Chronobiology International, Early Online: 1–15, (2013) ! Informa Healthcare USA, Inc. ISSN: 0742-0528 print / 1525-6073 online DOI: 10.3109/07420528.2013.823200

ORIGINAL REPORT

A randomized controlled trial with bright light and melatonin for delayed sleep phase disorder: Effects on subjective and objective sleep Ingvild West Saxvig1,2, Ane Wilhelmsen-Langeland1, Sta˚le Pallesen2,3, Øystein Vedaa4, Inger Hilde Nordhus2,5, and Bjørn Bjorvatn1,2 Chronobiol Int Downloaded from informahealthcare.com by Nyu Medical Center on 11/30/13 For personal use only.

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Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway, 2Norwegian Competence Center for Sleep Disorders, Haukeland University Hospital, Bergen, Norway, 3Department of Psychosocial Science, University of Bergen, Bergen, Norway, 4Division of Mental Health, Norwegian Institute of Public Health, Bergen, Norway, and 5Department of Clinical Psychology, University of Bergen, Bergen, Norway

Delayed sleep phase disorder (DSPD) is assumed to be common amongst adolescents, with potentially severe consequences in terms of school attendance and daytime functioning. The most common treatment approaches for DSPD are based on the administration of bright light and/or exogenous melatonin with or without adjunct behavioural instructions. Much is generally known about the chronobiological effects of light and melatonin. However, placebo-controlled treatment studies for DSPD are scarce, in particular in adolescents and young adults, and no standardized guidelines exist regarding treatment. The aim of the present study was, therefore, to investigate the short- and long-term effects on sleep of a DSPD treatment protocol involving administration of timed bright light and melatonin alongside gradual advancement of rise time in adolescents and young adults with DSPD in a randomized controlled trial and an open label follow-up study. A total of 40 adolescents and young adults (age range 16–25 years) diagnosed with DSPD were recruited to participate in the study. The participants were randomized to receive treatment for two weeks in one of four treatment conditions: dim light and placebo capsules, bright light and placebo capsules, dim light and melatonin capsules or bright light and melatonin capsules. In a follow-up study, participants were re-randomized to either receive treatment with the combination of bright light and melatonin or no treatment in an open label trial for approximately three months. Light and capsules were administered alongside gradual advancement of rise times. The main end points were sleep as assessed by sleep diaries and actigraphy recordings and circadian phase as assessed by salivary dim light melatonin onset (DLMO). During the two-week intervention, the timing of sleep and DLMO was advanced in all treatment conditions as seen by about 1 h advance of bed time, 2 h advance of rise time and 2 h advance of DLMO in all four groups. Sleep duration was reduced with approximately 1 h. At three-month follow-up, only the treatment group had maintained an advanced sleep phase. Sleep duration had returned to baseline levels in both groups. In conclusion, gradual advancement of rise time produced a phase advance during the two-week intervention, irrespective of treatment condition. Termination of treatment caused relapse into delayed sleep times, whereas long-term treatment with bright light and melatonin (three months) allowed maintenance of the advanced sleep phase. Keywords: Circadian rhythm, clinical trial, phase advanced, RCT, rise time, treatment

INTRODUCTION

patients themselves determine their timing of sleep, sleep quality and duration are normal (American Academy of Sleep Medicine, 2005; Saxvig et al., 2013). Patients with DSPD typically report problems initiating sleep, likely due to attempts to fall asleep at an early circadian phase (Weitzman et al., 1981). They also report problems waking up at socially acceptable times in the morning. DSPD is assumed to be common amongst adolescents and young adults (0.5–16%) (American

Delayed sleep phase disorder (DSPD) is a circadian rhythm sleep disorder characterized by a delay in the timing of the major sleep period in relation to desired sleep and wake times (American Academy of Sleep Medicine, 2005). A delayed endogenous circadian rhythm as measured by dim light melatonin onset (DLMO) or core body temperature minimum (CTmin) is assumed to underlie the sleep phase delay. When

Submitted January 29, 2013, Returned for revision June 24, 2013, Accepted July 4, 2013

Correspondence: Ingvild West Saxvig, Department of Public Health and Primary Care, University of Bergen, Postboks 7804, 5020 Bergen, Norway. Tel: +47 55586064. Fax: +47 55586130. E-mail: [email protected]

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Academy of Sleep Medicine, 2005; Gradisar et al., 2011b; Saxvig et al., 2012). Consequences of DSPD may be severe in terms of work participation, school functioning and social relationships. Associated features such as anxiety, depression, smoking and alcohol abuse may add to the burden of the disorder (Crowley et al., 2007; Saxvig et al., 2012). Hence, it seems important to offer these patients adequate treatment. Most treatment approaches for DSPD aim to correct the sleep phase delay by using bright light, melatonin and/or behavioural interventions to shift the endogenous circadian phase. Bright light is a potent synchronizer of endogenous time keeping system (Czeisler et al., 1989). Its effects (direction and size) largely depend on the time of exposure in relation to the circadian phase, as described by the phase-response curve for light (Khalsa et al., 2003; Minors et al., 1991). Light has a maximum phase advancing effect when administered shortly after CTmin whereas bright light exposure prior to CTmin produces a phase delay (Bjorvatn & Pallesen, 2009; Khalsa et al., 2003; Minors et al., 1991). Few controlled studies have investigated its effects in patients with DSPD. In a study by Rosenthal et al. (1990), CTmin was advanced with almost one and a half hour in patients with DSPD receiving 2500 lux for 2 h in the morning but not in a dim light control group. Similarly, Lack et al. (2007) reported a two and a half hour advance of DLMO in DSPD patients receiving morning blue light with no phase advance in the dim light control group. Hence, in line with current evidence and chronobiological principles, light after CTmin should produce an advance of the endogenous circadian rhythm in patients with DSPD. Bright light has usually been administered together with behavioural instructions such as gradual advancement of rise time (Cole et al., 2002; Gradisar et al., 2011a; Lack et al., 2007) or fixed advanced sleep/wake schedules (Sharkey et al., 2011). Interestingly, some of these studies have shown phase advancement also in dim light control groups (Cole et al., 2002; Sharkey et al., 2011). In the study by Sharkey et al. (2011), participants with subclinical DSPD advanced DLMO with approximately one and a half hour in both a blue light and a dim light condition by adherence to fixed advanced sleep/wake schedules. Hence, it appears that sleep schedules may act as a determinant for circadian phase in patients with DSPD. It is, however, possible that behavioural instructions are sufficient to produce a phase advance only in the patients with less severe phase delay. Accordingly, Cole et al. (2002) reported superior effects of the bright light condition in the participants whose initial circadian delay was most severe. The chronobiotic effect of melatonin is about 12 h out of phase with light, as described by the phase-response curve for melatonin (Lewy et al., 1992, 1998). Few controlled studies have addressed the effect of melatonin in treatment of DSPD. Kayumov et al. (2001) and

