Circadian rhythm disruption in bipolar disorder: Mechanisms, clinical significance, and rhythm-oriented interventions

Abstract

Circadian disruption is not merely a common symptom of bipolar disorder (BD) but also serves as a pivotal driver in its pathophysiology. Grounded in the “gene-brain-behavior-environment” multidimensional interaction model, this review established an integrative framework to examine recent advances across molecular, physiological, behavioral, and social scales. We systematically delineated the critical role and clinical significance of circadian disruption in the pathogenesis of BD and assessed the therapeutic potential and prognostic benefits of rhythm-oriented interventions. Future research should deepen the understanding of the network regulatory mechanisms underlying circadian rhythms in BD to foster the translational application of related therapeutic strategies in the prevention and treatment of psychiatric disorders.

Key Words: Bipolar disorder; Circadian rhythm disruption; Pathophysiological mechanisms; Therapeutic strategies; Psychiatric disorders

Core Tip: Based on the multifaceted role of circadian rhythm disruption in bipolar disorder, this review explored its underlying mechanisms and clinical implications. It highlighted rhythm-oriented interventions as emerging tools for refining diagnosis, improving treatment, and advancing precision psychiatry, ultimately aiming to improve long-term outcomes for patients with mood disorders.

INTRODUCTION

Bipolar disorder (BD) is a mood disorder with high rates of recurrence and disability and is characterized by alternating episodes of depression and mania or hypomania[1]. Beyond these core symptoms BD leads to broad functional impairments across multiple dimensions, including declines in mental health, cognitive dysfunction, and occupational and social difficulties[2,3]. At the same time BD markedly elevates the risk of premature death. Life expectancy is shortened by 12-14 years compared with the general population, the suicide rate is approximately 64 times higher, and mortality from cardiovascular disease and the prevalence of metabolic disorders are significantly increased[4].

Globally, the disease burden of BD continues to rise. The Global Burden of Disease study reported that globally the number of new cases of BD increased from 3.06 million to 4.53 million between 1990 and 2017, representing a 47.74% growth. Meanwhile, BD accounted for 9.29 million disability-adjusted life years. These figures indicate a continuous rise in the number of incident BD cases and underscore that BD has become a major public health challenge[5]. Current treatments for BD are diverse, encompassing both pharmacological and psychosocial strategies. Nevertheless, its core pathophysiology remains incompletely defined, and treatment responses vary substantially across individuals. Achieving sustained favorable outcomes remains challenging and is reflected in limited efficacy, prominent adverse effects, and complex treatment regimens[6-8].

Growing evidence indicates that circadian rhythm disruption may be a common clinical manifestation of BD as well as one of its core pathophysiological mechanisms[9,10]. We propose that rhythm dysregulation plays a causal role in the development and progression of BD rather than being a mere epiphenomenon. On this basis we propose a multidimensional interactive model that integrates gene, brain, behavior, and environment to explain how the circadian system through dynamic interactions with genetic susceptibility, neural circuitry function, behavioral patterns, and environmental factors drives the disease course of BD.

The circadian system is the key physiological mechanism that maintains synchrony between internal rhythms and the external environment. Its central structure is the suprachiasmatic nucleus (SCN) of the hypothalamus, which functions as the master pacemaker. SCN neurons possess intrinsic, cell-autonomous oscillatory capacity, and distinctive coupling mechanisms that sustain strong internal synchrony, thereby coordinating physiological and behavioral rhythms throughout the body[11,12]. At the molecular level the rhythm is driven by transcription and translation feedback loops formed by core clock genes such as CLOCK and BMAL1, creating a complex hierarchical network that underpins endogenous near 24-h oscillations[13-15]. The SCN receives photic input via the retinohypothalamic tract, adjusts the phase and period of the biological clock accordingly[16,17], and relays temporal information to peripheral tissues through endocrine and neural signals to ensure body wide rhythmic synchrony[18,19] (Figure 1). This precise, multilayered regulatory architecture provides essential physiological grounding for understanding the central role of circadian disruption in BD and other psychiatric disorders.

Figure 1 Molecular mechanisms and physiological regulation of the human circadian rhythm system. The central clock, located in the suprachiasmatic nucleus of the hypothalamus, maintains circadian rhythms through a hierarchical network of molecular clock genes composed of core clock genes such as CLOCK and BMAL1. The suprachiasmatic nucleus receives photic input and other environmental zeitgebers via the retinohypothalamic tract and coordinates whole-body rhythmic synchronization through endocrine and neural signals, thereby regulating the peripheral clock. SCN: Suprachiasmatic nucleus.

Despite frequent reports linking circadian disruption with BD, a cross-scale, systematic theoretical framework that treats it as a core pathophysiological mechanism is still lacking. A comprehensive synthesis and appraisal of this field is therefore needed to clarify the role of circadian dysregulation in BD and to open new perspectives for mechanistic research and therapeutic innovation. To better address the gap in the aforementioned theoretical framework, we summarized how factors at the molecular, physiological, behavioral, and social levels influence the onset of BD by driving circadian disruption as a core mechanism. This work systematically integrates cross-scale evidence, aiming to fill the gap in mechanistic connections from the molecular to the behavioral level. We then examined the clinical significance of circadian dysregulation across the disease course and evaluated rhythm-oriented interventions, including its value as a core symptom dimension and as a marker for recurrence, treatment response, and prognosis. Finally, we outlined future challenges to deepen understanding of the multidimensional model of gene, brain, behavior, and environment.

This review identified circadian disruption as a core pathophysiological mechanism of BD from a novel perspective and innovatively proposed a forward-looking framework that advances understanding of mechanisms, clinical significance, and rhythm-oriented therapeutic directions. These insights add value for BD care and point to new avenues for the prevention and treatment of mood and other psychiatric disorders.

MOLECULAR LEVEL: CLOCK GENE DISRUPTION AND NEUROENDOCRINE AND METABOLIC DYSREGULATION

Core clock gene variants associated with BD

Single nucleotide polymorphisms (SNPs) and abnormalities in the expression or function of core clock genes such as CLOCK, BMAL1, PER, and CRY are considered important biological contributors to the pathogenesis of BD. Substantial evidence indicates that variants in core clock genes including CLOCK, BMAL1 (ARNTL), the PER family (PER1, PER2, PER3), the CRY family (CRY1, CRY2), REV-ERBα (NR1D1), retinoid-related orphan receptor (ROR) α, TIMELESS, and CSNK1E are closely associated with BD phenotypes, disease course, and treatment response[20,21]. In humans the circadian cycle begins with dimerization of the positive regulators CLOCK and BMAL1, and their expression depends on the binding of enhancer sequences within the promoter regions of the negative regulators PER (PER1, PER2, PER3) and CRY (CRY1, CRY2). ROR and REV-ERB form an interconnected feedback loop that competes for ROR response elements on BMAL1 to regulate oscillator stability. Once the negative regulators PER and CRY proteins accumulate to sufficient levels, they suppress BMAL1/CLOCK-mediated transcription[22,23]. This section reviewed key variants in these core clock genes and the corresponding evidence in BD.

