Preliminary observations on the effectiveness of levetiracetam in the open adjunctive treatment of refractory bipolar disorder

OBJECTIVE: Levetiracetam is a recently approved, well-tolerated anticonvulsant with a unique mechanism of action yielding efficacy in treatment-refractory seizure disorders and positive effects in an animal model of mania. Given the effectiveness of a range of other anticonvulsants in bipolar disorder, we sought to evaluate levetiracetam in patients with treatment-resistant illness. METHOD: Thirty-four patients received 500 to 1000 mg of levetiracetam titrated to a target dose of 2000 mg/day (maximum dose = 3000 mg/day) as open, adjunctive treatment for clinically significant symptoms of depression (N = 13), mania (N = 7), or cycling (N = 14) despite ongoing treatment with mood stabilizers. Inventory for Depressive Symptomatology-Clinician version (IDS-C), Young Mania Rating Scale (YMRS), and Clinical Global Impressions scale for use in Bipolar Illness ratings were completed at each visit for 8 weeks, and partial responders were offered continuation treatment. Data were collected from July 2001 to December 2002. RESULTS: Five of 16 (31%; 13 depressed, 3 cycling) patients with initial depressive symptoms met the criterion for remission (IDS-C score of < or = 13) at last observation. All of these patients were less severely ill at baseline, whereas none of those more severely depressed at baseline responded. The majority of the 16 patients (7 manic, 9 cycling) with manic symptoms at baseline showed improvement in the YMRS in the first 2 weeks. While 7 of the 16 (44%) patients met the criterion for manic response and remission at last observation, 4 showed intervening periods of moderate to marked exacerbation. Levetiracetam was weight neutral. CONCLUSION: Other pilot trials should explore possible areas of psychotropic action of levetiracetam prior to the conduct of more controlled clinical trials.     

Antimanic efficacy of topiramate in 11 patients in an open trial with an on-off-on design

BACKGROUND: A series of open studies suggests that topiramate has efficacy in bipolar disorder. To further investigate the potential value of topiramate as an antimanic agent, we conducted an open trial in 11 manic patients. METHOD: Eleven patients with bipolar I disorder with an acute manic episode (DSM-IV) were treated with a mood stabilizer and/or antipsychotics in sufficient and fixed doses. All had a Young Mania Rating Scale (YMRS) score of at least 24 (mean +/- SD = 33.5+/-8.1). Topiramate was added after stable plasma levels of concomitant mood stabilizers had been reached and was titrated within 1 week to a final dose in the range of 25 to 200 mg/day, depending on clinical efficacy and tolerability. Topiramate was discontinued after 10 days, while concomitant medication remained unchanged. After 5 days, topiramate was reintroduced at similar or increased dosages for another 7 days. Patients were assessed with the YMRS; the Clinical Global Impressions scale version for bipolar patients; and the 21-item Hamilton Rating Scale for Depression. RESULTS: Seven of the 11 patients initially showed a good antimanic response with > 50% reduction in YMRS score. One patient showed psychotic features following rapid increase in topiramate dosage and dropped out on day 10. After discontinuation of topiramate, 7 of the remaining 10 patients worsened (increase of > or = 25% in YMRS score), 2 remained stable, and 1 discontinued follow-up after good recovery. After reintroducing topiramate, all patients improved again within a week, with 8 of 9 meeting the responder criterion of > or = 50% YMRS score reduction when comparing baseline values with those of day 22. With the exception of the patient who developed psychosis, topiramate was well tolerated. Concomitant medication did not interfere with plasma levels of drug, except for carbamazepine level in 1 patient. CONCLUSION: The antimanic response among patients in this study appears reproducibly linked to the addition of topiramate.     

