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Topiramate is an antiepileptic drug (AED) that is effective in treating various types of epilepsy. This study evaluated the bioequivalence and safety of two topiramate tablets in healthy Chinese subjects under fasting and fed conditions. We designed an open-label, randomized, single-dose, two-period, crossover trial protocol. Two independent trials were conducted, each including 26 volunteers. In the fed trial, subjects were randomly assigned to two groups (1:1 ratio) to receive either 100 mg of test formulation or reference formulation of topiramate. After a 21-day washout period, crossover administration was implemented. The fasting trial design was similar to that of the fed trial. Plasma concentrations of topiramate were determined using a validated method (high-performance liquid chromatography-tandem mass spectrometry, HPLC-MS/MS). Pharmacokinetic (PK) parameters such as maximum plasma drug concentration ( C max ), time to reach maximum concentration ( T max ), and the area under the plasma concentration-time curve from time 0 to 72 h (AUC 0-72 ) were calculated using a non-compartment model to evaluate the bioequivalence of two formulations. The safety of volunteers was monitored during the entire study. In the fasting trial, 90% confidence intervals (CIs) of geometric mean ratios (GMRs) of the test to reference formulations were 101.26–112.94% for C max and 98.50–102.69% for AUC 0-72 , all within the recognized bioequivalence range of 80.00–125.00%. In the fed trial, 90% CIs of GMRs of the test to reference formulations were 92.08–101.54% for C max and 95.81–99.79% for AUC 0-72 , both were within the bioequivalence range of 80.00–125.00%. Research findings indicated that the two topiramate formulations were bioequivalent and had a favorable safety profile.

Rationale Both topiramate and naltrexone have been shown to affect neural alcohol cue reactivity in alcohol use disorder (AUD). However, their comparative effects on alcohol cue reactivity are unknown. Moreover, while naltrexone has been found to normalize hyperactive localized network connectivity implicated in AUD, no studies have examined the effect of topiramate on intrinsic functional connectivity or compared functional connectivity between these two widely used medications. Objective This study compared topiramate versus naltrexone on alcohol cue-elicited brain activation and intrinsic functional connectivity in patients with alcohol use disorder. Methods Forty-seven participants with alcohol use disorder received daily topiramate (titrating the dose up to 200 mg/day n  = 21) or naltrexone (50 mg/day, n  = 26) for at least 6 weeks. Using functional magnetic resonance imaging (fMRI), we examined intrinsic functional connectivity during rest and alcohol cue-elicited neural activation during a visual alcohol cue reactivity task 120 min following treatment administration. Functional connectivity and alcohol cue reactivity and percentage of heavy drinking days (% HDD) associations were assessed. Results No differences in either intrinsic functional connectivity or alcohol cue-elicited neural activity were seen between topiramate and naltrexone-treated groups. Overall, participants showed increased alcohol cue-elicited activation in three clusters spanning occipital regions involved in visual recognition of stimuli, and hypoactivation to both alcohol and control cues in three clusters involved in salience attribution and processing of emotional valence of external stimuli. No differences between topiramate versus naltrexone were observed for either functional measure or associations with post-scan % HDD. Conclusions Topiramate and naltrexone enacted comparable alcohol cue reactivity and intrinsic functional connectivity patterns. Some overall responses of increased brain activation to alcohol cues in visual processing regions coupled with reduced activation to alcohol and control cues were evidenced for both treatments. These activation patterns were in regions expected to show attenuation of brain activity resulting from treatment. Topiramate and naltrexone may thus enact functional effects through similar modulation of functional neural activity in individuals with AUD. Trial registration ClinicalTrials.gov, NCT03479086 https://www.clinicaltrials.gov/study/NCT03479086 .

