Abstract
The unclear pathogenesis of bipolar disorder (BD) poses a challenge, especially with the striking rates of comorbid medical and psychiatric disorders, treatment resistance, and premature mortality in the absence of a specific diagnostic marker. We put forward the hypothesis of ferroptosis, a recently identified iron-dependent cell death, as a potential underlying mechanism of BD. We aimed to portray the possibility of ferroptosis involvement in BD pathogenesis as a doorway to encourage both animal and clinical studies on the topic. Ferroptosis is associated with multiple psychiatric disorders, including major depressive disorder, stress-induced anxiety, post-traumatic stress disorder, autism spectrum disorder, and alcohol use disorder. In addition, ferroptosis-related genes have been identified in schizophrenia, which shares genetic liabilities with BD. One of the top five most significant genes in BD in a recent genome-wide association study, FADS 2, is involved in ferroptosis. The three hallmarks of ferroptosis intersect with the pathogenesis of BD, including iron dysregulation, lipid peroxidation, and the failure of antioxidant systems. Other pieces of BD pathogenesis, including inflammation, mitochondrial dysfunction, calcium dysregulation, neurotransmission disturbance, and affection of synaptic plasticity and myelination, are either a preface or an aftermath of iron dysregulation. Additionally, circadian rhythm abnormalities and hypothalamic-pituitary-adrenal axis disturbances in BD could be another point where ferroptosis and BD intersect. Moreover, some BD treatments, such as lithium, haloperidol, olanzapine, clozapine, valproic acid, and electroconvulsive therapy, show anti-ferroptosis action in other contexts. These observations present a strong case for ferroptosis as a potential underlying mechanism of BD. Therefore, we call for studies that address iron accumulation in the brain in BD patients, postmortem tissues, and BD animal models. We call for genetic studies to look for the genetic signature of ferroptosis in BD patients. In addition, we call for studies on different BD models to assess the expression of ferroptosis markers. Our hypothesis has substantial implications if validated, including the use of ferroptosis-related genes and ferroptosis markers as a prognostic marker for BD and a potential therapeutic target based on ferroptosis inhibitors.
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Introduction
Bipolar disorder (BD) is a complex chronic mood disorder characterized by fluctuations of mania, hypomania, and depressive episodes with two main clinical subtypes: bipolar I and bipolar II disorders. According to the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5) [1], bipolar I disorder (BDI) is characterized by at least one manic episode, which could be followed or preceded by hypomanic or depressive episodes. However, depressive episodes are not necessary for the diagnosis of BDI. Bipolar II disorder (BD II) is distinguished by at least one hypomanic episode and at least one major depressive episode, with no manic episodes reported [2].
Despite the 1–2% global prevalence [3], BD is considered one of the leading causes of disability worldwide [4], especially with its early onset in adolescence or early adulthood [5]. BD patients show high rates of concomitant morbidity and mortality, with 10-20 years less life expectancy than the general population [6]. Cardiovascular disorders [7], tobacco smoking [8], metabolic syndrome [9], and suicide [10] are among the leading causes behind the premature mortality among BD patients. About 15–20% of BD patients die by suicide [11,12,13]. The course of BD is also intensified by other comorbid psychiatric disorders [14] such as anxiety disorders [15], attention deficit hyperactivity disorder (ADHD) [16], alcohol use disorder (AUD), substance use disorder [17], and binge eating disorder [18], as well as cognitive impairment [19], implying a potential intersection of their pathogenesis. Treatment resistance is a common dilemma in the course of BD management, despite the increasingly validated therapeutic options [20]. In a two-year prospective study of the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), only 58.4% of 1469 symptomatic patients showed recovery, and 48.5% of patients suffered from recurrences during the two-year follow-up [21]. Nierenberg et al. reported recovery rates of 4.6–23.8% in the STEP-BD study, using lamotrigine, inositol, and risperidone in 66 unresponsive patients to mood stabilizers and at least one antidepressant [22]. Adding to the failure of therapeutic options, another BD challenge stems from the partially unclear pathogenesis, which feeds into the other challenge of being solely diagnosed clinically with no specified diagnostic tests or biomarkers [23]. Thus, uncovering BD pathogenesis is imperative, as it would not only provide a clearer understanding of the nature of the disease but would also provide answers for diagnostic markers and novel therapeutic options. In this review, we put forward a hypothesis about ferroptosis as a part of BD pathogenesis, which would encourage both animal and clinical studies on the topic and add richness to the drastically deficient literature on the potential role of ferroptosis in BD pathogenesis. We consider this review to be the first step towards future studies on the role of ferroptosis in BD, which would provide potentially new biomarkers and therapeutic targets.
Overview of bipolar disorder pathogenesis
Despite the plausible hypothesis of an interplay between genetic, environmental, and neurochemical factors in BD, its pathogenesis is still elusive [24]. Heritability comprises a huge part of BD pathogenesis; over 80% in twin studies [25]. BD shows a non‐Mendelian inheritance, with the most recent genome-wide association study by the Psychiatric Genomics Consortium identifying 64 independent genetic loci associated with BD, each of which has a small effect [26]. Genetic correlation analyses have also shown strong positive genetic correlations between BD and schizophrenia, suggesting a shared genetic architecture between the two diseases [26]. Several environmental factors were reported to possibly affect the clinical course of BD, such as maternal smoking, intrauterine infection, childhood trauma, and viral infections in adulthood [27]. Additionally, the pathogenesis of BD was reported to include oxidative stress, mitochondrial dysfunction, and aberrant calcium signalling [24]. BD patients show evidence of low-grade systemic inflammation and potential neuroinflammation [28, 29]. Deficits in neurotransmission [30,31,32], myelination [33, 34], and neuroplasticity [24] were also reported as pieces of the BD puzzle. Moreover, BD patients show abnormalities in the hypothalamic-pituitary-adrenal (HPA) axis [35] and circadian rhythm, which evidently affect the course of the disease [36]. Lipid peroxidation, a hallmark of ferroptosis [37], and altered lipid-related cascades hold a crucial role in BD pathogenesis [38].
Cell death was repeatedly reported in both animal and clinical studies on BD. In an ouabain-induced rat model of mania, both frontal cortex and hippocampus showed a significantly high content of thiobarbituric acid reactive species (TBARS), a lipid peroxidation marker, and mitochondrial superoxide, indicating oxidative stress. That increase was associated with a higher expression of the proapoptotic protein, Bcl-2-associated X protein (Bax), and a lower expression of the antiapoptotic, B-cell lymphoma 2 (bcl-2) [39]. Using liquid chromatography–mass spectrometry and multi-analyte platforms, Herberth et al. identified about 60 differentially expressed molecules involved in cell death/survival in peripheral blood mononuclear cells (PBMCs) and serum from euthymic BD patients (n = 16 BDI and 16 BDII) compared to matched healthy controls [40]. Kim et al. reported higher expression of pro-apoptotic factors (Bax, caspase-9 and caspase-3) and a reduced expression of anti-apoptotic factors (brain-derived neurotrophic factor (BDNF) and Bcl-2) at both mRNA and protein levels in postmortem prefrontal cortex of BD patients (n = 10) compared to age-matched controls [41]. In addition, Scaini et al. reported similar findings in the peripheral blood mononuclear cells in BDI (n = 16). They found activated apoptotic pathways with higher levels of Bax and lower levels of Bcl-2 [42]. Interestingly, Mishra et al. found increased sensitivity to cell death in neural progenitor cells derived from lithium non-responsive after the administration of methamphetamine, which models the clinical features of mania [43]. Despite the multiple studies on apoptosis, as a type of regulated cell death [44], and the intense research efforts to clarify BD etiopathogenesis, no studies have addressed ferroptosis, another type of regulated cell death [44], as a potential part of BD pathogenesis, leaving an immense research gap that we aim to address.
Overview of ferroptosis and its molecular machinery
Ferroptosis, a term coined almost a decade ago, is a non-apoptotic iron-dependent form of regulated cell death [45] (reviewed in more detail in our previous publication [46]). Undergoing ferroptosis, cells get swollen, mitochondria decrease in size, and the plasma membrane thins out and eventually ruptures [47, 48]. Lipid peroxidation is the main event needed for a cell to die from ferroptosis. Lipid peroxidation can fulfill the ominous fate of ferroptosis in the presence of three prerequisites: accumulated lipid radicals, excessive labile reactive iron, and failed cell antioxidant defense systems [37].
Lipid peroxidation
Lipid peroxidation is the oxidative degradation of lipids as a consequence of oxygen interaction with unsaturated fatty acids, forming lipid radicals, including lipid peroxides (LOO•) and lipid hydroperoxides (LOOH•) [49], which can trigger a chain reaction of lipid radical formation [50,51,52] (for more details, refer to Fig. 3 in our previous publication [46]). This chain reaction ends up forming highly toxic lipid peroxidation degradation products such as malonaldehyde (MDA) and 4-Hydroxynonenal (4-HNE) [53]. These byproducts can change the structure and function of DNA and cellular proteins, fostering a state of cytotoxicity [53,54,55]. As the chain reaction progresses, the cell’s membrane lipid bilayer is damaged [56].
Ferroptosis sensitivity heightens when the content of polyunsaturated fatty acids (PUFA) increases. The abundance of PUFA in cell membrane phospholipids renders cell membranes vulnerable to lipid peroxidation because PUFA are susceptible to radical attacks and forming lipid radicals themselves [57]. Acyl-coenzyme A synthetase long-chain family member 4 (ACSL4) is a crucial enzyme for incorporating PUFA into phospholipids by binding them to coenzyme A to produce PUFA-CoAs [58]. Therefore, ACSL4 can induce ferroptosis by promoting a robust content of PUFA-containing phospholipids [59]. Lipid peroxidation and lipid hydroperoxide (LOOH•) formation can also occur enzymatically by cytochrome P450 oxidoreductase, cyclooxygenases (COXs), lipoxygenases (LOXs), and nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOXs), which can alter the lipid landscape and promote ferroptosis [60].
