Chronic interferon-alpha administration disrupts sleep continuity and depth in patients with hepatitis C: association with fatigue, motor slowing, and increased evening cortisol.
ABSTRACT Consequences of chronic exposure to cytokines of the innate immune system on sleep in humans and the association of cytokine-induced sleep alterations with behavior, motor performance, and cortisol secretion are unknown.
Thirty-one patients with hepatitis C without pre-existing sleep disorders underwent nighttime polysomnography, daytime multiple sleep latency testing, behavioral assessments, neuropsychological testing, and serial blood sampling at baseline and after ∼12 weeks of either treatment with the innate immune cytokine interferon (IFN)-alpha (n = 19) or no treatment (n = 12). Fatigue and sleepiness were assessed using the Multidimensional Fatigue Inventory and Epworth Sleepiness Scale.
Interferon-alpha administration led to significant increases in wake after sleep onset and significant decreases in stage 3/4 sleep and sleep efficiency. Rapid eye movement latency and stage 2 sleep were significantly increased during IFN-alpha treatment. Decreases in stage 3/4 sleep and increases in rapid eye movement latency were associated with increases in fatigue, whereas decreases in sleep efficiency were associated with reduced motor speed. Increased wake after sleep onset was associated with increased evening plasma cortisol. Despite IFN-alpha-induced increases in fatigue, daytime sleepiness did not increase. In fact, IFN-alpha-treated patients exhibited decreased propensity to fall asleep during daytime nap opportunities.
Chronic exposure to an innate immune cytokine reduced sleep continuity and depth and induced a sleep pattern consistent with insomnia and hyperarousal. These data suggest that innate immune cytokines may provide a mechanistic link between disorders associated with chronic inflammation, including medical and/or psychiatric illnesses and insomnia, which, in turn, is associated with fatigue, motor slowing, and altered cortisol.
- SourceAvailable from: Jennifer M Loftis[Show abstract] [Hide abstract]
ABSTRACT: Objective To prospectively evaluate for changes in objective cognitive performance (attention, memory, and executive function) and psychiatric symptom severity (depression, anxiety, fatigue, and pain) in patients before, during and after interferon-alpha based therapy (IFN) for chronic hepatitis C virus infection (HCV). Methods 33 HCV + adults were evaluated two months before IFN initiation (baseline), three months into IFN, and six months following IFN termination (IFN + Group). 31 HCV + adults who did not undergo IFN therapy were evaluated at baseline and six months later (IFN- Group). At each evaluation, participants completed the Neuropsychological Assessment Battery (NAB) Attention, Memory and Executive Functions Modules, the Beck Depression Inventory, Second Edition (BDI), Generalized Anxiety Disorder Inventory (GADI), Fatigue Severity Scale (FSS), and Brief Pain Inventory (BPI). Results Compared with the IFN- Group, the IFN + Group experienced significantly (p < 0.050) increased symptoms of depression, anxiety, fatigue and pain during IFN therapy relative to baseline. In the IFN + Group, psychiatric symptoms generally returned to baseline levels following IFN termination. Sustained viral response was associated with significantly lower depression and fatigue. No significant changes in cognitive performance were observed. Conclusions During IFN, patients with HCV evidence significantly increased psychiatric symptoms, including symptoms of depression, anxiety, fatigue and pain. These psychiatric symptoms are generally short-term and remit following IFN termination, with increased benefit if viral clearance is achieved. However, IFN is not associated with significant declines in objective cognitive performance during nor following IFN.Journal of Psychosomatic Research 08/2014; · 2.84 Impact Factor
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ABSTRACT: There is a sizeable literature suggesting that mercury (Hg) exposure affects cytokine levels in humans. In addition to their signaling role in the immune system, some cytokines are also integrally associated with sleep behavior. In this cross-sectional study of 9-11 year old children (N=100), we measured total blood Hg in whole blood, serum levels of tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6), and objectively measured sleep and activity using actigraphy. Increasing blood Hg was associated with significantly shorter sleep duration and lower levels of TNF-α. IL-6 was not associated with sleep or blood Hg. This study is the first to document an association between total blood Hg and sleep (albeit a small effect), and the first to consider the associations of total blood Hg with cytokines TNF-α and IL-6 in a pediatric sample. Further research using alternative designs (e.g., time-series) is necessary to determine if there is a causal pathway linking low-level Hg exposure to sleep restriction and reduced cytokines.Environmental research. 08/2014; 134C:228-232.