Background and purpose HER‐MES was the first head‐to‐head study of erenumab against topiramate (standard of care). This post hoc analysis of the HER‐MES study evaluated the effect of erenumab versus topiramate on patient‐reported outcomes at week 24. Methods Adult patients with episodic or chronic migraine (n = 777) were randomized (1:1) to monthly subcutaneous erenumab (n = 389) or daily oral topiramate (n = 388). Migraine‐related disability, as measured by the Headache Impact Test 6 (HIT‐6) and Short Form 36 Health Survey version 2 (SF‐36v2), was analysed in the entire study cohort and true completers. Results In the erenumab group (vs. topiramate), significant improvements were reported in Headache Impact Test 6 total scores (composite populations, −10.88 vs. −7.72; true completers, −11.92 vs. −10.61) and a higher proportion of patients achieved a ≥5‐point reduction from baseline with erenumab (composite populations, 72.2% vs. 53.9%; true completers, 79.64% vs. 71.43%). The adjusted mean change from baseline in the SF‐36v2 score was greater with erenumab for both physical component summary (composite population, 5.48 vs. 3.63; true completers, 5.95 vs. 5.23) and mental component summary (composite populations, 1.00 vs. −1.18; true completers, 1.74 vs. −0.33). A higher proportion of patients on erenumab versus topiramate had a ≥5‐point improvement in SF‐36v2 for the physical component summary (composite populations, 47.7% vs. 37.4%; true completers, 52.1% vs. 48.9%) and mental component summary (composite populations, 25.3% vs. 16.8%; true completers, 27.3% vs. 17.7%). Conclusions This post hoc analysis demonstrated that patients treated with erenumab had significant improvements in headache impact and quality of life as measured by patient‐reported outcomes versus patients treated with topiramate.

Polycystic ovary syndrome (PCOS) is often linked with obesity, and weight management can improve endocrine and cardiometabolic features. This work aimed to evaluate the effects of adding topiramate (TPM) to metformin (MTF) on weight control and hormonal and metabolic outcomes in women with PCOS. In a randomized, double-blind, placebo-controlled trial, participants with PCOS and body mass index of 30 or greater, or 27 or greater associated with hypertension, type 2 diabetes, or dyslipidemia followed a 20 kcal/kg diet in addition to 850 mg of MTF or a previous MTF regimen. They were randomly assigned to receive either TPM or placebo (P) alongside MTF. Anthropometric measurements, blood pressure, modified Ferriman-Gallwey score (mFGS), and adverse events were assessed every 4 weeks for 6 months. The primary end point was the percentage change in body weight from baseline in both groups. Secondary end points included changes in clinical, cardiometabolic, and hormonal parameters and psychosocial features. Thirty-one participants were in the MTF + P group and 30 in the MTF + TPM group. The MTF + TPM group showed greater mean weight loss at 3 months (-3.4% vs -1.6%; P = .03) and 6 months (-4.5% vs -1.4%; P = .03). Both groups had improved androgens, lipids, and psychosocial scores. Participants with 3% or greater weight loss at 6 months had improved mFGS (8.4 to 6.5; P = .026). Paresthesia was more common in the MTF + TPM group (23.3% vs 3.2%; P = .026). Combining TPM with MTF and a low-calorie diet may be an effective, low-cost, easy-to-use, and safe strategy for weight management in women with PCOS, with mild adverse effects.

Abstract RationalePharmacotherapies are an important clinical strategy for treating alcohol use disorder and an understanding of their functional mechanisms can inform optimal use. Behavioral economics provides a translational platform that may advance our understanding of the motivational impacts of pharmacotherapies.ObjectivesThis secondary analysis study examined the effect of topiramate, a promising pharmacotherapy for treating alcohol use disorder, on two behavioral economic domains, the reinforcing value of alcohol (alcohol demand and alcohol-specific monetary expenditures) and delayed reward discounting (preference for smaller immediate rewards over larger delayed rewards).MethodsA double-blind randomized placebo-controlled study (n = 99) was conducted with non-treatment seeking heavy drinkers, comparing topiramate (target dose of 200 mg/day titrated for 3 weeks and remained at the target dose for 2 weeks) to matched placebo.ResultsWe found that compared to placebo, topiramate reduced the reinforcing value of alcohol, as shown by a reduction in two alcohol demand indices (intensity and Omax), money spent per week on alcohol and an almost a 50% increase in days without expenditures on alcohol from baseline. Directionally consistent patterns were also present for breakpoint and elasticity (ps = .08). No significant effects were found for delayed reward discounting.Conclusions This study provides evidence that topiramate reduces alcohol’s reinforcing value as measured by alcohol demand and alcohol expenditure. More broadly, these findings support the utility of behavioral economics for understanding how medications reduce alcohol use.