Failure of antioxidant defence
Failure of antioxidant defence against lipid peroxidation is a prominent feature of ferroptosis induction [61]. Glutathione peroxidase 4 (GPX4) is one of the most dedicated phospholipid repair systems. The GPX4 enzyme is an oxidoreductase that reduces hydroperoxides (OOH•) to their corresponding non-harmful alcohols. Next, the oxidized GPX4 is reduced by glutathione (GSH), allowing GPX4 to repeat its action [62]. GSH is the most plentiful cellular antioxidant and is formed of glutamate, glycine, and cysteine [63]. A crucial component for GSH synthesis is the Cystine/Glutamate antiporter, or system Xc- [64]. System Xc- is formed of a heavy chain subunit and a light chain subunit called xCT, or Solute carrier family 7 member 11 (SLC7A11). SLC7A11 allows glutamate to be exported and cystine to be imported. Cystine, the oxidized form of cysteine, can then be reduced to cysteine, which is needed for GSH formation [65, 66] (see figure 4 in our previous publication [46]). GPX4 inactivation or deletion, GSH depletion, and SLC7A11 blunted expression strongly promote ferroptosis [61, 67, 68]. The decreased expression of nuclear factor erythroid 2-related factor 2 (NrF2) is also another strong promotor of ferroptosis [69]. NrF2 is the major transcriptional factor that controls the expression of GSH, its related transporters, and enzymes and directly activates the SLC7A11 [70, 71]. Tumor protein 53 (P53) is another transcriptional factor that controls the expression of SLC7A11. The higher the activation of P53, the lower the expression of SLC7A11, which enables the induction of ferroptosis [72].
Iron dysregulation
As the name suggests, iron plays an imperative role in ferroptosis. In the cell, iron is either used for various biological processes, exported, stored as ferritin, or resides freely in a redox state, forming the labile iron pool (LIP). LIP is the protein-unbound, exchangeable, and chelatable portion of iron, which has redox features (the ability to go through reduction-oxidation reactions) [73]. Iron can feed the production of lipid radicals through a Fenton-like reaction. The Fenton reaction is a sequence of redox reactions catalyzed by the labile ferrous iron (Fe+2) pool. Fe+2 reacts with LOOH•, forming a highly reactive alkoxyl (L-O•) radical [74, 75]. Iron helps the action of LOX to form LOOH• radicals, thereby fostering ferroptosis [76]. Under normal conditions, iron can enter the cell as transferrin through transferrin receptor 1 (TFR1) [77]. The non-transferrin-bound iron enters the cell through the divalent metal transporter 1 (DMT1) [78]. Iron can exit cells through ferroportin 1 (FPN1), which is the only iron exporter. FPN1 is under the control of hepcidin, the only hormonal regulator of iron. When iron systemic availability exceeds normal levels, hepcidin degrades FPN1, trapping iron into the cell [79] (see Figure 5 in our previous publication [46]). For iron to be released from its storage form in the cell, ferritin undergoes an autophagic degradation called ferritinophagy. Ferritinophagy is mediated by the nuclear receptor co-activator 4 (NCOA4), increasing the LIP [80, 81]. All iron-related proteins and transporters undergo molecular regulation through the iron regulatory proteins/iron-responsive elements (IRPs/IRE) system. IRP1 and IRP2 are cytosolic proteins that bind to IRE in different target genes mRNA, controlling their translation [82]. When the IRPs are activated, they promote the expression of TFR1 and DMT1 and inhibit that of FPN1 and ferritin, which favors the increment of the LIP [83, 84]. For iron to promote ferroptosis induction, it loses its tight regulation to amplify the LIP. TFR1 upregulation supplies the LIP with more iron uptake; therefore, TFR1 high expression is a prominent feature of ferroptosis [85]. In addition, the upregulation of DMT1 acts as a ferroptosis mediator [86]. The overexpression of IRPs [87], the downregulation of FPN1 [88, 89], and the enhanced hepcidin production [90] all lead to the same outcome. NCOA4-mediated ferritinophagy is aggravated by the decrease of NrF2, which releases more iron to the LIP and promotes ferroptosis [91]. Moreover, the decrease in NrF2 downregulates H (heavy chain) ferritin, leading to increased ferroptosis [92]. Clockophagy is the autophagic degradation of clock gene transcriptional factors, which also mediates ferroptosis. GPX4 inhibitors suppress the expression of BMAL1/ARNTL (brain and muscle ARNT-like 1 or aryl hydrocarbon receptor nuclear translocator-like protein 1), which is the main clock gene transcriptional factor. GPX4 inhibitors also decrease the expression of ARNTL-targeted clock genes (PER1 and CRY1). Both the suppressed expression and the autophagic degradation of BMAL1/ARNTL promote ferroptosis [93]. (Fig. 1)
Ferroptosis is an iron-dependent cell death which is executed by lipid peroxidation. Iron dysregulation, antioxidant failure, and lipid peroxidation are the three hallmarks of ferroptosis. 1- Iron dysregulation: the labile iron pool (LIP) or free redox iron increases during ferroptosis through three ways. First, imported iron through the upregulated divalent metal transporter 1 (DMT1) and transferrin receptors-1 (TFR1) adds up to the LIP. Second, iron exportation is limited by degradation of the only iron exporter, ferroportin 1 (FPN1), increasing the LIP. Third, iron is released from its ferritin stores by the nuclear receptor co-activator 4 (NCOA4)-mediated ferritinophagy or ferritin degradation. The highly available Ferrous iron (Fe+2) invokes lipid peroxidation and therefore ferroptosis through a Fenton-like reaction. 2-Failure of antioxidant defence: accumulated reactive oxygen species (ROS) overwhelms antioxidant defence system. During ferroptosis, the Solute carrier family 7 member 11 (SLC7A11) is downregulated by the decrease of nuclear factor erythroid 2-related factor 2 (NrF2) and the increase of P53, which prevents cystine entry into the cell and therefore decrease the formation of glutathione (GSH). 3- Lipid peroxidation: acyl-coenzyme A synthetase long-chain family member 4 (ACSL4) increases during ferroptosis and incorporates more polyunsaturated fatty acids (PUFA) into membrane phospholipid by converting them to PUFA-CoAs. ROS initiates a chain reaction of lipid peroxidation forming lipid hydroperoxides (PUFAOOH•), which is amplified by the increased LIP, promoting ferroptosis. Fe+3 ferric iron, TF transferrin.
Intersection of bipolar disorder pathogenesis and ferroptosis
We present the hypothesis of ferroptosis as one of the missing pieces of BD pathogenesis. We raise the question of whether ferroptosis is implicated in the pathogenesis of BD with a rationale based on the following five observations. (Fig. 2).
Our hypothesis of ferroptosis being implicated in the pathogenesis of bipolar disorder (BD) is supported by 1-Ferroptosis being involved in the pathogenesis of some of BD comorbidities, including Schizophrenia (SCZ), autism spectrum disorder (ASD), major depressive disorder (MDD), post-traumatic stress disorder (PTSD), and alcohol use disorder (AUD). 2-The existence of ferroptosis hallmarks in BD. 3- Hypothalamic-adrenal axis disturbance in BD pathogenesis, which could induce ferroptosis. 4- Circadian rhythm disturbance in BD, which is echoed by the ferroptosis-induced degradation of circadian rhythm transcriptional factors (clockophagy). 5- Drugs used in BD treatment have antiferroptosis effect in other contexts.
Ferroptosis in other psychiatric disorders
Despite being recently discovered [45], ferroptosis was reported to be involved in the pathogenesis of multiple psychiatric disorders. The role of ferroptosis in the pathological mechanism of major depressive disorder(MDD) was shown, where lower GSH and GPX and higher MDA were reported in the prefrontal cortex of depressed patients. Antidepressant drugs showed higher levels of hippocampal GPX4 and lower levels of ROS in depressed mice, with amelioration of depressive behavior [94]. Chen et al. reported the construction of three ferroptosis-related genes (ALOX15B, RPLP0, and HP) for MDD diagnosis {Chen, 2023 #231}. Interestingly, Shlien et al found a common deleted region including ALOX15B in patients with developmental disorder, bipolar disorder, and severe cognitive impairment {Shlien, 2010 #227}. In addition, RPLP0 was found to be downregulated in both MDD and BD {Feng, 2020 #228}. Li et al. showed that ferroptosis inhibition improves depressive behavior in a chronic unpredictable mild stress mouse model [95, 96] Stress induced anxiety after 14 day chronic restrain stress showed ferroptosis, with higher oxidative stress and lipid peroxidation markers [97]. Zhu et al. identified three crucial ferroptosis-related genes (ACSL4, ACO1, and GSS) and used them to establish a predictive model of post-traumatic stress disorder (PTSD) [98]. Intriguingly, ACO1 was found to be approximately 1.3 times higher in BD {Sahay, 2024 #229}. Zhang et al. reported ferroptosis in the BTBR T+ tf/J mouse model of autism spectrum disorder (ASD) [99], Moreover, ferroptosis was reported behind AUD-depressive and anxiety-like behaviors in mice [100, 101]. The course of BD is complicated by some of these disorders, including AUD [102], anxiety [103], and ASD [104], which implies a potential intersection of their pathogenesis at ferroptosis. On a more evident note, ferroptosis-related genes have been identified in schizophrenia [105, 106]. Such an observation sparks interest, especially since BD shares familial susceptibility [107], gene expression alterations [108], and some neuropharmacological mechanisms such as dopamine disturbance [109] and glutamatergic dysfunction [110] with schizophrenia. However, evidence of such an intersection is still warranted.
