Buse Beril Durdurak1*
Isabel Morales-Muñoz1
Angharad N. de Cates1,2,3Chantelle Wiseman1
Matthew R. Broome1,4
Steven Marwaha1,5- 1Institute for Mental Health, University of Birmingham, Edgbaston, Birmingham, United Kingdom
- 2Coventry and Warwickshire NHS Partnership Trust, Coventry, United Kingdom
- 3Department of Psychiatry, University of Oxford, Oxford, United Kingdom
- 4East Birmingham Early Intervention in Psychosis Service, Birmingham Women’s and Children’s NHS Foundation Trust, Birmingham, United Kingdom
- 5Specialist Mood Disorders Clinic, The Barberry Centre for Mental Health, Birmingham and Solihull NHS Trust, Birmingham, United Kingdom
Difficulties with emotion regulation (ER) are a key feature of bipolar disorder (BD) contributing to poor psychosocial and functional outcomes. Abnormalities within emotion processing and regulation thus provide key targets for treatment strategies and have implications for treatment response. Although biological mechanisms and ER are typically studied independently, emergent findings in BD research suggest that there are important ties between biological mechanisms and the disturbances in ER observed in BD. Therefore, in this narrative review, we provide an overview of the literature on biological mechanisms underlying emotional dysregulation in BD including genetic and epigenetic mechanisms, neuroimaging findings, inflammation, hypothalamic-pituitary-adrenal (HPA) axis dysfunction, neuroplasticity and brain-derived neurotrophic factor (BDNF), and circadian rhythm disturbances. Finally, we discuss the clinical relevance of the findings and provide future directions for research. The continued exploration of underlying biological mechanisms in ED in BD may not only elucidate fundamental neurobiological mechanisms but also foster advancements in current treatment strategies and the development of novel targeted treatments.
Introduction
Bipolar Disorder (BD) is a common and highly debilitating condition with recurrent mood episodes and subsyndromal mood symptoms (1, 2). Most contemporary treatment guidelines are designed around an episodic model of BD, emphasizing the management and prevention of acute episodes (3). However, mood in people with BD is often labile (1) and can fluctuate considerably even when euthymic (4), in contrast to the classical episodic presentation (5).
Emotion Dysregulation (ED) is a multidimensional transdiagnostic construct encompassing a wide range of mental disorders (6). In the literature, the term has been used interchangeably with mood instability, affective lability, affective dysregulation, and mood swings (7–9). Although no agreed-upon definition of the conceptual core of ED exists (10), one definition is that ED is defined as patterns of emotional experience and expression that interfere with goal-directed activity (11). Emotion regulation (ER) strategies are generally classified as adaptive or maladaptive based on their effectiveness and their positive or negative effects on mood (12). Difficulties in managing negative emotions, along with the use of maladaptive coping mechanisms like catastrophizing, self-blame, and rumination, are linked to higher rates of mental health issues (12), including BD (13).
Emotion dysregulation in bipolar disorder
People living with BD may have difficulties in ER across various dimensions regardless of current mood episodes (14). ER difficulties in patients with BD may then result in emotional extremes and mood instability, eventually contributing to the episodic mood states of the condition (15–18). ED contributes considerably to functional impairments and relapse risk (19, 20). For example, ED may increase the severity of manic symptoms and residual depressive symptoms (21). Additionally, people with BD may have difficulties in facial emotion recognition (22), feel emotions more intensely (23) and have stronger elevations of negative emotion as compared to positive affectivity problems (17). ED in BD may also show poor acceptance and differentiation of emotion, as well as difficulties in inhibiting impulsive actions, using appropriate regulation strategies to modulate emotions, and engaging in adaptive behaviours to achieve a desired goal when experiencing negative mood (14). Patients with BD also tend to feel less confident in their ability to use adaptive emotion regulation strategies (24). As such, findings have indicated that in the face of a given emotion state, those with BD report more difficulty controlling their speech and behaviour (23, 25). This phenomenon is known as emotion-related impulsivity (25), and individuals with BD report significantly greater concern about this specific type of impulsivity compared to other forms, even during periods of remission (23). Higher levels of emotion-related impulsivity have been linked to increased suicidality and aggression in individuals with remitted BD I (25). Unsurprisingly, this form of impulsivity is also strongly associated with significantly lower quality of life and poorer functional outcomes in individuals with BD I (23, 26, 27).
Patients with BD may also show decreased emotional reactivity in positive social scenarios, impaired ability to down-regulate positive emotion, as well as a specific deficit in the ability to recognise surprised facial displays of emotion (28). Poor access to ER strategies can predict depressive propensity in BD, while difficulty in controlling impulses may predict trait (hypo)mania (14). More specifically, increased sensitivity to reward and deficient emotion processing and regulation in BD may amplify affect, thereby triggering a spiral into both manic and/or depressive states (29). Many of the facets of emotionality can be observed before onset among those at risk for the disorder (30). Further, recent findings suggest that abnormal ER may serve as an endophenotype for BD (31). Specifically, difficulties with ER are observed not only during acute episodes (32, 33) but also during periods of remission (34), as well as in genetically predisposed, unaffected relatives of individuals with BD (35). Indeed, previous functional magnetic resonance imaging (fMRI) studies have shown abnormal fronto-limbic responses during emotional reactivity and regulation in both BD patients and high-risk groups (36–38). Further, a systematic review found that not only patients with BD but also their unaffected relatives exhibit behavioural and neural difficulties with emotion processing and regulation. This includes impairments in the recognition of facial displays of emotion, reduced ability to successfully down-regulate positive emotions, and increased cognitive interference of emotional stimuli (29).
Emotion dysregulation in bipolar disorder compared to other mental illnesses
When compared to other psychiatric diagnoses, a meta-analysis found that people with BD were quite similar to patients with Major Depressive Disorder (MDD) in both overall ED and adopted ER strategies, although they showed more positive rumination and risk-taking behaviours (13). Patients with BD exhibited a lower degree of ED when compared with Borderline Personality Disorder (BPD) patients, as they adopted more adaptive ER strategies and fewer maladaptive ones (13). A systematic review found that compared to both clinical and non-clinical controls, people with BD may also endorse putatively maladaptive strategies for regulating negative affect such as rumination, self-blame, suppression and catastrophising more strongly than non-clinical controls, but have a similar ER profile to people with unipolar depression (39). The review also found that although dampening positive affect was higher in BD than controls, it did not distinguish BD and MDD (39).
