The evolving role of topiramate among other mood stabilizers in the management of bipolar disorder. A randomized, placebo-controlled trial of topiramate in amyotrophic lateral sclerosis. A 12-week, randomized, open-label, parallel-group trial of topiramate in limiting weight gain during olanzapine treatment in patients with schizophrenia. Efficacy of olanzapine in combination with valproate or lithium in the treatment of mania in patients partially nonresponsive to valproate or lithium monotherapy. Topiramate treatment for women with borderline personality disorder: a double-blind, placebo-controlled study. Relapse prevention in bipolar I disorder: 18-month comparison of olanzapine plus mood stabiliser v. mood stabiliser alone. Topiramate as an adjuvant treatment with atypical antipsychotics in schizophrenic patients experiencing weight gain. Low-dose topiramate in adults with treatment-resistant partial-onset seizures. Acute and continuation risperidone monotherapy in bipolar mania: a 3-week placebo-controlled trial followed by a 9-week double-blind trial of risperidone and haloperidol.
Topiramate, a structurally novel anticonvulsant, is being evaluated for other neurological conditions such as migraine, neuropathic pain, and essential tremor, and also for psychiatric conditions such as bipolar disorder, bulimia, post-traumatic stress disorder, and schizoaffective disorder, in addition to obesity. This article will focus on the use of topiramate for bipolar disorder.
                The pharmacological profile of topiramate is compared to other established and putative mood stabilizers, and a rationale for its use in bipolar disorder is presented. Data from open clinical trials of topiramate for depression, mania, and rapid-cycling bipolar disorder are summarized. Preliminary data from one pilot dose-finding, double-blind, random-assignment, placebo-controlled, 3-week parallel group study of two doses of topiramate for acute bipolar I mania is reported. Safety data regarding topiramate was reviewed. Finally, the potential place of this agent in bipolar illness is considered.
                The pharmacological advantages for topiramate are low protein binding, minimal hepatic metabolism and mainly unchanged renal excretion, a 24-h half-life, and minimal drug interactions. Open clinical studies suggest a 50-65% response for refractory bipolar mania, and a 40-56% response for refractory bipolar depression in mainly add-on treatment. Open clinical studies of topiramate for rapid-cycling subjects and those for comorbid bulimia, substance abuse, post-traumatic stress, migraine, and obesity report effectiveness. The primary efficacy endpoint data (change from baseline Y-MRS total scores) of the placebo-controlled, random assignment parallel group phase II dose-finding study were not statistically significant. However, once the antidepressant-associated manias (28 of the sample, of 97 subjects) were excluded from the controlled study, the post-hoc analyses indicated the higher dose (512 mg/day) topiramate treatment group showed a statistically significant reduction in endpoint Y-MRS change scores as compared to placebo (p < 0.03). Adverse effects of topiramate in bipolar subjects include attention, concentration and memory problems, fatigue, sedation, transient paraesthesias, nausea, and anorexia. Some subjects experience word-finding difficulty. Weight loss may be seen in several topiramate-treated subjects with bipolar disorder.
                Topiramate appears to show promise as an addition to the agents available to treat bipolar disorder. More definitive controlled data on the efficacy of topiramate in the acute and continuation phases as well as for the prophylaxis either as monotherapy or as combination treatment of bipolar disorder are ongoing, and the results are awaited. To determine if long-term topiramate therapy is safe and slows disease progression in patients with ALS.
                A double-blind, placebo-controlled, multicenter randomized clinical trial was conducted. Participants with ALS (n = 296) were randomized (2:1) to receive topiramate (maximum tolerated dose up to 800 mg/day) or placebo for 12 months. The primary outcome measure was the rate of change in upper extremity motor function as measured by the maximum voluntary isometric contraction (MVIC) strength of eight arm muscle groups. Secondary endpoints included safety and the rate of decline of forced vital capacity (FVC), grip strength, ALS functional rating scale (ALSFRS), and survival.
                Patients treated with topiramate showed a faster decrease in arm strength (33.3%) during 12 months (0.0997 vs 0.0748 unit decline/month, p = 0.012). Topiramate did not significantly alter the decline in FVC and ALSFRS or affect survival. Topiramate was associated with an increased frequency of anorexia, depression, diarrhea, ecchymosis, nausea, kidney calculus, paresthesia, taste perversion, thinking abnormalities, weight loss, and abnormal blood clotting (pulmonary embolism and deep venous thrombosis).
