Case Study: Psychiatric Misdiagnosis of Non-24-HoursSleep-Wake Schedule Disorder Resolved by Melatonin

YARON DAGAN, M.D., D.SC. AND LIAT AYALON, PH.D.

ABSTRACT

This case study describes a 14-year-old male suffering from significant academic and personal difficulties, who has been

diagnosed with depression, schizotypal personality disorder, and learning disabilities. Because of excessive sleepiness,

assessment for a potential sleep disorder was performed. An overnight polysomnographic study revealed no primary sleep

disorders. Wrist actigraphy revealed a non-24-hour sleep-wake pattern. Delay in temperature rhythm and dissociation with

melatonin rhythms were also noted. Treatment with oral melatonin restored normal sleep-wake schedule. In a follow-up

psychiatric evaluation, none of the above diagnoses were present. Greater awareness of sleep disorders may prevent

psychiatric misdiagnosis of treatable sleep-wake schedule disorders. J. Am. Acad. Child Adolesc. Psychiatry, 2005;

44(12):1271–1275. Key Words: circadian rhythm sleep disorder, free running, non-24-hour sleep-wake syndrome, mel-

atonin, actigraphy.

In humans, sleep and wake episodes occur at regulartimes that match the 24-hour day-night cycle. This tem-poral organization, known as circadian rhythmicity(from the Latin circa, ‘‘about,’’ and dies, ‘‘day’’), is pres-ent in many behavioral and physiological functions.The circadian timing system is thought to play a centralrole in the generation, maintenance, and synchronizationof circadian rhythms to each other and to the environ-ment. At the core of this system are the suprachiasmaticnuclei (SCN) of the hypothalamus, which generate theendogenous component of circadian rhythms. The SCNis entrained by environmental factors, the most prom-inent of which is light. In response to input from theSCN, the pineal gland secretes melatonin during thenight (Dijk and Edgar, 1999).The interplay of endogenous and exogenous factors

required to maintain a normal sleep-wake rhythm can

become chronically impaired in some individuals, lead-ing to circadian rhythm sleep disorders (CRSD). CRSDinvolve alterations of the circadian timing system ora misalignment between the timing of the individual�ssleep-wake rhythm and the environment. In patientswith CRSD, sleep episodes occur at inappropriate timesoften leading to impairment in various areas of func-tioning (American Academy of Sleep Medicine, 2001).Changes in other biological rhythms often accompanyCRSD. In individuals with a normal sleep-wake cycle,melatonin secretion follows a circadian rhythm withhigher levels occurring at night, whereas body temper-ature follows the inverse time course of the melatoninrhythm. In individuals with CRSD, the timing andphase relationship of these rhythms are often changed(American Academy of Sleep Medicine, 2001).Non-24-hour sleep-wake syndrome consists of a

chronic steady pattern of 1- to 2-hour daily delays insleep onset and wake times. Patients with this syndromeexhibit a sleep-wake pattern that free runs with a period-icity of more than 24 hours. Because an incrementalphase delay in sleep occurs, the relationship betweenthe internal clock and the external clock varies fromcomplete synchrony to total asynchrony. As a result,the complaints will consist of difficulty initiating sleepat night coupled with daytime sleepiness. Patients mayalternate between being symptomatic and asymptom-atic, depending on the degree of synchrony between

Accepted May 10, 2005.Dr. Dagan is with the Institute for Fatigue and Sleep Medicine, Sheba Med-

ical Center, Tel-Hashomer and the Department of Behavioral Sciences, SacklerFaculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel; Dr. Ayalon is withthe Department of Psychiatry, University of California San Diego and VeteransAffairs San Diego Healthcare System, San Diego, CA.

Supported by NIMH 5 T32 MH18,399-17, M01 RR00,827 (L.A.).Correspondence to Dr. Yaron Dagan, Institute for Fatigue and Sleep Medi-

cine, Sheba Medical Center, Tel-Hashomer 52621, Israel; e-mail: daganyar@sheba.health.gov.il.

