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Keywords:

  • acute mania;
  • bipolar I disorder;
  • lithium;
  • topiramate;
  • weight loss

Abstract

  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results
  5. Discussion
  6. References

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 ≥1 previous manic or mixed episodes, and ≥20 Young Mania Rating Scale (YMRS) score were randomized 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 ≤ 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.

Acute mania is often a medical emergency in which the primary goal of treatment is to minimize potential harm to the patient and others by restoring behavioral control with rapid resolution of irritability, agitation, impulsivity, aggression, and risk taking. Despite the number of therapies evaluated in appropriately powered, placebo-controlled trials demonstrating antimanic efficacy, more treatment options are needed. Even when an agent is superior to placebo, clinical trials typically show that 50% or more of patients do not have a clinically significant response (1–5). Furthermore, bipolar disorder is a chronic disorder in which maintenance therapy is often needed. Effectiveness of treatment – acute or maintenance – can be compromised by side effects that increase the risk of non-adherence such as treatment-emergent weight gain (6).

Topiramate, a neuromodulator effective in controlling seizures and preventing migraine attacks (7–10), is associated with a low risk of weight gain in adults. Weight loss, particularly in those with high baseline body weight/body mass index (BMI), is a common clinical finding (11). In anecdotal reports and small open-label studies, addition of topiramate was associated with reduction in manic symptoms in patients with treatment-resistant mania (12–14); symptoms recurred when topiramate was withdrawn (12, 13). When evaluated as monotherapy in a pilot open-label study of acute mania (15), baseline Young Mania Rating Scale (YMRS) scores decreased with topiramate administration. Based on these findings and the interest in therapies with a lower potential for weight gain as an adverse effect, four double-blind, placebo-controlled trials were conducted with topiramate monotherapy (target dosages of 200, 400, and 600 mg/day) in acute mania associated with bipolar I disorder. Study protocols used identical inclusion/exclusion criteria and followed the same study procedures for the core 3-week double-blind study; three of the four trials had 9-week double-blind extension phases of differing designs. Findings from individual core 3-week studies as well as the 12-week studies are reported here.

Patients and methods

  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results
  5. Discussion
  6. References

The trials were multicenter randomized, double-blind, placebo-controlled, parallel-group trials conducted in the United States (PDMD-005 and PDMD-006) and 19 other countries (PDMD-004, Eastern and Western Europe, Argentina, India, Israel, and Australia; PDMD-008, Eastern Europe, South Africa, Latin America, and India). Performed in accordance with the revised Declaration of Helsinki (16), study protocols were reviewed by an independent ethics committee; patients or their legal representatives gave written informed consent.

Patients

Patients ≥16 years of age with a primary DSM-IV (17) diagnosis of bipolar I disorder and hospitalized with an acute manic or mixed episode, confirmed by a Structured Clinical Interview for DSM-IV Axis I Disorders, were eligible. Patients had to have a history of at least one previous manic or mixed episode. Patients with co-morbid diagnoses were included unless the primary diagnosis was schizoaffective or impulse control disorder or the patient had antisocial or borderline personality disorder. A YMRS score ≥20 at screening and randomization was required.

Other exclusion criteria included rapid cycling bipolar disorder, DSM-IV-defined alcohol or substance abuse/dependence within the previous 3 months, and symptoms associated with recent antidepressant/psychostimulant treatment or with intoxication or withdrawal from psychostimulants such as alcohol, (meth)amphetamines, cocaine, or hallucinogens. Patients were excluded if they were at high risk for suicide, violence, or alcohol/substance abuse, or were likely to require acute intervention with psychotropic medications that could not be discontinued.

Women of childbearing age were eligible if they were surgically incapable of bearing children or practicing a medically acceptable method of birth control, were not lactating, and had negative pregnancy tests at screening and baseline. Patients with unstable or serious medical conditions, seizure disorders, history of nephrolithiasis, or patients taking medication associated with nephrolithiasis were excluded. Exclusion criteria also included the use of substances with potentially confounding psychotropic effects (e.g., St. John's wort, calcium channel blockers administered for mania, or antidepressants) within the previous 4 weeks (5 weeks if fluoxetine), clozapine use within the previous 3 months, previous use of topiramate monotherapy for acute mania or mixed episodes for >4 weeks, previous participation in a topiramate trial, history of severe drug allergy, known hypersensitivity to topiramate, and treatment with an experimental drug or medical device within 30 days before screening. In the two studies in which lithium was an active comparator, known or suspected intolerance to lithium and low-salt diet were exclusion criteria.

Study design

Each of the four trials included a screening phase during which previous psychotropic medications were discontinued, followed by randomization to double-blind treatment for 3 weeks (core study); in three trials, double-blind treatment was continued for a total of 12 weeks (3-week core study + 9-week double-blind extension). Lithium (1500 mg/day) was an active comparator in two studies; in two studies, patients were converted from placebo to lithium (1500 mg/day) or topiramate (150 mg/day) during the double-blind extension. Treatments in the different study phases are summarized in Table 1.

