Progress in Neuropsychopharmacology & Biological Psychiatry 80 (2018) 189–204

Contents lists available at ScienceDirect

Progress in Neuropsychopharmacology
& Biological Psychiatry
journal homepage: www.elsevier.com/locate/pnp

Depressive disorders: Processes leading to neurogeneration and potential T

novel treatments
Gregory M. Browna,⁎, Roger S. McIntyreb, Joshua Rosenblatc, Rüdiger Hardelandd
a
Department of Psychiatry, University of Toronto, Centre for Addiction and Mental Health, 250 College St. Toronto, ON M5T 1R8, Canada
b
Psychiatry and Pharmacology, University of Toronto, Mood Disorders Psychopharmacology Unit, University Health Network, 399 Bathurst Street, MP 9-325, Toronto,
ON M5T 2S8, Canada
c
Resident of Psychiatry, Clinician Scientist Stream, University of Toronto, Mood Disorders Psychopharmacology Unit, University Health Network, 399 Bathurst Street, MP
9-325, Toronto, ON M5T 2S8, Canada
d
Johann Friedrich Blumenbach Institut für Zoologie und Anthropologie, Universität Göttingen, Buergerstrasse 50, D-37073 Göttingen, Germany

A R T I C L E I N F O A B S T R A C T

Keywords: Mood disorders are wide spread with estimates that one in seven of the population are affected at some time in
Depression their life (Kessler et al., 2012). Many of those affected with severe depressive disorders have cognitive deficits
Cognition which may progress to frank neurodegeneration. There are several peripheral markers shown by patients who
Neurodegeneration have cognitive deficits that could represent causative factors and could potentially serve as guides to the
Mechanisms
prevention or even treatment of neurodegeneration. Circadian rhythm misalignment, immune dysfunction and
Inflammation
Chronotherapy
oxidative stress are key pathologic processes implicated in neurodegeneration and cognitive dysfunction in
depressive disorders. Novel treatments targeting these pathways may therefore potentially improve patient
outcomes whereby the primary mechanism of action is outside of the monoaminergic system. Moreover,
targeting immune dysfunction, oxidative stress and circadian rhythm misalignment (rather than primarily the
monoaminergic system) may hold promise for truly disease modifying treatments that may prevent neurode-
generation rather than simply alleviating symptoms with no curative intent. Further research is required to more
comprehensively understand the contributions of these pathways to the pathophysiology of depressive disorders
to allow for disease modifying treatments to be discovered.

1. Introduction
1.1. Depressive disorders
Despite numerous scientific advances, the diagnosis of psychiatric
disorders is still based on phenomenology (ie: the constellations of
symptoms displayed by the depressed individual). It had been pre-
viously hoped that advances in a broad range of fields including brain
imaging, genetics, epigenetics, non-coding RNAs, microRNAs and
proteomics would lead to diagnostic markers but no markers have yet
been shown to have clinical utility (Nemeroff et al., 2013). Currently
psychiatric diagnosis is based on the Diagnostic and Statistical Manual of
Mental Disorders (DSM-5), the latest version of the diagnostic manual
published by the American Psychiatric Association (American
Psychiatric Association, 2013). Bipolar and related disorders have been
separated from Depressive disorders in the DSM-5 because of some
degree of phenomenological overlap between bipolar disorder and
schizophrenia.
Bipolar disorders are a group of disorders that present with both
episodes of major depression and episodes of mania or hypomania. A
manic or hypomanic episode not only requires a persistently elevated or
irritable mood, but also a persistently increased level of goal directed
activity. In addition, transition from a depressed episode to a main or
hypomanic episode during antidepressant treatment may be a diag-
nostic criterion (Kaltenboeck et al., 2016). Lifetime prevalence has been
estimated at about 1%.
The diagnosis of Major Depressive Disorder (MDD, a prominent type
of Depressive Disorder) requires that there has been one or more Major
Depressive Episodes (MDE) and the lifetime absence of mania or
hypomania. A MDE requires a period of two weeks during which at
least five of nine symptoms are present and completely excludes
episodes related to an exacerbation of a psychotic disorder such as
schizophrenia (Uher et al., 2014).
Despite the lack of diagnostic biological markers, biological findings
are frequently reported that are not yet accepted as diagnostic (Bilello
et al., 2015; Rothschild, 2015). Several of these are found in MDD and

⁎
Corresponding author at: 100 Bronte Rd., Oakville, ON L6L 6L5, Canada.
E-mail addresses: gregm.brown@utoronto.ca (G.M. Brown), roger.mcintyre@uhn.ca (R.S. McIntyre), rhardel@gwdg.de (R. Hardeland).

http://dx.doi.org/10.1016/j.pnpbp.2017.04.023
Received 20 January 2017; Accepted 1 April 2017
Available online 20 April 2017
0278-5846/ © 2017 Elsevier Inc. All rights reserved.
G.M. Brown et al.
in bipolar disorder and may cause or aggravate cognitive problems
which in some cases could lead to neurodegeneration. Among the
findings are alterations in circadian rhythms together with changes in
melatonin profiles, immune dysfunction with increased cytokines and
indicators of oxidative stress. The objective of this article is to review
these findings, their possible pathophysiological roles and potential
treatment implications.
2. Cognitive alterations
Cognitive dysfunction is a core dimension in MDD. In addition to
being a criterion item e.g. difficulty in thinking and making decisions,
sub-domains and cognitive functions are implicated in anhedonia,
psychomotor retardation, suicidality, and negativistic thought patterns
e.g. hopelessness (McIntyre et al., 2013). Cognitive dysfunction is a
persistent feature in some individuals, and in sub-populations cognitive
dysfunction is a progressive phenomenon.
The common occurrence of both episodic and between-episode-
cognitive symptoms has heuristic as well as illness prognostication
implications. For example, depression can be conceptualized as a multi-
dimensional syndrome comprised of psychological disturbances across
mood, cognitive and vegetative dimensions. In addition, disturbances in
cognition are a core dimensional disturbance in depression (Insel et al.,
2010). The multi-dimensional psychopathology of MDD is subserved by
neurobiological changes that could be described as neural circuits and
networks that are asynchronous in their reciprocity.
From a clinical perspective, cognitive disturbances in depression are
a principle mediator in psychosocial impairment and work place
disability (McIntyre and Lee, 2016). For example, results from the
International Mood Disorders Collaborative Project indicate that cog-
nitive disturbances account for more variability in workplace perfor-
mance than do the total depression symptoms (McIntyre et al., 2015a).
Further lines of evidence indicate that psychosocial recovery from an
indexed depressive episode is more strongly correlated with improve-
ment in cognitive measures rather than with changed depressive
symptom severity.
The domains of cognitive dysfunction that are affected in MDD
include executive function, memory and processing speed, as well as
attention plus concentration (Roiser and Sahakian, 2013). Results from
a meta-analysis indicate that the magnitude of the deficit in cognitive
function in MDD is approximately 0.2–0.7 (Cohens d) commensurate
with clinically significant cognitive impairment (Rock et al., 2014).
Conventional screening/rating instruments for depressive symptoms
[e.g. Patient health questionnaire 9 (PHQ-9)] do not provide sufficient
assessment of the cognitive symptoms of depression (Harrison et al.,
2016). More specifically, conventional depression methods rely on self-
report of cognitive function which is not correlated with objective
measures of cognitive function and do not capture the complexity and
circumstances of how cognitive function affects patient-reported out-
comes (PROs) and individuals with MDD. The first sensitive, valid and
reliable screening tool for detecting cognitive dysfunction has just
recently been made available: the THINC-it tool has been validated in
adults 18–65 with MDD and is capable of detecting deficits in overall
cognitive function. It is estimated that approximately 50% of adults
with MDD presenting with single, as well as with multiple, episode
depression have clinically significant cognitive impairment, as defined
by greater than 1 standard deviation (SD) below matched healthy
control performance (THINC-it is available for a fee at http://thinc.
progress.im/en).
Potential treatments are reviewed in Sections 5 and 7. Mitigating
cognitive deficits begins with prevention. For example, preventing
episode recurrence and reducing episode severity and duration may
improve cognitive performance. Moreover, chronotherapeutic ap-
proaches e.g. social rhythm therapy, and where appropriate, sedative
hypnotic agents may assist in some persons as sleep disruption is a well-
known anti-cognitive behaviour. Targeting comorbid conditions that
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interfere with cognition e.g. hypothyroidism, diabetes, as well as
alcohol and other substance abuse (eg cannabis), is also warranted.
Many antidepressants may also benefit measures of cognitive dysfunc-
tion with relatively few demonstrating direct independent effects on
cognitive functions. A surfeit of other psychotropic agents e.g. stimu-
lants, anti-inflammatory agents, antioxidants, are currently being
explored as strategies for treatment. Behavioural approaches are
aerobic exercise as well as cognitive remediation therapy which are
also currently being evaluated (McIntyre et al., 2015b).
3. Neurodegenerative changes
Neurodegeneration is not a diagnostic criterion for MDD. However
there is evidence both from volumetric magnetic resonance imaging
(MRI) and functional MRI (fMRI), among others, for changes in brain
structure and function that indicate neurodegeneration in many
patients with MDD.
It has been well documented in volumetric MRI studies that there
are decreases in prefrontal (especially orbital frontal) and anterior
cingulate cortex (ACC) volumes as well as in caudate nucleus, putamen
and hippocampus in patients with longstanding recurrent MDD (Bora
et al., 2012; Depping et al., 2016; Harrisberger et al., 2015; Jaworska
et al., 2016; Malykhin and Coupland, 2015; O'Connor and Agius, 2015;
Sexton et al., 2013; Stratmann et al., 2014), although only women with
a first episode seemed to show evidence of decreased habenula volume
(Carceller-Sindreu et al., 2015). These volumetric changes have been
associated with histopathological abnormalities in post-mortem studies
(Price and Drevets, 2012). There is a decrease in glial cells and a
corresponding increase in density of neurons in the same areas.
Evidence implicates that they form part of a functional circuit for
emotions in humans; hence it is theorized that these changes result in
abnormal functioning in MDD (Delvecchio et al., 2012; Price and
Drevets, 2010). Certain of these areas are also central to cognitive
dysfunction. The prefrontal cortex (PFC) is known to be important for
planning for or restraining from actions. Elevated activity in the PFC
and the ACC has been shown during non-affective cognitive tasks in
MDD patients as compared to controls using fMRI (Kerestes et al.,
2014). Emotional cognition, in contrast, seems to also involve area of
the amygdala and the hippocampus which show increased activation
with emotive negative visual challenges processing; effects which are
typically reversed by antidepressants (Jaworska et al., 2014; Kerestes
et al., 2014). In addition poor performance on hippocampal-related
memory tasks in MDD has been reported to precede any changes in
hippocampal volume (Malykhin and Coupland, 2015). An optical
coherence tomographic study reported that the ganglion cell and inner
plexiform retinal layers were decreased in volume in those with
recurrent MDD as compared with first episode patients thus extending
findings to the retina (Kalenderoglu et al., 2016). The decreased
hippocampal volumes in MDD have been shown to be reversed by
antidepressant treatment leading to the suggestion that increasing
neurogenesis by antidepressants may play a role in increasing the
hippocampal volume (Chi et al., 2015; Kalenderoglu et al., 2016).
Several reports have indicated that antdepressants can normalize limbic
PFC and ACC activity in MDD (Dusi et al., 2015; Qin et al., 2015; Wessa
and Lois, 2015).
Studies of MDD patients using magnetic resonance diffusion tensor
imaging (DTI) have shown changes indicating altered connectivity in
several areas including the left superior longitudinal fasciculus, right
caudate, corona radiate, genu of the corpus callusom, posterior
thalamic radiations and brain stem (Choi et al., 2015; Han et al.,
2017; Lener and Iosifescu, 2015; Liao et al., 2013; Murphy and Frodl,
2011; Sexton et al., 2009; Tymofiyeva et al., 2017). Because of these
numerous reports it has been proposed that depression may be a
syndrome with a disconnection between prefrontal and limbic areas
(Liao et al., 2013).
A recent positron emission tomography (PET) brain study of
G.M. Brown et al.
patients with MDD has shown the first direct evidence of microglia
activation in MDD, activation which is known to be associated with
neurogeneration. Activation was found not only in the PFC, ACC and
insula but in all brain areas studied (Setiawan et al., 2015). In the ACC
activation was correlated with greater depression severity on the
Hamilton rating scale. Reviews of magnetic resonance spectroscopy
(MRS) studies describe a variety of changes in metabolites which have
been associated with neuronal death and also abnormalities in neuro-
transmitter systems in some of the areas identified in MDD by MRI
(Frodl and Amico, 2014; Lener and Iosifescu, 2015). Moreover circulat-
ing inflammatory and antioxidant markers are associated with changes
on MRI and MRS (Frodl and Amico, 2014; Lindqvist et al., 2014; Young
et al., 2014). Post-mortem neuropathological studies have shown
decreased neuronal cell size and quantity, synaptic density and glial
cell quantity (Lener and Iosifescu, 2015). Whether these volumetric
changes represent a susceptibility to MDD, a result of or compensation
to MDD or even a response to treatment is not clearly established at this
time.
Studies using these and other techniques provide compelling
evidence of neurodegeneration, especially in patients with recurring,
longstanding MDD. A recent review describes the close relationship
between the neurodegenerative processes found in MDD and the
changes in the molecular processes involved in aging (Maurya et al.,
2016). Among other factors they include changes in telomere length,
enzymatic antioxidant activities and inflammatory cytokines together
with lower plasma concentrations of antioxidants.
4. Circadian rhythm misalignment and melatonin alterations
Most body functions have a 24 h rhythm that is closely synchronized
with the environment and allow optimal function in relation to the
external world. These fluctuations are controlled by a master body
clock located in the suprachiasmatic nucleus of the hypothalamus
(SCN). Because of the ubiquity of this control it is not surprising that
disrupted body rhythms would be present in most psychiatric disorders
(Boivin, 2000; Buzsáki and Watson, 2012; Byrne et al., 2014; Jones and
Benca, 2015). Circadian alterations in mood disorders are amply
documented and have been multiply reviewed very recently (Baron
and Reid, 2014; Bellivier et al., 2015; Dallaspezia and Benedetti, 2015;
Kripke et al., 2015; Martynhak et al., 2015; Nechita et al., 2015). MDD
has long been associated with alterations in body rhythms which range
from major alterations in the sleep/ wake cycle and rhythmic changes
in activity and mood to alterations in rhythms of blood pressure, body
temperature, hormones (including cortisol and melatonin) and brain
and body biochemistry (Albrecht, 2013; Jones and Benca, 2015;
McClung, 2013; Schnell et al., 2014). One of the diagnostic criteria of
MDD is various forms of insomnia or hypersomnia (Table 1).
Most body organs contain clocks that are synchronized to the
predominant cue, the light cycle, via the SCN while other lesser cues,
including exercise and feeding, primarily affect muscles and liver
respectively. These clocks consist of some 10 or more clock genes
which interact with each other to produce a rhythm with a period that
is close to 24 h (circadian) (Dibner et al., 2010; Hastings et al., 2014;
Jin et al., 1999; Lowrey and Takahashi, 2004; Shearman et al., 2000).
Light cues reach the SCN via a pathway from a small population of
Table 1
Circadian rhythm misalignment.
• Rhythm desynchronization is frequent in depression
• Mutations of circadian rhythm genes are found in MDD and BD
• Alterations in zeitgebers ie light cues, sleep schedule etc. may also cause
dysregulation
• Altered
response
HPA regulation occurs with a recent focus on the cortisol awakening
• There are variable melatonin findings perhaps because light exposure varies
• Desynchronization of rhythms is pro-neurodegenerative in animals
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intrinsically photosensitive ganglion cells that uniquely contain the
photopigment melanopsin and coordinate the SCN rhythm with the
outside world (Berson, 2007; Gooley et al., 2003). In addition to
entraining the SCN rhythm, light supresses synthesis of the hormone
melatonin (Gooley et al., 2011; Lewy and Sack, 1989; Nathan et al.,
1999). The SCN acts to synchronize rhythms in other tissues via neural,
autonomic and neuroendocrine pathways including the hormones
cortisol and melatonin.
Depression has to be seen as a complex of several forms and
subforms of disorders that differ with regard to their etiology.
Therefore, an optimal therapy should not be reduced to a uniform
symptomatic treatment, once the possible causes of the disorder
become apparent. Consequently, a differential diagnosis that discrimi-
nates between the forms of depressive disorders is of utmost impor-
tance. This may not always be easy, with regard to some overlap of
symptoms, but there are, at least, several types of depression that can be
related to circadian dysfunction. Evidence for this conclusion is, in part,
based on the associations with mutations in genes of core and accessory
elements of cellular circadian oscillators, such as Per2, Cry2, Bmal1
(= Arntl) and Npas2 in winter depression (Johansson et al., 2003;
Lavebratt et al., 2010a, 2010b; Partonen et al., 2007; Rajendran and
Janakarajan, 2016), as well as Per3, Cry2, Bmal1 (Arntl), Bmal2 (Arntl2),
Clock, Dbp, Tim, CsnK1ε and NR1D1 (Rev-erbα; Ear1) in bipolar disorder
(Benedetti et al., 2008; Dallaspezia et al., 2016; Dallaspezia and
Benedetti, 2015, 2011; Drago et al., 2015; Gonzalez et al., 2015;
Kripke et al., 2009; Le-Niculescu et al., 2009; Mansour et al., 2006;
Nievergelt et al., 2006; Partonen, 2014; Sjöholm et al., 2010). While the
role of the circadian system was discovered relatively early in seasonal
affective and bipolar disorders, involvement in MDD appeared to be
rather uncertain for quite some time. To date polymorphisms of Per3,
Cry1, Clock and Npas2 were reported to be associated with MDD (Hua
et al., 2014; Shi et al., 2016; Soria et al., 2010a, b), whereas several
other studies did not reveal significant findings. Moreover, time-of-
death expression levels of the oscillator genes Per1, Per2, Per3, Bmal1,
NR1D1, Dbp, Dec1 and Dec2 were shown to be changed in the brains of
MDD patients (Li et al., 2013). Another hint comes from an association
of a sirtuin 1 (Sirt1) variant with MDD (Kishi et al., 2010), a result of
relevance because of the role of SIRT1 as an accessory oscillator
component that is required for high circadian amplitudes (Bellet
et al., 2011; Chang and Guarente, 2013; Nakahata et al., 2008).
Nevertheless, the conclusions concerning MDD do not seem to be that
firm as in the cases of seasonal affective and bipolar disorders. The
reason may be sought in the divergence of MDD subforms with different
etiologies not all of which must be related to circadian dysfunction.
Uncertainties may also arise from the fact that alterations in the
circadian oscillator system can be caused by deviations other than
variant alleles. Among those which are not detected by polymorphism
screening, epigenetic modifications may play a significant role, as has
been recently discussed (Liu and Chung, 2015). In fact, the circadian
system is modulated in manifold ways by epigenetic mechanisms
(Hardeland, 2014a). The first evidence for epigenetic effects in the
circadian control by a microRNA (miR) was presented by Saus et al.
(Saus et al., 2010), who described an abnormal processing of pre-miR-
182 in MDD. Recently, a deviating DNA methylation pattern was
discovered in the Bmal1 gene of patients with bipolar disorder
(Bengesser et al., 2016).
Although such associations may only reveal the existence of risk
factors and their genetic penetrance may sometimes be moderate, these
findings are insofar important, as they are not easily compatible with
the assumption put forward that mood disorders and circadian mal-
function have a common cause instead of resulting from circadian
disruption (Bechtel, 2015). In fact, the genetic argument that relates
circadian malfunction to an affective disorder cannot be explained by
the same cause. Although the two deviations are, at first glance, only
statistically associated, a mere correlation of changes in circadian
patterns with depressive disorders is insufficient for ruling out a causal
G.M. Brown et al.
relationship.
The cause or causes of circadian rhythm disruption in individual
patients with MDD are stil not clear. And the extent to which circadian
misalignment is a cause or an effect of the mood disorder. That may
well vary between individuals. It has been argued that disruption of
circadian rhythms aggravates MDD and that treatment of the disrup-
tions may be helpful (Cardinali et al., 2011; Jones and Benca, 2015).
