Inclusion criteria:

1. (a) full-text articles;

2. (b) published in English;

3. (c) published in peer-reviewed journals;

4. (d) human studies;

5. (e) original research articles;

6. (f) meta-analyses.

Exclusion criteria:

1. (a) diagnoses other than bipolar disorder;

2. (b) non-human studies;

3. (c) lack of full-text availability;

4. (d) case reports;

5. (e) studies involving children or adolescents;

6. (f) studies with comorbidities;

7. (g) studies on neurodegeneration;

8. (h) other non-relevant topics;

9. (i) non-English articles;

10. (j) duplicate records.

Additionally, a manual search was conducted to identify specific biomarkers mentioned in the text, yielding 28 additional publications.

Publications meeting all the above criteria underwent a full-text review. Figure 2 presents a schematic representation of the publication selection process.

Figure 2.

Flow diagram of a selection of energetic metabolism in bipolar disorder publications according to. PRISMA guidelines. *Record excluded using automated tools built-in database and bibliography manager. **Record excluded by a researcher.

Redox imbalance, inflammatory pathways

Oxidative stress represents one of the central pathophysiological mechanisms in bipolar disorder (BD), linking mitochondrial dysfunction with widespread neuronal, immune, and metabolic abnormalities This persistent oxidative burden contributes to progressive molecular damage and functional deterioration across both central and peripheral systems in BD (Lu et al., Reference Lu, Yang, Zhao, Zhang, Sun, Liao, Kang, Feng, Sun and Yue2024).

Oxidative stress not only causes molecular damage but also directly interferes with mitochondrial energy metabolism. Excess ROS oxidise components of the electron transport chain (ETC), particularly complexes I and III, leading to reduced ATP synthesis and increased electron leakage, which further amplifies ROS production (Karabatsiakis et al., Reference Karabatsiakis, Böck, Salinas-Manrique, Kolassa, Calzia, Dietrich and Kolassa2014). ROS-mediated oxidation of mitochondrial lipids and DNA disrupts mitochondrial biogenesis and dynamics, contributing to the decreased efficiency of oxidative phosphorylation consistently observed in BD (Gimenez-Palomo et al., 2024). Dysregulation of antioxidant defense systems, including key enzymes such as superoxide dismutase, catalase (CAT), and glutathione peroxidase, results in the accumulation of oxidative damage in lipids, proteins, and nucleic acids, promoting mitochondrial dysfunction, impaired cellular signalling, and apoptosis (Jiménez-Fernández et al., Reference Jiménez-Fernández, Gurpegui, Garrote-Rojas, Gutiérrez-Rojas, Carretero and Correll2021; Valvassori et al., Reference Valvassori, Bavaresco, Feier, Cechinel-Recco, Steckert, Varela, Borges, Carvalho-Silva, Gomes, Streck and Quevedo2018; Kim et al., Reference Kim, Vadodaria, Lenkei, Kato, Gage, Marchetto and Santos2019).

From a neurobiological perspective, chronic oxidative stress disrupts mitochondrial function by reducing ATP production, altering mitochondrial membrane potential, and increasing mitochondrial permeability transition pore opening. These changes impair synaptic plasticity, enhance neuronal apoptosis, and dysregulate glutamatergic and dopaminergic neurotransmission- pathways strongly implicated in mood regulation and cognitive performance in BD (Kim et al., Reference Kim, Vadodaria, Lenkei, Kato, Gage, Marchetto and Santos2019; Kahyacı Kılıç et al., Reference Kahyacı Kılıç, Çinar, Görgülü and Sönmez2020; Romano et al., Reference Romano, Serviddio, Calcagnini, Villani, Giudetti, Cassano and Gaetani2017; van der Wijk et al., Reference van der Wijk, Bélteczki and Döme2024). The cumulative effect is neuroprogression, characterised by increasing structural and functional brain alterations over the course of the illness (Berk et al., Reference Berk, Kapczinski, Andreazza, Dean, Giorlando, Maes, Yücel, Gama, Dodd, Dean, Magalhães, Amminger, McGorry and Malhi2011; Cyrino et al., Reference Cyrino, Delwing-de Lima, Ullmann and Maia2021; Föcking et al., Reference Föcking, Dicker, Lopez, Hryniewiecka, Wynne, English, Cagney and Cotter2016).

