Transformation 2.0: The GLP-1 RAs as Psychiatric Medications?

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It is often stated that the modern psychopharmacologic revolution began in the 1950s. During that time, health care practitioners and individuals with mental disorders were introduced to conventional antipsychotics, monoaminergic antidepressants, benzodiazepines, and lithium. This truly remarkable decade was a prelude to 7 subsequent decades that ushered in an expansion of treatment options, with newer-generation agents generally being safer, better tolerated, and easier to administer.

Although the 1950s were transformative, the treatment, and prevention, of mental disorders are long overdue for Transformation 2.0. To be transformative, newer treatments should have considerable advantage over extant treatments with respect to overall efficacy, time to peak efficacy, and tolerability. In addition, no current psychiatric drug is disease modifying, a long overdue need that would transform the field. Surreal insights with respect to the pathophysiology of mental disorders have provided the basis for the discovery and development of treatments that target underlying mechanisms of the disease (eg, esketamine for the treatment of depressive disorders). This new zeitgeist of “mechanistically informed therapeutics” has introduced the possibility that Transformation 2.0 is no longer quixotic.

In the past 2 decades, convergent evidence has implicated disturbances in central nervous system (CNS) metabolic function as a core pathophysiologic disturbance, especially for general cognitive (eg, executive functions, learning, and memory) and reward functions (eg, motivation, anhedonia). Insulin, well known for its effect on peripheral glucoregulation, is also recognized as integral to neurodevelopment, neuroplasticity, and network resting state functional connectivity (RSFC). Contemporaneously, incretins (eg, glucagon-like peptide-1 [GLP-1]) were discovered to not only increase insulin biosynthesis and release (“an incretin effect”) but also exert protrophic and proplasticity processes in reward and cognitive control centers (Table 1; Sidebar).

TABLE 1. FDA Indications, Potential Future Indications, and Areas of Investigation for GLP-1 RAs

Incretin-Based Treatments

Individuals with mental disorders are differentially affected by conditions for which select GLP-1 receptor agonists (RAs) are approved by the FDA. For example, the rates of obesity, type 2 diabetes mellitus (T2DM), obstructive sleep apnea, and cardiovascular disease are at least 30% to 50% higher in those with mood and psychotic disorders when compared with the general population.¹ In addition, cardiovascular disease is the single largest cause of excess and premature mortality in persons with severe mental disorders.² The opportunity for GLP-1 RAs to reduce medical illness burden and/or mortality from cardiovascular disease would be transformative in psychiatry.

Individuals with mental disorders have significantly higher rates of other comorbid medical disorders that are under investigation as potential treatment targets for GLP-1 RAs, including binge eating disorder, polycystic ovarian syndrome, and noncirrhotic nonalcoholic steatohepatitis.^3-7 In addition to prescribing GLP-1 RAs for on- and possibly off-label indications, a replicated body of evidence also indicates that GLP-1 RAs are safe and highly effective in the treatment of psychotropic drug–related weight gain.⁸

Are GLP-1 RAs Psychiatric Drugs?

The rationale for conceptualizing and repurposing incretin-based agents as psychiatric drugs derives from their pleiotropic effects on the pathophysiologic substrates implicated in mental disorders (Table 2). For example, incretin receptors in the CNS are distributed in regions known to subserve brain functions that are altered across mental disorders (eg, striatum, hippocampus, anterior cingulate cortex, prefrontal cortex). In addition, preliminary evidence also suggests that incretin receptor gene expression within select regions of the CNS (eg, dorsolateral prefrontal cortex, hippocampus) is altered in persons with mental disorders.⁹

TABLE 2. Rationale for Repurposing Incretin-Based Pharmacologic Agents for Psychiatric Disorders

A “go-no-go” decision with respect to developing pharmacologic agents for mental disorders is whether the agent in question is CNS penetrant and able to target select regions implicated in the pathophysiology of mental disorders.¹⁰ Preclinical and clinical evidence for select GLP-1 RAs suggests that they are CNS penetrant and able to target critical brain regions, although to a limited extent.¹¹ The CNS penetration of GLP-1 RAs and their target engagement in regions of interest set the stage for hypothesizing that their effects on the CNS are direct and not only a consequence of their effects on peripheral metabolism and/or weight loss.¹¹

FIGURE. The Molecular and Cellular Effects of GLP-1 RAs

A separate and highly replicated finding is that GLP-1 RAs directly target molecular systems implicated in neurogenesis, neurodifferentiation, neuroplasticity (Neuro-GDP), neuroprotection, and apoptosis (Figure).¹² For example, GLP-1 RAs increase synthesis of cAMP response element-binding protein (CREB), brain-derived neurotrophic factor (BDNF), and glial-derived neurotrophic factor (GDNF), proteins integral to neurotrophic processes. In addition, GLP-1 RAs activate proteins (eg, mammalian target of rapamycin; mTOR) integral to neuroplasticity, synaptic density and strength, and long-term potentiation.¹² In accordance with their effects on neurotrophic and neuroplasticity processes, replicated neuroimaging studies have reported that GLP-1 RAs modulate RSFC in CNS networks (eg, default mode network) that are also targeted by extant psychiatric treatments (eg, ketamine).^13,14

In addition to proplasticity and synaptic density enhancing effects, GLP-1 RAs reduce proinflammatory imbalance as well as oxidative stress markers.¹² For example, GLP-1 RAs decrease the synthesis and release of proinflammatory cytokines and facilitate the phenotypic transition of microglia from their proinflammatory to anti-inflammatory functional state. Replicated evidence also indicates that GLP-1 RAs decrease nitric oxide, malondialdehyde, and other oxidative markers while increasing antioxidative markers (eg, superoxide dismutase).

