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

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.

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.

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.