Improvement of physical health and quality of life of alcohol-dependent individuals with topiramate treatment: US multisite randomized controlled trial.

BACKGROUND: Topiramate can improve drinking outcomes via a hypothesized mechanism of facilitating gamma-aminobutyric acid function and inhibiting glutaminergic pathways in the corticomesolimbic system. We sought to determine whether topiramate's antidrinking effects are bolstered by improvements in physical and psychosocial well-being. METHODS: In a 17-site, 14-week, double-blind, randomized controlled trial, we compared the effects of topiramate (up to 300 mg/d) vs placebo on physical health, obsessional thoughts and compulsions about using alcohol, and psychosocial well-being among 371 alcohol-dependent subjects who received weekly adherence enhancement therapy. RESULTS: Topiramate was more efficacious than placebo in reducing body mass index (calculated as weight in kilograms divided by height in meters squared) (mean difference, 1.08; 95% confidence interval [CI], 0.81-1.34; P < .001), all liver enzyme levels (P < .01 for all comparisons), plasma cholesterol level (mean difference, 13.30 mg/dL; 95% CI, 5.09-21.44 mg/dL; P = .002), and systolic (mean difference, 9.70 mm Hg; 95% CI, 6.81-12.60 mm Hg; P < .001) and diastolic (mean difference, 6.74 mm Hg; 95% CI, 4.57-8.90 mm Hg; P < .001) blood pressure to about prehypertension levels-effects that might lower the risk of fatty liver degeneration and cirrhosis as well as cardiovascular disease. Topiramate compared with placebo significantly (P < .05 for all comparisons) decreased obsessional thoughts and compulsions about using alcohol, increased subjects' psychosocial well-being, and improved some aspects of quality of life, thereby diminishing the risk of relapse and longer-term negative outcomes. Paresthesia, taste perversion, anorexia, and difficulty with concentration were reported more frequently for topiramate than for placebo. CONCLUSION: Topiramate appears to be generally effective at improving the drinking outcomes and physical and psychosocial well-being of alcoholic subjects.

Topiramate for treating alcohol dependence: a randomized controlled trial.

CONTEXT: Hypothetically, topiramate can improve drinking outcomes among alcohol-dependent individuals by reducing alcohol's reinforcing effects through facilitation of gamma-aminobutyric acid function and inhibition of glutaminergic pathways in the corticomesolimbic system. OBJECTIVE: To determine if topiramate is a safe and efficacious treatment for alcohol dependence. DESIGN, SETTING, AND PARTICIPANTS: Double-blind, randomized, placebo-controlled, 14-week trial of 371 men and women aged 18 to 65 years diagnosed with alcohol dependence, conducted between January 27, 2004, and August 4, 2006, at 17 US sites. INTERVENTIONS: Up to 300 mg/d of topiramate (n = 183) or placebo (n = 188), along with a weekly compliance enhancement intervention. MAIN OUTCOME MEASURES: Primary efficacy variable was self-reported percentage of heavy drinking days. Secondary outcomes included other self-reported drinking measures (percentage of days abstinent and drinks per drinking day) along with the laboratory measure of alcohol consumption (plasma gamma-glutamyltransferase). RESULTS: Treating all dropouts as relapse to baseline, topiramate was more efficacious than placebo at reducing the percentage of heavy drinking days from baseline to week 14 (mean difference, 8.44%; 95% confidence interval, 3.07%-13.80%; P = .002). Prespecified mixed-model analysis also showed that topiramate compared with placebo decreased the percentage of heavy drinking days (mean difference, 16.19%; 95% confidence interval, 10.79%-21.60%; P < .001) and all other drinking outcomes (P < .001 for all comparisons). Adverse events that were more common with topiramate vs placebo, respectively, included paresthesia (50.8% vs 10.6%), taste perversion (23.0% vs 4.8%), anorexia (19.7% vs 6.9%), and difficulty with concentration (14.8% vs 3.2%). CONCLUSION: Topiramate is a promising treatment for alcohol dependence. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00210925.

Efficacy and safety of topiramate monotherapy in civilian posttraumatic stress disorder: a randomized, double-blind, placebo-controlled study.

