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Later sleep schedule and depressive symptoms are associated with usage of multiple kinds of hypnotics
Accepted Manuscript Title: Later sleep schedule and depressive symptoms are associated with usage of multiple kinds of hypnotics Author: Akiyoshi Shimura, Yoshikazu Takaesu, Sayaka Aritake, Kunihiro Futenma, Yoko Komada, Yuichi Inoue PII: DOI: Reference:
S1389-9457(16)30036-3 http://dx.doi.org/doi: 10.1016/j.sleep.2016.04.011 SLEEP 3057
To appear in:
Sleep Medicine
Received date: Revised date: Accepted date:
7-7-2015 12-4-2016 14-4-2016
Please cite this article as: Akiyoshi Shimura, Yoshikazu Takaesu, Sayaka Aritake, Kunihiro Futenma, Yoko Komada, Yuichi Inoue, Later sleep schedule and depressive symptoms are associated with usage of multiple kinds of hypnotics, Sleep Medicine (2016), http://dx.doi.org/doi: 10.1016/j.sleep.2016.04.011. 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 proof before it is published in its final 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.
Later sleep schedule and depressive symptoms are associated with usage of multiple kinds of hypnotics
Akiyoshi Shimura
a,b,
Yoshikazu Takaesu a, Sayaka Aritake
b,c,
Kunihiro Futenma
a,b,
Yoko Komada b,d, Yuichi Inoue a,b,d
a
Department of Psychiatry, Tokyo Medical University, Tokyo, Japan
b
Department of Somnology, Tokyo Medical University, Tokyo, Japan
c
Japan Society for the Promotion of Science, Tokyo, Japan
d
Japan Somnology Center, Neuropsychiatric Research Institute, Tokyo, Japan
* Corresponding author. 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, Japan. Tel.: +81 3 3342 6111. E-mail address: [email protected] (Y. Inoue).
Highlights
Factors associated with high doses of hypnotics were examined.
Users of multiple kinds of hypnotics had later sleep schedule.
Users of multiple kinds of hypnotics had more depressive symptoms.
Eveningness and depression were associated with usage of multiple kinds of hypnotics.
Assessment of circadian rhythm and depression is needed in medication of insomnia.
Abstract: Objective: Usage of high doses of hypnotics possibly causes various adverse events. However, the risk factors of using multiple kinds of hypnotics have been
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inconclusive. To clarify this, we conducted a webbased cross-sectional questionnaire survey on the Japanese adult population. Methods: A cross-sectional Internet-linked survey was conducted on 10,016 individuals, and 1,030 participants (10.3%) having subjective insomnia proceeded to subsequent analyses. The analyzed subjects were categorized into non-users of hypnotics (n=833; 80.9%), users of a single kind of hypnotic (n=96; 9.3%), and users of multiple kinds of hypnotics (n=101; 9.8%). The descriptive variables including demographic data, scores of Center for Epidemiological Studies Depression Scale (CES-D), Short Form-8 Health-Related Quality of Life (QOL (SF-8)), Pittsburgh Sleep Quality Index (PSQI), and other parameters were compared among the groups. Results: The users of multiple kinds of hypnotics had the highest mean score of CES-D, the lowest mental component summary of QOL (SF-8), and the latest sleep schedule among the three groups (p<0.001). Logistic regression analyses revealed that sex (female: OR=2.38; p<0.001) and age (≥43 years old: OR=2.61; p<0.001) were independently associated with use of a single kind of hypnotic, while later sleep schedule (midpoint of sleep ≥5:30 a.m.: OR=2.26; p<0.001) and higher CES-D score (≥16 points: OR=2.41; p<0.001) were independently associated with use of multiple kinds of hypnotics. Conclusions: Characteristics of users of multiple kinds of hypnotics were different from users of a single kind of hypnotic.
Keywords: benzodiazepine; depression; eveningness; rhythm; hypnotic; insomnia; polypharmacy
Comment [A1]: Please supply an abstract of up to 250 words; please
1. Introduction
supply up to 6 keywords.
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Hypnotics, including benzodiazepines (BZDs) and Z-drugs (benzodiazepine receptor agonists), have long been widely accepted as important treatment choices for insomnia [1,2]. Although treatment with these kinds of hypnotics can alleviate insomnia symptoms, the drugs may cause acute side effects, such as hangover [3], falls and fractures [4–6], abnormal behavior during sleep [7], and deteriorated driving performance on the day after administration [8]. Moreover, long-term use of these hypnotics may possibly lead to increasing dosages of hypnotics due to tolerance or dependence [9,10]. A recent study has also shown that usage of sedative-hypnotics is associated with increased risk of suicidality independent of insomnia [11] and increased risk of premature mortality [12]. Of note, usage of high-dose hypnotics may cause serious adverse events more frequently. Reportedly, the risk of hip fractures is related with the dosage of BZDs and Z-drugs [4,13]. In elderly drivers, the risk of injurious motor vehicle accidents becomes higher as the daily dosage of BZDs and Z-drugs increases [14]. Considering these findings, governments of some developed countries have displayed a negative attitude toward long-term or high-dose usage of BZDs and Z-drugs. Following this approach, recommendations for avoiding inadequate use of these kinds of drugs have been raised
Comment [A2]: Author: Do you mean
in Western countries [15–17].
‘unnecessary’ here?
In order to establish a strategy for preventing the usage of high-dose BZDs and Z-drugs, risk factors for becoming a high-dose user have been ascertained. Previous studies have shown some correlations to usage of high-dose BZDs and Z-drugs. Younger age, existence of depressive disorder, and usage of antidepressants have been reported to be associated with the dosage of BZDs and Z-drugs [18]. Severity of mental illnesses such as schizophrenia, bipolar disorder, and major depression and co-occurrence of alcohol abuse were also associated with the high-dose usage of these drugs [19].
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However, most previous studies have focused on psychiatric patients, and to our knowledge, there have been no studies investigating factors associated with the usage of high-dose BZDs and Z-drugs among the general population with insomnia symptoms. Considering this, we set out to investigate the impact of usage of high doses and multiple kinds of hypnotics and their associated factors via a web-based questionnaire survey [20] targeting the Japanese general population with insomnia symptoms.