CLOCK encodes a principal positive regulator of the circadian clock, and its variants are closely linked to BD pathogenesis and clinical features. Animal models provide critical evidence: Mice carrying a deletion in exon 19 of CLOCK, a dominant-negative mutation, exhibit an extended circadian period, sleep disturbances, hyperactivity, mania-like and depression-like behaviors, enhanced cocaine reward, increased excitability of dopaminergic neurons, and metabolic dysregulation, which together model multiple core features of BD[24]. In humans several SNPs have been identified in CLOCK among which rs1801260 (3111T/C) has been most extensively studied. Patients with BD carrying the rs1801260C allele show significantly higher lifetime recurrence, poorer response to treatment for sleep disturbances, more frequent reports of insomnia during depressive episodes, and greater depressive severity[25].

BMAL1 (ARNTL), the essential dimerization partner of CLOCK, also harbors SNPs associated with BD susceptibility and clinical presentation. Multiple studies have linked BMAL1 SNPs to BD susceptibility and to lithium treatment response. For example, Maciukiewicz et al[26] reported that rs11022778 is associated with reduced appetite in patients with BD. Rybakowski et al[27] and Rybakowski et al[28] found that rs11824092 and other BMAL1 SNPs are significantly associated with the prophylactic efficacy of lithium, a relationship that may reflect the role of the gene in BD vulnerability. In addition, epigenetic analyses indicate BMAL1 hypermethylation in BD, suggesting dysregulated expression[29]. Although not all studies consistently show differences in BMAL1 expression between patients and controls, its expression varies markedly across mood states with lower levels during depressive episodes. BMAL1 expression also correlates strongly with monoamine oxidase A, underscoring its role in neurotransmitter regulation and mood stabilization[30]. Collectively, these findings support BMAL1 as a key clock gene involved in the pathophysiology of BD although validation in larger samples is still required.

The G allele at PER2 rs2304672 significantly increases the risk of BD, whereas the 5/5 repeat genotype of the PER3 variable number of tandem repeats shows a protective effect. Carriers display a higher proportion of hypomanic symptoms[25]. Mechanistic studies show that the CRY1 R263Q mutation disrupts circadian patterns of energy metabolism, locomotor activity, and feeding behavior in mice under constant darkness, and it leads to aberrant expression of circadian and metabolism-related genes in the liver[31]. Recent work also suggests that CRY1 risk alleles may be associated with elevated nocturnal cortisol levels[32]. In addition, downregulation of REV-ERBα induces widespread apoptosis in neural progenitor cells (NPCs) derived from both patients with BD and healthy controls. The agonist GSK4112 protects mouse neurons and control NPCs but does not alleviate apoptosis in NPCs derived from patients with BD[33]. Beyond core clock genes other variants are linked to BD as well. For example, studies using neurons derived from human induced pluripotent stem cells have shown that heterozygous mutations in AKAP11 can induce transcriptomic and chromatin homeostatic dysregulation, which markedly increases BD risk[34] (Table 1).

Table 1 Effects of multiple genes on the pathogenesis of bipolar disorder.

Gene	Type	Variation	Effect	Strength
CLOCK	Core clock gene	ClockΔ19, SNPs (rs1801260C)	Simulated several core characteristics of BD	Highly correlated
BMAL1		SNPs, hypermethylation	Increased the susceptibility of BD and participated in shaping its clinical phenotype	Highly correlated
PER2		SNPs (rs2304672G)	Significantly increased the risk of BD	Significant correlation
PER3 VNTR		5/5 repeat genotype	Reduced the risk of BD	Significant correlation
CRY1		R263Q mutation, risk allele	Caused abnormal circadian rhythm pattern and affected BD	Significant correlation
REV-ERBα		Downregulated expression	Induced extensive apoptosis of NPC in patients with BD	Significant correlation
AKAP11	Other genes	Heterozygous mutation	Significantly increased the risk of BD	Correlation

SNP: Single nucleotide polymorphism; BD: Bipolar disorder; NPC: Neural progenitor cell.

SCN pacemaker dysfunction and neuroendocrine and metabolic effects in BD

Rhythmic abnormalities in neurotransmitters: As the central pacemaker of circadian rhythms, SCN regulates sleep, wakefulness, body temperature, and cortisol secretion. Its dysfunction is viewed as a core hub for biological rhythm disruption and mood dysregulation in BD. The first manifestation of impaired SCN pacing is abnormal neurotransmitter rhythmicity. Circadian transcription of tyrosine hydroxylase, the rate limiting enzyme for dopamine synthesis, is driven by CLOCK and BMAL1. SCN dysrhythmia shifts the phase of the daytime peak of striatal dopamine, precipitating reward hyperresponsivity during mania, anhedonia during depression, and fragmentation of motor rhythms[35,36]. Notably, dopamine and dopamine receptors, especially D1 like dopamine receptors, can in turn modulate SCN neuronal oscillations[37].

The 5-hydroxytryptamine (5-HT) system is also regulated by the SCN. Serotonergic projections from the dorsal raphe nucleus (DRN) to the SCN form an anatomical bridge between circadian timing and mood control. When SCN pacing is disrupted, DRN 5-HT neurons lose circadian drive, leading to excessive nocturnal release and insufficient daytime secretion. This pattern contributes to delayed sleep onset and morning low mood in BD[38]. Irregular light schedules cause phase shifts in the SCN together with phase shifts and lower median levels in DRN 5-HT expression. Mice exhibit delayed sleep onset and morning depression-like behavior, and the severity of depressive behavior correlates positively with the duration of DRN 5-HT rhythm disruption[39]. A study in Science further showed that primary cilia in the SCN regulate oscillations of several core clock genes and neurotransmitters by rhythmically activating the Hedgehog pathway[40]. These findings suggest that abnormalities in primary cilia-mediated signaling may represent a new mechanism linking SCN pacemaker dysfunction to 5-HT dysregulation.

In recent years the focus has expanded from monoamines to inhibitory neurotransmission. Beyond monoamines the role of gamma aminobutyric acid (GABA)-ergic signaling has garnered increasing attention. The impact of SCN pacemaker dysfunction on GABA has become a key topic. GABA is widely expressed in SCN neurons. Although its intracellular actions are debated, the prevailing view is inhibitory[41]. Anatomical and electrophysiological evidence shows a monosynaptic GABA-ergic projection from the SCN to the paraventricular nucleus of the hypothalamus. Optogenetic stimulation of the SCN evokes fast inhibitory postsynaptic currents in the paraventricular nucleus that are mediated by GABA-A receptors, confirming a critical role for this pathway in circadian output control[11,42]. When SCN function is compromised, weakened rhythmic GABA-ergic output produces a glutamate to GABA imbalance, leading to excitation to inhibition imbalance in corticolimbic circuits and amplifying mood polarity in BD[43].

Dysregulation of the hypothalamic-pituitary-adrenal axis rhythm: The hypothalamic-pituitary-adrenal (HPA) axis is a core neuroendocrine stress pathway under SCN control and normally exhibits a cortisol rhythm with higher levels in the morning and lower levels at night[44]. In shift work models chronic nocturnal light exposure misaligns the SCN with the light and dark cycle, delays the cortisol peak, and reduces amplitude. Light therapy or timed melatonin can resynchronize the SCN and partially restore the cortisol rhythm, supporting the upstream regulatory role of the SCN in the HPA axis[45]. New mechanistic work indicates that stressors such as foot shock can induce phase delays in the central SCN pacemaker through glutamatergic inputs from the anterior paraventricular thalamus, potentially resulting in nocturnal hypercortisolemia and depressive-like behavior[46]. Although SCN control of HPA rhythmicity is well established, the dynamic interactions between the two under stress conditions require further study.

