Placebo-controlled Trial Of Topiramate Research Articles

Self-efficacy mediates the effects of topiramate and GRIK1 genotype on drinking.

Previous studies indicate that topiramate reduces alcohol use among problem drinkers, with one study showing that the effect was moderated by a polymorphism (rs2832407) in GRIK1, the gene encoding the GluK1 kainate subunit. We examined whether the interactive effect of medication and genotype (1) altered the association between daily self-efficacy and later-day drinking; and (2) had an indirect effect on drinking via self-efficacy. In a 12-week, placebo-controlled trial of topiramate, we used daily interactive voice response technology to measure self-efficacy (i.e. confidence in avoiding heavy drinking later in the day) and drinking behavior in 122 European-American heavy drinkers. Topiramate's effects on both self-efficacy and drinking level were moderated by rs2832407. C-allele homozygotes treated with topiramate showed higher levels of self-efficacy and lower levels of nighttime drinking across the 12-week trial. Further, the interactive effect of topiramate and genotype on mean nighttime drinking levels was mediated by mean levels of self-efficacy. By modeling topiramate's effects on nighttime drinking across multiple levels of analysis, we found that self-efficacy, a key psychologic construct, mediated the effect of topiramate, which was moderated by rs2832407 genotype. Thus, it may be possible to use an individualized assessment (i.e. genotype) to select treatment to optimize the reduction in heavy drinking and thereby provide a personalized treatment approach.

A double-blind, placebo-controlled trial of topiramate for pathological gambling

Objectives. Pathological gambling (PG) is an impulse control disorder characterized by recurrent gambling thoughts and behaviours that impair social functioning. Earlier studies suggested that topiramate may be effective in treating some impulse control disorders. We conducted the first randomized, controlled trial of topiramate in PG. Methods. PG patients were randomized to topiramate (N = 20) or placebo (N = 22) in this 14-week, double-blind, placebo-controlled, parallel-group trial. The primary outcome measure was change in the obsessions subscale of the Yale-Brown Obsessive-Compulsive Scale Modified for Pathological Gambling. Results. Mixed regression models (time [weeks] × treatment) revealed no significant treatment effect of topiramate on the primary or secondary outcome measures. The most statistically robust findings involved reducing the Barratt Impulsiveness Scale (BIS) total score and Motor and Non-Planning subscale scores, for which topiramate outperformed placebo at merely a trend level (P < 0.1). Conclusions. The observed trend in BIS score reductions may warrant further investigation to study whether topiramate reduces clinically important impulsivity in PG. Treatment studies with larger samples and less stringent exclusion criteria are needed to produce results that can be generalized to pathological gamblers in the community.

Changes in metabolic syndrome parameters in patients with schizoaffective disorder who participated in a randomized, placebo-controlled trial of topiramate

This study evaluated changes in the metabolic syndrome (MetS) parameters among patients with schizoaffective disorder–bipolar type who had previously participated in a randomized, placebo-controlled study of topiramate ( Chengappa et al., 2007). Topiramate (or placebo) was added to pre-existing mood-stabilizer and/or antipsychotic treatment. Nearly 41% of the 46 participants with fully available data met criteria for MetS at the pre-study baseline, and six (13%) additional subjects met criteria for MetS during the 16-week study. Several subjects (mostly topiramate treated) showed the hypothesized and expected loss in body weight and this correlated with improved glycosylated hemoglobin or systolic and diastolic blood pressure measurements or improvements in lipid levels, whereas a few patients had inconsistent results. Limitations of the study include the lack of targeted treatments for specific components of the metabolic syndrome, and no controls for exercise, diet or concomitant medications. Nevertheless, screening, monitoring and targeted treatment for the metabolic syndrome in psychiatric patients is increasingly becoming the standard of practice. Moreover and especially pertinent to the readership of this journal is that as the prevalence of overweight and MetS have increased worldwide, the World Health Organization has proposed lower cut-off thresholds for obesity in Asia. Furthermore, lower thresholds for waist circumference have also been recommended for Asians.

