Lithium versus anticonvulsants and the risk of physical disorders - Results from a comprehensive long-term nation-wide population-based study emulating a target trial.

Bipolar disorder is associated with increased rates of many physical disorders, but the effects of medication are unclear. We systematically investigated the associations between sustained use of first line maintenance agents, lithium versus lamotrigine and valproate, and the risk of physical disorders using a nation-wide population-based target trial emulation covering the entire 5.9 million inhabitants in Denmark. We identified two cohorts. Cohort 1: patients with a diagnosis of bipolar disorder prior to first purchase (N = 12.607). Cohort 2: all 156.678 adult patients who had their first ever purchase (since 1995) of either lithium, lamotrigine or valproate between 1997 and 2021 regardless of diagnosis. Main analyses investigated the effect of sustained exposure defined as exposure for all consecutive 6-months periods during a 10-year follow-up. Outcomes included a diagnosis of incident stroke, arteriosclerosis, angina pectoris, myocardial infarction, diabetes mellitus, myxedema, osteoporosis, dementia, Parkinson's disease, chronic kidney disease and cancer (including subtypes). In both Cohorts 1 and 2, there were no systematic statistically significant differences in associations between sustained use of lithium versus lamotrigine and valproate, respectively, and any physical disorder, including subtypes of disorders, except myxedema, for which exposure to lithium increased the absolute risk of myxedema with 7-10 % compared with lamotrigine or valproate. In conclusion, these analyses emulating a target trial of "real world" observational register-based data show that lithium does not increase the risk of developing any kind of physical disorders, except myxedema, which may be a result of detection bias.

Recurrent Painful Ophthalmoplegic Neuropathy Responding to Lamotrigine: A Case Report.

Recurrent painful ophthalmoplegic neuropathy (RPON) is a rare neurological disorder characterized by recurring ipsilateral headache and paresis of one or more ocular motor nerves. We report the case of a 56-year-old woman with systemic lupus erythematosus (SLE) and hypertension, who presented with severe recurring headaches, nausea, and vomiting. Initially misdiagnosed with cerebral venous sinus thrombosis, her symptoms persisted despite anticoagulant therapy. Further evaluation led to the diagnosis of RPON. Management included intravenous analgesia, hydration, and indomethacin for pain relief. Persistent headache episodes necessitated the introduction of lamotrigine, resulting in significant symptom improvement. However, discontinuation of lamotrigine led to a recurrence of symptoms, which resolved upon resuming the medication. This case contributes to the limited RPON literature, providing insights into its diagnosis and management, with the goal of enhancing awareness and improving patient care.

NF1 mutation-driven neuronal hyperexcitability sets a threshold for tumorigenesis and therapeutic targeting of murine optic glioma.

BACKGROUND: With the recognition that noncancerous cells function as critical regulators of brain tumor growth, we recently demonstrated that neurons drive low-grade glioma initiation and progression. Using mouse models of neurofibromatosis type 1 (NF1)-associated optic pathway glioma (OPG), we showed that Nf1 mutation induces neuronal hyperexcitability and midkine expression, which activates an immune axis to support tumor growth, such that high-dose lamotrigine treatment reduces Nf1-OPG proliferation. Herein, we execute a series of complementary experiments to address several key knowledge gaps relevant to future clinical translation. METHODS: We leverage a collection of Nf1-mutant mice that spontaneously develop OPGs to alter both germline and retinal neuron-specific midkine expression. Nf1-mutant mice harboring several different NF1 patient-derived germline mutations were employed to evaluate neuronal excitability and midkine expression. Two distinct Nf1-OPG preclinical mouse models were used to assess lamotrigine effects on tumor progression and growth in vivo. RESULTS: We establish that neuronal midkine is both necessary and sufficient for Nf1-OPG growth, demonstrating an obligate relationship between germline Nf1 mutation, neuronal excitability, midkine production, and Nf1-OPG proliferation. We show anti-epileptic drug (lamotrigine) specificity in suppressing neuronal midkine production. Relevant to clinical translation, lamotrigine prevents Nf1-OPG progression and suppresses the growth of existing tumors for months following drug cessation. Importantly, lamotrigine abrogates tumor growth in two Nf1-OPG strains using pediatric epilepsy clinical dosing. CONCLUSIONS: Together, these findings establish midkine and neuronal hyperexcitability as targetable drivers of Nf1-OPG growth and support the use of lamotrigine as a potential chemoprevention or chemotherapy agent for children with NF1-OPG.