                At the dose studied, topiramate did not have a beneficial effect for patients with ALS. High-dose topiramate treatment was associated with a faster rate of decline in muscle strength as measured by MVIC and with an increased risk for several adverse events in patients with ALS. Given the lack of efficacy and large number of adverse effects, further studies of topiramate at a dose of 800 mg or maximum tolerated dose up to 800 mg/day are not warranted. nan A 6-week double-blind, randomized, placebo-controlled trial was conducted to determine the efficacy of combined therapy with olanzapine and either valproate or lithium compared with valproate or lithium alone in treating acute manic or mixed bipolar episodes.
                The primary objective was to evaluate the efficacy of olanzapine (5-20 mg/d) vs placebo when added to ongoing mood-stabilizer therapy as measured by reductions in Young Mania Rating Scale (YMRS) scores. Patients with bipolar disorder (n = 344), manic or mixed episode, who were inadequately responsive to more than 2 weeks of lithium or valproate therapy, were randomized to receive cotherapy (olanzapine + mood-stabilizer) or monotherapy (placebo + mood-stabilizer).
                Olanzapine cotherapy improved patients' YMRS total scores significantly more than monotherapy (-13.11 vs -9.10; P = .003). Clinical response rates (> or = 50% improvement on YMRS) were significantly higher with cotherapy (67.7% vs 44.7%; P< .001). Olanzapine cotherapy improved 21-item Hamilton Depression Rating Scale (HAMD-21) total scores significantly more than monotherapy (4.98 vs 0.89 points; P< .001). In patients with mixed-episodes with moderate to severe depressive symptoms (DSM-IV mixed episode; HAMD-21 score of > or = 20 at baseline), olanzapine cotherapy improved HAMD-21 scores by 10.31 points compared with 1.57 for monotherapy (P< .001). Extrapyramidal symptoms (Simpson-Angus Scale, Barnes Akathisia Scale, Abnormal Involuntary Movement Scale) were not significantly changed from baseline to end point in either treatment group. Treatment-emergent symptoms that were significantly higher for the olanzapine cotherapy group included somnolence, dry mouth, weight gain, increased appetite, tremor, and slurred speech.
                Compared with the use of valproate or lithium alone, the addition of olanzapine provided superior efficacy in the treatment of manic and mixed bipolar episodes. Borderline personality disorder is a common and severe psychiatric illness. The goal of this study was to determine whether topiramate can influence patients' borderline psychopathology, health-related quality of life, and interpersonal problems. Women meeting the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition Structured Clinical Interview II criteria for borderline personality disorder were randomly assigned in a 1:1 ratio to topiramate titrated from 25 to 200 mg/d (n = 28) or placebo (n = 28) for 10 weeks. Primary outcome measures were changes on the Symptom-Checklist, on the SF-36 Health Survey, and on the Inventory of Interpersonal Problems. Body weight and additional side effects were assessed weekly. According to the intent-to-treat principle, significant changes (all P < 0.001) on the somatization, interpersonal sensitivity, anxiety, hostility, phobic anxiety, and Global Severity Index scales of the Symptom Checklist were observed in the topiramate-treated subjects after 10 weeks (no significant changes on the obsessive-compulsive, depression, paranoid ideation, and psychoticism scales). In the SF-36 Health Survey, significant differences were observed on all 8 scales (all P < 0.01 or P < 0.001). In the Inventory of Interpersonal Problems, significant differences (all P < 0.001) were found in the scales for overly autocratic, overly competitive, overly introverted, and overly expressive (no significant differences in the scales for overly cold, overly subassertive/subservient, overly exploitable/compliant, and overly nurturant/friendly). Weight loss was additionally observed (p < 0.001). Topiramate appears to be a safe and effective agent in the treatment in women with borderline personality disorder. Additional weight loss can be expected. Few controlled studies have examined the use of atypical antipsychotic drugs for prevention of relapse in patients with bipolar I disorder. Aims To evaluate whether olanzapine plus either lithium or valproate reduces the rate of relapse, compared with lithium or valproate alone.
                Patients achieving syndromic remission after 6 weeks'treatment with olanzapine plus either lithium (0.6-1.2 mmol/l) or valproate (50-125 microg/ml) received lithium or valproate plus either olanzapine 5-20 mg/day (combination therapy) or placebo (monotherapy), and were followed in a double-masked trial for 18 months.
                The treatment difference in time to relapse into either mania or depression was not significant for syndromic relapse (median time to relapse: combination therapy 94 days, monotherapy 40.5 days; P=0.742), but was significant for symptomatic relapse (combination therapy 163 days, monotherapy 42 days; P=0.023).
