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Hyperactivity Disorder and Chronic Sleep-Onset Insomnia
Delayed Circadian Rhythm in Adults with Attention-Deficit/Hyperactivity Disorder and Chronic Sleep-Onset Insomnia Maaike M. Van Veen, J.J. Sandra Kooij, A. Marije Boonstra, Marijke C.M. Gordijn, and Eus J.W. Van Someren Background: Previous studies suggest circadian rhythm disturbances in children with attention-deficit/hyperactivity disorder (ADHD) and sleep-onset insomnia (SOI). We investigate here sleep and rhythms in activity and melatonin in adults with ADHD. Methods: Sleep logs and actigraphy data were collected during 1 week in 40 adults with ADHD, of whom 31 reported SOI. Salivary melatonin levels were assessed during 1 night. Sleep measures, circadian activity variables, and dim light melatonin onset were compared between groups of ADHD adults with and without SOI and with matched healthy control subjects. Results: Compared with control subjects, both groups of ADHD adults had longer sleep-onset latency and lower sleep efficiency. Adults with ADHD and SOI showed a delayed start and end of their sleep period and a delayed melatonin onset compared with adults with ADHD without SOI (p ⫽ .006; p ⫽ .023; p ⫽ .02) and compared with healthy control subjects (p ⫽ .014; p ⫽ .019; p ⫽ .000). Adults with ADHD and SOI also showed an attenuated 24-hour amplitude in their rest-activity pattern, in contrast to those without SOI, who showed a higher day-to-day stability. Conclusions: These findings demonstrate diurnal rhythm deviations during everyday life in the majority of adults with ADHD that have SOI and suggest that potential benefits of rhythm-improving measures should be evaluated. Key Words: Actigraphy, attention-deficit/hyperactivity disorder, circadian rhythm, insomnia, melatonin, sleep
A
ttention-deficit/hyperactivity disorder (ADHD) is a common psychiatric disorder characterized by inattention and/or hyperactivity/impulsivity leading to impaired functioning. It starts in early childhood and persists into adulthood in many cases (1). Prevalence estimates range from 4% to 8% in children and from 1% to 5% in adults (2,3). Subjective sleep complaints are common in both adults and children diagnosed with ADHD. High nocturnal activity was a diagnostic criterion for ADHD in the DSM-III but was omitted from subsequent DSM editions as being nonspecific. However, several associations between sleep disorders and ADHD have been described over the past decades (see [4] for review). Apart from a higher prevalence of primary sleep disorders in ADHD and vice versa (5–7), studies have found evidence for reduced rapid eye movement sleep, increased nocturnal activity, and excessive daytime sleepiness in children with ADHD (8 –11). This overlap can be a challenge in the diagnostic process, as sleep disorders often result in sleepiness during the day and may present as inattention and behavioral disturbances, mimicking the core symptoms of ADHD.
From the PsyQ Psycho-Medical Programs (MMVV, JJSK, AMB), Program Adult ADHD, The Hague; Department of Psychology (AMB), Erasmus University, Rotterdam; Department of Chronobiology (MCMG), University of Groningen, Haren; Netherlands Institute for Neuroscience (EJWVS), Institute of the Royal Netherlands Academy of Arts and Sciences, Amsterdam; and Departments of Clinical Neurophysiology, Neurology, and Medical Psychology (EJWVS), VU University Medical Center, Amsterdam, The Netherlands. Address correspondence to Maaike M. Van Veen, M.D., PsyQ, Program Adult ADHD, Carel Reinierszkade 197, 2593 HR, Den Haag, The Netherlands; E-mail: [email protected]. Received Sep 16, 2009; revised Dec 16, 2009; accepted Dec 30, 2009.
0006-3223/$36.00 doi:10.1016/j.biopsych.2009.12.032
One study of children with ADHD and insomnia reported a delayed onset of melatonin production at night (dim light melatonin onset [DLMO]) with an otherwise normal sleep quality (12). Melatonin is synthesized in the pineal gland and its secretion is regulated by the circadian pacemaker in the suprachiasmatic nucleus. Daytime levels are low and a steep rise occurs in the evening (13). Because this rise, as quantified with the DLMO, is a reliable phase marker of the circadian clock (14), children with ADHD might have a delayed circadian clock function. Clinical experience from adults with ADHD suggests a similar pattern, as about 70% complain of a lifelong pattern of difficulty falling asleep and waking up (15,16) at normal times of the day. Studies in impulsive subjects and in adults with ADHD found a high proportion of self-reported late circadian preference (preferred timing of rest/activity), also known as “evening types” (17,18). Further support for a possible circadian rhythm anomaly in ADHD is found in the increased prevalence of seasonal affective disorder in adults with ADHD (19,20), a disorder also hypothesized by some to be associated with circadian rhythm disturbances (21). Previous studies of sleep problems in adults with ADHD invariably report complaints on sleep quality (22– 24). As in children, most investigations of sleep in adults with ADHD have focused on primary sleep disorders, such as restless legs syndrome, periodic limb movement disorder, obstructive sleep apnea syndrome, or hypersomnia (e.g., narcolepsy) (25– 31). We here present the first study investigating whether sleeponset problems in adults with ADHD could be related to alterations in circadian regulation.
