Cognitive behavioral treatment for insomnia is equally effective in insomnia patients with objective short and normal sleep duration

Accepted Manuscript Cognitive behavioral treatment for insomnia is equally effective in insomnia patients with objective short and normal sleep duration Tatjana Crönlein, Thomas Wetter, Rainer Rupprecht, Kai Spiegelhalder PII:

S1389-9457(18)30535-5

DOI:

https://doi.org/10.1016/j.sleep.2018.10.038

Reference:

SLEEP 3901

To appear in:

Sleep Medicine

Received Date: 13 August 2018 Revised Date:

8 October 2018

Accepted Date: 17 October 2018

Please cite this article as: Crönlein T, Wetter T, Rupprecht R, Spiegelhalder K, Cognitive behavioral treatment for insomnia is equally effective in insomnia patients with objective short and normal sleep duration, Sleep Medicine, https://doi.org/10.1016/j.sleep.2018.10.038. 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.

Short sleep and CBT-I

ACCEPTED MANUSCRIPT

Cognitive behavioral treatment for insomnia is equally effective in insomnia patients with

2

objective short and normal sleep duration

3

For running head: Short sleep and CBT-I

4

Tatjana Crönlein1, Thomas Wetter1, Rainer Rupprecht1, Kai Spiegelhalder2

RI PT

1

5 1

7 8

2

Department of Psychiatry and Psychotherapy, University of Regensburg, Germany

SC

6

Department of Psychiatry and Psychotherapy, Medical Centre – University of Freiburg, Faculty of Medicine, University of Freiburg, Germany

M AN U

9 10

Corresponding author:

11 12 13 14

Dr. Phil. Tatjana Crönlein Department of Psychiatry and Psychotherapy, University of Regensburg, Universitätsstraße 84, 93053 Regensburg, Germany. Tel.: ++49 941 941 1242; Fax.: ++49 941 941 1240 E-mail: [email protected]

TE D

15 Disclosure Statement

17

This was not an industry supported study. The authors have indicated no conflicts of interest related to

18

the study.

19

Total number of words: 4401, number of references: 30

20 21 22

Authors contributorship: Crönlein – study conceptualization, analysis, interpretation of findings, writing; Wetter – interpretation of results, writing; Rupprecht – interpretation of results, writing; Spiegelhalder – analysis, interpretation of findings, writing.

AC C

23

EP

16

1

Short sleep and CBT-I

ACCEPTED MANUSCRIPT

Abstract

2

It has been suggested that insomnia patients with short sleep duration and insomnia patients with

3

normal sleep duration may respond differently to cognitive behavioral treatment for insomnia (CBT-I).

4

To evaluate this hypothesis, we retrospectively examined a large sample of patients with chronic

5

insomnia regarding their outcome post-treatment and six months after participating in a two-week

6

standardized inpatient CBT-I program. Seventy-two women and 20 men with chronic insomnia

7

received standardized inpatient CBT-I and were examined with three nights of polysomnography (two

8

baseline nights and one post-treatment night directly following the two-week treatment). Follow-up

9

measurements of subjective insomnia symptoms were conducted after six months. The CBT-I

10

outcome was compared between insomnia patients with polysomnographically determined short (< 6

11

h) and normal (≥ 6 h) sleep duration. Concerning subjective outcomes, CBT-I was equally effective in

12

insomnia patients with objective short and normal sleep duration. Secondary analyses of

13

polysomnographic data collected at post-treatment revealed that insomnia patients with short sleep

14

duration showed a better treatment response in comparison to those with normal sleep duration. These

15

results suggest that the distinction in insomnia between objective short and normal sleep duration may

16

be of limited value for treatment decisions regarding CBT-I. However, as the overall picture of the

17

literature on this issue is not conclusive, we conclude that further prospective research is necessary to

18

investigate the clinical validity of phenotyping insomnia patients by objective sleep data.

20

21 22

SC

M AN U

TE D

EP

AC C

19

RI PT

1

Keywords: Insomnia, short sleep duration, cognitive behavioral therapy, inpatient setting, polysomnography.

23

2

Short sleep and CBT-I

ACCEPTED MANUSCRIPT

Introduction

2

The role of short sleep has attracted a significant amount of scientific interest in recent years. In

3

particular, short sleep was found to be related to higher mortality rates (Grandner, Hale, Moore, &

4

Patel, 2010), probably due to an increased risk for cardio-metabolic diseases (Buxton & Marcelli,

5

2010; Gangwisch et al., 2007; Patel & Hu, 2008). In insomnia patients, shortened sleep duration

6

caused by problems of falling and/or maintaining sleep, accompanied by daytime impairments, is the

7

main complaint according to the ICSD-3. It is noteworthy that subjective reports of sleep duration do

8

not agree with polysomnographically determined sleep in these patients (Carskadon et al., 1976;

9

Harvey & Tang, 2012). In particular, insomnia is associated with short objective sleep duration in

10

some patients (Frankel, Coursey, Buchbinder, & Snyder, 1976) and normal objective sleep duration in

11

others (Vgontzas, Bixler, Kales, Manfredi, & Tyson, 1994). Insomnia was seen as a “subjective”

12

problem for a long time, and polysomnography was only recommended to exclude other sleep

13

disorders (Edinger et al., 1989; Jacobs, Reynolds, Kupfer, Lovin, & Ehrenpreis, 1988; Littner et al.,

14

2003). However, the role and significance of objective sleep assessments in insomnia remained

15

obscure until recent data on the association of short sleep and several aspects of general health led to a

16

renaissance of research on objective sleep duration in insomnia (Fernandez-Mendoza et al., 2012;

17

Vgontzas et al., 2012). Based on this research, objective short sleep duration has been postulated to be

18

a biological marker for a specific phenotype of insomnia characterized by a long duration of illness

19

and an increased risk for cardio-metabolic diseases (Vgontzas, Fernandez-Mendoza, Liao, & Bixler,

20

2013). The distinction in insomnia patients with and without objective short sleep duration has also

21

been hypothesized to be of direct relevance for treatment: patients with objective short sleep duration

22

may particularly benefit from more biological treatments such as pharmacotherapy, and patients with

23

insomnia with normal sleep duration may particularly benefit from psychotherapeutic treatment

24

(Vgontzas et al., 2013).

AC C

EP

TE D

M AN U

SC

RI PT

1

3

Short sleep and CBT-I

ACCEPTED MANUSCRIPT

To our knowledge, only three studies have investigated the effect of objective sleep duration on

2

treatment outcomes in patients with insomnia, and there is conflicting evidence on this hypothesis.

3

Based on one night of polysomnography, individuals with short and normal sleep duration did not

4

differ with respect to the CBT-I outcome in one study (Lovato, Lack, & Kennaway, 2016). However,

5

Bathgate et al. (2016) as well as Miller et al. (2018) reported a blunted response to the CBT-I in those

6

insomnia patients with short sleep duration (Bathgate, Edinger, & Krystal, 2016), in line with the

7

hypothesis of Vgontzas et al. (Vgontzas et al., 2013).

SC

RI PT

1

In light of the limited and conflicting evidence on the role of objective short sleep duration for the

9

CBT-I response, we investigated a large group of patients with a severe and chronic form of insomnia

10

who participated in our inpatient CBT-I program concerning this research question. If short sleep turns

11

out to be a biomarker for treatment response in patients with insomnia, this would have a major impact

12

on the diagnostic procedure and treatment of insomnia, in particular with respect to the status of

13

polysomnography.

TE D

M AN U

8

14

Methods

EP

15

AC C

16

17

Participants

18

The current study included all patients with chronic insomnia according to DSM-5 who had

19

participated in the standardized inpatient CBT-I program of the Department of Psychiatry and

20

Psychotherapy of the University of Regensburg and who did not meet the exclusion criteria of this

21

study. All subjects gave their formal written consent for participating in the study, which has been

22

approved by the Ethical Committee of the University of Regensburg. Exclusion criteria were: sleep 4

Short sleep and CBT-I

ACCEPTED MANUSCRIPT

apnea syndrome, untreated restless leg syndrome and/ or periodic limb movement disorder, untreated

2

depression or any other unstable and untreated medical disease that leads to insomnia symptoms,

3

inability to participate in a group therapy setting (for example because of language problems), or age

4

younger than 20 years. Note that patients with stable and treated affective, anxiety or pain disorders

5

were not excluded. Hypnotic medication at baseline was another exclusion criterion because patients

6

with hypnotic medication were encouraged to discontinue their medication during the in-patient

7

treatment program and this would have been a major confounder of pre- to post-treatment changes in

8

outcome parameters. Exclusion criteria were checked in a clinical interview conducted by a

9

psychotherapist.

