Differences in 24-h autonomic nervous activity between hypersomnia and non-hypersomnia with major depressive disorder outpatients: An observational study

doi:10.21203/rs.3.rs-6478810/v1

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Differences in 24-h autonomic nervous activity between hypersomnia and non-hypersomnia with major depressive disorder outpatients: An observational study

https://doi.org/10.21203/rs.3.rs-6478810/v1

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published 29 Oct, 2025

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Background

Hypersomnia, defined as a total sleep time of over 10 h within a 24-h period, is common in patients with major depressive disorder (MDD). The circadian rhythm of patients with hypersomnia and depression is disturbed; however, the difference in patients with non-hypersomnia is unclear. We aimed to clarify the difference in autonomic nervous system (ANS) activity during a 24-h period between hypersomnia and non-hypersomnia patient groups with MDD.

Methods

This study included outpatients diagnosed with MDD, who were placed in either the hypersomnia or non-hypersomnia group based on the Diagnostic and Statistical Manual of Mental Disorders-5 criteria. Heart rate variability data were collected for 24 h using electrocardiograms. Group differences in ANS activity during daytime and nighttime were compared using the t-test. A general linear model was used with the following variables to compare continuous 24-h data between groups: heart rate; natural logarithm (ln) of the low frequency domain (LF) as sympathetic and parasympathetic nerve activity; ln of the high frequency domain (HF) as parasympathetic nerve activity; ln LF/HF as objective variables indicating sympathetic domination; the presence or absence of hypersomnia every hour during the 24-h period as explanatory variables; age and body mass index as variable effects.

Results

Nine out of the twenty-five participants with MDD exhibited hypersomnia. The hypersomnia group rarely showed differences in ln HF and ln LF/HF between daytime and nighttime. In the non-hypersomnia group, ln HF was significantly increased and ln LF/HF was significantly decreased in the nighttime compared with daytime. Ln HF was significantly higher in the hypersomnia group versus the non-hypersomnia group in the evening. However, LF/HF was significantly higher in the hypersomnia group early in the morning.

Conclusions

Patients with hypersomnia had no change in parasympathetic activity between daytime and nighttime. In the hypersomnia group, hourly changes showed that ln HF was significantly higher from 17:00 to 22:00 h and ln LF/HF was significantly higher before waking, at 3:00–4:00 h, relative to the non-hypersomnia group. We observed that ANS activity differed depending on whether hypersomnia, a risk factor for relapse and bipolar disorder, is present.

Autonomic nervous system

Major depressive disorder

Hypersomnia

Heart rate variability

Quick Inventory of Depressive Symptomatology-Self-Report

Circadian rhythm

Mood disorders, such as unipolar major depressive disorder (MDD) and bipolar disorder, are major global public health problems [1]. Hypersomnia is defined as a total sleep time of over 10 hours within a 24-hour period and is common in patients with mood disorders, including MDD [2]. Hypersomnia is predictive of the prognosis of patients with MDD. Furthermore, it is associated with treatment resistance, symptomatic relapse, increased risk of suicide, and functional impairment [3]. Reportedly, the prevalence of hypersomnia was lower than that of insomnia in patients with major depressive episodes [4, 5]. Residual symptoms worsen the prognosis of patients with MDD. In a study of 1,133 outpatients with non-psychotic MDD, the hazard ratio for hypersomnia was 1.19 after achieving remission with level 1 treatment (citalopram for up to 14 weeks) [6]. However, the risk of bipolar disorder in patients with comorbid hypersomnia and insomnia increased by two to three-fold [5, 6]. Sleeping for over 10 h in a 24-hour period is a crucial symptom for outpatients with MDD, regardless of whether their depressive state is mild.

Melancholic depression and atypical depression are two distinct subtypes of MDD. Hypersomnia is a typical symptom of atypical depression. Atypical depression also presents mood reactivity to positive events and at least two of the following symptoms: increased appetite or increased weight, hypersomnia, leaden paresis, and chronic rejection sensitivity [2]. In addition, the depressive symptoms are worse in the evening [7]. In contrast, melancholic depression presents with insomnia and reduced appetite, and the depressive symptoms are worse in the morning [7]. Therefore, the patterns of depressive symptoms differ between patients with hypersomnia and those with non-hypersomnia.

