Dose Response of Extended Release Dexmethylphenidate and Mixed Amphetamine Salts on Sleep of Youth with Attention Deficit/Hyperactivity Disorder

José Arturo Santisteban López

Department of Psychiatry, Faculty of Medicine

McGill University, Montreal

September 2013

A thesis submitted to McGill University in partial fulfillment of the requirements of the degree of Master of Science in Psychiatry

Table of Contents

Abstract English 2

Abstract French 3

Acknowledgements 4

Contribution of Authors 5

Introduction 6

Background 8

Methods 16

Results 22

Discussion 25

Conclusion 28

Tables and Figures 29

Bibliography 34

Abstract English

Background. Attention-Deficit/Hyperactivity Disorder (ADHD) is characterized by impulsivity, hyperactivity, and inattention, which affects 5-10% of school-age children. The first-line treatment for ADHD is stimulant medication, which increase levels dopamine (DA) and norepinephrine (NE). These medications are highly effective, but not always tolerated. Sleep side effects, such as insomnia, are reported for both stimulant classes and are usually, but not always, mild and transitory, which can lead to treatment discontinuation. Poor tolerability may limit efficacy by compromising the ability to prescribe effective doses. Few studies have assessed the comparative effectiveness of long-acting methylphenidate and amphetamine formulations in youth with ADHD, and it is unclear if there are differential effects of drug and/or dose on sleep. MAS increase NE and DA levels more than d-MPH and hence could be affecting sleep differently.

Objectives. We sought to determine if there are significant differences in the dose-response effects of ER D-MPH and ER MAS on objective measures of sleep.

Methods. Children, aged 10-17 (n=37), participated in a double-blind crossover study comparing two stimulants (extended release DMPH, MAS) at three doses (10, 20, 30 mg) and placebo. Each treatment session lasted one week, for a total protocol duration of eight weeks. Sleep was assessed in all conditions using actigraphy and questionnaires.

Results. Sleep schedule measures showed a significant effect for dosage on sleep start time (F(1,36)=6.284, p<0.05), with a significantly later sleep start time when children were on 20mg or 30mg dosages, compared to placebo (p<0.05). Sleep duration revealed a significant dose effect on actual sleep duration (F(1,36)=8.112, p<0.05), with significantly shorter actual sleep duration for subjects receiving 30mg compared to those on placebo (p<0.05). There were no significant differences between medications.

Conclusion. Higher dosages reduce sleep duration and lead to later sleep start times, regardless of medication.

Abstract French

Contexte. Le Trouble Déficitaire de l’Attention et de l’Hyperactivité (TDAH) est caractérisé par l’impulsivité, l’hyperactivité, et l’inattention. Le TDAH se produit dans 5-10% des enfants scolaires. Le traitement de première ligne pour le TDAH sont les stimulants. Les stimulants augmentent les niveaux de dopamine (DA) et de norépinephrine (NE). Ces médicaments sont hautement efficaces, mais ne sont pas tolérés par tous les enfants. Les effets indésirables, comme l’insomnie, sont souvent reportés pour ces stimulants. Par contre, leurs effets sont habituellement, mais pas toujours, bénins et transitoires. En général, les enfants souffrant d’insomnie sévère cessent le traitment. La faible tolérance peut limiter l’efficacité en compromettant la possibilité de prescrire des doses plus efficaces. Peu d’études ont mesuré l’efficacité comparative du methylphenidate á action prolongée et de l’amphétamine á action prolongée chez les enfants avec un TDAH. De plus, il n’est pas clair s’il y a un effet différentiel de médicament et/ou de dose sur le sommeil. Les MAS augmentent les niveaux de NE et DA plus que les d-MPH, et donc pourraient avoir une incidence sur le sommeil d’une manière différente.

Objectifs. Nous cherchons à déterminer s’il existe des différences significatives dans les effets de dose-réponse des d-MPH et MAS á actions prolongées sur des mesures objectives du sommeil.

Méthodes. Les enfants, âgés 10-17 (n=37), ont participé dans une étude croisée à double insu comparant trois doses (10, 20, et 30mg) de d-MPH ou MAS au placebo. Chaque séance de traitement a duré une semaine, pour une durée totale de protocole de huit semaines. Le sommeil a été mesuré dans toutes les conditions avec actimétrie et questionnaires.