M AN U

SC

RI PT

1

Overall, 242 patients were included in the inpatient CBT-I program between 2009 and 2015. Of

11

these, patients were excluded because they had a comorbid sleep apnea syndrome treated with CPAP

12

(N = 15), quit the program (N = 3) or had severe psychiatric disorders (N = 13). Also, 18 patients had

13

a considerable amount of missing polysomnographic data, leading to the exclusion of these datasets.

14

101 additional patients were excluded for taking hypnotic medication at baseline (benzodiazepine

15

receptor agonists [N = 51], benzodiazepines [N = 10], antidepressants [N = 31] or others [N = 9]).

16

Thus, 92 patients were included in the current analysis. Among this group, five patients had mild

17

depression and four patients had a chronic pain disorder; all of these patients were on stable

18

medication. Neither the onset of the disorders nor the onset of the medication was temporally related

19

to the onset of insomnia in these patients.

EP

AC C

20

TE D

10

21

Treatment program

22

At the Department of Psychiatry and Psychotherapy, an inpatient CBT-I program has been

23

developed for insomnia patients (Cronlein, Langguth, Geisler, Wetter, & Eichhammer, 2014). The 5

Short sleep and CBT-I

ACCEPTED MANUSCRIPT

program was designed for chronic types of insomnia defined by a duration of at least one year and a

2

lack of response to at least one form of evidence-based insomnia treatment. It includes the core

3

components of CBT-I (Belanger, Savard, & Morin, 2006; Riemann, 2017) namely a fixed bedtime

4

schedule, stimulus control, relaxation therapy, psychoeducation, and cognitive therapy. In all patients,

5

the program lasted for two weeks, and groups of 6 to 8 patients were admitted and dismissed together

6

on the same day. Three nights of polysomnography were performed, two at the beginning of the

7

program and one at the end. After baseline polysomnography, patients were encouraged to give up

8

hypnotic drugs to experience the program without a pharmacological sleep aid. Patients then had to

9

adhere to fixed bedtimes of six hours per night and daytime naps were not allowed. This schedule is a

10

variation of the original bedtime restriction introduced by Spielman (Spielman, Saskin, & Thorpy,

11

1987), which has been used to re-time patients at a fixed wake-up time (in this case 6 a.m.) to re-

12

establish regular sleep schedules (Borbely & Achermann, 1999). In line with stimulus control

13

instructions, patients were taught to get out of bed when they were unable to sleep. From early

14

morning until late evening, wakefulness was ensured by an obligatory program including sports,

15

playing games and daily group and/or individual psychotherapy sessions.

TE D

M AN U

SC

RI PT

1

EP

16

Polysomnography

18

Full cardio-respiratory polysomnographic recordings, including an EMG of the anterior tibialis

19

muscle bilaterally, were performed and scored by sleep specialists and assistants according to the

20

manual of the American Academy of Sleep Medicine (Iber, Ancoli-Israel, Chesson, & Quan, 2007). In

21

the two baseline nights, participants were free to choose their bedtimes, whereas in the third

22

polysomnography at the end of the inpatient treatment program patients had to maintain their six-hour

23

schedule. The following sleep parameters were analyzed: sleep onset latency (SOL), total sleep time

24

(TST), wake time after sleep onset (WASO), sleep efficiency (SE), defined as the ratio of total sleep

AC C

17

6

Short sleep and CBT-I

ACCEPTED MANUSCRIPT

1

time to time in bed, and the relative amounts of non-rapid eye movement (NREM) stage 1, NREM 2,

2

NREM 3 and REM sleep in % of sleep period time (SPT).

RI PT

3 4

Subjective sleep measures

5

In the current study, the Regensburg Insomnia Scale (RIS) (Cronlein et al., 2013) and the

Pittsburgh Sleep Quality Index (PSQI) (Buysse, Reynolds, Monk, Berman, & Kupfer, 1989) were used

7

at pre-treatment and at follow-up 6 months after the end of the inpatient treatment. The RIS was

8

developed for getting a detailed account of psychological and medical aspects of insomnia. It contains

9

ten Likert-type items (0 = never, 1 = seldom, 2 = sometimes, 3 = often, 4 = always) related to sleep

M AN U

SC

6

10

continuity, duration, and quality, sleep-related worries, hypnotics intake and daytime impairment. The

11

total score ranges from 0 to 40, a cut-off of 12 points has been shown to be clinically reliable.

12

The PSQI is a widely used instrument for measuring subjective sleep quality. It contains seven components based on 19 items measuring sleep quality, sleep onset latency, sleep duration, sleep

14

efficiency, sleep disorders, hypnotic intake, and daytime fatigue.

TE D

13

15 Statistical analysis

17

The sample was divided into two groups using a 6-hour cut-off for polysomnographically

18

determined sleep duration (TST < 6 hours: insomnia with objective short sleep duration; TST ≥ 6

19

hours: insomnia with objective normal sleep duration). As two baseline nights of polysomnography

20

were used for this procedure, only individuals with objective short sleep duration on both nights were

21

assigned to the short sleep duration group, and all other individuals were assigned to the normal sleep

22

duration group. The difference in the proportion of short sleepers in the first and second night was

23

analyzed using a chi-square test. Between-group (short and normal sleepers) differences in age, gender

AC C

EP

16

7

Short sleep and CBT-I

ACCEPTED MANUSCRIPT

1

distribution, number of patients with comorbid psychiatric disorders, and BMI were analyzed using t-

2

tests, chi-square tests or non-parametric tests. Variables that were different between groups were used

3

as covariates in further analyses. In the main analyses, insomnia patients with objective short and normal sleep duration in both

5

nights were compared regarding treatment response. For these analyses, pre-treatment to 6-month

6

follow-up difference scores were calculated for RIS and PSQI scores. Also, difference scores between

7

the mean of the two baseline nights and the post-treatment night were calculated for the following

8

polysomnographic parameters: TST, SOL, WASO, N3 %, and REM %. Between-group comparisons

9

were conducted for these difference scores using an unpaired T-test. The primary analyses were those

10

of the subjective sleep variables after six months (RIS and PSQI scores); polysomnographically

11

determined sleep parameters were investigated in exploratory secondary analyses. To reduce the

12

likelihood of false positive results, we set the alpha level at a conservative p < .01 for all analyses.

M AN U

SC

RI PT

4

15 16

Results

EP

14

TE D

13

Night-to-night variability of group status

18

On the first night, 62 patients had a total sleep time of fewer than six hours, and 46 patients slept

19

less than 6 hours on the second night. Of these, 39 patients had short sleep duration in both nights.

20

Group assignments differed significantly between nights 1 and 2 (Chi² = 14.218; p < .0005).

AC C

17

21 22

Clinical differences between patients with objective short and normal sleep duration

23

Table 1 shows clinical data of the sample illustrating high insomnia severity in the study 8

Short sleep and CBT-I

ACCEPTED MANUSCRIPT

participants. Insomnia patients with short sleep duration did not differ significantly from insomnia

2

patients with normal sleep duration regarding age, BMI, number of comorbid psychiatric conditions,

3

or scores in RIS or PSQI.

4

RI PT

1

Treatment outcome - insomnia symptoms

6

62 patients returned the RIS and PSQI after six months. Mean RIS score after six months was 11.1

7

(SD 3.7) in 29 short sleepers and 9.7 (SD: 4.1) in 33 normal sleepers. The mean PSQI score was 8.4

8

(SD 3.0) in 29 short sleepers and 7.3 (SD: 2.8) in 33 normal sleepers. No significant group differences

9

were seen between patients with objective short sleep duration and patients with objective normal

10

sleep duration regarding the pre-treatment to 6-month follow-up difference scores in the RIS sum

11

score and any of the 10 items (overall RIS difference scores: patients with objective short sleep

12

duration: 13.7 ± 4.5 vs. patients with objective normal sleep duration: 14.7 ± 4.5; T= -.857; p = .395).