Rahman et al. (2010) both reported reduced sleep onset latency (SOL) on an early imposed sleep schedule after treatment with melatonin. In a study by Nagtegaal et al. (1998), melatonin advanced DLMO with one and a half hour whereas CTmin remained unchanged. The authors speculated whether the results could be attributed to the soporific rather than chronobiotic actions of melatonin. In contrast, Mundey et al. (2005) found that melatonin advanced both DLMO and CTmin with about one and a half hour, but that sleep onset and offset remained unchanged. In a study by Dahlitz et al. (1991) sleep onset was advanced compared to the placebo group, but not compared to pre-treatment levels. Melatonin administered in children and adolescents with sleep onset difficulties (possibly due to a delayed sleep phase) appears to advance sleep onset and DLMO, and possibly also increase sleep duration (Eckerberg et al., 2012; Smits et al., 2001, 2003; Van der Heijden et al., 2007; Weiss et al., 2006). To our knowledge, the study by Gradisar et al. (2011a), in which a phase advance was produced through cognitive behavioural therapy in combination with morning bright light, is the only controlled treatment study conducted on adolescents diagnosed with DSPD. Little is known about long-term treatment of DSPD. Cole et al. (2002) reported maintenance of an advanced sleep onset time after four weeks in a bright light condition when compared to baseline but not compared to the dim light control group. Moreover, the contribution of the bright light to the effect was unclear due to inconsistent use. Based on clinical reports, it is assumed that the effect of light and melatonin fades out upon termination of treatment (Alvarez et al., 1992; Dagan et al., 1998; van Maanen et al., 2011). It is, however, possible that patients may be able to maintain an advanced sleep phase through strict sleep schedules. In line with this, Gradisar et al. (2011a) showed that DSPD-patients were able to maintain treatment effects for six months by adhering to a behavioural regime following initial short-term treatment with bright light and cognitive behavioural therapy. In a study by Czeisler et al. (1981), patients appeared able to maintain an advanced sleep schedule after chronotherapy. Appropriate timing for administration of bright light and melatonin in DSPD can be ensured by measuring DLMO or CTmin (Lockley, 2005; Mundey et al., 2005; Nagtegaal et al., 1998). When such biological markers of circadian phase are not available, DLMO and CTmin can be estimated from behaviour and anamnestic information (Bjorvatn & Pallesen, 2009; Revell et al., 2006), based on the facts that DLMO usually occurs approximately 2 h before habitual sleep onset (Revell et al., 2006) and CTmin approximately 2 h before habitual wake up time (Bjorvatn & Pallesen, 2009). Still, individual timing of treatment may not be superior to fixed times as described by Nagtegaal et al. (1998). In previous treatment studies, melatonin has often been administered at approximately the same time throughout the treatment Chronobiology International

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Treatment of delayed sleep phase disorder period (Dahlitz et al., 1991; Kayumov et al., 2001; Mundey et al., 2005; Nagtegaal et al., 1998; Rahman et al., 2010), despite the fact that a shift in circadian phase will cause a parallel phase shift of the phaseresponse curve for melatonin (Lewy et al., 1998). Gradual advancement of time for administration of bright light and/or melatonin alongside gradual advancement of the sleep schedule has proved effective in shifting circadian phase in healthy populations (Burgess et al., 2003; Revell et al., 2006) and several researchers have suggested DSPD treatment protocols based on this principle (Bjorvatn & Pallesen, 2009; Cole et al., 2002; Gradisar et al., 2011a; Lack et al., 2007; Revell et al., 2006). At present, no consensus exists regarding the use of bright light and/or melatonin in the treatment of DSPD with respect to timing, dosage, duration and adjunct behavioural instructions. The aim of the present study was, therefore, to investigate the effect on sleep of a DSPD treatment protocol suitable for use in primary health care as suggested by Bjorvatn and Pallesen (2009). The treatment protocol involves administration of bright light and exogenous melatonin alongside gradual advancement of rise times as based on spontaneous wake up time on the first day of treatment. A randomized, four-armed, double blinded, placebo-controlled design was applied to address the differential contributions of bright light and melatonin when used for two weeks. A randomized, two-armed follow-up study was subsequently conducted to investigate the long-term treatment effects of bright light and melatonin in combination compared with no treatment for three months. The main end points were subjective and objective measures of sleep as recorded by one week of sleep diary and actigraphy prior to treatment, the last week of the two-week intervention and the last week of the three-month follow-up. Circadian phase was assessed by measuring DLMO before and after the twoweek intervention.

METHODS Participants Participants were recruited from high schools, colleges and the University of Bergen to participate in a clinical trial (ClinicalTrials.gov NCT00834886). Recruitment was conducted via the project website, announced through emails, flyers, posters, media and recruitment meetings in agreement with high school/college/university administrations. The website contained information about the disorder as well as the study protocol. A total of 264 potential participants made initial contact. They were screened through a short telephone interview and by one week of sleep diary. Altogether 60 persons fulfilled the basic criteria for inclusion and were scheduled for a meeting at the sleep laboratory (Faculty of Psychology, University of Bergen), out of which 10 withdrew prior to inclusion. At the meeting, the !

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potential participants were screened with SCID-I (First et al., 1995), Raven’s matrices (Raven, 2000; Raven et al., 2000) and pregnancy tests (females) and further set up for a polysomnographic screening. A total of 40 participants were included and randomized for participation in the study. Figure 1 illustrates the participation flow in the study. Inclusion criteria for the study were (1) living in Bergen, Norway, (2) age 16–25 years, (3) good general health as specified by the exclusion criteria and (4) DSPD diagnosis. The participants were diagnosed according to the diagnostic criteria of the International Classification of Sleep Disorders (American Academy of Sleep Medicine, 2005) operationalized as: (1) problems falling asleep in the evening, (2) falling asleep after 2 am at least three days a week, (3) ability to sleep until early afternoon, (4) problems waking up in time for school/ studies, (5) early wake-up times associated with extreme daytime sleepiness, (6) good subjective sleep quality and duration when given the opportunity to sleep at selfpreferred times and (7) reporting the aforementioned sleep problems for more than six months. The diagnosis was confirmed by one week of sleep diary showing a delayed sleep phase with sleep onset later than 2 am at least three days per week. Exclusion criteria were sleep disorders other than DSPD based on subjective reports and polysomnography (apnea-hypopnea index 45 and periodic limb movement index 415), moderate to severe psychopathology or treatment for psychopathology within the last four weeks (based on SCID-I interview (First et al., 1995)), somatic disorders or conditions assumed to affect sleep (i.e. migraine, B12 deficiency), all serious somatic disorders (i.e. rheumatoid arthritis and diabetes), medications assumed to affect sleep (i.e. sedative anti-histamines, antidepressants and hypnotics), substance abuse or night work, IQ570 (Raven’s matrices (Raven, 2000; Raven et al., 2000)), breast feeding and pregnancy. Consent forms were signed at the first meeting at the sleep laboratory, prior to participation in the study. When participants were 518 years, written and verbal consent from both the adolescent and the parents were obtained. Participants received a compensation fee (approximately $80) for the time invested. The Regional Committee for Medical and Health Research Ethics approved the study, as did the Norwegian Social Data Service and the Norwegian Medicines Agency. The trial was conducted according to good clinical practice and conforms to established international ethical standards (Portaluppi et al., 2010).

