Melatonin and Depression: A Translational Perspective From Animal Models to Clinical Studies

Abstract

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.

Keywords: 6-sulfatoxymelatonin (aMT6s); behavior; biological rhythms; biomarker; chronobiology; mood disorder; neuropsychaitric disorders; psychiatry.

Figure 1

Environmental and internal regulation of biological rhythms, melatonin production and associations with behavior (A); the process of entrainment and alignment (B). The main environmental cue that synchronizes the circadian system is the light-dark cycle. The suprachiasmatic nucleus (SCN) receives photic information and projects to several structures in the body, coordinating peripheral tissues by modulating other oscillators according to light-dark transitions. Other stimuli of importance include feeding schedules, rest-activity rhythm and social cues. Peripheral tissues respond to timing neural and endocrine signals modulated by the SCN, including the release of melatonin to the bloodstream, as well as from feeding. On the other hand, endogenous circadian rhythms also influence daily patterns in behavior/exposure to environmental factors and might also influence melatonin production (see details in text). In (A), black arrows connect the environmental stimuli to the central and peripheral clocks and tissues and show the interconnection among systems. Continuous arrows represent higher levels of evidence and dashed arrows represent lower levels of evidence. Melatonin is produced in the pineal gland, as a result of darkness or on-demand via other pathways (see details in text), acting locally or transducing the dark signal to peripheral tissues (green arrows). Extra-pineal sources of melatonin include the skin, guts, and lungs, which only act locally with no known chronobiotic effect. While the physiological actions of melatonin potentially impact behavior, individual behavior might also determine the timing of light exposure, rest-activity rhythms and feeding behavior, thus regulating melatonin secretion. The first column at (B) shows rhythms of activity, temperature, and feeding behavior aligned with the light signal; the second depicts rhythms which are phase delayed. The rhythms at the third column are no longer entrained to the light signal and are not synchronous within themselves, determining a misalignment.

Figure 2

The canonical pathway of pineal melatonin production. The suprachiasmatic nucleus (SCN) receives environmental photic information collected by intrinsically photosensitive ganglion cells (ipRGC) in the retina. The ipRGCs express the photopigment melanopsin, which transduces light wavelengths into neural input through the retinohypothalamic tract (RHT) to the SCN. The SCN constitutively inhibits the hypothalamic paraventricular nucleus (PVN) via GABAergic projection. In the absence of light, the PVN activates the ganglion cervical nuclei (SCG, via the intermediolateral column of the medulla) triggering noradrenergic fibers that innervate the pineal gland (PG), ultimately releasing the co-transmitters noradrenaline and ATP. This sympathetic stimulus triggers the action of arylalkylamine N-acetyltransferase (AANAT) converting serotonin (5TH) into N-acetylserotonin (NAS) within the pinealocyte. With the constitutive action of N-acetylserotonin O-methyltransferase (ASMT), NAS is then converted to melatonin and immediately released into the cerebrospinal fluid and bloodstream. Through first-pass metabolism in the liver, melatonin is converted to 6-sulfatoxymelatonin (aMT6s), which is then excreted in the urine.