Most antipsychotics contribute to weight gain, with the highest risk associated with olanzapine and clozapine (Dayabandara M et al, Neuropsych Disease Treatment 2017;13:2231–2241; see Carlat’s weight gain fact sheet at www.tinyurl.com/mkck3r8a). The blockbuster glucagon-like peptide-1 (GLP-1) agonists have emerged as a solution, but costs are a major problem. That has changed with the generic release of liraglutide in summer 2024, and in this article, I’ll look at when and how to use it.

Background
Several medications reduce antipsychotic weight gain, including metformin, topiramate, and the partial opioid antagonist samidorphan (available as an olanzapine combination pill, Lybalvi). However, their benefits are mild compared to the GLP-1 agonists (McIntyre RS et al, Am J Psychiatry 2024;181:26–38). For example, metformin lowers weight by an average of six to nine pounds in three months, and those benefits are greater when it is started early. It also improves insulin sensitivity, dyslipidemia, and prolactinemia. Topiramate has similar benefits for weight reduction in psychiatric patients, but cognitive impairment limits its usage (McIntyre RS et al, Am J Psychiatry 2024;181(1):26–38).

Liraglutide for metabolic effects
Three GLP-1 agonists are FDA approved for the treatment of obesity. All three are also indicated for diabetes under different names and dosing schedules, which can be confusing (see the table “GLP Agonists for Obesity”). Liraglutide is the oldest of the three and has the most evidence for antipsychotic-induced weight gain, with positive results from two small RCTs in schizophrenic disorders at a dose of 1.8–3.0 mg/day (Lee K et al, Gen Hosp Psych 2022;78:58–67). In the first trial, liraglutide lowered weight by 12 pounds and improved glucose tolerance relative to placebo over 4 months in 103 patients with schizophrenia spectrum disorders (Larsen JR et al, JAMA Psych 2017;74(1):719–728). All patients were overweight or obese, prediabetic, and taking olanzapine or clozapine. The second trial included a broader array of antipsychotics, but liraglutide only showed nonsignificant trends toward lower weight and HbA1c, possibly because of a small sample size (47) (Whicher CA et al, Diabetes Obes Metab 2021;23(6):1262–1271). In a third trial, liraglutide significantly reduced weight by 8 pounds relative to placebo over 10 months in stable patients with bipolar disorder regardless of whether they were taking an antipsychotic (McElroy SL et al, J Clin Psychopharm 2024;44(2):89–95). Importantly, there was no exacerbation of psychiatric symptoms in these trials.

Generic liraglutide
Now that liraglutide is available as a generic, the cost should drop dramatically as more manufacturers enter the market over the next year. However, cost isn’t the sole concern. The version that has lost its patent is Victoza, which is approved for diabetes and packaged as an injection pen that is prefilled with the antidiabetic doses (0.6, 1.2, and 1.8 mg), which are lower than the typical antiobesity doses. One of those prefilled doses (1.8 mg) was tested in a schizophrenia trial. Clinicians can also match the 3 mg dose that is approved for obesity by combining the 1.8 mg and 1.2 mg prefilled sizes, but this will increase the cost and require two shots.

Although it has the most evidence in psychiatric populations, liraglutide has several disadvantages compared to other GLP-1 agonists. It requires daily dosing, compared to weekly dosing for semaglutide and tirzepatide. It is also less effective. In an analysis of patient records tracked by Epic Research, over 400,000 patients treated with GLP-1 agonists for one year at peak doses for diabetes or weight loss, liraglutide was the least effective (Bartelt K et al, Epic Research; published online March 14, 2024).

This begs the question. Is antipsychotic-induced weight gain fundamentally different from usual weight gain? GLP-1 agonists bring about similar degrees of weight loss regardless of psychiatric status, but there are reasons to think obesity is different in patients with psychiatric disorders. They have alterations in their gut microbiome and metabolic hormones. They are more likely to eat junk food and smoke nicotine, and less likely to exercise. Problems with cognition and motivation may get in the way of adherence. 

Other brain benefits
The GLP-1 agonists reduce central nervous system inflammation and stimulate brain growth factor proteins, suggesting neuroprotective benefits, but does that lead to benefits for neuropsychiatric disorders? In a small RCT of Alzheimer’s disease, liraglutide improved cognitive function and brain volume over one year (Edison P et al, Alzheimer’s & Dementia 2021;17(Suppl 9):e057848). Another GLP agonist, lixisenatide (which is not approved for obesity), improved motor function in early Parkinson’s disease (Meissner WG et al, N Eng J Med 2024;390:1176–1185). Patients who took GLP-1 agonists for diabetes and weight loss experienced improvements in depressive symptoms, although the patients in those trials did not have clinical depression. RCTs are in progress looking at possible benefits for alcohol or nicotine addiction. 

Risks
The GLP-1 agonists operate by inducing a sensation of fullness and delaying gastric emptying. This also causes their initial side effects, such as nausea, diarrhea, constipation, and vomiting. Those tend to abate within weeks of starting. Rare risks include acute pancreatitis and gallbladder disease (Seo YG, J Obes Metab Syndr 2021;30(1):12–19). Another concern with GLP-1 agonists is the loss of body mass, including fat and skeletal muscle, causing some patients to feel a loss of strength. This underscores the uncertainty surrounding the long-term effects of these agents, which patients may need to take indefinitely to sustain weight loss. 

How to use it
Liraglutide is FDA approved as adjunctive therapy to diet and exercise for weight management in adults with body mass index at or above 30 kg/m² (or 27 kg/m² with a weight-related condition such as hypertension, type 2 diabetes, or dyslipidemia). Start at 0.6 mg SQ per day and increase by 0.6 mg per week as tolerated. Doses above 3 mg/day are not FDA approved. 

Carlat Verdict: The GLP-1 agonists are potential game changers for the treatment of antipsychotic weight gain. Although liraglutide is the most studied GLP-1 agonist in psychiatric patients and is available in a generic form, it requires daily dosing and is less effective than the branded, once-weekly GLP-1 agonists semaglutide and tirzepatide.