title: Topiramate Add-on Lithium Carbonate for Treatment of Acute Mania Topiramate versus Valproate Sodium as Adjunctive Therapies to a Combination of Lithium and Risperidone for Adolescents with Bipolar I Disorder: Effects on Weight and Serum Lipid Profiles Topiramate versus bupropion SR when added to mood stabilizer therapy for the depressive phase of bipolar disorder: a preliminary single-blind study. Open-label adjunctive topiramate in the treatment of bipolar disorders Open-Label Adjunctive Topiramate in the Treatment of Unstable Bipolar Disorder Use of topiramate, a new anti-epileptic as a mood stabilizer. A pilot controlled trial of topiramate for mania in children and adolescents with bipolar disorder. Topiramate monotherapy in the management of acute mania: results of four double-blind placebo-controlled trials. Topiramate and divalproex in combination with risperidone for acute mania: a randomized open-label study Topiramate as an adjuvant treatment for obsessive compulsive symptoms in patients with bipolar disorder: a randomized double blind placebo controlled clinical trial. A randomized double-blind placebo-controlled study of the long-term efficacy and safety of topiramate in the treatment of obese subjects Adjunctive topiramate therapy in patients receiving a mood stabilizer for bipolar I disorder: a randomized, placebo-controlled trial.
abstract: Objective : The purpose of this study was to evaluate the effect of adjunctive topiramate in treating acute mania . Methods : In this study which was a double-blinded r and omized clinical trial , 46 bipolar patients in manic episode , were treated with lithium carbonate and topiramate versus lithium carbonate and placebo and treatment responses were assessed by Young Mania Rating Scale ( YMRS ) weekly . Results : In both intervention and control groups , YMRS score had significant decline after 8 weeks(p < 0.001 ) , but there was no statistically significant difference between the two groups ( p = 0.419 ) . The highest score decline was after two weeks . YMRS score at baseline did not have statistically significant difference between the intervention and control groups ( p = 0.709 ) . Conclusions : This study failed to show antimanic efficacy of adjunctive topiramate in the treatment of those with acute manic . Declaration of interest : None . Clinical Trial Registration : URL : http://www.i rct .ir . I RCT 201110317960N1 Objective To compare the effects of topiramate versus valproate sodium as an add-on therapy to a combination of lithium and risperidone ( Li+Ris ) on body weight and serum lipid profile in children and adolescents with bipolar disorder . Methods In a single-blind r and omized clinical trial , thirty children and adolescents with bipolar disorder type I in the manic or mixed phase , treated with the combination of Li+Ris at therapeutic doses for at least 4 weeks who had the indication of add-on therapy due to a recurrent episode ; a partial response or non response in the current episode or relapse were included . Participants were r and omly assigned to receive either topiramate or sodium valproate as the third drug add-on therapy for a total of 6 weeks . Weight , height and serum lipid profiles were determined at baseline and at the end of week 6 . Results Differences in the mean levels of lipid profiles at baseline and after week 6 evaluation were not significant in both treatment groups . BMI z-score increased in both treatment groups , being significant only in the Li+Ris/Valproate group , increasing from ( mean±SD ) 0.38±0.55 to 0.72±1.23 ( p<0.05 ) . Between group changes in BMI z-score was not significant . Among the BMI percentile categories , participants in the normal weight subgroup showed a significant increase in BMI z-score during the 6 week trial , compared to overweight/obese subgroup , in both Li+Ris/Valproate and Li+Ris/Topiramate treatment groups . Elevated mean serum level of triglyceride and a high proportion of participants with elevated total cholesterol ( ≥ 170 mg/dl ) , triglyceride ( ≥ 110 mg/dl ) , and BMI percentile 85-<95 at baseline ( before r and omization ) and at the end of 6 week study were noted . Conclusion When topiramate and valproate sodium are used for six weeks as adjunctive treatment to a combination of Li+Ris , they act alike on lipid milieu of children and adolescents with bipolar disorder . Both Li+Ris/Valproate and Li+Ris/Topiramate therapies can lead to an increase in BMI z-score . This increase is statistically significant with Li+Ris/Valproate therapy . This suggests that topiramate could attenuate the ongoing weight  gain from lithium and risperidone . In this study , the majority of participants who gained weight were those with BMI less than 85th