Characteristics of objective daytime sleep among individuals with earthquake-related posttraumatic stress disorder: A pilot community-based polysomnographic and multiple sleep latency test study

Author’s Accepted Manuscript Characteristics of Objective Daytime Sleep among Individuals with Earthquake-Related Posttraumatic Stress Disorder: A Pilot Community-Based Polysomnographic and Multiple Sleep Latency Test Study Yan Zhang, Yun Li, Hongru Zhu, Haofei Cui, Changjian Qiu, Xiangdong Tang, Wei Zhang

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S0165-1781(15)30266-3 http://dx.doi.org/10.1016/j.psychres.2016.09.030 PSY9964

To appear in: Psychiatry Research Received date: 1 September 2015 Revised date: 24 August 2016 Accepted date: 20 September 2016 Cite this article as: Yan Zhang, Yun Li, Hongru Zhu, Haofei Cui, Changjian Qiu, Xiangdong Tang and Wei Zhang, Characteristics of Objective Daytime Sleep among Individuals with Earthquake-Related Posttraumatic Stress Disorder: A Pilot Community-Based Polysomnographic and Multiple Sleep Latency Test Study, Psychiatry Research, http://dx.doi.org/10.1016/j.psychres.2016.09.030 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Characteristics of Objective Daytime Sleep among Individuals with Earthquake-Related Posttraumatic Stress Disorder: A Pilot Community-Based Polysomnographic and Multiple Sleep Latency Test Study Yan Zhanga,c1, Yun Lib,1, Hongru Zhua, Haofei Cuia, Changjian Qiua, Xiangdong Tangb**, Wei Zhang a***

aMental

Health Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan

University, Chengdu, China bSleep

Medicine Center, Translational Neuroscience Center, and State Key Laboratory of

Biotherapy, West China Hospital, Sichuan University, Chengdu, China cDepartment

of Psychosomatic Medicine, Suining Central Hospital, Suining, China

[email protected] [email protected] ***Corresponding

author. Wei Zhang, Mental Health Center, West China Hospital of Sichuan

University, 37 Guo Xue Xiang, Chengdu, Sichuan, 610041, China; Tel: +011-86-28 8542200; fax: +011-86-28 85582944 **Corresponding

author. Xiangdong Tang, West China Hospital, Sichuan University, Sleep Medicine Center, 28 Dian Xin Nan Jie, Chengdu, Sichuan, 610041, China; Tel: +011-86-28 8542 2733; fax: +011-86-28 85422632

Abstract Little is known about the objective sleep characteristics of patients with posttraumatic stress disorder (PTSD). The present study examines the association between PTSD symptom severity and objective daytime sleep characteristics measured using the Multiple Sleep Latency Test (MSLT) in therapy-naïve patients with earthquake-related PTSD. A total of 23 PTSD patients and 13 trauma-exposed non-PTSD (TEN-PTSD) subjects completed one-night

1

these authors contributed equally to this study. 1

in-lab polysomnography (PSG) followed by a standard MSLT. 8 of the 23 PTSD patients received paroxetine treatment. Compared to the TEN-PTSD subjects, no significant nighttime sleep disturbances were detected by PSG in the subjects with PTSD; however, a shorter mean MSLT value was found in the subjects with PTSD. After adjustment for age, sex, and body mass index, PTSD symptoms, particularly hyperarousal, were found to be independently associated with a shorter MSLT value. Further, the mean MSLT value increased significantly after therapy in PTSD subjects. A shorter MSLT value may be a reliable index of the medical severity of PTSD, while an improvement in MSLT values might also be a reliable marker for evaluating therapeutic efficacy in PTSD patients.

Keywords: posttraumatic stress disorder; sleep; daytime sleepiness; multiple sleep latency test

1. Introduction Posttraumatic stress disorder (PTSD) is a clinical syndrome that develops after one experiences or witnesses traumatic events. Sleep disturbances, prominent features of PTSD, are included in the diagnostic and statistical manual-IV (DSM-IV) (APA, 1994) diagnostic clusters for re-experiencing symptoms (i.e., nightmares) and hyperarousal (i.e., difficulty initiating and maintaining sleep). Previous

studies

demonstrated

a 2

consistent

correlation

between

self-reported sleep disturbances and PTSD symptom clusters (Ohayon and Shapiro, 2000; Babson et al., 2011), that is, PTSD symptoms were associated with self-reported sleep disturbances among the subjects with PTSD. In contrast to the consistent findings of high rates of PTSD-related sleep complaints; sleep-laboratory studies have yielded conflicting results. Some studies reported difficulty initiating and maintaining sleep, reduced sleep efficiency, and increased brief arousals during sleep (Hefez et al., 1987; Ross et al., 1994a; Mellman et al., 1995a, 1997a); however, other studies failed to find objective evidence of sleep disturbances in the subjects with PTSD (Mellman et al., 1995b; Hurwitz et al., 1998; Klein et al., 2003). A meta-analysis of 20 polysomnographic studies found that PTSD patients had more stage 1 sleep, less slow-wave sleep, and greater rapid eye movement (REM) density than individuals without PTSD (Kobayashi et al., 2007). The Epworth Sleepiness Scale (ESS) and the multiple sleep latency test (MSLT), respectively, are the most commonly used tools for evaluating daytime sleepiness subjectively and objectively. Higher scores on the ESS (> 10) and lower mean values in the MSLT (sleep onset latency < 8 min) indicate excessive daytime sleepiness. Several studies reported that subjects with PTSD had higher ESS scores than controls. For example, Capaldi II found that 65% of veterans returning from combat experienced daytime sleepiness according to their ESS scores (Capaldi II et al., 2011). Additionally, a study of 26 veterans found that higher ESS scores were associated with more self-rated posttraumatic symptoms, 3