Circadian disruption of mitochondrial energy metabolism: Mitochondrial functions, including fusion and fission dynamics and respiration, show marked circadian rhythmicity and depend on an intact molecular clock[47]. Mitochondrial dysfunction and oxidative stress are considered core pathophysiological features of BD[48-50]. Clock proteins can sense mitochondrial metabolites such as nicotinamide adenine dinucleotide⁺ and nicotinamide adenine dinucleotide and act as redox sensors that feed cellular energy status back to the nuclear clock to maintain energetic homeostasis[47]. Chronic sleep deprivation directly suppresses BMAL1 expression in the SCN, disrupts the periodicity of adenosine triphosphate production, and disturbs energy metabolic rhythms, ultimately altering neuronal excitability within the SCN[51]. Of particular importance, abnormalities in mitochondrial dynamics within vasoactive intestinal peptide-positive SCN neurons (e.g., for example loss of function of mitofusin 2) are sufficient to disrupt circadian oscillations of mitochondria, induce pronounced rhythm instability, and worsen BD-related episodes[52].

Epigenetic regulation and the plasticity of clock genes

BD shows pronounced seasonality in symptoms and episodes. Systematic reviews indicate that hospitalizations for depressive episodes peak around the winter solstice when the photoperiod is shortest, whereas the risk of manic episodes is greatest near the spring and autumn equinoxes when the photoperiod changes most rapidly[53]. Photoperiodic signals induce SCN to adjust the expression of core clock genes such as CLOCK, BMAL1, and PER2, which are key components of the transcription and translation feedback loop of the circadian clock. These adjustments in turn precipitate metabolic changes and mood fluctuations[9]. Beyond light-dark cycles viral infections like severe acute respiratory syndrome coronavirus 2 represent a significant environmental inducer of circadian disruption through epigenetic mechanisms. Research indicates that long coronavirus disease involves dysregulation of core clock genes (CLOCK, BMAL1, PER2) and mitochondrial dysfunction, which subsequently trigger epigenetic alterations such as DNA methylation. These modifications mediate the adaptation of circadian gene plasticity to environmental stressors, acting as a critical bridge between infection and persistent biorhythm disorder[54]. These processes highlight the crucial plastic role of epigenetic mechanisms in mediating environmental control over clock genes.

Epigenetic regulation in BD also involves histone modifications in which dynamic oscillations directly reflect the plasticity of clock genes. Histone methylation levels are tightly coupled to transcriptional rhythms across the circadian cycle and dynamically regulate gene activity through bidirectional control by activating and repressive marks. In the activating arm the methyltransferase MLL1 associates with the CLOCK and BMAL1 complex and rhythmically catalyzes H3K4me3 to increase chromatin accessibility, thereby promoting transcription of genes such as Per1. In contrast, the repressive arm involves SUV39H1 and SUV39H2, which catalyze H3K9me2/3, drive heterochromatin formation, and silence gene expression[55]. Unlike the bidirectional nature of methylation, histone acetylation such as H3K9Ac and H3K27Ac primarily marks transcriptional activation by weakening the interaction between histones and DNA, facilitating transcription factor binding[56].

Alterations in circadian clock genes and their expression compromise the timekeeping function of the SCN as the central pacemaker. This dysfunction manifests at the cellular and tissue levels as a diminished capacity for synchronization among SCN neurons and a weakened entrainment signal to peripheral tissues. Consequently, internal desynchronization and attenuated rhythm amplitude occur in downstream physiological systems, giving rise to a suite of biomarkers. These biomarkers represent key intermediate phenotypes bridging molecular disturbances and the emergence of clinical symptoms.

PHYSIOLOGICAL LEVEL: BIOMARKERS OF CIRCADIAN DISRUPTION

Abnormalities of the sleep and wake cycle

Patients with BD show an increased percentage of rapid eye movement sleep during depressive episodes, whereas manic or mixed episodes are characterized by shorter total sleep time, lower sleep efficiency, and longer sleep latency. Even during euthymia the duration and continuity of sleep display greater variability, suggesting that disruption of the sleep and wake cycle may reflect both pathophysiology and phenotypic features of the disorder[57-59]. Genetic evidence supports its validity as a biomarker. A study in Cell reported that familial delayed sleep phase disorder is associated with a dominant variant in the core clock gene CRY1[60]. Recent work further shows that patients with BD commonly exhibit delayed sleep phase together with altered tryptophan metabolism and circadian dysregulation, indicating potential markers for early identification[61].

Flattening of the core body temperature rhythm

Under normal conditions the rhythm of core body temperature peaks about 1-2 h before sleep, reaches a trough about 2 h before waking, and then rises steadily during the daytime. Night shift workers and individuals exposed to nocturnal light show reduced amplitude of core body temperature, suppression of the melatonin peak, and poorer sleep quality. These findings establish core body temperature as a key biomarker for assessing circadian disruption[62]. Animal models provide additional insight. Mice with bilateral lesions of the SCN together with conditional knockout of BMAL1 display disruption of the core body temperature rhythm and anxiety and depression-like behaviors[63]. In a chronic jet lag model, female mice and castrated male mice show reduced robustness of the core body temperature rhythm along with weakened rhythmic expression of clock genes in the liver and adrenal gland[64]. These observations indicate that reduced amplitude of the core body temperature rhythm is a potential biomarker for BD.

Phase shifts in endocrine rhythms

Cortisol is a circadian sensitive marker governed by the HPA axis and normally shows a morning peak and a nighttime trough[35,62]. A recent prospective study in patients with Cushing syndrome found markedly flattened circadian oscillations of CLOCK, PER1 to PER3, and TIMELESS in peripheral blood mononuclear cells, suggesting that phase shifts of the cortisol rhythm can mark circadian disruption[65]. Melatonin is a key downstream hormone of the circadian system. Through the melatonin (MT) receptors (i.e. MT1 receptor) it regulates the sleep phase, and through the MT2 receptor it calibrates circadian timing[66,67]. Notably, studies of shift working nurses observed preserved melatonin rhythms together with disorganized cortisol rhythms, indicating differential sensitivity of endocrine axes to circadian perturbation[68]. In summary, phase shifts in endocrine rhythms are important indicators for identifying circadian disruption.

Desynchronization of rhythms in peripheral tissues

The transcription and translation feedback loop that drives circadian timing oscillates autonomously in cells throughout the body and is synchronized by the SCN through neural and humoral pathways[22]. Metabolic disturbances that arise from misalignment between the environment and the central clock are influenced by peripheral clocks. Even under misalignment matching the periods of peripheral and central clocks can mitigate metabolic dysregulation[69]. Recent evidence has increasingly indicated that the failure of this central coordination function leads to desynchronization between the SCN and peripheral oscillators. In patients with attention deficit hyperactivity disorder, the PER1 rhythm in skin fibroblasts is markedly attenuated under norepinephrine stimulation, suggesting that reduced sensitivity of peripheral clocks may be a shared feature in BD[70]. Moreover, peripheral clock genes such as PER2 and BMAL1 can operate independently of SCN regulation, and their aberrant expression or desynchronization of peripheral rhythms disrupts the circadian blood pressure rhythm[71]. Notably, genes including PER2 and BMAL1 are also associated with BD, further suggesting the role of peripheral tissue rhythm desynchronization in BD. These observed disruptions in physiological rhythms are reflected to some extent in a diminished ability of individuals to maintain regular daily behaviors, manifesting as instability in behavioral and social rhythms (Table 2).