Several factors, including the absence of, or a limited number of
environmental zeitgebers, a delayed sleep schedule, absence of morning
light, and receiving more light during the evening, especially when
these occur in combination, can disrupt the normal phase relationships
between internal and external time keepers. Studies of sleep depriva-
tion, which keeps patients awake all or part of the night, have shown
that it provides a rapid antidepressant action in 40 to 60% of patients
with MDD which unfortunately may not be maintained (Bunney and
Bunney, 2013; Soria and Urretavizcaya, 2009). However, when supple-
mented with both medication and sleep phase advance by bright light
therapy (SPA) the response may be continued for up to several months.
In one study in post-mortem brain tissue it was shown that core clock
gene expression shows robust 24 h rhythms in six brain regions in
control subjects that were significantly disrupted in patients with MDD
(Bunney et al., 2015). Most robust changes were seen in the ACC. The
authors speculate that the antidepressant response seen in MDD
patients who respond to sleep deprivation is due to reset of the clock
genes to stabilize and synchronize body rhythms.
Changes in the hypothalamic pituitary adrenal (HPA) axis regula-
tion in MDD have long been known. The SCN regulates this axis by
synchronizing release of adrenocorticotrophic hormone (ACTH) from
the median eminence of the hypothalamus which in turn activates
synthesis and release of cortisol from the adrenal gland. As early as
1973 Sachar and colleagues reported on disrupted 24 h rhythms of
cortisol in patients with MDD (Sachar et al., 1973). In 1982 Carrol
reported on abnormalities in the dexamethasone suppression test (DST)
in MDD speculating that it might be a diagnostic test (Carroll, 1982),
however numerous factors severely restrict its specificity (Herbert,
2013). Serum cortisol levels, after correcting for time of day, are one
part of a nine component test that has been proposed as a diagnostic
procedure (Bilello et al., 2015; Papakostas et al., 2015), however it has
been questioned whether in its current form it would add any value to
the diagnosis of a trained physician (Rothschild, 2015). Recently
attention has been focused on the cortisol awakening response, a rise
in cortisol that occurs 30 min after waking (Elder et al., 2014). This
response has been shown to be exaggerated in those with MDD and
those at risk although exaggerated responses are also seen in a variety
of other conditions (Vreeburg et al., 2009; Vrshek-Schallhorn et al.,
2013). This altered response been interpreted as a response to stress, a
response that could affect the immune system. Alternatively it could
represent an inherent change in HPA regulation as the 24 h rhythm of
cortisol would be altered by desynchronized body rhythms (Nicolaides
et al., 2014).
Synthesis of the hormone melatonin is controlled by the SCN via a
pathway which travels down through the brain stem and thence via the
sympathetic outflow to the pineal gland. Because it is regulated by
light, melatonin blood levels have been used as an index of the SCN
rhythm rising in the evening under dim light, being high only during
dark so that it peaks 6 to 8 h later and then falling to virtually
undetectable levels. Moreover melatonin serves as a cue to sleepiness;
when administered in a low dose in the evening it will facilitate the
onset of sleep (Brzezinski et al., 2005; Kayumov et al., 2000).
In bipolar patients nocturnal serum melatonin are reported as
decreased (Kennedy et al., 1996; Lam et al., 1990) although there is
some dissent (Whalley et al., 1991). There is also a report that morning
CSF melatonin is decreased (Bumb et al., 2016). An initial report of
melatonin supersensitivity to light in bipolar patients (Lewy et al.,
1985) has been disputed (Whalley et al., 1991). Many groups have
reported decreased levels of nocturnal melatonin in MDD (Beck-Friis
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Progress in Neuropsychopharmacology & Biological Psychiatry 80 (2018) 189–204
et al., 1985, 1984; Brown et al., 1985; Frazer et al., 1985; Khaleghipour
et al., 2012; Naismith et al., 2012; Souetre et al., 1989)although there
are also contrary reports (Bouwmans et al., 2015; Rubin et al., 1992;
Stewart and Halbreich, 1989; Thompson et al., 1988) plus a report of
increased am serum melatonin (Bumb et al., 2016). These differences
may be related to the heterogeneity of MDD subforms.
Decreased levels of melatonin have been suggested to be a direct
result of MDD, however it is also possible that the reported decrease
could be secondary to alterations in sleep patterns. In those patients
who spend less time in darkness because of late bedtime, being up at
night, or early wakening the presence of light would suppress melato-
nin synthesis (Claustrat et al., 2005; Zawilska et al., 2009). It is clearly
essential that exposure to light occurs in a healthy circadian way in
order to maintain normal body rhythms including a normal nocturnal
melatonin rise (Bonmati-Carrion et al., 2014).
Circadian dysregulation is known to be a common feature of the
major neurodegenerative diseases: Alzheimer's, Huntington and
Parkinson disease. These disorders are all characterized by neurode-
generation and not by depression although they may result in depres-
sive features. Alzheimer's disease is occasionally preceded by depres-
sion. Although it is not yet established whether the rhythm dysregula-
tion is cause or effect, it has been suggested that treatments targeting
the sleep-wake cycle would be invaluable in these disorders (Videnovic
et al., 2014). All of these major neurodegenerative diseases are
characterized by aberrant protein aggregation. It has been postulated
that several types of pro-neurodegenerative processes can be aggra-
vated by circadian rhythm disruption and that circadian treatments
may be an important and novel approach (Barnard and Nolan, 2008;
Hastings and Goedert, 2013).
5. Potential treatments based on circadian rhythm
desynchronization
The symptomatic relationship between circadian malfunction and
mood disorders is a rather frequent phenomenon, which is not
surprising because of the circadian influence on sleep, since disturbed
sleep is a classic correlate of depression as well as of many other
psychiatric pathologies (Cardinali et al., 2011; Srinivasan et al., 2009b)
(Table 2).
On the background of these relationships between circadian dys-
function and, at least, subtypes of depressive disorders, several treat-
ment options can be designed. Since subtypes of depression with an
etiology of circadian malfunction may be more easily treated than other
subforms and may, additionally, respond to relatively harmless inter-
ventions without or with rather mild side effects, it may be recom-
mended to first analyze whether circadian abnormalities are present. In
the future, this may by done by screening for variants of clock genes.
This should be possible on the basis of DNA in peripheral blood
mononuclear cells (PBMCs) obtained from blood samples, as is increas-
ingly done in other polymorphism studies. Technological progress may
allow these techniques to become an important diagnostic tool.
Table 2
Potential treatments based on rhythm dysregulation.
• Determine whether rhythm dysregulation is present
• Three types of intervention are possible
o Light treatment in the morning
o Blue blocking glasses in the evening
o Melatonin treatment in the evening
•
Light treatment used successfully especially in winter depression and is also used
in combination treatments
• Short acting melatonin useful to reset rhythms
• Long acting agonists ramelteon and agomelatine are very unlikely to reset
rhythms and normalize sleep
• BB glasses were recently shown to be helpful additive treatment in mania
• Melatonin has variable effects on neuroinflammation and oxidative stress
depending on dose
G.M. Brown et al.
Alternate tests on the basis of sleep deviations will be only meaningful
or sufficient, if they reveal substantial deviations in free-running period
lengths or poor coupling to external time cues. If circadian rhythm sleep
disorders (CRSDs) have been diagnosed, such as familial advanced sleep
phase syndrome (FASPS) or delayed sleep phase syndrome (DSPS), this
should also suffice for trying a treatment of enforced circadian
entrainment. In all other cases, sleep difficulties cannot be taken as
an indication of an underlying circadian etiology, since the disturbance
of sleep is a general phenomenon associated not only with affective as
well as several other disorders.
In the case that a substantially aberrant circadian rhythm or
variants of oscillator genes have been detected, three modes of
intervention are possible, by which the alignment of rhythms may be
improved. These three types of treatment may be even combined,
because they may be applied in different phases of the circadian cycle.
The first one is light treatment in the morning, the second one
administration of melatonin or another melatonergic drug in the
evening or night and the third use of blue blocking glasses in the
evening or night. While light therapy is anyway devoid of pharmaco-
logical effects, melatonin is usually very well tolerated and side effects
or contraindications have to be only considered under certain specific
conditions.
Light therapy exists in several variations that are mostly conceived
as methods of chronotherapy, to readjust the circadian system. Bright
light therapy is the most common procedure in this category. It has
been used especially for the treatment of seasonal affective disorder
(Danilenko and Ivanova, 2015; Gordijn et al., 2012; Meesters et al.,
2016, 2011; Oldham and Ciraulo, 2014; Pail et al., 2011; Prasko, 2008;
Rastad et al., 2011), but also in bipolar disorder (Pail et al., 2011;
Prasko, 2008; Schwartz and Olds, 2015; Suzuki et al., 2016) and MDD
(Al-Karawi and Jubair, 2016; Bais et al., 2016; Dridi et al., 2014; Eniola
et al., 2016; Oldham and Ciraulo, 2014; Pail et al., 2011; Schwartz and
Olds, 2015), reportedly with a variable degree of therapeutic success.
Light therapy as a nonpharmaceutical treatment has been recom-
mended and is being tested as a method avoiding any pharmacological
load during pregnancy and in perinatal depression (Bais et al., 2016;
Crowley and Youngstedt, 2012).
However, bright light therapy is perceived by some patients as
discomfort. Since the circadian pacemaker SCN receives photic infor-
mation mainly from melanopsin-containing retinal ganglion cells that
most strongly absorb in the visible blue range between 400 and 530 nm,
blue-enriched bright light or low-level blue light have been tested
(Gordijn et al., 2012). Similar to white light, blue light causes phase
advances when administered in the early morning (Smith et al., 2009)
and phase delays when given in the evening (Smith and Eastman,
2009). Although this concept seems to be chronobiologically well-
founded, the use of blue light has given rise to concerns, because this
light quality causes reductions in photoreceptor sensitivity as measured
in the ERG (Gagné et al., 2011). On the other hand blue blocking glasses
(BB) have revealed minimal concerns. BB glasses prevent the suppres-
sant effect of evening light on melatonin and improve sleep (Burkhart
and Phelps, 2009; Kayumov et al., 2005; Sasseville et al., 2006). They
have been used successfully in pilot studies in permanent night workers
(Sasseville et al., 2009), shift workers (Rahman et al., 2013; Sasseville
and Hébert, 2010) and adolescents watching television (van der Lely
et al., 2015). Recently BB glasses have been used as an additive
treatment of mania with a marked effect size beginning after three
days and no side effects differing from the placebo group (Henriksen
et al., 2016). Other forms of chronotherapy such as dawn simulation
(Terman and Terman, 2006), total sleep deprivation, or sleep phase
advance, have been alternately used, but also chronotherapeutic
combinations including bright light (Benedetti et al., 2014; Gottlieb
and Terman, 2012; Wu et al., 2009). Additionally, combinations with
lithium have been tested, procedures in which lithium also acts on the
circadian system (Benedetti et al., 2014; Wu et al., 2009). Lithium has
been long known to lenthen the circadian period, which is of value for
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those patients that exhibit a shortened rhythm as seen in a subpopula-
tion of bipolar disorder (Atkinson et al., 1975; Moreira and Geoffroy,
2016). However, some bipolar patients display instead a lengthened
spontaneous period and are, therefore, nonresponders to lithium
therapy (Kripke et al., 1978). These differences shed light on the
necessity of knowing details on the circadian deviations of a patient
prior to treatment. Moreover, bright light treatment has also been used
as an adjunctive therapy to enhance the effects by conventional
antidepressants. A recent meta-analysis of randomized trials revealed
efficacy of this approach in bipolar depression and MDD (Penders et al.,
2016). An earlier systematic review had arrived at similar, but more
cautious conclusions, with regard to both light treatment as mono-
therapy and adjunctive therapy (Tuunainen et al., 2004). A retro-
respective meta-analysis of light therapy for the prevention of seasonal
affective disorder revealed a relatively modest outcome (Nussbaumer
et al., 2015). However, the relatively poor demonstrable efficacy was
largely caused by methodological limits and also by the heterogeneity
of cohorts.
If light therapy or BB glasses are capable of augmenting the efficacy
of other forms of chronotherapy as well as of antidepressant pharma-
cotherapy, this may also be possible with the use of melatonin or
synthetic melatonergic drugs. The phasing conditions of using both
light and melatonin for entraining circadian rhythms have been worked
out (Skene, 2003). In fact, the combination of appropriately phased
melatonin and bright light has already been used for symptomatic
therapies in elderly subjects (der Lek et al., 2008), including Alzheimer
patients (Dowling et al., 2008), and for treating DSPS (Saxvig et al.,
2014; Wilhelmsen-Langeland et al., 2013), whereas depressive disor-
ders still await respective studies on sufficiently large cohorts.
The possible usefulness of melatonin, also as a monotherapy, is
based on several considerations. Variants of the genes of melatonin
biosynthesis, Aanat (aralkylamine N-acetyltransferase) and Asmt (N-
acetylserotonin O-methyltransferase) were reported to be associated
with MDD (Soria et al., 2010a) or recurrent depression (Galecki et al.,
2010), respectively. However, decreases of melatonin levels were not
always found in the various forms of depressive disorders (Hardeland,
2012a). Bipolar and seasonal affective disorders were reported to be
associated with variants of the GPR50 gene (Delavest et al., 2012;
Macintyre et al., 2010; Thomson et al., 2005), which encodes a protein
with homology to melatonin receptors, but does not bind melatonin.
However, it heterodimerizes with MT1 and thereby inhibits agonist
binding and Gi protein coupling (Hardeland, 2009a; Levoye et al.,
2006). Recently, the GPR50 gene was reported to be directly targeted
by SIRT1 and to be, thus, associated with the modulation of circadian
rhythms (Leheste and Torres, 2015).
An advantage of melatonin is the application in subjects that are not
susceptible to phase resetting by light, such as blind people without
photoreception and others affected by degeneration of the SCN or its
neuronal connections. Moreover, one should take into account that
elderly persons frequently have a reduced sensitivity to blue light
especially because of decreased crystalline lens transmission or pupil-
lary miosis, changes that impair circadian photoreception by melanop-
sin (Hardeland, 2012a). Circadian deviations such as dysphased
rhythmicity or absence of light entrainment have been demostrated in
a subgroup of blind individuals (Flynn-Evans et al., 2014; Lockley et al.,
2007). In blind people and in other subjects with circadian disorders,
such as delayed sleep phase insomnia, melatonin was shown to be
effective in improving entrainment and sleep (Arendt et al., 1997;
Arendt and Skene, 2005; Lockley et al., 2000; Skene, 2003; Skene et al.,
1996). In blind people, a low dose of 0.5 mg melatonin was found to be
sufficient (Hack et al., 2003).
Theoretically, there may be a category of nonresponders to light
therapy who are also insensitive or poorly sensitive to melatonin
treatment, in terms of readjustment of circadian rhythms. This should
be assumed in three cases, (1) in advanced neurodegeneration of the
SCN and/or its afferent pathways, (2) inborn dysfunction of circadian
G.M. Brown et al.
oscillators because of severe mutations in oscillator genes, and (3) null
mutations of both melatonin receptor genes. The first case is present in
late stages of Alzheimer's disease, in which not only has melatonin
strongly declined but also the precision of the circadian system is
heavily impaired (Mishima et al., 1999). The two other cases have not
been clearly demonstrated in humans. In this regard, one should take
into account the multiplicity of parallel oscillators based on the
alternate use of homologs and paralogs of oscillator components, which
implies that the circadian system may not be completely lost in
mutants, but may persist in various cells and functions. Whether the
third case may be either extemely rare or even lethal is unknown. Even
if circadian rhythmicity is not corrected by melatonin, the pineal
hormone may not be entirely useless, but of some limited value, in
terms of improving symptoms and by providing some temporal
structure via direct actions not mediated by oscillators and through
influencing peripheral oscillators. This was observed in Alzheimer
patients, in which melatonin was poorly effective on sleep, according
to a large multicenter study (Singer et al., 2003), but still caused some
moderate improvements in cognitive functions as well as by reducing
sundowning (Brusco et al., 1999; Cardinali et al., 2002; Srinivasan
et al., 2006).
Melatonin monotherapy for treating depressive disorders requires
differentiated considerations. Although numerous publications have
addressed the possibility of alleviating depressive symptoms in seasonal
affective disorder by readjusting the circadian system using melatonin,
the direct clinical evidence for this is remarkably scarce. Since the
promising data of the early pilot study by Lewy et al. (Lewy et al.,
1998), very little supporting evidence has been added. In patients of
this category, melatonin was sometimes reported to mainly improve
sleep parameters (Leppämäki et al., 2003) or to not be efficacious, in
contrast to chronotherapy by sleep deprivation (Danilenko and Putilov,
2005). There are several possible reasons for this poor outcome. First,
there have been difficulties in raising money for large state-of-the-art
studies on the natural compound melatonin, which is not of sufficient
commercial interest to pharmaceutical companies. Second, a successful
treatment aiming to correct circadian deviations has to first identify
these deviations, especially with regard to phasing and abnormal period
length. As long as these alterations have not been assessed prior to
treatment, a promising strategy to reentrain circadian rhythms may be
missed. Moreover, differences between patients concerning phase
position and period length can completely obscure effects, since the
chronobiotic actions of melatonin follow a phase response curve (PRC),
in which a silent zone without substantial phase shifts, a delay part, a
transition phase and an advance part have to be distinguished (Lewy
et al., 1992). Therefore, a schematic administration “shortly before
bedtime” may completely miss the phase in which resetting is possible.
It it recommended to determine a temporal marker within the circadian
cycle, using a measure such as the dim-light melatonin onset (DLMO).
Investigators should be aware that the baseline DLMO is typically found
in the silent zone (Lewy et al., 1992). Although melatonin may be
capable of reducing sleep onset latency when given at that time, one
should not expect to resynchronize circadian rhythms by melatonin in
this phase. With regard to the extremely short half-life of melatonin
(between 20 and 30, maximally 45 min), melatonin will have presum-
ably disappeared from the circulation before a phase-shifting part of the
PRC has been reached (Claustrat et al., 2005; Hardeland, 2009b).
Moreover, the investigator has to take into consideration whether the
pathologically disturbed rhythm exhibits an unusually extended or a
shortend period length, or whether the rhythms are phase-delayed or
phase-advanced relative to the sleep/wake cycle; in other words,
whether treatment requires phase advances or phase delays. Both
changes have been observed in subgroups with winter depression.
The time points of melatonin administration, or bright light treatment,
to achieve phase advances or phase delays have been determined (Lewy
et al., 2009). To assure reentrainment, it may be necessary to re-
determine the DLMO in the course of treatment and to re-adapt the
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phase of administration. The disregard of these fundamental chron-
obiological aspects would only lead to inappropriate conclusions on
inefficacy. A further point concerns the dose of melatonin. As outlined
elsewhere (Hardeland, 2016), the conditions of circadian phase reset-
ting do not follow the pharmacokinetic rules an average pharmacologist
is familiar with. Especially, the area under curve (AUC) is not decisive
in this case, where melatonin is rapidly taken up and soon attains a
sufficient level of bioavailability. Notably, it is not an absolute long-
sustained level of the chronobiotic that conveys a synchronizing signal
but rather the velocity and extent of the change, in terms of the so-
called nonparametric resetting. In studies on entrainment of blind
individuals, it has turned out that relatively small amounts of melatonin
(0.5 or 0.3 mg) are much more effective than higher doses such as
10 mg, which can fail to entrain (Lewy et al., 2006, 2005, 2002). Two
reasons can be responsible for the inefficacy of higher doses. Elevated
levels of melatonin may either spill over into other parts of the PRC or
may cause desensitization of oversaturated receptors. The latter possi-
bility has been studied in cell cultures, but there is some uncertainty
concerning its physiological or pharmacological relevance (Hardeland,
2009a). The entraining capacity of very low melatonin levels is
astonishing. In the extreme, even 0.025 mg melatonin have been shown
to be sufficient for synchronizing a blind individual (Lewy, 2003). This
dose did not cause more than a brief spike of melatonin, a finding that
underlines the importance of the nonparametric, pulse-like and change-
dependent characteristics of a well-operating sychronizing signal. These
findings should be kept in mind when attempting a correction of
circadian rhythms to treat mood disorders with an etiology of circadian
malfunction.