2. Material and Methods The study protocol was approved by the Ethics Committee of the Neuropsychiatric Research Institute, Tokyo, Japan. In November 2005, data from a large number of individuals was accumulated using a cross-sectional internet-linked survey. An e-mail containing a link to an online questionnaire was sent to 22,784 randomly selected people throughout Japan who were stratified by district, sex, and age by a market research company, Macromill. In 2005, they held a panel community of 330,000 people who were recruited in several ways, including by search engine advertisement, their website, and newspapers. The individuals participating in the present study were paid volunteers. Subjects provided informed consent via the questionnaire website. The sample of the present study was consistent with our previous study investigating the factors associated with the awareness of insomnia and deteriorated quality of life as well as depression [20]. The questionnaire included demographic variables (district where the participants lived, sex, age, and job status), status of hypnotics usage (“How many kinds of prescription drugs for treating insomnia do you take nightly?”), Japanese version of the Pittsburgh Sleep Quality Index (PSQI) [21] for subjective evaluation of participants’ sleep disturbance, 16-item Japanese version of the Center for Epidemiological Studies
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Depression Scale (CES-D) [22,23] for assessing their depressive status, and the Japanese version of Short Form-8 (SF-8) for the assessment of Health-Related Quality of Life (QOL) including the Mental Component Summary (MCS) and Physical Component Summary (PCS) [24]. A total of 10,016 people gave informed consent and completed the answers to all the required items of the questionnaire. Of these, 8805 people (87.9%) answered that they did not have subjective insomnia and 181 people (1.8%) gave invalid answers and were excluded from this study. Finally, 1030 individuals (10.3%) who gave an answer “yes” to the item “Do you think that you have been suffering from insomnia for at least 1 month?” according to the DSM-IV-TR (2000) [25] underwent subsequent analyses. The participants were divided into the following three groups by their status of hypnotics usage: “non-users” (participants who answered that they had insomnia symptoms, but did not use any kind of hypnotic at the time of the investigation), “users of a single kind of hypnotic” (participants who answered that they had insomnia symptoms and that they used a single kind of hypnotic at the time of the investigation) and “users of multiple kinds of hypnotics” (participants who answered that they had insomnia symptoms and that they used two or more kinds of hypnotics at the time of the investigation). Since this survey was performed in 2005 in Japan, the available hypnotics were BZDs and Z-drugs; melatonin receptor agonists and orexin receptor antagonists were not included in this survey. At first, descriptive variables, including sex, age, job status (full-time, part-time, freelance, housewife, student, other occupations, or non-worker), and sleep schedule variables of the participants were compared among the three groups. For the group comparisons, the differences in sex and job status were analyzed by using the chi-square test followed by residual analysis, and comparisons of continuous variables
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were conducted by using ANOVA followed by the Tukey HSD test as a post hoc analysis. We had planned to compare the following sleep schedule variables obtained from the answers to the PSQI among the groups so as to investigate the relationship between sleep phase and hypnotics use: bed-in time, sleep-onset time, and sleep-offset time. However, simultaneous use of these parameters is likely to cause the problem of multicollinearity, especially when conducting multiple logistic regression analysis as indicated below. Actually, the Pearson product-moment correlation coefficient for time for going to bed and sleep-offset time in our study subjects with subjective insomnia was
r=0.683 (p<0.001), and that for sleep-onset time and sleep-offset time was r=0.689 (p<0.001). In order to avoid multicollinearity, the midpoint of sleep (the median clock time of self-reported sleep-onset time and sleep-offset time) was generated and used as a representative of sleep schedule measures according to previous studies [26,27]. Logistic regression analyses were performed to assess the association of the usage of hypnotics categories with sex, age, job status, midpoint of sleep, self-reported sleep time, CES-D, and PSQI total score without C6 (as C6 is a subcomponent score evaluating the usage frequency of any hypnotic) [28,29]. Age, self-reported total sleep time (TST), and PSQI without C6 were divided into two groups by the median values (age: 43 years old, TST: 360 min, PSQI without C6: 8 points). Midpoint of sleep was divided into two groups according to the criteria reported in previous studies, namely “normal sleepers” (participants with their midpoint of sleep at <05:30 h) and “late sleepers” (participants with their midpoint of sleep at ≥ 05:30 h) [26,27]. CES-D was divided into two groups using the already established cut-off score (16 points). Initially, univariate logistic regression tests were performed, and the variables that showed significant association in univariate models were put into the multivariate model as explanatory variables. IBM SPSS Statistics ver.20 was used in all the above analyses.
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Statistical significance level was set at p<0.01.
3. Results 3.1. Demographic data of parent population The parent population of 10,016 participants comprised 5022 males (50.1%) and 4994 females (49.9%) with a mean age of 42.0 years (standard deviation [SD] = 15.2 years). Three-thousand and eighty-eight people (35.1%) were full-time workers, 929 people (10.6%) were part-time workers, 942 people (10.7%) were freelance, 1894 people (21.5%) were housewives, 1081 people (12.3%) were students, and 871 people (9.9%) were in other occupations or non-workers. Among these, 1030 participants (10.3%) were positive for subjective insomnia and underwent subsequent analyses; this group was comprised of 469 males (45.5%) and 561 females (54.5%). Three-hundred and fifty people (34.0%) were full-time workers, 114 people (11.1%) were part-time workers, 98 people (9.5%) were freelance, 229 people (22.2%) were housewives, 128 people (12.4%) were students, and 111 people (10.8%) were in other occupations or non-workers. The mean age of participants with subjective insomnia was 42.2 years ± 15.6 years (mean ± standard deviation) and the median age was 42 years. The mean total score of PSQI was 8.9 ± 3.3, the mean total score of CES-D was 20.8 ± 11.2, the mean score of PCS on SF8 was 46.5 ± 7.1, and the mean score of MCS on SF8 was 41.6 ± 9.0. The chi-square test revealed that there was a significant difference in sex distribution between participants with and without insomnia (χ2=9.84; p=0.002). The residual analysis indicated that female participants had subjective insomnia more frequently (Z=3.137; p<0.001). No significant differences in the job status (χ2=2.731) and mean age (t=0.293) were found between participants with and without insomnia.
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3.2. Descriptive variables of the participants having subjective insomnia Among the total of 1030 participants having subjective insomnia, 833 (80.9%) people were determined as “non-users”, 96 (9.3%) people as “users of a single kind of hypnotic”, and 101 (9.8%) people as “users of multiple kinds of hypnotics” (Fig. 1). Table 1 shows the comparison of descriptive variables among the three groups. The chi-square test revealed that there was a significant difference in sex distribution among the groups (χ2=15.28; p<0.001). The residual analysis indicated that the rate of female participants was higher in the users of a single kind of hypnotic (Z=3.812; p<0.001). No significant differences in job status (χ2=2.402) and duration of prescription of hypnotics (χ2=5.852) were found among these three groups. ANOVA indicated that there were significant differences in age (F=11.72;
p<0.001), CES-D (F=18.44; p<0.001), score of MCS on SF-8 (F=16.89; p<0.001), and PSQI total score without C6 (F=5.402; p<0.001) among these three groups. However, there were no significant differences in the scores of PCS on SF-8 (F=2.361; p=0.095). Post hoc analysis with the Tukey HSD test showed the following results. The users of a single kind of hypnotic were older than the non-users and users of multiple kinds of hypnotics (p<0.001 for both), but there was no significant difference in age between the users of multiple kinds of hypnotics and the non-users (p=0.760). The CES-D scores of the users of multiple kinds of hypnotics were higher than the non-users and users of a single kind of hypnotic (p<0.001 for both). However, there were no significant differences in the scores between the users of a single kind of hypnotic and the non-users (p=0.979). The MCS scores on SF8 of the users of multiple kinds of hypnotics were lower than the non-users and the users of a single kind of hypnotic (p<0.001 for both), whereas there were no significant differences in the scores between the users of a single kind of hypnotic and the non-users (p=0.992). The PSQI total scores without C6 of
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the users of multiple kinds of hypnotics were higher than the non-users (p=0.008), but there were no significant differences in the scores between the users of a single kind of hypnotic and the non-users (p=0.218) and between the users of a single kind of hypnotic and the users of multiple kinds of hypnotics (p=0.608). 3.3. Comparisons of sleep schedule-related variables among the three groups Figure 2 shows the comparison of the sleep schedule variables. ANOVA revealed that sleep onset time (F=5.481; p=0.009), sleep offset time (F=13.69; p<0.001), and midpoint of sleep (F=10.73; p<0.001) were significantly different among the three groups. However, there were no significant differences in time for going to bed (F=3.646;
p=0.026) and TST (F=4.04; p=0.018). Post-hoc analysis with the Tukey HSD test revealed that sleep onset time, sleep offset time, and midpoint of sleep in the users of multiple hypnotics were later than those in the non-users (p=0.006, p<0.001, p<0.001, respectively) and the users of a single kind of hypnotic (p=0.009, p<0.001, p<0.001, respectively). However, there were no significant differences in these sleep schedule variables between the non-users and the users of a single kind of hypnotic. 3.4. Factors associated with the use of a single kind of hypnotic In order to investigate the factors associated with the use of a single kind of hypnotic, logistic regression analyses were performed on 1030 participants with subjective insomnia with the following seven independent variables: sex, age, job status, midpoint of sleep, self-reported TST, PSQI total score without C6, and CES-D score. Variables showing significant associations in the univariate logistic regression analyses were put into a multivariate model. Table 2 represents the factors associated with the use of a single kind of hypnotic. Univariate analyses showed that sex (female: OR=2.43; 99% confidence interval [CI]=1.31–4.49; p<0.001) and age (median age ≥43 years: OR=2.66; 99%
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CI=1.46–4.85; p<0.001) were significantly associated with the use of a single kind of hypnotic. By using these significant variables, multivariate analysis revealed that sex (female: OR=2.38; 99% CI=1.28–4.42; p<0.001) and age (≥43 years old: OR=2.61; 99% CI=1.42–4.78; p<0.001) appeared to be significantly associated with the use of a single kind of hypnotic. 3.5. Factors associated with the use of multiple kinds of hypnotics Logistic regression analyses were conducted again with the same independent variables (Table 3). Univariate analyses showed that midpoint of sleep (late-sleepers: OR=2.65; 99% CI=1.72–4.10; p<0.001), PSQI total score without C6 (≥ 8 points of median value: OR=1.11; 99% CI=1.01–1.21; p=0.005), and CES-D (≥16 points, the cut-off point: OR=2.82; 99% CI=1.45–5.48; p<0.001) were significantly associated with use of multiple kinds of hypnotics. Subsequent multivariate analysis using these variables revealed that midpoint of sleep (late-sleepers: OR=2.26; 99% CI=1.45–3.52; p<0.001), and CES-D (≥16 points, the cut-off point: OR=2.41; 99% CI=1.43–4.05; p<0.001) were significantly associated with use of multiple kinds of hypnotics.