The alteration of sleep-awake patterns, melatonin and cortisol secretion patterns, and changes in body temperature are the hallmarks of MDD [8]. Notably, depression is caused by abnormal regulation of the hypothalamic–pituitary–adrenal (HPA) axis and activation of inflammatory responses [9, 10]. Corticotropin releasing hormone (CRH) is released from the hypothalamus in response to stress and causes the secretion of adrenocorticotropic hormone (ACTH) from the anterior pituitary gland. This causes cortisol release from the adrenal cortex into the blood [11]. Increased cortisol levels suppress the secretion of CRH and ACTH through a negative feedback mechanism. Patients with melancholic depression exhibit HPA axis dysfunction, including excessive ACTH and cortisol secretion and non-suppression of cortisol secretion after dexamethasone administration [10, 12, 13]. Reportedly, CRH is reduced in the central nervous system of patients with atypical depression. In addition, HPA axis activity is reportedly reduced in atypical depression, compared to melancholic depression [14, 15]. Normally, HPA axis activation occurs under the influence of non-associated stress associated with circadian rhythm control, in which the highest cortisol levels are observed early in the morning [9, 11]. Cortisol secretion increases early in the morning in melancholic depression, similar to healthy individuals, and it peaks around 08:00, but the level of secretion is high relative to that of healthy individuals [16]. Stewart et al. reported that the regulation of cortisol secretion differed between atypical and melancholic depression [17]. Therefore, we consider that the circadian rhythm in atypical depression differs from that of melancholic depression.

Since hypersomnia is a characteristic of atypical depression with low cortisol levels which affect sleep-awake patterns, the circadian rhythm of patients with hypersomnia and MDD might differ from those with non-hypersomnia with MDD. Dysfunctional circadian rhythms have also been shown to be causally involved in the pathogenesis of bipolar disorder [18]. Since the risk of developing bipolar disorder in patients with hypersomnia and MDD is high [5], we consider that the circadian rhythm differs in hypersomnia or non-hypersomnia.

Heart rate variability (HRV) is a useful method for non-invasively comprehending the circadian rhythm of outpatients [19]. Previous research have been conducted on the circadian rhythm and autonomic nervous system (ANS) activity of patients with MDD [20–22]. Similar to healthy individuals, the Parasympathetic nervous system (PNS) index shows two levels in patients with depression, one high and one low, over 24 h; however, the transition has been shown to take approximately 10 h [23]. The PNS index, which is predominantly high during sleep, becomes low within 1 h of waking in healthy individuals [23]. The differences in ANS activity between patients with MDD and healthy individuals have been shown in previous studies. However, the differences in the circadian rhythm of the ANS between patients with hypersomnia with MDD and those with non-hypersomnia with MDD are still unclear.

To determine the difference in the ANS activity and circadian rhythm of patients with hypersomnia and non-hypersomnia, it is useful to discuss physiological risk factors which are associated with developing bipolar disorder or recurrent depression. Therefore, in this study, we aimed to identify differences in ANS activity during a 24-h period between hypersomnia and non-hypersomnia patient groups with MDD.

Participants

Data was collected at the outpatient department of one psychiatric hospital and two psychiatric clinics from February to August 2021. We included patients who (1) were aged > 20 years, (2) visited a doctor regularly at the outpatient departments of these institutions, (3) met the diagnostic criteria for MDD, (4) obtained approval from their doctor about participating in this study. We excluded postoperative patients, those with complications from any progressive physical disease, those receiving pacemaker implantation, and those requiring inpatient treatment.

Data collection

We recorded participants’ characteristics (age, sex, height, weight), psychological history, age of onset, and time from onset of depression. Data on medical history was obtained from medical records at the respective institutions. Subjective depressive symptoms were investigated using the 16-item Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR) [24]. This scale consists of nine categories and 16 items and is used to evaluate the severity of depression clinically. The Japanese version of QIDS-SR was used for this study. Participants answered 16 questions in four categories. These included four questions each on sleep and appetite, two on psychomotor self-evaluation, and one question each on low mood, impaired concentration/decision-making, negative self-view, suicidal ideation, lack of involvement, and loss of energy. A score of 0–3 points was assigned for each question. The score for all other items was directly included. Only the highest score among the questions on sleep, appetite, and psychomotor self-evaluation was recorded. The total scores ranged from 0–27 points. A score of 0–5 was considered normal, 6–10 as mild, 11–15 as moderate, 16–20 as severe, and 21–27 as extremely severe.