In bipolar disorder, in which circadian malfunction also seems to be
of relevance, the clinical basis for judging melatonin's efficacy is, again,
disappointingly small. Melatonin has been used in a couple of studies as
add-on therapy, but these approaches cannot be taken for supporting
melatonin's general usefulness. Other studies not discussed here in
detail concerned sleep improvements in these patients, effects that were
mainly restricted to sleep onset. In a case study (Robertson and
Tanguay, 1997), a child who was resistant to lithium, carbamazepine
and valproic acid responded well to melatonin, however, in combina-
tion with alprazolam. A small study on melatonin in patients with
rapid-cycling bipolar disorder arrived at the conclusion that melatonin
had no significant effects (Leibenluft et al., 1997). This finding is not
surprising in the light of the dose dependence of circadian resetting, as
discussed above in the context of seasonal affective disorders, because
those investigators applied a dose of 10 mg in the evening. Similar
conclusions may be drawn for the use of melatonin in MDD. Three small
add-on studies using between 5 and 10 mg slow-release melatonin did
not demonstrate substantial improvements (Dalton et al., 2000; Dolberg
et al., 1998; Serfaty et al., 2010). It seems that the lack of chronobio-
logical understanding is a major reason for unsuccessful treatments
with melatonin. The high doses applied are poor in resetting, and slow-
release formulations may be additionally counterproductive, in terms of
inappropriately covering different parts of the PRC. If meaningful
studies are to be conducted by aiming at readjustment of circadian
rhythms, low doses of immediate-release melatonin have to be used in
suitable phases for either advancing or delaying the circadian rhythms,
depending on the deviations found in the individual. Especially in
MDD, the prior assessment of presence or absence of circadian
malfunction seems to be essential, since this complex of disorders is
not at all uniform in its etiology. Importantly, investigators have to
dismiss the idea that melatonin may be another directly acting
antidepressant drug. However, it may be useful by readjusting circadian
clocks, if its indirect actions on subforms of depression are of relevance
and considered in the design of studies.
The same chronobiological limits of application have to be also
considered for synthetic melatonergic drugs. These other agonists have
been mostly developed with regard to improving sleep and their design
aimed to extend the halflife compared to the rapidly catabolized
G.M. Brown et al.
melatonin (Hardeland, 2016; Srinivasan et al., 2009a). However, such
an extension does not seem to be an improvement with regard to short,
nonparametric signals required for circadian resetting, which is possi-
ble with low doses of melatonin, whereas higher doses exhibit a
reduced resetting efficacy. The ramelteon metabolite M-II, which
displays melatonergic agonism, is extremely long-lived and attains
blood concentrations much above those of the parent compound (Karim
et al., 2006). The receptor affinities of the approved synthetic drugs are
similar to those of melatonin or, especially in the case of ramelteon,
even higher (Hardeland, 2012b). Despite high receptor affinities and
longer persistence in the blood, the recommended doses are usually
much higher than the 2 or 3 mg present in melatonin pills, such as 8 or
4 mg of ramelteon and 25 or 50 mg of agomelatine. These higher doses
have been selected with regard to improvements of sleep and, in
agomelatine, for antidepressant actions. However, their suitability for
phase resetting must be a matter of skepticism. Moreover, the question
arises as to whether high amounts of synthetic drugs should be
preferred over small doses of the extremely well tolerated natural
compound melatonin. This is especially important in the case of
agomelatine, which induces hepatotoxicity in a subpopulation of
patients (Hardeland, 2014b) and, therefore, requires surveillance. As
it can be fatal, it is now recommended that it never be administered to
anyone with pre-existing liver damage, moreover early discontinuation
is recommended in any with suspected damage (Demyttenaere, 2011;
Gahr et al., 2013; Gruz et al., 2014; Hardeland, 2014b; Montastruc
et al., 2014; Voican et al., 2014).
However, the antidepressant actions of agomelatine differ consider-
ably from those of melatonin and several other melatonergic agonists,
such as ramelteon. In addition to binding affinities to MT1 and MT2 in
the range of those of melatonin, agomelatine displays the additional
property of an antagonist at 5-HT2C serotonin receptors. The affinity to
5-HT2C is relatively moderate and may have been a reason for using
higher doses. The 5-HT2C antagonism has been interpreted as a basis of
direct antidepressant actions (Millan et al., 2003). Later, an interaction
between melatonergic agonism and 5-HT2C inhibition has been sug-
gested for explaining these effects (Racagni et al., 2011). In contrast to
melatonin, numerous investigators have tested the antidepressant
actions of agomelatine in seasonal affective disorder, bipolar disorder
and MDD. Superiority was reported over several other drugs both as an
antidepressant and in restoring sleep (Corruble et al., 2013;
Guilleminault, 2005; Ivanov and Samushiya, 2014; Kasper et al.,
2013; Kennedy and Eisfeld, 2007; Martinotti et al., 2012; Owen,
2009). However, the findings have been multiply reviewed, with
variable judgments (Anonymous, 2013; Bourin and Prica, 2009;
Demyttenaere, 2011; Dolder et al., 2008; Eser et al., 2009, 2007;
Goodwin, 2009; Guaiana et al., 2013; Howland, 2011a, 2011b;
Kaminski-Hartenthaler et al., 2015; Kennedy, 2009; Koesters et al.,
2013; Langan et al., 2011; MacIsaac et al., 2014; Pandi-Perumal et al.,
2009; Singh et al., 2012; Taylor et al., 2014). While positive opinions
prevailed especially in the earlier publications, an increasing number of
critical or negative conclusions were present later, especially in the
larger meta-analyses. The criticism also extended to methodological
problems and to publication bias. However it may be possible that
larger studies did not reveal overall positive effects, because of
heterogeneity of cohorts. Although such negative collective results
may have contributed to the final conclusions in the meta-analyses, no
specific advantage of agomelatine can be deduced as far as the
correction of circadian dysfunction is concerned, and the contribution
of 5-HT2C inhibition to antidepressant effects may be critically valued
as well, at the present state of knowledge.
As to the conclusion that efficient entrainment requires short
resetting signals and that, in the case of melatonin, rather low doses
are sufficient, the question remains of whether other beneficial effects
of melatonin can be also achieved under these conditions. This concerns
especially the reduction of neuroinflammation and oxidative stress. A
relationship between oxidative damage and circadian rhythms likely
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exists, since oscillator mutants have been shown to display enhanced
molecular damage by free radicals (Hardeland et al., 2003), but
oxidative stress can be also induced by numerous other pathological
processes. Some major sources of oxidants and reactive nitrogen
species, too, arise from inflammation, from mitochondrial dysfunction
and NADPH oxidase activation (Hardeland et al., 2015). Many pre-
clinical data indicate that melatonin attenuates mitochondrial dysfunc-
tion and can downregulate NADPH oxidase activation, but the rele-
vance to human pathophysiology, especially with regard to changes in
the depressive brain, are highly uncertain. Keeping in mind the usually
high doses applied to suppress these sources of damage, one may be
skeptic that the much lower amounts suitable for entrainment would
suffice. Perhaps, only damage caused by dysphased or misaligned
rhythms may be successfully treated that way, but presumably not that
by other, more severe causes. A further problem concerns the role of
melatonin in the immune system. Although one can frequently read that
melatonin is an antiinflammatory agent, such a statement is absolutely
inappropriate, since melatonin can alternately behave not only in an
antiinflammatory but also a proinflammatory way, in the latter case
becoming a prooxidant compound (Hardeland et al., 2015), contrary to
the otherwise prevailing view that melatonin is generally an antiox-
idant. The known immune stimulatory actions comprise more upregu-
lations of proinflammatory than antiinflammatory cytokines. However,
many preclinical studies revealed a prevailing antiinflammatory action
in relation to aging and in response to strong inflammatory insults.
Nevertheless, translation of these findings to the human remains
uncertain. Proinflammatory actions of melatonin in the human have
been observed in arthritis, in which the pineal hormone aggravated the
disease (Cutolo and Maestroni, 2005; Maestroni et al., 2005). For the
same reason, caution is likewise due in all autoimmune diseases.
Therefore, treatment with melatonin has some limits in the human.
6. Immunologic alterations and signs of oxidative stress
Immune dysfunction is strongly associated with numerous psychia-
tric and neurological conditions (Frick et al., 2013; Goldsmith et al.,
2016b). Replicated evidence has demonstrated a strong association
between elevated pro-inflammatory markers and both bipolar and
unipolar depression (Liu et al., 2012; Modabbernia et al., 2013;
Rosenblat et al., 2014; Rosenblat and McIntyre, 2016). This association
has been established by measuring central (i.e. cerebral spinal fluid
(CSF)) and peripheral (i.e. blood serum levels) cytokine levels, compar-
ing subjects with and without mood disorders during periods of
depression, hypomania, mania and euthymia. To date, over fifty studies
have been conducted to determine and carefully characterize the
associations between mood disorders and specific cytokine profiles
(Liu et al., 2012; Modabbernia et al., 2013; Rosenblat et al., 2014;
Rosenblat and McIntyre, 2016). These studies have provided insights
into the mechanistic underpinnings of the observed association between
immune dysfunction and mood disorders. Further analysis of these
mechanisms and markers may also lead to the discovery of clinically
relevant biomarkers along with novel treatment targets (Table 3).
In a meta-analysis pooling together the results of twenty-nine
Table 3
Immunologic alterations and oxidative stress.
• Pro-inflammatory cytokines chronically elevated in both MDD and BD
o They are elevated more in acute states
• Oxidative/nitrosative
stress (O & NS) is associated with mood disorders
o Effective antidepressants are associated with decreased (O & NS)
• Pro-inflammatory markers are associated with poorer cognitive function
o The association is likely bidirectional
• Multiple pathways by which cytokines may influence monoamines
o Possibly via the recently identified brain lymphatic system
• Chronic migroglial overactivation may damage vital neural circuitry
• Inflammation may up regulate the HPA axis
G.M. Brown et al.
studies, a strong association between major depressive disorder (MDD)
and pro-inflammatory cytokines (in peripheral serum and CSF) was
identified; interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α) and
soluble IL-2 receptor (sIL-2R) were elevated in MDD subjects compared
to health controls (Liu et al., 2012). Other inflammatory markers
associated with MDD include prostaglandin E2 (PGE2), acute phase
reactant C-reactive protein (CRP), IL-1β and IL-2(Felger and Lotrich,
2013; Goldsmith et al., 2016b; McNamara and Lotrich, 2012). These
studies have also suggested that pro-inflammatory cytokines are
chronically elevated in MDD, even during euthymic periods; however,
pro-inflammatory markers appear to be more prominently and consis-
tently elevated during major depressive episodes (MDEs). These results
suggest that depressive disorders are likely associated with a chronic
low grade inflammatory state with further perturbation of the innate
immune system during mood episodes.
For bipolar disorder (BD), meta-analytic data pooling together the
results of thirty studies revealed a strong association between BD and
higher serum levels of pro-inflammatory cytokines IL-4, TNF-α, sIL-2R,
IL-1β, IL-6, soluble receptor of TNF-alpha type 1 (STNFR1) and CRP in
BD subjects compared to healthy controls (Barbosa et al., 2014a;
Modabbernia et al., 2013; Munkholm et al., 2013a). While there is
some variability in cytokine levels during depressive, manic and
euthymic periods, accumulating evidence indicates that peripheral
cytokine abnormalities are persistent, suggesting that BD is also
associated with a chronic low-grade inflammatory state with potential
peaks of inflammation during depressive and manic episodes (Barbosa
et al., 2014a, 2014b, 2013, Brietzke et al., 2009a, 2009b, Munkholm
et al., 2015, 2013a, 2013b). During periods of euthymia, sTNFR1 and
CRP are the only consistently elevated inflammatory markers (Barbosa
et al., 2014a, 2013; Brietzke et al., 2009a; Fernandes et al., 2016).
During manic episodes, serum levels of CRP, IL-6, TNF-α, sTNFR1, IL-
RA, CXCL10, CXCL11, and IL-4 have been shown to be elevated
(Barbosa et al., 2014a, 2014b, 2013; Liu et al., 2004). During depressive
episodes, serum levels of CRP, sTNFR1 and CXCL10 are elevated
(Barbosa et al., 2014a, 2014b).
Oxidative/nitrosative stress (O & NS) has also been associated with
mood disorders and is intimately connected with immune dysregulation
as inflammation increases O & NS and O & NS increases inflammation
(Gill et al., 2010; Lee et al., 2013; Moylan et al., 2014). The O & NS is
defined as an imbalance between the production of reactive oxygen
species (ROS) and production of antioxidants responsible for neutraliz-
ing ROS. Replicated evidence has demonstrated increased ROS and
decreased antioxidants in both MDD and BD, leading to pathologic
neurodegeneration in key brain regions sub-serving mood and cogni-
tion (Aboul-Fotouh, 2013; Berk et al., 2011; Black et al., 2015; Palta
et al., 2014). More specifically, depressive disorders have been asso-
ciated with increased levels of pro-oxidant markers, namely, 8-hydroxy-
2′-deoxyguanosine (8-OHdG), F2-isoprostanes, malondialdehyde
(MDA) and decreased levels of anti-oxidant molecules, namely, glu-
tathione (gamma-glutamyl-cysteinyl-glycine; GSH), superoxide dismu-
tase (SOD) and glutathione peroxidase (GPx) (Maurya et al., 2016).
Further, antidepressant response has been associated with decreased
O & NS, suggesting a mediational role of O & NS reduction in the
effective treatment of depression (Jimenez-Fernandez et al., 2015). As
such, there has been great interest in further understanding the
mechanisms sub-serving increased O & NS along with the potential
novel drug targets these mechanisms may offer.
Of increasing interest has also been the association between
immune dysfunction, oxidative stress and specific trans-diagnostic
symptoms, such as cognitive dysfunction and anhedonia (Anderson
et al., 2014; Bauer et al., 2014; Rosenblat et al., 2015; Swardfager et al.,
2016). As discussed above, cognitive dysfunction is common and leads
to significant functional impairment in depressive disorders. Cognitive
dysfunction often persists throughout euthymic periods as these
symptoms often do not improve, even with the effective treatment of
mood symptoms. Given that cognitive symptoms often do not improve
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with current conventional therapies, there has been great interest in
new targets to specifically and effectively alleviate cognitive dysfunc-
tion in mood disorders. Immune dysfunction has presented as one
potential target of interest as pro-inflammatory markers have been
independently associated with poorer cognitive function in mood
disorders (Carvalho et al., 2014; Goldsmith et al., 2016a; Rosenblat
et al., 2015).
While the association between pro-inflammatory markers, mood
disorders and cognitive dysfunction has been well established, the
causative mechanisms underlying this association are still currently
being investigated (Rosenblat et al., 2014). Evidence from preclinical
and clinical studies have suggested that the association is likely
bidirectional in that dysfunction of the innate immune system may
predispose, precipitate and perpetuate depressive episodes and cogni-
tive dysfunction as well as vice versa (i.e. depressive episodes may
induce inflammatory changes) (McNamara and Lotrich, 2012; Miller
et al., 2009). Detailed descriptions of potential mechanisms sub-serving
this bidirectional interaction along with the experimental evidence
supporting these proposed mechanisms have been discussed extensively
elsewhere (McNamara and Lotrich, 2012; Miller et al., 2009; Rosenblat
et al., 2014). As such, these mechanisms will only be briefly summar-
ized herein.
Animal and human models have revealed several mechanisms
whereby increased activity of the innate immune system may directly
impact mood and cognition. With the recent finding of functional
lymphatic vessels in the central nervous system (in an animal model)
(Louveau et al., 2015), further merit and biologic plausibility is added
to the potential direct interaction between immune dysfunction and
neuropsychiatric pathology. The direct effect of cytokines on mono-
amine levels serves as one key mechanism whereby inflammation may
affect mood and cognition. Pro-inflammatory cytokines TNF-α, IL-2 and
IL-6 have been shown to directly alter monoamine levels (Capuron
et al., 2003). IL-2 and interferon (IFN) increase the enzymatic activity
of indolamine 2,3-dioxygenase (IDO), thus increasing the breakdown of
tryptophan leading to decreased levels of serotonin and the production
of depressogenic/anxiogenic tryptophan catabolites (TRYCATs) (Dunn
et al., 2005; Rosenblat et al., 2014). Serotonin levels may be further
modulated through the IL-6 and TNF-α dependent breakdown of 5-HT
to 5-hydroxyindoleacetic acid (5-HIAA) (Wang and Dunn, 1998; Zhang
et al., 2001). Pro-inflammatory cytokines may also induce GTP
cyclohydrolase I (GPT-CH1) leading to alterations in dopamine and
norepinephrine levels via the GTP pathway (Swardfager et al., 2016).
Over-activation of microglia had been identified as another key
mechanism of interest (Stertz et al., 2013). Under physiological
conditions, microglia perform an important role in neuroplasticity,
facilitating neural network pruning (Ekdahl, 2012; Harry and Kraft,
2012). Pruning of these pathways is essential for maintenance and
growth of more frequently utilized neural pathways (Harry and Kraft,
2012). However, the chronic inflammatory state associated with MDD
and BD leads to chronic microglia over activation resulting in neuro-
degeneration by aberrantly destroying important neural pathways
(Frick et al., 2013; Stertz et al., 2013). The microglial hypothesis has
been further supported by the previously discussed study by Setiawan
et al. (2015), which revealed (via PET imaging) increased microglial
activation in the ACC, PFC and insula in MDD subjects with a current
MDE, as compared to healthy controls (Setiawan et al., 2015). Post-
mortem studies have also shown increased markers of inflammation and
microglial activation in these key brain region (Bezchlibnyk et al.,
2001; Rao et al., 2010). The over-activation of microglia also increases
local O & NS, further damaging neural circuitry in key brain regions
sub-serving mood and cognition (Kraft and Harry, 2011; Stertz et al.,
2013).
Another key mechanism whereby inflammation may induce mood
dysfunction in MDD and BD is HPA axis dysregulation as discussed
above in Section 4. Increased levels of pro-inflammatory cytokines, IFN,
TNF-α and IL-6, up-regulate HPA activity thereby increasing systemic
G.M. Brown et al.
cortisol levels leading to hypercortisolemia (Beishuizen and Thijs,
2003; Harrison et al., 2009; Wright et al., 2005). Additionally, elevated
levels of inflammatory cytokines decrease glucocorticoid receptor
synthesis, transport and sensitivity in the hypothalamus and pituitary
(Pace and Miller, 2009; Turnbull and Rivier, 1999). Therefore, the
negative feedback loop, which usually down-regulates cortisol produc-
tion, is disabled thereby leading to chronic hypercortisolemia (Pace and
Miller, 2009; Turnbull and Rivier, 1999). Along with alterations in the
HPA axis, the brain-gut-microbiota axis may also be affected. The brain-
gut-microbiota axis has been of increasing interest as a potential
bidirectional pathway perpetuating depressive disorders via immune
dysfunction (Bercik, 2011; Cryan and Dinan, 2012).
7. Potential treatments based on immunologic changes
With the well-established association between immune dysfunction
and mood disorders, the immune system serves as a novel target in the
treatment of depression. Selecting an upstream target (i.e. immune
dysfunction) rather than the downstream effects, such as monoamine
alterations, may allow for potentially improved outcomes and addi-
tional treatment options in treatment resistant populations. Several
clinical trials have already been conducted evaluating the antidepres-
sant effects of anti-inflammatory agents in a variety of populations,
including but not limited to MDD, bipolar depression and sub-syndro-
mal depressive symptoms (Kohler et al., 2014; Rosenblat et al., 2016).
Anti-inflammatory and anti-oxidant agents such as non-steroidal anti-
inflammatories (NSAIDs), acetylsalicylic acid (ASA), minocycline, N-
acetylcysteine (NAC) and biologic cytokine inhibitors (e.g. monoclonal
antibody based agents such as infliximab) have been investigated for
their antidepressant effects (Rosenblat et al., 2014). Nutraceuticals with
anti-inflammatory properties, such as omega-3 poly-unsaturated fatty
acids (omega-3 s) and curcumin, have also been investigated (Bergman
et al., 2013; Bloch and Hannestad, 2012; Lopresti et al., 2014)
(Table 4).