Potential utility of understanding pathophysiological underpinnings of emotional dysregulation in bipolar disorder
Psychiatric diagnoses and symptomatology alone cannot fully capture the complexity of ED in BD, emphasizing the need for broader considerations (40). Contemporary classifications of mental disorders remain primarily based on clinical features (41), leading many individuals with mental illness to transition through multiple diagnostic categories over their lifetime (42). The absence of objective markers to confirm diagnoses often delays accurate treatment and early interventions, as overlapping symptoms (e.g., anxiety, insomnia, low mood, suicidal ideation, impulsivity) are common across various disorders (43). Moreover, these classifications fail to uncover the fundamental mechanisms driving the syndromes (44), underscoring the urgent need for objective biomarkers to refine diagnostic evaluations and predict illness trajectories (45).
BD is a highly heritable condition with a complex aetiology (46, 47). Its onset is thought to result from the interplay between genetic susceptibility and environmental factors that predispose, precipitate, and perpetuate the disorder (46). Emerging research highlights the role of genetics, environmental interactions, and prodromal features preceding episodes of (hypo)mania or depression in BD (48). Evidence suggests that BD involves alterations in numerous biological systems, including disrupted structural and functional brain connectivity (49–51), oxidative stress (52), mitochondrial dysfunction (53), inflammation (54), circadian rhythm disturbances (55), dopamine dysregulation (56), neurotrophic system abnormalities (e.g., elevated brain-derived neurotrophic factor levels), and calcium signaling disruptions (57–59).
Many of these biological mechanisms are also likely contributors to ED in BD. Brain regions critical to ER, such as the prefrontal cortex and limbic system, exhibit altered activation patterns in BD (38). fMRI studies have reported abnormal fronto-limbic responses during emotional reactivity and regulation in individuals with BD and those at high risk (37). Consequently, deficits in affective cognition (i.e., hot cognition) are increasingly recognized as core components of BD’s neurocognitive profile and potential treatment targets (60, 61). Affective cognition encompasses emotionally charged processes such as emotional processing and regulation, perceptual and attentional biases, feedback sensitivity, emotional decision-making, and reward-punishment processing (60, 62). Further, beyond cognition, multiple biological factors influence emotional processes in BD, including genetics (63), epigenetics (64), inflammation (65), hypothalamic-pituitary-adrenal axis dysfunction (66), brain-derived neurotrophic factor abnormalities (67), and circadian disruptions (68, 69).
To advance our understanding of ED in BD, precise definitions and a deeper exploration of its neural, molecular, and genetic mechanisms are essential (4). However, the relationship between BD and ED remains poorly understood. Given the pivotal role of ED in BD, it is imperative to elucidate its biological underpinnings. This narrative review aims to evaluate and synthesise current knowledge on the biological mechanisms involved in ER processes in BD, providing insights into the biological basis of ER in this disorder and identifying avenues for future research and intervention development.
Genetic and epigenetic mechanisms
Genetics
BD involves numerous risk loci, with most lead single nucleotide polymorphisms (SNPs) being noncoding and having small effect sizes (70). Findings so far highlight at least three genes; synaptic plasticity proteins (e.g., ANK3, located on chromosome 10q21.2; 71–73), ion channels (e.g., CACNA1C, located on chromosome 12p13; 74, 75), and TRANK1, a protein of unknown function that resides on chromosome 3p22 (76, 77).
Regarding ED, the genes most associated with this condition have previously been found to be associated with psychiatric disorders including BD (63). For example, a study examining genetic risk associated with ED found an overrepresentation of genes from the calcium signalling pathway and inflammation (i.e., IL2RA), also associated with risk for many psychiatric disorders including BD (63). Likewise, another study investigating genetic factors underlying emotional reactivity in BD patients found an association between ER and genetic variants in BD (78). The strongest associated SNP located in the 11q14 region has been implicated in nervous system development and the functional pathway of calcium ion binding (78). The second SNP retained, rs2064689 in the 1p31 region was located in the intron region of the interleukin 23 receptor precursor gene (i.e., IL23R NM_144701.2), which has also been implicated in inflammatory processes (78).
Epigenetic mechanisms
Histone deacetylase (HDAC) inhibitors have been shown to control epigenetic programming associated with the regulation of cognition and behaviour (79, 80). Genetic association and clinical pharmacology have been used to identify a potential role for HDACs in BD (79). Inhibition of class I or II HDACs can protect neurons from mitochondrial oxidative stress induced damage frequently observed in BD (79, 81, 82). A systematic analysis of GWAS studies found that HDAC2 may be linked to increased genetic risk for BD through its involvement in the development of the amygdala, nucleus accumbens and hippocampus and alterations in these regions could increase BD risk (83). Additionally, pharmacological treatments for BD act on HDACs (64, 84). Specifically, valproic acid has the ability to promote gene expression through inhibition of class I and II HDACs activity and increase of acetylated histone H3 and acetylated histone H4 levels (85–87), lithium downregulates HDAC1 at the translational level by targeting HDAC1 messenger RNA (88), and lamotrigine increases histone acetylation levels in vitro (89). Regarding ED, a study using in vivo imaging of HDAC- specific radiotracers in individuals with BD found that altered levels and activity of HDACs were related to attention and ER, further suggesting a role for HDACs in BD pathophysiology (64).
Structural and functional brain alterations
ER involves complex neural pathways integrating cognitive control and emotional responses (25). These pathways are categorized into implicit (automatic) and explicit (effortful) regulation (90), both of which involve distinct but interconnected brain regions. Individuals with BD exhibit abnormalities in these circuits, contributing to ED (91).
