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Gene therapy shows promise for hemophilia B... New cardiac imaging drug approved... Aspirin and heparin improve outcomes in recurrent pregnancy loss... Lamotrigine shows promise for myotonias... Cannabis use linked to higher head and neck cancer risk [ABSTRACT FROM AUTHOR]

Anti-NMDA receptor encephalitis is a complicated disease associated with paraneoplastic syndromes and autoimmune conditions. This case report highlights the importance of early identification and reviews the common clinical manifestations, diagnostic studies, and treatment modalities for this potentially catastrophic disease. [ABSTRACT FROM AUTHOR]

The article presents a case study of a 35-year-old patient who developed skin rash after taking antiepileptic drug lamotrigine for treatment of bipolar I disorder. It mentions that the rash was described by dermatologist as a hyperpigmented patch, recommending a topical corticosteroid cream to treat the rash.

The article presents an overview of medications used in treating opioid use disorder (OUD). It states naltrexone, buprenorphine, and methadone are approved in treating OUD and summarizes the mechanism of action for the three medication-assisted treatments. It mentions naltrexone is an antagonist with affinity for all opioid receptors but will induce immediate withdrawal symptoms for patients with dependence. It comments methadone is a mu opioid agonist while buprenorphine is a partial agonist.

Background and Objectives: To investigate whether children born to mothers who used carbamazepine during pregnancy had worse academic performance in adolescence., Methods: This population-based cohort study included all live-born singletons in Denmark between 1996 and 2002 who participated in the national ninth-grade exit examination (n = 370,859). Those born to mothers with prescription of antiseizure medications other than carbamazepine during pregnancy were excluded. We examined the association of in utero exposure to maternal carbamazepine redeemed during pregnancy (n = 290) with academic performance of offspring, defined by the scores in Danish and mathematics in ninth-grade exit examination. We estimated mean z-score difference with linear regression adjusted for socioeconomic factors and potential indications, including epilepsy and medication for other psychiatric disorders. Additional analyses addressing confounding by indication included comparison between in utero exposed vs past exposed and between past exposed and never exposed. In utero exposure to valproate monotherapy was used as a positive control and in utero exposure to lamotrigine as a negative control., Results: At the age of 16.1 (SD 0.4) years, adolescents in utero exposed to maternal carbamazepine monotherapy had lower scores both in Danish and mathematics in ninth-grade exit examination (adjusted z-score difference, -0.14 [95% CI -0.24 to -0.05] and -0.17 [95% CI -0.28 to -0.07], respectively). In utero exposure to carbamazepine monotherapy was associated with lower scores than past exposure only (adjusted z-score difference, -0.24 [95% CI -0.41 to -0.06] for Danish and -0.25 [95% CI -0.44 to -0.06] for mathematics), while past exposure to carbamazepine was associated with minor decrease in offspring's academic performance (adjusted z-score difference, -0.02 [95% CI -0.09 to 0.06] for Danish and -0.07 [95% CI -0.16 to 0.01] for mathematics). The association was also observed for in utero exposure to valproate monotherapy, but not for in utero exposure to lamotrigine., Discussion: In utero exposure to carbamazepine was associated with poorer academic performance in adolescence, as represented by lower scores in ninth-grade exit examination in Danish and mathematics. Additional studies are needed to confirm these findings because of limitations in this study and variable findings in prior studies., Classification of Evidence: This study provides Class III evidence that academic performance, as reflected in ninth-grade exit examinations in Danish and mathematics, was worse among those exposed to carbamazepine monotherapy in utero, compared with those without in utero exposure to antiseizure medications., (© 2022 American Academy of Neurology.)

Bipolar disorder is a complex and chronic mental illness. Individuals with this disorder usually have medical comorbidities needing management in primary care. This article focuses on bipolar disorder identification and medication management concerns for primary care nurse practitioners. [ABSTRACT FROM AUTHOR]

This updated version of the bipolar depression algorithm of the Psychopharmacology Algorithm Project at the Harvard South Shore Program aims to provide an organized, sequential, and evidence-supported approach for the treatment of that disorder. After initial evaluation and diagnosis, the psychiatrist should first assess whether there is an urgent indication for ECT. If ECT is not indicated, and the patient has psychotic symptoms, then an antipsychotic should be part of the medication regimen. Next, if the patient is not currently treated with mood stabilizers, there is a slight preference for lithium. If lithium is not effective or tolerated, treatment with quetiapine or lamotrigine should be initiated. If the patient is currently taking other mood stabilizers, their dosage should be optimized, and the clinician should consider adding or switching to lithium, quetiapine, or lamotrigine. Next, if the patient is not at especially high risk of mood destabilization, an antidepressant can be added in the bipolar depressed patient who has failed trials of lithium, quetiapine, and lamotrigine. Rapid-cycling depressed patients may require combinations of two or three mood stabilizers. ECT, along with other psychopharmacological options, could be reconsidered for the treatment of refractory bipolar depressed patients. [ABSTRACT FROM AUTHOR]