particularly hyperarousal (Westermeyer et al., 2010). However, using a linear regression model and controlling for confounding factors, Westermeyer et al. found that higher ESS scores were independently associated with impaired daytime function but not PTSD per se (Westermeyer et al., 2010). Relatively few studies have used the MSLT to objectively assess daytime sleepiness in subjects with PTSD, and those that did reported contradictory findings with respect to the association between MSLT values and PTSD. For example, Mellman et al. found that 8 of 11 subjects with combat-related PTSD fell asleep during MSLT nap opportunities and that 5 had sleep-onset rapid eye movement periods (SOREMPs) (Mellman, 1997b). By comparison, Hurwitz et al. found no evidence of significant daytime sleepiness according to the MSLT values of subjects with PTSD compared to those of healthy controls (Hurwitz et al., 1998). Another study with a relatively large sample size of young-adult community residents, 71 with PTSD and 212 without PTSD, also found no significant differences in mean MSLT values or SOREMPs between PTSD and non-PTSD subjects (Breslau et al., 2004). To date, most PTSD-related sleep studies have included subjects who experienced combat-related trauma. To our knowledge, no studies have assessed objective nighttime sleep and daytime sleepiness using polysomnography (PSG) and the MSLT in therapy-naïve subjects with PTSD arising from natural disasters (e.g., earthquakes). Here we hypothesized that a low MSLT value is independently associated with earthquake-related PTSD. We used an overnight PSG recording followed by the standard MSLT to assess objective nighttime sleep and daytime 4

sleepiness in subjects with PTSD arising from earthquake-related trauma. We also assessed pre- and post-therapy sleep in a subset of subjects treated with paroxetine.

2. Methods We conducted a between-group cross-sectional study using PSG and the MSLT in patients with PTSD versus trauma-exposed non-PTSD (TEN-PTSD) subjects at baseline, followed by an open-label 12-week study of paroxetine therapy in the PTSD patients as a pre- and post-control observation. This study was approved by the Research Ethics Board of West China Hospital of Sichuan University. Written informed consent was obtained from each subject after they were provided a complete study description.

2.1 Subjects and study design Subjects recruited into the PTSD group were therapy-naïve chronic PTSD patients (age range, 18–60 years) from the Qingchuan region of Sichuan province, which was significantly affected by the Great Wenchuan Earthquake in 2008, approximately 4 years after the event. A complete medical history was taken, and physical examination including a mental status assessment was performed. All potential research subjects completed a personal interview and a series of comprehensive questionnaires that assessed history of sleep complaints, mood status, general health, and history of medication use. The cutoff of the

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Clinician Administered PTSD Scale (CAPS) used in this study was 40 points (i.e., ≥40 suggested PTSD); a Structured Clinical Interview for DSM-IV Axis I Disorders-Patient Edition was used in subjects with a CAPS ≥ 40 to further aid a trained psychiatrist in diagnosing PTSD. Subjects with TEN-PTSD were recruited from the same region from among those who had experienced the Great Wenchuan Earthquake, and these subjects were interviewed using Structured Clinical Interview for DSM-IV Axis I Disorders-Non-Patient Edition. We excluded PTSD and TEN-PTSD subjects who (1) had trauma-induced brain injury or disturbances in consciousness; (2) had a current and/or past use of any psychotropic drug therapy or psychotherapy after the earthquake; (3) had been diagnosed with PTSD prior to this earthquake; (4) were currently pregnant or breastfeeding; or (5) currently had a significant sleep disorder (e.g., narcolepsy, severe sleep apnea, or periodic leg movements in sleep). During the recruitment period, 80 subjects completed all the interviews and assessments. Ultimately, 23 subjects with PTSD and 13 with TEN-PTSD met the selection criteria and completed the further sleep evaluation using in-hospital PSG. Flow diagrams illustrating of recruitment and the successive steps in the procedures are presented in Figure 1. Among the 23 PTSD subjects, 3 had a co-morbid depression disorder and 1 had a co-morbid general anxiety disorder according to the DSM-IV criteria. The TEN-PTSD and PTSD subjects were similar in terms of age, sex, and body mass index (BMI).

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2.2 Treatment procedure After completing the baseline assessment and PSG evaluation, all 23 subjects with PTSD agreed to therapy with paroxetine. The initial dose was 10 mg paroxetine in the first 4 days, followed by a daily dose of 20 mg. An experienced psychiatrist assessed the symptom severity, drug side effects, and medicine use every month. Paroxetine was titrated according to clinical efficacy and side effects, with a maximum dosage of 40 mg daily if clinical symptoms did not improve satisfactorily. After the 1-month assessment, seven PTSD subjects did not finish the 12-week therapy protocol because of drug side effects (n = 3) or lack of treatment compliance for more than 2 days (n = 4). Sixteen subjects completed the 12-week treatment course, but eight of them refused to return to the hospital for follow-up assessments for personal reasons. Thus, the remaining eight participants with PTSD underwent a second full-night evaluation using PSG, an MSLT to assess daytime sleepiness symptoms, and clinical assessment after the treatment period.

