Phase shift in adult ADHD of sleep and apetite.

In 80% of adults with ADHD there are chronic sleep-onset problems of which most
have commenced in childhood (van Veen et al, 2010).The sleep problems consist
of a chronic pattern of late sleep time and late rise time. People with this
sleep pattern are often referred to as 'nightowls', and their sleep pattern a
'delayed sleep phase'. The diagnosis of this condition is called the Delayed
Sleep Phase Syndrome (DSPS). Patients with DSPS cannot sleep at an earlier
preferred time, but often only around 2 or 3 AM. The consequence is a chronic
short sleep because they need to get up on time for their daily obligations.

There are clues that the delayed sleep phase in ADHD has a genetic foundation.
Our research has shown that this sleep pattern correlates with a late
endogeneous melatonin production in the evening (van Veen et al, 2010).
Melatonin is the sleep hormone that in healthy people rises around 9:30 PM (the
moment it reaches a threshold is termed Dim Light Melatonin Onset, or DLMO)so
that they can sleep around two hours later, around 11:30 PM. In adults with
ADHD the DLMO has a mean of 11:15 PM (van Veen et al, 2010). In adults with
ADHD and DSPS this is at 0:08 AM (Bijlenga et al, 2011b). The simple advice to
go to bed at an earlier time is not effective, because the sleep is only
supported by melatonin only late at night. Going to bed earlier results in an
even longer sleep onset duration or even insomnia.

A chronic short sleep has negative consequences for physical health. In healthy
people one night of short sleep has already shown to increase the blood glucose
and to decrease insulin resistence, which result in blood values that are
similar to the prestadium of diabetes (Spiegel et al., 2005). A onetime short
sleep also lead to direct increase of the apetite the next day, a preference
for more calory and carbon rich food, probably to compensate for the loss of
energy (Spiegel et al., 2004). On the long term a chronic short sleep is
associated with increase in weight, obesity, diabetes, hypertension, metabolic
syndrome, cardiovascular disease and even cancer (Maury, Ramsey & Bass, 2010;
Knutson, 2010). These alarming figures indicate that betekenen adults with
ADHD may have increased risk of these serious chronic conditions.

Possible interventions
The delayed sleep phase in ADHD can be advanced with treatment with melatonin
in the evening and/or with light therapy in the morning. Both are termed
'zeitgebers' because they influence the biological clock and the timing of the
sleep. By advancing the sleep phase the potential sleep duration increases. Our
hypothesis is that resetting the biological clock will also influence other
*timed* processes such as apetite, hormone production, and temperature.

In this study the best treatment of DSPS will be investigated by comparison of
existing treatments. We will investigate is patients with ADHD and DSPS have
less favorable blood values for biomarkers of chronic diseases in comparison
with norm values and a less favourable cardiovasculair profile, in treatment
with Melatonin has effect on sleep length, sleep phase, ADHD-symptoms, appetite
hormones and other biomarkers, and if light therapy in the morning in addition
to Melatonin treatment has an additive effect on the treatment. We will also
investigate the relationship between the delayed sleep phase and appetite in
adults with ADHD and DSPS. In addition, DNA samples will be collected for a
*Genome-wide association study*.

The study has a double-blind placebo controlled randomized design with three
intervention groups of 17 adults with ADHD and DSPS each; total N=51.

The effect of treament of DSPS will be evaluated by randomisation of patients
for:
1) Sleep education plus 0,5 mg dd Melatonin following individual medication
scheme during 3 weeks (MEL)
2) Sleep education plus 0,5 mg dd placebo following individual medication
scheme during 3 weeks (PLAC)
3) Sleep education plus 0,5 mg dd Melatonin following individual medication
scheme plus 30 minutes light therapy in the morning between 7 and 8 AM during
3 weeks (MEL+LT)

The individual medication scheme consists of administration of the study
medication 3, 4 and 5 hours before the individual's time of DLMO in the first,
second, and third intervention week, respectively.

Baseline (week 1)
All patients fill out questionnaires about demographic characteristics, sleep
characteristics (MCTQ), ADHD symptoms (ADHD-RS), life style, daytime
sleepiness, any illness or colds within the last week (to correct the
inflammation markers), food type preference, apetite, and quality of life
(AAQOL). A DNA sample will be collected. All patients will wear a holter and an
ambulant blood pressure monitor during 1 day and a wrist Actometer during 3
days and record their sleep in a sleep log; during 1 night the salivary
melatonin will be assessed between 8 PM and 3 AM on the hour, during 1 morning
salivary cortisol will be assessed (directly after wake-up, 15 minutes, and 30
minutes after wake-up), blood will be drawn sober at 8AM for the assessment of
leptin, ghrelin, insulin/glucose ratio, insulin resistentance (with OGTT),
IGF-1, CRP, vitamin B12, vitamin D, magnesium, iPTH, leukocyte count, and
ferritin; and the assessment of blood pressure, length and weight.