A recent meta-analysis of anti-inflammatory agents, excluding
nutraceuticals, in the treatment of depression and depressive symptoms
identified ten randomized controlled trials (RCTs) evaluating the use of
NSAIDs (n = 4258) and four RCTs investigating cytokine inhibitors
(n = 2004) (Kohler et al., 2014). The pooled effect size (standard mean
difference (SMD) of change in depression severity) suggested that anti-
inflammatory treatment reduced depressive symptom severity
(SMD = − 0.34; p = 0.004) compared with placebo. This effect was
observed in studies including subjects with depression (SMD = −0.54)
and depressive symptoms (SMD = − 0.27). Sub-analyses suggested
that the antidepressant effect of celecoxib (selective cyclooxygenase 2
inhibitor) was more reproducible compared to other agents studied.
Notably, meta-analysis of adverse effects suggested good tolerability
with no evidence of an increased number of infections, gastrointestinal
or cardiovascular events.
In another recent meta-analysis, the use of anti-inflammatory agents
in the treatment of bipolar depression was assessed (Rosenblat et al.,
2016). Eight RCTs (n = 312) assessing adjunctive NSAIDs (n = 53),
omega-3 s (n = 140), NAC (n = 76) and pioglitazone (n = 44) in the
treatment of BD were identified. The overall effect size (SMD) of
Table 4
Potential treatments based on immunologic changes.
• Anti-inflammatory agents, especially celecoxib reduce depression
• Anti-inflammatory
agents, especially NAC reduce depression in BP
• action
Monoclonal antibody based cytokine inhibitor Infliximab have an antidepressant
in those with elevated CRP and TNF-α
• InCurcumin and curcumin/saffron combination has antidepressive action especially
those with atypical depression
• remission
An Omega-3 study reported that those with high inflammation have a marked
rate with EPA (eicosapentaenoic acid)
• Immune modulating agents may only benefit those with immune dysfunction.
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Progress in Neuropsychopharmacology & Biological Psychiatry 80 (2018) 189–204
adjunctive anti-inflammatories on depressive symptom severity was
− 0.40 (p = 0.002), indicative of a moderate and statistically signifi-
cant antidepressant effect. Heterogeneity of the pooled sample was
notably low (I2 = 14%; p = 0.32). Additionally, no manic/hypomanic
induction or significant treatment emergent adverse events were
reported. Of the included agents, adjunctive NAC, an anti-inflammatory
and anti-oxidant agent, was shown to have the greatest antidepressant
effect in BD subjects (Berk et al., 2012, 2008). In a large placebo-
controlled, RCT, adjunctive NAC was shown to lower depression scores
throughout the trial with a statistically significant difference compared
to the placebo group by the primary endpoint of 24 weeks (Berk et al.,
2008). Of note, Soares et al. are currently conducting a phase 2, double-
blind RCT of ASA and NAC as adjunctive treatment for BD
(NCT01797575).
Interest has recently grown in the use of monoclonal antibody based
cytokine inhibitors as these agents may be engineered to specifically
target cytokines implicated in the inflammatory-mood pathway.
Infliximab (anti-TNF-α) and sirukumab (anti-IL-6) have been of parti-
cular interest. One key RCT assessed infliximab in treatment resistant
depression (including BD and MDD subjects) (Raison et al., 2013).
Overall, no greater antidepressant effect of infliximab compared to
placebo was observed; however, a significant antidepressant effect was
observed for a subgroup of subjects with elevated levels of serum CRP
and TNF-α (Raison et al., 2013). The results of this trial were of
particular interest as they suggested that stratification using inflamma-
tory biomarkers might help determine which patients may benefit from
anti-inflammatory therapies and called into question the validity of
previous negative RCTs that did not stratify subjects based on inflam-
matory status. Currently, a 12-week multisite, double-blind RCT
evaluating the efficacy, safety, and tolerability of adjunctive infliximab
for the treatment of BD subjects with an elevated serum CRP is
underway to a priori further characterize the utility of inflammatory
stratification (NCT02363738). Sirukumab is also being currently eval-
uated in a similarly designed RCT for MDD with sample stratification
based on CRP levels (NCT02473289). Results from future, stratified
RCTs of cytokine inhibitors may lead to novel treatments and poten-
tially move the field of psychiatry forward to a more personalized
medicine approach while simultaneously providing significant insight
into the pathophysiology of depression.
The use of naturally occurring anti-inflammatory agents in the
treatment of BD and MDD has remained of great interest; however, use
has been increasingly controversial due to the significant variability of
RCT results and presumed publication bias (Bloch and Hannestad,
2012; Sarris et al., 2012). Curcumin and omega-3 s have been of
greatest interest. Curcumin, an age-old spice, extracted from turmeric
(Curcuma longa) has long been used in complementary and alternative
medicine for its anti-oxidant and anti-inflammatory properties. More
recently, clinical and preclinical studies have shown promising results
for an antidepressant effect with good tolerability associated with daily
curcumin administration (Kaufmann et al., 2015; Sanmukhani et al.,
2014). Most recently, in a RCT (n = 123), MDD subjects were allocated
to one of four treatment conditions, comprising placebo, low-dose
curcumin extract (250 mg twice daily), high-dose curcumin extract
(500 mg twice daily), or combined low-dose curcumin extract plus
saffron (15 mg twice daily) for 12 weeks (Lopresti and Drummond,
2017). The active drug treatments (combined) were associated with
significantly greater improvements in depressive symptoms compared
to placebo (p = 0.03). Active drug treatments also had greater efficacy
in subjects with atypical depression compared to the remainder of
subjects (response rates of 65% versus 35% respectively, p = 0.01). No
differences were found between the differing doses of curcumin or the
curcumin/saffron combination.
Several RCTs have been conducted evaluating the effect of omega-
3 s for the acute treatment of depressive symptoms, MDD and BD (Bloch
and Hannestad, 2012; Sarris et al., 2012). Earlier studies suggested a
robust antidepressant effect in both MDD and BD, however, more recent
G.M. Brown et al.
studies have been negative (Keck et al., 2006) with recent meta-
analyses suggesting a minimal antidepressant effect with significant
publication bias skewing the interpretation of results (Bloch and
Hannestad, 2012; Sarris et al., 2012). Recently, Rapaport et al.
(Rapaport et al., 2016) successfully predicted antidepressant response
to omega-3s in MDD by stratifying subjects based on cytokine profiles.
Based on five inflammatory biomarkers (IL-ra, IL-6, hs-CRP, leptin and
adiponectin), subjects were separated into two categories, namely,
‘high’ and ‘low’ inflammation. Subjects with high inflammation had a
marked response to eicosapentaenoic acid (EPA) with a 40% remission
rate compared to a 25% remission rate in the placebo group. Interest-
ingly, in the low inflammation category, placebo outperformed EPA
with a 44% and 19% remission rate respectively. As such, combining all
subjects, there was no difference in antidepressant effect comparing
EPA with placebo. This study highlighted the importance of stratifica-
tion of samples and provided some insight into a significant potential
cause of heterogeneity in omega-3 RCTs and in anti-inflammatory
depression studies in general.
Taken together, several anti-inflammatory agents show great pro-
mise in the treatment of depression in BD and MDD. Several RCTs are
currently underway as the field of immuno-psychiatry rapidly pro-
gresses. The validity and clinical applicability of future studies will be
much greater than previous studies if sample stratification (i.e.
separating sample based on inflammatory status) is implemented.
Previous clinical trials assessing the antidepressant effects of immune
modulating agents assumed the traditional approach of administering a
test drug to subjects stratified solely by DSM diagnosis would be
adequate to discover novel antidepressant agents. However, more
recently, a more personalized medicine approach has been encouraged
as it is now recognized that immune dysfunction is an etiological factor
only in a subset of mood disorder patients. As such, immune modulating
agents may potentially be only of benefit to patients with immune
dysfunction. Including subjects with normal immune function in
clinical trials may obscure the results and could lead to invalidly
negative studies, as was demonstrated by the previously discussed
proof-of-concept studies of infliximab (Raison et al., 2013) and EPA
(Goldsmith et al., 2016b).
8. Conclusions
The reason for writing this article was to delineate the ways in
which MDD leads to neurodegeneration and to point the way to
practical treatments We have not yet completed that task as there are
still many unknowns. However, we have a good idea of the remaining
gaps.
We know that in depressive disorders as a group and in fact in many
psychiatric disorders there is oftentimes a dysjunction between body
rhythms. It is understandable that a tight coordination of brain,
let alone body procceses, is essential for normal functioning of such a
complicated being as a human. Much more knowledge is needed about
these processes including not only how they go awry but also how to
correct them in MDD. MDD patients differ widely from one another in
the type of rhythm disorder that they may manifest. Several strategies
for enforcing circadian entrainment are now known but require that the
type of rhythm dysfuntion is known. Sleep abnormalities will be only
helpful if they reveal substantial deviations in free-running period
lengths or poor coupling to external time cues. Of course, if a circadian
rhythm sleep disorder has been diagnosed, this will suffice for trying a
treatment of enforced circadian entrainment. In the future studies of
variants of clock genes may be helpful.
We know that MDD and especially recurrent MDD causes measur-
able cognitive problems that are accompanied by immune dysregula-
tion and increases in oxidative/nitrosative processes in the brain and
periphery that could lead to neurodegeneration. Why should that be the
case? What is the underlying mechanism that causes it to happen? What
is the optimal method to correct the problems? Several anti-inflamma-
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Progress in Neuropsychopharmacology & Biological Psychiatry 80 (2018) 189–204
tory agents show great promise in the treatment of depression in BD and
MDD. What has been discovered is that stratification of patients
according to immune status can be important as agents may only
benefit those with immune dysfunction. Further studies will clarify
these issues.
We are at a tantalizing point in these investigations. We have much
information on these processes but insufficient knowledge on key
issues. However, there are many, many tools being used to resolve
these issues and several very competent groups studying them so that
the answers will surely come.
Funding
This work did not receive any specific grant from funding agencies
in the public, commercial, or not-for-profit sectors.
References
Aboul-Fotouh, S., 2013. Coenzyme Q10 displays antidepressant-like activity with
reduction of hippocampal oxidative/nitrosative DNA damage in chronically stressed
rats. Pharmacol. Biochem. Behav. 104, 105–112. http://dx.doi.org/10.1016/j.pbb.
2012.12.027.
Al-Karawi, D., Jubair, L., 2016. Bright light therapy for nonseasonal depression: meta-
analysis of clinical trials. J. Affect. Disord. 198, 64–71.
Albrecht, U., 2013. Circadian clocks and mood-related behaviors. [review]. Handb. Exp.
Pharmacol. 217, 227–239.
American Psychiatric Association, 2013. Diagnostic and Statistical Manual of Mental
Disorders, Fifth Edition (DSM-5), fifth ed. American Psychiatric Association,
Washington, DC.
Anderson, G., Berk, M., Dean, O., Moylan, S., Maes, M., 2014. Role of immune-
inflammatory and oxidative and nitrosative stress pathways in the etiology of
depression: therapeutic implications. CNS Drugs 28, 1–10. http://dx.doi.org/10.
1007/s40263-013-0119-1.
Anonymous, 2013. Agomelatine: a review of adverse effects. Prescrire Int. 22, 70–71.
Arendt, J., Skene, D.J., 2005. Melatonin as a chronobiotic. Sleep Med. Rev. 9, 25–39.
Arendt, J., Skene, D.J., Middleton, B., Lockley, S.J., Deacon, S., 1997. Efficacy of
melatonin treatment in jet lag, shift work, and blindness. J. Biol. Rhythm. 12,
604–617.
Atkinson, M., Kripke, D.F., Wolf, S.R., 1975. Autorhythmometry in manic-depressives.
Chronobiologia 2, 325–335.
Bais, B., Kamperman, A.M., van der Zwaag, M.D., Dieleman, G.C., Harmsen van der Vliet-
Torij, H.W., Bijma, H.H., Lieverse, R., Hoogendijk, W.J., Lambregtse-van den Berg,
M.P., 2016. Bright light therapy in pregnant women with major depressive disorder:
study protocol for a randomized, double-blind, controlled clinical trial. BMC
Psychiatry 16, 381.
Barbosa, I.G., Bauer, M.E., Machado-Vieira, R., Teixeira, A.L., 2014a. Cytokines in bipolar
disorder: paving the way for neuroprogression. Neural Plast. http://dx.doi.org/10.
1155/2014/360481.
Barbosa, I.G., Machado-Vieira, R., Soares, J.C., Teixeira, A.L., 2014b. The immunology of
bipolar disorder. Neuroimmunomodulation 21, 117–122. http://dx.doi.org/10.
1159/000356539.
Barbosa, I.G., Rocha, N.P., Bauer, M.E., de Miranda, A.S., Huguet, R.B., Reis, H.J.,
Zunszain, P.A., Horowitz, M.A., Pariante, C.M., Teixeira, A.L., 2013. Chemokines in
bipolar disorder: trait or state? Eur. Arch. Psychiatry Clin. Neurosci. 263, 159–165.
http://dx.doi.org/10.1007/s00406-012-0327-6.
Barnard, A.R., Nolan, P.M., 2008. When clocks go bad: neurobehavioural conseuences of
disrupted ccircadian timing. PLoS Genet. 4, 1–8.
Baron, K.G., Reid, K.J., 2014. Circadian misalignment and health. Int. Rev. Psychiatry 26,
139–154. http://dx.doi.org/10.3109/09540261.2014.911149.
Bauer, I.E., Pascoe, M.C., Wollenhaupt-Aguiar, B., Kapczinski, F., Soares, J.C., 2014.
Inflammatory mediators of cognitive impairment in bipolar disorder. J. Psychiatr.
Res. 56, 18–27. http://dx.doi.org/10.1016/j.jpsychires.2014.04.017.
Bechtel, W., 2015. Circadian rhythms and mood disorders: Are the phenomena and
mechanisms causally related? Front. Psychiatry 6, 118.
Beck-Friis, J., Kjellman, B.F., Aperia, B., Unden, F., von Rosen, D., Ljunggren, J.G.,
Wetterberg, L., 1985. Serum melatonin in relation to clinical variables in patients
with major depressive disorder and a hypothesis of a low melatonin syndrome. Acta
Psychiatr. Scand. 71, 319–330.
Beck-Friis, J., Kjellman, B.F., Ljunggren, J.-G., Wetterberg, L., 1984. The pineal gland and
melatonin in affective disorders. In: Brown, G.M., Wainwright, S.D. (Eds.), The Pineal
Gland: Endocrine Aspects, Advances in the Biosciences. Pergamon Press, Oxford, pp.
313–325.
Beishuizen, A., Thijs, L.G., 2003. Endotoxin and the hypothalamo-pituitary-adrenal (HPA)
axis. J. Endotoxin Res. 6, 3–24. http://dx.doi.org/10.1179/096805103125001298.
Bellet, M.M., Orozco-Solis, R., Sahar, S., Eckel-Mahan, K., Sassone-Corsi, P., 2011. The
time of metabolism: NAD +, SIRT1, and the circadian clock. Cold Spring Harb. Symp.
Quant. Biol. 76, 31–38.
Bellivier, F., Geoffroy, P., Etain, B., Scott, J., 2015. Sleep- and circadian
rhythm—associated pathways as therapeutic targets in bipolar disorder. Expert Opin.
Ther. Targets 19, 747–763.
G.M. Brown et al.
Benedetti, F., Dallaspezia, S., Colombo, C., Pirovano, A., Marino, E., Smeraldi, E., 2008. A
length polymorphism in the circadian clock gene Per3 influences age at onset of
bipolar disorder. Neurosci. Lett. 445, 184–187. http://dx.doi.org/10.1016/j.neulet.
2008.09.002.
Benedetti, F., Riccaboni, R., Locatelli, C., Poletti, S., Dallaspezia, S., Colombo, C., 2014.
Rapid treatment response of suicidal symptoms to lithium, sleep deprivation, and
light therapy (chronotherapeutics) in drug-resistant bipolar depression. J. Clin.
Psychiatry 75, 133–140.
Bengesser, S.A., Reininghaus, E.Z., Lackner, N., Birner, A., Fellendorf, F.T., Platzer, M.,
Kainzbauer, N., Tropper, B., Hormanseder, C., Queissner, R., Kapfhammer, H.-P.,
Wallner-Liebmann, S.J., Fuchs, R., Petek, E., Windpassinger, C., Schnalzenberger, M.,
Reininghaus, B., Evert, B., Waha, A., 2016. Is the molecular clock ticking differently
in bipolar disorder? Methylation analysis of the clock gene ARNTL. World J. Biol.
Psychiatry 14, 1–9.
Bercik, P., 2011. The microbiota-gut-brain axis: learning from intestinal bacteria? Gut 60,
288–289. http://dx.doi.org/10.1136/gut.2010.226779.
Bergman, J., Miodownik, C., Bersudsky, Y., Sokolik, S., Lerner, P.P., Kreinin, A.,
Polakiewicz, J., Lerner, V., 2013. Curcumin as an add-on to antidepressive treatment:
a randomized, double-blind, placebo-controlled, pilot clinical study. Clin.
Neuropharmacol. 36, 73–76. http://dx.doi.org/10.1097/WNF.0b013e31828ef969.
Berk, M., Copolov, D.L., Dean, O., Lu, K., Jeavons, S., Schapkaitz, I., Anderson-Hunt, M.,
Bush, A.I., 2008. N-acetyl cysteine for depressive symptoms in bipolar disorder—a
double-blind randomized placebo-controlled trial. Biol. Psychiatry 64, 468–475.
http://dx.doi.org/10.1016/j.biopsych.2008.04.022.
Berk, M., Dean, O.M., Cotton, S.M., Gama, C.S., Kapczinski, F., Fernandes, B., Kohlmann,
K., Jeavons, S., Hewitt, K., Moss, K., Allwang, C., Schapkaitz, I., Cobb, H., Bush, A.I.,
Dodd, S., Malhi, G.S., 2012. Maintenance N-acetyl cysteine treatment for bipolar
disorder: a double-blind randomized placebo controlled trial. BMC Med. 10, 91.
http://dx.doi.org/10.1186/1741-7015-10-91.
Berk, M., Kapczinski, F., Andreazza, A.C., Dean, O.M., Giorlando, F., Maes, M., Yucel, M.,
Gama, C.S., Dodd, S., Dean, B., Magalhaes, P.V., Amminger, P., McGorry, P., Malhi,
G.S., 2011. Pathways underlying neuroprogression in bipolar disorder: focus on
inflammation, oxidative stress and neurotrophic factors. Neurosci. Biobehav. Rev. 35,
804–817. http://dx.doi.org/10.1016/j.neubiorev.2010.10.001.
Berson, D.M., 2007. Phototransduction in ganglion-cell photoreceptors. Pflügers Arch.
454, 849–855. http://dx.doi.org/10.1007/s00424-007-0242-2.
Bezchlibnyk, Y.B., Wang, J.F., McQueen, G.M., Young, L.T., 2001. Gene expression
differences in bipolar disorder revealed by cDNA array analysis of post-mortem
frontal cortex. J. Neurochem. 79, 826–834.
Bilello, J.A., Thurmond, L.M., Smith, K.M., Pi, B., Rubin, R., Wright, S.M., Taub, F.,
Henry, M.E., Shelton, R.C., Papakostas, G.I., 2015. MDDScore: Confirmation of a
blood test to aid in the diagnosis of major depressive disorder. J. Clin. Psychiatry 76,
e199–e206. http://dx.doi.org/10.4088/JCP.14m09029.
Black, C.N., Bot, M., Scheffer, P.G., Cuijpers, P., Penninx, B.W., 2015. Is depression
associated with increased oxidative stress? A systematic review and meta-analysis.
Psychoneuroendocrinology 51, 164–175. http://dx.doi.org/10.1016/j.psyneuen.
2014.09.025.
Bloch, M.H., Hannestad, J., 2012. Omega-3 fatty acids for the treatment of depression:
systematic review and meta-analysis. Mol. Psychiatry 17, 1272–1282. http://dx.doi.
org/10.1038/mp.2011.100.
Boivin, D.B., 2000. Influence of sleep-wake and circadian rhythm disturbances in
psychatric disorders. J. Psychiatry Neurosci. 25, 446–458.
Bonmati-Carrion, M.A., Arguelles-Prieto, R., Martinez-Madrid, M.J., Reiter, R.,
Hardeland, R., Rol, M.A., Madrid, J.A., 2014. Protecting the melatonin rhythm
through circadian healthy light exposure. Int. J. Mol. Sci. 15, 23448–23500. http://
dx.doi.org/10.3390/ijms151223448.
