Topiramate Treatment of Alcohol Use Disorders in Veterans With PTSD: A Pilot Controlled Trial of Augmentation Therapy

Condition(s) targeted: PTSD; Alcohol Abuse; Alcoholism

Intervention: Topiramate (Drug); Placebo administration (Other)

Phase: Phase 4

Status: Not yet recruiting

Sponsored by: University of California, San Francisco

Official(s) and/or principal investigator(s):
Steven L. Batki, MD, Principal Investigator, Affiliation: University of California, San Francisco; Department of Veteran's Affairs

Overall contact:
Brooke Lasher, BA, Phone: 415-221-4810, Ext: 4954, Email: brooke.lasher@va.gov

The proposed project aims to:

1. Obtain a preliminary assessment of the efficacy of topiramate treatment in reducing alcohol use in veterans with PTSD and alcohol dependence;

2. Obtain preliminary assessments of safety/tolerability of topiramate in these patients;

3. Assess the feasibility of recruitment and retention for topiramate treatment in this comorbid population; and 4) to inform the design of a planned subsequent larger controlled trial of topiramate.

PRIMARY HYPOTHESIS: Topiramate treatment combined with Medical Management alcohol counseling will be associated with a significant increase in percent days abstinent from baseline to end of treatment.

SECONDARY HYPOTHESIS: There will be a significantly greater percent of days abstinent from alcohol use in the topiramate treatment group compared to the placebo group.

Official title: Topiramate Treatment of Alcohol Use Disorders in Veterans With PTSD: A Pilot Controlled Trial of Augmentation Therapy

Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Primary outcome: Change in percent days abstinent

Secondary outcome:

The difference in percent days abstinent from alcohol between the topiramate and placebo arms of the study.

PTSD symptom severity in veterans with chronic PTSD and alcohol abuse/dependence

Detailed description: The goal of the proposed project is to improve the treatment of veterans with co-occurring PTSD and alcohol dependence. Exposure to the stresses of combat is known to be associated with risk for both PTSD and alcohol and other substance use. PTSD and alcohol use disorders occur frequently among returning OEF/OIF veterans. Alcohol and substance use are risk factors for the development of PTSD, moderators of PTSD symptom severity, and potential consequences of PTSD. Alcohol is by far the most common substance of abuse in patients with PTSD, and its use may represent an attempt by PTSD patients to "self-medicate" symptoms such as hyperarousal. However, to date there has been little research to develop pharmacotherapies that would, ideally, reduce both alcohol use and PTSD symptoms.

Topiramate is one of the few medications for alcohol dependence that has also been tested as a potential medication to treat PTSD. Topiramate's efficacy in alcohol dependence has been shown in two recent large controlled trials. Several open trials have suggested that topiramate may be effective in reducing PTSD symptoms while the results of two small controlled trials have been mixed.

A clinical trial of topiramate is therefore indicated in order to achieve the following specific aims:

The primary aim is to obtain a preliminary assessment of the efficacy of topiramate in increasing the percent of days abstinent from alcohol use from baseline to the end of treatment in veterans with PTSD and alcohol abuse/dependence who are drinking heavily.

The secondary aim is to obtain a preliminary assessment of the efficacy of topiramate in increasing the percent of days abstinent from alcohol as compared to placebo.

Additional aims include the following:

- To obtain a preliminary assessment of the efficacy of topiramate in reducing other

measures of alcohol use such as percent heavy drinking days, number of drinks per week, number of drinks per drinking day, and alcohol craving.

- To obtain a preliminary assessment of the efficacy of topiramate in reducing PTSD

symptom severity in veterans with chronic PTSD and alcohol abuse/dependence.

- Informing the design of a planned subsequent larger controlled trial of topiramate in

veterans with chronic PTSD and alcohol abuse/dependence

- To obtain an estimate of topiramate vs. placebo effect size for future studies. B. To

obtain a preliminary assessment of the effects of topiramate treatment on measures of risk-taking behavior in veterans with chronic PTSD and alcohol abuse/dependence.

To achieve these aims, we will conduct a prospective, parallel groups, randomized, double-blind, placebo-controlled flexible-dose pilot clinical trial of topiramate in veterans with PTSD and alcohol abuse/dependence who are already receiving standard treatment for PTSD but still drink heavily. The primary treatment outcome will be percent days abstinent from alcohol; secondary outcomes will include other alcohol use measures, PTSD symptom severity, adverse effects, recruitment and retention rates.

Minimum age: 18 Years. Maximum age: 59 Years. Gender(s): Both.

Criteria:

Inclusion Criteria:

- Male and female outpatient veterans.

