Zonisamide, an anticonvulsant medication primarily used to treat partial seizures in adults with epilepsy, has garnered attention for its off-label use in weight management. While its primary function is to stabilize electrical activity in the brain, clinical research suggests that zonisamide can also promote weight loss when combined with lifestyle modifications. This article delves into the mechanisms by which zonisamide may contribute to weight loss, its benefits, potential side effects, and important precautions.
What is Zonisamide?
Zonisamide is a sulfonamide-derived anticonvulsant medication available in immediate-release capsules, extended-release capsules, and an oral suspension. Initially approved for seizure control, it has been increasingly prescribed off-label for long-term weight management due to its ability to curb appetite and reduce cravings. The medication's long half-life, approximately sixty hours, allows for convenient once-daily dosing for most patients, promoting adherence over extended periods. It is also sold under the brand names Zonegran® and Zonisade®.
How Zonisamide Works for Weight Loss
The precise mechanism by which zonisamide promotes weight loss is not fully understood, but it appears to involve several neural actions that converge on appetite regulation. Zonisamide blocks voltage-gated sodium channels, dampens excitatory glutamate signaling, enhances inhibitory GABA activity, and weakly inhibits carbonic anhydrase enzymes.
These combined effects quiet neuronal circuits that drive hunger and food reward. A modest increase in metabolic rate may also contribute to a negative energy balance, further aiding weight loss.
Clinical Effectiveness of Zonisamide for Weight Loss
Randomized, placebo-controlled studies in adults with obesity have demonstrated that daily doses of 200 mg to 400 mg of zonisamide can augment lifestyle-based weight loss by an additional four to six kilograms over six to twelve months. Participants who continued treatment beyond one year often experienced further gradual reductions. Lower doses, ranging from 100 mg to 200 mg, can still be effective, particularly in individuals sensitive to cognitive side effects, although the magnitude of weight loss may be smaller.
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In one year-long clinical trial, participants who took a 200 mg daily dose lost an average of 3.9% of their total body weight, while those who took 400 mg daily shed an average of 6.8%. It is important to note that all participants in the study also implemented diet and lifestyle changes under the guidance of a dietitian. Safe weight loss is generally considered to be one to two pounds per week.
Additional Benefits of Zonisamide
Beyond treating certain seizures and promoting moderate weight loss, studies suggest that zonisamide may offer additional health benefits. These include:
- Heart Health Support: Zonisamide may help lower blood pressure, triglyceride levels, and blood sugar levels.
- Improved Sleep: It may reduce obstructive sleep apnea.
How to Use Zonisamide for Weight Loss
Zonisamide should be taken strictly as instructed by a qualified health care provider. Typically, it is taken daily, either as a single dose or divided into two doses. The medication should be stored at room temperature, away from heat and light.
Dosing
Zonisamide is typically available in capsule form, with doses of 25 mg, 50 mg, or 100 mg. A health care provider will customize the dosing based on individual factors, such as weight and tolerance to the medication. The dose may be gradually increased over time. To help prevent kidney stones, it is recommended to take each dose with a full glass of water, with or without food. The capsules should not be crushed, chewed, or divided.
If a dose is missed, it is important to consult with a health care provider for guidance. A double dose should never be taken. If discontinuing the medication is desired, it is crucial to consult with a health care provider to guide a safe tapering process.
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Potential Side Effects
Many individuals experience no side effects while taking zonisamide. However, some common side effects may include:
- Dizziness and lightheadedness
- Fatigue and drowsiness
- Language and speech difficulty
- Metallic or unpleasant taste in the mouth
- Nausea
Other possible side effects include:
- Trouble sleeping
- Lack of coordination
- Loss of appetite and weight loss
- Diarrhea
- Double vision
- Mood changes, such as depression or irritability
- Difficulty concentrating
These symptoms may subside as the body adjusts to the medication.
Precautions and Interactions
It is crucial to inform a health care provider about any allergies, especially to sulfa drugs, before taking zonisamide. A potentially fatal reaction can occur, including a life-threatening skin rash or a blood cell condition.
Before using zonisamide, it is essential to disclose your medical history to your health care provider, especially if you have kidney disease, liver disease, long-term diarrhea, lung or breathing problems, metabolic acidosis or diabetic ketoacidosis, high ketone levels in your blood or urine, use insulin or other diabetes medications, and/or have a history of psychiatric disorders or suicidal thoughts.
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It is also important to discuss any plans for pregnancy, or if you are pregnant or breastfeeding, with your health care provider.
Until you know how zonisamide affects you, avoid driving, operating heavy machinery, or performing any hazardous tasks.