Bora, E., Harrison, B.J., Davey, C.G., Yücel, M., Pantelis, C., 2012. Meta-analysis of
volumetric abnormalities in cortico-striatal-pallidal-thalamic circuits in major
depressive disorder. Psychol. Med. 42, 671–681. http://dx.doi.org/10.1017/
S0033291711001668.
Bourin, M., Prica, C., 2009. Melatonin receptor agonist agomelatine: a new drug for
treating unipolar depression. Curr. Pharm. Des. 15, 1675.
Bouwmans, M.E.J., Bos, E.H., Booij, S.H., van Faassen, M., Oldehinkel, A.J., de Jonge, P.,
2015. Intra- and inter-individual variability of longitudinal daytime melatonin
secretion patterns in depressed and non-depressed individuals. Chronobiol. Int. 32,
441–446. http://dx.doi.org/10.3109/07420528.2014.973114.
Brietzke, E., Kauer-Sant'Anna, M., Teixeira, A.L., Kapczinski, F., 2009a. Abnormalities in
serum chemokine levels in euthymic patients with bipolar disorder. Brain Behav.
Immun. 23, 1079–1082. http://dx.doi.org/10.1016/j.bbi.2009.04.008.
Brietzke, E., Stertz, L., Fernandes, B.S., Kauer-Sant'anna, M., Mascarenhas, M., Escosteguy
Vargas, A., Chies, J.A., Kapczinski, F., 2009b. Comparison of cytokine levels in
depressed, manic and euthymic patients with bipolar disorder. J. Affect. Disord. 116,
214–217. http://dx.doi.org/10.1016/j.jad.2008.12.001.
Brown, R., Kocsis, J.H., Caroff, S., Amsterdam, J., Winokur, A., Stokes, P.E., Frazer, A.,
1985. Differences in nocturnal melatonin secretion between melancholic depressed
patients and control subjects. Am. J. Psychiatry 142, 811–816.
Brusco, L.I., Fainstein, I., Marquez, M., Cardinali, D.P., 1999. Effect of melatonin in
selected populations of sleep-disturbed patients. Biol. Signals Recept. 8, 126–131.
Brzezinski, A., Vangel, M.G., Wurtman, R.J., Norrie, G., Zhdanova, I., Ben-Shushan, A.,
Ford, I., 2005. Effects of exogenous melatonin on sleep: a meta-analysis. Sleep Med.
Rev. 9, 41–50.
Bumb, J.M., Enning, F., Mueller, J.K., Van Der List, T., Rohleder, C., Findeisen, P., Noelte,
I., Schwarz, E., Leweke, F.M., 2016. Differential melatonin alterations in
cerebrospinal fluid and serum of patients with major depressive disorder and bipolar
disorder. Compr. Psychiatry 68, 34–39. http://dx.doi.org/10.1016/j.comppsych.
2016.03.005.
199
Progress in Neuropsychopharmacology & Biological Psychiatry 80 (2018) 189–204
Bunney, B., Li, J., Walsh, D., Stein, R., Vawter, M., Cartagena, P., Barchas, J., Schatzberg,
A., Myers, R., Watson, S., Akil, H., Bunney, W., 2015. Circadian dysregulation of
clock genes: clues to rapid treatments in major depressive disorder HHS Public
Access. Mol. Psychiatry 20138, 48–55. http://dx.doi.org/10.1038/mp.2014.138.
Bunney, B.G., Bunney, W.E., 2013. Mechanisms of rapid antidepressant effects of sleep
deprivation therapy: clock genes and circadian rhythms. Biol. Psychiatry 73,
1164–1171. http://dx.doi.org/10.1016/j.biopsych.2012.07.020.
Burkhart, K., Phelps, J.R., 2009. Amber lenses to block blue light and improve sleep: a
randomized trial. Chronobiol. Int. 26, 1602–1612. http://dx.doi.org/10.3109/
07420520903523719.
Buzsáki, G., Watson, B.O., 2012. Brain rhythms and neural syntax: implications for
efficient coding of cognitive content and neuropsychiatric disease. Dialogues Clin.
Neurosci. 14, 345–367. http://dx.doi.org/10.1097/ALN.0b013e318212ba87.
Byrne, E.M., Heath, A.C., Madden, P.A.F., Pergadia, M.L., Hickie, I.B., Montgomery, G.W.,
Martin, N.G., Wray, N.R., 2014. Testing the role of circadian genes in conferring risk
for psychiatric disorders. Am. J. Med. Genet. B Neuropsychiatr. Genet. 165, 254–260.
http://dx.doi.org/10.1002/ajmg.b.32230.
Capuron, L., Neurauter, G., Musselman, D.L., Lawson, D.H., Nemeroff, C.B., Fuchs, D.,
Miller, A.H., 2003. Interferon-alpha-induced changes in tryptophan metabolism.
Relationship to depression and paroxetine treatment. Biol. Psychiatry 54, 906–914.
Carceller-Sindreu, M., de Diego-Adeliño, J., Serra-Blasco, M., Vives-Gilabert, Y., Martín-
Blanco, A., Puigdemont, D., Álvarez, E., Pérez, V., Portella, M.J., 2015. Volumetric
MRI study of the habenula in first episode, recurrent and chronic major depression.
Eur. Neuropsychopharmacol. 25, 2015–2021. http://dx.doi.org/10.1016/j.
euroneuro.2015.08.009.
Cardinali, D.P., Brusco, L.I., Liberczuk, C., Furio, A.M., 2002. The use of melatonin in
Alzheimer's disease. Neuroendocrinol. Lett. 23, 20–23.
Cardinali, D.P., Pandi-perumal, S.R., Brown, G.M., 2011. Sleep and circadian
dysregulation in depressive illness pharmacological implications. Clin.
Neuropsychiatry 8, 321–338.
Carroll, B.J., 1982. The dexamethasone suppression test for melancholia. Br. J. Psychiatry
140, 292–304.
Carvalho, A.F., Miskowiak, K.K., Hyphantis, T.N., Kohler, C.A., Alves, G.S., Bortolato, B.,
Sales, P.M., Machado-Vieira, R., Berk, M., McIntyre, R.S., 2014. Cognitive
dysfunction in depression - pathophysiology and novel targets. CNS Neurol. Disord.
Drug Targets 13, 1814–1835.
Chang, H.-C., Guarente, L., 2013. SIRT1 mediates central circadian control in the SCN by
a mechanism that decays with aging. Cell 153, 1448–1460.
Chi, K.F., Korgaonkar, M., Grieve, S.M., 2015. Imaging predictors of remission to anti-
depressant medications in major depressive disorder. J. Affect. Disord. 186, 134–144.
http://dx.doi.org/10.1016/j.jad.2015.07.002.
Choi, S., Han, K.M., Won, E., Yoon, B.J., Lee, M.S., Ham, B.J., 2015. Association of brain-
derived neurotrophic factor DNA methylation and reduced white matter integrity in
the anterior corona radiata in major depression. J. Affect. Disord. 172, 74–80. http://
dx.doi.org/10.1016/j.jad.2014.09.042.
Claustrat, B., Brun, J., Chazot, G., 2005. The basic physiology and pathophysiology of
melatonin. Sleep Med. Rev. 9, 11–24.
Corruble, E., de Bodinat, C., Belaïdi, C., Goodwin, G.M., Belaidi, C., Goodwin, G.M.,
Agomelatine Study Group, 2013. Efficacy of agomelatine and escitalopram on
depression, subjective sleep and emotional experiences in patients with major
depressive disorder: a 24-wk randomized, controlled, double-blind trial. Int. J.
Neuropsychopharmacol. 16, 2219–2234. http://dx.doi.org/10.1017/
S1461145713000679.
Crowley, S.K., Youngstedt, S.D., 2012. Efficacy of light therapy for perinatal depression: a
review. J. Physiol. Anthropol. 31, 15.
Cryan, J.F., Dinan, T.G., 2012. Mind-altering microorganisms: the impact of the gut
microbiota on brain and behaviour. Nat. Rev. 13, 701–702. http://dx.doi.org/10.
1038/nrn3346.
Cutolo, M., Maestroni, G.J.M., 2005. The melatonin-cytokine connection in rheumatoid
arthritis. Ann. Rheum. Dis. 64, 1109–1111.
Dallaspezia, S., Benedetti, F., 2015. Chronobiology of bipolar disorder: therapeutic
implication. Curr. Psychiatry Rep. 17, 1–10. http://dx.doi.org/10.1007/s11920-015-
0606-9.
Dallaspezia, S., Benedetti, F., 2011. Chronobiological therapy for mood disorders. Expert.
Rev. Neurother. 11, 961–970. http://dx.doi.org/10.1586/ern.11.61.
Dallaspezia, S., Locatelli, C., Lorenzi, C., Pirovano, A., Colombo, C., Benedetti, F., 2016.
Sleep homeostatic pressure and PER3 VNTR gene polymorphism influence
antidepressant response to sleep deprivation in bipolar depression. J. Affect. Disord.
192, 64–69. http://dx.doi.org/10.1016/j.jad.2015.11.039.
Dalton, E.J., Rotondi, D., Levitan, R.D., Kennedy, S.H., Brown, G.M., 2000. Use of slow-
release melatonin in treatment-resistant depression. J. Psychiatry Neurosci. 25,
48–52.
Danilenko, K.V., Ivanova, I.A., 2015. Dawn simulation vs. bright light in seasonal
affective disorder: Treatment effects and subjective preference. J. Affect. Disord. 180,
87–89.
Danilenko, K.V., Putilov, A.A., 2005. Melatonin treatment of winter depression following
total sleep deprivation: waking EEG and mood correlates. Neuropsychopharmacology
30, 1345–1352.
Delavest, M., Even, C., Benjemaa, N., Poirier, M.-F., Jockers, R., Krebs, M.-O., 2012.
Association of the intronic rs2072621 polymorphism of the X-linked GPR50 gene
with affective disorder with seasonal pattern. Eur. Psychiatry 27, 369–371.
Delvecchio, G., Fossati, P., Boyer, P., Brambilla, P., Falkai, P., Gruber, O., Hietala, J.,
Lawrie, S.M., Martinot, J.L., McIntosh, A.M., Meisenzahl, E., Frangou, S., 2012.
Common and distinct neural correlates of emotional processing in bipolar disorder
and major depressive disorder: a voxel-based meta-analysis of functional magnetic
resonance imaging studies. Eur. Neuropsychopharmacol. 22, 100–113. http://dx.doi.
G.M. Brown et al.
org/10.1016/j.euroneuro.2011.07.003.
Demyttenaere, K., 2011. Agomelatine: a narrative review. Eur. Neuropsychopharmacol.
21 (Suppl. 4), S703–S709. http://dx.doi.org/10.1016/j.euroneuro.2011.07.004.
Depping, M.S., Wolf, N.D., Vasic, N., Sambataro, F., Thomann, P.A., Wolf, R.C., 2016.
Common and distinct structural network abnormalities in major depressive disorder
and borderline personality disorder. Prog. Neuropsychopharmacol. Biol. Psychiatry
65, 127–133. http://dx.doi.org/10.1016/j.pnpbp.2015.09.007.
der Lek, R., Swaab, D.F., Twisk, J., Hol, E.M., Hoogendijk, W.J., Van Someren, E.J., 2008.
Effect of bright light and melatonin on cognitive and noncognitive function in elderly
residents of group care facilities: a randomized controlled trial. J. Am. Med. Assoc.
299, 2642–2655.
Dibner, C., Schibler, U., Albrecht, U., 2010. The mammalian circadian timing system:
Organization and coordination of central and peripheral clocks. Annu. Rev. Physiol.
72, 517–549. http://dx.doi.org/10.1146/annurev-physiol-021909-135821.
Dolberg, O.T., Hirschmann, S., Grunhaus, L., 1998. Melatonin for the treatment of sleep
disturbances in major depressive disorder. Am. J. Psychiatry 155, 1119–1121.
Dolder, C.R., Nelson, M., Snider, M., 2008. Agomelatine treatment of major depressive
disorder. Ann. Pharmacother. 42, 1822–1823.
Dowling, G.A., Burr, R.L., Van Someren, E.J., Hubbard, E.M., Luxenberg, J.S., Mastick, J.,
Cooper, B.A., 2008. Melatonin and bright-light treatment for rest-activity disruption
in institutionalized patients with Alzheimer's disease. J. Am. Geriatr. Soc. 56,
239–246.
Drago, A., Monti, B., Ronchi, D. De, Serretti, A., Giovanni, I.R.C.C.S.S., 2015. CRY1
variations impacts on the depressive relapse rate in a sample of bipolar patients.
Psychiatry Investig. 12, 118–124.
Dridi, D., Zouiten, A., Mansour, H.Ben, 2014. Depression: chronophysiology and
chronotherapy. Biol. Rhythm. Res. 45, 77–91.
Dunn, A.J., Swiergiel, A.H., de Beaurepaire, R., 2005. Cytokines as mediators of
depression: what can we learn from animal studies? Neurosci. Biobehav. Rev. 29,
891–909. http://dx.doi.org/10.1016/j.neubiorev.2005.03.023.
Dusi, N., Barlati, S., Vita, A., Brambilla, P., 2015. Brain structural effects of antidepressant
treatment in major depression. Curr. Neuropharmacol. 13, 458–465. http://dx.doi.
org/10.2174/1570159X1304150831121909.
Ekdahl, C.T., 2012. Microglial activation - tuning and pruning adult neurogenesis. Front.
Pharmacol. 3, 41. http://dx.doi.org/10.3389/fphar.2012.00041.
Elder, G., Wetherell, M.A., Barclay, N.L., Ellis, J.G., 2014. The cortisol awakening
response—applications and implications for sleep medicine. Sleep Med. Rev. 18,
215–224. http://dx.doi.org/10.1016/j.smrv.2013.05.001.
Eniola, K., Bacigalupo, A., Mounsey, A., 2016. PURLs: light therapy for nonseasonal major
depressive disorder? J. Fam. Pract. 65, 486–488.
Eser, D., Baghai, T.C., Möller, H.-J., 2007. Evidence of agomelatine's antidepressant
efficacy: The key points. Int. Clin. Psychopharmacol. 22 (Suppl. 2), S15–S19.
Eser, D., Baghai, T.C., Möller, H.J., 2009. Agomelatine: the evidence for its place in the
treatment of depression. Core Evid. 4, 171–179. http://dx.doi.org/10.2147/CE.
S6005.
Felger, J.C., Lotrich, F.E., 2013. Inflammatory cytokines in depression: neurobiological
mechanisms and therapeutic implications. Neuroscience 246, 199–229. http://dx.
doi.org/10.1016/j.neuroscience.2013.04.060.
Fernandes, B.S., Steiner, J., Molendijk, M.L., Dodd, S., Nardin, P., Goncalves, C.A., Jacka,
F., Kohler, C.A., Karmakar, C., Carvalho, A.F., Berk, M., 2016. C-reactive protein
concentrations across the mood spectrum in bipolar disorder: a systematic review and
meta-analysis. Lancet Psychiatry 3, 1147–1156. http://dx.doi.org/10.1016/S2215-
0366(16)30370-4.
Flynn-Evans, E.E., Tabandeh, H., Skene, D.J., Lockley, S.W., 2014. Circadian rhythm
disorders and melatonin production in 127 blind women with and without light
perception. J. Biol. Rhythm. 29, 215–224.
Frazer, A., Brown, R., Kocsis, J., Caroff, S., Amsterdam, J., Winokur, A., Sweeney, J.,
Stokes, P., 1985. Patterns of melatonin rhythms in depression. J. Neural Transm.
Suppl. 21, 269–290.
Frick, L.R., Williams, K., Pittenger, C., 2013. Microglial dysregulation in psychiatric
disease. Clin. Dev. Immunol. http://dx.doi.org/10.1155/2013/608654.
Frodl, T., Amico, F., 2014. Is there an association between peripheral immune markers
and structural/functional neuroimaging findings? Prog. Neuropsychopharmacol.
Biol. Psychiatry 48, 295–303. http://dx.doi.org/10.1016/j.pnpbp.2012.12.013.
Gagné, A.-M., Lévesque, F., Gagné, P., Hébert, M., 2011. Impact of blue vs red light on
retinal response of patients with seasonal affective disorder and healthy controls.
Prog. Neuro-Psychopharmacol. Biol. Psychiatry 35, 227–231.
Gahr, M., Freudenmann, R.W., Connemann, B.J., Hiemke, C., Schonfeldt-Lecuona, C.,
2013. Agomelatine and hepatotoxicity: implications of cumulated data derived from
spontaneous reports of adverse drug reactions. Pharmacopsychiatry 46, 214–220.
http://dx.doi.org/10.1055/s-0033-1353156.
Galecki, P., Szemraj, J., Bartosz, G., Bienkiewicz, M., Galecka, E., Florkowski, A.,
Lewinski, A., Karbownik-Lewinska, M., 2010. Single-nucleotide polymorphisms and
mRNA expression for melatonin synthesis rate-limiting enzyme in recurrent
depressive disorder. J. Pineal Res. 48, 311–317. http://dx.doi.org/10.1111/j.1600-
079X.2010.00754.x.
Gill, R., Tsung, A., Billiar, T., 2010. Linking oxidative stress to inflammation: Toll-like
receptors. Free Radic. Biol. Med. 48, 1121–1132. http://dx.doi.org/10.1016/j.
freeradbiomed.2010.01.006.
Goldsmith, D.R., Haroon, E., Woolwine, B.J., Jung, M.Y., Wommack, E.C., Harvey, P.D.,
Treadway, M.T., Felger, J.C., Miller, A.H., 2016a. Inflammatory markers are
associated with decreased psychomotor speed in patients with major depressive
disorder. Brain Behav. Immun. 56, 281–288. http://dx.doi.org/10.1016/j.bbi.2016.
03.025.
Goldsmith, D.R., Rapaport, M.H., Miller, B.J., 2016b. A meta-analysis of blood cytokine
network alterations in psychiatric patients: comparisons between schizophrenia,
200
Progress in Neuropsychopharmacology & Biological Psychiatry 80 (2018) 189–204
bipolar disorder and depression. Mol. Psychiatry 21, 1696–1709. http://dx.doi.org/
10.1038/mp.2016.3.
Gonzalez, R., Gonzalez, S., Villa, E., Ramirez, M., Zavala, J., Armas, R., Contreras, J.,
Dassori, A., Leach, R.J., Flores, D., Jerez, A., Raventós, H., Ontiveros, A., Nicolini, H.,
Escamilla, M., 2015. Identification of circadian gene variants in bipolar disorder in
Latino populations. J. Affect. Disord. 186, 367–375. http://dx.doi.org/10.1016/j.jad.
2015.07.014.
Goodwin, G.M., 2009. Clinical studies on the efficacy of agomelatine on depressive
symptoms. CNS Drugs 23 (Suppl. 2), 35–39.
Gooley, J.J., Chamberlain, K., Smith, K.a., Khalsa, S.B.S., Rajaratnam, S.M.W., van Reen,
E., Zeitzer, J.M., Czeisler, C.a., Lockley, S.W., 2011. Exposure to room light before
bedtime suppresses melatonin onset and shortens melatonin duration in humans. J.
Clin. Endocrinol. Metab. 96, 463–472. http://dx.doi.org/10.1210/jc.2010-2098.
Gooley, J.J., Lu, J., Fischer, D., Saper, C.B., 2003. A broad role for melanopsin in
nonvisual photoreception. J. Neurosci. 23, 7093–7106.
Gordijn, M.C.M., Mannetje, D’t., Meesters, Y., 2012. The effects of blue-enriched light
treatment compared to standard light treatment in Seasonal Affective Disorder. J.
Affect. Disord. 136, 72–80.
Gottlieb, J.F., Terman, M., 2012. Outpatient triple chronotherapy for bipolar depression:
case report. J. Psychiatr. Pract. 18, 373–380.
Gruz, F., Raffa, S., Santucci, C., Papale, R.M., Videla, M.G., Fernandez, M.G., Yantorno, S.,
Descalzi, V.I., 2014. Agomelatine: fulminant liver failure in a patient with fatty liver.
Gastroenterol. Hepatol. 37, 92–94. http://dx.doi.org/10.1016/j.gastrohep.2013.04.
008.
Guaiana, G., Gupta, S., Chiodo, D., Davies, S.J., Haederle, K., Koesters, M., 2013.
