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.