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Effects of Chronotherapeutic Interventions in Adults with ADHD and Delayed Sleep Phase Syndrome (DSPS) on Regulation of Appetite and Glucose Metabolism

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Title: Effects of Chronotherapeutic Interventions in Adults with ADHD and Delayed Sleep Phase Syndrome (DSPS) on Regulation of Appetite and Glucose Metabolism
Language: English
Authors: Emma van Andel (ORCID 0000-0002-7987-8865), Suzan W. N. Vogel, Denise Bijlenga, Andries Kalsbeek, Aartjan T. F. Beekman, J. J. Sandra Kooij (ORCID 0000-0002-8644-6323)
Source: Journal of Attention Disorders. 2024 28(13):1653-1667.
Availability: SAGE Publications. 2455 Teller Road, Thousand Oaks, CA 91320. Tel: 800-818-7243; Tel: 805-499-9774; Fax: 800-583-2665; e-mail: journals@sagepub.com; Web site: https://sagepub.com
Peer Reviewed: Y
Page Count: 15
Publication Date: 2024
Document Type: Journal Articles
Reports - Research
Descriptors: Foreign Countries, Adults, Attention Deficit Hyperactivity Disorder, Sleep, Obesity, Diabetes, Comorbidity, Intervention, Metabolism, Biochemistry, Human Body
Geographic Terms: Netherlands
DOI: 10.1177/10870547241285160
ISSN: 1087-0547
1557-1246
Abstract: Background: ADHD is highly comorbid with Delayed Sleep Phase Syndrome (DSPS). Both are associated with obesity and diabetes, which can be caused by long-term dysregulations of appetite and glucose metabolism. This study explores hormones involved in these processes and the effects of chronotherapeutic interventions in a small sample of adults with ADHD and DSPS. Methods: Exploratory, secondary analysis of data from the PhASE study, a three-armed randomized clinical trial, are presented, including 37 adults (18-53 years) with ADHD and DSPS receiving three weeks of 0.5 mg/day (1) placebo, (2) melatonin, or (3) melatonin plus 30 minutes of bright light therapy (BLT). Leptin (appetite-suppressing), ghrelin (appetite-stimulating), insulin, insulin-like growth factor-1 (IGF-1), and glucose were measured from blood collected at 08:00 hours. Salivary cortisol was collected during the first 30 minutes after awakening and self-reported appetite was assessed. Results: Baseline leptin and IGF-1 levels were higher than reference ranges, and ghrelin and cortisol levels were lower, while insulin and glucose were normal. Melatonin treatment decreased leptin and insulin. Other outcomes remained unchanged and melatonin + BLT had no effects. Conclusion: Due to the small sample size and exploratory nature of the study, results should be interpreted with caution. Overall, these results show no strong indications for dysregulation of appetite and glucose metabolism to suggest high risk of obesity and diabetes in this small sample of adults with ADHD and DSPS. However, baseline appetite was suppressed, likely because measurements took place in the early morning which could be considered the biological night for this study population. Melatonin treatment seemed to cause subtle changes in appetite-regulating hormones suggesting increased appetite. Chronotherapeutic treatment may affect appetite-regulating hormones by advancing the biological rhythm and/or altering eating behaviors, but this remains to be investigated in larger samples using detailed food diaries.
Abstractor: As Provided
Entry Date: 2024
Accession Number: EJ1445022
Database: ERIC
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  Value: <anid>AN0180357939;gs001nov.24;2024Oct22.02:40;v2.2.500</anid> <title id="AN0180357939-1">Effects of Chronotherapeutic Interventions in Adults With ADHD and Delayed Sleep Phase Syndrome (DSPS) on Regulation of Appetite and Glucose Metabolism </title> <p>Background: ADHD is highly comorbid with Delayed Sleep Phase Syndrome (DSPS). Both are associated with obesity and diabetes, which can be caused by long-term dysregulations of appetite and glucose metabolism. This study explores hormones involved in these processes and the effects of chronotherapeutic interventions in a small sample of adults with ADHD and DSPS. Methods: Exploratory, secondary analysis of data from the PhASE study, a three-armed randomized clinical trial, are presented, including 37 adults (18–53 years) with ADHD and DSPS receiving three weeks of 0.5 mg/day (<reflink idref="bib1" id="ref1">1</reflink>) placebo, (<reflink idref="bib2" id="ref2">2</reflink>) melatonin, or (<reflink idref="bib3" id="ref3">3</reflink>) melatonin plus 30 minutes of bright light therapy (BLT). Leptin (appetite-suppressing), ghrelin (appetite-stimulating), insulin, insulin-like growth factor-1 (IGF-1), and glucose were measured from blood collected at 08:00 hours. Salivary cortisol was collected during the first 30 minutes after awakening and self-reported appetite was assessed. Results: Baseline leptin and IGF-1 levels were higher than reference ranges, and ghrelin and cortisol levels were lower, while insulin and glucose were normal. Melatonin treatment decreased leptin and insulin. Other outcomes remained unchanged and melatonin + BLT had no effects. Conclusion: Due to the small sample size and exploratory nature of the study, results should be interpreted with caution. Overall, these results show no strong indications for dysregulation of appetite and glucose metabolism to suggest high risk of obesity and diabetes in this small sample of adults with ADHD and DSPS. However, baseline appetite was suppressed, likely because measurements took place in the early morning which could be considered the biological night for this study population. Melatonin treatment seemed to cause subtle changes in appetite-regulating hormones suggesting increased appetite. Chronotherapeutic treatment may affect appetite-regulating hormones by advancing the biological rhythm and/or altering eating behaviors, but this remains to be investigated in larger samples using detailed food diaries.</p> <p>Keywords: ADHD; delayed sleep; biomarkers; chronotherapy; melatonin</p> <hd id="AN0180357939-2">Introduction</hd> <p>Up to 78% of adults with ADHD have a delayed biological rhythm, as measured by salivary melatonin ([<reflink idref="bib78" id="ref4">78</reflink>]). Melatonin is the main signaling molecule of the internal biological clock located in the brain. The time when salivary melatonin reaches a certain threshold, the Dim-Light Melatonin Onset (DLMO), is a commonly used biomarker for the phase of the biological clock ([<reflink idref="bib44" id="ref5">44</reflink>]). In adults with ADHD, sleep initiation occurs on average 2.5 hours after DLMO ([<reflink idref="bib9" id="ref6">9</reflink>]). A delayed DLMO may lead to a diagnosis of Delayed Sleep Phase Syndrome (DSPS; [<reflink idref="bib1" id="ref7">1</reflink>]). Common consequences of DSPS are chronic sleep loss and social jetlag, that is a mismatch between the internal biological clock and the external social clock ([<reflink idref="bib83" id="ref8">83</reflink>]). ADHD, sleep loss, and social jetlag have been associated with various negative health outcomes and chronic diseases, including obesity and diabetes ([<reflink idref="bib3" id="ref9">3</reflink>]; Bouman et al., 2022; [<reflink idref="bib23" id="ref10">23</reflink>]; [<reflink idref="bib27" id="ref11">27</reflink>]; [<reflink idref="bib29" id="ref12">29</reflink>]; [<reflink idref="bib33" id="ref13">33</reflink>]; [<reflink idref="bib35" id="ref14">35</reflink>]; [<reflink idref="bib61" id="ref15">61</reflink>]; [<reflink idref="bib64" id="ref16">64</reflink>]). ADHD has a complex, bidirectional relationship with the sleep-wake rhythm, and sleep problems can be consequences, causes, or intrinsic features of ADHD and vice versa ([<reflink idref="bib10" id="ref17">10</reflink>]; [<reflink idref="bib32" id="ref18">32</reflink>]). People with both ADHD and DSPS may thus be particularly at risk of chronic diseases like obesity and diabetes.</p> <p>Obesity and diabetes can develop as a consequence of long-term disturbances in the regulation of appetite and glucose metabolism ([<reflink idref="bib64" id="ref19">64</reflink>]). Hormones involved in appetite regulation are leptin and ghrelin, and glucose metabolism is regulated by insulin, insulin-like growth factor-1 (IGF-1) and cortisol.</p> <p>Appetite is suppressed by leptin ([<reflink idref="bib82" id="ref20">82</reflink>]) and stimulated by ghrelin ([<reflink idref="bib75" id="ref21">75</reflink>]). Leptin levels generally peak in the early morning ([<reflink idref="bib63" id="ref22">63</reflink>]), when ghrelin levels are lowest ([<reflink idref="bib50" id="ref23">50</reflink>]).</p> <p>Insulin suppresses appetite and lowers blood glucose levels by promoting the uptake of glucose in cells ([<reflink idref="bib2" id="ref24">2</reflink>]; [<reflink idref="bib70" id="ref25">70</reflink>]) and IGF-1 has insulin-like effects ([<reflink idref="bib20" id="ref26">20</reflink>]). Cortisol is produced in response to stress and low blood glucose and counteracts the effects of insulin. It stimulates the release of glucose into the bloodstream, inhibits insulin secretion, and decreases insulin sensitivity ([<reflink idref="bib2" id="ref27">2</reflink>]; [<reflink idref="bib48" id="ref28">48</reflink>]). Disturbances in glucose metabolism can ultimately lead to insulin resistance and impaired glucose tolerance, which are indicative of (pre-) diabetes ([<reflink idref="bib64" id="ref29">64</reflink>]). Figure 1 visualizes the processes involved in the regulation of appetite and glucose metabolism in a strongly simplified manner, only including the effects mentioned above.