4. Discussion This study is apparently the first to investigate the usage rate of multiple kinds of hypnotics and the differences in the impact on daytime functions among the user categories, as well as factors associated with usage of multiple kinds of hypnotics in the general population. Although this study was conducted as a web-based survey, age distribution of the study sample was quite similar to that of the general Japanese population [30]. Moreover, the 10.3% rate of participants having subjective insomnia in the present study was very similar to that previously conducted on the Japanese general population [31,32].
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Of note, the present study revealed that the scores of daytime function measures, including the scores of MCS and PCS on SF8, as well as CES-D, were significantly worse in the users of multiple kinds of hypnotics than in the other two groups, while the scores of these daytime function measures of the users of a single kind of hypnotic did not differ from those of the non-users. Moreover, the scores of PSQI manifesting the severity of sleep disturbance were significantly higher in the users of multiple kinds of hypnotics than in the other two groups. Although the reason for this phenomenon is unclear, at least we can say that the usage of multiple kinds of hypnotics is not likely to yield a better outcome for the improvement of nocturnal insomnia symptoms nor improve daytime function. Interestingly, in the present study, the associated factors were clearly different between the users of a single kind of hypnotic and those for users of multiple kinds of hypnotics. In the former group, female sex and higher age appeared as significant factors, similar to previous reports [32,33]. On the other hand, in the latter group, later sleep schedule and higher CES-D score independently appeared as associated factors, suggesting that the presence of depression or delayed phase of circadian rhythm possibly contributes to the formation of refractoriness to treatment with BZDs and Z-drugs, leading to the usage of higher doses of these kinds of drugs. With regard to the refractoriness of hypnotic treatment for insomnia symptoms in depression, the results of the present study were quite in line with some previous studies [18,19,34]. As for sleep schedule, some previous studies have indicated that BZDs and Z-drugs have limited effectiveness on insomnia symptoms resulting from circadian rhythm sleep disorder, especially the delayed sleep phase type (DSPT). Reportedly, the delay of the time period where one can fall asleep easily in the night can explain the refractoriness of insomnia symptoms to BZDs and Z-drugs in DSPT [35,36]. In addition,
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administration of BZDs and Z-drugs during the night would not change the sleep phase [37, 38]. Given these considerations, later sleep phase in the users of multiple kinds of hypnotics might not result from the usage of the drugs, but is inferred to become a risk factor for the high-dose usage of BZDs and Z-drugs. A longitudinal study in Japan indicated that sleep schedule has become later in the general population in the last two decades [39]. In modern society, the promotion of sleep hygiene for avoiding later sleep phase is important to prevent the general population from adopting the usage of high-dose hypnotics. The present study suggested the association of both the presence of depression and later sleep schedule to the usage of high doses of hypnotics. Notably, depressive symptoms appear commonly in patients with DSPT [40]. Moreover, the eveningness chronotype and insomnia are reportedly associated with non-remission of depression [41]. Taking these together, application of chronobiological treatment, such as exposure to bright light or administration of melatonin, rather than administration of BZDs and Z-drugs, should be considered for insomnia symptoms in depressed patients having the eveningness chronotype [42,43]. Comprehensive assessment and management of circadian rhythm problems and depression is desirable in the treatment of chronic insomnia. This study has several limitations. Firstly, the present study was conducted as a web-based survey and possibly had sampling bias. Although the age composition was similar to the general population, it was not an absolute random sampling from the general population. For this reason, it may be difficult to generalize the findings of this study. Since the stratification was performed only in district, sex, and age, the other profiles might have a bias. As former studies with online survey discussed, people without computer access who have certain socioeconomic backgrounds were excluded
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[44,45]. Furthermore, individuals with eveningness chronotype are likely to be interested in answering this kind of online questionnaire (especially at nighttime), possibly leading to a lifestyle bias for disproportionate emphasis on eveningness chronotype. Secondly, in this web-based survey there was a large number of people who did not complete the answers to the questionnaire, and we could not know how many people opened and read the email, accessed the website of the survey, or discontinued answering. For these reasons, validity of this survey might be limited; however, the total response rate of this survey was 44.0% (10,016/22,784), which was higher than former web-based studies [46,47]. Thirdly, all the sleep schedule parameters were self-reported by the study participants, and this might involve recall bias. Fourthly, we did not analyze the users of any other drugs that have a hypnotic effect, such as anti-psychotics and anti-depressants. Moreover, because the questionnaire was focused only on prescription drugs, the impact of over-the counter drugs could not be clarified. Finally, since the present study was conducted as a cross-sectional design, the causal relationship between the use of multiple kinds of hypnotics and the above-mentioned insomnia symptoms or daytime dysfunctions, as well as that between descriptive backgrounds and usage of multiple kinds of hypnotics, remain uncertain. A prospective longitudinal follow-up study is needed to clarify these issues.
5. Conclusions The present study revealed that the characteristics of users of multiple kinds of hypnotics were different from those of users of a single kind of hypnotic in this study sample population, and that both depressive symptoms and later sleep schedule were factors significantly associated with the former group. Conflicts of interest
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Yuichi Inoue has received clinically pertinent fees, lecture fees, and research funding from Hisamitsu Pharmaceutical Co., Inc., Nippon Boehringer Ingelheim Co., Ltd., Philips Respironics GK, Alfresa Pharma Corporation, Takeda Pharmaceutical Company Ltd., MSD K.K., Pacific Medico Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Eisai Co., Ltd., Mitsubishi Tanabe Pharma Corporation, GlaxoSmithKline K.K., Astellas Pharma Inc., Sanofi-Aventis K.K., and Yoshitomiyakuhin Corporation. Akiyoshi Shimura, Yoshikazu Takaesu, Sayaka Aritake, Kunihiro Futenma, and Yoko Komada declare that they have no conflicts of interest.
Acknowledgments The authors are indebted to the medical editors from the Department of International Medical Communications of Tokyo Medical University for editing and reviewing the initial English manuscript.
