Repurposing of Anti-Diabetic Agents for the Treatment of Cognitive Impairment and Mood Disorders

Abstract

Impairments in cognitive function represent a consistent, non-specific, and clinically significant feature in metabolic, mood, and dementing disorders. The foregoing observation is instantiated by evidence demonstrating that these disorders share pathophysiological mechanisms including, but not limited to, aberrant insulin signaling, inflammation, and glucocorticoid activity. Moreover, these mechanisms have been consistently reported to increase vulnerability to and/or exacerbate impairments in cognitive function. Notwithstanding evidence suggesting a bidirectional relationship between disturbances in the metabolic milieu, mood, and increased risk for dementia, efficacious treatments that target cognitive impairments in these populations do not presently exist. Taken together, it is proposed that anti-diabetic agents may aid the management of mood disorders and future risk for dementia through disease modification by targeting underlying pathophysiological mechanisms (e.g., aberrant metabolic function) rather than focusing solely on symptom mitigation. The current aim is to provide a brief narrative review of extant studies that report on the potential neurotherapeutic effects of anti-diabetic agents on disturbances in mood and impairments in cognitive function.

The diabetes drug liraglutide reverses cognitive impairment in mice and attenuates insulin receptor and synaptic pathology in a non‐human primate model of Alzheimer's disease

“…The studies in experimental models of the disease have led to clinical trials aimed at testing the efficacy of liraglutide in AD (ID: NCT01843075; ID: NCT01469351; ID: NCT02140983). Interestingly, liraglutide has been recently shown to improve cognition in individuals with mood disorders and Parkinson's disease . However, little is known to date about the cellular mechanisms of action of GLP‐1R agonists in the brain.…”

PINK1/Parkin Pathway Activation for Mitochondrial Quality Control – Which Is the Best Molecular Target for Therapy?

“…Studies have shown that metformin can also penetrate the blood-brain barrier and protect neurons. Repurposing of anti-diabetic agents for the treatment of cognitive impairment and mood disorders has been proposed ( Cha et al, 2016 ).…”

Clinical Considerations Regarding the Use of Obesity Pharmacotherapy in Adolescents with Obesity

“…Metformin‐associated lactic acidosis is quite rare, with incidence estimated to be 3‐10 per 100,000 person‐years , and although quite rare, there are a few cases reports of rhabdomyolysis in the literature . Metformin is usually a first‐line medication in a patient with insulin resistance, prediabetes, or metabolic syndrome given the minimal safety concerns and tolerability. Though the meta‐analyses showed only a small reduction in excess weight in youth, metformin has been effective for weight regain related to antipsychotic medications in nondiabetic children (−4.1% weight reduction [95% CI: 2.2‐6.0]) and in adults, for weight gain related to mood disorders, steroid exposure, stress eating, and emotional eating related to cognitive dysfunction, possibly related to aberrant insulin signaling, inflammation, and glucocorticoid activity, which may be emanated by iatrogenic causes . Metformin is extensively utilized for polycystic ovarian syndrome treatment with or without obesity diagnosis in children and adolescents, with improvement seen on lipid profile, hirsutism, and weight loss . Off‐label drug‐use documentation, along with consent for treatment from the patient’s parent or guardian, is recommended. Effect of metformin on pubertal development is unknown.…”