Methods and Materials Subjects Written informed consent was obtained from each subject and the study was approved by the local medical ethical committee. Subjects with ADHD (21 male subjects and 19 female subjects aged 18 –55 years) were consecutively recruited from our outpaBIOL PSYCHIATRY 2010;67:1091–1096 © 2010 Society of Biological Psychiatry
1092 BIOL PSYCHIATRY 2010;67:1091–1096 tient clinic between June 2006 and August 2007. All had been diagnosed with lifetime ADHD with childhood onset according to DSM-IV criteria by experienced clinicians, using a semistructured interview for ADHD and comorbidity (32,33). To be given a diagnosis of adult ADHD, subjects had to 1) meet six of nine DSM-IV criteria of inattention and/or hyperactivity/impulsivity in childhood and at least five of nine criteria in adulthood, 2) describe a chronic persisting course of ADHD symptoms, and 3) endorse a moderate to severe level of impaired functioning. Three ADHD subtypes were discriminated based on symptoms in adulthood: ADHD-predominantly inattentive (n ⫽ 6), ADHDpredominantly hyperactive/impulsive (n ⫽ 0), and ADHD-combined (n ⫽ 34) (meeting criteria for both). The interview also addressed current and lifetime symptoms of mood and anxiety disorders, psychosis, and substance use disorders. Detailed information on the diagnostic assessment has been published previously (34). Exclusion criteria were use of any medication influencing sleep (including antidepressants, hypnotics, antipsychotics, melatonin, and stimulants) within 1 month before enrollment, traveling within more than one time zone or participation in shift work in the last month, and any current severe comorbid psychiatric or medical disorder. Considering the high prevalence of comorbid disorders in adults with ADHD (3), subjects with mild current and/or lifetime psychiatric disorders were included to obtain a clinically representative sample. Directly following the regular diagnostic assessment procedure, subjects’ files were screened for eligibility. When found eligible and willing to participate in the study, subjects were screened a second time by a telephone interview to assess current comorbid anxiety or depressive symptoms based on the DSM-IV criteria. Furthermore, medication use, substance use, and recent life events were evaluated again. In case of any doubt considering exclusion criteria, subjects were evaluated face-to-face by an experienced clinician. Subjects reporting using more than 15 (women)/21 (men) alcohol units per week or currently using drugs were excluded from the study. Whereas the primary focus of the present study was to evaluate differences between adults with ADHD and sleep-onset complaints and those without, we also included reference values for actigraphy and melatonin variables from two groups of healthy volunteers without sleep complaints. Actigraphy data were obtained from 24 healthy control subjects, matched for age and gender (mean age 29.1 ⫾ 7.9, 50% male). Dim light melatonin onset data were obtained from 38 healthy control subjects, matched for age and gender (mean age 28.9 ⫾ 9.9, 53% male). All control subjects were physically healthy and had no symptoms or history of mental or sleeping disorders. Subjective Sleep Further examination consisted of a clinical history on sleep habits and difficulties getting to sleep or getting up. In case of insomnia, the duration was specified as being more or less than 6 months or present from early childhood. Sleep-onset insomnia (SOI) was defined as difficulty getting to sleep at a desired bedtime (later than 23:30) and/or a sleep-onset latency (time from bedtime to sleep start) of more than 30 minutes for at least 4 nights a week, existing for at least 6 months, and leading to impairment in several areas. The validated Dutch Sleep Disorders Questionnaire (SDQ) (35) was used to evaluate symptoms of several categories of sleep disturbances including insomnia, sleep apnea, and restless legs syndrome. A cutoff score of three www.sobp.org/journal
M.M. Van Veen et al. points on the SDQ subscales insomnia, apnea, and restless legs was used to identify subjects suspect for primary sleep disorders. Objective Sleep Estimates and Activity Rhythm Rest-activity patterns were measured over 7 consecutive days/nights using actigraphy (Actiwatch, Cambridge Neurotechnology, Ltd., Cambridge, United Kingdom), which is the 24-hour assessment of activity with a small wrist-worn device (36,37). All subjects kept daily sleep logs during the measurement week. No external limitations were set considering subjects’ usual sleeping behavior. Sleep measures were estimated from actigraphic data using a standard algorithm (Actiwatch Sleep Analysis version 5.08, Cambridge Neurotechnology, Ltd.) and included sleep start, sleep end, total sleep time, sleep-onset latency, and sleep efficiency (time in bed actually spent asleep). Activity patterns over days and nights were assessed by calculating previously validated nonparametric circadian variables (38 – 40). The interdaily stability (IS) quantifies the degree of resemblance between activity patterns on individual days as an indication of the stability of the diurnal rhythm. The intradaily variability (IV) quantifies the number and extent of transitions between periods restful versus active hours as an indication of the fragmentation of the diurnal rhythm. The amplitude (AMP) quantifies the difference between daytime and nighttime activity levels. All variables were calculated over seven 24-hour days. Melatonin Salivary melatonin samples were collected on 1 night at home by chewing on a cotton swab (Salivetten: Sarstedt, Numbrecht, Germany) five times at hourly intervals between 21:00 and 01:00. Attention-deficit/hyperactivity disorder subjects were instructed to stay at home during the measurements, with curtains closed and only one dim light on to avoid suppression of melatonin secretion by light (41). Melatonin concentrations were assayed at the laboratory of Gelderse Vallei Hospital in Ede, The Netherlands. Detailed information on sampling and processing has been described elsewhere (12,42). Dim light melatonin onset was calculated as the linearly interpolated time of the first sample above 3 pg/mL that was preceded by a lower value (43). In subjects whose melatonin levels had reached 3 pg/mL before 21:00 or had not yet reached 3 pg/mL by 01:00, we assumed that DLMO was at 21:00 or 01:00, respectively, as conservative estimates allowing for their inclusion in the data analysis. As season may affect the pattern of melatonin secretion (e.g., [13]), we registered average natural day length at the time of melatonin assessment in each subject, based on meteorologic data. Data Analysis Differences in group composition and the incidence of SDQ suprathreshold subscale scores were tested using chi-square tests. Actigraphic variables and DLMO were compared between groups using t tests. If homogeneity of variance (Levene’s test) could be assumed, Student t tests were used; if not, Welch’s t tests were used. Pearson correlations were calculated between DLMO and the average onset and the average end of the sleep period. The statistical significance threshold was set at p ⫽ .05.
Results Demographic data and data on ADHD subtype and substance use are shown in Table 1.
Four rightmost columns show p values of group mean comparisons. ADHD, attention-deficit/hyperactivity disorder; AMP, amplitude; a.u., arbitrary units; DLMO, dim light melatonin onset; HC, healthy control subjects; IS, interdaily stability; IV, intradaily variability; No-SOI, ADHD subjects without sleep-onset insomnia; SOI, ADHD subjects with sleep-onset insomnia.
.411 .430 .027 .021 .001 .002 .092 .345 .181 .014 .019 .926 .031 .004 .103 .053 .000 .000 .115 .019 .501 .015 .002 .476 .039 .000 .000 0:49 ⫾ 0:50 (n ⫽ 24) 8:27 ⫾ 0:53 (n ⫽ 24) 409.9 ⫾ 41.4 (n ⫽ 24) 87.88 ⫾ 3.73 (n ⫽ 24) 6.92 ⫾ 4.78 (n ⫽ 24) .75 ⫾ .09 (n ⫽ 24) .36 ⫾ .06 (n ⫽ 24) 46.1 ⫾ 3.2 (n ⫽ 24) 21:34 ⫾ 0:45 (n ⫽ 38) 1:42 ⫾ 1:22 (n ⫽ 30) 9:27 ⫾ 1:44 (n ⫽ 30) 413.2 ⫾ 69.2 (n ⫽ 30) 84.45 ⫾ 6.32 (n ⫽ 30) 17.70 ⫾ 16.05 (n ⫽ 30) .71 ⫾ .13 (n ⫽ 29) .41 ⫾ .11 (n ⫽ 29) 41.1 ⫾ 5.4 (n ⫽ 29) 23:15 ⫾ 1:19 (n ⫽ 26)
0:14 ⫾ 1:04 (n ⫽ 9) 8:26 ⫾ 0:48 (n ⫽ 9) 438.2 ⫾ 50.1 (n ⫽ 9) 84.86 ⫾ 4.29 (n ⫽ 9) 17.74 ⫾ 14.33 (n ⫽ 9) .83 ⫾ .04 (n ⫽ 9) .41 ⫾ .09 (n ⫽ 9) 45.1 ⫾ 2.5 (n ⫽ 9) 22:00 ⫾ 0:54 (n ⫽ 8)
p: no-SOI vs. HC p: SOI vs. HC
1:21 ⫾ 1:26 (n ⫽ 39) 9:13 ⫾ 1:37 (n ⫽ 39) 418.9 ⫾ 65.5 (n ⫽ 39) 84.54 ⫾ 5.87 (n ⫽ 39) 17.71 ⫾ 15.48 (n ⫽ 39) .74 ⫾ .12 (n ⫽ 38) .41 ⫾ .10 (n ⫽ 38) 42.1 ⫾ 5.1 (n ⫽ 38) 22:57 ⫾ 1:20 (n ⫽ 34) Sleep Start (hour) Sleep End (hour) Total Sleep Duration (minutes) Sleep Efficiency (%) Sleep-Onset Latency (minutes) IS (a.u.) IV (a.u.) AMP (minutes/hour) DLMO (hour)
Objective Sleep Estimates and Activity Rhythm Group means of sleep estimates and circadian variables are shown in Table 2. For one subject in the SOI group, nonparametric variables could not be calculated because of an insufficient number of successful 24-hour recordings. Analyses comparing all ADHD subjects with control subjects indicated that subjects with ADHD woke up significantly later than healthy control subjects, without differing with respect to sleep start. Sleep efficiency was 3.8 ⫾ 6.7% lower in the ADHD group than in the control group, with 11 minutes longer sleeponset latency. Attention-deficit/hyperactivity disorder subjects showed a 13.8 ⫾ 27.7% higher variability (IV) and 8.7 ⫾ 11.1% lower amplitude (AMP) of the circadian rhythm compared with healthy control subjects. Analyses separately comparing the two ADHD subgroups (SOI and no-SOI) with control subjects showed that subjects with ADHD and SOI started their sleep period 53 minutes later and woke up 60 minutes later than control subjects and had longer sleep latency and less efficient sleep (all differences significant). The circadian rhythm amplitude was 10.8 ⫾ 11.7% lower. Strikingly, subjects with ADHD without SOI slept 28 minutes longer than control subjects but still took longer to fall asleep and had less efficient sleep. Furthermore, they had a 10.7 ⫾ 5.3% more stable rhythm (IS) than control subjects. Other parameters did not differ significantly.