Determination of lamotrigine in human plasma by HPLC-PDA. Application to forensic samples.

PURPOSE: Therapeutic drug monitoring of plasma lamotrigine (LTG) has customarily been carried out in order to prevent some its adverse effects. For forensic purposes, determination of LTG in plasma is an useful tool in cases of accidental overdose or suicidal attempts. Currently, there are several analytical methods available including some based on LC tandem mass spectrometry techniques, but simple and accessible LC-UV methods still can be useful for the purpose. Here we report on a new high-performance liquid chromatography method for the determination of lamotrigine in human plasma which has been developed and validated including selectivity, sensitivity, accuracy, precision and recovery studies. METHODS: Lamotrigine and the internal standard chloramphenicol were extracted from plasma using liquid-liquid extraction using small volumes of buffer and ethylacetate. Detection was monitored at 305.7 and 276.0 nm for lamotrigine and chloramphenicol, respectively. RESULTS: The method was linear concentration dependence within the range of 0.1-10 µg/ml, with a mean coefficient of correlation r = 0.993. The limit of detection (LOD) was 0.04 µg/ml and the limit of quantification (LOQ) was 0.1 µg/ml. Intra and interday precision values were lower than 9.0% at all concentrations studied. The intra and interday accuracy values ranged from - 7.6 to 10.1%. Recovery was found to be 98.9% or higher. The method here described was successfully applied to 11 postmortem blood samples received at the Forensic Sciences Institute of Santiago de Compostela (Spain). CONCLUSION: A new HPLC method for the determination of lamotrigine in human plasma was developed and validated. A liquid-liquid extraction using small volumes of buffer and ethylacetate was optimized. The proposed method is suitable for forensic toxicological analysis.

Characterization of the intrahippocampal kainic acid model in female mice with a special focus on seizure suppression by antiseizure medications.

Despite special challenges in the medical treatment of women with epilepsy, in particular preclinical animal studies were focused on males for decades and females have only recently moved into the focus of scientific interest. The intrahippocampal kainic acid (IHKA) mouse model of temporal lobe epilepsy (TLE) is one of the most studied models in males reproducing electroencephalographic (EEG) and histopathological features of human TLE. Hippocampal paroxysmal discharges (HPDs) were described as drug resistant focal seizures in males. Here, we investigated the IHKA model in female mice, in particular drug-resistance of HPDs and the influence of antiseizure medications (ASMs) on the power spectrum. After injecting kainic acid (KA) unilaterally into the hippocampus of female mice, we monitored the development of epileptiform activity by local field potential (LFP) recordings. Subsequently, we evaluated the effect of the commonly prescribed ASMs lamotrigine (LTG), oxcarbazepine (OXC) and levetiracetam (LEV), as well as the benzodiazepine diazepam (DZP) with a focus on HPDs and power spectral analysis and assessed neuropathological alterations of the hippocampus. In the IHKA model, female mice replicated key features of human TLE as previously described in males. Importantly, HPDs in female mice did not respond to commonly prescribed ASMs in line with the drug-resistance in males, thus representing a suitable model of drug-resistant seizures. Intriguingly, we observed an increased occurrence of generalized seizures after LTG. Power spectral analysis revealed a pronounced increase in the delta frequency range after the higher dose of 30 mg/kg LTG. DZP abolished HPDs and caused a marked reduction over a wide frequency range (delta, theta, and alpha) of the power spectrum. By characterizing the IHKA model of TLE in female mice we address an important gap in basic research. Considering the special challenges complicating the therapeutic management of epilepsy in women, inclusion of females in preclinical studies is imperative. A well-characterized female model is a prerequisite for the development of novel therapeutic strategies tailored to sex-specific needs and for studies on the effect of epilepsy and ASMs during pregnancy.

