When fluoxetine launched in the 1980s, some psychiatrists were skeptical of the drug because it didn’t cause weight gain. Back then, antidepressants were reserved for severe depression, where low appetite and melancholia prevailed. Today, we have the opposite problem. Many patients won’t consider a medication that might tip the scales in the wrong direction.

In this article, I’ll highlight the few psychotropics with a potential to reduce weight. But first, a caveat. These reactions are highly individual and can go either way, so weight gain is also possible. We don’t know which factors predict weight loss on psychiatric meds, but weight gain is more likely in women, children/teens, and those who start out with either a high or low BMI (particularly with antipsychotics). 

Bupropion

Bupropion caused weight loss in both short- and long-term trials of depression (Serretti A and Mandelli L, J Clin Psychiatry 2010;71(10):1259–1272). Later, it was tested as a weight loss drug in 3 large, randomized trials lasting 6–24 months, where it helped obese patients lose 6%–14% of their body weight, about twice as much as placebo (Gadde KM and Xiong GL, Expert Rev Neurother 2007;7(1):17–24).

Bupropion achieves this effect by reducing appetite and increasing energy output through effects on the hypothalamus. Naltrexone, an opioid antagonist, has a synergistic effect there, and the two are approved as a combination pill (Contrave) for obesity. On average, the combination leads to a 10-pound weight loss over 1–2 years, twice as much as bupropion alone (Liu Y et al, Diabetol Metab Syndr 2024;16(1):93). While Contrave uses 32 mg of naltrexone with 360 mg of bupropion, generic substitutes have been tested in trials (eg, naltrexone 50 mg with bupropion extended release 300–450 mg).

One caution is in order. Patients with bulimia have a greater risk of seizures on bupropion, and the FDA labeling carries a warning about this.

Fluoxetine

Fluoxetine is the only other antidepressant with a claim to weight loss. In trials of depression, it reduced weight in the short term but not the long term. This selective serotonin reuptake inhibitor was also tested as a weight loss med, and in 19 trials of obese and overweight patients, it brought about a 6-pound weight loss relative to placebo, with greater effects in the 40–60 mg range (Serralde-­Zuñiga AE et al, Obes Facts 2022;15(4):473–486). Fluoxetine is the only antidepressant approved in bulimia (at a dose of 60 mg), and it has positive trials in binge eating disorder as well. 

In animal models, serotonergic drugs reduce stress-induced eating, particularly carbs, but only fluoxetine has proven this benefit in humans (among other serotonergic antidepressants, sertraline and vortioxetine have the lowest risk of weight gain).

Atomoxetine

Atomoxetine is weight neutral in ADHD and may promote weight loss in obesity. In a small, three-month trial of women with obesity, those on atomoxetine (100 mg) lost eight pounds more than those on placebo (Gadde KM et al, Int J Obes 2006;30:1138–1142). The mechanism is thought to be related to noradrenergic input on the hypothalamus.

Stimulants

Stimulants were once widely used for weight loss until the FDA cracked down in the 1970s. The reason is that their benefits are short lived, lasting a few months, while their risks of addiction, psychosis, and heart disease are serious. Furthermore, rebound overeating can occur after they are stopped (Orsini CA et al, Appetite 2014;78:76–80). Based on the limited trials, patients with obesity can expect to lose 10–25 pounds over 6 months, with greater weight loss for the amphetamine class than the methylphenidate class (Poulton AS et al, Front Endocrinol (Lausanne) 2015;6:14).

Lisdexamfetamine (Vyvanse) is approved for binge eating disorder at a dose of 50–70 mg. Patients also lost 5%–6% of body weight in those trials, although they were short term, lasting 3 months. That weight loss continued, but to a lesser degree, in the single study that tested it as maintenance over another three months (Grilo CM et al, Psychol Med 2024;54(12):1–11).

Appetite loss is a side effect of the novel stimulants modafinil and armodafinil, and they reduced weight by about eight pounds compared to placebo in trials of sleep apnea and shift work disorder (Kuan YC et al, Clin Ther 2016;38(4):874–888).

Lamotrigine vs lithium

Lamotrigine has the lowest risk of weight gain (and sedation) among the mood stabilizers, while lithium is a close second. Early on, there was hope that lamotrigine might treat obesity, but trials in binge eating disorder and in obesity clinics yielded only nonsignificant trends in weight loss (Merideth CH, J Clin Psychiatry 2006;67(2):258–262; Guerdjikova AI et al, Int Clin Psychopharmacol 2009;24(3):150–158). Lithium, on the other hand, was weight neutral in a meta-analysis but was associated with weight gain in some studies (Gomes-da-Costa S et al, Neurosci Biobehav Rev 2022;134:104266). 

Putting this together suggests that while lamotrigine and lithium are weight neutral on average, lamotrigine has a small chance of weight loss and lithium a slight chance of weight gain.

Topiramate and off-label therapies

Topiramate’s metabolic effects have a long history. Although approved for epilepsy and migraines, the drug is a modified fructose molecule that was originally developed as a sugar substitute for diabetes. After topiramate’s release as an anticonvulsant in 1996, clinicians noticed weight loss and better glycemic control in their patients who had epilepsy. Those observations have been confirmed in 10 randomized trials where patients lost 10–15 pounds on topiramate (100–200 mg/day), with greater loss in trials lasting more than 6 months (Kramer CK et al, Obes Rev 2011;12(5):e338–e347).

Topiramate is FDA approved for weight loss as a combo pill with phentermine (Qsymia, 7.5–15 mg phentermine with 46–92 mg topiramate). While Qsymia causes about twice as much weight loss as topiramate alone, phentermine has risks in psychiatric patients (eg, psychosis, mania, anxiety, and agitation). Topiramate is not FDA approved in psychiatry, but it did improve bulimia, binge eating, PTSD, OCD, schizophrenia, borderline personality disorder (mainly irritability), and alcohol and cocaine use disorders in small placebo-controlled trials. However, it can also cause neurocognitive side effects, mainly cognitive impairment but also, rarely, mood problems and hallucinations.

Three other off-label treatments are known to reduce weight, but here the support for both their metabolic and psychiatric benefits rests on small trials. They are amantadine (100–300 mg daily; potential benefits in tardive dyskinesia, depression, OCD, irritability, and cognition), probiotics (potential benefits in depression, anxiety, and cognition), and saffron (30 mg/day with 2% safranal; potential benefits in depression, OCD, and ADHD).

Carlat Verdict: Weight loss is an added benefit with a few meds that can enhance adherence. Bupropion and topiramate have the best evidence for long-term weight loss, while fluoxetine, stimulants, possibly lamotrigine, and atomoxetine may also help.