13

Also, no significant group differences were found between the two subgroups with respect to the pre-

14

treatment to 6-month follow-up improvement in the PSQI scores (N=92; PSQI difference scores:

15

patients with objective short sleep duration: 6.5 ± 3.0 vs. patients with objective normal sleep duration:

16

6.9 ± 2.4; T = -.463; p = .645).

EP

TE D

M AN U

SC

5

17

Treatment outcome – polysomnographic parameters

19

Polysomnographic parameters of the two groups are presented in Table 2 (N = 92 for all

20

AC C

18

variables).

21 22

Table 3 shows the results of unpaired T-Tests comparing insomnia patients with objective short

23

and normal sleep duration in terms of PSG pre- to post-treatment changes. The two groups differed 9

Short sleep and CBT-I

ACCEPTED MANUSCRIPT

regarding their improvement in objective sleep parameters after CBT-I. Patients with objective short

2

sleep duration showed a larger improvement in WASO, while only insomnia patients with objective

3

normal sleep duration had a pronounced reduction in TST from pre- to post-treatment.

4

RI PT

1

Discussion

6

In contrast to the hypothesis that insomnia patients with objective short sleep duration benefit less

7

from CBT-I than insomnia patients with objective normal sleep duration (Vgontzas & Fernandez-

8

Mendoza, 2013), our results indicate no group differences in the primary outcomes. Concerning the

9

secondary analyses of polysomnographically determined sleep parameters, patients with objective

M AN U

10

SC

5

short sleep duration showed a larger pre- to posttreatment improvement after CBT-I.

11

No group differences in CBT-I effects on subjective estimates of sleep

13

Our finding that patients with objective short sleep duration did not differ from those with

14

objective normal sleep duration regarding their improvement in subjective estimates of sleep weakens

15

the hypothesis of objective sleep duration being a biomarker for a psychotherapy outcome. In

16

comparison with previous studies on this issue (Bathgate et al., 2016; Lovato et al., 2016), it should be

17

noted that the current investigation had a fairly large sample size and was the only one that used

18

polysomnography, the gold standard for determining objective sleep parameters, that included a group

19

of comparably severe cases of insomnia and that investigated an intense inpatient CBT-I program. It

20

may be speculated that these differences in sample composition, methods and treatment modalities

21

may explain the inconclusive evidence of the four studies. However, in light of the above-mentioned

22

methodological strengths of the current study, it is not obvious why this study did not show the

23

expected group difference in subjective outcomes.

AC C

EP

TE D

12

10

Short sleep and CBT-I

ACCEPTED MANUSCRIPT

What are potential reasons for this negative finding? First and foremost, the current study used a

2

relatively short treatment time (two weeks), which may have resulted in comparably small overall

3

treatment effects. This may have reduced the statistical power to detect between-group differences in

4

treatment responses. Second, the current study was based on clinical data. Thus, we did not use the

5

rigorous inclusion and exclusion criteria of a randomized controlled trial. However, this fact increases

6

the ecological validity of the observations and questions the clinical importance of the hypothesis that

7

insomnia patients with objective short sleep duration show a blunted treatment response. Third, the

8

current study presented RIS and PSQI data and did not include the Insomnia Severity Index (Bastien,

9

Vallieres, & Morin, 2001), which has become the most commonly used outcome measure for CBT-I

10

trials (see clinicaltrials.gov). However, both the PSQI and the RIS are valid instruments for assessing

11

CBT-I treatment responses and moreover, there is a large overlap regarding items of ISI and RIS. Last,

12

it should be noted that the PSQI results of the current study might have been interpreted by others as a

13

statistical trend in the expected direction. In light of this, it seems to be reasonable to warrant further

14

research in this clinically important area.

16

SC

M AN U

TE D

15

RI PT

1

Group differences in pre- to posttreatment PSG data In our exploratory analyses, we found that patients with objective short sleep duration had a more

18

pronounced pre- to posttreatment reduction of polysomnographically determined wake time after sleep

19

onset and patients with objective normal sleep duration had a marked reduction of PSG total sleep

20

time after the CBT-I. Both findings appear to primarily reflect baseline differences in these variables

21

and the corresponding potential for changes, and may also be interpreted as a regression to the mean.

22

However, it should also be noted that the WASO finding is at odds with the Vgontzas hypothesis

23

(Vgontzas & Fernandez-Mendoza, 2013). Polysomnographically, the CBT-I is more effective in

24

reducing sleep-maintenance problems in those with objective short sleep duration than in those with

25

objective normal sleep duration. Concerning the finding on polysomnographically determined TST, 11

AC C

EP

17

Short sleep and CBT-I

ACCEPTED MANUSCRIPT

the overall sample of insomnia patients in the current study showed a decrease from pre- to post-

2

treatment (Cronlein et al., 2014). This is not an uncommon finding in CBT-I studies using objective

3

markers of sleep, probably caused by the reduction of bedtimes and may be related to potential side

4

effects of this treatment (Kyle et al., 2014). It is interesting to note, however, that we observed this

5

effect only in those patients with objective normal sleep duration, which warrants further research on

6

the side effects of the CBT-I in different subgroups of insomnia.

SC

7

RI PT

1

Night-to-night variability of group status

9

Recall that in this study there was a high night-to-night variability in the assignment of individuals

10

to the short and normal sleep duration groups. This is in line with previous studies on the night-to-

11

night variability of sleep parameters in insomnia (Bei, Wiley, Trinder, & Manber, 2016; Gaines et al.,

12

2015) and is of particular relevance, given that a large proportion of the literature on objective short

13

sleep duration in insomnia is based on studies that used only one night of polysomnography (Vgontzas

14

et al., 2013). In the current study, using group assignments based on the first night only did not reveal

15

significant group differences between insomnia patients with objective short and normal sleep duration

16

in terms of the CBT-I treatment response (data not shown).

17

EP

TE D

M AN U

8

Limitations

19

Two limitations of the current study need to be addressed. First, as mentioned above, our study is

20

a retrospective investigation of clinical data. Thus, conclusions about the significance of the findings

21

need to be drawn cautiously. Second, subjective and objective outcome parameters were assessed at

22

different points in time (post-treatment vs. 6-month follow-up). Because of this, the results of the

23

analysis of insomnia symptoms cannot be directly compared with the results on polysomnographic

24

variables.

AC C

18

12

Short sleep and CBT-I

ACCEPTED MANUSCRIPT

1 Conclusion

3

In contrast to the popular hypothesis that CBT-I treatment responses depend on objective sleep

4

duration, we did not observe this effect in a large number of well-characterized patients with severe

5

insomnia. As the overall picture of the literature on this issue is not conclusive, we conclude that

6

further research is necessary to investigate the clinical validity of phenotyping insomnia patients by

7

objective sleep data.

SC

RI PT

2

8

EP

TE D

Bastien, C. H., Vallieres, A., & Morin, C. M. (2001). Validation of the Insomnia Severity Index as an outcome measure for insomnia research. Sleep Med, 2(4), 297-307. Bathgate, C. J., Edinger, J. D., & Krystal, A. D. (2016). Insomnia Patients with Objective Short Sleep Duration have a Blunted Response to Cognitive Behavioral Therapy for Insomnia. Sleep. Bei, B., Wiley, J. F., Trinder, J., & Manber, R. (2016). Beyond the mean: A systematic review on the correlates of daily intraindividual variability of sleep/wake patterns. Sleep Med Rev, 28, 108124. doi:10.1016/j.smrv.2015.06.003 Belanger, L., Savard, J., & Morin, C. M. (2006). Clinical management of insomnia using cognitive therapy. Behav. Sleep Med, 4(3), 179-198. Borbely, A. A., & Achermann, P. (1999). Sleep homeostasis and models of sleep regulation. J Biol. Rhythms, 14(6), 557-568. Buxton, O. M., & Marcelli, E. (2010). Short and long sleep are positively associated with obesity, diabetes, hypertension, and cardiovascular disease among adults in the United States. Soc. Sci. Med, 71(5), 1027-1036. Buysse, D. J., Reynolds, C. F., III, Monk, T. H., Berman, S. R., & Kupfer, D. J. (1989). The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res, 28(2), 193-213. Carskadon, M. A., Dement, W. C., Mitler, M. M., Guilleminault, C., Zarcone, V. P., & Spiegel, R. (1976). Self-reports versus sleep laboratory findings in 122 drug-free subjects with complaints of chronic insomnia. Am. J Psychiatry, 133(12), 1382-1388. Cronlein, T., Langguth, B., Geisler, P., Wetter, T. C., & Eichhammer, P. (2014). Fourteen-day inpatient cognitive-behavioral therapy for insomnia: a logical and useful extension of the stepped-care approach for the treatment of insomnia. Psychother. Psychosom, 83(4), 255-256. doi:000360706 [pii];10.1159/000360706 [doi] Cronlein, T., Langguth, B., Popp, R., Lukesch, H., Pieh, C., Hajak, G., & Geisler, P. (2013). Regensburg Insomnia Scale (RIS): a new short rating scale for the assessment of psychological symptoms and sleep in insomnia; Study design: development and validation of a new short self-rating scale in a sample of 218 patients suffering from insomnia and 94 healthy controls. Health Qual. Life Outcomes, 11, 65.