Procedure Participants were randomized into one of four treatment conditions each lasting for two weeks in a double blinded, placebo-controlled design. The four treatment conditions were: dim light and placebo capsules (placebo group), bright light and placebo capsules (bright

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Figure 1. Participant flow in the study.

light group), dim light and melatonin capsules (melatonin group) and bright light and melatonin capsules (combination group). In all groups, dim/bright light and placebo/melatonin capsules were administered at gradually advanced times alongside gradual advancement of rise times. For a follow-up study, participants were immediately re-randomized into one of the two groups to receive treatment with the combination of bright light and melatonin at gradually advanced times alongside gradual advancement of rise times (treatment group) or no treatment (no-treatment group) in an open label trial for approximately three months. The participants kept a sleep diary and wore an actigraph for seven days prior to intervention (baseline assessment), during the last seven days of the two-week intervention (two-week

assessment) and during the last seven days of the three-month follow-up study (three-month assessment). At all three assessment points (baseline, twoweek and three-month), participants completed the Pittsburgh Sleep Quality Index (PSQI) and the Bergen Insomnia Scale (BIS). Saliva samples were collected at baseline and at the end of the two-week treatment period for estimation of DLMO.

Treatment protocol Participants were instructed to sleep until spontaneous awakening on the first day of treatment (if they woke much earlier than their habitual wake up time they were to stay in bed and try to go back to sleep). Rise time was advanced with 1 h each day until the preferred rise time Chronobiology International

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Treatment of delayed sleep phase disorder was reached (as chosen by the individual participant). The preferred rise time was to be maintained throughout the treatment period. Light was administered every day immediately upon awakening, for 30–45 min (Terman & Terman, 2011) with eyes directed towards the lamp and at a distance providing approximately 10 000 lux. In the evenings, 12 h after awakening, participants were to take a capsule. However, for safety reasons related to the soporific properties of melatonin, capsules were not to be taken before 8 pm. In the case of oversleeping, participants were to take light immediately upon awakening, melatonin 12 h later and to advance rise time with 1 h on the following days. No information was given regarding bed time. Use of alcohol was not allowed during the two-week intervention. No restrictions for alcohol use were given for the three-month follow-up study.

Bright white light and dim red light The light source was ML-10 000 manufactured by Miljølys Inc., Norway. ML-10 000 is a light box (47  17.5  29 cm) containing three fluorescent bulbs (Philips, Ecotone, P1-L, RA-index ¼ 80, light temperature 4000 K). Lamplight was either bright (approximately 10 000 lux on 50 cm distance) or dim red (approximately 400 lux on 50 cm distance, placebo). Dim light lamps have been used as placebo in previous studies (Cole et al., 2002; Pallesen et al., 2005b; Rosenthal et al., 1990; Sharkey et al., 2011) since dim light traditionally has been assumed to have minimal effect on the endogenous circadian rhythm (Lewy et al., 1980). Moreover, the circadian timing system appears minimally sensitive to light of long wavelength (e.g. red – 622–780 nm) (Figueiro & Rea, 2010). Melatonin capsules and placebo capsules For the two-week intervention, hard capsules were packed by Kragerø Tablettproduksjon Inc., Norway, and contained either melatonin (5-methoxy-N-acetyltryptamine) 3 mg or 3 mg of Maydis Amylum (maize starch, placebo). The melatonin was purchased from Nature’s One, Asman Inc., Avon, MA (www.asaman.com). For the three-month follow-up study, the original capsules from Nature’s One were used. Blinding The two-week intervention was double blinded. Participants were informed that they would receive either red or white light, but not that the light intensity was different. Lamps were given to the participants in boxes concealing the colour of the cover screen, and participants were instructed not to reveal the colour of the lamp to the study personnel upon return. Melatonin and placebo capsules were packed in identical containers, and participants were informed that the capsules contained either melatonin or maize starch. The three-month follow-up study was not blinded. !

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Randomization Two randomization lists were produced (four groups  two-week intervention, two groups  three-month follow-up), using the Internet–based program Research Randomizer (www.randomizer.org/form.htm). According to these lists, participants were chronologically assigned to the respective groups upon inclusion in the study. Settings The trial was conducted in Bergen, Norway at 60.39 N, yielding large differences in solar day length between midsummer and midwinter. Since the trial was conducted over a time period of almost four years with continuous enrolment in all groups across seasons, there were no obvious or systematic differences between the groups neither in terms of season of enrolment nor treatment. Instruments Demography and background information Data were collected regarding age, gender, self-reported school grades, whether they lived with their parents or not and whether they were high school students, college/university students, employed or unemployed. Sleep diary The sleep diary items included bed time and rise time, SOL, number and duration of awakenings, final wake up time and sleep quality (scale from 1 ¼ very light to 5 ¼ very deep). Based on these items we calculated wake after sleep onset (WASO), early morning awakening (EMA), time in bed (TIB), total wake time (TWT), total sleep time (TST) and sleep efficiency (SE). We also calculated mid-sleep (the midpoint of the sleep period from sleep onset to wake up) for weekdays and weekends separately. For all other variables, seven day average (five weekdays and two weekend days) was used for analyses. In cases where an item was missing on a weekday, it was replaced by the average of the remaining weekdays, whenever an item was missing on a weekend day it was replaced by the other weekend day. Actigraphy An actigraph is a wrist-worn movement sensor that objectively records motor activity. In the present study, the Actiwatch recorder AW7 (Cambridge Neurotechnology Ltd, England) was used for data acquisition. The Actiwatch is waterproof and the participants were instructed not to take it off at any time during the data collection periods. Patients used an event button on the unit to mark bed time and rise time. Data were collected with an epoch length of 1 min. Sensitivity was set to medium. Using Actigraphy Sleep Analysis software (Cambridge Neurotechnology Ltd, 2001) we calculated SOL, WASO, EMA, TWT, TST and SE.

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Pittsburgh sleep quality index The PSQI (Buysse et al., 1989) is a 19-item, self-rated questionnaire that assesses sleep quality and disturbances over a one-month time interval. Global score ranges from 0 to 21, higher scores indicating more sleep problems. The cut-off for problematic sleep is 5. A validated Norwegian version of the PSQI was used in the present study (Pallesen et al., 2005a). Bergen insomnia Scale BIS is a 6-item self-report instrument, constructed based upon current formal and clinical diagnostic criteria for insomnia. Each item is rated along an 8-point scale, ranging from 0 to 7 days per week, yielding a total score ranging from 0 to 42. The BIS has been validated in several samples (Pallesen et al., 2008). Dim light melatonin onset Saliva samples for estimation of DLMO were collected using SalivetteÕ tubes from Sarstedt, Germany and analysed using ELISA immunoassay (Direct Saliva ¨ hlmann MELATONIN from Bu laboratories, Switzerland). Analytical sensitivity of this kit is 0.5 pg/ ml and functional sensitivity is 1.6–20.5 pg/ml. Interassay coefficient of variation for this kit is 12.6%. Samples were analysed with Wallac plate reader from Perkin Elmer, Waltham, MA. DLMO was defined as the time at which salivary melatonin reached 4 pg/ml (Keijzer et al., 2011). Due to limitations in the saliva sampling protocol (participants were allowed to go to bed at a self-chosen time), DLMO could not be measured in all participants at both assessment points. DLMO was estimated in 23 participants at baseline and 29 participants at two-week assessment. Statistical analyses Data were analysed using IBM SPSS Statistics 20.0. In cases of drop-outs/missing data, values were moved forward from the baseline assessment (intention to treat). Of the 40 participants enrolled in the clinical trial, two participants dropped out during the two-week intervention whereas three participants withdrew from the study during the three-month follow-up period, see Figure 1. In addition, sleep diary data at two-week assessment were missing from two participants in the placebo group and one in the bright light group. Actigraphy data were missing from one participant in the placebo group, PSQI data were missing from two in the placebo group, two in the bright light group and one in the melatonin group, and BIS data were missing from one participant in the melatonin group. At three-month assessment, sleep diary data were missing from one participant in the no-treatment group. PSQI data were missing from one in the no-treatment group and from one in the treatment group. Analysis where drop-outs/ missing data were excluded yielded similar results as the intention to treat analyses (data not presented). Due to