Table 2 Some biomarkers of dysrhythmia that can provide basis for the diagnosis of bipolar disorder.

Biomarker	Rhythmic change	Related variant clock gene	BD performance	Ref.
Sleep-wake cycle	Sleep phase delayed	CRY1	Sleep wake cycle CBT rhythm disordered, accompanied by changes in tryptophan metabolism and circadian rhythm disorder	Marchetti et al[57]; Panchal et al[58]; Scott and McClung[59]; Patke et al[60]; Yavuz Ataşlar and Altınbaş[61]
CBT	Decreased rhythm amplitude	BMAL1	CBT rhythm disordered	National Toxicology Program[62]; Liang et al[63]; Ma et al[64]
Cortisol	Rhythmic phase shifted	CLOCK, PER1, PER2, PER3, TIMELESS	Circadian rhythm disordered	Rathor and Ch[35]; National Toxicology Program[62]; Hasenmajer et al[65]
Melatonin	Differed in rhythm phase shift and rhythm interference sensitivity		Circadian rhythm disordered	Yang et al[68]
Peripheral clock	Reduced sensitivity and rhythm desynchronization	PER2, BMAL1	SCN level control is broken, and the whole-body rhythm is not synchronized	Woodie et al[69]; Palm et al[70]; Costello and Gumz[71]

BD: Bipolar disorder; CBT: Cognitive behavior therapy; SCN: Suprachiasmatic nucleus.

BEHAVIORAL AND SOCIAL LEVEL: THE VICIOUS CYCLE OF RHYTHM INSTABILITY

Reduced stability of social rhythms

The etiology of BD is complex and may involve genetic susceptibility[72-74] and social and psychological factors[75]. Prior work indicates that dysfunction of social rhythms may be related to the development of the disorder. In a study of children at familial high risk, Veddum et al[76] found broadly impaired social responsivity, and such deficits were detectable early in life. Historical data converge on similar conclusions. Retrospective and longitudinal studies of adults with BD suggest that social impairment is already present during childhood and adolescence before illness onset[77]. These findings imply that reduced stability of social rhythms may play a role in the course of BD and underscore the importance of preventive interventions tailored to children with poor social competence. In patients with BD Walsh et al[78] observed greater irregularity of social rhythms. Cross sectional studies consistently report a robust association between social rhythm disruption and bipolar spectrum disorder, and longitudinal studies suggest that social rhythm dysregulation predicts mood symptoms[79,80].

The social rhythm metric (SRM) is a valid and reliable self-report tool that quantifies the regularity of daily habitual behaviors and interactions[81]. The SRM index reflects the regularity of an individual’s life, and higher scores indicate more consistent social rhythms[82]. Using the modified SRM, Shen et al[83] examined the predictive value of social rhythm regularity for time to mood episode in late adolescent and young adult participants with bipolar spectrum conditions. Participants with bipolar spectrum conditions reported lower social rhythm regularity than healthy controls, and social rhythm regularity prospectively predicted survival time to a mood episode.

Abnormal patterns of light exposure

External environmental factors such as artificial light have been shown to cause sleep disturbances and to affect the timing system of circadian rhythms and other intrinsic rhythms that align human behavior with daily changes in light and with seasonal cues[84,85]. Abnormal light exposure patterns, including increased blue light at night and insufficient daytime light, may impair photic entrainment pathways, increase rhythm instability, and may be involved in the occurrence of BD[86-88]. Several lines of evidence support this view. Nighttime blue light exposure can directly influence mood and cognition. In mice LeGates et al[89] demonstrated that abnormal light cycles increased depression-like behavior and impaired learning, and these effects were mediated by intrinsically photosensitive retinal ganglion cells. In humans nighttime blue light exposure correlates with more depressive symptoms, likely through suppression of melatonin secretion[90]. Nighttime light also disrupts physiological rhythms. It elevates cortisol levels and alters the expression of circadian clock genes[91], and it may enhance systemic inflammation by disturbing the circadian rhythmicity of inflammatory markers[92]. These physiological changes can further exacerbate mood instability and the risk of BD.

In patients with BD altered light exposure is closely linked to mood fluctuation. Nighttime light exposure is associated with the occurrence of manic symptoms, whereas insufficient daytime light may contribute to relapse of depressive episodes[93,94]. Circadian disruption is common in BD and may be driven by abnormal light exposure patterns[95]. Adjusting light exposure by increasing daylight and reducing nocturnal light may be an important strategy to improve mood stability in patients.

Bidirectional worsening between behavior and biological rhythms

The bidirectional worsening mechanism that links behavior and biological rhythms is complex. Irregular behavior can weaken the timing function of the SCN, and this process is closely related to the formation of BD. Multiple studies indicate that circadian disruption is involved in onset, progression, outcomes, and relapse and that dysfunction of the circadian system may partly cause the disorder[96]. In mice subjected to repeated inversions of the light dark cycle, simulating irregular schedules during adolescence, Gallego-Landin et al[97] observed disrupted PER2 rhythms in the hypothalamus that contains the SCN, and similar results were reported by Leise et al[98]. Ortiz et al[99] further proposed that changes in daily activity were among the earliest indicators of depressive symptoms in patients with BD. These findings suggest that behavioral and rhythm irregularities can weaken SCN timing. The resulting dysfunction promotes the development of BD. At present mood lability and impaired emotion regulation are recognized features of the disorder[100]. Numerous studies show that, relative to the premorbid state, patients exhibit more unstable mood and more disorganized behavior[101,102]. Thus, irregular behaviors disrupt biological rhythms, which in turn exacerbate behavioral instability, creating a positive feedback loop that drives illness progression.

Taken together, the interaction between behavioral irregularity and circadian disruption may form a vicious cycle. In the context of BD, circadian disruption is not only a consequence of worsening illness but may also be an etiological factor. This bidirectional worsening highlights the need to prioritize circadian regulation in both treatment and prevention in order to break this positive feedback loop and mitigate clinical deterioration.

Triggers related to seasonality and life events

For patients with psychiatric disorders, especially those with BD, relapse represents a challenging treatment failure. It can be defined as becoming ill again after clear recovery followed by clinical deterioration[103]. Many studies show that relapse rates are high, approximately 71%, and the risk relates to the psychosocial context of disease, environment, development, and cognition[104]. Disruption of social rhythms can trigger seasonal changes and life events that precipitate mood episodes, and this phenomenon is particularly evident in BD[15]. Kripke et al[105] were among the first to propose that seasonal changes in photoperiod may be related to the etiology of the disorder. Subsequent clinical evidence indicates that seasonal variation in photoperiod is a key environmental trigger for mood changes and may precipitate relapse[106,107]. In a systematic review of 51 studies, Geoffroy et al[108] reported seasonal patterns in admissions and symptom episodes. Manic episodes peak in spring and summer with a smaller peak in autumn. Depressive episodes peak in early winter and are less frequent in summer. Mixed episodes peak in early spring or summer.

