An editorial in Expert Opinion on Pharmacotherapy proposes that glucagon-like peptide-1 (GLP-1) receptor agonists may significantly improve health outcomes for individuals with serious mental illnesses (SMIs). The authors suggest these agents could address cardiometabolic factors contributing to excess morbidity and mortality, complementing rather than replacing existing psychiatric treatments.
Development and Expanding Uses of GLP-1 Receptor Agonists
The first GLP-1 receptor agonist, exenatide, received approval from the U.S. Food and Drug Administration in 2005 for type 2 diabetes (T2D). Since then, numerous GLP-1 mono-agonists and dual agonists, such as tirzepatide (targeting GLP-1 and GIP receptors), have been approved. Additional dual and triple agonists are currently in late-stage development.
Oral GLP-1 receptor agonists, including the currently available oral semaglutide and others expected by 2026, aim to improve access and supply of these medications.
Beyond T2D and weight management, GLP-1 receptor agonists are approved for a growing list of conditions:
- Metabolic dysfunction-associated steatohepatitis (with moderate or advanced fibrosis)
- Obstructive sleep apnea in obese adults
- Reduction of major adverse cardiovascular events in adults with T2D and cardiovascular disease
- Slowing chronic kidney disease progression and cardiovascular mortality in adults with both chronic kidney disease and T2D.
Cardiometabolic Burden in Serious Mental Illness
SMIs like schizophrenia, major depressive disorder, and bipolar disorder are associated with premature and excess mortality, often resulting in 5 to 25 years of life lost. This concerning statistic is largely attributed to higher rates and earlier onset of cardiovascular disease (CVD) in this population.
Interventions that are affordable, scalable, and effective are critically needed to extend healthspan and reduce cardiovascular-related mortality among people with SMIs.
GLP-1 receptor agonists represent a promising pharmacological class for reducing mortality and extending healthspan, provided challenges related to cost, equitable access, reimbursement, and supply are addressed.
Limitations of Current Psychiatric Treatments
While antipsychotics, lithium, and anticonvulsants are clinically effective, only specific agents such as second-generation long-acting antipsychotics, lithium, and clozapine have demonstrated reductions in healthspan loss and cardiovascular mortality. Despite its proven efficacy in bipolar disorder, lithium remains under-prescribed.
Current and Emerging Clinical Applications
GLP-1 receptor agonists are currently recommended for managing weight gain induced by psychotropic medications when continued psychiatric treatment is essential. Early evidence also suggests a potential protective effect against lithium-induced nephrotoxicity.
These agents are also being developed or repurposed for treating alcohol, tobacco, and opioid use disorders. Preclinical studies and preliminary clinical research further indicate potential benefits for mood disorders, cognitive dysfunction, and anhedonia.
Safety Considerations for SMI Populations
Specific safety considerations for individuals with SMIs include potential interactions between GLP-1 receptor agonist-induced constipation and psychotropic-related gastrointestinal motility issues. Clinicians also need to consider increased risks of pancreatitis and sarcopenia, conditions that disproportionately affect SMI populations.
Renally eliminated GLP-1 receptor agonists, such as lixisenatide and exenatide, are contraindicated in severe renal disease, a condition more prevalent in this group. While early reports suggested a link to suicidality, larger subsequent studies have not established a causal connection, although ongoing monitoring is advised.
Implications for Mortality Reduction
Individuals with SMIs contribute disproportionately to years of life lost and disability-adjusted life years. The mortality gap between the general population and people with SMIs has remained largely unchanged despite advances in psychopharmacology.
GLP-1 receptor agonists represent a promising pharmacological class for reducing mortality and extending healthspan, provided challenges related to cost, equitable access, reimbursement, and supply are addressed. Prioritizing individuals with SMIs within fair allocation frameworks may help reduce this excess and premature mortality.