Improving survival in people with severe psychiatric disorders

An expert article suggests that widely used diabetes and obesity drugs can help close the long-standing mortality gap faced by people with serious mental illness by tackling cardiovascular risk and metabolic disease head-on.

Editorial: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have the potential to transform health outcomes for people with bipolar disorder, schizophrenia, major depressive disorder, and other major mental illnesses, extending health duration and reducing excess and premature mortality. Image credit: AtlasStudio / Shutterstock

Recent article published in the journal Expert opinion on Pharmacotherapy discussed that glucagon-like peptide 1 (GLP-1) receptor agonists (RAs) can potentially transform health outcomes for people with serious mental illness (SMI). The authors emphasized that these agents are more likely to improve outcomes by addressing cardiometabolic factors of excess morbidity and mortality rather than replacing standard psychiatric treatments.

Indications for development and expansion of GLP-1 receptor agonists

In 2005, the United States (US) The Food and Drug Administration approved the first GLP-1 receptor agonist, exenatide, for the treatment of type 2 diabetes (T2D). Since then, several GLP-1 mono-agonists have been approved, along with tirzepatide, the first dual GLP-1 and insulinotropic glucose polypeptide (GIP) receptor agonist. Additional targeting of double and triple fighters GIP, GLP-1and glucagon receptors are in terminal development.

Beyond T2D and weight management in people who are overweight or obese, GLP-1 receptor agonists are approved for steatohepatitis associated with metabolic dysfunction in people with moderate or advanced fibrosis, obstructive sleep apnea in obese adults, reduction of major adverse cardiovascular events in adults with T2D and cardiovascular disease (CVD), and slowing the progression of CKD and cardiovascular mortality in adults with both CKD and T2D.

Synthetic micromolecular oral GLP-1 Receptor agonists are expected to be approved in 2026, while oral semaglutide is already available. These formulations may ease barriers related to manufacturing, supply chains, and access. There is broad consensus that GLP-1 receptor agonists have transformed its management T2Dobesity and associated morbidity and have been associated with reduced progression of kidney disease, cardiovascular disease and mortality in individuals with metabolic disorders.

Cardiometabolic burden in severe mental illness

Schizophrenia, major depressive disorder, bipolar disorder (BD), and others SMI are serious, prevalent and lifelong conditions that contribute significantly to disability, reduced health duration and reduced social and economic participation, particularly in younger populations. People with SMI experience premature and excess mortality, with years of life lost often estimated between 5 and 25 years, largely due to early onset and significantly higher rates CVD.

Accessible, scalable, and effective interventions are therefore essential to increase health duration and reduce cardiovascular-related mortality among people with SMI. Each condition for which GLP-1 Approved receptor agonists contribute differently to cardiometabolic risk and loss of health duration in this population. In addition, several agents are in mid- or late-stage development for chronic conditions, such as peripheral artery disease and atherosclerotic heart disease, that disproportionately affect people with SMI.

Limitations of Current Psychiatric Treatments on Mortality

Despite the availability and clinical efficacy of antipsychotics, lithium, antidepressants, and anticonvulsants, reductions in health loss and cardiovascular mortality have only been demonstrated for selected classes and agents, including long-acting second-generation antipsychotics, lithium, and clozapine. Lithium, in particular, remains under-prescribed despite its powerful efficacy BDlimiting its overall impact on public health.

Current and Emerging Clinical Applications of GLP-1 Receptor Agonists

GLP-1 Receptor agonists are recommended for the management of weight gain associated with psychotropic medications when discontinuation of psychiatric treatment is not feasible. Preliminary evidence also suggests a possible protective effect against lithium-induced nephrotoxicity, a condition for which there is currently no approved treatment. Moreover, several GLP-1 receptor agonists are being developed or repurposed to treat alcohol, tobacco, and opioid use disorders.

Preclinical studies, small controlled trials, and observational research further suggest this GLP-1 Receptor agonists may have beneficial effects in the prevention and treatment of mood disorders and areas of psychopathology that significantly affect quality of life, including cognitive dysfunction and anhedonia.

Safety issues in populations with serious mental illness

Many safety issues are especially important for people with SMI. For example, its constipating effects GLP-1 Receptor agonists may interact with psychotropic drug-induced gastrointestinal motility disorders.

Clinicians should also consider the increased risks of pancreatitis and sarcopenia, conditions that disproportionately affect people with SMI. In addition, GLP-1 receptor agonists that are eliminated by the kidneys, such as lixisenatide and exenatide, are contraindicated in severe renal disease, which is more prevalent in this population. Although early pharmacovigilance reports indicated a possible association with suicide, larger subsequent studies have not demonstrated a causal link, although continued monitoring is still recommended.

Implications for health duration and mortality reduction

Overall, people with SMI account for a disproportionate share of life-years lost and disability-adjusted life-years. Despite decades of advances in psychopharmacology, the mortality gap between the general population and individuals with SMI has not been substantially limited. Therefore, therapeutic strategies that directly reduce mortality and extend health duration are urgently needed.

In this context, GLP-1 Receptor agonists represent one of the most promising pharmacological classes, particularly if challenges related to cost, equitable access, reimbursement policy, and supply constraints are addressed. Prioritizing people with SMI within fair distribution frameworks can help reduce excess and premature mortality in this vulnerable population in the short term.