Drug-induced weight gain is a significant side effect that can impact both physical health and a patient's willingness to continue treatment [1.4.3]. While many medications can affect body weight, a few classes and specific drugs stand out for their profound impact. In 2017–2018, it was estimated that 20.3% of U.S. adults used at least one medication with the potential to cause weight gain (obesogenic) [1.2.2].
Atypical Antipsychotics: The Primary Culprits
Atypical antipsychotics as a class are associated with the most significant weight gain [1.2.1]. These medications are crucial for managing conditions like schizophrenia and bipolar disorder. However, their side effects, particularly weight gain, can lead to other health issues like type 2 diabetes and cardiovascular disease [1.4.3].
Among this class, two drugs are consistently cited for causing the most substantial weight gain:
- Clozapine (Clozaril): Often considered one of the most effective antipsychotics, clozapine is also linked to the largest weight gains. One study reported a mean weight gain of 11.2 kg (24.7 lbs) over 6.5 months [1.4.3].
- Olanzapine (Zyprexa): A meta-analysis identified olanzapine as causing the largest weight gain among several antipsychotics, with an average increase of 2.4 kg (5.3 lbs) over a median of 3 months in randomized trials [1.2.1]. Other studies have shown even more dramatic results, with some patients gaining around 12 kg (26.5 lbs) after a year on a high dose [1.4.3]. In one retrospective analysis, olanzapine treatment was associated with a weight gain of 0.76 kg (1.70 lbs) per week, significantly more than clozapine or risperidone in that study [1.3.1].
How Do Antipsychotics Cause Weight Gain?
The mechanisms are complex and not fully understood. However, research points to several factors:
- Receptor Blockade: These drugs block various neurotransmitter receptors, including histamine H1 and serotonin 5-HT2C receptors. This can increase appetite and reduce satiety (the feeling of being full) [1.15.1, 1.4.3].
- Hormonal Interference: Recent studies suggest antipsychotics interfere with dopamine signaling in the pancreas, leading to unchecked production of blood glucose-regulating hormones like insulin and glucagon. This dysregulation can lead to insulin resistance and diabetes [1.4.1]. Another study implicates the hormone leptin, which regulates fat storage and appetite, as a key driver of drug-induced obesity [1.4.2].
Other Notable Drug Classes That Cause Weight Gain
While antipsychotics are the most prominent, other common medications are also linked to weight gain.
Antidepressants
Weight gain is a common side effect for many antidepressants, especially with long-term use. Some of the most frequently associated drugs include:
- Mirtazapine (Remeron): Associated with a 1.5 kg (3.3 lbs) average weight gain in studies, mirtazapine is known to stimulate appetite through its potent antihistamine effects [1.2.1, 1.15.1].
- Tricyclic Antidepressants (TCAs): Older antidepressants like amitriptyline can cause weight gain, with one meta-analysis showing an average of 1.8 kg (4 lbs) [1.2.1].
- SSRIs: While some selective serotonin reuptake inhibitors (SSRIs) like fluoxetine are initially associated with weight loss, long-term use can lead to weight gain [1.2.1, 1.16.3]. Paroxetine (Paxil) is the SSRI most likely to cause weight gain [1.16.2].
Corticosteroids
Medications like prednisone are used to treat a wide range of inflammatory conditions, from asthma to autoimmune diseases [1.7.2]. They can cause weight gain through several mechanisms:
- Increased Appetite: Steroids are well-known for increasing hunger [1.7.1].
- Fluid Retention: They alter the body's electrolyte and water balance, causing fluid retention [1.7.2].
- Fat Redistribution: Long-term use can change how the body stores fat, leading to accumulations in the abdomen, face, and neck [1.5.3, 1.7.1].
Diabetes Medications
Ironically, some medications used to treat type 2 diabetes can themselves cause weight gain. This is often because they work by increasing insulin levels or insulin sensitivity, which can promote fat storage [1.8.2].
- Insulin: Treatment with insulin often leads to weight gain, with studies showing an average gain of 3 to 9 kg in the first year [1.8.3].
- Sulfonylureas: Drugs like glyburide and glipizide can cause a mean weight gain of around 4 kg in the first year [1.8.2].
- Thiazolidinediones (TZDs): Pioglitazone is associated with a weight gain of 2.6 kg (5.7 lbs) in trials [1.2.1].
Comparison of Weight Gain in Atypical Antipsychotics
| Medication | Average Weight Gain (in kg) | Time Frame | Source(s) |
|---|---|---|---|
| Olanzapine | 2.4 kg | ~3 Months | [1.2.1] |
| Clozapine | Not specified in direct comparison, but ranked as causing the most or second-most gain | Varied | [1.3.3] |
| Quetiapine | 1.1 kg | ~3 Months | [1.2.1] |
| Risperidone | 0.8 kg | ~3 Months | [1.2.1] |
| Aripiprazole | 0.6 kg | Varied | [1.2.1] |
| Ziprasidone | May be weight-neutral | Varied | [1.4.3] |
Note: Weight gain can vary significantly between individuals and studies. This table represents averaged data from a meta-analysis. [1.2.1]
Strategies for Managing Medication-Induced Weight Gain
It is crucial not to stop taking prescribed medication without consulting a healthcare provider [1.11.2]. Open communication with a doctor is the first step. Management strategies include:
- Lifestyle Modifications: The foundation of management involves diet and exercise. This includes practicing portion control, choosing nutrient-dense foods, limiting processed foods and sugary drinks, and increasing physical activity [1.5.1, 1.12.3]. Eating small, frequent meals and ensuring adequate protein intake can help manage an increased appetite [1.12.3].
- Switching Medications: If appropriate, a doctor may be able to switch to an alternative medication within the same class that has a lower risk of weight gain [1.11.1]. For example, switching from olanzapine to a more weight-neutral antipsychotic like ziprasidone or aripiprazole, or from paroxetine to fluoxetine in the SSRI class [1.4.3, 1.16.1].
- Adjunctive Medication: In some cases, another medication may be prescribed to counteract the weight gain. Metformin, a diabetes drug, has been shown to be effective in preventing or treating weight gain caused by antipsychotics and is sometimes recommended to be started at the same time as high-risk antipsychotics like olanzapine or clozapine [1.13.1, 1.13.2].
Conclusion
While many drugs can lead to weight gain, the evidence consistently points to the atypical antipsychotics clozapine and olanzapine as the agents that cause the most significant increases in body weight. This effect is driven by complex interactions with neurotransmitters and hormones that regulate appetite and metabolism. Other major contributors include certain antidepressants, corticosteroids, and insulin-related diabetes therapies. Managing this side effect requires a proactive approach involving lifestyle changes, regular monitoring, and a collaborative relationship with a healthcare provider to explore all treatment options, including potentially switching to a more weight-neutral drug or adding a mitigating agent like metformin.
For further reading, you may find this resource from the National Institutes of Health helpful: Drugs Commonly Associated With Weight Change