Hallmarks of ferroptosis intersect with bipolar disorder pathogenesis
Iron dysregulation
Iron disturbance is a recurring finding in the context of multiple psychiatric disorders. Both iron deficiency and iron overload actively play a role in the pathophysiology of numerous mental disorders, including depression, schizophrenia, PTSD, ASD, and ADHD, indicating that optimal iron economy is needed for optimal brain functionality [111]. In a nationwide population-based study, 2957 children and adolescents with iron deficiency anemia (IDA) showed a higher risk than their matched controls of developing unipolar depressive disorder, BD, anxiety disorder, ASD, ADHD, tic disorder, and developmental delay, with a higher risk of developing BD and tic disorder in female patients with IDA [112]. Lee et al. in a more recent nationwide population-based study, showed a similar outcome in 19,397 adults with IDA and 38,794 controls, with a higher incidence of anxiety disorders, depression, sleep disorders, and psychotic disorders in those with IDA. However, they further found a lower risk of psychiatric disorders in IDA subjects on iron supplementation compared to those with no iron supplementation [113]. We previously reported lower serum ferritin levels in COVID-19 patients with psychiatric comorbidities (n = 212) compared to COVID-19 patients without psychiatric comorbidities (n = 416) [114]. At the other end of the spectrum, using a proxy measure of brain iron concentration (1/nT2*) from 5 min resting-state fMRI data of publicly available cohorts of individuals with schizophrenia (n = 72) and matched controls (n = 73), Sonnenschein et al. reported a significantly higher amount of iron deposition in the ventral lateral thalamus of schizophrenia patients, which increased with age [115]. Lotan et al. detected higher iron accumulation in the prefrontal cortex of post-mortem brains of schizophrenia patients (n = 86) compared to their matched controls (n = 85). Interestingly, they further reported a paradoxical lower expression of ferritin, the iron storage protein that keeps iron in an inactive non-redox state, in schizophrenia patients [116]. Huang et al. reported higher serum ferritin levels in chronic hemodialysis patients with major depression (n = 15) compared to those with no major depression (n = 92) [117]. Zhu et al. also showed that patients with ischemic stroke (n = 196) who developed post-stroke depression (n = 56) two months post-stroke had higher serum ferritin levels at admission compared to those with no depression, with a significant association between both serum ferritin levels and depression [118]. Similarly, BD patients in a depressed state exhibited higher serum ferritin levels compared to those with euthymia [119], which implies a change in iron homeostasis even in different BD phases. In a study of serum trace elements in schizophrenia (n = 11) and BD patients (n = 7 lithium treated and n = 8 lithium non-treated), serum iron was significantly high in BD patients without lithium treatment compared to the healthy controls (n = 11) [120]. In addition, in a paradoxical sleep deprivation mania model, mice that received deferoxamine, an iron chelator, with n-acetylcysteine, an antioxidant, showed an improvement in manic-like behavior and oxidative damage in both the hippocampus and frontal cortex [121]. However, in a study of 137 patients (schizophrenia = 57 and bipolar disorder = 80), ferroportin was higher only in schizophrenia, with no changes in either condition in serum hepcidin or serum ferritin [122]. These findings should be considered with the limitation of measuring serum levels with no brain iron level detection. An interesting case study of treatment-resistant mania showed an underlying case of neurodegeneration with iron brain accumulation (NBIA), proposing a potential association of resistant mania with iron accumulation [123]. Despite that these studies indicate a plausibly important role of iron homeostasis in BD pathogenesis, the literature is extremely poor in clinical studies on brain iron accumulation in BD either in postmortem tissues or assessed by MRI-based quantitative susceptibility mapping (QSM). Nevertheless, our hypothesis is based on the concept that high brain iron contributes to ferroptosis, and the increased prevalence of bipolar disorder in patients with iron deficiency anemia could be attributed to a different mechanism besides ferroptosis, which necessitate both animal and clinical studies.
Neuroinflammation and iron
Low-grade systemic inflammation and neuroinflammation seem to comprise a piece of BD pathogenesis. For example, BD patients exhibit high plasma levels and brain mRNA expression of pro-inflammatory cytokines, such as interleukin (IL)-6 and tumor necrosis factor-α (TNF-α) [28], and high acute phase reactants, such as C-reactive protein (CRP) [124]. Similarly, in a meta-analysis of 18 studies, BD patients showed higher serum levels of pro-inflammatory cytokines, including IL-2 receptor, TNF-α, soluble TNF-α receptor type 1, soluble IL-6 receptor, and IL-4 [29]. Jakobsson et al. reported higher CSF levels of monocyte chemoattractant protein-1 (MCP-1) and chitinase-3-like protein 1 (YKL-40) in 125 BD patients and higher serum levels of soluble cluster of differentiation 14 (sCD14) and YKL-40 in 221 BD patients. They showed a correlation between the serum and CSF MCP-1 and YKL-40, which implies a state of systemic inflammation, neuroinflammation, and microglial activation [125]. Since iron dysregulation is heavily intertwined with inflammation and microglial activation in both directions [126], the reported inflammation in BD could be an inducer or a consequence of iron dysregulation. Interestingly, in a study of drug naïve first episode manic patients (n = 56), serum ferritin was positively correlated with the BPRS (Brief Psychiatric Rating Scale) and YMRS (Young Mania Rating Scale) scores and patients showed higher inflammatory indices compared to their matched controls [127]. Nevertheless, whether brain iron overload is associated with neuroinflammation in BD patient has not been investigated and needs further studies.
Neurotransmission and iron
Disrupted neurotransmission, especially of dopamine and glutamate, is another piece of the BD pathogenesis puzzle. Dopamine-increased activity is strongly implicated in manic episodes [128]. In addition, products of dopamine metabolism through monoamine oxidase are pro-oxidants, promoting hydrogen peroxide (H2O2) production and oxidative damage [30]. Glutamatergic dysfunction impacts disease severity [31], with higher levels of glutamate mostly in the anterior cingulate cortex and prefrontal cortex, as shown in magnetic resonance spectroscopy (1H-MRS) studies [32]. Iron is crucial for the function of multiple neurotransmitters, including dopamine, norepinephrine, and serotonin [129]. Iron and dopamine share a toxic relationship since dopamine can increase intracellular iron accumulation and, by doing so, promote an oxidative stress response [130]. On the other hand, iron promotes the toxicity of some of the dopamine metabolism neurotoxic products [131]. Dopamine itself can be auto-oxidized by iron, produces free radicals and be converted into 6-hydrodopamine that inhibits mitochondrial electron transport chain [132]. In addition, iron and glutamate interact, as iron is involved in the synthesis of glutamate by activating cytosolic aconitase enzyme [133] and glutamate can increase the total brain iron content by making it easier for iron to enter the cell through the upregulation of DMT1. Glutamate upregulates DMT1 through nuclear factor кB (NF-кB) and protein kinase C (PKC). PKC enhances DMT1 protein expression through inhibition of DMT1 mRNA degradation [134].
Myelination, neuroplasticity, and iron
Brains of BD patients show gray matter thinning with reduced myelin staining [34] and decreased expression of oligodendrocyte-related genes [33], indicating altered myelination. Iron happens to be indispensable for myelin formation [135]. In line with the disrupted myelination in BD and the possible role of iron dysregulation, Heidari et al. reported that neurodegeneration with brain iron accumulation, a rare group of neurogenetic diseases marked by iron buildup in the basal ganglia, shows both psychiatric features and iron-induced myelin disturbance [136]. Besides altered myelination, patients with BD show altered neurotrophic factors, especially BDNF which was reported to be deficient in both serum [137] and brains of BD patients [138]. Iron overload was repeatedly reported to decrease BDNF levels [139, 140]. Intriguingly, BDNF mimetics show anti-ferroptosis action [141]. Indeed, Li et al. found that, in addition to the anti-ferroptotic actions of electroconvulsive therapy (ECT), it also increased BDNF expression in a rat model of chronic, unpredictable mild stress [142]. Ferroptosis can be responsible for demyelination and loss of oligodendrocytes as shown by Li et al. in an autoimmune encephalomyelitis animal model through ferritinophagy [143].
Mitochondrial dysfunction, calcium influx, and iron
Several lines of evidence have shown that mitochondrial dysfunction and oxidative stress are integral to BD pathogenesis. For example, the mitochondria of BD patients showed morphological abnormalities in the prefrontal cortex neurons in postmortem brain tissues [144]. Mitochondria morphological changes are associated with dysfunction and altered energy metabolism, whereby adenosine triphosphate (ATP) production is insufficient to maintain the Na+/K+-ATPase neuronal activity, which leads to massive calcium (Ca+2) influx followed by glutamate toxicity [24]. This observation of higher calcium influx in BD is intriguing in the context of iron overload since calcium and iron have a bidirectional relationship where high Ca+2 influx causes increased LIP and iron overload promotes massive Ca+2 influx [145, 146]. In addition, high levels of intracellular Ca+2 and iron cause mitochondrial dysfunction, ROS generation, and ferroptosis [147]. This cyclic relation could have an important role in BD pathogenesis, which needs intensified directed research.
Lipid peroxidation and iron
Being a transition metal, iron can effortlessly exchange electrons and switch between ferrous (Fe+2) and ferric (Fe+3) forms [148]. This transition is tightly controlled to avoid piled-up free Fe+2 iron, which would let electrons loose and aid free radical production and oxidative stress [135, 149]. Due to this feature, iron accumulation can foster the production of lipid radicals through a Fenton-like reaction and the progression to lipid peroxidation [74].
Lipid peroxidation and failure of antioxidant systems
Lipid peroxidation, the executioner of ferroptosis [37], has been iteratively reported as a crucial part of BD pathophysiology. A meta-analysis of 60 BD studies showed that BD patients exhibit heightened levels of lipid peroxidation biomarkers, including MDA, 4-HNE, and peroxides. In addition, the ratio of all lipid peroxidation biomarkers to all lipid-associated antioxidant defenses was significantly higher in BD patients, than in both healthy controls and patients with major depressive disorder [150]. Moreover, a meta-analysis of 44 BD-focused studies showed higher levels of MDA and lower levels of GSH, a major part of the lipid peroxidation repair system, in BD patients compared to their healthy controls. They also reported lower levels of glutathione peroxidase (GPX), a lipid peroxidation antioxidant enzyme, in medication-free manic patients [151]. Similarly, a meta-analysis of 11 BD studies showed significantly increased levels of MDA in BD patients compared to healthy controls and decreased MDA levels in patients taking psychotropic medications [152]. Andreazza et al. reported higher levels of peripheral lipid hydroperoxides in 24 euthymic BD patients. Interestingly, peripheral lipid hydroperoxides explained more than half of the variance in white matter alterations in BD patients, using diffusion tensor imaging measures [153]. Post-mortem brain tissues of BD patients also revealed higher levels of HNE-4 compared to nonpsychiatric, non-neurologic controls [154].
Oxidative stress, which is tightly intertwined with lipid peroxidation, has also been heavily reported as an integral part of BD pathogenesis. A meta-analysis of 27 studies (n = 971 BD patients) showed higher DNA and ribonucleic acid (RNA) damage along with increased lipid peroxidation and nitric oxide levels, a potent free radical, which implies oxidative stress and the potential failure of antioxidant defenses [155]. To further demonstrate the prominent role of lipid peroxidation in the context of BD, a postmortem brain study of 10 BD patients revealed a disrupted pathway of arachidonic acid (AA), which is a major PUFA in brain cell membranes, in the frontal cortex [60]. They found higher expression of AA-selective cytosolic phospholipase A2 (CPLA2), COX-2, and membrane prostaglandin E synthase (mPGES) in the cortex of individuals with BD compared to controls [38]. CPLA2 releases AA from the membrane, and once AA is free, it can act as a precursor for proinflammatory substances. In addition, COX-2, which is encoded by prostaglandin-endoperoxide synthase (PTGS2), converts AA to multiple prostaglandins, including prostaglandin E2 (PGE2), which is also involved in inflammation. Higher expression of PTGS2, COX-2 and PGE2 is associated with ferroptosis induction [156], while mPGES deficiency is associated with ferroptosis inhibition [157]. Higher expression of PTGS2, COX-2, and mPGES in both ferroptosis and BD makes a compelling argument for ferroptosis being a key component of BD pathogenesis. As a further validation of our argument, lithium, valproate, carbamazepine, and lamotrigine, all lowered the AA turnover or metabolic cascade, showing lower expression of COX-2 and PGE2 in rat brains. While valproate decreased the expression of ACSL4, a major ferroptosis-induction marker [59], clozapine and olanzapine decreased AA plasma availability [158]. Together, these findings suggest the intersection of BD pathogenesis and the ferroptosis executioner, lipid peroxidation. This relationship is also evident at a genetic level, as the deletion of fatty acid desaturase 1/2 (FADS1/2) genes in mice showed BD-like behavior with both hypo and hyperactive episodes, which responded to lithium [159]. Further, in the most recent genome-wide association study performed by the Psychiatric Genomics Consortium BD work group, both FADS1 and FADS2 were part of the top five most significant genes (p = 1.62e–12 and p = 9.51e–13 for FADS1 and FADS2, respectively) [26]. Interestingly, FADS2 has been shown to be a ferroptosis inhibitor [160]. In addition, the expression of NrF2, the major antioxidant transcriptional factor, which is a strong negative regulator of ferroptosis [69], decreased in a study of 100 BD patients [161].
Hypothalamic-pituitary-adrenal axis (HPA) disturbance
Aberrant activity of the HPA is associated with the clinical course of BD [35]. A meta-analysis of 41 studies showed that BD is associated with a hyperactive HPA axis with increased levels of basal cortisol, post-dexamethasone cortisol, and adrenocorticotropic hormone (ACTH), which were positively associated with mania and increased risk of cognitive impairment [162]. However, Watson et al. showed persistent abnormalities in the HPA axis in euthymic BD patients [163]. In addition, BD patients, especially at a late stage, show decreased responsiveness of glucocorticoid receptors [164]. In a lateral hypothalamic-kindled rat model of acute mania, serum corticosterone levels increased with an altered dynamic in a mathematical model of the HPA axis [165]. Dexamethasone was found to induce ferroptosis through depleting GSH [166] and through the p53/SLC7A11/GPX4 pathway [167]. These findings suggest a potential intersection of BD and ferroptosis, even at the HPA axis.
Circadian rhythm abnormalities
Patients with BD suffer from sleep disturbance, which is intimately associated with circadian rhythm disturbances and an underlying deficiency or epigenetic modulation of BMAL1/ARNTL and CLOCK (circadian locomotor output cycles kaput), the two main transcriptional factors for circadian clock genes. CLOCK and BMAL1/ARNTL disruption is implicated in inflammation, mitochondrial dysfunction, dopamine, and serotonin disturbance in BD patients [36, 168], as well as in iron dysregulation [169]. The autophagic degradation of BMAL1 and CLOCK, termed “Clockophagy”, is a recently identified pathway for ferroptosis [93], which could intersect with BD pathogenesis.
Anti-ferroptosis action of bipolar disorder treatment
Lithium, the gold standard treatment for BD, exerts its therapeutic action mainly through inhibition of the glycogen synthase kinase-3β (GSK-3β) [170]. Interestingly, GSK-3β was reported as a positive regulator of ferroptosis. The pharmacological inhibition or genetic knockdown of GSK-3β caused an increase in ferroptosis resistance by preventing the disruption of iron homeostasis caused by GSK-3β [171]. Additionally, GSK-3β disrupts the antioxidant defense system by manipulating the expression of NrF2, thereby facilitating ferroptosis [172]. Interestingly, the pharmacological inhibition of GSK-3β by lithium activates NrF2, providing plausibility for certain aspects of lithium’s mechanism of action to occur through ferroptosis inhibition through the GSK-3β/ NrF2 pathway [173]. Lithium is also implicated in antagonizing lipid peroxidation. In a rat sleep deprivation model, lithium decreased the elevated MDA levels in the hippocampus and forebrain, indicating its role against lipid peroxidation [174]. Some of the antipsychotic medications used in treatment-resistant mania, such as olanzapine and clozapine, also show anti-ferroptotic action. Olanzapine and its derivative, which showed even more potent anti-ferroptosis action, inhibited ferroptosis in mice HT22 hippocampal cells through trapping free radicals, exerting an antioxidant action [175]. Interestingly, Liu et al. found an anti-ferroptosis action of olanzapine against pancreatitis in the mouse pancreatic acinar cell line 266-6 through its radical scavenging action, which reduced lipid peroxidation [176]. The clozapine metabolite, clozapine-N-Oxide, inhibited ferroptosis-induced dopaminergic cell death through inhibiting NCOA-4 mediated ferritinophagy [177]. Moreover, haloperidol, a first-generation antipsychotic, which can be used in acute mania, showed an anti-ferroptotic effect in hippocampal HT22 cells independent of its antagonistic action on dopamine receptors. Haloperidol decreased ferrous iron accumulation in lysosomes, which decreased ROS production [178]. Further, valproic acid, an anti-convulsant used in BD treatment [179], has been shown to have an anti-ferroptosis action in a cauda equina injury rat model through its known short-chain fatty acid histone deacetylase (HDAC) inhibition [180]. Quercetin is an antioxidant flavonoid that showed improvement in manic-like behavior in a paradoxical sleep deprivation mouse model through attenuation of lipid peroxidation and enhancement of GSH levels [181]. The same quercetin was repeatedly reported to have an anti-ferroptosis action [182]. N-acetylcysteine, an antioxidant, GSH precursor, and Xc system agonist could act as an adjuvant treatment in BD patients [183]. In a study of 28 treatment-resistant BD patients, ECT showed a decrease in the pre-treatment elevated levels of MDA, a lipid peroxidation biomarker, in responders compared to non-responders [184]. Strikingly, in a rat model of chronic unpredictable mild stress, rats that received ECT showed higher expression of ferroptosis negative regulators, including GPX4, NrF2, and ferritin heavy chain 1, in addition to lower expression of the ferroptosis-inducing ACSL4 [142]. The recently discovered anti-ferroptotic actions of some of the BD treatment is nothing but compelling to elucidate the interplay of ferroptosis molecular machinery and BD pathogenesis (Fig. 3).
BD shows high glutamate levels, which can increase the LIP by increasing expression of DMT1 through the NF-κB/PKC. The increased LIP, which could happen through higher iron importation by TFR1 and DMT1 or less exportation by FPN1, can promote the cytotoxicity of dopamine byproducts which is already increased in BD. The increased LIP can promote lipid radical formation (PUFAOOH•) through a Fenton-like reaction, which ends up in lipid peroxidation and ferroptosis. Mitochondrial dysfunction in BD can lead to overwhelming the antioxidant defence system with ROS production. The high dopamine levels in BD can also participate in the increased ROS levels. The antioxidant failure in BD can cause disturbance in GSH, GPX4, and NrF2 which leads eventually to high ROS, lipid peroxidation, and ferroptosis. BD shows decreased sensitivity of glucocorticoid receptors along with high basal levels of corticosterone, while dexamethasone can induce ferroptosis by activation of p53, which decreases the expression of SLC7A11 and, therefore, the entry of cystine and production of GSH. Epigenetic modulation of circadian transcriptional factors (BMAL1 and Clock) is a prominent event in BD and their degradation (clockophagy) induces ferroptosis. FADS2 is strongly implicated in both BD pathogenesis and ferroptosis induction. Multiple BD treatments inhibit ferroptosis. ECT inhibits ferroptosis by activating NrF2, which increases the expression of SLC7A11 and loads Fe+2 into ferritin, decreasing the LIP. ECT also activates GPX4 and inhibits ACSL4 and lipid peroxidation. Lithium inhibits ferroptosis by inhibiting the GSK3-β that inhibits NrF2, increasing the expression of SLC7A11. Lithium inhibits lipid peroxidation and ferroptosis by inhibiting both COX-2 and GSK3- β. Carbamazepine inhibits lipid peroxidation and ferroptosis by inhibiting COX-2. Clozapine N oxide, a metabolite of clozapine inhibits ferroptosis through inhibition of NCOA4-mediated ferritinophagy, which decreases ferritin degradation and build-up of the LIP. Haloperidol can inhibit iron dysregulation and thereby ferroptosis. Valproic acid inhibits HDAC, which in turn inhibits the epigenetic modulation of ferroptosis genes and ferroptosis. N -acetylcysteine inhibits ferroptosis by increasing both SLC7A11 and GSH. Both olanzapine and haloperidol inhibit ferroptosis through ROS scavenging action. Lamotrigine decreases the availability of PUFA. BD bipolar disorder, LIP labile iron pool, Fe+2 ferrous iron, Fe+3 ferric iron, DMT1 divalent metallic transporter 1, TFR1 transferrin receptor 1, TF transferrin, FPN1 ferroportin 1, NF-κB nuclear factor kappa B, PKC protein kinase C, NCOA4 nuclear receptor co-activator 4, ECT electroconvulsive therapy, NrF2 nuclear factor erythroid 2-related factor 2, HDAC histone deacetylase, BMAL1 brain and muscle ARNT-like 1 or aryl hydrocarbon receptor nuclear translocator-like protein 1, CLOCK circadian locomotor output cycles kaput, ROS reactive oxygen species, GSH glutathione, GPX4 glutathione peroxidase 4, SLC7A11 solute carrier family 7 member 11, ACSL4 acyl-coenzyme A synthetase long-chain family member 4, GSK3- β glycogen synthase kinase-3 beta, PUFA polyunsaturated fatty acid, FADS1/2 fatty acid desaturase1/2, COX-2 cyclooxygenase-2.