HRV data served as an indicator of ANS activity. The study participants were fitted with a Holter electrocardiograph (FM-960, Holter recorder, Fukuda Denshi, Tokyo, Japan) for 24-h, and electrocardiograms were obtained. We divided the electrocardiogram data into 5-min intervals, expressed the magnitude of variation in the RR interval as a function of frequency, and performed frequency analysis to quantify variables by dividing them into different components at different frequencies. We collected heart rate (HR) data in the low frequency domain (LF, 0.04–0.15 Hz) and high frequency domain (HF, 0.15–0.4 Hz) from the electrocardiogram data [25]. HRV is the variation in the RR interval of heartbeats and reflects the activity of the efferent sympathetic and vagus nerves [26]. The normal RR interval recorded on the electrocardiogram is due to the depolarization of the sinus node. LF reflects sympathetic and parasympathetic nerve activity. HF reflects parasympathetic or vagal nerve activity, whereas a higher LF/HF ratio reflects sympathetic domination [25, 27]. The average ANS activity index was calculated from the 24-h data on increases and decreases in HR and individual self-reports. We defined “nighttime” as the period from bedtime at night to waking the next day and “daytime” as the rest of the day after waking.

For the question on hypersomnia in the QIDS-SR, the participants who answered “0: no problem” were placed in the non-hypersomnia group. Those who answered “1: about 10 h of sleep, including nap time within a 24-h period”, or “2: about 12 h of sleep, including nap time within a 24-h period”, or “3: > 12 h of sleep, including nap time within a 24-h period”, were placed in the hypersomnia group. Group attributes, including body mass index (BMI), QIDS-SR score, and clinical characteristics, were calculated, along with their average for daytime and nighttime.

Statistical analysis

A t-test was conducted to determine if the hypersomnia and non-hypersomnia groups had different attributes. The average values of HR and ANS indicators (LF, HF, LH/HF) were calculated hourly and during the daytime and nighttime for each group. The normality of daytime and nighttime ANS indices and hourly values for each group were confirmed using the Shapiro-Wilk test. In each group, normality was observed only in HR during daytime and nighttime but not in the other ANS indicators, although there were some exceptions. Therefore, data for ANS indicators other than HR were logarithmically transformed to evaluate the differences in the ANS activity of each group between daytime and nighttime. A general linear model was used to compare continuous 24-h data between groups with HR, natural logarithm (ln) of LF, ln HF, and ln LF/HF as objective variables, the presence or absence of hypersomnia and every hour during the 24-h as explanatory variables, and age and BMI as variable effects. Multiple comparisons were not adjusted for in this exploratory data analysis. The IBM Statistical Package for Social Sciences (Ver. 29) was used for analysis. Statistical significance level was set at p < 0.05.

Ethics statement

This study was conducted according to the guidelines of the Declaration of Helsinki and was approved by the ethics review committee of the researchers’ institution (approval number: 20–129). The researchers provided written and verbal explanations to the participants about the study outline, its purpose, methods, protection of personal information, guarantee of free will participation, and publication of the results. Consent to participate in the study was obtained using a consent form.

Participants’ Attributes and clinical characteristics

This study included 25 study participants, nine were categorized as having hypersomnia and 16 as having non-hypersomnia. Of the nine participants with hypersomnia, six had sleep disturbances, difficulty falling asleep, arousal during sleep, and episodes of early-morning awakening. The hypersomnia group included five men (55.6%), with an average age of 50.44 years (standard deviation [SD] 11.65). The average length since MDD diagnosis was 9 years (SD 9.08), and the average BMI was 25.65 (SD 5.63) in this group. The non-hypersomnia group included 10 men (62.5%), with an average age of 52.31 years (SD 10.31). The average time since MDD diagnosis was 10.25 years (SD 5.73), and the average BMI was 28.30 (SD 5.56). The average QIDS-SR score was 8.78 (SD 3.80) and 7.75 (SD 6.87) in the hypersomnia and non-hypersomnia groups, respectively. No significant differences were observed between the hypersomnia and non-hypersomnia groups regarding average age, age at the time of MDD onset, time since MDD diagnosis, BMI, or the QIDS-SR scores. All patients had taken medication (antidepressants, antipsychotics, or sedative-hypnotics), but there was no difference in medication equivalent level between the hypersomnia and non-hypersomnia groups. None of the participants in either group were treated with bright light therapy (Table 1).

