Understanding What Drug Causes the Most Weight Gain?

October 5, 2025 •

4 min read

Studies show that antipsychotic medications, particularly olanzapine and clozapine, have the highest potential for causing significant and rapid weight gain. Understanding what drug causes the most weight gain can help patients and doctors make informed decisions and manage potential side effects.

Quick Summary

Several classes of medication can cause weight gain by increasing appetite, altering metabolism, or causing fluid retention. Antipsychotics like olanzapine and clozapine are frequently cited for significant increases, alongside certain antidepressants, diabetes drugs, and corticosteroids.

Key Points

Olanzapine (Zyprexa) is a top offender: This atypical antipsychotic consistently ranks among the highest for significant and often rapid weight gain.
Antipsychotics and antidepressants can stimulate appetite: Many psychiatric medications, including olanzapine, clozapine, mirtazapine, and TCAs, increase appetite by affecting brain receptors like histamine and serotonin.
Diabetes medications can promote fat storage: Insulin and certain oral diabetes drugs like sulfonylureas and thiazolidinediones can lead to weight gain by increasing insulin levels and promoting glucose and fat storage.
Corticosteroids cause fluid retention and hunger: Long-term use of oral steroids such as prednisone commonly results in increased appetite and water retention, altering fat distribution.
Not all drugs in a class are equal: Significant variability exists even within a single drug class. For instance, some antipsychotics like lurasidone are less likely to cause weight gain than others like clozapine.
Lifestyle changes are key: Regular exercise and a balanced diet can help mitigate medication-induced weight gain, and discussing concerns with a doctor can lead to viable alternatives.

Antipsychotics: The Highest-Risk Category

Among all medication classes, atypical antipsychotics are most consistently linked to substantial weight gain. Olanzapine (Zyprexa) is frequently cited as causing the highest potential for rapid weight increase, often starting within the first few weeks or months of treatment. Clozapine (Clozaril) is another high-risk antipsychotic known for causing significant weight changes. The mechanisms behind this weight gain include blocking histamine (H1) and serotonin (5-HT2C) receptors in the brain, which can lead to increased appetite, insulin resistance, and an overall metabolic slowdown. For many patients, the potential weight gain from these powerful medications is a significant concern that needs careful management.

Antidepressants with High Weight Gain Potential

While many people associate antidepressants with weight gain, the effect varies significantly between different drug types. Older antidepressants, and some newer ones, have a higher propensity for causing weight increase.

Tricyclic Antidepressants (TCAs): Older TCAs like amitriptyline (Elavil) are well-known culprits. They block histamine and serotonin receptors, leading to an increase in appetite and carbohydrate cravings.
Tetracyclic Antidepressants: Mirtazapine (Remeron) is an atypical antidepressant that powerfully blocks H1 histamine receptors, which can significantly stimulate appetite and result in weight gain.
Selective Serotonin Reuptake Inhibitors (SSRIs): Some SSRIs, especially paroxetine (Paxil), have a greater risk of long-term weight gain compared to others. The effect can be complex, involving changes to serotonin signaling and metabolism over time.

Diabetes Medications and Weight Gain

Paradoxically, some medications used to treat type 2 diabetes can cause weight gain, which can worsen other metabolic health issues.

Insulin: A crucial hormone for managing blood sugar, insulin promotes the storage of glucose in cells. If a patient consumes more calories than their body needs, this process can lead to the storage of excess glucose as fat, causing weight gain.
Sulfonylureas: This class of medication, which includes glipizide (Glucotrol) and glyburide (Diabeta), stimulates the pancreas to produce more insulin, leading to potential weight gain.
Thiazolidinediones (TZDs): Drugs like pioglitazone (Actos) and rosiglitazone (Avandia) increase the body's sensitivity to insulin but can cause weight gain and fluid retention.

Other Medications with Weight Gain Side Effects

Beyond psychiatric and diabetes medications, several other common drug classes carry a risk of weight gain.

Corticosteroids: Oral corticosteroids like prednisone are used to reduce inflammation but can cause increased appetite, fluid retention, and altered fat distribution, especially around the abdomen. Long-term use significantly increases this risk.
Mood Stabilizers: Lithium and valproic acid (Depakote) are used to treat bipolar disorder and other conditions and are frequently associated with weight gain. The mechanisms include appetite stimulation and metabolic changes.
Beta-Blockers: Prescribed for high blood pressure and other heart conditions, beta-blockers like metoprolol and atenolol can contribute to weight gain by slowing down metabolism and causing fatigue, which reduces physical activity.
Anticonvulsants: Certain anti-seizure medications, such as gabapentin (Neurontin) and pregabalin (Lyrica), can increase appetite.
Antihistamines: Some older, first-generation antihistamines like diphenhydramine (Benadryl), as well as chronic use of newer ones like cetirizine (Zyrtec), are linked to increased appetite and weight gain.