Prader–Willi Syndrome (PWS) is a rare genetic syndrome leading to severe behavioural disorders and mild cognitive impairment. The objective of this double-blind randomised placebo-controlled trial was to study the efficacy and tolerance of topiramate on behavioural disorders in patients with PWS. Participants (aged 12–45 years) had genetically confirmed PWS and severe irritability/impulsivity, eating disorders and/or obesity, and skin picking. Thirty-two participants received a placebo (PBO), and 30 participants received topiramate (TOP) (50–200 mg/day) for 8 weeks. The primary outcome was the rate of responders using the Clinical Global Impression-Improvement (CGI-I) scale. The secondary outcome measures included the Aberrant Behaviour Checklist, the Dykens Hyperphagia Questionnaire (DHK), the Self-Injurious Behaviour Scale (SIBS) and the body mass index (BMI). We found no significant difference in the primary outcome (the CGI-I): 9 (30%) patients were very much or much improved in the TOP group compared to 7 (22.6%) patients in the PBO group. However, the DHK behaviour and severity scores improved significantly more over time in patients treated with topiramate versus those receiving a placebo, with a significant dose–effect relationship. DHK scores were also significantly associated with genetic subtypes and hospitalisation status. The effects of topiramate on eating behaviours remained significant after adjusting for genetic subtype and hospitalisation. Topiramate had therefore a significant effect on eating disorders, with a dose–effect relationship. Given the burden of eating disorders in PWS, we believe that topiramate may become the first psychotropic option within the global care of obesity in individuals with PWS.

Background Head-to-head comparator trials between first-line oral migraine preventatives and the new monoclonal antibodies (mAbs) blocking the calcitonin gene-related peptide (CGRP) pathway have not been published to date. Objectives This study aimed to indirectly compare the clinical efficacy and safety of mAbs against CGRP or its receptor (CGRPR) and topiramate in episodic migraine prophylaxis using meta-analysis. Methods We included controlled trials testing efficacy and safety of erenumab, galcanezumab, fremanezumab, eptinezumab, and topiramate in adults diagnosed with episodic migraine. We searched PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov from January 2000 to November 2020. We used the Risk of Bias 2 (RoB2) tool to assess the risk of bias and report pooled mean effects (mean difference and risk ratio) as estimated in a random effect model. For efficacy analysis, we determined the reduction of monthly migraine days (MMDs), reduction of days with acute medication (AMDs), and 50% responder rates (50% RR). For safety, we determined adverse events (AEs) occurring in ≥ 2% of study participants and the number of patients who discontinue treatment due to AEs (DAEs). The number needed to treat (NNT) and to harm (NNH) were estimated as well as the likelihood to help or harm (LLH). Results We included 13 trials involving 7557 patients: three trials with erenumab, two trials with galcanezumab, two trials with fremanezumab, one trial with eptinezumab, and five trials with topiramate, for the prophylaxis of episodic migraine in adults. The placebo-subtracted reduction (pooled mean difference) of MMDs were − 1.55 (95% CI − 1.86 to − 1.24; active drug n  = 3326 vs placebo n  = 2219, 8 studies) for the CGRP(R) mAb and − 1.11 (95% CI − 1.62 to − 0.59; active drug n  = 1032 vs placebo n  = 543, 4 studies) for topiramate ( p for subgroup difference = 0.15). ‘Cognitive’ and ‘sensory & pain’-related adverse events occurred more often in patients treated with topiramate compared with those treated with a CGRP(R) mAb ( p for subgroup difference 0.03 and < 0.001, respectively). Based on the 50% RR and DAE, the NNT, NNH, and LHH for the CGRP(R) mAbs were 6, 130, and 24.3:1, respectively. For topiramate, these values were 7, 9, and 1.8:1, respectively. Conclusion The efficacy of CGRP(R) mAbs to reduce migraine days does not differ from topiramate. However, the safety profile is in favor of the CGRP(R) mAbs, with a higher likelihood to help than to harm compared with topiramate. The diversity of endpoint determination and the heterogeneity between studies for some endpoints cause some limitations for this study.