Résultats. Les mesures d’horaire du sommeil ont montré un effet significatif de dose à l’heure de début de sommeil (F(1,36)=6.284, p<0.05); les enfants recevant 20mg ou 30mg on débuté leur sommeil significativement plus tard que ceux qui ont reçu le placebo (p<0.05). Un effet significatif de dose sur la durée réelle du sommeil (F(1,36)=8.112, p<0.05) a été découverte, avec une durée de sommeil plus courte quand les sujets ont reçu 30 mg comparé au placebo (p<0.05). Aucune différence entre les deux médicaments n’a été trouvée.

Conclusion. Des doses plus élevées réduisent la durée du sommeil et conduisent à dormir plus tard, indépendamment de médicaments.

ACKNOWLEDGMENTS

First of all, I would like to express my gratitude for my supervisor, Dr. Reut

Gruber, for her mentorship during my studies. Her dedication and support allowed me to get the most out of the program. I have greatly benefited from the experience of working in her laboratory and the skills I have learned from her will prove invaluable in my future projects.

I would also like to thank the Mexican National Council for Science and

Technology (CONACYT) for providing the funds necessary for me to complete this project, as well as their support for the promotion of scientific research in

Mexico.

The help that the members of my lab have provided on every part of this project was instrumental for not only the success of this project, but making it an enjoyable endeavor. I especially want to thank Lana Bergame for her editing and feedback on the writing of this project. I would also like to express my appreciation for Alice Boom and Laura Fontil for showing me the ropes in using the measures.

Finally, I would like to thank my parents all their support during every step of my academic growth, my friend and classmate Michelle Lonergan for her help with statistics and motivating me to work hard through parallel writing, and my best friend Piell Angel Blanco for making Montreal home.

Contribution of Authors

This work is part of the Sleep and Tolerability of Extended Release

Dexmethylphenidate vs. Mixed Amphetamine Salts: A Double Blind, Placebo

Controlled Study (SAT STUDY), designed by Dr. Mark A. Stein. My role was to examine the data specifically relating to sleep depending on medication and dosage, as well as conducting the statistical analysis. Thus, I conducted the literature review, interpreted the statistical analyses, and wrote the present thesis, all of which was supervised and reviewed by Dr. Reut Gruber. Lana

Bergame aided the project by editing and providing feedback on the writing for this thesis.

Introduction

Attention-Deficit/Hyperactivity Disorder (ADHD) is characterized by impulsivity, hyperactivity, and inattention which affect a reported 5.29% of children and adolescents worldwide. The prefrontal cortex (PFC) regulates attention based on relevance, screening for distractions and sustaining attention and it is dependent on norepinephrine (NE) and dopamine (DA). Dysregulation of these have been found in individuals with ADHD. The first-line treatments for

ADHD are stimulant medications (methylphenidate and amphetamines) which increase the levels DA and NE by inhibiting their re-uptake. These have been found to be very effective for the treatment of ADHD. However, not all children tolerate them well. Sleep side effects in general, and specifically insomnia, are one of the most common side-effects, which are usually, but not always, mild and transitory. Children who develop insomnia are more likely to discontinue treatment. Poor tolerability of the stimulant may lead to lower doses being prescribed, and thus, may limit the efficacy of the treatment. While lower dosages are generally less effective, higher dosages are more likely to present side- effects.

There is a paucity of comparative tolerability data of the major stimulant classes currently used to treat ADHD. Amphetamine increases NE and DA levels more than methylphenidate and hence could be affecting sleep differently. With more information on the tolerability of these medications, it may be possible to choose a medication with fewer side-effects as the first one, controlling symptoms earlier by reducing time spent finding a tolerable formulation.

We sought to determine if there are significant differences in the dose- response effects of ER D-MPH and ER MAS on objective measures of sleep. We evaluated the effects of three doses of each drug on sleep in a within-subject, double-blind, randomized placebo-controlled trial.

Background

Attention-Deficit/Hyperactivity Disorder (ADHD) is characterized by impulsivity, hyperactivity, and inattention (4th ed., text rev.; Diagnostic and

Statistical Manual of Mental Disorders; American Psychiatric Association, 2000)., and affects a reported 5.29% of children and adolescents worldwide (Polanczyk, de Lima, Horta, Biederman, & Rohde, 2007). Males are more frequently diagnosed with ADHD than females; specifically, estimated gender ratios range from 2:1 to 9:1 (Rucklidge, 2008), with a greater gender difference in clinical populations (Staller & Faraone, 2006). Additionally, comorbid disorders are common in ADHD; 66.9% of patients present any disorder, including learning disorders (46.1%), conduct disorders (27.4%), anxiety (17.8%), depression

(13.9%), (6%) (Larson, Russ, Kahn, & Halfon, 2011).

