A Comparison of Fluoxetine and Divalproex for the Treatment of Intermittent Explosive Disorder
Study Details
Study Description
Brief Summary
This study will compare the medications fluoxetine (ProzacĀ®) and divalproex (DepakoteĀ®) for the treatment of aggressive behavior in individuals with Intermittent Explosive Disorder (IED).
Condition or Disease | Intervention/Treatment | Phase |
---|---|---|
|
Phase 2 |
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.
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
---|---|
Experimental: A Participants will to receive treatment with fluoxetine for 12 weeks |
Drug: Fluoxetine
Fluoxetine capsules by mouth, up to 60 mg daily
|
Experimental: B Participants will to receive treatment with divalproex for 12 weeks |
Drug: Divalproex
Divalproex ER capsules by mouth, up to 3000 mg daily
|
Placebo Comparator: C Participants will to receive treatment with placebo for 12 weeks |
Drug: Placebo
Placebo capsules by mouth, up to 8 capsules daily
|
Outcome Measures
Primary Outcome Measures
- 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 Outcome Measures
- OAS-M [Measured at Week 12]
Overt Aggression Scale Modified for Outpatient Use. Minimum value = 0 Maximum value = Infinity. Higher scores means worse outcome.
Eligibility Criteria
Criteria
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
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
---|---|---|---|---|---|
1 | The University of Chicago | Chicago | Illinois | United States | 60637 |
Sponsors and Collaborators
- University of Chicago
- National Institute of Mental Health (NIMH)
Investigators
- Principal Investigator: Emil F. Coccaro, MD, University of Chicago
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- R01MH066984
- R01MH066984
- DATR A5-ETMA
Study Results
Participant Flow
Recruitment Details | |
---|---|
Pre-assignment Detail |
Arm/Group Title | Group A - Fluoxetine Drug | Group B - Divalproex Drug | Group C - Placebo |
---|---|---|---|
Arm/Group Description | Participants will to receive treatment with fluoxetine for 12 weeks Fluoxetine: Fluoxetine capsules by mouth, up to 60 mg daily | Participants will to receive treatment with divalproex for 12 weeks Divalproex: Divalproex ER capsules by mouth, up to 3000 mg daily | Participants will to receive treatment with placebo for 12 weeks Placebo: Placebo capsules by mouth, up to 8 capsules daily |
Period Title: Overall Study | |||
STARTED | 29 | 30 | 31 |
COMPLETED | 14 | 11 | 16 |
NOT COMPLETED | 15 | 19 | 15 |
Baseline Characteristics
Arm/Group Title | Group A - Fluoxetine Drug | Group B - Divalproex Drug | Group C - Placebo | Total |
---|---|---|---|---|
Arm/Group Description | Participants will to receive treatment with fluoxetine for 12 weeks Fluoxetine: Fluoxetine capsules by mouth, up to 60 mg daily | Participants will to receive treatment with divalproex for 12 weeks Divalproex: Divalproex ER capsules by mouth, up to 3000 mg daily | Participants will to receive treatment with placebo for 12 weeks Placebo: Placebo capsules by mouth, up to 8 capsules daily | Total of all reporting groups |
Overall Participants | 29 | 30 | 31 | 90 |
Age (Count of Participants) | ||||
<=18 years |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
Between 18 and 65 years |
29
100%
|
30
100%
|
31
100%
|
90
100%
|
>=65 years |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