Neuroimaging studies have identified structural and functional abnormalities in BD, particularly within the limbic system (amygdala, hippocampus, and basal ganglia) and the prefrontal cortex (PFC). Meta-analyses of fMRI studies highlight hyperactivity in limbic structures, including the amygdala and hippocampus, alongside hypoactivity in the right inferior frontal gyrus (IFG), a key region involved in cognitive control over emotions (37). Similarly, another meta-analysis examining abnormal brain activation during ER in BD found clusters of hyperactivation in subcortical structures and limbic regions, including the caudate, amygdala, and parahippocampal gyrus, as well as cortical frontal structures such as the precentral and frontal gyri (92). Conversely, hypoactivation was observed in cortical regions such as the anterior cingulate and inferior frontal gyri in response to facial stimuli.
White matter (WM) abnormalities also contribute to ER deficits in BD (93). Studies have reported reduced fractional anisotropy in WM tracts connecting the PFC, dorsolateral PFC (dlPFC), ventrolateral PFC (vlPFC), medial PFC (mPFC), and left parietal cortex. Increased mean and radial diffusivity in the superficial WM of the right frontal cortex further supports structural connectivity disruptions in BD. These findings align with reports of microstructural abnormalities in the corpus callosum and corticospinal tract, both of which are associated with impaired emotional and cognitive functioning (94).
Youth at risk for BD also exhibit altered neural activation patterns during emotional processing (95). For example, increased right rostral anterior cingulate cortex (ACC) activity in response to happy stimuli and heightened amygdala-to-left caudal ACC connectivity in response to fearful stimuli have been observed (95). These findings suggest that neural circuits underlying ER are already compromised before illness onset, reinforcing the role of brain-based markers in identifying at-risk populations.
Overall, research underscores that BD involves widespread disruptions in ER-related neural circuits (25). FMRI studies introduced a new perspective to studying the neural foundations of psychological disorders associated with ER, offering insights into potential variations in brain network dynamics related to mood or cognition, as well as in their regulation by executive control or reward-related functions (4, 96). However, much of the existing literature is correlational, limiting causal inferences. Future studies should focus on elucidating the interplay between brain alterations, ER, and functional outcomes using longitudinal designs (25). Understanding these mechanisms will inform targeted interventions aimed at improving ER in BD (25).
Disruptions in neural circuits involved in ER in BD and other mental health illnesses
Since ED is a transdiagnostic construct, disruptions in neural circuits involved in emotional processing are found across a wide range of conditions (97). For example, a meta-analysis with a transdiagnostic sample identified hyperactivity in the amygdala, hippocampal/parahippocampal gyri, and dorso-medial thalamus, alongside reduced prefrontal cortex activity, not only in BD but also in anxiety, depressive, and substance use disorders, (98). Likewise, another study found common neural variability correlates of ED in the fronto-limbic system in BD, BPD and ADHD (97). Dysfunctions in the prefrontal cortex region has been linked to perseverative negative bias in depression (99), and this region may also contribute to rumination observed across disorders (98, 100).
The ventromedial PFC is a key neural region in social and affective function (101). It is also considered central to the pathophysiology of mood and anxiety disorders (102). For example, a meta-analysis by Hiser and Koenigs (103) examined the associations between different subregions of the ventromedial prefrontal cortex (vmPFC) and psychiatric disorders. Their findings indicated that dysfunctions in distinct vmPFC subregions are linked to various mental illnesses, including BD, major depressive disorder, and post-traumatic stress disorder. Specifically, the study found that addiction, BD, and ADHD-related neural activity overlap with the decision-making subregion of the vmPFC, while PTSD, schizophrenia, and social anxiety disorder exhibit dysfunctions in both the decision-making and social processing subregions. These findings emphasize the role of vmPFC dysfunction in emotional and cognitive dysregulation across psychiatric conditions (98, 103–105).
On the other hand, notable differences between disorders may reflect underlying psychopathological distinctions. For example, the previously mentioned meta-analysis above (98) found that while hyperactivity in the amygdala, hippocampal/parahippocampal gyri, and dorso-medial thalamus, alongside reduced prefrontal cortex activity was observed in BD, anxiety, depressive, and substance use disorders, there were also differences, suggesting that therapeutics tuned to specific disruptions within the network may be preferentially effective for some neurobehavioral phenotypes. They found that while anxiety disorders were marked by pronounced amygdala/hippocampal hyperactivation, whereas BD was marked by ventrolateral prefrontal cortex hypoactivation, unipolar disorders by amygdala hyperactivation, and substance use disorders by ventrolateral prefrontal cortex hypoactivation.
The challenge of differentiating between BD and MDD in clinical settings has prompted researchers to identify differences in the pathophysiological mechanisms underlying BD and MDD (106). While both patients with MDD and BD exhibit predominantly decreased fronto-limbic connectivity (107), their disorder-specific pathophysiological mechanisms may differ (33). For example, different activation patterns in neural networks including the amygdala, ACC, PFC, and striatum during emotion-, reward-, or cognition-related tasks have been reported between BD and MDD (108). More specifically, a stronger functional connectivity pattern in BD was pronounced in default mode and in frontoparietal networks and brain regions including the PFC, ACC, parietal and temporal regions, and thalamus compared to MDD. Lastly, BD showed reduced integrity in the anterior part of the corpus callosum and posterior cingulum compared to MDD. Another fMRI study investigating ER differences in medication-free patients with MDD and BD revealed that these differences are mood-state dependent (109). During remission, patients with BD, but not those with MDD, exhibited impaired ER across emotions, which was associated with increased dorsolateral PFC activity. However, during depressive episodes, MDD and BD patients differed in their ER of happy versus sad emotions. BD patients in a depressive phase demonstrated normal ER for happy stimuli but impairments for sad stimuli, whereas MDD patients rated sad pictures as less negative and happy pictures as less positive than BD patients. These ER differences were linked to activity in the dorsolateral PFC and rostral ACC.