</p> <p>Graph: Figure 1. Strongly simplified visualization of the processes involved in the regulation of appetite and glucose metabolism. The figure portrays only the relevant effects as mentioned in the Introduction and should not be considered a hypothetical model to be tested; many more interrelations between the components exist. Biological molecules (hormones and glucose) are indicated by rounded shapes, and edged shapes indicate the concepts appetite, obesity, diabetes. Solid arrow lines represent positive/stimulatory effects, dashed arrow lines represent negative/inhibitory effects.</p> <p>Secretion of cortisol follows a diurnal rhythm. Cortisol concentrations start to rise during the second half of the night, peak in the early morning and decrease throughout the day. After a quiescent phase in the evening, levels start rising again toward the morning peak ([<reflink idref="bib73" id="ref30">73</reflink>]; [<reflink idref="bib74" id="ref31">74</reflink>]). The cortisol awakening response (CAR) reflects the peak in cortisol concentration 30 to 45 minutes after awakening, whereas evening cortisol indicates basal levels ([<reflink idref="bib47" id="ref32">47</reflink>]). A delayed CAR and low morning cortisol have been associated with a delayed biological rhythm, or eveningness ([<reflink idref="bib4" id="ref33">4</reflink>], [<reflink idref="bib5" id="ref34">5</reflink>]; [<reflink idref="bib38" id="ref35">38</reflink>]; [<reflink idref="bib52" id="ref36">52</reflink>]; [<reflink idref="bib81" id="ref37">81</reflink>]). Cortisol is thus not only involved in the regulation of glucose metabolism, but is also a marker for daily rhythmicity. Since a delayed rhythm is highly prevalent in ADHD, cortisol may be an important player besides leptin, ghrelin, insulin, and IGF-1 in the vulnerability of this population for developing obesity and diabetes.</p> <p>The relationship between ADHD and appetite hormones has, to our knowledge, mainly been studied in children. Most previous studies found no differences in levels of leptin or ghrelin between children with and without ADHD ([<reflink idref="bib21" id="ref38">21</reflink>]; [<reflink idref="bib34" id="ref39">34</reflink>]; [<reflink idref="bib46" id="ref40">46</reflink>]; [<reflink idref="bib58" id="ref41">58</reflink>]). Medication status should be considered when interpreting findings as medication can impact ADHD symptoms, sleep/rhythm, and study outcomes. Two studies reported elevated leptin levels in medicated and unmedicated children with ADHD compared to controls ([<reflink idref="bib31" id="ref42">31</reflink>]; [<reflink idref="bib45" id="ref43">45</reflink>]), contrary to another study in 30 children with ADHD, of whom 50% were unmedicated, that found lower leptin levels in ADHD ([<reflink idref="bib54" id="ref44">54</reflink>]). Elevated ghrelin levels were reported in 48 unmedicated children with ADHD compared to 41 controls ([<reflink idref="bib28" id="ref45">28</reflink>]).</p> <p>Increased prevalence and risk of diabetes in children, adolescents, and adults with ADHD has been reported in large population studies from different countries ([<reflink idref="bib17" id="ref46">17</reflink>]; [<reflink idref="bib18" id="ref47">18</reflink>]; [<reflink idref="bib18" id="ref48">18</reflink>]; [<reflink idref="bib23" id="ref49">23</reflink>]; [<reflink idref="bib84" id="ref50">84</reflink>]). A recent meta-analysis including 19 studies reported that children with ADHD, both medicated and unmedicated, had lower basal cortisol levels and lower CAR than controls, probably reflecting a delay in the cortisol rhythm ([<reflink idref="bib16" id="ref51">16</reflink>]). In adults, no differences were found between ADHD and controls in morning cortisol levels ([<reflink idref="bib12" id="ref52">12</reflink>]; [<reflink idref="bib30" id="ref53">30</reflink>]; [<reflink idref="bib40" id="ref54">40</reflink>]; [<reflink idref="bib53" id="ref55">53</reflink>]; [<reflink idref="bib80" id="ref56">80</reflink>]) or CAR ([<reflink idref="bib51" id="ref57">51</reflink>]). One study did show a 2-hour delay in the peak of cortisol secretion in adults with ADHD compared to controls ([<reflink idref="bib6" id="ref58">6</reflink>]), which was likely associated with the high prevalence of eveningness in this population. The aforementioned studies on cortisol provided no information on the biological rhythm or sleep/wake times of the participants.</p> <p>Cortisol is thus strongly related to biological rhythms and sleep times. Several studies found that experimentally induced sleep deprivation increased cortisol concentrations in the morning ([<reflink idref="bib67" id="ref59">67</reflink>]) and evening ([<reflink idref="bib14" id="ref60">14</reflink>]; [<reflink idref="bib41" id="ref61">41</reflink>]; [<reflink idref="bib56" id="ref62">56</reflink>]; [<reflink idref="bib65" id="ref63">65</reflink>]), whereas others reported no changes ([<reflink idref="bib22" id="ref64">22</reflink>]; [<reflink idref="bib42" id="ref65">42</reflink>]; [<reflink idref="bib60" id="ref66">60</reflink>]). Since high cortisol levels reduce insulin sensitivity, long-term sleep loss might lead to diabetes as a result of chronically high cortisol levels ([<reflink idref="bib48" id="ref67">48</reflink>]; [<reflink idref="bib56" id="ref68">56</reflink>]). With regards to the cortisol rhythm, one study in 23 adult men found that sleep restriction (five nights of 4 hours) significantly delayed the peak of cortisol secretion by 16 minutes ([<reflink idref="bib77" id="ref69">77</reflink>]). A two-week sleep hygiene intervention in 22 adults with a delayed rhythm showed that advancing sleep and meal times by 2 hours similarly advanced the melatonin and cortisol rhythm ([<reflink idref="bib25" id="ref70">25</reflink>]).</p> <p>Regarding the other hormones, responses of leptin and ghrelin to sleep restriction have been investigated in many studies using diverse protocols, with varying results. Two meta-analyses have shown that leptin and ghrelin were not affected by sleep restriction ([<reflink idref="bib15" id="ref71">15</reflink>]; [<reflink idref="bib85" id="ref72">85</reflink>]), despite increases in subjective hunger and caloric intake ([<reflink idref="bib85" id="ref73">85</reflink>]). Several controlled laboratory studies in small groups of healthy young participants showed that short-term sleep restriction (one to six nights of 4 hours) led to decreased insulin sensitivity and impaired glucose tolerance symptomatic of a pre-diabetic state ([<reflink idref="bib22" id="ref74">22</reflink>]; [<reflink idref="bib56" id="ref75">56</reflink>]; [<reflink idref="bib60" id="ref76">60</reflink>]; [<reflink idref="bib65" id="ref77">65</reflink>], [<reflink idref="bib66" id="ref78">66</reflink>]; [<reflink idref="bib77" id="ref79">77</reflink>]; [<reflink idref="bib85" id="ref80">85</reflink>]).</p> <p>Taken together, ADHD and delayed, short sleep are both associated with disturbances in the regulation of appetite and glucose metabolism that can ultimately lead to obesity and diabetes. The current paper reports exploratory, secondary outcomes of the PhASE trial, which investigated the effects of chronotherapy in 51 adults with both ADHD and DSPS. We previously reported that treatment with melatonin advanced the biological rhythm by 1.5 hours as determined by DLMO and reduced ADHD symptoms by 14%, despite the absence of changes in sleep timing or duration ([<reflink idref="bib71" id="ref81">71</reflink>]). Secondary outcomes of the PhASE study included measures of leptin, ghrelin, insulin, IGF-1, glucose, cortisol, and a short questionnaire on self-reported appetite. In this paper, we report the results of these outcomes related to regulation of appetite and glucose metabolism. We explore whether there are any deviations at baseline and if chronotherapy had any effects on these outcomes.</p> <hd id="AN0180357939-3">Methods</hd> <p></p> <hd id="AN0180357939-4">Study Design</hd> <p>This study presents exploratory, secondary analysis of data from the PhASE study (Phase Shift in ADHD of Sleep and Appetite), which investigates the effects of DSPS treatment in adults with ADHD and DSPS on melatonin rhythm (DLMO), sleep, ADHD symptoms, and physical health outcomes. PhASE is a three-armed (1:1:1) placebo-controlled randomized clinical trial in which participants received sleep education plus 3 weeks of (<reflink idref="bib1" id="ref82">1</reflink>) 0.5 mg/day melatonin (MEL), (<reflink idref="bib2" id="ref83">2</reflink>) 0.5 mg/day placebo (PLAC), or (<reflink idref="bib3" id="ref84">3</reflink>) 0.5 mg/day melatonin plus bright light therapy (MEL + BLT). The MEL and PLAC conditions were double-blind. There was no PLAC + BLT condition. At the time the PhASE study was designed, melatonin was the gold standard in chronotherapy for advancing the circadian rhythm, whereas BLT was primarily used for clinical treatment of Seasonal Affective Disorder (SAD). PhASE therefore focused on the effects of melatonin and additionally investigated whether BLT had additive effects. The Medical Ethical Committee of Leiden approved PhASE, protocol #NL39579.058.12, and the study was registered in the Netherlands Trial Register, #NTR3831. The study protocol complies with the Helsinki Declaration of 1975, as revised in 2008. More details on the study design and randomization process have been reported previously ([<reflink idref="bib71" id="ref85">71</reflink>]).