Long-term Carbamazepine Treatment Research Articles

Effect of carbamazepine on the bone health of people with epilepsy: a systematic review and meta-analysis.

ImportanceIncreasing evidence indicates that carbamazepine (CBZ) treatment in people with epilepsy (PWE) has adverse effects on bone health.ObjectiveWe conducted a meta-analysis to investigate the effect of CBZ on the bone health of PWE.MethodsTwo independent reviewers systematically searched PubMed and EMBASE for eligible studies. Standard mean deviations (SMDs) with 95% confidence intervals were used as a measure to investigate the effect of CBZ on bone-related outcomes in PWE.ResultsLevels of vitamin D (standardized mean difference [SMD]: −0.62, 95% CI: −0.89 to −0.35) and calcium (SMD: −0.38, 95% CI: −0.67 to −0.09) were significantly lower in the CBZ group than controls. Additionally, significantly higher alkaline phosphatase (SMD: 0.67, 95% CI: 0.52–0.82) was observed in patients using CBZ than controls. However, no significant difference in BMD was found between the two groups (SMD: −0.06, 95% CI: −0.55 to 0.43).Conclusion and significance: This study provided evidence that CBZ treatment has a negative effect on bone health in PWE. Clinical implications are that long-term CBZ treatment may not be a good choice for PWE with skeletal diseases or osteoporosis.

Antiepileptic Drug Carbamazepine Binds to a Novel Pocket on the Wnt Receptor Frizzled-8.

Misregulation of Wnt signaling is common in human cancer. The development of small molecule inhibitors against the Wnt receptor, frizzled (FZD), may have potential in cancer therapy. During small molecule screens, we observed binding of carbamazepine to the cysteine-rich domain (CRD) of the Wnt receptor FZD8 using surface plasmon resonance (SPR). Cellular functional assays demonstrated that carbamazepine can suppress FZD8-mediated Wnt/β-catenin signaling. We determined the crystal structure of the complex at 1.7 Å resolution, which reveals that carbamazepine binds at a novel pocket on the FZD8 CRD. The unique residue Tyr52 discriminates FZD8 from the closely related FZD5 and other FZDs for carbamazepine binding. The first small molecule-bound FZD structure provides a basis for anti-FZD drug development. Furthermore, the observed carbamazepine-mediated Wnt signaling inhibition may help to explain the phenomenon of bone loss and increased adipogenesis in some patients during long-term carbamazepine treatment.

Cochlear Function in Adults with Epilepsy and Treated with Carbamazepine

Background: Epilepsy is a chronic medical disease and is associated with comorbid adverse somatic conditions due to epilepsy itself or its long-term treatment. Objectives: This study evaluated cochlear function in patients with idiopathic epilepsy and treated with carbamazepine (CBZ). Patients and Methods: Included were 47 patients (mean age = 34.56 ± 7.11 years and duration of illness = 17.84 ± 7.21 years) and 40 healthy subjects. They underwent pure-tone audiometry and transient evoked otoacoustic emission (TEOAE) analyses. Results: Hearing loss (mainly bilateral mild) was reported in one third of patients. Compared to controls, patients had lower TEOAE amplitudes at 1.0–4.0 kHz particularly at high frequencies (3 and 4 kHz). Significant correlations were identified between TEOAE amplitudes with CBZ dose (at 3 kHz: r = –0.554, p = 0.008; at 4 kHz: r = –0.347, p = 0.01), its serum level (at 4 kHz: r = –0.280, p = 0.045) and duration of treatment (at 3 kHz: r = –0.392, p = 0.008; at 4 kHz: r = –0.542, p = 0.001). Conclusions: Long-term CBZ treatment may result in cochlear dysfunction and auditory deficits.