0890-8567/05/4412–1271�2005 by the American Academy of Child

and Adolescent Psychiatry.

DOI: 10.1097/01.chi.0000181040.83465.48

J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 44:12, DECEMBER 2005 1271

their internal biological rhythm and the 24-hour world.This total disregard for environmental time cues leadsto educational and occupational problems (AmericanAcademy of Sleep Medicine, 2001). Behavioral andpsychiatric conditions are also frequently associatedwith CRSD (Dagan et al., 1996, 1998). Attempts bypatients with CRSD to adjust to daily activity often re-sults in mild to severe sleep deprivation, which in chil-dren frequently leads to symptoms of inattention,irritability, distractibility, impulsivity (Dahl, 1995),and decrements in performance (e.g., Randazzo et al.,1998).The present article is a case study of psychiatric

misdiagnosis of a non-24-hour sleep-wake syndrome.Diagnosis of CRSD led to successful treatment withmelatonin and disappearance of psychiatric symptoms.

CASE REPORT

A 14-year-old male was referred for sleep disorder as-sessment with the complaint of daytime sleepiness and

lack of motivation. During the 4 years before referral,the patient suffered from major functioning difficultiesincluding conflicts with teachers, parents, and peers. Hewas described by a licensed child psychologist as beingextremely introverted with severe narcissistic traits, pov-erty of thought, and disturbed thinking, includingthoughts with persecutory content and self-destructionthat led to a paralyzing anxiety, anhedonia, social iso-lation, and withdrawal. Assessment of learning disabil-ities revealed difficulties with written language and poorvisual and auditory memory. Assessment also revealedabove-average performances in verbal comprehensionand abstract reasoning.

Two years before referral, the patient dropped out ofschool and was sent to an inpatient child psychiatry cen-ter. Three months of psychiatric evaluation yielded di-agnoses of atypical depressive disorder with possibleschizotypal personality disorder. He was described assleepy and passive, especially in the mornings. The pa-tient�s psychiatrist suggested further assessment, includ-ing assessment of sleep disorders.

Fig. 1 Rest-activity rhythm (actogram) of the patient before treatment (double plot).

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1272 J . AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 44:12, DECEMBER 2005

SLEEP AND CIRCADIAN RHYTHM ASSESSMENT

During the assessment of sleep disorders and circa-dian rhythms the patient did not take any medications.

Sleep Testing

The patient underwent full-night polysomnographyduring which electroencephalogram, electroculogram,electromyogram, electrocardiogram, respiration, and legmovements were recorded. Polysomnographic results re-vealed normal sleep architecture with sleep efficiency of94.3%. Long sleep latency (111 min) was evident, sug-gesting difficulty falling asleep.

Sleep-Wake Rhythms Evaluation

Actigraphy. Three weeks of wrist actigraphy were per-formed. The actigraph (Actiwatch, activity monitors,Mini Mitter Company, 1-minute sampling interval)is a watchlike device that is attached to the wrist ofthe subject and differentiates between sleep and waking,based on the amount of movement in the limb (Ancoli-Israel et al., 2003). Actigraphy revealed a non-24-hoursleep-wake pattern (Fig. 1).Activity data, summed during 30-minute intervals,

were subjected to Fourier spectral analysis to detect dom-inant periods and to single cosine best-fit analysis to assessthe compatibility of the data to a simple sinusoidal waveof various periods (De Prins and Hecquet, 1992). Figure2 presents the best-fit model to the activity data. A 26-hour pattern was observed. Note the progressively grow-ing drift from 24 hours as time from the start of testing.

Temperature and Melatonin Rhythms

Oral temperature and level of melatonin secretion(using a melatonin direct saliva kit) were recorded every

2 hours during a 24-hour period of time at the Institutefor Fatigue and Sleep Medicine. Radioimmunoassaywas used for the quantitative determination of melato-nin in saliva.Cosine analysis of melatonin and oral temperature

rhythms revealed a significant 24-hour pattern of salivarymelatonin (p < .05); however, no significant circadian pat-tern was found for oral temperature rhythm and an un-coupling with melatonin rhythm was observed (Fig. 3).

