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Rapid antidepressant effects of sleep deprivation therapy correlates with serum BDNF changes in major depression
Brain Research Bulletin 80 (2009) 158–162
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Research report
Rapid antidepressant effects of sleep deprivation therapy correlates with serum BDNF changes in major depression Yasemin Gorgulu 1 , Okan Caliyurt ∗ Trakya University School of Medicine, Psychiatry Department, 22030 Edirne, Turkey
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Article history: Received 15 April 2009 Received in revised form 18 June 2009 Accepted 19 June 2009 Available online 1 July 2009 Keywords: Brain-derived neurotrophic factor Major depression Sertraline Total sleep deprivation therapy
a b s t r a c t Recent reports have suggested that brain-derived neurotrophic factor (BDNF) levels are reduced in individuals suffering major depressive disorder and these levels normalize following antidepressant treatment. Various antidepressants and electroconvulsive therapy are shown to have a positive effect on brainderived 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.
1. Introduction Neuroplasticity refers to the brain’s ability, at the level of the neuron, to recover structurally and/or functionally after injury or disease. Brain-derived neurotrophic factor (BDNF) has an important role in neuroplasticity and is the most widely distributed trophic factor in the brain. BDNF is a type of neurotrophic factor which regulates 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, neurotrophin3, and neurotrophin-4 [34]. BDNF is produced by astrocytes, in addition to neurons, and the noradrenergic system plays a role in controlling BDNF synthesis [19]. New studies on permeation of maternal BDNF to fetuses, showed the possibility that maternal
Abbreviations: BDNF, brain-derived neurotrophic factor; HAM-D, Hamilton Rating Scale for Depression; TSD, total sleep deprivation. ∗ Corresponding author. Tel.: +90 2842359460; fax: +90 2842359460. E-mail address: [email protected] (O. Caliyurt). Present address: Bakirkoy Research and Training Hospital for Psychiatry, Neurology and Neurochirurgie, Istanbul, Turkey. 1
0361-9230/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.brainresbull.2009.06.016
BDNF reaches the fetal brain through utero-placental barrier and might contribute to its development [22]. Depression is associated with regional impairments of structural plasticity and cellular resilience. Neuroplasticity is disrupted in mood disorders and in animal models of stress [27]. There are many studies which report decreased serum [2,20] and platelet [23] 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 [31]. 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 unpredictable stress than male mice. The results suggest loss of BDNF in the forebrain contributes to some aspects of depression-like behavior, with gender affecting the results [1]. 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 [11]. A meta-analyses by Sen et al. reported significant associations between serum BDNF
Y. Gorgulu, O. Caliyurt / Brain Research Bulletin 80 (2009) 158–162
levels and both depression status and pharmacologic antidepressant treatment [30]. Besides pharmacotherapy, electroconvulsive treatment was found to be associated with changes in BDNF levels in a group of drug resistant depressed patients [5]. Reduction of plasma BDNF level has also been found to be related to suicidal behavior in people 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 depression. Results were compared between depressive patients that were treated with sertraline and healthy volunteers who experienced single total sleep deprivation. 2. Method Fifty-one patients with major depression, diagnosed according to Diagnostic and Statistical Manual of Mental Disorders IV criteria and 33 healthy controls participated 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 abuse. All patients and controls were informed about the study. The local ethics committee of Trakya University Medical School approved the study and all patients and controls gave informed written consent. The patients were assigned to sertraline and total sleep deprivation (TSD) groups. 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 sertraline. Patients in both groups received a starting dose of 50 mg/day of sertraline but patients in the sleep deprivation group were delayed in receiving sertraline after the first TSD. The severity of depression was measured using the HAM-D at baseline, 7th, 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 deprivation 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 40 h sleep deprivation following a baseline sleep. For serum sampling, 10 ml of blood was obtained from the antecubital vein and was collected at baseline, 7th, 14th, and 42nd days. Additional blood samples were collected from the patients in the TSD group after the first sleep deprivation. All blood drawings performed between 10:00 AM and 14:00 PM then spun to isolate serum at 3000–4000 rpm 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 30 min in an ELISA reader set at 450 nm. Volunteers in the control group had one TSD. They were assessed by HAM-D and blood collection was obtained at baseline and after the sleep deprivation.
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level of significance was set at P < 0.05 and the test of significance was two tailed.
