Brain Research Bulletin 80 (2009) 158–162
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Brain Research Bulletin
journal homepage: www.elsevier.com/locate/brainresbull
Rapid antidepressant effects of sleep deprivation therapy correlates with
serum BDNF changes in major depression
Yasemin Gorgulu1, Okan Caliyurt∗
Trakya University School of Medicine, Psychiatry Department, 22030 Edirne, Turkey
a r t i c l ei n f o
Received 15 April 2009
Received in revised form 18 June 2009
Accepted 19 June 2009
Available online 1 July 2009
Brain-derived neurotrophic factor
Total sleep deprivation therapy
a b s t r a c t
uals suffering major depressive disorder and these levels normalize following antidepressant treatment.
Various antidepressants and electroconvulsive therapy are shown to have a positive effect on brain-
derived neurotrophic factor levels in depressive patients. The aim of this study was to assess the effect of
total sleep deprivation therapy on BDNF levels in major depressive patients.
Patients were assigned to two treatment groups which consisted of 22 patients in the sertraline group
and 19 patients in the total sleep deprivation plus sertraline group. Patients in the sleep deprivation
group were treated with three total sleep deprivations in the first week of their treatment and received
sertraline. Patients in sertraline group received only sertraline. BDNF levels were measured in the two
treatment groups at baseline, 7th, 14th, and 42nd days. Patients were also evaluated using the Hamilton
Rating Scale for Depression (HAM-D). A control group, consisting of 33 healthy volunteers had total sleep
deprivation, BDNF levels and depression measured at baseline and after the total sleep deprivation.
Results showed that serum BDNF levels were significantly lower at baseline in both treatment groups
compared to controls. Decreased levels of BDNF were also negatively correlated with HAM-D scores. First
single sleep deprivation and a series of three sleep deprivations accelerated the treatment response that
significantly decreased HAM-D scores and increased BDNF levels.
Total sleep deprivation and sertraline therapy is introduced to correlate with the rapid treatment
response and BDNF changes in this study.
© 2009 Elsevier Inc. All rights reserved.
Neuroplasticity refers to the brain’s ability, at the level of the
neuron, to recover structurally and/or functionally after injury or
role in neuroplasticity and is the most widely distributed trophic
factor in the brain. BDNF is a type of neurotrophic factor which reg-
ulates neuronal growth, survival, and function during development
in the adult brain. BDNF belongs to the neurotrophin family, which
also includes nerve growth factor, neurotrophin-1, neurotrophin-
3, and neurotrophin-4 . BDNF is produced by astrocytes, in
addition to neurons, and the noradrenergic system plays a role
in controlling BDNF synthesis . New studies on permeation of
maternal BDNF to fetuses, showed the possibility that maternal
Abbreviations: BDNF, brain-derived neurotrophic factor; HAM-D, Hamilton Rat-
ing Scale for Depression; TSD, total sleep deprivation.
∗Corresponding author. Tel.: +90 2842359460; fax: +90 2842359460.
E-mail address: firstname.lastname@example.org (O. Caliyurt).
1Present address: Bakirkoy Research and Training Hospital for Psychiatry, Neu-
rology and Neurochirurgie, Istanbul, Turkey.
BDNF reaches the fetal brain through utero-placental barrier and
might contribute to its development .
Depression is associated with regional impairments of struc-
tural plasticity and cellular resilience. Neuroplasticity is disrupted
in mood disorders and in animal models of stress . There are
many studies which report decreased serum [2,20] and platelet
 brain-derived neurotrophic factor levels in major depressed
patients. It has been suggested that low BDNF levels play a pivotal
role in the pathophysiology of Major Depressive Disorder . In
addition, most studies have found clear gender differences in the
prevalence of depressive disorders. Typically, studies report that
women have a prevalence rate for depression up to twice that
of men. Autry et al. demonstrated several behavioral paradigms
suggesting that female mice are more vulnerable to chronic unpre-
dictable stress than male mice. The results suggest loss of BDNF in
ior, with gender affecting the results .