Table 1.  Study design
 Core double-blind, 3 weeksDouble-blind extension, 9 weeks
  1. Patients were titrated to the assigned target dose or maximally tolerated dose.

PDMD-004Placebo 200 mg/day topiramate 400 mg/day topiramate Lithium 1500 mg/dayLithium 1500 mg/day 200 mg/day topiramate 400 mg/day topiramate Lithium 1500 mg/day
PDMD-005Placebo 400 mg/day topiramate 600 mg/day topiramatePlacebo 400 mg/day topiramate 600 mg/day topiramate
PDMD-006Placebo 400 mg/day topiramate 
PDMD-008Placebo 400 mg/day topiramate Lithium 1500 mg/day150 mg/day topiramate 400 mg/day topiramate Lithium 1500 mg/day

Screening/washout.  The screening-phase duration varied according to the time needed for medication washout. A 48-h washout was allowed if YMRS score worsened by ≥25% compared with screening. Otherwise, the washout period was equivalent to five half-lives of the medication in use or one treatment cycle for depot antipsychotic medications. During washout, short-acting benzodiazepine anxiolytics such as lorazepam (maximum, 8 mg/day) were allowed for agitation and insomnia. The washout period was extended for 1 week if YMRS score improved ≥25% from the screening score; if the patient's YMRS score was ≥20 after the 2-week washout, the patient could be randomized to double-blind treatment.

Randomization/titration.  Patients eligible after washout were randomized to topiramate, placebo, or lithium. The starting dose of 50 mg/day topiramate was increased to 100 mg/day at day 2 and in 100-mg increments each day for the next 1–5 days until the target dose (200, 400, or 600 mg/day) or the maximally tolerated dose was achieved. Investigators could slow titration by withholding doses or could reduce the dosage, with a maximum reduction of two tablets or capsules (100 mg/day topiramate) to improve tolerability. In studies with lithium as an active comparator (PDMD-004 and PDMD-008), the starting dose of 300 mg/day lithium was increased daily in 300-mg increments to 1200 mg/day at day 4 and 1500 mg/day at day 6; lithium dosage could be reduced a maximum of 600 mg/day. Lithium dosage was individualized based on target serum levels (titration, 0.8–1.2 mEq/L; stabilization, 0.6–1.2 mEq/L; maximum 1800 mg/day). To maintain study blinding, investigators received instructions from the central laboratory to increase/decrease the mid-day lithium dose to achieve target levels, with sham adjustments in the mid-day (inactive) dose for patients in topiramate and placebo groups.

In studies in which the only treatment arms were topiramate or placebo (PDMD-005 and PDMD-006), the study drug was administered in morning and evening doses. The study drug was administered in three daily doses in the two studies with lithium treatment arms (PDMD-004 and PDMD-008). In the topiramate arms of these studies, the mid-day dose was a placebo capsule.

Following randomization, patients were hospitalized for at least 4 days and remained hospitalized as clinically warranted during the core 3-week study. During the first 14 days of double-blind treatment, chloral hydrate, non-benzodiazepine short-acting sedative hypnotics, and short-acting benzodiazepine anxiolytics could be used as rescue medication. Patients requiring antipsychotics or mood stabilizers were discontinued. Non-pharmacologic interventions other than supportive or educational psychotherapy were prohibited.

In trials with 9-week double-blind extensions, placebo-treated patients were crossed over to lithium (target: 1500 mg/day; PDMD-004) or to topiramate (target: 150 mg/day; PDMD-008). Dose titration and adjustments for lithium-treated patients followed the same schedule as in the core double-blind study. For patients converted to topiramate, the starting dose was 50 mg/day increased in 50-mg increments on days 2 and 3.

Protocol-defined reasons for exiting double-blind treatment before completion of the core study or the double-blind extension included adverse events, inadequate effect, patient choice, and lost to follow-up.

Randomization and blinding

Patients were assigned to treatment groups based on a computer-generated randomization code that was balanced by using permuted blocks and stratified by study center. Based on this randomization code, the study drug was packaged and labeled for each patient, with patient numbers preprinted on study drug labels. Patients were assigned sequential numbers as they were randomized. Study treatment was blinded to patients, investigators and clinical staff, study monitors, data reviewers, and data entry personnel until the double-blind phase was completed and the database was finalized. The central laboratory had access to the randomization code in order to identify blood samples for assaying lithium blood levels.

Topiramate and placebo were supplied as matching 50- or 100-mg tablets (PDMD-005 and PDMD-006) or as identical-appearing capsules (PDMD-004 and PDMD-008) that contained two 25-mg topiramate tablets, placebo, or 300-mg lithium capsules.