3. Results 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 study and two patients’ blood samples could not be studied because of technical problems. Finally 22 patients in the sertraline group and 19 patients in the TSD group were included in the study and analyzed 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 deprivation 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 composed 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 50 mg/day, while patients in the TSD group had their first dosage of sertraline delayed until after the first sleep deprivation day. During the treatment course, the sertraline dosage increased to 100 mg/day in 8 patients in the sertraline group and 3 patients in TSD group and also 1 patient in the TSD group received sertraline 150 mg/day because of the inadequate treatment response. On the 42nd day, daily mean sertraline dosages were higher for the sertraline group (70.45 ± 29.52 mg) than the TSD group (63.16 ± 28.10 mg), with dosages being statistically similar (t = 0.81, P = 0.42). The baseline BDNF levels were significantly lower in both patient groups than the controls (F = 34.12, P = 0.000). The decreased levels 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
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 parametric comparisons, analysis of variance (ANOVA) was used. Correlation analysis was used to test whether there is a relationship between two or more variables. 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
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).
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Table 1 Sex, mean age distribution, HAM-D and BDNF changes of the groupsa . Groups Control
Sertraline
TSD
Statistics
Sex 20 Female 11 Male
15 Female 7 Male
15 Female 4 Male
2 = 1.18, P = 0.55
Age 35.00 ± 12.24
33.27 ± 11.18
40.00 ± 11.69
F = 1.78, P = 0.17
Groups Control
HAM-D scores Baseline Day 1 Day 7 Day 14 Day 42 BDNF (ng/ml) Baseline Day 1 Day 7 Day 14 Day 42 a b c
1.77 ± 2.07 2.30 ± 1.86
Sertraline
24.32 ± 5.02 15.73 ± 6.10 12.86 ± 5.75 6.41 ± 4.26
33.83 ± 7.14 33.38 ± 7.80
19.54 ± 4.26 27.01 ± 4.03 37.65 ± 8.58 52.29 ± 6.76
TSD
Statistics
25.53 17.42 7.37 8.68 6.53
± ± ± ± ±
4.46 6.07 4.02 5.56 7.21
21.59 26.81 30.95 37.76 45.20
± ± ± ± ±
4.34 4.40 5.57 7.87 8.85
Sertraline vs. TSDb
Baseline vs. Day 1c
t = −0.81, P = 0.42
Control: t = −0.76, P = 0.45 TSD: t = 7.16, P = 0.000
t = 5.09, P = 0.00 t = 2.36, P = 0.02 t = −0.06, P = 0.95 t = −1.53, P = 0.13
Control: t = 0.42, P = 0.67 TSD: t = −8.20, P = 0.000
t = −2.52, P = 0.02 t = −0.04, P = 0.97 t = 2.65, P = 0.01
Mean ± SD given. Independent samples t-test comparisons of the treatment groups on treatment days. Paired samples t-test comparisons of the before and after first sleep deprivation therapy.
sleep deprivation therapy was shown to decrease HAM-D scores and increase BDNF levels significantly in depressive patients (Fig. 2). 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 compared to the patients treated with sertraline alone. Better treatment 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 deprivation. 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 significant 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 with repeated measures revealed significant time effect (F = 253.53, df = 3, P = 0.000) and time × treatment group interaction effect (F = 10.36, df = 3, P = 0.000) but no significant treatment group effect (F = 0.12, df = 1, P = 0.73) on BDNF levels. 4. Discussion The main finding of this study was that total sleep deprivation 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 [26]. Furthermore, single total sleep deprivation did not change either mood 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 hypothesis 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 atrophy, death and decreased neurogenesis in limbic and cortical areas
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[12]. Furthermore, endogenous PGE2 contributes to either neurotoxicity or neuroprotection in the injured brain via the induction of BDNF release from microglial cells and astrocytes [18]. A recent meta-analysis supports the neurotrophin hypothesis of depression 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 [7]. Previous studies have found a relationship between sleep deprivation, neural plasticity, and BDNF changes. BDNF has been shown to induce sleep deprivation and spontaneous wakefulness [8]. Taishi et al. reported that sleep loss and a mild increase in ambient temperature enhance sleep in rats and affect the expression of BDNF mRNAs [33]. BDNF levels were reportedly increased by sleep deprivation in the cortex at postnatal 20th and 24th and only at 24th day in the hippocampus of rats [16]. Grassi et al. demonstrated that 12 h sleep deprivation in the rat stimulated significant neurogenesis in the hippocampal dentate gyrus by enhancing cell proliferation and survival of newly generated cells [15]. Although the short-term total 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 [24]. Zheng et al studied the signaling determinants for BDNF exon IV transcription in NMDA and BDNF stimulated neurons and demonstrated the induction and maintenance phases of BDNF transcription may be differentially regulated [38]. 