Serotonin System And Hormone Circadian Rhythm Research In Depression

Depression is a complex mental disorder, characterized by a set of symptoms including depressed mood, loss of interest and anhedonia. Depression is close related with abnormal patterns of circadian rhythms, such as behavioral (sleep-wakefulness), physiological (body temperature) and endocrine (melatonin, cortisol, testosterone). This study investigated salivary melatonin, serotonin, cortisol and testosterone in 13 outpatients with major depressive disorder and age- and sex-matched healthy controls. Depressed patients received six weeks fluoxetine (20mg/day) treatment, and saliva was collected before and four weeks after treatment. Sets of data were analyzed by using curve fitting. Following is the detail.1. Melatonin is an accurate indicator of circadian timing. Previous studies on circadian changes of melatonin in patients with major depression are equivocal. The purpose of this part is to explore the response of melatonin circadian rhythm to fluoxetine treatment and its relationship with clinical therapeutic effect. Salivary melatonin rhythm was studied with baseline consinus function (BCF). As a result, there was no difference of circadian melatonin rhythms in depressed patients, and melatonin was not significantly lower after fluoxetine treatment. To our surprise, the△melatonin amplitude (Before minus After) was positively correlated with the improvement in Hamilton Depression Rating Scale (HDRS) scores at day 42(R=0.775 P=0.024) whereas there was no such correlation at day 28(R=0.174 P=0.679). These data show that the difference of salivary melatonin amplitude might predict the clinical improvement to fluoxetine in several weeks, as for longer treatment effect deserve further study.2. The role of serotonin system in depression is well recognized. The whole blood 5-HT, platelet 5-HT and salivary 5-HT all show diurnal rhythmic patterns. However, it is not clear how about the 5-HT circadian rhythm in major depression. This part aimed to explore the circadian rhythm of salivary serotonin in patients with major depressive disorder before and after treatment with fluoxetine and its relationship with clinical therapeutic effect. Multioscillator cosinor model was used to fit the rhythms. We find serotonin concentration in saliva ranged from 0.32 ng/ml to 9.62 ng/mL Salivary serotonin showed prominent circadian rhythm in 91% depressed patients and 92% healthy subjects. Circadian amplitude tend to be higher after fluoxetine treatment in depressed patients, so as the ultradian cycle amplitude. The A serotonin circadian amplitude (After minus Before) was positively correlated with the decrease of Zung Self-Rating Depression Scale (SDS) scores at day 42(R=0.80 P=0.016) whereas there was no such correlation at day 28(R=0.63 P=0.095). There was no significant difference in the parameters of mesor, acrophase, harmonic and area under curve among three groups. In conclusion, salivary serotonin in patients with major depressive disorder showed clear circadian rhythm. The relationship between the increase of salivary serotonin amplitude and clinical response deserve further study.3. The abnormal function of hypothalamic-pituitary-adrenal axis is one of the most pronounced neuroendocrine alterations in depression. Hypercortisolemia and a less rhythmic pattern of cortisol release have been observed in major depression. The majority of these studies were about traditional antidepressants. This part aimed to explore the relationship between clinical response and circadian rhythms of free cortisol in major depression patients participating in a controlled trial of a serotonin selective reuptake inhibitor—fluoxetine. We did not find any significant differences between depressed patients and controls. Amplitude tend to be lower after fluoxetine treatment (P=0.068). Acrophase in normal control and depressed patients after treatment tended to be more aggregated. We found cortisol mesor was positively correlated with melatonin peak level in normal control subjects(R=0.639 P=0.047 n=10); Cortisol amplitude was negatively correlated with melatonin baseline level(R=-0.726 P=0.017 n=10). There was no similar correlation in depressed patients.4. Testosterone is related to depression and well-being. Only a few studies explored the relationship between testosterone rhythm and depression. This part aimed to evaluate testosterone circadian rhythm in patients with major depression before and after fluoxetine treatment. Multioscillator cosinor model was used to fit the rhythm. We did not. find any significant difference at mesor, amplitude, acrophase or area under curve between depressed patients and normal control. In depressed patients, the ultradian period was significantly shorter, and the acrophase tended to be more aggregate after fluoxetine treatment. Longer effect of fluoxetine deserves further study.