Table 2. Actigraphic Sleep Parameter Estimates, Circadian Rhythm Parameters, and DLMO Group Means Including Standard Deviations (⫾)
Subjective Sleep Of the 40 ADHD subjects included in the present study, 31 (78%) suffered from SOI, of whom in 23 (74%) cases difficulties in falling asleep at an appropriate time had been present from early childhood. The ADHD groups with and without SOI did not differ with regard to age (p ⫽ .586) or sex (2 ⫽ .302; p ⫽ .583). However, the ADHD-combined subtype was significantly more prevalent among ADHD subjects with SOI (29/31, 94%) than in those without SOI (5/9, 56%) (2 ⫽ 7.90; p ⫽ .005). The ADHD groups with and without SOI did not differ significantly with respect to the frequency of subjects scoring above cutoff on the insomnia, apnea, and restless legs subscales of the SDQ. According to the insomnia subscale, 9 out of 31 SOI subjects and 0 out of 9 no-SOI subjects were suspect for the diagnosis of insomnia. Due to the small sample size of the no-SOI group, this seeming difference still did not reach significance (p ⫽ .11). According to the apnea subscale, 1 out of 31 SOI subjects and 0 out of 9 no-SOI subjects were suspect for the diagnosis of apnea (p ⫽ .59). According to the restless legs subscale, 3 out of 31 SOI subjects and 0 out of 9 no-SOI subjects were suspect for the diagnosis of restless legs (p ⫽ .35).
p: ADHD vs. HC
ADHD, Attention-deficit/hyperactivity disorder; no-SOI, ADHD subjects without sleep-onset insomnia; SD, standard deviation; SOI, ADHD subjects with sleep-onset insomnia.
HC
30.0 ⫾ 11.9 4 (44%) 5 (56%) 4 (44%) 0 (0%) 5.67 1.11
No-SOI
28.2 ⫾ 7.6 17 (55%) 29 (94%) 2 (6%) 0 (0%) 6.76 8.16
SOI
No-SOI (n ⫽ 9, 22%)
ADHD, Total
Age in Years, mean ⫾ SD Male, n (%) ADHD-Combined Type, n (%) ADHD-Inattentive Type, n (%) ADHD-Hyperactive/Impulsive Type, n (%) Alcohol (units/week) Nicotine (cigarettes/day)
SOI (n ⫽ 31, 78%)
p: SOI vs. No-SOI
Table 1. Demographic, ADHD Subtype, and Substance Use Data
.006 .023 .320 .859 .994 .000 .994 .005 .02
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M.M. Van Veen et al. Moreover, no meaningful correlation was found between day length at the time of measurement and DLMO (r ⫽ .022; p ⫽ .901).
Discussion
Figure 1. Average activity level profiles during the 24-hour day, in 6-minute bins. ADHD, attention-deficit/hyperactivity disorder; no-SOI, ADHD subjects without sleep-onset insomnia; SOI, ADHD subjects with sleep-onset insomnia.
Comparing ADHD subjects with and without SOI, subjects with SOI started their sleep period later and woke up later than those without SOI (88 minutes and 61 minutes, respectively). The groups did not differ with respect to sleep-onset latency and sleep efficiency. Subjects with SOI had a 14.5 ⫾ 15.7% lower circadian rhythm stability (IS) and a 8.8 ⫾ 12.0% lower amplitude (AMP) compared with those without SOI (Figure 1). Melatonin Group means of DLMO are shown in Table 2. Melatonin outcomes were missing in five subjects because of insufficient saliva samples. In five subjects (19%) in the SOI group, salivary melatonin concentration did not reach 3 pg/mL before 01:00. For subsequent analyses, DLMO was conservatively estimated at the latest sample time, i.e., 01:00. In one subject in the SOI group and three in the group without SOI, melatonin levels already had reached the 3 pg/mL threshold at the first sample time; DLMO was conservatively estimated to be 21:00. Analyses comparing all ADHD subjects with control subjects indicated that nighttime melatonin production started 83 minutes later in subjects with ADHD than in healthy control subjects. This difference was primarily due to subjects with ADHD and SOI (23:15 ⫾ 1:19, p ⫽ .000), as no significant difference was observed in DLMO between subjects with ADHD without SOI (22:00 ⫾ 0:54, p ⫽ .345) and control subjects. Comparing ADHD subjects with and without SOI, DLMO was 75 minutes later in the SOI group (p ⫽ .02). Ancillary analyses omitting the cases where DLMO fell outside, i.e., earlier or later than, the sampling interval, rather than conservatively estimating their DLMO, confirmed the difference in DLMO between ADHD subjects and healthy control subjects (22:51 vs. 21:34; p ⫽ .000). Over all ADHD subjects, DLMO correlated significantly with the start (r ⫽ .65; p ⫽ .000) and end (r ⫽ .38; p ⫽ .028) of the sleep period (Figure 2). No significant differences were found in average natural day length at the time of melatonin measurement between the groups with and without SOI (12.9 ⫾ 3.1 vs. 13.5 ⫾ 2.6, p ⫽ .634). www.sobp.org/journal
We found subjective sleep-onset insomnia in 78% of a consecutive sample of adults with ADHD. In comparison with adults with ADHD without sleep problems and in comparison with healthy control subjects, actigraphy confirmed a markedly delayed sleep period, which was associated with a delayed nighttime melatonin onset, in ADHD with sleep-onset insomnia. Once in bed though, ADHD subjects with and without SOI did not differ with respect to sleep-onset latency, sleep efficiency, or total sleep duration. Yet, compared with healthy control subjects, subjects with ADHD in general took longer to fall asleep and slept less efficient. The most important differences found in circadian rhythm variables were a less stable rhythm (IS) and lower amplitude (AMP) in subjects with ADHD and SOI, compared with both healthy control subjects and ADHD subjects without SOI. A low stability is indicative of a less predictable, i.e., more variable, daily schedule of activity, while a low amplitude indicates a reduced difference between daytime and nighttime activity levels; both suggest a weak circadian rhythm. Compared with healthy control subjects, rhythm variability (IV) was higher in ADHD subjects, pointing to many transitions between restful and active hours and thus less consolidated periods of rest and activity.