Functional Impairment. ADHD causes functional impairment in areas of life such as work, interpersonal relationships, mood and impulse control, organization, and anti-social behaviour, and this impairment continues to be present into adulthood

(Surman, Hammerness, Pion, & Faraone, 2013). As ADHD symptoms impair functioning in many areas of life, adequate treatment of the disorder is important to improve quality of life. Pharmacological treatment of ADHD with stimulants has been shown to improve global functioning (Surman et al., 2013) as well as long- term academic performance in adolescents (Powers, Marks, Miller, Newcorn, &

Halperin, 2008).

Neuroanatomy and neurotransmissions. There are neuroanatomical differences across many brain areas between healthy participants and those with ADHD. In particular, cortical thickness is decreased in the parietal, temporal, frontal and occipital lobes in children with ADHD. There are also decreases in volume in the caudate, the thalamus, and the cerebellum in this population (Cortese, Imperati, et al., 2013). Furthermore, many brain networks have been found to be altered in ADHD, including the prefrontal-striatal network, frontoparietal network, the dorsal and ventral attentional networks, the visual network, the motor network, and the default network (Castellanos & Proal, 2012). The prefrontal-striatal- cerebellar circuit is the most studied network in ADHD. The prefrontal cortex

(PFC) regulates attention based on relevance, screening for distractions and sustaining attention. Moreover, it regulates behavior by inhibiting emotions and impulses. The activity of the PFC is highly dependent on norepinephrine (NE) and dopamine (DA). Low-levels and high levels of NE and DA impair the functioning of the PFC, following an inverted U function (del Campo,

Chamberlain, Sahakian, & Robbins, 2011). The most beneficial levels of these catecholamines are moderate, and this occurs during a state of alertness or interest (A. T. Arnsten, 2009). Hypoactivity of this network has been found in individuals with ADHD in comparison to normal controls (Castellanos & Proal,

2012). Dysregulation of the activity of catecholamines (DA and NE) and their receptors has been found in individuals with ADHD (Arnsten, 2011).

DA is synthesized in two steps from L-Tyrosine first with tyrosine hydroxilase, its rate limiting enzyme, and then with dihydroxyphenylalanine

(DOPA) decarboxylase. Degradation is through three enzymes, monoamino oxidase (MAO)-A, MAO-B, and catechol-O-methyltransferase (COMT), while DA reuptake is through the Dopamine Transporter (DAT). DA release is both tonic and phasic. Tonic release is the baseline, while phasic release occurs during exposure to positive reinforcement. DA binds to two main types of receptors, excitatory D1 (and D5) and inhibitory D2 (and D4). Moreover, it has has two main pathways, the mesostriatal and mesolimbic pathways. The former is involved in movement while the latter is involved in cognition, affect, and reward. DA decreases PFC activity in response to irrelevant stimuli, reducing noisy input and increasing efficiency (Arnsten & Pliszka, 2011). In children with ADHD, there is a decreased number of D2 and D3 receptors, as well as increased DAT in the caudate, compared to normal controls (Cortese, 2012).

NE is synthesized from DA with the Dopamine β-hydroxylase (DBH). It is then carried into the synaptic vesicles by the vesicular monoamine transporter

(VMAT-2). NE is degraded through MAO-A and COMT, and reuptake is through the NE transporter (NET). During selective attention, NE has a phasic release.

NE binds to α1 (arousal, alertness, attention, and memory formation), α2

(regulatory auto-inhibitor), and β receptors (somatic effects, as well as learning and memory consolidation). NE is mainly located in the locus ceruleus (LC), with axonal projections to almost all of the brain (Sofuoglu & Sewell, 2009), including the PFC. In fact, NET is present at higher densities in the PFC. Lower activity of

DBH in humans is associated with impulsiveness, decreased attention, and decreased executive function (Arnsten & Pliszka, 2011).

Treatment. The first-line treatment for ADHD is stimulant medication. Stimulants affect the levels DA and NE by altering the function of DAT and NET and, by inhibiting re-uptake of the chemicals at nerve endings, increasing their levels and activity on the post-synaptic neuron (Volkow et al., 2012). The increase in catecholamine levels corrects the hypodopaminergic conditions in the frontal cortex and the striatum, decreasing the cognitive and behavioural deficits present in children with ADHD (Arnsten, 2009). In addition, these medications affect levels of DA and NE preferentially in the PFC (Stein et al., 2011). Stimulants consist of methylphenidate (MPH) and amphetamines, as well as their variants.

