AIM Depression after Acute coronary syndrome (ACS - myocardial infarction and unstable
angina) is highly prevalent and associated with a 2.5 fold increased in all-cause morbidity
and mortality. Sleep disturbances is an integrated part of the pathology of depression and
have severe consequences for quality of life.
Melatonin has shown potential to reduce depressive symptoms and anxiety. Likewise melatonin
has shown sleep improving effects in several populations and also in patients with
depression. Melatonin can potentially reduce the incidence of depression and sleep
disturbances in patients after myocardial infarction.
The project sets to answer the following hypotheses:
Melatonin will due to its antidepressant effect prevent or reduce the incidence of
depressive symptoms in patients after an ACS.
Melatonin will due its anxiolytic effect prevent or reduce the incidence of anxiety in
patients after an ACS.
Melatonin will due to its hypnotic and circadian effects prevent development of sleep
and circadian disturbances in patients after an ACS.
BACKGROUND In Denmark about 8600 each year suffered an acute myocardial infarction. An acute
myocardial infarction is a life-changing event that affects people's lives long after the
blood clot. 20% develop a moderate to severe depression requiring pharmacological treatment
and up to 50% experience depressive symptoms after the initial treatment. Depression after a
acute coronary syndrome is associated with 2.5-fold increased mortality, and 1.5-fold
increased risk of a recurrence of thrombosis. Screening of patients for depression has
therefore been recommended by both the Danish cardiology Association and the American Heart
Association.
Depression in itself requires treatment because depression after myocardial infarction is
associated with reduced quality of life, reduced compliance with medication, reduced
participation in cardiac rehabilitation, and less likelihood of occupational activity.
Medical treatment of depression would traditionally be a selective serotonin reuptake
inhibitor (SSRI) as first-line treatment. SSRI are associated with side-effects such as sleep
disorders, sexual disorders and heart rhythm disturbances.
As an alternative to SSRIs, the investigators focus on the endogenous hormone melatonin which
is virtually side-effect free. Previous experiments have shown that 1000 mg of melatonin
daily for one month was only associated with mild drowsiness increased. Melatonin regulates
the body's circadian rhythm and plays an important role as a hypnotic and in stabilizing the
sleep during the night. Sleep disorders are an integral part of the pathogenesis of
depression and is important for the development of depression.
Method The investigators will perform a double-blind, placebo-controlled, randomized trial in
which patients allocated to either melatonin or placebo in a prophylactic setup. Participants
will be followed for 12 weeks, where they have three clinical visits and depression
measurements every two weeks.
Depression in the study is measured by Major Depression Inventory (MDI), a self-rating form
with 12 questions. The questionnaire is well studied and validated in a Danish population.
The questions covers the 10 ICD-10 symptoms of depression, and is recommended for use in
general practice. MDI is a flexible tool that can be used as a diagnostic tool and at the
same time as measuring instrument for severity of depressive disorder. MDI will be
administered during clinic visits and used in the outpatient phase, so the patients are
followed continuously every two weeks throughout the study. Should there be a treatment
demanding depression (moderate/severe) the participant will be referred to a dedicated
psychiatrist who will perform a Hamilton evaluation and make treatment recommendations.
Participants are also assessed for depression and anxiety by using the Hospital anxiety and
depression scale (HADS). A large Danish study of patients after myocardial infarction was
shown have a prevalence of depression in 20%, and HADS will also be used to compare included
with non-participating patients (external validity).
Melatonin has been shown ameliorative effect on sleep and circadian rhythm. Sleep and
circadian rhythm disorders are an integral part of the development and maintenance of
depression. These will be monitored intensively with actigraphy (objective sleep
measurements), Pittsburgh sleep quality index (PSQI), sleep diaries and visual analog scales
from inclusion meeting to first clinical control. Afterwards subjective sleep measurements
will be performed every two weeks.
Sample size is calculated on the basis of a conservative assumption that, 31 % of patients
following ACS will develop depressive symptoms, which the investigators assume can be reduced
to 15.5 % by Melatonin treatment. Power calculation is based on two-sided test, and with a
power of 0.80 and the significance level 5 % (alfa= 0.05), the required sample size in each
group is 116. There are no interim efficacy analyses planned. The study will proceed until
120 patients have been enrolled in each arm.
MEFACS subtrial (single center)
The objective of the MEFACS study is to investigate whether prophylactic treatment with
melatonin has an effect on endothelial dysfunction. Secondarily, our objective is to
investigate the effect of melatonin on inflammation markers.
The MEFACS trial is a sub-trial of the MEDACIS trial, and The MEFACS trial will be carried
out as a single center trial on a subpopulation of the patients enrolled in the MEDACIS
trial.
The MEFACS trial will include 2 x 15 patients.