Antipsychotic drugs (APDs), while crucial for managing mental health conditions, often come with a challenging side effect: weight gain, which can lead to obesity, diabetes, dyslipidemia, and cardiovascular disease. To mitigate this antipsychotic-induced weight gain, various pharmacological add-ons have been explored. Among these, metformin and topiramate have emerged as potential options, warranting a closer look at their efficacy and safety. This article aims to compare metformin and topiramate for weight loss, especially in the context of antipsychotic-induced obesity, synthesizing findings from various studies and meta-analyses.
The Challenge of Antipsychotic-Induced Weight Gain
Second-generation antipsychotics (SGAs) are associated with an increased risk of weight gain, hyperlipidemia, and impaired glucose metabolism, significantly elevating the risk of cardiovascular disease and mortality. Managing this weight gain remains a challenge, prompting the exploration of different strategies, including behavioral interventions, switching antipsychotics, and pharmacological interventions.
Pharmacological Interventions: An Overview
Several medications have been utilized to reduce weight gain induced by SGAs, including sibutramine, reboxetine, bupropion, orlistat, liraglutide, metformin, topiramate, and histamine 2 (H2) receptor antagonists. Among these, metformin and topiramate have been the most studied and are considered efficacious and safe in promoting weight reduction compared to placebo in patients with severe mental illness (SMI).
Metformin: An Antidiabetic Agent for Weight Management
Metformin, a biguanide drug commonly used as a first-line treatment for type 2 diabetes, has been extensively studied for weight management, even in the absence of diabetes. It improves the body's response to insulin, decreasing hepatic glucose output and increasing insulin-mediated glucose utilization in peripheral tissues.
Efficacy of Metformin
A meta-analysis reported that metformin was the most extensively studied drug regarding body weight, with a mean difference of -3.17 kg compared to placebo. Metformin has also been shown to improve insulin resistance and decrease blood lipid levels. Studies included a total of 904 patients, with most trials being short-term, ranging from 12 to 14 weeks. Some longer-duration trials (24-26 weeks) have demonstrated consistent and extended weight reduction over nearly 6 months.
Read also: Comprehensive Study: Metformin and Phentermine/Topiramate
Metformin in Combination Therapy
Some studies have explored metformin in combination with other interventions. One study compared metformin plus sibutramine versus metformin plus placebo, finding no significant difference between the treatment arms. In contrast, another study reported significantly greater weight loss with the combination of metformin plus lifestyle intervention compared to placebo plus lifestyle intervention.
Topiramate: An Anticonvulsant with Weight Loss Properties
Topiramate, a new antiepileptic drug increasingly used as a mood stabilizer in bipolar disorder, has also been explored as an adjunctive therapy for both the positive and negative symptoms of schizophrenia. It has demonstrated weight-loss properties and has been used as a treatment for adiposity caused by eating disorders.
Efficacy of Topiramate
Topiramate has shown the best performance in controlling BMI based on meta-analysis. It is an anticonvulsant that blocks α-amino-3-hydroxy-5-methylisoxazole-4-propionic (AMPA)/kainate-gated ion and sodium channels and positively modulates GABA receptors. Studies have explored different doses of topiramate, with higher doses (100 and 200 mg/d) showing superior results on weight parameters.
Safety and Tolerability
The adverse effects reported in studies using topiramate were generally mild to moderate, without serious adverse effects.
Head-to-Head Comparison: Topiramate vs. Metformin
Given the evidence supporting both metformin and topiramate for weight management, a direct comparison is essential.
Read also: Berberine and Metformin
Study Design and Methodology
One study randomized 62 stabilized outpatients with antipsychotic-induced obesity into a topiramate group and a metformin group for 16 weeks. The patients' weight, body mass index (BMI), waist-hip ratio, and side effects were assessed and compared. Both intention-to-treat and completer analyses were performed.
Results
Intention-to-treat analyses revealed that the topiramate group experienced marked decreases in weight, BMI, and waist-hip ratio at each follow-up, while the metformin group only showed a significant decrease in waist-hip ratio at 4 weeks. Compared to metformin, only weight and BMI in the topiramate group were significantly decreased at week 4, and at weeks 8-16, weight, BMI, and waist-hip ratio were remarkably declined.
Completer analyses showed similar results, with statistically significant reductions in weight, BMI, and W-H ratio from weeks 4 to 16 in the topiramate group. Compared with metformin, all BMI with topiramate were markedly decreased at week 4-16, and its weight and waist-hip ratio were also notably lowered at week 8.
Adverse Events
There were no significant differences in adverse events between the two groups. The topiramate group reported cases of dizziness, poor appetite, diarrhea, abnormal liver function, and exacerbation of illness, while the metformin group reported abnormal liver function and exacerbation of illness.
Interpretation
This study indicated that topiramate was significantly superior, or at least similar, to metformin in managing established weight gain or obesity caused by some second-generation antipsychotics, while keeping the patient’s illness stable and maintaining the original antipsychotic treatment. Topiramate demonstrated a faster and better therapeutic effect on obesity caused by SGAs.
Read also: Health Benefits of Metformin
Meta-Analysis Findings
Current published systematic reviews on add-ons controlling APD-induced weight gain were either focused on one particular medication or indirectly compared different medications in a qualitative way. A network meta-analysis, comparing the body weight change, BMI change, and number of patients withdrawn due to adverse events among different pharmacological add-ons, demonstrated that topiramate showed the lowest mean difference (MD) in body weight change at -3.07 kg, followed by Sibutramine MD = -2.97 kg, and Metformin MD = -2.50 kg.
Considerations and Limitations
- Sibutramine's Withdrawal: Although sibutramine ranked high in body weight and BMI reduction, its license has been withdrawn in many countries due to adverse effects, making it unsuitable for treating antipsychotic-induced weight gain.
- Study Duration: The relatively short follow-up period in many studies limits the ability to extrapolate findings to longer periods.
- Individual Variability: The response to these medications can vary significantly among individuals, highlighting the importance of personalized treatment approaches.
- Non-Pharmacological Interventions: Nutritional and behavioral interventions are crucial for weight control and should be considered alongside pharmacological add-ons.
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