Such stimulants differ in terms of the mechanisms of reuptake. Both MPH and amphetamines inhibit the reuptake of NE and DA; however, amphetamines also reverse the transporter and inhibit MAO. As a result amphetamines increase the levels of DA and NE more than MPH.

MPH is the most frequently prescribed stimulant medication for ADHD. It is a racemic mixture of dextro- and levo-isomers of methylphenidate.

Dextromethylphenidate (d-MPH) contains only the dextro-isomer, which is more biologically active than the levo-isomer. Amphetamine is available as mixed amphetamine salts (MAS), a racemic mixture, as well as dexamphetamine (the dextro-isomer) and lisdexamphetamine (a prodrug).

Immediate release (IR) Vs. Extended release (ER) Formulations. Extended release (ER) formulations are replacing immediate release (IR) formulations as first line treatments due to their longer duration of behavioral effects and convenience. The duration of the effect of IR formulations is 4 hours. This not

11 only increases the likelihood of missed dosages, but can also be problematic for children as they are required to take a second dosage at school. ER formulations of d-MPH have 12-hour duration of the effect. ER MAS provide half of the medication as an IR with a second pulse 4-6 hours later. These formulations provide an effect for morning and afternoon. The literature suggests that individuals with ADHD are satisfied with ER formulations and have increased compliance compared with IR (Spencer et al., 2011).

Efficacy. Stimulants have been found to be very effective for the treatment of

ADHD. As indicated by a decrease in scores on ADHD rating scales following the use of MPH, response rates have ranged between 61-95%. Similarly, response rates for amphetamines have ranged between 79-88% (reduction in ADHD rating scale scores) and 64-72% (symptomatic remission) (Faraone & Buitelaar, 2010).

It has also been found that those with more severe symptoms exhibit the most improvement with stimulant treatment (Fredriksen, Halmøy, Faraone, & Haavik,

2013).

Tolerability. Although these medications are highly effective, not all children tolerate them well. Stimulants’ increase of synaptic DA and NE enhance the wake-promoting pathways in the ascending arousal system while also inhibiting sleep-promoting neurons in the ventrolateral preoptic area (Mitchell &

Weinshenker, 2010) . Sleep side effects in general, and specifically insominia, are one of the most common side-effects, with 26% of patients reporting any sleep side effect. Side-effects are usually mild and transitory, with only 21% of those reporting any side effect describing them as very or extremely bothersome

(Cascade, Kalali, & Wigal, 2010). However, this is not always the case, and 17% of children develop severe insomnia (Lee et al., 2011). Consequently, they are more likely to discontinue treatment. Furthermore, sleep deprivation can cause or exacerbate ADHD symptoms such as inattention or behavioral dysregulation

(Volkow et al., 2012). In children with ADHD, only one hour less of sleep a night can cause clinically significant deterioration of neurobehavioral scores (Gruber et al., 2011). Furthermore, participants that had clinical improvement of ADHD symptoms also had improvement in self-rated sleep quality questionnaires (C. B.

Surman & Roth, 2011). Therefore, children that are affected by sleep side-effects such as insomnia may have worse clinical outcomes. This may work against the effectiveness of stimulant medication if insomnia secondary to these exacerbates

ADHD symptoms, especially considering the high prevalence of sleep side- effects.

Dosage. The most frequent reasons for discontinuing treatment are a lack of efficacy and not be able to tolerate the side-effects (Charach & Fernandez,

2013). Poor tolerability of the stimulant may lead to lower doses being prescribed, and thus, may limit the efficacy of the treatment. While lower dosages are generally less effective, higher dosages are more likely to present side- effects (Stein et al., 2011). Community providers tend to utilize lower stimulant dosages to prevent side effects, perhaps resulting in better tolerated albeit less effective treatment (Olfson, Marcus, & Wan, 2009). By optimizing dosage, patients are more likely to receive a correctly calibrated dosage; that is, one that

13 is high enough to be effective while still being tolerable (Cortese, Holtmann, et al., 2013).

Effects of ER methylphenidate and amphetamine formulations on sleep.

