Lamotrigine Therapy Research Articles

Lamotrigine augmentation in delirium tremens

Delirium tremens (DT) is most severe neurological complication of alcohol withdrawal with high mortality rate. DT is related to an altered balance of excitatory and inhibitory amino-acid neurotransmitters, which is basically due to upregulation of glutaminergic neurotransmission induced by chronic ethanol exposure. Lamotrigine (LTG) is believed to act by reducing excitatory glutamate release due to inhibition of Na (+) channels. The aim of this study was to investigate efficiency of the LTG therapy in the treatment of delirium tremens. This prospective clinical study included 240 patients with ICD-10 criteria for DT, who were randomly divided into control and experimental group. The patients were observed within 28 days at the Intensive Care Unit of the Centre for Urgent Psychiatric disorders, according to a specific protocol, which included CIWA-Ar and MDAS clinical scales. Control and experimental group were treated according to the NIAAA protocol for 2004, and experimental group with adding of LTG according to a specific program. CIWA and MDAS scores in the experimental and control group has statistical significant differences after the third day (p > 0.1), and especially after the fifth day (ECIWA5/KCIWA5 = 8.36 +/- 6.782/32 +/- 5.562; EMDAS5/KMDAS5 = 4.89 +/- 3.408/26.33 +/- 1.497) (p > 0.5). LTG is significantly efficient in the treatment of delirium tremens, but it does not decrease mortality rate.

The Role of Lamotrigine in the Treatment of Short-Lasting Unilateral Neuralgiform Headache Attacks with Conjunctival Injection and Tearing Syndrome

To evaluate the efficacy of lamotrigine for treatment of short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) syndrome. Literature was accessed through MEDLINE (1950-June 2010) using the terms lamotrigine, triazines, SUNCT, and trigeminal autonomic cephalgia. All articles in English and studies conducted in humans were identified and evaluated. SUNCT syndrome can be an extremely challenging headache type to manage and has been considered refractory to pharmacotherapy. Many anticonvulsants have been evaluated as promising SUNCT treatments, with lamotrigine specifically reported as an effective first-line treatment option. There is a lack of randomized placebo-controlled clinical trials evaluating lamotrigine in SUNCT syndrome therapy; however, 2 observational studies, 3 case series, and 5 case reports were reviewed. Lamotrigine appears to decrease the frequency and severity of SUNCT attacks, leading to complete resolution in some patients. A decrease in symptoms was achieved with doses ranging from 25 to 600 mg/day. In some cases, there was initial response to low doses, but dosage titrations were often necessary when symptoms returned several days after being managed at the same dose. Lamotrigine should be initiated at 25 mg/day and gradually titrated, guided by response and adverse effects. The risk of Stevens-Johnson syndrome, a dose-related adverse effect, can be minimized with gradual titration. According to case reports and observational studies, lamotrigine therapy has resulted in decreased frequency or resolution of SUNCT syndrome attacks. Randomized, controlled trials are necessary to confirm the efficacy of lamotrigine for this indication.

Adjunctive lamotrigine therapy for patients with bipolar II depression partially responsive to mood stabilizers

This naturalistic study explored long-term effectiveness of adjunctive lamotrigine therapy for bipolar II depression. We analyzed prospective data from 109 lamotrigine-treated outpatients with bipolar II depression inadequately responsive to mood stabilizers. Lamotrigine was added to prior treatment in a naturalistic fashion. Changes in depression severity were prospectively monitored for up to 52 weeks using a prospective mood chart and the Clinical Global Impressions-Bipolar Version-Severity (CGI-BP-S). Time to lamotrigine discontinuation during 52-week period was calculated using the Kaplan–Meier estimate. A significant reduction in the CGI-BP-S depression score was observed between baseline and week 52 with a large effect size. The discontinuation rates were 44.0% and 50.5% for the total sample and 14.3% and 22.9% for responders at 24 weeks and 52 weeks, respectively. A higher number of prior hospitalizations for depression and a history of attempted suicide were associated with poor response to adjunctive lamotrigine treatment. Sustained benefits of an open-label lamotrigine add-on were indicated in patients with bipolar II depression. Adjunctive usage of lamotrigine was safe and generally well-tolerated. The potential benefit of adjunctive lamotrigine treatment was suggested in patients with bipolar II disorder suffering from depressive symptoms. Large-scale controlled studies are needed to confirm the effectiveness of adjunctive lamotrigine therapy for bipolar II depression.