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ABSTRACT: BACKGROUND: Cross-sectional and retrospective studies have associated major depressive disorder with glial activation and injury as well as blood–brain barrier disruption, but these associations have not been assessed prospectively. Here, we aimed to determine the relationship between changes in depressive symptom severity and in blood levels of S-100 calcium-binding protein B (S-100B), high-sensitivity C-reactive protein, and interleukin-6 following an inflammatory challenge. METHODS: Fifty unselected participants were recruited from a randomized, controlled trial comparing coronary artery bypass grafting procedures performed with versus without cardiopulmonary bypass for the risk of neurocognitive decline. Depressive symptom severity was measured at baseline, discharge, and six-month follow-up using the Beck Depression Inventory II (BDI-II). The primary outcome of the present biomarker study was acute change in depressive symptom severity, defined as the intra-subject difference between baseline and discharge BDI-II scores. Blood biomarker levels were determined at baseline and 2 days postoperative. RESULTS: Changes in S-100B levels correlated positively with acute changes in depressive symptom severity (Spearman ρ, 0.62; P = 0.0004) and accounted for about one-fourth of their observed variance (R2, 0.23; P = 0.0105). This association remained statistically significant after adjusting for baseline S-100B levels, age, weight, body-mass index, or β-blocker use, but not baseline BDI-II scores (P = 0.064). There was no statistically significant association between the primary outcome and baseline S-100B levels, baseline high-sensitivity C-reactive protein or interleukin-6 levels, or changes in high-sensitivity C-reactive protein or interleukin-6 levels. Among most participants, levels of all three biomarkers were normal at baseline and markedly elevated at 2 days postoperative. CONCLUSIONS: Acute changes in depressive symptom severity were specifically associated with incremental changes in S-100B blood levels, largely independent of covariates associated with either. These findings support the hypothesis that glial activation and injury and blood–brain barrier disruption can be mechanistically linked to acute exacerbation of depressive symptoms in some individuals.PLoS ONE 10/2014; 9(10):e111110. · 3.53 Impact Factor
Chronic Interferon-Alpha Administration Disrupts
Sleep Continuity and Depth in Patients with Hepatitis
C: Association with Fatigue, Motor Slowing, and
Increased Evening Cortisol
Charles L. Raison, David B. Rye, Bobbi J. Woolwine, Gerald J. Vogt, Breanne M. Bautista, James R. Spivey,
and Andrew H. Miller
Background: Consequences of chronic exposure to cytokines of the innate immune system on sleep in humans and the association of
cytokine-induced sleep alterations with behavior, motor performance, and cortisol secretion are unknown.
Methods: Thirty-one patients with hepatitis C without pre-existing sleep disorders underwent nighttime polysomnography, daytime
multiple sleep latency testing, behavioral assessments, neuropsychological testing, and serial blood sampling at baseline and after ?12
were assessed using the Multidimensional Fatigue Inventory and Epworth Sleepiness Scale.
Results: Interferon-alpha administration led to significant increases in wake after sleep onset and significant decreases in stage 3/4 sleep
and sleep efficiency. Rapid eye movement latency and stage 2 sleep were significantly increased during IFN-alpha treatment. Decreases in
IFN-alpha-induced increases in fatigue, daytime sleepiness did not increase. In fact, IFN-alpha-treated patients exhibited decreased
propensity to fall asleep during daytime nap opportunities.
with insomnia and hyperarousal. These data suggest that innate immune cytokines may provide a mechanistic link between disorders
motor slowing, and altered cortisol.
Key Words: Cortisol, cytokines, depression, fatigue, hepatitis C,
hyperarousal, insomnia, interferon-alpha, neuropsychology, poly-
inflammation and have long been known to induce symptoms of
depression including alterations in sleep (1–11). For example,
studies in rodents have shown that acute administration of innate
immune cytokines or cytokine inducers such as lipopolysaccha-
ride (LPS) suppresses rapid eye movement (REM) sleep, while
increasing nonrapid eye movement (non-REM) sleep, especially
stage 3/4 sleep, also referred to as slow wave sleep (SWS)
(3,4,6,12). At high doses, however, innate immune cytokines can
disrupt non-REM sleep in rodents and reduce SWS (3). In
humans, acute effects of innate immune cytokines are more
complex and, like in rodents, appear to be dose-dependent. For
example, low-dose IL-6 suppresses non-REM sleep in the first
half of the night, while increasing non-REM sleep (and SWS) in
the second half of the night (7,8). In addition, low-dose LPS
ytokines of the innate immune system, including inter-
feron (IFN)-alpha, interleukin (IL)-1, IL-6, and tumor
necrosis factor (TNF)-alpha, are important mediators of
increases non-REM sleep, whereas high-dose LPS suppresses
non-REM sleep (13). Consistent with the effects of acute cytokine
administration on laboratory animals, acute administration of LPS
or innate immune cytokines to humans has been reliably re-
ported to suppress REM sleep (7,9–11).