Antidepressant treatment appears to normalize BDNF decrease
in depressed patients [3,14]. Antidepressants could mediate their
effects by increasing neurogenesis and modulating the signaling
pathways involved in plasticity and survival . A meta-analyses
by Sen et al. reported significant associations between serum BDNF
0361-9230/$ – see front matter © 2009 Elsevier Inc. All rights reserved.
Y. Gorgulu, O. Caliyurt / Brain Research Bulletin 80 (2009) 158–162
levels and both depression status and pharmacologic antidepres-
sant treatment .
Besides pharmacotherapy, electroconvulsive treatment was
found to be associated with changes in BDNF levels in a group of
drug resistant depressed patients . Reduction of plasma BDNF
level has also been found to be related to suicidal behavior in peo-
ple with major depression and BDNF levels are speculated to be a
biological marker of suicidal depression [10,21].
Total sleep deprivation for one whole night improves depressive
symptoms in 40–60% of treatments. Antidepressant effects peak
by the afternoon after a night of total sleep loss [13,36]. The best
predictor of a therapeutic effect is a large variability of mood or
diurnal pattern. Although the mechanism for the antidepressant
effects of sleep deprivation is not known, sleep deprivation therapy
may share the antidepressants ability to increase BDNF levels.
The aim of the present study was to determine the effects of
total sleep deprivation therapy on BDNF levels in major depres-
treated with sertraline and healthy volunteers who experienced
single total sleep deprivation.
Fifty-one patients with major depression, diagnosed according to Diagnostic
and Statistical Manual of Mental Disorders IV criteria and 33 healthy controls par-
ticipated in the present study. Patients were assessed with the Structured Clinical
Interview for DSM-IV Axis I Disorders Turkish version and subjects were excluded
who had co morbid Axis I disorder, had psychotic or seasonal depression, had
other major medical illness, or had scored<18 on the Hamilton Depression Rating
Scale Turkish version (HAM-D, 17 Item). Patients who had chronic medical diseases
and were receiving medication were excluded from the study. Patients receiving
antidepressant medication for current episodes prior to the participation were also
excluded from the study. The inclusion criteria for control subjects were between
the ages of 18–65, had no history of mental disorder, neurologic disease, or drug
All patients and controls were informed about the study. The local ethics com-
mittee of Trakya University Medical School approved the study and all patients and
controls gave informed written consent.
Patients in the sertraline group were treated only with sertraline and patients in the
TSD group were treated with three total sleep deprivation therapies and sertra-
line. Patients in both groups received a starting dose of 50mg/day of sertraline but
patients in the sleep deprivation group were delayed in receiving sertraline after the
14th, and 42nd days. Patients in the TSD group were also evaluated for depression
levels after the first TSD. All patients in the TSD group had their first sleep depriva-
tion in the first study day, 2nd TSD in the 4th study day and 3rd TSD in the 7th study
day. Three total sleep deprivation therapies were applied in the first study week.
Sleep deprivation therapies of the patients took place in the inpatient psychiatry
unit under the supervision of residents and nurses. Patients were not permitted to
take a nap during the sleep deprivation therapy, therefore they had approximately
40h sleep deprivation following a baseline sleep.
For serum sampling, 10ml of blood was obtained from the antecubital vein and
was collected at baseline, 7th, 14th, and 42nd days. Additional blood samples were
drawings performed between 10:00AM and 14:00PM then spun to isolate serum
at 3000–4000rpm in the ELISA laboratory at Trakya University Hospital. Serum was
collected and kept at −20◦C before assaying BDNF content. Promega BDNF Emax®
Immunoassay System G7611 (Madison, USA) enzyme-linked immunosorbent assay
(ELISA) kit was used to evaluate the BDNF levels. The plates were read within 30min
in an ELISA reader set at 450nm.
blood collection was obtained at baseline and after the sleep deprivation.