Effects of Topiramate on Smoking in Patients With Schizoaffective Disorder, Bipolar Type

To the Editors: It has been suggested that topiramate (Topamax®; Ortho-McNeil Neurologics, Inc.; Titusville, New Jersey USA) may have use for treating addictions including nicotine dependence due to its modulation of dopaminergic activity in the corticomesolimbic axis through actions on GABAergic and glutamatergic systems1. Topiramate has been shown to increase abstinence from alcohol2 and led to higher levels of spontaneous abstinence from smoking in participants receiving topiramate as treatment for alcohol dependence3. Few trials have examined topiramate specifically for smoking cessation and findings from these studies have been mixed. Khazaal et al4 reported that six out of 13 smokers given topiramate (maximum dose 50–225 mg/day for n=11, 500 mg/day for n=1, and 800 mg/day for n=1) were abstinent from smoking after two months with two additional participants reducing their smoking significantly (>50%). In contrast, Anthenelli et al5 found a trend (p=0.10) towards differences in smoking abstinence with topiramate (200 mg/day) versus placebo in male adult smokers (n=38); however, there was no difference in smoking abstinences rates for female smokers (n=49) by treatment group. Additional questions about the usefulness of topiramate for smoking cessation have been raised by studies reporting increased subjective report of nicotine withdrawal6 and enhanced rewarding effects of IV nicotine7 and smoked cigarettes6 with topiramate. Examining new medications for the treatment of tobacco dependence is important especially in groups of smokers with high prevalence of smoking and difficulty with smoking cessation (e.g, smokers with psychiatric conditions8). The purpose of the study was to report data on smoking behavior from a placebo-controlled trial of topiramate which primarily evaluated psychiatric symptoms (mood and psychotic symptoms) in patients with schizoaffective disorder, bipolar type. This report is based on a secondary analysis of an eight-week placebo-controlled, randomized clinical trial examining the safety and efficacy of topiramate for patients with schizoaffective disorder, bipolar type9. Patients in the study were randomly assigned to topiramate (TOP, 100–400 mg/d) or placebo (PLA) using a 2:1 ratio in favor of topiramate. Participants were not provided with any specific pharmacological or behavior treatment for smoking. Participants were included in this analysis if they reported that they were current smokers as defined by an expired breath carbon monoxide (CO) level ≥ 10 ppm at baseline. CO levels were assessed at baseline, week 4, and week 8 (end of study). Self-reported cigarette smoking was only assessed at the beginning of the trial, prior to medication randomization. The study protocol and consent forms were reviewed and approved by the Institutional Review Board of the University of Pittsburgh, and the Research Review Committee of Mayview State Hospital, and the Office of Mental Health and Substance Abuse Services, Harrisburg, PA. All participants gave their consent to participate after procedures and possible side effects were explained to them. Thirty-one out of the full sample of 48 participants (65%) reported daily smoking consistent with the high rates of smoking in this population10. The current analyses were conducted on the twenty-four participants (50% of the full sample; TOP n=13, PLA n=11) who both reported daily smoking and had a baseline CO level of at least 10 ppm. Participants were 50% male and 54% Caucasian (42% African-American, 4% Other) and reported smoking an average of 20.2 (SD=13.4) cigarettes per day. There were no baseline differences between the treatment groups on gender (p=0.68), race/ethnicity (p=0.52), age (p=0.22), weight (p=0.48), CO level (TOP M=24.6, SD=11.3; PLA M=24.6, SD=10.6; p=0.99) or number of cigarettes smoked per day (TOP M=23.2, SD=14.5; PLA M=16.6, SD=11.8, p=0.24). No differences were found in CO levels at week 4 (TOP M=21.6, SD=11.3; PLA M=25.6, SD=9.7; p=0.44) or week 8 (TOP M=23.7, SD=8.2; PLA M=21.4, SD=10.39; p=0.62) between treatment groups. A repeated measure analysis of variance (ANOVA) showed no effect of Time (p=0.56) and no Group × Time interaction (p=0.22), suggesting that CO levels remained generally unchanged for participants on topiramate and placebo during the course of the trial. There was no effect of Time (p=0.32) and no Group × Time interaction (p=0.38) on weight. No differences were found when the analyses were rerun including gender as a variable suggesting that CO did not change over the course of the study for male or female participants; however, these results should be interpreted with caution due to the low power to detect differences among these small groups. Both treatments (TOP and PLA) reduced scores on psychotic or mood symptoms and there were no significant differences in the reduction of psychiatric symptoms by treatment group (see Chengappa et al, 20079).

