Review
Neuropsychobiology Received: January 19, 2018
DOI: 10.1159/000489470
Pathophysiology of Depression:
Molecular Regulation of Melatonin
Homeostasis – Current Status
Monika Dmitrzak-Weglarz a Edyta Reszka b    
a Department
of Psychiatric Genetics, Department of Psychiatry, Poznan University of Medical Sciences,
Poznan, Poland; b Department of Molecular Genetics and Epigenetics, Nofer Institute of Occupational
Medicine, Lodz, Poland
Keywords
Depression · Melatonin synthesis and metabolism · Gene
expression · Single-nucleotide polymorphisms · Epigenetics
Abstract
Circadian rhythm alterations resulting in disturbed sleep and
disturbed melatonin secretion are flagship features of de-
pression. Melatonin, known as a hormone of darkness, is se-
creted by the pineal gland located near to the center of the
brain between the two hemispheres. Melatonin has an anti-
depressant effect by maintaining the body’s circadian
rhythm, by regulating the pattern of expression of the clock
genes in the suprachiasmatic nucleus (SCN) and modifying
the key genes of serotoninergic neurotransmission that are
linked with a depressive mood. Melatonin is produced via
the metabolism of serotonin in two steps which are cata-
lyzed by serotonin N-acetyltransferase (SNAT) and acetylse-
rotonin-O-methyltransferase (ASMT). Serotonin, SNAT, and
ASMT are key melatonin level regulation factors. Melatonin
acts mainly on the MT1 and MT2 receptors, which are present
in the SCN, to regulate physiological and neuroendocrine
functions including circadian entrainment, referred to as a
chronobiotic effect. Although melatonin has been known
© 2018 S. Karger AG, Basel
E-Mail karger@karger.com
www.karger.com/nps
Accepted after revision: April 19, 2018
Published online: June 13, 2018
about and refereed to for almost 50 years, the relationship
between melatonin and depression is still not clear. In this
review, we summarize current knowledge about the genetic
and epigenetic regulation of enzymes involved in melatonin
synthesis and metabolism as potential features of depres-
sion pathophysiology and treatment. Confirmation that
melatonin metabolism in peripheral blood partially reflects
a disorder in the brain could be a breakthrough in the stan-
dardization of measurements of melatonin level for the de-
velopment of treatment standards, finding new therapeutic
targets, and elaborating simple noninvasive clinical tests.
© 2018 S. Karger AG, Basel
Introduction
Depression has become common in modern society,
and it seriously affects human health. Globally, an esti-
mated 350 million people of all ages worldwide suffer
from depression. The burden of depression is 50% higher
for females than males. This illness may gradually become
chronic, with high recurrence and disability rates. What
is more, depression can lead to suicide, the second leading
cause of death in people aged 15–29 years [1]. Without
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Monika Dmitrzak-Weglarz
Center of Medical Biology
Rokietnicka St. 8
PL–60-806 Poznan (Poland)
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E-Mail mweglarz @ ump.edu.pl

5-Hydroxytryptophan
5-Hydroxytryptamine (serotonin)
N-acetylserotonin
N-acetyl-5-methoxytryptamine (melatonin)
6-Sulfatoxymelatonin (6SMT)
Fig. 1. Synthesis and metabolism of mela- MTNR1A
tonin. MTNR1A/1B, melatonin receptor
1A/1B.
active treatment, patients can suffer mental deterioration
and personality changes that make it difficult to adapt to
social life.
The exact etiology of depression is still not fully under-
stood. It is a heterogeneous disease caused by a different
environmental and genetic factors and their interactions
[2]. The development of depression may be precipitated
by various factors: biological, social, genetic, psychic, so-
matic, or biochemical, which, due to their multitude and
lack of specificity, are still not clearly defined [3, 4]. Ob-
servation of the action of antidepressants has allowed the
formulation of the basic hypothesis that depression is
caused by a deficiency of neurotransmitters in the brain,
particularly serotonin and noradrenaline [5–7]. In addi-
tion to neurotransmission disorders in the central ner-
vous system, neuroendocrine and immunological chang-
es are also indicated [8–10]. Moreover, there is a great
significance of psychological and social factors such as
socioeconomic conditions, stressful life events or specific
personality traits [11–13]. The studies carried out with
the methods of molecular genetics confirm the role of ge-
netic predisposition in the etiology of depression [2].
Polyetiological determinants of depressive disorders
(DDs) indicate a further need to look for the causes of
depression, both in a holistic way and using methods
without a priori assumptions.
Current treatments for depression are limited in their
efficacy because their therapeutic benefits can take sev-
eral weeks to set in, and they are only effective in approx-
imately one-third of people with the disease. There are
multiple variations of depression that a person can suffer
2 Neuropsychobiology
DOI: 10.1159/000489470
L-tryptophan
Tryptophan 5-hydroxylase
Aromatic L-amino acid decarboxylase
Serotonin N-acetylotransferase
(NAT/AANAT)
Hydroxindole-O-methyltransferase
(HIOMT/ASMT)
Cytochrome P450 1A2
(CYP1A2)
MTNR1B
from. The depressive episode may occur in the course of
bipolar disorder, unipolar disorder, or schizophrenia,
and can accompany other psychiatric conditions. This of-
ten results in patients with depression being misdiag-
nosed [14].
There are no clinically accepted biomarkers for diag-
nosing depression or predicting responses to individual
treatments. To develop effective predictive markers that
have a significant impact on the health and economy of
societies, we need to know and understand all the etio-
pathological pathways of depression. According to the
2013 WHO resolution, without a comprehensive, coordi-
nated response at a national level, this will not be possible
[1]. Circadian rhythm alterations, resulting in disturbed
sleep and melatonin secretion, are a flagship feature of
depression. In shift workers, abnormal melatonin secre-
tion has been reported to cause several psychiatric dis-
eases including depression [15].
Melatonin
Melatonin, known as a hormone of darkness, has a
relatively short history. In 1958, Lerner et al. [16] iso-
lated the substance from the pineal glands of cows; when
incorporated into the body of a frog, it changed the col-
or of the skin. Further research on melatonin revealed its
pleiotropic effects. Melatonin plays a regulatory role in
a wide range of physiological and behavioral processes
such as the sleep-wake cycle, seasonal adaptation, hor-
monal secretion, thermoregulation, reproduction, di-
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 Pinealocyte