Some medications, herbal supplements, and foods can interact with zonisamide, including:
- Carbonic anhydrase inhibitors (such as acetazolamide)
- Orlistat
- Phenobarbital
- Primidone
- Rifamycins
- Glucocorticoids
- St. John's wort
- Grapefruit or grapefruit juice
Alcohol should be avoided while taking zonisamide.
Zonisamide Use and Impact on Vascular Risk Factors and Hepatic Steatosis
Research has explored the effects of zonisamide (ZNS) therapy on reducing obesity and decreasing risks of vascular diseases and hepatic steatosis. A study assessed clinical and metabolic indicators, including body weight, body mass index (BMI), serum lipid profiles, glycated hemoglobin (HbA1c), homocysteine, and an inflammatory marker, high-sensitivity C-reactive protein (hs-CRP), at baseline and after 12 and 24 weeks of treatment. Nonalcoholic fatty liver disease was evaluated using the hepatic steatosis index (HSI).
The results showed a body weight reduction of ≥5% in 24.6% and 32.8% of patients after 12 and 24 weeks of ZNS treatment, respectively. After adjusting for age, sex, time, and the corresponding dependent variable at baseline, the generalized estimating equation analysis revealed that body weight, BMI, serum levels of HbA1c, triglycerides, hs-CRP, and the index for HSI were significantly declined.
Zonisamide: A Detailed Look at its Properties and Mechanisms
Zonisamide (1,2-benzisoxazole-3-methanesulfonamide, ZNS) is a unique chemical with antiepileptic and antioxidant properties. It was first approved in Japan in 1989 for treating epilepsy. While the precise mechanisms of action remain unclear, it's suggested that the blockage of voltage-gated sodium and T-type calcium channels underlies ZNS activity. ZNS is considered a broad-spectrum AED with favorable efficacy and is well-tolerated by patients with epilepsy. It has been approved in many countries as a monotherapy or adjunctive therapy for focal or generalized onset epilepsy in adults and children.
In addition to its antiepileptic property, ZNS is also reported to have antioxidant activities, which may protect neurons from oxidative damage, stabilize the neuronal membranes, and prevent epileptogenic focus formation. Pharmacological therapy in patients with epilepsy is usually associated with weight changes that may increase morbidity and drug noncompliance. ZNS and topiramate may lead to body weight loss; valproic acid, gabapentin, pregabalin, vigabatrin, and carbamazepine may increase weight gain.
Obesity and metabolic syndromes are associated with increased risks of cardiovascular diseases, cerebrovascular disease, type 2 diabetes, arthritis, cancers, and decreased life expectancy. They are common comorbidities in adult, adolescent, and pediatric patients with epilepsy. Long-term AED therapy may increase body weight, body mass index (BMI), metabolic consequences, and oxidative stress in patients with epilepsy, which may further lead to potential vascular risks and acceleration of atherosclerosis, particularly in patients who received liver enzyme-inducing AEDs such as phenobarbital, phenytoin, and carbamazepine. Thus, AEDs that promote weight gain and metabolic consequences should be avoided in patients with epilepsy who are also obese or with metabolic syndromes.
Body weight reduction is a well-recognized effect of ZNS therapy in patients with epilepsy or obese adults. Although enzyme-inducing AEDs may enhance clearance of ZNS, ZNS is not considered as an inducer of the liver enzyme system. Since ZNS is a non-enzyme-inducing AED that may reduce body weight, research aims to evaluate whether biochemical markers of vascular risk, along with body weight, are reduced with ZNS treatment in patients with epilepsy. Additionally, it evaluates whether ZNS therapy attenuates nonalcoholic fatty liver disease by measuring the fatty liver index and hepatic steatosis index (HSI).
Study on Zonisamide Effects on Weight and Vascular Risk Factors
A prospective case-control study was conducted at Kaohsiung Chang Gung Memorial Hospital in Taiwan. From June 2016 to May 2017, 126 adult patients with focal onset epilepsy (aged between 18 and 65 years) who visited the Epilepsy Outpatient Clinic of Kaohsiung Chang Gung Memorial Hospital were recruited. Among them, 81 patients (39 females and 42 males) who received ZNS monotherapy or adjunctive therapy were classified into the ZNS-treated group. Forty-five patients (20 females and 25 males) who were not receiving ZNS therapy were recruited as controls. Subjects having diabetes mellitus (fasting blood sugar ≥126 mg/dL), hypertension, smoking, alcohol use, hepatic diseases, renal insufficiency, pregnancy, major psychiatric disorders, nephrolithiasis history, endocrine diseases, hematological diseases, and autoimmune diseases were excluded. Subjects who took antipsychotic drugs, oral antidiabetic agents, or other medications that could affect blood sugar levels, lipid metabolism, or body weight, or who had deliberately attempted to control their body weight were also excluded.