Lamotrigine-Induced Vaginitis and Dysuria in an Adult Woman With Bipolar Depression

To the Editor: We report a case of lamotrigine-induced vaginitis and dysuria that resolved after cessation of lamotrigine therapy and recurred upon reintroduction of lamotrigine. Urogenital side effects have rarely been associated with lamotrigine therapy; however, there are no published case reports in the literature. Case report. Ms A, a 29-year-old white woman, presented to our clinic in July 2009 with the diagnosis of bipolar depression (DSM-IV-TR bipolar disorder type II). She had been taking quetiapine extended release for the last 6 months, but her symptoms of depression did not resolve and were interfering with her daily functioning at work and home and in relationships. She was prescribed lamotrigine 25 mg/d in a titrating dose. She was started on 25 mg for first 2 weeks, and the dosage was later increased to 25 mg twice a day. She was scheduled for follow-up at 4 weeks. Before her scheduled follow-up, Ms A requested an urgent appointment at the end of her third week of treatment secondary to intense itching and burning in the vulvar area with pain on micturition. She denied using any topical preparation on the vulvar area or taking any local or systemic medication. She denied having any sexual activity during the last 3 weeks. After careful detailed history was taken, no potential cause for her symptoms was discovered, and her vaginitis symptoms were temporally related to the start of lamotrigine. She was asked to stop lamotrigine, and a referral to a primary care physician was made. Gynecologic findings revealed normal external genitalia, and speculum examination was significant only for mild erythema. Bimanual examination was normal and revealed no uterine or adnexal tenderness. Saline wet mount of vaginal secretion was negative for trichomonads or cue cells. Potassium hydroxide wet mount was negative for budding yeast and hyphae. Complete blood picture and urinalysis results were within the normal range. Ms A's symptoms completely resolved after a week without any treatment. After detailed explanation and discussion about the possible role of lamotrigine in causing vaginitis and dysuria, Ms A consented to be rechallenged with lamotrigine. Her symptoms recurred within 3 days with similar intensity but without dysuria. The symptoms lasted for about 3 days and subsided by themselves without any treatment or stopping lamotrigine rechallenge. The patient acknowledged similar symptomatology and intensity as in the previous episode. She declined any further gynecologic examination. Lamotrigine treatment was stopped, and she was switched to a different class of medication for her bipolar depression symptoms. Lamotrigine is an antiepileptic agent originally developed as an anticonvulsant for seizure disorder, but now it appears to have wider applications for use in partial and generalized seizures; affective disorders, particularly bipolar depression; anxiety disorders; and pain conditions. Lamotrigine acts by inhibition of glutamate release through blockade of voltage-sensitive sodium channels and stabilization of neuronal membrane. Lamotrigine may selectively influence neurons that synthesize glutamate and aspartate.1 Common side effects include dizziness, headache, blurred or double vision, lack of coordination, sleepiness, nausea, vomiting, insomnia, tremor, rash, fever, abdominal pain, back pain, tiredness, and dry mouth.2 Vaginitis is an inflammatory condition in which the vaginal mucosa is inflamed due to a variety of insults such as infections, irritations from chemicals, and medications. Although rare, urogenital side effects attributed to lamotrigine include dysmenorrhea, urinary frequency, dysuria, and vaginitis. The product manufacturer's package insert reports vaginitis occurring in 4% of patients taking lamotrigine.3 The exact pathophysiology of lamotrigine-induced vaginitis is unknown. The symptoms of our patient were temporally associated with lamotrigine therapy and subsided after cessation of therapy. When she was rechallenged, symptoms recurred, thus establishing an association with lamotrigine therapy. Other possible contributing causes to her symptoms were excluded. This case highlights the importance of an uncommon side effect that should always be considered and discussed as part of psychoeducation with women taking lamotrigine therapy.

