severity in impulsive aggression behaviors were assessed using validated scales.

• Study Type: Interventional
• Enrollment (Actual): 7
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Florida
    • Lakeland, Florida, United States, 33805
      • Meridien Research aka Florida Clinical Research Center, LLC
    • Maitland, Florida, United States, 32751
      • Florida Clinical Research Center, LLC.
    • Tampa, Florida, United States, 33613
      • University of South Florida- Dept. of Psychiatry and Neurosciences

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 8 years to 12 years (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Otherwise healthy male or female subjects, aged 8-12 years, inclusive, at the time of screening with primary diagnosis of ADHD and currently receiving monotherapy treatment with an optimized US Food and Drug Administration (FDA)-approved ADHD medication.
• Impulsive aggression (IA) confirmed at screening using the R-MOAS and the Vitiello Aggression Scale.

Exclusion Criteria:

• Current or lifetime diagnosis of epilepsy, major depressive disorder, bipolar disorder, schizophrenia or related disorder, personality disorder, Tourette's disorder, fetal alcohol syndrome, or psychosis not otherwise specified.
• Currently meeting DSM criteria for autism spectrum disorder, pervasive developmental disorder, obsessive-compulsive disorder, post-traumatic stress disorder.
• Known or suspected IQ <70, pregnancy, substance or alcohol abuse.
• Known history of implanted brain stimulator, vagal nerve stimulator, ventriculoperitoneal shunt, cardiac pacemaker, orthodontic braces, or implanted medication port. Visual and hearing (≥25 dB) impairment.
• Pre-existing medical or psychological conditions that preclude being in the MRI scanner (e.g., claustrophobia, morbid obesity, or marked anxiety about the procedure).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: High dose SPN-810 (36 mg); Subjects were randomized to receive SPN-810 18 mg twice a day twice each day with and without food, in addition to the stable dose of the optimized ADHD medication.	Diagnostic test: Functional Magnetic Resonance Imaging (fMRI); Neural brain activity measured by fMRI; Diagnostic test: Magnetic Resonance Spectroscopy (MRS); Glutamate and GABA levels measured by MRS; Behavioral: Point Subtraction Aggression Paradigm (PSAP) Task; Aggression score measured by the PSAP task; Drug: SPN-810; Treatment of SPN-810 (36 mg) on neuronal brain activity, GABA and Glutamate levels and on the aggression score
Placebo Comparator: Placebo; Subjects were randomized to receive Placebo twice a day twice each day with and without food, in addition to the stable dose of the optimized ADHD medication.	Diagnostic test: Functional Magnetic Resonance Imaging (fMRI); Neural brain activity measured by fMRI; Diagnostic test: Magnetic Resonance Spectroscopy (MRS); Glutamate and GABA levels measured by MRS; Behavioral: Point Subtraction Aggression Paradigm (PSAP) Task; Aggression score measured by the PSAP task; Drug: Placebo; Treatment of placebo on neuronal brain activity, GABA and Glutamate levels and on the aggression score