</p> <hd id="AN0180357939-5">Participants</hd> <p>Participants were recruited from the highly specialized PsyQ out-patient adult ADHD clinic in The Hague, The Netherlands from June 2013 to August 2016 and from April 2018 to June 2019. A trained mental health-care nurse, psychologist, physician, or psychiatrist used the Diagnostic Interview for ADHD in adults (DIVA 2.0), based on DSM-IV TR criteria for ADHD ([<reflink idref="bib36" id="ref86">36</reflink>]) for diagnostic assessment of ADHD and the Mini-International Neuropsychiatric Interview (MINI-Plus 5.0.0; [<reflink idref="bib62" id="ref87">62</reflink>]; [<reflink idref="bib79" id="ref88">79</reflink>]) for the assessment of psychiatric comorbidities. A diagnosis of DSPS was made if a patient reported trouble initiating sleep at a preferred bed time later than 23:30 hours and had a sleep onset latency of more than 30 minutes, leading to daytime impairments in social and/or occupational functioning; these symptoms should have been present for a minimum of 6 months and could not be explained otherwise ([<reflink idref="bib1" id="ref89">1</reflink>]).</p> <p>Inclusion criteria were: age between 18 and 55 years; clinical diagnosis of both ADHD and DSPS; fluency in the Dutch language. Exclusion criteria were: psychotic disorder, epilepsy, anxiety, or depression requiring immediate treatment; alcohol intake > 21 (male) or > 15 (female) units per week; use of soft or hard drugs, ADHD medication, or medications affecting sleep within prior month (psychostimulants, mirtazapine, sleep medication, antipsychotics, clonidine, benzodiazepines, and beta blockers); (suspected) mental retardation, dementia, amnestic disorder, or other cognitive dysfunction; shift work within prior month; having crossed > 2 time zones within prior 2 weeks; having young children disturbing the participant's sleep; BLT within prior month; glaucoma or retinopathy; for women: pregnancy, lactating, or actively trying to conceive.</p> <p>Written informed consent was signed prior to inclusion. Fifty-one participants were included. This sample size (three randomization groups of 17 participants) was calculated on the basis of the primary outcome of the PhASE study, the DLMO ([<reflink idref="bib71" id="ref90">71</reflink>]). Complete baseline data (including DLMO) were available for <emph>N</emph> = 47 participants. We previously identified a subgroup of <emph>n</emph> = 10 who had early baseline DLMO, defined as DLMO before 21:00 hours ([<reflink idref="bib71" id="ref91">71</reflink>]). Since this paper investigates whether the advance in DLMO after chronotherapy was accompanied by improvements in health outcomes and this advance did not occur in the early-DLMO group, only data from the late-DLMO group (<emph>N</emph> = 37) were used for analyses. Due to the small sample size, results should therefore be considered exploratory.</p> <hd id="AN0180357939-6">Interventions</hd> <p>Prior to the medication intake on the first day of the 3-week intervention period, participants received one face-to-face psycho-education session on sleep, biological rhythms, and sleep hygiene recommendations from the researcher following standard protocol from the PsyQ Program Adult ADHD in The Hague, The Netherlands. Participants were informed about the structure and importance of sleep, the circadian rhythm and DSPS, and given advice on improving their sleep hygiene, for example, regarding exercise, light exposure, diet, and creating an environment conducive to good sleep. Further details on the interventions can be found in our previous report ([<reflink idref="bib71" id="ref92">71</reflink>]).</p> <hd id="AN0180357939-7">Melatonin or Placebo</hd> <p>Participants took the study medication (0.5 mg of either melatonin or placebo) daily for three weeks. Medication intake followed an individual schedule based on baseline DLMO, with intake starting 3 hours before individual DLMO ([<reflink idref="bib43" id="ref93">43</reflink>]; [<reflink idref="bib55" id="ref94">55</reflink>]) and weekly advancing by an hour to 5 hours before baseline DLMO in the third week ([<reflink idref="bib71" id="ref95">71</reflink>]).</p> <hd id="AN0180357939-8">Bright Light Therapy (BLT)</hd> <p>The MEL + BLT group received daily BLT with an intensity of 10,000 lux from a Philips Energy Lightbox<sups>®</sups> Type HF3308/01. Every morning between 07:00 and 08:00 hours, participants sat at 20 cm in front of the lamp for 30 minutes without glasses or lenses.</p> <hd id="AN0180357939-9">Study Assessments</hd> <p></p> <hd id="AN0180357939-10">Procedure</hd> <p>Participation took 7 weeks in total. Baseline measurements were performed in week 1 of the study (T0), followed by the allocated intervention in weeks 2 to 4. Follow-up measurements took place in week 5, directly after treatment (T1), and 2 weeks after the end of treatment in week 7 (T2).</p> <p>Participants filled out the Appetite Scale (AS; see below) on the first day of weeks 1, 5, and 7. On the morning of the third day of these weeks, participants collected their own saliva for cortisol assessment using Salivette<sups>®</sups> cotton swabs (Sarstedt, Nümbrecht, Germany) directly after waking up and 15 and 30 minutes later. They were instructed to fast from 22:00 hour the previous evening and not to eat, drink, smoke, or brush their teeth until all samples were collected. The next day, participants came to our location and blood samples were collected at 08:00 hour. At T0 and T1, an oral glucose tolerance test (OGTT) was performed: participants drank 200 mL (75 mg) glucose drink (Fagron NV) within 5 minutes after blood collection and additional blood samples were collected 30, 60, 90, and 120 minutes later. If venipuncture was unsuccessful or not possible, finger-pricks and FreeStyle<sups>®</sups> Lite test strips were used (Abbott Diabetes Care, Inc., Alameda, CA). Participants were instructed to remain seated and not eat, drink, smoke, or sleep during this time.</p> <hd id="AN0180357939-11">General Characteristics</hd> <p>Age, sex, and ADHD subtype were assessed at T0. Body mass index (BMI; kg/m<sups>2</sups>) was calculated at each time point. Baseline time of DLMO and ADHD Rating Scale (ADHD-RS; [<reflink idref="bib24" id="ref96">24</reflink>]; [<reflink idref="bib37" id="ref97">37</reflink>]) score are also reported.</p> <p>DLMO was determined on the basis of salivary melatonin samples collected hourly from 20:00 to 03:00 hours. A melatonin concentration of 3.0 pg/mL was used as threshold for DLMO ([<reflink idref="bib7" id="ref98">7</reflink>]), which was calculated by linear interpolations of melatonin concentrations between time points. Further details on DLMO assessment can be found in the Supplemental Methods.</p> <p>The adult Dutch version of the ADHD Rating Scale-IV (ADHD-RS-IV) is a validated self-evaluation of ADHD symptoms based on the 18 DSM-IV criteria for ADHD. It rates the frequency of various ADHD symptoms during the prior week on a 4-point Likert scale ranging from 0 (never) to 3 (very often). Five complex items are reformulated into paired statements, resulting in 23 items that are calculated back to the original 18 criteria, leading to a sum score (0–54). A cut-off score of ≥ 28 is widely used to indicate a clinical level of ADHD symptoms ([<reflink idref="bib24" id="ref99">24</reflink>]; [<reflink idref="bib37" id="ref100">37</reflink>]).</p> <hd id="AN0180357939-12">Hormones</hd> <p>An external laboratory performed the hormone measurements. Leptin and ghrelin were measured by the Millipore Human Leptin or Ghrelin radioimmunoassay (Millipore, St. Charles, MO, USA). Salivary cortisol levels were determined using isotope dilution liquid chromatography-tandem mass spectrometry (LC-MS/MS; [<reflink idref="bib76" id="ref101">76</reflink>]). The other blood markers were analyzed using Elecsys® assays.</p> <p>It was individually determined per participant whether they scored below, within, or above reference ranges for all outcomes at baseline. Reference ranges are presented in Supplemental Tables 1 and 2. Glucose tolerance was normal if glucose levels remained below 7.8 mmol/L throughout the OGTT, and impaired if glucose levels at 120 minutes were between 7.8 and 11.1 mmol/L. Glucose levels above 11.1 mmol/L indicated type 2 diabetes ([<reflink idref="bib68" id="ref102">68</reflink>]) and leptin reference ranges were based on both sex and BMI as determined by the external laboratory (Supplemental Table 2).</p> <p>For the OGTT and cortisol awakening response, the area under the curve was calculated both relative to the ground (AUCg) and with respect to the increase (AUCi), that is, relative to the first measurement using the trapezoidal rule ([<reflink idref="bib49" id="ref103">49</reflink>]). For cortisol, the AUCg indicates the total cortisol secretion over the first 30 minutes after awakening and the AUCi reflects the CAR.