A Comparison of Fluoxetine and Divalproex for the Treatment of Intermittent Explosive Disorder

Sponsor
University of Chicago (Other)
Overall Status
Completed
CT.gov ID
NCT00078754
Collaborator
National Institute of Mental Health (NIMH) (NIH)
90
1
3
65.1
1.4

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

Study Type:
Interventional
Actual Enrollment :
90 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Double (Participant, Investigator)
Primary Purpose:
Treatment
Official Title:
Fluoxetine and Divalproex: Treatment Correlates in IED
Study Start Date :
May 1, 2003
Actual Primary Completion Date :
Oct 1, 2008
Actual Study Completion Date :
Oct 1, 2008

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

  1. 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

  1. 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

Ages Eligible for Study:
21 Years to 55 Years
Sexes Eligible for Study:
All
Accepts 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

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.
Responsible Party:
University of Chicago
ClinicalTrials.gov Identifier:
NCT00078754
Other Study ID Numbers:
  • R01MH066984
  • R01MH066984
  • DATR A5-ETMA
First Posted:
Mar 8, 2004
Last Update Posted:
Apr 27, 2021
Last Verified:
Apr 1, 2021

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

1. Primary Outcome
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
2. Secondary Outcome
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

Most participants did not have stable OAS-M Aggression scores from screening to randomization. Note that this was not a requirement for this study; only that OAS-Aggression scores were 15 or higher at screening.

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
Email ecoccaro@yoda.bsd.uchicago.edu
Responsible Party:
University of Chicago
ClinicalTrials.gov Identifier:
NCT00078754
Other Study ID Numbers:
  • R01MH066984
  • R01MH066984
  • DATR A5-ETMA
First Posted:
Mar 8, 2004
Last Update Posted:
Apr 27, 2021
Last Verified:
Apr 1, 2021