Similar to the overlap between BD and MDD, BD and BPD share neuroimaging findings in addition to behavioural similarities (110). Shared features include aberrant connections between limbic regions and the PFC (111–113), reduced brain glucose metabolism in the brainstem, insula, and frontal white matter (114), gray matter alterations (115), and dysregulation of the HPA axis (116–119). Despite these similarities, key differences exist. For instance, a recent study found that patients with BPD had significantly increased WM components mostly regions in the left parietal and frontal lobes (120). This white matter component largely overlaps with the network involved in top-down cognitive control of emotions (121–124). The authors suggest that the increased white matter component in BPD may reflect attempts by these patients to exert control over their emotional reactions (120).
Lastly, BD and ADHD are neuropsychiatric disorders with a broad overlap in psychopathology, and possibly, pathophysiology (125). Both disorders are highly comorbid (126), and share several common symptoms, including impulsivity, psychomotor agitation, poor sleep, and cognitive impairments, including inattention and distractibility (125). The cognitive deficits observed in BD and ADHD follow a similar pattern across multiple cognitive domains (125), though their severity and presentation may vary between individuals (127, 128). Regarding ED, brain regions implicated in ED in BD are also implicated in ADHD (46, 129) including reduced gray matter volumes in the right insula and ACC (130). However, some neurobiological differences have been reported. For instance, ADHD patients exhibit reduced activation in the ventrolateral prefrontal cortex (VLPFC) compared to healthy controls (HC) and paediatric BD patients (131). Similarly, youth with bipolar spectrum disorders display abnormally heightened functional connectivity between the amygdala and regions of the ventral prefrontal cortex during emotion processing, a pattern not observed in youth with ADHD or HC (132). Furthermore, adolescents with BD show increased connectivity between the affective and ventral attention networks, as well as within the attention network, compared to those with ADHD (133).
Future studies should investigate whether altered functional connectivity serves as an endophenotype of BD and whether it can help identify youth with externalizing symptoms who may later develop bipolar spectrum disorders (132).
Overall, these differences suggest that while pleiotropy and inadequate validity of diagnostic categorization remain challenges in psychiatry, the multifactorial nature of causation leaves room for unique combinations of causal factors contributing to each disorder (42).
Investigating the effects of lithium on disturbances in limbic and emotion regulation circuits
Lithium has long been considered a key and gold-standard pharmacological treatment for BD (134, 135). However, the specific processes through which its therapeutic effects such as mood stabilisation are affected and maintained remain unclear (136, 137). Structural neuroimaging studies in patients with BD have suggested that treatment with lithium normalizes or increases gray matter volume in the anterior cingulate, subgenual cingulate cortex, amygdala and hippocampus, which are brain regions involved in ER (138, 139). Recent research investigating lithium’s effect on ER in BD (15) found that lithium’s effect on active reappraisal and emotional processing of negative images was seen in areas of the fronto-parietal and limbic network, and in superior and medial temporal structures. Further, they found that within the fronto-parietal network, lithium decreased activation in prefrontal areas (left anterior PFC or rostra-lateral PFC, and right superior frontal gyrus) and posterior parietal areas (left angular gyrus), during reappraisal. There were also connectivity changes within prefrontal and limbic areas following lithium administration. Further, response to lithium treatment in paediatric BD was associated with normalization of white matter microstructure in regions associated with emotion processing (140). Likewise, a study examining how treatment with quetiapine or lithium impacts limbic and ER brain circuitry in youth with BD found both treatments had a normalizing effect on brain function, although quetiapine induced a more rapid and widespread normalization of brain function (141). Lastly, a review examining fMRI studies evaluating the impact of lithium on brain functional activity and connectivity in patients with BD found that selective abnormalities in neural circuitries supporting emotional processing and regulation improve during lithium treatment in BD (142). However, further research is needed to understand the connection between ER circuitry and the therapeutic action of lithium in BD. Investigating the regional neurophysiological effects of antimanic treatments can offer insights into the mechanisms underlying their clinical efficacy at the systems level (141). This understanding may also inform strategies for testing new compounds and, in the long term, support clinical decision-making regarding the initiation or adjustment of therapeutic interventions (141).
Inflammation
Inflammation is a complex biological process involving cytokine cascades, immune cell responses, and elevated levels of acute-phase proteins and complement factors (59). Increasing evidence indicates that chronic, low-level inflammation in the body and brain (i.e., neuroinflammation) contributes to the pathophysiology of BD (143, 144), both as a state and a trait feature (48, 145) and can worsen the disease progression (146). The connection between BD and inflammation is further supported by shared genetic polymorphisms and gene expression patterns (147).
Chronic inflammation also impacts brain functions, such as the monoaminergic system, which plays a role in ER (78). A systematic review found that difficulty regulating emotion was associated with elevated inflammatory markers, while effective ER was linked to lower inflammation levels (148). Specifically, use of cognitive reappraisal has been associated with lower levels of C-reactive protein (CRP; 149) and interleukin-6 (IL-6; 150) whereas increased inflammation, specifically CRP, tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ), have been linked with routine expressive suppression use (149, 151–153). Negative self-referential processes (e.g., self-criticism, negative thoughts, and rumination) have also been linked to altered peripheral inflammatory markers and cortisol responses in healthy adults (148, 154–156).
Regarding ED in BD, research suggests that inflammation can affect brain structures, which might lead to a dysregulated stress response and, possibly, to ED disorders such as BD (110, 157). While the causal relationship between inflammation and brain imaging abnormalities in BD remains uncertain (65), inflammation’s neurotoxic effects may impair neural circuits involved in ER, reward processing, motivation, emotional control, and cognition (158–161). For example, higher inflammatory biomarkers have been identified in BD patients’ left hippocampus (162) and higher soluble IL-6 receptor levels were associated with increased functional connectivity between the medial PFC and several subcortical limbic structures, including the amygdala, pallidum, hippocampus, and insula (163). Moreover, high-sensitivity CRP has been proposed as a potential objective marker of ER difficulties in BD (164). In one study, remitted BD patients with emotional hyper-reactivity exhibited higher levels of low-grade inflammation (e.g., high-sensitivity CRP), hypertension, impaired glucose metabolism, and a greater number of suicide attempts compared to those without hyper-reactivity (165). Elevated high-sensitivity CRP levels were also observed in BD patients with emotional hypo-reactivity (164).
