Insomnia with Short Sleep Duration and Mortality: The Penn State
Cohort
Sleep. 2010 September 1; 33(9): 1159–1164. Alexandros N. Vgontzas, MD,1
Duanping Liao, MD, PhD,2 Slobodanka Pejovic, MD,1 Susan
Calhoun, PhD,1 Maria Karataraki, PsyD,1 Maria Basta, MD,1
Julio Fernández-Mendoza, PhD,1 and Edward O. Bixler, PhD1
1Sleep Research and Treatment
Center, Department of Psychiatry Pennsylvania State University College
of Medicine, Hershey,
PA 2Department of Public Health Sciences,
Pennsylvania State
University College
of Medicine, Hershey, PA
Address correspondence to: Alexandros N. Vgontzas, MD, Penn
State University College of Medicine, Department of Psychiatry H073, 500 University Dr., Hershey, PA 17033
Phone: (717) 531-7278Fax: (717) 531-6491, ; Email: avgontzas@psu.edu
Received November 2009; Revised March 2010; Accepted April
2010.
Abstract
Study Objectives:
Because insomnia with objective short sleep duration is
associated with increased morbidity, we examined the effects of this insomnia
subtype on all-cause mortality.
Design:
Longitudinal.
Setting:
Sleep laboratory.
Participants:
1,741 men and women randomly selected from Central
Pennsylvania.
Measurements:
Participants were studied in the sleep laboratory and were
followed-up for 14 years (men) and 10 years (women). “Insomnia” was defined by
a complaint of insomnia with duration ≥ 1 year. “Normal sleeping” was defined
as absence of insomnia. Polysomnographic sleep duration was classified into two
categories: the “normal sleep duration group” subjects who slept ≥ 6 h and the
“short sleep duration group” subjects who slept < 6 h. We adjusted for age,
race, education, body mass index, smoking, alcohol, depression, sleep
disordered breathing, and sampling weight.
Results:
The mortality rate was 21% for men and 5% for women. In men,
mortality risk was significantly increased in insomniacs who slept less than 6
hours compared to the “normal sleep duration, no insomnia” group, (OR = 4.00,
CI 1.14-13.99) after adjusting for diabetes, hypertension, and other
confounders. Furthermore, there was a marginally significant trend (P = 0.15) towards
higher mortality risk from insomnia and short sleep in patients with diabetes
or hypertension (OR = 7.17, 95% CI 1.41-36.62) than in those without these
comorbid conditions (OR = 1.45, 95% CI 0.13-16.14). In women, mortality was not
associated with insomnia and short sleep duration.
Conclusions:
Insomnia with objective short sleep duration in men is
associated with increased mortality, a risk that has been underestimated.
Citation:
Vgontzas AN; Liao D; Pejovic S; Calhoun S; Karataraki M;
Basta M; Fernández-Mendoza J; Bixler EO. Insomnia with short sleep duration and
mortality: the Penn State Cohort. SLEEP 2010;33(9):1159-1164.
Keywords: Insomnia,
short sleep duration, mortality, population-based study
MANY STUDIES HAVE ESTABLISHED THAT INSOMNIA, THE MOST COMMON
SLEEP
DISORDER, IS HIGHLY COMORBID WITH PSYCHIATRIC DISORDERS AND IS a risk
factor for the development of depression, anxiety, and suicide.1,2 In contrast to
sleep disordered breathing (SDB), the second most common sleep disorder, chronic insomnia
has not been associated with significant medical morbidity, e.g.,
cardiovascular disorders.3,4
Recently, we demonstrated that insomnia with objective short
sleep duration is associated with a high risk for hypertension and type 2 diabetes.5,6 These data
suggest that objective sleep measures in insomnia provide an index of the
severity of the disorder and that the more severe form of insomnia is most
likely associated with morbidity and possibly mortality. This hypothesis is
further supported by physiological studies which demonstrated that activation
of the hypothalamic-pituitary-adrenal (HPA) axis and autonomic system,
including increased heart rate, 24-hour metabolic rate, and impaired heart rate
variability, is present in insomniacs who meet both subjective and objective polysomnographic
criteria.7–12 Given the
association of hypertension, diabetes, and HPA axis and sympathetic system activation
with increased mortality,13
we expect insomnia with objective short sleep duration to be associated with
increased rates of death.