Long-term low-dose lamotrigine for paroxysmal kinesigenic dyskinesia: a two-year investigation of cognitive function in children.

Objective: While low-dose lamotrigine has shown effectiveness in managing paroxysmal kinesigenic dyskinesia (PKD) in pediatric populations, the cognitive consequences of extended use are yet to be fully elucidated. This study seeks to assess the evolution of cognitive functions and the amelioration of attention deficit and hyperactivity disorder (ADHD) symptoms following a two-year lamotrigine treatment in children. Methods: This investigation employed an open-label, uncontrolled trial design. Between January 2008 and December 2021, thirty-one participants, ranging in age from 6.5 to 14.1 years, were enrolled upon receiving a new diagnosis of PKD, as defined by the clinical diagnostic criteria set by Bruno in 2004. Comprehensive evaluation of PRRT2 variants and 16p11.2 microdeletion was achieved using whole-exome sequencing (WES) and bioinformatics analysis of copy number variant (CNV) for all subjects. Immediately after diagnosis, participants commenced treatment with low-dose lamotrigine. Cognitive function was assessed using the Wechsler Intelligence Scale for Children-Chinese Revised (WISC-CR) at baseline and after 2 years, with ADHD diagnoses and symptom severity simultaneously assessed by experts in accordance with the DSM-IV diagnostic criteria for ADHD and the ADHD Rating Scale-IV (ADHD-RS-IV). Results: Initially, twelve out of 31 patients (38.7%) presented with comorbid ADHD. The latency to treatment initiation was notably longer in PKD patients with ADHD (30.75 ± 12.88 months) than in those without ADHD (11.66 ± 9.08 months), t = 4.856, p<0.001. Notably, patients with a latency exceeding 2 years exhibited a heightened risk for comorbid ADHD (OR = 4.671, P=0.015) in comparison to those with shorter latency. Out of the cohort, twenty-five patients saw the clinical trial to its completion. These individuals demonstrated a marked elevation in WISC-CR scores at the 2-year mark relative to the outset across FSIQ (baseline mean: 108.72 ± 10.45 vs 24 months: 110.56 ± 10.03, p=0.001), VIQ (baseline mean: 109.44 ± 11.15 vs 24 months: 110.80 ± 10.44, p=0.028), and PIQ domains (baseline mean: 106.52 ± 9.74 vs 24 months: 108.24 ± 9.38, p=0.012). Concurrently, a substantial mitigation was observed in ADHD inattention at 2 years compared to baseline (p<0.001), with an average total subscale scores decrement from 9.04 ± 4.99 to 6.24 ± 4.05. Conclusion: Prolonged duration of untreated PKD in children may elevate the risk of ADHD comorbidity. Notably, following a 2-year lamotrigine regimen, enhancements were observed in both cognitive test outcomes and ADHD symptomatology.

Pregnancy, antiseizure medications and unexplained intrauterine foetal death.

OBJECTIVE: To assess the role of antiseizure medication (ASM) regimens and other factors in relation to the occurrence of intrauterine foetal death (IUFD) in pregnant women with epilepsy (WWE) enrolled in the Raoul Wallenberg Australian Pregnancy Register of Antiepileptic Drugs (APR). RESULTS: IUFDs occurred in 70 (3.01 %) of 2,323 prospective pregnancies from WWE with known outcomes in the APR. Factors associated with IUFD occurrence included older maternal age, enrolment in the APR at an earlier stage of pregnancy, history of pregnancies which did not result in livebirths, parental history of foetal malformations, and maternal use of carbamazepine, lamotrigine or ethosuximide. Individual ASM dosages were not associated with IUFD occurrence. Relative to no exposure, the risk of IUFD increased with the increasing number of ASMs used in combination (2 ASMs: relative risk, RR = 5.45 [95 % CI: 0.73-41.80]; 3 ASMs: RR = 10.70 [95 % CI: 1.27-90.17]), >3 ASMs: RR = 10.70 [95 % CI: 1.27-90.17]), but this finding was attenuated after adjusting for other factors implicated in IUFD occurrence. Several ASM pairs were associated with an increased risk of IUFD relative to no exposure, but these associations were lost after accounting for confounders. CONCLUSIONS: Although it is possible that prenatal ASM exposure may increase the risk of IUFD, other non-pharmacological factors are more relevant to the occurrence to IUFD in pregnant WWE.