OBJECTIVE: This double-blind, placebo-controlled trial assessed efficacy and safety of topiramate monotherapy in civilian posttraumatic stress disorder (PTSD). METHOD: Outpatients (18-64 years) with DSM-IV non-combat-related PTSD and Clinician-Administered PTSD Scale (CAPS) scores >or= 50 were eligible. Topiramate was started at 25 mg/day and titrated by 25-50 mg/week to 400 mg/day or maximum tolerated dose. Data were collected between April 26, 2002, and February 4, 2004. Primary efficacy, change in total CAPS score, and secondary efficacy measures were assessed by analysis of covariance in the intent-to-treat (ITT) population with last observation carried forward. RESULTS: The ITT population comprised 38 patients with mean +/- SD baseline total CAPS scores of 88.3 +/- 13.8 (topiramate, N = 19) and 91.1 +/- 13.7 (placebo, N = 19). Although a decrease in total CAPS score was noted (topiramate, -52.7; placebo, -42.0), this difference was not statistically significant (p = .232). Topiramate-treated patients exhibited significant reductions in reexperiencing symptoms (CAPS cluster B: topiramate, 74.9%; placebo, 50.2%; p = .038) and Treatment Outcome PTSD scale (topiramate, 68.0%; placebo, 41.6%; p = .025). Reductions approaching statistical significance, based on a nominal p value, were noted in mean total Clinical Global Impressions-Improvement Scale scores (topiramate, 1.9 +/- 1.2; placebo, 2.6 +/- 1.1; p = .055). CONCLUSION: These preliminary results suggest that further, adequately powered studies of topiramate for the treatment of civilian PTSD are warranted.

Topiramate for the treatment of binge eating disorder associated with obesity: a placebo-controlled study.

BACKGROUND: In a single-center, placebo-controlled study, topiramate reduced binge eating and weight in patients with binge eating disorder (BED) and obesity. The current investigation evaluated the safety and efficacy of topiramate in a multicenter, placebo-controlled trial. METHODS: Eligible patients between 18 and 65 years with >or= 3 binge eating days/week and a body mass index (BMI) between 30 and 50 kg/m2 were randomized. RESULTS: A total of 407 patients enrolled; 13 failed to meet inclusion criteria, resulting in 195 topiramate and 199 placebo patients. Topiramate reduced binge eating days/week (-3.5 +/- 1.9 vs. -2.5 +/- 2.1), binge episodes/week (-5.0 +/- 4.3 vs. -3.4 +/- 3.8), weight (-4.5 +/- 5.1 kg vs. .2 +/- 3.2 kg), and BMI (-1.6 +/- 1.8 kg/m2 vs. .1 +/- 1.2 kg/m2) compared with placebo (p < .001). Topiramate induced binge eating remission in 58% of patients (placebo, 29%; p < .001). Discontinuation rates were 30% in each group; adverse events (AEs) were the most common reason for topiramate discontinuation (16%; placebo, 8%). Paresthesia, upper respiratory tract infection, somnolence, and nausea were the most common AEs with topiramate. CONCLUSIONS: This multicenter study in patients with BED associated with obesity demonstrated that topiramate was well tolerated and efficacious in improving the features of BED and in reducing obesity.

A pilot controlled trial of topiramate for mania in children and adolescents with bipolar disorder.

OBJECTIVE: To assess the efficacy of topiramate monotherapy for acute mania in children and adolescents with bipolar disorder type I. METHOD: This double-blind, placebo-controlled study was discontinued early when adult mania trials with topiramate failed to show efficacy. Efficacy end points included the Young Mania Rating Scale (YMRS), Brief Psychiatric Rating Scale for Children, Children's Depression Rating Scale, Children's Global Assessment Scale, and Clinical Global Impressions-Improvement. RESULTS: Fifty-six children and adolescents (6-17 years) with a diagnosis of bipolar disorder type I received topiramate (n=29, 52%) or placebo (n=27, 48%). The only statistically significant differences in efficacy measures between treatment groups were the difference between slopes of the linear mean profiles of the YMRS (p=.003) using a post hoc repeated measures regression and the change in Brief Psychiatric Rating Scale for Children at day 28 (-14.9 versus-5.9, p=.048) using observed data. Adverse events with topiramate included decreased appetite, nausea, diarrhea, and paresthesia. CONCLUSIONS: Topiramate was well tolerated; however, the results are inconclusive because of premature termination resulting in a limited sample size. Adequately powered controlled trials are necessary to determine whether topiramate has efficacy in reducing symptoms of acute mania in children and adolescents.

Topiramate in the long-term treatment of binge-eating disorder associated with obesity.

BACKGROUND: This study assessed the long-term effectiveness and tolerability of topiramate in binge-eating disorder (BED) with obesity. METHOD: Sixty-one patients with BED (DSM-IV-TR criteria) and obesity enrolled in a 14-week, single-center, randomized, double-blind, placebo-controlled study. Completers (N = 35) were offered participation in a 42-week, open-label extension trial of topiramate. Fifteen patients who received topiramate and 16 patients who received placebo in the double-blind study entered the open-label trial. Topiramate was titrated from 25 mg/day to a maximum of 600 mg/day. The primary endpoint was change from baseline to final visit in weekly binge frequency using the last observation carried forward for all patients who received topiramate. Baseline for patients receiving double-blind topiramate was the beginning of the controlled study; for patients receiving placebo, baseline was the beginning of the open-label trial. Open-label data were gathered from December 1998 to November 2000. RESULTS: Forty-four patients (31 who received topiramate in the open-label trial plus 13 who received topiramate in the double-blind study only) received at least 1 dose of topiramate; 43 patients provided outcome measures at a median final dose of 250 mg/day. Mean weekly binge frequency declined significantly from baseline to final visit for all 43 patients (-3.2; p < .001), for the 15 patients who received topiramate during the controlled and open-label studies (-4.0; p < .001), and for the 15 patients who received topiramate only during the open-label trial (-2.5; p = .044). Patients also exhibited statistically significant reduction in body weight. The most common reasons for topiramate discontinuation were protocol nonadherence (N = 17) and adverse events (N = 14). CONCLUSION: Topiramate treatment was associated with enduring improvement in some patients with BED and obesity but was also associated with a high discontinuation rate.