</p> <hd id="AN0180357939-13">Self-Reported Appetite</hd> <p>The Appetite Scale (AS) was developed for this study and consists of five items assessing general appetite, appetite for carbohydrates, fruit and vegetables, protein, and alcohol, during the past week. Answers were given on a 10-point Likert scale ranging from 1 (very low) to 9 (very high) appetite for the particular category.</p> <hd id="AN0180357939-14">Statistical Analyses</hd> <p>Baseline outcomes were compared between the early-DLMO and late-DLMO subgroups (<emph>N</emph> = 47) using ANOVAs for continuous variables and Fisher's exact tests for categorical variables. Further analyses included only the late-DLMO group (<emph>N</emph> = 37). Due to the small sample size, analyses should be considered exploratory.</p> <p>Simple descriptives were used to examine general characteristics and outcomes at baseline and percentages of people scoring outside reference ranges. Linear mixed models corrected for baseline values and with T0 as reference studied the effects of the three interventions (MEL, PLAC, and MEL + BLT) on the study outcomes, using only continuous variables. The main focus was on MEL and MEL + BLT versus PLAC at T1; T2 measurements checked whether any effects found at T1 remained after the end of treatment, and comparisons between MEL and MEL + BLT tested if BLT had additive effects on treatment with MEL. Cohen's <emph>d</emph> effect sizes were calculated for all analyses as the absolute value of the mean difference between two groups divided by the pooled standard deviation (|difference between groups (β<subs>intervention</subs>)/pooled <emph>SD</emph><subs>outcome</subs>|) to indicate large (<emph>d</emph> ≥ 0.80), medium (<emph>d</emph> ≥ 0.50), and small (<emph>d</emph> ≥ 0.20) effect sizes. Any analyses with non-normally distributed variables, or mixed model analyses with non-normally distributed residuals, were repeated using ln-transformed data. Since these transformations did not impact the interpretation of the results, means, standard deviations, regression coefficients (β), and Cohen's <emph>d</emph> from the original (non-transformed) data are reported to keep the results interpretable. The <emph>p</emph>-values are based on analyses on ln-transformed data where applicable.</p> <p>Analyses were performed in SPSS version 25 (IBM Statistics). Statistical significance was inferred at <emph>p</emph> <.05. Corrections for multiple testing were not applied, since these would greatly reduce statistical power of the exploratory analyses of this already small sample.</p> <hd id="AN0180357939-15">Results</hd> <p></p> <hd id="AN0180357939-16">Baseline</hd> <p>General characteristics and baseline values of the outcome variables are displayed in Table 1. The number of people scoring outside reference ranges is reported by valid percentages, thereby taking into account any missing values. Most outcomes had 0 to 4 missing values, except for 6 missing values for OGTT variables.</p> <p>Table 1. General Characteristics and Study Outcomes at Baseline (T0) for the Late-DLMO Group (N = 37) and the Three Intervention Groups.</p> <p>Graph</p> <p> <ephtml> <table><colgroup><col align="left" /><col align="char" char="." /><col align="char" char="." /><col align="char" char="." /><col align="char" char="." /></colgroup><thead><tr><th /><th align="center">Total group</th><th align="center">MEL</th><th align="center">PLAC</th><th align="center">MEL + BLT</th></tr><tr><th /><th align="center"><italic>N</italic> = 37</th><th align="center"><italic>n</italic> = 12</th><th align="center"><italic>n</italic> = 12</th><th align="center"><italic>n</italic> = 13</th></tr></thead><tbody><tr><td>Age (years)</td><td>29.89 (8.94)</td><td>29.75 (9.03)</td><td>31.25 (6.70)</td><td>28.77 (10.99)</td></tr><tr><td colspan="5">Sex</td></tr><tr><td> Female</td><td>22 (59.5%)</td><td>6 (50.0%)</td><td>7 (58.3%)</td><td>9 (69.2%)</td></tr><tr><td> Male</td><td>15 (40.5%)</td><td>6 (50.0%)</td><td>5 (41.7%)</td><td>4 (30.8%)</td></tr><tr><td colspan="5">ADHD subtype</td></tr><tr><td> Combined</td><td>25 (67.6%)</td><td>8 (66.7%)</td><td>6 (50.0%)</td><td>11 (84.6%)</td></tr><tr><td> Inattentive</td><td>12 (32.4%)</td><td>4 (33.3%)</td><td>6 (50.0%)</td><td>2 (15.4%)</td></tr><tr><td>ADHD-RS (0–54)</td><td>32.31 (6.54)</td><td>30.58 (6.56)</td><td>32.91 (8.30)</td><td>33.38 (4.84)</td></tr><tr><td>Time of DLMO</td><td>23:40 hours (1 hour 45 minutes)</td><td>23:43 hours (2 hours 4 minutes)</td><td>23:41 hour (1 hour 58 minutes)</td><td>23:37 hour (1 hour 17 minutes)</td></tr><tr><td>BMI (kg/m2)</td><td>25.60 (5.49)</td><td>24.23 (3.20)</td><td>27.30 (7.65)</td><td>25.43 (5.02)</td></tr><tr><td colspan="5">BMI category</td></tr><tr><td> Underweight (< 18)</td><td>0 (0.0%)</td><td>0 (0.0%)</td><td>0 (0.0%)</td><td>0 (0.0%)</td></tr><tr><td> Normal (18–25)</td><td>18 (50.0%)</td><td>6 (50.0%)</td><td>5 (45.5%)</td><td>7 (53.8%)</td></tr><tr><td> Overweight (25–30)</td><td>14 (38.9%)</td><td>6 (50.0%)</td><td>3 (27.3%)</td><td>5 (38.5%)</td></tr><tr><td> Obese (> 30)</td><td>4 (11.1%)</td><td>0 (0.0%)</td><td>3 (27.3%)</td><td>1 (7.7%)</td></tr><tr><td> Total high (> 25)</td><td>18 (50.0%)</td><td>6 (50.0%)</td><td>6 (54.6%)</td><td>6 (46.2%)</td></tr><tr><td colspan="5">Leptin (ng/mL)</td></tr><tr><td> Female</td><td>26.37 (12.68)</td><td>24.24 (15.07)</td><td>30.39 (12.00)</td><td>24.19 (12.58)</td></tr><tr><td> Male</td><td>14.08 (15.65)</td><td>9.68 (10.23)</td><td>19.32 (24.57)</td><td>14.13 (8.88)</td></tr><tr><td>Leptin low<xref ref-type="table-fn" rid="tfn2">a</xref></td><td>0 (0.0%)</td><td>0 (0.0%)</td><td>0 (0.0%)</td><td>0 (0.0%)</td></tr><tr><td>Leptin high<xref ref-type="table-fn" rid="tfn2">a</xref></td><td>11 (32.4%)</td><td>3 (27.3%)</td><td>3 (27.3%)</td><td>5 (41.7%)</td></tr><tr><td>Ghrelin (pg/mL)</td><td>1,219.77 (596.86)</td><td>1,402.45 (488.09)</td><td>1,209.83 (739.63)</td><td>1,062.25 (526.25)</td></tr><tr><td>Ghrelin < 800 pg/mL</td><td>10 (28.6%)</td><td>1 (9.1%)</td><td>4 (33.3%)</td><td>5 (41.7%)</td></tr><tr><td>Ghrelin > 3,000 pg/mL</td><td>0 (0.0%)</td><td>0 (0.0%)</td><td>0 (0.0%)</td><td>0 (0.0%)</td></tr><tr><td colspan="5">Glucose (nmol/L)</td></tr><tr><td> Fasting</td><td>4.75 (0.60)</td><td>4.70 (0.54)</td><td>4.72 (0.65)</td><td>4.83 (0.65)</td></tr><tr><td> Fasting high (> 7.8 nmol/L)</td><td>0 (0.0%)</td><td>0 (0.0%)</td><td>0 (0.0%)</td><td>0 (0.0%)</td></tr><tr><td> OGTT 120 min</td><td>5.24 (1.37)</td><td>4.80 (1.33)</td><td>5.62 (1.26)</td><td>5.36 (1.51)</td></tr><tr><td> Normal GT</td><td>29 (93.5%)</td><td>11 (100.0%)</td><td>8 (88.9%)</td><td>10 (90.9%)</td></tr><tr><td> Impaired GT</td><td>2 (6.5%)</td><td>0 (0.0%)</td><td>1 (11.1%)</td><td>1 (9.1%)</td></tr><tr><td> T2DM profile</td><td>0 (0.0%)</td><td>0 (0.0%)</td><td>0 (0.0%)</td><td>0 (0.0%)</td></tr><tr><td> OGTT AUCg (nmol/L × hour)</td><td>12.58 (2.34)</td><td>11.95 (1.91)</td><td>13.03 (2.89)</td><td>12.85 (2.32)</td></tr><tr><td> OGTT AUCi (nmol/L × hour)</td><td>3.03 (2.05)</td><td>2.75 (1.30)</td><td>3.25 (2.08)</td><td>3.13 (2.70)</td></tr><tr><td>Insulin (mU/L)</td><td>9.64 (6.50)</td><td>7.05 (3.69)</td><td>12.25 (9.35)</td><td>9.85 (4.65)</td></tr><tr><td>Insulin > 29.1 mU/L</td><td>1 (2.9%)</td><td>0 (0.0%)</td><td>1 (9.1%)</td><td>0 (0.0%)</td></tr><tr><td>IGF-1 (nmol/L)</td><td>29.48 (8.63)</td><td>30.30 (7.69)</td><td>26.69 (8.54)</td><td>31.28 (9.54)</td></tr><tr><td>IGF-1 < 10.8 nmol/L</td><td>0 (0.0%)</td><td>0 (0.0%)</td><td>0 (0.0%)</td><td>0 (0.0%)</td></tr><tr><td>IGF-1 > 31.9 nmol/L</td><td>15 (44.1%)</td><td>6 (54.5%)</td><td>3 (27.3%)</td><td>6 (50.0%)</td></tr><tr><td>Cortisol 0 min (nmol/L)</td><td>5.58 (7.31)</td><td>7.85 (11.58)</td><td>4.42 (3.51)</td><td>4.65 (4.74)</td></tr><tr><td>Cortisol 15 min (nmol/L)</td><td>7.25 (4.70)</td><td>7.64 (5.90)</td><td>7.35 (4.08)</td><td>6.84 (4.41)</td></tr><tr><td>Cortisol 30 min (nmol/L)</td><td>9.54 (5.37)</td><td>9.64 (6.37)</td><td>9.61 (5.15)</td><td>9.40 (5.13)</td></tr><tr><td>Cortisol 0 min < 5 nmol/L</td><td>20 (57.1%)</td><td>5 (45.5%)</td><td>6 (54.5%)</td><td>9 (69.2%)</td></tr><tr><td>Cortisol 0 minutes > 29 nmol/L</td><td>1 (2.9%)</td><td>1 (9.1%)</td><td>0 (0.0%)</td><td>0 (0.0%)</td></tr><tr><td>Cortisol 15 minutes < 5 nmol/L</td><td>12 (34.3%)</td><td>5 (45.5%)</td><td>3 (27.3%)</td><td>4 (30.8%)</td></tr><tr><td>Cortisol 15 minutes > 29 nmol/L</td><td>0 (0.0%)</td><td>0 (0.0%)</td><td>0 (0.0%)</td><td>0 (0.0%)</td></tr><tr><td>Cortisol 30 minutes < 5 nmol/L</td><td>6 (18.2%)</td><td>2 (20.0%)</td><td>1 (9.1%)</td><td>3 (25.0%)</td></tr><tr><td>Cortisol 30 minutes > 29 nmol/L</td><td>0 (0.0%)</td><td>0 (0.0%)</td><td>0 (0.0%)</td><td>0 (0.0%)</td></tr><tr><td>Cortisol AUCg (nmol/L × hour)</td><td>3.46 (2.02)</td><td>3.44 (2.35)</td><td>3.59 (1.93)</td><td>3.35 (1.98)</td></tr><tr><td>Cortisol AUCi (nmol/L × hour)</td><td>1.21 (1.43)</td><td>1.22 (1.52)</td><td>1.38 (1.07)</td><td>1.05 (1.72)</td></tr><tr><td colspan="5">Questionnaires</td></tr><tr><td colspan="5">Appetite Scale (1–10)</td></tr><tr><td> Appetite</td><td>5.97 (1.54)</td><td>6.58 (1.17)</td><td>5.83 (1.70)</td><td>5.54 (1.61)</td></tr><tr><td> Carbohydrates</td><td>5.97 (1.98)</td><td>6.33 (1.56)</td><td>6.00 (2.41)</td><td>5.62 (1.98)</td></tr><tr><td> Fruit and vegetables</td><td>4.76 (1.99)</td><td>5.08 (2.11)</td><td>4.92 (2.28)</td><td>4.31 (1.65)</td></tr><tr><td> Protein</td><td>5.62 (1.32)</td><td>5.83 (1.64)</td><td>5.58 (1.44)</td><td>5.46 (0.88)</td></tr><tr><td> Alcohol</td><td>3.54 (2.24)</td><td>3.50 (1.93)</td><td>3.08 (2.28)</td><td>4.00 (2.55)</td></tr></tbody></table> </ephtml> </p> <p>1 <emph>Note</emph>. Data are <emph>n</emph> (valid %) or mean (<emph>SD</emph>). MEL: melatonin group. PLAC: placebo group. MEL + BLT: melatonin + bright light therapy group. Percentages indicate the percentage of participants scoring outside reference ranges (Supplemental Table 1). Percentages do not always add up to the total group size due to missing data points. ADHD-RS: ADHD Rating Scale. DLMO: Dim-Light Melatonin Onset. BMI: Body Mass Index. OGTT: Oral Glucose Tolerance Test. GT: glucose tolerance. T2DM: type 2 diabetes mellitus. AUCg:area under the curve relative to the ground. AUCi: area under the curve with respect to the increase. IGF-1: Insulin-like Growth Factor 1.