At the systemic level, oxidative stress acts as a key activator of pro-inflammatory signalling cascades, including the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway, which promotes the expression of inflammatory cytokines such as TNF-α, IL-1β, and IL-6 (Jones et al., Reference Young and Juruena2021; Kahyacı Kılıç et al., Reference Kahyacı Kılıç, Çinar, Görgülü and Sönmez2020; van der Wijk et al., Reference van der Wijk, Bélteczki and Döme2024). This establishes a self-reinforcing feedback loop between mitochondrial dysfunction, redox imbalance, and inflammation. Mitochondria also influence redox-sensitive signalling networks that regulate melatonin and kynurenine pathways, both of which modulate neuroinflammatory responses and neurotoxicity (Anderson et al., Reference Anderson, Jacob, Bellivier and Alexis Geoffroy2016). The interplay of these systems provides a mechanistic explanation for the overlap between metabolic, circadian, and affective disturbances frequently observed in BD (Andreazza, Reference Andreazza2019; Ahmed et al., Reference Ahmed, MahmoudianDehkordi, Bhattacharyya, Arnold, Liu, Neavin, Moseley, Thompson, Williams, Louie, Skime, Wang, Riva-Posse, McDonald, Bobo, Craighead, Krishnan, Weinshilboum, Dunlop, Millington, Rush, Frye and Kaddurah-Daouk2020; Jiménez-Fernández et al., Reference Jiménez-Fernández, Gurpegui, Garrote-Rojas, Gutiérrez-Rojas, Carretero and Correll2021; Ogawa et al., Reference Ogawa, Hattori, Ota, Hidese, Miyakawa, Matsumura, Yokota, Ishida, Matsuo, Yoshida, Yamazaki, Goodenowe and Kunugi2020).

Glucose metabolism and insulin resistance

Energy dysregulation in BD is not limited to mitochondrial dysfunction in neurons and peripheral cells but also involves substantial disturbances in glucose metabolism and the development of insulin resistance. These alterations consequently increase the risk of comorbid obesity, type 2 diabetes mellitus, and metabolic syndrome (Ahmed et al., Reference Ahmed, MahmoudianDehkordi, Bhattacharyya, Arnold, Liu, Neavin, Moseley, Thompson, Williams, Louie, Skime, Wang, Riva-Posse, McDonald, Bobo, Craighead, Krishnan, Weinshilboum, Dunlop, Millington, Rush, Frye and Kaddurah-Daouk2020; Miola et al., Reference Miola, Alvarez-Villalobos, Ruiz-Hernandez, De Filippis, Veldic, Prieto, Singh, Sanchez Ruiz, Nunez, Resendez, Romo-Nava, McElroy, Ozerdem, Biernacka, Frye and Cuellar-Barboza2023; Yu et al., Reference Yu, Oz and Sethi2023). Patients with BD frequently exhibit elevated fasting glucose and insulin levels, impaired glucose tolerance, and abnormal insulin responses, indicating deficits in energy homeostasis regulation in both peripheral tissues and the central nervous system (Campbell and Campbell, Reference Campbell and Campbell2019, Reference Campbell and Campbell2020).

Dysregulation of glucose metabolism in BD may directly affect brain function by limiting energy availability in key regions such as the prefrontal cortex and hippocampus, which are critically involved in mood regulation, cognitive processing, and impulse control. Glucose deficiency in neuronal tissue may exacerbate mood instability, contribute to cognitive deficits, and increase vulnerability to manic and depressive episodes. Simultaneously, these metabolic disturbances may enhance oxidative stress, activate pro-inflammatory pathways, and impair mitochondrial function, forming pathological feedback loops between energy metabolism and CNS functioning (Cyrino et al., Reference Cyrino, Delwing-de Lima, Ullmann and Maia2021).

At the systemic level, insulin resistance promotes chronic inflammation by increasing the production of pro-inflammatory cytokines and chemokines, including TNF-α, IL-6, and MCP-1, which can cross the blood–brain barrier, modulate microglial activity, and disrupt neurotransmission (Bortolasci et al., Reference Bortolasci, Voigt, Turner, Mohebbi, Gray, Dodd, Walder, Berk, Cotton, Malhi, Ng, Dowling, Sarris and Dean2020; Kageyama et al., Reference Kageyama, Deguchi, Kasahara, Tani, Kuroda, Inoue and Kato2022, Reference Kageyama, Okura, Sukigara, Matsunaga, Maekubo, Oue, Ishihara, Deguchi and Inoue2025).This process further destabilises cerebral energy balance, increasing the risk of disease relapse and cognitive decline (Papageorgiou and Filiou, Reference Papageorgiou and Filiou2024). Moreover, these metabolic abnormalities often correlate with the metabolic phenotype of BD patients, including hyperphagia, central obesity, and dyslipidemia, emphasizing the need to consider metabolic parameters in the comprehensive assessment and treatment of BD (Miola et al., Reference Miola, Alvarez-Villalobos, Ruiz-Hernandez, De Filippis, Veldic, Prieto, Singh, Sanchez Ruiz, Nunez, Resendez, Romo-Nava, McElroy, Ozerdem, Biernacka, Frye and Cuellar-Barboza2023; Yu et al., Reference Yu, Oz and Sethi2023).