Figure 2. Correlation between DLMO and sleep onset/sleep end. ADHD, attention-deficit/hyperactivity disorder; DLMO, dim light melatonin onset; no-SOI, ADHD subjects without sleep-onset insomnia; SOI, ADHD subjects with sleep-onset insomnia.
M.M. Van Veen et al. Another notable finding is the higher prevalence of the ADHD inattentive subtype in the group without SOI. Previous research in children and adolescents describes that inattentive subtypes sleep longer and are sleepier during the day (44,45). It has been suggested previously that motor restlessness might be an important symptom of decreased vigilance and sleepiness (46). Recent findings in nonmedicated adults with ADHD show associations of hyperactive/impulsive symptoms with self-reported shorter sleep duration, lower sleep efficiency, and lower overall sleep quality (47). In our study, ADHD subjects without SOI slept significantly longer and had a more stable rhythm compared with ADHD subjects with SOI and control subjects. If replicated in larger studies, this finding could contribute to further differentiation of the clinically very different inattentive subtype. It may also indicate that certain sleep and rhythm characteristics, as found in the inattentive type, could protect against sleep-onset problems within the ADHD population. Compared with healthy control subjects, the DLMO occurred on average almost an hour and a half later in ADHD subjects with SOI. This finding suggests a delayed endogenous circadian phase in association with the delayed sleep in ADHD. Whether the shifted DLMO reflects an etiologic contribution or a consequence of the delayed sleep-wake rhythm cannot be concluded from the present dataset. Possible etiologic mechanisms could be a weaker internal generation of rhythm, a longer period of the endogenous pacemaker, or an altered susceptibility to external timing cues or “Zeitgebers” (48). Our findings are in accordance with the outcomes of the study by Van der Heijden et al. (12), measuring DLMO in children with ADHD, where 73% of subjects met the criteria for sleep-onset insomnia. Children with ADHD and SOI were found to have a markedly delayed sleep onset, sleep end, and melatonin onset compared with subjects with ADHD without SOI, whereas total sleep duration was similar. Some caution should be exerted in interpreting the promising data of this study considering the relatively small sample size of the group without SOI, which limited the investigation of possible confounding factors. We aimed to include comparable numbers in both groups but we had great difficulty identifying subjects without SOI. Although we screened for symptoms of comorbid sleep disorders, we did not obtain the objective measurement to fully exclude restless legs syndrome, periodic limb movement disorder, or obstructive sleep apnea syndrome and cannot exclude the possibility that some of the ADHD subjects could be diagnosed with a primary sleep disorder as well. Another possible limitation is that we relied on subjects’ self-reports on substance use and did not obtain blood or urine samples. Still, substance use could be a way of dealing with the effects of chronic insomnia, as well as be involved in its cause, considering the lifelong pattern of symptoms in most subjects. Group differences in nicotine use could contribute to insomnia, but the effect of nicotine on melatonin secretion is yet unclear (13). Furthermore, the limited validity of actigraphy for determining sleep-onset latency may have obscured possible differences in sleep-onset latency. Even slight imprecision of the lights out time reported in sleep logs has a considerable effect on latency estimates—while affecting the other sleep estimates only marginally. The difficulty we had in the exact establishment of DLMO before 21:00 and after 01:00 in several subjects is a further practical limitation of this study, and collection of melatonin samples in a wider time range is necessary in future studies of DLMO in adults with ADHD.
BIOL PSYCHIATRY 2010;67:1091–1096 1095 Despite these limitations, our findings strongly suggest the involvement of chronobiological disturbances in sleep-onset problems in adults with ADHD. Although sleep itself seems normal in efficiency and duration, when trying to function properly in a 9-to-5 society, a rhythm delay will often lead to chronically shortened sleep. Both circadian misalignment and short sleep duration are known to be associated with major general health problems, like obesity and other metabolic and cardiovascular risk factors (49,50). Furthermore, chronically disturbed sleep has a strong impact on daytime functioning and quality of life (48,51,52). Our findings warrant further studies to assess the contribution of the biological clock in the pathogenesis and symptoms of ADHD and to investigate the efficacy of bright light and melatonin as chronobiological approaches for symptom management in these patients. We thank Azadeh Banaei-Kashani, M.D., for her contribution to data collection. J.J.S. Kooij has been speaker for Janssen Cilag BV and Eli Lilly and has received unrestricted research funding from Janssen Cilag BV for this study. M.M. Van Veen, A.M. Boonstra, M.C.M. Gordijn, and E.J.W. Van Someren reported no biomedical financial interests or potential conflicts of interest. 1. Biederman J, Monuteaux MC, Mick E, Spencer T, Wilens TE, Silva JM, et al. (2006): Young adult outcome of attention deficit hyperactivity disorder: A controlled 10-year follow-up study. Psychol Med 36:167–179. 2. Faraone SV, Sergeant J, Gillberg C (2003): The worldwide prevalence of ADHD: Is it an American condition? World Psychiatry 2:104 –113. 3. Fayyad J, de Graaf R, Kessler R, Alonso J, Angermeyer M, Demyttenaere K, et al. (2007): Cross-national prevalence and correlates of adult attention-deficit hyperactivity disorder. Br J Psychiatry 190:402– 409. 4. Walters AS, Silvestri R, Zucconi M, Chandrashekariah R, Konofal E (2008): Review of the possible relationship and hypothetical links between attention deficit hyperactivity disorder (ADHD) and the simple sleep related movement disorders, parasomnias, hypersomnias, and circadian rhythm disorders. J Clin Sleep Med 4:591– 600. 5. Konofal E (2008): Relationship between attention deficit hyperactivity disorder and sleep disturbances. Int J Sleep Wakefulness 1:109 –117. 6. Lecendreux M, Cortese S (2007): Sleep problems associated with ADHD: A review of current therapeutic options and recommendations for the future. Expert Rev Neurother 7:1799 –1806. 7. Cohen-Zion M, Ancoli-Israel S (2004): Sleep in children with attentiondeficit hyperactivity disorder (ADHD): A review of naturalistic and stimulant intervention studies. Sleep Med Rev 8:379 – 402. 8. Sadeh A, Pergamin L, Bar-Haim Y (2006): Sleep in children with attention-deficit hyperactivity disorder: A meta-analysis of polysomnographic studies. Sleep Med Rev 10:381–398. 9. Golan N, Shahar E, Ravid S, Pillar G (2004): Sleep disorders and daytime sleepiness in children with attention-deficit/hyperactive disorder. Sleep 27:261–266. 10. Picchietti DL, Underwood DJ, Farris WA, Walters AS, Shah MM, Dahl RE, et al. (1999): Further studies on periodic limb movement disorder and restless legs syndrome in children with attention-deficit hyperactivity disorder. Mov Disord 14:1000 –1007. 11. O’Brien LM, Ivanenko A, Crabtree VM, Holbrook CR, Bruner JL, Klaus CJ, Gozal D (2003): Sleep disturbances in children with attention deficit hyperactivity disorder. Pediatr Res 54:237–243. 12. Van der Heijden KB, Smits MG, Van Someren EJW, Gunning WB (2005): Idiopathic chronic sleep onset insomnia in attention-deficit/hyperactivity disorder: A circadian rhythm sleep disorder. Chronobiol Int 22:559 – 570. 13. Arendt J (2005): Melatonin: Characteristics, concerns, and prospects. J Biol Rhythms 20:291–303. 14. Klerman EB, Gershengorn HB, Duffy JF, Kronauer RE (2002): Comparisons of the variability of three markers of the human circadian pacemaker. J Biol Rhythms 17:181–193. 15. Kooij JJS, Aeckerlin LP, Buitelaar JK (2001): Functioning, comorbidity and treatment of 141 adults with attention deficit hyperactivity disorder
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A
ttention-deficit/hyperactivity disorder (ADHD) is a common psychiatric disorder characterized by inattention and/or hyperactivity/impulsivity leading to impaired functioning. It starts in early childhood and persists into adulthood in many cases (1). Prevalence estimates range from 4% to 8% in children and from 1% to 5% in adults (2,3). Subjective sleep complaints are common in both adults and children diagnosed with ADHD. High nocturnal activity was a diagnostic criterion for ADHD in the DSM-III but was omitted from subsequent DSM editions as being nonspecific. However, several associations between sleep disorders and ADHD have been described over the past decades (see [4] for review). Apart from a higher prevalence of primary sleep disorders in ADHD and vice versa (5–7), studies have found evidence for reduced rapid eye movement sleep, increased nocturnal activity, and excessive daytime sleepiness in children with ADHD (8 –11). This overlap can be a challenge in the diagnostic process, as sleep disorders often result in sleepiness during the day and may present as inattention and behavioral disturbances, mimicking the core symptoms of ADHD.