</p> <p>2 References ranges for leptin were based on individual BMI and sex, see Supplemental Table 2.</p> <hd id="AN0180357939-17">Leptin, Ghrelin, Insulin, IGF-1, Glucose, BMI, Appetite Scale</hd> <p>Blood samples were collected at 08:14 hours (<emph>SD</emph> = 0 hour 22 minutes): 1 hour 22 minutes (<emph>SD</emph> = 2 hours 02 minutes) before habitual wake time of these late sleepers. In two participants, finger-prick tests were used for the glucose measurements from 30 to 120 minutes, and in two others for the 120-minute measurements only.</p> <p>Eleven participants (32.4%) had leptin levels above the normal range for their individual sex and BMI, and ghrelin levels were low in 10 (28.6%; Table 1). These were largely not the same people; only 4 (11.8%) had both high leptin and low ghrelin. Nobody had low leptin or high ghrelin. Insulin levels were high in 1 participant (2.9%) and 15 (44.1%) had high IGF-1 levels. Fasting glucose was normal in all participants, and 2 (6.5%) showed impaired glucose tolerance. BMI was normal in 18 (50.0%) participants, 14 (38.9%) were overweight, and 4 (11.1%) had obesity. The participant with high insulin had a higher BMI than those with normal insulin levels (45.54 vs. 24.35). Additional ANOVAs showed that BMI was not different between people with high and normal leptin (23.89 (<emph>SD</emph> = 2.94) vs. 25.72 (<emph>SD</emph> = 5.84), <emph>p</emph> =.334), low and normal ghrelin (26.08 (<emph>SD</emph> = 7.06) vs. 24.73 (<emph>SD</emph> = 4.17), <emph>p</emph> =.492), high and normal IGF-1 (23.45 (<emph>SD</emph> = 3.39) vs. 26.24 (<emph>SD</emph> = 5.85), <emph>p</emph> =.113), or impaired or normal glucose tolerance (27.14 (<emph>SD</emph> = 3.90) vs. 24.92 (<emph>SD</emph> = 5.25), <emph>p</emph> =.566); not shown in tables. Self-reported appetite for the different categories lay between 3.54 and 5.97 on a scale from 1 to 10 (Table 1). There were no differences in any of these outcomes between the early- and late-DLMO subgroups (Supplemental Table 3).</p> <hd id="AN0180357939-18">Cortisol</hd> <p>The first cortisol samples were collected at 06:36 hours (<emph>SD</emph> = 0 hour 50 minutes): 2.18 (<emph>SD</emph> = 3.37) minutes after waking, 3 hour 12 minute (<emph>SD</emph> = 1 hour 51 minutes) before habitual wake time. Cortisol levels directly after waking were low in 20 participants (57.1%). Compared to the late-DLMO group, the early-DLMO group had higher cortisol 15 minutes after waking (11.93 nmol/L vs. 7.25 nmol/L, <emph>p</emph> =.017) and a larger AUCg of the CAR (5.50 nmol/L × hour vs. 3.46 nmol/L × hour, <emph>p</emph> =.028; Supplemental Table 3; Supplemental Figure 1). Additional linear regression analyses showed that within the late-DLMO group, later DLMO was associated with a smaller AUCg (β = -.450, 95% CI [-0.82; -0.07], <emph>p</emph> =.021, <emph>d</emph> = 0.22), but not smaller AUCi (β = -.202, 95% CI [-0.45; 0.08], <emph>p</emph> =.155, <emph>d</emph> = 0.14; not shown in tables).</p> <hd id="AN0180357939-19">Effects of Interventions</hd> <p>Table 2 shows the effects of MEL and MEL + BLT compared to PLAC at T1. Supplemental Table 4 includes results for T2 and comparisons between MEL and MEL + BLT.</p> <p>Table 2. Effects of Interventions on Biomarkers and Appetite Questionnaire for the Late-DLMO Group (N = 37) at T1: Linear Mixed Models.</p> <p>Graph</p> <p> <ephtml> <table><colgroup><col align="left" /><col align="char" char="." /><col align="char" char="." /><col align="char" char="." /><col align="char" char="." /><col align="char" char="." /><col align="char" char="." /></colgroup><thead><tr><th /><th align="center" colspan="3">MEL vs. PLAC (ref)</th><th align="center" colspan="3">MEL + BLT vs. PLAC (ref)</th></tr><tr><th /><th align="center">β [95% CI]</th><th align="center"><italic>p</italic></th><th align="center"><italic>d</italic></th><th align="center">β [95% CI]</th><th align="center"><italic>p</italic></th><th align="center"><italic>d</italic></th></tr></thead><tbody><tr><td>BMI (kg/m2)</td><td>0.01 [−0.37, 0.40]</td><td>.944</td><td>0.00</td><td>0.31 [−0.06, 0.68]</td><td>.097</td><td>0.06</td></tr><tr><td>Leptin (µg/L)</td><td>−5.27 [−10.22, −0.32]</td><td>.037<xref ref-type="table-fn" rid="tfn8">*</xref></td><td>0.29<xref ref-type="table-fn" rid="tfn5">b</xref></td><td>−2.76 [−7.57, 2.05]</td><td>.256</td><td>0.15</td></tr><tr><td>Ghrelin (µg/L)</td><td>188.48 [−28.22, 405.18]</td><td>.087</td><td>0.32<xref ref-type="table-fn" rid="tfn5">b</xref></td><td>−34.70 [−242.50, 173.11]</td><td>.739</td><td>0.06</td></tr><tr><td>Fasting glucose (mmol/L)</td><td>0.20 [−0.15, 0.55]</td><td>.266</td><td>0.36<xref ref-type="table-fn" rid="tfn5">b</xref></td><td>0.16 [−0.19, 0.51]</td><td>.372</td><td>0.29<xref ref-type="table-fn" rid="tfn5">b</xref></td></tr><tr><td>Glucose 120 min (mmol/L)</td><td>−0.11 [−1.01, 0.80]</td><td>.813</td><td>0.08</td><td>−0.02 [−0.92, 0.87]</td><td>.956</td><td>0.02</td></tr><tr><td>OGTT AUCg (nmol/L × hour)</td><td>0.05 [−1.06, 1.16]</td><td>.923</td><td>0.03</td><td>0.52 [−0.60, 1.64]</td><td>.350</td><td>0.26<xref ref-type="table-fn" rid="tfn5">b</xref></td></tr><tr><td>OGTT AUCi (nmol/L × hour)</td><td>−0.47 [−1.64, 0.70]</td><td>.415</td><td>0.26<xref ref-type="table-fn" rid="tfn5">b</xref></td><td>0.43 [−0.74, 1.61]</td><td>.459</td><td>0.24<xref ref-type="table-fn" rid="tfn5">b</xref></td></tr><tr><td>Insulin (mU/L)</td><td>−3.92 [−7.53, 0.31]</td><td>.034<xref ref-type="table-fn" rid="tfn8">*</xref></td><td>0.57<xref ref-type="table-fn" rid="tfn6">c</xref></td><td>−2.39 [−5.96, 1.18]</td><td>.185</td><td>0.35<xref ref-type="table-fn" rid="tfn5">b</xref></td></tr><tr><td>IGF-1 (nmol/L)</td><td>−0.18 [−4.85, 4.49]</td><td>.938</td><td>0.02</td><td>1.27 [−3.51, 6.05]</td><td>.595</td><td>0.15</td></tr><tr><td>Cortisol 0 min (nmol/L)<xref ref-type="table-fn" rid="tfn4">a</xref></td><td>1.53 [−2.00, 5.07]</td><td>.141</td><td>0.35<xref ref-type="table-fn" rid="tfn5">b</xref></td><td>0.88 [−2.48, 4.24]</td><td>.501</td><td>0.20<xref ref-type="table-fn" rid="tfn5">b</xref></td></tr><tr><td>Cortisol 15 min (nmol/L)</td><td>−2.63 [−6.65, 1.40]</td><td>.197</td><td>0.49<xref ref-type="table-fn" rid="tfn5">b</xref></td><td>−1.95 [−5.83, 1.94]</td><td>.319</td><td>0.36<xref ref-type="table-fn" rid="tfn5">b</xref></td></tr><tr><td>Cortisol 30 min (nmol/L)</td><td>−1.83 [−5.58, 1.92]</td><td>.332</td><td>0.34<xref ref-type="table-fn" rid="tfn5">b</xref></td><td>−0.62 [−4.35, 3.10]</td><td>.739</td><td>0.12</td></tr><tr><td>Cortisol AUCg (nmol/L × hour)</td><td>−0.49 [−2.16, 1.17]</td><td>.554</td><td>0.21<xref ref-type="table-fn" rid="tfn5">b</xref></td><td>−0.34 [−2.00, 1.31]</td><td>.679</td><td>0.14</td></tr><tr><td>Cortisol AUCi (nmol/L × hour)</td><td>−1.65 [−2.72, −0.58]</td><td>.003<xref ref-type="table-fn" rid="tfn8">*</xref></td><td>1.21<xref ref-type="table-fn" rid="tfn7">d</xref></td><td>−0.63 [−1.70, 0.44]</td><td>.245</td><td>0.46<xref ref-type="table-fn" rid="tfn6">c</xref></td></tr><tr><td colspan="7">Appetite Scale questionnaire</td></tr><tr><td>Appetite (0–10)</td><td>−0.73 [−1.79, 0.32]</td><td>.168</td><td>0.54<xref ref-type="table-fn" rid="tfn6">c</xref></td><td>−0.08 [−1.11, 0.95]</td><td>.864</td><td>0.06</td></tr><tr><td>Carbohydrates (0–10)</td><td>−0.16 [−1.64, 1.32]</td><td>.831</td><td>0.08</td><td>1.14 [−0.32, 2.61]</td><td>.125</td><td>0.60<xref ref-type="table-fn" rid="tfn6">c</xref></td></tr><tr><td>Fruit and vegetables (0–10)</td><td>−0.93 [−2.25, 0.40]</td><td>.167</td><td>0.50<xref ref-type="table-fn" rid="tfn6">c</xref></td><td>−0.55 [−1.86, 0.76]</td><td>.407</td><td>0.30<xref ref-type="table-fn" rid="tfn5">b</xref></td></tr><tr><td>Protein (0–10)</td><td>1.48 [−0.36, 2.60]</td><td>.010<xref ref-type="table-fn" rid="tfn8">*</xref></td><td>1.04<xref ref-type="table-fn" rid="tfn7">d</xref></td><td>1.26 [0.15, 2.37]</td><td>.026<xref ref-type="table-fn" rid="tfn8">*</xref></td><td>0.89<xref ref-type="table-fn" rid="tfn7">d</xref></td></tr><tr><td>Alcohol (0–10)</td><td>−0.84 [−2.19, 0.52]</td><td>.222</td><td>0.40<xref ref-type="table-fn" rid="tfn5">b</xref></td><td>1.19 [−0.15, 2.53]</td><td>.080</td><td>0.57<xref ref-type="table-fn" rid="tfn6">c</xref></td></tr></tbody></table> </ephtml> </p> <ulist> <item>3 <emph>Note</emph>. Regression coefficients (<emph>β</emph>) with 95% confidence intervals (95% CI), <emph>p</emph>-values, and Cohen's <emph>d</emph> effect sizes. MEL: melatonin group. PLAC: placebo group. MEL + BLT: melatonin + bright light therapy group. OGTT: oral glucose tolerance test. AUCg: area under the curve relative to the ground. AUCi: area under the curve with respect to the increase. IGF-1: Insulin-like Growth Factor 1.