Lamotrigine In Patients Research Articles

Improved mood states with lamotrigine in patients with epilepsy

Lamotrigine (LTG) was added to other antiepileptic drugs (AEDs) in a study of adjunctive therapy. In addition to seizure control and adverse effects, patients were evaluated for changes in mood states and quality of life. The Profile of Mood States (POMS) and 31-item Quality of Life in Epilepsy (QOLIE-31) instruments were administered at baseline ( N = 196), after addition of LTG as adjunctive treatment ( N = 155), and after withdrawal of other drugs to LTG monotherapy ( N = 51). POMS scores correlated highly with the QOLIE-31 Emotional Well-Being subscale, a known measure of mood. All POMS subscales were significantly improved (all P < 0.0001) at the end of the adjunctive therapy phase. POMS scores remained significantly better than baseline among patients completing the conversion to monotherapy (all P < 0.003). Minimal clinically important changes were determined for POMS scores. These data indicate that LTG improves mood states to a clinically important degree, even in the presence of other AEDs. The improvement likely was not a synergy but attributable only to LTG because it remained stable after withdrawal of the other AEDs.

Lamotrigine for patients with juvenile myoclonic epilepsy following prior treatment with valproate: results of an open-label study

This open-label study was designed to evaluate lamotrigine monotherapy as a possible alternative in patients with juvenile myoclonic epilepsy who previously failed treatment with valproate. Patients ( n=63) were transitioned from valproate to lamotrigine during an 8-week escalation phase followed by 24 weeks of lamotrigine monotherapy. On Week 24 of the treatment phase, investigators judged that 50 and 67% of patients completing the study had shown mild, moderate, or marked improvement in adverse events and global clinical status, respectively, and 76% of patients rated lamotrigine as somewhat better (13%) or much better (63%) than valproate. The majority of patients completing the study experienced no deterioration of seizure control when switching from valproate to lamotrigine. These results support additional research on lamotrigine in juvenile myoclonic epilepsy.

Drug dreams in outpatients with bipolar disorder and cocaine dependence.

Patients with substance abuse or dependence often have dreams about alcohol or drugs during early recovery. However, the literature on drug dreams in rehabilitating patients with drug-related disorders remains limited. No data are available on drug dreams in people with substance-related disorders and other major mental illness. As part of a large study on the use of lamotrigine in patients with bipolar disorder and cocaine dependence, the frequency and nature of drug dreams, triggers for dreams, and response to the dreams during study participation were assessed in 37 outpatients for as long as 36 weeks. Altogether, 74% of participants experienced at least one drug dream during the study. Furthermore, drug dreams rapidly decreased during study participation. The presence of drug dreams at baseline did not predict mood, cocaine craving, or drug use at exit. No clear risk factors for drug dreams were identified. However, drug dreams were related to survival in the study by a negative U-shaped curve relationship in which those participants with the highest and lowest frequency of drug dreams discontinued from the study the earliest. Content of the dreams frequently included drug use or refusing to use the drug. Dreams of drug use tended to occur during the first few weeks of study participation. Most dreams were associated with triggers for drug use. The findings suggest that drug dreams are common in patients with bipolar disorder and cocaine dependence and are similar in nature to those previously reported in people with pure substance abuse.

Lamotrigine as adjunctive therapy in patients with refractory epilepsy and mental retardation