AC C

10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38

M AN U

9

13

Short sleep and CBT-I

ACCEPTED MANUSCRIPT

EP

TE D

M AN U

SC

RI PT

Edinger, J. D., Hoelscher, T. J., Webb, M. D., Marsh, G. R., Radtke, R. A., & Erwin, C. W. (1989). Polysomnographic assessment of DIMS: empirical evaluation of its diagnostic value. Sleep, 12(4), 315-322. Fernandez-Mendoza, J., Vgontzas, A. N., Liao, D., Shaffer, M. L., Vela-Bueno, A., Basta, M., & Bixler, E. O. (2012). Insomnia with objective short sleep duration and incident hypertension: the Penn State Cohort. Hypertension, 60(4), 929-935. doi:HYPERTENSIONAHA.112.193268 [pii];10.1161/HYPERTENSIONAHA.112.193268 [doi] Frankel, B. L., Coursey, R. D., Buchbinder, R., & Snyder, F. (1976). Recorded and reported sleep in chronic primary insomnia. Arch. Gen. Psychiatry, 33(5), 615-623. Gaines, J., Vgontzas, A. N., Fernandez-Mendoza, J., Basta, M., Pejovic, S., He, F., & Bixler, E. O. (2015). Short- and Long-Term Sleep Stability in Insomniacs and Healthy Controls. Sleep, 38(11), 1727-1734. doi:sp-00765-14 [pii];10.5665/sleep.5152 [doi] Gangwisch, J. E., Heymsfield, S. B., Boden-Albala, B., Buijs, R. M., Kreier, F., Pickering, T. G., . . . Malaspina, D. (2007). Sleep duration as a risk factor for diabetes incidence in a large U.S. sample. Sleep, 30(12), 1667-1673. Grandner, M. A., Hale, L., Moore, M., & Patel, N. P. (2010). Mortality associated with short sleep duration: The evidence, the possible mechanisms, and the future. Sleep Med Rev, 14(3), 191203. Harvey, A. G., & Tang, N. K. (2012). (Mis)perception of sleep in insomnia: a puzzle and a resolution. Psychol. Bull, 138(1), 77-101. doi:2011-22582-001 [pii];10.1037/a0025730 [doi] Iber, C., Ancoli-Israel, S., Chesson, A., & Quan, S. F. (2007). The AASM Manual for the Scoring of Sleep and Associated Events: Rules, Terminology and Technical Specifications. Westchester III: American Academy of Sleep Medicine. Jacobs, E. A., Reynolds, C. F., III, Kupfer, D. J., Lovin, P. A., & Ehrenpreis, A. B. (1988). The role of polysomnography in the differential diagnosis of chronic insomnia. Am. J. Psychiatry, 145(3), 346-349. Kyle, S. D., Miller, C. B., Rogers, Z., Siriwardena, A. N., MacMahon, K. M., & Espie, C. A. (2014). Sleep restriction therapy for insomnia is associated with reduced objective total sleep time, increased daytime somnolence, and objectively impaired vigilance: implications for the clinical management of insomnia disorder. Sleep, 37(2), 229-237. doi:10.5665/sleep.3386 [doi] Littner, M., Hirshkowitz, M., Kramer, M., Kapen, S., Anderson, W. M., Bailey, D., . . . Woodson, B. T. (2003). Practice parameters for using polysomnography to evaluate insomnia: an update. Sleep, 26(6), 754-760. Lovato, N., Lack, L., & Kennaway, D. J. (2016). Comparing and contrasting therapeutic effects of cognitive-behavior therapy for older adults suffering from insomnia with short and long objective sleep duration. Sleep Med, 22, 4-12. doi:10.1016/j.sleep.2016.04.001 Miller, C. B., Espie, C. A., Bartlett, D. J., Marshall, N. S., Gordon, C. J., & Grunstein, R. R. (2018). Acceptability, tolerability, and potential efficacy of cognitive behavioural therapy for Insomnia Disorder subtypes defined by polysomnography: A retrospective cohort study. Sci Rep, 8(1), 6664. doi:10.1038/s41598-018-25033-3 Patel, S. R., & Hu, F. B. (2008). Short sleep duration and weight gain: a systematic review. Obesity (Silver Spring), 16(3), 643-653. doi:10.1038/oby.2007.118 Riemann, D. B., E.; Cohrs, S. Crönlein, T.; Hajak, G., Hertenstein, E., et al. (2017). S3 - Leitlinie Nichterholsamer Schlaf/Schlafstörungen. Somnologie, 21(1). doi:DOI 10.1007/s11818-0160097-x Spielman, A. J., Saskin, P., & Thorpy, M. J. (1987). Treatment of chronic insomnia by restriction of time in bed. Sleep, 10(1), 45-56.

AC C

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48

14

Short sleep and CBT-I

ACCEPTED MANUSCRIPT

Vgontzas, A. N., Bixler, E. O., Kales, A., Manfredi, R. L., & Tyson, K. (1994). Validity and clinical utility of sleep laboratory criteria for insomnia. Int. J. Neurosci, 77(1-2), 11-21. Vgontzas, A. N., & Fernandez-Mendoza, J. (2013). Insomnia with Short Sleep Duration: Nosological, Diagnostic, and Treatment Implications. Sleep Med. Clin, 8(3), 309-322. doi:10.1016/j.jsmc.2013.04.009 [doi] Vgontzas, A. N., Fernandez-Mendoza, J., Bixler, E. O., Singareddy, R., Shaffer, M. L., Calhoun, S. L., . . . Chrousos, G. P. (2012). Persistent insomnia: the role of objective short sleep duration and mental health. Sleep, 35(1), 61-68. doi:10.5665/sleep.1586 [doi] Vgontzas, A. N., Fernandez-Mendoza, J., Liao, D., & Bixler, E. O. (2013). Insomnia with objective short sleep duration: the most biologically severe phenotype of the disorder. Sleep Med. Rev, 17(4), 241-254. doi:S1087-0792(12)00104-9 [pii];10.1016/j.smrv.2012.09.005 [doi]

RI PT

1 2 3 4 5 6 7 8 9 10 11

SC

12 13

M AN U

14 15 16

20 21 22 23 24

EP

19

AC C

18

TE D

17

25 26 27 15

Short sleep and CBT-I

ACCEPTED MANUSCRIPT

Cognitive behavioral treatment for insomnia is equally effective in insomnia patients with

2

objective short and normal sleep duration

3

For running head: Short sleep and CBT-I

4

Tatjana Crönlein1, Thomas Wetter1, Rainer Rupprecht1, Kai Spiegelhalder2

RI PT

1

5 1

7 8

2

Department of Psychiatry and Psychotherapy, University of Regensburg, Germany

SC

6

Department of Psychiatry and Psychotherapy, Medical Centre – University of Freiburg, Faculty of Medicine, University of Freiburg, Germany

M AN U

9 10

Corresponding author:

11 12 13 14

Dr. Phil. Tatjana Crönlein Department of Psychiatry and Psychotherapy, University of Regensburg, Universitätsstraße 84, 93053 Regensburg, Germany. Tel.: ++49 941 941 1242; Fax.: ++49 941 941 1240 E-mail: [email protected]

TE D

15 Disclosure Statement

17

This was not an industry supported study. The authors have indicated no conflicts of interest related to

18

the study.

19

Total number of words: 4401, number of references: 30

20 21 22

Authors contributorship: Crönlein – study conceptualization, analysis, interpretation of findings, writing; Wetter – interpretation of results, writing; Rupprecht – interpretation of results, writing; Spiegelhalder – analysis, interpretation of findings, writing.

