How to treat antipsychotic-related weight gain and metabolic disturbances: Is there a role for GLP-1 receptor agonists?

Patients with mental disorders have a significantly reduced lifespan,¹ with overweight/obesity and cardiometabolic-related death being the biggest contributors. Both the underlying mental illness and treatments, especially antipsychotics, contribute to this increased cardiometabolic risk, creating a dilemma between efficacy and desired safety. As a point in fact, clozapine is a second-generation antipsychotic with proven antipsychotic efficacy in otherwise treatment-resistant patients with a diagnosis of schizophrenia. However, clozapine is also linked to a substantial increase in body weight and carries a high risk for metabolic disturbances,² making clinicians, patients, and caretakers reluctant against its use. Additionally, sedentary lifestyle and unhealthy food intake have become a public health issue for populations in the Western world in general. However, they are an even bigger problem among people with severe mental disorders, such as schizophrenia and bipolar disorder. Also, the use of antipsychotics has expanded beyond schizophrenia and bipolar disorder, being used frequently on-label for unipolar depression, but also off-label for impulsive behaviors, insomnia, and anxiety among other conditions.³

Over the last decade, more focus has been paid to monitoring body weight and uncovering potential dysmetabolism by blood sample analysis in people treated with antipsychotics, which are important steps in the right direction. However, clear, and well-established strategies for an effective treatment against overweight/obesity and dysmetabolism in people with mental illness and, especially, those receiving antipsychotics or being mentally ill, remain underdeveloped or, at least, underutilized.⁴

The most effective strategy for preventing antipsychotic-induced weight gain and dysmetabolism is using these medications only when needed or starting with the antipsychotic with the lowest weight gain potential.⁴ When weight gain and metabolic adverse effects occur, secondary preventive efforts include switching to an antipsychotic linked to less weight gain and dysmetabolism, although the desired weight loss may be limited.⁵ Moreover, in the case of clozapine, which is used in otherwise partial or complete treatment-resistant patients, switching to a less effective antipsychotic, even if it may impose fewer dysmetabolic problems and less increase in body weight, may not be an applicable strategy.⁶ Nonpharmacological interventions such as lifestyle changes against overweight and dysmetabolism are well-known strategies⁷ but-as for the background population-are difficult to implement broadly.

Traditionally, the adjunctive pharmacological interventions against antipsychotic-associated weight gain have included topiramate and metformin. However, the weight-lowering effects of these compounds are somewhat modest—typically in the range of 3–4 kg over 12–24 weeks.^{8, 9} This leaves a great need for additional and more effective antipsychotic augmentation strategies that mitigate, reverse, or prevent antipsychotic-related weight gain, and for antipsychotics devoid of any cardiometabolic adverse effects.¹⁰

Glucagon-like peptide-1 (GLP-1) is an incretin hormone synthesized in the L-cells of the intestine and released in response to food intake, causing delayed stomach emptying. GLP-1 receptor stimulation increases insulin secretion and reduces glucagon secretion, thereby stabilizing glucose homeostasis.¹¹ GLP-1 is also synthesized in the nucleus of the solitary tract in the brain stem and is released in the hypothalamus and other brain areas involved in satiety, where it is believed to decrease appetite and thereby influence body weight.¹² GLP-1 receptor agonists (GLP-1 RAs) have been used in the clinic against type 2 diabetes mellitus since 2007 and against overweight/obesity since 2020, and newer GLP-1 RAs, for example, dulaglutide, semaglutide, and tirzepatide, have shown even more potent weight-lowering effects.¹³