Long-term efficacy of valproate versus lamotrigine in treatment of idiopathic generalized epilepsies in children and adolescents

Purpose In order to estimate and compare the long-term effectiveness of lamotrigine (LTG) versus valproate (VPA) monotherapy in treatment of newly diagnosed idiopathic generalized epilepsies (IGE) the following study was performed. Methods Medical records of 214 children and adolescents suffering from IGE were analyzed. 132 of them were on VPA monotherapy, 82 on LTG. The majority of patients had juvenile myoclonic epilepsy – 98, the rest: juvenile absence epilepsy – 32, childhood absence epilepsy – 53 and epilepsy with a tonic–clonic seizures on awakening – 12, others – 19. Mean age of the patients was 8.9 years (range 4–16 years). The mean time of treatment was 28 months, time of observation 40 months. In order to estimate retention rates and factors predicting successful treatment with LTG and VPA we used Kapplan–Meyer analysis and Gehan tests. Results Data analysis showed significantly longer retention rates with VPA versus LTG treatment in overall rates as well in all syndromes subgroups. After 12 months of therapy 69% stayed on LTG therapy versus 89% on VPA, after 24 months 57% versus 83% respectively. VPA showed comparable efficacy in all IGE syndromes where LTG showed better efficacy in childhood and juvenile absence epilepsy than in juvenile myoclonic epilepsy. The shorter duration of treatment with LTG was due to lack of efficacy. Conclusions Our results show the superiority of VPA versus LTG treatment in idiopathic generalized epilepsy syndromes.

Lamotrigine and twin pregnancy, incidental event or possible correlation?

Lamotrigine is frequently used to manage epilepsy during pregnancy. However, some major and minor birth defects are reported with lamotrigine monotherapy. This study is a case series report on 20 epileptic women who were receiving lamotrigine in their pregnancy. Apart from the normal pregnancies and births, in our study three patients gave birth to healthy twins, two vanished twin syndromes occurred and one patient had abortion. Twin pregnancy in association with lamotrigine therapy has not been clearly described before. Our observational study raises the idea that lamotrigine may induce twin pregnancy but larger studies need to investigate the presence or absence of such association more decently.

Development and Validation of a Rapid Column-Switching High-Performance Liquid Chromatographic Method for the Determination of Lamotrigine in Human Serum

This study describes a simple and sensitive column-switching high-performance liquid chromatographic method with UV detection for the determination of Lamotrigine in 50 microL of serum. After solid-phase extraction of Lamotrigine on an Oasis HLB extraction precolumn (20 x 3.9 mm; dp: 25 microm), chromatographic separation was achieved at 30 degrees C on a Chromolith RP-18e column (50 mm x 4.6 mm i.d.) using a solution of 20% acetonitrile in 15 mM phosphate buffer (pH 7.0) as the mobile phase, at a flow-rate of 2.0 mL/min. The eluant was detected at 215 nm. The retention time for Lamotrigine was 1.28 min. The total analysis time was ca. 5 min. However, the overlap of sample preparation, analysis, and reconditioning of the precolumn increased the overall sample throughput to one injection every 3 min. The method was validated for system suitability, linearity, precision, accuracy, robustness, and limit of quantitation. The linearity of the calibration lines, expressed by the linear correlation coefficient, was better than 0.9996. Recovery studies achieved from Lamotrigine spiked plasma samples showed values greater than 93%, demonstrating the excellent extraction efficiency of the precolumn. Intra- and inter-day precision were generally acceptable; the coefficient of variation was < 2.3% in all cases. The detection limits for Lamotrigine at a signal-to-noise ratio of 3 was 0.002 microg/mL when a sample volume of 50 microL was injected. However, it was possible to enhance the sensitivity further by injecting larger volumes, up to 200 microL. The method was shown to be robust and the results were within the acceptable range. The method was successfully applied to the determination of Lamotrigine in human serum samples of patients submitted to Lamotrigine therapy.

Reversible Lamotrigine-Induced Neurobehavioral Disturbances in Children With Epilepsy

A retrospective review was performed in patients who developed neurobehavioral adverse reactions to lamotrigine. Data were obtained from interviews, examinations, and routine medical records. There were 7 male and 2 female patients with epilepsy with a mean age of 5 years. All 9 patients became hyperactive and agitated over a broad range of lamotrigine dosing (0.7-14.0 mg/kg per d). Five patients developed self-injurious and violent behaviors. Two patients developed severe insomnia. The most affected patient was a 6-year-old boy whose mood and affect became extremely volatile. He also experienced threatening visual and auditory hallucinations and insomnia. All 9 patients had dramatic improvement and/or resolution of the adverse neurobehavioral effects following discontinuation or reduction of lamotrigine. Reversible, severe neurobehavioral disturbances associated with lamotrigine therapy have not been reported in the literature. While idiosyncratic and uncommon, this is a potentially significant, clinical side effect. Further studies are necessary to clarify the population at risk.