Severe cutaneous adverse reactions (SCARs) are associated with over 200 medicines including lamotrigine, an antiepileptic drug. Previous studies have suggested the involvement of immune mechanisms in the development of drug-induced SCARs.High-resolution HLA genotyping was performed for 65 patients of European ancestry treated with lamotrigine (22 cases with lamotrigine-induced SCARs and 43 controls on lamotrigine without SCAR-related symptoms). Association of HLA genetic variants with SCARs in these patients were evaluated by contrasting allele frequencies between the cases and the controls for each of 112 HLA four-digit alleles.Five alleles were observed with higher frequencies in the cases compared with the treated controls with exact P values less than 0.05. These include B∗5801 (P = 0.037), previously reported to be associated with allopurinol-induced SCARs. Marginal association evidence was also observed for alleles Cw∗0718 and DQB1∗0609, both of which were strongly correlated with B∗5801. Other alleles identified were A∗6801 (P = 0.012) and DRB1∗1301 (P = 0.045). In contrast to the study of carbamazepine-induced Stevens-Johnson syndrome in Han Chinese patients, none of the cases carried B∗1502. Accounting for the large number of hypothesis tests conducted, none of the associations identified were statistically significant.No single major HLA-related genetic risk factor was identified for lamotrigine-induced SCARs in patients of European origin. Only suggestive evidence was obtained for B∗5801, A∗6801, Cw∗0718, DQB1∗0609, and DRB1∗1301. Confirmation of these results in a larger, independent sample is needed to determine whether any of the HLA alleles identified are truly associated with the development of lamotrigine-induced SCARs. [ABSTRACT FROM AUTHOR]

Major depressive disorder (MDD) is highly prevalent, potentially disabling, and sometimes fatal. Antidepressants (ADs) have improved its treatment, but incomplete response, sustained morbidity, recurrences, agitation, substance abuse, excess medical mortality, and suicide remain unsolved problems among mood disorder patients. AD treatment itself sometimes induces adverse behavioral responses. Several anticonvulsants (ACs) used to treat bipolar disorder (BPD) might also be of value for MDD. Accordingly, we reviewed published reports on ACs for MDD, identifying studies by computerized searches. We excluded reports dealing only with BPD patients or with sedatives, classified trials by design quality, and evaluated treatment of acute episodes and recurrences of adult MDD. We found 36 reports involving 41 relevant trials of carbamazepine (12 trials), valproate (11), lamotrigine (9), gabapentin (3), topiramate (3), phenytoin (2), and tiagabine (1). They include 9 blinded, controlled trials (of 28-70 days), involving carbamazepine (3 trials), lamotrigine (3), phenytoin (2), or topiramate (1) as primary treatments (5) or AD adjuncts (4). Some of these trials, as well as 7 of lesser quality, suggest benefits of carbamazepine, lamotrigine, and valproate, mainly as adjuncts to ADs. Another 20 anecdotes or small trials further suggest that these ACs might be useful as AD adjuncts—specifically to treat irritability or agitation in MDD. Overall, these reports provide suggestive evidence of beneficial effects of carbamazepine, lamotrigine, and valproate that require further study, especially for long-term adjunctive use, particularly in patients with recurring MDD with prominent irritability or agitation. [ABSTRACT FROM AUTHOR]

Abstract: To assess the efficacy and tolerability of lamotrigine in pain associated with diabetic neuropathy, two replicate randomized, double-blind, placebo-controlled studies were conducted. Patients (n =360 per study) with painful diabetic neuropathy were randomized to receive lamotrigine 200, 300, or 400mg daily or placebo during the 19-week treatment phase, including a 7-week dose-escalation phase and a 12-week, fixed-dose maintenance phase. The mean reduction in pain-intensity score from baseline to week 19 (primary endpoint) was greater (p ⩽0.05) in patients receiving lamotrigine 400mg than placebo in Study 2 (observed scores, −2.7 versus −1.6 on a 0- to 10-point scale). This finding was not replicated in Study 1. Lamotrigine 200 and 300mg did not significantly differ from placebo at week 19 in either study. Lamotrigine 300 and 400mg were only occasionally more effective than placebo for secondary efficacy endpoints. The 200-mg dose did not separate from placebo. In a post hoc analysis of pooled data including only patients who reached their target dose, lamotrigine 400mg conferred greater (p ⩽0.05) mean reduction in pain-intensity score from baseline to week 19 than placebo (−2.5 for 300mg and −2.7 for 400mg versus −2.0 for placebo). Adverse events were reported in 71–82% of lamotrigine-treated patients compared with 63–70% of placebo-treated patients. The most common adverse events with lamotrigine were headache and rash. Compared with placebo, lamotrigine (300 and 400mg daily) was inconsistently effective for pain associated with diabetic neuropathy but was generally safe and well tolerated. [Copyright &y& Elsevier]

Background: The use of psychotropic medications—in particular, mood stabilizers—in youths with psychiatric illness has grown. There are trends toward polypharmacy and the increased use of newer mood stabilizers in youths with psychiatric illness despite a paucity of studies examining the short- and long-term efficacy and safety of these agents in the pediatric population. Method: PubMed was used to identify peer-reviewed publications from the past 30 years (January 1975 to August 2005) studying lithium and anticonvulsants in youths with psychiatric illness. Results: Evidence supporting the use of lithium and valproate in the treatment of juvenile bipolar disorder and reactive aggression has grown. Evidence for the use of other anticonvulsants in youths with psychiatric illness is sparse. Side effects from lithium and anticonvulsants are typically mild to moderate. Data are accumulating in regard to the longer-term safety of lithium and DVPX in the juvenile psychiatric population. Although data in regard to the newer anticonvulsants are limited, they may have more desirable side-effect profiles. Conclusion: Double-blind, placebo-controlled trials of lithium and anticonvulsants are greatly needed as clinical use of these agents has risen without sufficient evidence supporting their efficacy in the pediatric population. [ABSTRACT FROM AUTHOR]