This study evaluated the effects of lamotrigine as adjunctive therapy for refractory epilepsy in patients with mental retardation. Patients with epilepsy and mental retardation having uncontrolled seizures despite treatment with other antiepileptic drugs were eligible ( n=67). The open-label study comprised a Baseline Phase, an Escalation Phase during which lamotrigine was titrated to a target dose, an 8-week Maintenance Phase during which doses of lamotrigine and concomitant antiepileptic drugs were maintained, and a 12-week Optimization Phase during which doses of lamotrigine and other antiepileptic drugs could be adjusted. Almost half (44%) of patients experienced a 50% reduction in seizure frequency during the Maintenance Phase after addition of lamotrigine; 15% of patients became seizure-free. A similar pattern of results was reported for the Optimization Phase. Investigator-rated clinical status was improved relative to baseline in 66 and 74% of patients at the end of the Maintenance and Optimization Phases, respectively. Most patients experienced improvements in seizure frequency, duration, and intensity during the Maintenance Phase (62 to 72%) and the Optimization Phase (65 to 74%). Many patients were rated as having improved social functioning during the Maintenance Phase (42%) and the Optimization Phase (46%). The Aberrant Behavior Checklist score for lethargy and the mean Habilitative Improvement Scale score were improved at the ends of the Maintenance and Optimization Phases relative to baseline ( P⩽0.04). One limitation of this study is its open-label design, which limits the ability definitively to attribute the clinical improvements to lamotrigine. Adjunctive lamotrigine in patients with refractory epilepsy and mental retardation appears to decrease seizure frequency and improve behavior while permitting a reduction in dose of concomitant antiepileptic drugs.

Lamotrigine in Patients With Bipolar Disorder and Cocaine Dependence

Bipolar disorder is associated with the highest substance abuse rates of any psychiatric illness. Therefore, treatments that stabilize mood and decrease drug use or cravings are of great interest. Open-label lamotrigine was examined in 30 outpatients with DSM-IV bipolar disorder and cocaine dependence. Lamotrigine was either added to existing medication regimens or used as monotherapy. Lamotrigine was started at a dose of 25 mg/day (12.5 mg/day in those taking valproic acid) and titrated to a maximum dose of 300 mg/day. Subjects received a baseline evaluation including a structured clinical interview and weekly assessments for 12 weeks with the Hamilton Rating Scale for Depression (HAM-D), Young Mania Rating Scale (YMRS), Brief Psychiatric Rating Scale (BPRS), and Cocaine Craving Questionnaire (CCQ). At each appointment, a urine sample was obtained, and participants reported drug use during the previous week. The subjects consisted of 13 men and 17 women with cocaine dependence and bipolar I disorder (N = 22), bipolar II disorder (N = 7), or bipolar disorder not otherwise specified (N = 1), with a mean +/- SD age of 35.4 +/- 7.2 years. Data were analyzed using the last observation carried forward on all subjects who completed the baseline evaluation and at least 1 postbaseline assessment. Significant improvement was observed in HAM-D, YMRS, and BPRS scores (p < or =.02). Cravings also significantly decreased as measured by the CCQ (p <.001). Dollar amount spent on drugs decreased nonsignificantly. Lamotrigine was well tolerated, with no subjects discontinuing due to side effects. Lamotrigine treatment was well tolerated in this sample and associated with statistically significant improvement in mood and drug cravings but not drug use. The findings suggest that larger controlled trials of lamotrigine are needed in this population.

Therapeutic Drug Monitoring of Lamotrigine in Patients Suffering from Resistant Partial Seizures

Sixty patients, all potential candidates for ongoing lamotrigine (LTG) treatment as add-on therapy for resistant partial seizures and receiving carbamazepine (CBZ) and/or valproate (VPA) treatment, were submitted to therapeutic drug monitoring (TDM). The aim was to evaluate the possible relation between serum levels and the clinical effect of LTG, to verify whether CNS toxicity has to be considered the result of a pharmacokinetic or a pharmacodynamic interaction with CBZ, and to investigate whether possible changes in the clinical response during long-term treatment are dependent on LTG serum level variations. Sixteen patients achieved complete control, 26 a ≧50% reduction in seizures, the remainder did not respond. Mean LTG serum concentrations were higher in responders than in nonresponders, the difference being statistically insignificant. The best results were observed in VPA-cotreated patients with the highest LTG blood levels. CNS toxicity occurred after giving LTG to subjects who subsequently developed the highest LTG concentrations, whereas CNS toxicity seemed unrelated to CBZ and CBZ-epoxide serum concentrations. No decrease in LTG, CBZ and VPA serum levels was observed even in patients showing a reduction in the response during long-term treatment.