Tryptophan

5-Hydroxytryptophan
AANAT

Light Enzyme synthesis Serotonin

In
hi
bi

Amino acids
N-acetyloserotonin
tio
n

RHT NN A cAMP Nucleus

PVN SCG NE Melatonin
ATP PZR/RORα
n Retina SCN
a tio
ul
im
St
Pleiotrpic effects: Calreticulin
Sleep modulator Tubulin
Antidepresssant Calmodulin
Night Anxiolytic
Neuroprotective
Anti-inflammatory Antioxidant
Regulating reproductive
Antihypertensive
Antinociceptive

Fig. 2. The pathway leading to melatonin synthesis and its impact on other systems. Based on [17] (modified and
supplemented). RHT, retinohypothalamic tract; SCN, suprachiasmatic nucleus; PVN, paraventricular nucleus of
the hypothalamus; SCG, superior cervical ganglion; NN, adrenergic neurons; NE, norepinephrine; A, adrenore-
ceptor; RZR/RORα, retinoid-related orphan nuclear hormone receptor.

gestion, and many others. It also has antidepressant, melatonin [21]. Melatonin biosynthesis and secretion are
neuroprotective, anti-inflammatory, and antioxidant ef- controlled by the noradrenergic system. Thus, a decreased
fects [17]. melatonin level may also reveal serotonin function disor-
ders, as serotonin is a precursor of melatonin (Fig. 1) [22,
23].
Melatonin Synthesis

Melatonin is secreted by the pineal gland in the dark –
the nocturnal serum melatonin level amounts to 25–85
pg/mL in adults [18]. Melatonin level reaches its peak be-
tween 01:00 and 04:00 h with a focal point of 03:00 h [19].
Although melatonin level shows a constant rhythmic am-
plitude in each individual, there are large differences
across different individuals [20]. It is produced via the
metabolism of serotonin in two steps which are catalyzed
by arylalkylamine N-acetyltransferase (AANAT)/sero-
tonin N-acetyltransferase (SNAT) and hydroxyindole-O-
methyltransferase (HIOMT)/acetylserotonin-O-methyl-
transferase (ASMT). N-acetylation of serotonin by
AANAT produces N-acetylserotonin (NAS), and O-
methylation of NAS by HIOMT, eventually producing
Role of Melatonin Receptors
The master biological clock in mammals and human
is localized in the hypothalamic suprachiasmatic nucleus
(SCN). Light input causes the release of γ-aminobutyric
acid (GABA) by the SCN, and the inhibitory signal is
transmitted to the pineal gland to inhibit melatonin pro-
duction [24]. Therefore, decreased melatonin levels may
reflect hypothalamic dysfunction in the regulation of os-
cillatory melatonin secretion. On the other hand, envi-
ronmental factors that disturb rhythms of sleep and
wakefulness affect melatonin synthesis and secretion
[25]. The pathway leading to melatonin synthesis and its
impact on other systems is presented in Figure 2.
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Melatonin Homeostasis in Depression Neuropsychobiology 3