AC C

23

EP

16

16

Short sleep and CBT-I

ACCEPTED MANUSCRIPT

Abstract

2

It has been suggested that insomnia patients with short sleep duration and insomnia patients with

3

normal sleep duration may respond differently to cognitive behavioral treatment for insomnia (CBT-I).

4

To further evaluate this hypothesis, we retrospectively examined a large sample of patients with

5

chronic insomnia regarding their outcome post-treatment and six months after participating in a two-

6

week standardized inpatient CBT-I program. Seventy-two women and 20 men with chronic insomnia

7

received standardized inpatient CBT-I and were examined with three nights of polysomnography (two

8

baseline nights and one post-treatment night directly following the two-week treatment). Follow-up

9

measurements of subjective insomnia symptoms were conducted after six months. The CBT-I

10

outcome was compared between insomnia patients with polysomnographically determined short (< 6

11

h) and normal (≥ 6 h) sleep duration. Concerning subjective outcomes, CBT-I was equally effective in

12

insomnia patients with objective short and normal sleep duration. Secondary analyses of

13

polysomnographic data collected at post-treatment revealed that insomnia patients with short sleep

14

duration showed a better treatment response in comparison to those with normal sleep duration. These

15

results suggest that the distinction in insomnia with objective short and normal sleep duration may be

16

of limited value for treatment decisions regarding CBT-I. However, as the overall picture of the

17

literature on this issue is not conclusive, we conclude that further prospective research is necessary to

18

investigate the clinical validity of phenotyping insomnia patients on the basis of objective sleep data.

20

21 22

SC

M AN U

TE D

EP

AC C

19

RI PT

1

Keywords: Insomnia, short sleep duration, cognitive behavioral therapy, inpatient setting, polysomnography.

23

17

Short sleep and CBT-I

ACCEPTED MANUSCRIPT

Introduction

2

The role of short sleep has gained a significant amount of scientific interest in recent years. In

3

particular, short sleep was found to be related to higher mortality rates (Grandner, Hale, Moore, &

4

Patel, 2010), probably due to an increased risk for cardio-metabolic diseases (Buxton & Marcelli,

5

2010; Gangwisch et al., 2007; Patel & Hu, 2008). In insomnia patients shortened sleep duration caused

6

by problems falling and/or maintaining sleep accompanied by daytime impairments is the main

7

complaint according to the ICSD-3. It is noteworthy that subjective reports of sleep duration do not

8

agree with polysomnographically determined sleep in these patients (Carskadon et al., 1976; Harvey &

9

Tang, 2012). In particular, insomnia is associated with short objective sleep duration in some patients

10

(Frankel, Coursey, Buchbinder, & Snyder, 1976) and normal objective sleep duration in others

11

(Vgontzas, Bixler, Kales, Manfredi, & Tyson, 1994). Insomnia was seen as a “subjective” problem for

12

a long time, and polysomnography was only recommended to exclude other sleep disorders (Edinger

13

et al., 1989; Jacobs, Reynolds, Kupfer, Lovin, & Ehrenpreis, 1988; Littner et al., 2003). However, the

14

role and significance of objective sleep assessments in insomnia remained obscure until recent data on

15

the association of short sleep and several aspects of general health led to a renaissance of research on

16

objective sleep duration in insomnia (Fernandez-Mendoza et al., 2012; Vgontzas et al., 2012). Based

17

on this research, objective short sleep duration has been postulated to be a biological marker for a

18

specific phenotype of insomnia characterized by a long duration of illness and an increased risk for

19

cardio-metabolic diseases (Vgontzas, Fernandez-Mendoza, Liao, & Bixler, 2013). The distinction in

20

insomnia patients with and without objective short sleep duration has also been hypothesized to be of

21

direct relevance for treatment: patients with objective short sleep duration may particularly benefit

22

from more biological treatments such as pharmacotherapy, and patients with insomnia with normal

23

sleep duration may particularly benefit from psychotherapeutic treatment (Vgontzas et al., 2013).

AC C

EP

TE D

M AN U

SC

RI PT

1

18

Short sleep and CBT-I

ACCEPTED MANUSCRIPT

To our knowledge, only three studies have investigated the effect of objective sleep duration on

2

treatment outcomes in patients with insomnia, and there is conflicting evidence on this hypothesis.

3

Based on one night of polysomnography, individuals with short and normal sleep duration did not

4

differ with respect to the CBT-I outcome in one study (Lovato, Lack, & Kennaway, 2016). However,

5

Bathgate et al. (2016) as well as Miller et al. (2018) reported a blunted response to the CBT-I in those

6

insomnia patients with short sleep duration (Bathgate, Edinger, & Krystal, 2016; Miller et al., 2018),

7

in line with the hypothesis of Vgontzas et al. (Vgontzas et al., 2013).

SC

RI PT

1

In light of the limited and conflicting evidence on the role of objective short sleep duration for the

9

CBT-I response, we investigated a large group of patients with a severe and chronic form of insomnia

10

who participated in our inpatient CBT-I program concerning this research question. If short sleep turns

11

out to be a biomarker for treatment response in patients with insomnia, this would have a severe

12

impact on the diagnostic procedure and treatment of insomnia, in particular with respect to the status

13

of polysomnography.

TE D

M AN U

8

14

Methods

EP

15

AC C

16

17

Participants

18

The current study included all patients with chronic insomnia according to DSM-5 that

19

participated in the standardized inpatient CBT-I program of the Department of Psychiatry and

20

Psychotherapy of the University of Regensburg and that did not meet exclusion criteria of this study.

21

All subjects gave their formal written consent for participating in the study, which has been approved

22

by the Ethical Committee of the University of Regensburg. Exclusion criteria were: sleep apnea 19

Short sleep and CBT-I

ACCEPTED MANUSCRIPT

syndrome, untreated restless leg syndrome and/ or periodic limb movement disorder, untreated

2

depression or any other unstable and untreated medical disease that leads to insomnia symptoms,

3

inability to participate in a group therapy setting (for example because of language problems), or age

4

younger than 20 years. Of note, patients with stable and treated affective, anxiety or pain disorders

5

were not excluded. Hypnotic medication at baseline was another exclusion criterion because patients

6

with hypnotic medication were encouraged to discontinue their medication during the in-patient

7

treatment program and this would be a major confounder of pre- to post-treatment changes in outcome

8

parameters. Exclusion criteria were checked in a clinical interview conducted by a psychotherapist.

SC

RI PT

1

Overall, 242 patients were included in the inpatient CBT-I program between 2009 and 2015. Of

10

these, patients were excluded because they had a comorbid sleep apnea syndrome treated with CPAP

11

(N = 15), quit the program (N = 3) or had severe psychiatric disorders (N = 13). Also, 18 patients had

12

a considerable amount of missing data in polysomnographic data also leading to the exclusion of these

13

datasets. 101 further patients were excluded because of taking hypnotic medication at baseline

14

(benzodiazepine receptor agonists [N = 51], benzodiazepines [N = 10], antidepressants [N = 31] or

15

others [N = 9]). Thus, 92 patients were included in the current analysis. Among this group, five

16

patients had mild depression, and four patients had a chronic pain disorder, and all of these patients

17

were on stable medication. Neither the onset of the disorders nor the onset of the medication was

18

temporally related to the onset of insomnia in these patients.

TE D

EP

AC C

19

M AN U

9

20

Treatment program

21

At the Department of Psychiatry and Psychotherapy, an inpatient CBT-I program has been

22

developed for insomnia patients (Cronlein, Langguth, Geisler, Wetter, & Eichhammer, 2014). The

23

program was designed for chronic types of insomnia defined by duration of at least one year and a lack 20

Short sleep and CBT-I

ACCEPTED MANUSCRIPT

of response to at least one form of evidence-based insomnia treatment. It includes the core components

2

of CBT-I (Belanger, Savard, & Morin, 2006; Riemann, 2017) namely a fixed bedtime schedule,

3

stimulus control, relaxation therapy, psychoeducation, and cognitive therapy. In all patients, the

4

program lasted for two weeks, and groups of 6 to 8 patients were admitted and dismissed together on

5

the same day. Three nights of polysomnography were performed, two at the beginning of the program

6

and one at the end. After baseline polysomnography, patients were encouraged to give up hypnotic

7

drugs to experience the program without a pharmacological sleep aid. Patients then had to adhere to

8

fixed bedtimes of six hours per night, and daytime naps were not allowed. This schedule is a variation

9

of the original bedtime restriction introduced by Spielman (Spielman, Saskin, & Thorpy, 1987), which

10

has been used to retime patients at a fixed wake-up time (in this case 6 a.m.) in order to re-establish

11

regular sleep pressure (Borbely & Achermann, 1999). In line with stimulus control instructions,

12

patients were taught to get out of bed when they were unable to sleep. From early morning until late

13

evening, wakefulness was ensured by an obligatory program including sports, playing games and daily

14

group and/or individual psychotherapy sessions.