Efficacy evaluations

Efficacy analyses were based on the intent-to-treat population, i.e., all randomized patients with at least one postbaseline efficacy evaluation during double-blind treatment. Efficacy was evaluated using the 11-item YMRS administered by trained clinicians over a 15–30 min interview. A symptom severity rating (0–4 or 0–8) was assigned to each YMRS item, based on the patient's subjective assessment for the previous 7 days (or interval since last assessment if less than 7 days) and the clinician's behavioral observations during the interview, with emphasis on the latter evaluation. Body weight was obtained at screening, baseline, and periodically during double-blind treatment.

The primary efficacy endpoint was mean YMRS change from baseline in the core 3-week double-blind study. Secondary efficacy measures included mean YMRS change from baseline after 12 weeks and mean percent change in baseline body weight after 3 and 12 weeks. Other planned efficacy measures were changes from baseline in Clinical Global Impression-Severity (CGI-S), Global Assessment Scale (GAS), Brief Psychiatric Rating Scale (BPRS), and Montgomery–Åsberg Depression Rating Scale (MADRS).

When primary efficacy analyses failed to show a significant difference between topiramate and placebo, data from the core 3-week studies for placebo, topiramate 400 mg/day, and lithium groups were pooled for greater statistical power in exploratory post hoc analyses of potential efficacy signals. Between-group differences in YMRS, CGI, BPRS, MADRS, and GAS score changes, as well as changes in baseline weight and BMI were explored. Percentage of patients with ≥50% change in YMRS, YMRS ≤12 at final visit, ≥10% increase from baseline YMRS, patients who no longer met DSM-IV diagnostic criteria for manic or mixed episode of bipolar I disorder (DSM-IV Responder), and patients with treatment-emergent depression (MADRS ≥18 and a change of ≥4 points from baseline on at least two consecutive visits or at the last visit) were also determined.

Tolerability and safety analyses

The study drug was titrated to the assigned target dose or maximally tolerated dose. Tolerability/safety analyses included all randomized patients who took at least one dose of study medication and provided postbaseline safety data during double-blind treatment. Tolerability/safety measures included treatment-emergent adverse events, clinical laboratory values, vital signs, and re-hospitalization. Adverse event data were pooled by treatment/dose across studies for this report.

Sample size determination/statistical analyses

The sample size of 104 randomized patients per treatment group in each trial gave 90% power at a significance level of 0.05 (two-sided test) to detect a between-group difference of 5.0 ± 10.0 (SD) in change from baseline. Missing YMRS or weight values were imputed using the last-observation-carried-forward approach. Analysis of covariance (ANCOVA) was used to compare between-group differences. The ANCOVA model included factors for treatment, study center, and baseline value as a covariate. The least squares means within the ANCOVA model was used to compare topiramate and placebo/lithium treatments.

In post hoc analyses of pooled data, changes in YMRS, CGI, BPRS, MADRS, GAS scores, weight, and BMI were analyzed with the same methodology as for the primary efficacy parameter in individual studies, using the ANCOVA model with terms for treatment, center, and baseline values to compare topiramate 400 mg/day versus placebo, lithium versus placebo, and topiramate 400 mg/day versus lithium. The p-values for other analyses (percentage of patients with ≥50% change in YMRS, YMRS ≤12 at final visit, ≥10% increase from baseline in YMRS, DSM-IV Responder, and percentage of patients with treatment-emergent depression) were computed with Fisher's exact test.

Results

  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results
  5. Discussion
  6. References

Core 3-week double-blind study

Table 2 shows the disposition of patients in each trial following randomization to placebo, to topiramate (200, 400, or 600 mg/day), or to 1500 mg/day lithium. Demographic and baseline characteristics for each treatment group are shown in Table 3. In general, groups were well matched. The mean (SD) modal daily dosages during the core 3-week study are shown in Table 4.

Table 2.  Patient disposition in each trial during core 3-week study: randomized population
 PlaceboTopiramate, mg/dayLithium, 1500 mg/day
200400600
  1. aPatients who were randomized and had baseline and at least one post-baseline efficacy evaluation.

PDMD-004
Randomized, n111110110 113
Intent-to-treata, n111108107 113
Completed, %746872 74
Withdrawals, %263228 26
 Adverse events, %325 7
 Lack of efficacy, %161812 12
 Patient choice, %776 6
 Lost to follow-up, %030 0
 Other, %025 0
PDMD-005
Randomized, n100 112102 
Intent-to-treata, n99 108101 
Completed, %72 6157 
Withdrawals, %28 3943 
 Adverse events, %1 97 
 Lack of efficacy, %11 1424 
 Patient choice, %9 1110 
 Lost to follow-up, %3 41 
 Other, %4 22 
PDMD-006
Randomized, n106 109  
Intent-to-treata, n106 107  
Completed, %74 56  
Withdrawals, %26 44  
 Adverse events, %5 4  
 Lack of efficacy, %9 21  
 Patient choice, %8 13  
 Lost to follow-up, %4 3  
 Other, %0 4  
PDMD-008
Randomized, n112 116 114
Intent-to-treata, n112 115 114
Completed, %87 87 82
Withdrawals, %13 13 18
 Adverse events, %0 1 8
 Lack of efficacy, %13 8 5
 Patient choice, %1 3 2
 Lost to follow-up, %0 1 2
 Other, %0 1 2
Table 3.  Baseline demographics and patient characteristics: intent-to-treat population in individual studies
 PlaceboTopiramate, mg/dayLithium, 1500 mg/day
200400600
  1. YMRS = Young Mania Rating Scale.

