Brian Miller, MD, PhD, MPH. Professor of Psychiatry at the Medical College of Georgia, Augusta, and President of the Georgia Psychiatric Physicians Association.
Dr. Miller, author of this educational activity, receives research support from Augusta University; the National Institute of Mental Health; the Brain and Behavior Research Foundation; and the Stanley Medical Research Institute. Relevant financial relationships listed for the author have been mitigated.
Antipsychotic-induced weight gain can decrease medication adherence, with a domino effect of negative consequences on the psychiatric illness. Recently the FDA approved the first therapy to address this problem: Lybalvi, a combination of olanzapine and samidorphan. In this article, I’ll look at how it compares with other treatments for antipsychotic-induced weight gain.
An ounce of prevention
Prevention starts before prescribing an antipsychotic. When taking a medical history, check baseline weight/BMI and look for metabolic risk factors, including hypertension, hyperlipidemia, and a family history of diabetes—this confers a four-fold increased odds of the patient having diabetes (Chung J and Miller BJ, Schizophr Res 2020;216:41–47). Genetic factors influence the risk of metabolic side effects, so ask if the patient or their family members have diabetes or other metabolic problems. Younger patients and those starting an antipsychotic for the first time are also at greater risk for weight gain.
When possible, choose antipsychotics with a favorable weight/metabolic profile, such as aripiprazole, brexpiprazole, lumateperone, lurasidone, or ziprasidone. When starting an antipsychotic, especially one with greater weight/metabolic liability, I give patients the option either to start an adjunctive treatment to help mitigate risk, or to closely monitor the effects of the antipsychotic on their weight.
When weight gain develops, the most common treatment approach is to switch to a different agent with a more favorable weight/metabolic profile. However, my adage is, “The best antipsychotic is the one that the patient will take and that controls their symptoms.” If the patient is willing to continue the current medication and is clinically stable, then I generally prefer to continue their current antipsychotic and use an adjunctive treatment for weight gain, although I make this decision collaboratively with the patient.
Olanzapine is an efficacious antipsychotic in schizophrenia based on head-to-head comparisons with other agents (Leucht S et al, Lancet 2013;382(9896):951–962), but its use is limited by its high risk of weight gain and metabolic problems. The opioid system plays a role in that weight gain, as antipsychotics increase the rewarding effects of high-calorie foods. Lybalvi offers a novel solution by combining olanzapine with the opioid receptor antagonist samidorphan.
Three randomized controlled trials (lasting up to six months) compared olanzapine-samidorphan versus olanzapine alone in 1116 patients with schizophrenia (Srisurapanont M et al, Sci Rep 2021;11(1):7583). Patients still gained weight on both treatments but had statistically significant less weight gain on olanzapine-samidorphan versus olanzapine (6.9 versus 10.7 lb), especially in patients with lower BMI. Both olanzapine-samidorphan and olanzapine were associated with similar improvements in symptom ratings and adverse effect profiles. Although samidorphan curbed some of the weight gain, it did not protect against elevations in glucose or lipids.
These trials tested the preventive effects of samidorphan, enrolling only non-obese patients (mean BMI 25.7). We don’t know if samidorphan will work in those who have already gained significant weight, which unfortunately is the population most likely to get this $1,300/month drug authorized by their insurer. Most insurers require significant weight gain on an antipsychotic or clinical failure of two generic antipsychotics before they will cover Lybalvi.
Lybalvi should not be started within seven days of taking a short-acting or 14 days of taking a long-acting opioid.
Other pharmacologic treatments
Lybalvi may hold FDA approval, but metformin and topiramate have better evidence to reduce both weight gain and metabolic problems on antipsychotics. The antidiabetic agent metformin may reduce weight by both decreasing insulin resistance and suppressing appetite. In a meta-analysis of 10 studies involving 681 adults on second-generation antipsychotics, most of which lasted three months, adjunctive metformin was associated with a 7.1-lb weight decrease versus placebo. That sounds like a bigger effect than Lybalvi, but the figures can’t be easily compared because the metformin studies enrolled patients who were already obese.