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 The regulation of circadian rhythm by melatonin acts
via specific receptors located at a high density in the SCN
[26–28]. This effect is mediated by two types of melatonin
receptors, well characterized in mammals by Dubocovich
et al. [29]. Thanks to these studies, the main types of re-
ceptors were finally distinguished and characterized: MT1
and MT2 (MEL1A and MEL1B or MTNR1A and MTN-
R1B) (review [30–32]). Both receptors are G-coupled
7-transmembrane receptors [33]. For a more detailed de-
scription of melatonin receptor signaling pathways, the
reader is referred to other expert reviewers [34, 35]. In
short, both receptors are tightly coupled to the Gi/cAMP
pathway. They can also activate other major signaling
pathways such as the ERK1/2 and the PI3K/AKT path-
ways. Peculiarly, the MT1 receptor has been shown to
couple to the Gq/PLC/Ca2+ pathway, while MT2 inhibits
cGMP levels. Both receptors can also create MT1/MT2
heteromers, likely combining the capabilities of both re-
ceptors. Thus, multiple signaling pathways are mediated
by melatonin receptor activation. Focusing on the SCN,
both melatonin receptors are involved in regulating the
expression of the core clock genes (Per1, Per2, Bmal1, and
Clock) [26, 36, 37]. Although the circadian machinery is
present in every cell, the effect of melatonin on rhythmic
clock gene expression is not yet clear.
In humans, MT1 and MT2 receptors are expressed not
only in the brain and retina but also in several peripheral
organs and tissue. Cecon et al. [34] prepared lists of hu-
man tissues in which melatonin receptors have been
identified. Thus melatonin, via MT1 and MT2 receptors,
regulates a variety of physiological and neuroendocrine
functions. However, studies in humans are still limited
[38].
Melatonin receptor signaling is significantly more di-
verse than initially suspected. Depending on the cellular
context, homo- and heteromeric complexes of melatonin
receptors can be formed. Recruitment of various G pro-
teins and regulatory proteins to these complexes further
differentiates the receptor signaling capacity [39]. Addi-
tionally, receptor gene variants may cause receptor ex-
pression and function as well as increase the risk of dis-
ease and affect drug efficacy. Jockers et al. [32] reported
several nonsynonymous variants in both types of recep-
tors; this list will be extended along with subsequent tests.
To date, the role of melatonin receptors in mood dis-
turbances is based on animal models and has not yet been
directly translated in humans. Comai et al. [40] demon-
strated that MT1 receptor knockout mice mimic behav-
ioral and circadian changes like what is observed in mel-
ancholic depression. Similarly, deletion of the MT2 recep-
4 Neuropsychobiology
DOI: 10.1159/000489470
tor increases anxiety-like behavior and cognition deficits
[41]. Liu et al. [42] confirmed previous reports, indicating
that deletion of the MT1 and MT2 receptors causes defi-
cits in hedonic and social interaction behavior and in-
creases anxiety-like behavior.
Recent progress in understanding the role of melato-
nin receptors in the circadian rhythm and mood disor-
ders has facilitated the creation of a novel class of melato-
nin agonists, i.e., –synthetic ligands mediated by MT re-
ceptor activation. Clinical and preclinical results are very
promising, and indicate that selective ligands targeting
melatonin receptors may improve the efficacy of pharma-
cotherapy [32, 43].
Circadian Rhythm and Melatonin in Depression
Impairment of biological rhythms occurs in a number
of psychiatric symptoms. Disturbances manifest in the
rhythm of activity and sleep. Patients with mania feel a
decreased need for sleep, while patients with depression
may suffer from hypersomnia (sleep of long duration, but
ineffective) or insomnia (i.e., difficulty in initiating or
maintaining sleep, or sleep of such poor quality that sig-
nificant consequences are experienced). With both types,
patients suffer from excessive drowsiness and a feeling of
constant tiredness during the day. There are also changes
in the severity of depressed mood throughout the day.
Melancholic depression is characterized by the worst
mood occurring in the morning and a partial recovery in
the evening. These symptoms can interfere with cognitive
functions such as memory and attention.
With depression, many metabolic and hormonal pat-
terns dependent on the circadian rhythm are disrupted.
For instance, alterations in body temperature [44, 45],
feeding schedules [46], glucose metabolism [47, 48], and
cortisol secretion [49–51] have been observed circumfer-
entially outside the central nervous system. The studies
describe abnormalities in secretion rhythms, with ad-
vanced phases and/or decreases in nocturnal amplitude
of melatonin rhythm in depression [52, 53]. On this basis,
hypomelatoninemia in DD was categorized as “low mela-
tonin syndrome” [54]. Subsequent studies have found
some inconsistent results, i.e., increases as well as no dif-
ferences in nocturnal melatonin levels in depressive ill-
ness [55–58]. Differences between studies may reflect the
use of antidepressants, β-blockers, or hormonal drugs as
well as the factors age, exposure to light, and season [52].
Other problems encountered are difficulties in obtaining
complete overnight melatonin secretion profiles (from
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Table 1. Key points of melatonin synthesis regulation in depression as measured in serum by ELISA
Protein Serum level in Ref.
depression patients
vs. healthy controls
Serotonin ↓ [103]
Melatonin No difference [104]
↓ [105]
↓ [106]
↓ [105]
AANAT – –
ASMT ↓ [83]
onset to offset, especially in very disturbed patients), as-
say difficulties, differences between a home and hospital
environment, the effects of medication, and the heteroge-
neity of patient samples.
The main monoamine hypothesis of the pathophysiol-
ogy of depression indicates that depression is induced by
a change in the level of ≥1 monoamines such as serotonin
(5-HT), noradrenaline (NE), and dopamine (DA). The
evidence for the serotonergic theory is an observation
that antidepressants such as tricyclic antidepressants
(TCA), selective serotonin reuptake inhibitors (SSRIs),
and noradrenaline reuptake inhibitors (SNRIs) increase
the level of serotonin in the brain. A detailed analysis is
outside of the aim of this review and can be found else-
where (review [59]).
We focus on serotonin as a neurotransmitter which is
a precursor of melatonin synthesis. In a depressed pa-
tient, serotonin synthesis is impaired [60] and the poor
precursor availability may prevent the formation of an
adequate amount of melatonin. However, only a few
studies have analyzed the relationship between serotonin
and melatonin levels and the correlation with the blood
serum. Modai et al. [61] analyzed 10 healthy men, and
Chojnacki et al. [62] presented serotonin and melatonin
secretion in postmenopausal women with eating disor-
ders. To the best of our knowledge, only Rao et al. [63]
and Bozhko et al. [64] provided an analysis of depressed
patients after they had received light therapy.
A metabolic pathway responsible for converting sero-
tonin into melatonin has been observed in animal mod-
Melatonin Homeostasis in Depression
Link
Serum serotonin abnormality in depression