Understanding the interplay among glycemic dysregulation, insulin resistance, mitochondrial dysfunction, and oxidative stress is crucial for developing targeted therapeutic interventions. Such approaches should integrate pharmacological modulators of metabolism with dietary and lifestyle strategies to restore energy balance and stabilize mood in individuals with BD.

purinergic pathways

Disturbances in purinergic signalling represent a mechanism contributing to the neurobiological alterations observed in BD. These abnormalities are closely integrated with mitochondrial impairment, oxidative stress, and dysregulated inflammatory activity. The purinergic system encompasses two primary classes of receptors: P1 receptors responsive to adenosine, and P2 receptors responsive to ATP. The P2 family is further categorised into ionotropic P2X channels and metabotropic P2Y receptors (Ortiz et al., Reference Ortiz, Ulrich, Zarate and Machado-Vieira2015). In addition to receptor signalling, altered metabolism of purine derivatives such as adenosine and uric acid (UA), along with dysfunction of enzymes including xanthine dehydrogenase (XDH) and adenosine deaminase (ADA), has been implicated in the pathophysiology of BD (El Sabbagh et al., Reference El Sabbagh, Machado, Pappis, Beroncal, Ji, Nader, Chander, Choi, Duong, Jeong, Panizzutti, Bortolasci, Szatmari, Carlen, Hahn, Attisano, Berk, Walder and Andreazza2025; Malewska et al., Reference Malewska, Rybakowski and Rybakowski2024). Clinical and molecular studies reveal that individuals with BD often show elevated plasma levels of adenosine and ATP, accompanied by increased expression of P2X7 receptors in microglial and immune cells. This receptor overactivation promotes the release of pro-inflammatory cytokines, particularly IL-1β, IL-6, and TNF-α – driving a sustained inflammatory response within both the peripheral and central nervous systems (Ahmed et al., Reference Ahmed, MahmoudianDehkordi, Bhattacharyya, Arnold, Liu, Neavin, Moseley, Thompson, Williams, Louie, Skime, Wang, Riva-Posse, McDonald, Bobo, Craighead, Krishnan, Weinshilboum, Dunlop, Millington, Rush, Frye and Kaddurah-Daouk2020; Skokou et al., Reference Skokou, Oikonomakis, Andreopoulou, Kypreos, Gourzis and Halaris2023; Malewska-Kasprzak et al., Reference Malewska-Kasprzak, Sikorski, Dmitrzak-Weglarz and Rybakowski2025; Young et al., Reference Young, Kim, Andreazza and Kim H.K.2018). The inflammatory model of BD proposes that chronic immune activation contributes to illness progression, as reflected in consistently elevated serum IL-6 levels among affected patients (Ozkaya et al., Reference Ozkaya, Gürbüzer, Tozoğlu, Akyildirim and Mercantepe2025). Inflammasomes, cytosolic multiprotein complexes that detect cellular stress or pathogen-related signals, have also been recognised as crucial mediators linking immunity and neuronal dysfunction in BD (Świerczyński and Fichna, Reference Świerczyński and Fichna2021), (Malewska-Kasprzak et al., Reference Malewska-Kasprzak, Jowik and Tyszkiewicz-Nwafor2023). In particular, hyperactivation of the NLRP3 inflammasome within microglia induces chronic neuroinflammation that exacerbates mood instability and cognitive decline. Sustained activation of this pathway disrupts neuronal signalling and plasticity, leading to alterations in dopaminergic, serotonergic, and glutamatergic neurotransmission (Kim, Reference Kim2022; Han et al., Reference Han, Li, Chen, Wang, Bao, Huang, Liu and Chen2023).

Excessive stimulation of P2X7 receptors further amplifies inflammatory cascades and contributes to oxidative stress–related neuronal damage. Together with mitochondrial dysfunction, these processes facilitate apoptosis and synaptic loss (Glausier, Reference Glausier2025; Malewska et al., Reference Malewska, Rybakowski and Rybakowski2024; Malewska-Kasprzak et al., Reference Malewska-Kasprzak, Permoda and Rybakowski2022). Such neuroinflammatory and metabolic alterations correlate strongly with symptom severity and cognitive impairment in BD.

Additionally, purinergic dysregulation influences cellular energy dynamics. Overactivation of ATP/P2X7 signalling can elevate metabolic demand and accelerate ATP depletion within neurons and peripheral cells (Bertocci et al., Reference Bertocci, Yushmanov, Moon, Abdul-Waalee, Versace, Phillips, Birmaher, Hetherington and Pan2021; Malewska-Kasprzak et al., Reference Malewska-Kasprzak, Permoda-Osip and Rybakowski2019; Scott and McClung, Reference Scott and McClung2023). The purinergic system also interacts with redox-sensitive pathways, including those dependent on the NAD⁺/NADH ratio, thereby modulating oxidative phosphorylation efficiency. Persistent disturbances in these interconnected mechanisms – when combined with chronic inflammation – create self-reinforcing loops between immune activation, oxidative imbalance, and impaired energy metabolism (Lindberg et al., Reference Lindberg, Shan, Ayers-Ringler, Oliveros, Benitez, Prieto, McCullumsmith and Choi2015; Ahmed et al., Reference Ahmed, MahmoudianDehkordi, Bhattacharyya, Arnold, Liu, Neavin, Moseley, Thompson, Williams, Louie, Skime, Wang, Riva-Posse, McDonald, Bobo, Craighead, Krishnan, Weinshilboum, Dunlop, Millington, Rush, Frye and Kaddurah-Daouk2020; Permoda-Pachuta et al., Reference Permoda-Pachuta, Malewska-Kasprzak, Skibińska, Rzepski and Dmitrzak-Węglarz2023) (Figure 3).