percentile . This suggests that normal weight patients may have greater weight gain potential than overweight/obese patients .High proportion of metabolic abnormalities among the patients at baseline , which remained elevated throughout the trial , warrants cardiometabolic monitoring in this population OBJECTIVE Antiepileptic drugs ( AEDs ) are commonly employed in the treatment of bipolar disorder . The efficacy and tolerability of topiramate , a novel anticonvulsant , and bupropion SR when added to mood stabilizer therapy were compared under single-blind conditions ( rater-blinded ) in patients meeting DSM-IV criteria for bipolar I/II depression . METHODS A total of 36 out- patients with Hamilton Depression Rating Scale ( HDRS-17 ) scores > or = 16 were r and omized to receive escalating doses of either topiramate ( 50 - 300 mg/day ) or bupropion SR ( 100 - 400 mg/day ) for 8 weeks . Data were analyzed on an intent-to-treat basis using the last observation carried forward method . RESULTS The percentage of patients meeting a priori response criteria ( > or = 50 % decrease from baseline in mean HDRS-17 total score ) was significant for both topiramate ( 56 % ) and bupropion SR ( 59 % ) [ t(17 ) = 2.542 , p = 0.04 and t(17 ) = 2.661 , p = 0.03 , respectively ] . Baseline demographic and clinical parameters were comparable between the two treatment groups . The mean doses of study medication were 176 mg/day ( SD = 102 mg/day ) for the topiramate-treated group and 250 mg/day ( SD = 133 mg/day ) for the bupropion SR-treated group . A significant and comparable reduction in depressive symptoms was observed from baseline to endpoint following topiramate and bupropion SR treatment , according to a > or = 50 % reduction in the HDRS-17 . Total mean HDRS-17 scores significantly decreased from baseline to endpoint in both groups ( p = 0.001 ) , however , differences between the topiramate-treated group and the bupropion SR-treated group were not significant [ t(36 ) = 1.754 , p = 0.097 ] . Both topiramate and bupropion SR were generally well tolerated .  Thirteen patients discontinued the study : 2 because of lack of efficacy  , 1 due to withdrawal of consent and 10 following side-effects ( six in the topiramate and four in the bupropion SR-treated group ) . There were no cases of affective switch in either arm . Weight loss was experienced by patients in both groups ( mean weight loss at endpoint was 1.2 kg in bupropion SR and 5.8 kg in topiramate ) [ t(17 ) = 2.325 , p = 0.061 and t(17 ) = 2.481 , p = 0.043 , respectively ] . CONCLUSIONS These preliminary data suggest that adjunctive topiramate may reduce depressive symptom severity in acute bipolar depression . The antidepressant efficacy of this compound requires confirmation via double-blind placebo controlled investigation BACKGROUND To preliminarily explore the spectrum of effectiveness and tolerability of the new antiepileptic drug topiramate in bipolar disorder , we evaluated the response of 56 bipolar out patients in the Stanley Foundation Bipolar Outcome Network ( SFBN ) who had been treated with adjunctive topiramate in an open-label , naturalistic fashion . METHODS In this case series , response to topiramate was assessed every 2 weeks for the first 3 months according to st and ard ratings in the SFBN , and monthly thereafter while patients remained on topiramate .  Patients ' weights , body mass indices ( BMI s ) , and side effects were also assessed . RESULTS Of the 54 patients who completed at least 2 weeks of open-label , add-on topiramate  treatment , 30 had manic , mixed , or cycling symptoms , 11 had depressed symptoms , and 13 were relatively euthymic at the time topiramate was begun . Patients who had been initially treated for manic symptoms displayed significant reductions in st and ard ratings scores after 4 weeks , after 10 weeks , and at the last evaluation . Those patients who were initially depressed or treated while euthymic showed no significant changes . Patients as a group displayed significant decreases in weight and BMI from topiramate initiation to week 4 , to week 10 , and to the last evaluation . The most common adverse side effects were neurologic and gastrointestinal . CONCLUSIONS These preliminary open observations of adjunctive topiramate treatment suggest that it may have antimanic or anticycling effects in some patients with bipolar disorder , and may be associated with appetite suppression and weight loss that is often viewed as beneficial by the patient and clinician . Controlled studies of topiramate 's acute and long-term efficacy and side effects in bipolar disorder appear warranted Objective : To assess open-label adjunctive topiramate in the treatment of out patients with unstable bipolar