Evidence from neuroimaging studies further supports the role of fronto-limbic network disruptions in ER difficulties associated with BD (166), including abnormalities in WM microstructure (15). Studies also show an association between neuroinflammation (e.g., circulating pro-inflammatory cytokines) and WM integrity (167). The balance of immune cell subsets, such as T cells and cytokine-producing natural killer cells, may be crucial for maintaining the brain’s structural and functional integrity in BD (168), while also contributing to the chronic low-grade inflammation observed in the disorder (169). For example, circulating natural killer cell counts, and particularly cytokine-producing natural killer cells, positively associated with Diffusion Tensor Imaging (DTI) measures of WM integrity and corticolimbic functional response and connectivity during emotional processing (170). More specifically, the study found an effect of CD56+TNFα+, CD56+INFγ+, and CD56+GMCSF+ on functional connectivity and response in brain regions which exert a crucial role in defining emotional experience and mood control such as dorsolateral pre-frontal cortex, hippocampus, precuneus, cuneus and amygdala connections with parahippocampal gyrus and temporal pole (93, 170). Lastly, they found a positive effect of lithium on cytokine-producing natural killer cell counts (170), which may in return reduce ED (15).
Although the connection between inflammation and ED in BD requires further exploration, preliminary evidence suggests a relationship between specific inflammatory markers and both behavioural changes and neuroanatomical alterations in regions involved in ER (157). Utilising biomarkers during the early stages of BD may aid in diagnostics and provide potential therapeutic avenues (171). Notably, anti-inflammatory treatments have shown promise in alleviating BD symptoms, particularly depressive symptoms (172–175). Additionally, antipsychotics and lithium have been observed to reduce the expression of several inflammatory genes, which are more frequently upregulated in monocytes from BD patients and their offspring than in healthy individuals (176, 177). Further research exploring the interplay between inflammation and ER in BD, particularly through longitudinal studies incorporating multiple timepoints, is warranted (110). Evaluating dimensions related to ER (e.g., levels of emotional reactivity) alongside accessible biomarkers such as blood pressure, CRP, and glycaemia, in addition to monitoring mood symptoms in BD patients, may help implement interventions more aligned with the underlying pathophysiology of BD (178). Finally, psychosocial interventions targeting inflammation through ER skills, such as cognitive-behavioral therapy and mindfullness, may serve as effective strategies for symptom management (148, 179).
Hypothalamic-pituitary-adrenal axis dysfunction
Hypothalamic–pituitary– adrenal axis (HPA) is one of the main biological systems involved in response to stress and shaping the central nervous system (CNS) structures along the lifespan (180). Chronic stress and HPA axis dysregulation can disrupt inhibitory control, leading to heightened emotional responses (181). HPA axis dysregulations are also considered to play a major role in the pathophysiology and progression of BD (182). For example, state and trait hyperactivity of the HPA axis is associated with BD and abnormalities of glucocorticoid signalling are found in several key brain areas which in return may contribute to ED observed in BD (180). Disturbance in the HPA axis could also increase treatment resistance and relapse, worsen illness outcome, cause cognitive deficits and exacerbate depressive symptoms (183).
The link between ER and HPA-axis function has not been extensively investigated. Some research, however, indicates that positive ER strategies, such as problem-solving, are associated with lower cortisol levels over time (184) and with increased immediate cortisol responses (185, 186). It is still uncertain whether HPA-axis dysfunctions in BD are directly related to issues with ER (66). However, trauma experienced in childhood or later in life may influence both HPA-axis function and ER abilities (66). Both childhood trauma and chronic stress have been associated with dysregulations of the HPA axis (187) and alterations across various stages of ER (66), including emotion-related attentional biases and reward processing disturbances (188, 189).
Childhood trauma also plays a pervasive role in the development and course of BD (190, 191). For example, individuals with BD report higher rates of ED and individuals with BD who report childhood trauma also endorse higher rates of ED and impulsivity compared with those without trauma histories (191–193) and show poor response to lithium (192, 193). Less genetic risk may be needed to develop a more unstable form of BD when exposed to childhood maltreatment (194). This may suggest that some ER patterns seen in individuals with BD may not be unique to BD but could instead reflect the effects of early trauma (66) as childhood adversity, particularly emotional abuse, is associated with affective lability and ER in adulthood across psychiatric disorders (195). Research further suggests that childhood trauma, particularly emotional abuse, is associated with increased affective instability and less adaptive ER in BD (196–198). This could explain the relationship between childhood trauma and poor BD outcomes (191). Thus, it is important to consider contextual factors such as trauma that might contribute to the overlap between biological mechanisms (e.g., HPA-axis dysfunctions) and ER difficulties in BD before concluding that biological mechanisms are truly a central driver for other outcomes (25). Future research on BD-specific ER should account for the influence of early trauma, which may have either an additive effect or an interactive one, where childhood trauma combined with a genetic predisposition to BD shapes distinct ER patterns (66).
Neuroplasticity and brain-derived neurotrophic factor
Brain-derived neurotrophic factor (BDNF) is a multifunctional neurotrophin with numerous functions in the brain such as neuronal plasticity and maintenance of the CNS (199), modulating reactivity to stress (200, 201). BDNF has been implicated in the pathophysiology of several psychiatric disorders (202), including BD (203, 204) even in at-risk stages (205). Research shows that the pattern of neurotrophin expression during mood episodes changes (206–208). For example, serum BDNF levels decrease during manic and depressive episodes in both treated and drug-free subjects when compared to normal controls and to unipolar depression (209). In relation to ER in BD, BDNF could serve as an objective marker for assessing ER interventions in BD (210).
One of the functional SNP of the BDNF gene in humans is in exon 11 and results in an amino-acid substitution from valine (Val) to methionine (Met) at codon 66 (rs6265, also known as Val66Met). Associations have been reported between ED and the 66Met allele of the BDNF, which is associated with reduced amygdala habituation to emotional stimuli during fMRI (211). Abnormal neural responses of amygdala networks during habituation to repeated emotional stimuli may be a putative endophenotype of psychiatric disorders characterized by ED (211). The Met allele may also interact with childhood abuse to predict an impaired ability to downregulate negative affect (212). Patients with BD who carry the Met allele at the BDNF Val66Met polymorphism have been shown to be more likely to develop depressive episodes following stressful life events than Val allele homozygous (67).