TREATMENT

Chronic treatment with oral melatonin (5 mg at8 p.m.) restored normal sleep-wake schedule withina month, and a follow-up actigraphy after 6 monthsof melatonin treatment revealed a full entrainment toa 24-hour day (Fig. 4). Melatonin and temperaturerhythms were not recorded after treatment becausethe patient and his parents did not want to disrupthis sleep schedule once synchronized by treatment. Inaddition, the parents did not want their child to gothrough nocturnal measurements.The possibilities of light treatment and behavioral in-

terventions were considered. Given the patient�s historyof an inability to control time of awakening, however,both the parents and the patient expected difficulties

Fig. 2 Rhythmicity in activity pattern of the patient before melatonin treat-

ment. Activity levels are approximated by a sinusoidal function with a peri-

odicity of 26 hours.

Fig. 3 Rhythmicity in salivary melatonin and oral temperature measured

every 2 hours for 24 hours.

SLEEP-WAKE SCHEDULE DISORDER AND MELATONIN

J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 44:12, DECEMBER 2005 1273

waking up for the morning light exposure and wereskeptical about the patient�s ability to comply with be-havioral interventions.The patient returned to school after a 1 year�s absence

and succeeded in filling the gaps ofmissing studies. At theend of the first semester, his school report showed excel-lent results. His parents also reported an improvement inthe patient�s relationship with his family and peers.In a psychiatric evaluation by licensed psychiatrists,

none of the previously described severe diagnoses werepresent, and the boy showed no evidence of psychopa-thology, as was previously thought.

DISCUSSION

This case study presents a psychiatric misdiagnosis ofa non-24-hour sleep-wake schedule disorder. A 26-hoursleep-wake schedule as well as dissociation between oraltemperature and salivary melatonin rhythms have been

found. Failure to make a correct diagnosis led to psy-chological distress and personal turmoil for a boy whosesleep disorder was easily diagnosable and treatable withmelatonin.

This study highlights the strong relationship betweensleep problems and other psychological and medicalproblems. This is consistent with other studies reportingcorrelations between sleep quality and neurobehavioralfunctioning (Gozal, 1998; Sadeh et al., 2002) and be-tween sleep schedule and daytime functioning (Wolfsonand Carskadon, 1998).

In addition, sleep problems are related to childhoodlearning and behavioral problems (Corkum et al., 1998)and an increased risk of learning and behavioral prob-lems in healthy preadolescents (Kahn et al., 1989).Parental reports of sleep problems have also been asso-ciated with child psychiatric disorders, includingattention-deficit/hyperactivity disorder (Corkum et al.,1998) and childhood depression (Sadeh et al., 1995).

Fig. 4 Rest-activity rhythm (actogram) of the patient after melatonin treatment (double plot) 1 month following initiation of melatonin treatment during

vacation (A) and follow-up after 6 months of treatment during summer vacation (B).

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1274 J . AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 44:12, DECEMBER 2005

Failure to adjust to daily activity in individuals withCRSD often leads to sleep deprivation that frequentlyresults in symptoms of inattention, irritability, andimpulsivity (Dahl, 1995), as well as performance andpsychological changes (e.g., Carskadon et al., 1998).Given that our findings are based on a single case

study, one should be cautious in drawing conclusions.The strong relationship between sleep and the regulationof emotion and behavior, combined with the possibilityof clinical improvement in behavior after optimiza-tion of sleep, however, highlight the importance ofCRSD evaluation and treatment in children and adoles-cents presenting with behavioral and academic con-cerns. Asking parents about the child�s bedtime andwake-up time as well as teachers� reports of sleepinessin the classroom are important. Reports of delayed orirregular sleep-wake rhythms and daytime sleepinessshould trigger referral for a circadian rhythmevaluation.

Disclosure: The authors have no financial relationships to disclose.

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