PDMD-004
n111108107 113
Age, mean (SD), years42 (13)42 (14)43 (14) 43 (14)
Gender, M/F, %51/4945/5554/46 41/59
Race, White/Black/Asian/other, %93/0/0/793/0/0/790/2/0/8 90/1/0/9
Weight, mean (SD), kg74.3 (16.3)75.5 (14.9)74.6 (19.2) 75.8 (17.1)
BMI, mean (SD)26.1 (4.7)26.6 (5.0)26.3 (5.9) 27.0 (5.5)
Type of current episode, %
 Mixed121717 18
 Manic888383 82
Current episode severity, %
 Mild110 2
 Moderate373138 38
 Severe without psychotic feature353736 28
 Severe with mood-congruent psychotic feature242621 32
 Severe with mood-incongruent psychotic feature366 0.0
Baseline YMRS score, mean (SD)30.0 (6.3)30.8 (7.8)30.2 (7.1) 30.1 (7.4)
PDMD-005
n99 108101 
Age, mean (SD), years37 (10) 40 (12)39 (11) 
Gender, M/F, %40/60 42/5858/42 
Race, White/Black/Asian/other, %72/15/2/11 79/11/2/881/13/0/6 
Weight, mean (SD), kg83.0 (21.8) 86.3 (21.9)91.3 (25.7) 
BMI, mean (SD)29.4 (8.3) 29.9 (7.4)31.1 (8.9) 
Type of current episode, %
 Mixed59 5349 
 Manic41 4751 
Current episode severity, %
 Mild4 23 
 Moderate48 4846 
 Severe without psychotic feature20 2325 
 Severe with mood-congruent psychotic feature27 2224 
 Severe with mood-incongruent psychotic feature1 53 
Baseline YMRS score, mean (SD)28.3 (5.8) 29.1 (5.5)29.3 (5.8) 
PDMD-006
n106 107  
Age, mean (SD), years40 (11) 41 (12)  
Gender, M/F, %63/37 64/36  
Race, White/Black/Asian/other, %76/18/0/6 65/24/0/10  
Weight, mean (SD), kg87.9 (25.3) 85.5 (20.3)  
BMI, mean (SD)29.1 (7.7) 29.0 (6.7)  
Type of current episode, %
 Mixed32 36  
 Manic68 64  
Current episode severity, %
 Mild0 0  
 Moderate44 43  
 Severe without psychotic feature23 23  
 Severe with mood-congruent psychotic feature32 31  
 Severe with mood-incongruent psychotic feature1 3  
Baseline YMRS score, mean (SD)29.5 (5.7) 30.4 (7.3)  
PDMD-008
n112 115 114
Age, mean (SD), years41 (12) 40 (12) 42 (11)
Gender, M/F, %40/60 36/64 36/64
Race, White/Black/Asian/other, %61/3/9/28 62/2/10/26 60/1/10/30
Weight, mean (SD), kg68.9 (16.6) 66.9 (14.8) 69.4 (16.6)
BMI, mean (SD)25.4 (5.6) 25.4 (5.9) 26.2 (5.8)
Type of current episode, %
 Mixed11 12 10
 Manic89 88 90
Current episode severity, %
 Mild3 2 3
 Moderate39 43 46
 Severe without psychotic feature35 30 36
 Severe with mood-congruent psychotic feature22 23 15
 Severe with mood-incongruent psychotic feature1 4 1
Baseline YMRS score, mean (SD)31.7 (7.3) 30.8 (6.8) 30.7 (7.5)
Table 4.  Mean (SD) modal daily dosage during double-blind treatment
 Target dose
Topiramate, mg/dayLithium, 1500 mg/day
200400600
  1. aModal daily dosage = most frequent dosage.

Core 3-week studies
 n109446101227
Mean (SD) modal daily dosagea, mg/day176 (25)313 (71)409 (118)1258 (221)
Core 3-week studies + 9-week double-blind extensions
 n109337101227
 Mean (SD) modal daily dosagea, mg/day178 (27)329 (76)435 (131)1337 (266)

The mean reduction in YMRS among topiramate-treated patients (range, 5.1–8.2) was not different from placebo (range, 6.4–8.4) after 3 weeks (Table 5). In trials in which lithium was an active comparator, the improvement in YMRS scores among lithium-treated patients (mean reduction, 12.9 and 13.8) at 3 weeks was significantly (p ≤ 0.001) greater versus placebo and topiramate.