2.1. Data analysis
For descriptive purposes, means and standard deviations were calculated.
The chi-squared test was used for the categorical variables, and Student’s t-test
was employed for the continuous variables. For the multiple group paramet-
ric comparisons, analysis of variance (ANOVA) was used. Correlation analysis
was used to test whether there is a relationship between two or more vari-
ables. Pearson’s correlation was used to examine whether the improvement of
depression (measured by HAM-D) was related to the increase of BDNF levels. A
repeated measures ANOVA was used to determine significant differences between
groups and to examine the treatment, time and the interaction time×treatment
effects in our model – we used BDNF and HAM-D as dependent variables. The
level of significance was set at P<0.05 and the test of significance was two
Twenty-eight patients were included in the sertraline group,
but 6 of the patients’ blood samples could not be studied because
of technical laboratory problems. Twenty-three patients were
included in the TSD group, two of them could not complete the
19 patients in the TSD group were included in the study and ana-
lyzed statistically. All patients in the TSD group were treated in the
inpatient psychiatry unit and with the exception of two patients
in the sertraline group, the rest of them followed on an outpatient
basis. One subject in the control group showed abnormal reactions
to the sleep deprivation and could not complete the sleep depri-
vation and another subject’s blood sample could not be studied
because of technical problems. A total of 31 subjects in the control
group were included in the study.
Sex distribution of the groups was similar. The study was com-
posed of 15 women, 7 men in the sertraline group; 15 women, 4
men in the TSD group; and 20 women 11 men in the control group
(?2=1.18, P=0.55). The mean age (±SD) was 33.27±11.18 years
in the sertraline group, 40.00±11.69 years in the TSD group and
35.00±12.24 years in the control group (F=1.78, P=0.17).
All the patients in the sertraline and TSD groups were given
sertraline 50mg/day, while patients in the TSD group had their
first dosage of sertraline delayed until after the first sleep depri-
vation day. During the treatment course, the sertraline dosage
increased to 100mg/day in 8 patients in the sertraline group and
3 patients in TSD group and also 1 patient in the TSD group
received sertraline 150mg/day because of the inadequate treat-
ment response. On the 42nd day, daily mean sertraline dosages
were higher for the sertraline group (70.45±29.52mg) than the
TSD group (63.16±28.10mg), with dosages being statistically sim-
ilar (t=0.81, P=0.42).
groups than the controls (F=34.12, P=0.000). The decreased lev-
els of BDNF were also negatively correlated with HAM-D scores
(r=−0.72, P=0.000). Mean BDNF levels and HAM-D scores of the
groups over the course of the treatment are presented in Table 1.
Patients in both of the treatment groups were successfully treated
and BDNF levels normalized at the end of the study (Fig. 1). Single
Fig. 1. HAM-D scores and BDNF level changes of the groups over the treatment
course. Mean±SEM given. *P<0.05, Student’s t-test (for independent samples).
Y. Gorgulu, O. Caliyurt / Brain Research Bulletin 80 (2009) 158–162
Sex, mean age distribution, HAM-D and BDNF changes of the groupsa.
Control SertralineTSD Statistics
Sertraline vs. TSDb
Baseline vs. Day 1c
1.77 ± 2.07
2.30 ± 1.86
24.32 ± 5.02 25.53 ± 4.46
17.42 ± 6.07
7.37 ± 4.02
8.68 ± 5.56
6.53 ± 7.21
t=−0.81, P=0.42Control: t=−0.76, P=0.45
TSD: t=7.16, P=0.000
15.73 ± 6.10
12.86 ± 5.75
6.41 ± 4.26
33.83 ± 7.14
33.38 ± 7.80
19.54 ± 4.26 21.59 ± 4.34
26.81 ± 4.40
30.95 ± 5.57
37.76 ± 7.87
45.20 ± 8.85
t=−1.53, P=0.13Control: t=0.42, P=0.67
TSD: t=−8.20, P=0.000
27.01 ± 4.03
37.65 ± 8.58
52.29 ± 6.76
bIndependent samples t-test comparisons of the treatment groups on treatment days.
