Alcohol dependence afflicts 14 million individuals in the U.S. The alcohol related costs to
society are enormous and alcohol dependence is a significant public health problem. Although
pharmacotherapy for the treatment of alcohol dependence and relapse prevention has expanded,
the identification of evidence based treatment strategies is of critical importance.
Anticonvulsants, including the divalproex sodium (DVP) formulation of valproate, have
established effectiveness for mood disorders, and therapeutic response of mood and anxiety
symptoms to DVP has been demonstrated in a number of psychiatric conditions. While DVP has
been demonstrated as a treatment option for the acute alcohol withdrawal syndrome, a clear
treatment effect has not been found in studies examining DVP for ongoing relapse prevention
in alcohol dependence. These latter studies had limited power and excluded subjects with
co-morbid mood and anxiety disorders, individuals who may, by extension of the former
studies, show the greatest response to treatment with DVP. Despite the exclusion of subjects
with mood and anxiety disorders, alcohol dependent individuals treated with DVP compared to
placebo showed greater improvement in irritability and a trend toward greater decreases on
measures of impulsivity and aggression. A strategy integrating the above findings would
target treatment with DVP more specifically to alcohol dependent individuals with mood and
anxiety disturbances.
This randomized, double-blind clinical trial will examine the effectiveness of extended
release DVP (Depakote-ER) in the treatment of co-morbid mood and anxiety disturbance in
alcohol dependent subjects. The primary hypothesis is that subjects treated with Depakote-ER
will have significantly lower scores on the Symptom Checklist (SCL-90-R) than will placebo
treated subjects over the course of the study. Secondary hypotheses include: 1) Compared to
placebo treated subjects, subjects treated with Depakote-ER will demonstrate significantly
lower scores on additional measures of depression, anxiety, and irritability, 2) will have
fewer alcohol use days and fewer drinks per drinking day, and 3) will evidence better
retention in alcohol dependence treatment.
Eligible subjects will complete baseline assessments and a 7-day run on Depakote-ER prior to
randomization. After the 7-day baseline period and run in with Depakote-ER, subjects will be
randomized and then transition to either 12 weeks of Depakote-ER or placebo, to begin upon
completion of the 7-day run-in baseline period. Valproic acid level obtained at the end of
the baseline period will be used to adjust the dose of Depakote-ER (or matched placebo) as
needed to target a valproic level of 70-120 ug/ml. Dose increase, if needed, will occur with
the study medication dispensed at the next follow up visit (scheduled for the end of the 1st
week of active study medication or placebo). Subjects with valproic acid levels > 120 ug/ml
at the end of the baseline period will be contacted as soon as possible and instructed to
decrease their dose of Depakote-ER (or matched placebo) accordingly. Subjects randomized to
the placebo condition will receive a placebo matched in number and appearance to the dosage
of Depakote-ER prescribed during the 7-day baseline period. If needed, the number of placebo
pills will be adjusted to match the change in the Depakote-ER dosage determined necessary
based on the valproic acid level obtained at the end of the 7-day baseline period.
Duration of Subject Participation: Subjects will receive either divalproex sodium extended
release (Depakote-ER) or matched placebo for 12 weeks. Subjects will continue to receive
other "treatment as usual" within the Addiction Treatment Center in accordance with their
ongoing clinical program treatment plan. The standard expectation within the context of
treatment as usual is for at least 6 months of treatment involvement. A limited number of
psychotropic medications will be allowed during the study. A benzodiazepine (usually
chlordiazepoxide or lorazepam, in accordance with standard practice and generally given in an
as needed symptom triggered manner) can be prescribed during the acute detoxification period
(first 7 days). Hydroxyzine can be prescribed PRN for anxiety, and zolpidem PRN (not to
exceed 5 nights per week) for insomnia, throughout the course of the study.