</item> <item>4 Non-normally distributed variable: <emph>p-</emph>values based on ln-transformed data, regression coefficient (β) and Cohen's <emph>d</emph> based on original data for interpretability.</item> <item>5 Small effect size (Cohen's <emph>d</emph> ≥.20).</item> <item>6 Medium effect size (Cohen's <emph>d</emph> ≥ 0.50).</item> <item>7 Large effect size (Cohen's <emph>d</emph> ≥ 0.80).</item> <item>8 <emph>p</emph> <.05.</item> </ulist> <p>BMI remained stable after interventions. At T1, the MEL group had 5.27 µg/L lower leptin (<emph>t</emph>(<reflink idref="bib65" id="ref104">65</reflink>) = -2.125, <emph>p</emph> =.037, small effect size; <emph>d</emph> = 0.29) and 3.92 mU/L lower insulin (<emph>t</emph>(<reflink idref="bib56" id="ref105">56</reflink>) = -2.176, <emph>p</emph> =.034, medium effect size; <emph>d</emph> = 0.57) than PLAC. Ghrelin and IGF-1 did not differ between the groups (all <emph>p</emph> >.05). These effects are shown in Figure 2. Cortisol AUCi was 1.65 nmol/L × hour lower in MEL than PLAC (<emph>t</emph>(<reflink idref="bib59" id="ref106">59</reflink>) = -3.092, <emph>p</emph> =.003, large effect size; <emph>d</emph> = 1.21), other cortisol variables showed no changes. Glucose parameters did not differ between any of the groups at any time point (all <emph>p</emph> >.05). CAR and OGTT curves are displayed in Figure 3. Effects of MEL and MEL + BLT did not differ, except for 223.18 µg/L lower ghrelin in MEL+ BLT than MEL at T1 (<emph>t</emph>(<reflink idref="bib58" id="ref107">58</reflink>) = -2.117, <emph>p</emph> =.039, small effect size; <emph>d</emph> = 0.38; Supplemental Table 4). Compared to PLAC, appetite for protein at T1 was 1.48 higher in the MEL group (<emph>t</emph>(<reflink idref="bib63" id="ref108">63</reflink>) = 2.641, <emph>p</emph> =.010, large effect size; <emph>d</emph> = 1.04) and 1.26 higher in MEL + BLT (<emph>t</emph>(<reflink idref="bib62" id="ref109">62</reflink>) = 2.277, <emph>p</emph> =.026, large effect size; <emph>d</emph> = 0.89). These effects did not remain at T2 (Supplemental Table 4). Appetite Scale outcomes did not differ between MEL and MEL + BLT, except that appetite for alcohol was 2.03 higher in MEL + BLT than MEL at T1 (<emph>t</emph>(<reflink idref="bib61" id="ref110">61</reflink>) = 3.193, <emph>p</emph> =.002, large effect size; <emph>d</emph> = 0.97) and 1.94 higher at T2 (<emph>t</emph>(<reflink idref="bib61" id="ref111">61</reflink>) = 3.052, <emph>p</emph> =.003, large effect size; <emph>d</emph> = 0.93; Supplemental Table 4).</p> <p>Graph: Figure 2. Plots showing changes in leptin, ghrelin, insulin, and IGF-1 levels at T1 relative to T0 for MEL and MEL + BLT compared to PLAC (N = 37). Vertical lines at 0 indicate baseline values. Dots represent regression coefficients (β) from linear mixed model analyses, horizontal lines indicate 95% confidence intervals.* p <.05.</p> <p>Graph: Figure 3. Plots displaying curves of the Cortisol Awakening Response (CAR) and Oral Glucose Tolerance Test (OGTT) for the three intervention groups at T1 compared to T0 (N = 37). Error bars indicate 95% confidence intervals.</p> <hd id="AN0180357939-20">Discussion</hd> <p>The majority of adults with ADHD have a delayed biological sleep-wake rhythm ([<reflink idref="bib78" id="ref112">78</reflink>]). ADHD and delayed, short sleep have been associated with obesity and diabetes. This paper presents exploratory findings on secondary outcomes of the PhASE study, exploring the hormonal regulation of appetite and glucose metabolism as indicators for risk of obesity and diabetes in adults with both ADHD and a delayed sleep-wake rhythm and the effects of chronotherapeutic interventions. In a small sample, we found no dysregulations to suggest this population has a high risk of developing obesity and diabetes, but did find that chronotherapeutic treatment may cause subtle changes in appetite-regulating hormones.</p> <p>At baseline, leptin was high and ghrelin was low, suggesting suppressed appetite. This may be explained by the fact that blood samples were collected on average 1 hour 22 minutes before habitual wake time, that is, probably much earlier than when reference values were determined, and thus during the biological night of this late-sleeping study population when appetite is still low ([<reflink idref="bib50" id="ref113">50</reflink>]; [<reflink idref="bib59" id="ref114">59</reflink>]; [<reflink idref="bib63" id="ref115">63</reflink>]). After treatment with melatonin, decreased leptin and slightly elevated ghrelin levels suggested increased appetite. This was however not reflected by any changes in subjective appetite, except an increase in appetite for protein. The subtle changes in appetite-regulating hormones could be a result of the advanced melatonin rhythm, meaning the 08:00 hours blood sampling time after treatment was closer to the body's internal biological day than at baseline. Unexpectedly, however, these effects were not found in the MEL + BLT group. We previously reported that ADHD symptoms did not change in this group, despite a 2-hour advance in DLMO. We suggested this may have been due to this group being strictly instructed to get up early for BLT, which half of the participants reported to find very difficult. Especially considering that sleep times had not advanced, this schedule may have prevented or counteracted any positive effects of an advanced rhythm ([<reflink idref="bib71" id="ref116">71</reflink>], [<reflink idref="bib72" id="ref117">72</reflink>]). The finding that changes in appetite-regulating hormones were only seen in the melatonin-only condition could also mean that these changes were driven by the reduction of ADHD symptoms rather than by the advance in melatonin rhythm per se. ADHD symptoms have been linked to unstable eating patterns ([<reflink idref="bib8" id="ref118">8</reflink>]), so perhaps the reduced ADHD symptoms after melatonin-only treatment contributed to healthier or more structured eating patterns, which in turn affected appetite hormones. However, this remains speculative and at present cannot be confirmed without detailed information on timing and quality of food intake.</p> <p>Baseline cortisol levels were low, which may also be explained by the fact that measurements took place during the biological night of this study population (on average 3 hours 12 minutes before habitual wake time), when cortisol is generally low ([<reflink idref="bib73" id="ref119">73</reflink>]; [<reflink idref="bib74" id="ref120">74</reflink>]). We found no increases in cortisol concentrations or awakening response (CAR) after intervention, even though the DLMO had advanced. The lack of an association between DLMO and CAR within this late-sleeping sample supports the suggestion from earlier studies that sleep timing affects cortisol more strongly than the biological clock per se ([<reflink idref="bib4" id="ref121">4</reflink>], 2001; [<reflink idref="bib38" id="ref122">38</reflink>]; [<reflink idref="bib52" id="ref123">52</reflink>]; [<reflink idref="bib81" id="ref124">81</reflink>]). Since sleep times did not advance along with the melatonin rhythm in our study ([<reflink idref="bib72" id="ref125">72</reflink>]), this might explain why cortisol concentrations and the CAR remained unchanged. The lower AUCi after melatonin treatment might be the result of subtle, non-significant differences in cortisol concentrations between the groups. Future work in larger samples is needed to determine whether this was a chance finding.</p> <p>We found no indications for (pre-) diabetes. Furthermore, the BMI distribution of our study population was similar to that of the general adult Dutch population ([<reflink idref="bib57" id="ref126">57</reflink>]). Since obesity and diabetes can develop over time as a consequence of long-term dysregulation of appetite and glucose metabolism, we wanted to assess the <emph>risk</emph>, rather than the actual <emph>prevalence</emph>, of these diseases in relatively young and physically healthy adults with ADHD and DSPS. High IGF-1 levels, found in 44.1%, have been associated with insulin resistance ([<reflink idref="bib26" id="ref127">26</reflink>]). However, the other parameters showed no evidence of this; there were no deviations in fasting glucose, glucose tolerance, or insulin levels. Treatment with melatonin decreased insulin, but had no effect on the other glucose-related outcomes. Melatonin is known to impact glucose metabolism, although the mechanisms are not yet understood. Since there was no discernible pattern in these findings, it is unclear whether these results from a small study population have any clinical relevance regarding the regulation of glucose metabolism.