Effects of morning versus evening dose of hydroxyzine 50 mg on cognition in healthy subjects

One of the most prominent side effects of antihistamines is sedation. Due to
this sedation there is a decrease in workproductivity, an increased absenteïsm
from work or school, and an increased risk for traffic accident.
Antihistamines are dicided in first and second generation medications. First
generation antihistamines cause sedation, whereas second generation
antihistamines have been found to be mildly sedative, or even mildly
stimulating. It is assumed that this difference in sedation could be explained
by their capacity to enter the brain. However, this mechanism alone can not
explain the difference between first and second generation antihistamines.
Other factors may also determine the presence or absence of sedation, such as
the circadian rhythm. It is assumed that although the firing of histaminergic
neurons stops during several stages of sleep, the synthesis of histamine might
continue.
Because of that, the mechanism responsible for the reversion of sedative
effects might be mediated by restoring the balance between histamine release
and synthesis after sleep. This would mean that the histamine availability will
be greatest shortly after awakening. Because of that, the antihistamine will
have less binding potential during that time compared to other times of
administration. Therefore, it is hypothesized that the behavioural effect of an
antihistamine is apparent in the evening after an evening dose condition, but
will be smaller in the morning after a morning dose condition due to the
excessive release of histamine shortly after awaking.

Primary: To explore the effect of the H1-antagonist hydroxyzine 50 mg on motor
response, attention and impulsivity, using a test battery and task
manipulations.
Secondary: To explore the effect of the H1-antagonist hydroxyzine 50 mg on
electrocortical indicators using event related potentials.

Double blind, placebo controlled, 3-way crossover design

During the study, alle volunteers will experience the following testconditions:
1. Hydroxyzine 50mg and placebo
2. Placebo and Hydroxyzine
3. Placebo and placebo

Subjects will visit the study centre and be monitored by one of the
investigators for examination during medical screening (45 minutes); for
training of cognitive tests and one habituation period (13 hours); and three
treatment periods consisting of an evening, night and following morning (15
hours in each treatment period, in total 58.75 hours including 32 hours of
sleep). Blood samples are drawn during screening (10ml) and three treatment
periods (5ml). During treatment periods subjects perform cognitive tests and
ERPs are measured. The investigational product hydroxyzine is a first
generation antihistamine. Its principal indications are: treatment of allergic
pruritis, nausea and anxiety. Administration of hydroxyzine is possible to
cause side-effects, as mentioned in chapter 6. However, the reported effects
generally disappear within 24 hours after administration. This study is
relevant in order to get better insights about the mechanism of H1-antagonists.
With more insights in these mechanisms, the administration of antihistamines
can be adjusted in order to be more effective and less sedative.