Conclusion
Ferroptosis can be a missing piece of the unclear pathogenesis of BD. This hypothesis is rooted in multiple observations. First, the association of ferroptosis with multiple psychiatric disorders, which already exist as comorbidities in BD, supports a potential intersection of their mechanisms. The identification of ferroptosis-related genes in schizophrenia, which already shares genetic alterations with BD. Second, the three hallmarks of ferroptosis, iron dysregulation, lipid peroxidation, and antioxidant system failure, are evident in BD patients. Lipid peroxidation, the executioner of ferroptosis, holds an undeniable role in the pathogenesis of BD. Iron disruption, the inducer of ferroptosis, could result in or from inflammation, mitochondrial dysfunction, calcium disturbance, neurotransmission disturbance, and affection of synaptic plasticity and myelination, which are all elements of BD pathogenesis. Third and fourth, HPA axis and circadian rhythm abnormalities are intersection points between ferroptosis and BD. Finally, multiple treatments of BD show anti-ferroptosis action in different contexts. Therefore, we call for studies that address iron accumulation in the brain in BD patients, using QSM and in postmortem tissues of BD patients. We call for genetic studies to look for the genetic signature of ferroptosis in BD patients. In addition, we call for studies on different BD models to assess the expression of ferroptosis markers. Validating our hypothesis would fill an existing gap in the literature and would have tremendous implications for finding both diagnostic and prognostic biomarkers for BD and for expanding the management possibilities.
References
American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 5th ed. American Psychiatric Publishing; 2013. pp. 591–643.
McIntyre RS, Berk M, Brietzke E, Goldstein BI, López-Jaramillo C, Kessing LV, et al. Bipolar disorders. Lancet. 2020;396:1841–56.
Moreira ALR, Van Meter A, Genzlinger J, Youngstrom EA. Review and meta-analysis of epidemiologic studies of adult bipolar disorder. J Clin Psychiatry. 2017;78:e1259–e69.
Carvalho AF, Firth J, Vieta E. Bipolar disorder. N Engl J Med. 2020;383:58–66.
McGrath JJ, Al-Hamzawi A, Alonso J, Altwaijri Y, Andrade LH, Bromet EJ, et al. Age of onset and cumulative risk of mental disorders: a cross-national analysis of population surveys from 29 countries. Lancet Psychiatry. 2023;10:668–81.
Laursen TM. Life expectancy among persons with schizophrenia or bipolar affective disorder. Schizophr Res. 2011;131:101–4.
Biazus TB, Beraldi GH, Tokeshi L, Rotenberg LS, Dragioti E, Carvalho AF, et al. All-cause and cause-specific mortality among people with bipolar disorder: a large-scale systematic review and meta-analysis. Mol Psychiatry. 2023;28:2508–24.
Grant BF, Hasin DS, Chou SP, Stinson FS, Dawson DA. Nicotine dependence and psychiatric disorders in the United States: results from the national epidemiologic survey on alcohol and related conditions. Arch Gen Psychiatry. 2004;61:1107–15.
McIntyre RS, Danilewitz M, Liauw SS, Kemp DE, Nguyen HT, Kahn LS, et al. Bipolar disorder and metabolic syndrome: an international perspective. J Affect Disord. 2010;126:366–87.
Schaffer A, Isometsä ET, Tondo L, H Moreno D, Turecki G, Reis C, et al. International society for bipolar disorders task force on suicide: meta‐analyses and meta‐regression of correlates of suicide attempts and suicide deaths in bipolar disorder. Bipolar Disord. 2015;17:1–16.
Pompili M, Gonda X, Serafini G, Innamorati M, Sher L, Amore M, et al. Epidemiology of suicide in bipolar disorders: a systematic review of the literature. Bipolar Disord. 2013;15:457–90.
Kleine-Budde K, Touil E, Moock J, Bramesfeld A, Kawohl W, Rössler W. Cost of illness for bipolar disorder: a systematic review of the economic burden. Bipolar Disord. 2014;16:337–53.
Dong M, Lu L, Zhang L, Zhang Q, Ungvari GS, Ng CH, et al. Prevalence of suicide attempts in bipolar disorder: a systematic review and meta-analysis of observational studies. Epidemiol Psychiatr Sci. 2019;29:e63.
Merikangas KR, Akiskal HS, Angst J, Greenberg PE, Hirschfeld RM, Petukhova M, et al. Lifetime and 12-month prevalence of bipolar spectrum disorder in the National Comorbidity Survey replication. Arch Gen Psychiatry. 2007;64:543–52.
Yapici Eser H, Kacar AS, Kilciksiz CM, Yalçinay-Inan M, Ongur D. Prevalence and associated features of anxiety disorder comorbidity in bipolar disorder: a meta-analysis and meta-regression study. Front Psychiatry. 2018;9:229.
Onyeka IN, Collier Høegh M, Nåheim Eien EM, Nwaru BI, Melle I. Comorbidity of physical disorders among patients with severe mental illness with and without substance use disorders: a systematic review and meta-analysis. J Dual Diagn. 2019;15:192–206.
Messer T, Lammers G, Müller-Siecheneder F, Schmidt R-F, Latifi S. Substance abuse in patients with bipolar disorder: a systematic review and meta-analysis. Psychiatry Res. 2017;253:338–50.
McElroy SL, Winham SJ, Cuellar-Barboza AB, Colby CL, Ho AM, Sicotte H, et al. Bipolar disorder with binge eating behavior: a genome-wide association study implicates PRR5-ARHGAP8. Transl Psychiatry. 2018;8:40.
Xu N, Huggon B, Saunders KEA. Cognitive impairment in patients with bipolar disorder: impact of pharmacological treatment. CNS Drugs. 2020;34:29–46.
Gitlin M. Treatment-resistant bipolar disorder. Mol Psychiatry. 2006;11:227–40.
Perlis RH, Ostacher MJ, Patel JK, Marangell LB, Zhang H, Wisniewski SR, et al. Predictors of recurrence in bipolar disorder: primary outcomes from the systematic treatment enhancement program for bipolar disorder (STEP-BD). Am J Psychiatry. 2006;163:217–24.
Nierenberg AA, Ostacher MJ, Calabrese JR, Ketter TA, Marangell LB, Miklowitz DJ, et al. Treatment-resistant bipolar depression: a STEP-BD equipoise randomized effectiveness trial of antidepressant augmentation with lamotrigine, inositol, or risperidone. Am J Psychiatry. 2006;163:210–6.
Grande I, Berk M, Birmaher B, Vieta E. Bipolar disorder. Lancet. 2016;387:1561–72.
Scaini G, Valvassori SS, Diaz AP, Lima CN, Benevenuto D, Fries GR, et al. Neurobiology of bipolar disorders: a review of genetic components, signaling pathways, biochemical changes, and neuroimaging findings. Braz J Psychiatry. 2020;42:536–51.
Smoller JW, Finn CT. Family, twin, and adoption studies of bipolar disorder. Am J Med Genet C Semin Med Genet. 2003;123C:48–58.
Mullins N, Forstner AJ, O’Connell KS, Coombes B, Coleman JRI, Qiao Z, et al. Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology. Nat Genet. 2021;53:817–29.
Aldinger F, Schulze TG. Environmental factors, life events, and trauma in the course of bipolar disorder. Psychiatry Clin Neurosci. 2017;71:6–17.
Rao JS, Harry GJ, Rapoport SI, Kim HW. Increased excitotoxicity and neuroinflammatory markers in postmortem frontal cortex from bipolar disorder patients. Mol Psychiatry. 2010;15:384–92.
Munkholm K, Braüner JV, Kessing LV, Vinberg M. Cytokines in bipolar disorder vs. healthy control subjects: a systematic review and meta-analysis. J Psychiatr Res. 2013;47:1119–33.
Berk M, Dodd S, Kauer-Sant’anna M, Malhi GS, Bourin M, Kapczinski F, et al. Dopamine dysregulation syndrome: implications for a dopamine hypothesis of bipolar disorder. Acta Psychiatr Scand. 2007:41–9. https://doi.org/10.1111/j.1600-0447.2007.01058.x.
Frye MA, Watzl J, Banakar S, O’Neill J, Mintz J, Davanzo P, et al. Increased anterior cingulate/medial prefrontal cortical glutamate and creatine in bipolar depression. Neuropsychopharmacology. 2007;32:2490–9.
Yüksel C, Öngür D. Magnetic resonance spectroscopy studies of glutamate-related abnormalities in mood disorders. Biol Psychiatry. 2010;68:785–94.
Tkachev D, Mimmack ML, Ryan MM, Wayland M, Freeman T, Jones PB, et al. Oligodendrocyte dysfunction in schizophrenia and bipolar disorder. Lancet. 2003;362:798–805.
Regenold WT, Phatak P, Marano CM, Gearhart L, Viens CH, Hisley KC. Myelin staining of deep white matter in the dorsolateral prefrontal cortex in schizophrenia, bipolar disorder, and unipolar major depression. Psychiatry Res. 2007;151:179–88.
Daban C, Vieta E, Mackin P, Young AH. Hypothalamic-pituitary-adrenal axis and bipolar disorder. Psychiatr Clin. 2005;28:469–80.
McCarthy MJ, Gottlieb JF, Gonzalez R, McClung CA, Alloy LB, Cain S, et al. Neurobiological and behavioral mechanisms of circadian rhythm disruption in bipolar disorder: a critical multi-disciplinary literature review and agenda for future research from the ISBD task force on chronobiology. Bipolar Disord. 2022;24:232–63.
Dixon SJ, Stockwell BR. The hallmarks of ferroptosis. Ann Rev Cancer Biol. 2019;3:35–54.
Kim HW, Rapoport SI, Rao JS. Altered arachidonic acid cascade enzymes in postmortem brain from bipolar disorder patients. Mol Psychiatry. 2011;16:419–28.
Valvassori SS, Resende WR, Lopes-Borges J, Mariot E, Dal-Pont GC, Vitto MF, et al. Effects of mood stabilizers on oxidative stress-induced cell death signaling pathways in the brains of rats subjected to the ouabain-induced animal model of mania: mood stabilizers exert protective effects against ouabain-induced activation of the cell death pathway. J Psychiatr Res. 2015;65:63–70.
Herberth M, Koethe D, Levin Y, Schwarz E, Krzyszton ND, Schoeffmann S, et al. Peripheral profiling analysis for bipolar disorder reveals markers associated with reduced cell survival. Proteomics. 2011;11:94–105.
Kim H-W, Rapoport SI, Rao JS. Altered expression of apoptotic factors and synaptic markers in postmortem brain from bipolar disorder patients. Neurobiol Dis. 2010;37:596–603.
Scaini G, Fries G, Valvassori S, Zeni C, Zunta-Soares G, Berk M, et al. Perturbations in the apoptotic pathway and mitochondrial network dynamics in peripheral blood mononuclear cells from bipolar disorder patients. Transl Psychiatry. 2017;7:e1111.
Mishra HK, Mandyam AD, Trenet W, Wei H, Nievergelt CM, Maihofer AX, et al. Neural progenitor cells derived from lithium responsive and non-responsive bipolar disorder patients exhibit distinct sensitivity to cell death following methamphetamine. Neuropharmacology. 2023;226:109410.