</p> <p>A major strength of the study is that interventions took place in the participants' naturalistic home environment, yet several limitations should be considered. The main limitation of this study is the small sample size, which was even further reduced by the unexpected finding of the early-DLMO group. Moreover, PhASE was not specifically designed to answer the current questions, so the present findings should be considered exploratory and the results need to be interpreted with caution. The small sample size did not allow looking at covariates, such as age or sex, or performing mediation analyses to investigate the driving mechanisms behind the changes in hormones after treatment. Moreover, we had no detailed information on timing and quality of food intake and can therefore not establish whether the decrease in ADHD symptoms after melatonin treatment resulted in changes in eating behavior that might have affected the appetite-regulation hormones. The Appetite Scale is not validated and assessed appetite over the past week, so it would be useful to have additional assessments of subjective appetite at the times of blood sampling and detailed food diaries. Furthermore, blood and saliva samples were only collected at fixed clock times in the early morning. This can be considered the biological night for this study population, hence providing no information on potential dysregulations during the biological day. Cortisol generally peaks 30 to 45 minutes after awakening ([<reflink idref="bib73" id="ref128">73</reflink>]; [<reflink idref="bib74" id="ref129">74</reflink>]), so this peak might have been missed by measuring the CAR during the first 30 minutes after forced early awakening (on average 3 hours 12 minutes before habitual wake time). Future studies in larger samples should include measurements at different times during the day, monitor cortisol for a longer time after awakening, and take internal biological time into account. In addition, sleep times had not advanced along with the biological rhythm. Sleep timing may have a stronger impact on the current outcomes than biological rhythm per se, so future work should focus primarily on advancing sleep times, not merely the biological rhythm. Also, we recommend individualizing and gradually advancing BLT timing along with melatonin intake to make this intervention more feasible and effective. The current fixed, early timing of BLT was based on the use of BLT for treatment of Seasonal Affective Disorder (SAD) in our clinic at the time of study implementation, but may not be optimal for treating DSPS ([<reflink idref="bib11" id="ref130">11</reflink>]; [<reflink idref="bib39" id="ref131">39</reflink>]; [<reflink idref="bib69" id="ref132">69</reflink>]; [<reflink idref="bib71" id="ref133">71</reflink>]). Finally, our study consisted of relatively young and healthy participants with little comorbidity, so the current results cannot be generalized to the whole adult ADHD population.</p> <p>Despite these limitations, some careful conclusions may be drawn from these exploratory findings. In summary, no disturbances in the regulation of appetite or glucose metabolism were found that would suggest high risk of developing obesity and diabetes in this small population of adults with ADHD and DSPS, at least when assessed in the early morning and thus during the participants' biological night. Collecting blood samples at different times, and salivary cortisol over a longer period after (habitual) awakening, would provide more information on appetite and glucose metabolism regulation during the biological day. Treatment with melatonin seemed to cause subtle changes in appetite hormones that were possibly driven by the reduction in ADHD symptoms rather than by the advance in DLMO per se. Whether this resulted in changes in dietary behavior remains to be investigated in larger samples using detailed food diaries. We recommend complementing the current biological interventions with extensive behavioral coaching to advance sleep times along with the biological rhythm and to get a clearer picture of the effects of chronotherapeutic treatment. While these findings remain exploratory and should be interpreted with caution, they may provide a starting point for future studies to look more specifically at regulation of appetite and glucose metabolism in relation to ADHD, sleep, and the circadian rhythm in larger samples.</p> <hd id="AN0180357939-21">Supplemental Material</hd> <p>Graph: Supplemental material, sj-docx-1-jad-10.1177_10870547241285160 for Effects of Chronotherapeutic Interventions in Adults With ADHD and Delayed Sleep Phase Syndrome (DSPS) on Regulation of Appetite and Glucose Metabolism by Emma van Andel, Suzan W. N. Vogel, Denise Bijlenga, Andries Kalsbeek, Aartjan T. F. Beekman and J. J. 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This work was supported by an unrestricted grant from research fund Fonds NutsOhra under Grant FNO #1102-026.</bibtext> </blist> <blist> <bibtext> Emma van Andel</bibtext> </blist> <blist> <bibtext>Graph</bibtext> </blist> <blist> <bibtext>https://orcid.org/0000-0002-7987-8865 J. J. Sandra Kooij</bibtext> </blist> <blist> <bibtext>Graph https://orcid.org/0000-0002-8644-6323</bibtext> </blist> <blist> <bibtext> Supplemental material for this article is available online.</bibtext> </blist> </ref> <aug> <p>By Emma van Andel; Suzan W. N. Vogel; Denise Bijlenga; Andries Kalsbeek; Aartjan T. F. Beekman and J. J. Sandra Kooij</p> <p>Reported by Author; Author; Author; Author; Author; Author</p> <p></p> <p>Emma van Andel is a PhD candidate and senior researcher at the PsyQ Expertise Center Adult ADHD in The Hague, The Netherlands. Her research focuses on sleep problems and circadian rhythm disturbances in adult ADHD.</p> <p>Suzan W. N. Vogel, MD, PhD, is a child and youth psychiatrist at Youz. Her PhD research at the PsyQ Expertise Center Adult ADHD focused on seasonality, stress, sleep, and societal impact in adult ADHD.</p> <p>Denise Bijlenga, PhD, is a Senior Researcher, psychologist, and somnologist at the Sleep-Wake Center of SEIN in Heemstede, The Netherlands, and Leiden University Medical Center. Her research mainly focuses on the relationship between sleep and mental health, with specific expertises in psychometrics, methodology, and statistics.</p> <p>Andries Kalsbeek, PhD, is a Professor of Experimental Neuroendocrinology at the Amsterdam University Medical Center, University of Amsterdam, The Netherlands and leader of the Hypothalamic Integration Mechanisms group at the Netherlands Institute for Neuroscience (NIN).</p> <p>Aartjan T. F. Beekman, MD, PhD, is a Psychiatrist and head of the department of Psychiatry at the Amsterdam University Medical Center. He is member of the board of directors of the specialised mental health institution GGZ inGeest and program leader of the Mental Health program of the Amsterdam Public Health research institute.</p> <p>J. J. Sandra Kooij, MD, PhD, is a Professor of Adult ADHD at the Amsterdam University Medical Centre, psychiatrist at the PsyQ Program Adult ADHD, and head of the PsyQ Expertise Center Adult ADHD in The Netherlands. She is chair of The European Network Adult ADHD and the International DIVA Foundation. Her research focuses on the long-term impact of sleep problems in ADHD on health and on the effects of hormonal mood changes during the lifespan in female ADHD.</p> </aug> <nolink nlid="nl1" bibid="bib78" firstref="ref4"></nolink> <nolink nlid="nl2" bibid="bib44" firstref="ref5"></nolink> <nolink nlid="nl3" bibid="bib83" firstref="ref8"></nolink> <nolink nlid="nl4" bibid="bib23" firstref="ref10"></nolink> <nolink nlid="nl5" bibid="bib27" firstref="ref11"></nolink> <nolink nlid="nl6" bibid="bib29" firstref="ref12"></nolink> <nolink nlid="nl7" bibid="bib33" firstref="ref13"></nolink> <nolink nlid="nl8" bibid="bib35" firstref="ref14"></nolink> <nolink nlid="nl9" bibid="bib61" firstref="ref15"></nolink> <nolink nlid="nl10" bibid="bib64" firstref="ref16"></nolink> <nolink nlid="nl11" bibid="bib10" firstref="ref17"></nolink> <nolink nlid="nl12" bibid="bib32" firstref="ref18"></nolink> <nolink nlid="nl13" bibid="bib82" firstref="ref20"></nolink> <nolink nlid="nl14" bibid="bib75" firstref="ref21"></nolink> <nolink nlid="nl15" bibid="bib63" firstref="ref22"></nolink> <nolink nlid="nl16" bibid="bib50" firstref="ref23"></nolink> <nolink nlid="nl17" bibid="bib70" firstref="ref25"></nolink> <nolink nlid="nl18" bibid="bib20" firstref="ref26"></nolink> <nolink nlid="nl19" bibid="bib48" firstref="ref28"></nolink> <nolink nlid="nl20" bibid="bib73" firstref="ref30"></nolink> <nolink nlid="nl21" bibid="bib74" firstref="ref31"></nolink> <nolink nlid="nl22" bibid="bib47" firstref="ref32"></nolink> <nolink nlid="nl23" bibid="bib38" firstref="ref35"></nolink> <nolink nlid="nl24" bibid="bib52" firstref="ref36"></nolink> <nolink nlid="nl25" bibid="bib81" firstref="ref37"></nolink> <nolink nlid="nl26" bibid="bib21" firstref="ref38"></nolink> <nolink nlid="nl27" bibid="bib34" firstref="ref39"></nolink> <nolink nlid="nl28" bibid="bib46" firstref="ref40"></nolink> <nolink nlid="nl29" bibid="bib58" firstref="ref41"></nolink> <nolink nlid="nl30" bibid="bib31" firstref="ref42"></nolink> <nolink