15

TE D

M AN U

SC

RI PT

1

Polysomnography

17

Full cardio-respiratory polysomnographic recordings, including an EMG of the anterior tibialis

18

muscle bilaterally, were performed and scored by sleep specialists and assistants according to the

19

manual of the American Academy of Sleep Medicine (Iber, Ancoli-Israel, Chesson, & Quan, 2007). In

20

the two baseline nights, participants were free to choose their bedtimes, whereas in the third

21

polysomnography at the end of the inpatient treatment program patients had to keep their six-hour

22

schedule. The following sleep parameters were analyzed: sleep onset latency (SOL), total sleep time

23

(TST), wake time after sleep onset (WASO), sleep efficiency (SE), defined as the ratio of total sleep

AC C

EP

16

21

Short sleep and CBT-I

ACCEPTED MANUSCRIPT

1

time to time in bed, and the relative amounts of non-rapid eye movement (NREM) stage 1, NREM 2,

2

NREM 3 and REM sleep in % of sleep period time (SPT).

RI PT

3 4

Subjective sleep measures

5

In the current study, the Regensburg Insomnia Scale (RIS) (Cronlein et al., 2013) and the

Pittsburgh Sleep Quality Index (PSQI) (Buysse, Reynolds, Monk, Berman, & Kupfer, 1989) were used

7

at pre-treatment as well as at follow-up 6 months after the end of the inpatient treatment. The RIS was

8

developed for getting a detailed account of psychological and medical aspects of insomnia. It contains

9

ten Likert-type items (0 = never, 1 = seldom, 2 = sometimes, 3 = often, 4 = always) related to sleep

M AN U

SC

6

10

continuity, duration, and quality, sleep-related worries, hypnotic intake and daytime impairment. The

11

total score ranges from 0 to 40, a cut-off of 12 points has been shown to be clinically reliable.

12

The PSQI is a widely used instrument for measuring subjective sleep quality. It contains seven components based on 19 items measuring sleep quality, sleep onset latency, sleep duration, sleep

14

efficiency, sleep disorders, hypnotic intake, and daytime fatigue.

TE D

13

15 Statistical analysis

17

The sample was divided into two groups using a 6-hour cut-off for polysomnographically

18

determined sleep duration (TST < 6 hours: insomnia with objective short sleep duration; TST ≥ 6

19

hours: insomnia with objective normal sleep duration). As two baseline nights of polysomnography

20

were used for this procedure, only individuals with objective short sleep duration on both nights were

21

assigned to the short sleep duration group, and all other individuals were assigned to the normal sleep

22

duration group. The difference in the proportion of short sleepers in the first and second night was

23

analyzed using a chi-squared test. Between-group (short and normal sleepers) differences in age,

AC C

EP

16

22

Short sleep and CBT-I

ACCEPTED MANUSCRIPT

1

gender distribution, number of patients with comorbid psychiatric disorders, and BMI were analyzed

2

using t-tests, chi-squared tests or non-parametric tests. Variables that were different between groups

3

were used as covariates in further analyses. In the main analyses, insomnia patients with objective short and normal sleep duration in both

5

nights were compared in terms of treatment response. For these analyses, pre-treatment to 6-month

6

follow-up difference scores were calculated for RIS and PSQI scores. Also, difference scores between

7

the mean of the two baseline nights and the post-treatment night were calculated for the following

8

polysomnographic parameters: TST, SOL, WASO, N3 %, and REM %. Between-group comparisons

9

were conducted for these difference scores using unpaired T-test. The primary analyses were those of

10

the subjective sleep variables after six months (RIS and PSQI scores), polysomnographically

11

determined sleep parameters were investigated in exploratory secondary analyses. To reduce the

12

likelihood of false positive results, we set the alpha level at a conservative p < .01 for all analyses.

M AN U

SC

RI PT

4

15 16

Results

EP

14

TE D

13

Night-to-night variability of group status

18

In the first night, 62 patients had a total sleep time of fewer than six hours, and 46 patients slept

19

less than 6 hours in the second night. Of these, 39 patients had short sleep duration in both nights.

20

Group assignments differed significantly between nights 1 and 2 (Chi² = 14.218; p < .0005).

AC C

17

21 22

Clinical differences between patients with objective short and normal sleep duration

23

Table 1 shows clinical data of the sample illustrating high insomnia severity in the study 23

Short sleep and CBT-I

ACCEPTED MANUSCRIPT

participants. Insomnia patients with short sleep duration did not differ significantly from insomnia

2

patients with normal sleep duration regarding age, BMI, number of comorbid psychiatric conditions,

3

or scores in RIS or PSQI.

4

RI PT

1

Treatment outcome - insomnia symptoms

6

62 patients returned the RIS and PSQI after six months. Mean RIS score after six months was

7

11.1 (SD 3.7) in 29 short sleepers and 9.7 (SD: 4.1) in 33 normal sleepers. The mean PSQI score was

8

8.4 (SD 3.0) in 29 short sleepers and 7.3 (SD: 2.8) in 33 normal sleepers. No significant group

9

differences were seen between patients with objective short sleep duration and patients with objective

10

normal sleep duration regarding the pre-treatment to 6-month follow-up difference scores in the RIS

11

sum score and any of the 10 items (overall RIS difference scores: patients with objective short sleep

12

duration: 13.7 ± 4.5 vs. patients with objective normal sleep duration: 14.7 ± 4.5; T= -.857; p = .395).

13

Also, no significant group differences were found between the two subgroups with respect to the pre-

14

treatment to 6-month follow-up improvement in the PSQI scores (N=92; PSQI difference scores:

15

patients with objective short sleep duration: 6.5 ± 3.0 vs. patients with objective normal sleep

16

duration: 6.9 ± 2.4; T = -.463; p = .645).

EP

TE D

M AN U

SC

5

17

Treatment outcome – polysomnographic parameters

19

Polysomnographic parameters of the two groups are presented in Table 2 (N = 92 for all

20

AC C

18

variables).

21 22

Table 3 shows the results of unpaired T-Tests comparing insomnia patients with objective short

23

and normal sleep duration in terms of PSG pre- to post-treatment changes. The two groups differed 24

Short sleep and CBT-I

ACCEPTED MANUSCRIPT

regarding their improvement in objective sleep parameters after CBT-I. Patients with objective short

2

sleep duration showed a larger improvement in WASO, while only insomnia patients with objective

3

normal sleep duration had a pronounced reduction in TST from pre- to post-treatment.

4

RI PT

1

Discussion

6

In contrast to the hypothesis that insomnia patients with objective short sleep duration benefit less

7

from CBT-I than insomnia patients with objective normal sleep duration (Vgontzas & Fernandez-

8

Mendoza, 2013), our results indicate no group differences in the primary outcomes. Concerning the

9

secondary analyses of polysomnographically determined sleep parameters, patients with objective

M AN U

10

SC

5

short sleep duration showed a larger pre- to posttreatment improvement after CBT-I.

11

No group differences in CBT-I effects on subjective estimates of sleep

13

Our finding that patients with objective short sleep duration did not differ from those with

14

objective normal sleep duration regarding their improvement in subjective estimates of sleep weakens

15

the hypothesis of objective sleep duration being a biomarker for a psychotherapy outcome. In

16

comparison with previous studies on this issue (Bathgate et al., 2016; Lovato et al., 2016), it should be

17

noted that the current investigation had a fairly large sample size and was the only one that used

18

polysomnography, the gold standard for determining objective sleep parameters, included a group of

19

comparably severe cases of insomnia and investigated an intense inpatient CBT-I program. It may be

20

speculated that these differences in sample composition, methods and treatment modalities may

21

explain the inconclusive evidence of the four studies. However, in light of the above-mentioned

22

methodological strengths of the current study, it is not obvious why this study did not show the

23

expected group difference in subjective outcomes.