Kopeina GS, Zhivotovsky B. Programmed cell death: past, present and future. Biochem Biophys Res Commun. 2022;633:55–8.
Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012;149:1060–72.
Yehia A, Abulseoud OA. Melatonin: a ferroptosis inhibitor with potential therapeutic efficacy for the post-COVID-19 trajectory of accelerated brain aging and neurodegeneration. Mol Neurodegener. 2024;19:36.
Agmon E, Solon J, Bassereau P, Stockwell BR. Modeling the effects of lipid peroxidation during ferroptosis on membrane properties. Sci Rep. 2018;8:5155.
Chen X, Comish PB, Tang D, Kang R. Characteristics and biomarkers of ferroptosis. Front Cell Dev Biol. 2021;9:637162.
Wang W, Yang H, Johnson D, Gensler C, Decker E, Zhang G. Chemistry and biology of ω-3 PUFA peroxidation-derived compounds. Prostaglandins Other Lipid Mediat. 2017;132:84–91.
Yin H, Xu L, Porter NA. Free radical lipid peroxidation: mechanisms and analysis. Chem Rev. 2011;111:5944–72.
Checa J, Aran JM. Reactive oxygen species: drivers of physiological and pathological processes. J Inflamm Res. 2020;13:1057–73.
Sies H, Belousov VV, Chandel NS, Davies MJ, Jones DP, Mann GE, et al. Defining roles of specific reactive oxygen species (ROS) in cell biology and physiology. Nat Rev Mol Cell Biol. 2022;23:499–515.
Pizzimenti S, Ciamporcero E, Daga M, Pettazzoni P, Arcaro A, Cetrangolo G, et al. Interaction of aldehydes derived from lipid peroxidation and membrane proteins. Front Physiol. 2013;4:242.
Guéraud F, Atalay M, Bresgen N, Cipak A, Eckl PM, Huc L, et al. Chemistry and biochemistry of lipid peroxidation products. Free Radic Res. 2010;44:1098–124.
Taso OV, Philippou A, Moustogiannis A, Zevolis E, Koutsilieris M. Lipid peroxidation products and their role in neurodegenerative diseases. Ann Res Hosp. 2019;3 https://doi.org/10.21037/arh.2018.12.02.
Pamplona R. Membrane phospholipids, lipoxidative damage and molecular integrity: a causal role in aging and longevity. Biochim Biophys Acta. 2008;1777:1249–62.
Rodencal J, Dixon SJ. A tale of two lipids: lipid unsaturation commands ferroptosis sensitivity. Proteomics. 2023;23:2100308.
Kuwata H, Hara S. Role of acyl-CoA synthetase ACSL4 in arachidonic acid metabolism. Prostaglandins Other Lipid Mediat. 2019;144:106363.
Doll S, Proneth B, Tyurina YY, Panzilius E, Kobayashi S, Ingold I, et al. ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition. Nat Chem Biol. 2017;13:91–8.
Lee JY, Kim WK, Bae KH, Lee SC, Lee EW. Lipid metabolism and ferroptosis. Biology. 2021;10:184.
Ursini F, Maiorino M. Lipid peroxidation and ferroptosis: the role of GSH and GPx4. Free Radic Biol Med. 2020;152:175–85.
Weaver K, Skouta R. The selenoprotein glutathione peroxidase 4: from molecular mechanisms to novel therapeutic opportunities. Biomedicines. 2022;10:891.
Lu SC. Glutathione synthesis. Biochim Biophys Acta. 2013;1830:3143–53.
Li FJ, Long HZ, Zhou ZW, Luo HY, Xu SG, Gao LC, et al. System Xc −/GSH/GPX4 axis: an important antioxidant system for the ferroptosis in drug-resistant solid tumor therapy. Front Pharmacol. 2022;13:910292.
Mandal PK, Seiler A, Perisic T, Kölle P, Banjac Canak A, Förster H, et al. System x(c)- and thioredoxin reductase 1 cooperatively rescue glutathione deficiency. J Biol Chem. 2010;285:22244–53.
Lewerenz J, Hewett SJ, Huang Y, Lambros M, Gout PW, Kalivas PW, et al. The cystine/glutamate antiporter system x(c)(-) in health and disease: from molecular mechanisms to novel therapeutic opportunities. Antioxid Redox Signal. 2013;18:522–55.
Forcina GC, Dixon SJ. GPX4 at the crossroads of lipid homeostasis and ferroptosis. Proteomics. 2019;19:e1800311.
Seibt TM, Proneth B, Conrad M. Role of GPX4 in ferroptosis and its pharmacological implication. Free Radic Biol Med. 2019;133:144–52.
Dodson M, Castro-Portuguez R, Zhang DD. NRF2 plays a critical role in mitigating lipid peroxidation and ferroptosis. Redox Biol. 2019;23:101107.
Shih AY, Johnson DA, Wong G, Kraft AD, Jiang L, Erb H, et al. Coordinate regulation of glutathione biosynthesis and release by Nrf2-expressing glia potently protects neurons from oxidative stress. J Neurosci. 2003;23:3394–406.
Harvey CJ, Thimmulappa RK, Singh A, Blake DJ, Ling G, Wakabayashi N, et al. Nrf2-regulated glutathione recycling independent of biosynthesis is critical for cell survival during oxidative stress. Free Radic Biol Med. 2009;46:443–53.
Jiang L, Kon N, Li T, Wang SJ, Su T, Hibshoosh H, et al. Ferroptosis as a p53-mediated activity during tumour suppression. Nature. 2015;520:57–62.
Cabantchik ZI. Labile iron in cells and body fluids: physiology, pathology, and pharmacology. Front Pharmacol. 2014;5:45.
Minotti G, Aust SD. The role of iron in oxygen radical mediated lipid peroxidation. Chem Biol Interact. 1989;71:1–19.
Cheng Z, Li Y. What is responsible for the initiating chemistry of iron-mediated lipid peroxidation: an update. Chem Rev. 2007;107:748–66.
Kühn H, Borchert A. Regulation of enzymatic lipid peroxidation: the interplay of peroxidizing and peroxide reducing enzymes. Free Radic Biol Med. 2002;33:154–72.
Kawabata H. Transferrin and transferrin receptors update. Free Radic Biol Med. 2019;133:46–54.
Yanatori I, Kishi F. DMT1 and iron transport. Free Radic Biol Med. 2019;133:55–63.
Katsarou A, Pantopoulos K. Basics and principles of cellular and systemic iron homeostasis. Mol Aspects Med. 2020;75:100866.
Santana-Codina N, Mancias JD. The role of NCOA4-mediated ferritinophagy in health and disease. Pharmaceuticals. 2018;11:114.
Quiles Del Rey M, Mancias JD. NCOA4-mediated ferritinophagy: a potential link to neurodegeneration. Front Neurosci. 2019;13:238.
Muckenthaler MU, Galy B, Hentze MW. Systemic iron homeostasis and the iron-responsive element/iron-regulatory protein (IRE/IRP) regulatory network. Annu Rev Nutr. 2008;28:197–213.
Styś A, Galy B, Starzyński RR, Smuda E, Drapier JC, Lipiński P, et al. Iron regulatory protein 1 outcompetes iron regulatory protein 2 in regulating cellular iron homeostasis in response to nitric oxide. J Biol Chem. 2011;286:22846–54.
Recalcati S, Gammella E, Buratti P, Cairo G. Molecular regulation of cellular iron balance. IUBMB Life. 2017;69:389–98.
Feng H, Schorpp K, Jin J, Yozwiak CE, Hoffstrom BG, Decker AM, et al. Transferrin receptor is a specific ferroptosis marker. Cell Rep. 2020;30:3411–23.e7.
Song Q, Peng S, Sun Z, Heng X, Zhu X. Temozolomide drives ferroptosis via a DMT1-dependent pathway in glioblastoma cells. Yonsei Med J. 2021;62:843–9.
Yao F, Cui X, Zhang Y, Bei Z, Wang H, Zhao D, et al. Iron regulatory protein 1 promotes ferroptosis by sustaining cellular iron homeostasis in melanoma. Oncol Lett. 2021;22:1–12.
Geng N, Shi B, Li S, Zhong Z, Li Y, Xua W, et al. Knockdown of ferroportin accelerates erastin-induced ferroptosis in neuroblastoma cells. Eur Rev Med Pharmacol Sci. 2018;22:3826–36.
Bao W-D, Pang P, Zhou X-T, Hu F, Xiong W, Chen K, et al. Loss of ferroportin induces memory impairment by promoting ferroptosis in Alzheimer’s disease. Cell Death Differ. 2021;28:1548–62.
Zhang H, Ostrowski R, Jiang D, Zhao Q, Liang Y, Che X, et al. Hepcidin promoted ferroptosis through iron metabolism which is associated with DMT1 signaling activation in early brain injury following subarachnoid hemorrhage. Oxid Med Cell Longev. 2021;2021:9800794.
Liu N, Liang Y, Wei T, Zou L, Huang X, Kong L, et al. The role of ferroptosis mediated by NRF2/ERK-regulated ferritinophagy in CdTe QDs-induced inflammation in macrophage. J Hazard Mater. 2022;436:129043.
Cheng Y, Gao Y, Li J, Rui T, Li Q, Chen H, et al. TrkB agonist N-acetyl serotonin promotes functional recovery after traumatic brain injury by suppressing ferroptosis via the PI3K/Akt/Nrf2/Ferritin H pathway. Free Radic Biol Med. 2023;194:184–98.
Yang M, Chen P, Liu J, Zhu S, Kroemer G, Klionsky DJ, et al. Clockophagy is a novel selective autophagy process favoring ferroptosis. Sci Adv. 2019;5:eaaw2238.
Wang L, Xu R, Huang C, Yi G, Li Z, Zhang H, et al. Targeting the ferroptosis crosstalk: novel alternative strategies for the treatment of major depressive disorder. Gen Psychiatr. 2023;36:e101072.
Chen J, Jiang X, Gao X, Wu W, Gu Z, Yin G, et al. Ferroptosis-related genes as diagnostic markers for major depressive disorder and their correlations with immune infiltration. Frontiers in Medicine. 2023;10:1215180.
Li E, Yin H, Su M, Li Q, Zhao Y, Zhang L, et al. Inhibition of ferroptosis alleviates chronic unpredictable mild stress-induced depression in mice via tsRNA-3029b. Brain Res Bull. 2023;204:110773.