Results suggest that the melatonin production is phase-shifted in
major depression
Serum melatonin levels in depressed patients were lower than in
controls
Serum melatonin levels in depressed patients were lower than in
controls; the highest melatonin secretion was observed at 3:00 a.m.
in severely depressed females
Nocturnal serum melatonin levels in depressed patients were lower
than in controls
–
Decreased mRNA and protein expression levels of the ASMT gene
and cognitive impairment in depression patients
els, including those based on the knockout of the genes
encoding the key enzymes ASMT and AANAT [65].
AANAT is believed to control the rate-limiting step.
However, biochemical analyses performed on blood
platelets and/or cultured cells have revealed a highly sig-
nificant decrease in ASMT activity and melatonin level in
individuals with autism spectrum disorders [66]. Thus,
the activity of both AANAT and ASMT might influence
the concentration of N-acetylserotonin, which influences
the expression of tyrosine receptor kinase B (a BDNF re-
ceptor) [67].
The mechanism of melatonin synthesis in the brain is
well-established, but there is no comprehensive study of
this pathway and changes in the periphery in mood dis-
order patients. Data on metabolites of melatonin mea-
sured in the serum by ELISA test are presented in Table
1. Genetic polymorphism, aberrant gene expression, and
epigenetic modulation can easily affect melatonin synthe-
sis and metabolism which can lead to depression patho-
physiology. In the following paragraphs, we present the
mechanisms that regulate the metabolism of melatonin at
various molecular levels.
Gender Difference in Mood Disorders and Melatonin
Circadian Profiles
Epidemiological research suggests that bipolar disor-
der, particularly type I, affects both genders equally [68];
type II affects women slightly more often [69]. Depres-
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Neuropsychobiology 5
DOI: 10.1159/000489470
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sion is twice as common in women than in men (major
depression: 20.3 vs. 11.4% and dysthymia: 2.6 vs. 1.6%)
[70]. Parker and Brotchie [71] hypothesized that hor-
monal changes during adolescence are responsible for the
differences observed. Such changes lead to greater “hy-
peractivation” of the limbic system in women. The pos-
sible influence of the sex hormones estrogen and proges-
terone on neurotransmitter systems (i.e., noradrenergic,
serotonergic, and GABAergic), should also be taken into
consideration. After puberty, women more often show
hyperactivation of the limbic system in response to nega-
tive stressors, a result of the influence of gonadal hor-
mones. Therefore, higher results of “neuroticism” are de-
terminants of a tendency towards an emotional response
which generates differences in the frequency of anxiety
and depression.
In the light of recent studies, it seems that gender dif-
ferences in the incidence of depression should be correct-
ed by age. Forlani et al. [72] showed that after the age of
81 years, depression occurrence decreases as age increas-
es. The association of depression with functional mea-
sures such as household activity, mobility, and disability
in performing household chores, was stronger in men
than in women. Similarly, severely disabling conditions
like stroke were more strongly associated with depression
in men than in women.
There is conflicting evidence about differences be-
tween men and women in circadian rhythm, evaluated by
measuring melatonin and cortisol in the plasma and urine.
Gunn et al. [73] conducted controlled studies on healthy
volunteers (14 women and 14 men) aged 19––33 years.
Women showed significantly higher levels of plasma mel-
atonin and cortisol than men. Women also showed a
much higher rhythm of the amplitude of both hormones.
Men had a higher level of cortisol in the urine than wom-
en, while in the case of the melatonin metabolite, –6-sulf-
atoxymelatonin, no differences were found between the
sexes. Some women were taking oral hormones which can
affect metabolic pathways; however, their impact on the
melatonin and cortisol levels could not be distinguished.
Further research on a larger population and with a more
restrictive selection of subjects is still necessary.
Genetic Association Study of Melatonin Homeostasis
Variation in Depression
ASMT catalyzes the last stage of melatonin biosynthe-
sis. This rate-limiting melatonin synthesis enzyme is thus
the most likely genetic factor in melatonin disturbances
6 Neuropsychobiology
DOI: 10.1159/000489470
and the development of depression. Galecki et al. [74]
evaluated 2 single-nucleotide polymorphisms (SNPs;
rs4446909 and rs5989681) of the ASMT gene in recurrent
DD-affected patients. The presence of the AA genotype
of the rs4446909 polymorphism and the GG genotype of
the rs5989681 polymorphism was associated with a lower
risk of recurrent DD. They also discovered that the ASMT
transcript level depended on a genotype in both polymor-
phisms. In contrast, Kripke et al. [67] did not confirm an
association of these 2 ASMT SNPs with depression. How-
ever, the abovementioned polymorphisms located in the
promoter were more frequent in autism spectrum disor-
der patients than in controls, and associated with a dra-
matic decrease in ASMT transcripts in blood cell lines.
Geoffroy et al. [75] found an association of rs4446909
with 3 variables of sleep measured by actigraphy in bipo-
lar disorder patients.
The second significant enzyme in melatonin synthesis
is AANAT. Soria et al. [76] assessed the contribution of
AANAT gene variability to susceptibility to major de-
pression, by considering 2 SNPs located in the promoter
region of AANAT (rs3760138 and rs4238989) as signifi-
cant. Using multimarker analysis, they found significant
associations between 2 three-marker protective haplo-
types and the susceptibility of the three-marker haplotype
containing the rare alleles of rs3760138-rs4238989-rs8150
and major depression. These 3 polymorphisms were not
replicated in depression patients. However, they showed
a relationship between susceptibility to autism and breast
cancer.
Physiological functions of melatonin are mediated via
2 high-affinity membrane melatonin receptor subtypes,
MT1 and MT2, the activation of which may lead to differ-
ential cellular responses. Interestingly, none of the MT1
gene polymorphisms have been previously studied in
DDs. The promoter SNP rs2119882 (–184T/C) of MT1
has been associated with schizophrenia and the insomnia
symptoms of schizophrenia [77]. In the case of the MT2
gene, an increased risk for recurrent DD in patients with
the C allele and a decreased risk in patients with the T al-
lele (rs4753426) have been found. Patients with the AT
heterozygote of rs794837 have an increased mRNA level
of the MT2 gene [78].
Melatonin is metabolized in the liver almost exclusive-
ly by cytochrome P450 enzyme CYP1A2 to its primary
metabolite 6-hydroxymelatonin, conjugated with a sul-
fate, and excreted in the urine. Several reports have indi-
cated that SNPs in the CYP1A gene are associated with
increased inducibility and decreased (or even loss of) ac-
tivity of the enzyme when compared with the wild-type
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Table 2. Single nucleotide polymorphisms connected with neuropsychiatric symptoms