The objective was to investigate the effectiveness of lamotrigine for the treatment of spinal cord injury pain and clinical signs of neuronal hyperexcitability. Thirty patients with spinal cord injury (SCI) and at or below level neuropathic pain participated in a randomized double blind, placebo-controlled, crossover trial. A 1-week baseline period was followed by two treatment periods of 9 weeks duration with lamotrigine slowly increased to a maximum of 400 mg or placebo separated by a 2-week washout period. The primary outcome measure was the change in median pain score from baseline week to the last week of treatment. Secondary outcome measures included thresholds to standardized sensory stimuli using quantitative sensory testing. Twenty-two patients completed the trial. We found no statistically significant effect of lamotrigine as evaluated in the total sample. However, in patients with incomplete SCI, lamotrigine significantly reduced pain at or below SCI level. Patients with brush evoked allodynia and wind-up-like pain in the area of maximal pain were more likely to have a positive effect to lamotrigine than patients without these evoked pains (7 of 7 vs. 1 of 14). Lamotrigine was generally well tolerated. While this trial showed no significant effect on spontaneous and evoked pain in complete and incomplete spinal cord injury, lamotrigine reduced spontaneous pain in patients with incomplete spinal cord injury and evoked pain in the area of spontaneous pain. [Copyright &y& Elsevier]

Accumulating evidence suggests that at least some novel anticonvulsants may have mood-stabilizing properties. This paper reviews the literature for empirical studies of this topic. Lamotrigine has the most evidence in favor of its efficacy, with two double-blind studies in which it was more efficacious than placebo in the treatment of bipolar depression. However, it is associated with a 1/1000 risk of potentially fatal Stevens-Johnson syndrome. Gabapentin, although safe and well-tolerated, has been found in two doubleblind studies not to be efficacious in treatment-refractory mania or refractory bipolar depression. Topiramate is currently supported only by naturalistic evidence of mild to moderate mood-stabilizing efficacy, but it has the advantage of often producing weight loss. Based on these data, lamotrigine may be effective, in monotherapy or as an adjunct, for treating depression in type I bipolar disorder, but suggestions regarding gabapentin and topiramate await further efficacy data. Most of the current findings derive from small, non-double-blind studies, and further research is required before clinicians can consider any of these agents to be mood stabilizers. [ABSTRACT FROM AUTHOR]

The article reports that Lamotrigine (Lamictal) has been used to treat epilepsy and bipolar disorder since its approval in 1994.Topisc discussed include the Food and Drug Administration (FDA) has been evaluating in vitro studies of lamotrigine's effect on the heart; and FDA has issued a Drug Safety Communication to warn that lamotrigine has the potential to increase the risk of arrythmias in patients with heart disease.

Anticonvulsant hypersensitivity syndrome (AHS) is a potentially life-threatening adverse drug reaction presenting with fever, skin eruptions, and internal organ involvement. We describe a case of AHS with fulminant hepatitis that occurred two weeks after introduction of lamotrigine in a 40-year-old female patient with a recently diagnosed bipolar disorder, no pre-existent systemic organ involvement, and no other medication. Lamotrigine was introduced at a dosage of 25 mg daily and increased to 50 mg daily 12 days later. The patient had favorable evolution with cessation of lamotrigine and supportive treatment. This report suggests that AHS with fulminant hepatitis may occur idiosyncratically, independent of dosage, titration and comedication with other potentially hepatotoxic drugs. [ABSTRACT FROM AUTHOR]

The article presents a case study of a 15-year-old female who was diagnosed with a partial complex seizure disorder with secondary generalization and was given zonisamide (Zonegran) as treatment for seizures. The patient was also given valproic acid, carbamazepine (Tegretol), and lamotrigine (Lamictal). The U.S. Food & Drug Administration approved zonisamide in March 2000 as adjunctive therapy in the treatment of partial seizures in adults with epilepsy.

Periodic catatonia is a rare form of catatonia, characterized by episodes occurring in a cyclic pattern with clinical features of combined stupor and excitement, with intervals of remission. Although periodic catatonia is not common, it is an urgent condition, requiring hospitalization for evaluation and treatment. The management of periodic catatonia is quite challenging, mainly because of the unknown pathophysiological mechanisms involved in the onset of this clinical entity, which are less clear than in other forms of catatonia. Although positive trials of several medications in the acute phase of periodic catatonia have been published, available literature concerning the prevention of recurrent catatonic episodes is scarce. Here, we present the case of a patient with periodic catatonia in which long-term treatment with lamotrigine appears to have acted prophylactically in reducing the occurrence and severity of new catatonic episodes. A better understanding of the mechanisms involved in the pathophysiology of periodic catatonia and increasing psychiatrists' and physicians' awareness of the presentation of this clinical entity could be of benefit in shedding light on the most appropriate treatment approach. However, further clinical studies are needed before any firm recommendations can be made., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

The article explores how lamotrigine or carbamazepine more effective as first-line treatment for epilepsy. Topics discussed include people with active epilepsy may achieve long-term remission shortly after starting drug therapy; antiepileptic drugs suppress seizures by reducing neuronal excitability; and recommended by National Institute for Health and Care Excellence as first-line treatment for newonset focal seizures and as second-line treatment for generalized onset tonic-clonic seizures.