Previous studies on the association of insomnia with
mortality have been inconsistent.14–20 The most recent
ones that included very large samples of a wide age range reported no
association or even a negative association between insomnia and mortality.19,20 A limitation of
all these studies is that the presence of sleep disturbances was based on
subjective questionnaires, did not include any criteria of frequency or
severity, and did not control for polysomnographically documented obstructive sleep apnea, a sleep disorder whose association with medical
morbidity and mortality is well established.21 Thus, the
question whether insomnia is associated with an increased risk for death
remains open to further investigation.
The objective of this study was to examine the joint effects
of chronic
insomnia and objective sleep duration on mortality risk in a large
prospective population-based sample from Central
Pennsylvania (Penn State Cohort), after controlling for various
confounders including sleep apnea.
METHODS
Population
The data presented here were collected as part of a
two-phase protocol whose primary purpose was to establish the age distribution
of sleep disordered breathing.22,23 In the first
phase of the study, a sample of adult men and women (aged ≥ 20 years) was
randomly selected from local telephone households in 2 counties of Central
Pennsylvania (Dauphin and Lebanon) using the Mitofsky–Waksberg 2-stage random
digit dialing procedure.24
A within-household selection procedure described by Kish was used to select the specific man or
woman to be interviewed.25
Telephone interviews were conducted with 4,364 age-eligible men and 12,219
age-eligible women residing in the sample households, for a total sample of
16,583 with a response rate of 73.5% and 74.1%, respectively. The questionnaire
employed in this interview included basic demographic and sleep information.
In the second phase of this study, a subsample of 741 men
and 1,000 women selected from those subjects previously interviewed by
telephone were studied in our sleep laboratory. The response rate for this
phase was 67.8% and 65.8% for men and women, respectively. We contrasted those
subjects who were recorded in the laboratory with those who were selected but
not recorded in terms of age, self-reported BMI, reported use of medication for
hypertension or diabetes, and prevalence of sleep disorders.
There were no significant differences between these 2 groups on any of these
variables. Each subject selected for laboratory evaluation completed a
comprehensive sleep history and physical examination. All subjects were
evaluated for one night in the sleep laboratory in sound-attenuated, light- and
temperature-controlled rooms. During this evaluation, each subject was
continuously monitored for 8 h using 16-channel polygraphs, including
electroencephalogram, electrooculogram, and electromyogram. Bedtimes were
adjusted to conform to subjects' usual bedtimes, and subjects were recorded
between 22:00-23:00 and 06:00-07:00. The sleep records were subsequently scored
independently according to standardized criteria.26
Percent sleep time is total sleep time (duration of sleep) divided by recorded
time in bed and multiplied by 100. Respiration was monitored throughout the
night by use of thermocouples at the nose and mouth and thoracic strain gauges.
All-night recordings of hemoglobin oxygen saturation (SpO2) were
obtained with an oximeter attached to the finger.
Key Measurements
As part of this protocol we assessed for the presence of all
sleep disorders. The presence of sleep disorders was based on a standardized
questionnaire completed by the subjects on the evening of their sleep
laboratory visit. This questionnaire consists of 53 questions (7 demographic,
20 sleep related, and 26 general health questions). In addition, women
responded to 8 questions related to menstrual history, menopause, and hormone
therapy. Sleep related questions were qualified in terms of severity on a scale
of 0-4 (0 = none, 1 = mild, 2 = moderate, 3 = severe) and duration. Health
complaints were also qualified in terms of severity and type of treatment on a
scale of 0-7 and duration. The presence of “insomnia” was defined by a
complaint of insomnia with a duration of at least 1 year. “Normal sleeping” was
defined as the absence of insomnia.
From the objectively recorded sleep time data, we regrouped
the entire study sample into 2 ordinal groups: the top 50% of persons above the
median percent sleep time (normal sleep duration group), and the 50% of persons
in the bottom half (short sleep duration group). We then rounded the cut-off
points to meaningful numbers and thus created the following 2 sleep duration
groups: the normal sleep duration group consisted of those who slept ≥ 6 h, and
the short sleep duration group of those who slept < 6 h.
To control for possible confounding variables influencing
the relation between insomnia and mortality, in the subsample of 1,741 we
ascertained whether the respondent was currently treated for depression
(including a history of suicidal thoughts or attempts), hypertension, or
diabetes. Hypertension was defined as a diastolic blood pressure > 90 mm Hg
or a systolic blood pressure > 140 mm Hg at the time of the sleep laboratory
evaluation, or the use of antihypertensive medication. Diabetes was defined as
being treated for diabetes or having a fasting blood sugar > 126 mg/dl from
blood drawn the morning after the subjects slept in the sleep laboratory.
