Melatonin and depression : a translational perspective from animal models to clinical studies

Daily rhythm of melatonin synchronizes the body to the light/dark environmental cycle. Several hypotheses have been raised to understand the intersections between melatonin and depression, in which changes in rest-activity and sleep patterns are prominent. This review describes key experimental and clinical evidence that link melatonin with the etiopathology and symptomatology of depressive states, its role in the follow up of therapeutic response to antidepressants, as well as the clinical evidence of melatonin as MDD treatment. Melatonin, as an internal temporal cue contributing to circadian organization and best studied in the context of circadian misalignment, is also implicated in neuroplasticity. The monoaminergic systems that underly MDD and melatonin production overlap. In addition, the urinary metabolite 6-sulfatoxymelatonin (aMT6) has been proposed as biomarker for antidepressant responders, by revealing whether the blockage of noradrenaline uptake has taken place within 24 h from the first antidepressant dose. Even though animal models show benefits from melatonin supplementation on depressive-like behavior, clinical evidence is inconsistent vis-à-vis prophylactic or therapeutic benefits of melatonin or melatonin agonists in depression. We argue that the study of melatonin in MDD or other psychiatric disorders must take into account the specificities of melatonin as an integrating molecule, inextricably linked to entrainment, metabolism, immunity, neurotransmission, and cell homeostasis

A phase II, randomized, double-blind, placebo controlled, dose-response trial of the melatonin effect on the pain threshold of healthy subjects

Background: Previous studies have suggested that melatonin may produce antinociception through peripheral and central mechanisms. Based on the preliminary encouraging results of studies of the effects of melatonin on pain modulation, the important question has been raised of whether there is a dose relationship in humans of melatonin on pain modulation. Objective: The objective was to evaluate the analgesic dose response of the effects of melatonin on pressure and heat pain threshold and tolerance and the sedative effects. Methods: Sixty-one healthy subjects aged 19 to 47 y were randomized into one of four groups: placebo, 0.05 mg/kg sublingual melatonin, 0.15 mg/kg sublingual melatonin or 0.25 mg/kg sublingual melatonin. We determine the pressure pain threshold (PPT) and the pressure pain tolerance (PPTo). Quantitative sensory testing (QST) was used to measure the heat pain threshold (HPT) and the heat pain tolerance (HPTo). Sedation was assessed with a visual analogue scale and bispectral analysis Results: Serum plasma melatonin levels were directly proportional to the melatonin doses given to each subject. We observed a significant effect associated with dose group. Post hoc analysis indicated significant differences between the placebo vs. the intermediate (0.15 mg/kg) and the highest (0.25 mg/kg) melatonin doses for all pain threshold and sedation level tests. A linear regression model indicated a significant association between the serum melatonin concentrations and changes in pain threshold and pain tolerance (R2 = 0.492 for HPT, R2 = 0.538 for PPT, R2 = 0.558 for HPTo and R2 = 0.584 for PPTo). Conclusions: The present data indicate that sublingual melatonin exerts well-defined dose-dependent antinociceptive activity. There is a correlation between the plasma melatonin drug concentration and acute changes in the pain threshold. These results provide additional support for the investigation of melatonin as an analgesic agent

6-Sulfatoxymelatonin predicts treatment response to fluoxetine in major depressive disorder

Background: To date, no biomarker has been able to predict antidepressant response at an early blockade of norepinephrine or serotonin uptake. The transient nocturnal increase in plasma melatonin levels is upregulated by blocking these uptakes. The aim of this study was to test whether fluoxetine increase in urinary 6-sulfatoxymelatonin (aMT6s) is an indicator of serotonin uptake blockade. Methods: A total of 20 women (35–45 years of age) recruited from the community had a diagnosis of major depressive disorder confirmed by the Structured Clinical Interview for DSM-IV. Depressive symptoms were evaluated by the Beck Depression Inventory (BDI). Participants were instructed to take 20 mg of fluoxetine every morning. Every 4 weeks, the dose could be increased by 20 mg until symptom remission. The concentration of aMT6s was evaluated in overnight urine samples collected 1 day before and 1 day after the first fluoxetine dose. Results: An increase in aMT6s correlated to a decrease in BDI score evaluated on day 45 (ρ=−0.67, p = 0.024) was observed. Conclusions: Nocturnal increase in urinary aMT6s after the first day of medication use links the early mechanism of action of fluoxetine to its clinical output 45 days later. Thus, the relationship between urinary aMT6s excretion 1 day before/1 day after is a biomarker for predicting clinical output earlier, reducing illness burden and health care costs