Agomelatine versus other antidepressive agents for major depression. Cochrane
database Syst. Rev. 12. http://dx.doi.org/10.1002/14651858.CD008851.pub2.
Guilleminault, C., 2005. Efficacy of agomelatine versus venlafaxine on subjective sleep of
patients with major depressive diorder. Eur. Neuropsychopharmacol. 15, S419.
Hack, L.M., Lockley, S.W., Arendt, J., Skene, D.J., 2003. The effects of low-dose 0.5-mg
melatonin on the free-running circadian rhythms of blind subjects. J. Biol. Rhythm.
18, 420–429.
Han, K.-M., Kim, D., Sim, Y., Kang, J., Kim, A., Won, E., Tae, W.-S., Ham, B.-J., 2017.
Alterations in the brainstem volume of patients with major depressive disorder and
their relationship with antidepressant treatment. J. Affect. Disord. 208, 68–75.
http://dx.doi.org/10.1016/j.jad.2016.08.066.
Hardeland, R., 2016. Melatonin and synthetic melatoninergic agonists in psychiatric and
age-associated disorders: successful and unsuccessful approaches. Curr. Pharm. Des.
22, 1086–1100.
Hardeland, R., 2014a. Melatonin, noncoding RNAs, messenger RNA stability and
epigenetics—evidence, hints, gaps and perspectives. Int. J. Mol. Sci. 15,
18221–18252. http://dx.doi.org/10.3390/ijms151018221.
Hardeland, R., 2014b. Agomelatine and the risk of hepatotoxicity. J. Symptoms Signs 3,
341–346.
Hardeland, R., 2012a. Melatonin in aging and disease ― multiple consequences of
reduced secretion, options and limits of treatment. Aging Dis. 3 (3), 194–225.
Hardeland, R., 2012b. Rationale and Problems of Melatonergic Treatment. vol. 16. pp.
7–14.
Hardeland, R., 2009a. Melatonin: signaling mechanisms of a pleiotropic agent. Biofactors
35, 183–192. http://dx.doi.org/10.1002/biof.23.
Hardeland, R., 2009b. New approaches in the management of insomnia: weighing the
advantages of prolonged-release melatonin and synthetic melatoninergic agonists.
Neuropsychiatr. Dis. Treat. 5, 341–354.
Hardeland, R., Cardinali, D.P., Brown, G.M., Pandi-Perumal, S.R., 2015. Melatonin and
brain inflammaging. Prog. Neurobiol. 127–128, 46–63. http://dx.doi.org/10.1016/j.
pneurobio.2015.02.001.
Hardeland, R., Coto-Montes, A., Poeggeler, B., 2003. Circadian rhythms, oxidative stress
and antioxidative defense mechanisms. Chronobiol. Int. 20, 921–962.
Harrisberger, F., Smieskova, R., Schmidt, A., Lenz, C., Walter, A., Wittfeld, K., Grabe, H.J.,
Lang, U.E., Fusar-Poli, P., Borgwardt, S., 2015. BDNF Val66Met polymorphism and
hippocampal volume in neuropsychiatric disorders: a systematic review and meta-
analysis. Neurosci. Biobehav. Rev. 55, 107–118. http://dx.doi.org/10.1016/j.
neubiorev.2015.04.017.
Harrison, J., Lam, R., Baune, B., McIntyre, R.S., 2016. Selection of cognitive tests for trials
of therapeutic agents. Lancet Psychiatry 3, 499.
Harrison, N.A., Brydon, L., Walker, C., Gray, M.A., Steptoe, A., Critchley, H.D., 2009.
Inflammation causes mood changes through alterations in subgenual cingulate
activity and mesolimbic connectivity. Biol. Psychiatry 66, 407–414. http://dx.doi.
org/10.1016/j.biopsych.2009.03.015.
Harry, G.J., Kraft, A.D., 2012. Microglia in the developing brain: a potential target with
lifetime effects. Neurotoxicology 33, 191–206. http://dx.doi.org/10.1016/j.neuro.
2012.01.012.
Hastings, M.H., Brancaccio, M., Maywood, E.S., 2014. Circadian pacemaking in cells and
circuits of the suprachiasmatic nucleus. J. Neuroendocrinol. 26, 2–10. http://dx.doi.
org/10.1111/jne.12125.
Hastings, M.H., Goedert, M., 2013. Circadian clocks and neurodegenerative diseases: time
to aggregate? Curr. Opin. Neurobiol. 23, 880–887. http://dx.doi.org/10.1016/j.conb.
2013.05.004.
Henriksen, T.E., Skrede, S., Fasmer, O.B., Schoeyen, H., Leskauskaite, I., Bjørke-
Bertheussen, J., Assmus, J., Hamre, B., Grønli, J., Lund, A., 2016. Blue-blocking
glasses as additive treatment for mania: a randomized placebo-controlled trial.
Bipolar Disord. 18, 221–232. http://dx.doi.org/10.1111/bdi.12390.
Herbert, J., 2013. Cortisol and depression: three questions for psychiatry. Psychol. Med.
43, 449–469. http://dx.doi.org/10.1017/S0033291712000955.
Howland, R.H., 2011a. A benefit-risk assessment of agomelatine in the treatment of major
depression. Drug Saf. 34, 709–731. http://dx.doi.org/10.2165/11593960-
G.M. Brown et al.
000000000-00000.
Howland, R.H., 2011b. Publication bias and outcome reporting bias: agomelatine as a
case example. J. Psychosoc. Nurs. Ment. Health Serv. 49 (9), 11–14. http://dx.doi.
org/10.3928/02793695-20110809-01.
Hua, P., Liu, W., Chen, D., Zhao, Y., Chen, L., Zhang, N., Wang, C., Guo, S., Wang, L., Xiao,
H., Kuo, S.H., 2014. Cry1 and Tef gene polymorphisms are associated with major
depressive disorder in the Chinese population. J. Affect. Disord. 157, 100–103.
http://dx.doi.org/10.1016/j.jad.2013.11.019.
Insel, T., Cuthbert, B., Garvey, M., Heinssen, R., Pine, D.S., Quinn, K., Sanislow, C., Wang,
P., 2010. Research Domain Criteria (RDoC): Toward a new classification framework
for research on mental disorders. Am. J. Psychiatry 167, 748–751. http://dx.doi.org/
10.1176/appi.ajp.2010.09091379.
Ivanov, S.V., Samushiya, M.A., 2014. Agomelatine in the treatment of depressive
disorders in clinical practice: multicenter observational CHRONOS study.
Neuropsychiatr. Dis. Treat 10, 631–639. http://dx.doi.org/10.2147/NDT.S58994.
Jaworska, N., Yang, X.-R., Knott, V., Macqueen, G., 2014. A review of fMRI studies during
visual emotive processing in major depressive disorder. World J. Biol. Psychiatry
7321, 1–24. http://dx.doi.org/10.3109/15622975.2014.885659.
Jaworska, N., Yücel, K., Courtright, A., Macmaster, F.P., Sembo, M., Macqueen, G., 2016.
Subgenual anterior cingulate cortex and hippocampal volumes in depressed youth:
the role of comorbidity and age. J. Affect. Disord. 190, 726–732. http://dx.doi.org/
10.1016/j.jad.2015.10.064.
Jimenez-Fernandez, S., Gurpegui, M., Diaz-Atienza, F., Perez-Costillas, L., Gerstenberg,
M., Correll, C.U., 2015. Oxidative stress and antioxidant parameters in patients with
major depressive disorder compared to healthy controls before and after
antidepressant treatment: results from a meta-analysis. J. Clin. Investigation 76,
1658–1667. http://dx.doi.org/10.4088/JCP.14r09179.
Jin, X., Shearman, L.P., Weaver, D.R., Zylka, M.J., de Vries, G.J., Reppert, S.M., 1999. A
molecular mechanism regulating rhythmic output from the suprachiasmatic circadian
clock. Cell 96, 57–68.
Johansson, C., Willeit, M., Smedh, C., Ekholm, J., Paunio, T., Kieseppä, T., Lichtermann,
D., Praschak-Rieder, N., Neumeister, A., Nilsson, L.-G., Kasper, S., Peltonen, L.,
Adolfsson, R., Schalling, M., Partonen, T., 2003. Circadian clock-related
polymorphisms in seasonal affective disorder and their relevance to diurnal
preference. Neuropsychopharmacology 28, 734–739. http://dx.doi.org/10.1038/sj.
npp.1300121.
Jones, S.G., Benca, R.M., 2015. Circadian disruption in psychiatric disorders. Sleep Med.
Clin. 10, 481–493. http://dx.doi.org/10.1016/j.jsmc.2015.07.004.
Kalenderoglu, A., Çelik, M., Sevgi-Karadag, A., Egilmez, O.B., 2016. Optic coherence
tomography shows inflammation and degeneration in major depressive disorder
patients correlated with disease severity. J. Affect. Disord. 204, 159–165. http://dx.
doi.org/10.1016/j.jad.2016.06.039.
Kaltenboeck, A., Winkler, D., Kasper, S., 2016. Bipolar and related disorders in DSM-5 and
ICD-10. CNS Spectr. 21, 318–323. http://dx.doi.org/10.1017/S1092852916000079.
Kaminski-Hartenthaler, A., Nussbaumer, B., Forneris, C.A., Morgan, L.C., Gaynes, B.N.,
Sonis, J.H., Greenblatt, A., et al., 2015. Melatonin and agomelatine for preventing
seasonal affective disorder. Cochrane Database Syst. Rev. 11.
Karim, A., Tolbert, D., Cao, C., 2006. Disposition kinetics and tolerance of escalating
single doses of ramelteon, a high-affinity MT1 and MT2 melatonin receptor agonist
indicated for treatment of insomnia. J. Clin. Pharmacol. 46, 140–148.
Kasper, S., Corruble, E., Hale, A., Lemoine, P., Montgomery, S.A., Quera-Salva, M.A.,
2013. Antidepressant efficacy of agomelatine versus SSRI/SNRI: results from a pooled
analysis of head-to-head studies without a placebo control. Int. Clin.
Psychopharmacol. 28, 12–19. http://dx.doi.org/10.1097/YIC.0b013e328359768e.
Kaufmann, F.N., Gazal, M., Bastos, C.R., Kaster, M.P., Ghisleni, G., 2015. Curcumin in
depressive disorders: an overview of potential mechanisms, preclinical and clinical
findings. Eur. J. Pharmacol. 76, 1658–1667. http://dx.doi.org/10.1016/j.ejphar.
2016.05.026.
Kayumov, L., Casper, R.F., Hawa, R.J., Perelman, B., Chung, S.A., Sokalsky, S., Shapiro,
C.M., 2005. Blocking low-wavelength light prevents nocturnal melatonin suppression
with no adverse effect on performance during simulated shift work. J. Clin.
Endocrinol. Metab. 90, 2755–2761. http://dx.doi.org/10.1210/jc.2004-2062.
Kayumov, L., Zhdanova, I.V., Shapiro, C.M., 2000. Melatonin, sleep, and circadian
rhythm disorders. Semin. Clin. Neuropsychiatry 5, 44–55.
Keck Jr., P.E., Mintz, J., McElroy, S.L., Freeman, M.P., Suppes, T., Frye, M.A., Altshuler,
L.L., Kupka, R., Nolen, W.A., Leverich, G.S., Denicoff, K.D., Grunze, H., Duan, N.,
Post, R.M., 2006. Double-blind, randomized, placebo-controlled trials of ethyl-
eicosapentanoate in the treatment of bipolar depression and rapid cycling bipolar
disorder. Biol. Psychiatry 60, 1020–1022. http://dx.doi.org/10.1016/j.biopsych.
2006.03.056.
Kennedy, S.H., 2009. Agomelatine: Efficacy at each phase of antidepressant treatment.
CNS Drugs 23 (Suppl. 2), 41–47.
Kennedy, S.H., Eisfeld, B.S., 2007. Agomelatine and its therapeutic potential in the
depressed patient. Neuropsychiatr. Dis. Treat. 3, 423–428.
Kennedy, S.H., Kutcher, S.P., Ralevski, E., Brown, G.M., 1996. Nocturnal melatonin and
24-hour 6-sulphatoxymelatonin levels in various phases of bipolar affective disorder.
Psychiatry Res. 63, 219–222.
Kerestes, R., Davey, C.G., Stephanou, K., Whittle, S., Harrison, B.J., 2014. Clinical
functional brain imaging studies of youth depression: a systematic review.
NeuroImage Clin. 4, 209–231. http://dx.doi.org/10.1016/j.nicl.2013.11.009.
Kessler, R.C., Petukhova, M., Sampson, N.A., Zaslavsky, A.M., Wittchen, H.-U., 2012.
Twelve-month and lifetime prevalence and lifetime morbid risk of anxiety and mood
disorders in the United States. Int. J. Methods Psychiatr. Res. 21, 169–184.
Khaleghipour, S., Masjedi, M., Ahade, H., Enayate, M., Pasha, G., Nadery, F., Ahmadzade,
G., 2012. Morning and nocturnal serum melatonin rhythm levels in patients with
major depressive disorder: an analytical cross-sectional study. Sao Paulo Med. J. 130,
201
Progress in Neuropsychopharmacology & Biological Psychiatry 80 (2018) 189–204
167–172. http://dx.doi.org/10.1590/S1516-31802012000300006.
Kishi, T., Yoshimura, R., Kitajima, T., Okochi, T., Okumura, T., Tsunoka, T., Yamanouchi,
Y., Kinoshita, Y., Kawashima, K., Fukuo, Y., Naitoh, H., Umene-Nakano, W., Inada, T.,
Nakamura, J., Ozaki, N., Iwata, N., 2010. SIRT1 gene is associated with major
depressive disorder in the Japanese population. J. Affect. Disord. 126, 167–173.
http://dx.doi.org/10.1016/j.jad.2010.04.003.
Koesters, M., Guaiana, G., Cipriani, A., Becker, T., Barbui, C., 2013. Agomelatine efficacy
and acceptability revisited: systematic review and meta-analysis of published and
unpublished randomised trials. Br. J. Psychiatry 203, 179–187. http://dx.doi.org/10.
1192/bjp.bp.112.120196.
Kohler, O., Benros, M.E., Nordentoft, M., Farkouh, M.E., Iyengar, R.L., Mors, O., Krogh, J.,
2014. Effect of anti-inflammatory treatment on depression, depressive symptoms, and
adverse effects: a systematic review and meta-analysis of randomized clinical trials.
JAMA Psychiatry 71, 1381–1391. http://dx.doi.org/10.1001/jamapsychiatry.2014.
1611.
Kraft, A.D., Harry, G.J., 2011. Features of microglia and neuroinflammation relevant to
environmental exposure and neurotoxicity. Int. J. Environ. Res. Public Heal. 8,
2980–3018. http://dx.doi.org/10.3390/ijerph8072980.
Kripke, D., Mullaney, D., Atkinson, M., Wolf, S., 1978. Circadian rhythm disorders in
manic-depressives. Biol. Psychiatry 13, 335–351.
Kripke, D.F., Elliott, J.A., Welsh, D.K., Youngstedt, S.D., 2015. Photoperiodic and
circadian bifurcation theories of depression and mania. F1000Res. 4, 107. http://dx.
doi.org/10.12688/f1000research.6444.1.
Kripke, D.F., Nievergelt, C.M., Joo, E., Shekhtman, T., Kelsoe, J.R., 2009. Circadian
polymorphisms associated with affective disorders. J. Circadian Rhythms 7, 2. http://
dx.doi.org/10.1186/1740-3391-7-2.
Lam, R.W., Berkowitz, A.L., Berga, S.L., Clark, C.M., Kripke, D.F., Gillin, J.C., 1990.
Melatonin suppression in bipolar and unipolar mood disorders. Psychiatry Res. 33,
129–134.
Langan, J., Shajahan, P., Martin, D., Carleton, R., 2011. Agomelatine in unipolar
depression in clinical practice: a retrospective chart review. Ther. Adv.
Psychopharmacol. 1, 175–180.
Lavebratt, C., Sjöholm, L.K., Partonen, T., Schalling, M., Forsell, Y., 2010a. PER2
variantion is associated with depression vulnerability. Am. J. Med. Genet. B
Neuropsychiatr. Genet. 153, 570–581. http://dx.doi.org/10.1002/ajmg.b.31021.
Lavebratt, C., Sjöholm, L.K., Soronen, P., Paunio, T., Vawter, M.P., Bunney, W.E.,
Adolfsson, R., Forsell, Y., Wu, J.C., Kelsoe, J.R., Partonen, T., Schalling, M., 2010b.
CRY2 is associated with depression. PLoS One 5, 1–8.
Le-Niculescu, H., Patel, S.D., Bhat, M., Kuczenski, R., Faraone, S.V., Tsuang, M.T.,
McMahon, F.J., Schork, N.J., Nurnberger, J.I., Niculescu, A.B., 2009. Convergent
functional genomics of genome-wide association data for bipolar disorder:
Comprehensive identification of candidate genes, pathways and mechanisms. Am. J.
Med. Genet. B Neuropsychiatr. Genet. 150, 155–181. http://dx.doi.org/10.1002/
ajmg.b.30887.
Lee, S.Y., Lee, S.J., Han, C., Patkar, A.A., Masand, P.S., Pae, C.U., 2013. Oxidative/
nitrosative stress and antidepressants: targets for novel antidepressants. Prog. Neuro-
Psychopharmacol. Biol. Psychiatry 46, 224–235. http://dx.doi.org/10.1016/j.pnpbp.
2012.09.008.
Leheste, J.R., Torres, G., 2015. Resveratrol: brain effects on SIRT1, GPR50 and
photoperiodic signaling. Front. Mol. Neurosci. 8, 61.
Leibenluft, E., Feldman-Naim, S., Turner, E.H., Wehr, T.A., Rosenthal, N.E., 1997. Effects
of exogenous melatonin administration and withdrawal in five patients with rapid-
cycling bipolar disorder. J. Clin. Psychiatry 58, 383–388.
Lener, M.S., Iosifescu, D.V., 2015. In pursuit of neuroimaging biomarkers to guide
treatment selection in major depressive disorder: a review of the literature. Ann. N. Y.
Acad. Sci. 1344, 50–65. http://dx.doi.org/10.1111/nyas.12759.
Leppämäki, S., Partonen, T., Vakkuri, O., Lonnqvist, J., Partinen, M., Laudon, M., 2003.
Effect of controlled-release melatonin on sleep quality, mood, and quality of life in
subjects with seasonal or weather-associated changes in mood and behaviour. Eur.
Neuropsychopharmacol. 13, 137–145.
Levoye, A., Dam, J., Ayoub, M.A., Guillaume, J.L., Couturier, C., Delagrange, P., Jockers,
R., 2006. The orphan GPR50 receptor specifically inhibits MT1 melatonin receptor
function through heterodimerization. EMBO J. 25, 3012–3023.
Lewy, A.J., 2003. Clinical applications of melatonin in circadian disorders. Dialogues
Clin. Neurosci. 5, 399–413.
Lewy, A.J., Ahmed, S., Jackson, J.M., Sack, R.L., 1992. Melatonin shifts human circadian
rhythms according to a phase-response curve. Chronobiol. Int. 9, 380–392.
Lewy, A.J., Bauer, V.K., Cutler, N.L., Sack, R.L., 1998. Melatonin treatment of winter
depression: a pilot study. Psychiatry Res. 77, 57–61.
Lewy, A.J., Emens, J., Jackman, A., Yuhas, K., 2006. Circadian uses of melatonin in
humans. Chronobiol. Int. 23, 403–412.
Lewy, A.J., Emens, J., Songer, J.B., Sims, N., Laurie, A.L., Fiala, S.C., Buti, A.L., 2009.
Winter depression: integrating mood, circadian rhythms, and the sleep/wake and
light/dark cycles into a bio-psycho-social-environmental model. Sleep Med. Clin. 4,
285–299.
Lewy, A.J., Emens, J.S., Lefler, B.J., Yuhas, K., Jackman, A.R., 2005. Melatonin entrains
free-running blind people according to a physiological dose-response curve.
Chronobiol. Int. 22, 1093–1106.
Lewy, A.J., Emens, J.S., Sack, R.L., Hasler, B.P., Bernert, R.A., 2002. Low, but not high,
doses of melatonin entrained a free-running blind person with a long circadian
period. Chronobiol. Int. 19, 649–658.