Titania-based fabric phase sorptive extraction approach for the determination of antiepileptic drugs, levetiracetam and lamotrigine in urine samples using high-performance liquid chromatography-photo diode array detection.

A new fabric phase sorptive extraction (FPSE) based separation and enrichment method was developed for sensitive determination of two antiepileptic drug molecules, Levetiracetam (LEV) and Lamotrigine (LTG). The analysis of these drug molecules was performed with high-performance liquid chromatography equipped with photodiode array detector (HPLC-PDA) after FPSE. HPLC analysis was carried out by using phenyl hexyl column, under isocratic conditions with the mobile phase composed of pH 3.0 buffer-acetonitrile (77:23 v: v). All parameters affecting the separation and enrichment process were studied and optimized step by step. The linear working range of the developed method was calculated in the range of 10.0-1000.0 ng mL-1 for both the drug molecules (LEV and LTG). The limits of detection of the method (LODs) were calculated as 2.72 and 3.64 ng mL-1, respectively. The relative standard deviation (%RSD) values of the developed method as an indicator of precision were varied between 4.0 and 7.3. The accuracy of the optimized FPSE method was determined by the recovery tests utilizing spiked samples and results were assessed in the range from 94.6 to 106.3%. This is the first application of sol-gel Titania polycaprolactone-polydimethylsiloxane-polycaprolactone (Ti-PCAP-PDMS-PCAP) based FPSE membrane in the determination of antiepileptic drug molecules.

Neurodevelopmental outcomes after prenatal exposure to lamotrigine monotherapy in women with epilepsy: a systematic review and meta-analysis.

BACKGROUND: Lamotrigine has become one of the most commonly prescribed antiseizure medications (ASM) in epileptic women during pregnancy and therefore requires regular updates regarding its safety. The aim of this study was to estimate the association between in utero exposure to lamotrigine monotherapy and the occurrence of neurodevelopmental outcomes. METHODS: All comparative studies assessing the occurrence of neurodevelopmental outcomes after epilepsy-indicated lamotrigine monotherapy exposure during pregnancy were searched. First, references were identified through a snowballing approach, then, through electronic databases (Medline and Embase) from 2015 to June 2022. One investigator evaluated study eligibility and extracted data and a second independent investigator reviewed the meta-analysis (MA). A systematic review and random-effects model approach were performed using a collaborative WEB-based meta-analysis platform (metaPreg.org) with a registered protocol (osf.io/u4gva). RESULTS: Overall, 18 studies were included. For outcomes reported by at least 4 studies, the pooled odds ratios and 95% confidence interval obtained with the number of exposed (N1) and unexposed children (N0) included were: neurodevelopmental disorders as a whole 0.84 [0.66;1.06] (N1 = 5,271; N0 = 22,230); language disorders or delay 1.16 [0.67;2.00] (N1 = 313; N0 = 506); diagnosis or risk of ASD 0.97 [0.61;1.53] (N1 = at least 5,262; N0 = 33,313); diagnosis or risk of ADHD 1.14 [0.75;1.72] (N1 = at least 113; N0 = 11,530) and psychomotor developmental disorders or delay 2.68 [1.29-5.56] (N1 = 163; N0 = 220). The MA of cognitive outcomes included less than 4 studies and retrieved a significant association for infants exposed to lamotrigine younger than 3 years old but not in the older age groups. CONCLUSION: Prenatal exposure to lamotrigine monotherapy is not found to be statistically associated with neurodevelopmental disorders as a whole, language disorders or delay, diagnosis or risk of ASD and diagnosis or risk of ADHD. However, the MA found an increased risk of psychomotor developmental disorders or delay and cognitive developmental delay in less than 3 years old children. Nevertheless, these findings were based exclusively on observational studies presenting biases and on a limited number of included children. More studies should assess neurodevelopmental outcomes in children prenatally exposed to lamotrigine.