What sets metformin apart from Lybalvi is metformin’s ability to improve not just weight but also the patient’s metabolic profile. Insulin resistance, fasting glucose, triglycerides, and even hyperprolactinemia improved when metformin was added to an antipsychotic. There was no evidence of worsening psychopathology with metformin. The average metformin dose was 1000 mg (500 mg twice daily), although doses ranged from 750 to 2500 mg/day. In these trials, the most common adverse effects were nausea, vomiting, and diarrhea. Contraindications to metformin use include severe kidney disease (GFR <30) and metabolic acidosis.
Compared to metformin, topiramate has similar effects on weight reduction, with an average weight reduction of 6.8 lb versus placebo in seven studies of 439 adults taking second-generation antipsychotics. An extra benefit of topiramate is that in trials of its weight benefits, it also improved positive and negative symptoms of schizophrenia with a medium effect size (0.6). Only one of the seven trials reported on blood glucose and lipids, with results favoring topiramate. Most of the trials lasted three to four months. The average dose was about 200 mg/day, although doses ranged from 50 to 400 mg/day.
Topiramate also has some evidence of efficacy in many common psychiatric disorders, including PTSD, OCD, and bulimia, as well as alcohol, cocaine, and methamphetamine use disorders. Its main risk is renal stones, and most of its side effects—cognitive problems, imbalance, and paresthesias—are dose related.
Other second-line options for patients who cannot tolerate or fail to respond to metformin and topiramate are the glucagon-like peptide-1 (GLP-1) receptor agonists. Liraglutide (Victoza, Saxenda), which is FDA approved in diabetes and obesity, currently has the most evidence. In a 16-week study of 103 patients treated with clozapine or olanzapine, the GLP-1 agonist liraglutide was associated with an average weight reduction of 11.7 lb versus placebo, as well as improvements in glucose tolerance, blood pressure, cholesterol, and visceral fat (Larsen JR et al, JAMA Psychiatry 2017;74(7):719–728). Similarly, a six-month study of 790 overweight or obese antipsychotic-treated patients found an average weight reduction of 13.2 lb with liraglutide versus placebo and reduced HbA1c (Whicher CA et al, Diabetes Obes Metab 2021;23(6):1262–1271).
Liraglutide requires slow titration due to risk of nausea and is administered as a subcutaneous injection (see table). It is also costly and—pending further evidence—should be reserved for severe cases.
Regardless of the pharmacologic approach, lifestyle modification is important for every patient. I discuss physical activity, nutrition, sleep hygiene, and tobacco smoking cessation, then work with the patient to set realistic, incremental, achievable goals. If they don’t exercise, a five-minute daily walk is a good starting point. Small dietary changes like cutting back on sodas, increasing fruits and vegetables, and shifting to baked instead of fried foods can also add up.
So how best to proceed?
Use the psychiatric and medical history as a “risk assessment” to guide antipsychotic selection and collaborate with the patient on adjunctive treatment. Younger patients and those starting an antipsychotic for the first time are at particularly heightened risk for weight gain. In obese patients, I favor adjunctive treatments if they are clinically stable. My first-line choices for antipsychotic-induced weight gain are either metformin or topiramate. Consider metformin if there is a family history of diabetes or if using medications with greater weight gain liability, and consider topiramate if there are residual symptoms of psychosis. I typically say, “We can try metformin or topiramate, and if it’s not helpful or you have side effects, we can try the other one.” Lybalvi is a second-line option, as patients do not lose weight on this medication (only experience less weight gain) and there is no evidence for improvements in glucose, lipids, or symptoms.
Perform a baseline “risk assessment” for antipsychotic-induced weight gain, and discuss lifestyle modifications with every patient. To treat weight gain, first decide whether or not to switch agents. If using adjunctive treatments, either metformin or topiramate are good options for weight loss that may also benefit metabolic parameters (glucose/insulin, lipids) or symptoms, respectively.
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