Lewy, A.J., Nurnberger Jr., J.I., Wehr, T.A., Pack, D., Becker, L.E., Powell, R.L., Newsome,
D.A., 1985. Supersensitivity to light: possible trait marker for manic-depressive
illness. Am. J. Psychiatry 142, 725–727.
Lewy, A.J., Sack, R.L., 1989. The dim light melatonin onset as a marker for circadian
phase position. Chronobiol. Int. 6, 93–102.
G.M. Brown et al.
Li, J.Z., Bunney, B.G., Meng, F., Hagenauer, M.H., Walsh, D.M., Vawter, M.P., 2013.
Circadian patterns of gene expression in the human brain and disruption in major
depressive disorder. PNAS 110, 9950–9955. http://dx.doi.org/10.1073/pnas.
1305814110/-/DCSupplemental.www.pnas.org/cgi/doi/10.1073/pnas.
1305814110.
Liao, Y., Huang, X., Wu, Q., Yang, C., Kuang, W., Du, M., Lui, S., Yue, Q., Chan, R., Kemp,
G., Gong, Q., 2013. Is depression a disconnection syndrome? Meta- analysis of
diffusion tensor imaging studies in patients with MDD. J. Psychiatry Neurosci. 38,
49–56. http://dx.doi.org/10.1503/jpn.110180.
Lindqvist, D., Mueller, S., Mellon, S.H., Su, Y., Epel, E.S., Reus, V.I., Rosser, R., Mahan, L.,
Scott Mackin, R., Yang, T.T., Wolkowitz, O.M., 2014. Peripheral antioxidant markers
are associated with total hippocampal and CA3/dentate gyrus volume in MDD and
healthy controls-preliminary findings. Psychiatry Res. Neuroimaging 224, 168–174.
http://dx.doi.org/10.1016/j.pscychresns.2014.09.002.
Liu, C., Chung, M., 2015. Genetics and epigenetics of circadian rhythms and their
potential roles in neuropsychiatric disorders. Neurosci. Bull. 31, 141–159. http://dx.
doi.org/10.1007/s12264-014-1495-3.
Liu, H.C., Yang, Y.Y., Chou, Y.M., Chen, K.P., Shen, W.W., Leu, S.J., 2004. Immunologic
variables in acute mania of bipolar disorder. J. Neuroimmunol. 150, 116–122. http://
dx.doi.org/10.1016/j.jneuroim.2004.01.006.
Liu, Y., Ho, R.C., Mak, A., 2012. Interleukin (IL)-6, tumour necrosis factor alpha (TNF-
alpha) and soluble interleukin-2 receptors (sIL-2R) are elevated in patients with
major depressive disorder: A meta-analysis and meta-regression. J. Affect. Disord.
139, 230–239. http://dx.doi.org/10.1016/j.jad.2011.08.003.
Lockley, S.W., Arendt, J., Skene, D.J., 2007. Visual impairment and circadian rhythm
disorders. Dialogues Clin. Neurosci. 9, 301–314.
Lockley, S.W., Skene, D.J., James, K., Thapan, K., Wright, J., Arendt, J., 2000. Melatonin
administration can entrain the free-running circadian system of blind subjects. J.
Endocrinol. 164, R1–R6.
Lopresti, A.L., Drummond, P.D., 2017. Efficacy of curcumin, and a saffron/curcumin
combination for the treatment of major depression: a randomised, double-blind,
placebo-controlled study. J. Affect. Disord. 207, 188–196. http://dx.doi.org/10.
1016/j.jad.2016.09.047.
Lopresti, A.L., Maes, M., Maker, G.L., Hood, S.D., Drummond, P.D., 2014. Curcumin for
the treatment of major depression: a randomised, double-blind, placebo controlled
study. J. Affect. Disord. 167, 368–375. http://dx.doi.org/10.1016/j.jad.2014.06.001.
Louveau, A., Smirnov, I., Keyes, T.J., Eccles, J.D., Rouhani, S.J., Peske, J.D., Derecki,
N.C., Castle, D., Mandell, J.W., Lee, K.S., Harris, T.H., Kipnis, J., 2015. Structural and
functional features of central nervous system lymphatic vessels. Nature 523,
337–341. http://dx.doi.org/10.1038/nature14432.
Lowrey, P.L., Takahashi, J.S., 2004. Mammalian circadian biology: elucidating genome-
wide levels of temporal organization. Annu. Rev. Genomics Hum. Genet. 5, 407–441.
http://dx.doi.org/10.1146/annurev.genom.5.061903.175925.
Macintyre, D.J., McGhee, K.A., Maclean, A.W., Afzal, M., Briffa, K., Henry, B., Thomson,
P.A., Muir, W.J., Blackwood, D.H., 2010. Association of GPR50, an X-linked orphan G
protein-coupled receptor, and affective disorder in an independent sample of the
Scottish population. Neurosci. Lett. 475, 169–173. http://dx.doi.org/10.1016/j.
neulet.2010.03.072.
MacIsaac, S.E., Carvalho, A.F., Cha, D.S., Mansur, R.B., McIntyre, R.S., 2014. The
mechanism, efficacy, and tolerability profile of agomelatine. Expert Opin.
Pharmacother. 15, 259–274. http://dx.doi.org/10.1517/14656566.2014.862233.
Maestroni, G.J.M., Cardinali, D.P., Esquifino, A.I., Pandi-Perumal, S.R., 2005. Does
melatonin play a disease-promoting role in rheumatoid arthritis? J. Neuroimmunol.
158, 106–111.
Malykhin, N.V., Coupland, N.J., 2015. Hippocampal neuroplasticity in major depressive
disorder. Neuroscience 309, 200–213. http://dx.doi.org/10.1016/j.neuroscience.
2015.04.047.
Mansour, H.A., Wood, J., Logue, T., Chowdari, K.V., Dayal, M., Kupfer, D.J., Monk, T.H.,
Devlin, B., Nimgaonkar, V.L., 2006. Association study of eight circadian genes with
bipolar I disorder, schizoaffective disorder and schizophrenia. Genes. Brain. Behav. 5,
150–157. http://dx.doi.org/10.1111/j.1601-183X.2005.00147.x.
Martinotti, G., Sepede, G., Gambi, F., Di Iorio, G., De Berardis, D., Di Nicola, M., Onofrj,
M., Janiri, L., Di Giannantonio, M., 2012. Agomelatine versus venlafaxine XR in the
treatment of anhedonia in major depressive disorder: a pilot study. J. Clin.
Psychopharmacol. 32, 487–491. http://dx.doi.org/10.1097/JCP.
0b013e31825d6c25.
Martynhak, B.J., Pereira, M., de Souza, C.P., Andreatini, R., 2015. Stretch, shrink, and
shatter the rhythms: the intrinsic circadian period in mania and depression. CNS
Neurol. Disord. Drug Targets 14, 963–969.
Maurya, P.K., Noto, C., Rizzo, L.B., Rios, A.C., Nunes, S.O.V., Barbosa, D.S., Sethi, S., Zeni,
M., Mansur, R.B., Maes, M., Brietzke, E., 2016. The role of oxidative and nitrosative
stress in accelerated aging and major depressive disorder. Prog. Neuro-
Psychopharmacol. Biol. Psychiatry 65, 134–144. http://dx.doi.org/10.1016/j.pnpbp.
2015.08.016.
McClung, C.A., 2013. How might circadian rhythms control mood? Let me count the
ways. Biol. Psychiatry 74, 242–249. http://dx.doi.org/10.1016/j.biopsych.2013.02.
019.
McIntyre, R.S., Cha, D.S., Soczynska, J.K., Woldeyohannes, H.O., Gallaugher, L.A.,
Kudlow, P., Alsuwaidan, M., Baskaran, A., 2013. Cognitive deficits and functional
outcomes in major depressive disorder: determinants, substrates, and treatment
interventions. Depress. Anxiety 30, 515–527. http://dx.doi.org/10.1002/da.22063.
McIntyre, R.S., Lee, Y., 2016. Cognition in major depressive disorder: a “Systemically
Important Functional Index” (SIFI). Curr. Opin. Psychiatry 29, 48–55. http://dx.doi.
org/10.1097/YCO.0000000000000221.
McIntyre, R.S., Soczynska, J.Z., Woldeyohannes, H.O., Alsuwaidan, M.T., Cha, D.S.,
Carvalho, A.F., Jerrell, J.M., Dale, R.M., Gallaugher, L.A., Muzina, D.J., Kennedy,
202
Progress in Neuropsychopharmacology & Biological Psychiatry 80 (2018) 189–204
S.H., 2015a. The impact of cognitive impairment on perceived workforce
performance: results from the international mood disorders collaborative project.
Compr. Psychiatry 56, 279–282. http://dx.doi.org/10.1016/j.comppsych.2014.08.
051.
McIntyre, R.S., Xiao, H.X., Syeda, K., Vinberg, M., Carvalho, A.F., Mansur, R.B.,
Maruschak, N., Cha, D.S., 2015b. The prevalence, measurement, and treatment of the
cognitive dimension/domain in major depressive disorder. CNS Drugs 29, 577–589.
http://dx.doi.org/10.1007/s40263-015-0263-x.
McNamara, R.K., Lotrich, F.E., 2012. Elevated immune-inflammatory signaling in mood
disorders: A new therapeutic target? Expert. Rev. Neurother. 12, 1143–1161. http://
dx.doi.org/10.1586/ern.12.98.
Meesters, Y., Dekker, V., Schlangen, L.J.M., Bos, E.H., Ruiter, M.J., 2011. Low-intensity
blue-enriched white light (750 lux) and standard bright light (10,000 lux) are equally
effective in treating SAD. A randomized controlled study. BMC Psychiatry 11, 17.
Meesters, Y., Winthorst, W.H., Duijzer, W.B., Hommes, V., 2016. The effects of low-
intensity narrow-band blue-light treatment compared to bright white-light treatment
in sub-syndromal seasonal affective disorder. BMC Psychiatry 16, 27.
Millan, M.J., Gobert, A., Lejeune, F., Dekeyne, A., Newman-Tancredi, A., Pasteau, V.,
Rivet, J.M., Cussac, D., 2003. The novel melatonin agonist agomelatine (S20098) is
an antagonist at 5-hydroxytryptamine2C receptors, blockade of which enhances the
activity of frontocortical dopaminergic and adrenergic pathways. J. Pharmacol. Exp.
Ther. 306, 954–964.
Miller, A.H., Maletic, V., Raison, C.L., 2009. Inflammation and its discontents: the role of
cytokines in the pathophysiology of major depression. Biol. Psychiatry 65, 732–741.
http://dx.doi.org/10.1016/j.biopsych.2008.11.029.
Mishima, K., Tozawa, T., Satoh, K., Matsumoto, Y., Hishikawa, Y., Okawa, M., 1999.
Melatonin secretion rhythm disorders in patients with senile dementia of Alzheimer's
type with disturbed sleep-waking. Biol. Psychiatry 45, 417–421.
Modabbernia, A., Taslimi, S., Brietzke, E., Ashrafi, M., 2013. Cytokine alterations in
bipolar disorder: a meta-analysis of 30 studies. Biol. Psychiatry 24, 15–25. http://dx.
doi.org/10.1016/j.biopsych.2013.01.007.
Montastruc, F., Scotto, S., Vaz, I.R., Guerra, L.N., Escudero, A., Sainz, M., Falomir, T.,
Bagheri, H., Herdeiro, M.T., Venegoni, M., Montastruc, J.L., Carvajal, A., Sáinz, M.,
Falomir, T., Bagheri, H., Herdeiro, M.T., Venegoni, M., Montastruc, J.L., Carvajal, A.,
2014. Hepatotoxicity related to agomelatine and other new antidepressants: a case/
noncase approach with information from the Portuguese, French, Spanish, and Italian
pharmacovigilance systems. J. Clin. Psychopharmacol. 34, 327–330. http://dx.doi.
org/10.1097/JCP.0000000000000094.
Moreira, J., Geoffroy, P.A., 2016. Lithium and bipolar disorder: impacts from molecular
to behavioural circadian rhythms. Chronobiol. Int. 33, 35–373.
Moylan, S., Berk, M., Dean, O.M., Samuni, Y., Williams, L.J., O'Neil, A., Hayley, A.C.,
Pasco, J.A., Anderson, G., Jacka, F.N., Maes, M., 2014. Oxidative & nitrosative stress
in depression: why so much stress? Neurosci. Biobehav. Rev. 45, 46–62. http://dx.
doi.org/10.1016/j.neubiorev.2014.05.007.
Munkholm, K., Brauner, J.V., Kessing, L.V., Vinberg, M., 2013a. Cytokines in bipolar
disorder vs. healthy control subjects: a systematic review and meta-analysis. J.
Psychiatr. Res. 47, 1119–1133. http://dx.doi.org/10.1016/j.jpsychires.2013.05.018.
Munkholm, K., Vinberg, M., Kessing, L.V., 2013b. Cytokines in bipolar disorder: a
systematic review and meta-analysis. J. Affect. Disord. 144, 16–27. http://dx.doi.
org/10.1016/j.jad.2012.06.010.
Munkholm, K., Weikop, P., Kessing, L.V., Vinberg, M., 2015. Elevated levels of IL-6 and
IL-18 in manic and hypomanic states in rapid cycling bipolar disorder patients. Brain
Behav. Immun. 43, 205–213. http://dx.doi.org/10.1016/j.bbi.2014.09.021.
Murphy, M.L., Frodl, T., 2011. Meta-analysis of diffusion tensor imaging studies shows
altered fractional anisotropy occurring in distinct brain areas in association with
depression. Biol. Mood Anxiety Disord. 1, 3.
Naismith, S.L., Hermens, D.F., Ip, T.K.C., Bolitho, S., Scott, E., Rogers, N.L., Hickie, I.B.,
2012. Circadian profiles in young people during the early stages of affective disorder.
Transl. Psychiatry 2, e123. http://dx.doi.org/10.1038/tp.2012.47.
Nakahata, Y., Kaluzova, M., Grimaldi, B., Sahar, S., Hirayama, J., Chen, D., Guarente,
L.P., Sassone-Corsi, P., 2008. The NAD+-dependent deacetylase SIRT1 modulates
CLOCK-mediated chromatin remodeling and circadian control. Cell 134, 329–340.
Nathan, P.J., Burrows, G.D., Norman, T.R., 1999. Melatonin sensitivity to dim white light
in affective disorders. Neuropsychopharmacology 21, 408–413.
Nechita, F., Pirlog, M.-C., Chiriţă, A.L., 2015. Circadian malfunctions in depression -
neurobiological and psychosocial approaches. [review]. Romanian J. Morphol.
Embryol. 56, 949–955.
Nemeroff, C.B., Weinberger, D., Rutter, M., MacMillan, H.L., Bryant, R.A., Wessely, S.,
Stein, D.J., Pariante, C.M., Seemüller, F., Berk, M., Malhi, S., Preisig, M., Brüne, M.,
Lysaker, P., 2013. Forum. Current controversires in psychiatry: DSM-5: a collection of
psychiatrist views on the changes, controversies, and future directions. BMC Med. 11,
1–19.
Nicolaides, N.C., Charmandari, E., Chrousos, G.P., Kino, T., 2014. Circadian endocrine
rhythms: The hypothalamic-pituitary-adrenal axis and its actions. Ann. N. Y. Acad.
Sci. 1318, 71–80. http://dx.doi.org/10.1111/nyas.12464.
Nievergelt, C.M., Kripke, D.F., Barrett, T.B., Burg, E., Remick, R.A., Sadovnick, A.D.,
McElroy, S.L., Keck Jr., P.E., Schork, N.J., Kelsoe, J.R., 2006. Suggestive evidence for
association of the circadian genes PERIOD3 and ARNTL with bipolar disorder. Am. J.
Med. Genet. B Neuropsychiatr. Genet. 141B, 234–241. http://dx.doi.org/10.1002/
ajmg.b.30252.
Nussbaumer, B., Kaminski-Hartenthaler, A., Forneris, C.A., Morgan, L.C., Sonis, J.H.,
Gaynes, B.N., Greenblatt, A., Wipplinger, J., Lux, L.J., Winkler, D., Van Noord, M.G.,
Hofmann, J., Gartiehner, G., 2015. Light therapy for preventing seasonal affective
disorder. Cochrane Database Syst. Rev. 11.
O'Connor, S., Agius, M., 2015. A systematic review of structural and functional MRI
differences between psychotic and nonpsychotic depression. Psychiatr. Danub. 27,
G.M. Brown et al.
S235–S239. http://dx.doi.org/10.1016/S0924-9338(14)78463-9.
Oldham, M.A., Ciraulo, D.A., 2014. Bright light therapy for depression: a review of its
effects on chronobiology and the autonomic nervous system. Chronobiol. Int. 31,
305–319.
Owen, R.T., 2009. Agomelatine: a novel pharmacological approach to treating
depression. Drugs Today (Barc) 45, 599–608.
Pace, T.W., Miller, A.H., 2009. Cytokines and glucocorticoid receptor signaling.
Relevance to major depression. Ann. N. Y. Acad. Sci. 1179, 86–105. http://dx.doi.
org/10.1111/j.1749-6632.2009.04984.x.
Pail, G., Huf, W., Pjrek, E., Winkler, D., Willeit, M., Praschak-Rieder, N., Kasper, S., 2011.
Bright-light therapy in the treatment of mood disorders. Neuropsychobiology 64,
152–162.
Palta, P., Samuel, L.J., Miller 3rd, E.R., Szanton, S.L., 2014. Depression and oxidative
stress: results from a meta-analysis of observational studies. Psychosom. Med. 76,
12–19. http://dx.doi.org/10.1097/PSY.0000000000000009.
Pandi-Perumal, S.R., Trakht, I., Srinivasan, V., Spence, D.W., Poeggeler, B., Hardeland, R.,
Cardinali, D.P., 2009. The effect of melatonergic and non-melatonergic
antidepressants on sleep: weighing the alternatives. World J. Biol. Psychiatry 10,
342–354.
Papakostas, G.I., Shelton, R.C., Henry, M.E., Bilello, J.A., 2015. Letters to the Editor. J.
Clin. Psychiatry 76, e1038. http://dx.doi.org/10.1176/appi.ajp.2015.15060750.
Partonen, T., 2014. Circadian clock proteins in mood regulation. Front. Psychiatry 5, 195.
Partonen, T., Treutlein, J., Alpman, A., Frank, J., Johansson, C., Depner, M., Aron, L.,
Rietschel, M., Wellek, S., Soronen, P., Paunio, T., Koch, A., Chen, P., Lathrop, M.,
Adolfsson, R., Persson, M.L., Kasper, S., Schalling, M., Peltonen, L., Schumann, G.,
2007. Three circadian clock genes Per2, Arntl, and Npas2 contribute to winter
depression. Ann. Med. 39, 229–238.
Penders, T.M., Stanciu, C.N., Schoemann, A.M., Ninan, P.T., Bloch, R., Saeed, S.A., 2016.
Bright light therapy as augmentation of pharmacotherapy for treatment of
depression: a systematic review and meta-analysis. Prim. Care Companion CNS
Disord. 18. http://dx.doi.org/10.4088/PCC.15r01906.
Prasko, J., 2008. Bright light therapy. Neuroendocrinol. Lett. 29, 33–64.
Price, J.L., Drevets, W.C., 2012. Neural circuits underlying the pathophysiology of mood
disorders. Trends Cogn. Sci. 16, 61–71. http://dx.doi.org/10.1016/j.tics.2011.12.
011.
Price, J.L., Drevets, W.C., 2010. Neurocircuitry of mood disorders.
Neuropsychopharmacology 35, 192–216. http://dx.doi.org/10.1038/npp.2009.104.
Qin, J., Shen, H., Zeng, L.-L., Jiang, W., Liu, L., Hu, D., 2015. Predicting clinical responses
in major depression using intrinsic functional connectivity. Neuroreport 26, 675–680.
http://dx.doi.org/10.1097/WNR.0000000000000407.
Racagni, G., Riva, M.A., Molteni, R., Musazzi, L., Calabrese, F., Popoli, M., Tardito, D.,
2011. Mode of action of agomelatine: synergy between melatonergic and 5-HT2C
receptors. World J. Biol. Psychiatry 12, 574–587. http://dx.doi.org/10.3109/
15622975.2011.595823.