B Learning Objectives: b Hemophagocytic lymphohistiocytosis (HLH) is an aggressive and life-threatening syndrome of excessive immune activation. Lumbar puncture revealed CSF WBC count 88, bands 69%, PMN 20%, glucose 48, protein 171. She met HLH criteria with elevated triglycerides, ferritin, fibrinogen, soluble CD 25 assay, prolonged fevers, bone marrow histiocytosis and absent NK cell activity. [Extracted from the article]

The article informs that the Food and Drug Administration (FDA) has warned that seizure and bipolar disorder treatment lamotrigine is associated with lifethreatening immune reaction hemophagocytic lymphohistiocytosis (HLH).

This update covers the results of a randomized, placebo-controlled study that provides evidence that lamotrigine is effective in treating nondystrophic myotonias. Next, an overview of adverse effects of immune checkpoint inhibitors is provided, and the association of autoimmune myopathy and these monoclonal antibody therapies is discussed in light of recent reports. Last, the utility of electrodiagnostic testing in patients with intensive care unit weakness is addressed with emphasis on the high sensitivity and specificity of prolonged compound muscle action potential amplitudes in diagnosing critical illness myopathy.

This section presents updates on drugs in the U.S. The Food and Drug Administration (FDA) added risk of aseptic meningitis to the label warning for lamotrigine. Off-label use of quinine sulfate, which was approved for uncomplicated malaria due to Plasmodium falciparum, was discovered in the country. FDA approved ulipristal acetate as an emergency contraceptive.

The article describes the case of a 14-year-old girl who experience hallucinations, 7 days after taking lamotrigine together with valproic acid and amitriptyline for partial complex seizures with secondary generalization. She also developed a low-grade temperature and complained of ankle pain, as well as fine lacy rash over her arms and legs. Lamotrigine was discontinued and the visual and auditory hallucinations were resolved as well as her rash. The results of her laboratory examinations were given, which include valproic acid level and liver enzymes.

Presents news items related to various drugs, available as of June 2003. Approval to use lamotrigine tablets as add-on therapy in treatment of partial seizures in children; Effect of hydroxyurea in relieving pain of patients with sickle-cell anemia; Use of Avelox in treatment for community acquired pneumonia.

ABSTRACT: Little information exists about the effects of newer antiepileptic drugs (AEDs) on sexual function in men with epilepsy. We report a series of three male veterans whose sexual disorders improved with lamotrigine. All three had partial seizures. One patient was taking phenobarbital and gabapentin and complained of decreased potency and anorgasmia. After lamotrigine was added for better seizure control and the dosage of gabapentin was tapered, anorgasmia improved. The second patient complained of impotence after a rash while taking phenytoin and carbamazepine. Impotence persisted with phenobarbital, valproate, and gabapentin. Eight months after gabapentin was replaced with lamotrigine, impotence improved. The third patient complained of long-standing impotence. Treatment with five AEDs had no effect on the dysfunction. Lamotrigine was added to the carbamazepine regimen; impotence improved with decrease in carbamazepine and increase in lamotrigine. The favorable effect of lamotrigine on sexual disorders in these three patients suggests this drug should be considered under appropriate circumstances for men who have sexual dysfunction while taking other antiepileptic agents. [ABSTRACT FROM AUTHOR]

