Chronobiology, cognitive function and depressive symptoms in surgical patients

Biological rhythms are essential for the regulation of many life processes. Disturbances of the circadian rhythm are known to affect human health, performance and well-being and the negative consequences are numerous and widespread. Cognitive dysfunction, fatigue, pain, sleep disturbances and mood disorders, such as anxiety and depression, are common problems arising around the time of surgery or in the course of a cancer diagnosis and subsequent treatment period. The importance of investigating prevention or treatment possibilities in these populations is significant due to the extent of the problems and the derived consequences on morbidity and mortality. Genetic predisposition to these problems is also an issue in focus. In this thesis we initially investigated whether the specific clock gene genotype PER(5/5) was associated with the development of postoperative cognitive dysfunction one week after non-cardiac surgery. We did not find any association, although this could have been due to the size of the study. Yet, if PER3(5/5) is associated with a higher incidence of postoperative cognitive dysfunction, the risk seems to be only modestly increased and by less than 10%. Melatonin is a hormone with well-known chronobiotic and hypnotic effects. In addition, exogenous melatonin is also known to have anxiolytic, analgesic, antidepressant and positive cognitive effects. Based on the lack of studies investigating these effects of melatonin, we conducted the MELODY trial in which we investigated the effect of 6 mg oral melatonin on depressive symptoms, anxiety, sleep, cognitive function and fatigue in patients with breast cancer in a three month time period after surgery. Melatonin had an effect on reducing the risk of developing depressive symptoms and also increased sleep efficiency perioperatively and total sleep time postoperatively. No effect was found on anxiety, sleep quality, sleepiness, general well-being or pain, however melatonin seemed to positively influence the ability to complete trial participation compared to placebo. Postoperative cognitive dysfunction was not a problem in this limited population. With regard to safety in our study, melatonin treatment for three months did not cause any serious adverse effects. Finally, we systematically reviewed the literature on the prophylactic or therapeutic effect of melatonin for depression or depressive symptoms in adult patients and assessed the safety of melatonin in these studies. The quantity, size and quality of trials investigating this question were not high and there was no clear evidence of an effect, although some studies were positive. In conclusion, further research is warranted with regard to the prophylactic effect and treatment effect of melatonin in depression, depressive symptoms, cognitive disturbances and symptom clusters of cancer patients in general. In addition, more hypothesis-generating studies with regard to the genetic heritability of POCD are needed.