Melatonin receptors in GtoPdb v.2023.1

Melatonin receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Melatonin Receptors [40]) are activated by the endogenous ligands melatonin and clinically used drugs like ramelteon, agomelatine and tasimelteon

Melatonin receptors in GtoPdb v.2021.3

Melatonin receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Melatonin Receptors [40]) are activated by the endogenous ligands melatonin and clinically used drugs like ramelteon, agomelatine and tasimelteon

Melatonin receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

Melatonin receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Melatonin Receptors [36]) are activated by the endogenous ligands melatonin and clinically used drugs like ramelteon, agomelatine and tasimelteon

AGE-RELATED-CHANGES IN NEURONAL UPTAKE OF CATECHOLAMINES

UNIV SAO PAULO,INST CIENCIAS BIOMED,DEPT FARMACOL,AV LINEU PRESTES 1524,BR-05508 SAO PAULO,SP,BRAZILESCOLA PAULISTA MED,DEPT FARMACOL,BR-04023 SAO PAULO,SP,BRAZILESCOLA PAULISTA MED,DEPT FARMACOL,BR-04023 SAO PAULO,SP,BRAZILWeb of Scienc

AGE-RELATED-CHANGES IN THE REACTIVITY OF THE RAT JEJUNUM TO CHOLINOCEPTOR AGONISTS

ESCOLA PAULISTA MED,DEPT FARMACOL,CP 20372,BR-01000 SAO PAULO,BRAZILESCOLA PAULISTA MED,DEPT FARMACOL,CP 20372,BR-01000 SAO PAULO,BRAZILWeb of Scienc

Melatonin and the time window for the expression of the alpha 8 nicotinic acetylcholine receptor in the membrane of chick retinal cells in culture

We have previously shown that melatonin influences the development of alpha 8 nicotinic acetylcholine receptor (nAChR) by measurement of the acetylcholine-induced increase in the extracellular acidification rate (ECAR) in chick retinal cell cultures. Cellular differentiation that takes place between DIV (days in vitro) 4 and DIV 5 yields cells expressing alpha 8 nAChR and results in a significant increase in the ECAR acetylcholine-induced. Blocking melatonin receptors with luzindole for 48 h suppresses the development of functional alpha 8 nAChR. Here we investigated the time window for the effect of melatonin on retinal cell development in culture, and whether this effect was dependent on an increase in the expression of alpha 8 nAChR. First, we confirmed that luzindole was inhibiting the effects of endogenous melatonin, since it increases 2-[(125)I] iodomelatonin (23 pM) binding sites density in a time-dependent manner. Then we observed that acute (15, 60 min, or 12 h) luzindole treatment did not impair acetylcholine-induced increase in the ECAR mediated by activation of alpha 8 nAChR at DIV 5, while chronic treatment (from DIV 3 or DIV 4 till DIV 5, or DIV 3.5 till DIV 4.5) led to a time-dependent reduction of the increase in the acetylcholine-induced ECAR. The binding parameters for [(125)I]-alpha-bungarotoxin (10 nM) sites in membrane were unaffected by melatonin suppression that started at DIV 3. Thus, melatonin surges in the time window that occurs at the final stages of chick retinal cell differentiation in culture is essential for development of the cells expressing alpha 8 nAChR subtype in full functional form. (C) 2010 ISDN. Published by Elsevier Ltd. All rights reserved.FAPESP[00/0659-2]Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)PROINT/UFPA[CETCCEN9-PROINT 2004-2005]PROINT/UFP