Valproate for Mood Swings and Alcohol Use Following Head Injury

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
United States Department of Defense
Information provided by (Responsible Party):
University of Colorado, Denver
ClinicalTrials.gov Identifier:
NCT01760785
First received: November 8, 2012
Last updated: May 9, 2016
Last verified: May 2016
  Purpose

Successful treatment of traumatic brain injury (TBI)-induced mood lability may reduce or eliminate drinking behaviors in persons with alcohol abuse/dependence (AA/D) and affective lability following TBI. Observed clinically, the symptoms of poorly regulated affective expression of AA/D+TBI patients who reach alcohol abstinence do not appear to be those of an idiopathic mood or anxiety disorder. These symptoms do not present the severity or the same natural courses as do Major Depressive Disorder, Bipolar Illness, or Anxiety Disorder, for example. Instead, both symptoms and course appear more characteristic of the sustained affect lability often observed following TBI. This observation suggests that TBI survivors represent a patient group for whom treatment of neuropsychiatric symptoms following TBI may alleviate both TBI-related affect lability and also heavy ethanol use by treating the condition that is contextually related to excessive alcohol use.

Based on this concept of consequently treating AA/D through the management of post-TBI affective lability, this study was conducted observing the efficacy of divalproex sodium on the severity of affective lability and AA/D in persons suffering from a moderate TBI. Divalproex sodium has been shown to ameliorate mood disorders, even in those with substance abuse problems. This drug has also shown positive results as an alternate medication to benzodiazapines in the treatment of alcohol withdrawal, significantly reducing the progression of withdrawal symptoms in patients.


Condition Intervention
Traumatic Brain Injury (TBI)
Alcoholism
Drug: divalproex sodium
Drug: Placebo

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Double Blind Trial of Divalproex Sodium for Affective Lability and Alcohol Use Following Traumatic Brain Injury

Resource links provided by NLM:


Further study details as provided by University of Colorado, Denver:

Primary Outcome Measures:
  • Severity of Affective Lability Based on Shortened Agitated Behavior Scale [ Time Frame: Weeks 2 through 8 ] [ Designated as safety issue: No ]
    Severity of affective lability was measured using a shortened version of the Agitated Behavior Scale (ABS). The ABS is used to assess the nature and extent of present agitation. Eight items from the 14-item scale were used, which measured the presence and severity of various affective lability symptoms including: short attention span, impulsivity, uncooperative behavior, violent tendencies, restlessness, rapid or excessive talking, sudden changes in mood, and easily initiated or excessive crying and/or laughter. Each of the eight items was scored using a 1-4 Likert scale, where 1 stands for absence of symptom and 4 stands for presence to an extreme degree. The minimum possible score for this measure was 8, and the maximum possible score was 32. Due to the nature of the measure, a lower score indicated less severe affective lability, while conversely higher scores indicated more severe affective lability. The mean of scores for weeks 2 through 8 for each group were reported.


Secondary Outcome Measures:
  • Frequency of Alcohol Use [ Time Frame: Weeks 1-10 ] [ Designated as safety issue: No ]
    Frequencies of alcohol use/misuse will be measured weekly utilizing the Timeline Followback assessment. Participants will also be given an alcohol breath test at every clinic visit.


Enrollment: 50
Study Start Date: September 2008
Estimated Study Completion Date: June 2016
Primary Completion Date: August 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: divalproex sodium Drug: divalproex sodium
Doses will be given in 250mg increments and titrated over the first four days of study until a starting dose of 750 mg is reached. The Study Oversight Team, who is not involved in any clinical visits, will be un-blinded to study drug assignment and will have plasma concentration results and adverse event reports available to them. If a subject has no adverse events and is not at therapeutic level as indicated by the blood levels, the Study Oversight Team may inform the research pharmacy to increase the dose by 1 tablet of 250 mg to 1000 mg per day. The Study Oversight Team may also inform the research pharmacy to reduce the daily dosage back down to 750 mg per day if plasma concentrations or adverse events become intolerable. The maximum dose for the purpose of this study will be 1250 mg daily and the minimum dose will be 750 mg daily. Subjects who cannot tolerate the minimum dose will be excluded from any further study participation.
Placebo Comparator: sugar pill Drug: Placebo
Doses will be titrated over the first four days of study in the same manner as the active study drug. After titration, the research pharmacy may increase the dose by 1 tablet per day, in the same fashion that the active drug may be adjusted, so that the participant and clinical team remain blinded to the drug assignment. The research pharmacy may also reduce the daily dosage back down by one tablet per day for the same reason.
Other Name: sugar pill