Dose-dependent effect of lamotrigine on quetiapine serum concentration in patients using instant release tablets.

PURPOSE: Lamotrigine was previously reported to reduce serum concentration of quetiapine. The aim of this study was to investigate whether lamotrigine dose or quetiapine formulation was of importance for the drug interaction. METHODS: Patients combining lamotrigine with quetiapine (cases) were included retrospectively from a routine therapeutic drug monitoring (TDM) service, as were a control group of patients using quetiapine without any interacting drugs. The case and control groups were divided into groups using immediate release (IR) and extended release (XR) quetiapine. The case group was further split into high-dose (> 200 mg/day) and low-dose (≤ 200 mg/day) lamotrigine users. Quetiapine concentration-to-dose (C/D) ratio and metabolite-to-parent ratio (MPR) were compared between the control group and dose-separated case groups using ANOVA test and t-tests. RESULTS: In total, 406 patients were included. The mean C/D ratio of IR quetiapine was 46% lower in the high-dose lamotrigine group compared with the control group (P < 0.001), while no interaction effect was present in the low dose lamotrigine group (P = 0.7). Regardless of lamotrigine dose, there was no difference in quetiapine C/D ratio for patients using the XR formulation (P = 0.4). The quetiapine MPR was unaffected regardless of formulation and lamotrigine dose (P ≥ 0.06). CONCLUSION: The effect of lamotrigine in reducing quetiapine concentration is only significant for patients using quetiapine IR tablets who are treated with lamotrigine doses > 200 mg/day. Because of high variability in the interaction effect, TDM of quetiapine should be recommended during co-prescription of high-dose lamotrigine.

Association of antiseizure medications and adverse cardiovascular events: A global health federated network analysis.

OBJECTIVE: A diagnosis of epilepsy has been associated with adverse cardiovascular events (CEs), but the extent to which antiseizure medications (ASMs) may contribute to this is not well understood. The aim of this study was to compare the risk of adverse CEs associated with ASM in patients with epilepsy (PWE). METHODS: A retrospective case-control cohort study was conducted using TriNetX, a global health federated network of anonymized patient records. Patients older than 18 years, with a diagnosis of epilepsy (International Classification of Diseases, 10th Revision code G40) and a medication code of carbamazepine, lamotrigine, or valproate were compared. Patients with cardiovascular disease prior to the diagnosis of epilepsy were excluded. Cohorts were 1:1 propensity score matched (PSM) according to age, sex, ethnicity, hypertension, heart failure, atherosclerotic heart disease, atrial and cardiac arrythmias, diabetes, disorders of lipoprotein metabolism, obesity, schizophrenia and bipolar disorder, medications, and epilepsy classification. The primary outcome was a composite of adverse CEs (ischemic stroke, acute ischemic heart disease, and heart failure) at 10 years. Cox regression analyses were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) following 1:1 PSM. RESULTS: Of 374 950 PWE included; three cohorts were established after PSM: (1) carbamazepine compared to lamotrigine, n = 4722, mean age 37.4 years; (2) valproate compared to lamotrigine, n = 5478, mean age 33.9 years; and (3) valproate compared to carbamazepine, n = 4544, mean age 37.0 years. Carbamazepine and valproate use were associated with significantly higher risk of composite cardiovascular outcome compared to lamotrigine (HR = 1.390, 95% CI = 1.160-1.665 and HR = 1.264, 95% CI = 1.050-1.521, respectively). Valproate was associated with a 10-year higher risk of all-cause death than carbamazepine (HR = 1.226, 95% CI = 1.017-1.478), but risk of other events was not significantly different. SIGNIFICANCE: Carbamazepine and valproate were associated with increased CE risks compared to lamotrigine. Cardiovascular risk factor monitoring and careful follow-up should be considered for these patients.

SUNCT, SUNA and short-lasting unilateral neuralgiform headache attacks: Debates and an update.