Figure 3.

Inflammatory and purinergic pathways in BD: Interac9ons between uric acid, P2X7,. adenosine, xanthine oxidase, and adenosine deaminase. P2X7, P2X7 receptor; ADO, adenosine; ADA, deaminase adenosine; XDH, xanthine oxidase; UA, uric acid; IL-1, interleukin.

Figure 3. Long description

A diagram of the inflammatory and purinergic pathways in bipolar disorder. Microglia contain the NRLP inflammasome, which includes NRLP3, ASC, and Nacht, leading to the activation of pro-caspase and pro IL-1, resulting in IL-1 beta. P2X7 activation is shown near the microglia. Astrocytes release ATP, which is involved in energetic stress. Uric acid (UA) and adenosine (ADO) interact through xanthine oxidase (XDH) and adenosine deaminase (ADA), contributing to neuroinflammation and exacerbation of bipolar disorder.

Neuroplasticity and glutamatergic–Astrocytic function in bipolar disorder

Energy dysregulation represents a pathological feature of BD, profoundly influencing synaptic plasticity, glutamatergic signalling, and astrocytic function. Impairments in mitochondrial bioenergetics within both neurons and astrocytes disrupt neuron–astrocyte metabolic coupling, an essential mechanism for maintaining glutamate synthesis, recycling, and uptake. Consequently, limited ATP availability compromises the activity of astrocytic glutamate transporters, leading to excessive extracellular glutamate accumulation and excitotoxic stress (Anderson et al., Reference Anderson, Almulla, Reiter and Maes2023).

Astrocytic dysfunction is further characterised by downregulation of excitatory amino acid transporters EAAT1 and EAAT2, reducing the efficiency of synaptic glutamate clearance. The resulting glutamate excess promotes overactivation of NMDA receptors, particularly at extrasynaptic sites, which induces sustained calcium influx, oxidative stress, and activation of pro-apoptotic signalling cascades. In contrast, synaptic NMDA receptor activation supports neuronal survival and adaptive synaptic remodelling, highlighting the location-dependent duality of NMDA receptor function. Under physiological conditions (Rybakowski et al., Reference Rybakowski, Permoda-Osip and Bartkowska-Sniatkowska2017).

Energy deficits in BD also constrain the synthesis and release of neurotrophic factors, particularly brain-derived neurotrophic factor (BDNF), a key regulator of synaptic growth, dendritic spine formation, and neuronal resilience. Reduced BDNF availability has been consistently associated with cognitive dysfunction, emotional dysregulation, and the severity of both manic and depressive episodes. Collectively, these disturbances underscore the interdependence between cellular energy metabolism, glutamatergic homeostasis, and astrocytic support in maintaining neuroplastic integrity (Permoda-Pachuta et al., Reference Permoda-Pachuta, Malewska-Kasprzak, Skibińska, Rzepski and Dmitrzak-Węglarz2023; Rybakowski et al., Reference Rybakowski, Permoda-Osip and Bartkowska-Sniatkowska2017).

Taken together, the mechanisms described above support several of the leading contemporary hypotheses of bipolar disorder. The mitochondrial hypothesis is reinforced by evidence of impaired oxidative phosphorylation, reduced ATP availability, altered redox balance, and disrupted neuron, astrocyte metabolic coupling, all of which may contribute to neuronal vulnerability and mood instability. Simultaneously, the immunological hypothesis is supported by persistent activation of inflammatory pathways, including NF-κB signalling, increased pro-inflammatory cytokine production, and NLRP3 inflammasome activation, which interact bidirectionally with mitochondrial dysfunction and oxidative stress. In parallel, the purinergic hypothesis is substantiated by abnormalities in ATP-mediated signalling, altered adenosine and UA metabolism, and enhanced P2X7 receptor activity, linking cellular energy deficits with neuroinflammatory processes (Malewska et al., Reference Malewska, Permoda-Osip, Kasprzak, Niemiec and Rybakowski2017; Malewska-Kasprzak et al., Reference Malewska-Kasprzak, Dmitrzak-Weglarz and Rybakowski2026; Malewska-Kasprzak et al., Reference Malewska-Kasprzak, Dmitrzak-Weglarz and Rybakowski2026). Rather than representing independent models, these hypotheses appear highly interconnected, converging on a common framework in which bioenergetic dysfunction, immune activation, and purinergic dysregulation mutually reinforce one another and contribute to the development and progression of BD. This integrated perspective may provide a useful conceptual basis for biomarker development and the design of mechanism-based therapeutic interventions.