Table 5.  Change from baseline in Young Mania Rating Scale scores for core 3-week studies (intent-to-treat)
 PlaceboTopiramate, mg/dayLithium, 1500 mg/day
200400600
PDMD-004
n111107107 113
Baseline mean (SD)30.0 (6.3)30.8 (7.8)30.2 (7.1) 30.1 (7.4)
Mean change (SD)−7.7 (11.5)−5.8 (12.3)−6.2 (11.9) −12.9 (11.8)
p-value
 Versus placebo 0.2230.324 0.001
 Versus lithium <0.001<0.001  
PDMD-005
n98 10798 
Baseline mean (SD)28.1 (5.8) 29.0 (5.5)29.2 (5.8) 
Mean change (SD)−7.7 (10.3) −8.2 (9.6)−7.9 (11.4) 
p-value versus placebo  0.7290.808 
PDMD-006
n106 105  
Baseline mean (SD)29.5 (5.7) 30.2 (7.3)  
Mean change (SD)−6.4 (10.0) −5.1 (10.1)  
p-value versus placebo  0.263  
PDMD-008
n112 115 114
Baseline mean (SD)31.7 (7.3) 30.8 (6.8) 30.7 (7.5)
Mean change (SD)−8.4 (11.8) −8.2 (11.8) −13.8 (11.9)
p-value
 Versus placebo  0.976 <0.001
 Versus lithium  <0.001  

The mean percentage change in baseline body weight (Table 6) ranged from −2.3% to −1.4% among topiramate-treated patients and from −1.0% to +0.2% for patients receiving placebo; for lithium-treated patients, the mean percentage change in baseline body weight was −0.4% and +0.3%. Most weight changes (loss) associated with topiramate were significant versus change with placebo or lithium.

Table 6.  Percent change from baseline in body weight for core 3-week studies (intent-to-treat)
 PlaceboTopiramate, mg/dayLithium, 1500 mg/day
200400600
PDMD-004
n111107106 111
Baseline mean, kg (SD)74.3 (16.3)75.7 (14.9)74.7 (19.2) 75.6 (17.1)
Mean % change (SD)−1.0 (2.7)−2.1 (2.7)−1.7 (2.9) −0.4 (2.8)
p-value
 Versus placebo 0.0040.063 0.059
 Versus lithium <0.001<0.001  
PDMD-005
n96 105100 
Baseline mean, kg (SD)82.8 (21.8) 86.5 (21.9)91.2 (25.7) 
Mean % change (SD)0.2 (2.3) −2.3 (3.0)−1.4 (3.4) 
p-value versus placebo  <0.001<0.001 
PDMD-006
n106 106  
Baseline mean, kg (SD)87.9 (25.3) 85.4 (20.3)  
Mean % change (SD)−0.1 (3.3) −1.9 (2.6)  
p-value versus placebo  <0.001  
PDMD-008
n112 115 114
Baseline mean, kg (SD)68.9 (16.6) 66.9 (14.8) 69.4 (16.6)
Mean % change (SD)−1.0 (3.0) −2.1 (3.2) 0.3 (3.8)
p-value
 Versus placebo  0.007 0.002
 Versus lithium  <0.001  

Core study + 9-week double-blind extension

The disposition of patients in studies with 9-week double-blind extensions is shown in Table 7. For the 9-week extension, placebo-treated patients in the PDMD-004 core study were converted to a 1500 mg/day target dose of lithium (placebo/lithium group), whereas placebo-treated patients in the PDMD-008 core study were converted to 150 mg/day topiramate (placebo/topiramate group). Mean (SD) modal daily dosages during the core study plus double-blind extension (12 weeks) are shown in Table 4.

Table 7.  Patient disposition: core 3-week studies + 9-week double-blind extensions (all randomized patients)
 PlaceboPlacebo/topiramate, 150 mg/dayTopiramate, mg/dayLithium, 1500 mg/dayPlacebo/lithium, 1500 mg/day
200400600
PDMD-004
n  110110 113111
Completed, %   23 31  42 38
Withdrawals, %   77 69  58 62
 Adverse events, %    8 13  14 13
 Lack of efficacy, %   51 39  26 36
 Patient choice, %   11 10  12 12
 Lost to follow-up, %    3  0   3  1
 Other, %    5  7   4  1
PDMD-005
n100  112102  
Completed, % 20   20 23  
Withdrawals, % 80   80 77  
 Adverse events, %  5   15 11  
 Lack of efficacy, % 50   45 47  
 Patient choice, % 13   13 12  
 Lost to follow-up, %  7    5  2  
 Other, %  5    3  6  
PDMD-008
n 112 116 114 
Completed, %  35  34  59 
Withdrawals, %  65  66  41 
 Adverse events, %   4   4  12 
 Lack of efficacy, %  48  45  14 
 Patient choice, %   8   9   6 
 Lost to follow-up, %   4   3   3 
 Other, %   1   4   6 

The mean reduction in YMRS among topiramate-treated patients (range, 7.4–10.0) was not different than placebo or placebo/topiramate (7.4 and 9.4) after 12 weeks (Table 8). In trials in which lithium was an active comparator for 12 weeks of double-blind treatment, the improvement in YMRS scores among patients treated with lithium for 12 weeks (mean reduction, 16.3 and 18.4) was significantly greater than in patients converted from placebo to topiramate (p < 0.001) but not in patients converted from placebo to lithium (placebo/lithium, p = 0.098); improvement in YMRS scores with 12-week lithium treatment was greater than with 12-weeks topiramate administration (p < 0.001).