cPaired samples t-test comparisons of the before and after first sleep deprivation therapy.
sleep deprivation therapy was shown to decrease HAM-D scores
Effects of single sleep deprivation therapy on HAM-D scores were
correlated with changes in BDNF levels (r=−0.46, P=0.001). A
series of 3 sleep deprivation therapies in a week accelerated the
treatment response and increased the BDNF levels rapidly com-
response in the TSD group was also correlated with the statistically
significant increase of BDNF levels in the 7th day compared to the
sertraline group. There were no significant changes observed on
HAM-D scores or BDNF levels in the control group with single sleep
BDNF increase during the course of the treatment was quicker
in the first week of the treatment in the TSD group and at the
end of the second week it equalized. Interestingly at the end of
the study, 42nd day mean HAM-D scores of both treatment groups
were similar (t=0.06, P=0.95) but patients in the sertraline group
Fig. 2. Effects of single sleep deprivation on HAM-D scores and BDNF levels in
controls and depressive patients. Mean±SEM given. *P<0.05, Student’s t-test (for
independent samples).#P<0.05, Student’s t-test (for paired samples).
showed significantly higher mean BDNF levels (t=2.65, P=0.01).
Repeated measures ANOVA on HAM-D scores data revealed sig-
nificant time effect (F=157.89, df=3, P=0.000), time×treatment
group interaction effect (F=11.85, df=3, P=0.000) and treatment
group effect (F=4.8, df=1, P=0.034). On the other hand, ANOVA
df=3, P=0.000) and time×treatment group interaction effect
(F=0.12, df=1, P=0.73) on BDNF levels.
The main finding of this study was that total sleep depri-
vation and sertraline therapy rapidly increased BDNF levels in
major depressive patients. Increase in BDNF levels correlated with
treatment response. Previous studies show that antidepressant
therapies increase BDNF levels in major depression [17,37]. This
study introduced for the first time that rapid antidepressant effects
of sleep deprivation therapy correlate with the rapid BDNF level
changes in depressive patients. Although both methods in each of
the treatment groups were found effective for treating depression,
treatment response was quicker in patients treated with TSD plus
sertraline. The results are in accordance with the study introduced
by Matrisciano et al. that a significant increase is shown in BDNF
serum levels after 5 weeks of treatment with sertraline . Fur-
or serum BDNF levels in the healthy control group. But single sleep
deprivation without an antidepressant ameliorated depression and
significantly increased BDNF levels. BDNF increase after 1 day of
sleep deprivation is an important finding of our study and as far as
we know this is the first human study with such a result.
Our results are in accordance with the neurotrophic hypothe-
sis of depression which proposes that reduced brain BDNF levels
predisposes depression, whereas increases in brain BDNF levels
produce an antidepressant action. Stress decreases the expression
of BDNF in the hippocampus. Stress also induces neuronal atro-
phy, death and decreased neurogenesis in limbic and cortical areas
Y. Gorgulu, O. Caliyurt / Brain Research Bulletin 80 (2009) 158–162
. Furthermore, endogenous PGE2 contributes to either neuro-
toxicity or neuroprotection in the injured brain via the induction
of BDNF release from microglial cells and astrocytes . A recent
meta-analysis supports the neurotrophin hypothesis of depres-
sion suggesting that major depressive disorder improvement is
associated with neuroplasticity and that different antidepressant
treatments are associated with an increase in BDNF. This suggests
that this neuropeptide might be a ‘final common pathway’ in major
depressive disorder treatment .