Neuroimaging indicators of energetic dysfunction

Neuroimaging studies employing proton (¹H) and phosphorus (³¹P) MRS, as well as functional near-infrared spectroscopy (fNIRS), have provided convergent evidence for impaired mitochondrial oxidative metabolism in individuals with BD (Bertocci and Diler, Reference Bertocci and Diler2025; Colasanti et al., Reference Colasanti, Russo, Örzsik, Imrak, Kartar, Caddye, Pizzamiglio, Pitceathly, Asllani and Ronen2025; Dudley et al., Reference Dudley, Lee, Durling, Strakowski and Eliassen2015; Föcking et al., Reference Föcking, Dicker, Lopez, Hryniewiecka, Wynne, English, Cagney and Cotter2016).

Across multiple studies, significant reductions in NAD⁺, citrate, and other intermediates of the tricarboxylic acid (TCA) cycle have been reported, indicating compromised neuronal capacity for efficient energy generation via oxidative phosphorylation (Yoshimi et al., Reference Yoshimi, Futamura, Bergen, Iwayama, Ishima, Sellgren, Ekman, Jakobsson, Pålsson, Kakumoto, Ohgi, Yoshikawa, Landén and Hashimoto2016; Du et al., Reference Du, Yuksel, Chouinard, Huynh, Ryan, Cohen and Öngür2018; Campbell and Campbell, Reference Campbell and Campbell2019; Ahmed et al., Reference Ahmed, MahmoudianDehkordi, Bhattacharyya, Arnold, Liu, Neavin, Moseley, Thompson, Williams, Louie, Skime, Wang, Riva-Posse, McDonald, Bobo, Craighead, Krishnan, Weinshilboum, Dunlop, Millington, Rush, Frye and Kaddurah-Daouk2020). In parallel, decreased concentrations of PCr and adenosine triphosphate (ATP) within the prefrontal cortex, along with slower creatine kinase forward reaction rate constants (CK kf), reflect a limited energetic reserve and a diminished adaptive capacity of neurons to meet increased metabolic demands (Stork and Renshaw, Reference Stork and Renshaw2005; Bertocci et al., Reference Bertocci, Yushmanov, Moon, Abdul-Waalee, Versace, Phillips, Birmaher, Hetherington and Pan2021).These findings collectively suggest a global impairment in cerebral energy transfer systems that may underlie affective instability and cognitive dysfunction in BD.

Importantly, such energetic abnormalities are observed not only during manic or depressive episodes but also persist during euthymic phases, suggesting that mitochondrial dysfunction represents a trait-like feature rather than a mere state-dependent phenomenon (Bertocci et al., Reference Bertocci, Yushmanov, Moon, Abdul-Waalee, Versace, Phillips, Birmaher, Hetherington and Pan2021). This persistence supports the hypothesis that impaired bioenergetics may serve as an early predictor of relapse risk and a stable pathophysiological marker throughout the course of the disorder.

The advent of ultra–high-field magnetic resonance imaging (7T MRI) has further advanced our ability to map metabolic alterations with greater spatial and spectral resolution. These high-resolution studies reveal abnormal cortical accumulation of lactate, consistent with impaired oxidative phosphorylation and a metabolic shift towards anaerobic glycolysis (Yoshimi et al., Reference Yoshimi, Futamura, Bergen, Iwayama, Ishima, Sellgren, Ekman, Jakobsson, Pålsson, Kakumoto, Ohgi, Yoshikawa, Landén and Hashimoto2016; Ahmed et al., Reference Ahmed, MahmoudianDehkordi, Bhattacharyya, Arnold, Liu, Neavin, Moseley, Thompson, Williams, Louie, Skime, Wang, Riva-Posse, McDonald, Bobo, Craighead, Krishnan, Weinshilboum, Dunlop, Millington, Rush, Frye and Kaddurah-Daouk2020; Bertocci et al., Reference Bertocci, Yushmanov, Moon, Abdul-Waalee, Versace, Phillips, Birmaher, Hetherington and Pan2021). Lactate accumulation is interpreted as a compensatory response to reduced mitochondrial ATP production, reflecting an adaptive yet inefficient attempt to maintain energy supply under mitochondrial stress. Such findings are particularly significant as they link functional neuroimaging markers to the biochemical signatures of mitochondrial distress, bridging molecular and systems-level evidence.

