Molecular underpinning of light therapy in seasonal affective disorder

Depression is a prevalent and disabling disorder. Light therapy is effective in
depressive disorders and especially well established in seasonal affective
disorder (SAD). The mechanism by which light therapy is effective is only
beginning to be elucidated and contains apparent contradictions. One of the
hypotheses is that a change in light sensitivity is underlying winter
depression. In a recent collaboration between the departments of chronobiology
in Groningen and Zürich (Switzerland) we found a strong association between
melatonin suppression (often used as a marker of light sensitivity) measured in
healthy humans and cellular excitability (CREB induction) measured in
fibroblasts collected from these same individuals. This finding shows that the
degree of cellular excitability is individually determined and probably similar
throughout several parts in the body (central and peripheral). Melatonin
production might not only be determined by stimulatory or inhibitory (light
exposure) signals but also by cellular degree of excitability. From this
finding we hypothesize that SAD patients have lowered cellular excitability in
general and this results in lowered serotonin levels, which contribute to the
development of depression. Light therapy is hypothesized to be effective by
compensating for this subsensitivity in cellular excitability levels. We aim to
link the molecular study of human fibroblasts in vitro with measures of
melatonin suppression in vivo in both SAD patients and healthy controls to test
this hypothesis. Recently some indications have been found that a missense
variation in a gene coding for melanopsin may be involved in seasonal affective
disorder and in light sensitivity. Since we are also interested in the
background of light sensitivity we propose to analyse gene variation in this
OPN4 gene. In addition another gene, thought to be involved in cellular
excitabitilty, adenelyl cyclase, is know in various forms, and we hypothesize
that differences between individuals in the cellular excitability may be
explained by differences in this gene.

Link inter-individual differences in light sensitivity (measured by melatonin
suppression) to molecular pathways in primary fibroblasts in SAD patients and
healthy controls and with light therapy succes in SAD patients and with gene
variation in two candidate genes involved in these processes.

The data collection will take place in the winter of 2011-2012 and will
continue in the winter of 2012-2013.
Each subject will be asked to give two 2 mm skin biopsies for fibroblast
collection. A drop of blood that will be available because of this procedure
will be collected to obtain serum. The fibroblasts and serum will be send
anonymously to the Institute for Pharmacology and Toxicology, of the University
of Zurich, for further analysis. Subjects will stay one night in the lab.
Timing of measurements will depend on an individual's sleep timing. Each half
hour, starting at habitual sleep onset, saliva samples will be collected for
melatonin analysis. Subjects will stay in dim light from one hour before
habitual sleep onset until bedtime and from 2.5 hours after habitual sleep
onset until the end. During these periods subjects are allowed to sleep. Acute
melatonin suppression will be determined by exposing subject to a light pulse
of 1.5 hours starting one hour after habitual sleep onset. During this period
subjects have to stay awake. Subjects are asked to give one extra saliva sample
in the beginning of the night for candidate gene analysis. The effect of light
therapy will be measured by SIGH SAD ratings immediately prior to the start of
light therapy, immediately following the last light therapy, and 1 week later.

Subjects will have two small skin biopsies (2 mm) taken for dermal/fibroblast
cell sampling. A drop of blood that accompany this procedure will be collected
to obtain serum. This will be performed by a doctor experienced with the
procedure and subjects are free to ask for anaesthetics. The biopsy may leave a
small scar on their buttocks or upper arm. No extra burden is necessary to
obtain serum.
Healthy and SAD subjects will be brought into our time-isolation facility once
to measure melatonin suppression in response to a light pulse of 1.5 hours (600
lx) and to collect one saliva sample for gene variation analysis. Subjects will
arrive at 1.5 hours before habitual sleep onset and will be brought to their
own room where they will stay in dim light starting half an hour later.
Subjects are asked to go to bed at habitual bedtime and lights will be turned
off during sleep. From habitual bedtime till 5 hours later each half hour
saliva samples for melatonin analyses will be collected, by chewing a cotton
swab. Subjects are restricted in the timing and type of food and drinks that
are allowed: eating and drinking is not allowed during 30 min prior to saliva
sample, no coffee, black tea, alcohol, bananas, chocolate, and toothpaste are
allowed during the entire sampling period of saliva. Because saliva will be
collected each half hour, subjects are only allowed to drink water starting at
half an hour before the first sample. One hour after habitual sleep onset
subjects are woken up for a period of 1.5 hours during which they stay in
medium intensity full spectrum light (600 lux). During this period acute
melatonin suppression will be determined. Half hour saliva collections will
continue for a period of 2.5 hours after the light pulse to measure the timing
and level of the recurrence of melatonin production. Subjects are asked to go
back to sleep during this period, although they will be briefly woken up for
the collection of saliva. After the last collection subjects are allowed to
sleep further until they naturally wake up.
There are no specific risks associated with participation. Patients will
receive regular light treatment as usual, which will be evaluated during three
interviews. The in vivo measurements have to be scheduled prior to the start of
the light treatment. This may result in a slight delay of the start of the
light treatment with a maximum of one week.