- Current DSM-IV diagnosis of PTSD.

- Current (past month) DSM-IV diagnosis of an Alcohol Use Disorder.

- Must meet criteria for "heavy" or "at-risk" drinking by NIAAA thresholds.

- Receiving treatment for PTSD.

- Must express desire to reduce alcohol consumption.

- Female subjects must have negative urine pregnancy test and must be either

postmenopausal for at least one year, or practicing an effective method of birth control.

- Must have a BAC of less than 0. 02% when signing the informed consent.

Exclusion Criteria:

- Psychotic disorders, bipolar disorder, dementia, or other psychiatric disorders

judged to be unstable.

- Subjects known to have clinically significant unstable medical conditions, including

but not limited to: clinically significant renal disease and/or impaired renal function as defined by clinically significant elevation of BUN or creatinine or an estimated creatinine clearance of < 60 mL/min; AST (SGOT) and/or ALT (SGPT) >3 times the upper limit of the normal range and/or an increased serum bilirubin >2 times the upper limit of normal; seizure disorders.

- Subjects with glaucoma.

- Subjects with a history of kidney stones.

- Subjects with a history of renal disease.

- Concurrent participation in another treatment study.

- Female patients who are pregnant or lactating.

- Current topiramate use or use within the past 4 weeks.

- Current medications for alcohol dependence or use within the past 4 weeks.

- Needing acute medical detoxification from alcohol based on a score of 12 or more on

the Clinical Institute Withdrawal Assessment of Alcohol Scale (CIWA-AD);

- Subjects who are legally mandated to participate in an alcohol treatment program.

- Subjects who have had a suicide attempt or suicidal ideation in the 6 months prior to

enrollment.

- Subjects who have previously been treated with topiramate for any reason and

discontinued treatment due to an adverse event or due to a hypersensitivity reaction to topiramate,

- Subjects with seizure disorders that require anticonvulsant medications

- Subjects currently being treated with another anticonvulsant.

- Subjects who in the opinion of the investigator should not be enrolled in the study

because of the precautions,warnings or contraindications outlined in the topiramate package insert.

Brooke Lasher, BA, Phone: 415-221-4810, Ext: 4954, Email: brooke.lasher@va.gov

San Francisco VA Medical Center, San Francisco, California 94121, United States

Related publications:

Alderman CP, McCarthy LC, Condon JT, Marwood AC, Fuller JR. Topiramate in combat-related posttraumatic stress disorder. Ann Pharmacother. 2009 Apr;43(4):635-41. Epub 2009 Mar 31.

Anton RF, O'Malley SS, Ciraulo DA, Cisler RA, Couper D, Donovan DM, Gastfriend DR, Hosking JD, Johnson BA, LoCastro JS, Longabaugh R, Mason BJ, Mattson ME, Miller WR, Pettinati HM, Randall CL, Swift R, Weiss RD, Williams LD, Zweben A; COMBINE Study Research Group. Combined pharmacotherapies and behavioral interventions for alcohol dependence: the COMBINE study: a randomized controlled trial. JAMA. 2006 May 3;295(17):2003-17.

Anton RF, Moak DH, Latham P. The Obsessive Compulsive Drinking Scale: a self-rated instrument for the quantification of thoughts about alcohol and drinking behavior. Alcohol Clin Exp Res. 1995 Feb;19(1):92-9.

Baker F, Johnson MW, Bickel WK. Delay discounting in current and never-before cigarette smokers: similarities and differences across commodity, sign, and magnitude. J Abnorm Psychol. 2003 Aug;112(3):382-92.

Batki SL, Dimmock JA, Wade M, Gately PW, Cornell M, Maisto SA, Carey KB, Ploutz-Snyder R. Monitored naltrexone without counseling for alcohol abuse/dependence in schizophrenia-spectrum disorders. Am J Addict. 2007 Jul-Aug;16(4):253-9.

Beckham JC, Crawford AL, Feldman ME. Trail making test performance in Vietnam combat veterans with and without posttraumatic stress disorder. J Trauma Stress. 1998 Oct;11(4):811-9.

Berlant J, van Kammen DP. Open-label topiramate as primary or adjunctive therapy in chronic civilian posttraumatic stress disorder: a preliminary report. J Clin Psychiatry. 2002 Jan;63(1):15-20.

Berlant JL. Prospective open-label study of add-on and monotherapy topiramate in civilians with chronic nonhallucinatory posttraumatic stress disorder. BMC Psychiatry. 2004 Aug 18;4:24.

Starting date: April 2010
Last updated: March 31, 2010