Influence of light exposure on cerebral monoamine oxidase A in SAD

Background and aim: Recent years have produced compelling evidence that commonly experienced seasonal variations in mood are mainly mediated by increases and decreases in the activity of the monoaminergic neurotransmitter systems, specifically the serotonergic system. Although seasonal serotonergic variation is observed to some degree in most individuals, the environmental stress of light reduction during fall and winter can induce seasonal affective disorder (SAD) in vulnerable people. Several studies emphasize the impact of seasonal light deprivation on monoamine oxidase A (MAO-A). The proposed prospective study, assessing the individual light exposure and using Positron Emission Tomography (PET), gives us a unique opportunity to evaluate the actual involvement of one of the main actors of the serotonergic system in patients suffering from SAD and healthy controls (HC). Objectives: (1) To assess differences in MAO-A binding in the brain between SAD patients and HCs. (2) To investigate seasonal variation in MAO-A specific distribution volume (MAO-A DV s ) in SAD patients and HCs. (3) To demonstrate the impact of light therapy on MAO-A DV s 1 . Hypotheses: (1) SAD patients will have higher MAO-A DV s compared HCs (2) PET measurements carried out in fall/winter will reveal higher MAO-A DV s than in spring/summer in both patients and HCs (3) Non-treated SAD patients and HCs will have higher MAO-A DV s compared to treated patients and HCs respectively, whereas treated patients will still have higher MAO-A DV s than HCs 1 . (4) In SAD patients, symptom severity assessed with the SIGH-ADS and BDI will be associated with MAO-A DV s . Study design: Randomized, cross-sectional, longitudinal, double-blind, cohort-control study1 . Twenty-four patients with DSM-IV diagnose of SAD and 24 age- and sex-matched HCs will be examined. Each SAD patient and HC will undergo three PET sessions. (1) Baseline measurement of MAO-A DV s in the fall-winter season2 ; (2) Measurement of MAO-A DV s in the fall-winter season after application of bright light therapy vs. placebo; (3) Measurement of MAO-A DV s in the spring-summer season1 . We propose an overall study duration of 36 months. Material/Methods: PET measurements will be obtained using the highly specific radioligand [ 11C]harmine for MAO-A. Additional structural Magnetic Resonance Imaging (MRI) will be carried out for every participant. Quantitative tracer kinetic modeling will be performed using tools implemented in the biomedical image quantification software PMOD 3.1. Light exposure will be measured with light dosimeters. Statistical analysis: MAO-A DV s will be quantified applying a voxel-based and a ROI-based approach. To uncover significant differences of MAO-A DV s in patients and HCs an independent-samples t-test will be performed. To investigate the impact of seasonality and light therapy on MAO-A DV s a repeated measures ANCOVA will be used with light exposure data and psychological test scores as covariates3 . Relevance of the study: This study will be the first prospective investigation to compare SAD patients and HCs with regard to seasonal differences on the MAO-A. By including randomly assigned light exposure during the fall- winter season in the analysis and measuring every participant in spring-summer and fall-winter season, we will gain comprehensive information about the quantifiable impact of season on the MAO-A as one of the major regulators of the serotonergic homeostasis and its involvement in the pathophysiology of SAD.

Seasonal affective disorder (SAD) is a common ailment that affects millions of people world-wide. It is a sub-form of major depressive disorder that is characterized by depressive symptoms that occur in fall and winter, then remit in spring and summer. Patients typically express symptoms understood as atypical depressive symptoms, such as increased sleep and appetite. Numerous studies have shown that non-seasonal depression is associated with changes to the serotonergic system. Among these results, increased brain monoamine oxidase A (MAO-A) is considered a central finding in depression. MAO- A is an enzyme which degrades serotonin, and is therefore fundamentally involved in regulation of serotonin neurotransmission. Considering that, based on its function as a degrading enzyme, higher MAO-A levels are associated with lower serotonin levels, higher MAO-A in depression is in accordance with the hyposerotonergic hypothesis of depression, the concept that depression is fostered by low levels of monoamin neurotransmitters (serotonin, noradrenaline, dopamine). It has also been shown, that serotonergic molecules are affected by season and light, to which the development of SAD is also closely related. We therefore aimed to assess changes to brain MAO-A levels in patients with SAD in comparison to healthy controls (HC), in fall/winter in comparison to spring/summer, as well as before and after treatment with bright light therapy, which is the first-line treatment for SAD. To do so, we utilized positron emission tomography. We found that, while SAD and HC did not differ in regards to brain MAO-A levels, MAO-A levels changed between fall/winter and spring/summer in HC, while they did not change in SAD. Interestingly, we also found that BLT resulted in a reduction in brain MAO-A, while no effect was found after treatment with placebo. To our knowledge, this is the first study to demonstrate an influence of BLT on human cerebral MAO-A levels in-vivo. Furthermore, we showed that SAD may lack dynamic seasonal changes to brain MAO-A levels. The fact that we did not find differences in brain MAO-A between SAD and HC, in contrast to studies in non-seasonal depression, may be a result of the milder symptoms typically shown by patients with SAD.