Table 8.  Change from baseline in Young Mania Rating Scale score for core 3-week studies + 9-week double-blind extensions (intent-to-treat)
 PlaceboPlacebo/ topiramate, 150 mg/dayTopiramate, mg/dayLithium, 1500 mg/dayPlacebo/ lithium, 1500 mg/day
200400600
PDMD-004
n  107107 113111
Baseline mean (SD)  30.8 (7.8)30.2 (7.1) 30.1 (7.4)30.0 (6.3)
Mean change (SD)  −7.4 (15.2)−8.1 (14.4) −16.3 (14.3)−13.0 (14.8)
p-value
 Versus placebo/lithium  0.0020.008 0.098 
 Versus lithium  <0.001<0.001   
PDMD-005
n98  10798  
Baseline mean (SD)28.1 (5.8)  29.0 (5.5)29.2 (5.8)  
Mean change (SD)−7.4 (10.4)  −8.2 (10.9)−7.7 (12.5)  
p-value versus placebo   0.6210.902  
PDMD-008
n 112 115 114 
Baseline mean (SD) 31.7 (7.3) 30.8 (6.8) 30.7 (7.5) 
Mean change (SD) −9.4 (14.1) −10.0 (14.6) −18.4 (12.9) 
p-value
 Versus placebo/topiramate   0.730 <0.001 
 Versus lithium   <0.001   

Mean percentage change in baseline body weight (Table 9) ranged from −3.6% to −2.3% among topiramate-treated patients and from −2.0% to −0.2% for patients receiving placebo, placebo/topiramate, or placebo/lithium. For patients receiving 12 weeks lithium treatment, mean change in baseline body weight was −0.3% and +0.9%. Weight loss was significantly greater with topiramate than with either placebo or lithium.

Table 9.  Percent change from baseline in body weight for core 3-week studies + 9-week double-blind extensions (intent-to-treat)
 PlaceboPlacebo/ topiramate, 150 mg/dayTopiramate, mg/dayLithium, 1500 mg/dayPlacebo/ lithium, 1500 mg/day
200400600
PDMD-004
n  107107 111111
Baseline mean, kg (SD)  75.7 (14.9)74.6 (19.2) 75.6 (17.1)74.3 (16.3)
Mean % change (SD)  −2.9 (3.9)−2.8 (4.1) −0.3 (4.8)−0.9 (4.5)
p-value
 Versus placebo/lithium  0.0010.002 0.183 
 Versus lithium  <0.001<0.001   
PDMD-005
n96  105100  
Baseline mean, kg (SD)82.8 (21.8)  86.5 (21.9)91.2 (25.7)  
Mean % change (SD)−0.2 (3.1)  −3.2 (4.5)−2.3 (4.7)  
p-value versus placebo   <0.0010.001  
PDMD-008
n 112 115 114 
Baseline mean, kg (SD) 68.9 (16.6) 66.9 (14.8) 69.4 (16.6) 
Mean % change (SD) −2.0 (4.6) −3.6 (4.7) 0.9 (5.2) 
p-value
 Versus placebo/topiramate   0.007 <0.001 
 Versus lithium   <0.001   

Post hoc analyses of pooled data

In exploratory analyses of potential efficacy signals, pooled data in placebo (n = 427), 400 mg/day topiramate (n = 433), and lithium (n = 227) groups for patients with both baseline and day 21 scores showed no significant therapeutic effect of topiramate versus placebo in mean change from baseline YMRS [least squares mean difference, 0.60 ± 0.73 (SE); p = 0.41], CGI (0.08 ± 0.08; p = 0.31), and GAS (−0.38 ± 1.07; p = 0.73). The percentage of patients with ≥50% reduction in YMRS at day 21 was 28% and 27% with placebo and topiramate, respectively, compared with 46% in the lithium group; 23%, 24%, and 41%, respectively, scored ≤12 on YMRS at the final visit of the core study. The proportion of patients classifiable as DSM-IV responders at day 21 was 22% for placebo, 25% for topiramate, and 37% for lithium. Mania exacerbation (YMRS increase ≥10% from baseline) was reported in 16% of placebo patients, 18% of those receiving topiramate (p = 0.72 versus placebo), and 10% in the lithium group. A significant difference favoring placebo versus topiramate was observed in change in MADRS (1.39 ± 0.47; p = 0.003) and BPRS (1.77 ± 0.74; p = 0.02). Treatment-emergent depression (MADRS ≥18 and ≥4 change in baseline MADRS at two consecutive visits or final visit) was detected in 12% of placebo patients, 14% of those receiving topiramate (p = 0.42 versus placebo), and 7% in the lithium group. Mean differences favored lithium over both topiramate and placebo (p < 0.001) in all psychometric measures except MADRS (lithium versus placebo, p =0.13). Differences between lithium and placebo or topiramate were significant (p < 0.05) for all parameters, whereas those between topiramate and placebo were not.