Dark therapy for mania: a pilot study

BACKGROUND: Recent findings suggest that extended bed rest and darkness could stabilize mood swings in rapid cycling bipolar patients. METHOD: We exposed 16 bipolar inpatients affected by a manic episode to a regimen of 14 h of enforced darkness from 6 p.m. to 8 a.m. each night for three consecutive days [dark therapy (DT)]. Pattern of mood changes were recorded with the Young Mania Rating Scale (YMRS) and compared with a control group of 16 inpatients matched for age, sex, age at onset, number of previous illness episodes and duration of current episode, and were treated with therapy as usual (TAU). RESULTS: Adding DT to TAU resulted in a significantly faster decrease of YMRS scores when patients were treated within 2 weeks from the onset of the current manic episode. When duration of current episode was longer, DT had no effect. Follow-up confirmed that good responders needed a lower dose of antimanic drugs and were discharged earlier from the hospital. CONCLUSIONS: Chronobiological interventions and control of environmental stimuli can be a useful add-on for the treatment of acute mania in a hospital setting.     

Levetiracetam in der Kombinationsbehandlung fokaler Epilepsien

BACKGROUND: Levetiracetam was released in 2000 as an antiepileptic drug for add-on treatment of focal epilepsies. Its efficacy and tolerability were investigated in this retrospective study. METHODS: The effects of add-on treatment with levetiracetam on seizure frequency and side effects were analyzed retrospectively in 80 consecutive patients with focal epilepsy. RESULTS: With a mean follow-up of 12.3 months, 18.8% of patients treated with levetiracetam became seizure-free, and additional 15.0% and 3.8% had reductions in seizure frequency of 75% and 50%, respectively. Increasing the dosage to more than 3,500 mg/day did not improve efficacy but could induce a paradoxical increase in seizure frequency and psychic side effects. Levetiracetam was efficacious against all seizure types independently of focus localization. There was no evidence for the development of tolerance with longer periods of treatment. The most common adverse effects were somnolence and aggressiveness; tolerability did not decrease with rapid titration. CONCLUSIONS: Levetiracetam is a potent and generally well tolerable new antiepileptic drug which is also efficacious in patients with difficult-to-treat focal epilepsies.     

Efficacy and safety of levetiracetam: an add-on trial in children with refractory epilepsy.

The aim of this multicentric, prospective and uncontrolled study was to evaluate the efficacy and safety of levetiracetam in 110 children with refractory epilepsy, of whom 21 were less than 4 years old. After a median follow-up period of 7 months, levetiracetam administration was effective (responders with >50% decrease in seizure frequency) in 39% of children, of whom 10 (9%) became seizure-free. The efficacy was higher in patients with localization-related epilepsy (58% of responders) than in those with generalized epilepsy (37% of responders). Levetiracetam was well tolerated. The main side effects of somnolence and irritability occurred in 14% of patients. In one patient acute choreoathetosis occurred after few doses of levetiracetam. Overall, the adverse effects were not severe. Children younger than 4 years were particularly tolerant. In conclusion, the present study confirms that levetiracetam is effective and well tolerated as an add-on treatment in children with refractory epilepsy. Our preliminary data also indicate that levetiracetam may be a valid therapeutic option for epilepsy in infants and young children.     

Levetiracetam in patients with cortical myoclonus: a clinical and electrophysiological study.

Levetiracetam is a new antiepileptic agent that exerts antimyoclonic effects. We conducted an open-label trial to evaluate the effect of levetiracetam in chronic cortical myoclonus of diverse etiologies and to determine whether levetiracetam affects electrophysiological findings. Sixteen patients, aged between 19 and 72 years, with refractory, chronic, cortical myoclonus were recruited. We assessed myoclonus severity with the Unified Myoclonus Rating Scale (UMRS). The electrophysiological study comprised jerk-locked averaging, somatosensory evoked potentials (SEPs), and long loop reflex I. Levetiracetam was administered add-on at a starting dose of 500 mg twice per day up to the target dose of 50 mg/kg/day. Patients were reevaluated clinically and electrophysiologically 2 weeks after the titration phase. Fourteen patients completed the trial. Posttreatment UMRS scores showed an improvement of myoclonus in all cases. Pretreatment, 9 patients had "giant" SEPs. Posttreatment, the amplitude of these SEPs was reduced by more than 50% in 3 of 9 patients, and the mean N20-P25 amplitude was reduced significantly. Pre- and posttreatment SEP amplitude was not related to myoclonus severity or duration. Levetiracetam is a promising and a relatively easy-to-test antimyoclonic agent, which has the potential to improve significantly the patient's disability; however, its long-term efficacy should be verified in larger controlled studies.     