2.3 Polysomnography The subjects who underwent PSG were evaluated for one night in the sleep laboratory in sound-attenuated and light- and temperature-controlled rooms. During this evaluation, the subjects were allowed to sleep ad libitum based on their habitual sleep time, with the recording times ranging from 22:00 or 23:00

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to 6:00 or 7:00. The subjects were continuously monitored with 16-channel polygraphs including electroencephalography, bilateral electrooculography, electromyography, and electrocardiography. All sleep parameters recorded using PSG were analyzed and scored according to the international criteria of the American Academy of Sleep Medicine (Iber and Chesson, 2007) by a senior technician who was blind to the patients’ diagnoses.

2.4 Multiple sleep latency test The MSLT was performed on the day immediately after the overnight PSG recording and comprised four 20-min nap opportunities at 2-hour intervals (9:00, 11:00, 13:00, and 15:00). Subjects were monitored by technical staff between naps to prevent unscheduled sleep episodes. The identification of “sleep onset” required the presence of any sleep stage for at least 30 sec. If no sleep occurred, the trial was terminated at 20 min and a sleep latency of 20 min was assigned. The mean MSLT sleep latency was the average sleep latency of all four naps.

2.5 Epworth Sleepiness Scale Subjective daytime sleepiness was measured using the ESS (Johns, 1991) completed during the sleep laboratory visit. The ESS is an eight-item self-administered questionnaire that asks the subject how likely he/she is to doze off or fall asleep in different situations of daily life. Scores ranged from 0 to 24, with higher scores indicating more daytime sleepiness in daily life. 8

2.6 Clinician Administered PTSD Scale The CAPS is a structured interview-based measure that is widely used in PTSD assessments (Blake et al., 1995). The structure corresponds to the DSM-IV criteria, with re-experiencing, avoidance of stimuli, and hyperarousal symptoms rated in terms of both frequency and intensity; these two scores are summed to provide severity ratings. The CAPS was used in the diagnostic process, assessment phase, and post-therapy interview. All subjects were interviewed by a trained psychiatrist who was blind to the diagnoses. In this study, we summed all 17 symptom questions and the 3 symptom clusters.

2.7 Other key measurements The self-reported Pittsburgh Sleep Quality Index (PSQI; Buysse et al., 1989) was used to assess subjects’ sleep quality during the past month. A PSQI total score ≥ 5 points suggests clinically significant sleep disturbances in healthy populations. Depression and anxiety symptoms were assessed with the 24-item Hamilton Depression Scale (24-HAMD) and 14-item Hamilton Anxiety Scale (14-HAMA) by a trained psychiatrist. On the morning after the overnight PSG recording, all subjects were required to finish a questionnaire including questions related to sleep quantity and quality such as “how long in total did you sleep last night,” “how long did it take for you to fall asleep last night,” and “how long were you awake after sleep onset.” BMI based on measured height (cm) and

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weight (kg) was calculated when the subjects visited the sleep laboratory.

2.8 Statistical analyses Data are presented as mean ± standard deviation (SD) for continuous variables and as frequency and percentage for categorical variables. Bivariate comparisons between groups were conducted using independent sample t-tests or Mann-Whitney U-tests for normally and non-normally distributed continuous variables and the chi-square test for categorical variables. Paired t-tests were used to compare pre- and post-therapy findings. Bivariate correlations were analyzed to explore significant associations between daytime sleepiness (mean MSLT values and ESS scores), and relevant predictors (p < 0.1) were then inserted into linear regression models to control for possible confounders, that is, sex, age, and BMI. An alpha level of p < 0.05 was used to determine statistical significance. Data were analyzed using SPSS version 21.0 for Windows.

3. Results 3.1 TEN-PTSD subjects versus therapy-naïve PTSD subjects The demographic, clinical, and sleep characteristics of the TEN-PTSD and therapy-naïve PTSD subjects are presented in Tables 1 and 2. No differences were found in sex, age, or BMI between the TEN-PTSD and PTSD subjects. As shown in Table 1, subjects with PTSD had higher CAPS (t = 11.5, df = 34; p = 0.000), 14-HAMA (t = 4.68, df = 34; p = 0.000), 24-HAMD (t = 7.61, df = 34; p = 0.000), and global PQSI (t = 7.70, df = 34; p = 0.000) scores than subjects with TEN-PTSD. 10

As shown in Table 2, compared to the TEN-PTSD subjects, those with PTSD reported poor subjective nighttime sleep in terms of shorter sleep duration (t = -3.17, df = 34; p = 0.003), longer sleep latency (t = 2.36, df = 34; p = 0.025), increased wake after sleep onset (WASO; t = 2.56, df = 34; p = 0.015), and poor sleep perception (t = -2.57, df = 34; p= 0.015). However, in terms of PSG-recorded nighttime sleep, no differences were found in other sleep characteristics between the PTSD and TEN-PTSD subjects. Further, subjects with PTSD had significantly shorter mean MSLT values (t = -2.89, df = 34; p = 0.007) than TEN-PTSD subjects, particularly at the 11:00 (t = -2.32, df = 34; p = 0.027) and 15:00 (t = -3.38, df = 34; p = 0.002) nap times, but no difference was found in ESS scores between the groups. Bivariate correlations were conducted using the Pearson correlation between daytime sleepiness (mean MSLT value and ESS score) and symptom scales. Objective daytime sleepiness (mean MSLT value) was associated with the global CAPS score (r = -0.356, p = 0.033), CAPS re-experiencing score (r = -0.394, p = 0.017), CAPS hyperarousal score (r = -0.423, p = 0.010), and 24-HAMD score (r = -0.306, p = 0.069); however, no association was found between subjective daytime sleepiness (ESS values) and symptom scales. With regard to objective daytime sleepiness, as shown in Table 3, two separate linear regression analyses were run with the global CAPS score and the re-experiencing and hyperarousal CAPS scores since the global CAPS score was 11

