Intermittent Explosive Disorder
Conditions
Brief summary
This study will compare the medications fluoxetine (Prozac®) and divalproex (Depakote®) for the treatment of aggressive behavior in individuals with Intermittent Explosive Disorder (IED).
Detailed description
IED is a condition characterized by a failure to resist aggressive impulses. IED is a behavioral defined condition for which effective treatments have not been identified. Research suggests that serotonin (5-HT), a chemical that helps regulate mood and emotions, may play a role in the response to pharmacological IED treatments. This study will examine the relationship between 5-HT receptors and response to treatment with fluoxetine or divalproex. In addition, this study will examine people with IED and those without the condition to determine whether there are differences in their 5-HT receptor and transporter systems. Participants in this study will be randomly assigned to receive either fluoxetine, divalproex, or placebo for 12 weeks. Scale ratings will be used to assess the aggression levels of participants. Biologic evaluations of the 5-HT system will be conducted throughout the study.
Interventions
DRUGFluoxetine
Fluoxetine capsules by mouth, up to 60 mg daily
DRUGDivalproex
Divalproex ER capsules by mouth, up to 3000 mg daily
DRUGPlacebo
Placebo capsules by mouth, up to 8 capsules daily
Sponsors
National Institute of Mental Health (NIMH)
University of Chicago
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
21 Years to 55 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosis of Intermittent Explosive Disorder (IED) * In good physical health * Overt Aggression Scale-Modified (OAS-M) score of 15 or higher at screening * Willing and able to comply with the study requirements
Exclusion criteria
* Life history of bipolar disorder, schizophrenia, organic mental syndrome, or mental retardation * Current major depressive disorder, with a Hamilton Depression (HAM-D) Scale score higher than 18 * Current alcohol or drug abuse or dependence * Active medical conditions that will interfere with the study * Thymoleptic or neuroleptic treatments * Presence of the following serious and active medical conditions: demyelinating or progressive degenerative disorders; central nervous system infection; progressive degenerative neurological disorder; ischemic heart disease; respiratory, renal, or liver disease; Type I diabetes; malignant neoplasm; hyper- or hypo-coagulopathy; Acquired Immune Deficiency Syndrome (AIDS); or seizure disorder. Participants with a history of more than two febrile seizures prior to 1 year of age are eligible. * Chronic, ongoing treatment with the following classes of medications: antidepressants, neuroleptics, mood stabilizers, antianxiety agents, hypnotics, narcotics or synthetic narcotics, barbiturates, stimulants, anti-migraine agents, anti-epileptics, non-beta-blocking or Ca-channel blocking anti-arrhythmic agents prescribed to treat cardiac arrhythmia, anticoagulants, immunomodulators, anti-neoplastic agents, or HIV antiviral agents * Ongoing psychotherapeutic treatment for the treatment of IED or anger that was started less than 3 months before study entry * Hypersensitivity to fluoxetine or divalproex * Pregnancy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overt Aggression Scale-Modified for Outpatient Use (OAS-M) | Measured at Week 12 | OAS-M is a validated instrument that measures aggression. Anti-aggressive effect of the drug/placebo was measured by the aggression score from OAS-M. Possible scores for aggression range from 0 (no aggression) to infinity (because the score is calculated by the number of times an aggressive behavior occurred, which theoretically has no possible maximum). Therefore the bigger number, the worse anti-aggression effect, thus the worse outcome. In each weekly visit, OAS-M score was calculated for the past week. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| OAS-M | Measured at Week 12 | Overt Aggression Scale Modified for Outpatient Use. Minimum value = 0 Maximum value = Infinity. Higher scores means worse outcome. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Group A - Fluoxetine Drug Participants will to receive treatment with fluoxetine for 12 weeks
Fluoxetine: Fluoxetine capsules by mouth, up to 60 mg daily | 29 |
| Group B - Divalproex Drug Participants will to receive treatment with divalproex for 12 weeks
Divalproex: Divalproex ER capsules by mouth, up to 3000 mg daily | 30 |
| Group C - Placebo Participants will to receive treatment with placebo for 12 weeks
Placebo: Placebo capsules by mouth, up to 8 capsules daily | 31 |
| Total | 90 |
Baseline characteristics
| Characteristic | Group A - Fluoxetine Drug | Group B - Divalproex Drug | Group C - Placebo | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 29 Participants | 30 Participants | 31 Participants | 90 Participants |
| overt aggression scale-modified (OAS-M). | 36.75 units on a scale STANDARD_DEVIATION 46.88 | 36.96 units on a scale STANDARD_DEVIATION 26.42 | 66.08 units on a scale STANDARD_DEVIATION 77.99 | 47.30 units on a scale STANDARD_DEVIATION 56.68 |
| Sex: Female, Male Female | 14 Participants | 10 Participants | 16 Participants | 40 Participants |
| Sex: Female, Male Male | 15 Participants | 20 Participants | 15 Participants | 50 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 23 / 29 | 23 / 30 | 24 / 31 |
| serious Total, serious adverse events | 1 / 29 | 0 / 30 | 0 / 31 |
Outcome results
Primary
Overt Aggression Scale-Modified for Outpatient Use (OAS-M)
OAS-M is a validated instrument that measures aggression. Anti-aggressive effect of the drug/placebo was measured by the aggression score from OAS-M. Possible scores for aggression range from 0 (no aggression) to infinity (because the score is calculated by the number of times an aggressive behavior occurred, which theoretically has no possible maximum). Therefore the bigger number, the worse anti-aggression effect, thus the worse outcome. In each weekly visit, OAS-M score was calculated for the past week.
Time frame: Measured at Week 12
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group A - Fluoxetine Drug | Overt Aggression Scale-Modified for Outpatient Use (OAS-M) | 7.86 units on a scale | Standard Error 4.11 |
| Group B - Divalproex Drug | Overt Aggression Scale-Modified for Outpatient Use (OAS-M) | 15.73 units on a scale | Standard Error 10.15 |
| Group C - Placebo | Overt Aggression Scale-Modified for Outpatient Use (OAS-M) | 8.88 units on a scale | Standard Error 3.51 |
p-value: 0.622ANCOVA
Secondary
OAS-M
Overt Aggression Scale Modified for Outpatient Use. Minimum value = 0 Maximum value = Infinity. Higher scores means worse outcome.
Time frame: Measured at Week 12
Population: OAS-M Scores in Placebo, Fluoxetine, Divalproex Arms as a function of LHA Score.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group A - Fluoxetine Drug | OAS-M | Medium Aggression Group | 25.1 score on a scale | Standard Error 7.6 |
| Group A - Fluoxetine Drug | OAS-M | High Aggression Group | 13.2 score on a scale | Standard Error 5 |
| Group B - Divalproex Drug | OAS-M | Medium Aggression Group | 29.6 score on a scale | Standard Error 8 |
| Group B - Divalproex Drug | OAS-M | High Aggression Group | 13.7 score on a scale | Standard Error 4.8 |
| Group C - Placebo | OAS-M | Medium Aggression Group | 26.9 score on a scale | Standard Error 7.1 |
| Group C - Placebo | OAS-M | High Aggression Group | 19.5 score on a scale | Standard Error 5.1 |
Comparison: The hypothesis was that subjects with LHA Scores = 18 or more would respond better to divalproex (than fluoxetine) while those with LHA scores = or \< 17 would respond better to fluoxetine (than divalproex).p-value: 0.029ANCOVA
Comparison: ANCOVA at endpoint with baseline OAS-M AGG score as covariate.p-value: 0.8ANCOVA