Additional information obtained during the polysomnographic evaluation included
history of smoking (current use of any type of tobacco product) and alcohol use
(> 2 alcohol drinks per day) and objective sleep data including sleep apnea
and periodic limb movement assessment. For the purpose of this
study, sleep apnea was defined as an obstructive apnea or hypopnea index
≥ 5 (OHI ≥ 5). The condition of periodic limb movement was considered present when there
were five or more movements per hour of sleep. A leg movement was scored when
it lasted > 0.5 sec, < 5.0 sec, and in intervals of < 90 sec between
movements.27
Body mass index was based on measured height (cm) and weight (kg) during the subjects'
sleep laboratory visit, and data are presented in terms of mean, percentile
distribution, and prevalence within each category.
Mortality Follow-up
Deaths in the cohort occurring up to December 31, 2007 were
identified by matching social security numbers with 2 death record services:
the U.S. Social Security Death Index and the Pennsylvania State Bureau of
Healthy Information and Policy Vital Records Section. Duration of follow-up was
calculated from the time of the baseline evaluation to the date of death.
Statistical Analyses
The design of this study included oversampling of those at
higher risk for sleep disordered breathing (SDB) and women with markedly higher
levels of BMI to increase the precision of the risk estimates. Because of this
sampling strategy, numeric sampling weights were developed for the analysis so
that the estimates could be inferred to the original target population.22,23 Specifically, 3
weights were created for the men. First, in the telephone sample, 32 of the 963
clusters of phone numbers in the first stage were “exhausted” before the target sample size was obtained.
A compensatory weight was computed which corrected for this problem. A second
weight was computed because the within-household screening deliberately
introduced unequal probabilities of selection across the 3 age groups in order
to oversample
the middle-aged group. The final weight for the men was computed to account for
the oversampling of subjects for the sleep laboratory study (Phase II); those
with larger counts of the 4 possible risk factors (snoring, daytime sleepiness,
obesity, and hypertension) had substantially higher probability of being
selected. For the women, the only weight required was to account for the
oversampling of subjects for the sleep laboratory study. To eliminate any
possible sample bias due to oversampling different strata of the target population, we
calculated 32 unique weights for the women and 16 unique weights for the men,
corresponding to all possible combinations of the 5 risk factors for the women
(menopause was the fifth risk factor) and 4 for the men. Any individual weight
that had too small of a cell size was combined with adjacent cells, so that
less than 10% of the cells had a sample < 25 and no cell had a size < 10.25
All statistical analyses were adjusted for the sampling weight to make
appropriate inference to the target population.
Finally we used the BMI and race distributions by age decade
from the NHANES III laboratory data as the standard28
to adjust both the men and women in terms of BMI and race to be more representative
of the national population.
Logistic regression models were used to assess the
independent associations of the insomnia complaints and objective sleep
duration with mortality. We did not use proportional hazard models since
Kaplan-Meier survival curves comparing sleep complaints crossed each other.
Furthermore, because the follow-up duration was different between men and
women, we performed separate analyses within each gender. We calculated the
odds ratios and the 95% confidence intervals (95% CI) from this model to
estimate the risk of death associated with the four combinations of insomnia
(yes/no) and objective sleep duration (< 6 h / ≥ 6 h), simultaneously
adjusting for age, race, education, BMI, diabetes, smoking status, alcohol
consumption, depression, SDB, and sampling weight. The reference group was
persons with ≥ 6 h of objective sleep duration and no insomnia complaints.
RESULTS
The demographic and clinical characteristics, as well as
number (%) of deaths, are presented in Table 1
for men and Table 2
for women. After about 10 years of follow-up for women and 14 years for men,
248 out of the 1,741 individuals at baseline were deceased. The mortality rate
adjusted for sampling weight for men was 21% (145/741) and 5% (103/1,000) for
women. Because the follow-up period was different between men and women, we
analyzed the two cohorts separately, and the results are presented separately.
|
Table
1
Demographic and clinical characteristics and mortality
rates of Penn State Cohort: men
|
|
Table
2
Demographic and clinical characteristics and mortality
rates of Penn State Cohort: women
|
Men
The 14-year adjusted mortality rate was 9.1%, 12.6%, 31.0%,
and 51.1% in normal sleep duration and no insomnia, normal sleep duration with
insomnia, short sleep duration with no insomnia, and short sleep duration with
insomnia groups, respectively. Mortality risk was significantly increased only
in insomniacs who slept < 6 h, OR = 4.33, CI 1.25-15.04 (Table 3).