                Patients taking olanzapine added to lithium or valproate experienced sustained symptomatic remission, but not syndromic remission, for longer than those receiving lithium or valproate monotherapy. Schizophrenic patients commonly suffer weight gain, which is often associated with widely prescribed antipsychotic medicines. It is distressing to most patients who experience it and may affect their response to treatment of schizophrenia. Weight gain is also associated with treatment noncompliance and several medical conditions. This study explored the efficacy and tolerability of topiramate as an adjuvant treatment of patients with schizophrenia who were carrying excess weight. In this 12-week, randomized, placebo-controlled prospective study, 66 hospitalized patients with schizophrenia who were carrying excess weight were given topiramate at doses of 100 mg/day or 200 mg/day, or a placebo. The primary measures made were body weight, body mass index, waist measurement, hip measurement, and waist-to-hip ratio. Safety measures included physical examinations and the monitoring of adverse effects, clinical laboratory data, and vital signs. The Clinical Global Impression-Severity of Illness scale (CGI-S) and the Brief Psychiatric Rating Scale (BPRS) were used to quantify changes in schizophrenic symptoms and signs. In the 200-mg/day topiramate group, body weight, body mass index, waist measurement, and hip measurement decreased significantly compared with the 100-mg/day topiramate and placebo groups over 12 weeks. However, the waist-to-hip ratio did not change in any group. Scores on the CGI-S and BPRS decreased significantly over the 12-week period in both topiramate groups, but the decrease was not clinically meaningful. These results suggest that a higher dose of topiramate is efficacious as an adjuvant treatment of patients with schizophrenia experiencing excess weight gain. Further clinical research is required to establish guidelines for the use of topiramate as an antiobesity agent in schizophrenic patients. Based on dose predictions from animal and human volunteer studies, most patients enrolled in initial randomized controlled trials of topiramate as adjunctive therapy in adults with partial-onset seizures were randomized to >or= 600 mg/day topiramate. Subsequent experience suggests that dosage needs were overestimated. This double-blind, placebo-controlled study evaluated 200 mg/day topiramate in adults with treatment-resistant partial-onset seizures receiving a concurrent enzyme-inducing antiepileptic agent (carbamazepine).
                After a 4-week baseline, 263 adults receiving carbamazepine who had at least three partial-onset seizures during the baseline period were randomized to placebo or one of two topiramate 200 mg/day treatment arms: topiramate escalated weekly 25 mg/day(8-week escalation) or 50 mg/day(4-week escalation). Therapy was then maintained for the remainder of the 12-week double-blind study.
                Median percent reduction in seizure frequency from baseline to study end was 44% with topiramate and 20% with placebo (P <or= 0.001). A significant therapeutic effect was present at 2 weeks with a dose of 100 mg/day. The most common adverse events (>or=10% incidence in topiramate-treated patients) were somnolence, fatigue, paresthesia, nervousness and anorexia; 8% of topiramate-treated patients and 2% of placebo-treated patients discontinued because of adverse events. As a result of the low incidence of adverse events, differences between titration rates in terms of tolerability were not detected.
                Topiramate 200 mg/day is an appropriate target dose as adjunctive therapy in adults with treatment-resistant partial-onset seizures, even when receiving an enzyme-inducing agent; 100 mg/day also appears to be effective. A significant therapeutic effect may be seen in the second week of treatment with a dose of 100 mg/day. In a randomized, double-blind trial, patients with acute bipolar mania received 1-6 mg/day of risperidone, 2-12 mg/day of haloperidol, or placebo for 3 weeks, followed by double-blind risperidone or haloperidol for 9 weeks. Of 438 patients, 154 were randomized to risperidone, 144 to haloperidol, and 140 to placebo. The mean+/-S.D. modal doses were 4.2+/-1.7 mg/day of risperidone and 8.0+/-3.6 mg/day of haloperidol during the initial 3-week phase and 4.1+/-1.8 and 7.4+/-3.7 mg/day during the 12-week period. At week 3, mean Young Mania Rating Scale (YMRS) score reductions from baseline were significantly greater in patients receiving risperidone than placebo (p<0.001). Differences between risperidone and haloperidol on this efficacy measure were not significant. Further reductions in YMRS scores were seen in patients receiving risperidone or haloperidol during the subsequent 9 weeks. No unexpected adverse events were reported. Extrapyramidal disorder and hyperkinesias, the most commonly reported adverse events with antipsychotic use, occurred less frequently with risperidone than haloperidol. We conclude that risperidone monotherapy was an effective and well-tolerated treatment for bipolar mania and that efficacy was maintained over the long term.
There is insufficient evidence on which to base any recommendations regarding the use of topiramate in any phase of bipolar illness, either in monotherapy or as an adjunctive treatment.