strongly associated with CAPS symptom cluster scores. In backward multivariate linear regression models, after adjustment for age, sex, and BMI, higher global CAPS scores (beta = -0.06, p = 0.004) and CAPS hyperarousal cluster symptom scores (beta = -0.21, p = 0.001) were independently associated with a low mean MSLT value. However, depression symptoms and PTSD cluster symptoms of re-experiencing failed to show an independent correlation with mean MSLT value. Given that daytime sleepiness is considered a marker of depression, we used the 24-HAMD score as a confounding factor in model 2. After adjustment for age, sex, BMI, and 24-HAMD score, the hyperarousal cluster symptom was independently associated with a low MSLT value (beta = -0.28, p = 0.016). These results suggest that objective daytime sleep characteristics were affected by PTSD, whereas subjective daytime characteristics appeared to be affected by the individual’s sleep propensity.

3.2 Pre- versus post-therapy PTSD subjects Eight subjects with PTSD completed the 12-week paroxetine therapy protocol. No differences were found in terms of demographic, clinical, or sleep characteristics between these eight subjects and the total group of 23 therapy-naïve PTSD subjects. The clinical and sleep characteristics of pre- and post-therapy PTSD subjects are presented in Tables 1 and 2, respectively. The mean MSLT value was significantly increased (t = -2.74; p = 0.029) and the ESS score was significantly decreased (t = 3.02; p = 0.019) after the 12-week 12

paroxetine therapy regimen (Table 2, Figure 2).

4. Discussion This is the first study, to our knowledge, to use objective methodology, that is, PSG and the MSLT, to assess the characteristics of nighttime sleep and daytime sleepiness in therapy-naïve subjects with chronic earthquake-related PTSD. Our findings suggest that a shorter MSLT sleep onset latency was independently associated with PTSD after adjustment for conditions frequently associated with daytime sleepiness, such as age, sex, BMI, and depression symptoms. This association was further supported by the significant improvement in mean MSLT values after the 12-week paroxetine therapy regimen in the PTSD subjects. Additionally, our findings suggest that a low MSLT value may be a reliable marker of the severity and medical impact of PTSD.

4.1 Sleep misperception We used a questionnaire and standard overnight PSG recording to test subjective and objective characteristics of sleep and found significantly shorter self-reported sleep duration as well as longer sleep latency and WASO in subjects with PTSD than in those with TEN-PTSD. However, we failed to find objective evidence of nighttime sleep disturbances in subjects with PTSD. The findings of our study support previous conclusions that PTSD is more closely associated with sleep misperception problems than with objective sleep disturbances. Previous studies have shown that most PTSD subjects underestimate their sleep 13

duration and overestimate sleep onset latency and WASO, but none found objective evidence of disturbances during nighttime sleep (Dagan et al., 1997; Hurwitz et al., 1998). These findings suggest that sleep misperception problems may outweigh objective sleep disturbances in subjects with PTSD (Woodward et al., 1996; Engdahl et al., 2000). Despite various research methods, almost all studies demonstrated that subjective sleep disturbance is one of the most frequent problems after trauma of either natural or man-made origin (Lavie, 2001). Sleep disturbances have been the most common problems after subjects survived from catastrophic earthquakes (Wood, et al., 1992; Kato, et al., 1996; Geng, et al., 2013; Tempesta, et al., 2013), hurricans (Mellman, et al., 1995c), floods (Ollendick and Hoffmann, 1982), industrial disasters (Weisaeth, 2001), traffic accidents(Koren, et al.,1999; Klein, et al., 2003), wars (Engdahl, et al., 2000; McLay, et al., 2010; Capaldi II, et al., 2011; Wright, et al., 2011; Plumb, et al., 2014), and sexual assaults (Krakow, et al., 2001; Nishith, et al., 2001). Mellman et.al compared twenty-five patients with combat-related PTSD, which included 16 men with a principal diagnosis of MD, and 10 asymptomatic male controls by PSG under medication and substance-free conditions (Mellman, et al., 1997a). Their findings supported sleep maintenance being impaired in chronic PTSD patients (Mellman, et al., 1997a). Most of previous PSG studies with PTSD focused on war-related male patients with PTSD. However potential divergences in subjective and objective sleep characteristics in subjects with PTSD suffered from natural disasters are 14

not clearly understood. A cohort study of adolescent survivors of the Wenchuan Earthquake reported subjective complaints of poor sleep quality, including reduced total sleep time (TST), problems with falling and staying asleep, and impaired function during daytime hours (Geng et al., 2013). Another study found that after the earthquake, subjects who were exposed to the trauma showed a significant deterioration in subjective sleep quality (Tempesta et al., 2013). Thus far, no study has investigated objective PSG, MSLT assessment of sleep and daytime sleepiness in subjects with earthquake-related PTSD together. Besides, sex, age, type of trauma, and the duration from initial trauma may have effect on sleep perception. A meta-analytic review of 20 studies suggested several conclusions: 1) younger PTSD patients had reduced objective TST than participants without PTSD; 2) studies with only male participants, those with PTSD slept less than those without PTSD; 3) whereas only small differences in TST were found in studies on both men and women or women only (Kobayashi et al., 2007). In our study, we found no statistically significant differences in objective TST between PTSD and TEN-PTSD subjects, which may be explained by the fact that our cohort included both men (n [%] = 4 [17.4%]) and women (n [%] = 19 [82.6%]) with similarly aged subjects. The differences between the subjective and objective sleep complaints of subjects with PTSD related to a natural disaster compared to those without PTSD require further research. The explanation for the discrepancy between subjective complaints of disturbed sleep, including insomnia, nightmares, and recurrent 15

distressing dreams about the trauma, and objective evidence of normal or adequate sleep remains to be determined.

