levetiracetam and Mood-Disorders

Levetiracetam is a newer antiepileptic agent that was first approved by the US FDA in 1999 as an adjunctive therapy for the treatment of refractory partial epilepsy in adults. Since then, it has been approved for a wider patient population, i.e. as adjunctive therapy for partial seizures in patients >4 years of age (worldwide) and as first-line monotherapy for partial seizures in patients >16 years of age (in Europe); and as adjunctive therapy for juvenile myoclonic seizures (in Europe and the US). It has a favourable pharmacokinetic profile and appears to act at a specific site in the CNS. Pharmacodynamic evidence indicates that levetiracetam indirectly facilitates GABAergic function, and an increasing body of evidence suggests an important role for GABA in the pathophysiology of mood disorders. Preclinical studies using animal models of depression, anxiety and mania provide evidence for levetiracetam as a mood stabiliser. Preliminary clinical evidence from case reports and open-label pilot studies indicates that the drug, both as add-on therapy and as monotherapy, has efficacy in a wide range of bipolar spectrum disorders. Most recently, a 31% remission rate was reported in patients with bipolar disorder who were in the depressed phase at baseline and who received levetiracetam as add-on therapy for 8 weeks in an open-label trial. While these results are encouraging, placebo-controlled data are needed to further clarify the role of levetiracetam in the treatment of mood disorders.

Topics: Animals; Anticonvulsants; Clinical Trials as Topic; Humans; Levetiracetam; Mood Disorders; Piracetam; Treatment Outcome

This report reviews behavioral adverse events occurring among adults receiving levetiracetam (LEV) or placebo who participated in short-term, placebo-controlled studies in epilepsy (1023), cognitive disorders (719), or anxiety disorders (1510) and epilepsy patients (1393) observed in long-term trials. Behavioral events (affective, psychotic, and suicidal symptoms) were significantly more common among epilepsy patients than cognition or anxiety patients treated with LEV for similar durations (P=0.022). Affective symptoms occurring at 1% or more often in epilepsy placebo-controlled trials included depression (3.8% LEV-2.1% placebo), nervousness (3.8%-1.8%), hostility (2.3%-0.9%), anxiety (1.8%-1.1%), and emotional lability (1.7%-0.2%). Patients with cognitive and anxiety disorders had lower incidences of these symptoms. The incidence of behavioral events in LEV-treated epilepsy patients was lower than rates reported for some other antiepileptic drugs. These data support the hypothesis that some feature related to epilepsy is the cause of many behavioral events rather than the addition of a specific antiepileptic drug.

Topics: Anticonvulsants; Anxiety Disorders; Cognition Disorders; Cross-Over Studies; Double-Blind Method; Drug Administration Schedule; Epilepsy; Follow-Up Studies; Humans; Levetiracetam; Mood Disorders; Outcome Assessment, Health Care; Periodicity; Piracetam; Psychotic Disorders; Randomized Controlled Trials as Topic; Suicide, Attempted

A randomized, double-blind, placebo-controlled study (N01103, NCT00105040) evaluated behavioral and emotional effects of adjunctive levetiracetam (LEV) treatment in children and adolescents (4-16years old) with uncontrolled partial-onset seizures. Patients received adjunctive LEV 20-60mg/kg/day (n=64) or placebo (n=34) for 12weeks. The Achenbach Child Behavior Checklist (CBCL) and portions of the Child Health Questionnaire-Parent Form 50 (CHQ-PF50) were used to assess behavioral and emotional functioning at baseline and end of the treatment period. Worsening of the mean CBCL Aggressive Behavior score occurred for LEV but not placebo, leading to similar results for Externalizing Syndromes and Total Problems (all P<0.05 vs placebo). The change in the CBCL Activities Competence score favored LEV (P<0.05). These results are in line with the known safety profile of LEV.

Topics: Adolescent; Anticonvulsants; Behavioral Symptoms; Checklist; Child; Child, Preschool; Double-Blind Method; Epilepsies, Partial; Female; Humans; Levetiracetam; Male; Mood Disorders; Piracetam; Psychiatric Status Rating Scales; Surveys and Questionnaires

Mood-modulating profiles of antiepileptic drugs (AEDs) have been classified by Ketter, Post, and Theodore [Neurology 1999; 53 (5, Suppl. 2) S53-76] into two classes: the first class is assumed to have deactivating effects related to GABA potentiation, and the second class is assumed to have activating effects that are associated with glutamate attenuation. We tested this hypothesis by reviewing the multiple mechanisms of action of topiramate (TPM) and levetiracetam (LEV) together with clinical behavioral side effects of patients who had been treated with TPM and LEV in a tertiary referral center for epilepsy. We found LEV to manifest activating and deactivating side effects equally and TPM to act as a deactivating AED, with tiredness/sleepiness side effects being predominant. TPM, in comparison to LEV, was found to be associated with a high incidence of side effects. Testing the hypothesis of Ketter et al. (1999) the deactivating effects of TPM may be coupled to a predominance of potentiation of GABA, but the oversimplified basis of the model needs to be acknowledged.