Abstract Context Glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors reduce weight and improve insulin sensitivity via different mechanisms. Objective The efficacy of once-weekly exenatide (EQW) and dapagliflozin (DAPA) alone and coadministered (EQW/DAPA), DAPA/extended-release (ER) metformin (DAPA/MET), and phentermine topiramate extended release (PHEN/TPM) on metabolic parameters, body composition, and sex hormones were examined in obese women with PCOS. Methods Nondiabetic women (n = 119; aged 18-45 years) with a body mass index (BMI) greater than 30 and less than 45 and polycystic ovary syndrome (National Institutes of Health criteria) were randomly assigned in a single-blinded fashion to EQW (2 mg weekly); DAPA (10 mg daily), EQW/DAPA (2 mg weekly/10 mg daily), DAPA (10 mg)/MET (2000 mg XR daily), or PHEN (7.5 mg)/TPM (46 mg ER daily) treatment for 24 weeks. Study visits at baseline and 24 weeks included weight, blood pressure (BP), waist (WC) measures, and body composition evaluated by dual-energy x-ray absorptiometry (DXA). Oral glucose tolerance tests were conducted to assess glycemia and mean blood glucose (MBG), and compute insulin sensitivity (SI) and secretion (IS) measures. Sex steroids, free androgen index (FAI), and lipid profiles were measured in the fasting sample. Results EQW/DAPA and PHEN/TPM resulted in the most loss of weight and total body fat by DXA, and WC. Despite equivalent reductions in BMI and WC with PHEN/TPM, only EQW/DAPA and EQW resulted in significant improvements in MBG, SI, and IS. Reductions in fasting glucose, testosterone, FAI, and BP were seen with all drugs. Conclusion Dual therapy with EQW/DAPA was superior to either alone, DAPA/MET and PHEN/TPM in terms of clinical and metabolic benefits in this patient population.

To assess the efficacy and safety of topiramate in treating binge eating disorder (BED), using a systematic review and meta-analysis of the available randomized clinical trials (RCTs). The RCTs assessing topiramate vs placebo with or without adjunctive psychotherapy in BED were reviewed using a systematic search in the PubMed, Web of Science, PsycINFO, Cochrane Database of Systematic Review, and ClinicalTrials.gov search Websites, from inception to November 2019. Main outcomes were the changes in binge frequency, quality of life, and weight, respectively. Effect estimates were pooled using random-effect models and presented as risk ratios (RRs) or mean differences (MDs) and their 95% confidence interval (95% CI). Data extraction was performed by two independent reviewers. Three studies were eligible for inclusion, involving 528 BED patients. Topiramate was found to be significantly more efficacious than placebo in reducing: (a) the number of binge episodes per week (MD = -1.31; 95% CI = -2.58 to -0.03; I2 = 94%); (b) the number of binge days per week (MD = -0.98; 95% CI = -1.80 to -0.16; I2 = 94%); and (c) weight (MD = -4.91 kg; 95% CI = -6.42 to -3.41; I2 = 10%). However, participants in the topiramate groups withdrew significantly more frequently for safety reasons, relative to placebo participants (RR = 1.90; 95% CI = 1.13-3.18, I2 = 0%). Preliminary findings support a possible efficacy of topiramate for the treatment of BED, even if safety concerns could limit the practical use of this treatment in BED subjects.

Oral Topiramate therapy is associated with systemic adverse effects including paresthesia,abdominal pain, and fluctuations in plasma levels. The purpose of this research was to develop an intranasal in situ  gel based system comprising Topiramate polymeric nanoparticles and evaluate its potential both in vitro and in vivo . Poly (lactic-co-glycolic acid) (PLGA)nanoparticles prepared by nanoprecipitation method were added into the in situ gelling system of Poloxamer 407 and HPMC K4M. Selected formulation (TG5) was evaluated for physicochemical properties, nasal permeation and in vivo pharmacokinetics in rats. PLGAnanoparticles (O1) exhibited low particle size (~ 144.4 nm), good polydispersity index (0.202), negative zeta potential (-12.7 mV), and adequate entrapment efficiency (64.7%). Developed in situ gel showed ideal pH (6.5), good gelling time (35 s), gelling temperature(37℃), suitable viscosity (1335 cP)and drug content of 96.2%. In vitro drug release conformedto Higuchi release kinetics, exhibiting a biphasic pattern of initial burst release and sustained release for 24 h. Oral administration of the drug to Sprague–Dawley rats (G3) showed higher plasma C max (504 ng/ml, p  < 0.0001) when compared to nasal delivery of in situ gel (G4) or solution (G5). Additionally, AUC 0-α of G3 (8786.82 ng/ml*h) was considerably higher than othergroups. Brain uptake data indicates a higher drug level with G4 (112.47 ng /ml) at 12 h when compared to G3. Histopathological examination of groups; G1 (intranasal saline), G2(intranasal placebo), G3, G4, and G5 did not show any lesions of pathological significance. Overall, the experimental results observed were promising and substantiated the potential of developed in situ gel for intranasal delivery. Graphical Abstract