Clinical experience with levetiracetam in childhood epilepsy: an add-on and mono-therapy trial.

We examined the efficacy, optimum dosage and adverse effects of levetiracetam in two prospective trials in children with epilepsy. In the add-on trial, 67 children between 6 months and 16 years were included. In the mono-therapy trial, 10 children between 4 years and 16 years were included. Levetiracetam was titrated up to an optimal dosage for every individual patient, depending on efficacy and tolerability, and reflecting clinical practice. The range of dosages used was between 12 and 62 mg/kg/day, with a median of 33 mg/kg/day. Overall, 20 weeks after the start of levetiracetam, there was a median seizure reduction of 60% (add-on trial 50%; mono-therapy trial 81%). Levetiracetam was equally effective for partial and generalized seizures. Side effects were less common in the mono-therapy trial. Tiredness (7.8%) and aggressiveness (5%) were the most common side effects, and were dose-related, but were no reason to discontinue levetiracetam. In 25% of the children, a positive effect was seen on behaviour and/or alertness. This could not be related directly to seizure control. Overall, these two clinical trials confirm that levetiracetam is a broad spectrum anti-epileptic drug with a favourable safety profile. The positive effect on behaviour needs further quantitative study.     

Risperidone in combination with mood stabilizers: a 10-week continuation phase study in bipolar I disorder

BACKGROUND: Combination therapy (risperidone and a mood stabilizer) for patients with a history of bipolar disorder (DSM-IV) and hospitalized for treatment of a manic episode was assessed in a 13-week study. METHOD: Subjects received flexible doses of a mood stabilizer (lithium or divalproex) plus placebo, risperidone, or haloperidol in a 3-week double-blind study. They could then enter a 10-week open-label study during which they received risperidone combined with a mood stabilizer. RESULTS: Of the 156 patients enrolled in the 3-week study, 85 entered the 10-week open-label extension, of whom 48 completed 10 weeks of treatment. The mean +/- SE doses of risperidone were 3.8 +/- 0.3 mg/day during the 3-week study and 3.1 +/- 0.2 mg/day during the 10-week study. At double-blind endpoint, mean reductions in Young Mania Rating Scale (YMRS) scores were significantly greater in patients receiving risperidone plus mood stabilizer than in those receiving placebo plus mood stabilizer (-14.3 vs. -8.2, p <.001). Further significant (p <.001) reductions were seen during the 10 weeks of treatment with risperidone plus mood stabilizer. Symptom remission (YMRS score 相似文献   

Efficacy and safety of levetiracetam 1000-3000 mg/day in patients with refractory partial-onset seizures: a multicenter, open-label single-arm study

PURPOSE: To evaluate the efficacy and tolerability of levetiracetam as add-on therapy in patients with refractory partial-onset seizures in a protocol designed to reflect clinical practice. METHODS: All patients in this open-label, single-arm study entered an 8-week baseline period followed by a 4-week titration period and a 12-week maintenance period. Patients initially received levetiracetam 1000 mg/day (administered bid) and could increase to 2000 mg/day after 2 weeks, and to 3000 mg/day after another 2 weeks, to obtain adequate seizure control. During the 12-week maintenance period, the dose of levetiracetam could not be increased but could be decreased once if tolerability warranted. Seizure count and adverse events were recorded by patients in a diary. Quality of life and global evaluation of disease evolution were also evaluated. RESULTS: Ninety-nine patients were enrolled and 91 completed the study. A steady dose was maintained over the last 8 weeks of treatment or longer in 84 patients, with 89.3% of these patients receiving 3000 mg/day, 9.5% receiving 2000 mg/day, and 1.2% receiving 1000 mg/day. A 35.9% median percent reduction from baseline in weekly frequency of partial-onset seizures was observed over the entire treatment period. The median partial-onset seizure count decreased from 2.3 per week during the baseline period to 1.3 per week over the treatment period. A total of 42.4% of patients were responders (> or = 50% reduction from baseline in weekly seizure frequency) over the treatment period; two patients were seizure-free from the first day of treatment throughout the treatment period. The most frequent drug-related adverse events were fatigue (27.3% of patients), somnolence (11.1%), headache (8.1%), and dizziness (8.1%). CONCLUSION: Levetiracetam as add-on therapy at doses up to 3000 mg/day effectively reduced the frequency of partial-onset seizures in patients with refractory epilepsy and was well-tolerated in this study, bridging conditions of placebo-controlled clinical trials and clinical practice.     