Dai Y, Guo J, Zhang B, Chen J, Ou H, He R-R, et al. Lycium barbarum (Wolfberry) glycopeptide prevents stress-induced anxiety disorders by regulating oxidative stress and ferroptosis in the medial prefrontal cortex. Phytomedicine. 2023;116:154864.
Zhu J, Zhang Y, Ren R, Sanford LD, Tang X. Blood transcriptome analysis: Ferroptosis and potential inflammatory pathways in post-traumatic stress disorder. Front Psychiatry. 2022;13:841999.
Zhang Q, Wu H, Zou M, Li L, Li Q, Sun C, et al. Folic acid improves abnormal behavior via mitigation of oxidative stress, inflammation, and ferroptosis in the BTBR T+ tf/J mouse model of autism. J Nutr Biochem. 2019;71:98–109.
Liu C-Y, Wang M, Yu H-M, Han F-X, Wu Q-S, Cai X-J, et al. Ferroptosis is involved in alcohol-induced cell death in vivo and in vitro. Biosci Biotechnol Biochem. 2020;84:1621–8.
Xu C, Xiong Q, Tian X, Liu W, Sun B, Ru Q, et al. Alcohol exposure induces depressive and anxiety-like behaviors via activating ferroptosis in mice. Int J Mol Sci. 2022;23:13828.
Frye MA, Salloum IM. Bipolar disorder and comorbid alcoholism: prevalence rate and treatment considerations. Bipolar Disord. 2006;8:677–85.
Freeman MP, Freeman SA, McElroy SL. The comorbidity of bipolar and anxiety disorders: prevalence, psychobiology, and treatment issues. J Affect Disord. 2002;68:1–23.
Joshi G, Biederman J, Petty C, Goldin RL, Furtak SL, Wozniak J. Examining the comorbidity of bipolar disorder and autism spectrum disorders: a large controlled analysis of phenotypic and familial correlates in a referred population of youth with bipolar I disorder with and without autism spectrum disorders. J Clin Psychiatry. 2013;74:6865.
Feng S, Chen J, Qu C, Yang L, Wu X, Wang S, et al. Identification of Ferroptosis-related genes in schizophrenia based on Bioinformatic analysis. Genes. 2022;13:2168.
Lian K, Li Y, Yang W, Ye J, Liu H, Wang T, et al. Hub genes, a diagnostic model, and immune infiltration based on ferroptosis-linked genes in schizophrenia. IBRO Neurosci Rep. 2024;16:317–28.
Berrettini W. Evidence for shared susceptibility in bipolar disorder and schizophrenia. Am J Med Genet C Semin Med Genet. 2003;123C:59–64.
Shao L, Vawter MP. Shared gene expression alterations in schizophrenia and bipolar disorder. Biol Psychiatry. 2008;64:89–97.
Murray RM, Sham P, Van Os J, Zanelli J, Cannon M, McDonald C. A developmental model for similarities and dissimilarities between schizophrenia and bipolar disorder. Schizophr Res. 2004;71:405–16.
Li C-T, Yang K-C, Lin W-C. Glutamatergic dysfunction and glutamatergic compounds for major psychiatric disorders: evidence from clinical neuroimaging studies. Front Psychiatry. 2019;9:422826.
Wu Q, Ren Q, Meng J, Gao W-J, Chang Y-Z. Brain iron homeostasis and mental disorders. Antioxidants. 2023;12:1997.
Chen M-H, Su T-P, Chen Y-S, Hsu J-W, Huang K-L, Chang W-H, et al. Association between psychiatric disorders and iron deficiency anemia among children and adolescents: a nationwide population-based study. BMC Psychiatry. 2013;13:1–8.
Lee H-S, Chao H-H, Huang W-T, Chen SC-C, Yang H-Y. Psychiatric disorders risk in patients with iron deficiency anemia and association with iron supplementation medications: a nationwide database analysis. BMC Psychiatry. 2020;20:1–9.
Abulseoud OA, Yehia A, Egol CJ, Nettey VN, Aly M, Qu Y, et al. Attenuated initial serum ferritin concentration in critically ill coronavirus disease 2019 geriatric patients with comorbid psychiatric conditions. Front Psychiatry. 2022;13:1035986.
Sonnenschein SF, Parr AC, Larsen B, Calabro FJ, Foran W, Eack SM, et al. Subcortical brain iron deposition in individuals with schizophrenia. J Psychiatr Res. 2022;151:272–8.
Lotan A, Luza S, Opazo CM, Ayton S, Lane DJ, Mancuso S, et al. Perturbed iron biology in the prefrontal cortex of people with schizophrenia. Mol Psychiatry. 2023;28:2058–70.
Huang T-L, Lee C-T. Low serum albumin and high ferritin levels in chronichemodialysis patients with major depression. Psychiatry Res. 2007;152:277–80.
Zhu L, Han B, Wang L, Chang Y, Ren W, Gu Y, et al. The association between serum ferritin levels and post-stroke depression. J Affect Disord. 2016;190:98–102.
Munkholm K, Jacoby AS, Vinberg M, Kessing LV. Ferritin as a potential disease marker in patients with bipolar disorder. J Affect Disord. 2023;332:247–53.
Santa Cruz EC, Madrid KC, Arruda MAZ, Sussulini A. Association between trace elements in serum from bipolar disorder and schizophrenia patients considering treatment effects. J Trace Elem Med Biol. 2020;59:126467.
Arent CO, Valvassori SS, Steckert AV, Resende WR, Dal-Pont GC, Lopes-Borges J, et al. The effects of n-acetylcysteine and/or deferoxamine on manic-like behavior and brain oxidative damage in mice submitted to the paradoxal sleep deprivation model of mania. J Psychiatr Res. 2015;65:71–9.
Altun İK, Atagün Mİ, Erdoğan A, Yenilmez DO, Yusifova A, Şenat A, et al. Serum hepcidin/ferroportin levels in bipolar disorder and schizophrenia. J Trace Elem Med Biol. 2021;68:126843.
Patwal R, Pai NM, Ganjekar S, Udupi GA, Kesavan M, Desai G. Atypical idiopathic NBIA (neurodegeneration with brain iron accumulation) associated with treatment‐resistant bipolar mania responding to clozapine. Bipolar Disord. 2022;24:840–3.
Dickerson F, Stallings C, Origoni A, Boronow J, Yolken R. Elevated serum levels of C-reactive protein are associated with mania symptoms in outpatients with bipolar disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2007;31:952–5.
Jakobsson J, Bjerke M, Sahebi S, Isgren A, Ekman CJ, Sellgren C, et al. Monocyte and microglial activation in patients with mood-stabilized bipolar disorder. J Psychiatry Neurosci. 2015;40:250–8.
Urrutia PJ, Bórquez DA, Núñez MT. Inflaming the brain with iron. Antioxidants. 2021;10:61.
Yeşilkaya ÜH, Bişgin E. The investigation of inflammation in drug-naive first-episode mania by measuring ferritin, peripheral inflammatory markers, and their ratios. Neuropsychiatr Investig. 2024;62:15–21.
Ashok AH, Marques TR, Jauhar S, Nour MM, Goodwin GM, Young AH, et al. The dopamine hypothesis of bipolar affective disorder: the state of the art and implications for treatment. Mol Psychiatry. 2017;22:666–79.
Burhans MS, Dailey C, Beard Z, Wiesinger J, Murray-Kolb L, Jones BC, et al. Iron deficiency: differential effects on monoamine transporters. Nutr Neurosci. 2005;8:31–8.
Dichtl S, Haschka D, Nairz M, Seifert M, Volani C, Lutz O, et al. Dopamine promotes cellular iron accumulation and oxidative stress responses in macrophages. Biochem Pharmacol. 2018;148:193–201.
Hare DJ, Double KL. Iron and dopamine: a toxic couple. Brain. 2016;139:1026–35.
Berk M, Kapczinski F, Andreazza AC, Dean OM, Giorlando F, Maes M, et al. Pathways underlying neuroprogression in bipolar disorder: Focus on inflammation, oxidative stress and neurotrophic factors. Neurosci Biobehav Rev. 2011;35:804–17.
McGahan MC, Harned J, Mukunnemkeril M, Goralska M, Fleisher L, Ferrell JB. Iron alters glutamate secretion by regulating cytosolic aconitase activity. Am J Physiol Cell Physiol. 2005;288:C1117–C24.
Yu P, Zhang M, Ding H, Di X, Guan P, Wang S, et al. Effect of glutamate on brain iron metabolism and the regulation mechanism. J Drug Metab Toxicol. 2015;6:2.
Todorich B, Pasquini JM, Garcia CI, Paez PM, Connor JR. Oligodendrocytes and myelination: the role of iron. Glia. 2009;57:467–78.
Heidari M, Johnstone DM, Bassett B, Graham R, Chua A, House M, et al. Brain iron accumulation affects myelin-related molecular systems implicated in a rare neurogenetic disease family with neuropsychiatric features. Mol Psychiatry. 2016;21:1599–607.
de Oliveira GS, Ceresér KM, Fernandes BS, Kauer-Sant’Anna M, Fries GR, Stertz L, et al. Decreased brain-derived neurotrophic factor in medicated and drug-free bipolar patients. J Psychiatr Res. 2009;43:1171–4.
Ray MT, Weickert CS, Wyatt E, Webster MJ. Decreased BDNF, trkB-TK+ and GAD67 mRNA expression in the hippocampus of individuals with schizophrenia and mood disorders. J Psychiatry Neurosci. 2011;36:195–203.
Alcalde LA, de Freitas BS, Machado GDB, de Freitas Crivelaro PC, Dornelles VC, Gus H, et al. Iron chelator deferiprone rescues memory deficits, hippocampal BDNF levels and antioxidant defenses in an experimental model of memory impairment. Biometals. 2018;31:927–40.
Zhang Y, Bai X, Zhang Y, Yao S, Cui Y, You L-H, et al. Hippocampal iron accumulation impairs synapses and memory via suppressing furin expression and downregulating BDNF maturation. Mol Neurobiol. 2022;59:5574–90.
Jakaria M, Belaidi AA, Southon A, Dent KA, Lane DJ, Bush AI, et al. Receptor-independent anti-ferroptotic activity of TrkB modulators. Int J Mol Sci. 2022;23:16205.
Li X, Hu J, Zang X, Xing J, Mo X, Hei Z, et al. Etomidate improves the antidepressant effect of electroconvulsive therapy by suppressing hippocampal neuronal ferroptosis via upregulating BDNF/Nrf2. Mol Neurobiol. 2023;60:6584–97.