Differences in ANS activity between daytime and nighttime in patients with MDD with and without hypersomnia

ANS activity was compared between the hypersomnia and non-hypersomnia groups during daytime and nighttime. In the hypersomnia group, HR was significantly decreased during nighttime compared to daytime, whereas other indices showed no significant differences. In the non-hypersomnia group, HR and ln LF/HF were significantly reduced,

Table 1

Demographic and clinical characteristics of the participants
	Hypersomnia (n = 9)	Non-hypersomnia (n = 16)	t-value	p-value
Age [years, mean(SD)]	50.44 (11.65)	52.31 (10.31)	-0.415	0.682 ^a
Sex [men, n (%)]	5 (55.6)	10 (62.5)		0.734 ^b
Age of onset [years, mean(SD)]	41.44 (12.36)	42.06 (8.97)	-0.144	0.886 ^a
Length since diagnostic of MDD [years, mean(SD)]	9 (9.08)	10.25 (5.73)	-0.424	0.676 ^a
BMI [mean(SD)]	25.65 (5.63)	28.30 (5.56)	-1.142	0.265 ^a
QIDS-SR [mean(SD)]	8.78 (3.80)	7.75 (6.87)	0.412	0.684 ^a
Sleep disturbance [n (%)]	9 (100.0)	14 (87.5)
Difficulty getting to sleep [n (%)]	4 (44.4)	9 (56.2)
Arousal during sleep [n (%)]	6 (66.7)	10 (62.5)
Early-morning awakeing [n (%)]	4 (44.4)	9 (56.2)
Hypersomnia [ n (%)]	9 (100.0)	0 (0.0)
Daytime length [mean]	16hours 18min	16hours 39min
Nghttime length [mean]	7hours 41min	7hours 20min
Sleep-onset time [mean]	22:51	23:13
Arising time [mean]	6:32	6:33
Antidepressant medication use [n (%)]	8 (88.9)	13 (62.5)
Tricyclic [n (%)]	0 (0.0)	2 (12.5)
SSRI [n (%)]	3 (33.3)	6 (37.5)
SNRI [n (%)]	5 (55.6)	6 (37.5)
NaSSA [n (%)]	1 (11.1)	3 (18.8)
Imipramine equivalents (mg / day) [mean (SD)]	189.06 (111.69)	145.19 (93.20)	0.972	0.343^a
Sedative-hypotic medication use [n (%)]	6 (66.7)	14 (87.5)
Diazepam equivalents ( mg / day) [mean (SD)]	8.95 (6.16)	6.99 (5.84)	0.679	0.506^a
Antipsychotic medication use [n (%)]	4 (44.4)	9 (56.2)
Chlorpromazine equivalents (mg / day) [mean (SD)]	93.75 (37.50)	116.67 (135.21)	-0.326	0.750^a

SD, standard deviation; BMI, Body Mass Index; QIDS, Quick Inventory of Depressive Symptomatology Self-Report; Tricyclic, tricyclic antidepressant; SSRI, serotonin selective reuptake inhibitor; SNRI, serotonin norepinephrine reuptake inhibitor; NaSSA, noradrenergic and specific serotonergic antidepressant.

a, t-test; b, Fisher’s exact test.

whereas ln HF was significantly increased during nighttime compared to daytime (Figs. 1–4).

(insert Figs. 1–4 here)

Differences in ANS activity every hour in patients with MDD with and without hypersomnia

An hourly assessment of HR and ANS activity in the participants with hypersomnia and non-hypersomnia showed a significant difference in all measured indices. HR was significantly lower in the hypersomnia group than in the non-hypersomnia group from 11:00–13:00 hours, at 15:00 h, and from 17:00–19:00. In addition, ln LF was significantly higher in the hypersomnia group relative to the non-hypersomnia group at 12:00 h and from 19:00–22:00 h. Further, ln HF was significantly higher in the hypersomnia group than in the non-hypersomnia group from 17:00–22:00 h. In the hypersomnia group, ln LF/HF was significantly higher at 3:00 and 4:00 h and significantly lower at 17:00 h, compared to the non-hypersomnia group (Fig. 5).

(insert Fig. 5 here)

To our knowledge, this is the first study to show differences in ANS activity between daytime and nighttime in patients with MDD with and without hypersomnia, which identified hypersomnia as over 10 h of sleep in a 24-hour period, according to the DSM-5 criteria. Previous studies had used the Pittsburg Sleep Quality Index and Epworth Sleepiness Scale (ESS) to evaluate hypersomnia [28–31]. These studies measured the frequency of sleepiness in daily life, unlike our study, which solely used DSM-5 criteria for identifying hypersomnia. Yang et al. had previously reported that daytime sleepiness was not associated with ANS activity [32]. In their study, hypersomnia was evaluated by measuring daytime sleepiness using the ESS. One possible reason for observing a correlation between hypersomnia and ANS activity was because the present study criterion was hypersomnia.