Life events, particularly stressful ones, are widely recognized as triggers of BD[109]. Recent work by Cusell and Kok[110] confirmed this view. In older patients followed for 5 years, relapse or recurrence was common, and about half of the episodes were preceded by a life event. Koenders et al[111] found that negative life events are strongly associated with subsequent severity of manic and depressive symptoms, whereas positive life events precede manic symptoms only. Although methods for distinguishing whether life events are causes or consequences of mood symptoms have limitations, the importance of life events as potential triggers of relapse is clear. More comprehensive studies are needed to clarify the association between life events and relapse. Such knowledge could support the use of life events as predictive biomarkers and lead to updated pharmacologic and nonpharmacologic strategies to maximize symptom reduction and quality of life.

Social jetlag, defined as misalignment between sleep times on workdays and weekends, is a specific form of sleep disruption. Late bedtimes and wake times on weekends with early rising on workdays can create misalignment that affects circadian rhythms[112]. Smith et al[113] reported that individuals with bipolar spectrum disorder may be more vulnerable to the adverse effects of social jetlag, which is associated with greater depressive symptoms in patients and in those at risk. These observations suggest that social jetlag may act as a relapse trigger. Future research should clarify its role in onset, progression, and prognosis. The destabilization of rhythms and their persistent negative interaction with the environment ultimately manifest as clinical features that impact disease progression, prognosis, and treatment.

CLINICAL IMPLICATIONS IN THE COURSE OF BD

Circadian dysregulation as a core symptom dimension

Circadian rhythm disruption is closely linked to the pathophysiology of BD. It modulates daily feeding behavior[114], regulation of the sleep and wake cycle[115], neuroendocrine hormone release[116], and homeostatic and metabolic processes[117]. Dysregulation of these functions is among the most common clinical features in patients with BD[118]. During manic or depressive episodes, characteristic rhythm disturbances are prominent. Sleep problems typically present as reduced sleep need during mania and near daily insomnia or hypersomnia during depression, which can affect emotion regulation and the course of illness[119]. Circadian disruption is also associated with suicide risk, and this association may vary across bipolar subtypes[120].

Predictive marker for relapse

Although treatment has advanced, the risk of relapse remains high[104]. The role of circadian disruption in BD has been widely investigated, and many studies suggest it may serve as a core symptom dimension or a predictor of relapse[121]. In a 48-week prospective study, Takaesu et al[122] found that circadian rhythm sleep wake disorders, primarily delayed sleep wake phase disorder, may be important predictors of relapse in patients with BD. Cretu et al[123] further showed that in remitted patients, poor sleep quality was associated with residual mood symptoms and independently predicted recurrence of mood episodes. Taken together, indices of rhythm stability are likely to serve as early warning markers of relapse risk, and circadian disruption may promote mood instability and increased relapse risk in BD[124].

Biomarker of treatment response

Since approval in the 1970s, lithium has remained the gold standard for treatment, and its regulatory effects on circadian rhythms have received extensive attention[125]. Lithium can influence treatment response by modulating the expression of clock genes[126]. In particular, lithium affects expression of genes such as NR1D1, which may serve as biomarkers of therapeutic response[127]. The impact of lithium on circadian rhythms appears to be closely related to its clinical efficacy, especially in improving mood symptoms[128,129].

In mixed states, rapid cycling, and in the presence of comorbid anxiety or substance use disorders, the efficacy of lithium may be limited. In such cases valproic acid (VPA) can be used alone or in combination with lithium as an effective alternative[130]. The effects of VPA on clock gene expression have been studied extensively. For example, Griggs et al[131] reported that VPA altered expression of genes in both the positive limb (BMAL1) and the negative limb (CRY1 and CRY2) of the clock with effects depending on dosing time at circadian time 0 vs circadian time 12. By altering the oscillatory patterns of core clock transcription factors, VPA modulates circadian function[131]. In line with these findings, Ferraro et al[132] observed abnormal BMAL1 expression patterns in the SCN of both male and female mice exposed to VPA, suggesting changes to core clock mechanisms[132]. Landgraf et al[133] provided in vivo and in vitro cross species evidence that VPA shortens the circadian period in fibroblasts from patients with BD and from controls. These results suggest that VPA improves mood in patients with BD by normalizing a prolonged circadian period. This condition appears to stem from reduced dopamine transporter function and consequent elevated dopamine levels. By correcting this period the treatment helps synchronize the patients’ internal rhythm with the external 24-h light-dark cycle[133]. Thus, VPA related clock effects may serve as biomarkers of treatment response.

Comorbid insomnia and circadian rhythm sleep disorders

Circadian disruption not only shapes symptom expression but also interacts with comorbid insomnia and circadian rhythm sleep disorders (CRSD), thereby influencing prognosis[134,135]. Circadian dysregulation correlates strongly with insomnia severity and may exacerbate symptoms by impairing mood and cognitive function[136]. In a prospective cohort study by Bertrand et al[137], insomnia in patients with BD complemented depressive and anxiety symptoms as a potential signal of suicidal ideation and influenced prognosis.

In mammals sleep is tightly regulated by the circadian system. Misalignment between internal timing and the external environment, such as shift work, jet lag, or nocturnal light exposure, can lead to CRSD[138]. Findings by Liu et al[139] indicate that such disorders are associated with mutations in related genes including PER2, CRY1, CRY2, and PER3. As noted earlier these genes belong to the core clock gene set implicated in BD. These observations indirectly suggest that comorbid CRSD in BD may produce bidirectional amplification that worsens prognosis.

CHRONOBIOLOGICAL INTERVENTIONS

Integrated intervention models

At present pharmacologic approaches are recommended as first line therapies for BD with lithium monotherapy and combination regimens being the mainstays[140-142]. These approaches are not invariably effective[143], and patient acceptance varies[144]. This variability increases the need for multidisciplinary treatment that includes psychosocial and behavioral interventions[145,146]. Interpersonal and social rhythm therapy (IPSRT) is an evidence-based psychotherapy that targets disrupted social rhythms by integrating the core elements of interpersonal psychotherapy for unipolar depression with SRT[147]. IPSRT is applicable to the acute treatment of bipolar depression and to the prevention of mood episodes[148,149].

A randomized controlled trial (RCT) in 2020 suggested that IPSRT may be clinically effective for major depressive disorder (MDD)[150]. Using data from clinical trials, Moot et al[151] found that compared with treatment as usual IPSRT produced positive effects over 18 months on two subscales of the social adjustment scale self-report, indicating beneficial effects of IPSRT. In a study of 38 older outpatients with a mean age of 65.4 ± 10.0 years who had MDD or BD, twice weekly group-based IPSRT was feasible and acceptable[152]. In a clinical effectiveness trial, Crowe et al[153] reported functional improvement although the combination of IPSRT and medication management for more than 18 months did not significantly reduce mood relapse.