Although early interest in sleep abnormalities in psychiatric
disturbances focused on REM sleep (with the observation that
decreased REM latency may be a biological marker of major
depression) (14–16), subsequent studies have suggested that
patients with major depression perhaps even more reliably
exhibit disruptions in non-REM sleep, especially impairments in
sleep initiation/continuity (i.e., latency to sleep onset, wake after
sleep onset, and sleep efficiency) as well as reductions in SWS
(17–19). This general pattern of sleep disruption is also highly
prevalent in a variety of medical illnesses including cancer,
cardiovascular disease, and autoimmune and inflammatory dis-
orders. Indeed, these illnesses have all been associated with
various measures of sleep disruption and secondary insomnia,
including reduced sleep efficiency and increased wake after
sleep onset (20–23). Given the association of these medical
illnesses as well as major depression with evidence of chronic
activation of innate immune responses, these data suggest that
innate immune cytokines may serve as a mediator of sleep
alterations in these disorders. Nevertheless, there are limited data
on the effects of chronic exposure to innate immune cytokines
on sleep, and no study to our knowledge has employed poly-
somnography (PSG) in this regard. Moreover, while much animal
literature and a handful of human studies have reported on the
effects of short-term cytokine exposure (3–11), these findings
BMB, AHM), Neurology (DBR), and Medicine, Division of Digestive Dis-
eases (JRS), Emory University School of Medicine, Atlanta, Georgia.
Received Jan 27, 2010; revised Apr 2, 2010; accepted Apr 8, 2010.
BIOL PSYCHIATRY 2010;xx:xxx
© 2010 Society of Biological Psychiatry
ARTICLE IN PRESS
may provide limited insight into sleep changes associated with
chronic inflammation as might be expected in chronic medical
and/or psychiatric disease (24).
Patients undergoing long-term treatment with the innate
immune cytokine IFN-alpha provide a unique opportunity to
address how—and to what degree—chronic inflammation
affects sleep in humans (25). While an effective therapy for
hepatitis C virus (HCV) infection and cancer, IFN-alpha induces
significant behavioral changes including depression, fatigue, and
sleep disturbances in a high percentage of patients (26–29).
Much like other inflammatory stimuli (e.g., LPS) that induce
behavioral changes, IFN-alpha also activates other innate im-
mune cytokines, including TNF-alpha, IL-1, IL-6, and their solu-
ble receptors (25,30–33), which have been shown to correlate
with development of behavioral disturbances including sleep
changes during IFN-alpha treatment (25,31,33). For example, in
patients receiving IFN-alpha for HCV, unidirectional relation-
ships among inflammation, sleep, and mood disturbance were
observed, such that plasma IL-6 predicted poor sleep and poor
sleep, in turn, predicted development of depression (25). In
addition, IFN-alpha has been shown to induce neurocognitive
changes (motor slowing), a flattened diurnal cortisol slope, and
increased evening cortisol (31,34). These neurocognitive and
neuroendocrine changes are typical of those observed following
experimental sleep disruption (35–38).
To determine the impact of chronic exposure to an innate
immune cytokine on human sleep architecture, a longitudinal,
case-controlled design using overnight PSG and daytime multi-
ple sleep latency testing (MSLT) in patients receiving IFN-alpha
plus ribavirin for HCV was conducted. In addition, the relation-
ship between cytokine-induced changes in sleep parameters and
changes in behavioral symptoms, neurocognitive function, and
circadian neuroendocrine activity known to be affected by sleep
disruption was examined. Finally, associations between IFN-
alpha and other innate immune cytokines and sleep changes
Methods and Materials
Thirty-one HCV-positive subjects (17 male subjects, 14 female
subjects) as determined by serum anti-HCV antibodies or HCV-
RNA by reverse transcription-polymerase chain reaction were
enrolled. To ensure medically stable HCV patients without an
urgent need for IFN-alpha therapy or psychiatric treatment,
exclusion criteria included decompensated liver disease; liver
disease from any cause other than HCV; unstable cardiovascular,
endocrinologic, hematologic, renal, or neurologic disease (as
determined by physical examination and laboratory testing);
?24 on the Mini Mental State Examination (39); and history of
schizophrenia or bipolar disorder and/or diagnosis of major
depression or substance abuse/dependence within 6 months of
study entry (determined by Structured Clinical Interview for
DSM-IV) (40). Subjects with evidence of a preexisting sleep
disorder, as determined by an apnea-hypopnea index ?15 (i.e.,
?15 sleep apnea-hypopnea episodes per hour of sleep) or a
periodic leg movement index ?25 (i.e., ?25 leg movements with
or without arousal per hour of sleep) during adaptation or
baseline sleep nights, were also excluded. Subjects were re-
quired to be off all antidepressants, antipsychotics, and mood
stabilizers for at least 4 weeks (8 weeks for fluoxetine) before
study entry and throughout the study. Subjects were also re-
quired to be off other medications known to affect sleep
including narcotics, benzodiazepines, and nonbenzodiazepine
sedative/hypnotics for 2 weeks before baseline and 48 hours
before the 12-week sleep assessment. Of the 31 subjects included
in this study, 25 (15 IFN-alpha-treated, 10 control subjects)
participated in a study of IFN-alpha effects on neuroendocrine
function and 24 (15 IFN-alpha-treated, 9 control subjects) partic-
ipated in a study of IFN-alpha effects on neurocognition (31,34).