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[29] Romigi A, Izzi F, Placidi F, Zannino S, Evangelista E, Del Bianco C, et al. Effects of zonisamide as add-on therapy on sleep-wake cycle in focal epilepsy: a polysomnographic study. Epilepsy & behavior : E&B. 2013;26:170-4. 10.1016/j.yebeh.2012.11.049 [30] Statistics Bureau Ministry of Internal Affairs and Communications Japan. Population of Japan 2005. 2005:20. [31] Soldatos CR, Allaert FA, Ohta T, Dikeos DG. How do individuals sleep around the world? Results from a single-day survey in ten countries. Sleep Med. 2005;6:5-13. 10.1016/j.sleep.2004.10.006 [32] Doi Y, Minowa M, Okawa M, Uchiyama M. Prevalence of sleep disturbance and hypnotic medication use in relation to sociodemographic factors in the general Japanese adult
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10.1185/030079906x112589 [35] Lemmer B. The sleep–wake cycle and sleeping pills. Physiology & behavior. 2007;90:285-93. 10.1016/j.physbeh.2006.09.006 [36] Sack RL, Auckley D, Auger RR, Carskadon MA, Wright KP, Vitiello MV, et al. Circadian rhythm sleep disorders: part II, advanced sleep phase disorder, delayed sleep phase disorder, free-running disorder, and irregular sleep-wake rhythm. An American Academy of Sleep Medicine review. Sleep. 2007;30:1484-501. [37] Allen NH, Smythe PJ, Martin N, Plaskett L, Osola K, Childs P, et al. The effect of temazepam on melatonin secretion and light sensitivity. Journal of psychopharmacology
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(Oxford, England). 1994;8:94-7. 10.1177/026988119400800204 [38] Norman TR, Piccolo J, Voudouris N, Burrows GD. The effect of single oral doses of zopiclone on nocturnal melatonin secretion in healthy male volunteers. Progress in neuro-psychopharmacology & biological psychiatry. 2001;25:825-33. [39] NHK Broadcasting culture research institute. The cross-national survey of time use Tokyo, Japan: Ozorasha; 2006. http://www.nhk.or.jp/bunken/english/ [40] Abe T, Inoue Y, Komada Y, Nakamura M, Asaoka S, Kanno M, et al. Relation between morningness–eveningness score and depressive symptoms among patients with delayed sleep phase syndrome. Sleep Med. 2011;12:680-4. 10.1016/j.sleep.2010.12.017 [41] Chan JW, Lam SP, Li SX, Yu MW, Chan NY, Zhang J, et al. Eveningness and insomnia: independent risk factors of nonremission in major depressive disorder. Sleep. 2014;37:911-7. 10.5665/sleep.3658 [42] Golden RN, Gaynes BN, Ekstrom RD, Hamer RM, Jacobsen FM, Suppes T, et al. The efficacy of light therapy in the treatment of mood disorders: a review and meta-analysis of the evidence. Am J Psychiatry. 2005;162:656-62. 10.1176/appi.ajp.162.4.656 [43] Bogen S, Legenbauer T, Bogen T, Gest S, Jensch T, Schneider S, et al. Morning light therapy for juvenile depression and severe mood dysregulation: study protocol for a randomized controlled trial. Trials. 2013;14:178. 10.1186/1745-6215-14-178 [44] Leger D, Morin CM, Uchiyama M, Hakimi Z, Cure S, Walsh JK. Chronic insomnia, quality-of-life, and utility scores: comparison with good sleepers in a cross-sectional international survey. Sleep Med. 2012;13:43-51. 10.1016/j.sleep.2011.03.020 [45] Powell NB, Schechtman KB, Riley RW, Guilleminault C, Chiang RP, Weaver EM. Sleepy driver near-misses may predict accident risks. Sleep. 2007;30:331-42. [46] Allen RP, Kushida CA, Atkinson MJ. Factor analysis of the International Restless Legs Syndrome Study Group's scale for restless legs severity. Sleep Med. 2003;4:133-5.
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[47] Cook C, Heath F, Thompson RL. A meta-analysis of response rates in web-or internet-based surveys. Educational and psychological measurement. 2000;60:821-36. Figure captions
Comment [A5]: Author: Please provide
Figure 1. Sample flow of participants
figure captions for Figs 1 and 2.
Fig. 2. Sleep phase outline of each group
A: significantly later than a B: significantly later than b ** :p<0.001, *:p<0.01 Midpoint of sleep = (sleep offset time - sleep onset time) / 2 Each sleep phase parameter was calculated from the results of the Pittsburgh Sleep Quality Index
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Tables
Comment [A6]: Author: please provide
Table 1. Comparison of descriptive variables of participants with subjective insomnia among non-users, users of a single kind of hypnotic, and users of
tables 1-3.
multiple kinds of hypnotics Users of a Total
Non-users single kind of
Users of multiple kinds of hypnotics
hypnotic (n=1030) Sex
Job
(n=833)
(n=96)
(n=101)
Female
561 (54.5%)
442 (53.1%) 70 (72.9%)1),3)
49 (48.5%)
Male
469 (45.5%)
391 (46.9%) 26 (27.1%)1),3)
52 (51.5%)
Full-time
350 (34.0%)
291 (34.9%) 27 (28.1%)
32 (31.7%)
Not full-time
680 (66.0%)
542 (65.1%) 69 (71.9%)
69 (68.3%)
Duration of
＜1 month
30 (2.9%)
-
20 (20.6%)
10 (9.9%)
prescription
≧1 month, ＜6 months
25 (2.4%)
-
14 (14.6%)
11 (10.9%)
142 (13.8%)
-
62 (64.6%)
80 (79.2%)
≧6 months
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Age
42.2±15.6
41.6±15.5 49.4±15.01),3)
CES-D
20.8±11.2
20.1±10.8
19.9±11.0
27.1±12.61),2)
PCS
46.5±7.1
46.6±6.9
46.7±6.7
45.0±8.8
MCS
41.6±9.0
42.2±8.9
42.1±8.9
36.7±9.31),2)
Total score without C6
8.0±2.9
7.9±2.8
8.4±3.2
8.8±3.31)
0:32(a.m.)±1:54 0:32±1:53
0:12±1:45
0:56±2:06
Sleep onset time
1:14(a.m.)±2:05 1:11±2:02
0:59±1:50
1:51±2:331),2)
Sleep offset time
7:20(a.m.)±2:04 7:14±1:58
7:09±1:48
8:21±2:481),2)
Midpoint of sleep
4:17(a.m.)±1:54 4:13±1:50
4:04±1:44
5:06±2:261),2)
Total sleep time
352.3(min.)±74.2 349.4±70.6 358.1±68.3
370.7±101.7
QOL(SF-8)
PSQI
Sleep schedule Time for going to bed
40.5±14.9
CES-D: The Center for Epidemiologic Studies Depression Scale QOL(SF-8): Short Form-8 for the assessment of Health-Related Quality of Life MCS: Mental Component Summary; PCS: Physical Component Summary PSQI: The Pittsburgh Sleep Quality Index
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Age, CES-D, QOL, PSQI, and Sleep schedule: mean±1SD 1)
p<0.01 vs. non-users. 2)p<0.01 vs. users of a single kind of hypnotic. 3)p<0.01 vs. users of multiple kinds of hypnotics.
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Table 2. Logistic regression analysis of associated factors for users of a single kind of hypnotic among insomniacs Users of
Total
a single kind of hypnotic
n Sex
n
%
Univariate relative risk (99% confidence interval)
469
26 27.1%
Female
561
70 72.9% 2.43 (1.31-4.49) <0.001
＜43 *1
516
28 29.2%
≧43
514
68 70.8% 2.66 (1.46-4.85) <0.001
Full-time
350
27 28.1%
Others
680
69 71.9%
Midpoint of sleep
Normal sleepers*2
832
81 84.4%
(clock time)
Late sleepers*2
198
15 15.6%
Job
(99% confidence interval)
p
Male
Age (years)
Multivariate relative risk
p
2.38 (1.28-4.42)
<0.001
2.61 (1.42-4.78)
<0.001
n.s.
n.s.