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 between treatment groups of the BDNF levels at the end of the study showed that TSD helped to control excessive increase in BDNF levels. 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 [35]. Although, antidepressant drug therapy and sleep deprivation therapy induces manic episodes, better regulation of BDNF levels with combination therapy might be beneficial for controlling the antidepressant induced mania. There is also a discrepancy between BDNF and HAM-D scores 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 discrepancy. Past research supports the role of sleep in synaptic plasticity [4]. The positive effects of sleep on learning and memory have been presented. Disruption of REM sleep on learning impairment has also been reported. Those studies suggest negative effect of sleep deprivation 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 therapy 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 levels is related with the antidepressant effect and plasticity, effects 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 [32]. On the other hand sleep deprivation produces stress and stress has important effects on learning and synaptic plasticity. Sei et al. reported that 6 h 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
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the memory function in parallel with the neural trophic function [29]. On the other hand caffeine restores cognitive performance and objective alertness to well-rested levels during total sleep deprivation. 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 and withdrawal with a concomitant increase in the immunocontent of BDNF and its receptor TrkB [9]. Circadian rhythm disturbances were shown in depressive patients and a circadian hypothesis of depression highlights that depression is closely tied to circadian rhythm disorders [6]. The therapeutic effect of sleep deprivation is hypothesized to be linked to changes in disturbed circadian- and sleep–wake-dependent phase relationships [36]. BDNF-mediated signaling suggested it play an important role in the circadian regulation of SCN pacemaker sensitivity to light [25]. Sei et al. reported significant increase in BDNF levels in the rat hippocampus after a single 8 h phase advance [28]. These results connote a possible connection between circadian disturbances in depression and BDNF changes. There were some limitations in the present study. Firstly, the patients were followed for 6 weeks. This short period makes it difficult to interpret the results. Secondly, the sertraline group consisted 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 brain, it is unclear if peripheral BDNF accurately reflects BDNF levels 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 with initiating treatment, hospitalization or interaction with health 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 therapy 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 antidepressant response and BDNF changes in major depression. Conflict of interest BDNF kit used in the study was provided by Pfizer Inc. References [1] A.E. Autry, M. Adachi, P. Cheng, L.M. Monteggia, Gender-specific impact o brain-derived neurotrophic factor signaling on stress-induced depression-like behavior, Biol. Psychiatry 66 (2009) 84–90. [2] C. Aydemir, E.S. Yalcin, S. Aksaray, C. Kisa, S.G. Yildirim, T. Uzbay, Brain-derived neurotrophic factor (BDNF) changes in the serum of depressed women, Prog. Neuropsychopharmacol. Biol. Psychiatry 30 (7) (2006) 1256–1260. [3] O. Aydemir, A. Deveci, F. Taneli, The effect of chronic antidepressant treatment on serum brain-derived neurotrophic factor levels in depressed patients: a preliminary study, Prog. Neuropsychopharmacol. Biol. Psychiatry 29 (2) (2005) 261–265. [4] J.H. Benington, M.G. Frank, Cellular and molecular connections between sleep and synaptic plasticity, Prog. Neurobiol. 69 (2) (2003) 71–101. [5] L. Bocchio-Chiavetto, R. Zanardini, M. Bortolomasi, M. Abate, M. Segala, M. Giacopuzzi, Electroconvulsive therapy (ECT) increases serum brain derived neurotrophic factor (BDNF) in drug resistant depressed patients, Eur. Neuropsychopharmacol. 16 (8) (2006) 620–624. [6] D.B. Boivin, Influence of sleep–wake and circadian rhythm disturbances in psychiatric disorders, J. Psychiatry Neurosci. 25 (5) (2000) 446–458. [7] A.R. Brunoni, M. Lopes, F. Fregni, A systematic review and meta-analysis of clinical studies on major depression and BDNF levels: implications for the role of neuroplasticity in depression, Int. J. Neuropsychopharmacol. 11 (8) (2008) 1169–1180. [8] C. Cirelli, Cellular consequences of sleep deprivation in the brain, Sleep Med. Rev. 10 (5) (2006) 307–321.