Gene name rs# Alternative Link with mental Ref. SNPedia (summarizing link with
ID gene disorders other diseases)

AANAT rs8150 C>G depression [76] autism

(serotonin-N- (UTR-3) night work and breast cancer
acetyltransferase) rs3760138 G>T depression [76] autism
ID: 15 (intron) night work and breast cancer
rs4238989 C>G depression [76] night work and breast cancer
(intron)
ASMT rs4446909 G>A depression [107] autism
(acetylserotonin-O- (promoter) bipolar disorder
methyltransferase) rs5989681 G>A autism [66] autism
ID: 438 (promoter)
MTNR1B rs4753426 C>T depression [78] insomnia in
(melatonin receptor 1B) (promoter) schizophrenia
ID: 4544 multiple sclerosis
delirium
diabetes mellitus
rs10830963 C>G delirium [108] type 2 diabetes
(intron) glucose metabolism
autism
polycystic ovary
rs156244 T>G delirium [108] –
MTNR1A rs2119882 –184T>C schizophrenia + [77] polycystic ovary
(melatonin receptor 1A) (promoter) insomnia in diabetes mellitus
ID: 4543 schizophrenia oral cancer
CYP1A2 rs2470890 –1545C>T clozapine effect [80] colorectal cancers
(cytochrome P450 1A2) (promoter) (antipsychotic) lung cancers
ID: 1544 rs762551 –163C>A olanzapine effect [109] tobacco consumption
(intron) (antipsychotic/mood breast cancer
stabilizer)
rs2472304 A>G schizophrenia + [80] leukemia
(promoter) tardive dyskinesia lung cancer
breast cancer
obesity
metabolic syndrome
type 2 diabetes
CYP1A2 rs1056836 C>G depression [110] risk of cancer (prostate, breast lung,
(cytochrome P450 1B1) (exon) colorectal)
ID: 1545 Leu432Val