the smaller sample, intention to treat was not used for DLMO analyses. Background and demographic variables were compared between groups (two-week intervention  four groups, three-month follow-up  two groups) using one-way analysis of variance (ANOVA) and t-tests for independent samples (age and self-reported school grades) and Pearson 2 tests (girls/boys, high school/ college or university, living with parents or living alone). Effects of the two-week intervention were compared between the groups (placebo, bright light, melatonin and combination) using two-way ANOVA for repeated measures between the baseline and the two-week assessment on sleep diary and actigraphy parameters, scores on the PSQI and the BIS as well as on DLMO (four groups  two assessment points). At three-month follow-up, sleep diary and actigraphy parameters, and scores on the PSQI and the BIS were compared between the groups (no-treatment/treatment) with respect to both the baseline assessment and to the two-week assessment using two-way ANOVA for repeated measures (two groups  two assessment points). Interaction effects were followed up by t-tests for paired samples within each group. Cohen’s d was calculated between baseline and the two-week assessment and between qffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi baseline and the three-month assessment using the ffi formula d ¼ M1 M2 = ðSD21 þSD22 Þ=2 .

RESULTS Baseline assessment No major differences in demography and background variables were found between the subgroups (Table 1). Participants in the three-month treatment group were slightly older than participants in the no-treatment group (p ¼ 0.042). Before the intervention, sleep diaries showed mean bed time across the groups at 02:19  109 min with no differences between the twoweek groups F(3,36) ¼ 0.21, p ¼ 0.888 or between the three-month groups (p ¼ 0.779). Mean rise time was 11:06  130 min with no differences between the twoweek groups F(3,36) ¼ 0.37, p ¼ 0.779 or between the three-month groups (p ¼ 0.629), and mean TST was 7 h 27  58 min with no differences between the two-week groups F(3,36) ¼ 0.520, p ¼ 0.671 or between the threemonth groups (p ¼ 0.060). At baseline assessment DLMO was estimated in 23 participants, yielding mean DLMO at 00:21  128 min across the groups, with no difference between the two-week groups F(3,19) ¼ 0.41, p ¼ 0.746. Two-week assessment Compared with baseline levels, sleep diary and actigraphy recordings from the last 7 days of the two-week intervention period revealed earlier timing for sleep (mid-sleep, bed time and rise time) and reduced TST and TWT across all four groups, but as seen by the lack Chronobiology International

Treatment of delayed sleep phase disorder

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Table 1. Demographic and background variables described for the whole sample (N ¼ 40), for the two-week intervention subgroups and for the three-month follow-up subgroups. Subgroups, two-week intervention

Characteristic Placebo (n ¼ 10)

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Age (years) 20.8  3.4 Gender (girl/boy) 7/3 High school/college 4/6 and university* Living with/without 4/6 parents Self-reported school 4.3  0.5 gradesa

Subgroups, three-month follow-up

Bright light Melatonin Combination (n ¼ 10) (n ¼ 10) (n ¼ 10) p Value

Total sample

No treatment (n ¼ 20)

Treatment (n ¼ 20)

p Value

All participants (n ¼ 40)

20.7  3.4 8/2 6/4

21.2  2.7 5/5 2/8

20.3  3.3 8/2 4/5

0.940 0.414 0.339

19.8  2.9 15/5 11/9

21.7  3.0 13/7 5/14

0.042 0.490 0.069

20.7  3.1 28/12 16/23

3/7

2/8

3/7

0.813

6/14

6/14

1.000

12/28

4.5  0.6

4.5  0.4

4.0  0.9

0.168

4.2  0.6

4.5  0.6

0.228

4.3  0.6

Placebo group, dim light lamp and placebo capsules; Bright light group, bright light lamp and placebo capsules; Melatonin group, dim light lamp and melatonin capsules; Combination group, bright light lamp and melatonin capsules; No-treatment group, no treatment; Treatment group, bright light lamp and melatonin capsules. p Values from one-way ANOVA or Pearson’s 2 test. a Grade scale from 1 ¼ worst to 6 ¼ best. *n ¼ 39 (one participant was employed and not a student).

of interaction effects, no differences were observed between the four treatment groups (Table 2). At two-week assessment, DLMO was estimated in 29 participants with a mean DLMO at 21:54  113 min across the groups, with no difference between the groups. A total of 16 participants had their DLMO estimated both at baseline and at two-week assessment (five placebo, four bright light, two melatonin and five combination). Within these 16 participants, DLMO was estimated across the groups to 23:56  74 at baseline and at 21:56  117 (d ¼ 1.23) at two-week assessment. There was a main effect of time F(1,12) ¼ 25.34, p50.0005, but no interaction between the groups (p ¼ 0.575). Results from the PSQI and the BIS, confirmed an overall effect of treatment on sleep across the groups as seen by reduced scores compared with baseline levels with no interaction effects (Table 3).

Three-month assessment The two groups at three-month follow-up were composed of approximately an equal number of participants from each of the four two-week treatment conditions (no-treatment group/treatment group: 6/4 placebo, 5/5 bright light, 5/5 melatonin and 4/6 combination), p ¼ 0.849. Since no differential effects of the two-week intervention were observed between the four treatment conditions, the two-week data were collapsed when they were used in the three-month follow-up analysis. At three-month follow-up compared to baseline assessment, sleep diary showed that SOL and WASO were reduced and SE increased across groups as seen by main effects of time, with no interaction effects (Table 4). There were significant interaction effects on mid-sleep, bed time, rise time and TWT. As illustrated in Figures 2 and 3, there were no differences from baseline to three-month assessment in the no-treatment group with respect to bed time (p ¼ 0.339), rise time (p ¼ 0.521) and TWT (p ¼ 0.070), whereas the treatment group had !

