Theoretical ReviewDelayed sleep phase syndrome and bipolar disorder: Pathogenesis and available common biomarkers
Introduction
Circadian rhythm sleep-wake disorders (CRSWD) are due to abnormalities in the circadian time-keeping system characterized by a misalignment between the endogenous circadian rhythm and the environment. CRSWDs are associated with difficulties in initiating sleep, excessive daytime sleepiness, and functional or cognitive impairment [1]. Delayed sleep-wake phase syndrome (DSWPD) is the most studied CRSWD. It has a typical onset during the second decade of life and is associated with abnormalities in sleep initiation [2], [3]. Individuals with DSWPD exhibit delayed sleep/wake times by at least 2 h from socially desired times [4]. DSWPD has been identified as a possible risk factor for bipolar affective disorder (BD), a psychiatric condition characterized by cyclical fluctuations in mood [5], ∗[6], [7]. BD has a prevalence of approximately 2% and is a major cause of psychiatric disability [3], ∗[6].
There is significant evidence linking BD and DSWPD and both disorders exhibit similar pathophysiological and clinical characteristics [8], [9]. This could be due to shared biological pathways and overlapping genetic profiles. We hypothesize that biomarkers for DSWPD such as melatonin levels or circadian rhythm genes may be associated with BD. Examining these biomarkers and genes can represent a novel approach to better understand the evolution and progression of BD. Biomarkers can provide insight into the underlying mechanisms of these disorders and may assist in the development of treatment modalities [10]. In this manuscript, we will examine candidate biomarkers for DSWPD and BD, and focus on the role of circadian genes and their expression profiles that may represent common denominators for both conditions.
Section snippets
Methods
When the review was conceptualized, we opted for a systematic review approach as per the Cochrane guidelines for systematic reviews. MEDLINE, PubMed, and Google Scholar were queried using standardized terms related to BD and DSWPD. Non-peer reviewed studies were excluded to ensure methodological integrity [11]. All articles evaluating biomarker for DSWPD in individuals with BD up to March 2017 were selected for review. Additionally, articles examining links between BD and DSWPD were also
Delayed sleep-wake phase syndrome
The suprachiasmatic nucleus (SCN) maintains the endogenous circadian rhythm [12]. The SCN receives and processes information from the retina via the retinohypothalamic pathway and modulates the secretion of the hormone melatonin from the pineal gland via the autonomic nervous system [6]. Many physiologic functions exhibit circadian rhythmicity, these include: endocrine functions, core body temperature (CBT), and alertness [6]. Synchronization or entrainment of the endogenous circadian rhythm
Behavioral factors
Behavioral factors have been shown to contribute to the pathogenesis of DSWPD [16], ∗[17]. Circadian phase delayed individuals were found to have an evening chronotype and when forced to rise earlier than their preferred times they were irritable, lethargic, and dysphoric [15]. Individuals with DSWPD frequently engage in activities such as late night socializing, using electronic devices at bedtime, and increased stimulant use (nicotine and caffeine) that perpetuate the disorder. Delayed
DSWPD and BD: common factors and pathways
The circadian timing system plays an important role in many physiologic functions. In BD it is unclear whether the rhythm disturbances are a primary pathological process or secondary to the disorder itself [43]. Sleep disturbances appear to be present during all stages of BD [44]. Yoshikazu et al. [45] demonstrated that DSWPD appears to be more prevalent among BD patients (32.4%) than the general population. Dagan et al. [12], showed that those with personality disorders and BD had high rates
Conclusion
Genetic, behavioral, and environmental factors have been implicated in the development of BD and DSWPD. A phase delay in melatonin rhythms was observed in both disorders and melatonergic drugs were found to be effective in treating both conditions. Circadian genes have been implicated in the pathogenesis of both BD and DSWPD. Haplotypes of the ARNTL and PER3 circadian genes were found to be significantly associated with BD. Circadian genes were shown to be potential biomarkers for the
Conflicts of interest
Disclosure: Dr. Ferri has consulted for Fidia Farmaceutici (Italy).
Remaining authors declare no conflict of interest.
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