From the PsyQ Psycho-Medical Programs (MMVV, JJSK, AMB), Program Adult ADHD, The Hague; Department of Psychology (AMB), Erasmus University, Rotterdam; Department of Chronobiology (MCMG), University of Groningen, Haren; Netherlands Institute for Neuroscience (EJWVS), Institute of the Royal Netherlands Academy of Arts and Sciences, Amsterdam; and Departments of Clinical Neurophysiology, Neurology, and Medical Psychology (EJWVS), VU University Medical Center, Amsterdam, The Netherlands. Address correspondence to Maaike M. Van Veen, M.D., PsyQ, Program Adult ADHD, Carel Reinierszkade 197, 2593 HR, Den Haag, The Netherlands; E-mail: [email protected]. Received Sep 16, 2009; revised Dec 16, 2009; accepted Dec 30, 2009.
0006-3223/$36.00 doi:10.1016/j.biopsych.2009.12.032
One study of children with ADHD and insomnia reported a delayed onset of melatonin production at night (dim light melatonin onset [DLMO]) with an otherwise normal sleep quality (12). Melatonin is synthesized in the pineal gland and its secretion is regulated by the circadian pacemaker in the suprachiasmatic nucleus. Daytime levels are low and a steep rise occurs in the evening (13). Because this rise, as quantified with the DLMO, is a reliable phase marker of the circadian clock (14), children with ADHD might have a delayed circadian clock function. Clinical experience from adults with ADHD suggests a similar pattern, as about 70% complain of a lifelong pattern of difficulty falling asleep and waking up (15,16) at normal times of the day. Studies in impulsive subjects and in adults with ADHD found a high proportion of self-reported late circadian preference (preferred timing of rest/activity), also known as “evening types” (17,18). Further support for a possible circadian rhythm anomaly in ADHD is found in the increased prevalence of seasonal affective disorder in adults with ADHD (19,20), a disorder also hypothesized by some to be associated with circadian rhythm disturbances (21). Previous studies of sleep problems in adults with ADHD invariably report complaints on sleep quality (22– 24). As in children, most investigations of sleep in adults with ADHD have focused on primary sleep disorders, such as restless legs syndrome, periodic limb movement disorder, obstructive sleep apnea syndrome, or hypersomnia (e.g., narcolepsy) (25– 31). We here present the first study investigating whether sleeponset problems in adults with ADHD could be related to alterations in circadian regulation.
Methods and Materials Subjects Written informed consent was obtained from each subject and the study was approved by the local medical ethical committee. Subjects with ADHD (21 male subjects and 19 female subjects aged 18 –55 years) were consecutively recruited from our outpaBIOL PSYCHIATRY 2010;67:1091–1096 © 2010 Society of Biological Psychiatry
1092 BIOL PSYCHIATRY 2010;67:1091–1096 tient clinic between June 2006 and August 2007. All had been diagnosed with lifetime ADHD with childhood onset according to DSM-IV criteria by experienced clinicians, using a semistructured interview for ADHD and comorbidity (32,33). To be given a diagnosis of adult ADHD, subjects had to 1) meet six of nine DSM-IV criteria of inattention and/or hyperactivity/impulsivity in childhood and at least five of nine criteria in adulthood, 2) describe a chronic persisting course of ADHD symptoms, and 3) endorse a moderate to severe level of impaired functioning. Three ADHD subtypes were discriminated based on symptoms in adulthood: ADHD-predominantly inattentive (n ⫽ 6), ADHDpredominantly hyperactive/impulsive (n ⫽ 0), and ADHD-combined (n ⫽ 34) (meeting criteria for both). The interview also addressed current and lifetime symptoms of mood and anxiety disorders, psychosis, and substance use disorders. Detailed information on the diagnostic assessment has been published previously (34). Exclusion criteria were use of any medication influencing sleep (including antidepressants, hypnotics, antipsychotics, melatonin, and stimulants) within 1 month before enrollment, traveling within more than one time zone or participation in shift work in the last month, and any current severe comorbid psychiatric or medical disorder. Considering the high prevalence of comorbid disorders in adults with ADHD (3), subjects with mild current and/or lifetime psychiatric disorders were included to obtain a clinically representative sample. Directly following the regular diagnostic assessment procedure, subjects’ files were screened for eligibility. When found eligible and willing to participate in the study, subjects were screened a second time by a telephone interview to assess current comorbid anxiety or depressive symptoms based on the DSM-IV criteria. Furthermore, medication use, substance use, and recent life events were evaluated again. In case of any doubt considering exclusion criteria, subjects were evaluated face-to-face by an experienced clinician. Subjects reporting using more than 15 (women)/21 (men) alcohol units per week or currently using drugs were excluded from the study. Whereas the primary focus of the present study was to evaluate differences between adults with ADHD and sleep-onset complaints and those without, we also included reference values for actigraphy and melatonin variables from two groups of healthy volunteers without sleep complaints. Actigraphy data were obtained from 24 healthy control subjects, matched for age and gender (mean age 29.1 ⫾ 7.9, 50% male). Dim light melatonin onset data were obtained from 38 healthy control subjects, matched for age and gender (mean age 28.9 ⫾ 9.9, 53% male). All control subjects were physically healthy and had no symptoms or history of mental or sleeping disorders. Subjective Sleep Further examination consisted of a clinical history on sleep habits and difficulties getting to sleep or getting up. In case of insomnia, the duration was specified as being more or less than 6 months or present from early childhood. Sleep-onset insomnia (SOI) was defined as difficulty getting to sleep at a desired bedtime (later than 23:30) and/or a sleep-onset latency (time from bedtime to sleep start) of more than 30 minutes for at least 4 nights a week, existing for at least 6 months, and leading to impairment in several areas. The validated Dutch Sleep Disorders Questionnaire (SDQ) (35) was used to evaluate symptoms of several categories of sleep disturbances including insomnia, sleep apnea, and restless legs syndrome. A cutoff score of three www.sobp.org/journal