Chrono-rhythmic disturbances
Circadian rhythm disturbances are integral to the pathophysiology of BD (213). For example, many circadian genes have previously been associated with BD, including ARNTL1, CLOCK, NPAS2, NR1D1, PER3, RORB, TIMELESS (214–218). In addition, some evidence suggests that genes involved in circadian rhythm regulation (e.g., CRY1 variants) may be associated with increased risk of relapse of depressive episodes in patients with BD (219). Disruptions in sleep-wake cycles, social rhythms, and hormonal fluctuations can also significantly influence ER (220).
The role of the suprachiasmatic nucleus
Many individuals with BD have circadian rhythm alterations of sleep-wake, activity, melatonin, and other hormones even in euthymic periods (221). Circadian rhythms (e.g., sleep/wake cycles, body temperature control, and the release of neurotransmitters and hormones) are produced and coordinated by a central biological clock, the SCN, which is located in the anterior hypothalamus (222). Dysregulation in these rhythms can stem from enduring disruptions within the SCN’s own pacemaking functions or from impairments in how the SCN aligns with external cues (223). Although weakly, multiple SNPs in the genes encoding the core components of the molecular clock have been demonstrated to be associated with schizophrenia, BD and MDD, suggesting a causal role for clock dysfunction in psychiatric disorders (224). Furthermore, when individuals with or at-risk for BD experience life events that alter their daily routines or social rhythms (e.g., changes in sleep, meals, or work schedules), these disturbances can unsettle their circadian patterns, triggering physical symptoms that may eventually escalate into mood episodes (68).
Sleep-wake cycles
Delayed sleep-wake and activity patterns are commonly seen in the depressive phase of BD (55, 225–229), particularly in adolescents and young adults (226, 227, 229–231). Changes in sleep phase, structure and duration are also reported across all mood states in BD (232). Several studies using an interview-based assessment of biological rhythm disturbances including sleep and activity have reported that young adults with BD have greater biological rhythm disruption than healthy controls (233, 234).
Chronic sleep disruption including insomnia would lead to ER as a result of diminished cognitive functioning by affecting frontal brain regions and diminishing control over executive functions (235–237). For example, people suffering from insomnia show dysfunctions in the neural circuitry underlying ER (238–240) and impairments in both basic cognitive functions and higher-order cognitive processing involved in supervisory control, problem solving, flexibility and self-control (241, 242). As such, insomnia is frequently seen in BD (243–246) and related to emotional hyper-reactivity during remitted phases (247, 248). Further, a cross-sectional study assessing the potential association between insomnia, ED and suicidality in subjects with BD found that insomnia symptoms significantly predicted the severity of depressive symptoms, ED, and suicidality in subjects with BD (69).
Evening chronotype
Morningness-eveningness, or chronotype, reflects individual variations in diurnal preferences (249). The evening chronotype appears to be independently linked to ER, regardless of factors like sleep quality, duration, timing, or debt (250). For instance, individuals with a morning chronotype report fewer attentional and emotional difficulties, supported by evidence at the brain structural level (251). Additionally, research investigating the association between later chronotypes and amygdala reactivity to negative (e.g., fearful) facial expressions found that evening chronotypes exhibit heightened amygdala responses to negative stimuli and reduced dorsal ACC-amygdala functional connectivity (249). This suggests impaired ER circuitry independent of sleep quality, depression diagnosis, and family history (249). Additionally, research shows a negative bias in emotion processing in late chronotypes and increased difficulty in anger and sadness recognition for expressive suppressor morning-types, highlighting further the importance of chronotype as a relevant variable in ER and emotional functioning (252).
Studies consistently show that individuals with BD are more likely than healthy controls to display an evening chronotype, characterized by a preference for later sleep, wakefulness, and activity patterns (55, 225). This relationship is corroborated by findings using objective chronotype measures, such as actigraphy (253, 254). The evening chronotype is thought to have a genetic basis, as evidenced by heritability studies (255, 256). While disrupted circadian rhythms and evening chronotypes are commonly observed in BD, their specific roles in mood episodes or emotionality remain uncertain (55). However, chronotype has been proposed as a potential biomarker for lithium treatment response in BD (257, 258).
Lithium may exert its mood-stabilizing effects partially through modulating the circadian system (43), as alterations in circadian CLOCK genes have been implicated in lithium response (259, 260). Notably, lithium has been shown to extend the circadian period and enhance circadian rhythm amplitude (261). More specifically, lithium inhibits glycogen synthase kinase-3 beta, which phosphorylates and stabilizes the circadian nuclear receptor rev-erbalpha (262) and rev-erbalpha influences mood regulation through circadian control of the dopaminergic system (263, 264). These finding may suggest that targeting circadian mechanisms could be a key avenue for improving ED in BD.
Clinical relevance of the findings
Assessment
ER difficulties may be detected as part of a standard clinical psychiatric assessment. Specific tools such as the Difficulties in Emotion Regulation Scale (DERS) and the Affective Lability Scale (ALS) may also be used to assess emotional reactivity and poor emotional clarity at individual time points (265). However, digital tools such as ecological momentary assessment (EMA) allow real-time tracking of emotional states and therefore can provide insights into dynamic fluctuations that may be missed with traditional tools (266). Behavioural neuropsychological assessments, particularly those relating to executive function, can be used to further clarify cognitive impairments associated with emotional dysregulation (267). Neuroimaging and physiological measures like heart rate variability, may also potential as adjunctive methods for assessment, although these are not used widely in clinical practice (267).
Treatments
Psychotherapeutic interventions, such as Dialectical Behaviour Therapy (DBT) and Cognitive Behavioral Therapy (CBT), teach skills such as mindfulness, distress tolerance, and cognitive restructuring that may help to support emotional regulation in patients with BD (268). Emotion-focused therapies, such as emotion regulation group therapy (ERGT), have specifically shown efficacy in reducing emotional reactivity, but this modality is less widely available (268).