nlid="nl31" bibid="bib45" firstref="ref43"></nolink> <nolink nlid="nl32" bibid="bib54" firstref="ref44"></nolink> <nolink nlid="nl33" bibid="bib28" firstref="ref45"></nolink> <nolink nlid="nl34" bibid="bib17" firstref="ref46"></nolink> <nolink nlid="nl35" bibid="bib18" firstref="ref47"></nolink> <nolink nlid="nl36" bibid="bib84" firstref="ref50"></nolink> <nolink nlid="nl37" bibid="bib16" firstref="ref51"></nolink> <nolink nlid="nl38" bibid="bib12" firstref="ref52"></nolink> <nolink nlid="nl39" bibid="bib30" firstref="ref53"></nolink> <nolink nlid="nl40" bibid="bib40" firstref="ref54"></nolink> <nolink nlid="nl41" bibid="bib53" firstref="ref55"></nolink> <nolink nlid="nl42" bibid="bib80" firstref="ref56"></nolink> <nolink nlid="nl43" bibid="bib51" firstref="ref57"></nolink> <nolink nlid="nl44" bibid="bib67" firstref="ref59"></nolink> <nolink nlid="nl45" bibid="bib14" firstref="ref60"></nolink> <nolink nlid="nl46" bibid="bib41" firstref="ref61"></nolink> <nolink nlid="nl47" bibid="bib56" firstref="ref62"></nolink> <nolink nlid="nl48" bibid="bib65" firstref="ref63"></nolink> <nolink nlid="nl49" bibid="bib22" firstref="ref64"></nolink> <nolink nlid="nl50" bibid="bib42" firstref="ref65"></nolink> <nolink nlid="nl51" bibid="bib60" firstref="ref66"></nolink> <nolink nlid="nl52" bibid="bib77" firstref="ref69"></nolink> <nolink nlid="nl53" bibid="bib25" firstref="ref70"></nolink> <nolink nlid="nl54" bibid="bib15" firstref="ref71"></nolink> <nolink nlid="nl55" bibid="bib85" firstref="ref72"></nolink> <nolink nlid="nl56" bibid="bib66" firstref="ref78"></nolink> <nolink nlid="nl57" bibid="bib71" firstref="ref81"></nolink> <nolink nlid="nl58" bibid="bib36" firstref="ref86"></nolink> <nolink nlid="nl59" bibid="bib62" firstref="ref87"></nolink> <nolink nlid="nl60" bibid="bib79" firstref="ref88"></nolink> <nolink nlid="nl61" bibid="bib43" firstref="ref93"></nolink> <nolink nlid="nl62" bibid="bib55" firstref="ref94"></nolink> <nolink nlid="nl63" bibid="bib24" firstref="ref96"></nolink> <nolink nlid="nl64" bibid="bib37" firstref="ref97"></nolink> <nolink nlid="nl65" bibid="bib76" firstref="ref101"></nolink> <nolink nlid="nl66" bibid="bib68" firstref="ref102"></nolink> <nolink nlid="nl67" bibid="bib49" firstref="ref103"></nolink> <nolink nlid="nl68" bibid="bib59" firstref="ref106"></nolink> <nolink nlid="nl69" bibid="bib72" firstref="ref117"></nolink> <nolink nlid="nl70" bibid="bib57" firstref="ref126"></nolink> <nolink nlid="nl71" bibid="bib26" firstref="ref127"></nolink> <nolink nlid="nl72" bibid="bib11" firstref="ref130"></nolink> <nolink nlid="nl73" bibid="bib39" firstref="ref131"></nolink> <nolink nlid="nl74" bibid="bib69" firstref="ref132"></nolink>
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  Data: SAGE Publications. 2455 Teller Road, Thousand Oaks, CA 91320. Tel: 800-818-7243; Tel: 805-499-9774; Fax: 800-583-2665; e-mail: journals@sagepub.com; Web site: https://sagepub.com
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  Label: Peer Reviewed
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  Data: Y
– Name: Pages
  Label: Page Count
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  Data: 15
– Name: DatePubCY
  Label: Publication Date
  Group: Date
  Data: 2024
– Name: TypeDocument
  Label: Document Type
  Group: TypDoc
  Data: Journal Articles<br />Reports - Research
– Name: Subject
  Label: Descriptors
  Group: Su
  Data: <searchLink fieldCode="DE" term="%22Foreign+Countries%22">Foreign Countries</searchLink><br /><searchLink fieldCode="DE" term="%22Adults%22">Adults</searchLink><br /><searchLink fieldCode="DE" term="%22Attention+Deficit+Hyperactivity+Disorder%22">Attention Deficit Hyperactivity Disorder</searchLink><br /><searchLink fieldCode="DE" term="%22Sleep%22">Sleep</searchLink><br /><searchLink fieldCode="DE" term="%22Obesity%22">Obesity</searchLink><br /><searchLink fieldCode="DE" term="%22Diabetes%22">Diabetes</searchLink><br /><searchLink fieldCode="DE" term="%22Comorbidity%22">Comorbidity</searchLink><br /><searchLink fieldCode="DE" term="%22Intervention%22">Intervention</searchLink><br /><searchLink fieldCode="DE" term="%22Metabolism%22">Metabolism</searchLink><br /><searchLink fieldCode="DE" term="%22Biochemistry%22">Biochemistry</searchLink><br /><searchLink fieldCode="DE" term="%22Human+Body%22">Human Body</searchLink>
– Name: Subject
  Label: Geographic Terms
  Group: Su
  Data: <searchLink fieldCode="DE" term="%22Netherlands%22">Netherlands</searchLink>
– Name: DOI
  Label: DOI
  Group: ID
  Data: 10.1177/10870547241285160
– Name: ISSN
  Label: ISSN
  Group: ISSN
  Data: 1087-0547<br />1557-1246
– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: Background: ADHD is highly comorbid with Delayed Sleep Phase Syndrome (DSPS). Both are associated with obesity and diabetes, which can be caused by long-term dysregulations of appetite and glucose metabolism. This study explores hormones involved in these processes and the effects of chronotherapeutic interventions in a small sample of adults with ADHD and DSPS. Methods: Exploratory, secondary analysis of data from the PhASE study, a three-armed randomized clinical trial, are presented, including 37 adults (18-53 years) with ADHD and DSPS receiving three weeks of 0.5 mg/day (1) placebo, (2) melatonin, or (3) melatonin plus 30 minutes of bright light therapy (BLT). Leptin (appetite-suppressing), ghrelin (appetite-stimulating), insulin, insulin-like growth factor-1 (IGF-1), and glucose were measured from blood collected at 08:00 hours. Salivary cortisol was collected during the first 30 minutes after awakening and self-reported appetite was assessed. Results: Baseline leptin and IGF-1 levels were higher than reference ranges, and ghrelin and cortisol levels were lower, while insulin and glucose were normal. Melatonin treatment decreased leptin and insulin. Other outcomes remained unchanged and melatonin + BLT had no effects. Conclusion: Due to the small sample size and exploratory nature of the study, results should be interpreted with caution. Overall, these results show no strong indications for dysregulation of appetite and glucose metabolism to suggest high risk of obesity and diabetes in this small sample of adults with ADHD and DSPS. However, baseline appetite was suppressed, likely because measurements took place in the early morning which could be considered the biological night for this study population. Melatonin treatment seemed to cause subtle changes in appetite-regulating hormones suggesting increased appetite. Chronotherapeutic treatment may affect appetite-regulating hormones by advancing the biological rhythm and/or altering eating behaviors, but this remains to be investigated in larger samples using detailed food diaries.
– Name: AbstractInfo
  Label: Abstractor
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  Data: As Provided
– Name: DateEntry
  Label: Entry Date
  Group: Date
  Data: 2024
– Name: AN
  Label: Accession Number
  Group: ID
  Data: EJ1445022
PLink https://search.ebscohost.com/login.aspx?direct=true&site=eds-live&db=eric&AN=EJ1445022
RecordInfo BibRecord:
  BibEntity:
    Identifiers:
      – Type: doi
        Value: 10.1177/10870547241285160
    Languages:
      – Text: English
    PhysicalDescription:
      Pagination:
        PageCount: 15
        StartPage: 1653
    Subjects:
      – SubjectFull: Foreign Countries
        Type: general
      – SubjectFull: Adults
        Type: general
      – SubjectFull: Attention Deficit Hyperactivity Disorder
        Type: general
      – SubjectFull: Sleep
        Type: general
      – SubjectFull: Obesity
        Type: general
      – SubjectFull: Diabetes
        Type: general
      – SubjectFull: Comorbidity
        Type: general
      – SubjectFull: Intervention
        Type: general
      – SubjectFull: Metabolism
        Type: general
      – SubjectFull: Biochemistry
        Type: general
      – SubjectFull: Human Body
        Type: general
      – SubjectFull: Netherlands
        Type: general
    Titles:
      – TitleFull: Effects of Chronotherapeutic Interventions in Adults with ADHD and Delayed Sleep Phase Syndrome (DSPS) on Regulation of Appetite and Glucose Metabolism
        Type: main
  BibRelationships:
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            NameFull: Emma van Andel
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            NameFull: Suzan W. N. Vogel
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            NameFull: Denise Bijlenga
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            NameFull: Andries Kalsbeek
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            NameFull: Aartjan T. F. Beekman
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            – D: 01
              M: 11
              Type: published
              Y: 2024
          Identifiers:
            – Type: issn-print
              Value: 1087-0547
            – Type: issn-electronic
              Value: 1557-1246
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            – Type: volume
              Value: 28
            – Type: issue
              Value: 13
          Titles:
            – TitleFull: Journal of Attention Disorders
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