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Self-reported
＜360 *1
434
36 37.5%
total sleep time (min)
≧360
596
60 62.5%
PSQI without C6
＜8 *1
446
38 39.6%
(points)
≧8
584
58 60.4%
n.s.
CES-D (points)
＜16 *3
401
33 34.4%
n.s.
≧16
629
63 65.6%
n.s.
*1: divided by median value *2: divided by former study's criteria: 5:30 a.m. *3: divided by cut-off point
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Table 3. Logistic regression analysis of associated factors for users of multiple kinds of hypnotics among insomniacs Users of
Total
multiple kinds of hypnotics
n Sex
%
Univariate relative risk (99% confidence interval)
469
52 51.5%
Female
561
49 48.5%
＜43 *1
516
59 58.4%
≧43
514
42 41.6%
Full-time
350
32 31.7%
Others
680
69 68.3%
Midpoint of sleep
Normal sleepers*2
832
64 63.4%
(clock time)
Late sleepers*2
198
37 36.6% 2.65 (1.72-4.10) <0.001
Job
(95% confidence interval)
p
Male
Age (years)
Multivariate relative risk
p
n.s.
n.s.
n.s.
2.26 (1.45-3.52)
<0.001
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Self-reported
＜360 *1
434
32 31.7%
total sleep time (min)
≧360
596
69 68.3%
PSQI without C6
＜8 *1
446
36 35.6%
(points)
≧8
584
65 64.4% 1.11 (1.01-1.21) 0.005
CES-D (points)
＜16 *3
401
20 19.8%
≧16
629
81 80.2% 2.82 (1.45-5.48) <0.001
n.s.
n.s.
2.41 (1.43-4.05)
<0.001
*1: divided by median value *2: divided by former study's criteria: 5:30 a.m. *3: divided by cut off point
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S1389-9457(16)30036-3 http://dx.doi.org/doi: 10.1016/j.sleep.2016.04.011 SLEEP 3057
To appear in:
Sleep Medicine
Received date: Revised date: Accepted date:
7-7-2015 12-4-2016 14-4-2016
Please cite this article as: Akiyoshi Shimura, Yoshikazu Takaesu, Sayaka Aritake, Kunihiro Futenma, Yoko Komada, Yuichi Inoue, Later sleep schedule and depressive symptoms are associated with usage of multiple kinds of hypnotics, Sleep Medicine (2016), http://dx.doi.org/doi: 10.1016/j.sleep.2016.04.011. 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 proof before it is published in its final 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.
Later sleep schedule and depressive symptoms are associated with usage of multiple kinds of hypnotics
Akiyoshi Shimura
a,b,
Yoshikazu Takaesu a, Sayaka Aritake
b,c,
Kunihiro Futenma
a,b,
Yoko Komada b,d, Yuichi Inoue a,b,d
a
Department of Psychiatry, Tokyo Medical University, Tokyo, Japan
b
Department of Somnology, Tokyo Medical University, Tokyo, Japan
c
Japan Society for the Promotion of Science, Tokyo, Japan
d
Japan Somnology Center, Neuropsychiatric Research Institute, Tokyo, Japan
* Corresponding author. 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, Japan. Tel.: +81 3 3342 6111. E-mail address: [email protected] (Y. Inoue).
Highlights
Factors associated with high doses of hypnotics were examined.
Users of multiple kinds of hypnotics had later sleep schedule.
Users of multiple kinds of hypnotics had more depressive symptoms.
Eveningness and depression were associated with usage of multiple kinds of hypnotics.
Assessment of circadian rhythm and depression is needed in medication of insomnia.
Abstract: Objective: Usage of high doses of hypnotics possibly causes various adverse events. However, the risk factors of using multiple kinds of hypnotics have been
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inconclusive. To clarify this, we conducted a webbased cross-sectional questionnaire survey on the Japanese adult population. Methods: A cross-sectional Internet-linked survey was conducted on 10,016 individuals, and 1,030 participants (10.3%) having subjective insomnia proceeded to subsequent analyses. The analyzed subjects were categorized into non-users of hypnotics (n=833; 80.9%), users of a single kind of hypnotic (n=96; 9.3%), and users of multiple kinds of hypnotics (n=101; 9.8%). The descriptive variables including demographic data, scores of Center for Epidemiological Studies Depression Scale (CES-D), Short Form-8 Health-Related Quality of Life (QOL (SF-8)), Pittsburgh Sleep Quality Index (PSQI), and other parameters were compared among the groups. Results: The users of multiple kinds of hypnotics had the highest mean score of CES-D, the lowest mental component summary of QOL (SF-8), and the latest sleep schedule among the three groups (p<0.001). Logistic regression analyses revealed that sex (female: OR=2.38; p<0.001) and age (≥43 years old: OR=2.61; p<0.001) were independently associated with use of a single kind of hypnotic, while later sleep schedule (midpoint of sleep ≥5:30 a.m.: OR=2.26; p<0.001) and higher CES-D score (≥16 points: OR=2.41; p<0.001) were independently associated with use of multiple kinds of hypnotics. Conclusions: Characteristics of users of multiple kinds of hypnotics were different from users of a single kind of hypnotic.
Keywords: benzodiazepine; depression; eveningness; rhythm; hypnotic; insomnia; polypharmacy
Comment [A1]: Please supply an abstract of up to 250 words; please
1. Introduction
supply up to 6 keywords.
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Hypnotics, including benzodiazepines (BZDs) and Z-drugs (benzodiazepine receptor agonists), have long been widely accepted as important treatment choices for insomnia [1,2]. Although treatment with these kinds of hypnotics can alleviate insomnia symptoms, the drugs may cause acute side effects, such as hangover [3], falls and fractures [4–6], abnormal behavior during sleep [7], and deteriorated driving performance on the day after administration [8]. Moreover, long-term use of these hypnotics may possibly lead to increasing dosages of hypnotics due to tolerance or dependence [9,10]. A recent study has also shown that usage of sedative-hypnotics is associated with increased risk of suicidality independent of insomnia [11] and increased risk of premature mortality [12]. Of note, usage of high-dose hypnotics may cause serious adverse events more frequently. Reportedly, the risk of hip fractures is related with the dosage of BZDs and Z-drugs [4,13]. In elderly drivers, the risk of injurious motor vehicle accidents becomes higher as the daily dosage of BZDs and Z-drugs increases [14]. Considering these findings, governments of some developed countries have displayed a negative attitude toward long-term or high-dose usage of BZDs and Z-drugs. Following this approach, recommendations for avoiding inadequate use of these kinds of drugs have been raised
Comment [A2]: Author: Do you mean
in Western countries [15–17].
‘unnecessary’ here?
In order to establish a strategy for preventing the usage of high-dose BZDs and Z-drugs, risk factors for becoming a high-dose user have been ascertained. Previous studies have shown some correlations to usage of high-dose BZDs and Z-drugs. Younger age, existence of depressive disorder, and usage of antidepressants have been reported to be associated with the dosage of BZDs and Z-drugs [18]. Severity of mental illnesses such as schizophrenia, bipolar disorder, and major depression and co-occurrence of alcohol abuse were also associated with the high-dose usage of these drugs [19].
