Regular Article Circadian rhythm sleep disorders in adolescents: Clinical trials of combined treatments based on chronobiology

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1 Psychiatry and Clinical Neurosciences (1998), 52, Regular Article Circadian rhythm sleep disorders in adolescents: Clinical trials of combined treatments based on chronobiology MASAKO OKAWA, MO, MAKOTO UCHYAMA, MO, SHGERU OZAK, MO, KAYO SHBU, MOl AND HRONOBU CHKAWA, M0 2 Department of Psychophysiology. National nstitute of Mental Health. National Center of Neurology and Psychiatry. chikawa. and 2Department of Psychiatry. Tokyo Metropolitan Umegaoka Child and Adolescent Psychiatric Ho.\pital. Chiba. Japan Abstract Key words Delayed sleep phase syndrome (DSPS) and non-24-h sleep-wake rhythm are circadian rhythm sleep disorders that are common in adolescents. Most patients have difficulty adjusting to school life, poor class attendance or refuse to go to school. Since a treatment has not been established, the present paper is presented to propose a strategy for treating circadian rhythm sleep disorders in adolescents, based on our clinical studies. Twenty subjects (12 males and eight females, mean age 16.2 ± 1.7 years) participated in the study. The onset of sleep disorder occurred between the ages of and 17. The most common factors affecting the onset of disorders were changes in social environment. The subjects kept a sleep-log for the periods before and during treatments. The treatments were based on chronobiology: resetting the daily life schedule, chronotherapy, regulation of the lighting environment, methylcobalamin, and/or melatonin. Bright light exposure was successful in 10 patients, of whom four were treated with methylcobalamin. Melatonin treatment was successful in two patients (one with and one without chronotherapy). Thirteen of the 20 patients were successfully, treated with therapies based on chronobiology. After consideration of these results, a step-by-step procedure of combined treatments for the circadian rhythm sleep disorders is proposed. chronotherapy, delayed sleep phase syndrome, light therapy, melatonin, methylcobalamin, non 24-h sleep-wake syndrome. NTRODUCTON The delayed sleep phase syndrome (DSPS) is a common cause of insomnia in adolescents. n half of adult patients with DSPS the symptoms appeared in childhood or adolescence. L2 The number of cases of DSPS and related disorders seems to have increased in the last few decades. Children stay up late and their total sleep time has decreased by min.3-6 Refusal to attend school has also increased recently, which could be partially but not entirely caused by disorders in the sleep-wake schedule The syndrome is multifactorial: social, psychological and environmental factors as well as biological factors play important roles in the onset of the symptoms,3.6 but no single factor is suffi- Correspondence address: Masako Okawa. MD. Department of Psychophysiology. National nstilute of Mental Health. NCNP. Kohnodai chikawa-shi. Chiba Japan. Received 19 February 1998; revised 15 June 1998; accepted 20 June cient to explain the syndrome. The mechanism of treatments is not understood and treatments have not been established. Attempts to treat the syndrome, by a phase advance to an early bed-time, failed,3,8,9 but a program of progressive delay in sleep-onset time resulted in rescheduling of the sleep-wake cycle. 7 Czeisler et al. introduced the progressive sleep delayed program as chronotherapy.lo However, the effect of chronotherapy is not consistent, and the symptoms of DSPS reappear once patients stay up late. Recently, the treatments with bright light, melatonin or vitamin B have been reported to be effective against circadian rhythm sleep disorders. The purpose of the present paper is to propose a strategy for treating the circadian rhythm sleep disorders in adolescents. SUBJECTS AND METHODS The criteria for the diagnosis of DSPS and non-24-h sleep-wake disorders (non-24) were adopted from

2 484 M. Okawa ('{ ill. those of the nternational Classification (if'sleep Disorde/'S.17 Adolescent patients, with ages between 10 and 19 years, were chosen for the study from our regular outpatients, who visited the sleep-wake disorder clinic. During the period , 20 adolescents (12 men and eight women) aged years (16.2 ± 1.7) were seen, and took part in our study. Clinical evaluation All subjects had a standard clinical evaluation. We designed a structured interview for all of the patients to find psychological environmental or psychiatric factors that could explain the symptoms of DSPS or non-24. A sleep-wake subjective diary (sleep log) was kept over periods of 4 weeks before the patient visited our hospital. Motor activity (rest-activity cycles) was recorded by an actigraph monitor (AM Co., Ardsley. NY, USA) on the non-dominant wrist, to evaluate the accuracy of the self-recording sleep log. Attempted treatment We allowed enough time, before the treatment, to discuss the sleep problems with each patient and respective parents, and provide them with sufficient information about circadian rhythm sleep disorders as well as other causes of interference by social, psychological and environmental factors. Finally, we arranged with parents that therapy could be used to modify the school life of the patients; for example: to encourage the patients to keep a scheduled bed-time and wake-time, and organize the patient's bedroom environment. Light exposure The mother or father was expected to perform the following early morning procedures (6-7 a.m.) whether or not the patient was sleeping: (i) open the shades and curtains in the patient's bedroom; (ii) switch on the radio, TV or the music cassette recorder to increase the chance of the patient waking up; (iii) seat the patient at a window-side chair and encourage the patient to keep awake for at least h; and (iv) for more intensive treatment and/or to maintain the improved sleep-wake schedules a light box could be used for min to give an early morning exposure ( lux). f the patient felt sleepy after light exposure, the patient was allowed to nap for no longer than h. When the patient did not show any improvements after 2-4 weeks oflight treatment, we later added methylcobalamin. Methylcobalamin is known to enforce the effect of light on the circadian clock system.'x f the patient shows extreme difficulty waking up in the morning, light therapy could be introduced after chronotherapy (see the next section). Chronotherapy We asked parents' cooperation to accomplish the chronotherapy. The procedure of chronotherapy was as follows: (i) stabilization on the patient's usual bed time-wake time for 3 days; (ii) a gradual realignment to the desired schedule by setting the patient's bed timewake time 3 h later every day for,,-,5 days; and (iii) the last sleep schedule (or similar schedule adequate for the patient's needs) was then strictly maintained. During the course of chronotherapy, the patients had to avoid napping and when possible should have had physical activity and bright light exposure (such as walking outside) after waking up in each cycle. During the first 2-3 weeks following chronotherapy, the settled wakeup time had to be strictly followed for 7 days a week. Later, if the patient wanted to stay up late on a weekend night, we allowed him or her to do so. for no more than or 2 h after his or her settled bedtime. Chronotherapy could be applied as a pre-treatment introducing light therapy or melatonin therapy, because chronotherapy seems easily acceptable to the patient who has difficulty waking up early in the morning, and it takes a short time to settle on desirable times of sleep onset and offset during chronotherapy. M ethylcobalamin (vitamin B12) We administered mg/day of methylcobalamin, three times a day after meals for 12 patients. When single methylcobalamin treatment for month is not effective, we introduce the bright light therapy with methylcobalamin treatment. On the other hand for the patient who did not respond to light therapy, we administer methylcobalamin during light therapy. Four of the 12 patients had simultaneous methylcobalamin and bright light therapy, four patients had methylcobalamin treatment in the daytime with benzodiazepine administration before bedtime (see the following section), and four patients had only methylcobalamin therapy. Ben=odia=epine We administered mg of triazolam orally, 30 min before the patient's desired (or scheduled) bedtime, to six patients. Two of the patients were given bright light therapy during the morning, and four during methylcobalamin therapy. RESULTS The clinical background of the patients and treatments is summarized in Table. The age at onset of the sleep disorder was between and 17 (14.6 ± 1.5) years; the

3 Table. Clinical background of the patients School attendance Factors affecting the onset Complication DX Age /sex Age at onset ntention Occasional* Psychol Social Physical Psychiatric Physical Treatment Procedure*** Response DSPS 16/f S + Headache 2 DSPS 12/m DSPS 14/f Hypotension 4 DSPS 14/f Vacation 5 DSPS 14/m 13 + Lumbago 6 DSPS 15/m Moving 7 DSPS 16/m DSPS 16/m S + + School** 9 DSPS 17/f Headache 10 DSPS 17/f School DSPS 17/f S + + Hypotension 12 DSPS 17/m Conflict 13 DSPS 17/m Headache 14 DSPS 17/m Vacation Headache S DSPS 17/m Vacation Lumbago 16 DSPS 18/m DSPS 19/f Conflict 18 DSPS 19/f 16 + Vacation Withdrawal 19 N24 16/m N24 17/m Sun + Sun+B12 + Sun + Sun+ B2 + B12+ BZ Sun + ME + Sun+ BZ + Sun+B12 + B2 B12+ BZ Sun+B12 + Bright light + B2 + Chrono+ ME + Sun+ BZ + B2 B12+ BZ B12+ BZ B2 * +, occasional attendance; -, no attendance; ** school, going to distant school; *** sun, morning sunbathing; B12, methy1cobalamin; BZ. benzodiazepine; ME. melatonin; Chrono, chronotherapy. n ~. ~ 0 5:" ::l on r;- ("0 '0 ~ on o a.. ("0.., on 5" ~ 0 or;- on ("0 n :::. on 00 """ V>