Rationale: Sodium valproate (VPA) and lamotrigine (LTG) are widely used antiepileptic drugs, disabling postural, and action tremors after using LTG with VPA were reported in 1993. However, in this study, we describe a patient in whom disabling resting-type tremor induced by 2-year use of VPA and LTG., Patient Concerns: A 50-year old man was referred to department of neurology because of involuntary upper limbs resting-type tremor with high amplitude that had begun 6 months previously and progressively worsened, and he could not work on the day of visit. Furthermore, he had been treated with VPA, LTG, and benzhexol for 2 years as he suffered from twitch of eyelids and facial region, and amantadine, monolithic compound preparation (flupentixol and melitracen) were added in the last 2 months because of tremor and anxiety. However, the treatment had no benefit on improving involuntary movements of the patient., Diagnoses: Drug-induced disabling tremor was diagnosed., Interventions and Outcomes: LTG, amantadine, and VPA were withdrawn, the remaining 2 drugs, benzhexol and compound preparation (flupentixol and melitracen), were continued to use, and the patient improved in 2.5 months after discontinuation of 3 drugs. There was no recurrence at 6 months follow-up., Lessons: Considering the wide and long-term utilization of VPA and LTG, healthcare providers should be aware of them as a possible cause of tremor. When necessary, an attempt of discontinuing the suspected drugs should be made to confirm the diagnosis, instead of symptomatic treatment, especially when the adverse event was severe and fatal., (Copyright © 2017 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To characterize pretreatment behavioral problems and differential effects of initial therapy in children with childhood absence epilepsy (CAE)., Methods: The Child Behavior Checklist (CBCL) was administered at baseline, week 16-20, and month 12 visits of a randomized double-blind trial of ethosuximide, lamotrigine, and valproate. Total problems score was the primary outcome measure., Results: A total of 382 participants at baseline, 310 participants at the week 16-20 visit, and 168 participants at the month 12 visit had CBCL data. At baseline, 8% (95% confidence interval [CI] 6%-11%) of children with CAE had elevated total problems scores (mean 52.9 ± 10.91). At week 16-20, participants taking valproic acid had significantly higher total problems (51.7 [98.3% CI 48.6-54.7]), externalizing problems (51.4 [98.3% CI 48.5-54.3]), attention problems (57.8 [98.3% CI 55.6-60.0]), and attention-deficit/hyperactivity problems (55.8 [98.3% CI 54.1-57.6]) scores compared to participants taking ethosuximide (46.5 [98.3% CI 43.4-49.6]; 45.8 [98.3% CI 42.9-48.7]; 54.6 [98.3% CI 52.4-56.9]; 53.0 [98.3% CI 51.3-54.8]). Lack of seizure freedom and elevated week 16-20 Conner Continuous Performance Test confidence index were associated with worse total problems scores. At month 12, participants taking valproic acid had significantly higher attention problems scores (57.9 [98.3% CI 55.6-60.3]) compared to participants taking ethosuximide (54.5 [95% CI 52.1-56.9])., Conclusions: Pretreatment and ongoing behavioral problems exist in CAE. Valproic acid is associated with worse behavioral outcomes than ethosuximide or lamotrigine, further reinforcing ethosuximide as the preferred initial therapy for CAE., Clinicaltrialsgov Identifier: NCT00088452., Classification of Evidence: This study provides Class II evidence that for children with CAE, valproic acid is associated with worse behavioral outcomes than ethosuximide or lamotrigine., (© 2017 American Academy of Neurology.)

Background: The aim was to study the impact of therapeutic drug monitoring (TDM) on patients on lamotrigine (LTG) therapy and the evaluation of possible drug interactions, especially in triple antiepileptic drug combinations., Methods: During the period of 2001-2014, 3118 predose samples were taken from 1137 patients >15 years of age as part of their routine TDM. Drug interactions were evaluated using calculation of LTG clearance (CL)., Results: Valproic acid (VPA) decreased LTG CL by 66% in bitherapy, and by 35% and 31% in triple therapy with carbamazepine (CBZ) and phenytoin (PHT), respectively. CBZ and PHT increased LTG CL by 52% and 96% in respective bitherapies but by 88% in triple therapy. Clonazepam, levetiracetam, and topiramate had no effect. The LTG therapeutic range (TR) was exceeded in 1% of cases in monotherapy, and in 4%-5% of cases in combination therapy. Only 54% of results were within the TR during 2001-2005, whereas 60%-62% were within the TR during 2006-2014. Adverse drug reactions (ADRs) were reported in 88 cases and occurred more frequently during TR during 2001-2005. Higher number of supratherapeutic levels in combination therapy led to a 3-fold higher incidence of ADR and poorer seizure control, as seizures occurred more often monthly (2.5%) or a few per year (41%) and fewer patients were seizure free (18%). Seizures occurred more often daily and monthly during the first period and in patients with 3 or 4 drugs in combination., Conclusions: A significantly higher number of supratherapeutic levels were found in combinations with VPA, despite lower doses of LTG. Hepatic enzyme inducers, such as CBZ and PHT only partially compensated for the inhibitory effect of VPA. Decrease of both the frequency of seizures and the incidence of ADRs after TDM implementation suggests that TDM may have given clinicians the opportunity to achieve more optimal patient treatment.

This study was conducted to evaluate the effectiveness of lamotrigine (LTG) over 2 years and the usefulness of measuring its blood levels during the follow-up of patients with epilepsy. We measured peak blood LTG levels of 32 patients with epilepsy (9.16 ± 3.34 years old; mean ± SD). The blood levels were measured at 6 months, 1 year, and 2 years after reaching the LTG maintenance dosage. The effectiveness of LTG was evaluated to determine the seizure reduction rate. The patients were classified as effective cases (mean of own seizure reduction rates >50%) and ineffective cases (≤50%). The results were that the dosage and blood level showed positive correlations in the case of combination use with sodium valproate (VPA) (r = 0.690), carbamazepine and/or phenobarbital (r = 0.940), and others (r = 0.548). In several groups, the blood levels and efficacies did not show any positive correlations. In the cases of combination use with VPA, the blood levels of effective cases and ineffective cases were significantly different (P = 0.001). The optimal range was 8-11.5 μg/mL based on the average and SD values in the effective cases. No patients had any side effects. In conclusion, no precise definition of the therapeutic range was possible because of the incomplete correlation between the blood level and seizure frequency. We recommend the optimal range of LTG as a therapeutic target without any side effects, and it was established that the range in the combination with VPA was 8-11.5 μg/mL.