Activation of proapoptotic and cell death mechanisms are implicated in the pathophysiology of many mental disorders. GLP-1 RAs may reverse this process, as evidenced by their effect on the proapoptotic cellular processes. For example, GLP-1 RAs reduce the ratio of BCL2–associated X protein (BAX) to the antiapoptotic B-cell lymphoma protein 2 (BCL2) via stimulation of BCL2 activity (ie, BAX: BCL2).

GLP-1 RAs also reduce molecular hallmarks of major neurocognitive disorders. For example, GLP-1 RAs reduce aggregates of α-synuclein, the accumulation of amyloid β-plaques, and the formation of hyperphosphorylated tau neurofibrillary tangles. Taken together, these molecular observations provide the basis for speculating that GLP-1 RAs may improve cognitive outcomes and/or modify the disease course of major neurocognitive disorders such as Alzheimer disease and Parkinson disease (PD).¹⁵

In keeping with this view, several observational cohort studies reported that individuals prescribed GLP-1 RAs primarily for T2DM were less likely to be diagnosed or treated for select mental disorders (eg, major depressive disorder, alcohol use disorder), suggesting preventive effects.^16,17 Subsequent translational research in individuals with mental disorders (eg, mood disorders) provided evidence that GLP-1 RAs improve disparate measures of psychopathology (eg, cognitive dysfunction), which correlate with changes in brain structure/function.^17,18

Several GLP-1 RAs have entered mid-late phase development in the treatment of select psychiatric disorders. For example, a 1-year phase 2 study with lixisenatide in adults with PD suggested modest but significant beneficial effects on the progression of motor abnormalities.¹⁹ Subsequently, a 2-year phase 3 study of PD with exenatide failed to identify significant benefits on motor symptoms when compared with placebo.²⁰ Preliminary phase 2 evidence suggests beneficial effects of GLP-1 RAs (eg, semaglutide) on measures of craving, heavy drinking, and/or hospitalizations in persons with alcohol use disorders.^21-23 Phase 2/3 trials are currently evaluating whether GLP-1 RAs reduce illness progression in persons with mild cognitive impairment or amyloid-positive mild dementia due to Alzheimer disease (ie, semaglutide). Finally, several phase 2/3 relapse prevention studies with GLP-1 RAs in the acute maintenance of alcohol use disorder, as well as other mental disorders (eg, mood and psychotic disorders), are planned or underway.^24-26

Concluding Thoughts

GLP-1 RAs have transformed the treatment of T2DM and obesity. Practitioners providing care to patients with mental disorders should be highly familiar with FDA indications for respective GLP-1 RAs, as each of the current indications are overrepresented in persons with mental disorders. In addition, ameliorating psychotropic drug-related weight gain and potential off-label benefits in other conditions commonly encountered in persons with mental disorders (eg, substance use disorder, alcohol use disorder, binge eating disorder) are also potential near-term clinical applications (Table 3).

TABLE 3. Takeaway Messages

Reports appeared in 2023 of suicidality causally related to the prescription of GLP-1 RAs. Precedent exists for the possibility of cause and effect insofar as other interventions that lead to weight loss (eg, bariatric surgery, rimonabant) are known to be associated with new-onset psychopathology (eg, depression) and suicidality. Subsequent pharmacovigilance studies replicated the initial observation of an association between GLP-1 prescription and suicidality.^27-29 Separately, multiple observational cohort studies, however, reported either no effect or a reduction in suicidality associated with GLP-1 RA prescription.^30-32 An investigation by the FDA, European Medicines Agency, and the United Kingdom’s Medicines and Healthcare Products Regulatory Agency concluded that current evidence does not support a causal link between GLP-1 RAs and suicidality.³³ Nonetheless, the potential that aspects of suicidality could be engendered and/or intensified in individual cases cannot be excluded.²⁹

Incretin-based agents have notable adverse effects which may affect acceptability. For example, nausea, vomiting, constipation, muscle wasting, and reduced gastric motility can be treatment-limiting. Moreover, many psychiatric drugs (eg, clozapine, olanzapine, opioids) also have adverse effects on gut motility, which may be additive or synergistic with GLP-1 RAs and should be a point of caution when coprescribing these agents. In addition to their tolerability and safety profile, access, availability, and affordability of GLP-1 RAs have been limited due to the extraordinary demand outstripping supply chain capability. Supply chain shortages and high acquisition costs have prompted increased use of online and compound pharmacies to access GLP-1 RAs, which increases the risk of accidental overdose.³⁴ A triangulation of evidence has provided the basis for hypothesizing that GLP-1 RAs could be conceptualized as psychiatric drugs capable of targeting pathophysiologic mechanisms implicated in the symptomatic presentation and progression of mental disorders. It is a transformative possibility that GLP-1 RAs may also be capable of preventing and/or forestalling the declaration of a mental, neurologic, or substance use disorder. During the next 1 to 3 years, results from the early-late phase studies with GLP-1 RAs will be available to confirm or refute this hypothesis. Whether dual and/or triple incretin agonists have advantages over monoagonists with respect to impact on mental disorders is also a near-term priority research vista.

Dr McIntyre is a professor of psychiatry and pharmacology at the University of Toronto and head of the Mood Disorders Psychopharmacology Unit at the University Health Network in Toronto, Canada. He is also the executive director of the Brain and Cognition Discovery Foundation and director and cochair of the scientific advisory board of the Depression and Bipolar Support Alliance. He is a professor and Nanshan Scholar at Guangzhou Medical University in China, an adjunct professor at Korea University College of Medicine in Seoul, a clinical professor at the State University of New York Upstate Medical University in Syracuse, and a clinical professor in the Department of Psychiatry and Neurosciences at the University of California Riverside School of Medicine. He is the founder of the Canadian Rapid Treatment Centre of Excellence and CEO of Braxia Scientific Corp.

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