Few studies have assessed the comparative effectiveness of ER methylphenidate and amphetamine formulations in youth with ADHD and it remains unclear if there are differential effects of drug and/or dose on sleep. Due to different pharmacokinetics (longer duration of effect) and posology (one dosage per day), it may be possible that side-effects in the evening and night are different. In the absence of comparative data, choice of stimulant and dose is often based upon a trial and error basis. With knowledge of the effects of dosage on sleep, it may be possible to initiate treatment at higher dosages that are more likely to be more effective while also having a lower risk of side-effects such as insomnia (Stein et al., 2011). There is a paucity of comparative tolerability data of the major stimulant classes currently used to treat ADHD (methylphenidate and amphetamine). Although it is generally thought that methylphenidate or amphetamine, have equal efficacy and similar side effect profiles, MAS increase

NE and DA levels more than methylphenidate and hence could be affecting sleep differently. With more information on the tolerability of these medications, it may be possible to choose a medication with fewer side-effects as the first one, controlling symptoms earlier by reducing time spent finding a tolerable formulation.

The Present Study. In the present study, we sought to determine if there are significant differences in the dose-response effects of ER D-MPH and ER MAS on objective measures of sleep. We evaluated the effects of three doses of each drug on sleep in a within-subject, double-blind, randomized placebo-controlled trial. We hypothesized that: 1) both formulations would shorten sleep; 2) higher doses would be associated with greater decrease of sleep duration regardless of the formulation; 3) amphetamine would have greater negative impact on sleep duration compared to dexmethylphenidate.

Methods

Participants

77 participants were screened for inclusion in the study. 12 participants were excluded as they did not meet the inclusion criteria or met the exclusion criteria. 65 participants were randomized, with 9 discontinuing as they decided not to participate or were non-compliant. Of these, 37 Children and adolescents with ADHD between the ages of 10-17 (M= 11.6, SD= 1.956) were included in the analyses for this project. They were recruited from the investigator's practices, clinic referrals, and radio advertisements. The Kiddie-Schedule for

Affective Disorders-Present and Lifetime (K-SADS-PL) was used to diagnose

ADHD and comorbid disorders. Exclusion criteria were: 1) IQ lower than 75; 2) history of drug or alcohol use in the last 3 months; 3) a positive urinary toxic screen; 4) a medical condition that contraindicates stimulant treatment (e.g. cardiovascular disease); 5) sleep disorders that interfere with sleep measurements (such as sleep disordered breathing or restless leg syndrome); and. 6) comorbid bipolar disorder, psychosis, or those taking other psychotropic medication.

27 participants were male (73%) and 10 were female (27%). 12 of participants were inattentive subtype (32.4%) and 25 combined sub-type

(67.4%). Comorbid disorders in the sample included 11 subjects with

16 oppositional defiant disorder (29.7%), 3 subjects with enuresis (8.1%), 1 with generalized anxiety disorder (2.7%) and 1 with separation anxiety (2.7%).

Procedure.

The children were treated with MAS and d-MPH in a double-blind, randomized placebo controlled, crossover dose-response study with weekly switches. They were assessed at baseline for diagnosis of ADHD, assessment of comorbidities, baseline measures, and screening for exclusion criteria. After screening, there was a washout period of 2 days for those that were under stimulant treatment and 2 weeks for those treated with atomoxetine. They were then assigned into different treatment groups that randomized whether the initial treatment was with d-MPH or MAS, with the dose increasing every week for 4 weeks. The dosage was 10 mg, 20mg, and 30 mg. The placebo period was randomized to occur at any week of treatment, except the week before the highest dosage to prevent large fluctuation. After the four weeks, the participants were switched to the other medication for another 4 weeks of treatment. The total treatment time was 8 weeks. Sleep data were measured every daily during treatment. No sleep hygiene counseling was given during the trial. Figure 1 is a diagram an example treatment schedule.

Measures.

Actigraphy and Sleep Logs. Actigraphs (AW64 series) were used to assess participant’s sleep patterns in their natural home environment. These computerized wristwatch-like devices collect data generated by movements.

They are minimally invasive and allow sleep to be recorded reliably without interfering with the family’s routine. Actigraphy has been widely used to assess sleep and has been validated against polysomnography with agreement rates for minute-by-minute sleep-wake identification >90% (Meltzer, Walsh, Traylor, &

Westin, 2012). One-minute epochs were used to analyze actigraphic sleep data.

Bedtimes and wake times were reported for each participant using sleep logs, and these times were used as the start and end times for the analyses. For each

1-minute epoch, the total sum of activity counts was computed. If they exceeded a threshold (threshold sensitivity value = mean score in active period/45), then the epoch was considered waking. If it fell below that threshold, then it was considered sleep.