Detailed Description:

Despite the body's natural healing during the first year after a head injury, many veterans who have suffered even mild brain injuries find themselves easily upset or fearful as they go about their daily lives. While these reactions to the world around them were easily managed before the head injury, they now occur with little or no interruption and are exceedingly difficult to manage. Such reactions include a sense of always being upset or fearful that often makes it difficult to get along with family members, friends, coworkers, and employers. This may lead to broken marriages, unemployment, and even homelessness.

Some people with head injuries try to manage their unmanageable moods by drinking alcohol because it can create a sense of calm. However, alcohol's actions are short in duration. Most find that they have to drink more and more for a similar calming effect, and they soon become dependent on alcohol. This makes working and being part of their families even more difficult.

To treat the unmanageable mood, we tried a medicine called valproate, one that eases mood problems in people without head injury. We gave valproate to head injured persons with mood problems in a "non-blinded" study where both the doctor and the patient knew that the medicine was valproate and both were optimistic that it would work. In a small sample of eighteen people, 85% found mood relief and most of those either stopped drinking alcohol or drank much less than before. However, this might have been because both the doctor and patient were hopeful that the medication would make the patient feel better or because the medicine actually worked.

The only way to know for sure if the medicine works is to perform a study in which people receive either valproate or a sugar pill while neither they nor their doctor know which one they are taking. This is called a double blind study, as proposed here, and will involve nearly three times as many head injured persons as the first study.

If it is successful, the new study will show that valproate treatment helps head injured people manage their moods and allows them to return to families, friends, and work. It will also show that they drink alcohol less or not at all, improving their health even further. Then doctors will know that they can use this medicine for large numbers of people who suffer from head injury and help them to lead normal lives. If the outcome of the study shows that the medicine works well, doctors can then use this medicine to treat people with head injury immediately after the study results are published.

  Eligibility

Ages Eligible for Study:   18 Years to 65 Years   (Adult)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Veteran
  • history of closed-head traumatic brain injury (TBI) at least one year prior to enrollment
  • symptoms of affective lability such as mood swings, irritability, frustration and anxiety
  • currently using alcohol

Exclusion Criteria:

  • history of Axis I bipolar disorder or anxiety disorder prior to the TBI
  • skull opened either surgically or traumatically
  • history of stroke
  • current diagnosis or past history of major psychosis as defined by Diagnostic and Statistical Manual of Mental Disorders (DSM-IV)
  • active liver disease
  • evidence of the alcohol amnesic syndrome
  • history of seizure disorder other than those caused by ethanol withdrawal
  • any type of dementia
  • current suicidal/homicidal ideations
  • symptomatic thiamine, folate or Vitamin B-12 deficiency
  • HIV positive
  • any medical conditions that would constitute contraindications to treatment with divalproex sodium
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01760785

Locations
United States, Colorado
Denver Veteran's Affairs Medical Center
Denver, Colorado, United States, 80220
Sponsors and Collaborators
University of Colorado, Denver
United States Department of Defense
Investigators
Principal Investigator: Thomas P Beresford, MD Denver Veteran's Affairs Medical Center
  More Information

Responsible Party: University of Colorado, Denver
ClinicalTrials.gov Identifier: NCT01760785     History of Changes
Other Study ID Numbers: 08-0582  PT075168 
Study First Received: November 8, 2012
Results First Received: March 28, 2016
Last Updated: May 9, 2016
Health Authority: United States: Institutional Review Board
United States: Food and Drug Administration

Keywords provided by University of Colorado, Denver:
Veterans
Traumatic Brain Injury(TBI)
Alcoholism

Additional relevant MeSH terms:
Wounds and Injuries
Brain Injuries
Alcoholism
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Craniocerebral Trauma
Trauma, Nervous System
Alcohol-Related Disorders
Substance-Related Disorders
Chemically-Induced Disorders
Mental Disorders
Valproic Acid
Anticonvulsants
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
GABA Agents
Neurotransmitter Agents
Physiological Effects of Drugs
Antimanic Agents
Tranquilizing Agents
Central Nervous System Depressants
Psychotropic Drugs

ClinicalTrials.gov processed this record on July 27, 2016