A pilot study of loading versus titration of valproate in the treatment of acute mania

Objective:  This double-blind pilot study compares the effectiveness and incidence of adverse effects of oral loading versus titration schedules of valproate in acute mania.
Method:  Consecutive new admissions for an acute manic episode were prescribed either an oral loading dose (20 mg/kg/day; n=5; mean age=33.4) or slower titration dose (10 mg/kg/day; n=6, mean age=30.6) of valproate for 7 days without other psychotropic agents, with the exception of benzodiazepines. Daily outcome measures included: serum valproic acid levels, the Young Mania Rating Scale (YMRS), the Brief Psychiatry Rating Scale (BPRS), the Clinical Global Impression Scale (CGI) and the Adverse Effect Rating Scale.
Results:  The mean serum valproic acid levels were significantly higher in the loading group when compared with the titration group after 1 and 2 days following the initiation of treatment (p < 0.05). After 3 days of treatment there was a trend for the group that received the loading regimen to have slightly more improvement in YMRS scores compared with the titration group. Side-effects were minor for both treatments, however, a higher incidence of side-effects was reported in the titration group, with 50% of patients reporting sedation most likely because of increased use of benzodiazepines.
Conclusion:  This suggests that a loading dose of valproate is likely safe and may provide an earlier onset of antimanic effects in patients with bipolar disorder. Future studies with larger sample sizes are indicated.     

Efficacy and tolerability of 1000-4000 mg per day of levetiracetam as add-on therapy in patients with refractory epilepsy

The aim of this study was to determine the efficacy and tolerability of 1000-4000 mg/day of levetiracetam (LEV, Keppra) as add-on treatment for refractory epilepsy. This was a dose-escalation study of 29 patients with refractory epilepsy. Patients received placebo for 4 weeks (baseline) followed by levetiracetam 1000 and 2000 mg per day each for 2 weeks, and then 3000 and 4000 mg per day each for 4 weeks. Primary efficacy was assessed by seizure frequency (number/week). Tolerability was assessed by adverse events, laboratory parameters, clinical evaluations, and electrocardiogram. All the study periods were completed by 27 of the 29 patients. A substantially lower median seizure frequency was observed at all levetiracetam dosing periods (1000 mg per day, 1.0 seizures per week; 2000 mg per day, 1.5 seizures per week; 3000 mg per day, 1.0 seizures per week; 4000 mg per day, 0.75 seizures per week) compared with the placebo treatment (2.06 seizures per week). In addition, 22-33% of these patients were seizure free during treatment with levetiracetam compared with only 14% with placebo. Levetiracetam was well tolerated. The most common adverse events were somnolence and asthenia; frequency and severity increased with increasing doses of levetiracetam. Levetiracetam in doses from 1000 to 4000 mg per day is effective. Somnolence and asthenia were more frequent with the highest dose, suggesting that 4000 mg per day may be the upper limit in some patients, although individual susceptibility to somnolence was variable.     

Acute antimanic efficacy and safety of oxcarbazepine in an open trial with an on-off-on design