Toxic Epidermal Necrolysis Due to Lamotrigine Monotherapy for Bipolar Disorder

Toxic epidermal necrolysis (TEN) is a life-threatening mucocutaneous reaction to drugs. Lamotrigine is an antiepileptic agent not chemically related to the aromatic anticonvulsants that is also prescribed for mood disorder. Although adverse reaction from lamotrigine have been reported after a low initial dosage, the risk of developing TEN during lamotrigine therapy is rare when recommended guidelines for the dosing schedule are carefully followed. We present a 35-year-old woman with a mood disorder who developed TEN after about 10 days of lamotrigine (50 mg daily) monotherapy. She developed generalized maculopapular eruptions that progressed until more than 90% of her body surface area was involved, with extensive epidermal detachment. The lesions affected her conjunctival, oral, nasopharyngeal, genital, and vaginal mucosa. Lamotrigine was immediately discontinued. After receiving systemic antihistamine and corticosteroid treatment, the patient had a complete recovery.

Attenuation of Amygdala Atrophy With Lamotrigine in Patients Receiving Corticosteroid Therapy

Excessive corticosteroid exposure is associated with atrophic effects on the human hippocampus and amygdala. These effects seem to be, at least in part, mediated through corticosteroid-induced release of glutamate. We previously reported that lamotrigine, a glutamate release inhibitor, significantly improved declarative memory but did not change hippocampal volume, as compared with placebo, in corticosteroid-treated patients. To our knowledge, no data are available on preventing or reversing the impact of corticosteroids on the amygdala. We examined the effects of 24 weeks of randomized placebo-controlled lamotrigine therapy on amygdala volume and mood in 28 corticosteroid-treated patients (n = 12, placebo; n = 16, lamotrigine). Amygdala volumes were measured from tracings of the magnetic resonance images from weeks 0 and 24. Mood was assessed every 2 weeks with the Hamilton Depression Rating Scale and the Young Mania Rating Scale. An analysis of covariance revealed that patients on lamotrigine had significantly larger left amygdala volume at week 24 than patients on placebo after controlling for baseline volume. Neither exit nor week 24 analysis of covariance of Hamilton Depression Rating Scale and Young Mania Rating Scale revealed a significant difference between lamotrigine and placebo groups. Results suggest that lamotrigine attenuated the effects of corticosteroids on the left amygdala. Larger trials are warranted to confirm these findings.

Life-Threatening Organ Failure After Lamotrigine Therapy

We describe an 11-year-old girl with a seizure disorder who developed fever, rash, rhabdomyolysis, and multiorgan failure 2 weeks after commencing a transition from sodium valproate to lamotrigine therapy. To our knowledge, this patient represents the most severe life-threatening hypersensitivity lamotrigine reaction described in the pediatric literature. We recommend caution when prescribing lamotrigine to children on concomitant sodium valproate, and immediate discontinuation of lamotrigine and the provision of aggressive supportive care in patients with features of lamotrigine hypersensitivity.

Long-term Tolerability and Efficacy of Lamotrigine in Infants 1 to 24 Months Old

This open-label study was designed to evaluate the long-term tolerability and efficacy of lamotrigine in 1- to 24-month-old infants with partial seizures. The study enrolled both lamotrigine-naïve patients and patients who had been previously exposed to lamotrigine in a randomized, double-blind, placebo-controlled study. Patients (n = 204) received lamotrigine according to a dosing schedule that depended on prior experience with lamotrigine and concurrent antiepileptic drug therapy for up to 48 weeks or their second birthday, whichever occurred last. Total duration of lamotrigine exposure (which included exposure during the placebo-controlled study in lamotrigine-experienced patients) was >/=24 weeks in 92% of patients, >/=48 weeks in 70% of patients, and >/=72 weeks in 20% of patients. A total of 20 (10%) patients (8 lamotrigine-naïve patients and 12 lamotrigine-experienced patients) transitioned to lamotrigine monotherapy. The most common adverse events were pyrexia (45% of patients), upper-respiratory tract infection (28%), and ear infection (22%). The only adverse event considered reasonably attributable to study medication in >2% of patients was irritability (n = 10; 5% of patients). No cases of serious rash were reported. The median percent reduction from baseline in partial seizure frequency in the sample as a whole was 74%. Seizure frequency was reduced by >/=50% from pre-lamotrigine baseline in 62% of patients in the sample as a whole, 60% of the lamotrigine-naïve subgroup, and 63% of the lamotrigine-experienced subgroup. In the sample as a whole, 13% of patients were seizure free during the Treatment Phase. Investigators considered clinical status at the last clinic visit to be improved (mildly, moderately, or markedly) relative to prelamotrigine clinical status in 76% of patients (150/197) and to be unchanged in 19% (37/197). In this study-the first large prospective investigation of the long-term tolerability and efficacy of an antiepileptic drug in a patient population 2 years and younger-lamotrigine administered for up to approximately 72 weeks was well tolerated and associated with good seizure control.