At day 21, the mean (±SD) change from baseline in weight and BMI was −0.44 ± 2.3 kg and −0.16 ± 0.81 kg/m2 in placebo-treated patients; −1.60 ± 2.28 kg and −0.57 ± 0.83 kg/m2 with topiramate 400 mg/day; and −0.16 ± 2.38 kg and −0.06 ± 0.87 kg/m2 with lithium. The least squares mean difference in weight for topiramate versus placebo was −1.15 ± 0.15 (SE) kg and −1.54 ± 0.19 kg for topiramate versus lithium (p < 0.001). Lithium was associated with 0.38 ± 0.19 kg greater weight increase versus placebo (p = 0.048). Consistent with the pattern of weight changes, topiramate produced larger declines in BMI versus placebo (least squares mean difference −0.40 ± 0.05, p < 0.001) and lithium (−0.55 ± 0.07, p < 0.001), whereas lithium was associated with significantly greater increase in BMI (+0.15 ± 0.07, p = 0.025) when compared with placebo.

Tolerability/safety

The most common treatment-emergent adverse events (≥5% difference in incidence in any treatment group versus placebo) are listed in Tables 10 (core 3-week studies) and 11 (total double-blind treatment). When adverse event data were pooled, paresthesia, appetite decrease, dry mouth, and weight loss were reported more frequently (≥3% higher incidence rate) in topiramate-treated patients than with placebo; most adverse events were dose related.

Table 10.  Incidence of adverse events during core 3-week studiesa (safety population, n = 1,312)
 Patients, %
Placebo (n = 429)Topiramate, mg/dayLithium, 1500 mg/day (n = 227)
200 (n = 109)400 (n = 446)600 (n = 101)
  1. a≥5% difference in incidence in any treatment group versus placebo.

Headache214203411
Nausea95131710
Diarrhea87111313
Dizziness719166
Paresthesia4715303
Constipation424113
Appetite decrease458135
Tremor221312
Dry mouth206143
Insomnia25473
Pain20271
Hypoesthesia11370
Language problems11160
Memory difficulty11370
Vision abnormal1238<1
Taste perversion<11390
Weight loss18321
Psychomotor slowing0125<1
Table 11.  Incidence of adverse events during entire double-blind treatment perioda (safety population, n = 1,312)
 Patients, %
Placebo (n = 206)Placebo/topiramate, 150 mg/day (n = 112)Topiramate, mg/dayLithium, 1500 mg/day (n = 227)Placebo/lithium, 1500 mg/day (n = 111)
200 (n = 109)400 (n = 446)600 (n = 101)
  1. a≥5% difference in incidence in any treatment group versus placebo.

Nausea111271417129
Diarrhea913101113159
Dizziness9121101865
Paresthesia769163231
Vomiting611566104
Constipation55251233
Appetite decrease596101364
Hypoesthesia21139<10
Memory difficulty2013700
Dry mouth24061432
Language problems1012600
Tremor14223186
Weight decrease<14106244
Polyuria<1101071
Vision abnormal<1023912
Taste perversion<1123901
Psychomotor slowing00125<10
Acidosis0052000
Thirst0521272

Among patients discontinuing prematurely from the core 3-week studies, adverse events were reported in 2% of those receiving placebo, 2–7% with topiramate, and 7% with lithium. Premature discontinuations from the core studies plus double-blind extensions were related to adverse events in 7% of placebo-treated patients, 4% with placebo/topiramate, 8–11% with topiramate, 13% with lithium, and 13% with placebo/lithium.

The incidence of serious adverse events was 2% during placebo treatment, 3% during topiramate treatment, and 1.5% during lithium treatment. One patient died during double-blind treatment; this death was reported as a suicide and was considered by the investigator as unrelated to the study drug (topiramate). During the core 3-week studies, suicidal attempt was reported in two of 656 (<1%) topiramate-treated patients (both withdrew early); suicidal ideation was reported in four of 656 (<1%) topiramate-treated patients (with two withdrawals) and three of 429 (<1%) placebo-treated patients (one withdrawal); and increasing symptoms of depression with suicidality was reported in one topiramate-treated patient. Suicide attempt/suicidal ideation were not reported among patients in the other treatment groups (i.e., placebo/topiramate, placebo/lithium, or lithium). Re-hospitalizations were reported in 4% of placebo-treated patients, 9% with placebo/topiramate, 8–12% with topiramate, 5% with lithium, and 5% with placebo/lithium.