The risk for death remained significant even after further adjusting for
hypertension and diabetes (OR = 4.00, CI 1.14-13.99). The P-value for the
interaction between insomnia and sleep duration with diabetes and hypertension
status was 0.15, not statistically significant. However, since it showed a trend
toward significance, we explored whether comorbidity
of hypertension and/or diabetes with insomnia at baseline increased the
mortality risk compared to insomniac patients who did not have
diabetes/hypertension at baseline. The odds ratio was significantly increased
in the insomniacs with < 6 h of sleep and who were diabetic or hypertensive
at baseline (OR = 7.17, CI 1.40-36.62) compared to the normal sleep duration
and no insomnia group (Table 4).
In contrast, in insomniacs with short sleep duration but without diabetes or
hypertension at baseline, the mortality risk was not increased compared to the
reference group (OR = 1.45, CI 0.13-16.14). The wide confidence intervals were
due to the low number of deceased insomniacs with or without short sleep
duration.
|
Table
3
Mortality risk by insomnia/ objective sleep duration
category in men: adjusted odds ratios
|
|
Table
4
Mortality risk with insomnia/objective sleep duration by
hypertension/ diabetes status at baseline: men
|
Women
In women, the 10-year adjusted mortality rate was 2.3%,
2.5%, 10.2%, and 2.5% in normal sleep duration and no insomnia, normal sleep
duration with insomnia, short sleep duration and no insomnia, and short sleep
duration with insomnia groups, respectively. The mortality risk was not
significantly increased in the short sleep duration with insomnia group after
adjusting for age, race, education, BMI, smoking status, alcohol use,
depression, SDB, diabetes, hypertension, and sampling weight (Table 5).
|
Table
5
Mortality risk by insomnia/ objective sleep duration in
women: adjusted odds ratios
|
CONCLUSIONS
This is the first study to demonstrate that in men, chronic
insomnia with objectively measured short sleep duration is associated with
increased mortality. This increased risk is independent of comorbid conditions
frequently associated with mortality, such as age, race, obesity,
alcohol consumption, smoking, sleep disordered breathing, or depression.
Furthermore, our findings suggest that objective measures of sleep duration in
insomnia may be a useful marker of the biological severity and medical impact
of the disorder. We tested the hypothesis that the association between
mortality and insomnia and short sleep duration might be attributable to
chronic comorbidity,
especially hypertension and type 2 diabetes. However, the odds ratio (4.33) from a model
not adjusted for hypertension and type 2 diabetes was not attenuated in the
model adjusted for hypertension and diabetes (OR = 4.00). Thus, these data did
not support that the association between mortality and insomnia and sleep
duration was largely attributable to these two chronic conditions.
Several studies have examined the association of sleep disturbances
or insomnia with mortality risk with inconsistent findings.14–20 Studies on two
large cohorts, 1 million American Cancer Volunteers19 and 13,000
well-characterized participants in the Atherosclerosis Risk in Communities
(ARIC)20
reported no association or even reduced mortality rate of individuals
complaining of sleep difficulty. Limitations of these studies included a
liberal definition of insomnia, and lack of information about duration of
insomnia complaints as well as lack of objective measures of sleep. Those
studies that reported a positive association of insomnia complaints were rather
small, and focused on the elderly,14,17 whereas a
Swedish study that included middle-aged men and women after controlling for
various confounders reported an increased risk for coronary
artery disease associated death but not for “all-cause mortality” in men.18 Importantly in
all these studies the possible confounding effect of sleep disordered breathing
could not be controlled for, since no polysomnographic data were obtained.
In previously published studies, based on the same cohort,
we reported a significant association between insomnia with objective short
sleep duration and hypertension and type 2 diabetes.5,6 Given the known
association of these two conditions with increased mortality, we explored
whether these two factors are mediators of the increased mortality risk
associated with insomnia. Controlling for diabetes and/or hypertension reduced
the mortality risk by only a small percentage. This finding suggests that
conditions other than diabetes or hypertension mediate the increased all-cause
mortality risk of insomnia in men. An alternative explanation is that the small
effect of hypertension/diabetes on the association of insomnia with all-cause
mortality may be related to the relatively small number of deceased subjects in
our study.
We further examined whether the presence of diabetes or
hypertension at baseline modifies the effect of insomnia on the risk for death.
Indeed the impact of insomnia with short sleep duration was much stronger in
those with diabetes and hypertension at baseline versus those who were healthy.