Dose-Dependent Carbamazepine-Induced Agranulocytosis Following Bariatric Surgery (Sleeve Gastrectomy): A Possible Mechanism

Agranulocytosis is a serious, potentially life-threatening disorder that frequently occurs as an adverse reaction to drugs. Carbamazepine is a known culprit and a very common drug used as an anti-epileptic. The case is reported of a 49-year-old epileptic woman on long-term carbamazepine treatment who developed agranulocytosis following bariatric surgery (sleeve gastrectomy), likely due to carbamazepine-altered oral exposure resulting in high plasma levels. A reduction in the drug dose resulted in normalization of carbamazepine levels and improvement of the neutrophil count without the use of granulocyte colony-stimulating factor (GCSF). This observation could explain a dose-dependent drug-induced cytopenia rather than an idiosyncratic effect. This is the first case of drug-induced agranulocytosis following bariatric surgery, which illustrates the need for careful postoperative monitoring of specific drugs. A literature search of the use of GCSF in agranulocytosis and the status of drug absorption following bariatric surgery was also performed.

New TB treatments hiding in plain sight.

As tuberculosis (TB) toll is revised upward according to the WHO's last estimates, the lack of vaccine strategy and the lengthy antibiotic treatments that unfortunately promote the emergence of drug resistance are a major set back in the fight against this pathogen. In this issue of EMBO Molecular Medicine, Schiebler et al (Mtb) propose a novel and compelling new approach to target Mycobacterium tuberculosis (Mtb) by pharmacologically stimulating intracellular mycobacteria clearance through autophagy.

Autophagy Enhancer Carbamazepine Alleviates Memory Deficits and Cerebral Amyloid-β Pathology in a Mouse Model of Alzheimer's Disease

Autophagy plays an important role in Alzheimer's disease (AD). It has been reported that autophagic flux is altered in patients with AD, and application of the autophagy enhancer rapamycin may alleviate the cognitive impairment and amyloid-β (Aβ) neuropathology in transgenic animal model of AD. Since rapamycin is also an immune suppressor, there is a concern that long-term use of rapamycin may bring severe unwanted side effects. The aim of this study is to test if carbamazepine (CBZ), an anti-epileptic drug that has a potent autophagy enhancement effect, has anti-AD effects in APP(swe)/PS1(deltaE9) transgenic mice model of AD. We found that APP(swe)/PS1(deltaE9) mice display increased autophagic activity accompanied by decreased mTOR activity. After three months treatment with CBZ in the APP(swe)/PS1(deltaE9) mice, we demonstrated that the spatial learning and memory deficits in these mice are significantly alleviated. We also documented that the cerebral amyloid plaque burden and Aβ42 levels in these mice are significantly reduced. Furthermore, we showed that CBZ significantly enhances the autophagic flux in the APP(swe)/PS1(deltaE9) mice which is unlikely via mTOR-dependent autophagy pathway. These data suggest that long-term CBZ treatment may have a protective effect in AD mouse model possibly through enhancing the autophagic flux.

Effects of SCN1A and GABA Receptor Genetic Polymorphisms on Carbamazepine Tolerability and Efficacy in Chinese Patients with Partial Seizures: 2‐Year Longitudinal Clinical Follow‐Up

To investigate the tolerability and efficacy of carbamazepine treatment in patients with partial-onset seizures and the association with polymorphisms in the sodium channel α-subunit type 1 (SCN1A), and gamma-aminobutyric acid (GABA) receptor genes among the Chinese Han population. 448 patients were genotyped for single nucleotide polymorphisms selected of the SCN1A and GABA-receptor genes. Monotherapy with carbamazepine (CBZ) was administered to the patients. The effectiveness of CBZ treatment was evaluated with regard to efficacy by the decrease in seizures and tolerability by retention rates. SCN1A rs3812718 A/G with CBZ tolerability (P= 0.038) throughout 24 months of clinical follow-up and the GABRA1 rs2290732 A/G were significantly associated with CBZ tolerability (P= 0.001). The maintenance dose and serum level of CBZ in AA genotype carriers of rs3812718 A/G were significantly higher than those of GG genotype carriers between 3 and 12 months of follow-up. The proportion of AA genotype carriers of rs2298771 A/G with seizure free was significantly higher than that of AG+GG genotype carriers from 3 months to 15 months of follow-up (P < 0.05). rs3812718 A/G and rs2290732 A/G polymorphisms affected the tolerability of CBZ. rs2298771 A/G was associated with efficacy of CBZ treatment.

Influence of carbamazepine on serum thyroxine and triiodothyronine in patients with epilepsy.

Hypothyroidism induced by anti-epileptic drug treatment gave rise to thyroid function test studies in patients treated with carbamazepine (CBZ) only. In 42 patients on long-term CBZ treatment thyroxine (T4), free T4-index (FT4I), and triiodothyronine (T3) concentrations in serum were significantly lower than in controls, while triiodothyronine uptake (T3U) and thyrotropin (TSH) concentrations did not differ between patients and controls. In 12 patients starting on CBZ, means T4, calculated FT4 and thyroxine binding globulin (TBG) were 1-5 months later reduced compared to the initial levels. Thus, CBZ reduced thyroid hormones, TBG and FT4I. A CBZ-induced increase in conversion and metabolism of the thyroid hormones could explain this effect. The normal T3U values and decreased concentrations of TBG make a competitive CBZ binding to TBG less probable. Although the thyroid hormones levels were found lowered in the patients, all remained clinically euthyroid during the study.

Antiepileptic drugs alter reproductive endocrine hormones in men with epilepsy

Disturbances of reproductive endocrine hormones are more often found in men with epilepsy than in the general population. There is an ongoing debate whether this can be attributed to chronic use of antiepileptic drugs or to the epilepsy itself. The aim of the present study was to evaluate the degree of endocrine disturbances in men with epilepsy compared with healthy controls, and to investigate whether there was a drug-specific effect of valproate (VPA) or carbamazepine (CBZ). Men with epilepsy, 20-40 years old, having used either VPA (n = 16) or CBZ (n = 19) as monotherapy for >2 years were included and compared with age-matched controls. Men with epilepsy (VPA + CBZ) had significantly lower FSH values and higher C-peptide values compared with controls. Regarding possible drug-specific effects, the VPA treated patients had significantly higher dehydroepiandrosterone (DHEAS) levels and lower FSH and LH concentrations compared with the controls, whereas there were no differences in testosterone, testosterone/sexhormone-binding globulin (SHBG) ratio or androstenedione levels. Men on VPA also had significantly lower free carnitine/total carnitine, which may have implications for sperm motility, and also higher insulin and C-peptide concentrations. The CBZ treated patients had significantly lower testosterone/SHBG ratio than the controls. Compared with the CBZ treated patients, men on VPA had significantly higher DHEAS concentrations and lower levels of follicle stimulating hormone (FSH), luteinizing hormone (LH) as well as a lower free carnitine/total carnitine ratio. A marked age dependency was found in all three groups regarding several of the endocrine hormones. In conclusion, drug-specific endocrine effects of VPA and CBZ were found in men with epilepsy. Long-term VPA treatment leads to significant changes in DHEAS, FSH, LH, insulin, C-peptide and carnitine ratio. Long-term CBZ treatment leads to significant lower testosterone/SHBG ratio. A strict age matching were found to be of importance in the evaluation of endocrine function in men.

Reproductive dysfunction in women with epilepsy

Reproductive endocrine disorders, such as polycystic ovary syndrome (PCOS), hypothalamic amenorrhea, premature menopause, and hyperprolactinemia, are reported to be more common in women with epilepsy than in the general female population. Epilepsy itself may affect reproductive endocrine function. For example, the prevalence of PCOS appears to be high even among women with epilepsy who do not take antiepileptic drugs (AEDs). However, AEDs also induce various changes in endocrine function. The hepatic enzyme-inducing AEDs phenytoin and carbamazepine (CBZ) have been shown to increase serum levels of sex hormone-binding globulin (SHBG). This increase leads in time to a diminished estradiol:SHBG ratio and decreased bioactivity of estradiol, which may result in menstrual disorders in some women receiving long-term CBZ treatment. Enzyme-inducing AEDs also can reduce the efficacy of oral contraceptives. In women with epilepsy who are treated with valproate (VPA), especially in those who have gained weight during treatment, polycystic ovaries, hyperandrogenism, and menstrual disorders appear to be common. After the start of VPA therapy in a woman with epilepsy, the length of the menstrual cycles and body weight should be monitored. Transvaginal ultrasonography of the ovaries is indicated if the menstrual cycles are prolonged and serum testosterone levels are elevated, especially if there is associated weight gain. The endocrine effects of the new AEDs have not been widely studied. However, treatment with these agents should be considered in women who develop reproductive endocrine dysfunction during treatment with the older AEDs.

