Carbamazepine and Weight Loss: What You Need to Know for Effective Results

Carbamazepine is a medication primarily used to treat epilepsy and bipolar disorder. It works by balancing signals between nerves, helping to prevent seizures and manage nerve pain. Available in various forms, including tablets, chewable tablets, suspensions, and extended-release options, carbamazepine requires careful storage at room temperature, away from light and moisture.

While carbamazepine is effective for its intended purposes, it's crucial to be aware of potential side effects and interactions. Regular check-ups with a doctor are essential to monitor progress and detect any unwanted effects through blood and urine tests.

Potential Side Effects and Precautions

Common Side Effects:

Dizziness
Drowsiness
Unsteadiness while walking
Nausea or vomiting

If these side effects become bothersome, consult your healthcare provider.

Serious Side Effects:

Severe Skin Reactions: Including Acute Generalized Exanthematous Pustulosis (AGEP), Stevens-Johnson Syndrome (SJS), and Toxic Epidermal Necrolysis (TEN). Discontinue carbamazepine and seek immediate medical attention if a rash develops or if you experience painful, red, or purple skin that looks burned and peels off, or flat red rash or blisters on the skin, mouth, nose, and genitals, or red, painful, watery eyes.
Blood Disorders: Such as agranulocytosis, aplastic anemia, low platelet levels (thrombocytopenia), and low white blood cell levels (leukopenia). Seek immediate medical attention if you experience fever, shortness of breath, pale or yellowish skin, easy bruising or bleeding, frequent infection, unusual weakness or tiredness, dizziness, lightheadedness, headache, or fast or abnormal heartbeat.
Heart Rhythm Changes: Carbamazepine may cause heart rhythm problems, especially in individuals with existing heart disease or those taking other medications that affect the heart. Get emergency help for chest pain, shortness of breath, feeling dizzy, lightheaded, or fainting, or changes in your heart rate or rhythm.
Liver Damage (Hepatotoxicity): Regular blood tests are necessary to monitor liver function. Report symptoms like nausea or vomiting, stomach or belly pain, fever, weakness or unusual tiredness, itching, loss of appetite, light-colored poop, dark-colored pee, or jaundice.
Low Sodium Level (Hyponatremia): Symptoms include headache, drowsiness, muscle weakness or cramps, nausea, vomiting, loss of appetite, tiredness or sleepiness, dizziness, weight gain, restlessness or irritability, change in your mental condition such as hallucinations, confusion, decreased awareness, or alertness or seizures.
Suicidal Thoughts or Actions: Seek immediate help if you experience new or increased thoughts of suicide or death, suicide attempt, or new or increased feelings of anxiety, depression, or other unusual changes in your mood or behavior.
Severe Allergic Reactions: Including DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms), which can affect multiple organs. Stop the medicine and get help right away if you have any of the following symptoms of a serious allergic reaction such as breathing problems or wheezing, swelling of the face, lip, mouth, tongue, or throat or racing heart, itching, skin rash or pale red bumps on the skin called hives, fever or general ill feeling, swollen lymph nodes or shortness of breath, trouble swallowing, or throat tightness or swelling in your feet, ankles, or legs or nausea or vomiting or dizziness, feeling lightheaded, or fainting or stomach cramps or joint pain or dark-colored pee or Your skin or the whites of your eyes turning yellowish in color (also called jaundice).

Important Precautions:

Pregnancy: Using carbamazepine during pregnancy can harm the unborn baby. Use effective birth control to prevent pregnancy. If you become pregnant while using carbamazepine, inform your doctor immediately and consider registering with the North American Antiepileptic Drug Pregnancy Registry.
Breastfeeding: Carbamazepine passes into breast milk. Consult your healthcare provider about whether to stop breastfeeding or carbamazepine.
Drug Interactions: Carbamazepine interacts with many medications, including MAOIs, nefazodone, and certain HIV/AIDS medicines. Inform your doctor about all medications, supplements, and herbal products you are taking.
Alcohol and CNS Depressants: Carbamazepine can enhance the effects of alcohol and other CNS depressants, leading to increased drowsiness and dizziness.
Photosensitivity: Carbamazepine may increase sensitivity to sunlight. Use sun protection measures, such as wearing protective clothing, sunglasses, and sunscreen with an SPF of at least 15.

Who Should Not Use Carbamazepine:

Individuals with allergies to carbamazepine or tricyclic antidepressants.
People with bone marrow depression.
Those currently taking certain medications like MAOIs or nefazodone.
People with fructose intolerance (if the medication contains sorbitol).

Carbamazepine and Weight Gain: Exploring the Connection

While carbamazepine is known for its therapeutic benefits, it has also been associated with weight gain in some patients. Studies suggest that carbamazepine can influence adipogenesis, the process by which pre-adipocytes differentiate into mature adipocytes, which are cells specialized for storing fat.