Sex: Female, Male (Count of Participants) | ||||
Female |
14
48.3%
|
10
33.3%
|
16
51.6%
|
40
44.4%
|
Male |
15
51.7%
|
20
66.7%
|
15
48.4%
|
50
55.6%
|
overt aggression scale-modified (OAS-M). (units on a scale) [Mean (Standard Deviation) ] | ||||
Mean (Standard Deviation) [units on a scale] |
36.75
(46.88)
|
36.96
(26.42)
|
66.08
(77.99)
|
47.30
(56.68)
|
Outcome Measures
Title | Overt Aggression Scale-Modified for Outpatient Use (OAS-M) |
---|---|
Description | 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 |
Outcome Measure Data
Analysis Population Description |
---|
[Not Specified] |
Arm/Group Title | Group A - Fluoxetine Drug | Group B - Divalproex Drug | Group C - Placebo |
---|---|---|---|
Arm/Group Description | Participants will to receive treatment with fluoxetine for 12 weeks Fluoxetine: Fluoxetine capsules by mouth, up to 60 mg daily | Participants will to receive treatment with divalproex for 12 weeks Divalproex: Divalproex ER capsules by mouth, up to 3000 mg daily | Participants will to receive treatment with placebo for 12 weeks Placebo: Placebo capsules by mouth, up to 8 capsules daily |
Measure Participants | 14 | 11 | 16 |
Mean (Standard Error) [units on a scale] |
7.86
(4.11)
|
15.73
(10.15)
|
8.88
(3.51)
|
Statistical Analysis 1
Statistical Analysis Overview | Comparison Group Selection | Group A - Fluoxetine Drug, Group B - Divalproex Drug, Group C - Placebo |
---|---|---|
Comments | ||
Type of Statistical Test | Superiority or Other (legacy) | |
Comments | ||
Statistical Test of Hypothesis | p-Value | 0.622 |
Comments | ||
Method | ANCOVA | |
Comments |
Title | OAS-M |
---|---|
Description | Overt Aggression Scale Modified for Outpatient Use. Minimum value = 0 Maximum value = Infinity. Higher scores means worse outcome. |
Time Frame | Measured at Week 12 |
Outcome Measure Data
Analysis Population Description |
---|
OAS-M Scores in Placebo, Fluoxetine, Divalproex Arms as a function of LHA Score. |
Arm/Group Title | Fluoxetine | Divalproex | Placebo |
---|---|---|---|
Arm/Group Description | 20-60 mg po qd for up to 12 weeks. | Up to 3000 mg po qd for up to 12 weeks. | Up to 8 capsules po qd for up to 12 weeks. |
Measure Participants | 29 | 30 | 31 |
High Aggression Group |
13.2
(5.0)
|
13.7
(4.8)
|
19.5
(5.1)
|
Medium Aggression Group |
25.1
(7.6)
|
29.6
(8.0)
|
26.9
(7.1)
|
Statistical Analysis 1
Statistical Analysis Overview | Comparison Group Selection | Group A - Fluoxetine Drug |
---|---|---|
Comments | 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). | |
Type of Statistical Test | Superiority | |
Comments | ||
Statistical Test of Hypothesis | p-Value | 0.029 |
Comments | LHA score main effect. | |
Method | ANCOVA | |
Comments | The LHA Score F[1,83] = 4.91, p = 0.029; Condition F[2,83] = 0.20, p = 0.815; Condition x LHA Score F[2,83] = 0.255, p = 0.799. |
Statistical Analysis 2
Statistical Analysis Overview | Comparison Group Selection | Group A - Fluoxetine Drug, Group B - Divalproex Drug |
---|---|---|
Comments | ANCOVA at endpoint with baseline OAS-M AGG score as covariate. | |
Type of Statistical Test | Superiority | |
Comments | ||
Statistical Test of Hypothesis | p-Value | 0.80 |
Comments | ||
Method | ANCOVA | |
Comments | Baseline OAS-M Aggression score as covariate. | |
Method of Estimation | Estimation Parameter | Mean Difference (Final Values) |
Estimated Value | 19.0 | |