Background: Defining a drug's therapeutic index (TI) is important for patient safety and regulating the development of generic drugs. For many drugs, the TI is unknown. A systematic approach was developed to characterize the TI of a drug using therapeutic drug monitoring and electronic health record (EHR) data with pharmacokinetic (PK) modeling. This approach was first tested on phenytoin, which has a known TI, and then applied to lamotrigine, which lacks a defined TI., Methods: Retrospective EHR data from patients in a tertiary hospital were used to develop phenytoin and lamotrigine population PK models and to identify adverse events (anemia, thrombocytopenia, and leukopenia) and efficacy outcomes (seizure-free). Phenytoin and lamotrigine concentrations were simulated for each day with an adverse event or seizure. Relationships between simulated concentrations and adverse events and efficacy outcomes were used to calculate the TI for phenytoin and lamotrigine., Results: For phenytoin, 93 patients with 270 total and 174 free concentrations were identified. A de novo 1-compartment PK model with Michaelis-Menten kinetics described the data well. Simulated average total and free concentrations of 10-15 and 1.0-1.5 mcg/mL were associated with both adverse events and efficacy in 50% of patients, resulting in a TI of 0.7-1.5. For lamotrigine, 45 patients with 53 concentrations were identified. A published 1-compartment model was adapted to characterize the PK data. No relationships between simulated lamotrigine concentrations and safety or efficacy endpoints were seen; therefore, the TI could not be calculated., Conclusions: This approach correctly determined the TI of phenytoin but was unable to determine the TI of lamotrigine due to a limited sample size. The use of therapeutic drug monitoring and EHR data to aid in narrow TI drug classification is promising, but it requires an adequate sample size and accurate characterization of concentration-response relationships.

Objectives: Lamotrigine (LTG) is a drug commonly used to treat epilepsy and can also be used to manage mood disorders, such as bipolar disorder. One of the most dangerous adverse effects of LTG is skin rash, which can make early cessation necessary. Here, we examine the adverse effects associated with long-term use of LTG for the treatment of mood disorders., Methods: Data were obtained from the medical records of 101 psychiatric patients who were prescribed long-term treatment with LTG. Patients were retrospectively divided into those who discontinued treatment within 6 months and those who continued for longer, and the groups were compared for adverse effects. We also compared the incidence of adverse effects in high and low doses., Results: Fifty-four patients continued LTG treatment for 6 months or longer; 47 discontinued within 6 months. A history of allergy was more prevalent among the patients who discontinued treatment early than in those who continued. Of the patients who continued treatment for 6 months or longer, only 2 later discontinued treatment because of adverse effects. Lamotrigine monotherapy showed no difference in the incidence of adverse effects for different doses of LTG (>200 mg = 4.8% vs >100 mg, ≤200 mg = 7.7%; P = 1, vs >50 mg, ≤100 mg = 0%; P = 1 vs ≤50 mg = 0%; P = 1)., Conclusions: Clinicians must be mindful of the adverse effects occurring early during the titration phase. However, long-term use of LTG was very well tolerated, even at high maintenance doses.

Lamotrigine (LTG) is a widely used second-generation antiepileptic drug for long-term therapy of epileptic patients. Although LTG monotherapy during pregnancy is assumed to be relatively safe, teratogenic effects related to LTG has been reported previously. The presence of fetal malformations and maternal drug-induced lupus erythematosus concurrently in a pregnant women using LTG have not been reported before. We herein report a term infant with coarctation of aorta and ventricular septal defect, who was born to a mother treated with LTG for epilepsy before conception and throughout pregnancy. The mother was diagnosed with drug-induced lupus erythematosus at the 36th gestational week, and the symptoms resolved after discontinuation of the drug. Fetal cardiac anomalies should be searched in mothers who were exposed to LTG during pregnancy.

Background: Eslicarbazepine acetate (ESL) is a new anti-epileptic drug (AED) chemically related to oxcarbazepine (OXC) and carbamazepine (CBZ) and is increasingly used in clinical practice. The purpose of the study was to investigate 2-way pharmacokinetic interactions between ESL and other AEDs as compared to OXC and CBZ., Methods: Anonymous data regarding age, gender, use of AEDs, daily doses and serum concentration measurements of ESL, OXC, CBZ and lamotrigine (LTG) and other AEDs were retrieved from 2 therapeutic drug monitoring (TDM) databases in Norway. Drugs were categorized according to their known potential for interactions. Concentration/dose (C/D) ratios were calculated., Results: Data from 1100 patients were available. The C/D ratios of ESL and OXC were unchanged in combination with enzyme-inducing AEDs or valproate (VPA). The C/D ratio of CBZ decreased by 40% and 22% in combination with other enzyme-inducing AEDs or VPA, respectively, pointing to an increased clearance. ESL demonstrated no significant enzyme-inducing effect on LTG metabolism although there was a 20% and 34% decrease in the C/D ratio of LTG in combination with OXC and CBZ, respectively., Conclusions: Possible pharmacokinetic interactions have been studied for ESL as compared to OXC and CBZ. The pharmacokinetics of ESL is not affected by enzyme-inducing AEDs or VPA and does not affect the metabolism of LTG in contrast to OXC and CBZ. The study demonstrates the value of using TDM databases to explore the potential for pharmacokinetic interactions of new AEDs.

