The role of metformin as a treatment for neuropsychiatric illness

Dodd, Seetal; Sominsky, Luba; Siskind, Dan; Bortolasci, Chiara C.; Carvalho, André F.; Maes, Michaël; Walker, Adam J.; Walder, Ken; Yung, Alison R.; Williams, Lana J.; Myles, Hannah; Watson, Tayler; Berk, Michael

doi:10.1016/j.euroneuro.2022.09.002

Cited by 19 publications

(5 citation statements)

References 85 publications

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“…An alternative is drug repurposing, which is strongly supported by governments and funding bodies as an efficient and effective option [ 108 ] (see [ 109 ] for detailed benefits). In addition, drug repurposing may be particularly appropriate in conditions with high oxidative stress and comorbidities [ 110 , 111 ]. We propose that trimetazidine is a promising drug that can be repurposed to target mitochondrial dysfunction, inflammation and oxidative stress to treat bipolar depression.…”

Section: Trimetazidinementioning

confidence: 99%

Metabolic regulation to treat bipolar depression: mechanisms and targeting by trimetazidine

et al. 2023

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Bipolar disorder’s core feature is the pathological disturbances in mood, often accompanied by disrupted thinking and behavior. Its complex and heterogeneous etiology implies that a range of inherited and environmental factors are involved. This heterogeneity and poorly understood neurobiology pose significant challenges to existing drug development paradigms, resulting in scarce treatment options, especially for bipolar depression. Therefore, novel approaches are needed to discover new treatment options. In this review, we first highlight the main molecular mechanisms known to be associated with bipolar depression–mitochondrial dysfunction, inflammation and oxidative stress. We then examine the available literature for the effects of trimetazidine in said alterations. Trimetazidine was identified without a priori hypothesis using a gene-expression signature for the effects of a combination of drugs used to treat bipolar disorder and screening a library of off-patent drugs in cultured human neuronal-like cells. Trimetazidine is used to treat angina pectoris for its cytoprotective and metabolic effects (improved glucose utilization for energy production). The preclinical and clinical literature strongly support trimetazidine’s potential to treat bipolar depression, having anti-inflammatory and antioxidant properties while normalizing mitochondrial function only when it is compromised. Further, trimetazidine’s demonstrated safety and tolerability provide a strong rationale for clinical trials to test its efficacy to treat bipolar depression that could fast-track its repurposing to address such an unmet need as bipolar depression.

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Section: Trimetazidinementioning

confidence: 99%

Metabolic regulation to treat bipolar depression: mechanisms and targeting by trimetazidine

et al. 2023

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“…The cited data show that the interaction of antipsychotic drugsmicrobiota-metformin can be very complex, and only well-designed clinical trials will allow to optimize and individualize such therapy. Metformin administration is of interest not only for the treatment of metabolic disorders caused by SGA treatment (Skonieczna-Żydecka et al, 2020b), in which dysbiosis plays a significant role (Skonieczna-Żydecka et al, 2019) but above all, the possibility of a beneficial effect of this drug for mental disorders (Dodd et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

Clinical significance of microbiota changes under the influence of psychotropic drugs. An updated narrative review

et al. 2023

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Relationship between drugs and microbiota is bilateral. Proper composition thus function of microbiota is a key to some medications used in modern medicine. However, there is also the other side of the coin. Pharmacotherapeutic agents can modify the microbiota significantly, which consequently affects its function. A recently published study showed that nearly 25% of drugs administered to humans have antimicrobial effects. Multiple antidepressants are antimicrobials,. and antibiotics with proven antidepressant effects do exist. On the other hand, antibiotics (e.g., isoniaside, minocycline) confer mental phenotype changes, and adverse effects caused by some antibiotics include neurological and psychological symptoms which further supports the hypothesis that intestinal microbiota may affect the function of the central nervous system. Here we gathered comprehensively data on drugs used in psychiatry regarding their antimicrobial properties. We believe our data has strong implications for the treatment of psychiatric entities. Nevertheless the study of ours highlights the need for more well-designed trials aimed at analysis of gut microbiota function.

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“…Future research should examine other possible mechanisms leading to IR in Long COVID including hypercoagulation, endothelial injuries, microvascular inflammation, thrombosis, and mitochondrial functions during acute COVID-19 infection, and the onset of autoimmune responses in Long COVID. One possibility could be to evaluate treatments with metformin which may be useful to treat depression (82) and improving the outcome of COVID-19 patients and patients with pre-existing T2DM (83,84) .…”

Section: Discussionmentioning

confidence: 99%

Increased insulin resistance due to Long COVID is associated with depressive symptoms and partly predicted by the inflammatory response during acute infection

Al‐Hakeim

Al-Rubaye²,

Jubran

et al. 2022

Preprint

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Background. Some months after the remission of acute COVID-19 infection, some people show depressive symptoms, which are predicted by increased peak body temperature (PBT) and lowered blood oxygen saturation (SpO2). Nevertheless, no data indicate whether Long COVID is associated with increased insulin resistance (IR) in association with depressive symptoms and immune, oxidative, and nitrosative (IO&NS) processes. Methods. We used the homeostasis Model Assessment 2 (HOMA2) calculator to compute beta-cell function, insulin sensitivity and resistance (HOMA2-IR) and measured the Beck Depression Inventory (BDI) and the Hamilton Depression Rating Scale (HAMD) in 86 Long COVID patients and 39 controls. We examined the associations between the HOMA2 indices and PBT and SpO2 during acute infection, and depression, IO&NS biomarkers (C-reactive protein, NLRP3 activation, myeloperoxidase, and advanced oxidation protein products) 3-4 months after the acute infection. Results. Long COVID is accompanied by increased HOMA2-IR, fasting blood glucose, and insulin levels. We found that 33.7% of the patients versus 0% of the controls had HOMA2-IR values >1.8, suggesting IR. PBT, but not SpO2, during acute infection significantly predicted IR, albeit with a small effect size. Increased IR was significantly associated with depressive symptoms as assessed with the BDI and HAMD above and beyond the effects of IO&NS pathways. There were no significant associations between increased IR and the activated IO&NS pathways during Long COVID. Conclusion. Long COVID is associated with new-onset IR in a subset of patients. Increased IR may contribute to the onset of depressive symptoms due to Long COVID by enhancing overall neurotoxicity.

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The role of metformin as a treatment for neuropsychiatric illness

Cited by 19 publications

References 85 publications

Metabolic regulation to treat bipolar depression: mechanisms and targeting by trimetazidine

Metabolic regulation to treat bipolar depression: mechanisms and targeting by trimetazidine

Clinical significance of microbiota changes under the influence of psychotropic drugs. An updated narrative review

Increased insulin resistance due to Long COVID is associated with depressive symptoms and partly predicted by the inflammatory response during acute infection

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