disorder ( BD ) . Method : Out patients with DSM-IV – defined BD ( I or II ) exhibiting mood instability were enrolled in this 16-week , open-label , multicentre study . Topiramate was added to existing mood stabilizers and other psychotropic treatments . The primary effectiveness measure was the Clinical Global Impression of Severity ( CGI-S ) scale ; other scales included the Young Mania Rating Scale ( YMRS ) and the Montgomery – Asberg Depression Rating Scale ( MADRS ) . Safety assessment s included monitoring adverse events , measuring tremor , monitoring vital signs and weight , and laboratory indices . We also evaluated patient satisfaction with treatment . Results : A total of 109 patients were enrolled . Intent-to-treat analysis showed significant improvement from baseline in the CGI-S , YMRS , and MADRS , starting at Week 2 ( P < 0.001 ) , with further accrual of benefit between Week 2 and Week 16 ( P < 0.001 ) . The mean modal dosage of topiramate during the stable dosing period was 180 mg daily . There was a mean 1.8 kg decrease in patient weight  from topiramate initiation to Week 16 ( P < 0.001 ) . Topiramate was well tolerated by most patients ; 11 % withdrew from the study owing to adverse events . We noted a significant reduction in the mean severity score for preexisting tremor by Week 8 of treatment ( P < 0.005 ) ; no notable changes in vital signs were observed . At Week 16 , 50 % of the patients were “ completely satisfied ” with topiramate treatment . Conclusions : Adjunctive topiramate treatment can reduce the severity of manic and depressive symptoms , as well as reducing tremor and weight in out patients with BD I or II RATIONALE Because some anti-epileptic drugs ( AEDs ) are effective in bipolar affective disorders , the new AED topiramate ( TPM ) may be effective in psychiatric illnesses . TPM was evaluated in mood disorders refractory to previous therapies including newer AEDs . METHODS Charts of 58 consecutive patients , 39 out patients ( 15 males , 24 females ) and 19 in patients ( 6 males , 13 females ) were review ed .  TPM 25 mg . b.i.d . was added to existing therapy and titrated in 50 mg increments every 3 - 7 days . Improvement was rated on a Likert global assessment scale of marked , moderate , mild , or no improvement or worse , based on quality of sleep , appetite , mood , and concentration . RESULTS Of the 58 patients with psychiatric disorders , 44 patients had rapid cycling bipolar disorders characterized by manic , hypomanic , or mixed episodes . Eighteen patients had previously failed to respond to lamotrigine and /or gabapentin in addition to conventional mood stabilizers . Fourteen were Bipolar I , six Bipolar II , and seven mixed , ten patients had cyclothymic disorder , seven had bipolar disorder not otherwise specified . Of the remaining 14 patients , nine had schizoaffective disorder , three patients had dementia and two had psychosis . Mean duration of TPM treatment was 16.0 weeks ; mean TPM dosage approximately 200 mg/day . Thirty-six of 58 ( 62 % ) patients exhibited marked or moderate improvement , usually within days or weeks . Twenty-three of 44 ( 52 % ) patients with bipolar affective disorders showed marked or moderate improvement . Minimal/no improvement was observed in 16 ; six were rated as worse . Adverse events included delirium in one patient with Bipolar Disorder Type I who overmedicated with TPM ( 800 mg ) and tranylcypromine sulfate ( 170 mg ) combined with alcohol . Other adverse effects were minor and included : paresthesias , somnolence , fatigue , impaired concentration and memory , nausea , and diarrhoea . LIMITATIONS This study was performed in a nonr and om open and retrospective fashion . Therefore , any findings are limited by the design of this study . CONCLUSION TPM may be useful in patients with mood disorders unresponsive to traditional therapy and warrants further clinical investigation 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 result ing 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 OBJECTIVE To evaluate the efficacy and tolerability of topiramate monotherapy in adults with acute manic or mixed episodes of bipolar I disorder . METHODS In four trials , adults hospitalized with acute mania , a diagnosis of bipolar I disorder , history of > or = 1 previous manic or mixed episodes , and > or = 20 Young Mania Rating Scale ( YMRS ) score were r and omized to double-blind treatment with topiramate ( target doses : 200 , 400 , or 600 mg/day ) or placebo ; two trials included an active comparator ( lithium , 1500 mg/day ) . The core study duration in all trials was 3 weeks ; three trials also had 9-week double-blind extensions . The primary efficacy variable was mean change from