AC C

EP

TE D

12

25

Short sleep and CBT-I

ACCEPTED MANUSCRIPT

What are potential reasons for this negative finding? First and foremost, the current study used a

2

relatively short treatment time (two weeks), which may have resulted in comparably small overall

3

treatment effects. This may have reduced the statistical power to detect between-group differences in

4

treatment responses. Second, the current study was based on clinical data. Thus, we did not use the

5

rigorous inclusion and exclusion criteria of a randomized controlled trial. However, this fact increases

6

the ecological validity of the observations and questions the clinical importance of the hypothesis that

7

insomnia patients with objective short sleep duration show a blunted treatment response. Third, the

8

current study presented RIS and PSQI data and did not include the Insomnia Severity Index (Bastien,

9

Vallieres, & Morin, 2001), which has become the most commonly used outcome measure for CBT-I

10

trials (see clinicaltrials.gov). However, both the PSQI and the RIS are valid instruments for assessing

11

CBT-I treatment responses and moreover, there is a large overlap regarding items of ISI and RIS. Last,

12

it should be noted that the PSQI results of the current study might have been interpreted by others as a

13

statistical trend in the expected direction. In light of this, it seems to be reasonable to warrant further

14

research in this clinically important area.

16

SC

M AN U

TE D

15

RI PT

1

Group differences in pre- to posttreatment PSG data In our exploratory analyses, we found that patients with objective short sleep duration had a more

18

pronounced pre- to posttreatment reduction of polysomnographically determined wake time after sleep

19

onset and patients with objective normal sleep duration had a marked reduction of PSG total sleep

20

time after the CBT-I. Both findings appear to primarily reflect baseline differences in these variables

21

and the corresponding potential for changes, and may also be interpreted as regression to the mean.

22

However, it should also be noted that the WASO finding is at odds with the Vgontzas hypothesis

23

(Vgontzas & Fernandez-Mendoza, 2013). Polysomnographically, the CBT-I is more effective in

24

reducing sleep-maintenance problems in those with objective short sleep duration than in those with

25

objective normal sleep duration. With respect to the finding on polysomnographically determined 26

AC C

EP

17

Short sleep and CBT-I

ACCEPTED MANUSCRIPT

TST, the overall sample of insomnia patients in the current study showed a decrease from pre- to post-

2

treatment (Cronlein et al., 2014). This is not an uncommon finding in CBT-I studies using objective

3

markers of sleep, probably caused by the reduction of bedtimes and may be related to potential side

4

effects of this treatment (Kyle et al., 2014). It is interesting to note, however, that we observed this

5

effect only in those patients with objective normal sleep duration, which warrants further research on

6

the side effects of the CBT-I in different subgroups of insomnia.

SC

7

RI PT

1

Night-to-night variability of group status

9

Importantly, there was a high night-to-night variability in the assignment of individuals to the

10

short and normal sleep duration groups. This is in line with previous studies on the night-to-night

11

variability of sleep parameters in insomnia (Bei, Wiley, Trinder, & Manber, 2016; Gaines et al., 2015)

12

and of particular importance given that a large proportion of the literature on objective short sleep

13

duration in insomnia is based on studies that used only one night of polysomnography (Vgontzas et al.,

14

2013). Of note, in the current study, using group assignments based on the first night only did not

15

reveal significant group differences between insomnia patients with objective short and normal sleep

16

duration with respect to the CBT-I treatment response (data not shown).

17

EP

TE D

M AN U

8

Limitations

19

Two limitations of the current study need to be addressed. First, as mentioned above, our study is

20

a retrospective investigation of clinical data. Thus, conclusions about the significance of the findings

21

need to be drawn cautiously. Second, subjective and objective outcome parameters were assessed at

22

different points in time (post-treatment vs. 6-month follow-up). Because of this, the results of the

23

analysis of insomnia symptoms cannot be directly compared with the results on polysomnographic

24

variables.

AC C

18

27

Short sleep and CBT-I

ACCEPTED MANUSCRIPT

1 Conclusion

3

In contrast to the popular hypothesis that CBT-I treatment responses depend on objective sleep

4

duration, we did not observe this effect in a large number of well-characterized patients with severe

5

insomnia. As the overall picture of the literature on this issue is not conclusive, we conclude that

6

further research is necessary to investigate the clinical validity of phenotyping insomnia patients on

7

the basis of objective sleep data.

SC

RI PT

2

8

References

M AN U

9 10

EP

TE D

Bastien, C. H., Vallieres, A., & Morin, C. M. (2001). Validation of the Insomnia Severity Index as an outcome measure for insomnia research. Sleep Med, 2(4), 297-307. Bathgate, C. J., Edinger, J. D., & Krystal, A. D. (2016). Insomnia Patients with Objective Short Sleep Duration have a Blunted Response to Cognitive Behavioral Therapy for Insomnia. Sleep. Bei, B., Wiley, J. F., Trinder, J., & Manber, R. (2016). Beyond the mean: A systematic review on the correlates of daily intraindividual variability of sleep/wake patterns. Sleep Med Rev, 28, 108124. doi:10.1016/j.smrv.2015.06.003 Belanger, L., Savard, J., & Morin, C. M. (2006). Clinical management of insomnia using cognitive therapy. Behav. Sleep Med, 4(3), 179-198. Borbely, A. A., & Achermann, P. (1999). Sleep homeostasis and models of sleep regulation. J Biol. Rhythms, 14(6), 557-568. Buxton, O. M., & Marcelli, E. (2010). Short and long sleep are positively associated with obesity, diabetes, hypertension, and cardiovascular disease among adults in the United States. Soc. Sci. Med, 71(5), 1027-1036. Buysse, D. J., Reynolds, C. F., III, Monk, T. H., Berman, S. R., & Kupfer, D. J. (1989). The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res, 28(2), 193-213. Carskadon, M. A., Dement, W. C., Mitler, M. M., Guilleminault, C., Zarcone, V. P., & Spiegel, R. (1976). Self-reports versus sleep laboratory findings in 122 drug-free subjects with complaints of chronic insomnia. Am. J Psychiatry, 133(12), 1382-1388. Cronlein, T., Langguth, B., Geisler, P., Wetter, T. C., & Eichhammer, P. (2014). Fourteen-day inpatient cognitive-behavioural therapy for insomnia: a logical and useful extension of the stepped-care approach for the treatment of insomnia. Psychother. Psychosom, 83(4), 255-256. doi:000360706 [pii];10.1159/000360706 [doi] Cronlein, T., Langguth, B., Popp, R., Lukesch, H., Pieh, C., Hajak, G., & Geisler, P. (2013). Regensburg Insomnia Scale (RIS): a new short rating scale for the assessment of psychological symptoms and sleep in insomnia; Study design: development and validation of