Discussion

  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results
  5. Discussion
  6. References

Anecdotal reports (12, 14, 18, 19) and small open-label studies (13, 20–22) provided initial evidence that topiramate, when added to traditional treatment, was associated with a reduction in manic symptoms. Topiramate also reduced depressive symptom severity in a single-blind study (23). In two reports (12, 13), the addition of topiramate to mood stabilizers with or without antipsychotics in patients with severe mania was associated with ≥50% reduction in YMRS scores, which increased when topiramate therapy was discontinued, then decreased when topiramate was restarted. The temporal relationship to ‘off–on–off’ topiramate therapy provided additional circumstantial evidence that combination therapy with topiramate may be effective in severe mania.

However, such data are difficult to interpret in terms of the effect of topiramate per se. They may simply reflect the fluctuating nature of manic episodes. Alternatively, topiramate may have an independent but additive effect in the overall population of bipolar patients, an effect in a specific patient subset, or a synergistic action in which topiramate does not have a robust therapeutic effect of its own but enhances the efficacy of lithium or other mood stabilizers. In a pilot open-label study (15) in 10 hospitalized patients with acute mania, YMRS scores were reduced during topiramate monotherapy from a mean baseline score of 32 to 22 at study end; YMRS scores were moderate/markedly improved in 50% of patients. In another small open-label study (24), 50% (four of eight) of patients treated with topiramate monotherapy showed ≥50% reduction in symptoms. These data suggest a possible effect, perhaps modest, in at least some patients with acute bipolar disorder, although the numbers are small and the studies are not placebo controlled.

In contrast to these open-label studies, the four double-blind, placebo-controlled studies reported here failed to detect a significant difference between placebo and 200–600 mg/day topiramate in a battery of mood measures during 3 or 12 weeks of double-blind treatment. The findings were consistent across studies. Despite pooling the data in placebo, topiramate 400 mg/day, and lithium 1500 mg/day groups for increased statistical power, no efficacy signal favoring topiramate over placebo was detected.

In the absence of a positive control group such as lithium, a finding of no difference between topiramate and placebo might be interpreted as a lack of study sensitivity because (a) mania was too severe and unresponsive to an agent with a modest therapeutic effect, (b) inter-/intra-individual variability created excessive ‘noise’ in the data, masking a modest treatment effect, or (c) mania at baseline was too mild for treatment-related changes to be detected. However, two of the four studies reported here (PDMD-004 and PDMD-008) included lithium treatment arms. Virtually all efficacy measures after 3 and 12 weeks demonstrated significantly greater improvements with lithium compared with placebo and topiramate. The study design and patient population were therefore sufficiently sensitive to detect the significant treatment effect associated with lithium.

Topiramate was not associated with mood destabilization measured as mania exacerbation or treatment-emergent depression. As reported here, one completed suicide occurred in a patient with bipolar disorder during double-blind topiramate treatment. Isolated cases of suicidal ideation and suicidal behavior have been reported in topiramate-treated patients. During double-blind treatment with topiramate in clinical trials for approved (i.e., epilepsy and migraine) and investigational uses, suicide attempts occurred at a rate of 3/1000 patient years (13 events/3999 patient years) versus none (0/1430 patient years) among patients receiving placebo.

Patients with bipolar disorder are at high risk of weight gain and obesity due to medications as well as psychiatric comorbidities involving eating behaviors and sedentary lifestyle. In the studies in this report, weight changes with topiramate were primarily weight loss, which emerged within the first 3 weeks and continued for the 12 weeks of double-blind treatment. Longer-term studies of topiramate in other populations have shown that weight loss in adults generally plateaus after 12–18 months and may be accompanied by the improvements in blood pressure and lipids (11, 25), as well as glycemic control in diabetic patients (26).

The double-blind, placebo-controlled studies reported here do not support a role of topiramate as monotherapy in adults with acute bipolar disorder. The findings in these studies illustrate that even though various agents with different structures and putative mechanisms of action such as valproate, carbamazepine, lamotrigine, and topiramate have anti-seizure effects, these effects are not necessarily predictive of a therapeutic profile in bipolar disorder. Valproate is effective in acute mania/mixed episodes but evidence of its effectiveness against bipolar depression is limited (1, 27, 28). Lamotrigine seems to have greater benefit in bipolar depression than in acute mania (27, 29, 30). Thus, the effects of antiepileptic drugs on the central nervous system appear to be distinctly different with respect to efficacy in bipolar disorder. Although the potential advantage of this heterogeneity is the ability to individualize therapy, it also highlights the need for each agent to be evaluated in randomized controlled trials in order to define its usefulness in bipolar disorder.

References

  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results
  5. Discussion
  6. References