Hyperandrogenism, ovulatory dysfunction, and polycystic ovary syndrome with valproate versus lamotrigine

To evaluate development of components of polycystic ovary syndrome (PCOS) and PCOS in women with epilepsy initiating valproate or lamotrigine therapy. Female individuals with epilepsy and regular menstrual cycles were eligible for this prospective study. Participants were randomized to 12 months of valproate (n = 225) or lamotrigine (n = 222) therapy. Serum androgen levels were measured every 3 months. Urinary pregnanediol glucuronide levels were measured weekly for two 3-month periods. The primary end point was development of PCOS components (ie, hyperandrogenism or ovulatory dysfunction). A post hoc analysis was conducted in women more than 2 years after menarche (177 lamotrigine, (HA) 186 valproate) to exclude OD the confounding effect of puberty. More women in the valproate group than the lamotrigine group developed (OD) in the prospective (54% valproate, 38% lamotrigine; p = 0.010) and the post hoc (HA) analyses (36% valproate, 23% lamotrigine; p = 0.007). More women in the valproate group than the lamotrigine group developed PCOS (9 vs 2%; p = 0.007). Development of HA was more frequent with OD valproate than lamotrigine among those initiating treatment at age younger than 26 years (44% valproate, 23% lamotrigine; p = 0.002) but was similar if treatment was started at age 26 years or older (24% valproate, 22% lamotrigine). Development of HA occurred more frequently with valproate than lamotrigine, especially if medication was started at age younger than 26 years.

Changes in Lamotrigine Pharmacokinetics during Pregnancy and the Puerperium

To assess changes in the pharmacokinetics of the anti-epileptic drug lamotrigine (LTG) during pregnancy, plasma LTG concentrations at steady-state were determined at different intervals during 11 pregnancies in 10 women with epilepsy stabilized on long-term LTG therapy. In the five pregnancies that could be assessed both during gestation and after delivery, plasma LTG concentrations increased on average by 164% (range +75 to +351%) between the last observation during pregnancy and the puerperium (P < 0.05). When all pregnancies monitored during pregnancy were considered, plasma LTG concentrations declined by an average of 20% (range -64% to +13%) between the first and the last assessment before delivery. These findings confirm that plasma LTG concentrations decrease markedly during pregnancy and that, at least in some cases, this effect occurs as early as the first trimester. Because there is a large interindividual variability in the magnitude and time course of the pregnancy-associated pharmacokinetic changes, it is desirable to establish baseline plasma LTG concentrations in all women of childbearing potential and to monitor LTG levels at frequent intervals during pregnancy and the puerperium.

States of serum leptin and insulin in children with epilepsy: Risk predictors of weight gain

Background and objectives Weight gain is an adverse metabolic effect in some children with epilepsy. The studies done to detect the effect of antiepileptic drugs and weight homeostatic hormones, insulin and leptin, were limited and controversial. Materials and methods We evaluated the serum leptin and insulin as predictors of weight gain in children receiving long-term treatment with valproate (VPA), carbamazepine (CBZ), lamotrigine (LTG). This study included 90 patients (treated: 70; untreated: 20). Serum lipid profile, insulin and leptin were measured. Results BMI, serum leptin and insulin were significantly elevated in VPA compared with controls, untreated patients and those treated with CBZ, LTG and combined therapy with LTG. Girls on VPA had higher BMI and leptin levels than boys. With VPA, serum insulin was correlated with BMI ( r = 0.625, p < 0.01), leptin ( r = 0.823, p < 0.001), treatment duration ( r = 0.775, p < 0.01) and VPA dose ( r = 0.975, p < 0.0001). Serum leptin was correlated with age ( r = 0.980, p < 0.0001), BMI ( r = 0.704, p < 0.01), serum insulin ( r = 0.823, p < 0.001), LDL-c ( r = 0.630, p < 0.01), HDL-c ( r = −0.880, p < 0.001), treatment duration ( r = 0.770, p < 0.01) and VPA dose ( r = 0.970, p < 0.001). BMI is correlated with serum insulin, leptin, LDL-c ( r = 0.835, p < 0.001) and HDL-c ( r = −0.955, p < 0.0001). Conclusion Hyperinsulinemia and hyperleptinemia are common with VPA and marked among epileptic children who gained weight suggesting states of insulin and leptin resistances. These alterations were not demonstrated with CBZ or LTG. The relationship between VPA, leptin and weight seems to be gender specific. Serum leptin may serve as a sensitive parameter for weight gain and reduction with intervention programs during follow-up of girls with epilepsy.