4.2 Daytime sleepiness and hyperarousal symptom Traditionally, nighttime sleep disturbance, that is, difficulty initiating and maintaining sleep and nightmares, has been an important characteristic of PTSD. Various objective anomalous sleep parameters have been detected between PTSD and non-PTSD subjects, such as dysfunctional REM sleep (Ross et al., 1994a, Ross et al., 1994b; Woodward et al., 1996; Mellman, et al., 2002; Mellman and Hipolito, 2006; Mellman, et al., 2014). Animal studies found that the stress had a long-term effect on REM sleep after the original stressful experience

(Pawlyk,

et al., 2008; Suchecki, et al., 2012), especially leading to disruption of sleep and fragmentation of REM sleep (Sanford, et al., 2015). Moreover, a number of studies about rats exposed to a model of chronic mild stress have observed that an increase in the amount of REM sleep (Cheeta, et al., 1997; Gronli, et al., 2004). These evidences may raise the possibility that sleep alteration may also play a role in physiopathology of PTSD. Only a few studies have examined the association between daytime sleepiness characteristics in subjects with PTSD, while no studies have used the MSLT to objectively examine daytime sleepiness characteristics in subjects with earthquake-related PTSD. To date, the characteristics of objective daytime sleepiness in subjects with PTSD therefore remain unclear. In a large-scale,

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longitudinal community study of young adults, Breslau et al. reported no significant differences in MSLT values among subjects with PTSD, subjects with TEN-PTSD, and non-exposed normal controls (Breslau et al., 2004). Hurwitz et al. also found no evidence of excessive daytime sleepiness and no significant differences in MSLT values in subjects with combat-related PTSD and non-combat-exposed normal controls (Hurwitz et al., 1998). Our findings were not in line with those of these previous studies. Our study indicates that subjects with earthquake-related PTSD had significantly low MSLT values than those with TEN-PTSD. Further, a significant improvement in MSLT values was noted in the PTSD subjects after 12 weeks of paroxetine therapy, which further supports our conclusion that earthquake-related PTSD is associated with low MSLT values. These discrepancies might be related to the different degrees of PTSD severity among the subjects. For example, we used subjects with chronic current PTSD (around 4 years after trauma exposure), whereas the other studies used either subjects with lifetime PTSD or those with psychiatric disorder co-morbidities. Different traumatic experiences, sex-based differences, and the use of TEN-PTSD subjects as controls might have also contributed to these discrepancies, but further studies are required to verify this hypothesis. Hyperarousal symptoms comprise one of the three PTSD symptom clusters and include difficulty falling or staying asleep, irritability or anger, difficulty concentrating, hypervigilance, and an exaggerated startle response (APA, 1994). Several studies have shown that physiological hyperarousal is associated with 17

activation of the hypothalamic-pituitary-adrenal (HPA) axis (Vgontzas et al., 2001), short objective sleep duration (Vgontzas et al., 2001), and high MSLT values (Li et al., 2015). In the present study, we found that more severe hyperarousal was independently associated with low MSLT values based on the hyperarousal score on the CAPS as well as no significant correlation between hyperarousal and objective sleep duration. In addition, numerous studies have reported that subjects with PTSD exhibit lower basal cortisol levels than non-PTSD subjects (Mason et al., 1986; Yehuda et al., 1990, 1995; Boscarino 1996; Goenjian et al., 1996; King et al., 2001; Rohleder et al., 2004; Wessa et al., 2006). Physiological hyperarousal shortens objective nighttime sleep duration and lengthens daytime MSLT values. However, we found low MSLT values in PTSD subjects and that severe hyperarousal was independently associated with low MSLT values, based on the hyperarousal score on the CAPS in PTSD subjects; additionally, a significant improvement in MSLT value was noted in PTSD subjects after 12 weeks of paroxetine therapy. Furthermore, “hyperarousal” in primary insomnia patients need to be considered. Studies have shown that MSLT values in insomniacs were longer than normal controls (Stepanski, et al., 1988; Bonnet and Arand, 1995). However, to date, only a single study has shown “hyperarousal” on concurrent physiological measures, that is increased metabolic rates in conjunction with elevated MSLTs (Bonnet and Arand, 1995). A large sample study of MSLT in primary insomnia has shown that mean daily sleep latency measured by MSLT of insomniacs was significantly higher than those of 18