Study Design and Polysomnography Assessments
A prospective, longitudinal, case-control design was used to
examine sleep in HCV patients before (visit 1) and following ?12
weeks (visit 2) of either treatment with IFN-alpha plus ribavirin
(treatment group) or no treatment (control group). All IFN-alpha-
treated subjects received pegylated IFN-alpha-2b (Pegintron,
Schering Plough, Kennilworth, New Jersey) or pegylated IFN-
alpha-2a (PEGASYS, Roche, Basel, Switzerland) administered
subcutaneously once weekly. Participation in treatment versus
control groups as well as type of IFN-alpha was determined by
patients and their physicians and was not controlled by study
protocol. Because of lack of urgency of IFN-alpha therapy in this
stable population of HCV patients, decisions regarding initiation
of IFN-alpha were largely based on scheduling convenience. In
the event that a patient met criteria for IFN-alpha-induced major
depression during the study, the patient immediately underwent
research assessment and was referred for psychiatric care.
All study procedures took place in the Emory General Clinical
Research Center (GCRC). To allow for accommodation to the
GCRC environment and to screen for sleep disorders, subjects
underwent 1 night of PSG in the GCRC 1 week before study
initiation. On study visits 1 and 2, subjects underwent 2 nights of
PSG (Methods and Materials in Supplement 1). For statistical
analyses, PSG results were averaged across these 2 nights during
each visit. Each night, lights out occurred at 10:00 PM, and each
morning, subjects were awakened at 7:15 AM. On the second full
day of the GCRC stay, MSLT was conducted in a subset of
subjects (IFN-alpha: n ? 17; control: n ? 10) at 10:00 AM, 12:00
noon, 2:00 PM, and 4:00 PM (Methods and Materials in Supple-
ment 1) (41). Multiple sleep latency testing results, including
latency to sleep onset and cumulative sleep time, were averaged
across the day for statistical analyses.
During each GCRC admission, blood was withdrawn from an
indwelling catheter into ethylenediaminetetraacetic acid-coated
tubes hourly from 9:00 AM to 9:00 PM for assessment of plasma
cortisol, as well as TNF-alpha and its soluble receptor, soluble
TNF receptor 2 (sTNFR2). Following sampling, blood was imme-
diately centrifuged at 1000g for 10 minutes at 4°C. Plasma was
removed and frozen at ?80°C until assay. For IFN-alpha-treated
subjects, visit 2 was scheduled 4 to 5 days following the last
IFN-alpha injection. Plasma IFN-alpha was assessed at 4:00 PM on
both visits to ensure treatment adherence and to correlate with
sleep measures. Urine drug screens were conducted at each visit
to rule out substance abuse.
Subjects provided written informed consent, and study pro-
cedures received a priori approval by Emory University Institu-
tional Review Board.
Behavioral and Neuropsychological Assessments
Depression was evaluated by trained clinician-raters using the
mood disorders module of the Structured Clinical Interview for
DSM-IV and the Montgomery-Asberg Depression Rating Scale
(40,42) (Methods and Materials in Supplement 1). Due to the
profound nature of IFN-alpha effects on behavior, it was not
considered feasible to uniformly blind clinician-raters to treat-
2 BIOL PSYCHIATRY 2010;xx:xxx
C.L. Raison et al.
ARTICLE IN PRESS
ment assignment. To evaluate severity of fatigue, subjects com-
pleted the self-report, 20-item Multidimensional Fatigue Inven-
tory (MFI) (43). Higher MFI scores represent greater symptoms of
fatigue (Methods and Materials in Supplement 1). The Epworth
Sleepiness Scale (ESS) was used to assess subjective sense of
daytime sleepiness (44). The ESS is a 24-point scale with eight
different situations rated 0 to 3 according to likelihood of falling
asleep. Higher scores signify greater daytime sleepiness.
Motor speed (choice movement time) was measured at each
visit in a subset of subjects (n ? 25) using a touchscreen
computer and reaction time task of the Cambridge Neuropsycho-
logical Test Automated Battery as previously described (34,45).
Assessment of Plasma Cortisol and Immune Variables
Cortisol and the cytokines IFN-alpha, TNF-alpha, and sTNFR2
were measured using radioimmunoassay and enzyme-linked
immunosorbent assay, respectively. Assays were run in duplicate
according to manufacturer’s specifications as previously de-
scribed (Methods and Materials in Supplement 1) (31). Biological
samples were analyzed by research staff blinded to clinical status
of study participants.
Differences between groups at baseline (visit 1) were as-
sessed using t tests for continuous measures and Fisher’s exact
test for categorical variables. To evaluate effects of IFN-alpha/
ribavirin on sleep and the behavioral variables, repeated mea-
sures analysis of covariance was conducted. In the case of
significant main effects of group or visit or a group ? visit
interaction, post hoc comparisons between specific means were
conducted using Fisher’s least significant difference test. Where
indicated, correlation coefficients were computed to evaluate
associations among changes in PSG measures. All statistical
analyses included the following covariates: age, sex, race, body
mass index (BMI), and history of substance abuse and history of
depression (both coded individually as present or absent). Each
of these factors has been shown to contribute to risk of sleep
disorders and/or depression (46–52).