BACKGROUND: Short-lasting unilateral neuralgiform headache attacks (SUNHA) have the features of both short-lasting unilateral neuralgiform pain, such as trigeminal neuralgia or stabbing headache, and associated trigeminal autonomic symptoms, such as paroxysmal hemicrania or cluster headache. Recognizing and adequately treating SUNHA is essential but current treatment methods are ineffective in treating SUNHA. METHODS: We reviewed the changes in the concept of short-lasting unilateral neuralgiform headache attacks and provide a narrative review of the current medical and surgical treatment options, from the first choice of treatment for patients to treatments for selective intractable cases. RESULTS: Unlike the initial impression of an intractable primary headache disorder affecting older men, SUNHA affects both sexes throughout their lifespan. One striking feature of SUNHA is that the attacks are triggered by cutaneous or intraoral stimulation. The efficacy of conventional treatments is disappointing and challenging, and preventive therapy is the mainstay of treatment because of highly frequent attacks of a very brief duration. Amongst them, lamotrigine is effective in approximately two-third of the patients with SUNHA, and intravenous lidocaine is essential for the management of acute exacerbation of intractable pain. Topiramate, oxcarbazepine and gabapentin are considered good secondary options for SUNHA, and botulinum toxin can be used in selective cases. Neurovascular compression is commonly observed in SUNHA, and surgical approaches, such as neurovascular compression, have been reported to be effective for intractable cases. CONCLUSIONS: Recent advances in the understanding of SUNHA have improved the recognition and treatment approaches for this unique condition.

UHPLC-MS/MS for plasma lamotrigine analysis and comparison with a homogenous enzyme immunoassay.

Aims: To develop and validate a UHPLC-MS/MS method for lamotrigine (LTG) analysis in human plasma and evaluate its agreement with a homogenous enzyme immunoassay (HEIA). Materials & methods: The UHPLC-MS/MS method was developed and validated according to the USFDA/EMA guidelines. A Bland-Altman plot was used to evaluate the agreement between UHPLC-MS/MS and HEIA. Results: Samples were pretreated with one-step protein precipitation and separated in 2.6 min. The intra- and inter-day bias and imprecisions were -15.8 to 15.0% and less than 11.17%, respectively. The recovery and matrix factor were 98.30 to 111.97%. The mean overestimation of UHPLC-MS/MS compared with HEIA was 21.57%. Conclusion: A rapid, sensitive and robust UHPLC-MS/MS method for plasma LTG analysis was developed and validated and was a 21.57% overestimation compared with HEIA.

The teratogenesis risk associated with antiseizure medication duotherapy in women with epilepsy.

PURPOSE: To investigate rates of occurrence of pregnancies associated with a foetal malformation (FM pregnancy rates) following simultaneous intrauterine exposure to two antiseizure medications in 524 pregnancies in women with epilepsy from the Australian Pregnancy Register who were treated simultaneously with various combinations and dosages of two antiseizure medications (duotherapy). RESULTS: FM pregnancy rates tended to be higher in those exposed simultaneously to two antiseizure medications, each of which was a statistically significant teratogen (valproate, topiramate, or carbamazepine), than when there was exposure to only one such teratogen. When there was exposure to only one such teratogen together with clonazepam or levetiracetam, for neither of which there was statistically significant evidence of heightened teratogenicity, the FM pregnancy rates also tended to be higher, but less so. When lamotrigine was the other component of the duotherapy with an established teratogen, FM pregnancy rates tended to be lower than that for the teratogen used as monotherapy. CONCLUSION: Leaving aside issues in relation to seizure control, our data suggest that it would be best to avoid using established teratogenic antiseizure medications (carbamazepine, valproate and topiramate) in combination with each other due to the increased FM risks. When combining an established teratogenic medication with a less teratogenic one, i.e. lamotrigine, levetiracetam or clonazepam, lamotrigine appears to be the safer option.

Long-term protective effects of lamotrigine in a rat ovarian ischemia-reperfusion model.