Clinical pharmacology and therapeutic use of the new antiepileptic drugs Fundamental and Clinical Pharmacology (2001) 15 405–417

In Table V of the above article, the suggested titration rate for lamotrigine in patients receiving enzyme inducing comedication should read as follows: Enzyme inducing comedication: Start with 25 or 50 mg/day for 2 weeks, then increase to 50 or 100 mg/day for 2 weeks. Further increases by 50–100 mg/day every 2 weeks. We apologise for any inconvenience.

Population pharmacokinetics of lamotrigine.

The present study estimated the population pharmacokinetics of lamotrigine in patients receiving oral lamotrigine therapy with drug concentration monitoring, and determined intersubject and intrasubject variability. A total of 129 patients were analyzed from two clinical sites. Of these, 124 patients provided sparse data (198 concentration-time points); nine patients (four from a previous group plus five from the current group) provided rich data (431 points). The population analysis was conducted using P-PHARM (SIMED Scientific Software, Cedex, France), a nonlinear mixed-effect modeling program. A single exponential elimination model (first-order absorption) with heteroscedastic weighting was used. Apparent clearance (CL/F) and volume of distribution (V/F) were the pharmacokinetic parameters estimated. Covariate analysis was performed to determine which factors explained any of the variability associated with lamotrigine clearance. Population estimates of CL/F and V/F for lamotrigine generated in the final model were 2.14 +/- 0.81 L/h and 78.1 +/- 5.1 L/kg. Intersubject and intrasubject variability for clearance was 38% and 38%, respectively. The covariates of concomitant valproate and phenytoin therapy accounted for 42% of the intersubject variability of clearance. Age, gender, clinic site, and other concomitant antiepileptic drugs did not influence clearance. This study of the population pharmacokinetics of lamotrigine in patients using the drug clinically provides useful data and should lead to better dosage individualization for lamotrigine.

Assessment of Seizure Severity with Adjunctive Lamotrigine Therapy: Results from a U.S. Observational Study

The Adjunctive Lamictal™ (lamotrigine) in Epilepsy: Response to Treatment (ALERT) study was an observational study designed to assess the safety of lamotrigine in patients with refractory partial seizures when used in a general practice setting. We measured the impact of adjunctive lamotrigine therapy for 16 weeks on the severity of seizures using the Liverpool Seizure Severity Scale (LSSS). This questionnaire was scored using a revised scoring procedure that assesses the impact of treatment on the patients “most severe seizure.” Data from the LSSS were also compared with physician-rated changes of seizure severity. Patients who completed 16 weeks of lamotrigine treatment showed a significant reduction in LSSS scores when compared with patients who discontinued lamotrigine (change scores: patient's taking lamotrigine at Week 16, 9.2 ± 23.4; patients who discontinued lamotrigine by Week 16, 0.8 ± 23.4, P < 0.05). These findings were supported by significant reductions in physician ratings of seizure severity in patients who completed 16 weeks of lamotrigine therapy. Seizure severity is an important outcome in the study of antiepileptic medication. Data from this observational study suggest that lamotrigine is effective in reducing seizure severity when used as an adjunctive therapy in patients with refractory partial seizures.

The long-term use of vigabatrin and lamotrigine in patients with severe childhood onset epilepsy

Our purpose was to compare the initial efficacy and retention at 5 years of lamotrigine (LTG) and vigabatrin (VGB) in patients with severe childhood-onset epilepsies, especially with regard to loss of efficacy. Add-on therapy in 95 young patients with severe epilepsies in a neuropaediatric department was prospectively followed in open label studies for up to 5 years. VGB group: 56 patients (mean age: 11.1 years). LTG group: 39 patients (mean age: 13.6 years). Definition of initial responders: more than 50% reduction in seizure-frequency after 6 weeks of VGB treatment or after 4 months of LTG treatment. Definition of retention at 5 years: percentage of patients still taking LTG or VGB after 5 years. Definition of loss of efficacy: return to the baseline seizure frequency. The results were: VGB group: after 6 weeks 18 of 56 patients (32%) were initial responders. The retention at 5 years was five of 56 patients (8.9%). One patient (1.8%) was still seizure free. A loss of efficacy occurred in 10 of the 18 initial responders, usually within the first 9 months after the initial response. In the LTG group, after 4 months, 11 of 39 patients (28%) were initial responders. The retention at 5 years was 10 of 39 patients (25.6%). Five patients (12.8%) were still seizure free. The rate of adverse events was equal in both groups (41%). All but one occurred within the first 6 months of treatment. Our study in patients with difficult to treat childhood epilepsies suggests that in clinical practice patients were less likely to be discontinued from LTG than from VGB within 5 years, after similiar initial efficacy. This was mainly due to a loss of efficacy in VGB treatment early after initial response.