In our study, the hypersomnia group rarely showed differences in ln HF between daytime and nighttime. An earlier study reported that the HF during sleep increased compared to the HF when awake [33]. In this study, the lack of difference in PNS activity between daytime and nighttime sleep observed in the hypersomnia group might be due to PNS activation during daytime sleep. In the non-hypersomnia group, nighttime ln HF was significantly higher than during the daytime, while ln LF/HF was lower— these findings differed from that of the hypersomnia group. According to previous reports, nighttime HF was significantly higher than daytime HF, whereas ln LF/HF was lower [19, 34]. Therefore, the lack of change in HF and LF/HF between nighttime and daytime can be considered a characteristic of the circadian rhythm in hypersomnia. The participants in this current study had mild depression. However, daytime and nighttime ANS activity differed between patients in the hypersomnia and non-hypersomnia groups.

Hourly changes showed that ln HF, an indicator of PNS activity, was significantly higher from 17:00–22:00 h in the hypersomnia group compared to the non-hypersomnia group. This difference can be attributed to the increase in ln HF at 22:00 h in the hypersomnia group and the decrease in ln HF of non-hypersomnia group from the afternoon. In the non-hypersomnia group, In HF was lowest at 19:00 h during the 24-h period and increased toward sleep-onset time. A previous study reported that the ln HF of patients with depression peaks at 04:30 h but is lowest at approximately 16:30 h and then increased 04:30h again [23]. This indicates that in the hypersomnia group, ln HF peaked before falling asleep and only decreased slightly upon waking. In addition, it decreased toward evening and increased from evening upwards, as seen in patients with depression.

Furthermore, ln LF/HF, an indicator of sympathetic activity, was significantly higher before waking, at 03:00 and 04:00 h, in the hypersomnia group, compared to the non-hypersomnia group. The significant differences can be attributed to the variation in ln LF/HF patterns. In the hypersomnia group, ln LF/HF increased from 23:00 h and peaked at 03:00 h. In contrast, in the non-hypersomnia group, ln LF/HF was lowest from 01:00–03:00 h within a 24-hour period and rapidly increased from 04:00 h. There are a few studies on the LF/HF ratio of patients with MDD during a 24-h period. Previous research indicated that the LF/HF of male patients with depression was highest from 10:30–12:00 h, whereas that of female patients was highest at approximately 18:00 h [21]. However, the participants included not only patients with MDD but also those in the depressive state of bipolar disorder. Thus, the 24-h LF/HF of patients with MDD was not fully clarified. Hypersomnia is a symptom of atypical depression. Geovanni et al. reported that cortisol secretion level is lower in atypical depression than in melancholic depression, which lowers the activity of the HPA axis, but no significant difference was observed [35]. Thus, the present study showed that the ln LF/HF in participants with hypersomnia was significantly lower than that in those with non-hypersomnia at 17:00 h. However, evidence supporting this is unclear because no previous research has reported similar findings. In patients with hypersomnia, there appears to be no change from parasympathetic to sympathetic activity when transitioning from sleep to the waking state, whereas high parasympathetic activity in the evening indicates a disrupted circadian rhythm.

In the present study, ln HF, a measure of parasympathetic activity, decreased from early morning, stayed low during the daytime, and increased at night in the non-hypersomnia group. Parasympathetic activity becomes dominant when patients in the non-hypersomnia group transition from being awake to a sleeping state. Previous studies report that the parasympathetic activity of healthy individuals peaks at 5:00 or 06:00 h before waking, with peak levels approximately twice as high as the lowest levels [34, 36]. In healthy individuals, sympathetic activity becomes dominant when translating from sleep to being awake, sympathetic activity becomes dominant [19, 23]. Furthermore, ln LF/HF, an indicator of sympathetic activity, becomes rapidly active, increases by approximately 0.4 points within 1 h after 04:00 or 05:00 h in the non-hypersomnia group, stays active during daytime hours, and reduces at night. HR increases around waking time shows no dynamic reduction during daytime hours and decreases from 19:00 h to midnight. According to a previous study, in healthy individuals, LF/HF was observed to peak at high noon, which was the highest level during daytime, and then decrease until midnight [37]. Therefore, patients in the non-hypersomnia group display a pattern of ANS activity similar to healthy individuals throughout the day.