control sample, and the insomniacs with the highest MSLTs had the shortest total sleep times (TST) (Roehrs, et al., 2011). We suppose that most of insomniacs are much likely to have physiological hyperarousal, while PTSD patients are cognitive-emotional hyperarousal. Further studies are needed to explore the differences of hyperarousal, sleepiness, TST and MSLT values (shorter MSLT values in natural-trauma PTSD and longer MSLT values in insomniacs) between insomnia and PTSD patients. Thus, we suspect that subjects with PTSD are much more likely to have cognitive-emotional hyperarousal (i.e., sleep misperception, obsessive, anxious, ruminative, and dysthymic personality traits) rather than physiological hyperarousal (i.e., elevated cortisol secretion, short objective sleep duration, and long MSLT values). As stated above, considering both previous findings and our results, low basal cortisol levels might be a potential mediating mechanism linking low MSLT values and PTSD. This hypothesis requires investigation in a future study. Some potential factors impacting MSLT value should be considered. First, we conducted one-night PSG observations, and the pre-therapy PSG tests may have acted as an acclimation; thus, the lengthened MSLT values in post-therapy PTSD subjects may have been influenced by the improved post-therapy versus pre-therapy nighttime sleep. Importantly, shortened MSLT value is indicative of heightened sleep pressure and, in the case of PTSD, the most likely explanation for this would be sleep disruption on the preceding night. Kobayashi et al. found that reduction in slow wave sleep (SWS) to be one ubiquitous feature of PTSD 19

versus controls (Kobayashi et al., 2007). Although the percentage of SWS did not differ in present study, there might have been SWS fragmentation or reduced delta power. Second, the effect of paroxetine should been considered. A previous study found that paroxetine not only changed sleep architecture, reduced REM sleep, and increased REM latency but also increased awakening and reduced actual sleep duration and sleep efficiency (Sharpley et al., 1996). Paroxetine has significant disruptive effects on sleep (Sharple et al., 1996) that may shorten the mean MSLT value by disrupting sleep during the preceding night. Third, the effects of hyperarousal itself should be considered, it may lengthen MSLT values due to the inherent alerting effects of a physiological hyperarousal state(i.e., elevated cortisol secretion, short objective sleep duration, and long MSLT values), but physiological hyperarousal may also shorten MSLT values by disturbing the preceding night’s sleep. In Addition, the effects of hyperarousal on REM should be considered. REM fragmentation is seen in insomnia (Riemann et al., 2012) and may predict PTSD following trauma (Mellman et al., 2002, Mellman et al., 2007). Increased REM density is a consistent finding in PTSD and is also potentially indicative of hyperarousal (Kobayashi et al., 2007). Therefore, decreased REM continuity may be another effect of hyperarousal that would decrease sleep quality and increase daytime sleepiness. REM suppression can be considered a sign of a good response to antidepressant medication since these drugs alter REM latency, REM density, WASO, and short-wave sleep (Silvestri et al., 2001). And finally, as mentioned above, subjects with PTSD are much more likely to have 20

cognitive-emotional hyperarousal (i.e., sleep misperception, obsessive, anxious, ruminative, and dysthymic personality traits which may shorten MSLT values because of the inherent alerting effects of an aroused state in PTSD and decreased cognitive-emotional hyperarousal which may lengthen MSLT values in subjects with post-therapy PTSD. The findings of the present study also suggested that low MSLT values might be a marker of PTSD severity, particularly in the PTSD hyperarousal symptom cluster. First, the global CAPS score and the PTSD hyperarousal symptoms cluster score were independently associated with MSLT values after adjustment for confounding factors. Since HPA axis activation suppresses sleepiness, lower cortisol secretion may lead to shorter MSLT values. Several studies have shown that PTSD is associated with lower cortisol secretion. A study using Wenchuan Great Earthquake–related PTSD subjects found lower hair cortisol levels after the traumatic event compared to non-PTSD controls (Luo et al., 2012). A recent systematic and meta-analytic study reported that daily, particularly morning and afternoon/evening, cortisol secretions were lower in subjects with PTSD than in normal controls that had not been exposed to trauma. In addition, daily and morning cortisol secretions did not significantly differ between non-PTSD subjects and normal controls (Morris et al., 2012). Further, Mason et al. showed that elevated urinary catecholamine levels and lower urinary cortisol levels were noted in the same samples (Mason et al., 1986). These findings suggested that the HPA axis and sympathetic-adrenal medulla system, which are commonly 21

activated simultaneously, can be dissociated in subjects with PTSD. Therefore, we believe that hyperarousal symptoms and low MSLT values could be dissociated in subjects with PTSD as well. Our findings suggest that MSLT values may provide an alternative to cortisol secretion levels as a reliable index of the medical significance and severity of PTSD. Our present findings suggest that there was no significant difference in ESS scores between PTSD and TEN-PTSD subjects. This finding was inconsistent with those of many previous studies that reported higher ESS scores in PTSD subjects ( Dodson and Morris, 2010; Westermeyer et al., 2010; Capaldi II et al., 2011; Collen et al., 2012; Tamanna et al., 2014). This inconsistent finding might be related to the fact that our study used TEN-PTSD subjects as a control group, while other studies used subjects who had not been exposed to trauma. In addition, most previous studies used male subjects with combat-related PTSD and sleep apnea as co-morbidity. The different traumatic experiences and sex-based differences might be other potential explanations for these discrepancies.

3. Limitations This study has some limitations that must be acknowledged. First, the results were based on a single night of PSG recording, which may not be representative of the subjects’ habitual sleep and may not fully capture the severity of sleep disturbance. However, no evidence has been found of a 22

first-night effect specific to PTSD (Agnew, Jr, et al., 1966; Ross et al., 1999). In addition, in a preliminary study of short- and long-term stability of sleep measures, Vgontzas et al. found that TST, sleep latency, and WASO were moderately to substantially stable over 3 or 4 subsequent nights or 2.5 years later in both insomniacs and controls (Gaines et al., 2015). Second, we did not assess TEN-PTSD subjects in the same period as the PTSD subjects, after 12 weeks of paroxetine therapy. Thus, we lack a direct comparison between groups after the PTSD patients received therapy. Finally, the high dropout rate after paroxetine therapy and the small sample size in the post-therapy comparison reduced the statistical power of our findings. Further studies with larger samples sizes are warranted to address this issue.