The large magnitude of difference between the two odds ratios (1.45 vs. 7.17)
presented in Table 4,
although the P-value for the interaction between insomnia and sleep duration
with diabetes and hypertension status was 0.15 (not statistically significant,
largely due to small sample size and lack of statistical power) may indicate an
important potential effect modification by hypertension and diabetes on the
insomnia and mortality relationship, implying that persons with insomnia and
short sleep duration may have a much higher risk of dying if they also have
hypertension and diabetes. From a clinical standpoint, this finding suggests that
treatment of insomnia in individuals with impaired physical health should be a
medical priority.
Previous studies have reported an association between
self-reported sleep duration (but not objective sleep duration) and mortality
risk.29–32 In our study we
found no association between objective short sleep duration and mortality. The
inconsistencies between self-reported and objective sleep duration have been
well-described in large epidemiological studies (SHHS, CARDIA, Penn State
Cohort).6,33,34 In all three
studies the average self-reported sleep duration is about seven hours whereas
the average objective sleep duration is about six hours. Thus, it is possible
that the answer to the question “how many hours do you usually sleep” is
influenced by several other factors such as age, sex, sleep
disturbance, and psychosocial factors besides objective sleep duration.
Future studies are needed to address this epistemological challenge.
Our study, due to the relatively small number of deceased
subjects did not have the statistical power to explore whether more severe
short sleep duration, i.e., sleep duration < 5 hours is associated with
increased mortality. Even with our current definition of short sleep duration,
i.e., < 6 hours, the four insomnia-sleep duration subgroups stratified by
gender were based on a small number of deaths (Table 1
and and2).2). As a consequence, the resulting odds ratios
all had large 95% confidence intervals. Finally, the mortality risk was
increased in men but not in women, which might be related to the fact that
women were followed-up for a shorter period and that a smaller number were
deceased at the time of the follow-up compared to the men. The question whether
women compared to men are subject to the same death risk associated with
insomnia or if there is a specific-gender association would require a larger study
with a longer follow-up period.
The findings of this study suggest that polysomnographic
measurements may provide a reliable index of the severity of chronic insomnia
and the associated biological and medical significance. Given that the use of
the sleep laboratory to predict the medical severity of chronic insomnia is
costly and impractical, the validity and usefulness of other simpler methods,
such as actigraphy,
should be tested.
The data on the association of insomnia with hypertension,
diabetes and mortality, as well as previous reports on insomnia and the stress
system7–9 and the
autonomic system,10–12 provide the
basis for a meaningful subtyping of chronic insomnia based on objective
duration of sleep. One subtype is associated with physiological hyperarousal
(short sleep duration, activation of the stress system) and significant medical
morbidity (hypertension, diabetes and/or neurocognitive deficits)5,6,35 and mortality.
The other subtype is not associated with physiological hyperarousal, i.e.,
normal sleep duration, normal activity of the stress system, and lack of
significant medical sequelae. The diagnostic validity and utility of this
subtyping should be tested in future studies.
The objective sleep duration in this study was based on one
night of polysomnography,
which may not be representative of the subjects' habitual sleep duration.
However, in our previous studies, the association between objective sleep
duration and hypercortisolemia was based on a 4 consecutive night sleep
laboratory protocol, which should better represent the typical sleep profile of
the subjects.7,8 Objective sleep
duration was used as an internally valid marker of the severity of insomnia and
not as a recommended optimum sleep duration for the general population, which is beyond the scope of our
study. The consistency of the findings on the role of objective sleep duration
in predicting insomnia severity between the physiological studies with multiple
night recordings7,8 and the current
epidemiological study based on a single night recording increases our
confidence about the replicability and generalizability of the present
findings. Future studies should explore the association between insomnia, sleep
duration, and mortality using multiple night recordings.
In conclusion, insomnia with short sleep duration in men is
associated with a significant risk for death, in a degree comparable to the
other most common sleep disorder, sleep disordered breathing.21 Given the high
prevalence of the disorder in the
general population and the widespread misconception that this is a disorder
of the “worried well,” its diagnosis and appropriate treatment should become
the target of public health policy. Objective measures of sleep duration of
insomnia may serve as clinically useful predictors of the medical severity of
chronic insomnia and there is a need for validation of practical, easy to use,
inexpensive methods, e.g., actigraphy, to measure sleep duration outside of the sleep
laboratory. Finally, insomnia with objective short sleep duration may represent
a subtype within chronic insomnia that may respond differentially to treatment.
DISCLOSURE STATEMENT
This was not an industry supported study. The authors have
indicated no financial conflicts of interest.
ACKNOWLEDGMENTS
We thank Barbara Green for her overall preparation of this
manuscript.
This research is funded in part by the National Institutes
of Health grants RO1 51931, RO1 40916, and RO1 64415.
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