Dietary Carbamazepine Administration Decreases Liver Pyruvate Carboxylase Activity and Biotinylation by Decreasing Protein and mRNA Expression in Rats

Clinical data demonstrate that certain antiepileptic drugs including carbamazepine (CBZ) decrease serum biotin concentration 45-50% and increase urine and serum organic acids, which is suggestive of reduced function of biotin-dependent enzymes. However, little is known about biotin-dependent enzyme function at the tissue level in patients undergoing long-term CBZ treatment. We recently established that dietary CBZ administration to rats increases brain lactate and also decreases specific enzymatic activity and the relative abundance of hepatic biotinylated pyruvate carboxylase (PC). To examine the mechanism of altered activity and abundance of biotinylated PC, the effect of orally administered CBZ on hepatic PC protein and mRNA expression was examined in rats consuming a physiologically relevant level of dietary biotin (0.06 mg/kg). Rats were fed 0 or 3.4 g CBZ/kg diet for 28 d, a dose designed to achieve clinically relevant serum CBZ concentrations. Hepatic biotinylated PC and PC activity were significantly reduced by approximately 43 and 30%, respectively, in the drug-treated group. Liver PC protein expression and mRNA were approximately 43 and 35% lower, respectively, in the drug-treated group than in controls. Brain biotinylated PC was significantly lower (29%), whereas specific enzymatic activity was 175% higher in rats consuming the 3.4 g CBZ/kg diet. Brain, but not serum, lactate was significantly higher in rats consuming CBZ. Taken together, the lower PC protein and mRNA expression provide a plausible biochemical mechanism to explain the decreased abundance of biotinylated hepatic PC observed in previous studies.

Atracurium–induced neuromuscular block is not affected by chronic anticonvulsant therapy with carbamazepine

Patients on chronic anticonvulsant therapy are relatively resistant to some nondepolarizing neuromuscular blockers. Because of the controversial reports on atracurium, the purpose of the present study was to determine the effect of long-term carbamazepine treatment on the neuromuscular block produced by this muscle relaxant. Eighteen otherwise healthy individuals scheduled for neurosurgical interventions were studied. Eight patients had received carbamazepine for an average of 41 weeks (range 4-156 weeks) prior to surgery. Ten patients without carbamazepine exposure served as controls. After premedication with oral diazepam, anaesthesia was induced with fentanyl and thiopental and maintained with nitrous oxide and isoflurane in oxygen. Atracurium was given for neuromuscular blockade and the evoked electromyogram (EMG) was recorded with a Datex Monitor NMT. The lag time, the onset time, the duration 10%, 25%, 50%, 75% and the interval 25-75% did not differ between the groups. Our results with atracurium differ from previous data demonstrating an influence of carbamazepine therapy on the pharmacokinetics and/or pharmacodynamics of other non-depolarizing muscle relaxants. As documented in this study, atracurium produces adequate neuromuscular block in patients chronically exposed to carbamazepine. Chronic carbamazepine therapy does not influence the onset time and duration of action of atracurium-induced neuromuscular block.