Converging biochemical data reinforce these neuroimaging observations. Elevated oxidative stress, reduced activity of mitochondrial electron transport chain complexes, and disturbances in purinergic homeostasis have been consistently reported in BD, underscoring the multifaceted nature of energetic dysfunction in this disorder (Yoshimi et al., Reference Yoshimi, Futamura, Bergen, Iwayama, Ishima, Sellgren, Ekman, Jakobsson, Pålsson, Kakumoto, Ohgi, Yoshikawa, Landén and Hashimoto2016; Ahmed et al., Reference Ahmed, MahmoudianDehkordi, Bhattacharyya, Arnold, Liu, Neavin, Moseley, Thompson, Williams, Louie, Skime, Wang, Riva-Posse, McDonald, Bobo, Craighead, Krishnan, Weinshilboum, Dunlop, Millington, Rush, Frye and Kaddurah-Daouk2020; Bertocci et al., Reference Bertocci, Yushmanov, Moon, Abdul-Waalee, Versace, Phillips, Birmaher, Hetherington and Pan2021). Moreover, abnormalities in brain bioenergetics have been associated with alterations in neurovascular coupling and impaired cortical oxygen utilisation, providing a broader physiological context for understanding cognitive and affective symptoms in BD (Dudley et al., Reference Dudley, Lee, Durling, Strakowski and Eliassen2015)

Integration of neuroimaging findings with mitochondrial functional assays and oxidative stress markers offers a multidimensional framework for characterising BD pathophysiology. The identification of neuroenergetic markers as quantifiable biomarkers enables early recognition of patients at elevated relapse risk, objective monitoring of treatment response to metabolic and pharmacological interventions, and the design of precision therapeutic strategies aimed at restoring normal cerebral bioenergetics (Du et al., Reference Du, Yuksel, Chouinard, Huynh, Ryan, Cohen and Öngür2018; Ahmed et al., Reference Ahmed, MahmoudianDehkordi, Bhattacharyya, Arnold, Liu, Neavin, Moseley, Thompson, Williams, Louie, Skime, Wang, Riva-Posse, McDonald, Bobo, Craighead, Krishnan, Weinshilboum, Dunlop, Millington, Rush, Frye and Kaddurah-Daouk2020; Bertocci et al., Reference Bertocci, Yushmanov, Moon, Abdul-Waalee, Versace, Phillips, Birmaher, Hetherington and Pan2021).

In this context, neuroimaging-derived measures of mitochondrial metabolism may serve as a critical interface between molecular, metabolic, and clinical dimensions of BD research, facilitating the development of a coherent and mechanistically informed model of disease progression (Giménez-Palomo et al., Reference Giménez-Palomo, Guitart-Mampel, Roqué, Sánchez, Borràs, Meseguer, García-García, Tobías, Valls-Roca, Anmella, Valentí, Olivier, de Juan, Ochandiano, Andreu, Radua, Verdolini, Berk, Vieta, Garrabou, Roca, Alsina-Restoy and Pacchiarotti2024).

Peripheral and cellular markers

Mitochondrial dysfunction in BD extends beyond the central nervous system, encompassing peripheral cells and tissues. This systemic nature of bioenergetic disruption offers a unique opportunity to monitor mitochondrial processes through accessible peripheral biomarkers, thereby facilitating translational research and clinical application. Studies of peripheral blood mononuclear cells (PBMCs) and leukocytes have consistently demonstrated significant impairments in the activity of mitochondrial respiratory chain complexes I and IV, leading to decreased ATP synthesis and increased generation of reactive oxygen species (ROS) (Bertocci et al., Reference Bertocci, Yushmanov, Moon, Abdul-Waalee, Versace, Phillips, Birmaher, Hetherington and Pan2021; Gimenez-Palomo et al., 2024; Young et al., Reference Young, Kim, Andreazza and Kim H.K.2018). This imbalance promotes chronic oxidative stress and subclinical inflammatory states, which may interact with neural circuits to influence disease progression, episode recurrence, and treatment resistance.

An important index of cellular redox homeostasis – the NAD⁺/NADH ratio – provides valuable insights into the energetic state of peripheral cells. Decreased NAD⁺/NADH ratios observed in BD patients indicate a limited capacity for oxidative phosphorylation and impaired regeneration of cellular energy pools. These alterations also suggest deficits in antioxidant defense mechanisms, which are essential for maintaining metabolic stability and protecting against oxidative injury (Bertocci et al., Reference Bertocci, Yushmanov, Moon, Abdul-Waalee, Versace, Phillips, Birmaher, Hetherington and Pan2021; Gimenez-Palomo et al., 2024; Young et al., Reference Young, Kim, Andreazza and Kim H.K.2018). In parallel, reduced levels of oxidised cytochrome c oxidase (oxCOX) in peripheral tissues reflect diminished efficiency of oxidative phosphorylation and reduced mitochondrial competence, supporting the notion of a systemic impairment in electron transport across multiple biological compartments.