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Aggression-related Change in the Whole Brain in BOLD (Blood Oxygenation Level-dependent) Signal fMRI Contrast in Response to the PSAP Task	The primary endpoint was the aggression-related change in the whole brain in BOLD signal fMRI contrast in response to the PSAP task. BOLD fMRI contrast (neural activation) investigates brain activity by measuring the change in blood oxygenation. Change in brain activity was measured by a change in BOLD response in brain regions during the aggressive response relative to the monetary response, where the aggression was defined as the number of Option 2 presses (aggressive response) divided by the total number of button presses and the number of provocations. Change of aggression-related MRI signal was acquired at baseline and 4 weeks after SPN-810 treatment. A positive number represents an increase in activity. Region of interest is described by the location of the peak value and described by Montreal Neurological Institute (MNI) X, Y, Z coordinates. Data represent the post-treatment minus baseline change in BOLD contrast Aggressive Response> Monetary Response.	Baseline/Visit 2 (Day -5) to Visit 5 (Day 28) for a total of 4 weeks.
Provocation Event - Related Change in the Whole Brain in BOLD Signal fMRI Contrast in Response to the PSAP Task	BOLD (blood oxygenation level-dependent) fMRI contrast (neural activation) investigates brain activity by measuring the change in blood oxygenation. It was collected during the PSAP behavioral task while playing the game: the participants play a computer game in which they can steal points (simulating an aggressive behavior) or have points stolen by the opponent (provocation event) by pressing Option 1, 2 or 3 on a keypad a set number of times to achieve a specific outcome. A positive number represents an increase in activity. The region of interest is described by the location of the peak value within that cluster and described by Montreal Neurological Institute (MNI) X, Y, and Z coordinates. Data represent the post-treatment minus baseline change in BOLD contrast Provocation Event >Monetary Response.	Baseline/Visit 2 (Day -5) to Visit 5 (Day 28) for a total of 4 weeks.
Effect of SPN-810 on the Aggressions Score	The Point Subtraction Aggression Paradigm (PSAP) is a behavioral aggression paradigm consisting of a computer game in which each participant plays against a computer to earn points. The subject can steal points (i.e., aggressive behavior) or have points stolen by the opponent (i.e., provocation). The subject can press 1 of 3 buttons on a keypad a set number of times. By pressing the button for Option 1, 100 times, the subject will earn a point; pressing the button for Option 2, 20 consecutive times is the "aggression" action that results in stealing a point from the opponent; pressing Option 3, 20 times protects the subject from the opponent's attempt to steal points (i.e., money). The aggression score is averaged across two sessions and calculated as the number of Option 2 button presses divided by the sum of total button presses and the number of provocation events received, with a range minimum = 1, maximum = 143. The higher scores reflect increased aggression.	Baseline/Visit 2 (Day -5) to Visit 5 (Day 28) for a total of 4 weeks.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Effect of SPN-810 on GABA and Glutamate Levels Using Magnetic Resonance Spectroscopy (MRS)	GABA and Glutamate concentrations (mM) were measured in the anterior cingulate cortex using magnetic resonance spectroscopy (MRS). Data represent the change from Baseline (Visit 2) to Visit 5.	Baseline/Visit 2 (Day -5) to Visit 5 (Day 28) for a total of 4 weeks.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Effect of SPN-810 on Impulsive Aggression Measured by the Clinical Global Impression-Severity (CGI-S) Scale	The Clinical Global Impression - Severity of Illness (CGI-S) is a single item clinician rating of clinician's assessment of the severity of IA behaviors. CGI-S was evaluated by the Investigator on a 7- point scale with 1=Normal, 2=Borderline ill, 3=Mildly ill, 4=Moderately ill, 5=Markedly ill, 6=Severely ill, and 7=Extremely ill. Data represent the change between Baseline (Visit 1/Day -30) and two time points: Visit 4 (Day 21) and Visit 6 (Day 35).	From Visit 1 (Day -30) to two time points: Visit 4 (Day 21) and Visit 6 (Day 35).
Effect of SPN-810 on Impulsive Aggression Measured by the Clinical Global Impression-Improvement (CGI-I) Scale	The Clinical Global Impression - Improvement Scale (CGI-I) is an assessment of how much the patient's illness has improved or worsened relative to a baseline state at the beginning of treatment. CGI-I was evaluated by the Investigator on a 7-point scale with 1=very much improved, 2= much improved, 3= minimally improved, 4= no change, 5= minimally worse, 6= much worse, 7= very much worse.	Visit 4 (Day 21) and Visit 6 (Day 35), for a total of 2 weeks.
Effect of SPN-810 on the Retrospective-Modified Overt Aggression Scale (R-MOAS) Score	R-MOAS scale gauges the severity of aggressive behavior: the frequency of the 16 behaviors is rated over the past week in 4 areas (a-d). For each open question in each area, the parent rates the aggressive behaviors on a scale from 0 to 5 or more times. To each area corresponds a weighted category: 1(a), 4(b), 2(c) and 3(d). Therefore, the sum of each area yields a maximum weighted score of 20 (a), 120 (b), 60 (c) and 90 (c). The total score is the sum of the four area scores or 0-290, the higher the score, the more severe the aggressive behavior is. Data represent the change from baseline at each visit.	Visit 1 (Day -30) to Visit 4 (Day 21) and Visit 6 (Day 35).

Collaborators and Investigators

• Sponsor: Supernus Pharmaceuticals, Inc.

Publications and helpful links

General Publications

• Cherek DR, Moeller FG, Schnapp W, Dougherty DM. Studies of violent and nonviolent male parolees: I. Laboratory and psychometric measurements of aggression. Biol Psychiatry. 1997 Mar 1;41(5):514-22. doi: 10.1016/s0006-3223(96)00059-5.
• Bubenzer-Busch S, Herpertz-Dahlmann B, Kuzmanovic B, Gaber TJ, Helmbold K, Ullisch MG, Baurmann D, Eickhoff SB, Fink GR, Zepf FD. Neural correlates of reactive aggression in children with attention-deficit/hyperactivity disorder and comorbid disruptive behaviour disorders. Acta Psychiatr Scand. 2016 Apr;133(4):310-23. doi: 10.1111/acps.12475. Epub 2015 Aug 21.

Study record dates

Study Major Dates

• Study Start (Actual): May 30, 2019
• Primary Completion (Actual): November 7, 2019
• Study Completion (Actual): November 7, 2019

Study Registration Dates

• First Submitted: August 16, 2018
• First Submitted That Met QC Criteria: August 16, 2018
• First Posted (Actual): August 20, 2018

Study Record Updates

• Last Update Posted (Actual): May 2, 2025
• Last Update Submitted That Met QC Criteria: April 30, 2025
• Last Verified: February 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Aberrant Motor Behavior in Dementia; Neurologic Manifestations; Nervous System Diseases; Mental Disorders; Behavioral Symptoms; Neurodevelopmental Disorders; Attention Deficit and Disruptive Behavior Disorders; Dyskinesias; Hyperkinesis; Attention Deficit Disorder with Hyperactivity; Aggression; Impulsive Behavior
• Other Study ID Numbers: 810P204

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No