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However, most previous studies have focused on psychiatric patients, and to our knowledge, there have been no studies investigating factors associated with the usage of high-dose BZDs and Z-drugs among the general population with insomnia symptoms. Considering this, we set out to investigate the impact of usage of high doses and multiple kinds of hypnotics and their associated factors via a web-based questionnaire survey [20] targeting the Japanese general population with insomnia symptoms.
2. Material and Methods The study protocol was approved by the Ethics Committee of the Neuropsychiatric Research Institute, Tokyo, Japan. In November 2005, data from a large number of individuals was accumulated using a cross-sectional internet-linked survey. An e-mail containing a link to an online questionnaire was sent to 22,784 randomly selected people throughout Japan who were stratified by district, sex, and age by a market research company, Macromill. In 2005, they held a panel community of 330,000 people who were recruited in several ways, including by search engine advertisement, their website, and newspapers. The individuals participating in the present study were paid volunteers. Subjects provided informed consent via the questionnaire website. The sample of the present study was consistent with our previous study investigating the factors associated with the awareness of insomnia and deteriorated quality of life as well as depression [20]. The questionnaire included demographic variables (district where the participants lived, sex, age, and job status), status of hypnotics usage (“How many kinds of prescription drugs for treating insomnia do you take nightly?”), Japanese version of the Pittsburgh Sleep Quality Index (PSQI) [21] for subjective evaluation of participants’ sleep disturbance, 16-item Japanese version of the Center for Epidemiological Studies
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Depression Scale (CES-D) [22,23] for assessing their depressive status, and the Japanese version of Short Form-8 (SF-8) for the assessment of Health-Related Quality of Life (QOL) including the Mental Component Summary (MCS) and Physical Component Summary (PCS) [24]. A total of 10,016 people gave informed consent and completed the answers to all the required items of the questionnaire. Of these, 8805 people (87.9%) answered that they did not have subjective insomnia and 181 people (1.8%) gave invalid answers and were excluded from this study. Finally, 1030 individuals (10.3%) who gave an answer “yes” to the item “Do you think that you have been suffering from insomnia for at least 1 month?” according to the DSM-IV-TR (2000) [25] underwent subsequent analyses. The participants were divided into the following three groups by their status of hypnotics usage: “non-users” (participants who answered that they had insomnia symptoms, but did not use any kind of hypnotic at the time of the investigation), “users of a single kind of hypnotic” (participants who answered that they had insomnia symptoms and that they used a single kind of hypnotic at the time of the investigation) and “users of multiple kinds of hypnotics” (participants who answered that they had insomnia symptoms and that they used two or more kinds of hypnotics at the time of the investigation). Since this survey was performed in 2005 in Japan, the available hypnotics were BZDs and Z-drugs; melatonin receptor agonists and orexin receptor antagonists were not included in this survey. At first, descriptive variables, including sex, age, job status (full-time, part-time, freelance, housewife, student, other occupations, or non-worker), and sleep schedule variables of the participants were compared among the three groups. For the group comparisons, the differences in sex and job status were analyzed by using the chi-square test followed by residual analysis, and comparisons of continuous variables
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were conducted by using ANOVA followed by the Tukey HSD test as a post hoc analysis. We had planned to compare the following sleep schedule variables obtained from the answers to the PSQI among the groups so as to investigate the relationship between sleep phase and hypnotics use: bed-in time, sleep-onset time, and sleep-offset time. However, simultaneous use of these parameters is likely to cause the problem of multicollinearity, especially when conducting multiple logistic regression analysis as indicated below. Actually, the Pearson product-moment correlation coefficient for time for going to bed and sleep-offset time in our study subjects with subjective insomnia was
r=0.683 (p<0.001), and that for sleep-onset time and sleep-offset time was r=0.689 (p<0.001). In order to avoid multicollinearity, the midpoint of sleep (the median clock time of self-reported sleep-onset time and sleep-offset time) was generated and used as a representative of sleep schedule measures according to previous studies [26,27]. Logistic regression analyses were performed to assess the association of the usage of hypnotics categories with sex, age, job status, midpoint of sleep, self-reported sleep time, CES-D, and PSQI total score without C6 (as C6 is a subcomponent score evaluating the usage frequency of any hypnotic) [28,29]. Age, self-reported total sleep time (TST), and PSQI without C6 were divided into two groups by the median values (age: 43 years old, TST: 360 min, PSQI without C6: 8 points). Midpoint of sleep was divided into two groups according to the criteria reported in previous studies, namely “normal sleepers” (participants with their midpoint of sleep at <05:30 h) and “late sleepers” (participants with their midpoint of sleep at ≥ 05:30 h) [26,27]. CES-D was divided into two groups using the already established cut-off score (16 points). Initially, univariate logistic regression tests were performed, and the variables that showed significant association in univariate models were put into the multivariate model as explanatory variables. IBM SPSS Statistics ver.20 was used in all the above analyses.
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Statistical significance level was set at p<0.01.
3. Results 3.1. Demographic data of parent population The parent population of 10,016 participants comprised 5022 males (50.1%) and 4994 females (49.9%) with a mean age of 42.0 years (standard deviation [SD] = 15.2 years). Three-thousand and eighty-eight people (35.1%) were full-time workers, 929 people (10.6%) were part-time workers, 942 people (10.7%) were freelance, 1894 people (21.5%) were housewives, 1081 people (12.3%) were students, and 871 people (9.9%) were in other occupations or non-workers. Among these, 1030 participants (10.3%) were positive for subjective insomnia and underwent subsequent analyses; this group was comprised of 469 males (45.5%) and 561 females (54.5%). Three-hundred and fifty people (34.0%) were full-time workers, 114 people (11.1%) were part-time workers, 98 people (9.5%) were freelance, 229 people (22.2%) were housewives, 128 people (12.4%) were students, and 111 people (10.8%) were in other occupations or non-workers. The mean age of participants with subjective insomnia was 42.2 years ± 15.6 years (mean ± standard deviation) and the median age was 42 years. The mean total score of PSQI was 8.9 ± 3.3, the mean total score of CES-D was 20.8 ± 11.2, the mean score of PCS on SF8 was 46.5 ± 7.1, and the mean score of MCS on SF8 was 41.6 ± 9.0. The chi-square test revealed that there was a significant difference in sex distribution between participants with and without insomnia (χ2=9.84; p=0.002). The residual analysis indicated that female participants had subjective insomnia more frequently (Z=3.137; p<0.001). No significant differences in the job status (χ2=2.731) and mean age (t=0.293) were found between participants with and without insomnia.