As previously described, cortisol slope was calculated by
log-transforming cortisol values and using the beta value of the
regression of all cortisol concentrations obtained across the
diurnal cycle (31). Larger beta values (i.e., values closer to zero)
reflect a flatter slope. Evening (PM) cortisol was calculated as the
lowest value among the last three blood draws (i.e., 7:00 PM to
To determine the relationship between changes in relevant
PSG variables and changes in behavioral, neurocognitive, neu-
roendocrine, and immune outcomes, linear regression models
were employed. Automated stepwise and forward elimination
strategies were used to identify independent variable(s) of most
consistent predictive value. Tests of significance were two-tailed
with an alpha level of .05.
Age, race, gender, BMI, and history of substance abuse were
similar in IFN-alpha/ribavirin-treated subjects and control sub-
jects (Table 1). Of note, there was a trend toward an increase in
history of major depression in IFN-alpha/ribavirin-treated sub-
jects. One African American female subject treated with IFN-
alpha met symptom criteria for major depression at 4 weeks and
immediately underwent study assessments. All other patients
were studied after 12 weeks of IFN-alpha administration. Three
patients in the IFN-alpha group were prescribed sleep medica-
tions by their treating physicians (two received low-dose non-
benzodiazepine sedative/hypnotics as needed three times per
week and one received 1 mg lorazepam daily). These sleep aids
were discontinued 48 hours before week 12 PSG.
As indicated by significant group by visit interactions, a
number of sleep parameters including wake after sleep onset
[F(1,23) ? 7.04, p ? .014], sleep efficiency [F(1,23) ? 6.83, p ?
.016], stage 2 sleep [F(1,23) ? 4.48, p ? .045], stage 3/4 sleep
[F(1,23) ? 8.58, p ? .008], and REM latency [F(1,23) ? 4.69, p ?
.041] changed differentially across visits as a function of group
(Table 2). Based on post hoc testing, compared with control
subjects, IFN-alpha/ribavirin-treated subjects exhibited significant
increases in wake after sleep onset, stage 2 sleep, and REM latency
(all p ? .05). In addition, sleep efficiency and stage 3/4 sleep
significantly decreased in IFN-alpha-treated subjects compared with
of group on mean sleep latency in the MSLT [F(1,20) ? 4.70, p ?
.042], with IFN-alpha-treated subjects exhibiting significantly longer
mean sleep latency times compared with control subjects at visit 2
(p ? .05) (Table 3). Despite significant IFN-alpha-induced increases
in wake after sleep onset, no differences were found between
groups in spontaneous arousals.
Similar differences in delta sleep parameters between groups
were revealed when IFN-alpha-treated patients with history of
depression (n ? 6) were removed from the analyses. Moreover,
there were no differences in delta nighttime sleep parameters
between IFN-alpha-treated patients with and without history of
depression. Finally, similar results were obtained when IFN-
alpha-treated patients who were receiving sedative/hypnotics
before visit 2 (n ? 3) were removed from the analyses.
Of note, several significant correlations were found among
sleep variables that differed as a function of IFN-alpha/ribavirin
treatment, including significant correlations between delta (visit2
? visit1) stage 3/4 sleep and delta sleep efficiency (r ? .40, df ?
23, p ? .045); delta stage 3/4 sleep and delta REM latency (r ?
?.44, df ? 23, p ? .029); and delta sleep efficiency and delta
wake after sleep onset (r ? ?.64, df ? 23, p ? .001) (Table S1 in
There were significant group by visit interactions for both
depression and fatigue [F(1,23) ? 10.81, p ? .003 and F(1,23) ?
Table 1. Baseline Demographic and Psychiatric Characteristics of Study
(n ? 19)
(n ? 12)p Value
Age (mean, SD)
Gender (n, %)
Race (n, %)
Past MD (n, %)
Past Substance Abuse (n, %)
48.6 (5.8)47.0 (7.3).53
BMI, body mass index; MD, major depression; SD, standard deviation.
aFisher’s exact test.
C.L. Raison et al.
BIOL PSYCHIATRY 2010;xx:xxx 3
ARTICLE IN PRESS
18.33, p ? .001, respectively], with IFN-alpha/ribavirin-treated
patients exhibiting significant increases in these symptoms dur-
ing treatment compared with control subjects (Table 4). Interest-
ingly, there were no main effects or interactions for daytime
sleepiness (ESS), which showed no change across visits for either
Relationship Between Sleep Parameters and Behavioral
Changes, Motor Slowing, and Cortisol
of choice movement time on the reaction time task of the Cam-
bridge Neuropsychological Test Automated Battery, which, in turn,
correlates with fatigue (34), a finding that was replicated in the
current sample (Table S3 in Supplement 1). In addition, IFN-
alpha has been shown to be associated with significant increases
in PM cortisol and flattening of the cortisol curve (31), both effects
that were also replicated in these subjects (data not shown).