Actigraphic data were analyzed using sleep software (Actiware Sleep 3.4,

Mini-Mitter), and included the following parameters: (a) Bedtime – the time the child got in bed. (b) Sleep Start – the beginning of sleep. (c) Sleep End – the end of sleep (d) Get Up Time – the time the child got out of bed. (e) Actual Sleep

Time – the amount of time (in minutes) between Sleep Start and Sleep End, scored as sleep according to the Actiware-Sleep algorithm.

Sleep start and sleep end were used as measures of sleep schedule, actual sleep time was used as a measure of average sleep duration, and sleep efficiency, sleep latency, sleep bouts and wake bouts ( which are the time asleep

18 and awake during the rest period, respectively) were used as measures of sleep continuity. Actual sleep time was used in the analyses, instead of estimated sleep (as provided in the sleep logs), as it is a more objective and precise measure

Subjective Sleep Questionnaires. The Pediatric Sleep Questionnaire (PSQ)

(Chervin, Hedger, Dillon, & Pituch, 2000)was used to exclude children with sleep disorders. It screens for sleep-disordered breathing, snoring, and sleepiness. The measure contains a validated, reliable, 22-item SDB scale, including a 4-item subscale for snoring, and another for excessive daytime sleepiness. The cut off score for inclusion was ≥ 0.33 (33% answered positively);

The Periodic Leg Movement Disorder (PLMD) questionnaire was used to exclude subjects with PLMD. This is a validated, reliable, 6-item scale measuring period limb movement symptoms. The cut off score for inclusion was ≥ 0.33

(33% answered positively).

The Children’s Sleep Habits Questionnaire (CSHQ), a retrospective, 45- item parent questionnaire that has been used in a number of studies to examine sleep behavior in young children , was employed to exclude children with sleep disorders. The CSHQ includes items relating to a number of key sleep domains, such as bed time behaviour, snoring, daytime sleepiness, parasomnias, and insomnia, that comprise the major clinical sleep complaints in school-age children. A cut-off total score of 41 yields a sensitivity of 80% and a specificity of

72% (J. A. Owens, Spirito, & McGuinn, 2000).

The ADHD Rating Scale-IV (ADHD-RS) was also used in this study to assess baseline ADHD severity. The measure consists of 18 items assessing

DSM-IV criteria for Inattention and Hyperactivity, and yields a Total Score as well as Hyperactivity/Impulsivity and Inattention Subscale scores (DuPaul, Power,

Anastopoulos, & Reid, 1998). A diagnosis of ADHD is established when scores are higher than the 93rd percentile for age group and sex. For females, this is a score of 20 (ages 8-13) and 22 (ages 14-18). For males, scores of 27 (ages 8-10,

14-18) and 34 (ages 11-13) are the cut-off scores. The questionnaire has been validated in child populations within the United States and Europe, with high interrater reliability and moderate to high validity when compared to other ADHD symptom scales (Zhang, Faries, Vowles, & Michelson, 2005) .

The Clinical Global Impressions – Severity (CGI-S) scale (Guy, 1976) was also employed in the study. It is a widely used measure of overall ADHD symptoms severity, and consists of one item with a score ranging from 1 (normal) to 7 (most severe). This scale is recognized as being valid as well as having good reliability, with a correlation between the CGI-I and the CGI-S of 0.71 (Berk et al., 2008).

Analyses

Descriptive Statistics

Demographic and clinical characteristics at baseline were recorded for all participants. Means and standard deviations were calculated for sleep measures at baseline and during each period of medication at different doses.

Comparing the Impact of Medication and Dose on Sleep

All hypotheses were examined using two-way ANOVAs with two within- subject factors (medication and dosage), and with sleep measures (sleep start time, sleep end time, and sleep duration) as the dependent variables. Missing data were imputed with last observation carried forward (LOCF) by repeating the measure from the previous, lower dosage of the same medication. Subjects that did not have sleep measurements for each week after imputing were excluded from analysis. When significant effects were found for either dose or for an interaction between medication and dose, pairwise comparisons were performed to determine where the differences were located. Dose was treated as a categorical variable during such comparisons, to facilitate analysis. The assumptions of normality and homogeneity of the variance were verified by examining residuals derived from the mixed effects models. Violations to the assumption of sphericity were corrected with the lower-bound correction. Post- hoc comparisons were performed with a Bonferroni correction. Significant differences were set at a p level of 0.05.

Results

Descriptive Results

Demographic and descriptive data of the study population are presented on Table 1.