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3.2. Descriptive variables of the participants having subjective insomnia Among the total of 1030 participants having subjective insomnia, 833 (80.9%) people were determined as “non-users”, 96 (9.3%) people as “users of a single kind of hypnotic”, and 101 (9.8%) people as “users of multiple kinds of hypnotics” (Fig. 1). Table 1 shows the comparison of descriptive variables among the three groups. The chi-square test revealed that there was a significant difference in sex distribution among the groups (χ2=15.28; p<0.001). The residual analysis indicated that the rate of female participants was higher in the users of a single kind of hypnotic (Z=3.812; p<0.001). No significant differences in job status (χ2=2.402) and duration of prescription of hypnotics (χ2=5.852) were found among these three groups. ANOVA indicated that there were significant differences in age (F=11.72;
p<0.001), CES-D (F=18.44; p<0.001), score of MCS on SF-8 (F=16.89; p<0.001), and PSQI total score without C6 (F=5.402; p<0.001) among these three groups. However, there were no significant differences in the scores of PCS on SF-8 (F=2.361; p=0.095). Post hoc analysis with the Tukey HSD test showed the following results. The users of a single kind of hypnotic were older than the non-users and users of multiple kinds of hypnotics (p<0.001 for both), but there was no significant difference in age between the users of multiple kinds of hypnotics and the non-users (p=0.760). The CES-D scores of the users of multiple kinds of hypnotics were higher than the non-users and users of a single kind of hypnotic (p<0.001 for both). However, there were no significant differences in the scores between the users of a single kind of hypnotic and the non-users (p=0.979). The MCS scores on SF8 of the users of multiple kinds of hypnotics were lower than the non-users and the users of a single kind of hypnotic (p<0.001 for both), whereas there were no significant differences in the scores between the users of a single kind of hypnotic and the non-users (p=0.992). The PSQI total scores without C6 of
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the users of multiple kinds of hypnotics were higher than the non-users (p=0.008), but there were no significant differences in the scores between the users of a single kind of hypnotic and the non-users (p=0.218) and between the users of a single kind of hypnotic and the users of multiple kinds of hypnotics (p=0.608). 3.3. Comparisons of sleep schedule-related variables among the three groups Figure 2 shows the comparison of the sleep schedule variables. ANOVA revealed that sleep onset time (F=5.481; p=0.009), sleep offset time (F=13.69; p<0.001), and midpoint of sleep (F=10.73; p<0.001) were significantly different among the three groups. However, there were no significant differences in time for going to bed (F=3.646;
p=0.026) and TST (F=4.04; p=0.018). Post-hoc analysis with the Tukey HSD test revealed that sleep onset time, sleep offset time, and midpoint of sleep in the users of multiple hypnotics were later than those in the non-users (p=0.006, p<0.001, p<0.001, respectively) and the users of a single kind of hypnotic (p=0.009, p<0.001, p<0.001, respectively). However, there were no significant differences in these sleep schedule variables between the non-users and the users of a single kind of hypnotic. 3.4. Factors associated with the use of a single kind of hypnotic In order to investigate the factors associated with the use of a single kind of hypnotic, logistic regression analyses were performed on 1030 participants with subjective insomnia with the following seven independent variables: sex, age, job status, midpoint of sleep, self-reported TST, PSQI total score without C6, and CES-D score. Variables showing significant associations in the univariate logistic regression analyses were put into a multivariate model. Table 2 represents the factors associated with the use of a single kind of hypnotic. Univariate analyses showed that sex (female: OR=2.43; 99% confidence interval [CI]=1.31–4.49; p<0.001) and age (median age ≥43 years: OR=2.66; 99%
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CI=1.46–4.85; p<0.001) were significantly associated with the use of a single kind of hypnotic. By using these significant variables, multivariate analysis revealed that sex (female: OR=2.38; 99% CI=1.28–4.42; p<0.001) and age (≥43 years old: OR=2.61; 99% CI=1.42–4.78; p<0.001) appeared to be significantly associated with the use of a single kind of hypnotic. 3.5. Factors associated with the use of multiple kinds of hypnotics Logistic regression analyses were conducted again with the same independent variables (Table 3). Univariate analyses showed that midpoint of sleep (late-sleepers: OR=2.65; 99% CI=1.72–4.10; p<0.001), PSQI total score without C6 (≥ 8 points of median value: OR=1.11; 99% CI=1.01–1.21; p=0.005), and CES-D (≥16 points, the cut-off point: OR=2.82; 99% CI=1.45–5.48; p<0.001) were significantly associated with use of multiple kinds of hypnotics. Subsequent multivariate analysis using these variables revealed that midpoint of sleep (late-sleepers: OR=2.26; 99% CI=1.45–3.52; p<0.001), and CES-D (≥16 points, the cut-off point: OR=2.41; 99% CI=1.43–4.05; p<0.001) were significantly associated with use of multiple kinds of hypnotics.
4. Discussion This study is apparently the first to investigate the usage rate of multiple kinds of hypnotics and the differences in the impact on daytime functions among the user categories, as well as factors associated with usage of multiple kinds of hypnotics in the general population. Although this study was conducted as a web-based survey, age distribution of the study sample was quite similar to that of the general Japanese population [30]. Moreover, the 10.3% rate of participants having subjective insomnia in the present study was very similar to that previously conducted on the Japanese general population [31,32].
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Of note, the present study revealed that the scores of daytime function measures, including the scores of MCS and PCS on SF8, as well as CES-D, were significantly worse in the users of multiple kinds of hypnotics than in the other two groups, while the scores of these daytime function measures of the users of a single kind of hypnotic did not differ from those of the non-users. Moreover, the scores of PSQI manifesting the severity of sleep disturbance were significantly higher in the users of multiple kinds of hypnotics than in the other two groups. Although the reason for this phenomenon is unclear, at least we can say that the usage of multiple kinds of hypnotics is not likely to yield a better outcome for the improvement of nocturnal insomnia symptoms nor improve daytime function. Interestingly, in the present study, the associated factors were clearly different between the users of a single kind of hypnotic and those for users of multiple kinds of hypnotics. In the former group, female sex and higher age appeared as significant factors, similar to previous reports [32,33]. On the other hand, in the latter group, later sleep schedule and higher CES-D score independently appeared as associated factors, suggesting that the presence of depression or delayed phase of circadian rhythm possibly contributes to the formation of refractoriness to treatment with BZDs and Z-drugs, leading to the usage of higher doses of these kinds of drugs. With regard to the refractoriness of hypnotic treatment for insomnia symptoms in depression, the results of the present study were quite in line with some previous studies [18,19,34]. As for sleep schedule, some previous studies have indicated that BZDs and Z-drugs have limited effectiveness on insomnia symptoms resulting from circadian rhythm sleep disorder, especially the delayed sleep phase type (DSPT). Reportedly, the delay of the time period where one can fall asleep easily in the night can explain the refractoriness of insomnia symptoms to BZDs and Z-drugs in DSPT [35,36]. In addition,
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administration of BZDs and Z-drugs during the night would not change the sleep phase [37, 38]. Given these considerations, later sleep phase in the users of multiple kinds of hypnotics might not result from the usage of the drugs, but is inferred to become a risk factor for the high-dose usage of BZDs and Z-drugs. A longitudinal study in Japan indicated that sleep schedule has become later in the general population in the last two decades [39]. In modern society, the promotion of sleep hygiene for avoiding later sleep phase is important to prevent the general population from adopting the usage of high-dose hypnotics. The present study suggested the association of both the presence of depression and later sleep schedule to the usage of high doses of hypnotics. Notably, depressive symptoms appear commonly in patients with DSPT [40]. Moreover, the eveningness chronotype and insomnia are reportedly associated with non-remission of depression [41]. Taking these together, application of chronobiological treatment, such as exposure to bright light or administration of melatonin, rather than administration of BZDs and Z-drugs, should be considered for insomnia symptoms in depressed patients having the eveningness chronotype [42,43]. Comprehensive assessment and management of circadian rhythm problems and depression is desirable in the treatment of chronic insomnia. This study has several limitations. Firstly, the present study was conducted as a web-based survey and possibly had sampling bias. Although the age composition was similar to the general population, it was not an absolute random sampling from the general population. For this reason, it may be difficult to generalize the findings of this study. Since the stratification was performed only in district, sex, and age, the other profiles might have a bias. As former studies with online survey discussed, people without computer access who have certain socioeconomic backgrounds were excluded
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[44,45]. Furthermore, individuals with eveningness chronotype are likely to be interested in answering this kind of online questionnaire (especially at nighttime), possibly leading to a lifestyle bias for disproportionate emphasis on eveningness chronotype. Secondly, in this web-based survey there was a large number of people who did not complete the answers to the questionnaire, and we could not know how many people opened and read the email, accessed the website of the survey, or discontinued answering. For these reasons, validity of this survey might be limited; however, the total response rate of this survey was 44.0% (10,016/22,784), which was higher than former web-based studies [46,47]. Thirdly, all the sleep schedule parameters were self-reported by the study participants, and this might involve recall bias. Fourthly, we did not analyze the users of any other drugs that have a hypnotic effect, such as anti-psychotics and anti-depressants. Moreover, because the questionnaire was focused only on prescription drugs, the impact of over-the counter drugs could not be clarified. Finally, since the present study was conducted as a cross-sectional design, the causal relationship between the use of multiple kinds of hypnotics and the above-mentioned insomnia symptoms or daytime dysfunctions, as well as that between descriptive backgrounds and usage of multiple kinds of hypnotics, remain uncertain. A prospective longitudinal follow-up study is needed to clarify these issues.