Recently, Swartz et al[154] innovated on IPSRT by developing an online IPSRT-based intervention for BD called rhythms and you (RAY). A randomized pilot study showed that remote delivery of RAY was feasible and acceptable, and time spent on RAY correlated positively with improvement in social rhythm regularity[154]. By contrast, an RCT by Douglas et al[155] found that combining IPSRT with cognitive remediation may attenuate the effect of IPSRT when targeting symptoms and cognitive or functional recovery simultaneously. These findings indicate that further comprehensive research is needed to evaluate the short-term and long-term efficacy of IPSRT and the effectiveness of combinations with other therapies.

SRT

SRT is a component of IPSRT that focuses on behavioral strategies. It has been tested separately in comprehensive interventions for MDD[156] and for BD[154]. Among patients with BD aged 15-35 years, the SRT component of IPSRT has been shown to be most helpful for maintenance over more than 5 years[157]. Crowe et al[158] found that SRT has multiple features that can be translated into clinical practice across different settings, showing consistency with recent findings by Darwish et al[159]. Sankar et al[160] delivered a modified SRT remotely to 13 adolescents and young adults with BD and showed that telehealth-based SRT was feasible and acceptable and could reduce mood symptoms and suicide risk. These results suggest that SRT stabilizes daily activity anchors and rebuilds zeitgeber signals. It is a promising adjunct for future recommendations in the treatment of BD.

Bright light therapy

Bright light therapy (BLT) has developed over the past 50 years and has proven to be highly versatile[161]. It is widely used to treat seasonal affective disorder[162] and depressive symptoms in non-seasonal MDD[163]. Bright light stimulates intrinsically photosensitive retinal ganglion cells and induces a cascade of changes that involve melatonergic, neurotrophic, GABAergic, glutamatergic, noradrenergic, and serotonergic systems as well as the HPA axis. Although the exact mechanism remains incompletely understood, bright light is thought to modulate circadian dysfunction and autonomic function and thereby improve mood symptoms[164]. The International Society for BDs task force recommends BLT for acute treatment of bipolar depression[165].

An increasing number of RCTs has examined the efficacy of BLT for depressive symptoms in BD with most showing benefit[166,167]. In contrast, a meta-analysis by Takeshima et al[168] that included six RCTs reported that BLT did not significantly improve depressive symptoms in BD. Given the high heterogeneity and small number of trials, these results are not definitive. Larger studies with appropriate control groups are needed to determine efficacy and safety. A recent dose escalation phase 1 and 2 randomized double blind trial by Geoffroy et al[169] further confirmed that BLT is a feasible antidepressive strategy in BD.

In a cohort of 799 patients with BD receiving antidepressant light therapy, Benedetti[170] observed that the highest reported rate of switch to mania after light therapy approximated the expected 4% switch rate during placebo treatment in BD. This finding suggests no specific concern about manic switch with light therapy, and the switch rate was unrelated to treatment parameters that included light intensity, duration, and circadian timing. This potential risk is theorized to stem from a mechanism shared with many antidepressants: Increased serotonergic activity[171,172] and use of BLT without a mood stabilizer may increase the risk of a manic switch.

Melatonin receptor agonists

Abnormalities in melatonin secretion and regulation have been documented in unipolar and bipolar depression[116]. In BD these abnormalities may reflect reduced pineal secretion or dysregulated secretion due to internal or external causes[173,174]. Studies have begun to examine whether melatonin receptor agonists such as ramelteon and agomelatine can serve as adjunctive therapies for BD[175]. A 2022 systematic review and meta-analysis that included 11 studies, 6 RCTs and 5 feasibility studies, reported only partial evidence that ramelteon prevented recurrent depression in BD[176]. Agomelatine is both a melatonin receptor agonist and a 5-HT2C receptor antagonist. The two mechanisms act synergistically to restore circadian rhythms, improve depressive symptoms, and benefit anxiety, sleep, and sexual function[177].

Agomelatine is an effective antidepressant for MDD. A recent systematic review by Li et al[178] suggested that agomelatine showed significant efficacy and good tolerability in bipolar depression. These studies provide encouraging signals for melatonin receptor agonists as antidepressant therapies while emphasizing the need for rigorously designed trials with large samples to establish definitive efficacy. Reduced sleep need is a core symptom of mania, and insomnia or hypersomnia is a core feature of depression. Sleep disruption is a hallmark of BD[179]. These features are crucial for diagnosis, prognosis, and clinical decision making[180,181]. A promising therapeutic target is to adjust and improve sleep and circadian rhythms[165].

Chronotherapy

Sleep deprivation (SD), also called wake therapy, is defined as a period of enforced wakefulness. Since the 1970s it has been considered an effective antidepressant intervention with potential utility for major depressive episodes and can be used alone or combined with medication as part of chronotherapy[182]. The evidence base is largely from noncontrolled clinical trials[183,184] with relatively few RCTs[185], and its true effectiveness remains debated[186]. For example, Sarzetto et al[187] treated 11 inpatients with bipolar depression using three cycles of total SD combined with daily light therapy for 1 week. Polysomnography before and after treatment showed significant improvement in depressive symptoms, supporting a positive effect of the combined chronotherapy for bipolar depression. The composite design, however, makes it difficult to attribute effects to SD alone.

A meta-analysis of rapid antidepressant chronotherapy found benefits that included 5-7 days of SD, but the effect size in randomized trials was smaller than in open label case series with 33% vs 62% of patients classified as responders. This difference suggests that some of the apparent effectiveness of SD may arise from nonspecific factors such as expectancy rather than from true efficacy[188]. In a systematic review and meta-analysis of 29 RCTs, Mitter et al[186] concluded that adding SD to treatment regimens did not enhance antidepressant effects.

More recent work by Gottlieb et al[189] analyzed SD in acute bipolar depression and found a response rate close to 50%, supporting enhanced early efficacy. In line with this conclusion, a systematic review and meta-analysis by Ramirez-Mahaluf et al[190] reported that adding medication to total SD produced positive acute effects with lithium being especially recommended, and higher response rates were maintained at 3 months. Therefore, while SD shows rapid antidepressant effects, its utility as a standalone, sustained treatment is limited, and it may be most effective as part of a combined chronotherapeutic protocol (Table 3).

Table 3 Research on the effects of some drugs and therapies on bipolar disorder.

Ref.	Year	Type	Medication/therapy	Impact on BD
Crowe et al[150]	2020	IPSRT	IPSRT	Reduced depressive symptoms
Moot et al[151]	2022		IPSRT within 18 months	Improved social adaptation
Orhan et al[152]	2024		Twice weekly group IPSRT	Feasibility demonstrated
Crowe et al[153]	2020		IPSRT exceeding 18 months	No significant effect on relapse
Swartz et al[154]	2021		Online intervention of BD based on IPSRT	Improved social rhythm regularity
Douglas et al[155]	2022		Combining IPSRT and CR	Reduced the effectiveness of IPSRT
Crowe et al[158]	2020	SRT	SRT	Feasibility demonstrated in clinical practice
Sankar et al[160]	2021		Improved SRT	Reduced emotional symptoms and suicide risk
Takeshima et al[168]	2020	BLT	BLT	No significant improvement in depressive symptoms
Geoffroy et al[169]	2025		BLT	Reduced depressive symptoms
Benedetti[170]	2018		BLT	Found the phase change rate of mania was not related to the treatment method
McGowan et al[176]	2022	Melatonin receptor agonist	Ramelteon	Prevented recurrent depressive symptoms in patients with BD
Li et al[178]	2024		Agomelatine	Significant therapeutic effect and good tolerability Excellent treatment and tolerance
Sarzetto et al[187]	2022	SD	3 cycles of TSD + daily one week BLT	Had a positive therapeutic effect on BD depressive episodes
Humpston et al[188]	2020		SD	Not the actual therapeutic effect
Mitter et al[186]	2022		SD	Unable to prove the effect of antidepressant treatment
Gottlieb et al[189]	2021		SD	Enhanced early efficacy
Ramirez-Mahaluf et al[190]	2020		TSD + drug therapy (such as lithium)	Had a positive impact on acute reactions

BD: Bipolar disorder; IPSRT: Interpersonal and social rhythm therapy; SRT: Social rhythm therapy; BLT: Bright light therapy; CR: Cognitive remediation; TSD: Total sleep deprivation; SD: Sleep deprivation.