The Role of Adipogenesis

Adipogenesis is a crucial step in the development of obesity. It involves the formation of new fat cells, which increases the body's capacity to store fat. This process is regulated by various factors, including transcription factors and signaling pathways.

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Carbamazepine's Impact on Adipogenesis:

Increased Expression of Adipogenic Factors: Research indicates that carbamazepine can increase the expression levels of peroxisome proliferator-activated receptor γ (PPARγ), CCAAT/enhancer-binding protein β (C/EBPβ), and fatty acid synthase (FASN). These factors play key roles in adipocyte differentiation and lipid accumulation.
Inhibition of Wnt/β-catenin Signaling: Carbamazepine has been shown to inhibit the Wnt/β-catenin signaling pathway, which is a negative regulator of adipogenesis. By suppressing this pathway, carbamazepine promotes adipocyte differentiation.
Reduced β-catenin Expression: Carbamazepine reduces β-catenin expression by lowering the levels of phospho-low density lipoprotein receptor-related protein 6 (p-LRP6) and phospho-glycogen synthase kinase 3β (p-GSK3β) in Wnt/β-catenin signaling.
Decreased Wnt mRNA Expression: Carbamazepine reduces Wnt mRNA expression and decreases the promoter activities of TCF, the target of β-catenin during adipogenesis.

Clinical Observations:

Weight Gain in Patients: Clinical studies have reported that carbamazepine treatment can lead to an increase in body weight. For example, one study found that carbamazepine treatment of 600-1000 mg/day for 8 weeks increased body weight from 14.6% to 22.4% in epileptic patients.
Increased Body Mass Index (BMI): Another study showed that carbamazepine treatment with 400-800 mg/dL for 2-10 years in primary idiopathic epileptic children increased body mass index by 15%.

Effects on Cholesterol Metabolism:

Recent studies suggest that carbamazepine may affect cholesterol metabolism by increasing the levels of total cholesterol (TC), high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and triglyceride concentrations in serum.

The Study of Carbamazepine on Adipocyte Differentiation

To further investigate the effect of carbamazepine on adipogenesis, a study was conducted using 3T3-L1 cells, which are commonly used to study adipocyte differentiation.

Methods:

Cell Culture: 3T3-L1 cells were maintained in Dulbecco’s modified Eagle’s medium (DMEM) with 10% calf serum, seeded onto 6-well-plates and cultured for 2 days. After that, pre-adipocytes were maintained in DMEM with 10% FBS. For adipocyte differentiation, pre-adipocytes were treated with DMI (dexamethasone, 3-isobutyl-1-methylxanthine, insulin) cocktail containing 1 μM dexamethasone (DEX), 0.5 mM 3-isobutyl-1-methylxanthine (IBMX), and 5.0 μg/mL insulin for 2 days. Cells were further incubated with 5.0 μg/mL insulin and treated with fresh media every 2 days. The differentiation process to mature adipocyte was completed after 6 days of differentiation. Human embryonic kidney (HEK) 293T cells were maintained in DMEM supplemented with 10% FBS in 5% CO2 at 37 °C, and used for luciferase assay.
Carbamazepine Treatment: The carbamazepine was purchased from Sigma-Aldrich (St. Louis, MO, USA). The stock concentration of carbamazepine was 100 mM, dissolved in 100% ethanol. The stock solution was diluted to a concentration of 80 μM with culture medium, and serially diluted to concentration of 40, 20, and 10 μM before use. We used an ethanol solution for vehicle (Veh) treatment, and carried out serial dilution in the same way as carbamazepine solution. Ethanol levels were kept below 0.5% in all cells, which did not affect differentiation. 3T3-L1 cells were treated with carbamazepine on day 0 of differentiation process. When the differentiation medium was replaced at 2-day intervals, carbamazepine was added together at a similar concentration.
Oil Red O Staining: The Oil Red O powder was purchased from Sigma-Aldrich (St. Louis, MO, USA). Fully differentiated cells were fixed with 10% formalin for 1 h at room temperature (RT), rinsed with 60% isopropanol, and stained with filtered Oil Red O for 20 min. These cells were then visualized under a light microscope. The absorbance of the Oil Red O eluted by adding 100% isopropanol was measured at 500 nm wavelength by spectrophotometry.
Western Blot Analysis: Whole cell extracts were fractionated by SDS-PAGE, and transferred to a polyvinylidene fluoride (PVDF) membrane using a transfer apparatus, according to the manufacturer’s protocol (Bio-Rad, Hercules, CA, USA). The membranes were incubated with primary antibodies in Tris-Buffered Saline, and 0.1% Tween 20 detergent (TBS-T) containing 3% bovine serum albumin for overnight at 4 °C. After washing three times for 10 min with TBS-T, the membranes were incubated with secondary antibodies for 1 h at RT, followed by washing thrice with TBS-T, and developed with ECL system (Thermo, Waltham, MA, USA), according to the manufacture’s protocol.
MTT Assay: The 3T3-L1 cells were seeded onto 96-well-plates and maintained in growth media for 24 h. The medium was replaced and cells were incubated with various concentrations of carbamazepine for 24 h. Cells were further incubated at 37 °C for 1 h with 1 mg/mL 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). Precipitates were dissolved with 200 μL DMSO. Cell viability was then measured at 570 nm wavelength using a microplate reader.
RT-PCR: Total RNA was extracted using Trizol reagent (Invitrogen, Waltham, MA, USA), according to the manufacturer’s instructions. The cDNA synthesis was carried out with 1 μg of total RNA using the RevertAid First cDNA Synthesis kit (Thermo). Gene expression was determined by RT-PCR (SimpliAmp Thermal Cycler, Applied Biosystem, Foster City, CA, USA) using gene specific primers.
Quantitative PCR: The quantitative PCR analysis was performed with QuantStudio 6 Flex System Applied Biosystem (Carlsbad, CA, USA). The PCR mixture contains cDNA (2 μg), SYBR green qPCR PreMIX (Enzynomics, Seoul, Korea) primers, and ultrapure RNase free water. PCR reactions were subjected to 45 cycles of 95 °C for 15 min, 95 °C for 15 s, and 60 °C for 1 min.
siRNA Transfection: The β-catenin siRNA (si-β-catenin) and non-silencing siRNA (si-NS) were purchased from Macrogen (Seoul, Korea). For siRNA transfection, pre-adipocytes were seeded onto 6-well-plate for 24 h. Cells were transfected with either si-β-catenin or si-NS at a concentration of 50 nM using Lipofectamine RNAi max (Invitrogen, Waltham, MA, USA), according to the manufacturer’s protocol.
Gene Overexpression: The plasmid expressing β-catenin was purchased from Addgene (Watertown, MA, USA). For gene overexpression, cells were transfected with plasmids expressing either β-catenin or pcDNA3 (vector) using Lipofectamine 2000 (Invitrogen), according to the manufacturer’s protocol.
Luciferase Assay: The HEK293T cells were transfected with reporter vector and expression plasmid using TransIT-LT1 (Mirus, Singapore). Cells were lysed with cell lysis buffer (Promega, Madison, WI, USA) at two days after addition of differentiation stimulus. Luciferase activity was determined by luminometer (Promega) according to the manufacturer’s instruction.
Statistical Analysis: Data are presented as mean ± standard error of the mean (SEM). The main and interactive effects were analyzed using Student’s t-test (unpaired, two-tail). Differences between individual group means were analyzed using two-tailed t-tests. P value of less than 0.05 was considered significant.

Results:

Carbamazepine Increases Adipocyte Differentiation: Oil Red O staining revealed that the number and size of lipid droplets were markedly increased in carbamazepine treated cells, compared to those in vehicle-treated cells. The enhancing effect of carbamazepine on adipogenesis was first observed at concentration of 10 μM. The highest level of lipid accumulation was observed after treatment with carbamazepine at 40 μM. However, a high concentration of carbamazepine (80 μM) did not further enhance lipid accumulation.
Time-Dependent Effect: The mRNA expression levels of PPARγ, C/EBPβ, ACC, and FASN were increased by treatment with carbamazepine in a time-dependent manner. Protein levels of PPARγ were also increased by carbamazepine in a time-dependent manner. Protein levels of FASN were enhanced in the late stage (day 7), whereas those of C/EBPβ were increased in the early stage (days 2-4) of adipocyte differentiation upon treatment with carbamazepine
Cell Viability: At concentration up to 80 μM, cell viability was not significantly affected by carbamazepine
Late Stage Differentiation: Carbamazepine was more effective at late phase rather than at early phase. These results suggest that carbamazepine primarily has effect on the late stage of adipocyte differentiation and enhances adipogenesis by controlling PPARγ expression.

Other Considerations

Effects of Weight Loss on Carbamazepine Pharmacokinetics

A study on obese subjects showed that weight loss could significantly alter carbamazepine pharmacokinetics. After a mean weight reduction of 30.0 kg over 11.3 months, the plasma elimination half-life of carbamazepine was significantly shortened, and the total plasma clearance increased.

Implications for Obese Patients:

Whenever carbamazepine is initiated in obese subjects, steady-state concentrations should be expected only after twice the time required to achieve steady state in lean subjects.

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