5. Conclusions The present study revealed that the characteristics of users of multiple kinds of hypnotics were different from those of users of a single kind of hypnotic in this study sample population, and that both depressive symptoms and later sleep schedule were factors significantly associated with the former group. Conflicts of interest
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Yuichi Inoue has received clinically pertinent fees, lecture fees, and research funding from Hisamitsu Pharmaceutical Co., Inc., Nippon Boehringer Ingelheim Co., Ltd., Philips Respironics GK, Alfresa Pharma Corporation, Takeda Pharmaceutical Company Ltd., MSD K.K., Pacific Medico Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Eisai Co., Ltd., Mitsubishi Tanabe Pharma Corporation, GlaxoSmithKline K.K., Astellas Pharma Inc., Sanofi-Aventis K.K., and Yoshitomiyakuhin Corporation. Akiyoshi Shimura, Yoshikazu Takaesu, Sayaka Aritake, Kunihiro Futenma, and Yoko Komada declare that they have no conflicts of interest.
Acknowledgments The authors are indebted to the medical editors from the Department of International Medical Communications of Tokyo Medical University for editing and reviewing the initial English manuscript.
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[47] Cook C, Heath F, Thompson RL. A meta-analysis of response rates in web-or internet-based surveys. Educational and psychological measurement. 2000;60:821-36. Figure captions
Comment [A5]: Author: Please provide
Figure 1. Sample flow of participants
figure captions for Figs 1 and 2.
Fig. 2. Sleep phase outline of each group
A: significantly later than a B: significantly later than b ** :p<0.001, *:p<0.01 Midpoint of sleep = (sleep offset time - sleep onset time) / 2 Each sleep phase parameter was calculated from the results of the Pittsburgh Sleep Quality Index
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Tables
Comment [A6]: Author: please provide
Table 1. Comparison of descriptive variables of participants with subjective insomnia among non-users, users of a single kind of hypnotic, and users of
tables 1-3.
multiple kinds of hypnotics Users of a Total
Non-users single kind of
Users of multiple kinds of hypnotics
hypnotic (n=1030) Sex
Job
(n=833)
(n=96)
(n=101)
Female
561 (54.5%)
442 (53.1%) 70 (72.9%)1),3)
49 (48.5%)
Male
469 (45.5%)
391 (46.9%) 26 (27.1%)1),3)
52 (51.5%)
Full-time
350 (34.0%)
291 (34.9%) 27 (28.1%)
32 (31.7%)
Not full-time
680 (66.0%)
542 (65.1%) 69 (71.9%)
69 (68.3%)
Duration of
＜1 month
30 (2.9%)
-
20 (20.6%)
10 (9.9%)
prescription
≧1 month, ＜6 months
25 (2.4%)
-
14 (14.6%)
11 (10.9%)
142 (13.8%)
-
62 (64.6%)
80 (79.2%)
≧6 months
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Age
42.2±15.6
41.6±15.5 49.4±15.01),3)
CES-D
20.8±11.2
20.1±10.8
19.9±11.0
27.1±12.61),2)
PCS
46.5±7.1
46.6±6.9
46.7±6.7
45.0±8.8
MCS
41.6±9.0
42.2±8.9
42.1±8.9
36.7±9.31),2)
Total score without C6
8.0±2.9
7.9±2.8
8.4±3.2
8.8±3.31)
0:32(a.m.)±1:54 0:32±1:53
0:12±1:45
0:56±2:06
Sleep onset time
1:14(a.m.)±2:05 1:11±2:02
0:59±1:50
1:51±2:331),2)
Sleep offset time
7:20(a.m.)±2:04 7:14±1:58
7:09±1:48
8:21±2:481),2)
Midpoint of sleep
4:17(a.m.)±1:54 4:13±1:50
4:04±1:44
5:06±2:261),2)
Total sleep time
352.3(min.)±74.2 349.4±70.6 358.1±68.3
370.7±101.7
QOL(SF-8)
PSQI
Sleep schedule Time for going to bed
40.5±14.9
CES-D: The Center for Epidemiologic Studies Depression Scale QOL(SF-8): Short Form-8 for the assessment of Health-Related Quality of Life MCS: Mental Component Summary; PCS: Physical Component Summary PSQI: The Pittsburgh Sleep Quality Index
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Age, CES-D, QOL, PSQI, and Sleep schedule: mean±1SD 1)
p<0.01 vs. non-users. 2)p<0.01 vs. users of a single kind of hypnotic. 3)p<0.01 vs. users of multiple kinds of hypnotics.
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Table 2. Logistic regression analysis of associated factors for users of a single kind of hypnotic among insomniacs Users of
Total
a single kind of hypnotic
n Sex
n
%
Univariate relative risk (99% confidence interval)
469
26 27.1%
Female
561
70 72.9% 2.43 (1.31-4.49) <0.001
＜43 *1
516
28 29.2%
≧43
514
68 70.8% 2.66 (1.46-4.85) <0.001
Full-time
350
27 28.1%
Others
680
69 71.9%
Midpoint of sleep
Normal sleepers*2
832
81 84.4%
(clock time)
Late sleepers*2
198
15 15.6%
Job
(99% confidence interval)
p
Male
Age (years)
Multivariate relative risk
p
2.38 (1.28-4.42)
<0.001
2.61 (1.42-4.78)
<0.001
n.s.
n.s.
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Self-reported
＜360 *1
434
36 37.5%
total sleep time (min)
≧360
596
60 62.5%
PSQI without C6
＜8 *1
446
38 39.6%
(points)
≧8
584
58 60.4%
n.s.
CES-D (points)
＜16 *3
401
33 34.4%
n.s.
≧16
629
63 65.6%
n.s.
*1: divided by median value *2: divided by former study's criteria: 5:30 a.m. *3: divided by cut-off point
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Table 3. Logistic regression analysis of associated factors for users of multiple kinds of hypnotics among insomniacs Users of
Total
multiple kinds of hypnotics
n Sex
%
Univariate relative risk (99% confidence interval)
469
52 51.5%
Female
561
49 48.5%
＜43 *1
516
59 58.4%
≧43
514
42 41.6%
Full-time
350
32 31.7%
Others
680
69 68.3%
Midpoint of sleep
Normal sleepers*2
832
64 63.4%
(clock time)
Late sleepers*2
198
37 36.6% 2.65 (1.72-4.10) <0.001
Job
(95% confidence interval)
p
Male
Age (years)
Multivariate relative risk
p
n.s.
n.s.
n.s.
2.26 (1.45-3.52)
<0.001
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Self-reported
＜360 *1
434
32 31.7%
total sleep time (min)
≧360
596
69 68.3%
PSQI without C6
＜8 *1
446
36 35.6%
(points)
≧8
584
65 64.4% 1.11 (1.01-1.21) 0.005
CES-D (points)
＜16 *3
401
20 19.8%
≧16
629
81 80.2% 2.82 (1.45-5.48) <0.001
n.s.
n.s.
2.41 (1.43-4.05)
<0.001
*1: divided by median value *2: divided by former study's criteria: 5:30 a.m. *3: divided by cut off point
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