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Metabolic psychiatry is an emerging field of research revealing robust connections between metabolic dysfunction and psychiatric conditions, with mitochondria suggested to be at the core of these connections.
Metabolism impacts every cell, tissue, and organ of the body, with its role in brain health being particularly significant. As the body’s most metabolically active organ, the brain is highly sensitive to alterations in metabolism, with its functions influenced by metabolic regulation and dysregulation of its cells. Mitochondrial function is vital to overall systemic and brain metabolism, with a growing body of research underscoring its role in mental health.
Mitochondria play a critical role in converting food and oxygen into cellular energy, while also serving important functions beyond energy production. In addition to providing the building blocks for cellular structures and supporting neuronal function, mitochondria are involved in the dynamic allocation of resources that modulate various metabolic and mental health processes.
Each cell contains hundreds to thousands of mitochondria that influence gene expression and cellular development. These organelles also participate in the synthesis, modulation and release of neurotransmitters, which, in turn, affect mitochondrial function. Moreover, mitochondria have a key role in genetic expression, including the regulation of inflammation, energy balance, fatigue, and responses to drugs and alcohol. They are also pivotal in the production of essential hormones, serving as the initial step in creating hormones imperative for mental health.
Mitochondrial function is modulated by mitophagy— the removal of damaged mitochondria through autophagy and biogenesis— the production of new mitochondria.
Dysregulation in metabolic functions, therefore, can greatly impede mitochondrial function and brain metabolism by compromising the mitochondria’s ability to generate cellular energy and neutralizing free radicals, leading to marked changes in neuroplasticity, neuronal circuitry and synaptic signaling, which have been demonstrated in psychiatric conditions. Such disruptions in cellular and metabolic functions may also cause parts of the brain to become overactive or underactive.
Indeed, comorbidities exist between mental health and metabolic conditions, as evidenced by a growing body of research. A 2024 study published in The International Journal of Molecular Sciences demonstrated marked dysregulations in various metabolic processes in patients with schizophrenia, bipolar disorder or major depressive disorder, including glycolysis, gluconeogenesis, glycogenesis, glycogenolysis, ketogenesis, lactate shuttle between astrocytes and neurons, electron transport chain (ETC), tricarboxylic acid (TCA) and urea cycles, fatty acid synthesis and oxidation, and pentose phosphate and glutathione pathways.
Findings revealed the most significant alterations in the expression of genes encoding enzymes for metabolic pathways involved in glycolysis, the TCA cycle and ETC across these psychiatric conditions, echoing results of previous research. These pathways are critical for energy production, and alterations in their functioning can impede metabolic and mental health.
Several studies have also shown disruptions in a series of metabolic reactions across various mental health conditions, including impeded glycolytic enzyme activity, astrocyte-neuron coupling and lactate metabolism, ETC and TCA enzyme levels, antioxidant metabolism and pentose phosphate metabolism— further underscoring these connections.
Psychiatric conditions are complex in their etiology, with genes, trauma, adverse childhood experiences (ACEs) and lifestyle factors—including stress, sleep and circadian rhythm, exercise and nutrition are all suggested to have relevance.
Metabolic psychiatry theorizes that these factors all affect biochemical processes in the body and brain that influence metabolic and mental health. For instance, chronic stress can compromise the immune response and increase levels of circulating proinflammatory cytokines, such as interleukin IL-6. Alterations in the HPA axis and sympathetic nervous system have also been observed from the effects of prolonged stress, further causing alterations in metabolism. Stress can also induce changes in the gut microbiome—impeding homeostatic functions related to neurotransmitter synthesis, microbial diversity, gut motility and inflammation— affecting mood and metabolism.
Mitochondria are suggested to have bidirectional relationship with many of these contributing factors to impeded metabolic and mental health. They influence the production and regulation of hormones that have roles in metabolic and mental health— including cortisol, testosterone, estrogen and progesterone. They also have roles in governing the inflammatory response, glucose metabolism, the immune response, the gut microbiome, oxidative stress, and synthesis and modulation of neurotransmitters important for mental health— GABA, dopamine, norepinephrine, and serotonin.
Mitochondrial function is impacted by stress, trauma, ACEs, substance abuse, genetics/epigenetics, sleep, hormones, infection and inflammation. The gut microbiome also influences mitochondria, as does exercise and nutrition
The intricate relationship between metabolism, mitochondria and brain function provides insight into how impeded metabolic processes may contribute to psychiatric conditions, as the functioning of the brain is governed by these processes. This perspective allows for a more comprehensive approach to psychiatric conditions that address the whole body as a unified system. These findings highlight the need for more refined regimens that address the complex etiology of these conditions, including metabolic dysregulation.
In conjunction with traditional psychotherapies and medication—if warranted—a holistic approach to mental health that addresses metabolic and cellular functions is encouraged through nutrition and lifestyle factors—including adequate sleep, movement and stress management.
While diet is bio-individual to support optimal cellular metabolism, with many factors at play, the ketogenic diet has been shown to support restoration of metabolic homeostasis through the production of ketone bodies in response to low carbohydrate intake, providing a vital energy source for the brain. Ketone bodies including β-hydroxybutyrate and acetoacetate sustain the metabolic requirements of the brain as they cross the blood-brain barrier to fuel neurons and other brain cells.
This metabolic adaptation supports brain function and metabolism under conditions of metabolic distress or dysregulation. The ketogenic diet has been shown to have promising benefits for patients with psychiatric conditions by improving metabolic health markers, modulating the gut microbiome, and reducing oxidative stress and inflammation, as demonstrated in a 2024 review in The Journal of Clinical Medicine.
A previous review also highlighted the impacts the ketogenic diet has on various factors related to psychiatric conditions—including glutamate/GABA crosstalk, monoamine levels, neurotrophic activity, mitochondrial function and biogenesis, insulin resistance, oxidative stress, and the inflammatory response. Ketosis also stimulates mitophagy and mitochondrial biogenesis helping to promote cellular health and metabolism.
While further research is needed, metabolic psychiatry offers an encouraging and cohesive perspective to psychiatric and metabolic health conditions by addressing their shared underlying metabolic pathways.
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