of the enzyme. Among mental disorders, only autism [79]
and schizophrenia [80] have been analyzed according to
the CYP1A2 gene polymorphism. Other research has re-
lated to the metabolic rate of psychiatric drugs such as
olanzapine or clozapine. Significant association reports
are summarized in Table 2.
Association studies on melatonin-related genes are
poor and often not replicable in mental disorders; in de-
pression, in some cases, there is a total lack of them.
Melatonin Related-Gene Expression Profile in
Depression
Melatonin is primarily produced by the pineal gland
from the amino acid tryptophan. Melatonin is also pro-
duced in and secreted by various extrapineal organs, tis-
sues, and cells. Its synthesizing enzyme, AANAT, is also
expressed in various extrapineal organs, tissues, and cells.
A small amount of melatonin is produced in the gut, bone
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marrow, epithelial hair follicles, skin, or salivary glands.
However, the physiological significance of melatonin
from these extrapineal sites is still unresolved [81]. The
central biological clock, with the use of pineal melatonin,
synchronizes peripheral (tissue) clock effects. Thus, dis-
turbances in the central secretion may be reflected in the
peripheral expression. Pozo et al. [82] presented the
mRNA expression of nuclear receptor RZR/RORα, mela-
tonin membrane receptor MT, and ASMT in human B
lymphocytes for the first time. To our knowledge, there
are only 2 studies in the literature that characterize mRNA
expression of ASMT in the peripheral blood of recurrent
DD. Galecki et al. [74] and Talarowska et al. [83] have
demonstrated the reduced mRNA expression of ASMT in
patients with depression and cognitive impairment. Sur-
prisingly, these studies, despite promising results, have
not been replicated. Moreover, no analysis of other mela-
tonin related-genes as potential biomarkers of depression
has been provided. It should be mentioned that mRNA
level changes normally outdistance protein changes.
However, mRNA level may increase due to decreased
translational efficiency or protein stability to maintain
the protein. Thus, a simple correlation between proteins
and their mRNA levels may not be observed and an anal-
ysis of both at the very same time is necessary.
Epigenetics in Depression
Though the assumption that environmental stressors
affecting epigenetics may also explain depression etiol-
ogy, epigenetic regulation in psychiatric disorders that
include DNA methylation, histone modifications, and
control of mRNA processing as well as translation by
noncoding RNAs has been investigated only very recent-
ly [84]. Global DNA methylation may be an outcome of
DD. Indeed, several studies have reported on global
DNA methylation level in the peripheral blood of pa-
tients with depression. In an Australian study on 24
monozygotic twin pairs (half were females), there were
no differences in global methylation related to depres-
sion. Among female discordant monozygotic twins, de-
pression was associated with lower global mean meth-
ylation levels [85]. It has also been observed that anxious
individuals have significantly higher levels of global
methylation (measured by the 5-mC level in the blood)
than controls [86].
It is thought that epigenetic changes at the DNA level
are due to both methylation and hydroxymethylation.
Quantification of 5-mC content for global DNA methyla-
8 Neuropsychobiology
DOI: 10.1159/000489470
tion determination in human samples could provide a
very useful biomarker, but the biological function of
5-hmC is unknown. However, it is postulated that both
5-mC and 5-hmC in DNA present possibly different
functions in epigenetic regulation. It is important to de-
termine the contents of these 2 modified nucleotides and
their ratios in order to examine their complete role in
psychiatric disorders. Two studies have observed a de-
creased level of 5-hmC in patients with major DD [87]
and bipolar disorder [88]. The results of most of these
studies indicate reduced levels of 5-mC and 5-hmC. It
should be emphasized that the 5-mC level was deter-
mined using the ELISA assay, but not using Alu and
LINE-1 indicative sequences.
As the hypermethylation of the promoter regions of
several genes may influence their expression, it would be
of interest to investigate the epigenetic regulation of
MTNR1A and MTNR1B, both possessing CpG islands
around the transcription start site. Unfortunately, there
are no data supporting the putative impact of methylation
on melatonin synthesis and input.
Melatonin in Treatment for Depression
Depressed patients often show an altered circadian
rhythm, sleep disturbances, and diurnal mood variation.
Thus, chronotherapies, including bright light exposure,
sleep deprivation, and social rhythm therapies, seem to be
useful adjuncts in nonseasonal and seasonal depression
[89]. However, antidepressant drugs have marked effects
on circadian processes and sleep. Surprisingly, pharma-
cotherapy using melatonin and pure melatonin receptor
agonists, while improving sleep, has not been shown to
improve the symptoms of depression [90]. A novel anti-
depressant, agomelatine, combines 5HT2c antagonist and
melatonin agonist action, and has shown promising ef-