Pharmacological treatments, including mood stabilizers like lithium and valproate, may be pivotal in managing ED. As discussed before, lithium, not only stabilises mood but also appears to modulate neural circuits involved in ER, including the prefrontal cortex and amygdala (134). It has been shown to reduce emotional lability, impulsivity, and aggression, providing long-term protection against mood destabilization (134). Likewiese, Valproate, a commonly-used mood stabiliser in BD, enhances gamma-aminobutyric acid (GABA) activity in the brain, which reduces hyperactivity in ER pathways (269), mitigating emotional reactivity and impulsivity. However, recent UK MHRA guidance on valproate is limiting its ongoing use in both males and females of reproductive age (MHRA 2024). Nonetheless, these medications, often used in combination with psychotherapeutic approaches, continue to play a critical role in improving ER and preventing relapse. Furthermore, emerging technologies, such as smartphone-based interventions and virtual reality platforms, show promise as novel supportive therapies to enhance ER assessment and management (269), which will be discussed further in detail in “Future Directions”.
In addition to the psychotherapeutic and pharmacological treatments, there is growing interest in the ketogenic diet as a treatment for BD (270, 271). This is due to BD being recognised more as a disorder of energy dysregulation (272) and mitochondrial dysfunction (59). However, although evidence for mitochondrial dysfunction in BD is well-established, the genetic association of mitochondria with BD remains weak (79). This implies that mitochondrial dysfunction may act as an intermediate phenotype shaped by other causal risk factors, including environmental influences, infections, and drug exposure, rather than being a direct result of genetic factors (79).
Ketogenic diet may improve metabolic and biochemical features of BD (271) such as reduction in oxidative stress and inflammation, improved mitochondrial function and biogenesis, improved glutamate/GABA transmission and reductions in intracellular sodium and calcium (273), increase of BDNF (274), reduction of BMI and control of obesity (275) and regulation of mood (276). Thus, the ketogenic diet presents a promising avenue for exploring dietary interventions as potential therapeutic strategies for BD, providing an opportunity to assess its effects within specific domains of psychopathology such as cognition and mood (270). A comprehensive understanding of how the ketogenic diet can ameliorate mitochondrial function, related gene expression, reward neural network, dopaminergic and GABAergic neurotransmission abnormalities in BD is also crucial to help guide personalized interventions and provide targets for novel therapies for BD (79).
Future directions
Digital phenotyping
Diagnosis in BD have centred on identifying episodes, with clinical outcomes often reduced to a binary approach (4). This approach is particularly problematic in BD, where mood can vary significantly, often in both directions, within any given evaluation period (4). A potential solution involves implementing more frequent and real-time mood assessments (e.g., ESM/EMA). Leveraging new technologies can enhance our ability to capture mood and mental state data with greater efficiency and accuracy, and it can push BD research beyond a sole focus on psychopathology by incorporating physiological, behavioural, and environmental data (4). For example, actigraphy has been used to derive objective measures of sleep characteristics (277, 278). An actigraphy study examining the interactive relationships among impulsivity, sleep disturbance, and circadian rhythm disturbance as predictors of mood symptoms in a high-risk and recent-onset BD sample found that less total actigraphic sleep time predicted more next-day depressive symptoms (220). Longer total sleep time was associated with fewer next-day hypomanic symptoms when participants had low, but not high, behavioural impulsivity. Additionally, for participants with high self-reported impulsivity, later dim light melatonin onset time was associated with higher next-day depressive symptoms. Another study looking at rest-activity cycles in euthymic BD patients found patients who presented with unstable rest-activity cycles had delayed sleep-wake timing and greater mood variability, and younger age (279). Lastly, patients who had later/irregular rest-activity patterns had greater lifetime manic-hypomanic and depressive symptoms (228).
Actigraphy has also been used in 24-hour patterns of motor activity (280), sedentary behaviour (281), and physical activity or exercise (282). A case-control study of 242 patients with BD found bidirectional associations between motor activity with subjectively rated energy level and sleep duration as well as unidirectional associations between motor activity and mood level (283). Further, a systematic review looking at motor activity patterns in patients with BD and MDD found lower mean activity (284, 285). In addition, patients with BD and MDD with lower amplitude of the 24-h rest-activity rhythm report greater mood instability (286).
Widespread availability of connected and wearable devices (e.g., smartphones) had led to digital phenotyping based on high-resolution measurement of remotely captured data streams (287). Given that the primary characteristic of BD is a biphasic energy shift, monitoring the corresponding phasic dysregulation in mood, sleep, and behaviour is gaining attention (288). This comprehensive approach may uncover biological correlates and, ultimately, the underlying mechanisms of the disorder, such as ED. Digital technologies for example in metabolomics, with further exploration, may also assist in moving towards more personalised and stratified healthcare approaches (289).
Measurement issues
Previous studies using subjective measures of ER have generally not identified any abnormalities in patients with BD (35, 266, 290, 291). This may be due to the limited sensitivity of the self- report measures used (292). While neuroimaging is a sensitive method for detecting subtle neural changes during ER, it is not practical for diagnostic evaluations in routine clinical practice (292). Therefore, there is a need for research into improved, cost-effective measures with sensitivity to detect abnormalities in the reactivity to and regulation of emotions in BD to use in diagnostic evaluations in routine clinical practice (292). A multidisciplinary approach combining subtle behavioural measures (e.g., eye-tracking and facial expressions) with subjective responses during emotion reactivity and regulation may offer a more sensitive and cost-effective alternative for detecting aberrant ER in BD (292). Supporting this, a study investigating trait-related abnormalities in emotional reactivity and regulation in BD using novel behavioural measures, such as facial expressions and eye movements, found subtle differences in visual gaze patterns and facial displays of emotion between remitted BD patients and healthy controls during emotion processing and regulation (292). The authors suggest that these subtle differences in visual gaze and facial expressions may provide sensitivity comparable to neuroimaging techniques, while being less costly and more feasible for clinical applications. Further, evidence from fMRI studies is often inconsistent (60). On the contrary, studies using eye‐tracking methodology revealed relatively consistent abnormalities such as oculomotor abnormalities including slower inhibitory control during facial emotion processing in remitted and symptomatic patients (293–295). The consistency within eye-tracking studies may suggest that this may be a sensitive measure to detect subtle behavioural differences in ER, particularly implicit ER (60).