The impact of migraine on daily activities: effect of topiramate compared with placebo

ABSTRACTObjective: Assess the impact of migraine preventive therapy on patient-reported routine daily activities using the Migraine Specific Questionnaire (MSQ) and the Medical Outcomes Study Short Form-36 (SF-36) in patients with migraine who participated in a 26-week, randomized, double-blind, placebo-controlled trial of topiramate for migraine prevention.Methods: Patients were required to have 3–12 migraines and ≤ 15 headache days/month during the baseline phase. Patients who failed > 2 adequate regimens of migraine preventive therapy were excluded. MSQ and SF‐36 data were collected at baseline, weeks 8, 16, and 26 from 469 patients receiving either topiramate 50, 100, or 200 mg/day or placebo. Patients entered a double-blind, 8‐week titration period followed by an 18‐week maintenance period. Two activity-related MSQ domains (Role Restrictive [RR] and Role Prevention [RP]) and two activity-related SF‐36 domains (Role Physical [SF‐36‐RP] and Vitality [SF‐36‐VT]) were prospectively designated as the outcome measures. Changes in MSQ and SF‐36 scores during the double-blind phase relative to prospective baseline scores were compared between topiramate- and placebo-treated groups. Specifically, a mixed-effect piecewise linear regression model was used to estimate average domain score over time, and areas under the domain-over-time curve (AUC) were compared using a 2‐sided t‐test, with multiplicity adjustment.Results: In the intent-to-treat population (N = 469), topiramate (all doses) significantly improved mean MSQ‐RR domain scores versus placebo (topiramate 50 mg/day, p = 0.035; topiramate 100 mg/day; p < 0.001; topiramate 200 mg/day, p = 0.001). Topiramate-associated improvements in mean MSQ‐RP domain scores were significant versus placebo only for topiramate 100 mg/day ( p = 0.045). SF‐36‐RP and SF‐36‐VT domain scores improved (not significant versus placebo) for topiramate 100 and 200 mg/day. Changes in these MSQ and SF‐36 domain scores significantly correlated with changes in mean monthly migraine frequency.Conclusion: Improvements in patient-reported outcomes specific for migraine (measured by the MSQ) were significantly better for patients receiving topiramate than for those receiving placebo. Improvements in the prospectively selected MSQ and SF‐36 domains were significantly correlated with the decrease in mean monthly migraine frequency observed with topiramate treatment.

A randomized, double-blind, placebo-controlled trial of topiramate in adults with epilepsy and intellectual disability: Impact on seizures, severity, and quality of life

This randomized, double-blind, placebo-controlled UK trial evaluated the effect of topiramate as add-on therapy on seizure frequency, seizure severity, and quality of life in patients with epilepsy and intellectual disability. There were three phases: 4 weeks baseline, 18 weeks titration to 200-400 mg topiramate/day (adults) or 5-9 mg/kg/day (children), 12 weeks maintenance. Recruitment was low (88/120); analyses were underpowered. Seizure frequency varied enormously (median 17.7, maximum 1706.2). There was no significant difference in reduction in mean total seizure frequency or number of responders between the groups. Topiramate reduced seizure frequency by >30% from baseline (placebo 1%); post hoc analyses showed a trend toward significance (R ratio, P=0.052). There were no significant differences between the groups with respect to mean seizure severity or other outcome measures. Topiramate was generally well tolerated; body weight (P=0.015) and systolic blood pressure (P=0.043) were reduced. The study suggests that topiramate reduces seizure frequency in patients with epilepsy and intellectual disability without the added burden of behavior effects, and was potentially advantageous to physical well-being.