M.M. Van Veen et al. points on the SDQ subscales insomnia, apnea, and restless legs was used to identify subjects suspect for primary sleep disorders. Objective Sleep Estimates and Activity Rhythm Rest-activity patterns were measured over 7 consecutive days/nights using actigraphy (Actiwatch, Cambridge Neurotechnology, Ltd., Cambridge, United Kingdom), which is the 24-hour assessment of activity with a small wrist-worn device (36,37). All subjects kept daily sleep logs during the measurement week. No external limitations were set considering subjects’ usual sleeping behavior. Sleep measures were estimated from actigraphic data using a standard algorithm (Actiwatch Sleep Analysis version 5.08, Cambridge Neurotechnology, Ltd.) and included sleep start, sleep end, total sleep time, sleep-onset latency, and sleep efficiency (time in bed actually spent asleep). Activity patterns over days and nights were assessed by calculating previously validated nonparametric circadian variables (38 – 40). The interdaily stability (IS) quantifies the degree of resemblance between activity patterns on individual days as an indication of the stability of the diurnal rhythm. The intradaily variability (IV) quantifies the number and extent of transitions between periods restful versus active hours as an indication of the fragmentation of the diurnal rhythm. The amplitude (AMP) quantifies the difference between daytime and nighttime activity levels. All variables were calculated over seven 24-hour days. Melatonin Salivary melatonin samples were collected on 1 night at home by chewing on a cotton swab (Salivetten: Sarstedt, Numbrecht, Germany) five times at hourly intervals between 21:00 and 01:00. Attention-deficit/hyperactivity disorder subjects were instructed to stay at home during the measurements, with curtains closed and only one dim light on to avoid suppression of melatonin secretion by light (41). Melatonin concentrations were assayed at the laboratory of Gelderse Vallei Hospital in Ede, The Netherlands. Detailed information on sampling and processing has been described elsewhere (12,42). Dim light melatonin onset was calculated as the linearly interpolated time of the first sample above 3 pg/mL that was preceded by a lower value (43). In subjects whose melatonin levels had reached 3 pg/mL before 21:00 or had not yet reached 3 pg/mL by 01:00, we assumed that DLMO was at 21:00 or 01:00, respectively, as conservative estimates allowing for their inclusion in the data analysis. As season may affect the pattern of melatonin secretion (e.g., [13]), we registered average natural day length at the time of melatonin assessment in each subject, based on meteorologic data. Data Analysis Differences in group composition and the incidence of SDQ suprathreshold subscale scores were tested using chi-square tests. Actigraphic variables and DLMO were compared between groups using t tests. If homogeneity of variance (Levene’s test) could be assumed, Student t tests were used; if not, Welch’s t tests were used. Pearson correlations were calculated between DLMO and the average onset and the average end of the sleep period. The statistical significance threshold was set at p ⫽ .05.
Results Demographic data and data on ADHD subtype and substance use are shown in Table 1.
Four rightmost columns show p values of group mean comparisons. ADHD, attention-deficit/hyperactivity disorder; AMP, amplitude; a.u., arbitrary units; DLMO, dim light melatonin onset; HC, healthy control subjects; IS, interdaily stability; IV, intradaily variability; No-SOI, ADHD subjects without sleep-onset insomnia; SOI, ADHD subjects with sleep-onset insomnia.
.411 .430 .027 .021 .001 .002 .092 .345 .181 .014 .019 .926 .031 .004 .103 .053 .000 .000 .115 .019 .501 .015 .002 .476 .039 .000 .000 0:49 ⫾ 0:50 (n ⫽ 24) 8:27 ⫾ 0:53 (n ⫽ 24) 409.9 ⫾ 41.4 (n ⫽ 24) 87.88 ⫾ 3.73 (n ⫽ 24) 6.92 ⫾ 4.78 (n ⫽ 24) .75 ⫾ .09 (n ⫽ 24) .36 ⫾ .06 (n ⫽ 24) 46.1 ⫾ 3.2 (n ⫽ 24) 21:34 ⫾ 0:45 (n ⫽ 38) 1:42 ⫾ 1:22 (n ⫽ 30) 9:27 ⫾ 1:44 (n ⫽ 30) 413.2 ⫾ 69.2 (n ⫽ 30) 84.45 ⫾ 6.32 (n ⫽ 30) 17.70 ⫾ 16.05 (n ⫽ 30) .71 ⫾ .13 (n ⫽ 29) .41 ⫾ .11 (n ⫽ 29) 41.1 ⫾ 5.4 (n ⫽ 29) 23:15 ⫾ 1:19 (n ⫽ 26)
0:14 ⫾ 1:04 (n ⫽ 9) 8:26 ⫾ 0:48 (n ⫽ 9) 438.2 ⫾ 50.1 (n ⫽ 9) 84.86 ⫾ 4.29 (n ⫽ 9) 17.74 ⫾ 14.33 (n ⫽ 9) .83 ⫾ .04 (n ⫽ 9) .41 ⫾ .09 (n ⫽ 9) 45.1 ⫾ 2.5 (n ⫽ 9) 22:00 ⫾ 0:54 (n ⫽ 8)
p: no-SOI vs. HC p: SOI vs. HC
1:21 ⫾ 1:26 (n ⫽ 39) 9:13 ⫾ 1:37 (n ⫽ 39) 418.9 ⫾ 65.5 (n ⫽ 39) 84.54 ⫾ 5.87 (n ⫽ 39) 17.71 ⫾ 15.48 (n ⫽ 39) .74 ⫾ .12 (n ⫽ 38) .41 ⫾ .10 (n ⫽ 38) 42.1 ⫾ 5.1 (n ⫽ 38) 22:57 ⫾ 1:20 (n ⫽ 34) Sleep Start (hour) Sleep End (hour) Total Sleep Duration (minutes) Sleep Efficiency (%) Sleep-Onset Latency (minutes) IS (a.u.) IV (a.u.) AMP (minutes/hour) DLMO (hour)
Objective Sleep Estimates and Activity Rhythm Group means of sleep estimates and circadian variables are shown in Table 2. For one subject in the SOI group, nonparametric variables could not be calculated because of an insufficient number of successful 24-hour recordings. Analyses comparing all ADHD subjects with control subjects indicated that subjects with ADHD woke up significantly later than healthy control subjects, without differing with respect to sleep start. Sleep efficiency was 3.8 ⫾ 6.7% lower in the ADHD group than in the control group, with 11 minutes longer sleeponset latency. Attention-deficit/hyperactivity disorder subjects showed a 13.8 ⫾ 27.7% higher variability (IV) and 8.7 ⫾ 11.1% lower amplitude (AMP) of the circadian rhythm compared with healthy control subjects. Analyses separately comparing the two ADHD subgroups (SOI and no-SOI) with control subjects showed that subjects with ADHD and SOI started their sleep period 53 minutes later and woke up 60 minutes later than control subjects and had longer sleep latency and less efficient sleep (all differences significant). The circadian rhythm amplitude was 10.8 ⫾ 11.7% lower. Strikingly, subjects with ADHD without SOI slept 28 minutes longer than control subjects but still took longer to fall asleep and had less efficient sleep. Furthermore, they had a 10.7 ⫾ 5.3% more stable rhythm (IS) than control subjects. Other parameters did not differ significantly.