Confidence Interval |
(2-Sided) % to |
|
Parameter Dispersion |
Type: Standard Error of the Mean Value: 2.7 |
|
Estimation Comments |
Adverse Events
Time Frame | ||||||
---|---|---|---|---|---|---|
Adverse Event Reporting Description | ||||||
Arm/Group Title | Group A - Fluoxetine Drug | Group B - Divalproex Drug | Group C - Placebo | |||
Arm/Group Description | Participants will to receive treatment with fluoxetine for 12 weeks Fluoxetine: Fluoxetine capsules by mouth, up to 60 mg daily | Participants will to receive treatment with divalproex for 12 weeks Divalproex: Divalproex ER capsules by mouth, up to 3000 mg daily | Participants will to receive treatment with placebo for 12 weeks Placebo: Placebo capsules by mouth, up to 8 capsules daily | |||
All Cause Mortality |
||||||
Group A - Fluoxetine Drug | Group B - Divalproex Drug | Group C - Placebo | ||||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | / (NaN) | / (NaN) | / (NaN) | |||
Serious Adverse Events |
||||||
Group A - Fluoxetine Drug | Group B - Divalproex Drug | Group C - Placebo | ||||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | 1/29 (3.4%) | 0/30 (0%) | 0/31 (0%) | |||
Blood and lymphatic system disorders | ||||||
hyponatremia/hypokalemia | 1/29 (3.4%) | 0/30 (0%) | 0/31 (0%) | |||
Other (Not Including Serious) Adverse Events |
||||||
Group A - Fluoxetine Drug | Group B - Divalproex Drug | Group C - Placebo | ||||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | 23/29 (79.3%) | 23/30 (76.7%) | 24/31 (77.4%) | |||
Investigations | ||||||
Headaches | 7/29 (24.1%) | 6/30 (20%) | 8/31 (25.8%) | |||
Trembling | 2/29 (6.9%) | 3/30 (10%) | 1/31 (3.2%) | |||
Faintness or dizziness | 2/29 (6.9%) | 3/30 (10%) | 4/31 (12.9%) | |||
Numbness or tingling in parts of your body | 5/29 (17.2%) | 4/30 (13.3%) | 3/31 (9.7%) | |||
Feeling tense or keyed up | 14/29 (48.3%) | 11/30 (36.7%) | 14/31 (45.2%) | |||
Nervousness or shakiness inside | 6/29 (20.7%) | 6/30 (20%) | 4/31 (12.9%) | |||
Soreness in your muscle, back, joints | 13/29 (44.8%) | 17/30 (56.7%) | 16/31 (51.6%) | |||
Spells of terror or panic | 2/29 (6.9%) | 3/30 (10%) | 2/31 (6.5%) | |||
Hot or cold spells | 3/29 (10.3%) | 6/30 (20%) | 4/31 (12.9%) | |||
Heart pounding or racing | 6/29 (20.7%) | 6/30 (20%) | 5/31 (16.1%) | |||
Pains in the heart or chest | 2/29 (6.9%) | 4/30 (13.3%) | 2/31 (6.5%) | |||
Trouble getting your breath | 1/29 (3.4%) | 6/30 (20%) | 6/31 (19.4%) | |||
Trouble remembering things | 9/29 (31%) | 6/30 (20%) | 7/31 (22.6%) | |||
Feeling that familiar things are strange or unreal | 2/29 (6.9%) | 4/30 (13.3%) | 0/31 (0%) | |||
Nausea or upset stomach | 5/29 (17.2%) | 9/30 (30%) | 9/31 (29%) | |||
Drowsiness | 8/29 (27.6%) | 12/30 (40%) | 10/31 (32.3%) | |||
Dry mouth | 5/29 (17.2%) | 9/30 (30%) | 4/31 (12.9%) | |||
Blurred vision | 2/29 (6.9%) | 2/30 (6.7%) | 2/31 (6.5%) | |||
Increased salivation | 1/29 (3.4%) | 4/30 (13.3%) | 2/31 (6.5%) | |||
Sweating | 6/29 (20.7%) | 9/30 (30%) | 4/31 (12.9%) | |||
Diarrhea | 2/29 (6.9%) | 5/30 (16.7%) | 5/31 (16.1%) | |||
Difficulty urinating | 1/29 (3.4%) | 1/30 (3.3%) | 1/31 (3.2%) |
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Name/Title | Dr. Emil F. Coccaro, MD |
---|---|
Organization | The University of Chicago |
Phone | 773-834-4083 |
ecoccaro@yoda.bsd.uchicago.edu |
- R01MH066984
- R01MH066984
- DATR A5-ETMA