baseline in YMRS in the core 3-week study . RESULTS Changes in YMRS score during 3 weeks were not significantly different for topiramate versus placebo ( mean YMRS reductions , -5.1 to -8.4 ) . Mean YMRS reductions in lithium-treated groups were significantly greater ( p < or = 0.001 versus placebo and topiramate ) . A similar pattern was observed after 12 weeks of double-blind treatment in studies with double-blind extensions . Paresthesia , appetite decrease , dry mouth , and weight loss were more frequently associated with topiramate than with placebo . CONCLUSIONS These studies do not support the efficacy of topiramate as monotherapy in acute mania or mixed episodes in adults with bipolar I disorder . Topiramate was not associated with mood destabilization measured as mania exacerbation or treatment-emergent depression . Lithium was confirmed as an effective therapy in this population Mood stabilizers and atypical antipsychotics are commonly combined for the treatment of bipolar mania . The aim of this study was to compare the effectiveness and tolerability of topiramate and divalproex in combination with risperidone for treating acute mania patients in a naturalistic treatment setting . Seventy-four patients who met the DSM-IV criteria for bipolar mania were enrolled in this study . In order to assess the efficacy and the extrapyramidal symptoms ( EPS ) , the Young Mania Rating Scale ( YMRS ) , Clinical Global Impression ( CGI ) and Simpson-Angus Rating Scale ( SARS ) were measured at the baseline and at weeks 1 , 3 and 6 . From the baseline to the endpoint , the YMRS and CGI scores were reduced by 67.9 % and 56.6 % in the topiramate plus risperidone group ( TPMG ) . The YMRS and CGI scores were also reduced by 63.7 % and 58.2 % in the divalproex plus risperidone group ( DVPG ) . The weight and body mass index ( BMI ) increased significantly by 3.6 % and 3.3 % from the baseline to the endpoint in the DVPG , while they decreased by 0.5 % and 0.4 % , respectively , with no significant difference in the TPMG . There were no serious adverse events in either group . Despite the method ological limitations , topiramate was effective and tolerable for treating acute mania and may also be a promising alternative to a weight-gain liable mood stabilizer ( MS ) such as divalproex BACKGROUND It has not been examined trialed whether obsessive compulsive symptoms in patients with bipolar disorder respond to topiramate as an adjuvant treatment . METHODS This 4-month double-blind placebo-controlled r and omized clinical trial examined the efficacy and safety of augmentation with topiramat for treating the patients with bipolar disorder , manic phase type-I , and obsessive compulsive disorder symptoms . Both groups received lithium+olanzapine+clonazepam . However , one group received topiramate and the other group placebo as adjuvant medications . Yale Brown obsessive compulsive behavior scale was used to assess the outcome . Adverse effects were also recorded . RESULTS A total of 32 patients completed this trial . The mean score decreased from 24.2(4.8 ) to 17.6(8.7 ) in the topiramate group ( P<0.003 ) and from 20.9(2.9 ) to 9.6(3.5 ) in the placebo group during this trial ( P<0.0001 ) . Additionally , 9(52.9 % ) out of 17 patients in the topiramate group and 2(12.5 % ) out of 16 patients in the placebo group showed more than 34 % decline in YBOC score ( x2=6.0 , df=1 , P<0.01 ) . No serious adverse effects were detected . LIMITATIONS The limitations of the present study were its small sample size and the fact that it was conducted in a single center . CONCLUSIONS The combination of lithium+olanzapine+clonazepam decreased the symptoms of obsessive compulsive disorder in the patients with bipolar disorder type I. However , topiramate had a more significant effect than placebo on improvement of the patients with bipolar disorder and obsessive compulsive symptoms . This combination seems to be without serious adverse effects BACKGROUND : Treatment of obese subjects with topiramate has recently been associated with significant weight loss in a 6-month dose-ranging study . OBJECTIVE : To investigate the long-term efficacy and safety of topiramate in obese subjects . DESIGN : R and omised , double-blind , placebo-controlled study investigating three doses of topiramate : 96 , 192 , and 256 mg/day . All subjects also participated in a nonpharmacological weight-loss programme . SUBJECTS : The study included 1289 subjects 18–75 y with a body mass index ≥30 kg/m2 and < 50 kg/m2 in the absence of comorbidities , or ≥27 kg/m2 and < 50 kg/m2 in the presence of controlled hypertension and /or dyslipidaemia . DURATION : The original study design was for a 6-week , single-blind , placebo run-in phase