Table 2. Actigraphic Sleep Parameter Estimates, Circadian Rhythm Parameters, and DLMO Group Means Including Standard Deviations (⫾)
Subjective Sleep Of the 40 ADHD subjects included in the present study, 31 (78%) suffered from SOI, of whom in 23 (74%) cases difficulties in falling asleep at an appropriate time had been present from early childhood. The ADHD groups with and without SOI did not differ with regard to age (p ⫽ .586) or sex (2 ⫽ .302; p ⫽ .583). However, the ADHD-combined subtype was significantly more prevalent among ADHD subjects with SOI (29/31, 94%) than in those without SOI (5/9, 56%) (2 ⫽ 7.90; p ⫽ .005). The ADHD groups with and without SOI did not differ significantly with respect to the frequency of subjects scoring above cutoff on the insomnia, apnea, and restless legs subscales of the SDQ. According to the insomnia subscale, 9 out of 31 SOI subjects and 0 out of 9 no-SOI subjects were suspect for the diagnosis of insomnia. Due to the small sample size of the no-SOI group, this seeming difference still did not reach significance (p ⫽ .11). According to the apnea subscale, 1 out of 31 SOI subjects and 0 out of 9 no-SOI subjects were suspect for the diagnosis of apnea (p ⫽ .59). According to the restless legs subscale, 3 out of 31 SOI subjects and 0 out of 9 no-SOI subjects were suspect for the diagnosis of restless legs (p ⫽ .35).
p: ADHD vs. HC
ADHD, Attention-deficit/hyperactivity disorder; no-SOI, ADHD subjects without sleep-onset insomnia; SD, standard deviation; SOI, ADHD subjects with sleep-onset insomnia.
HC
30.0 ⫾ 11.9 4 (44%) 5 (56%) 4 (44%) 0 (0%) 5.67 1.11
No-SOI
28.2 ⫾ 7.6 17 (55%) 29 (94%) 2 (6%) 0 (0%) 6.76 8.16
SOI
No-SOI (n ⫽ 9, 22%)
ADHD, Total
Age in Years, mean ⫾ SD Male, n (%) ADHD-Combined Type, n (%) ADHD-Inattentive Type, n (%) ADHD-Hyperactive/Impulsive Type, n (%) Alcohol (units/week) Nicotine (cigarettes/day)
SOI (n ⫽ 31, 78%)
p: SOI vs. No-SOI
Table 1. Demographic, ADHD Subtype, and Substance Use Data
.006 .023 .320 .859 .994 .000 .994 .005 .02
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M.M. Van Veen et al. Moreover, no meaningful correlation was found between day length at the time of measurement and DLMO (r ⫽ .022; p ⫽ .901).
Discussion
Figure 1. Average activity level profiles during the 24-hour day, in 6-minute bins. ADHD, attention-deficit/hyperactivity disorder; no-SOI, ADHD subjects without sleep-onset insomnia; SOI, ADHD subjects with sleep-onset insomnia.
Comparing ADHD subjects with and without SOI, subjects with SOI started their sleep period later and woke up later than those without SOI (88 minutes and 61 minutes, respectively). The groups did not differ with respect to sleep-onset latency and sleep efficiency. Subjects with SOI had a 14.5 ⫾ 15.7% lower circadian rhythm stability (IS) and a 8.8 ⫾ 12.0% lower amplitude (AMP) compared with those without SOI (Figure 1). Melatonin Group means of DLMO are shown in Table 2. Melatonin outcomes were missing in five subjects because of insufficient saliva samples. In five subjects (19%) in the SOI group, salivary melatonin concentration did not reach 3 pg/mL before 01:00. For subsequent analyses, DLMO was conservatively estimated at the latest sample time, i.e., 01:00. In one subject in the SOI group and three in the group without SOI, melatonin levels already had reached the 3 pg/mL threshold at the first sample time; DLMO was conservatively estimated to be 21:00. Analyses comparing all ADHD subjects with control subjects indicated that nighttime melatonin production started 83 minutes later in subjects with ADHD than in healthy control subjects. This difference was primarily due to subjects with ADHD and SOI (23:15 ⫾ 1:19, p ⫽ .000), as no significant difference was observed in DLMO between subjects with ADHD without SOI (22:00 ⫾ 0:54, p ⫽ .345) and control subjects. Comparing ADHD subjects with and without SOI, DLMO was 75 minutes later in the SOI group (p ⫽ .02). Ancillary analyses omitting the cases where DLMO fell outside, i.e., earlier or later than, the sampling interval, rather than conservatively estimating their DLMO, confirmed the difference in DLMO between ADHD subjects and healthy control subjects (22:51 vs. 21:34; p ⫽ .000). Over all ADHD subjects, DLMO correlated significantly with the start (r ⫽ .65; p ⫽ .000) and end (r ⫽ .38; p ⫽ .028) of the sleep period (Figure 2). No significant differences were found in average natural day length at the time of melatonin measurement between the groups with and without SOI (12.9 ⫾ 3.1 vs. 13.5 ⫾ 2.6, p ⫽ .634). www.sobp.org/journal
We found subjective sleep-onset insomnia in 78% of a consecutive sample of adults with ADHD. In comparison with adults with ADHD without sleep problems and in comparison with healthy control subjects, actigraphy confirmed a markedly delayed sleep period, which was associated with a delayed nighttime melatonin onset, in ADHD with sleep-onset insomnia. Once in bed though, ADHD subjects with and without SOI did not differ with respect to sleep-onset latency, sleep efficiency, or total sleep duration. Yet, compared with healthy control subjects, subjects with ADHD in general took longer to fall asleep and slept less efficient. The most important differences found in circadian rhythm variables were a less stable rhythm (IS) and lower amplitude (AMP) in subjects with ADHD and SOI, compared with both healthy control subjects and ADHD subjects without SOI. A low stability is indicative of a less predictable, i.e., more variable, daily schedule of activity, while a low amplitude indicates a reduced difference between daytime and nighttime activity levels; both suggest a weak circadian rhythm. Compared with healthy control subjects, rhythm variability (IV) was higher in ADHD subjects, pointing to many transitions between restful and active hours and thus less consolidated periods of rest and activity.
Figure 2. Correlation between DLMO and sleep onset/sleep end. ADHD, attention-deficit/hyperactivity disorder; DLMO, dim light melatonin onset; no-SOI, ADHD subjects without sleep-onset insomnia; SOI, ADHD subjects with sleep-onset insomnia.