Serum Steroid Hormones and Pituitary Function in Female Epileptic Patients During Carbamazepine Therapy

Ten regularly menstruating women with epilepsy were studied in a 12-month prospective follow-up study to evaluate the short-term effects of carbamazepine (CBZ) on serum sex hormone balance and pituitary function. Thirteen female epilepsy patients receiving long-term CBZ monotherapy (mean medication duration 5.3 years) were also studied. Controls were 17 regularly menstruating healthy volunteers. Untreated patients had higher free testosterone (FT) and luteinizing hormone (LH) serum concentrations than control subjects, whereas the other parameters did not differ between these two groups. However, serum sex hormone binding globulin (SHBG) levels increased and dehydroepiandrosterone sulfate (DHEAS) levels decreased during CBZ treatment. Although calculated free androgen index (FAI) decreased during CBZ therapy, the directly measured FT levels remained unaltered. These changes were found after 2 months and continued after 12 months of CBZ treatment. Moreover, patients with long-term CBZ also had high SHBG levels, low serum DHEAS levels, and low FAI values. Basal LH serum levels decreased during the first year of CBZ treatment and luteinizing hormone-releasing hormone (LH-RH)-stimulated LH concentrations were lower after 2 months of CBZ treatment. Although the serum basal follicle-stimulating hormone (FSH) and prolactin (PRL) levels were unaffected during the first year of CBZ therapy, the LH-RH-stimulated FSH concentrations and metoclopramide (MC)-stimulated PRL concentrations were lower after 12 months of CBZ treatment than before CBZ. Both basal and stimulated gonadotropin and PRL serum levels of long-term CBZ patients were unaffected. No changes were found in estradiol (E2), testosterone (T), or cortisol (C) serum concentrations during short or long-term CBZ treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Exaggerated corticotrophic cell response to human corticotropin-releasing hormone in two patients during long-term carbamazepine treatment

Carbamazepine, a tricyclic anticonvulsant with chemical resemblance to imipramine, has been recently successfully introduced as a prophylactic agent and acute treatment modality for manic-depressive illness (Ballenger and Post 1980; Okuma 1983; Post et al. 1984). The interest in carbamazepine emerges from its ability to dampen paroxysmal neuronal activity not only in epilepsy, but also in those particular systems that appear to be involved in the etiology of episodic affective illness (Post et al. 1983). These affective episodes are frequently associated with endocrine irregularities of the hypothalamic-pituitary-adrenocortical (HPA) axis, including increased cortisol secretion (Halbreich et al. 1985), nonsuppression of corticosteroids following dexamethasone, and blunted corticotropin (ACTH) release after stimulation with human corticotropin-releasing hormone (h-CRH) (Holsboer et al. 1986, 1987) or its heterologous ovine analog (Gold et al. 1986). Some recent reports have shown that carbamazepine treatment may interfere with HPA physiology, as it induces Dexamethasone Suppression Test (DST) nonsuppression (Privitera et al. 1982; Rubinow et al. 1984) and enhances mean urinary free cortisol secretion (Rubinow et al. 1986). To further explore the pathophysiology of this phenomenon of an altered HPA function, we conducted h-CRH tests in six patients in stable remission from major depression during long-term carbamazepine treatment to look for possibly drug-induced modulations. In two of six patients, we observed highly abnormal ACTH responses.

Effects of long-term carbamazepine treatment on water metabolism and plasma vasopressin concentration.

Plasma osmolality, sodium and vasopressin were measured in 7 patients before and during long-term treatment with carbamazepine, under resting conditions, and following an oral water load of 20 ml/kg body weight. During carbamazepine treatment, the ability to excrete the oral water load was decreased, the urine/plasma osmolality ratio was higher, and the free water clearance was lower. In two patients, the ability to excrete the oral water load was severely impaired, and the free water clearance remained negative following water loading. Plasma osmolality and sodium concentration were significantly lower during carbamazepine administration, but despite this the plasma vasopressin concentration remained unchanged or was even slightly increased. Four patients showed inappropriately high vasopressin concentrations in relation to the corresponding plasma osmolality when taking carbamazepine. The findings suggest a decrease in plasma osmolality during carbamazepine treatment, which might account for the inappropriate secretion of vasopressin. The latter might cause clinical symptoms of water intoxication, as has previously been reported in a few patients on carbamazepine therapy.