Epilepsia y embarazo

Treatment of the epileptic patient during pregnancy poses a major clinical dilemma. For one thing the patient has to be kept free of seizures, but she also should be kept on monotherapy at the lowest possible dose, due to the effect such medication may have on the unborn child.There is a syndrome related to intra uterine exposure to the classical antiepileptic drugs, but which is not associated with any particular drug. However, the effect of the new antiepileptic drugs on unborn children is still unknown. To date, no specific pattern of malformations has been described in relation to any of these drugs. Lamotrigine is the one with which there is most clinical experience. Although there are still not enough cases studied to permit definite conclusions to be drawn, at the moment the incidence of congenital anomalies is the same as in the general population.The new anti-epileptic drugs have a major therapeutic advantage, not only in the management of epilepsy in different clinical situations, but also in the good results observed when using lamotrigine in patients of fertile age.

Saliva and Serum Concentration of Lamotrigine in Patients With Epilepsy

The authors examined the interindividual correlation between saliva and serum concentrations of lamotrigine (LTG) and the relationship between LTG concentration in saliva and the free LTG concentration in serum in 40 patients with epilepsy, aged 16 to 73 years, receiving stable doses of LTG and comedication. Saliva was collected before and after stimulation of salivary flow. The free LTG fraction was determined by equilibrium dialysis and ultrafiltration. Drug analysis was performed by high-performance liquid chromatography. The correlation between LTG daily dose and serum concentration was weak but significant (r = 0.47). There was high correlation between LTG concentration in serum and unstimulated (r = 0.85) or stimulated (r = 0.94) saliva, and between total LTG concentration in serum and the free LTG fraction as determined by ultrafiltration (r = 0.95) and equilibrium dialysis (r = 0.93). Lamotrigine concentration in stimulated saliva was significantly correlated to the free LTG fraction. Protein binding of LTG calculated from concentration in stimulated saliva, as determined by ultrafiltration and equilibrium dialysis, was 51.8% +/- 13.03%, 68.05% +/- 7.59%, and 58.72% +/- 7.68% (mean +/- standard deviation) respectively. The differences between the three methods were significant. The authors conclude that saliva sampling may be a useful alternative to blood tests for monitoring LTG treatment.

Monotherapy with Lamotrigine in patients with Alzheimer's disease and seizures

We used Lamotrigine LTG (50-600mg /24h) in 12 patients, 58-to 95-years-old (A Group) and other antiepileptics in nine patients (B Group) with the diagnosis of probable Alzheimer's disease (AD) and seizures. We also administered LTG (50-700mg/24h) in 16 patients (C Group) and other antiepileptics in nine patients (D Group) with other neurological disorders with cognitive disorders and seizures. The results showed that in eight from 12 patients with AD, and in nine from 16 with other neurological disorders, seizures stopped after treatment with LTG—while in five from nine patients with AD and six from 18 with other neurological disorders, seizures stopped after treatment with other antiepileptic drugs. Side effects in 28 patients treated with LTG included only three mild rashes, while side effects in 18 patients treated with other antiepileptic drugs included—six patients with fatigue, two with rashes, one with dizziness, one with low platelets, one with sleepiness and one with loss of hair. Conclusively, this study shows that LTG is an effective and safe monotherapy in patients with cognitive disorders and AD.

Population pharmacokinetics of lamotrigine adjunctive therapy in adults with epilepsy.