The circadian rhythm of patients with MDD in the hypersomnia group differed from those in the non-hypersomnia group because of the following reasons: (1) hypersomnia parasympathetic and sympathetic activities did not differ between daytime and nighttime in the hyposomnia group. In contrast, in the non-hypersomnia group, nighttime parasympathetic activity was higher than that in the daytime, and nighttime sympathetic activity was lower; (2) parasympathetic activity was significantly higher in the hypersomnia group from 17:00–22:00 h compared to the non-hypersomnia group; and (3) sympathetic activity peaked at 03:00 h in the hypersomnia group, which was significantly higher than that in the non-hypersomnia group. Previous research reports that dysregulation or instability of circadian patterns and sleep-wake cycles contribute to the development of bipolar disorder because circadian rhythm is associated with emotion or activity regulation. The mood stabilizer, lithium, affects the genes of the circadian clock, indicating a link between the regulation of circadian rhythm genes and bipolar disorder [18]. Impaired circadian rhythms in patients with hypersomnia might be the cause of bipolar disorder.

This study has some limitations. All participants received medications. We found no difference in any medication dose between the hypersomnia and non-hypersomnia groups; however, the earlier research reported that tricyclic antidepressants had a significant decreasing effect on HR [38]. Thus, medication could have affected the HRV measurements in our study.

This study included participants with mild depressive symptoms. Many studies reporting ANS activity in patients with MDD typically compared them with healthy controls. Similarly, in the present study, if we can further clearly characterize ANS activity in patients with and without hypersomnia, it may help to identify physiological factors that increase the risk of recurrence.

This present study reported differences in ANS activity within a 24-h period in hypersomnia and non-hypersomnia groups of patients with MDD. Patients with hypersomnia had no change in parasympathetic activity between daytime and nighttime. In the hypersomnia group, hourly changes showed that ln HF was significantly higher from 17:00–22:00 h and ln LF/HF was significantly higher before waking, at 3:00 and 4:00 h, compared to the non-hypersomnia group. ANS activity depending on whether hypersomnia, a risk factor for relapse and bipolar disorder, is present.

ACTH

adrenocorticotropic hormone

ANS

autonomic nervous system

BMI

body mass index

CRH

corticotropin releasing hormone

DSM-5

Diagnostic and Statistical Manual of Mental Disorders Fifth Edition

ESS

Epworth Sleepiness Scale

high frequency domain

HPA

hypothalamic–pituitary–adrenal

heart rate

HRV

heart rate variability

low frequency domain

Natural logarithm

MDD

major depressive disorder

PNS

Parasympathetic nervous system QIDS-SR:Quick Inventory of Depressive Symptomatology-Self-Report

Ethics approval and consent to participate

This study was conducted according to the guidelines of the Declaration of Helsinki. The researchers provided written and verbal explanations to the participants regarding the study’s outline, purpose, methods, protection of personal information, guarantee of free will participation, and publication of the results. Informed consent to participate in the study was obtained using a consent form. The Nagoya University Graduate School of Medicine approved this study (approval number: 20-129).

Consent for publication

Written informed consent for publication was obtained from all participants involved in this study. All personal identifiers were removed to ensure anonymity.

Availability of data and materials

The datasets used and analyzed during the current study are available from the corresponding author upon reasonable request.

Competing interests

The authors declare no competing interests.

Funding

This work was supported by the Japan Society for the Promotion of Science (JSPS) Grants-in-Aid for Scientific Research (KAKENHI) (grant number JP22K10826).

Authors’ contributions

EK conceptualized the study, wrote the first draft of the manuscript, and conducted the statistical analysis. MN, YM, AK, SO, CI, and MK assisted in the statistical analysis and in editing the manuscript. NN designed the study and supervised the implementation of the study. All authors have read and approved the final manuscript.

Acknowledgments

This study acknowledges the cooperation and support of the patients who participated. We thank Dr. Michiharu Sekiya, director of Younan Hospital, Dr. Hirohiko Kuroda, director of Gifu Stress Care Clinic, Dr. Kenji Hamanaka, director of Suzuka Mental Clinic, and all hospital staff who cooperated with the survey. We also thank Editage for English language editing.