Ovarium torsion is a gynecological emergency that is common in women of reproductive age and requires early diagnosis and intervention. In this study, we aimed to investigate the long-term anatomical, histological and biochemical protective effects of lamotrigine in ovariums in the ischemia - reperfusion (I-R) model created experimentally in rats. A total of 40 female Sprague-Dawley rats, 14 weeks old, weighing 220-270 g were used in the study. The subjects were randomly distributed to form 4 groups named SHAM group, I - R group, I - R + Lamotrigine (LTG) group and R + LTG group. Under general anesthesia, the ovaries of the rats were reached and ischemia was created for 3 h with vascular clamps. 20 mg / kg LTG was administered intraperitoneally (ip.) to group 3 30 min before ischemia and to group 4 30 min before reperfusion. At the third hour of ischemia, the vascular clamps were opened and the abdomen of the rats was closed according to the surgical procedure. The rats were followed up for 28 days postoperatively and the ovarium tissues taken on the 28th day were examined anatomically and histologically. Biochemically, estradiol (E2), follicle stimulating hormone (FSH) and antimullerian hormone (AMH) levels were measured from blood samples taken from their hearts. Granulosa cells with diffuse vaculations were observed in degenerative follicles in group I-R. Again in this group, severe hemorrhage, fibrosis and edematous areas were observed in the ovarium stroma (Ovarian Histopathological Scoring (OHS): 7). In the I - R + LTG group, OHS was statistically significantly lower than the I - R group (OHS: 2; p < 0.000). In the R + LTG group, although the OHS score was calculated to be lower than the I - R group, there was no statistically significant difference (OHS: 6; p > 0.05). The protective effect of LTG against experimentally created ischemia and reperfusion damage was determined anatomically and histologically. No protective effect of LTG was observed in terms of FSH, E2 and AMH values measured from the blood sera of rats. These findings may provide a basis for future studies using LTG to treat ovarian ischemia-reperfusion injury.

The reference range of lamotrigine in the treatment of epilepsy in children: a systematic review.

PURPOSE: This study intends to assess the reference range of lamotrigine concentration for treating childhood epilepsy. METHODS: PubMed, Ovid-Embase, The Cochrane Library, CNKI, WanFang data and VIP databases were searched from database inception to January 2022. RCT, cohort study, case-control study, cross-sectional study that estimated the reference range of lamotrigine for children epilepsy treatment were included. The data extracted included basic information, statistical methods, data type, and results of reference range. Descriptive analysis was performed for them. RESULTS: 8 studies were included and estimated the reference range, and all of them were calculated based on efficacy data and/or concentration data. Statistical methods including ROC curve, concentration-effect curve, mean ± standard deviation, 95% confidence interval and percentile interval were utilized. For lamotrigine monotherapy, the lower limits ranged from 2.06 mg/L to 3.99 mg/L, and the upper limits ranged from 8.43 mg/L to 9.08 mg/L, showing basic consistency. However, for lamotrigine concomitant with valproate, the lower limits ranged from 2.00 mg/L to 8.00 mg/L, and the upper limit was 11.50 mg/L, for lamotrigine concomitant with other antiepileptics, the lower limits ranged from 1.00 mg/L to 3.09 mg/L, and the upper limits varied from 5.90 mg/L to 16.24 mg/L, indicating inconsistency. CONCLUSION: Several studies have estimated the reference range of lamotrigine for childhood epilepsy, while controversy exist and no studies have determined the upper limit of the range based on safety data. To establish the optimal reference range, further high-quality studies are necessary that consider both efficacy and safety data.

Curcumin protects against lamotrigine-induced chronic ovarian and uterine toxicity in rats by regulating PPAR-γ and ROS production.