AC C

11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37

28

Short sleep and CBT-I

ACCEPTED MANUSCRIPT

EP

TE D

M AN U

SC

RI PT

a new short self-rating scale in a sample of 218 patients suffering from insomnia and 94 healthy controls. Health Qual. Life Outcomes, 11, 65. Edinger, J. D., Hoelscher, T. J., Webb, M. D., Marsh, G. R., Radtke, R. A., & Erwin, C. W. (1989). Polysomnographic assessment of DIMS: empirical evaluation of its diagnostic value. Sleep, 12(4), 315-322. Fernandez-Mendoza, J., Vgontzas, A. N., Liao, D., Shaffer, M. L., Vela-Bueno, A., Basta, M., & Bixler, E. O. (2012). Insomnia with objective short sleep duration and incident hypertension: the Penn State Cohort. Hypertension, 60(4), 929-935. doi:HYPERTENSIONAHA.112.193268 [pii];10.1161/HYPERTENSIONAHA.112.193268 [doi] Frankel, B. L., Coursey, R. D., Buchbinder, R., & Snyder, F. (1976). Recorded and reported sleep in chronic primary insomnia. Arch. Gen. Psychiatry, 33(5), 615-623. Gaines, J., Vgontzas, A. N., Fernandez-Mendoza, J., Basta, M., Pejovic, S., He, F., & Bixler, E. O. (2015). Short- and Long-Term Sleep Stability in Insomniacs and Healthy Controls. Sleep, 38(11), 1727-1734. doi:sp-00765-14 [pii];10.5665/sleep.5152 [doi] Gangwisch, J. E., Heymsfield, S. B., Boden-Albala, B., Buijs, R. M., Kreier, F., Pickering, T. G., . . . Malaspina, D. (2007). Sleep duration as a risk factor for diabetes incidence in a large U.S. sample. Sleep, 30(12), 1667-1673. Grandner, M. A., Hale, L., Moore, M., & Patel, N. P. (2010). Mortality associated with short sleep duration: The evidence, the possible mechanisms, and the future. Sleep Med Rev, 14(3), 191203. Harvey, A. G., & Tang, N. K. (2012). (Mis)perception of sleep in insomnia: a puzzle and a resolution. Psychol. Bull, 138(1), 77-101. doi:2011-22582-001 [pii];10.1037/a0025730 [doi] Iber, C., Ancoli-Israel, S., Chesson, A., & Quan, S. F. (2007). The AASM Manual for the Scoring of Sleep and Associated Events: Rules, Terminology and Technical Specifications. Westchester III: American Academy of Sleep Medicine. Jacobs, E. A., Reynolds, C. F., III, Kupfer, D. J., Lovin, P. A., & Ehrenpreis, A. B. (1988). The role of polysomnography in the differential diagnosis of chronic insomnia. Am. J. Psychiatry, 145(3), 346-349. Kyle, S. D., Miller, C. B., Rogers, Z., Siriwardena, A. N., MacMahon, K. M., & Espie, C. A. (2014). Sleep restriction therapy for insomnia is associated with reduced objective total sleep time, increased daytime somnolence, and objectively impaired vigilance: implications for the clinical management of insomnia disorder. Sleep, 37(2), 229-237. doi:10.5665/sleep.3386 [doi] Littner, M., Hirshkowitz, M., Kramer, M., Kapen, S., Anderson, W. M., Bailey, D., . . . Woodson, B. T. (2003). Practice parameters for using polysomnography to evaluate insomnia: an update. Sleep, 26(6), 754-760. Lovato, N., Lack, L., & Kennaway, D. J. (2016). Comparing and contrasting therapeutic effects of cognitive-behavior therapy for older adults suffering from insomnia with short and long objective sleep duration. Sleep Med, 22, 4-12. doi:10.1016/j.sleep.2016.04.001 Miller, C. B., Espie, C. A., Bartlett, D. J., Marshall, N. S., Gordon, C. J., & Grunstein, R. R. (2018). Acceptability, tolerability, and potential efficacy of cognitive behavioural therapy for Insomnia Disorder subtypes defined by polysomnography: A retrospective cohort study. Sci Rep, 8(1), 6664. doi:10.1038/s41598-018-25033-3 Patel, S. R., & Hu, F. B. (2008). Short sleep duration and weight gain: a systematic review. Obesity (Silver Spring), 16(3), 643-653. doi:10.1038/oby.2007.118 Riemann, D. B., E.; Cohrs, S. Crönlein, T.; Hajak, G., Hertenstein, E., et al. (2017). S3 - Leitlinie Nichterholsamer Schlaf/Schlafstörungen. Somnologie, 21(1). doi:DOI 10.1007/s11818-0160097-x

AC C

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48

29

Short sleep and CBT-I

ACCEPTED MANUSCRIPT

RI PT

Spielman, A. J., Saskin, P., & Thorpy, M. J. (1987). Treatment of chronic insomnia by restriction of time in bed. Sleep, 10(1), 45-56. Vgontzas, A. N., Bixler, E. O., Kales, A., Manfredi, R. L., & Tyson, K. (1994). Validity and clinical utility of sleep laboratory criteria for insomnia. Int. J. Neurosci, 77(1-2), 11-21. Vgontzas, A. N., & Fernandez-Mendoza, J. (2013). Insomnia with Short Sleep Duration: Nosological, Diagnostic, and Treatment Implications. Sleep Med. Clin, 8(3), 309-322. doi:10.1016/j.jsmc.2013.04.009 [doi] Vgontzas, A. N., Fernandez-Mendoza, J., Bixler, E. O., Singareddy, R., Shaffer, M. L., Calhoun, S. L., . . . Chrousos, G. P. (2012). Persistent insomnia: the role of objective short sleep duration and mental health. Sleep, 35(1), 61-68. doi:10.5665/sleep.1586 [doi] Vgontzas, A. N., Fernandez-Mendoza, J., Liao, D., & Bixler, E. O. (2013). Insomnia with objective short sleep duration: the most biologically severe phenotype of the disorder. Sleep Med. Rev, 17(4), 241-254. doi:S1087-0792(12)00104-9 [pii];10.1016/j.smrv.2012.09.005 [doi]

SC

1 2 3 4 5 6 7 8 9 10 11 12 13

AC C

EP

TE D

M AN U

14

30

ACCEPTED MANUSCRIPT Table 1: Clinical data from patients with objective short and normal sleep duration at baseline. Normal sleep

Difference

subgroup

subgroup

N

39

53

Women

30

42

Age (years)

53.0 ±11.7

49.2± 11.4

BMI (kg/m²)

25.3 ± 4.5

24.1 ±4.9

Psychiatric comorbidities*

5

4

RIS scores

24.7± 4.5

23.9±4.5

t = .802; p = .425

PSQI scores

14.8 ± 2.4

13.9±2.4

t = 1.584; p = .117

RI PT

Short sleep

M AN U

SC

Chi²= .071; p= .790 t = 1.655; p = .101 t = 1.159; p= .250

Chi²= 5.704; p = .058

AC C

EP

TE D

* Number of patients showing stable and treated depression or chronic pain disorder

ACCEPTED MANUSCRIPT

Table 2: Polysomnographic parameters of the two subgroups (insomnia patients with objective short sleep duration and insomnia patients with objective normal sleep duration) averaged over the two baseline nights and at the post-treatment night after two weeks of an inpatient CBT program (means and standard deviations).

Normal sleep subgroup (n = 53)

Baseline

Post-treatment

Baseline

TIB (min.)

434.3±25.6

380.2±31.9

446.9±22.9

SOL (min.)

23.8± 26.6

7.4± 8.5

13.8±17.8

5.1±5.4

WASO (min.)

101.9±51.2

55.6±34.6

54.7± 23.2

33.8±21.8

TST (min.)

294.6±52.7

311.8±47.0

374.5±30.4

335.3±32.2

SE (%)

73.7±37.2

82.0±10.3

83.2± 6.6

87.0±11.1

REM (%)

14.8± 13.8

15.4±5.7

12.9±5.2

16.5± 5.2

N1(%)

10.3±3.7

10.3±4.2

11.4± 5.7

9.7±5.4

N2 (%)

39.6±8.7

43.5±9.7

45.0± 8.1

45.6± 9.4

N3 (%)

11.3±7.3

14.5±8.7

14.5± 8.1

18.8±12.7

Post-treatment 379.6± 29.4

SC

M AN U

TE D

EP

AC C

RI PT

Short sleep subgroup (n = 39)

RI PT

ACCEPTED MANUSCRIPT

Normal sleep

subgroup

subgroup

16.4 ±27.7

Dif WASO (min)

46.2 ± 52.5

Dif TST (min)

-17.2 ± 58.7

Dif N3 (%)

-3.30 ± 7.9

Dif REM (%)

-.52± 12.1

EP AC C

P

8.7 ± 16.7

1.670

.098

20.8 ± 29.8

2.948

.004

39.1 ± 41.7

-5.387

.0005

-4.3 ±10.0

.534

.594

-.17± 5.1

-.189

.851

TE D

Dif SOL (min)

T

M AN U

Short sleep

SC

Table 3: Differences (means and standard deviations) in objective sleep parameters from the mean of the two baseline nights to post-treatment. The analyses of group differences are based on unpaired T-tests.

ACCEPTED MANUSCRIPT

RI PT

Highlights Cognitive behavioral treatment for insomnia is equally effective in insomnia patients with

• • •

AC C

EP

TE D

•

It has been suggested that insomnia patients with short sleep duration differ from insomnia patients with normal sleep duration. Both groups may respond differently to cognitive behavioral treatment for insomnia (CBT-I). CBT-I outcome was compared between insomnia patients with polysomnographically determined short (< 6 h) and normal (≥ 6 h) sleep duration. CBT-I in this sample was equally effective in insomnia patients with objective short and normal sleep duration. These results suggest that the distinction in insomnia with objective short and normal sleep duration may be of limited value for treatment decisions regarding CBT-I.

M AN U

•

SC

objective short and normal sleep duration