4 486 M. Okawa et al. chief complaints were difficulty in rising in 17 of 20 patients (85.0%), sleepiness in the daytime in four patients (20.0%) and sleep onset insomnia in one patient (5.0%). All of the patients wanted to attend school, but 17 (85.0%) could do this only occasionally (3 days or less in 5 week days) and the remaining three patients (15.0%) were completely absent for more than 3 months. The most common factors affecting the onset of disorders was a change in social environment: patients who had an increased journey to school had to wake up much earlier than before and had difficulty awakening in time to attend their classes. Sometimes they had to shorten their total sleep time. This factor of a long ride to school affected two of the 20 patients (10.0%). Disorders started just after the long summer vacation in four patients (20.0%). n the remaining 14 patients (70.0%), no social factors affecting the onset of the disorder were found. Psychological factors affected two patients (10.0%) who seemed to be involved in conflicts between parents, or in the classroom. Two patients had back pain and ceased their sport club activity. Physical complications were seen in six patients. When the patients were forced to rise in the morning, three had headaches and three developed orthostatic hypotension. Treatments We evaluated the effects of treatments as follows. (1) The number of days that the patient attended school increased by more than 50% after the treatment for 3 months compared to that before the treatment for 3 months. (2) For DSPS patients, the time of awakening was advanced by more than h and almost reached the desired time. (3) For non-24 patients, non-24-h sleep-wake rhythm was returned to a 24 h cycle. A breakdown of treatments is shown in Table 2. Natural bright light exposure (sunbathing) was successful in three patients without additional treatment, in four patients with methylcobalamin and in two patients with benzodiazepine. Bright light therapy using a light box was successful in a patient without additional treatment. Thus, bright light therapy with or without additional treatment was successful in all 10 patients under treatment. Chronotherapy was useful with short-term (6 days) administration of triazolam during the stabilizing period following a scheduled gradual delay of the sleep phase. Single methylcobalamin therapy was successful in one of four patients (25%). Finally, 13 of 20 patients (65.0%) who completed the study were successfully treated by the therapy based on chronobiology. All Table 2. Procedures Response to treatments Sunbathing Sunbathing + MB2 Sunbathing + BZ Bright light (Light box) Chronotherapy + melatonin Drugs MBl2 + BZ MB2 Melatonin MB2. methylcobalamin (vitamin B2); BZ, benzodiazepine. CASE REPORTS Case 1 Favorable response/total 3/3(100%) 4/4 (100%) 2/2 (OO'Yo) j (100%) j (100%) 0/4 (0%) 1/4 (25%) (100%) seven patients who did not show any improvement were treated with single methylcobalamin (four cases) or with methylcobalamin and benzodiazepin (three cases). Three representative patients were selected from a group of 20 patients who showed a favorable result in the treatment. A 16-year-old girl with DSPS was treated with light therapy (Fig. ). Her mother had difficulty in waking her up every morning since she started elementary school. During the first semester in high school, she had further difficulty in waking up in the morning and irregularly attended school when she woke up early. She was completely absent from school from the 2nd DEC 21 FEB' -- --' -' 20 ==:;:. ~ ~ ' h Figure 1. Sleep record and treatment procedure of case. The horizontal bars indicate sleep and the following open areas indicate wakefulness ' 1:' MAR '1'=;;;;;;;;;"'-'_ g> h