fects in both acute treatments of major depression and
preventing relapse. This drug does not induce an increase
in serotonin levels, and it has considerably fewer side ef-
fects on the gastrointestinal tract, sexual sphere, or meta-
bolic processes, which are characteristic of many other
antidepressants [91]. As the use of serotonergic agents to
treat depression has increased, so has the incidence of se-
rotonin syndrome. Thus, searching for new drugs pre-
venting serotonergic toxicity is necessary. However, an
association between serotonin syndrome and melatonin
has not been established through clinical research.
The use of medication to regulate the melatonin path-
way may be crucial [92]. For example, in Poland, the
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Agency for Health Technology Assessment and Tariff
System approved the recommendation of agomelatine in
2014. According to the experts, clinical agomelatine is an
antidepressant, which can be a therapeutic option for a
subpopulation of patients with an episode of major de-
pression with the presence of sleep disorders, anxiety, or
anhedonia [93]. This means that Polish patients can now
benefit from this drug.
State-of-the-art pharmacological treatment of depres-
sion or its subtypes requires more studies evaluating the
effectiveness of melatonin analogs in different subpopu-
lations. Liu et al. [43] have summarized the clinical and
preclinical specific therapeutic effects of melatonin prep-
arations (i.e., Circadin) and other synthetic ligands (i.e.,
ramelteon and tasimelteon) mediated through MT recep-
tor activation. The results are very promising. Therefore,
development of new specific and selective drugs targeting
melatonin receptors is necessary for more effective phar-
macotherapy of sleep and circadian rhythm disturbances,
mood disorders, learning and memory, or neuroprotec-
tion.
Clinical Effects of Drugs Targeting MT1 and MT2
Receptors
Synthetic elaboration of information on drugs used
and tested for effects on MT1 and MT2 receptors was pre-
pared by Liu et al. [43]. Four preparations are listed, the
use of which is approved in specific indications and in
others subject to further testing. For example, the use of
melatonin (Circadin) is approved for insomnia in older
people, but clinical trials are being conducted in sleep dis-
orders in children, seasonal affective disorders, and the
treatment of breast and prostate cancer. Ramelteon is ap-
proved for the treatment of primary chronic insomnia
and is being tested in the phase advance when given be-
fore bedtime. Tasimelteon is approved for sleep disorders
of blind people and is being tested for temporary insom-
nia due to, for example, shift work. Agomelatine is ap-
proved in major depression and is being studied for the
improvement of disturbed sleep patterns and seasonal
disturbances of the biological rhythm [43]. Detailed in-
formation can also be found at Drug Bank [94]. Research
into the role of various selective ligands of melatonin MT1
and MT2 receptors in the modulation of circadian rhythms
in animal models is ongoing, with the aim of ultimately
discovering new drugs with different effects on MT1 and
MT2 receptors [32].
Melatonin Homeostasis in Depression
Diets with Tryptophan and Melatonin
Both melatonin and serotonin are synthesized from
the same amino acid,– tryptophan. Melatonin is synthe-
sized in the pineal gland, which is outside the blood-brain
barrier. Overproduction of melatonin may lead to in-
creased tryptophan uptake from the blood. Its reduced
supply and difficult passage through the blood-brain bar-
rier to serotoninergic neurons can lead to a decrease in
serotonin synthesis. Therefore, a diet rich in both trypto-
phan and exogenous melatonin may have a beneficial ef-
fect on wellbeing [23].
Tryptophan is an exogenous amino acid that must be
provided to the body within the diet. It is well known that
the most abundant sources of this amino acid are protein-
rich products such as lean meat, fish, yellow and white
cheese, milk, soy products, legume seeds, pumpkin seeds,
and eggs [95]. The content of tryptophan in various foods
can be traced in the Food Composition Databases con-
ducted by the Nutrient Data Laboratory, United States
Department of Agriculture, Beltsville, MD, USA [96]. Re-
search carried out by Lindseth et al. [97] confirmed that
people on a high tryptophan diet (>10 mg/kg body weight
per day) have a significantly lower level of depressive
symptoms, irritation, and anxiety than people on a low
tryptophan diet (<5 mg/kg body weight per day).
Melatonin can also be supplied in food. Its presence
has been identified in various foods ranging from fungi
to animals and plants. In foods of animal origin, the high-
est content of melatonin has been found in eggs and fish.
In plants, the highest content is in nuts. Some types of
mushrooms, cereals, and germinating legumes or seeds
are also good dietary sources of melatonin. The review
prepared by Meng et al. [98] presents a detailed list of
products containing melatonin. It has been proven that
products rich in melatonin such as pineapple, orange, or
banana increase the concentration of circulating melato-
nin in human serum [99]. Unfortunately, we do not have