Plasma concentrations of lamotrigine, an antiepileptic drug obtained in three adult controlled clinical trials conducted in the United States were pooled and analyzed using NONMEM, a population pharmacokinetic computer program, to facilitate development of dosing guidelines. A total of 2,407 lamotrigine plasma concentrations from 527 patients with epilepsy were analyzed. Regression equations for oral clearance were developed as a function of body size, age (18-64 years), gender, race, and use of concomitant antiepileptic drugs. The population mean apparent oral clearance of lamotrigine in adult patients receiving one concomitant enzyme-inducing antiepileptic drug and not valproic acid was estimated to be 1 mL/min/kg. Gender and age did not affect clearance significantly. On average, clearance was reduced by 25% in non-whites and increased by 13% in patients receiving more than one concomitant enzyme-inducing antiepileptic agent. Lamotrigine did not influence the disposition of phenytoin or carbamazepine. Dosing adjustments for lamotrigine in patients receiving concomitant enzyme-inducing antiepileptic drugs and not valproic acid should not be necessary for age, gender, or the number of concomitant enzyme-inducing antiepileptic drugs. Lamotrigine does not influence the dosing requirements for phenytoin or carbamazepine.

Aggressive behaviour in intellectually challenged patients with epilepsy treated with lamotrigine.

Lamotrigine (LTG) is a valuable addition to the medical management of epilepsy with wide spectrum of efficacy and good outcomes for quality of life. We report the emergence of a syndrome of aggressive behavior provoked by LTG in patients with epilepsy and intellectual challenge. On recognition of a tendency to aggression in intellectually challenged patients whose epilepsy was treated with LTG, a survey was conducted of those from centers specializing in management of patients with intellectual disability who were treated with LTG. Responses to LTG were sought and patient's behavioral profiles were determined. Nineteen patients were identified (16 men, 3 women, aged 17-54 years). Five patients discontinued LTG due to unprovoked aggressive behavior subsequent to its use; 2 had aggressive behavior sufficient to justify discontinuation of LTG but required reintroduction to control the epilepsy; 1 required reduction in LTG dosage; 1 had aggression that responded to psychiatric intervention; and 1 had aggression unrelated to LTG. Four patients had behavioral problems other than aggression, 4 had no change in behavior, and the behavior of 1 was improved by LTG treatment. LTG may provoke aggressive behavior and violence in intellectually handicapped patients with epilepsy, which may limit its use in such patients. Acknowledgment of the potential for such disturbance justifies greater surveillance of these patients and early discontinuation of LTG if necessary.

Comparison of the pharmacokinetics of lamotrigine in patients with chronic renal failure and healthy volunteers

Aims The aim of this study was to compare the pharmacokinetics of the anti‐epileptic agent, lamotrigine, in patients with chronic renal failure and healthy volunteers. Methods Non‐compartmental pharmacoknetics of a single oral dose (200 mg) of the anti‐epileptic agent, lamotrigine, and its main metabolite, lamotrigine N2‐glucuronide, were determined for 10 patients with chronic renal failure of mean estimated creatinine clearance 18ml min−1 and a control group of 11 healthy volunteers, matched for age and gender. Results For lamotrigine, there were no significant differences in Cmax, tmax, AUC, t 1/2, z, CL/F and amount excreted in urine although t 1/2, z, tended to be longer for the renal failure group with a mean (± s.d.) of 35.9 ± 10.7 h vs 27.8 ± 4.3 h for the control group. For the renal failure group, Vz/F was 18% higher (95% Cl 1% to 39%) compared with controls and CLR was reduced to 61% (95% Cl 46% to 80%) of the control group value. For lamotrigine glucuronide, Cmax, was increased 4‐fold (95% Cl 3.1 to 5.3) and AUC 7.8–fold (95% Cl 6.0 to 10.1) in the renal failure group compared with controls. CLR was approximately 9‐fold lower and apparent t1/2 was increased by 53% (95% Cl 27% to 84%). Concentrations of an N2 ‐methylated cardo‐active metabolite, previously observed in dogs, were below the limit of detection (2 ng ml−7) of the ASTED/h.p.l.c. assay in the renal failure group as well as controls. Conclusions These results indicate that impaired renal function will have little effect on the plasma concentrations of lamotrigine achieved for a given dosing regimen.