World Health Organization. Depression and Other Common Mental Disorders: Global Health Estimates. 2017. https://iris.who.int/bitstream/handle/10665/254610/WHO-MSD-MER-2017.2-eng.pdf. Accessed 12 Feb 2025.
American Psychiatric Association. Diagnostic and statistical manual of mental disorders: DSM-5. 5th ed. Washington, DC: American Psychiatric Publishing; 2013.
Plante DT. Hypersomnia in mood disorders: a rapidly changing landscape. Curr Sleep Med Rep. 2015;1:122-30.
Murru A, Guiso G, Barbuti M, Anmella G, Verdolini N, Samalin L, et al. The implications of hypersomnia in the context of major depression: results from a large, international, observational study. Eur Neuropsychopharmacol. 2019;29:471-81.
Geoffroy PA, Hoertel N, Etain B, Bellivier F, Delorme R, Limosin F, et al. Insomnia and hypersomnia in major depressive episode: prevalence, sociodemographic characteristics and psychiatric comorbidity in a population-based study. J Affect Disord. 2018;226:132-41.
Sakurai H, Suzuki T, Yoshimura K, Mimura M, Uchida H. Predicting relapse with individual residual symptoms in major depressive disorder: a reanalysis of the STAR*D data. Psychopharmacol. 2017;234:2453-61.
Gold PW. The organization of the stress system and its dysregulation in depressive illness. Mol Psychiatry. 2014;20:32-47.
Vadnie CA, McClung CA. Circadian rhythm disturbances in mood disorders: insights into the role of the suprachiasmatic nucleus. Neural Plast. 2017;2017:1504507.
Mikulska J, Juszczyk G, Gawrońska-Grzywacz M, Herbet M. HPA axis in the pathomechanism of depression and schizophrenia: new therapeutic strategies based on its participation. Brain Sci. 2021;11:1298.
Hassamal S. Chronic stress, neuroinflammation, and depression: an overview of pathophysiological mechanisms and emerging anti-inflammatories. Front Psychiatry. 2023;14:1130989.
Herman JP, McKlveen JM, Ghosal S, Kopp B, Wulsin A, Makinson R, et al. Regulation of the hypothalamic-pituitary-adrenocortical stress response. Compr Physiol. 2016;6:603-21.
Antonijevic I. HPA axis and sleep: identifying subtypes of major depression. Stress. 2008;11:15-27.
Sachar EJ, Puig-Antich J, Ryan ND, Asnis GM, Rabinovich H, Davies M, et al. Three tests of cortisol secretion in adult endogenous depressives. Acta Psychiatr Scand. 1985;71:1-8.
Gold PW, Loriaux DL, Roy A, Kling MA, Calabrese JR, Kellner CH, et al. Responses to corticotropin-releasing hormone in the hypercortisolism of depression and Cushing's disease. Pathophysiologic and diagnostic implications. N Engl J Med. 1986;314:1329-35.
Juruena MF, Bocharova M, Agustini B, Young AH. Atypical depression and non-atypical depression: is HPA axis function a biomarker? A systematic review. J Affect Disord. 2018;233:45-67.
Wong ML, Kling MA, Munson PJ, Listwak S, Licinio J, Prolo P, et al. Pronounced and sustained central hypernoradrenergic function in major depression with melancholic features: relation to hypercortisolism and corticotropin-releasing hormone. Proc Natl Acad Sci U S A. 2000;97:325-30.
Stewart JW, Quitkin FM, McGrath PJ, Klein DF. Defining the boundaries of atypical depression: evidence from the HPA axis supports course of illness distinctions. J Affect Disord. 2005;86:161-7.
Murray G, Harvey A. Circadian rhythms and sleep in bipolar disorder. Bipolar Disord. 2010;12:459-72.
Sammito S, Sammito W, Böckelmann I. The circadian rhythm of heart rate variability. Biol Rhythm Res. 2016;47:717-30.
Conrad A, Wilhelm FH, Roth WT, Spiegel D, Taylor CB. Circadian affective, cardiopulmonary, and cortisol variability in depressed and nondepressed individuals at risk for cardiovascular disease. J Psychiatr Res. 2008;42:769-77.
Koga N, Komatsu Y, Shinozaki R, Ishida I, Shimizu Y, Ishimaru S, et al. Simultaneous monitoring of activity and heart rate variability in depressed patients: a pilot study using a wearable monitor for 3 consecutive days. Neuropsychopharmacol Rep. 2022;42:457-467.
Chang LH, Huang MH, Lin IM. Developing a five-minute normative database of heart rate variability for diagnosing cardiac autonomic dysregulation for patients with major depressive disorder. Sensors (Basel). 2024;24:4003.