Topics: Adult; Anticonvulsants; Chi-Square Distribution; Demography; Drug Therapy, Combination; Epilepsy; Female; Follow-Up Studies; Fructose; gamma-Aminobutyric Acid; Glutamic Acid; Humans; Levetiracetam; Male; Middle Aged; Models, Biological; Mood Disorders; Odds Ratio; Piracetam; Time Factors; Topiramate

In this postlicensing surveillance study in a large unselected population, data were collected prospectively on all patients prescribed levetiracetam (LEV) at a regional epilepsy clinic over a 2-year period. Two hundred forty-five (69.2%) patients remained on LEV, with 8.8% achieving remission and some improvement in seizure control in 49.3%. Sedation was the most common adverse effect (10.7%), but mood disturbance was more likely to lead to discontinuation (4.8%). Cumulative probability of remaining on LEV at 12 months was 0.74 (95% CI 0.69 to 0.79). Factors predictive of a poorer retention were a greater number of previous antiepileptic drugs and a faster initial titration regimen.

Topics: Anticonvulsants; Consciousness Disorders; Drug Administration Schedule; Drug Resistance; Drug Therapy, Combination; Epilepsy; Female; Follow-Up Studies; Humans; Levetiracetam; Life Tables; Male; Mood Disorders; Patient Dropouts; Piracetam; Product Surveillance, Postmarketing; Prospective Studies; Remission Induction; Treatment Outcome

Limited population-based data are available on antiepileptic drug (AED) treatment patterns in women of childbearing age with epilepsy; the current population risk is not clear.. To examine the AED treatment patterns and identify differences in use of valproate sodium and topiramate by comorbidities among women of childbearing age with epilepsy.. A retrospective cohort study used a nationwide commercial database and supplemental Medicare as well as Medicaid insurance claims data to identify 46 767 women with epilepsy aged 15 to 44 years. The eligible study cohort was enrolled between January 1, 2009, and December 31, 2013. Data analysis was conducted from January 1, 2017, to February 22, 2018.. Cases required an International Classification of Diseases, Ninth Revision, Clinical Modification-coded epilepsy diagnosis with continuous medical and pharmacy enrollment. Incident cases required a baseline of 2 or more years without an epilepsy diagnosis or AED prescription before the index date. For both incident and prevalent cases, focal and generalized epilepsy cohorts were matched by age, payer type, and enrollment period and then compared.. Antiepileptic drug treatment pattern according to seizure type and comorbidities.. Of the 46 767 patients identified, there were 8003 incident cases (mean [SD] age, 27.3 [9.4] years) and 38 764 prevalent cases (mean [SD] age, 29.7 [9.0] years). Among 3219 women in the incident epilepsy group who received AEDs for 90 days or more, 3173 (98.6%) received monotherapy as first-line treatment; among 28 239 treated prevalent cases, 18 987 (67.2%) received monotherapy. In 3544 (44.3%) incident cases and 9480 (24.5%) prevalent cases, AED treatment was not documented during 180 days or more of follow-up after diagnosis. Valproate (incident: 35 [5.81%]; prevalent: 514 [13.1%]) and phenytoin (incident: 33 [5.48%]; prevalent: 178 [4.53%]) were more commonly used for generalized epilepsy and oxcarbazepine (incident: 53 [8.03%]; prevalent: 386 [9.89%]) was more often used for focal epilepsy. Levetiracetam (incident: focal, 267 [40.5%]; generalized, 271 [45.0%]; prevalent: focal, 794 [20.3%]; generalized, 871 [22.2%]), lamotrigine (incident: focal, 123 [18.6%]; generalized, 106 [17.6%]; prevalent: focal, 968 [24.8%]; generalized, 871 [22.2%]), and topiramate (incident: focal, 102 [15.5%]; generalized, 64 [10.6%]; prevalent: focal, 499 [12.8%]; generalized, 470 [12.0%]) were leading AEDs prescribed for both focal and generalized epilepsy. Valproate was more commonly prescribed for women with comorbid headache or migraine (incident: 53 of 1251 [4.2%]; prevalent: 839 of 8046 [10.4%]), mood disorder (incident: 63 of 860 [7.3%]; prevalent: 1110 of 6995 [15.9%]), and anxiety and dissociative disorders (incident: 57 of 881 [6.5%]; prevalent: 798 of 5912 [13.5%]). Topiramate was more likely prescribed for those with comorbid headache or migraine (incident: 335 of 1251 [26.8%]; prevalent: 2322 of 8046 [28.9%]).. Many women appear to be treated with valproate and topiramate despite known teratogenicity risks. Comorbidities may affect selecting certain AEDs despite their teratogenicity risks.