Conclusion No clinically significant sleep disturbances were detected using standard PSG, but significant self-reported sleep disturbances were noted in subjects with earthquake-related

PTSD

compared

to

TEN-PTSD

subjects.

Further,

earthquake-related PTSD, particularly regarding the PTSD cluster symptoms of hyperarousal, was associated with low MSLT values, which may be a reliable index of the medical severity of chronic PTSD. Our findings suggest that MSLT values might be a reliable marker for evaluating the therapeutic efficacy of PTSD treatment.

23

Acknowledgments The work was performed at the Sleep Medicine Center at the West China Hospital, Sichuan University, and our technical staff (Fei Lei and Lina Du) is especially commended for their efforts. The authors would like to thank Dr. Larry D. Sanford at Eastern Virginia Medical School for his help in editing the manuscript.

Disclosures and Funding All authors report no biomedical financial interests or potential conflicts of interest. This research was funded by the National Natural Science Foundation of China (81170072, 81328010 and 81371484), the Chinese German Joint Center for Sleep Medicine (GZ538), the National Basic Research Program of China (2015CB856400),

National

Key

Technologies

R&D

Program

of

China

(2012BAI01B03), and the Support Plan of Sichuan (2011SZ0292).

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31

Fig 1 Flow diagram of recruitment and procedures. PTSD, posttraumatic stress disorder; PSG, polysomnography; MSLT, multiple sleep latency test.

Fig 2 Characteristics of mean ± SEM of MSLT and mean ± SEM of ESS score in TEN-PTSD, pre-therapy PTSD and post-therapy PTSD subjects. MSLT, multiple sleep latency test; ESS, Epworth sleepiness scale; TEN-PTSD, trauma-exposed non-PTSD; PTSD, posttraumatic stress disorder. ** p value < 0.01，* p value < 0.05. 32

Table 1 Demographic and clinical characteristics of study subjects

Female gender, n (%)

TEN-PT SD (n=13) 9 (69.23 %)

Age (years)

44.38 ± 11.03

BMI (kg/m2)

22.76 ± 1.96

Global CAPS score

16.38 ± 10.79

Re-experie ncing

5.46 ± 4.39

Avoidance of stimuli

3.15 ± 3.69

Hyperarou sal

7.77 ± 6.76

Nightmare

1.08 ± 1.50

s Difficult in initiation and maintaining sleep

2.23 ± 2.17

14-HAMA

7.62 ± 6.81

24-HAMD

5.62 ± 3.48

PSQI

6.85 ± 3.74

PTSD (n=23) 19 (82.60 %) 47.2 2± 7.22 22.9 5± 2.70 72.7 8 ± 15.69 22.0 9± 5.13 27.0 0± 8.73 23.7 0± 4.70 4.8 3± 2.10 5.7 8± 1.76 19.1 3± 7.23 20.2 6± 6.40 15.0 9± 2.66

t

-

p

-

0.35 0.93 8 0.82 0.23 3

pre-ther apy (n=8) 7 (87.50% ) -

post-ther apy (n=8) 7 (87.50%)

t

p -

-

-

-

-

-

-

11.4 8

0.000* **

71.13 ± 18.64

9.82

0.000* **

23.00 ± 5.45

5.00 ± 4.90

14.3 5

11.4 2

0.000* **

25.88 ± 9.91

5.63 ± 10.42

5.96

8.32

0.000* **

22.25 ± 5.47

5.88 ± 7.22

8.08

5.65

0.000* **

5.13 ± 1.13

0.75 ± 1.49

13.5 1

5.36

0.000* **

5.75 ± 1.39

0.50 ± 1.41

9.39

4.68

0.000* **

14.75 ± 7.27

6.63 ± 11.61

3.85

0.00 6**

7.61

0.000* **

17.63 ± 7.31

5.13 ± 7.53

5.51

0.00 1**

7.70

0.000* **

17.50 ± 3.63

2.00 ± 1.77

10.0 9

33

16.50±22. 10.1 16 1

0.000* ** 0.000* ** 0.00 1** 0.000* ** 0.000* **

0.000* **

0.000* **

PTSD, posttraumatic stress disorder; TEN-PTSD, trauma-exposed non-PTSD; BMI, Body mass index; CAPS, Clinician administered PTSD scale; 14- HAMA, 14-item Hamilton anxiety rating scale; 24-HAMD, 24-item Hamilton depression rating scale; PSQI, Pittsburgh sleep quality index. *** p value < 0.001, ** p value < 0.01, * p value < 0.05.