We compared persistence of antiepileptic drugs (AEDs) including carbamazepine, oxcarbazepine, gabapentin, lamotrigine, topiramate, valproic acid, and phenytoin in an Asian population with epilepsy.A retrospective cohort study was conducted by analyzing Taiwan's National Health Insurance Research Database (NHIRD). Adult epilepsy patients newly prescribed with AEDs between 2005 and 2009 were included. The primary outcome was persistence, defined as the treatment duration from the date of AED initiation to the date of AED discontinuation, switching, hospitalization due to seizure or disenrollment from databases, whichever came first. Cox proportional hazard models were used to estimate the risk of non-persistence with AEDs.Among the 13,061 new users of AED monotherapy (mean age: 58 years; 60% men), the persistence ranged from 218.8 (gabapentin) to 275.9 (oxcarbazepine) days in the first treatment year. The risks of non-persistence in patients receiving oxcarbazepine (adjusted hazard ratio [HR], 0.78; 95% CI, 0.74-0.83), valproic acid (0.88; 0.85-0.92), lamotrigine (0.72; 0.65-0.81), and topiramate (0.90; 0.82-0.98) were significantly lower than in the carbamazepine group. Compared with carbamazepine users, the non-persistence risk was higher in phenytoin users (1.10; 1.06-1.13), while gabapentin users (1.03; 0.98-1.09) had similar risk. For risk of hospitalization due to seizure and in comparison with carbamazepine users, oxcarbazepine (0.66; 0.58-0.74) and lamotrigine (0.46; 0.35-0.62) users had lower risk, while phenytoin (1.35; 1.26-1.44) users had higher risk. The results remained consistent throughout series of sensitivity and stratification analyses.The persistence varied among AEDs and was better for oxcarbazepine, valproic acid, lamotrigine, and topiramate, but worse for phenytoin when compared with carbamazepine., Competing Interests: The authors have no conflicts of interest to disclose.

Background: The authors have previously shown that an early therapeutic response to lamotrigine augmentation therapy is dependent on its plasma concentration and that a plasma lamotrigine concentration of 12.7 μmol/L may be a threshold for a good therapeutic response in treatment-resistant depressive disorder. The present study investigated whether or not an optimal dose of lamotrigine could be predicted from plasma lamotrigine concentration at week 2., Methods: The subjects were 37 depressed patients who had already shown insufficient response to at least 3 psychotropics including antidepressants, mood stabilizers, and atypical antipsychotics. The diagnoses were major depressive disorder (n = 15), bipolar I disorder (n = 6), and bipolar II disorder (n = 16). They received augmentation therapy with lamotrigine for 8 weeks. The final doses of lamotrigine were 100 mg/d for 16 subjects who were not taking valproate and 75 mg/d for 21 subjects taking valproate, respectively. Blood sampling was performed at weeks 2 and 8. Plasma concentrations of lamotrigine were measured by high-performance liquid chromatography., Results: There were significant linear relationships between the plasma lamotrigine concentrations at week 2 (x) and those at week 8 (y) for subjects who were not taking valproate (P < 0.01) and those taking valproate (P < 0.01). Regression equations were y = 2.032x + 2.549 for the former and y = 3.599x + 5.752 for the latter, respectively. Based on the equations, a nomogram to estimate an optimal dose of lamotrigine could be calculated., Conclusions: The present study suggests that an optimal dose of lamotrigine for augmentation therapy in treatment-resistant depressive disorder can be predicted from a plasma lamotrigine concentration at week 2.

Background: Valproic acid (VPA) is widely used in the treatment of children with epilepsy. Genetic polymorphisms in genes encoding drug-metabolizing enzymes may be an important source of interindividual variability in VPA metabolism. VPA is a substrate of uridine diphosphate glucuronosyltransferase 2B7 (UGT2B7). In this study, we seek to evaluate the effects of genetic polymorphisms of the UGT2B7 gene on serum VPA concentrations in epileptic children comedicated with lamotrigine (LTG)., Methods: We recruited 166 Chinese children with epilepsy who were treated with VPA in combination with LTG. Serum VPA and LTG concentrations were measured by fluorescence polarization immunoassay and high performance liquid chromatography, respectively. The UGT2B7 -161C > T in the 5'-upstream regions and 211 G > T, 372A > G, 735A > G, and 802C > T in the coding regions were genotyped using polymerase chain reaction amplification followed by direct automated DNA sequencing., Results: Our data show that patients carrying the variant UGT2B7 -161C > T or 802C > T genotypes had significantly higher adjusted VPA concentrations than those carrying the wild-type genotypes. The significant associations were potentiated after adjusted by age and adjusted LTG concentration. However, no associations were detected between the other studied UGT2B7 genotypes and adjusted VPA concentrations, even after adjusting by age and comedication., Conclusions: These results suggest that the UGT2B7 -161C > T or 802C > T mutations affect VPA pharmacokinetics, which are potentially enhanced by age and concomitant LTG administration. These findings provide a potential mechanism underlying interindividual variation in the disposition of VPA in combination with LTG.

Purpose of Review: Treatment of epilepsy starts with antiepileptic drug (AED) monotherapy. Knowledge of the spectrum of efficacy, clinical pharmacology, and modes of use for individual AEDs is essential for optimal treatment for epilepsy. This article addresses AEDs individually, focusing on key pharmacokinetic characteristics, indications, and modes of use., Recent Findings: Older-generation AEDs are effective but have tolerability and pharmacokinetic disadvantages. Several newer-generation AEDs have undergone comparative trials demonstrating efficacy equal to and tolerability at least equal to or better than older AEDs as first-line therapy. The list includes lamotrigine, oxcarbazepine, levetiracetam, topiramate, and, more recently, zonisamide. Pregabalin was found to be less effective than lamotrigine. Lacosamide, pregabalin, and eslicarbazepine have undergone successful trials of conversion to monotherapy. Other newer-generation AEDs with a variety of mechanisms of action are suitable for adjunctive therapy. Rational AED combinations should avoid AEDs with unfavorable pharmacokinetic interactions or pharmacodynamic interactions related to mechanism of action., Summary: Knowledge of AED pharmacokinetics, efficacy, and tolerability profiles facilitates the choice of appropriate AED therapy for patients with epilepsy.