FUTURE PERSPECTIVES

In depth analysis of the gene, brain, and behavior pathway

When dissecting pathways involved in the onset and progression of BD, researchers often focus on the complex relationships among gene expression, brain function, and observable behavior. By integrating multiple methods such as functional magnetic resonance imaging and genomic analyses, the pathophysiology of the disorder can be understood more comprehensively. At the level of clock genes, BD shows substantial heritability[191], and multiple studies have identified evidence for variants and expression abnormalities in core clock genes associated with the disorder[192], including SNPs in CLOCK[25], BMAL1[193], PER[194], and CRY[194]. These findings highlight the importance of altered gene expression and provide direction for models that trace disease development in depth.

At the brain level patients show marked functional alterations across clinical stages that are closely related to heterogeneity in gene expression. For example, a functional magnetic resonance imaging study reported significantly increased regional homogeneity in the bilateral precuneus and posterior cingulate cortex as well as the lateral occipital cortex, and the connectivity features of these regions were closely linked to clinical symptoms[195]. The spatial correspondence between these imaging features and gene expression suggests that biological pathways involving limbic circuitry may operate at different stages of the disorder.

Multiple studies also indicate rhythmic abnormalities in neurotransmission during the course of the illness. Disrupted oscillations of dopamine, serotonin, and GABA can perturb limbic circuits, produce manic and depressive symptoms, and profoundly influence cognition, memory, and the regulation of circadian timing and other behaviors[196]. The environment acts as a trigger, maintainer, and modulator. Seasonality and life events are principal triggers, and stability of social rhythms, light exposure, and substance misuse are key factors for maintenance[104,113].

Manic, depressive, and mixed states are the core observable symptom clusters and represent the final outputs of gene and brain abnormalities under specific environmental conditions. Circadian and sleep disturbances are not only core symptoms but also important triggers and maintaining factors[121], and they interact closely with brain function and environmental cues[138]. Epidemiologic evidence shows that individuals with genetic vulnerability, such as children of mothers with BD, display marked fragility in behavioral phenotypes related to circadian regulation. In the pathway from maternal diagnosis to offspring emotional and behavioral problems, as much as 75% of the effect is mediated by the child’s own circadian disruption[197]. This finding underscores the deep interaction between genetic susceptibility and behavior.

Genes, brain, behavior, and environment all contribute to onset and progression to varying degrees. Their interactions shape relapse, treatment, and prognosis. Different individuals may ultimately develop the disorder through different combinations of gene, brain, behavior, and environment. Building on the preceding discussion, we propose a multidimensional interactive model that integrates gene, brain, behavior, and environment. This model not only reveals potential biological mechanisms but also provides a scientific basis for new therapeutic strategies. Future work should explore these interactions more deeply and comprehensively in order to deliver more effective prevention and intervention for patients (Figure 2).

Figure 2 Establishment of a “gene-brain-behavior-environment” multidimensional interaction. Model to elucidate the biological mechanisms and therapeutic strategies of bipolar disorder (BD). The model is described as follows: At the genetic level variations and abnormal expression of core clock genes (e.g., CLOCK, BMAL1, PER, CRY) form the basis of genetic susceptibility to BD. At the brain level abnormalities in limbic system circuit mechanisms and rhythmic disturbances of neurotransmitters such as dopamine, 5-hydroxytryptamine, and gamma-aminobutyric acid contribute to the development of symptoms including mania and depression. The environmental level encompasses triggering factors (e.g., seasonal changes, life events) and maintaining factors (e.g., social rhythm stability, substance abuse). The behavioral level affects the regulation of cognition, memory, sleep, and circadian rhythms, ultimately manifesting as core BD symptoms such as manic episodes, depressive episodes, and mixed states. These dimensions interact with each other, and multiple factors collectively promote the onset and progression of BD. This model not only provides an integrated framework for elaborating the pathological mechanisms of BD but also points out directions for BD intervention and therapeutic strategies, such as the development of dynamic rhythm monitoring technologies, the design of drugs targeting the molecular clock, the optimization of environmental zeitgebers, and transdiagnostic rhythm research. BD: Bipolar disorder; 5-HT: 5-hydroxytryptamine; GABA: Gamma-aminobutyric acid.

Development of dynamic rhythm monitoring technologies

In applied technology the combination of artificial intelligence and wearable devices offers new possibilities for the critical area of dynamic rhythm monitoring. With artificial intelligence wearables can continuously track physiological parameters and thereby support individualized health management[198]. Several studies show that new real time mobile tools for dynamic rhythm monitoring can derive individualized multilevel dynamical representations of multiple homeostatic systems. These tools can inform clinical research by identifying heterogeneity in presentation and can provide more objective indicators of treatment response in real world settings[199].

Recently, a prospective observational study monitored sleep using wearable devices and assessed emotional symptoms via smartphones in 139 patients with mood disorders (including patients with BD). The study found that 66.7% of patients with MDD and 85.7% of patients with BDI exhibited a causal relationship in which circadian rhythm phase disruption preceded the onset of emotional symptoms. This finding provides evidence for individualized treatments targeting circadian rhythms, such as light intervention[200].

In a randomized sham controlled double blind trial, Yeom et al[201] found that algorithms using daily self-monitoring and feedback through wearables and smartphones predicted mood fluctuations 3 days in advance with accuracy of about 90%-95% when compared with clinician assessments conducted every 3 months. Their earlier positive findings indicated that digital data and circadian parameters can provide useful clinical information, support individualized rhythm phenotyping, and guide subsequent treatment decisions[201]. These conclusions have been supported by additional studies using diverse designs[202]. With these technologies we can achieve precise individualized dynamic monitoring and implement closed-loop interventions (e.g., recommending light exposure based on real-time rhythm data), thereby enabling more accurate medical interventions and providing support for therapies such as precision drug design.

Precision drug design targeting the molecular clock

Research on the biological clock has become a key field in modern medicine. The development of novel timing agents such as agonists of REV-ERB and ROR is based on a deep understanding of circadian biology and may offer future treatments for BD. REV-ERBα, a core nuclear receptor of the circadian system, plays an important role in regulating rhythms and metabolism. It modulates transcriptional amplitude of clock genes through interaction with FBXW7[203]. REV-ERBα is also linked to midbrain dopamine production and mood regulation, and its role in treating circadian-related mood disorders is being clarified[204].