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earlier bed time (p ¼ 0.013) and rise time (p50.0005) as well as less TWT (p ¼ 0.003). With respect to actigraphy, SE was increased across groups as seen by the main effect of time, and there was an interaction effect for TWT (Table 4). TWT was significantly reduced at threemonth follow-up compared to baseline assessment in the treatment group (p ¼ 0.005) but not in the notreatment group (p ¼ 0.492). When comparing threemonth follow-up to the two-week assessment, TIB and TST were increased across groups as seen by main effects of time (Figure 3), and there was an interaction effect on rise time (Table 4). In the no-treatment group, rise time was significantly delayed at three-month follow-up when compared to the two-week assessment (p ¼ 0.001), whereas rise time in the treatment group had remained unchanged (p ¼ 0.429) from two-week assessment (Figure 2). At three-month follow-up compared to baseline, there were significant interaction effects on the PSQI global scores (Table 5). Scores were significantly reduced in the treatment group (p5.0005) but not in the no-treatment group (p ¼ 0.100). At three-month follow-up compared with baseline, there was an interaction effect on the BIS (Table 5) where scores were significantly reduced in the treatment group (p50.0005) but not in the no-treatment group (p ¼ 0.137). When comparing three-month follow-up to the two-week assessment there was a significant interaction effect, on the PSQI global score (Table 5). Scores were significantly reduced in the treatment group (p ¼ 0.001) but not in the no-treatment group (p ¼ 0.217). At threemonth follow-up compared with the two-week assessment, there was a main effect of time on the BIS (Table 5), but no interaction effects.

DISCUSSION A four-armed, randomized, double blinded, placebocontrolled design was used to investigate the differential

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Table 2. Subjective and objective sleep parameters in participants with DSPD before (baseline assessment) and during the last seven days of two-week intervention with bright light and melatonin in a randomized, double blinded, placebo-controlled design (two-week assessment). Placebo (n ¼ 10)

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Mean  SD

Bright light (n ¼ 10)

Melatonin (n ¼ 10)

Mean  SD

Mean  SD

Combination (n ¼ 10)

p Values

d

Mean  SD

02:10  58 0.51 00:56  87*

1.00

02:04  118 01:28  106

0.32 50.0005

0.744

Rise time (hh:mm  min) Baseline assessment 11:09  124 11:37  167 Two-week assessment 09:03  169* 0.85 08:40  148*

10:35  81 1.12 08:26  98*

1.43

11:03  147 08:50  121*

0.99 50.0005

0.794

TIB (min) Baseline assessment Two-week assessment

524  79 448  90*

0.90

536  57 424  114*

1.24

505  71 450  52

0.88

539  71 443  55*

1.51 50.0005

0.538

SOL (min) Baseline assessment Two-week assessment

49  42 35  37*

0.35

49  36 39  20

0.34

36  29 21  12

0.68

42  37 19  11

0.84

0.001

0.781

WASO (min) Baseline assessment Two-week assessment

14  20 55

0.62

15  16 9  14

0.40

77 45

0.49

18  44 34

0.48

0.044

0.753

EMA (min) Baseline assessment Two-week assessment

22  20 23  25

0.00

38  34 23  36*

0.43

11  10 6  11

0.48

14  11 13  23

0.06

0.176

0.403

TWT (min) Baseline assessment Two-week assessment

85  63 62  58

0.38

102  57 71  49*

0.58

54  35 31  19

0.82

74  73 41  40

0.56

0.003

0.963

TST (min) Baseline assessment Two-week assessment

439  67 386  69*

0.78

434  71 353  88*

1.01

451  53 419  47

0.64

465  41 401  51*

SE (%) Baseline assessment Two-week assessment

84.2  9.8 86.6  9.1

0.25

81.3  9.9 84.1  7.7

0.32

89.8  5.3 93.1  4.3

0.68

87.5  9.9 91.1  7.4

0.41

0.019

0.987

0.26

0.00

0.353

0.221

d

Sleep diary Bed time (hh:mm  min) Baseline assessment 02:24  129 02:40  130 Two-week assessment 01:35  148* 0.35 01:36  120*

d

d

Time

1.38 50.0005

Group  time

0.496

Sleep qualitya Baseline assessment 3.4  0.6 3.1  0.6 Two-week assessment 3.1  0.6 0.50 3.3  0.9 Mid-sleep weekday Baseline assessment 06:23  122 06:55  163 Two-week assessment 05:01  133* 0.64 05:10  126*

3.4  0.4 3.7  0.5

0.66

3.6  0.5 3.6  0.5

06:12  82 0.72 04:35  98*

1.07

06:19  146 05:08  106

1.03 50.0005

0.896

Mid-sleep weekend Baseline assessment 08:31  129 08:01  118 Two-week assessment 06:26  195* 0.76 05:32  126*

07:31  80 1.22 05:18  105* 1.42

07:47  107 05:23  114*

1.30 50.0005

0.973

Actigraphy SOL (min) Baseline assessment Two-week assessment

19  15 24  11

WASO (min) Baseline assessment Two-week assessment

0.38

19  11 15  10

0.38

23  19 21  19

0.11

23  13 11  8*

1.11

0.267

0.258

60  15 43  16*

1.10

59  27 47  22

0.49

50  20 45  19

0.26

52  23 41  16

0.56

0.005

0.694

EMA (min) Baseline assessment Two-week assessment

97 67

0.43

52 73

0.00

0.775

0.445

TWT (min) Baseline assessment Two-week assessment

89  30 73  24

0.59

83  32 69  28

0.47

80  32 75  34

0.15

81  26 58  20

0.99

0.011

0.720

TST (min) Baseline assessment Two-week assessment

448  53 391  58*

1.03

429  47 375  64

0.96

433  62 405  49

0.50

448  66 393  45*

SE (%) Baseline assessment Two-week assessment

83.2  4.5 84.7  3.9

0.36

84.0  5.1 83.5  6.0

0.09

84.6  5.0 84.7  5.7

0.02

85.0  4.6 87.4  2.7

0.78

75 86

0.18

66 64

0.97 50.0005

0.64

0.276

0.761

0.571

Placebo group, dim light lamp and placebo capsules; Bright light group, bright light lamp and placebo capsules; Melatonin group, dim light lamp and melatonin capsules; Combination group, bright light lamp and melatonin capsules. p Values: Overall 2  4 ANOVA, main effects of time (time) and interaction effects (grouptime). d, Cohen’s d for paired samples. a Sleep quality scale: 1 ¼ very light to 5 ¼ very deep. *p50.05 based on paired samples t-tests within each group.

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Table 3. Scores on the PSQI and the BIS in participants with DSPD before (baseline assessment) and after two-week intervention with bright light and melatonin in a randomized, double blinded, placebo-controlled design (two-week assessment). Placebo (n ¼ 10)

Bright light (n ¼ 10)

Melatonin (n ¼ 10)

Combination (n ¼ 10)

p Value

Mean  SD

d

Mean  SD

d

Mean  SD

d

Mean  SD

d

Time

Grouptime

PSQI – global score Baseline assessment Two-week assessment

8.1  2.4 6.8  1.6

0.64

7.4  3.0 6.5  2.6

0.32

8.2  2.8 6.5  3.6*

0.53

8.5  2.5 6.7  3.1

0.64

0.002

0.950

BIS Baseline assessment Two-week assessment

14.2  8.2 11.1  3.9

0.48

16.9  8.4 15.2  8.1*

0.21

0.54

16.2  6.6 11.5  5.9*

0.75

50.0005

0.535

16.3  5.3 13.1  6.4

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Placebo group, dim light lamp and placebo capsules; Bright light group, bright light lamp and placebo capsules; Melatonin group, dim light lamp and melatonin capsules; Combination group, bright light lamp and melatonin capsules. p Values: Overall 2  4 ANOVA, main effects of time (time) and interaction effects (grouptime). d, Cohen’s d for paired samples. *p50.05 based on paired samples t-tests within each group.