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Research report
Rapid antidepressant effects of sleep deprivation therapy correlates with serum BDNF changes in major depression Yasemin Gorgulu 1 , Okan Caliyurt ∗ Trakya University School of Medicine, Psychiatry Department, 22030 Edirne, Turkey
a r t i c l e
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Article history: Received 15 April 2009 Received in revised form 18 June 2009 Accepted 19 June 2009 Available online 1 July 2009 Keywords: Brain-derived neurotrophic factor Major depression Sertraline Total sleep deprivation therapy
a b s t r a c t Recent reports have suggested that brain-derived neurotrophic factor (BDNF) levels are reduced in individuals suffering major depressive disorder and these levels normalize following antidepressant treatment. Various antidepressants and electroconvulsive therapy are shown to have a positive effect on brainderived 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.
1. Introduction Neuroplasticity refers to the brain’s ability, at the level of the neuron, to recover structurally and/or functionally after injury or disease. Brain-derived neurotrophic factor (BDNF) has an important role in neuroplasticity and is the most widely distributed trophic factor in the brain. BDNF is a type of neurotrophic factor which regulates 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, neurotrophin3, and neurotrophin-4 [34]. BDNF is produced by astrocytes, in addition to neurons, and the noradrenergic system plays a role in controlling BDNF synthesis [19]. New studies on permeation of maternal BDNF to fetuses, showed the possibility that maternal
Abbreviations: BDNF, brain-derived neurotrophic factor; HAM-D, Hamilton Rating Scale for Depression; TSD, total sleep deprivation. ∗ Corresponding author. Tel.: +90 2842359460; fax: +90 2842359460. E-mail address: [email protected] (O. Caliyurt). Present address: Bakirkoy Research and Training Hospital for Psychiatry, Neurology and Neurochirurgie, Istanbul, Turkey. 1
0361-9230/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.brainresbull.2009.06.016
BDNF reaches the fetal brain through utero-placental barrier and might contribute to its development [22]. Depression is associated with regional impairments of structural plasticity and cellular resilience. Neuroplasticity is disrupted in mood disorders and in animal models of stress [27]. There are many studies which report decreased serum [2,20] and platelet [23] 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 [31]. 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 unpredictable stress than male mice. The results suggest loss of BDNF in the forebrain contributes to some aspects of depression-like behavior, with gender affecting the results [1]. 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 [11]. A meta-analyses by Sen et al. reported significant associations between serum BDNF
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levels and both depression status and pharmacologic antidepressant treatment [30]. Besides pharmacotherapy, electroconvulsive treatment was found to be associated with changes in BDNF levels in a group of drug resistant depressed patients [5]. Reduction of plasma BDNF level has also been found to be related to suicidal behavior in people 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 depression. Results were compared between depressive patients that were treated with sertraline and healthy volunteers who experienced single total sleep deprivation. 2. Method Fifty-one patients with major depression, diagnosed according to Diagnostic and Statistical Manual of Mental Disorders IV criteria and 33 healthy controls participated 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 abuse. All patients and controls were informed about the study. The local ethics committee of Trakya University Medical School approved the study and all patients and controls gave informed written consent. The patients were assigned to sertraline and total sleep deprivation (TSD) groups. 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 sertraline. Patients in both groups received a starting dose of 50 mg/day of sertraline but patients in the sleep deprivation group were delayed in receiving sertraline after the first TSD. The severity of depression was measured using the HAM-D at baseline, 7th, 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 deprivation 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 40 h sleep deprivation following a baseline sleep. For serum sampling, 10 ml of blood was obtained from the antecubital vein and was collected at baseline, 7th, 14th, and 42nd days. Additional blood samples were collected from the patients in the TSD group after the first sleep deprivation. All blood drawings performed between 10:00 AM and 14:00 PM then spun to isolate serum at 3000–4000 rpm 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 30 min in an ELISA reader set at 450 nm. Volunteers in the control group had one TSD. They were assessed by HAM-D and blood collection was obtained at baseline and after the sleep deprivation.
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level of significance was set at P < 0.05 and the test of significance was two tailed.