Rationale and Objectives:  Carbamazepine has shown reasonable antimanic properties, but its use has been limited because of enzyme-inducing effects. The keto-derivative oxcarbazepine (OXC) is very similar to carbamazepine, however, the metabolic pathway is different. OXC is not metabolized to the 10, 11–epoxide, which seems to be responsible for several undesirable side-effects of carbamazepine and furthermore OXC has less enzyme-inducing properties.
Methods:  In this non-random open label study, patients were treated with OXC for 14 days, crossed over to no OXC for 7 days, and then crossed back over to OXC for the remaining 14 days. OXC was titrated to a final dose in a range of 900–2100 mg due to individual response. Treatment success was defined as a reduction of the original Young Mania Rating Scale (YMRS) score of more than 50% at the end of study period.
Results:  Four of the 12 included patients (33%) met defined response criteria at the end of study period. Fifty percentage of the patients had to be prematurely excluded from the trial. The mean YMRS scores of the on-periods were obviously different from the off-period. Forty-two percentage of the patients experienced side-effects leading to premature discontinuation in two of 12 patients.
Conclusion:  Antimanic activity of OXC was demonstrated in this pilot study only for patients with mild or moderate manic symptoms. Further studies are encouraged to clarify OXC's role as mood-stabilizer and assess whether it has a profile similar to that of carbamazepine.     

Safety Profile of Levetiracetam

Summary: Levetiracetam was approved in November 1999 as add-on therapy for the treatment of partial-onset seizures in adults (age 16 years and older). This review focuses on recently published data from four well-controlled studies in patients with partial-onset seizures with or without secondary generalization. When levetiracetam was given along with other antiepileptic drugs (AEDs), the most frequently reported adverse events were central nervous system related. Adverse events were usually mild to moderate in intensity, with the most frequently reported events occurring predominantly during the first 4 weeks of treatment. No relationship was apparent between the dose of levetiracetam and the most commonly reported adverse events in well-controlled clinical trials within the recommended dose range of 1,000–3,000 mg/day. Levetiracetam is a Pregnancy Category C drug. Overall, when used in combination with other AEDs, levetiracetam was generally well tolerated as add-on treatment for partial-onset seizures.     

The development of study exit criteria for evaluating antimanic compounds

BACKGROUND: There is increasing interest on the part of investigators and the public at large in finding ways to study and improve treatments for the seriously mentally ill without exposing such individuals to unnecessary risks. One group of particular interest in this regard are patients suffering from acute mania. We set out to define "exit" criteria or novel clinical endpoints that might help to assess the efficacy of antimanic compounds. We sought a method that would be safer, more economical, and less sensitive to nonspecific factors in the clinical environment while still allowing unambiguous assessment of efficacy. METHOD: From a pool of subjects being screened for or already participating in intervention studies, we retrospectively identified 76 admissions of patients with a manic or mixed episode according to DSM-IV. We fit a mixed-effects regression model to all available data obtained using the Bech-Rafaelsen Mania Scale from admission to day 28 of treatment. Using the estimated model coefficients, we obtained empirical Bayes (EB) estimates of each subject's trend coefficients based on (1) all available data and (2) data through day 11 of treatment for mania. RESULTS: We found a high correlation (r = .67) between EB estimates of final response at day 28 and actual day 28 scores on the Bech-Rafaelsen scale based on scores through day 11. When subjects were categorized as full, partial, or nonresponders according to their final Bech-Rafaelsen score, we were able to show that only 2 of the 23 predicted nonresponders became full responders, 27 of the 31 predicted full responders became full responders, and 16 of the 22 predicted partial responders became partial or full responders. CONCLUSION: We conclude on the basis of this chart review study that it should be possible to define exit criteria for trials assessing the efficacy of antimanic compounds on the basis of relatively short duration exposure to experimental treatment.     

Clinical response of quetiapine in rapid cycling manic bipolar patients and lactate level changes in proton magnetic resonance spectroscopy

The aim of the current study was to evaluate the relationship between quetiapine's effect on the improvement of mood symptoms in bipolar patients and brain metabolite level changes as measured by proton magnetic resonance spectroscopy ((1)H-MRS). Rapid cycling bipolar patients in the manic state were recruited and treated with quetiapine for 12 weeks. Clinical assessment was performed using the Young Mania Rating Scale (YMRS), the 17-item Hamilton Depression Rating Scale (HDRS) and the Clinical Global Impression-Severity scale (CGI-S) at baseline and weekly intervals during the 12-week period. In order to evaluate metabolite level changes over time, (1)H-MRS scans were acquired at baseline and week 12. There were significant reductions in YMRS scores (by 43.0%), HDRS scores (by 27.5%) and CGI-S score (by 44.6%) over the 12 week-period. Lactate levels significantly decreased over the 12-week study period (22.4%). This change in lactate levels was more prominent in quetiapine responders than in non-responders. Additionally, there was a positive correlation between changes in lactate levels and those in YMRS scores (r=0.52, p=0.003). Our findings suggest that quetiapine's antimanic and antidepressant efficacy in patients with rapid cycling bipolar disorder may potentially be related to decreased lactate levels in frontal regions of the brain.     