Table 4. Subjective and objective measures of sleep in participants with DSPD at three-month follow-up compared with baseline assessment (baseline – three-month) and to two-week assessmenta (two-week – three-month). During three-month follow-up, participants received either no treatment (no-treatment group) or treatment with bright light and melatonin (treatment group). No treatment (n ¼ 20) Mean  SD

Treatment (n ¼ 20)

p Values baseline – three-month

p Values two-week – three-month

d

Mean  SD

d

Time

Grouptime

Time

Grouptime

0.12

02:24  112 01:24  126* 01:05  67*

0.86

0.006

0.041

0.612

0.138

0.10

11:16  126 08:50  128* 09:15  73*

1.18

50.0005

0.003

0.002

0.039

0.02

531  76 446  63* 491  63y

0.57

0.119

0.132

50.0005

0.241

0.35

54  41 35  30* 26  17*

0.89

0.002

0.103

0.478

0.205

0.00

19  33 56 6  7*

0.54

0.039

0.053

0.226

0.580

0.33

28  29 23  33 23  32

 0.16

0.119

0.749

0.764

0.767

0.40

101  73 66  57* 55  43*

0.77

50.0005

0.033

0.730

0.219

0.22

430  60 379  46* 436  65y

0.10

0.446

0.800

50.0005

0.498

0.46

82.0  11.0 86.0  9.6 89.0  7.7*

0.74

50.0005

0.059

0.172

0.300

Sleep diary Bed time (hh:mm  min) Baseline assessment Two-week assessment Three-month assessment

02:14  109 01:23  104* 02:02  85

Rise time (hh:mm  min) Baseline assessment Two-week assessment Three-month assessment

10:55  137 08:40  139* 10:42  111y

TIB (min) Baseline assessment Two-week assessment Three-month assessment

521  61 437  94* 520  62y

SOL (min) Baseline assessment Two-week assessment Three-month assessment

34  25 22  12* 25  27

WASO (min) Baseline assessment Two-week assessment Three-month assessment

7  10 5  10 7  10

EMA (min) Baseline assessment Two-week assessment Three-month assessment

15  11 9  11 12  7

TWT (min) Baseline assessment Two-week assessment Three-month assessment

56  29 37  24* 43  36

TST (min) Baseline assessment Two-week assessment Three-month assessment

465  52 400  84* 477  59y

SE (%) Baseline assessment Two-week assessment Three-month assessment

89.4  4.9 91.4  4.6 91.9  6.0

(continued )

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I. W. Saxvig et al. Table 4. Continued No treatment (n ¼ 20)

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Mean  SD Sleep qualityb Baseline assessment Two-week assessment Three-month assessment

3.5  0.6 3.5  0.7 3.5  0.6

Mid-sleep weekday Baseline assessment Two-week assessment Three-month assessment

06:19  131 04:59  114* 06:17  109y

Mid-sleep weekend Baseline assessment Two-week assessment Three-month assessment

07:45  96 05:30  121* 07:13  109y

Treatment (n ¼ 20) d

Mean  SD

p Values baseline – three-month

p Values two-week – three-month

d

Time

Grouptime

Time

Grouptime

0.00

3.1  0.5 3.4  0.6 3.4  0.5*

0.60

0.113

0.136

0.613

0.879

0.02

06:36  128 04:58  115* 04:42  72*

1.10

50.0005

50.0005

0.102

0.016

0.31

08:11  120 05:49  154* 06:30  78*

1.00

0.002

0.095

0.004

0.189

26  16 20  15 18  14

0.53

0.066

0.111

0.754

0.731

58  23 42  17* 49  19

0.43

0.079

0.242

0.041

0.484

86 65 63

0.42

0.235

0.288

0.329

0.269

0.08

92  32 68  27* 73  26*

0.65

0.004

0.025

0.298

0.601

0.15

439  63 381  53* 406  45

0.60

0.229

0.060

0.004

0.362

0.09

82.7  4.9 85.3  4.7 84.8  4.6*

0.44

0.01

0.078

0.589

0.223

Actigraphy SOL (min) Baseline assessment Two-week assessment Three-month assessment

16  11 16  12 16  11

WASO (min) Baseline assessment Two-week assessment Three-month assessment

52  20 47  19 50  21

EMA (min) Baseline assessment Two-week assessment Three-month assessment

64 75 65

TWT (min) Baseline assessment Two-week assessment Three-month assessment

74  24 70  27 72  27

TST (min) Baseline assessment Two-week assessment Three-month assessment

440  50 402  54* 448  59y

SE (%) Baseline assessment Two-week assessment Three-month assessment

85.7  3.9 84.9  5.1 86.1  4.7

0.00

0.10

0.00

p Values: Main effects of time (time) and interaction effects (grouptime) using overall 2  2 ANOVA between two assessment points. d, Cohen’s d for paired samples between baseline assessment and three-month assessment. a At two-week assessment participants had received treatment consisting either of bright light, melatonin, neither or both on a gradual rise time advancement schedule. Since no differential effects of these interventions were observed, the two-week intervention subgroups were collapsed when comparing the three-month assessment to the two-week assessment b Sleep quality scale: 1 ¼ very light to 5 ¼ very deep. *p50.05 based on paired samples t-tests within each group compared with baseline assessment. yp50.05 based on paired samples t-tests within each group compared with two-week assessment.

contributions of bright light and melatonin alongside gradual advancement of rise times in the treatment of DSPD. After two weeks of treatment with bright light, melatonin, neither or both, subjective bed time across the groups was advanced by 1 h from 02:19 to 01:24 and rise time by almost two and a half hours from 11:06 to 08:44, yielding large effect sizes. No differences were observed between the four groups. DLMO was advanced by 2 h from 23:56 to 21:56, with no difference between

groups. The size of the phase advance produced in the present study is comparable with reports from previous controlled DSPD treatment studies, both with respect to bright light treatment (Cole et al., 2002; Lack et al., 2007; Rosenthal et al., 1990; Sharkey et al., 2011) and melatonin administration (Dahlitz et al., 1991; Mundey et al., 2005; Nagtegaal et al., 1998). In the present study, bright light and melatonin were equally effective in treating the sleep phase delay in DSPD, with no additional effects of Chronobiology International

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Figure 2. Bed time and rise time at all three assessment points (baseline, two-week and three-month) based on sleep diary. *p50.05 compared with baseline assessment levels. yp50.05 compared with two-week assessment levels.

Figure 3. TST and TWT at all three assessment points (baseline, two-week and three-month) based on sleep diary. *p50.05 compared with baseline assessment levels using paired samples t-test. yp50.05 compared with two-week assessment levels using paired samples t-test.

