What Is It?
Medication-related weight gain often presents with food cravings and bingeing. It tends to be most rapid in the first three months, slows over the following year, and then may plateau. A gain of at least 7% above baseline is the FDA definition of weight gain.

What Medications Can Cause It?
Weight gain is commonly caused by antipsychotics, especially clozapine, olanzapine, and quetiapine, and to a lesser extent risperidone and paliperidone. It may also occur with antidepressants such as mirtazapine, tricyclics, and paroxetine, and with mood stabilizers such as lithium and valproic acid.

What Causes It?
It is thought to result from histamine and serotonin 2A receptor blockade, which increases hunger.

How Is It Managed?

• Monitor weight, BMI, and waist circumference every 4 weeks for 3 months, then every 3 months.
• Encourage exercise and dietary changes when feasible.
• Switch to a more weight-neutral medication if possible.

What Are First-Line Medications?

• Topiramate (Topamax) 100–300 mg/day.
• Metformin extended-release 500–2000 mg/day.
• Olanzapine/samidorphan (Lybalvi) instead of olanzapine alone.
• Orlistat (Xenical) 120 mg 3 times daily after meals.
• Aripiprazole (Abilify) 15 mg/day as adjunct in some cases.

What Are Second-Line Medications?

• Bupropion sustained-release (Wellbutrin SR) 300–400 mg daily.
• Methylphenidate- or amphetamine-class stimulants.
• Naltrexone/bupropion (Contrave).
• Phentermine (Suprenza).
• Phentermine/topiramate (Qsymia).
• GLP-1 agonists such as liraglutide, semaglutide, or tirzepatide.
• Nizatidine (Axid).
• Amantadine (Symmetrel) 100–300 mg/day.

What Else Should I Know?

• Weight gain is often most noticeable in the first six weeks of antipsychotic treatment.
• If a patient gains 5% or more of body weight, switching drugs should be considered.
• Ziprasidone and aripiprazole are among the most weight-neutral antipsychotics.
• Ask about dry mouth, since sugary drinks used to relieve it can contribute to weight gain.
• Consider a GLP-1 agonist in patients with significant weight gain and BMI of 30 kg/m² or higher.

Fun fact: Some researchers think treatment-emergent weight gain may correlate with clinical response, while others think it mainly reflects medication adherence.