Recent metabolomic analyses have further identified alterations in peripheral lipid metabolism, particularly in ethanolamine plasmalogens and phosphatidylethanolamines, key phospholipids involved in membrane structure, redox signalling, and mitochondrial dynamics. Changes in these compounds observed in blood plasma of BD patients suggest disrupted lipid remodelling and oxidative vulnerability of cellular membranes, providing an additional dimension to the systemic bioenergetic dysregulation associated with the disorder.

Markers of oxidative stress, such as malondialdehyde (MDA) and 8-hydroxy-2’-deoxyguanosine (8-OHdG), are elevated both in serum and in peripheral cells of BD patients, reflecting persistent activation of oxidative and proinflammatory pathways (Andreazza, Reference Andreazza2019; Ahmed et al., Reference Ahmed, MahmoudianDehkordi, Bhattacharyya, Arnold, Liu, Neavin, Moseley, Thompson, Williams, Louie, Skime, Wang, Riva-Posse, McDonald, Bobo, Craighead, Krishnan, Weinshilboum, Dunlop, Millington, Rush, Frye and Kaddurah-Daouk2020; Gimenez-Palomo et al., 2024). Elevated MDA levels indicate increased lipid peroxidation, whereas 8-OHdG serves as a marker of oxidative DNA damage – both contributing to mitochondrial genome instability and progressive energetic failure. The persistence of these markers even during euthymic phases underscores the systemic and trait-like nature of mitochondrial and oxidative dysregulation in BD, extending beyond localised neuronal effects to encompass the entire organism’s metabolic response to chronic stress (Andreazza, Reference Andreazza2019; Ahmed et al., Reference Ahmed, MahmoudianDehkordi, Bhattacharyya, Arnold, Liu, Neavin, Moseley, Thompson, Williams, Louie, Skime, Wang, Riva-Posse, McDonald, Bobo, Craighead, Krishnan, Weinshilboum, Dunlop, Millington, Rush, Frye and Kaddurah-Daouk2020). Elevated levels of 8-OHdG and MDA have been also associated with greater severity of manic and depressive episodes, longer illness duration, and higher relapse frequency. In contrast, normalisation of antioxidant enzyme activity during remission suggests that dynamic redox balance may reflect illness phase and treatment response. These associations highlight the translational potential of oxidative biomarkers as objective indicators of disease activity and therapeutic efficacy (Andreazza, Reference Andreazza2019; Ahmed et al., Reference Ahmed, MahmoudianDehkordi, Bhattacharyya, Arnold, Liu, Neavin, Moseley, Thompson, Williams, Louie, Skime, Wang, Riva-Posse, McDonald, Bobo, Craighead, Krishnan, Weinshilboum, Dunlop, Millington, Rush, Frye and Kaddurah-Daouk2020; Jiménez-Fernández et al., Reference Jiménez-Fernández, Gurpegui, Garrote-Rojas, Gutiérrez-Rojas, Carretero and Correll2021; Ogawa et al., Reference Ogawa, Hattori, Ota, Hidese, Miyakawa, Matsumura, Yokota, Ishida, Matsuo, Yoshida, Yamazaki, Goodenowe and Kunugi2020).

Circulating mitochondrial DNA (mtDNA) has also emerged as a promising biomarker of systemic inflammation and cellular stress. Elevated plasma mtDNA levels in BD may reflect enhanced mitochondrial turnover, impaired mitophagy, or leakage of mitochondrial components into the extracellular space, which can activate innate immune responses through toll-like receptor signaling (Cordeiro et al., Reference Cordeiro, Lima, Fries, Zunta-Soares, Soares, Quevedo and Scaini2023; Shao et al., Reference Shao, Zou, Kennedy, Dimick, Andreazza, Young, Goncalves, MacIntosh and Goldstein2024; Teng et al., Reference Teng, Xu, Chen, Qiu, Li, Chen, Tang, Xiang, Wang, Tan and Wu2024). These findings strengthen the concept of a bidirectional relationship between mitochondrial dysfunction and inflammation, positioning mtDNA as a potential bridge between metabolic dysregulation and immune activation in BD pathophysiology.

Recent studies confirm that peripheral mitochondrial biomarkers also reflect metabolic vulnerability in BD. Elevated plasma lactate has been associated with higher fasting glucose, triglycerides, and blood pressure, indicating a link between mitochondrial energy imbalance and metabolic syndrome. In contrast, circulating cell-free mitochondrial DNA showed no such association, suggesting that lactate may serve as a more sensitive marker of systemic energetic stress. Mitochondrial-targeted metabolomics further revealed distinct metabolic patterns in patients with concurrent lactate elevation and metabolic syndrome, highlighting changes in TCA cycle intermediates and redox balance (Zachos et al., Reference Zachos, Choi, Godin, Chernega, Kwak, Jung, Aouizerate, Aubin, Bellivier, Belzeaux-R, Courtet, Dubertret, Etain, Haffen, Lefrere, Llorca, Olié, Polosan, Samalin, Schwan, Roux, Barau, Richard, Tamouza, Leboyer and Andreazza2024).