5 Circadian sleep disorders in adolescents 487 semester. She usually slept until noon. The girl visited our sleep clinic at the age of 16 in the high school. She complained about dizziness and headache when she woke up early in the morning. Her sleep diary, kept for a month before the treatment, showed a typical delayed sleep. An examination of oral temperature and blood pressure at home also showed a delay of peak time. We asked her mother to keep the window-shade open in her bed room, and to call her up every morning. Two weeks later. she fell asleep between 22:00 and 23:00, woke up at 7:00 every morning. and attended school without any hesitation. Case 2 A 12-year-old boy with DSPS was treated with methylcobalamin and light therapy (Fig. 2). The patient had no problem with sleep habits in his early childhood, but by the middle elementary school years he had difficulty waking up in the morning and was often late for class. He had been away from school for 6 months because of late waking-up time. When he visited our sleep clinic he had no psychological or psychiatric problems in the interview and the examinations. He was cooperative for his treatment and expressed his willingness to attend classes when he woke up early. 20 Sept i- ' i-- =.: 812 Cl c.c ~.0 C ::J '" Cl c The sleep record showed that he stayed awake for h in the bed trying to sleep, finally went to sleep between 0:00 and 1:00 h, and woke up between 9:00 and 11:00. We gave him 1.5mg ofmethylcobalamin per day (three times a day after each meal, orally), in late August. He usually went to sleep at 0:00 and woke up at 9:00. We advised him to take early morning sunbathing, in the second week of September. Since then he began to fall asleep between 22:00 and 23:00 and to wake up at 7:00 and he was back at school. Case 15 A 17 year-old boy with DSPS was treated with chronotherapy and melatonin (Fig. 3). He had no specific sleep problems at pre-school age and during the period of elementary school. When he entered junior high-school he had difficulty in waking up in the morning and was often late for class. n the first grade of high school, his bed times and wake times gradually delayed and he usually slept between 2:00 and 11:00. During the summer vacation, he had late sleep-wake schedules and afterwards his delayed bed and wake times became more marked. He attended school only 2 days in a week. The patient visited our clinic at the age of 16 and we found no significant psychiatric or physical problems. His sleep diary showed delayed sleep onsets between 0:00 and 4:00 and sleep offsets between 10:00 and 14:00 (Fig. 3). We selected the melatonin treatment and started the chronotherapy beforehand: a scheduled 3-h delay of retiring time was used every day = 0 10 :2 - ~l h h Figure 2. Sleep record and treatment procedure of case 2. Figure 3. Sleep record and treatment procedure of case 15. (T), 1.0 mg of melatonin; (e). attending school.

6 488 M. Okawa ef al. for 5 days and the retiring time was set at 22:00. After the successful chronotherapy we administered 1.0 mg of melatonin at 21 :00 every night. He has regularly attended school from the second day of melatonin administration, and after a 3-month administration of melatonin he stopped taking it. Nevertheless, he has attended school every day. DSCUSSON Adolescents usually go to bed late, but have to get up early in the morning to attend school. This sometimes causes a morning struggle at home. Some adolescents only miss class because they wake up late or are often late for school. They sometimes get depressed or feel unhappy because they failed to attend class. These adolescents should be differentiated from school refusals who show a DSPS-like sleep schedule as a means of avoiding school. f they spend a long period out of school, many of them fail to advance to the upper grade. Subjects in the present study appear to belong to quite a homogeneous group in the following aspects: (i) the age at onset ranged between 11 and 17; (ii) within 1-3 years after the symptoms developed, they visited our hospital; they seemed to be in the early stage of the disorder; (iii) they were willing to visit our sleep-wake disorder clinic because they considered their problems to be sleep onset insomnia and difficulty awakening and not psychiatric disorder, which was verified by using our structured interview: and (iv) the social factors, such as long vacations, traveling to a distant school. or moving. more commonly affected the onset of the diseases than psychological factors. The children in our study could be different from those who would not go to school for their psychological factors in their class or home environment. f these children had to spend a long time struggling. they would be in trouble with their friends, school teachers or parents. which could cause psychotic and/ or psychiatric disorders. They could become complete school refusers in future if they did not receive any treatment. n the present study. two of seven patients who did not respond to any treatment waited 3 years before visiting us. whereas all 13 patients who showed improvement waited less than 2 years. However, the interval between the onset age of disease and the age of first visiting in responders and non-responders did not show significant