Li B, Guo S, Xu H, Zhou Y, Zhang M, Wang J, et al. Abnormal circadian rhythm of heart rate variability and their association with symptoms in patients with major depressive disorder. J Affect Disord. 2024;362:14-23.
Rush AJ, Trivedi MH, Carmody TJ, Ibrahim HM, Markowitz JC, Keitner GI, et al. Self-reported depressive symptom measures: sensitivity to detecting change in a randomized, controlled trial of chronically depressed, nonpsychotic outpatients. Neuropsychopharmacology. 2005;30:405-16.
Malik M, Camm AJ, Bigger JT, Breithardt Gn, Cerutti S, Cohen RJ, et al. Heart rate variability: Standards of measurement, physiological interpretation, and clinical use. Circulation. 1996;93:1043-65.
Heart rate variability: standards of measurement, physiological interpretation and clinical use. Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Circulation. 1996;93:1043-65.
Shaffer F, Ginsberg JP. An overview of heart rate variability metrics and norms. Front Public Health. 2017;5:258.
Yeo H, Lee J, Jeon S, Hwang Y, Kim J, Lee S, et al. Moderating effect of shift work on sleep and depression in individuals at high risk of bipolar disorder. J Affect Disord. 2024;359:206-14.
Maruani J, Boiret C, Leseur J, Romier A, Bazin B, Stern E, et al. Major depressive episode with insomnia and excessive daytime sleepiness: A more homogeneous and severe subtype of depression. Psychiatry Res. 2023;330:115603.
Nevsimalova S, Skibova J, Galuskova K, Prihodova I, Dostalova S, Maurovich-Horvat E, et al. Central disorders of hypersomnolence: association with fatigue, depression and sleep inertia prevailing in women. Brain Sci. 2022;12:1491.
Kollar B, Siarnik P, Valovicová K, Hanus O, Turcani P, Klobucnikova K. Mood disorders in patients with hypersomnia: comparison of sleep-related breathing disorders versus narcolepsy. Neuro Endocrinol Lett. 2021;42:395-402.
Yang AC, Tsai SJ, Yang CH, Kuo CH, Chen TJ, Hong CJ. Reduced physiologic complexity is associated with poor sleep in patients with major depression and primary insomnia. J Affect Disord. 2011;131:179-85.
Boudreau P, Yeh WH, Dumont GA, Boivin DB. Circadian variation of heart rate variability across sleep stages. Sleep. 2013;36:1919-28.
Adamopoulos S, Ponikowski P, Cerquetani E, Piepoli M, Rosano G, Sleight P, et al. Circadian pattern of heart rate variability in chronic heart failure patients. Effects of physical training. Eur Heart J. 1995;16:1380-6.
Cizza G, Ronsaville DS, Kleitz H, Eskandari F, Mistry S, Torvik S, et al. Clinical subtypes of depression are associated with specific metabolic parameters and circadian endocrine profiles in women: the power study. PLoS One. 2012;7:e28912.
Nakagawa M, Iwao T, Ishida S, Yonemochi H, Fujino T, Saikawa T, et al. Circadian rhythm of the signal averaged electrocardiogram and its relation to heart rate variability in healthy subjects. Heart. 1998;79:493-6.
Boudreau P, Yeh WH, Dumont GA, Boivin DB. A circadian rhythm in heart rate variability contributes to the increased cardiac sympathovagal response to awakening in the morning. Chronobiol Int. 2012;29:757-68.
Kemp AH, Brunoni AR, Santos IS, Nunes MA, Dantas EM, Carvalho de Figueiredo R, et al. Effects of depression, anxiety, comorbidity, and antidepressants on resting-state heart rate and its variability: an ELSA-Brasil cohort baseline study. Am J Psychiatry. 2014;171:1328-34.

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published 29 Oct, 2025

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Differences in 24-h autonomic nervous activity between hypersomnia and non-hypersomnia with major depressive disorder outpatients: An observational study

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Abstract

Background

Methods

Results

Conclusions

Figures

Background

Methods

Participants

Data collection

Statistical analysis

Ethics statement

Results

Participants’ Attributes and clinical characteristics

Differences in ANS activity every hour in patients with MDD with and without hypersomnia

Discussion

Conclusions

Abbreviations

Declarations

References

Status:

Journal Publication

Version 1