Sleep parameters that showed significant differences between
groups across visits 1 and 2 were entered into linear regression
models to determine their association with IFN-alpha-induced
behavioral changes, motor slowing, and alterations in cortisol
secretion. Changes in nighttime sleep parameters were entered
as independent variables, and delta depression and fatigue, delta
choice movement time, delta cortisol slope, and delta PM cortisol
were entered as dependent variables in separate analyses. Age,
race, sex, BMI, history of substance abuse, and history of
depression were also entered into the models as covariates.
Stepwise and forward elimination were used to determine vari-
ables that were significant predictors of the indicated dependent
measures. In all analyses, these automated elimination strategies
yielded similar results.
Both delta stage 3/4 sleep and delta REM latency were
significant predictors of changes in fatigue, together accounting
for 34.1% of the variance (R2) in delta MFI scores [F(1,30) ? 7.25,
p ? .003]. More specifically, decreases in stage 3/4 sleep and
increases in REM latency were associated with increased fatigue
(beta ? ?.36, t ? ?2.19, df ? 2,30, p ? .037, and beta ? .60,
t ? 2.21, df ? 2,30, p ? .035, respectively). Delta sleep efficiency
was a significant predictor of changes in choice movement time
[F(1,24) ? 5.06, p ? .034] with decreases in sleep efficiency
being associated with increased choice movement time (beta ?
?.42, t ? ?2.25, df ? 1,24, p ? .034) (Figure 1). Regarding
diurnal cortisol secretion, delta REM latency was a significant
predictor of changes in cortisol slope [F(1,29) ? 6.14, p ? .020]
with increases in REM latency being associated with increases in
(flattening of) cortisol slope (beta ? .42, t ? ?2.48, df ? 1,29,
p ? .020). Finally, delta sleep after wake onset was a significant
predictor of changes in PM cortisol [F(1,29) ? 5.6, p ? .025] with
increases in wake after sleep onset being associated with in-
creases in evening cortisol (beta ? .41, t ? 2.37, df ? 1,29, p ?
.025) (Figure 2).
Regarding daytime sleep assessments (MSLT), no significant
associations were found between delta sleep latency and any
behavioral, neurocognitive, or neuroendocrine variable. More-
over, no sleep measures were associated with changes in depres-
sion scores. Finally, a comprehensive listing of bivariate correla-
tions between delta sleep variables (as well as a composite sleep
factor derived from principal components analysis) and the
noted behavioral, neurocognitive, and neuroendocrine measures
is provided in Table S2 in Supplement 1.
Relationship Between Sleep Parameters and Immune
Interferon-alpha, TNF-alpha, and sTNFR2 have been found to
correlate with development of IFN-alpha-induced depression
and/or fatigue (31). These correlations were also apparent with
Table 3. Mean Sleep Latency Test Parameters (?SD) in Interferon-Alpha-Treated and Control Subjects
Interferon-Alpha (n ? 17) Control (n ? 10)
Visit 1Visit 2Delta Visit 1Visit 2Delta
Mean Sleep Latencya
Cumulative Sleep Time
SD, standard deviation.
aSignificant group effect.
bSignificantly different from respective control value (p ? .05 using Fishers least significance difference test).
Table 2. Mean (?SD) Sleep Parameters in Interferon-Alpha-Treated and Control Subjects
Interferon-Alpha (n ? 19) Control (n ? 12)
Visit 1 Visit 2Delta Visit 1Visit 2Delta
Sleep Period Time (min)
Total Sleep Time (min)
Total Sleep Efficiencyb
Stage 1 (min)
Stage 2 (min)b
Stage 3/4 (min)b
REM latency (min)b
REM, rapid eye movement sleep; SD, standard deviation; WASO, wake after sleep onset.
aSignificantly different from respective control value (p ? .05 using Fisher’s least significance difference test).
bSignificant group ? visit interaction (p ? .05); sleep efficiency ? 1 ? (wake after sleep onset/sleep period time).
4 BIOL PSYCHIATRY 2010;xx:xxx
C.L. Raison et al.
ARTICLE IN PRESS
IFN-alpha and sTNFR2 in the current sample (Table S3 in
Supplement 1). To determine the relationship between changes
in these cytokines and sleep variables that were altered by
IFN-alpha, linear regression analyses were conducted entering
delta IFN-alpha, delta TNF-alpha, and delta sTNFR2 as indepen-
dent variables and the sleep variables as the dependent variables
in separate analyses. Analyses were controlled for age, race, sex,
BMI, history of substance abuse, and history of depression. Delta
IFN-alpha was found to significantly predict changes in delta
stage 2 sleep [F(1,24) ? 10.6, p ? .003], with increases in
IFN-alpha being associated with increases in delta stage 2 sleep
(beta ? .56, t ? 3.26, df ? 1,24, p ? .003). Similar relationships
were observed with sTNFR2 when IFN-alpha was removed from
the model [F(1,29) ? 5.2, p ? .031; beta ? .40, t ? 2.28, df ?