Table 2 Characteristics of nighttime sleep and daytime sleepiness of study subjects

Subjectiv e TST (min) Subjectiv e sleep latency (min) Subjectiv e WASO (min) Time in bed (min) Objective TST (min) Objective sleep latency (min)

TEN-PT SD (n=13)

PTSD (n=23 )

pre-thera py (n=8)

post-thera py (n=8)

t

t

p

423.1 ± 79.5

333.9 ± 82.1

-3.1 7

360.0 ± 55.5

412.5 ± 81.4

-1.7 0

0.133

21.2 ± 8.2

36.1 ± 28.4

2.36

0.025*

45.6 ± 28.7

21.9 ± 18.1

2.53

0.039*

33.5 ± 32.4

68.7 ± 50.1

2.56

0.015*

57.5 ± 42.3

24.4 ± 22.4

4.08

0.005* *

524.8 ± 37.3

520.0 ± 40.0

-0.3 5

0.726

523.1 ± 48.1

509.0 ± 34.1

1.08

0.315

437.98± 47.4

414.0 ± 51.2

-1.3 8

0.177

414.3 ± 64.2

427.7 ± 67.7

-0.8 3

0.435

9.6 ± 9.0

8.8 ± 14.2

-0.1 8

0.857

5.9 ± 2.9

19.5 ± 16.6

-2.2 9

0.056

p

0.003* *

34

Objective WASO (min) Stage NREM 1 (% TST) Stage NREM 2 (% TST) Stage NREM 3 (% TST) Stage REM (% TST) Sleep efficiency Sleep perceptio n REM latency (min) AHI (/h) MSLT (min) 09:00 Nap (min) 11:00 Nap (min) 13:00 Nap (min) 15:00 Nap (min) SOREMP s, n (%) ESS

77.4 ± 49.8

97.5 ± 42.9

1.27

0.212

103.5 ± 42.9

61.8 ± 35.0

3.88

22.1 ± 13.9

17.6 ± 9.8

-1.1 5

0.257

17.1 ± 7.1

20.0 ± 5.3

-1.1 7

0.280

48.1 ± 11.1

53.9 ± 11.2

1.51

0.139

57.9 ± 9.5

52.6 ± 9.2

2.00

0.085

13.6 ± 8.2

11.0 ± 6.8

-1.0 1

0.320

10.2 ± 6.5

6.3 ± 4.8

1.19

0.274

16.2 ± 7.4

17.5 ± 5.9

0.57

0.575

14.8 ± 5.0

21.1 ± 9.9

-1.7 5

0.123

83.6 ± 8.5

79.7 ± 8.6

-1.3 0

0.201

79.0 ± 8.0

83.7 ± 9.2

-2.0 9

0.075

97.0 ± 17.8

80.8 ± 18.4

-2.5 7

0.015*

88.0 ± 15.0

98.8 ±27.2

-1.3 4

0.222

109.7 ± 41.9

128.5 ± 81.8

0.91

0.369

135.0 ± 77.9

165.5 ± 95.0

-0.6 1

0.560

4.4 ± 7.3 14.1 ± 2.9

3.3 ± 4.0 10.8 ± 3.6

-0.5 8 -2.8 9

0.569

3.1 ± 3.2

3.2 ± 4.8

0.007* *

10.5 ± 3.4

14.0 ± 3.7

15.8 ± 6.9

15.3 ± 6.6

-0.2 1

0.832

15.1 ± 7.3

16.3 ± 6.3

-0.3 5

0.740

12.7 ± 7.0

7.3 ± 6.5

-2.3 2

10.2 ± 7.1

15.8 ± 5.9

-1.8 5

0.107

11.1 ± 7.9

9.7 ± 6.9

-0.5 7

0.573

7.8 ± 4.9

9.8 ± 7.1

-0.6 4

0.545

17.0 ± 3.7

10.7 ± 6.0

-3.3 8

0.002* *

9.1 ± 5.2

14.0 ± 7.7

-1.9 9

0. 087

-

1 (12.5%)

1 (12.5%)

0.625

9.63 ± 5.42

3.50 ± 4.11

0 (0%) 9.62 ± 4.54

3 (13% ) 8.7 8±

-0.4 9

0.027*

35

-0.0 7 -2.7 4

0.006* *

0.948 0.029*

3.02

0.019*

5.05

PTSD, posttraumatic stress disorder; TEN-PTSD, trauma-exposed non-PTSD; TST, total sleep time; WASO, wake after sleep onset; AHI, apnea-hypopnea index; NREM, non-rapid eye movement sleep; REM, rapid eye movement; Sleep efficiency, objective TST/ time in bed * 100; MSLT, multiple sleep latency test; SOREMPs, sleep-onset REM periods; ESS, Epworth sleepiness scale; *** p value < 0.001, ** p value < 0.01, * p value < 0.05

Table 3 Individual variable contributions in predicting MSLT sleep onset latency value Model 1 Regression1 Regression2

Global CAPS 24-HAMD Re-experiencing Hyperarousal 24-HAMD

beta -0.06 0.17 -0.16 -0.21 0.08

p 0.004* 0.015 0.593 0.001* 0.471

Model 2 beta -0.51 -0.25 -0.28 -

p 0.124 0.425 0.016* -

Model 1 ENTER, age, sex and BMI; Backward, global CAPS score/ Re-experiencing score and Hyperarousal score, and 24-HAMD score. Model 2 ENTER, age, sex, BMI and 24-HAMD score; Backward, global CAPS score/ Re-experiencing score and Hyperarousal score. MSLT, multiply sleep latency test; CAPS, Clinician administered PTSD scale; 24-HAMD, 24-item Hamilton depression rating scale. * indicated that statistical significance and did not excluded from regression equation.

Highlights 

No clinically significant sleep disturbances were detected by standard PSG in 36

 

subjects with earthquake-related PTSD compared to trauma-exposed non-PTSD subjects. However significant self-reported sleep disturbances were found in subjects with earthquake-related PTSD. Earthquake-related PTSD, particularly the PTSD cluster symptoms of hyperarousal, was associated with shorter MSLT values. Shorter MSLT values may be a reliable index of medical severity of subjects with chronic PTSD. MSLT values might be a reliable marker for evaluating therapy efficacy in the treatment of PTSD

37