Randomisation and intervention (weeks 2-4); patients will be randomised for one
of the following interventions:
1) Sleep education plus 0,5 mg dd Melatonin 3 hours before DLMO during 3 weeks
(MEL)
2) Sleep education plus 0,5 mg dd placebo 3 hours before DLMO during 3 weeks
(PLAC)
3) Sleep education plus 0,5 mg dd Melatonin 3 hours before DLMO plus 30 minutes
light therapy in the morning between 7 and 8 AM during 3 weeks (MEL+LT)

Followup 1 (week 5): directly after intervention
All patients fill out the same questionnaires about sleep characteristics
(MCTQ), ADHD symptoms (ADHD-RS), life style, daytime sleepiness, any illness or
colds within the last week (to correct the inflammation markers), food type
preference, apetite, quality of life (AAQOL), and also treatment satisfaction.
All patients will again wear a holter and an amulant blood pressure monitor
during 1 day and a wrist Actometer during 3 days and record their sleep in a
sleep log; during 1 night the salivary melatonin will be assessed between 8 PM
and 3 AM on the hour, during 1 morning salivary cortisol will be assessed
(directly after wake-up, 15 minutes, and 30 minutes after wake-up), blood will
be drawn sober at 8 AM for the assessment of leptin, ghrelin, insulin/glucose
ratio, insulin resistentance (with OGTT), IGF-1, CRP, vitamin B12, vitamin D,
magnesium, iPTH, and leukocyte count; and the assessment of blood pressure and
weight.

Followup 2 (week 7): delayed effect
All patients fill out the same questionnaires about sleep characteristics
(MCTQ), ADHD symptoms (ADHD-RS), life style, daytime sleepiness, any illness or
colds within the last week (to correct the inflammation markers), food intake,
apetite, quality of life (AAQOL), and also treatment satisfaction. All patients
will again wear a wrist Actometer during 3 days and record their sleep in a
sleep log; during 1 night the salivary melatonin will be assessed between 8 PM
and 3 AM on the hour, during 1 morning salivary cortisol will be assessed
(directly after wake-up, 15 minutes, and 30 minutes after wake-up), blood will
be drawn at 8 AM for the assessment of leptin, ghrelin, insulin/glucose ratio,
insulin resistentance, IGF-1, CRP, vitamin B12, vitamin D, magnesium, iPTH, and
leukocyte count; and the assessment of blood pressure and weight.

The burden of participation will be held to a minimum. Participants are asked
to visit our clinic 9 times in 7 weeks. Travel expenses are covered and they
will receive ¤100 for study participation. Filling out the questionnaires is
not burdening. The keeping of the sleep logs is minimally burdening and will
take 5 minutes per dag durig 3 weeks. To wear the wrist Actometer during 3 days
per measurement is also not burdening.

The assessment of Melatonine in saliva can be somewhat burdening because they
may experience loss of some night rest . The patient is asked to chew on the
cotton swabs under dim light and is asked not to take certain foods and drinks
(caffeine, alcohol, and banana). In total, 8 cotton swabs need to be chewed in
one night. If one cotton swab takes 1 minute then the time investment for this
part of the study is about 8 swabs x 3 measurements = 24 minutes.

To draw blood three times can be somewhat burdening. For each draw the patient
needs to be sober and at the clinic at 8:00 AM . At Baseline and at Followup 1
a venflon will be inserted to draw blood, or we will collect blood by
venipuncture or from finger pricks if it is not possible to insert a
venflon.After first blood draw an OGTT will be performed using standard
protocol. The patient needs to stat at the clinic for the OGTT for 2 hours but
can work on a computer or laptop or can sit quietly and read. For the OGTT the
patients need to drink a glucose containing solution after which every 30
minutes blood is drawn. After the OGTT the patient will receive a breakfast. At
Followup 2 there is no OGTT but the blood will be drawn without a venflon.

To wear a holter and an ambulant blood pressure monitor for 24 hours is not
very burdening. The collection of a DNA sample is also regarded as not very
burdening.

The risics of complications because of study participation are deemed minimal.