1,29, p ? .031], suggesting that sTNFR2-induced effects on stage
2 sleep may be collinear with those of IFN-alpha. No other
relationships between cytokines and sleep parameters were
found (Table S2 in Supplement 1).
Subjects chronically administered IFN-alpha demonstrated
increased wake after sleep onset, decreased sleep efficiency, and
reduced stage 3/4 sleep. These non-REM sleep disturbances are
common in major depression and many medical illnesses and are
consistent with the disruption of SWS seen in laboratory animals
and humans acutely exposed to high doses of cytokines and
cytokine inducers (3,7,8,13,53–55). By providing the first longi-
tudinal evidence that cytokine exposure disrupts non-REM sleep
in humans, these data suggest that dysregulation of inflammatory
signaling pathways may be an important pathophysiologic
mechanism for development of sleep disturbances including
insomnia found in medical and psychiatric illnesses. Moreover,
the current findings reinforce results from recent studies showing
that pharmacological antagonism of innate immune cytokines
(i.e., TNF-alpha) can reverse similar sleep disturbances in pa-
tients with rheumatoid arthritis and alcoholism (56,57).
Interferon-alpha treatment increased REM latency, an effect
also observed in humans following acute administration of
cytokines (7,9–11), including IFN-alpha (10), but an effect that is
opposite to the reduced REM latency that is a hallmark of major
depression (58,59). Although little is known regarding REM sleep
patterns in depressed individuals with a known source of chronic
innate immune system activation (i.e., medically ill individuals
with major depression), these findings raise the intriguing pos-
sibility that cytokine-induced behavioral disturbances may have
a unique REM phenotype.
In the current study, disturbances in REM and non-REM sleep
independently predicted development of behavioral symptoms
and physiological changes that are common in both major
depression and medical illness, including fatigue, psychomotor
slowing, and disruptions in the diurnal rhythm of cortisol.
Table 4. Mean (?SD) Behavioral Parameters in Interferon-Alpha-Treated and Control Subjects
Interferon-Alpha (n ? 19)Control (n ? 12)
Visit 1 Visit 2 DeltaVisit 1 Visit 2 Delta
ESS, Epworth Sleepiness Scale; MADRS, Montgomery Asberg Depression Rating Scale; MFI, Multidimensional Fatigue Inventory; SD, standard deviation.
aSignificant group ? visit interaction.
bSignificantly different from respective control value (p ? .05 using Fishers least significance difference test).
Figure 1. Correlation between change in sleep efficiency and change in motor
speed. Decreased sleep efficiency (%) across visits 1 and 2 in interferon-alpha-
treated and control patients was significantly associated with decreased motor
in evening cortisol concentration. Increased wake after sleep onset (mea-
sured in minutes) across visits 1 and 2 in interferon-alpha-treated and con-
trol patients was significantly associated with increased evening plasma
after sleep onset.
C.L. Raison et al.
BIOL PSYCHIATRY 2010;xx:xxx 5
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Fatigue and loss of the normal descending diurnal cortisol
rhythm have been repeatedly associated with increased markers
of inflammation (31,37,60–68). Psychomotor slowing is also
highly prevalent in depression and medical illness and has been
linked to central nervous system effects of innate immune
cytokines (34,69). The current study raises the possibility that
cytokine-induced sleep disturbances may contribute to the ef-
fects of innate immune cytokines on development of these
behavioral and physiological abnormalities that are widespread
in sickness and depression and have been associated with innate
immune cytokines. Numerous studies show that sleep loss—
whether naturalistic (i.e., insomnia) or experimentally induced—
promotes fatigue and impedes psychomotor performance. Stud-
ies show that experimentally induced sleep loss also increases PM
cortisol concentrations (36), all of which provide additional
support for the hypothesis that sleep changes may represent a
pathway by which cytokines affect behavior and physiological
Although acute infection and certain types of depression can
be associated with hypersomnia, chronic cytokine exposure to
IFN-alpha produced sleep alterations more consistent with in-
somnia. Despite significant increases in fatigue—a cardinal
symptom of insomnia (70,71)—IFN-alpha administration did not
increase subjective reports of daytime sleepiness, suggesting
that, in the context of chronic inflammation, these two constructs
(fatigue and sleepiness) are dissociable. Of note, a similar
dissociation between fatigue and sleepiness has been observed
in primary insomnia (72), a condition that has been repeatedly
associated with prolonged sleep latency during the day (as
observed in IFN-alpha-treated subjects) as well as increased
inflammatory markers (73–78).