Clinical records were reviewed and registered, including age at seizure onset, seizure semiology, seizure etiology, average seizure frequency per month during the previous year, and concomitant AED use. All patients underwent interviews and physical examinations. Blood samples were collected at baseline (pre-ZNS treatment) for analysis of biochemical markers. Body weight and height were recorded, and BMI was calculated. In the ZNS-treated group, the initial dose of ZNS was 100 mg/day, and it was increased by 100 mg/day every 2 weeks. The target and maintenance doses were dependent on the patient’s tolerability and the drug’s efficacy. During the study period, the dosage and type of AEDs were maintained in both the ZNS-treated and control groups. Twelve and 24 weeks after initiating ZNS treatment, the body weight, height, and BMI were recorded, and the second and third blood samples were collected for analysis of biochemical markers in both groups.
Blood samples were collected after overnight fasting and analyzed at the Central Laboratory of the hospital for serum levels of fasting sugar, glycated hemoglobin (HbA1c), high-sensitivity C-reactive protein (hs-CRP), creatinine, aspartate transaminase (AST), alanine transaminase (ALT), total homocysteine (tHcy), triglycerides, total cholesterol, high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C). A fatty liver index, HSI, was introduced to evaluate nonalcoholic fatty liver disease.
Results of the Study
Of the 81 patients in the ZNS-treated group, 20 patients (24.7%) discontinued the study. Among the 61 ZNS-treated patients, four had newly diagnosed epilepsy, received ZNS monotherapy, and remained seizure-free during the study period. In the others, ZNS was combined with concomitant AEDs including valproic acid (n = 28), levetiracetam (n = 25), lamotrigine (n= 20), carbamazepine (n = 16), oxcarbazepine (n= 6), phenytoin (n = 5), vigabatrin (n = 2), phenobarbital (n = 2), and pregabalin (n = 1). In the ZNS-treated group, the maintenance doses of ZNS were 100 mg/day (n = 13), 200 mg/day (n = 17), 300 mg/day (n = 14), 400 mg/day (n = 14), and 500 mg/day (n = 3).
The average body weight decreased 2.48% and 2.75% after 12 and 24 weeks of ZNS treatment, respectively. A body weight reduction was observed in 55.7% (34/61) of patients after 12 weeks of ZNS treatment and 65.6% (40/61) of patients after 24 weeks of ZNS treatment. Weight loss of at least 5% was observed in 24.6% (15/61) and 32.8% (20/61) of patients after 12 and 24 weeks of ZNS treatment, respectively. Regarding BMI, there was 2.56% and 2.82% reduction after 12 and 24 weeks of ZNS treatment, respectively. The serum levels of hs-CRP, HbA1c, triglycerides, and LDL-C were significantly decreased after 12 weeks of ZNS treatment compared with baseline values. At the end of week 24, the serum levels of hs-CRP, HbA1c, and triglycerides remained significantly decreased. The serum levels of AST, ALT, and HSI were significantly reduced as compared with the baseline values.
The study confirmed that ZNS therapy significantly reduced body weight and BMI. Additionally, ZNS therapy might reduce vascular risk factors, including serum levels of HbA1c, triglycerides, and hs-CRP.
Zonisamide's Mechanism of Action on Weight Loss
The precise mechanism of ZNS-induced body weight loss remains unknown. According to Gadde et al., the effect of weight loss might be related to brain serotonin and dopamine systems. ZNS is a sulfonamide that acts as a weak carbonic anhydrase inhibitor in vivo, which is comparable to acetazolamide, another medication for treating epilepsy. However, the carbonic anhydrase inhibitory activity of acetazolamide was not suggested as the primary antiepileptic mechanism of ZNS. Carbonic anhydrase inhibitors of the sulfonamide and sulfamate type are clinically emerging drugs for the treatment of obesity, epilepsy, hypertension, glaucoma, and high-altitude disease.
Evidence has demonstrated that some AEDs, such as ZNS and topiramate, potently inhibit both cytosolic and mitochondrial carbonic anhydrases involved in lipogenesis. Therefore, it has been proposed that ZNS-induced weight loss in patients is partly related to inhibition of the mitochondrial carbonic anhydrases involved in lipogenesis. The analysis demonstrated statistically significant decreases in triglycerides after ZNS treatment in patients with epilepsy.
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