Lamotrigine (LTG) is an antiepileptic drug with possible adverse effects on the female reproductive system. Curcumin was declared to improve ovarian performance. Therefore, this study aimed to clarify ovulatory dysfunction (OD) associated with LTG and the role of curcumin in ameliorating this dysfunction. Adult female Wister albino rats were assigned into four groups: negative control (received saline), positive control (received curcumin only), LTG, and LTG with curcumin groups. Drugs were administered for 90 days. The hormonal profile, including testosterone, estrogen, progesterone, luteinizing hormone, and follicle-stimulating hormone, in addition to the lipid profile and glycemic analysis, were tested. Oxidative stress biomarkers analysis in the ovaries and uterus and peroxisome proliferator-activated receptor-γ (PPAR-γ) gene expression were also included. Histopathological examination of ovarian and uterine tissues and immunohistochemical studies were also performed. Curcumin could improve the OD related to chronic LTG intake. That was proved by the normalization of the hormonal profile, glycemic control, lipidemic status, oxidative stress markers, and PPAR-γ gene expression. The histopathological and immunohistochemical examination of ovarian and uterine tissues revealed an improvement after curcumin administration. The results describe an obvious deterioration in ovarian performance with LTG through the effect on lipidemic status, PPAR-γ gene, and creating an oxidative stress condition in the ovaries of chronic users, with a prominent improvement with curcumin addition to the treatment protocol.

Time-Course Changes in Lamotrigine Concentration after Addition of Valproate and the Safety and Long-Term Tolerability of Lamotrigine-Valproate Combination Therapy.

The aim of this study was to evaluate the time-course changes in lamotrigine (LTG) concentration after addition of valproate (VPA) and the safety and tolerability of the combination therapy. We reviewed our therapeutic drug monitoring (TDM) database and found 345 patients on LTG who received add-on therapy with VPA. VPA had been added at least 12 weeks after patients finished stepwise LTG titration. Also, we retrospectively evaluated the LTG concentration after addition of VPA and the safety and long-term tolerability of LTG-VPA combination therapy. Plasma LTG concentration increased more than 1.5-fold within 15 d of addition of VPA and reached a peak at 30 d. The rate of increase in LTG concentration occurred in a VPA concentration-dependent manner. During the first 120 d after addition of VPA, adverse events were reported by 58 patients (16.8%), but no patient developed cutaneous reactions. Kaplan-Meier analysis showed estimated retention rates for LTG-VPA combination therapy of 74.5% at 5 years. At 5 years, the mean concentration of LTG was 11.1 µg/mL (43.3 µmol/L). Because addition of VPA leads to a marked increase in LTG concentration over a short period, TDM for LTG should be performed at the earliest from 14 d after starting VPA. At 120 d after starting VPA therapy, the higher LTG concentration due to addition of VPA is not associated with an increased risk of cutaneous reactions. Although LTG-VPA combination therapy increases LTG concentration, it is well tolerated and has a high long-term retention rate.

A naturalistic effectiveness study of maintenance therapies for the bipolar disorders.

BACKGROUND: Treatment decision-making for individuals with bipolar disorder can be difficult. Recommendations from clinical practice guidelines can be affected by multiple methodological limitations, while pharmaco-epidemiological data suggest great variety in prescription practices across regions. Given these inconsistencies, this study aimed to provide an alternative perspective on the effectiveness of common bipolar disorder maintenance treatments through considering naturalistic data. METHODS: A total of 246 individuals with bipolar disorder (84 bipolar I [BP-I], 162 bipolar II [BP-II]) were recruited through clinics and/or websites. All were euthymic and had trialled at least one mood stabiliser. They completed an online survey containing questions on demographics, clinical variables, symptomatology, and the effectiveness/side effect profiles of any mood stabilisers (MSTs) or atypical antipsychotics (AAPs) that they have taken. RESULTS: Lithium and lamotrigine were the most commonly prescribed MSTs and the most effective at mood stabilisation. Lithium and lamotrigine appeared marginally more effective for BP-I and BP-II respectively, however, only the latter difference was statistically significant. Furthermore, lamotrigine had the more favourable side effect profile. Amongst the AAPs, quetiapine and olanzapine were the most commonly prescribed, but they were negligibly superior to other AAPs. CONCLUSION: This study clearly established a preference for lamotrigine in the maintenance treatment of BP-II. While the literature consistently emphasises the primacy of lithium in bipolar disorder treatment, its side effect profile as observed in this study remains a concern. Future research considering moderators of treatment response and concomitant medications could help to identify further nuances to consider for treatment decision-making.