Like with primary insomnia (79,80), results from the current
study suggest that chronic cytokine exposure may impair sleep
quality by inducing a state of physiological hyperarousal that
interferes with sleep continuity and depth and impedes attain-
ment of restorative SWS. An adaptive, evolutionary perspective
on this phenomenon suggests that hyperarousal may be a
potentially beneficial tradeoff, given the increased danger a
sleepy, infected, or wounded animal might face from predation.
Several strengths and weaknesses of the study design warrant
consideration. Strengths include use of an objective measure of
sleep architecture (PSG) in humans prescreened for sleep disor-
ders and chronically exposed to a standardized dose of an innate
immune cytokine in the absence of medications known to affect
sleep. The use of a control group not receiving IFN-alpha but
participating in all study procedures is also a strength, especially
given that several sleep parameters improved in this group,
including wake after sleep onset and sleep efficiency, likely
secondary to continuing adaptation to the GCRC environment. In
terms of weaknesses, only IFN-alpha was administered, and
therefore it is possible that administration of other cytokines may
have different effects. Nevertheless, it should be noted that
IFN-alpha induces multiple other cytokines (including TNF-
alpha, IL-1, and IL-6), and both TNF-alpha and IL-6 have been
shown to be related to sleep changes during IFN-alpha treatment
(25,81). Moreover, as noted above, IFN-alpha-induced sleep
changes are consistent with those reported following adminis-
tration of high doses of innate immune cytokines or cytokine
inducers to laboratory animals and humans, as well as being
consistent with the clinical literature on sleep disturbances in
medically ill patients and depressed patients, who have been
shown to exhibit increased peripheral blood concentrations of
multiple innate immune cytokines (82). It should also be noted
that subjects were not randomized to treatment or control
groups, thus potentially contributing to bias in group assignment.
Nevertheless, all subjects were required to have been seen by a
hepatologist and approved for IFN-alpha treatment, thus ensur-
ing that all subjects had equal access to appropriate medical care
for hepatitis C. Similarities in baseline sleep parameters between
groups suggest group equivalency. However, by chance, six
patients in the IFN-alpha-treated group had a history of major
depression compared with zero control subjects, potentially
confounding reported group differences. Nevertheless, when
groups were compared excluding patients with history of de-
pression, similar results were obtained, and no significant differ-
ences in delta nighttime sleep parameters were found between
IFN-alpha-treated patients with and without a depression history.
Three patients had as needed (n ? 2) or standing (n ? 1)
sedative/hypnotic medications withheld 48 hours before the
12-week sleep study, thereby potentially leading to sleep alter-
ations secondary to medication withdrawal. Nevertheless, when
groups were compared excluding patients using sedative/hyp-
notics, similar results were found. Finally, we chose to study
patients at 12 weeks because behavioral changes have been
shown to plateau at this time during IFN-alpha treatment (83).
Nevertheless, this later time point would not capture sleep
difficulties during early stages of IFN-alpha therapy, which have
been found to predict later development of depression (25).
In summary, results from this study support the notion that
chronic cytokine exposure as a result of chronic medical or
psychiatric illness and/or chronic stress may be a relevant causal
mechanism in the association of these conditions with insomnia.
Moreover, given studies demonstrating that sleep deprivation
can activate innate immune cytokines and their signaling path-
ways (84), these data suggest that a feedforward cascade may
exist between sleep and inflammation, whereby chronic inflam-
mation can impair sleep, which, in turn, can lead to increased
inflammation. Treatments focused on specific targets in this
inflammatory cascade, including cytokines themselves (e.g.,
TNF-antagonists) as well as their signaling pathways (e.g., inhib-
itors of nuclear factor-kappaB), may be especially relevant in
reversing this potentially vicious cycle.
This study was supported by Grants from the National Insti-
tutes of Health to CLR (K23 MH064619, R01 MH070553) and
AHM (K05 MH069124, R01 HL073921, T32 MH020018), as well
as the Centers for Disease Control and Prevention. In addition,
the study was supported by US Public Health Service Grant UL1
RR025008 from the Clinical and Translational Science Award
Program and US Public Health Service Grant M01 RR0039 from
the General Clinical Research Center Program, National Insti-
tutes of Health, National Center for Research Resources.
We thank Joseph “Max” Beck (deceased) for his assistance
with the polysomnography scoring.
Charles L. Raison has served as a speaker for Lilly and Wyeth
and as a consultant or an advisory board member for Lilly and
Wyeth and owns equity in Contemplative Health; David B. Rye
has served as a consultant for Schering-Plough; Andrew H. Miller
has served as a consultant for Schering-Plough, AstraZeneca,
Janssen, and Centocor and has received research funding from
Centocor, GlaxoSmithKline, and Schering-Plough; Bobbi J.
Woolwine, Gerald J. Vogt, Breanne M. Bautista, and James R.
Spivey reported no biomedical financial interests or potential
conflicts of interest.
6 BIOL PSYCHIATRY 2010;xx:xxx
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