Topics: Adolescent; Adult; Anticonvulsants; Anxiety Disorders; Comorbidity; Dissociative Disorders; Epilepsies, Partial; Epilepsy, Generalized; Female; Headache Disorders; Humans; Lamotrigine; Levetiracetam; Mental Disorders; Migraine Disorders; Mood Disorders; Oxcarbazepine; Phenytoin; Retrospective Studies; Risk; Teratogens; Topiramate; Valproic Acid; Young Adult

A common side effect of levetiracetam is the onset of neuropsychiatric symptoms such as mood changes including depression, anxiety, agitation, and sometimes psychosis. We performed a retrospective analysis to examine the effect of sleep pattern and chronotype on individual susceptibility to levetiracetam-induced mood changes. We reviewed records of 110 adults with epilepsy presenting to our clinic during a 3-month period, and categorized them into those currently on levetiracetam, and those no longer taking it because of mood-related adverse effects. Patients were administered Morningness-Eveningness Questionnaire (MEQ), Beck's Depression Inventory-II, and Neurological Disorders Depression Inventory in Epilepsy. Using various statistical methods, we analyzed the comparison of these 3 different scales amongst one another and between those subjects who tolerated levetiracetam and those who did not. Of 110 patients, 74 (67%) tolerated levetiracetam and 36 (33%) did not tolerate it because of mood changes with chronotype being a significant determining factor. Of those who tolerated the drug, 62% were intermediate chronotypes and 20.3% and 17.6% were morning and evening chronotypes, respectively. For those intolerant, 86.1% were morning chronotypes, 13.9% were intermediate chronotypes, and none were evening chronotypes (p<0.001). Thirty-two percent of morning chronotypes, 100% of evening chronotypes, and 90.2% of intermediate chronotypes were tolerant of levetiracetam (p<0.001). Chronotype significantly affected toleration of levetiracetam. Chronotype, but not depression, was a significant factor in determining tolerability of mood-altering side effects of levetiracetam, via statistically significant trend for an increasing ability to tolerate levetiracetam as chronotype would shift from morning to intermediate to evening. Additional research may help establish if this is related to possible underreporting of poor mood with evening chronotypes, and morning chronotypes having more stringent sleep schedules, genetic factors, or other reasons.

Topics: Adult; Analysis of Variance; Anticonvulsants; Anxiety Disorders; Circadian Rhythm; Depressive Disorder; Epilepsy; Female; Humans; Incidence; Levetiracetam; Male; Middle Aged; Mood Disorders; Piracetam; Retrospective Studies; Sleep; Surveys and Questionnaires; Young Adult

There is little literature on a possible link between the use of antiepileptic drugs (AEDs) and the occurrence of suicidal ideation. Nevertheless, its occurrence needs to be promptly recognized because it may trigger suicidal attempts. We retrospectively evaluated a case registry of 517 patients taking levetiracetam (LEV) for suicidal ideation, looking at possible clinical variables involved. Suicidal ideation was reported by four patients (0.7%). All cases occurred in the context of a mood disorder presenting early during LEV therapy. Psychopathological characteristics of suicidal ideation were consistent in all subjects and similar to some features that are described as typical of the so-called interictal dysphoric disorder of epilepsy.

Topics: Adult; Affective Symptoms; Anticonvulsants; Epilepsy; Female; Humans; Levetiracetam; Male; Mood Disorders; Piracetam; Retrospective Studies; Self-Injurious Behavior; Suicide, Attempted

To report the case of a patient who experienced adverse events in succession to antiepileptic medications being used for both antiepileptic and mood-stabilization benefit.. A 46-year-old white woman developed hyponatremia with carbamazepine, hyperammonemia with divalproex, cognitive impairment with topiramate, and hyponatremia with oxcarbazepine. The patient was stabilized physically and psychiatrically on levetiracetam without any noted adverse events.. The adverse events in this report have been associated with the medications in question. The patient's presentation is unique, as she developed adverse events in succession to antiepileptic drugs being used to treat both a seizure disorder and symptoms of mood instability. The Naranjo rankings for the reported adverse events indicated the associations were probable (carbamazepine, divalproex, oxcarbazepine) and possible (topiramate). After repeated incidences of intolerability to these drugs, levetiracetam was initiated and provided both seizure control and mood-stabilizing benefits, which eventually led to hospital discharge.. Levetiracetam may provide mood-stabilizing qualities through a mechanism that is unique from that of other antiepileptic agents used for their mood-stabilizing properties. There are potential advantages with levetiracetam, as no specific therapeutic drug monitoring parameters need to be followed after its introduction. Additionally, this case emphasizes the importance of therapeutic drug monitoring and frequent assessments to prevent physical and psychiatric adverse reactions.

Topics: Anticonvulsants; Carbamazepine; Drug Therapy, Combination; Female; Fructose; Humans; Levetiracetam; Middle Aged; Mood Disorders; Oxcarbazepine; Piracetam; Seizures; Topiramate; Treatment Outcome; Valproic Acid