Cost‐Effectiveness of Topiramate in Migraine Prevention: Results From a Pharmacoeconomic Model of Topiramate Treatment

Patients whose migraines are frequent, cause disruptions of daily routines, or are unresponsive to acute treatment are primary candidates for preventive migraine therapy. This cost-effectiveness model assesses the clinical and economic impact of topiramate (TPM) therapy versus no preventive treatment for migraine headache in the United States. Despite significant progress in treatment options, the economic burden of migraine to patients, employers, health systems, and society is substantial. Treatment strategies for migraine are directed toward managing acute episodes. However, preventive therapy should be used for patients with frequent migraine attacks (>2 per month) or those experiencing attacks that disrupt daily routines. Data for the model were obtained from the published literature and pooled results of two randomized, double-blinded, placebo-controlled trials of TPM in migraine prevention. Model inputs included baseline migraine frequency (the base case assumed 6 per month, consistent with the average rate in the TPM trials), treatment discontinuation (including discontinuation due to adverse events), treatment response (ie, > or = 75%, 50% to 75%, and <50% reduction in migraine frequency), cost of preventive therapy (TPM plus physician visits for medication titration), cost of acute treatment per attack (including pharmacy and medical service costs), hours of disability per attack, hourly wage, and quality-of-life (utility) weights. Model outcomes included the number of migraines averted, disability hours, total cost of acute and preventive treatment, and lost wages. Results were expressed as cost per migraine averted and cost per quality-adjusted life years (QALY). All costs were stated as 2002 U.S. dollars. We also conducted sensitivity analyses to assess the robustness of model findings with respect to variation in key parameters. We estimated that the use of TPM would prevent 1.85 migraines per patient and almost 5 hours of disability per month versus no preventive treatment. Resulting savings in cost of acute treatment (dollar 27) and work loss (dollar 51) offset 68% of the expected monthly cost of TPM (dollar 113). The incremental cost per migraine averted was dollar 19, while the incremental cost per QALY was estimated to be dollar 10,888 (dollar 26,191 when indirect costs were excluded from the analysis). Model results were sensitive to baseline migraine rate and gain in health utility from migraine prevention. Economic savings associated with reduced migraine frequency offset approximately two thirds of the cost of preventive TPM therapy. The cost-effectiveness of TPM depends on utility gains associated with a reduced frequency of migraine headaches, which is the subject of ongoing research. However, results from our model suggest that the use of TPM in prevention of migraine may offer reasonable value for money relative to many well-accepted medical interventions.

1509 Incidences of adverse events during the titration and maintenance phases of placebo-controlled trials of topiramate for migraine prevention

1509 Incidences of adverse events during the titration and maintenance phases of placebo-controlled trials of topiramate for migraine prevention

Effectiveness, Tolerability, and Safety of Topiramate in Children with Partial‐Onset Seizures

Children with partial-onset seizures, with or without secondary generalization, participating in a double-blind, placebo-controlled trial of topiramate (TPM) as adjunctive therapy were eligible to participate in an open-label, long-term extension study. A total of 83 children (mean age, 9 years) continued long-term open-label TPM therapy in which the dosages of TPM and concomitant antiepileptic drugs (AEDs) were adjusted according to clinical response (mean TPM dosage, 9 mg/kg/day). Seizure frequency over the last 3 months of therapy was reduced > or =50% in 57% of children; 14% of children were seizure-free > or =6 months at the last visit. During treatment periods up to 2 1/2 years (mean, 15 months), 6% of children discontinued because of treatment-emergent adverse events; 13% discontinued because of inadequate seizure control. From these findings, TPM is well tolerated and provides long-term seizure control in children with partial-onset seizures.