In recent studies, bipolar patients exhibited significant alterations in key purinergic enzymes, including ADA, XDH, and the P2X7 receptor. Concentrations of XDH, adenosine, and ADA were significantly lower in both manic and depressive episodes, as well as during remission, compared to healthy controls, suggesting trait-dependent dysfunction of purinergic signaling. Conversely, UA levels were elevated, particularly in female patients, consistent with enhanced purine catabolism and oxidative burden. Importantly, P2X7 and NACHT levels were markedly increased after treatment in both manic and depressive states, indicating persistent activation of immune and inflammasome pathways despite symptomatic improvement. These findings support the hypothesis that purinergic dysregulation contributes to the chronic inflammatory milieu observed in BD and may modulate mitochondrial and energetic homeostasis. Moreover, XDH and ADA have been proposed as potential biomarkers for distinguishing mood episode polarity and monitoring treatment response, while persistent P2X7 activation could represent a biological substrate of relapse vulnerability. Gender differences – such as higher baseline ADA, NACHT, and P2X7 in women – further emphasise the modulatory role of hormonal and metabolic factors in purinergic signalling within BD pathology (Malewska et al., Reference Malewska, Rybakowski and Rybakowski2024; Malewska-Kasprzak et al., Reference Malewska-Kasprzak, Sikorski, Dmitrzak-Weglarz and Rybakowski2025; Malewska-Kasprzak et al., Reference Malewska-Kasprzak, Permoda and Rybakowski2022).

Additionally, neurotrophic and inflammatory markers provide complementary insights into BD pathophysiology. Decreased levels of BDNF in serum and plasma of BD patients have been associated with impaired neuronal plasticity, cognitive deficits, and mood episode severity. Elevated proinflammatory cytokines, including interleukin-6 (IL-6), interleukin-1β (IL-1β), and tumour necrosis factor-alpha (TNF-α), are frequently observed in both manic and depressive episodes, reflecting chronic systemic inflammation that may exacerbate mitochondrial dysfunction (Machado-Vieira et al., Reference Machado-Vieira, Courtes, Zarate, Henter and Manji2023).

From a translational perspective, the assessment of mitochondrial and oxidative biomarkers in peripheral cells offers a minimally invasive, reproducible, and clinically feasible approach for precision psychiatry. Monitoring redox ratios (NAD⁺/NADH), mitochondrial respiratory activity (oxCOX), and oxidative stress markers (MDA, 8-OHdG), metabolic indicators such as plasma lactate and purinergic mediators including ADA, XDH, and P2X7 receptor levels could enable early detection of relapse risk, real-time evaluation of pharmacological and metabolic interventions, and refined patient stratification in clinical trials (Cikankova et al., Reference Cikankova, Sigitova, Zverova, Fisar, Raboch and Hroudova2017; Shao et al., Reference Shao, Zou, Kennedy, Dimick, Andreazza, Young, Goncalves, MacIntosh and Goldstein2024).

When integrated with neuroimaging findings and detailed clinical phenotyping, peripheral mitochondrial markers contribute to a unified systems-level model of BD pathophysiology – one that connects central and peripheral energetic dysfunction. This model not only enhances mechanistic understanding but also provides a scientific basis for developing precision therapeutic strategies aimed at restoring mitochondrial function, reducing oxidative stress, and promoting long-term mood stability (Ahmed et al., Reference Ahmed, MahmoudianDehkordi, Bhattacharyya, Arnold, Liu, Neavin, Moseley, Thompson, Williams, Louie, Skime, Wang, Riva-Posse, McDonald, Bobo, Craighead, Krishnan, Weinshilboum, Dunlop, Millington, Rush, Frye and Kaddurah-Daouk2020; Bertocci et al., Reference Bertocci, Yushmanov, Moon, Abdul-Waalee, Versace, Phillips, Birmaher, Hetherington and Pan2021; Gimenez-Palomo et al., 2024) (Table 1).

Table 1.

Peripheral and cellular markers in bipolar disorder (BD)

Table 1. Long description

A table with 18 rows and 5 columns. The columns are labeled Marker, Category, Measured in, Change in BD, Function in the body, and Effect of change in BD. The table lists different markers such as NAD+/NADH, ATP, PCr, Lactate, MDA, 8-OHdG, oxCOX, mtDNA, ADA, XDH, P2X7 receptor, UA, BDNF, IL-6, IL-1β, TNF-α, NACHT/NLRP3, Ethanolamine plasmalogens, and Phosphatidylethanolamines. Each row provides details on the category, where the marker is measured, the change observed in bipolar disorder, its function in the body, and the effect of this change in bipolar disorder.