Under placebo treatment, the mean duration of actual sleep was 459.6 minutes (SD 73.6). By dosage for both medications combined, the mean duration of actual sleep for 10mg, 20mg, and 25/30mg of stimulants were 446.7 (SD

63.58), 432.17 (SD 64.6), and 425.5 (SD 61.5), respectively. The mean duration for actual sleep during MAS treatment was 438.82 (SD 67.2) and for d-MPH,

443.2 (66.9).

The mean sleep start time during placebo treatment was 22:49 (SD

00:12:19). By dosage, the mean sleep start times for 10mg, 20mg, and 25/30mg of the stimulants were 23:04 (SD 00:10:40), 23:19 (SD 00:12:21) and 23:25 (SD

00:11:17), respectively. For MAS, the mean sleep start time was 23:09 (SD

00:11:05), and for d-MPH the mean time was 23:09 (SD 00:11:19). The mean sleep end time during placebo treatment was 07:42 (SD 00:15:36). By dosage, the mean sleep end times for 10mg, 20mg, and 25/30mg of the stimulants were

07:28 (SD 00:09:54), 07:35 (SD 00:10:46) and 07:32 (SD 00:11:09), respectively.

For MAS, the mean sleep start time was 07:35 (SD 00:10:40), and for d-MPH the mean time was 07:34 (SD 00:10:04).

The Impact of Differing Dosages on Sleep

The ANOVAs that were conducted to determine the impact of the dose of stimulant medications on sleep duration revealed a significant dose effect

(F(1,36)=9.560, p<0.01). Post-hoc comparisons revealed significantly shorter sleep duration for participants receiving 20mg and 30mg compared to both those on placebo and on 10mg (p<0.05). No other significant differences were found in the post-hoc comparisons. Tables 2 shows the means and standard deviations of sleep duration for all dosages on sleep duration. Figure 1 shows the means and standard errors of sleep start time for both medications at different dosages on sleep duration.

The ANOVAs that were conducted to determine the impact of the dose of stimulant medications on sleep start time showed a significant dose effect

(F(1,36)=7.005), p<0.05). Post-hoc contrasts showed a significantly later sleep start time when children were on 20mg or 30mg dosages, compared to when they were on placebo (p<0.05), regardless of medication. They also showed significantly later sleep start times when comparing subjects on 30mg with those on 10mg (p<0.05). There were no significant differences for the other contrasts.

Figure 2 shows the means and standard errors of sleep start time for both medications at different dosages on sleep start time. Means and standard deviations for sleep start time and sleep end time are presented in table 2.

The impact of Dexmethylphenidate vs. Mixed Amphetamine Salts on Sleep

There were no significant differences in the impact of the two formulations on sleep duration (F(1,36)=0.416, p>0.05), sleep start time (F(1,36)=0.000, p>0.05), and sleep end time(F(1,36)=0.004, p>0.05). No significant interactions between stimulant medications and dosage were found for sleep duration (F(1,36)=2.183, p>0.05), sleep start time (F(1,36)=2.736, p>0.05), and sleep end time

(F(1,36)=0.636, p>0.05) between. Table 2 shows the means and standard deviations of sleep duration and sleep schedule for both medications.

Discussion

The goal of this study was to compare the effect of different formulations and different dosages of MAS and d-MPH on sleep schedule and sleep duration.

We found that both formulations decreased sleep duration. When the impact of medication dosages on sleep were compared, sleep duration was shorter among those receiving the highest dosage compared with placebo regardless of the formulation. Analysis of sleep schedule showed that this was due to a later sleep start time. There was a statistically significant mean reduction of 34 minutes between placebo and the highest dosage (25 or 30mg), as well as 21 minutes between the lowest dosage (10mg) and the highest dosage. The mean sleep duration for the highest dosage was 7 hours and 5 minutes. There was a non- significant trend between all dosages towards shorter sleep durations with each increasing dosage. No differences were found in the impact of MAS and d-MPH on sleep duration or schedule. Therefore, as far as sleep is concerned, there is no benefit in using one medication over the other.

These results have important implications to clinical practice; for example, the findings have implications for dose optimization and could lead to enhanced treatment outcomes for children with ADHD under stimulant treatment. Although higher doses could improve ADHD symptoms more effectively (Stein et al.,

2011), this study shows that, regarding the side effects of sleep, there are benefits to using lower dosages. If a patient’s sleep duration is decreased at higher dosages, reducing the dosage may increase sleep duration to an amount that is comparable to his or her sleep duration without treatment. It may, thus, be

25 advisable for clinicians to initiate treatment with lower dosages to prevent sleep side effects or to reduce the dosage of patients that present these side effects.