such detailed knowledge about the bioavailability of mel-
atonin in other food products. However, controlled stud-
ies in which volunteers took intravenous or oral melato-
nin preparations indicated poorer bioavailability than
with intravenous administration. The biochemical modi-
fications of the administered melatonin turned out to be
significant. There were also bioavailability differences be-
tween the genders– (it is higher in women). Various sci-
entific bodies and dietary societies indicate that, with age,
when the level of endogenous melatonin synthesis drops,
a supplementary diet can bring positive health effects. It
is recommended to take 1 mg melatonin at bedtime [100].
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Neuropsychobiology 9
DOI: 10.1159/000489470
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 Significance and the Future Direction of Melatonin
Studies for Depression
Evidence has shown that melatonin secretion decreas-
es during the onset of depression, but goes up again after
remission. Therefore, the melatonin level might be used
as an effective indicator for the diagnosis of depression
[101]. However, melatonin is not effective for treating all
forms of depression [102]. Above all, one needs to under-
stand that the relationship between melatonin and de-
pression is very complex. Studies on the role of melatonin
in the pathogenesis and treatment of depression still con-
stitute an important topic in the field of depression re-
search.
Although melatonin was discovered and has been
widely referred to 50 years ago, the relationship between
melatonin and mental disorders, especially depression,
has not been clearly established. There is little research
into melatonin treatment for mental disease. The results
of biochemical measurements indicate that melatonin
treatment does not have serious negative consequences,
so melatonin will likely be widely used in clinical practice.
Understanding the mechanism of melatonin action is
crucial for its proper administration, an increase in its ef-
ficacy, and to avoid potential side effects. This is essential
for the efficient treatment of depression patients.
The research reported to date has shown widespread
effects of melatonin on cell metabolism, but the mecha-
nisms responsible for its mood-stabilizing effect have re-
mained unresolved. A detailed and precise description of
the biological background of melatonin treatment in rela-
tion to behavioral symptoms will help develop a more
personalized approach in pharmacotherapy. Confirma-
tion of the fact that the metabolism of melatonin in pe-
ripheral blood partially reflects a disorder in the brain
could be a breakthrough, leading to the standardization
of measurements of melatonin levels, the development of
treatment standards, finding new therapeutic targets, and
devising simple noninvasive clinical tests. Additionally,
the main problem in human studies is the lack of oppor-
tunities to analyze the effect of melatonin gene expression
in the brain and its direct correlation with behavioral
changes, so where postmortem analysis is not an option,
using peripheral blood as a noninvasive material for the
analysis is warranted. Only this material makes it possible
to prepare a fast, low-cost, and widely applicable clinical
test. However, this will not be possible without examina-
tion of all the basic mechanisms of the disease pathology.
A comprehensive investigation of the melatonin path-
way at the level of genes, their transcripts, and proteins,
10 Neuropsychobiology
DOI: 10.1159/000489470
through all the steps in the synthesis and metabolism of
melatonin, will facilitate a deeper understanding of mood
disorders and the development of novel mood-stabilizers.
At the same time, measurements of the effects of melato-
nin will become standardized and effective.
Conclusions
Future research should verify the following hypothe-
ses:
−− Disturbances in the melatonin biosynthesis pathway
are observable in the blood serum.
−− There are differences in the melatonin biosynthesis
pathway in patients with depression and healthy con-
trols.
−− There is a different ratio of the key components of the
melatonin pathway in the course of unipolar versus
bipolar depression.
−− mRNA profiling that focuses on key melatonin path-
way components is a more visible and tangible early
biomarker of the state and type of depression.
−− Total methylation and the methylation pattern of
genes encoding receptors involved in the melatonin
action are characteristic for depression and relate to
the gene expression level.
−− SNPs of selected candidate genes connected with the
melatonin pathway are associated with the efficacy of
melatonin synthesis, depression risk, and the severity
of symptoms.
An understanding of complex melatonin regulation
mechanisms (from genes to proteins and vice versa) may
provide novel insights and avenues into the development
of new pharmacological and behavioral treatment strate-
gies for depression and prevent the serotonin syndrome.
Acknowledgement
This work was supported by the National Science Centre, Po-
land (grant No. 2016/23/B/NZ5/02634).
Disclosure Statement
The authors have no conflicts of interest to declare.
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