M.M. Van Veen et al. Another notable finding is the higher prevalence of the ADHD inattentive subtype in the group without SOI. Previous research in children and adolescents describes that inattentive subtypes sleep longer and are sleepier during the day (44,45). It has been suggested previously that motor restlessness might be an important symptom of decreased vigilance and sleepiness (46). Recent findings in nonmedicated adults with ADHD show associations of hyperactive/impulsive symptoms with self-reported shorter sleep duration, lower sleep efficiency, and lower overall sleep quality (47). In our study, ADHD subjects without SOI slept significantly longer and had a more stable rhythm compared with ADHD subjects with SOI and control subjects. If replicated in larger studies, this finding could contribute to further differentiation of the clinically very different inattentive subtype. It may also indicate that certain sleep and rhythm characteristics, as found in the inattentive type, could protect against sleep-onset problems within the ADHD population. Compared with healthy control subjects, the DLMO occurred on average almost an hour and a half later in ADHD subjects with SOI. This finding suggests a delayed endogenous circadian phase in association with the delayed sleep in ADHD. Whether the shifted DLMO reflects an etiologic contribution or a consequence of the delayed sleep-wake rhythm cannot be concluded from the present dataset. Possible etiologic mechanisms could be a weaker internal generation of rhythm, a longer period of the endogenous pacemaker, or an altered susceptibility to external timing cues or “Zeitgebers” (48). Our findings are in accordance with the outcomes of the study by Van der Heijden et al. (12), measuring DLMO in children with ADHD, where 73% of subjects met the criteria for sleep-onset insomnia. Children with ADHD and SOI were found to have a markedly delayed sleep onset, sleep end, and melatonin onset compared with subjects with ADHD without SOI, whereas total sleep duration was similar. Some caution should be exerted in interpreting the promising data of this study considering the relatively small sample size of the group without SOI, which limited the investigation of possible confounding factors. We aimed to include comparable numbers in both groups but we had great difficulty identifying subjects without SOI. Although we screened for symptoms of comorbid sleep disorders, we did not obtain the objective measurement to fully exclude restless legs syndrome, periodic limb movement disorder, or obstructive sleep apnea syndrome and cannot exclude the possibility that some of the ADHD subjects could be diagnosed with a primary sleep disorder as well. Another possible limitation is that we relied on subjects’ self-reports on substance use and did not obtain blood or urine samples. Still, substance use could be a way of dealing with the effects of chronic insomnia, as well as be involved in its cause, considering the lifelong pattern of symptoms in most subjects. Group differences in nicotine use could contribute to insomnia, but the effect of nicotine on melatonin secretion is yet unclear (13). Furthermore, the limited validity of actigraphy for determining sleep-onset latency may have obscured possible differences in sleep-onset latency. Even slight imprecision of the lights out time reported in sleep logs has a considerable effect on latency estimates—while affecting the other sleep estimates only marginally. The difficulty we had in the exact establishment of DLMO before 21:00 and after 01:00 in several subjects is a further practical limitation of this study, and collection of melatonin samples in a wider time range is necessary in future studies of DLMO in adults with ADHD.
BIOL PSYCHIATRY 2010;67:1091–1096 1095 Despite these limitations, our findings strongly suggest the involvement of chronobiological disturbances in sleep-onset problems in adults with ADHD. Although sleep itself seems normal in efficiency and duration, when trying to function properly in a 9-to-5 society, a rhythm delay will often lead to chronically shortened sleep. Both circadian misalignment and short sleep duration are known to be associated with major general health problems, like obesity and other metabolic and cardiovascular risk factors (49,50). Furthermore, chronically disturbed sleep has a strong impact on daytime functioning and quality of life (48,51,52). Our findings warrant further studies to assess the contribution of the biological clock in the pathogenesis and symptoms of ADHD and to investigate the efficacy of bright light and melatonin as chronobiological approaches for symptom management in these patients. We thank Azadeh Banaei-Kashani, M.D., for her contribution to data collection. J.J.S. Kooij has been speaker for Janssen Cilag BV and Eli Lilly and has received unrestricted research funding from Janssen Cilag BV for this study. M.M. Van Veen, A.M. Boonstra, M.C.M. Gordijn, and E.J.W. Van Someren reported no biomedical financial interests or potential conflicts of interest. 1. Biederman J, Monuteaux MC, Mick E, Spencer T, Wilens TE, Silva JM, et al. (2006): Young adult outcome of attention deficit hyperactivity disorder: A controlled 10-year follow-up study. Psychol Med 36:167–179. 2. Faraone SV, Sergeant J, Gillberg C (2003): The worldwide prevalence of ADHD: Is it an American condition? World Psychiatry 2:104 –113. 3. Fayyad J, de Graaf R, Kessler R, Alonso J, Angermeyer M, Demyttenaere K, et al. (2007): Cross-national prevalence and correlates of adult attention-deficit hyperactivity disorder. Br J Psychiatry 190:402– 409. 4. Walters AS, Silvestri R, Zucconi M, Chandrashekariah R, Konofal E (2008): Review of the possible relationship and hypothetical links between attention deficit hyperactivity disorder (ADHD) and the simple sleep related movement disorders, parasomnias, hypersomnias, and circadian rhythm disorders. J Clin Sleep Med 4:591– 600. 5. Konofal E (2008): Relationship between attention deficit hyperactivity disorder and sleep disturbances. Int J Sleep Wakefulness 1:109 –117. 6. Lecendreux M, Cortese S (2007): Sleep problems associated with ADHD: A review of current therapeutic options and recommendations for the future. Expert Rev Neurother 7:1799 –1806. 7. Cohen-Zion M, Ancoli-Israel S (2004): Sleep in children with attentiondeficit hyperactivity disorder (ADHD): A review of naturalistic and stimulant intervention studies. Sleep Med Rev 8:379 – 402. 8. Sadeh A, Pergamin L, Bar-Haim Y (2006): Sleep in children with attention-deficit hyperactivity disorder: A meta-analysis of polysomnographic studies. Sleep Med Rev 10:381–398. 9. Golan N, Shahar E, Ravid S, Pillar G (2004): Sleep disorders and daytime sleepiness in children with attention-deficit/hyperactive disorder. Sleep 27:261–266. 10. Picchietti DL, Underwood DJ, Farris WA, Walters AS, Shah MM, Dahl RE, et al. (1999): Further studies on periodic limb movement disorder and restless legs syndrome in children with attention-deficit hyperactivity disorder. Mov Disord 14:1000 –1007. 11. O’Brien LM, Ivanenko A, Crabtree VM, Holbrook CR, Bruner JL, Klaus CJ, Gozal D (2003): Sleep disturbances in children with attention deficit hyperactivity disorder. Pediatr Res 54:237–243. 12. Van der Heijden KB, Smits MG, Van Someren EJW, Gunning WB (2005): Idiopathic chronic sleep onset insomnia in attention-deficit/hyperactivity disorder: A circadian rhythm sleep disorder. Chronobiol Int 22:559 – 570. 13. Arendt J (2005): Melatonin: Characteristics, concerns, and prospects. J Biol Rhythms 20:291–303. 14. Klerman EB, Gershengorn HB, Duffy JF, Kronauer RE (2002): Comparisons of the variability of three markers of the human circadian pacemaker. J Biol Rhythms 17:181–193. 15. Kooij JJS, Aeckerlin LP, Buitelaar JK (2001): Functioning, comorbidity and treatment of 141 adults with attention deficit hyperactivity disorder
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