Efficacy and safety of lamotrigine monotherapy in children and adolescents with epilepsy

Lamotrigine (LTG) has shown to confer broad-spectrum, well-tolerated control of epilepsy. Monotherapy is preferable over polytherapy because of better compliance, fewer adverse events, less interactions, lower teratogenicity and lower cost. The aim of this study is to evaluate the efficacy and safety of LTG monotherapy on seizure control in a cohort of children and adolescents with epilepsy. We retrospectively reviewed the records of children and adolescents treated with LTG monotherapy at our institution between 2001 and 2006. Data collected included demographics, seizure type, etiology of seizures, age at onset of seizures and at initiation of LTG treatment, number of antiepileptic drugs (AEDs) prior to LTG, dose of LTG, length of follow-up, treatment response, and adverse events. Seventy-two children and adolescents were identified (mean age 12.1 years); 37.5% had mental retardation. Age at onset of epilepsy was 5.7 years (0–16). Twenty three percent had symptomatic focal epilepsy, 15.5% idiopathic focal epilepsy, 19.4% symptomatic generalized epilepsy and 41.6% idiopathic generalized epilepsy. LTG was used as first-line monotherapy in 26.4% of patients and as a second-line monotherapy in 73.6%. Age at initiation of LTG therapy was 10 years (2.8–19). Mean number of AEDs tried prior to LTG was 1.3 (0–6). Mean dose of LTG was 5.5 mg/kg/day (1.1–13.7). Mean follow-up period was 33 months (3 weeks to 11.5 years). The degree of seizure reduction was as follows: seizure free in 42%, 75–90% reduction in 17.4%, 50–74% in 11.6%, 25–49% in 10%. Sixteen percent had no change in seizure control and 3% became worse. The most common adverse event was rash (6.9%). Six (8.3%) patients discontinued LTG because of the adverse events. No patient had Stevens–Johnson syndrome. In conclusion, LTG was effective and well-tolerated as monotherapy in children and adolescents for both focal and generalized epilepsies.

Comparative daily profiles with different preparations of lamotrigine: A pilot investigation

Comparative pharmacokinetic data obtained with different preparations of lamotrigine (LTG) are reported for the first time. Nine outpatients reporting problems attributed to shifts in the preparation of LTG used were admitted to hospital. Patients were treated with proprietary LTG for at least 2 weeks prior to admission. Daily profiles (DPs) spanning 24 hours were obtained by blood sampling at 3- or 4-hour intervals on Day 3 after admission. A second DP was obtained under similar conditions after generic LTG therapy for at least 7 days. LTG concentrations were determined by HPLC, and DPs were generated to compare pharmacokinetic parameters. In five of nine patients, parameters deviated beyond ±10%. Even with the narrower bioequivalence requirements for mandatory substitution in Denmark, there are some patients who experienced serious clinical consequences (relapse in a seizure-free patient, status epilepticus, epidural hematoma due to ataxia with falls) in association with a change in preparation, and significant corresponding alterations in plasma levels could be demonstrated by comparative pharmacokinetic testing.