Comparing High-Risk Medications for Weight Gain

To help illustrate the differences in weight gain potential, the following table compares some of the most frequently cited medications associated with this side effect.


Drug Class	Examples	Weight Gain Potential	Primary Mechanism	Management/Alternatives
Atypical Antipsychotics	Olanzapine, Clozapine	High	H1/5-HT2C receptor antagonism, metabolic changes	Lower-risk options (lurasidone, ziprasidone)
Tricyclic Antidepressants	Amitriptyline	High	H1 receptor blockade, appetite increase	Switch to weight-neutral (bupropion) or lower-risk SSRI
Diabetes Medications	Insulin, Sulfonylureas (Glyburide), TZDs (Pioglitazone)	Moderate to High	Increased insulin levels, fat storage	Consider metformin or GLP-1 agonists (Ozempic)
Mood Stabilizers	Lithium, Valproic Acid	Moderate to High	Appetite increase, metabolic disruption, fluid retention	Alternatives like lamotrigine can be weight-neutral
Corticosteroids	Prednisone	High (long-term)	Increased appetite, fluid retention, fat redistribution	Use lowest effective dose for shortest duration; lifestyle changes
Anticonvulsants	Gabapentin, Pregabalin	Moderate	Appetite increase	Weight-loss alternatives like topiramate

The Importance of a Patient-Centered Approach

It's crucial to remember that not everyone experiences the same side effects. Genetic factors, baseline body mass index, and lifestyle habits can all influence an individual's response to a medication. The goal should never be to stop a necessary medication without consulting a doctor due to fear of weight gain, as the underlying condition could pose a more significant health risk. Instead, patients should work closely with their healthcare providers to discuss their concerns. In many cases, it may be possible to switch to a weight-neutral alternative or implement lifestyle strategies to counteract the side effect.

Conclusion

While it is challenging to pinpoint a single drug that causes the most weight gain for every individual, strong evidence indicates that certain medications carry a significantly higher risk than others. Atypical antipsychotics like olanzapine and clozapine top this list, followed by other drug classes such as older antidepressants, some diabetes treatments, mood stabilizers, and corticosteroids. For individuals concerned about weight gain, an open conversation with a healthcare provider is the most important step. They can help navigate treatment options, consider alternatives, or recommend lifestyle modifications to manage weight effectively while ensuring the primary medical condition remains under control. For more authoritative information on this topic, consider consulting the National Institutes of Health (NIH) website.

Frequently Asked Questions

While it can vary by individual, clinical studies consistently show that the atypical antipsychotics olanzapine (Zyprexa) and clozapine (Clozaril) carry the highest potential for significant and rapid weight gain among all commonly prescribed drugs.

Medications can cause weight gain through several mechanisms, including increasing appetite, causing fluid retention, slowing down metabolism, or affecting how the body stores fat. Many psychiatric drugs, for example, interfere with neurotransmitters that regulate hunger and metabolism.

Yes, some antidepressants, particularly older tricyclic antidepressants (like amitriptyline) and atypical antidepressants (like mirtazapine), are known to cause significant weight gain. Certain SSRIs, such as paroxetine, also carry a higher risk over long-term use.

No. While some diabetes medications like insulin, sulfonylureas, and thiazolidinediones can cause weight gain, others are considered weight-neutral or even promote weight loss. For example, metformin, GLP-1 agonists (like Ozempic), and SGLT-2 inhibitors are often associated with weight loss.

Yes. Certain medications are known to be weight-neutral or even cause weight loss. Examples include the antidepressant bupropion (Wellbutrin), some newer antipsychotics like lurasidone and ziprasidone, and specific diabetes drugs like metformin and GLP-1 agonists.

If you are concerned about weight gain from your medication, you should first speak with your doctor. They can help you explore alternatives, adjust your dose, or provide strategies to manage your weight through diet and exercise. Never stop a prescribed medication without consulting a healthcare professional.

The risk of weight gain with corticosteroids like prednisone is highly dependent on the dose and duration of treatment. While long-term, high-dose use is strongly linked to weight gain, short-term or localized applications (e.g., nasal sprays) typically do not pose a significant risk.