Rahman, S.A., Shapiro, C.M., Wang, F., Ainlay, H., Kazmi, S., Brown, T.J., Casper, R.F.,
2013. Effects of filtering visual short wavelengths during nocturnal shiftwork on sleep
and performance. Chronobiol. Int. 30, 951–962. http://dx.doi.org/10.3109/
07420528.2013.789894.
Raison, C.L., Rutherford, R.E., Woolwine, B.J., Shuo, C., Schettler, P., Drake, D.F.,
Haroon, E., Miller, A.H., 2013. A randomized controlled trial of the tumor necrosis
factor antagonist infliximab for treatment-resistant depression: the role of baseline
inflammatory biomarkers. JAMA Psychiatry 70, 31–41. http://dx.doi.org/10.1001/
2013.jamapsychiatry.4.
Rajendran, B., Janakarajan, V.N., 2016. Circadian clock gene aryl hydrocarbon receptor
nuclear translocator-like polymorphisms are associated with seasonal affective
disorder: an Indian family study. Indian J. Psychiatry 58, 57–60.
Rao, J.S., Harry, G.J., Rapoport, S.I., Kim, H.W., 2010. Increased excitotoxicity and
neuroinflammatory markers in postmortem frontal cortex from bipolar disorder
patients. Mol. Psychiatry 15, 384–392. http://dx.doi.org/10.1038/mp.2009.47.
Rapaport, M.H., Nierenberg, A.A., Schettler, P.J., Kinkead, B., Cardoos, A., Walker, R.,
Mischoulon, D., 2016. Inflammation as a predictive biomarker for response to omega-
3 fatty acids in major depressive disorder: a proof-of-concept study. Mol. Psychiatry
21, 71–79. http://dx.doi.org/10.1038/mp.2015.22.
Rastad, C., Ulfberg, J., Lindberg, P., 2011. Improvement in fatigue, sleepiness, and health-
related quality of life with bright light treatment in persons with seasonal affective
disorder and subsyndromal SAD. Depress. Res. Treat. http://dx.doi.org/10.1155/
2011/543906.
Robertson, J.M., Tanguay, P.E., 1997. Case study: the use of melatonin in a boy with
refractory bipolar disorder. J. Am. Acad. Child Adolesc. Psychiatry 36, 822–825.
Rock, P.L., Roiser, J.P., Riedel, W.J., Blackwell, A.D., 2014. Cognitive impairment in
depression: a systematic review and meta-analysis. Psychol. Med. 44, 2029–2040.
http://dx.doi.org/10.1017/S0033291713002535.
Roiser, J.P., Sahakian, B.J., 2013. Hot and cold cognition in depression. CNS Spectr. 18,
139–149. http://dx.doi.org/10.1017/S1092852913000072.
Rosenblat, J.D., Brietzke, E., Mansur, R.B., Maruschak, N.A., Lee, Y., McIntyre, R.S., 2015.
Inflammation as a neurobiological substrate of cognitive impairment in bipolar
disorder: evidence, pathophysiology and treatment implications. J. Affect. Disord.
188, 149–159. http://dx.doi.org/10.1016/j.jad.2015.08.058.
Rosenblat, J.D., Cha, D.S., Mansur, R.B., McIntyre, R.S., 2014. Inflamed moods: a review
of the interactions between inflammation and mood disorders. Prog. Neuro-
Psychopharmacol. Biol. Psychiatry 53, 23–34. http://dx.doi.org/10.1016/j.pnpbp.
2014.01.013.
Rosenblat, J.D., Gregory, J.M., McIntyre, R.S., 2016. Pharmacologic implications of
inflammatory comorbidity in bipolar disorder. Curr. Opin. Pharmacol. 29, 63–69.
http://dx.doi.org/10.1016/j.coph.2016.06.007.
Rosenblat, J.D., McIntyre, R.S., 2016. Bipolar disorder and inflammation. Psychiatr. Clin.
203
Progress in Neuropsychopharmacology & Biological Psychiatry 80 (2018) 189–204
N. Am. 39, 125–137. http://dx.doi.org/10.1016/j.psc.2015.09.006.
Rothschild, A.J., 2015. A blood test for depression? J. Clin. Psychiatry 76, e218–e219.
http://dx.doi.org/10.4088/JCP.14com09515.
Rubin, R.T., Heist, E.K., McGeoy, S.S., Hanada, K., Lesser, I.M., 1992. Neuroendocrine
aspects of primary endogenous depression. XI. Serum melatonin measures in patients
and matched control subjects. Arch. Gen. Psychiatry 49, 558–567.
Sachar, E.J., Hellman, L., Roffwarg, H.P., Halpern, F.S., Fukushima, D.K., Gallagher, T.F.,
1973. Disrupted 24-hour patterns of cortisol secretion in psychotic depression. Arch.
Gen. Psychiatry 28, 19–24.
Sanmukhani, J., Satodia, V., Trivedi, J., Patel, T., Tiwari, D., Panchal, B., Goel, A.,
Tripathi, C.B., 2014. Efficacy and safety of curcumin in major depressive disorder: a
randomized controlled trial. Phytother. Res. 28, 579–585. http://dx.doi.org/10.
1002/ptr.5025.
Sarris, J., Mischoulon, D., Schweitzer, I., 2012. Omega-3 for bipolar disorder: meta-
analyses of use in mania and bipolar depression. J. Clin. Psychiatry 73, 81–86. http://
dx.doi.org/10.4088/JCP.10r06710.
Sasseville, A., Benhaberou-Brun, D., Fontaine, C., Charon, M.-C., Hebert, M., 2009.
Wearing blue-blockers in the morning could improve sleep of workers on a
permanent night schedule: a pilot study. Chronobiol. Int. 26, 913–925. http://dx.doi.
org/10.1080/07420520903044398.
Sasseville, A., Hébert, M., 2010. Using blue-green light at night and blue-blockers during
the day to improves adaptation to night work: a pilot study. Prog.
Neuropsychopharmacol. Biol. Psychiatry 34, 1236–1242. http://dx.doi.org/10.1016/
j.pnpbp.2010.06.027.
Sasseville, A., Paquet, N., Sévigny, J., Hébert, M., 2006. Blue blocker glasses impede the
capacity of bright light to suppress melatonin production. J. Pineal Res. 41, 73–78.
http://dx.doi.org/10.1111/j.1600-079X.2006.00332.x.
Saus, E., Soria, V., Escaramís, G., Vivarelli, F., Crespo, J.M., Kagerbauer, B., Menchòn,
J.M., Urretavizcaya, M., Gratacòs, M., Estivill, X., 2010. Genetic variants and
abnormal processing of pre-miR-182, a circadian clock modulator, in major
depression patients with late insomnia. Hum. Mol. Genet. 19, 4017–4025. http://dx.
doi.org/10.1093/hmg/ddq316.
Saxvig, I.W., Wilhelmsen-Langeland, A., Pallesen, S., Vedaa, Ø., Nordhus, I.-H., Bjorvatn,
B., 2014. A randomized controlled trial with bright light and melatonin for delayed
sleep phase disorder: effects on subjective and objective sleep. Chronobiol. Int. 31,
72–86.
Schnell, A., Albrecht, U., Sandrelli, F., 2014. Rhythm and mood: relationships between
the circadian clock and mood-related behavior. Behav. Neurosci. 128, 326–343.
http://dx.doi.org/10.1037/a0035883.
Schwartz, R.S., Olds, J., 2015. The psychiatry of light. Harv. Rev. Psychiatry 23, 188–194.
Serfaty, M.A., Osborne, D., Buszewicz, M.J., Blizard, R., Raven, P.W., 2010. A randomized
double-blind placebo-controlled trial of treatment as usual plus exogenous slow-
release melatonin (6 mg) or placebo for sleep disturbance and depressed mood. Int.
Clin. Psychopharmacol. 25, 132–142.
Setiawan, E., Wilson, A.A., Mizrahi, R., Rusjan, P.M., Miler, L., Rajkowska, G., Suridjan, I.,
Kennedy, J.L., Rekkas, P.V., Houle, S., Meyer, J.H., 2015. Role of translocator protein
density, a marker of neuroinflammation, in the brain during major depressive
episodes. JAMA Psychiatry 72, 268–275. http://dx.doi.org/10.1001/jamapsychiatry.
2014.2427.
Sexton, C.E., Mackay, C.E., Ebmeier, K.P., 2009. A systematic review of diffusion tensor
imaging studies in affective disorders. Biol. Psychiatry 66, 814–823. http://dx.doi.
org/10.1016/j.biopsych.2009.05.024.
Sexton, C.E., MacKay, C.E., Ebmeier, K.P., 2013. A systematic review and meta-analysis of
magnetic resonance imaging studies in late-life depression. Am. J. Geriatr. Psychiatry
21, 184–195. http://dx.doi.org/10.1016/j.jagp.2012.10.019.
Shearman, L.P., Sriram, S., Weaver, D.R., Maywood, E.S., Chaves, I., Zheng, B., Kume, K.,
Lee, C.C., van der Horst, G.T., Hastings, M.H., Reppert, S.M., 2000. Interacting
molecular loops in the mammalian circadian clock. Science 288, 1013–1019. http://
dx.doi.org/10.1126/science.288.5468.1013.
Shi, S.Q., White, M.J., Borsetti, H.M., Pendergast, J.S., Hida, A., Ciarleglio, C.M., de
Verteuil, P.A., Cadar, A.G., Cala, C., McMahon, D.G., Shelton, R.C., Williams, S.M.,
Johnson, C.H., 2016. Molecular analyses of circadian gene variants reveal sex-
dependent links between depression and clocks. Transl. Psychiatry 6, e748. http://dx.
doi.org/10.1038/tp.2016.9.
Singer, C., Tractenberg, R.E., Kaye, J., Schafer, K., Gamst, A., Grundman, M., Thomas, R.,
Thal, L.J., 2003. A multicenter, placebo-controlled trial of melatonin for sleep
disturbance in Alzheimer's disease. Sleep 26, 893–901.
Singh, S.P., Singh, V., Kar, N., 2012. Efficacy of agomelatine in major depressive disorder:
meta-analysis and appraisal. Int. J. Neuropsychopharmacol. 15, 417–428.
Sjöholm, L.K., Backlund, L., Cheteh, E.H., Ek, I.R., Frisén, L., Schalling, M., Ösby, U.,
Lavebratt, C., Nikamo, P., 2010. CRY2 is associated with rapid cycling in bipolar
disorderpatients. PLoS One 5, 1–6. http://dx.doi.org/10.1371/journal.pone.
0012632.
Skene, D.J., 2003. Optimization of light and melatonin to phase-shift human circadian
rhythms. J. Neuroendocrinol. 15, 438–441.
Skene, D.J., Deacon, S., Arendt, J., 1996. Use of melatonin in circadian rhythm disorders
and following phase shifts. Acta Neurobiol. Exp. (Wars) 56, 359–362.
Smith, M.R., Eastman, C.I., 2009. Phase delaying the human circadian clock with blue-
enriched polychromatic light. Chronobiol. Int. 26, 709–725. http://dx.doi.org/10.
1080/07420520902927742.
Smith, M.R., Revell, V.L., Eastman, C.I., 2009. Phase advancing the human circadian
clock with blue-enriched polychromatic light. Sleep Med. 10, 287–294.
Soria, V., Martinez-Amoros, E., Escaramis, G., Valero, J., Crespo, J.M., Gutierrez-Zotes,
A., Bayes, M., Martorell, L., Vilella, E., Estivill, X., Menchon, J.M., Gratacos, M.,
Urretavizcaya, M., 2010a. Resequencing and association analysis of arylalkylamine
N-acetyltransferase (AANAT) gene and its contribution to major depression
G.M. Brown et al.
susceptibility. J. Pineal Res. 49, 35–44. http://dx.doi.org/10.1111/j.1600-079X.
2010.00763.x.
Soria, V., Martínez-Amorós, E., Escaramís, G., Valero, J., Pérez-Egea, R., García, C.,
Gutiérrez-Zotes, A., Puigdemont, D., Bayés, M., Crespo, J.M., Martorell, L., Vilella, E.,
Labad, A., Vallejo, J., Pérez, V., Menchón, J.M., Estivill, X., Gratacòs, M.,
Urretavizcaya, M., 2010b. Differential association of circadian genes with mood
disorders: CRY1 and NPAS2 are associated with unipolar major depression and
CLOCK and VIP with bipolar disorder. Neuropsychopharmacology 35, 1279–1289.
http://dx.doi.org/10.1038/npp.2009.230.
Soria, V., Urretavizcaya, M., 2009. Circadian rhythms and depression. Actas Españolas
Psiquiatr. 37, 222–232.
Souetre, E., Salvati, E., Belugou, J.L., Pringuey, D., Candito, M., Krebs, B., Ardisson, J.L.,
Darcourt, G., Souêtre, E., Salvati, E., Belugou, J.L., Pringuey, D., Candito, M., Krebs,
B., Ardisson, J.L., Darcourt, G., 1989. Circadian rhythms in depression and recovery:
evidence for blunted amplitude as the main chronobiological abnormality. Psychiatry
Res. 28, 263–278. http://dx.doi.org/10.1016/0165-1781(89)90207-2.
Srinivasan, V., Pandi-Perumal, S.R., Cardinali, D.P., Poeggeler, B., Hardeland, R., 2006.
Melatonin in Alzheimer's disease and other neurodegenerative disorders. Behav.
Brain Funct. 2, 15.
Srinivasan, V., Pandi-Perumal, S.R., Trahkt, I., Spence, D.W., Poeggeler, B.H., Hardeland,
R., Cardinali, D.P., 2009a. Melatonin and melatonergic drugs on sleep: possible
mechanisms of action. Int. J. Neurosci. 119, 821–846.
Srinivasan, V., Pandi-Perumal, S.R., Trakht, I., Spence, D.W., Hardeland, R., Poeggeler, B.,
Cardinali, D.P., 2009b. Pathophysiology of depression: role of sleep and the
melatonergic system. Psychiatry Res. 165, 201–214.
Stertz, L., Magalhaes, P.V., Kapczinski, F., 2013. Is bipolar disorder an inflammatory
condition? The relevance of microglial activation. Curr. Opin. Psychiatry 26, 19–26.
http://dx.doi.org/10.1097/YCO.0b013e32835aa4b4.
Stewart, J.W., Halbreich, U., 1989. Plasma melatonin levels in depressed patients before
and after treatment with antidepressant medication. Biol. Psychiatry 25, 33–38.
Stratmann, M., Konrad, C., Kugel, H., Krug, A., Schöning, S., Ohrmann, P., Uhlmann, C.,
Postert, C., Suslow, T., Heindel, W., Arolt, V., Kircher, T., Dannlowski, U., 2014.
Insular and hippocampal gray matter volume reductions in patients with major
depressive disorder. PLoS One 9. http://dx.doi.org/10.1371/journal.pone.0102692.
Suzuki, M., Dallaspezia, S., Locatelli, C., Uchiyama, M., Colombo, C., Benedetti, F., 2016.
Discrepancy between subjective and objective severity as a predictor of response to
chronotherapeutics in bipolar depression. J. Affect. Disord. 204, 48–53.
Swardfager, W., Rosenblat, J.D., Benlamri, M., McIntyre, R.S., 2016. Mapping
inflammation onto mood: inflammatory mediators of anhedonia. Neurosci. Biobehav.
Rev. 64, 148–166. http://dx.doi.org/10.1016/j.neubiorev.2016.02.017.
Taylor, D., Sparshatt, A., Varma, S., Olofinjana, O., 2014. Antidepressant efficacy of
agomelatine: meta-analysis of published and unpublished studies. BMJ 348, g1888.
http://dx.doi.org/10.1136/bmj.g1888.
Terman, M., Terman, J.S., 2006. Controlled trial of naturalistic dawn simulation and
negative air ionization for seasonal affective disorder. Am. J. Psychiatry 163,
2126–2133.
Thompson, C., Franey, C., Arendt, J., Checkley, S.A., 1988. A comparison of melatonin
secretion in depressed patients and normal subjects. Br. J. Psychiatry 152, 260–265.
Thomson, P.A., Wray, N.R., Thomson, A.M., Dunbar, D.R., Grassie, M.A., Condie, A.,
Walker, M.T., Smith, D.J., Pulford, D.J., Muir, W., Blackwood, D.H., Porteous, D.J.,
2005. Sex-specific association between bipolar affective disorder in women and
GPR50, an X-linked orphan G protein-coupled receptor. Mol. Psychiatry 10, 470–478.
Turnbull, A.V., Rivier, C.L., 1999. Regulation of the hypothalamic-pituitary-adrenal axis
by cytokines: actions and mechanisms of action. Physiol. Rev. 79, 1–71.
Tuunainen, A., Kripke, D.F., Endo, T., 2004. Light therapy for non-seasonal depression.
204
Progress in Neuropsychopharmacology & Biological Psychiatry 80 (2018) 189–204
Cochrane Database Syst. Rev, CD004050. http://dx.doi.org/10.1002/14651858.
CD004050.pub2.
Tymofiyeva, O., Connolly, C.G., Ho, T.C., Sacchet, M.D., Henje Blom, E., LeWinn, K.Z.,
Xu, D., Yang, T.T., 2017. DTI-based connectome analysis of adolescents with major
depressive disorder reveals hypoconnectivity of the right caudate. J. Affect. Disord.
207, 18–25. http://dx.doi.org/10.1016/j.jad.2016.09.013.
Uher, R., Payne, J.L., Pavlova, B., Perlis, R.H., 2014. Major depressive disorder in DSM-5:
implications for clinical practice and research of changes from DSM-IV. Depress.
Anxiety 31, 459–471. http://dx.doi.org/10.1002/da.22217.
van der Lely, S., Frey, S., Garbazza, C., Wirz-Justice, A., Jenni, O.G., Steiner, R., Wolf, S.,
Cajochen, C., Bromundt, V., Schmidt, C., 2015. Blue blocker glasses as a
countermeasure for alerting effects of evening light-emitting diode screen exposure in
male teenagers. J. Adolesc. Health 56, 113–119. http://dx.doi.org/10.1016/j.
jadohealth.2014.08.002.
Videnovic, A., Lazar, A.S., Barker, R.A., Overeem, S., 2014. “The clocks that time
us”—circadian rhythms in neurodegenerative disorders. Nat. Rev. Neurol. 10,
683–693.
Voican, C.S., Corruble, E., Naveau, S., Perlemuter, G., 2014. Antidepressant-induced liver
injury: a review for clinicians. Am. J. Psychiatry 171, 404–415. http://dx.doi.org/10.
1176/appi.ajp.2013.13050709.
Vreeburg, S.A., Hoogendijk, W.J., van Pelt, J., Verhagen, J.C., van Dyck, R., Smit, J.H.,
Zitman, F.G., Penninx, B.W., 2009. Major depressive disorder and hypothalamic-
pituitary-adrenal Axis activity. Arch. Gen. Psychiatry 66, 617–626.
Vrshek-Schallhorn, S., Doane, L.D., Mineka, S., Zinbarg, R.E., Craske, M.G., Adam, E.K.,
2013. The cortisol awakening response predicts major depression: predictive stability
over a 4-year follow-up and effect of depression history. Psychol. Med. 43, 483–493.
http://dx.doi.org/10.1017/S0033291712001213.
Wang, J., Dunn, A.J., 1998. Mouse interleukin-6 stimulates the HPA axis and increases
brain tryptophan and serotonin metabolism. Neurochem. Int. 33, 143–154.
Wessa, M., Lois, G., 2015. Brain functional effects of psychopharmacological treatment in
major depression: a focus on neural circuitry of affective processing. Curr.
Neuropharmacol. 13, 466–479. http://dx.doi.org/10.2174/
1570159X13666150416224801.
Whalley, L.J., Perini, T., Shering, A., Bennie, J., 1991. Melatonin response to bright light
in recovered, drug-free, bipolar patients. Psychiatry Res. 38, 13–19.
Wilhelmsen-Langeland, A., Saxvig, I.W., Pallesen, S., Nordhus, I.-H., Vedaa, Ø.,
Lundervold, A.J., Bjorvatn, B., 2013. A randomized controlled trial with bright light
and melatonin for the treatment of delayed sleep phase disorder: effects on subjective
and objective sleepiness and cognitive function. J. Biol. Rhythm. 28, 306–321.
Wright, C.E., Strike, P.C., Brydon, L., Steptoe, A., 2005. