Levetiracetam for Managing Neurologic and Psychiatric Disorders

Muhammad U. Farooq; Archit Bhatt; Arshad Majid; Rishi Gupta; Atul Khasnis; Mounzer Y. Kassab

Disclosures

Am J Health Syst Pharm. 2009;66(6):541-561. 

In This Article

Clinical Uses and Efficacy of Levetiracetam in Neurologic Disorders

Seizure Disorders

The efficacy and tolerability of levetiracetam as an adjunctive therapy in the management of partial-onset seizures with or without secondary generalization has been demonstrated in adults[18,19,20,21] and children.[22] Data have shown its efficacy as an adjunctive therapy in myoclonic seizures[23] and generalized tonic and clonic seizures in patients with idiopathic generalized epilepsies.[24] Levetiracetam as a monotherapy has also been shown to be equally effective to controlled-release carbamazepine in adults with partial or generalized tonic-clonic seizures.[25] During initial stages of the clinical development of levetiracetam, three randomized, double-blind, placebo-controlled trials were carried out.[18,19,20] The data were qualitatively homogeneous across the trials and demonstrated levetiracetam to be safe and effective in refractory partial epilepsy as an add-on therapy.

Ben-Menachem and Falter[18] conducted a multicenter, double-blind, placebo-controlled, parallel-group, responder-selected study to evaluate the efficacy and tolerability of levetiracetam monotherapy in selected patients with refractory partial seizures. The patients were randomized to receive oral levetiracetam 1500 mg twice daily or placebo during a 12-week add-on phase. The patients with a reduction in partial seizure frequency of 50% or more compared with baseline entered a monotherapy phase. This phase included a maximum 12-week down-titration period and 12 weeks of monotherapy at 1500 mg twice daily. In both phases, responder rate (defined as a reduction in partial seizure frequency of 50% or more compared with baseline), seizure frequency, and adverse events were analyzed. A total of 286 patients (placebo, n = 105; levetiracetam, n = 181) entered the add-on phase. Eighty-six patients (placebo, n = 17; levetiracetam, n = 69) were eligible for the monotherapy phase. Thirty-six of 181 patients (19.9%) who received levetiracetam completed the entire study, compared with only 10 of 105 patients (9.5%) in the placebo group (p = 0.029). The responder rate during the add-on phase was significantly higher in the levetiracetam group compared with the placebo group (42.1% versus 16.7%, respectively; p < 0.001). In the levetiracetam monotherapy group, the median percent reduction in partial seizure frequency compared with baseline was 73.8% (p = 0.037), with a responder rate of 59.2%. Nine patients (18.4%) remained seizure free on levetiracetam monotherapy. This study showed that the conversion to levetiracetam monotherapy (1500 mg twice daily) was effective and well tolerated in patients with refractory partial seizures who responded to 3000 mg/day levetiracetam as add-on therapy.

Cereghino et al.[19] evaluated the efficacy and safety of levetiracetam 500 mg twice daily and 1500 mg twice daily as adjunctive therapy for refractory partial seizures in a double-blind, randomized, placebo-controlled, parallel-group, multicenter trial. They studied patients with uncontrolled partial seizures (minimum of 12 seizures per 12 weeks for 38 weeks). A 12-week baseline was followed by random assignment to adjunctive therapy with placebo (n = 95), levetiracetam 500 mg twice daily (n = 98), or levetiracetam 1500 mg twice daily (n = 101). Upward titration over 4 weeks was followed by 14 weeks of fixed-dose treatment. Of 294 patients, 268 completed the study. Partial seizure frequency during the entire evaluation period was lower with levetiracetam compared with placebo (p < 0.001 for both groups). More patients responded (defined as a minimum 50% reduction in partial seizure frequency) to levetiracetam than placebo, with rates of 33.0% in the 1000-mg/day group and 39.8% in the 3000-mg/day group, compared with 10.8% in the placebo group (p < 0.001). Of 199 patients receiving levetiracetam, 11 became seizure free. None of the patients became seizure free in the placebo group. Treatment-emergent adverse events were mostly mild to moderate in severity. At least one adverse event was reported by most patients during the study—88.4% in the placebo group, 88.8% in the levetiracetam 1000 mg/day group, and 89.1% in the levetiracetam 3000 mg/day group. These included asthenia, dizziness, flu syndrome, headache, infection, rhinitis, and somnolence. This study showed that the adjunctive therapy with levetiracetam was effective and well tolerated in controlling partial seizures.[19]

Shorvon et al.[20] conducted a multicenter, double-blind, randomized, placebo-controlled trial to evaluate the efficacy and tolerability of levetiracetam as add-on therapy in patients with refractory partial seizures. Either 500 or 1000 mg twice daily of levetiracetam as an add-on therapy was used in 324 patients with uncontrolled simple or complex partial seizures, or both, with or without secondary generalization. After enrollment, three parallel groups were assessed during a baseline period of 8 or 12 weeks, followed by a 4-week titration interval and a 12-week evaluation period. Levetiracetam significantly decreased partial seizure frequency compared with placebo. A reduction in seizure frequency of ≥50% occurred in 22.8% of patients in the 1000-mg group and 31.6% of patients in the 2000-mg group, compared with 10.4% of patients in the placebo group. In this study, the administration of levetiracetam did not affect plasma concentrations of concomitant antiepileptic drugs or alter vital signs or laboratory parameters. No significant difference in the incidence of adverse events was observed between treatment groups or between the levetiracetam and placebo groups. The most commonly reported adverse effects in the levetiracetam group were asthenia, headache, and somnolence. The antiepileptic efficacy and tolerability of 1000 mg/day and 2000 mg/day levetiracetam as add-on therapy was established in patients with refractory partial seizures in this clinical study.

Morrell et al.[21] conducted Phase IV prospective, open-label, multi-center, community-based, placebo-controlled trials to demonstrate the safety and efficacy of levetiracetam as add-on therapy for partial-onset seizures. The purpose of this study was to gather additional safety and efficacy data on levetiracetam in a community-based practice. A total of 1030 patients at least 16 years old (mean = 42.2 years) with partial- onset seizures were enrolled at different study sites. Patients whose partial-onset seizures were inadequately controlled on their current medications had levetiracetam 500 mg twice daily added to their regimens. The levetiracetam dosage was increased by 500 mg twice daily at the end of weeks 2 and 4 to a maximum dosage of 1500 mg twice daily, unless the patient had been seizure free during the previous 2-week period. The dose remained the same for 12 weeks. The main outcome measures were reductions in seizure frequency, global evaluation scale (a measurement of a change in the patient's clinical condition after treatment), and adverse events. During the 16 weeks of the trial, 57.9% of patients (542 of 936) experienced at least a 50% reduction in the frequency of partial-onset seizures, 40.1% (375 of 936) experienced at least a 75% reduction, and 20% (187 of 936) demonstrated a 100% seizure reduction. During the last 6 weeks of the study, 66.7% of patients (500 of 750) experienced at least a 50% reduction in the frequency of partial seizures, 52.4% (393 of 750) experienced at least a 75% reduction, and 42.1% (316 of 750) demonstrated a 100% seizure reduction. About 74.3% (734 of 988) of patients were considered improved, and 37% of patients showed marked improvement. However, 38.3% of patients reported at least one drug-related adverse effect. The most common adverse events (5% or more of patients) were somnolence, dizziness, asthenia, and headache, which were mild to moderate in nature. Three patients had serious drug-related adverse effects, including urinary incontinence, confusion, and ataxia, which resolved after discontinuation of the drug. Behavioral adverse effects, including hostility (1.7%), emotional liability (1.7%), depression (1.5%), agitation (1.2%), anxiety (1.2%), and depersonalization (0.1%), were also reported. The results of this study provide further evidence regarding the efficacy and safety of levetiracetam as adjunctive treatment for partial-onset seizures.

Additionally, Betts et al.[26] evaluated levetiracetam in patients with refractory epilepsy in a well-controlled trial as an adjunctive therapy. The aim of this study was to determine the tolerability and efficacy of two oral regimens of levetiracetam—1000 and 2000 mg twice daily—as add-on treatment without titration in patients with refractory epilepsy. One hundred nineteen patients were randomized to receive levetiracetam 2000 mg daily, 4000 mg daily, or placebo for a 24-week, double-blind period and then levetiracetam 4000 mg daily in a 24-week open-label phase. The responder rates (defined as the proportions of patients achieving a reduction in total seizure frequency by ≥50% compared with baseline) were higher with levetiracetam 2000 and 4000 mg daily (48.1% [p < 0.05] and 28.6% [p not significant], respectively) than with placebo (16.1%). In the open-label phase, the overall responder rate was 43.0%. Switching from placebo to levetiracetam increased the overall responder rate from 16.7% to 44.0%. No such increase was observed with patients initiated on levetiracetam 2000 mg daily.

The incidence of adverse events was similar among study groups (placebo = 84.6%, levetiracetam 2000 mg/day = 83.3%, levetiracetam 4000 mg/day = 84.2%) in the double-blind treatment period.[26] The most frequently reported adverse effects were somnolence and asthenia, with a higher percentage in patients taking higher doses (4000 mg) of levetiracetam. The incidence of somnolence was 26.2% and 44.7% in patients taking levetiracetam 2000 and 4000 mg/day, respectively. The incidence of somnolence in the placebo group was 25.6%, which was comparable to the levetiracetam 2000-mg/day group. Asthenia was most commonly reported by patients in the levetiracetam 4000-mg/day group (31%). It was similar between the levetiracetam 2000-mg/day group and placebo: 13.2% and 15.4%, respectively. During the open-label study period, somnolence occurred in 8.1% and asthenia in 3.5% of the 86 patients. The other most commonly reported adverse events in the double-blind treatment period were accidental injury, infection, nausea, dizziness, and urinary tract infection. These adverse events generally appeared within the first month of treatment. During the open-label period, 3 patients had serious adverse effects, including convulsions in 2 patients and hallucinations in 1 patient, that were considered to be related to levetiracetam. This study showed that levetiracetam can be safely initiated at higher therapeutic dosages from 2000 to 4000 mg/day and seizure control can be rapidly achieved without the need for titration. This is one of the advantages of levetiracetam over other AEDs in terms of ease of use in clinical practice. The main concern with higher dosages is the higher incidence of somnolence. However, it is important to note that the higher dosage is not necessarily more effective than the lower dosage, which suggests a therapeutic window of efficacy of levetiracetam.

The Safety of Keppra as Adjunctive Therapy in Epilepsy (SKATE) trial was an open-label trial to evaluate the safety and efficacy of levetiracetam as add-on therapy for refractory partial seizures in clinical practice.[27] A total 1541 patients 16 years of age or older who had treatment-resistant partial seizures were recruited. Levetiracetam 1000 mg/day was added to a stable, concomitant, AED regimen, and the maximum dosage of levetiracetam used was 3000 mg/day. About 87% of patients completed the study. The median reduction from baseline in the frequency of all seizures was 50.2%. About 16% of patients were seizure free, and 50.1% had seizure frequency reduction of ≥50%. At the end of the study, 60.4% of patients were considered to show marked or moderate improvement. There was a significant improvement in health- related quality of life (QOL) as assessed with the Quality of Life in Epilepsy Inventory-10 (QOLIE-10-P) (total score increasing from 55.6 to 61.6, p < 0.001). About 51% of patients reported at least one adverse event that was considered related to levetiracetam treatment. The most frequent adverse events reported in this study were mild to moderate in severity and included somnolence (18.3%), fatigue (12.9%), dizziness (6.9%), and headache (6.3%). The drug-related psychiatric adverse events were depression (2.4%), aggression (1.9%), and irritability (1.8%). This community-based study suggested that levetiracetam is well tolerated and effective as add-on therapy for refractory partial seizures in adults. These data provide supportive evidence for the safety and efficacy of levetiracetam demonstrated in the pivotal Phase III placebo-controlled studies.

Brodie et al.[25] conducted a randomized, controlled, prospective study of the efficacy and tolerability of levetiracetam in comparison with controlled-release carbamazepine as the first treatment in newly diagnosed epilepsy. It was a multi-center, double-blind, noninferiority, parallel-group trial. The data from this study showed that levetiracetam monotherapy is equally effective to controlled-release carbamazepine in partial and generalized tonic-clonic seizures. In this study, 288 adults with two or more partial or generalized tonic-clonic seizures in the previous year were randomly assigned to a therapy group of levetiracetam 500 mg twice daily, and 291 patients were assigned to a therapy group of controlled-release carbamazepine 200 mg twice daily. The maximum dose of levetiracetam used was 1500 mg twice daily. The maximum dosage of carbamazepine used was 600 mg twice daily. The patients with a six-month seizure-free period continued on treatment for another six-month maintenance period. Of all patients achieving six-month and one-year remission periods, 80.1% and 86.0%, respectively, did so at the lowest dose level in the levetiracetam group, and 85.4% and 89.3%, respectively, did so at the lowest dose level in the carbamazepine group. The most common adverse events reported in this study with levetiracetam and carbamazepine use were headache (relative risk [RR] levetiracetam/carbamazepine, 0.81), fatigue (RR levetiracetam/carbamazepine, 1.17), somnolence (RR levetiracetam/carbamazepine, 1.21), dizziness (RR levetiracetam/carbamazepine, 0.79), depression (RR levetiracetam/carbamazepine, 3.06), insomnia (RR levetiracetam/carbamazepine, 2.48), weight gain (RR levetiracetam/carbamazepine, 0.48) and back pain (RR levetiracetam/carbamazepine, 0.41). Withdrawal rates for adverse events were 14.4% with levetiracetam and 19.2% with carbamazepine. This study showed that levetiracetam and controlled-release carbamazepine produced equivalent seizure-free rates in newly diagnosed epilepsy at optimal dosing. Moreover, levetiracetam has potential to be used as initial monotherapy in newly diagnosed epilepsy.[25]

Berkovic et al.,[24] in a multicenter, randomized, double-blind, placebo-controlled study, showed the efficacy and tolerability of levetiracetam for treating generalized tonic-clonic seizures in patients with idiopathic generalized epilepsy. Adults and children (4-65 years old) with idiopathic generalized epilepsy experiencing three or more generalized tonic-clonic seizures during the 8-week baseline period, despite receiving stable doses of one or two AEDs, were enrolled in this study. Patients were randomized to levetiracetam (target dosage of 3000 mg/day for adults or 60 mg/kg/day for children) or placebo. A 4-week titration period was followed by a 20-week evaluation period. Of the 229 patients screened, 164 were randomized (levetiracetam, n = 80; placebo, n = 84). Levetiracetam produced a greater mean reduction in generalized tonic-clonic seizure frequency per week over the treatment period (56.5%) than placebo (28.2%, p = 0.004). The percentage of patients who had ≥50% reduction of generalized tonic-clonic seizure frequency per week during the treatment period was 72.2% for levetiracetam and 45.2% for placebo (p < 0.001). During the first 2-week treatment, 64.6% of patients on levetiracetam and 45.2% on placebo (p = 0.018) were classified as responders. During the evaluation period, the percent of patients free of generalized tonic-clonic seizures (34.2% versus 10.7%, p < 0.001) and all seizure types (24.1% versus 8.3%, p = 0.009) was greater for levetiracetam than placebo. Levetiracetam was well tolerated, and only 1.3% of patients discontinued therapy because of adverse events. Drug-related adverse effects were reported in 31 patients (39.2%) in the levetiracetam group and 25 patients (29.8%) in the placebo group during the treatment period.

Psychiatric disorders were the most common drug-related adverse effects, occurring in 18 of 79 (22.8%) levetiracetam-treated patients and 12 of 84 (14.3%) placebo-treated patients.[24] However, the only drug-related adverse effects reported in ≥5% of patients in either group were fatigue (10.1% levetiracetam and 6.0% placebo), somnolence (5.1% levetiracetam and 4.8% placebo), headache (5.1% levetiracetam and 3.6% placebo), and irritability (5.1% levetiracetam and 1.2% placebo). Serious adverse effects resulting in hospitalization or disability were reported in 3 levetiracetam-treated patients (3.8%) during the treatment period, compared with 8 patients (9.5%) in the placebo group. The drug-related serious psychiatric adverse effects included aggression, depression, and suicidal ideation.

Levetiracetam is also an effective therapy in patients with different myoclonic seizures, including severe myoclonic epilepsy of infancy (SMEI) and juvenile myoclonic epilepsy (JME).[23,28,29] SMEI, also called Dravet syndrome, is a severe form of epilepsy that appears during the first year of life with frequent febrile seizures. Later, other types of seizures typically arise, including myoclonus. Striano et al.[28] conducted an open-label, add-on trial on safety and efficacy of levetiracetam in SMEI. SMEI patients were recruited from different centers according to the following criteria: age of at least three years, at least four tonic-clonic seizures per month during the last 8 weeks, and previous use of at least two drugs. Levetiracetam was orally administered at a starting dosage of approximately 10 mg/kg/day, up to 50-60 mg/kg/day in two doses. The treatment period included a 5-6-week up-titration phase and a 12-week evaluation phase. Efficacy variables were responder rate by seizure type and reduction of the mean number per week of each seizure type. Twenty-eight patients (mean ± S.D. age, 9.4 ± 5.6 years) entered the study.[28] Sixteen patients (57.1%) showed mutations in SCN1A genes. The mean number of concomitant drugs was 2.5. The mean levetiracetam dose achieved was 2016 mg/day. Twenty-three patients (82.1%) completed the trial. Responders were 64% for tonic-clonic, 60% for myoclonic, 60% for focal, and 44% for absence seizures. The number per week of tonic-clonic seizures (median = 3 versus 1, p = 0.0001), myoclonic seizures (median = 21 versus 3, p = 0.002), and focal seizures (median = 7.5 versus 3, p = 0.031) was significantly decreased compared with baseline. Levetiracetam's effect was not related to age at onset and duration of epilepsy, genetic status, and concomitant therapy. Levetiracetam was well tolerated by patients who completed the study. To date, follow-up ranges from 6 to 36 months (mean ± S.D., 16.2 ± 13.4 months). According to this study, levetiracetam add-on is effective and well tolerated in SMEI.

JME is an idiopathic, generalized, epileptic syndrome characterized by myoclonic jerks, generalized tonic-clonic seizures, and sometimes absence seizures. In a recent study, Verrotti et al.[29] evaluated the efficacy and tolerability of levetiracetam monotherapy in JME. The study group consisted of 32 patients with epilepsy (20 men and 12 women) with a mean ± S.D. age of 13 years 3 months ± 7 years 11 months at seizure onset. Levetiracetam was administered as the first drug. All patients were followed up at 6 and 12 months. The dosage that achieved seizure control ranged from 1000 to 2500 mg/day. At the 6-month evaluation, 15 patients were seizure free, 14 patients were responders (>50% reduction in seizures), and 3 patients had marginal effects (<50% reduction in seizures). At the 12-month evaluation, 29 patients were seizure free and 3 patients were responders. No patients reported adverse events. These data provide preliminary evidence that levetiracetam may be effective for treating patients with newly diagnosed JME.[29]

Levetiracetam also has a potential role in the treatment of nonconvulsive status epilepticus (NCSE), but there are limited data about the use of levetiracetam in these patients.[30,31] Rupprecht et al.[30] retrospectively analyzed 8 patients with NCSE who received levetiracetam. They compared these 8 patients with 11 patients with NCSE treated with conventional i.v. status medication as controls. The patients treated with levetiracetam showed a marked clinical improvement, with final cessation of ictal electroencephalography (EEG) activity and clinical symptoms of NCSE after initiation of levetiracetam therapy within three days. The response to conventional treatment was similarly effective, but there were severe adverse effects, whereas no relevant adverse effects in the levetiracetam-treated group were noticed. These researchers found no significant differences in hospitalization time, time in intensive care unit, and outcome between the levetiracetam group and the control group.

Farooq et al.[31] reported two patients with NCSE who responded favorably to i.v. levetiracetam. The first patient was an 83-year-old man with a history of complex partial seizure disorder who had an impaired level of consciousness. The second patient was an 82-year-old man with a history of old-left, middle-cerebral, artery-ischemic infarction who had confusion. Both patients were found to have NCSE on EEG and were treated with i.v. levetiracetam. In both cases, electrographic status epilepticus stopped with marked clinical improvement. Both patients tolerated the medication well without any significant adverse effects.[31] These limited data suggest that levetiracetam may be a well-tolerated, effective treatment option in NCSE.

Seizure Control in Patients With Cognitive Disorders

Patients with severe dementia, including Alzheimer's disease (AD) and other cognitive disorders, are at a higher risk of having seizures as compared with non-demented patients of similar age.[32,33] The treatment of seizures in these patients is a challenging task because of the central nervous system adverse effects of most of the AEDs. These medications can result in further impairment of cognitive functions and can also result in different behavioral adverse effects in the elderly population. Levetiracetam at a dosage of 1000-1500 mg/day is efficacious and well tolerated in elderly patients with advanced AD and new-onset epileptic seizures.[34] Levetiracetam has shown a good safety profile for use in elderly patients with psychiatric and neurologic disorders. The safety profile was related with cognitive and behavioral issues in these patients.[35]

Assessments of QOL can be used to document the overall progress of epilepsy patients before and after starting a new medication or other treatment changes. Cramer and Van Hammee[36] evaluated the health-related quality of life (HRQOL) of patients on levetiracetam and showed improvement both at short-term and at long-term follow up. In this study, correlations between the QOLIE-31-P distress items and domain items were assessed. QOLIE-31 is a survey of HRQOL for adults with epilepsy. The results of this study indicated that distress was significantly lower when HRQOL was better (p < 0.0001). At long-term, highest- priority, QOLIE-31-P domains were social function, cognitive function, and overall QOL. The gains in HRQOL were maintained during long-term levetiracetam treatment irrespective of the levetiracetam starting point.

Data for epilepsy treatment with levetiracetam are encouraging. Other additional data are described in Table 1 . Future research to study levetiracetam as a frontline monotherapeutic agent is warranted. More data for patients with high-risk subgroups for adverse effects (e.g., advanced age, renal failure) are needed. Moreover, systematic efficacy and tolerability of levetiracetam as a parenteral therapeutic agent in NCSE also need to be determined.

Parkinson's Disease and Huntington's Disease

Parkinson's disease (PD) is a neurodegenerative disease that is caused by a loss of dopaminergic neurons in the nigrostriatal pathway. Levodopa is used to control the motor symptoms of the disease, but long-term therapy with levodopa often results in dyskinesia. Dyskinesia in these patients can disrupt activities of daily living, resulting in a significant disability. The exact mechanism of action of levetiracetam in levodopa-induced dyskinesia is not clear. Levetiracetam appears to modify multiple mechanisms that produce levodopa-induced dyskinesia.[43] It has been shown to reduce neuronal synchronization in animal models of epilepsy.[44] The antidyskinetic effects of levetiracetam seem to be related with the desynchronization of abnormal neuronal firing patterns of internal globus pallidus and substantia nigra pars reticulate neurons.[45,46] Levetiracetam also potentiates the antidyskinetic effects of other medications, such as amantadine, in similar disorders.[47] The potential efficacy of levetiracetam in the treatment of levodopa-induced dyskinesia has been demonstrated by a number of studies.[43,45,46,48,49]

In an open-label pilot study, Zesiewicz et al.[48] recruited patients with PD who experienced peak-dose dyskinesia for at least 25% of their awake time. Nine patients (three women and six men) with PD were given incremental dosages of levetiracetam from 250 up to 3000 mg/day. The mean ± S.D. dosage of levetiracetam at endpoint was 625 ±277 mg/day. There was a reduction in dyskinesias (23% versus 11%, p = 0.13), which was not statistically significant. The increase in "on time" (a period of good symptom control or unimpeded motor function) (43% versus 61%) in these patients (p = 0.02) was, however, significant. The authors reported a 53% nondose-dependent dropout rate, which was substantially caused by somnolence. This adverse effect of levetiracetam should be considered while using levetiracetam in the elderly population.

Tousi and Subramanian[46] described four patients with PD who developed disabling levodopa- induced dyskinesia. These patients were treated with levetiracetam, and the dose of levetiracetam was increased gradually over several weeks. This gradual titration of levetiracetam was well tolerated, except for dose-related excessive sedation, by all four patients. None of the four patients reported any significant worsening of their parkinsonian symptoms. The Unified Parkinson's Disease Rating Scale (UPDRS) dyskinesia score was used to assess the effect of levetiracetam on dyskinesia in these patients. Dyskinesia improved in two of these four patients. The duration of therapy for the other two patients was too short for the beneficial effects of levetiracetam to be assessed.

Meco et al.[49] performed an open-label study by using levetiracetam in 16 patients with PD with levodopa-induced dyskinesia. Levetiracetam was given in gradually increasing dosages, starting at 125 mg twice daily. This dosage was increased by 125 mg twice daily every week until a dosage of 500 mg twice daily was reached. The dosage was then increased by 500 mg every five days up to 2000 mg/day, or until a satisfactory result was achieved. The patients in this study were followed for three months by means of monthly checkups using the UPDRS motor scale and Abnormal Involuntary Movement Scale (AMIS) each time. According to this study, levetiracetam is an ineffective treatment of levodopa-induced dyskinesia and is associated with a high incidence of dropouts caused by somnolence.

Huntington's disease (HD) is an autosomal dominant condition characterized by the coexistence of involuntary movements and progressive dementia. Levetiracetam has a potential role in HD because of its action on the basal ganglia; it produces a selective N-type calcium channel blockage in the striatum in animal models.[50] It causes a significant decrease in single-unit neuronal firing in the substantia nigra pars reticulate. The effect of levetiracetam on hyperkinetic movements in HD seems in line with its antidyskinetic effects in levodopa-induced dyskinesias. It includes desynchronization of abnormal neuronal firing patterns of internal globus pallidus and substantia nigra pars reticulata neurons as mentioned above.

Zesiewicz et al.[51] conducted a prospective open-label pilot study in nine patients with HD chorea. They were treated with levetiracetam dosages up to 3000 mg/day for up to 48 days. These patients were evaluated by the Unified Huntington Disease Rating Scale (UHDRS) before and after the levetiracetam treatment. The primary endpoint measure was the UHDRS chorea subscore. The mean ± S.D. dosage of levetiracetam at endpoint was 2583.3 ± 1020.6 mg/day. The mean ± S.D. UHDRS chorea score decreased from 12.6 ± 3.0 at baseline to 6.7 ± 4.3 at endpoint (p = 0.01). There was no significant change in the mean ± S.D. UHDRS total motor scores (38.8 ±11.4 at baseline and 33.6 ±26.7 at endpoint, p = 0.24). Somnolence contributed to a 33% dropout rate, and three patients developed parkinsonism.[51]

De Tommaso et al.[52] conducted a single-center, short-term, open-label, controlled study on 22 patients with genetically confirmed HD. Fifteen patients were assigned to the levetiracetam group and 7 were enrolled as the control group. Patients had levetiracetam as add-on therapy for six months. Levetiracetam was added at the dosage of 500 mg twice daily for the first two months, and then the dosage was increased to 1000 mg twice daily for the next four months. All patients underwent an initial clinical evaluation consisting of consecutive visits performed before the initiation of therapy and then again every two months for six months. To assess the efficacy of therapy, patients underwent the motor section of the UHDRS. The evaluation of disability was carried out by the total functional capacity score. In addition, patients were evaluated by the Mini-Mental State Examination to estimate cognitive impairment. The patients on levetiracetam showed a significant reduction of involuntary movements with a slight improvement of functional capacity compared with the control group in this study (p < 0.01). The reduction of involuntary movements helped to improve the QOL for these patients. All the patients (except 3) completed the study. One patient dropped out because he developed somnolence and aggressive behavior soon after drug intake. Two patients were lost to follow-up for noncompliance, 1 at the time of the second visit and the other at the time of the fourth visit. No serious adverse effects were experienced by any other treated patients.[52]

On the contrary, Zesiewicz et al.[53] described a case where levetiracetam induced parkinsonism in a patient treated for Huntington's chorea. This was reversible, and the patient was back to his baseline on day 7 after discontinuing levetiracetam. Chorea returned back to its pretreatment baseline. This emphasizes that extrapyramidal effects of levetiracetam may not always be favorable and its role in these disorders is not well defined. The current data are insufficient to recommend the use of levetiracetam in neurodegenerative disorders including PD and HD.

Tardive Dyskinesia

Tardive dyskinesia (TD) is a well-known complication of chronic antipsychotic medication use, especially with conventional antipsychotics. Preclinical evidence suggests that levetiracetam inhibits neuronal hypersynchronization.[54] This may help reduce neuronal firing and thus reduce dyskinesias. Clinical studies have indicated that levetiracetam is a potential treatment in controlling TD in patients taking these medications. There was some improvement in the AIMS score in patients with TD in these studies as described below.

Konitsiotis et al.[55] conducted an open-label study in eight patients. Patients received levetiracetam 1000 mg/day for a month with pretreatment and posttreatment blinded evaluations. The study patients were evaluated by means of the AIMS, the Goetz Dyskinesia Scale, the Clinical Global Impressions (CGI) scale, and the Brief Psychiatric Rating Scale (BPRS). After one month of treatment with levetiracetam at a dosage of 1000 mg/day, abnormal movements, as measured with AIMS, were significantly reduced (p = 0.001). In the Goetz Dyskinesia Scale, scores were reduced from 2.6 to 1.5 (p = 0.026). The BPRS scores did not show significant changes during the study. There was a high dropout rate (33%, n = 3) attributed to somnolence.

Meco et al.[56] conducted an open-label observational study on 16 patients with chronic psychosis and TD. Levetiracetam was given in gradually increasing dosages, starting with 125 mg twice daily until the best clinical response was achieved. The mean dosage of levetiracetam used was 2290 mg daily (range, 1000-3000 mg daily). TD was assessed using the AIMS at baseline and after one and three months of treatment with levetiracetam. Compared with baseline, there was a significant improvement in the AIMS score after one month, which was still present after three months (p < 0.001). All patients tolerated levetiracetam except one, who dropped out of the trial after the first two weeks because of excessive drowsiness.

Bona[57] studied the effect of levetiracetam on neuroleptic-induced TD in 17 patients. Levetiracetam was added to their therapeutic regimen, and no changes were made in the antipsychotic treatment regimen during this open-label trial. The average dosage of levetiracetam used was 2089 mg/day (range, 1000-4000 mg/day). All patients experienced some improvement in their symptoms of TD after starting levetiracetam therapy. The AIMS scores improved, on average, by 80% (range, 37-100%). The average reduction in the AIMS score, from 18.3 to 4.0, was statistically significant (p = 0.00001526). The mean time to maximum improvement was 22.8 days (range, 3-105 days). Levetiracetam was well tolerated in these patients. Three inpatients reported mild sedation, but no dose adjustment was necessary. One of the outpatients reported depression, and the dosage of levetiracetam was reduced from 4000 to 3000 mg/day. None of the patients discontinued the medication because of adverse effects. Five outpatients were lost to follow-up.

McGavin et al.[58] described a patient with TD whose dyskinesias resolved with levetiracetam therapy. This patient was started on levetiracetam 500 mg, and his examination three weeks after starting the therapy demonstrated marked improvement in his symptoms (AIMS score decreased from 35 to 3). Dyskinesias returned when levetiracetam was stopped and resolved again after reinstitution of the therapy. Levetiracetam was gradually increased to 1000 mg/day. No definite conclusions can be drawn from these studies; further double-blind, controlled clinical trials to evaluate the role of levetiracetam in the treatment of TD are warranted.

Dystonia and Meigs' Syndrome

Dystonia is one of the most prevalent hyperkinetic movement disorders. The exact mechanism responsible for the effect of levetiracetam in dystonia is not clear. The desynchronization of abnormal neuronal firing patterns is the most likely mechanism, which has already been explained in the PD and HD sections. Open-label clinical trials have been conducted to assess if levetiracetam is helpful in the treatment of cervical and generalized dystonia.[59,60,61]

Tarsy et al.[59] conducted an open-label trial of levetiracetam in 10 patients (5 men and 5 women) with primary idiopathic cervical dystonia (CD). This trial did not show any improvement in CD, and the dropout rate was high. The mean ± S.D. age of the patients was 54.1 ±12.4 years, and the mean ± S.D. duration of CD was 9.6 ± 7.4 years. Patients were examined at weeks 0, 1, 3, 5, and 7 and were contacted by telephone at weeks 2 and 4. After an initial baseline visit at week 0, levetiracetam 250 mg twice daily was started at week 1. The dosage was increased to 500 mg twice daily after week 2 and 1000 mg twice daily after week 3. This dosage was maintained at 1000 mg twice daily until the medication was discontinued at week 5. A posttreatment evaluation was carried out at week 7. The severity of CD was assessed with the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) at each visit, and a standardized video recording was recorded at base line and week 5. The primary outcome measure was change in the TWSTRS score from baseline to final visit on medication. The secondary outcomes were improvement in CD as determined by review of the video recording and the patient's global impression of change. This trial showed no improvement in patients with CD. The most common adverse effect was drowsiness with fatigue. Other adverse effects included gastrointestinal symptoms, dizziness, headaches, and increased neck pain.

Hering et al.[60] studied the efficacy of levetiracetam in a daily dosage of 3000 mg in 10 consecutive patients (7 women and 3 men, median age = 51 years) with therapy refractory segmental or generalized dystonia. Levetiracetam was started at 500 mg twice daily and increased by 500 mg every five days to a maintenance dosage of 3000 mg daily. The movement subscale of the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) served as the primary outcome measure. At baseline, the median BFMDRS motor score was 51. With treatment, the score did not improve, as the follow-up median BFMDRS score was 55. At the week 4 follow-up, none of the patients showed improvement of dystonia. Mild adverse effects, including somnolence, nausea, and dizziness, were noticed in 3 patients. According to this study, the daily dosage of 3000 mg of levetiracetam is ineffective in patients with segmental or generalized dystonia.[60]

Sullivan et al.[61] reported the case of a 46-year-old woman with generalized dystonia whose symptoms improved with the use of levetiracetam. She had been on different medications, including antispasticity medications, dopaminergics, and benzodiazepines, before starting on levetiracetam. She also had received botulinum toxin injections in her limbs every three months for two years with minimal improvement in her limb dystonia. She was treated with levetiracetam 500 mg daily, and the dosage was slowly increased to 2000 mg daily. She was seen after 4 weeks of starting levetiracetam and had marked improvement on the BFMDRS. Her baseline BFMDRS score was 72 out of 120, and during treatment with levetiracetam it decreased to 58 out of 120. The subscore for blepharospasm before treatment was 6 and improved to 0.5 after treatment. The CD score before treatment was 6 and decreased to 4 after treatment. The score for truncal dystonia improved from 12 to 8. She remained on levetiracetam for a total of 20 weeks and experienced sustained improvement of symptoms as described above.

Meigs' syndrome is characterized by spontaneous blepharospasm and dystonic movements of the facial muscles, especially perioral and mandibular muscles. Levetiracetam has shown its beneficial effects in a patient with Meigs' syndrome ( Table 2 ).[62,63] Yardimci et al.[62] reported a case of a 64-year-old woman with Meigs' syndrome whose symptoms improved with levetiracetam therapy. She had been suffering from blepharospasm and oromandibular dystonia for the last 15 years. Levetiracetam was started at 250 mg daily. After 1 week, the dosage was increased to 250 mg daily, then to 500 mg daily after 2 weeks, and to 1000 mg twice daily after 3 weeks. The increase in the levetiracetam dosage was associated with relief in dystonic symptoms. This patient developed somnolence, and the dosage was later reduced to 500 mg twice daily. Her somnolence improved on reducing the dosage, but her moderate dystonic symptoms recurred. Zesiewicz et al.[63] reported a case of a 56-year-old woman with long-standing (10 years) Meigs' syndrome resistant to multiple medications, including gabapentin, clozepate, and botulism toxin, but which responded to levetiracetam. The authors used levetiracetam 500 mg daily for 5 days and titrated the medication to 500 mg three times daily within the next 10 days. The patient showed some improvement over the next 19 weeks. The improvement was confirmed, quantified, and validated by blinded (video) evaluation on and off levetiracetam by the BFMDRS. After treatment, the patient was able to read, watch television, chew, and eat more comfortably because of improvement in blepharospasm and oromandibular dystonia. The available data are based on patient case reports, and it is difficult to infer any conclusion about the efficacy of levetiracetam in other patients with Meigs' syndrome.

Tremors and Spasticity in Multiple Sclerosis

Multiple sclerosis (MS) patients often have disabling tremors that are very difficult to treat. The mechanism by which levetiracetam improves cerebellar tremors is not clear. It has been suggested that hyperactivity in thalamic ventralis intermedius nucleus, cortico-cerebello-thalamo-cortical, and cortico-ponto-cerebellar pathways and the high- frequency repetitive firing of neuronal cells may play an important role in the pathogenesis of cerebellar temors in MS patients. Levetiracetam affects these mechanisms because of its inhibitory action on hypersynchronization in neuronal tissues.[44,64,65,66,67,68] In their open-label trial, Striano et al.[67] showed that levetiracetam could be useful for the treatment of cerebellar tremors in these patients and levetiracetam's good tolerability makes it easy to use. Fourteen MS patients, ages 27-57 years, were enrolled in this study. Tremor duration ranged from 3 to 14 years. The tremor clinical rating scale, the spiral drawing scale, and the ataxia clinical scale were used to assess the severity of tremors. Data about the tremor-induced disability were obtained by using the specific Activities of Daily Living Questionnaire. Levetiracetam was orally used at a starting dosage of 500 mg twice daily for one week followed by increments of 500 mg twice daily each week up to the target dosage of 50 mg/kg/day. The study patients were evaluated at baseline and again two weeks after the end of the titration phase. Levetiracetam administration was associated with subjective and objective improvement of the tremors and significant lowering of all tremor measurements' sums of scores between baseline and follow-up evaluation. In particular, the mean ± S.D. tremor index score changed from 16.4 ± 2.34 to 10.4 ± 1.63 (p < 0.05), the spiral drawings mean ± S.D. score from 6.09 ± 1.14 to 3.18 ± 0.6 (p < 0.05), and the ataxia clinical scale mean ± S.D. score from 4.18 ± 1.33 to 2.43 ± 1.79 (p < 0.05), reflecting the patients' subjective benefit. Levetiracetam was well tolerated by the study patients, and only 1 patient reported transitory mild somnolence that did not require drug discontinuation.[67]

Spasticity is another common and debilitating symptom of MS. The mechanism of action of levetiracetam in relieving spasticity is not clear, but it most likely involves modulation of GABA A, glycine, and voltage-activated calcium channels.[50,69] Hawker et al.[70] evaluated effects of levetiracetam in MS-related spasticity. The researchers used variable dosages (250-3000 mg daily) in divided doses in 12 MS patients with spasticity. The main outcome measure was a change in the Peen spasm score (PSS) or modified Ashworth score (MAS)—both measured on a scale of 0-4. There was some improvement in phasic spasticity scores without any meaningful improvement in tonic spasticity. The PSS (a measure of phasic spasticity) was decreased for all patients following treatment with levetiracetam. There was no difference in the MAS (a measure of tonic spasticity). The improvement in phasic spasticity was also not statistically significant. Five patients reported adverse effects, including drowsiness, nausea, constipation, and edema. The edema resolved with the discontinuation of the drug. The levetiracetam therapy was not discontinued, except in 1 patient with edema, as the rest of the adverse effects were mild. Three of these patients incidentally reported improvement in neuropathic pain.[70]

Levetiracetam can be useful for the management of cerebellar tremors and spasticity in patients with MS. There is a need for further prospective placebo-controlled studies to assess levetiracetam's long-term efficacy in these patients.

Headache Syndromes

Headache is a common neurologic problem in pediatric and adult populations. Levetiracetam's exact mechanism of action in patients with headaches is not clear, but it has been proposed that levetiracetam might act on the SV2A brain-binding site.[71]

The role of levetiracetam for prophylaxis of refractory migraines and other headache syndromes was first described by Krusz.[72] Thirty patients who had been treated with different neuron-stabilizing agents (anticonvulsants) were enrolled in an open-label study for prophylaxis therapy with levetiracetam. Each patient in this study tried up to two different agents, and 18 patients tried up to four different agents. Levetiracetam was started at 250 mg in the evening with weekly increases. Further dosage adjustments were made during active therapy, in some cases to 4500 mg daily in two or three doses. The patients kept headache diaries and rated the severity of a headache on a 0-10 numeric rating scale. Fourteen patients reported more than a 50% reduction in their migraine frequency and severity within three months of active therapy. Eight patients had no response or they discontinued levetiracetam treatment because of adverse effects.

In their study, Drake et al.[73] showed levetiracetam as a promising agent in headache prophylaxis. They gave 62 patients levetiracetam, beginning at 500 mg twice daily and increasing as needed to 1500 mg twice daily. Headache frequency and severity of refractory migraines reduced with levetiracetam therapy but not during the first month of initiation of the treatment and not on levetiracetam less than 1500 mg/day. Ten patients discontinued levetiracetam because of adverse effects, including drowsiness, vomiting, headache, and tics.[73]

One retrospective study of 19 pediatric patients (9 girls and 10 boys, mean age = 11.9 years) showed the efficacy and safety of oral levetiracetam in the treatment of migraine.[74] The dosage of levetiracetam used was 125-250 mg twice daily. The frequency of headache attacks before treatment was 6.3 per month and fell to 1.7 per month after treatment in this study (p < 0.0001). In 10 patients (52.6%), use of levetiracetam resulted in elimination of migraine. Seven patients (36.8%) had less severe and less frequent headaches, and 2 patients (10.5%) did not appear to have any benefit from levetiracetam. No adverse effects were reported in 82.4% of patients. However, 10.5% of patients discontinued treatment because of adverse effects, including somnolence, dizziness, and irritability ( Table 3 ).

Pakalnis et al.[71] prospectively evaluated the tolerability and efficacy of levetiracetam in an open-label study in 20 pediatric patients, 6-17 years old, with migraine. Levetiracetam was started at 20 mg/kg/day, and later the dosage of levetiracetam was increased to 40 mg/kg/day if migraine frequency had not changed by at least 50% at the time of the second follow-up visit after two months. Eighteen out of 20 patients had a significant reduction in headache frequency (≥ 50% reduction in monthly headache frequency). The mean ± S.D. monthly headache frequency after levetiracetam treatment was 2.0 ± 1.9, which was significantly decreased from pretreatment (p < 0.001). Four of the treated patients were migraine free. Levetiracetam was well tolerated by most of the patients, and none of the patients discontinued the drug because of its adverse effects. The adverse effects included behavioral changes, irritability, aggressiveness, and mild memory problems. These limited data are insufficient to make a convincing case for the routine use of levetiracetam in adult and pediatric patients with headache ( Table 3 ).

Recent preliminary work has also shown the efficacy of i.v. levetiracetam in treating refractory headaches.[77] Levetiracetam is a potential candidate to treat status migrainosus, cluster, and other refractory headaches in the acute setting. Farooq et al.[78] described a patient with status migrainosus who responded well to the i.v. levetiracetam. However, there are very limited data about the use of levetiracetam in acute headache patients, and it is not FDA approved for the treatment of status migrainosus.

Neuropathic Pain

Neuropathic pain (NP) results from injury to or disease of the peripheral or central nervous system. AEDs might be used in the treatment of NP because of the similarities between the pathophysiologic phenomena observed in epilepsy and in NP. AEDs, including gapapentin, pregabalin, oxcarbazepine, topiramate, zonisamide, and levetiracetam, are being assessed for their roles in the treatment of NP.[79,80] Although gapapentin and pregabalin are the first-line AEDs being used for NP currently, levetiracetam has shown promising results in the treatment of NP in some recent series. The exact mechanism by which levetiracetam helps to relieve NP is not clear. One of the mechanisms by which NP occurs is related to an increased excitability of central neurons. Although its precise mechanism of action in NP remains unknown, levetiracetam is believed to exert antineuralgic activity by suppressing the neuronal hyperexcitability state that characterizes NP.

Price[81] reported three cases of mild-to-severe sensorimotor axonal and demyelinating polyneuropathy that resulted in 60% resolution of symptoms in one patient and 100% resolution in two patients within a few weeks. The daily doses used were 3000, 500, and 2000 mg, respectively. Levetiracetam should not be used as an initial treatment for NP because of the limited data supporting this indication at this point.

Cerebrovascular Disorders

Levetiracetam has a potential neuro-protective role in cerebrovascular disorders, including ischemic strokes. Hanon and Klitgaard[82] described a rat model in which cerebral ischemia was induced by occlusion of the internal carotid artery. With levetiracetam pretreatment, a dose-dependent reduction in infarct size was observed. It has also been proposed that levetiracetam has potential use in stroke and other disorders because of its neuroprotective effects.[83,84,85] However, an in vitro study failed to show a neuroprotective effect of levetiracetam.[86] Further, there are no clinical trials evaluating levetiracetam for ischemic stroke. Piracetam, a close analogue of levetiracetam, was evaluated by a pilot study in 1997.[87] It was a placebo-controlled, multicenter, randomized, double-blind trial (n = 927). Patients received either placebo or piracetam 12 g as an initial intravenous bolus, 12 g daily for 4 weeks, and 4.8 g daily for 8 weeks. The primary endpoint was neurologic outcome after 4 weeks as assessed by the Orgogozo scale. Functional status at 12 weeks as measured by the Barthel index was the major secondary outcome. Piracetam did not influence 4-week neurologic outcomes if given within 12 hours of symptom onset. But subgroup analysis (moderate-to-severe strokes) showed improvement in Barthel index scores at 12 weeks, which was statistically significant.[87] Post hoc analysis in the early treatment subgroup showed a trend toward improvement. An additional analysis of patients with strokes of moderate and severe degrees showed significant differences in favor of piracetam.[87] Further studies are warranted to examine the role of levetiracetam in ischemic stroke.

Psychiatric Disorders

Anxiety, Panic, and Stress Disorders. Levetiracetam indirectly facilitates GABAergic function, and there is strong evidence that GABA plays a key role in the pathophysiology of mood, anxiety, and stress disorders.[88] Social anxiety disorder is a disabling condition, and patients often have excessive fear and avoid social and performance situations. Many patients with this disorder do not fully respond to or have adverse effects from the available medications.

Simon et al.[89] demonstrated the safety and potential efficacy of levetiracetam for the treatment of social anxiety disorder. Twenty patients who met the Diagnostic and Statistical Manual (DSM)-IV criteria for social anxiety disorder were enrolled in this eight-week open-label study. Levetiracetam was initiated at 250 mg daily for the first week and titrated up to a maximum of 3000 mg daily in divided doses. The primary outcome measure was change in the Liebowitz Social Anxiety Scale (LSAS) score at endpoint. There was a clinically significant 20.5-point decrease in the LSAS (p < 0.01). Thirteen patients completed the trial for eight weeks. Three patients dropped out because of adverse effects, including drowsiness and nervousness. One of the patients discontinued use because of the lack of efficacy. Three patients were lost to follow-up. In the patients who completed the study, a significant improvement on the LSAS was evident by week 2, and this improvement persisted through the end of the trial.

Papp[90] conducted an open-label trial that showed promising results in the treatment of panic disorders with levetiracetam. Eighteen patients with panic disorder, with and without agoraphobia, were treated with levetiracetam 250 mg twice daily for 12 weeks. Outcome was assessed with the CGI—Severity of Illness scale, the CGI—Improvement (CGI-I) scale, and the 14-Item Hamilton Rating Scale for Anxiety as well as by the number of panic attacks during the previous week. Thirteen patients completed the study. Eleven of these patients were rated either very much or much improved on the CGI-I scale. Panic attack frequency, anxiety, and global severity ratings also demonstrated significant improvements (p < 0.00). For most of the patients, clinical benefits were apparent after only 1-2 weeks of treatment. Levetiracetam was well tolerated with minimal adverse effects. The most common adverse effects in the study patients were sedation, headache, and irritability. One patient complained of slightly diminished libido and delayed orgasm. These adverse effects resulted in the study termination only 2 patients, one because of sedation and the other because of irritability. Four patients with insomnia also reported significant improvement without any daytime sedation.

Levetiracetam may be an effective drug in combination with antidepressants for treatment of patients with posttraumatic stress disorders (PTSDs) who remain symptomatic after initial treatment. Kinrys et al.[91] conducted a retrospective analysis of 23 patients with the diagnosis of PTSD who received levetiracetam therapy because of no significant response to antidepressants. The primary outcome measure was the PTSD Checklist—Civilian Version. Levetiracetam at a mean ± S.D. dosage of 1976 ±650 mg/day for mean ± S.D. duration of 9.7 ± 3.7 weeks was well tolerated. Nineteen patients were taking this with some concomitant medication. Patients improved significantly on all outcome measures (p < 0.001). Thirteen patients met respondent criteria at the endpoint, and 6 patients met remission criteria. Adverse effects were mild, and no patient discontinued levetiracetam therapy because of adverse effects ( Table 4 ).

The available data on the role of levetiracetam in anxiety, panic, and stress disorders are very limited, and controlled trials with appropriate sample sizes are warranted. Levetiracetam should be used with caution in these patients because of its potential behavioral adverse effects as explained later in this article.

Mood and Bipolar Disorders. Levetiracetam affects different parts of the brain, including the hippocampus and the amygdala, which are involved in mood disorders.[9,10,94,95,96] Studies have shown that increased levels of hippocampal Y-1- and Y-5-like receptors might be responsible for mood-stabilizing properties of levetiracetam.[10] Levetiracetam, both as add-on and as monotherapy, has shown its efficacy in a broad spectrum of bipolar disorders.

Bersani[97] investigated the potential efficacy of levetiracetam in outpatients affected by bipolar spectrum disorders as an add-on therapy to previous pharmacologic treatments. Twenty patients, 13 men and 7 women, were enrolled in this pilot study. These patients received oral levetiracetam 500 mg twice daily for 60 days. Fifteen patients completed the study, and for all of these patients the BPRS and the Bech-Raphaelsen scale of mania scores showed a rapid decrease following levetiracetam add-on therapy; this effect was significant at day 60. The tolerability of levtiracetam was assessed by the dosage record and treatment-emergent symptom scale. Five patients dropped out during the study, one because his symptoms worsened and the others for reasons independent of treatment response. The rest of the patients tolerated levetiracetam therapy without significant adverse effects. This study was the first to show the positive effect of levetiracetam in manic syndrome, including mood and behavioral symptoms.[97]

In an open-label trial, 34 patients with treatment-refractory bipolar I disorder (13 depressed, 7 manic, and 14 cycling) were enrolled.[92] These patients received 500-1000 mg of levetiracetam titrated to a target dosage of 2000 mg/day. The dosage was increased to 3000 mg/day as needed. Levetiracetam was an add-on therapy for eight weeks. The patients were rated weekly or once every other week with the Young Mania Rating Scale (YMRS), the Inventory for Depressive Symptomatology—Clinical version, and the Clinical Global Impressions scale for use in bipolar illness for severity of mania, depression, and overall illness. A 31% remission rate was reported in patients who were depressed at baseline and who received levetiracetam as an add-on therapy. A 44% remission rate was noted in patients with mania at baseline. Four patients dropped out within the first week of treatment for administrative reasons, drug intolerance, or mood worsening. Another eight patients dropped out before week 3 because of lack of efficacy. Only 1 patient experienced psychosis. This was a high early-withdrawal rate for this open-label study. Moreover, severely depressed patients did not show any good response ( Table 4 ).

Grunze et al.[93] conducted an open-label study in 10 patients with a history of bipolar I disorder who were in an acute manic state. Levetiracetam was used as an add-on therapy with off-and-on design. All patients were treated with haloperidol 5-10 mg/ day. Levetiracetam was added until day 14, then discontinued, and reintroduced at day 21. The maximum dosage of levetiracetam used was 4000 mg/day. The mean dosage of levetiracetam was 3125 mg/day. The YMRS was used to assess the psychopathologic changes. After a mean decrease of the YMRS scores from 29.6 to 17.2 during the first on phase, manic symptoms worsened during the off period and ameliorated again during the second on phase, with a decrease of the mean YMRS score to 14.7 at the end of the study. At day 14, only 2 patients responded compared with 7 at the end of the study at day 28. Levetiracetam showed some additional antimanic effects in this study. The important adverse effects noted in this study were sedation (3 patients), dizziness (1 patient), and asthenia (1 patient). The abrupt discontinuation of drug caused no withdrawal effects except worsening of manic symptoms ( Table 4 ).[93]

Levetiracetam has a potential role in treating refractory bipolar patients with different comorbidities that are difficult to manage even with multiple medications. Kaufman[98] described a 21-year-old white woman with treatment-resistant, rapid-cycling, bipolar disorder who did not respond to 15 different psychotropics. She responded well to levetiracetam monotherapy, which was started at 1000 mg at bedtime and then increased to 2500 mg at bedtime. She remained without bipolar features during 1 year of maintenance treatment, except for one week during which she was noncompliant.[98]

The results of these studies suggest the need for further controlled trials to see the efficacy and tolerability of levetiracetam in patients with different mood and bipolar disorders. It is premature to recommend the use of levetiracetam in patients with these mood disorders in routine clinical practice.

Autism and TS. The safety and efficacy of levetiracetam in the treatment of children with autism have been studied ( Table 3 ).[75,76] In their open-label prospective study, Rugino and Samsock[76] showed that levetiracetam may reduce hyperactivity, impulsivity, mood instability, and aggression in autistic children. Twelve autistic boys (4-10 years old) were recruited; 10 out these 12 boys completed the study. The boys were compared pretreatment and while on levetiracetam therapy for an average of 4.1 weeks. The therapy was started with 13 mg/kg, rounding down to the nearest 125-mg increment, divided into twice-daily dosing. The maximum dosage was 54 mg/kg/ day, not to exceed 3000 mg daily. The Achenbach Attention Problems Scale, the Conners DSM-IV total scale, and the Conners Attention Deficit- Hyperactivity Disorder Index Scale were used to evaluate inattention, hyperkinesis, and impulsivity. The evaluations were repeated no less frequently than every 14 days. The results from this study were statistically significant (inattention, hyperkinesis, and impulsivity [p ≤ 0.05]; mood stability [p < 0.01]). Adverse effects were mild to moderate with only 1 patient withdrawing from the study ( Table 3 ).

Wasserman et al.[97] conducted an open-label, placebo-controlled, double-blind study to determine the safety and efficacy of levetiracetam; this study did not show any improvement in the behavioral disturbances in patients with autism. Twenty patients with autism ranging from 5-17 years of age were enrolled. The mean ± S.D. maximum dosage used was 862.50 ± 27.19 mg/day. The global improvement was assessed by the CGI-I scale, and aggression and effective instability were assessed with the Aberrant Behavior Checklist parent and teaching ratings. This study did not show any significant difference between levetiracetam and placebo groups comparing the change in the CGI-I scale. The adverse effects reported with levetiracetam in this study included aggression (20%), agitation (10%), hyperactivity (10%), impulsivity (10%), loss of appetite (10%), self-injurious behavior (10%), weight gain (10%), and weight loss (10%). This study was limited by the small sample size and lack of stratification of the autistic sample at baseline.

A recent study was conducted to investigate the effectiveness of levetiracetam for the treatment of tics in children with TS.[99] This double-blind, randomized, placebo-controlled, crossover trial was performed in children with moderate-to-moderately severe tics. Twenty-two children (21 boys and 1 girl) with TS were enrolled in this study. In a randomized sequence, these children received four weeks of levetiracetam with a maximum dosage of 30 mg/kg/day or placebo with a two-week intervening washout period between cycles. The primary outcome measures included two separate scales from the Yale Global Tic Severity Scale: the total tic score and the total overall score. Measurements were done at the baseline, before randomization, on day 28 at the end of Phase I, on day 42 (the baseline for Phase II), and on day 70 (the end of Phase II). This study did not show any significant differences between treatment and placebo groups. Therefore, levetiracetam therapy is not beneficial in autistic children based on the results of this study. There are no large-scale, double-blind studies available on the use of levetiracetam in mood disorders so far.

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