3. Results 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 study and two patients’ blood samples could not be studied because of technical problems. Finally 22 patients in the sertraline group and 19 patients in the TSD group were included in the study and analyzed 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 deprivation 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 composed 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 50 mg/day, while patients in the TSD group had their first dosage of sertraline delayed until after the first sleep deprivation day. During the treatment course, the sertraline dosage increased to 100 mg/day in 8 patients in the sertraline group and 3 patients in TSD group and also 1 patient in the TSD group received sertraline 150 mg/day because of the inadequate treatment response. On the 42nd day, daily mean sertraline dosages were higher for the sertraline group (70.45 ± 29.52 mg) than the TSD group (63.16 ± 28.10 mg), with dosages being statistically similar (t = 0.81, P = 0.42). The baseline BDNF levels were significantly lower in both patient groups than the controls (F = 34.12, P = 0.000). The decreased levels 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
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 parametric comparisons, analysis of variance (ANOVA) was used. Correlation analysis was used to test whether there is a relationship between two or more variables. 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
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).
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Table 1 Sex, mean age distribution, HAM-D and BDNF changes of the groupsa . Groups Control
Sertraline
TSD
Statistics
Sex 20 Female 11 Male
15 Female 7 Male
15 Female 4 Male
2 = 1.18, P = 0.55
Age 35.00 ± 12.24
33.27 ± 11.18
40.00 ± 11.69
F = 1.78, P = 0.17
Groups Control
HAM-D scores Baseline Day 1 Day 7 Day 14 Day 42 BDNF (ng/ml) Baseline Day 1 Day 7 Day 14 Day 42 a b c
1.77 ± 2.07 2.30 ± 1.86
Sertraline
24.32 ± 5.02 15.73 ± 6.10 12.86 ± 5.75 6.41 ± 4.26
33.83 ± 7.14 33.38 ± 7.80
19.54 ± 4.26 27.01 ± 4.03 37.65 ± 8.58 52.29 ± 6.76
TSD
Statistics
25.53 17.42 7.37 8.68 6.53
± ± ± ± ±
4.46 6.07 4.02 5.56 7.21
21.59 26.81 30.95 37.76 45.20
± ± ± ± ±
4.34 4.40 5.57 7.87 8.85
Sertraline vs. TSDb
Baseline vs. Day 1c
t = −0.81, P = 0.42
Control: t = −0.76, P = 0.45 TSD: t = 7.16, P = 0.000
t = 5.09, P = 0.00 t = 2.36, P = 0.02 t = −0.06, P = 0.95 t = −1.53, P = 0.13
Control: t = 0.42, P = 0.67 TSD: t = −8.20, P = 0.000
t = −2.52, P = 0.02 t = −0.04, P = 0.97 t = 2.65, P = 0.01
Mean ± SD given. Independent samples t-test comparisons of the treatment groups on treatment days. Paired samples t-test comparisons of the before and after first sleep deprivation therapy.
sleep deprivation therapy was shown to decrease HAM-D scores and increase BDNF levels significantly in depressive patients (Fig. 2). 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 compared to the patients treated with sertraline alone. Better treatment 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 deprivation. 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 significant 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 with repeated measures revealed significant time effect (F = 253.53, df = 3, P = 0.000) and time × treatment group interaction effect (F = 10.36, df = 3, P = 0.000) but no significant treatment group effect (F = 0.12, df = 1, P = 0.73) on BDNF levels. 4. Discussion The main finding of this study was that total sleep deprivation 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 [26]. Furthermore, single total sleep deprivation did not change either mood 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 hypothesis 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 atrophy, death and decreased neurogenesis in limbic and cortical areas
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[12]. Furthermore, endogenous PGE2 contributes to either neurotoxicity or neuroprotection in the injured brain via the induction of BDNF release from microglial cells and astrocytes [18]. A recent meta-analysis supports the neurotrophin hypothesis of depression 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 [7]. Previous studies have found a relationship between sleep deprivation, neural plasticity, and BDNF changes. BDNF has been shown to induce sleep deprivation and spontaneous wakefulness [8]. Taishi et al. reported that sleep loss and a mild increase in ambient temperature enhance sleep in rats and affect the expression of BDNF mRNAs [33]. BDNF levels were reportedly increased by sleep deprivation in the cortex at postnatal 20th and 24th and only at 24th day in the hippocampus of rats [16]. Grassi et al. demonstrated that 12 h sleep deprivation in the rat stimulated significant neurogenesis in the hippocampal dentate gyrus by enhancing cell proliferation and survival of newly generated cells [15]. Although the short-term total 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 [24]. Zheng et al studied the signaling determinants for BDNF exon IV transcription in NMDA and BDNF stimulated neurons and demonstrated the induction and maintenance phases of BDNF transcription may be differentially regulated [38]. 