difference, which could be caused by the small sample size. We summarize effectiveness of therapies for circadian rhythm sleep disorders as follows: (i) light therapy was the most useful treatment with or without additional treatments, 10 of 20 patients showed a favorable response to light therapy: (ii) methylcobalamin is effective with light therapy; and (iii) single methylcobalamin or methylcobalamin with benzodiazepine was not effective for resetting the sleep-wake cycle. Recently we reported that single methylcobalamin administration in a double-blind study did not show a favorable effect on DSPS patients, X which would support our present study. Seven of eight patients who did not respond to therapies were treated with methylcobalamin without light therapy. These suggest that light and methylcobalamin may have a close relation to the therapeutic mechanism of circadian rhythm sleep disorders as referred to in the following section. The study could propose a conventional treatment strategy for these patients. The schematic illustration of the treatment procedure is shown in Fig. 4. For the first step it is important to encourage the patients to keep a scheduled bed time and wake time. organizing the patients' bedroom environment, and avoiding special behavior that contributes to bad sleep habits such as particular late night activities, and erratic napping. We had several patients whose sleep disorders improved only by keeping a scheduled daily life. These patients, however, were not included in the present study because they were not diagnosed as having circadian rhythm sleep disorders. The lighting environment seems important for patients who did not show improvement in sleep disorders by resetting the Figure 4. + Resetting the daily-life schedule Regulation of lighting environment Opening shades, curtains Outdoor sunbathing Chronotherapy 1 1 1~;9htbo' ~ VB1 +.1 Melatonin ~ Benzodiazepine r 1 Maintaining strictly regular life schedule Treatment procedures.

7 Circadian sleep disorders in adolescents 489 daily life schedule. Because we obtained favorable effects of natural light or bright light therapy using fluorescent light, we recommend that the bedroom shade is kept open so that the patients get morning light before they wake up. When patients do not respond to the natural light. bright light therapy will be recommended. However, for patients who are accustomed to waking up very late, for example around noon, chronotherapy for a week will be a convenient and practical step to starting the light therapy in the early morning. The patients easily delay their retiring and waking until a desirable sleep-wake schedule is achieved, and can then undertake light therapy early in the morning. For the next step, if light therapy is not helpful in restoring regular school life, vitamin B2 administration should be introduced during the light therapy. Hashimoto et al. reported a significantly increased suppression of melatonin levels by light in the vitamin B12-administered group in humans,19 and Uchiyama et al. noted an increased rectal temperature when vitamin B2 was given in the daytime in humans. 2o t can be inferred from these results that vitamin B12 might be helpful in increasing daytime activity. For the last few years, patients with DSPS have been successfully treated with a combined treatment of bright light and vitamin B2, and chronotherapy was used conventionally for phase-setting before starting the vitamin B12 treatment. 16 Although the mechanism of these treatments has not been clarified, we have exploited the possible treatments and attempted a systematic combination of them for patients with DSPS. As a last step, drug therapy such as benzodiazepine or melatonin would be recommended. Benzodiazepine appeared to be a useful sleep inducer during the stabilizing period of the sleep-wake schedule in chronotherapy or bright light therapy. A drug-administration period of a few days or a week could be enough for this treatment. Melatonin is known to be effective for jet lag syndrome,2j.24 and Dahlitz et al. reported the efficacy of melatonin for DSPS patients in advancing rectal temperature rhythm. 25 However, it is not clear if the patients' sleep improved. Melatonin treatment for circadian rhythm sleep disorders has not been well established because the mechanism of melatonin is not clear, and further studies are needed if the melatonin is to be effective for phase-setting, for sleep inducing or for mediating the autonomic system. So far, from our study, melatonin should be administered 1-2 h before the patient's usual delayed bed time, which should be gradually advanced until the desired time. 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