followed by an 8-week titration phase and 2 y of maintenance at the assigned dose . Sponsor ended study early in order to develop a new controlled-release formulation with the potential to enhance tolerability and simplify dosing in this patient population . Therefore , none of the subjects completed the full 2 y of treatment . Efficacy results are based on subjects who were enrolled early enough to have had an opportunity to complete 1 y at their assigned dose ( modified intent-to-treat population , MITT ) before learning of the decision to terminate the study . Safety results are based on all subjects who took at least one dose of study medication . RESULTS : The safety population consisted of 1282 subjects , and the MITT efficacy population was 854 subjects . At 60 weeks , subjects in the placebo group lost 1.7 % of their baseline body weight , while subjects in the topiramate 96 , 192 , and 256 mg/day treatment groups lost 7.0 , 9.1 , and 9.7 % , respectively ( P<0.001 , MITT , last observation carried forward ) . Weight loss ≥5 % of baseline weight was achieved by 18 % of subjects in the placebo arm vs 54 , 61 , and 67 % of subjects receiving topiramate 96 , 192 , and 256 mg/day , respectively ; weight loss ≥10 % was achieved by 6 vs 29 , 40 , and 44 % , respectively ( P<0.001 ) . Weight loss was accompanied by significant improvements in blood pressure ( systolic/diastolic changes of + 0.4/+1.0 , −3.1/−1.3 , −5.7/−3.4 , and −4.6/−2.4 mmHg were observed for placebo , topiramate 96 mg/day , 192 mg/day , and 256 mg/day , respectively , P<0.001 ) and glucose and insulin . The most common adverse events more frequently observed in topiramate-treated subjects occurred mostly during the titration phase and were related to the central or peripheral nervous system and included paresthesia , difficulty with concentration/attention , depression , difficulty with memory , language problems , nervousness , and psychomotor slowing . CONCLUSION : Topiramate treatment of obese subjects over the course of 1 y result ed in clinical ly significant weight loss . Improvements were also observed in blood pressure and glucose tolerance OBJECTIVE To investigate the efficacy and safety of topiramate versus placebo as adjunctive therapy for the outpatient management of bipolar I disorder . METHOD In this 12-week , r and omized , double-blind , placebo-controlled trial , adults with bipolar I disorder ( DSM-IV criteria ) experiencing a manic or mixed episode with a Young Mania Rating Scale ( YMRS ) score of > or= 18 while taking therapeutic levels of valproate or lithium received adjunctive topiramate or placebo . Topiramate was titrated from 25 to 400 mg/day over 8 weeks and was continued for 4 additional weeks . The study was conducted from October 2001 through October 2003 . The primary outcome measure was the change in YMRS score from baseline to last study visit during the double-blind phase . RESULTS The mean + /- SD change in YMRS score from baseline was -10.1 + /- 8.7 ( -40.1 % ) in the topiramate group ( N = 143 ) and -9.6 + /- 8.2 ( -40.2 % ) in the placebo group ( N = 144 , p = .797 ) . Greater than 50 % reduction in YMRS was achieved by 39 % of the topiramate group and 38 % of the placebo group ( p = .914 ) . No significant treatment differences were observed for secondary efficacy measures . Compared with adjunctive placebo , adjunctive topiramate did not worsen mania or induce depression . Paresthesia , diarrhea , and anorexia were more common in the topiramate group . The topiramate group achieved greater reductions than the placebo group in body weight ( -2.5 vs. 0.2 kg , p < .001 ) and body mass index ( -0.84 vs. 0.07 kg/m(2 ) , p < .001 ) . CONCLUSION In patients treated with lithium or valproate , there was no difference in the reduction of YMRS score in the topiramate and placebo groups . Both groups showed declines of 40 % . Topiramate reduced body weight significantly relative to placebo without worsening depressive or manic symptoms
target: It is not possible to draw any firm conclusions about the use of topiramate in clinical practice from this evidence .
background: BACKGROUND Bipolar disorder is a common recurrent illness with high levels of chronicity .
  Previous trials have suggested that the anticonvulsant topiramate may be efficacious in bipolar disorder .
  This is an up date of a previous Cochrane review ( last published 2006 ) on the role of topiramate in bipolar disorder .
  OBJECTIVES To assess the effects of topiramate for acute mood episodes  in bipolar disorder in adults compared to placebo , alternative pharmacological treatment , and combination pharmacological treatment as measured by treatment of symptoms on specific rating scales for individual episodes .