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 between treatment groups of the BDNF levels at the end of the study showed that TSD helped to control excessive increase in BDNF levels. 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 [35]. Although, antidepressant drug therapy and sleep deprivation therapy induces manic episodes, better regulation of BDNF levels with combination therapy might be beneficial for controlling the antidepressant induced mania. There is also a discrepancy between BDNF and HAM-D scores 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 discrepancy. Past research supports the role of sleep in synaptic plasticity [4]. The positive effects of sleep on learning and memory have been presented. Disruption of REM sleep on learning impairment has also been reported. Those studies suggest negative effect of sleep deprivation 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 therapy 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 levels is related with the antidepressant effect and plasticity, effects 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 [32]. On the other hand sleep deprivation produces stress and stress has important effects on learning and synaptic plasticity. Sei et al. reported that 6 h 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
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the memory function in parallel with the neural trophic function [29]. On the other hand caffeine restores cognitive performance and objective alertness to well-rested levels during total sleep deprivation. 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 and withdrawal with a concomitant increase in the immunocontent of BDNF and its receptor TrkB [9]. Circadian rhythm disturbances were shown in depressive patients and a circadian hypothesis of depression highlights that depression is closely tied to circadian rhythm disorders [6]. The therapeutic effect of sleep deprivation is hypothesized to be linked to changes in disturbed circadian- and sleep–wake-dependent phase relationships [36]. BDNF-mediated signaling suggested it play an important role in the circadian regulation of SCN pacemaker sensitivity to light [25]. Sei et al. reported significant increase in BDNF levels in the rat hippocampus after a single 8 h phase advance [28]. These results connote a possible connection between circadian disturbances in depression and BDNF changes. There were some limitations in the present study. Firstly, the patients were followed for 6 weeks. This short period makes it difficult to interpret the results. Secondly, the sertraline group consisted 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 brain, it is unclear if peripheral BDNF accurately reflects BDNF levels 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 with initiating treatment, hospitalization or interaction with health 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 therapy 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 antidepressant response and BDNF changes in major depression. Conflict of interest BDNF kit used in the study was provided by Pfizer Inc. References [1] A.E. Autry, M. Adachi, P. Cheng, L.M. Monteggia, Gender-specific impact o brain-derived neurotrophic factor signaling on stress-induced depression-like behavior, Biol. Psychiatry 66 (2009) 84–90. [2] C. Aydemir, E.S. Yalcin, S. Aksaray, C. Kisa, S.G. Yildirim, T. Uzbay, Brain-derived neurotrophic factor (BDNF) changes in the serum of depressed women, Prog. Neuropsychopharmacol. Biol. Psychiatry 30 (7) (2006) 1256–1260. [3] O. Aydemir, A. Deveci, F. Taneli, The effect of chronic antidepressant treatment on serum brain-derived neurotrophic factor levels in depressed patients: a preliminary study, Prog. Neuropsychopharmacol. Biol. Psychiatry 29 (2) (2005) 261–265. [4] J.H. Benington, M.G. Frank, Cellular and molecular connections between sleep and synaptic plasticity, Prog. Neurobiol. 69 (2) (2003) 71–101. [5] L. Bocchio-Chiavetto, R. Zanardini, M. Bortolomasi, M. Abate, M. Segala, M. Giacopuzzi, Electroconvulsive therapy (ECT) increases serum brain derived neurotrophic factor (BDNF) in drug resistant depressed patients, Eur. Neuropsychopharmacol. 16 (8) (2006) 620–624. [6] D.B. Boivin, Influence of sleep–wake and circadian rhythm disturbances in psychiatric disorders, J. Psychiatry Neurosci. 25 (5) (2000) 446–458. [7] A.R. Brunoni, M. Lopes, F. Fregni, A systematic review and meta-analysis of clinical studies on major depression and BDNF levels: implications for the role of neuroplasticity in depression, Int. J. Neuropsychopharmacol. 11 (8) (2008) 1169–1180. [8] C. Cirelli, Cellular consequences of sleep deprivation in the brain, Sleep Med. Rev. 10 (5) (2006) 307–321.
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