Rash and Liver Dysfunction Related to Lamotrigine Therapy

Objective: To report a case of rash and liver dysfunction associated with lamotrigine treatment. Case Summary: An 81-year-old woman with a history of bipolar disorder presented to the emergency department with complaints of fever, chills, nausea, and headache. Two weeks prior to presentation, liver enzymes were normal. Lamotrigine 50 mg/day and sustained-release bupropion 200 mg/day were started after discontinuation of citalopram. The patient had previous exposure to bupropion and documented rash with exposure to penicillin and sulfa. On admission, laboratory tests revealed slightly elevated liver enzymes and slightly low serum albumin. All medications were continued. On hospital day 3, a diffuse maculopapular rash developed on the patient's chest, abdomen, neck, and upper extremities, which was pruritic and warm to the touch. Both lamotrigine and bupropion were discontinued. Liver enzymes increased to more than 3 times the upper limit of normal, and serum albumin decreased. Liver function tests improved on day 6, and the rash resolved. Discussion: Predictive risk factors associated with lamotrigine-induced rash and liver dysfunction include rapid dose titration, previously reported rash with other medications, age, and concurrent interacting medications. More serious adverse effects, such as Stevens–Johnson syndrome and fulminant hepatic failure, have also been associated with lamotrigine treatment. If rash appears at any time during treatment, lamotrigine must be discontinued. According to the Naranjo probability scale, an association between lamotrigine and rash and liver dysfunction could be considered probable in this case. Conclusions: A faster than recommended dose titration may lead to lamotrigine-induced adverse effects such as rash and liver dysfunction in patients with risk factors.

Attenuation of the Effects of Corticosteroids on Declarative Memory with Lamotrigine

An extensive animal literature suggests that excessive corticosteroid exposure is associated with changes in memory and the hippocampus. Agents that decrease glutamate attenuate corticosteroid effects on the hippocampus. Minimal data are available on preventing or reversing corticosteroid effects on the human hippocampus. We previously reported that open-label lamotrigine was associated with significant improvement in declarative memory in corticosteroid-treated patients. We now examine the impact of 24 weeks of randomized, placebo-controlled lamotrigine therapy on declarative memory (primary aim) and hippocampal volume (secondary aim) in 28 patients (n=16 for lamotrigine, n=12 for placebo) taking prescription corticosteroids. All participants with data from at least one postbaseline assessment (n=9 for lamotrigine, n=11 for placebo) were included in the analysis. Declarative memory was assessed with the Rey Auditory Verbal Learning Test (RAVLT) at baseline and weeks 12 and 24. Hippocampal and total brain volumes were manually traced from MRI scans obtained at baseline and week 24. On the basis of an ANCOVA analysis, total words learned on the RAVLT at exit were significantly greater in the lamotrigine group (n=8, missing data or dropouts n=8) compared to the placebo group (n=11, dropout n=1). RAVLT scores in the lamotrigine group increased from mildly impaired to average range. Hippocampal volume changes were small in both lamotrigine (n=7) and placebo (n=7) groups during the 24-week assessment period and between-group differences were not significant. Results suggest that lamotrigine may improve declarative memory in patients taking prescription corticosteroids although differential dropout rate in the two groups is a concern.

Effect of Open-Label Lamotrigine as Monotherapy and Adjunctive Therapy on the Self-Assessed Cognitive Function Scores of Patients With Bipolar I Disorder

Cognitive deficits in patients with bipolar disorder are likely to impair occupational and social functioning. In a post hoc analysis of data from a prospective, open-label study of lamotrigine in 1175 patients 13 years or older with bipolar I disorder, changes in the self-rated cognitive function scores of patients receiving lamotrigine as monotherapy or as adjunctive therapy were evaluated. Lamotrigine was given for 12 weeks, with a target dosage of 200 mg/d. Cognitive function was assessed at baseline and week 12 with the self-rated Medical Outcomes Study Cognitive (MOS-Cog) Scale. Mean MOS-Cog scores improved significantly from baseline in the overall group (+8.4 +/- 22.55 points, P < 0.0001) and in subgroups of patients receiving and not receiving concomitant valproate, antidepressants, or antipsychotics. Patients receiving lamotrigine and not receiving concomitant antipsychotics, however, exhibited a small but significantly greater degree of improvement than patients who were receiving concomitant antipsychotics (adjusted mean difference = 4.05; 95% confidence interval, 1.30-6.81; P = 0.0039). Statistically significant improvement was seen in patient subgroups with a depressive (mean change from baseline, 8.8 +/- 21.97; P < 0.0001) or a manic (mean change from baseline, 7.5 +/- 22.62; P = 0.0007) index episode. Improvements in MOS-Cog scores significantly correlated with improvement in both depressive (correlation coefficient, -0.339; P < 0.0001) and manic (correlation coefficient, -0.151; P < 0.0001) symptoms. Overall, self-rated cognitive function scores improved during open-label lamotrigine therapy in patients with bipolar I disorder whether or not they were receiving concomitant valproate, antidepressants, or antipsychotics. Additional research is needed to explore the clinical relevance of these findings.