Table 5. Scores on the PSQI and the BIS in participants with DSPD at three-month follow-up compared with baseline assessment (baseline – three-month) and to two-week assessmenta (two-week – three-month). During three-month follow-up, participants received either no treatment (no-treatment group) or treatment with bright light and melatonin (treatment group). No treatment (n ¼ 20) Mean  SD PSQI – global score Baseline assessment Two-week assessment Three-month assessment BIS Baseline assessment Two-week assessment Three-month assessment

7.3  2.6 5.7  2.6* 6.4  2.1 14.4  6.7 12.4  5.8 11.7  7.1

Treatment (n ¼ 20)

p Values baseline – three-month

p Values two-week – three-month

d

Mean  SD

d

Time

Grouptime

Time

Grouptime

0.38

8.8  2.5 7.6  2.6* 5.5  2.6*y

1.29

50.0005

0.015

0.060

0.001

0.39

17.4  7.2 13.1  6.8* 9.3  6.3*y

1.20

50.0005

0.035

0.023

0.118

p Values: Main effects of time (time) and interaction effects (grouptime) using overall 2  2 ANOVA for repeated measures between two assessment points. d, Cohen’s d for paired samples between baseline assessment and three-month assessment. a At two-week assessment participants had received treatment consisting either of bright light, melatonin, either or both on a gradual wake up time advancement schedule. Since no differential effects of these interventions were observed, the four different two-week intervention subgroups were collapsed when comparing the three-month assessment to the two-week assessment. *p50.05 based on paired samples t-tests within each group compared with baseline assessment. yp50.05 based on paired samples t-tests within each group compared with two-week assessment.

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I. W. Saxvig et al.

bright light and melatonin in combination. This contrasts findings of additive effects of bright light and melatonin in healthy persons on a gradual advancement of rise time schedule (Burgess et al., 2003; Revell et al., 2006). More surprisingly, in the present study, a similar phase advance was produced in the placebo group who was instructed to gradually advance rise time. Although previous studies have suggested that sleep timing may be advanced through behavioural instructions, at least in less severe cases (Cole et al., 2002; Sharkey et al., 2011), most evidence suggests that DLMO is more affected by bright than dim light (Lack et al., 2007; Rosenthal et al., 1990). In the present study, DLMO was advanced also in the placebo group, hence supporting recent reports of advancement of DLMO in a sample of subclinical DSPD participants on a fixed, advanced sleep schedule irrespective of light condition (blue or dim) (Sharkey et al., 2011). In contrast to the study by Sharkey et al. (2011), participants in the present study were diagnosed with DSPD, indicating that strict rise time schedules may effectively phase advance also more severe cases of delayed sleep phase. It is, however, possible that early rise times did promote exposure to outdoor light during optimal phase advancing times in the dim light control group or that the 400 lux dim light, although red, had an effect on the circadian timing system. Hence, advancement of the endogenous circadian rhythm may be attributed to light also in this group. Furthermore, early rise times can contribute to a sleep phase advance through homeostatic processes by inducing a sleep debt which in turn instigates earlier sleep onset (Borbely, 1982). In the present study, sleep diary showed reduced sleep duration (from 7.5 to 6.5 h) and wake time (79–51 min) across the groups after two weeks, with similar results from the actigraphy recordings. This finding confirms reports from previous bright light treatment studies (Alvarez et al., 1992; Watanabe et al., 1999), and is in contrast to studies showing that melatonin administration maintains or increases sleep duration (reviewed by van Geijlswijk et al. (2010)). Whereas bright light treatment is often combined with early rise schedules to ensure light exposure in close proximity to CTmin, melatonin is usually administered without concurrent behavioural instructions, although otherwise has been suggested by several authors (Mundey et al., 2005; Nagtegaal et al., 1998). The fact that all groups in the present study, including the melatonin group, received instructions for gradual advancement of the sleep schedule may explain the reduced sleep duration across groups and hence the discrepancies between the present and previous melatonin studies. In the present study, sleep diary scores on sleep quality improved across the groups and taken together with reduced scores on the PSQI and the BIS it appears that short-term effects of the present treatment protocol were beneficial, also in the face of reduced sleep duration.

A two-armed, randomized design was used to investigate the long-term treatment effects of bright light and melatonin versus no treatment for three months. At three-month follow-up, subjective and objective measures of sleep showed that participants that terminated treatment after two weeks (no-treatment group) had relapsed to baseline levels in terms of sleep timing (later bed times and rise times, Figure 1) and sleep duration (Figure 2). Hence, the advanced sleep schedule appeared to be maintained only for the duration of active treatment, despite the fact that participants had become familiar with the principals of the gradual rise time advancement and maintenance protocol (Brown et al., 2002). Accordingly, although behavioural interventions in the form of rise time schedules may be capable of producing a sleep phase advance in patients with DSPD, information and training on these concepts do not appear to suffice for sustained effects, and relapse seems to occur within three months. It should be noted that upon termination of treatment in the present study, participants were neither encouraged nor discouraged to maintain an early rise time schedule. It is possible that some patients with DSPD may prevent relapse through strict adherence to early sleep schedules alone, as appears to be the case in studies by Czeisler et al. (1981) and to some extent Gradisar et al. (2011a). Motivational therapy can possibly increase adherence to advanced sleep schedules. In contrast, sustained treatment involving advanced rise times together with bright light and melatonin enabled the three-month treatment group to maintain the sleep schedule achieved at two-week assessment (Figure 1). Interestingly, at three-month assessment, sleep duration had increased to baseline levels in the treatment group (Figure 2). Hence, it may seem that although the treatment protocol may induce a sleep phase advance at the cost of sleep duration in the initial phase, baseline sleep duration seems to be resumed as treatment is maintained over sustained periods of time. Since sleep duration relies on the timing of the sleep period in relation to the endogenous phase (Borbely, 1982; Dijk & Czeisler, 1995), the resumption of normal sleep duration can be taken as support for a welladapted sleep schedule. At three-month follow-up, the PSQI and the BIS scores were reduced not only with respect to the baseline levels but also with respect to the two-week assessment, indicating that the treatment effect increased as the sleep schedule stabilized.

