International Journal For Multidisciplinary Research

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The mTOR-AMPK Axis in Mental Illness: Energy Metabolism, Neuroplasticity and Psychiatric Disorders

Author(s) Mr. Mukesh Kumar G, Mr. Suraj Patel, Ms. Nirmola Sharma, Ms. Tamanna Khasa, Dr. Lucky Patidar, Dr. Rishi Panday
Country India
Abstract Psychiatric disorders constitute a significant worldwide health burden and are increasingly understood to involve not only dysregulation of the neurotransmitter system but also fundamental disturbances in cellular energy metabolism. Emerging research identifies the AMP-activated protein kinase (AMPK) and mechanistic target of rapamycin (mTOR) pathways as key regulators linking metabolic status to neuroplasticity, synaptic function, and neuronal survival. AMPK functions as a cellular energy sensor, restoring metabolic homeostasis under conditions of energy stress by activating catabolic pathways and inhibiting mTOR signalling. In contrast, mTOR promotes anabolic processes essential for synapse formation, protein synthesis, and neurogenesis. A balanced interaction between mTOR and AMPK is therefore critical for maintaining synaptic remodelling, learning and adaptive stress responses within the central nervous system.
This literature review summarises preclinical and clinical evidence linking dysregulation of the mTOR-AMPK axis to major psychiatric disorders, including depression, schizophrenia, bipolar disorder, anxiety disorders, and selected neurodevelopmental conditions. Accumulating studies consistently demonstrate that stress-related and psychotic disorders are associated with mTORC1 hypofunction, impaired neural plasticity and disrupted AMPK-mediated energy sensing and mitochondrial homeostasis. Rapid-acting antidepressants such as ketamine exert therapeutic effects through mTOR-dependent synaptogenesis, while metabolic modulators, including metformin and lifestyle interventions, influence mood and cognitive function primarily through AMPK activation. In addition, it is increasingly recognised that psychotropic medications exert indirect effects on this metabolic axis, contributing to both therapeutic efficacy and metabolic adverse outcomes.
Collectively, the evidence supports a paradigm shift in psychiatry that integrates brain energy metabolism with neuroplasticity and behavioural regulation. Targeting the mTOR-AMPK axis offers promising opportunities for biomarker development, personalised therapeutic strategies, and novel treatment approaches. Future translational research integrating metabolic profiling, neuroimaging and longitudinal clinical studies is essential to clarify causality and optimise metabolism-informed intervention for mental illness.
Keywords mTOR, AMPK, mental illness, Psychiatric disorder and Neuroplasticity
Field Medical / Pharmacy
Published In Volume 7, Issue 6, November-December 2025
Published On 2025-12-22
DOI https://doi.org/10.36948/ijfmr.2025.v07i06.64295
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E-ISSN 2582-2160
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