Although some studies have reported a relationship between hoarding and bipolar disorder, we are unaware of any previous description of how they may interact with each other and how they should be managed appropriately. A 48-year-old male depressed patient with hoarding symptoms and obsessive-compulsive disorder (OCD) was diagnosed with bipolar II disorder after 2 hypomanic episodes. The patient was treated unsuccessfully with different high-dose serotonin reuptake inhibitors and atypical antipsychotics, maintaining a pattern of 6 to 8 discrete, but severe, depressive episodes each year, always in association with a drastic worsening of his OCD and hoarding symptoms. T.he patient did not improve until the dose of the serotonin reuptake inhibitor was decreased and a combination of lamotrigine and methylphenidate was initiated. On this treatment regimen, the patient did not show clinically significant levels of depression or hoarding or other OCD symptoms. This case suggests that, in some patients, (1) hoarding-related cognitions and behaviors may be a part of bipolar depression, (2) the episodic nature of rapid cycling bipolar II disorder may protect against the development of severe clutter, and (3) treatment focusing on bipolar depression (eg, lamotrigine plus methylphenidate) may result in an improvement of hoarding symptoms when these are present in patients with rapid cycling bipolar II disorder.

Background: Recently, a turbidimetric immunoassay method has been developed for use in the form of a QMS lamotrigine (LTG) commercial immunoassay. This study was designed to evaluate the performance of this immunoassay using a validated high-performance liquid chromatography-ultraviolet (HPLC-UV) method as the reference., Methods: The performance of QMS was initially tested using drug-free plasma spiked with different amounts of LTG and, subsequently, by analyzing 61 trough plasma samples from epileptic patients given the drug as part of their maintenance antiepileptic therapies., Results: The correlation between LTG concentrations measured by QMS and HPLC was good, with a Pearson coefficient of 0.968 (P < 0.0001). The Bland-Altman approach showed that LTG concentrations measured with QMS exceeded HPLC on an average by 15.6% (limits of agreement, -18% to +63%), with a concentration-dependent performance (mean percent bias, 49.5 ± 8.2% and 0.6 ± 12.7% for concentrations less than 2 mg/L and greater than 14.9 mg/L, respectively)., Conclusions: The QMS provided acceptable analytical performance across a wide concentration range for routine LTG measurements, being at least comparable with the other commercial immunoassays. It could be, therefore, considered as a viable alternative to HPLC methods for routine LTG monitoring in the clinical practice, although its suitability for accurate analysis of samples with low concentration is limited.

Objective: To assess the risk of major congenital malformations (MCMs) in association with maternal use of valproic acid (VPA) in monotherapy or adjunctive therapy, and its relationship with dose., Methods: The analysis was based on prospectively acquired data from EURAP, a registry enrolling women treated with antiepileptic drugs (AEDs) in early pregnancy, in which the primary outcome is presence of MCMs at 1 year after birth. Exposure was defined as type and dose of AEDs at time of conception. A comparison was made among 3 exposure types: (1) VPA monotherapy (n = 1,224); (2) VPA combined with lamotrigine (LTG) (n = 159); and (3) VPA combined with another AED but not LTG (n = 205)., Results: The frequency of MCMs at 1 year after birth was 10.0% for VPA monotherapy, 11.3% for exposures to VPA and LTG, and 11.7% for exposures to VPA + another (non-LTG) AED. Regardless of exposure group, the frequency of MCMs increased with dose of VPA, being highest at doses ≥1,500 mg/d (24.0% for monotherapy, 31.0% for VPA + LTG, and 19.2% for VPA + other AEDs), and was similar across treatment groups at the lowest VPA dose level of <700 mg/d (5.9% for monotherapy, 7.0% for VPA + LTG, and 5.4% for VPA + other AEDs)., Conclusions: The risk of MCMs associated with VPA exposure increases with increasing VPA dose, both in the presence and in the absence of one concomitant AED, and appears to be related primarily to the dose of VPA., (© 2015 American Academy of Neurology.)

Lamotrigine (LTG) has shown benefits in animal models of cerebral ischemia, but the mechanism involved was not fully studied. This study was carried out to examine the effects of LTG on cognitive dysfunction, β-amyloid1-42 accumulation, and tau protein hyperphosphorylation in the hippocampus of ischemic rats. Transient ischemic stroke was induced by middle cerebral artery occlusion. The Morris water maze test was used to evaluate the cognitive function of rats. We found that LTG significantly attenuated ischemia-induced cognitive deficits and decreased neuronal injury in the hippocampal CA1 zone. Moreover, LTG reduced β-amyloid1-42 and phosphorylated tau (AT8) in the hippocampus after ischemia. These results suggested that the cognition-protective effects of LTG after cerebral ischemia might involve inhibition of toxic β-amyloid accumulation and tau hyperphosphorylation in the hippocampus., (Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.)