The need for longitudinal data
To determine whether an etiological mechanism precedes the development of ED in BD, the biomarkers should be assessed before the development of BD. Thus, prospective studies investigating biomarkers underlying ED in BD before the onset of the first episode are necessary. This is crucial also because there is a lack of reliable disease biomarkers in BD (296, 297) and this is partly due to the cross-sectional nature of the biomarker studies (298). The results can help develop novel treatments (e.g., preventive emotion-based treatments) that aim to improve emotion resilience in at-risk individuals by enhancing their emotional knowledge, and regulation which in return delay the onset of the disorder or reduce the severity of pathological affective states and ED (29, 299). The identification of specific endophenotypes (e.g., aberrant ER and emotion and reward processing) that reflect underlying pathophysiological processes could later be implemented in the clinical assessments to improve future diagnostic discrimination between UD and BD (29). However, despite the need for large cohort studies, obtaining funding has been a hurdle (300). Many cohort studies (e.g., Iowa 500, STEP- BD, EMBLEM, WAVE-BD, the Stanley Foundation Network, FACE-BD, CIBERSAM) were limited in time due to short-term funding, missing the opportunity of following the participants over a long time (300). Therefore, the creation of an international early BD data network could coordinate international big data approaches and integrate with real-world clinical interventions (298). In addition to the promising “Big Data” and machine learning approaches, there is also a need for an overarching theoretical framework (301). Recently, Mansur et al. (301) proposed a comprehensive disease model of BD. According to the model, disruptions in the network that regulates energy homeostasis, within its paths and/or nodes, leads to “BD-like phenomena” and a “BD-like clinical trajectory”, applying the equifinality principle and the “homeostatic property cluster” concept (301). This disease model could also be tested longitudinally in its relation to ED in BD as research showed that subjective mood in BD is directly affected by subjective energy and objectively measured activity (283).
Conclusions
ED is a transdiagnostic construct observed in individuals with BD and is significantly correlated with its symptomatology (40). While ED is recognized as a transdiagnostic dimension and a potential target for personalized interventions, it is essential to delineate the aspects of ED that are specific to BD versus those shared with other psychiatric disorders (13). Various biological mechanisms, including altered structural and functional brain alterations, inflammation, HPA axis, dysfunction, genetics and circadian rhythm disruptions, have been linked to ED in BD. Despite this, ER has often been studied independently of these biological underpinnings. Given the strong evidence connecting biological mechanisms to ER difficulties in BD, adopting a more integrative perspective is both timely and necessary.
If robust evidence supports the hypothesis that biological mechanisms underpin emotional difficulties in BD, it could offer a novel framework for understanding and treating these challenges (25). However, no biomarker for BD has yet demonstrated sufficient robustness, specificity, or clinical utility for diagnostic or therapeutic use (302). This gap in understanding the pathophysiology of BD and the lack of reliable biomarkers have constrained clinical practice to a trial-and-error approach (303). To address these limitations, larger-scale and more comprehensive studies are needed to generate conclusive results and identify potential clinico-pathological correlates and subgroups within BD (302). Longitudinal, international cohort studies with repeated multiple biomarkers that integrate peripheral blood measures, electrophysiology, neuroimaging and cognitive neuroscience, coupled by deep clinical phenotyping may overcome current methodological problems in biomarker studies in psychiatry (296).
Integrating advanced biomarker research with investigations into emotional processes in BD could promote a more holistic understanding of functionality and vulnerability, ultimately informing novel treatment interventions (25). Such research may also facilitate the development of a new biological model of emotion in BD, focusing on the interaction of various biological systems involved in both voluntary and automatic processes of ER. This model could not only elucidate the biological basis of ER in BD but also be extended to youth at risk for BD, enabling earlier interventions and preventive strategies. Furthermore, exploring how ER difficulties respond to targeted biological interventions, such as treatments addressing inflammation or cognitive impairments, could clarify the directional relationship between biological factors and ER in BD. This knowledge has the potential to significantly advance the understanding and treatment of ED in BD (25).
Author contributions
BBD: Conceptualization, Methodology, Project administration, Writing – original draft. IMM: Conceptualization, Methodology, Supervision, Writing – review & editing. AC: Conceptualization, Methodology, Supervision, Writing – review & editing. CW: Conceptualization, Methodology, Supervision, Writing – review & editing. MRB: Conceptualization, Methodology, Supervision, Writing – review & editing. SM: Conceptualization, Methodology, Supervision, Writing – review & editing.
Funding
The author(s) declare that financial support was received for the research and/or publication of this article. All authors are supported by National Institutes of Health and Research (NIHR) Mental Health Translational Research Collaboration. MRB is also supported by Wellcome Trust (Grant Ref: 226603/Z/22/Z). The views expressed are those of the author(s) and not necessarily those of the NIHR, the Department of Health and Social Care or the Wellcome Trust. The funding organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Generative AI statement
The author(s) declare that no Generative AI was used in the creation of this manuscript.
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Keywords: bipolar disorder, emotion regulation, biological, mechanisms, underlying
Citation: Durdurak BB, Morales-Muñoz I, de Cates AN, Wiseman C, Broome MR and Marwaha S (2025) Underlying biological mechanisms of emotion dysregulation in bipolar disorder. Front. Psychiatry 16:1552992. doi: 10.3389/fpsyt.2025.1552992
Received: 29 December 2024; Accepted: 28 March 2025;
Published: 09 May 2025.
Edited by:
Trine Vik Lagerberg, Oslo University Hospital, NorwayReviewed by:
Adrian Andrzej Chrobak, Jagiellonian University, PolandMargherita Barbuti, University of Pisa, Italy
Copyright © 2025 Durdurak, Morales-Muñoz, de Cates, Wiseman, Broome and Marwaha. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Buse Beril Durdurak, Yi5kdXJkdXJha0BiaGFtLmFjLnVr