Mishra et al[126] compared NPCs from patients and from mice and found that reduced REV-ERBα expression caused more severe cell death in cells from patients than in controls, supporting REV-ERB as a potential therapeutic target for the link between circadian disruption and neuronal loss in the disorder. Elevated risks of premature mortality include nearly doubled cardiovascular mortality and increased prevalence of metabolic disease. The role of REV-ERB in cardiovascular and metabolic disorders has been widely studied[205-208]. For example, Wang et al[209] reported that REV-ERBα protects against atherosclerosis, myocardial infarction and reperfusion injury, and heart failure by regulating myocardial energy metabolism. Raza et al[210] identified REV-ERB as an attractive target that can beneficially affect metabolic dysregulation, inflammation, and fibrosis. Synthetic REV-ERB agonists have been shown to modulate circadian behavior and expression of metabolic genes and to improve sleep disorders, obesity, and metabolic disease[211,212].

Recently, a study conducted by Liu et al[213] has revealed that ROR-β, as a susceptibility gene for BD, exerts an impact on hippocampal neuronal activity and the fluctuations of depressive/mania-like behaviors by regulating the circadian rhythm of pancreatic insulin secretion. Targeting ROR-β (e.g., via the use of its antagonist 4-OA) or modulating its downstream insulin signaling pathways (e.g., phosphatidylinositol 3-kinase-α) can ameliorate circadian rhythm disturbances and behavioral abnormalities[213]. These findings indicate that REV-ERB agonists may help maintain circadian stability, control symptoms, and prevent or manage comorbidities. Targeted timing agents that act on REV-ERB and ROR for the disorder require further comprehensive research and development.

In mammals the cell autonomous molecular clock relies on interconnected transcription and translation feedback loops composed of positive activators CLOCK and BMAL1 and inhibitors PER1 and PER2 and cryptochromes CRY1 and CRY2 that together generate a stable 24-h rhythm. Nuclear receptors of the ROR family regulate transcription of BMAL1 and ensure stability and robustness of rhythms[214]. Recent studies show that the feedback loop formed by ROR and BMAL1 regulates diverse metabolic pathways across organs. He et al[215] demonstrated that the ROR agonist nobiletin, a small molecule that enhances clock amplitude, markedly strengthens circadian rhythms and counters metabolic disease through the circadian gene network[215]. These data suggest that ROR agonists may serve as novel timing agents that target the molecular clock in the disorder. Further studies and drug design efforts are needed.

Optimization of environmental zeitgebers

Environmental factors are widely recognized contributors to the disorder. The condition is closely related to circadian disruption, and pronounced rhythmic behavioral instability can aggravate onset and becomes even more unstable after onset. Growing attention has been paid to optimizing environmental zeitgebers in treatment, especially the design of artificial lighting and community-based rhythm support[216]. In modern society artificial lighting and luminous devices have altered the temporal pattern of human life. Nocturnal light disrupts molecular clock rhythms and produces circadian dysregulation[217,218]. Designed artificial lighting such as BLT can improve mood although long-term effects require further study[169]. Rational lighting that is tailored in real time to the clinical state is therefore essential. These observations indicate that well designed artificial lighting environments may become viable strategies for optimizing environmental zeitgebers as adjuncts to treatment.

Rhythm-oriented interventions discussed earlier, such as SRT and IPSRT, show beneficial effects. By stabilizing daily activities and social rhythms, these therapies help reduce mood fluctuations and relapse risk[158]. Such multilayered strategies have important potential in clinical care. By resynchronizing the biological clock and stabilizing social rhythms, they can improve mood and reduce relapse, offering a comprehensive treatment package. Future studies should evaluate long-term effects and mechanisms to better guide practice.

Transdiagnostic paradigm for rhythm research

BD, depression, and schizophrenia are common psychiatric disorders with substantial clinical heterogeneity. These conditions may share transdiagnostic features of rhythm disruption that include disturbances of sleep, biological timing, mood, and cognition. Circadian dysregulation plays an important role in the onset and progression of these disorders and may predict relapse and treatment response[219]. It is also closely associated with mood instability, cognitive impairment, and increased suicide risk[220].

In BD circadian disturbance presents as irregular sleep and wake cycles, an evening chronotype, abnormal melatonin secretion, and susceptibility related to clock genes[221]. These abnormalities are evident during episodes and may persist during euthymia[222]. In mood disorders circadian disruption is tightly linked to reduced functioning and quality of life[136]. In schizophrenia sleep and circadian disturbances are also common and interact in complex ways with alterations in dopamine signaling[223]. Rhythm abnormalities are observed in other psychiatric conditions as well. The link between seasonal affective disorder and BD suggests that the former may serve as a marker of severity of the latter[224].

Among adolescents and college students, circadian disruption is associated with high rates of depression and anxiety, which may relate to pubertal biology, academic stress, and widespread use of electronic devices[225]. Interventions that target circadian disruption, including light therapy, chronotherapy, and cognitive behavioral therapy, may play important roles in improving diagnosis and treatment across these conditions[226]. Future research should continue to clarify the role of circadian rhythms in these disorders in order to develop more personalized and effective therapeutic strategies.

CONCLUSION

Over the past several decades, circadian disruption has become a research focus because of its broad associations with the course of psychiatric disorders, including BD, depression, and schizophrenia. This review centered on its pivotal regulatory role in BD and analyzed the underlying pathophysiology. Variants in core clock genes such as CLOCK, BMAL1, PER, and CRY produce downstream effects of SCN dysfunction. These effects manifest as biomarkers of circadian disruption, including abnormalities in the sleep and wake cycle, reduced rhythmic amplitude, phase shifts in endocrine rhythms, and desynchronization of rhythms in peripheral tissues, leading to rhythmic disturbances in behavior. At the same time environmental feedback such as abnormal light exposure patterns, life events, and social jetlag intensifies the vicious cycle of behavioral and circadian instability, triggers new mood fluctuations, and contributes to the onset of BD. We reviewed theoretical and clinical studies from roughly the past 15 years on the relationship between circadian disruption and BD to improve understanding of rhythm-oriented interventions and to elucidate its clinical implications for diagnosis, prediction of relapse, and treatment personalization.

In practice, however, these interventions still face many challenges. Evidence for the efficacy of approaches such as BLT and SD relies mainly on noncontrolled and nonrandomized studies or on trials that primarily enrolled participants with unipolar depression. Results may differ when only RCTs are included. In addition, it remains unclear whether combinations of multiple interventions can better stabilize illness and produce synergistic effects that exceed simple additivity. More specifically, research gaps in therapeutic areas are manifested in the need to integrate wearable monitoring into clinical practice and accelerate the development of molecularly targeted drugs in the future. There is little doubt that research on circadian resynchronization will expand rapidly. Such work will help further evaluate and refine multidimensional, integrated, rhythm-oriented interventions for BD.

This review provided a reference for continued study of the multidimensional interactive model that integrates gene, brain, behavior, and environment. It also offers guidance for developing precision, individualized, time-based treatments that target circadian disruption. Ultimately, targeting circadian rhythm disruption represents a paradigm shift from symptomatic management to addressing a core pathophysiological mechanism in BD. We anticipate that circadian resynchronization strategies will inform future applications across diverse diseases and offer new therapeutic directions for psychiatric disorders.