Gabapentin and lamotrigine: novel antiepileptic drugs.

The pharmacokinetics, efficacy, and adverse effects of gabapentin and lamotrigine, two new antiepileptic drugs (AEDs), are reviewed. Gabapentin and lamotrigine are promising advances in the treatment of epilepsy, which has not been satisfactorily controlled by available agents in 25-41% of patients. Gabapentin is chemically similar to gamma-aminobutyric acid, but it is able to pass into the central nervous system. It is effective for the treatment of partial-onset seizures that are refractory to other AEDs. It has no known drug-drug interactions and a relatively benign adverse effect profile, but its short half-life necessitates at least thrice-daily dosing. Lamotrigine is structurally unrelated to the other available AEDs. Its role is currently limited to add-on therapy in patients with partial seizures, with or without secondary generalization, that are resistant to current treatment. The efficacy of lamotrigine in patients with primary generalized tonic-clonic seizures, absence seizures, and Lennox-Gastaut syndrome remains to be validated. The adverse effect profile also remains to be determined. A rash may appear in up to 5% of patients, possibly necessitating discontinuation of the drug. Although lamotrigine does not seem to affect the pharmacokinetics of the other AEDs, the other AEDs affect lamotrigine pharmacokinetics. Lamotrigine can be given once or twice daily. Gabapentin and lamotrigine may be useful in treating patients whose epilepsy is not controlled by other available AEDs; however, further research is needed to confirm their roles in epilepsy treatment.

Lamotrigine: a review of antiepileptic efficacy.

Lamotrigine (LTG) is a chemically novel antiepileptic drug (AED) that blocks voltage-sensitive sodium channels, leading to inhibition of neurotransmitter release, principally glutamate. LTG is active in a wide range of pharmacologic models of epilepsy, demonstrating a potency and duration of action generally superior to currently available AEDs. Preliminary evidence of efficacy was provided by single-dose studies showing effects on reducing interictal spike activity and photoconvulsive response. A total of eight randomized, double-blind, placebo-controlled, crossover trials have established the efficacy of LTG in patients with refractory partial epilepsy. Literature reports suggest LTG also is effective in patients with idiopathic generalized epilepsy, including absence seizures, and in patients with Lennox-Gastaut syndrome. Other reports suggest that LTG is useful in the pediatric population, and an interim report of an open monotherapy trial suggests that the efficacy of LTG was comparable to that of carbamazepine (CBZ) but the adverse experiences leading to discontinuation were less frequent.

Overview of the Clinical Efficacy of Lamotrigine

Testing the efficacy of lamotrigine (LTG) in epileptic patients has been approached in several ways. The first pilot study examined the effect of a single dose of LTG in patients with frequent interictal spikes, and a reduction in spike frequency was observed. Subsequently, single doses reduced photosensitivity in appropriate patients. Single-blind administration of LTG for 1 week in addition to the patients' regular antiepileptic drugs (AEDs), in patients with refractory seizures, reduced seizures despite the short duration of therapy. This regimen was continued using a placebo-controlled crossover study with 1-week duration of treatment. Efficacy in partial and tonic-clonic seizures was subsequently confirmed in four double-blind crossover studies; a meta-analysis of these four studies showed a 30% reduction in partial seizures despite the intractable nature of the seizures in the patients included. Current studies aim at evaluating the drug as monotherapy and in different seizure types.

A randomised double-blind placebo-controlled crossover add-on trial of lamotrigine in patients with treatment-resistant partial seizures

Efficacy and safety of lamotrigine (LTG) as add-on therapy was assessed in a randomised double-blind placebo-controlled trial of this drug in 23 adult patients with refractory partial seizures. Fifteen patients showed an improvement on LTG treatment, with a greater than 50% decrease in total seizure count in 7 patients. Fourteen patients experienced fewer simple and complex partial seizures, with 8 patients benefitting by more than a 50% decrease in seizure frequency. The drug was well tolerated over the 2 month treatment period. The plasma concentration of concomitant antiepileptic drugs remained. No haematological or chemical abnormalities were noted.