Strengths and limitations The present study is, to the best of our knowledge, the first study that systematically investigates the differential contributions of bright light and melatonin in the treatment of DSPD in a four-armed, randomized, double blinded and placebo-controlled design. Moreover, although previous bright light treatment studies have included concurrent behavioural instructions, the effect of melatonin when administered alongside gradual Chronobiology International

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Treatment of delayed sleep phase disorder advancement of rise time has not previously been explored in this patient group. Another novelty of the present study is the assessment of long-term treatment effects of combined bright light and melatonin treatment in a controlled setting. Treatment effects (both short-term and long-term) were investigated by both subjective and objective measures of sleep. The impact of short-term treatment on the endogenous circadian phase was also assessed. Whereas the effect of melatonin in children and adolescents with sleep onset difficulties has been extensively explored (Eckerberg et al., 2012; Smits et al., 2001, 2003; Van der Heijden et al., 2007; Weiss et al., 2006), most DSPD treatment studies have been performed in adult populations, despite the fact that the disorder is assumed to be more prevalent in adolescents and young adults (American Academy of Sleep Medicine, 2005). Treatment of adolescents and young adults can involve special challenges with respect to motivation and compliance, and thus it seems important to address treatment issues in studies within this age group. The treatment protocol used was based on current chronobiological knowledge (Bjorvatn & Pallesen, 2009), previous studies (Burgess et al., 2003; Lack et al., 2007; Revell et al., 2006) and years of clinical experience. The results showed a solid effect across groups comparable with previous treatment studies, suggesting that this protocol was effective in the treatment of DSPD. Since times for bright light and melatonin administration were based on behavioural measures, the treatment is well suited for use in primary healthcare settings. Hence, the study may contribute importantly to the clinical management of DSPD. There are some limitations to the present study that should be noted. Despite a large overall sample size, group sizes in the four-armed trial were small, in particular for the DLMO assessment. Hence, statistical power in the short-term intervention may have been too low for detection of possible minor and moderate group specific differences. There was a slight age difference between the two follow-up groups, which theoretically may account for some of the differences between the no-treatment and the treatment group in terms of effects. However, no other differences were found on background variables, and sleep parameters at baseline or at two-week assessment did not differ between the groups. Hence, it seems unlikely that the age difference can fully account for the results. In the two-week intervention study, a special limitation was induced by the placebo light condition. Although early studies found no phase shifting effects of dim light (Lewy et al., 1980), later studies have indicated that dim light at optimal exposure times may affect the circadian phase, in particular when of higher intensity than background light (Hebert et al., 1998; Smith et al., 2004; Zeitzer et al., 2000), as reviewed by Duffy and Wright (2005). Thus, the dim light, although red, may have been of sufficient intensity to affect the circadian timing system. In a !

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home-based study, it was not possible to control environmental illumination over longer periods of time. Accordingly, it is possible that the sleep phase advance produced in the placebo group in the present study may be attributed to the effects of the dim light lamps rather than to the behavioural interventions. However, in such case a superior effect of brighter light would still be expected (Zeitzer et al., 2000), which was not found. Moreover, although participants were blinded with respect to light intensity and expected effects, it is likely that some participants realized that the red light represented the placebo condition (this was not assessed in the study). Hence, some participants may not have been blinded with respect to the light condition. It should also be considered that the duration of the short-term intervention may have been too short to produce observable differences in phase shifts, explaining the lack of group specific effects. With respect to the three-month follow-up study, the no-treatment group did not receive instructions to maintain their advanced sleep schedule. In line with the diagnostic criteria of DSPD (American Academy of Sleep Medicine, 2005) it is unlikely that patients with DSPD can maintain an advanced sleep schedule for long periods of time. Hence, it seems that bright light and/or melatonin are required in order to prevent relapse. The follow-up study design did not yield information as of the effectiveness of bright light and melatonin alone. In some studies, patients have been able to maintain treatment effects by strict adherence to advanced sleep schedules (Czeisler et al., 1981; Gradisar et al., 2011a), and further studies are warranted to resolve this issue. Moreover, it is not known whether daily use of bright light and/or melatonin is needed to avoid a sleep phase delay, or if intermittent or occasional use of either bright light or melatonin may be adequate treatment.

CONCLUSION Taken together, short-term treatment of patients with DSPD involving bright light and exogenous melatonin alongside gradual advancement of rise time in a fourarmed, randomized controlled design produced a phase advance irrespective of treatment condition. Long-term treatment with bright light and melatonin alongside gradual advancement of rise time allowed maintenance of the sleep rhythm whereas termination of treatment caused relapse into delayed sleep times, indicating that long-term treatment with bright light and melatonin may allow patients with DSPD to maintain an advanced sleep schedule over time. Since times for bright light and melatonin administration were based on behavioural measures, the protocol is well suited for use in primary health care settings. Hence, the study may provide important guidelines for the clinical management of DSPD.

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I. W. Saxvig et al.

ACKNOWLEDGEMENTS The authors thank the participants for their generous contribution in this research project. We also thank Nina Harkestad, staff engineer at the Research Group on Experimental and Clinical Stress and Sleep (RECSS), University of Bergen, Norway for analysing the saliva samples. The work was carried out at the University of Bergen, Norway.

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DECLARATION OF INTEREST This was not an industry supported study. Financial support was obtained through PhD grants from the University of Bergen and the Research Council of Norway and a 10 000euro grant from the Meltzer foundation, Norway. Bjorvatn has had paid speaking engagements for different businesses (Glaxo, Nycomed, ResMed, Confex and Medi3). Wilhelmsen-Langeland has had paid speaking engagements for Sanofi-Aventis and Novo Nordisk. Saxvig has received a young scientist award from Philips. The other authors report no conflict of interests. REFERENCES Alvarez B, Dahlitz MJ, Vignau J, Parkes JD. (1992). The delayed sleep phase syndrome: Clinical and investigative findings in 14 subjects. J Neurol Neurosurg Psychiatry. 55:665–70. American Academy of Sleep Medicine. (2005). The international classification of sleep disorders: Diagnostic and coding manual. Westchester, IL: American Academy of Sleep Medicine. Bjorvatn B, Pallesen S. (2009). A practical approach to circadian rhythm sleep disorders. Sleep Med Rev. 13:47–60. Borbely AA. (1982). A two process model of sleep regulation. Hum Neurobiol. 1:195–204. Brown FC, Buboltz Jr WC, Soper B. (2002). Relationship of sleep hygiene awareness, sleep hygiene practices, and sleep quality in university students. Behav Med. 28:33–8. Burgess HJ, Crowley SJ, Gazda CJ, et al. (2003). Preflight adjustment to eastward travel: 3 days of advancing sleep with and without morning bright light. J Biol Rhythms. 18: 318–28. Buysse DJ, Reynolds 3rd CF, Monk TH, et al. (1989). The Pittsburgh Sleep Quality Index: A new instrument for psychiatric practice and research. Psychiatry Res. 28:193–213. Cole RJ, Smith JS, Alcala YC, et al. (2002). Bright-light mask treatment of delayed sleep phase syndrome. J Biol Rhythms. 17: 89–101. Crowley SJ, Acebo C, Carskadon MA. (2007). Sleep, circadian rhythms, and delayed phase in adolescence. Sleep Med. 8: 602–12. Czeisler CA, Kronauer RE, Allan JS, et al. (1989). Bright light induction of strong (type 0) resetting of the human circadian pacemaker. Science. 244:1328–33. Czeisler CA, Richardson GS, Coleman RM, et al. (1981). Chronotherapy: Resetting the circadian clocks of patients with delayed sleep phase insomnia. Sleep. 4:1–21. Dagan Y, Yovel I, Hallis D, et al. (1998). Evaluating the role of melatonin in the long-term treatment of delayed sleep phase syndrome (DSPS). Chronobiol Int. 15:181–90. Dahlitz M, Alvarez B, Vignau J, et al. (1991). Delayed sleep phase syndrome response to melatonin. Lancet. 337:1121–4.

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