Correlates of rapid neuroleptic response in male patients with schizophrenia

Correlates of neuroleptic response latency were assessed in 16 male schizophrenic inpatients during 4 weeks of fixed dose (20 mg/day) haloperidol treatment. Rapid responders showed a mean 40% reduction in Brief Psychiatric Rating Scale (BPRS) positive symptom scores by day 10 of treatment. Rapid responders had significantly lower plasma homovanillic acid (pHVA) concentrations compared to non-rapid responders during week 4 of haloperidol treatment. However, rapid versus non-rapid responders did not differ with respect to demographics, baseline positive or negative BPRS symptom scores, performance on tests of neuropsychological function, or mean plasma haloperidol concentrations.     

Levetiracetam as add-on therapy in generalised epilepsies.

Levetiracetam is highly effective as add-on treatment in refractory partial-onset seizures but there are only limited data supporting its benefit in generalised epilepsies. We have reviewed the clinical records of 25 consecutive adult patients with generalised epilepsies (84% females; mean age 34 (range 16-75) years) prescribed levetiracetam for at least six months. The epilepsy was considered idiopathic in 22 patients (88%)--including 13 with juvenile myoclonic epilepsy--and symptomatic in three. Most patients (68%) reported some improvement in seizure frequency on levetiracetam including 16% who became seizure free. Levetiracetam was generally well tolerated although 11/25 (44%) of patients reported some tiredness, weight change or rash. Levetiracetam was stopped in five patients, four because of side effects and one though lack of efficacy. In four cases, pre-existing antiepileptic medication was withdrawn, leaving levetiracetam as monotherapy. We conclude that levetiracetam is a useful add-on treatment for patients with refractory generalised epilepsies.     

A pilot trial of levetiracetam in eyelid myoclonia with absences (Jeavons syndrome)

OBJECTIVE: Eyelid myoclonia with absences (EMA) or Jeavons syndrome characterized by eyelid myoclonia (EM) (with or without absences), eye closure-induced EEG paroxysms, and photosensitivity. We conducted an open-label trial of levetiracetam in EMA. PATIENTS AND METHODS: Patients were recruited in different Italian Epilepsy Centres. Levetiracetam was administrated at starting dose of 10 mg/kg/day up to 50-60 mg/kg/day in two doses. Treatment period included a 5-6 week up-titration phase and a 12-week evaluation phase. The number of days with EM (i.e., days with seizures, DwS) and number of generalized tonic-clonic seizures (GTCS) were evaluated. Analysis of intent-to-treat population was performed using Fisher's and Wilcoxon tests. RESULTS: Thirty-five patients (23 F) with a mean age of 19 +/- 6 years were recruited. Twenty-seven had previously undergone one to five adequate trials of antiepileptic drugs. The median number of DwS/month was 12 +/- 8.2. Twenty-one patients experienced GTCS (median number/month: 1 +/- 0.2). Thirty-four subjects completed the trial. Levetiracetam was well tolerated (mean dose: 1985 mg/day). Responders were 28/35 (80%) patients, nine taking levetiracetam as monotherapy. Six patients were seizure-free, 15 had > or =75% and seven >50% seizure reduction. GTCS remitted in 14 out of 21 (66.6%) patients. The number/month of DwS (median: 12 vs 5; p = 0.0001) and of GTCS (median: 1 vs 0; p = 0.0001) decreased compared to baseline period. Disappearance or clear reduction in paroxysmal abnormalities at eye closure occurred in 20 of the responders and photoparoxysmal response in 19. Mean follow-up was 23.9 +/- 18.5 months. CONCLUSION: Levetiracetam is effective and well tolerated in EMA. Placebo-controlled studies should confirm these findings.