To date, only a few studies have investigated the effects of GLP-1 RAs specifically in antipsychotic-treated patients, and data from these studies have been incorporated in a recent systematic review and meta-analysis by Bak et al. showing beneficial effects of GLP-1 RAs on dysmetabolism and overweight.¹⁴ What are the potential risks of GLP-1 RAs among patients with a psychiatric diagnosis? The most common adverse events were nausea, vomiting, and diarrhea that were generally tolerable¹⁴ and similar to data in the type 2 diabetes and weight loss trials. However, due to preclinical evidence that GLP-1 RAs interact with brain homeostasis, for example, reducing dopamine increases caused by drugs of abuse,¹⁵ concern have been raised whether GLP-1 RAs could induce anhedonia, depression, and suicidal ideation, or worsen psychiatric symptoms in patients with preexisting mental health issues. Recent data from cohort studies¹⁶ and post hoc analysis from clinical trials¹⁷ do not indicate such a risk. However, in the general population weight loss and type 2 diabetes trials, patients with known severe mental illnesses were excluded. Therefore, trials including patients with preexisting mental health problems are essential to ensure that GLP-1 RAs are also safe in psychiatric populations. In the studies reviewed by Bak et al., psychopathology was assessed with different rating scales. Therefore, changes in psychopathology were transformed into one single scale: the 7-point Clinical Global Impression Severity scale (CGI), and no significant global psychopathology changes were observed.¹⁴ However, this approach clearly lacks precision, the number of participants across only four trials with psychopathology data was very small, and mean changes do not identify individual patients who may worsen significantly or become suicidal. Therefore, further studies in patients with antipsychotic-related weight increase and dysmetabolism are needed to fully assess the potential cardiometabolic but also psychopathology effects of GLP-1 RAs in people with mental illness.

Why are GLP-1 RAs not more commonly used in psychiatry? One argument could be that more data on the effects of GLP-1 RAs in patients with antipsychotic-related weight increases and cardiometabolic abnormalities are needed. Fortunately, several studies investigating the effects of the GLP-1 RA have finished recruitment (ClinicalTrials.gov ID NCT05333003; ClinicalTrials.gov ID NCT05193578). Hence, more data on this specific patient population are expected to become available soon. One could also hope that pharmaceutical companies would initiate larger RCTs in specific psychiatric populations, for example, people with schizophrenia, bipolar disorders, or unipolar depression who frequently are prescribed antipsychotics and who are particularly vulnerable to cardiometabolic burden. However, as GLP-1 RAs are already approved for weight loss in people with diabetes, and obesity or overweight and metabolic risk factors, independent of other disorders or medication treatment, a specific indication in the subgroup of people with mental illness may not provide sufficient incentive, although such data would be very important to justify widespread use for the treatment or even more important prevention of antipsychotic-induced weight gain when initiating treatment with antipsychotics with relevant cardiometabolic burden. Another issue is the somewhat high costs of GLP-1RAs at present, which carry treatment barriers and health equity issues already known from the use of GLP-1RAs against type 2 diabetes and obesity in non-psychiatric populations. However, some GLP-1 RA patents expire soon, so cheaper GLP-1 RAS will most likely be available and the cost of preventable cardiometabolic disorders is likely far higher. In the meantime, one could hope that governments would be willing to cover the cost of GLP-1 RA treatment of patients with mental illness, especially those on clozapine treatment.

AFJ has received two unrestricted research grants from Novo Nordisk A/S and is a member of a Novo Nordisk advisory board for a clinical study (no honorary). CUC has been a consultant and/or advisor to or has received honoraria from: AbbVie, Alkermes, Allergan, Angelini, Aristo, Boehringer-Ingelheim, Bristol-Meyers Squibb, Cardio Diagnostics, Cerevel, CNX Therapeutics, Compass Pathways, Darnitsa, Delpor, Denovo, Eli Lilly, Gedeon Richter, Hikma, Holmusk, IntraCellular Therapies, Jamjoom Pharma, Janssen/J&J, Karuna, LB Pharma, Lundbeck, MedInCell, MedLink, Merck, Mindpax, Mitsubishi Tanabe Pharma, Maplight, Mylan, Neumora Therapeutics, Neurocrine, Neurelis, Newron, Noven, Novo Nordisk, Otsuka, PPD Biotech, Recordati, Relmada, Reviva, Rovi, Saladax, Sanofi, Seqirus, Servier, Sumitomo Pharma America, Sunovion, Sun Pharma, Supernus, Tabuk, Takeda, Teva, Terran, Tolmar, Vertex, Viatris, and Xenon Pharmaceuticals. He provided expert testimony for Janssen, Lundbeck, and Otsuka. He served on a Data Safety Monitoring Board for Compass Pathways, IntraCellular Therapies, Relmada, Reviva, and Rovi. He has received grant support from Boehringer-Ingelheim, Janssen, and Takeda. He received royalties from UpToDate and is also a stock option holder of Cardio Diagnostics, Kuleon Biosciences, LB Pharma, Medlink, Mindpax, Quantic, and Terran.