Treatment of bulimia nervosa with topiramate in a randomized, double-blind, placebo-controlled trial, part 1: improvement in binge and purge measures.

BACKGROUND: This randomized, double-blind, placebo-controlled trial was designed to assess the efficacy and safety of topiramate in bulimia nervosa. METHOD: Patients with DSM-IV bulimia nervosa were randomly assigned in equal proportions to receive topiramate (N = 35) or placebo (N = 34) for 10 weeks (between April 1999 and Dec. 2000). Topiramate treatment was started at 25 mg/day and titrated by 25 to 50 mg/week to a maximum of 400 mg/day. The primary efficacy measure was mean weekly number of binge and/or purge days. Related outcome measures included mean weekly number of binge days and binge frequency, as well as mean weekly number of purge days and purge frequency. RESULTS: Sixty-four outpatients (33 placebo, 31 topiramate) were included in the intent-to-treat analysis. The median topiramate dose was 100 mg/day (range, 25-400 mg/day). Mean +/- SD baseline number of weekly binge and/or purge days was 5.0 +/- 1.6 for topiramate patients and 5.1 +/- 1.5 for placebo patients. The primary efficacy measure, mean weekly number of binge and/or purge days, decreased 44.8% from baseline with topiramate versus 10.7% with placebo (p =.004). The mean weekly number of binge days decreased 48.2% with topiramate versus 17.7% with placebo (p =.015), and mean binge frequency decreased 49.2% with topiramate versus 28.0% with placebo (p =.071). The mean weekly number of purge days decreased 43.4% with topiramate versus 16.6% with placebo (p =.016), and mean purge frequency decreased 49.8% with topiramate versus 21.6% with placebo (p =.016). Three patients (2 placebo, 1 topiramate) discontinued from the trial due to adverse events. CONCLUSION: Topiramate was associated with significant improvements in both binge and purge symptoms in this study population and represents a potential treatment for bulimia nervosa.

Treatment of bulimia nervosa with topiramate in a randomized, double-blind, placebo-controlled trial, part 2: improvement in psychiatric measures.

BACKGROUND: We conducted a 10-week, randomized, double-blind, placebo-controlled trial to examine the efficacy of topiramate in the treatment of bulimia nervosa. Primary efficacy analyses showed that topiramate treatment significantly reduced days on which patients binged and/or purged. This article describes further analyses investigating topiramate's effect on psychological symptoms associated with disordered eating. METHOD: Patients with DSM-IV bulimia nervosa were randomly assigned to receive topiramate (N = 35) or placebo (N = 34) for 10 weeks. Topiramate treatment was started at 25 mg/day and titrated by 25 to 50 mg/week to a maximum of 400 mg/day. Secondary psychiatric endpoints, including the Eating Disorder Inventory (EDI), Eating Attitudes Test (EAT), Hamilton Rating Scale for Anxiety (HAM-A), Hamilton Rating Scale for Depression (HAM-D), and Patient Global Improvement (PGI) were assessed for change from baseline in the topiramate versus placebo group. RESULTS: Thirty-one patients receiving topiramate and 33 receiving placebo were included in the intent-to-treat analysis. Percent change from baseline on the EDI indicated significantly greater improvement in the topiramate group compared with the placebo group for subscales measuring bulimia/uncontrollable overeating (p =.005), body dissatisfaction (p =.007), and drive for thinness (p =.002). The EAT showed significant improvement in the topiramate group compared with the placebo group for the bulimia/food preoccupation (p =.019) and dieting (p =.031) subscales and the total score (p =.022). For the topiramate group, the reduction in mean HAM-A score was significantly greater (p =.046) than that in the placebo group, while reduction in HAM-D scores was greater in the topiramate group compared with the placebo group but did not reach statistical significance (p =.069). Significantly more patients treated with topiramate compared with placebo reported improvement on the PGI (p =.004). CONCLUSION: Topiramate treatment improves multiple behavioral dimensions of bulimia nervosa. Binge and purge behaviors are reduced, and treatment is associated with improvements in self-esteem, eating attitudes, anxiety, and body image. These results support topiramate as a viable therapeutic option for the treatment of bulimia nervosa. Additional, longer-term multicenter trials are indicated.