Previous studies have found a relationship between sleep depri-
vation, neural plasticity, and BDNF changes. BDNF has been shown
et al. reported that sleep loss and a mild increase in ambient tem-
perature enhance sleep in rats and affect the expression of BDNF
mRNAs . BDNF levels were reportedly increased by sleep depri-
vation in the cortex at postnatal 20th and 24th and only at 24th day
sleep deprivation in the rat stimulated significant neurogenesis in
the hippocampal dentate gyrus by enhancing cell proliferation and
sleep deprivation appears to up-regulate the expression of BDNF in
various regions of the brain, paradoxical sleep deprivation in rats
showed no alteration of BDNF expression . Zheng et al studied
and BDNF stimulated neurons and demonstrated the induction and
maintenance phases of BDNF transcription may be differentially
Patients in both groups demonstrated significantly higher BDNF
levels compared to baseline levels at the 42nd study day. Another
interesting result revealed at the end of the study was that patients
treated with sertraline showed significantly higher BDNF levels
than patients treated with combination therapy sertraline plus
three total sleep deprivations. Statistically significant differences
showed that TSD helped to control excessive increase in BDNF lev-
els. BDNF overactivity in depressive patients could be important
because, it has been suggested that BDNF overactivity plays a key
role in the pathogenesis of the manic state . Although, antide-
episodes, better regulation of BDNF levels with combination ther-
apy might be beneficial for controlling the antidepressant induced
on days 14 and 42 (Fig. 1). BDNF level changes reflect biological
changes whereas HAM-D changes are related to the symptoms
of depression. The questionnaire rates the severity of symptoms
observed in depression and this difference may explain the dis-
Past research supports the role of sleep in synaptic plasticity .
sented. Disruption of REM sleep on learning impairment has also
been reported. Those studies suggest negative effect of sleep depri-
vation on synaptic plasticity. While there is conflicting evidence
about the negative effects of sleep deprivation on memory and
learning most of the evidence suggests that sleep deprivation ther-
apy shows an antidepressant effect. Besides the successful usage of
sleep deprivation therapy in major depression, its impact on BDNF
changes were introduced in this study. While the increase in BDNF
of sleep deprivation on depression must be interpreted carefully.
The role of REM sleep on memory consolidation has been found to
be weak and contradictory . On the other hand sleep depriva-
tion produces stress and stress has important effects on learning
and synaptic plasticity. Sei et al. reported that 6h selective REM
sleep deprivation causes a decrease of BDNF in the cerebellum and
brainstem and they concluded REM sleep may be associated with
the maintenance of neurotrophic factors and thus contribute to
the memory function in parallel with the neural trophic function
objective alertness to well-rested levels during total sleep depriva-
tion. Costa et al. studied effects of caffeine on mice performance in
an object recognition task and they reported a connection between
cognitive enhancer properties of a short administration of caffeine
of BDNF and its receptor TrkB .
Circadian rhythm disturbances were shown in depressive
patients and a circadian hypothesis of depression highlights that
depression is closely tied to circadian rhythm disorders . The
therapeutic effect of sleep deprivation is hypothesized to be linked
to changes in disturbed circadian- and sleep–wake-dependent
phase relationships . BDNF-mediated signaling suggested it
sensitivity to light . Sei et al. reported significant increase in
disturbances in depression and BDNF changes.
There were some limitations in the present study. Firstly, the
mostly of outpatients which resulted in higher drop-outs. Thirdly,
we measured serum BDNF levels in this study. Although animal
studies reported that BDNF could cross the blood–brain barrier,
suggesting that serum BDNF levels may reflect BDNF levels in the
in the brain. Finally this study is not blinded and the effects of sleep
deprivation with an appropriate attentional control treatment in
depressed patients was not used. Factors like the hope associated
professionals involved in the treatment may be involved.
In conclusion, our results support the BDNF reduction in major
depression. Rapid antidepressant effects of sleep deprivation ther-
apy appear to relate to the rapid BDNF increase in major depressive
patients. Although drug therapy alone increased the serum BDNF
levels in depressive patients, effects of sleep deprivation therapy
on BDNF levels was outstanding in our study. These results give an
opportunity to explore the relationship between fast antidepres-
sant response and BDNF changes in major depression.
Conflict of interest
BDNF kit used in the study was provided by Pfizer Inc.
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