It is also possible that sleep duration reduction might increase ADHD symptoms or reduce the effectiveness of treatment, as there is evidence that reductions in sleep duration affect neurobehavioural scores (Gruber et al., 2011).

ADHD symptom scales and sleep duration during stimulant treatment was not compared in this study, however a future study could look into this interaction.

The main limitation of this study was the small sample size. While this does reduce the statistical power to detect changes, the sample size is similar to other studies with objective sleep measures in a clinical ADHD population

(Cortese, Faraone, Konofal, & Lecendreux, 2009). Furthermore, the sample size was much bigger than interventional studies of sleep on children with ADHD

(Cohen-Zion & Ancoli-Israel, 2004). Future studies with a larger sample size might be able to detect the significance of smaller reductions in sleep duration between similar dosages.

While the within-subject comparisons provide control for individual response to medication, it can also leads to patients being excluded if they did not complete measurements for every week. To prevent a bias from non-random exclusion due to incomplete measures, LOCF was used to impute data. This method is commonly used in clinical studies to replace missing data. In this case,

LOCF leads to underestimating the differences between dosages, so any significant findings are not due to the use of this method.

The Actiwatch was worn at home by the participants, and therefore provided measurements in an environment closer to real, day-to-day conditions as opposed to sleep measurements recorded in an artificial sleep setting (such as in a sleep clinic). In using this methodology, however, there is also less control over the participants’ behaviors, and compliance is more dependent on the participants themselves and their parents. It may be possible to increase compliance with more frequent reminders between check-ups to properly wear the recording device. In this study, participants did not receive reminders between the weekly visits. An additional strength of this study was that the use of an objective measurement for sleep increases reliability for measures of sleep duration; The alternative use of subjective sleep measures tends to underestimate changes in sleep duration (Owens et al., 2009).

Conclusion

Overall, both ER MAS and ER d-MPH were associated with significant, dose dependent reductions in sleep duration. Higher dosages were associated with shorter sleep durations due to later sleep initiation times. There were no differences between stimulant classes. Future studies with a larger sample size may elucidate smaller differences between dosages, which may improve dose optimization strategies.

Tables and Figures

Table 1. Demographic and clinical characteristics of study participants Variables Mean Standard Deviation

Age 11.60 1.95 Weight 44.40 14.40 Height 152.04 13.07 ADHD-RS 40.08 9.43 CGI-S 5.03 0.76 CSHQ 49.53 9.99 N % Gender Male 27 73 Female 10 27 ADHD Subtype Inattentive 12 32.4 Combined 25 67.4

Table 2. Sleep Duration and Schedule by medication and dosage Dosage M (SD) Sleep duration Sleep Start Time Sleep End Time (minutes) Placebo 459.6 (73.7) 22:49 (00:12:19) 07:42 (00:15:36) 10 mg 446.7 (63.6) 23:04 (00:10:40) 07:28 (00:09:54) 20 mg 432.2(64.6) 23:19 (00:12:21) 07:35 (00:10:46) 30 mg 425.6 (61.5) 23:25 (00:11:17) 07:32 (00:11:09) Medication MAS 438.821(67.2) 23:09 (00:11:05) 07:35 (00:10:40) d-MPH 443.218 (66.9) 23:09 (00:11:19) 07:34 (00:10:04) MAS: Mixed Amphetamine Salts, d-MPH: dextromethylphenidate

Figure 1. This is an example of a treatment schedule. Each treatment modality lasts for one week, for a total of 8 weeks.

650

600

550

500

450

Sleep Duration Sleep

400

350

300 Placebo 10 mg 20 mg 30 mg

MAS dMPH

Figure 2. Sleep duration for MAS and d-MPH at all dosages. Mean sleep duration decreases with higher dosages for both medications. There are significant differences in mean duration during both placebo and 10 mg treatment compared to 20mg and 30mg treatment.

01:55:12

01:26:24

00:57:36

00:28:48

00:00:00

23:31:12

23:02:24 Sleep Start Time Sleep 22:33:36

22:04:48

21:36:00

21:07:12 Placebo 10 mg 20 mg 30 mg

MAS d-MPH

Figure 3. Sleep Schedule: Sleep start time for MAS and d-MPH at all dosages. Mean sleep start time occurs later with higher dosages for both medications. There are significant differences in mean sleep start time during placebo compared to 20mg and 30mg treatment.

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