Li X, Chu Y, Ma R, Dou M, Li S, Song Y, et al. Ferroptosis as a mechanism of oligodendrocyte loss and demyelination in experimental autoimmune encephalomyelitis. J Neuroimmunol. 2022;373:577995.
Cataldo AM, McPhie DL, Lange NT, Punzell S, Elmiligy S, Nancy ZY, et al. Abnormalities in mitochondrial structure in cells from patients with bipolar disorder. Am J Pathol. 2010;177:575–85.
Hidalgo C, Núñez MT. Calcium, iron and neuronal function. IUBMB Life. 2007;59:280–5.
Pelizzoni I, Macco R, Zacchetti D, Grohovaz F, Codazzi F. Iron and calcium in the central nervous system: a close relationship in health and sickness. Biochem Soc Trans. 2008;36:1309–12.
Gleitze S, Paula-Lima A, Núñez MT, Hidalgo C. The calcium–iron connection in ferroptosis-mediated neuronal death. Free Radic Biol Med. 2021;175:28–41.
Sousa RA, Yehia A, Abulseoud OA. Attenuation of ferroptosis as a potential therapeutic target for neuropsychiatric manifestations of post-COVID syndrome. Front Neurosci. 2023;17:1237153.
Thirupathi A, Chang Y-Z. Brain iron metabolism and CNS diseases. Adv Exp Med Biol. 2019;1173:1–19.
Almulla AF, Thipakorn Y, Algon AAA, Tunvirachaisakul C, Al-Hakeim HK, Maes M. Reverse cholesterol transport and lipid peroxidation biomarkers in major depression and bipolar disorder: a systematic review and meta-analysis. Brain Behav Immun. 2023;113:374–88.
Jiménez-Fernández S, Gurpegui M, Garrote-Rojas D, Gutiérrez-Rojas L, Carretero MD, Correll CU. Oxidative stress parameters and antioxidants in patients with bipolar disorder: Results from a meta-analysis comparing patients, including stratification by polarity and euthymic status, with healthy controls. Bipolar Disord. 2021;23:117–29.
Capuzzi E, Ossola P, Caldiroli A, Auxilia AM, Buoli M. Malondialdehyde as a candidate biomarker for bipolar disorder: a meta-analysis. Prog Neuropsychopharmacol Biol Psychiatr. 2022;113:110469.
Versace A, Andreazza AC, Young L, Fournier JC, Almeida JR, Stiffler RS, et al. Elevated serum measures of lipid peroxidation and abnormal prefrontal white matter in euthymic bipolar adults: toward peripheral biomarkers of bipolar disorder. Mol Psychiatry. 2014;19:200–8.
Wang J-F, Shao L, Sun X, Young LT. Increased oxidative stress in the anterior cingulate cortex of subjects with bipolar disorder and schizophrenia. Bipolar Disord. 2009;11:523–9.
Brown NC, Andreazza AC, Young LT. An updated meta-analysis of oxidative stress markers in bipolar disorder. Psychiatry Res. 2014;218:61–8.
Sun Y, Chen P, Zhai B, Zhang M, Xiang Y, Fang J, et al. The emerging role of ferroptosis in inflammation. Biomed Pharmacother. 2020;127:110108.
Zhong D, Quan L, Hao C, Chen J, Qiao R, Lin T, et al. Targeting mPGES-2 to protect against acute kidney injury via inhibition of ferroptosis dependent on p53. Cell Death Dis. 2023;14:710.
Rapoport SI. Lithium and the other mood stabilizers effective in bipolar disorder target the rat brain arachidonic acid cascade. ACS Chem Neurosci. 2014;5:459–67.
Yamamoto H, Lee-Okada H-C, Ikeda M, Nakamura T, Saito T, Takata A, et al. GWAS-identified bipolar disorder risk allele in the FADS1/2 gene region links mood episodes and unsaturated fatty acid metabolism in mutant mice. Mol Psychiatry. 2023;28:2848–56.
Jiang Y, Mao C, Yang R, Yan B, Shi Y, Liu X, et al. EGLN1/c-Myc induced lymphoid-specific helicase inhibits ferroptosis through lipid metabolic gene expression changes. Theranostics. 2017;7:3293.
Hashemi M, Ghanbarirad M, Saberi SM, Majd A. Nrf2 dysregulation in major depressive and bipolar disorders. Galen Med J. 2021;10:e2074.
Belvederi Murri M, Prestia D, Mondelli V, Pariante C, Patti S, Olivieri B, et al. The HPA axis in bipolar disorder: systematic review and meta-analysis. Psychoneuroendocrinology. 2016;63:327–42.
Watson S, Gallagher P, Ritchie JC, Ferrier IN, Young AH. Hypothalamic-pituitary-adrenal axis function in patients with bipolar disorder. Br J Psychiatry. 2004;184:496–502.
Fries GR, Vasconcelos-Moreno MP, Gubert C, dos Santos BT, Sartori J, Eisele B, et al. Hypothalamic-pituitary-adrenal axis dysfunction and illness progression in bipolar disorder. Int J Neuropsychopharmacol. 2014;18:pyu043.
Abulseoud OA, Ho MC, Choi D-S, Stanojević A, Čupić Ž, Kolar-Anić L, et al. Corticosterone oscillations during mania induction in the lateral hypothalamic kindled rat—Experimental observations and mathematical modeling. PLoS ONE. 2017;12:e0177551.
von Mässenhausen A, Zamora Gonzalez N, Maremonti F, Belavgeni A, Tonnus W, Meyer C, et al. Dexamethasone sensitizes to ferroptosis by glucocorticoid receptor–induced dipeptidase-1 expression and glutathione depletion. Sci Adv. 2022;8:eabl8920.
Sun F, Zhou JL, Liu ZL, Jiang ZW, Peng H. Dexamethasone induces ferroptosis via P53/SLC7A11/GPX4 pathway in glucocorticoid-induced osteonecrosis of the femoral head. Biochem Biophys Res Commun. 2022;602:149–55.
Courtin C, Marie-Claire C, Gross G, Hennion V, Mundwiller E, Guégan J, et al. Gene expression of circadian genes and CIART in bipolar disorder: a preliminary case-control study. Prog Neuropsychopharmacol Biol Psychiatry. 2023;122:110691.
Tissot N, Przybyla-Toscano J, Reyt G, Castel B, Duc C, Boucherez J, et al. Iron around the clock. Plant Sci. 2014;224:112–9.
Snitow ME, Bhansali RS, Klein PS. Lithium and therapeutic targeting of GSK-3. Cells. 2021;10:255.
Wang L, Ouyang S, Li B, Wu H, Wang F. GSK-3β manipulates ferroptosis sensitivity by dominating iron homeostasis. Cell Death Discov. 2021;7:334.
Wu X, Liu C, Li Z, Gai C, Ding D, Chen W, et al. Regulation of GSK3β/Nrf2 signaling pathway modulated erastin-induced ferroptosis in breast cancer. Mol Cell Biochem. 2020;473:217–28.
Castillo-Quan JI, Li L, Kinghorn KJ, Ivanov DK, Tain LS, Slack C, et al. Lithium promotes longevity through GSK3/NRF2-dependent hormesis. Cell Rep. 2016;15:638–50.
Vosahlikova M, Roubalova L, Cechova K, Kaufman J, Musil S, Miksik I, et al. Na+/K+-ATPase and lipid peroxidation in forebrain cortex and hippocampus of sleep-deprived rats treated with therapeutic lithium concentration for different periods of time. Prog Neuropsychopharmacol Biol Psychiatry. 2020;102:109953.
Jiang X, Teng X, Shi H, Cao L, He L, Gu Q. Discovery and optimization of olanzapine derivatives as new ferroptosis inhibitors. Bioorg Chem. 2023;133:106393.
Liu K, Liu J, Zou B, Li C, Zeh HJ, Kang R, et al. Trypsin-mediated sensitization to ferroptosis increases the severity of pancreatitis in mice. Cell Mol Gastroenterol Hepatol. 2022;13:483–500.
Sun Q, Wang Y, Hou L, Li S, Hong J-S, Wang Q, et al. Clozapine-N-oxide protects dopaminergic neurons against rotenone-induced neurotoxicity by preventing ferritinophagy-mediated ferroptosis. Free Radic Biol Med. 2024;212:384–402.
Hirata Y, Oka K, Yamamoto S, Watanabe H, Oh-Hashi K, Hirayama T, et al. Haloperidol prevents oxytosis/ferroptosis by targeting lysosomal ferrous ions in a manner independent of dopamine D2 and sigma-1 receptors. ACS Chem Neurosci. 2022;13:2719–27.
Cipriani A, Reid K, Young AH, Macritchie K, Geddes J. Valproic acid, valproate and divalproex in the maintenance treatment of bipolar disorder. Cochrane Database Syst Rev. 2013;2013:CD003196.
Kong Q, Li F, Sun K, Sun X, Ma J. Valproic acid ameliorates cauda equina injury by suppressing HDAC2-mediated ferroptosis. CNS Neurosci Ther. 2024;30:e14524.
Kanazawa LK, Vecchia DD, Wendler EM, Hocayen PAS, Dos Reis Lívero FA, Stipp MC, et al. Quercetin reduces manic-like behavior and brain oxidative stress induced by paradoxical sleep deprivation in mice. Free Radic Biol Med. 2016;99:79–86.
Cruz-Gregorio A, Aranda-Rivera AK. Quercetin and ferroptosis. Life. 2023;13:1730.
Bauer IE, Green C, Colpo GD, Teixeira AL, Selvaraj S, Durkin K, et al. A double-blind, randomized, placebo-controlled study of aspirin and N-acetylcysteine as adjunctive treatments for bipolar depression. J Clin Psychiatry. 2018;80:18m12200.
Lv Q, Hu Q, Zhang W, Huang X, Zhu M, Geng R, et al. Disturbance of oxidative stress parameters in treatment-resistant bipolar disorder and their association with electroconvulsive therapy response. Int J Neuropsychopharmacol. 2020;23:207–16.
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Concept: OAA and AY. AY wrote the first draft under the supervision of OAA. LMMB, MCH, JMB and MAF provided critical revision of the manuscript for important intellectual content. Supervision: OAA.
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Yehia, A., Melhuish Beaupre, L.M., Ho, M.C. et al. Ferroptosis as a potential molecular mechanism of bipolar disorder. Transl Psychiatry 15, 205 (2025). https://doi.org/10.1038/s41398-025-03429-w
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DOI: https://doi.org/10.1038/s41398-025-03429-w
