Discussion
Main findings
In this cross-sectional study of 1022 Chinese infertility patients, we observed that morning and neutral chronotypes individuals were less likely to experience depressive symptoms during assisted reproductive treatment compared to evening chronotype, based on comparative analysis of chronotype and PHQ-9 scores, and this protective association appeared stronger in persons aged ≥30 years and among individuals with nighttime sleep duration <8h or social jetlag ≥1h. As far as we know, this is the first observational study to investigate the relationship between chronotype and depressive status among the infertility population who underwent assisted reproductive technology treatment. However, findings should be interpreted cautiously as the chronotype were based on self-reported MEQ-5 scores that may be misclassified.
Strengths and limitations
Several strengths of the current study in regard to the methods and design, including selected infertile couples with more fully displayed psychological characteristics as research objects, which ensured the credibility of the research results to a certain extent. Additionally, in terms of exposure assessment, we systematically collected sleep characteristics through the 22-item Sleep Factor Questionnaire (SFQ)37. Meantime, we also adjusted for other sleep factors that may influence the outcome for incident depression in the analysis. We were also the first group to explore the relationships between chronotype and depressive symptoms in infertile couple, although no partner interdependence effects may not be found in the relationships.
Whereas, some limitations to the present study should be noted. First, since our design was cross-sectional studies rather than longitudinal studies or randomized clinical trials, which may describe associations, but are limited to causal inference. However, this study can still provide clues about risk factors for depressive symptoms and may provide the scientific basis for future studies. Second, participants’ chronotype and depressive symptoms were self-reported on the day of oocyte retrieval based on validated scales with good reliability and validity, which still may lead to bias and reduce the power of our evidence in some respects. Third, the study was based on couples undergoing infertility treatment, and the findings may not be directly generalizable to other populations. Also, the data on sleep characteristics in this study was based on the past six months, which may not reflect long-term sleep habits. Also, this study lacks objective indicators to explain the biological mechanism behind the relationship between chronotype and depressive symptoms in infertile couples, future studies need to be further verified.
Interpretation
Previous studies of chronotype and depression in infertility patients were quite limited, First, most studies agree that chronotype may be significantly associated with negative affect, including the general population, the elderly, pregnant women, children, or adolescents, which is consistent with our findings in the infertility population. Similar findings were observed in a Mendelian randomization study, where earlier diurnal preference was shown to be associated with a 23% lower risk of major depressive disorder 38. Secondly, an animal study of cortisol-induced depression-like behavior, suggested that circadian rhythms may cause or predict episodes of depression39. However, a recently conducted longitudinal study showed that chronotype did not predict the duration of depression or anxiety disorders 40. The above differences may be due to the study subjects, whether the findings from animal experiments are directly analogous to humans, as well as how well chronotype predict the course of depressive illness, further clinical trials or cohort studies are still needed to investigate these aspects of health effects. Thirdly, Chronotype not only to be associated with a depressive disorder diagnosis but also with the severity of the disorder40. Interestingly, a 7-year follow-up study showed that changes in chronotype was only associated with the severity of depressive symptoms but not with anxiety symptoms 41. Next, the independent role of chronotype has also been reported. A study found that daytime sleepiness and sleep debt mediated the effects of evening chronotype preferences in young adult college students increasing the risk of depression and anxiety, but not in the general population of young adults 42. Moreover, studies have confirmed that evening chronotype have a higher risk of depression than other chronotypes and that the association exists independently of perceived stress, poor sleep, and insufficient sleep duration43, 44. Undoubtedly, the findings of these studies reinforce the importance of studying the role of chronotype in depression. Additionally, chronotype studies in infertility populations have shown that morning chronotype may be the risk factor for IVF-ET outcomes, with the lowest rates of clinical pregnancy and live birth and the highest rate of miscarriage 30. Another prospective study also showed that mid-sleep time (MST) earlier than 2:21 a.m. (<2:21 a.m.) or later than 3:00 a.m. (≥3:00 a.m.) was negatively associated with fertilization rates 29. The effect of chronotype on health varies across studies with different outcome variables observed. Although morning chronotype was shown to be a protective factor for depressive symptoms in our study, it may also be a risk factor for physical health, more studies with larger sample sizes are necessary to determine the effect of time type on the infertility population.
Our results confirm and extend previous epidemiological studies showing the sex-specific effects of chronotype on depressive status. A study among 5,550 non-shift working adults in Korea found that late chronotype was associated with a 2.9-fold increased risk of depression in women, but not in men 45. Our findings are broadly consistent with previous studies and extend these observations further into the infertility population. Specifically, we found through APIM that own depressive symptoms may not be influenced by the chronotype of the partner. Notably, our findings also showed a significant interaction between age and chronotype on the odds of developing depressive symptoms, whereby the health benefits of depressive symptoms were greater for morning chronotype and neutral chronotype in participants aged ≥30 years. The chronotype depend on genetic and age-related factors, and it becomes earlier as aging progresses46, generally adolescents and young adults show the evening chronotype 47. A study with a predominantly rural population reported that mild to severe depression was significantly associated with later chronotype and higher social jetlag (> 2h), especially in ages 31-40 years48, which is broadly consistent with our study. In addition, we observed that sleep deprivation and high social jetlag may be another cause of depressive symptoms, morning chronotype and neutral chronotype produced stronger health benefits for depressive symptoms in subjects with high social jetlag (≥1h) and sleep deprivation (<8h). A large number of epidemiological studies have explored the relationship between sleep deprivation and depression, showing sleep deprivation to be an important risk factor for the development of depression and this association may be driven by the pathway of sleep disorder. Also, one recent study has shown that social jetlag is significantly associated with depression and independent of sleep debt49. It is partially consistent with our conjecture, but further clinical trials or cohort studies are needed to validate these health effects in the future.
Although the underlying mechanisms on the association between chronotype and depressive symptoms are poorly understood, there are possible mechanisms. First, it has been well-documented that the amygdala reactivity plays a crucial role in emotional outcomes50. Specifically, the later chronotype was associated with increased reactivity of the amygdala to negative affective stimuli, and similar findings have been reported in patients with depression and in high-risk populations, including highly neurotic and with family history of depression 51. Secondly, apart from the degree of amygdala activation related to emotional processing, there are also differences in the functional connectivity of the amygdala and dorsal anterior cingulate cortex. Horne and colleagues found significantly reduced functional connectivity between amygdala and dorsal anterior cingulate cortex in the later chronotype51. It means that the evening chronotype may produce a stronger emotional response to negative stimuli, which inhibits the dorsal anterior cingulate regulation to the amygdala and thus affects emotion modulation.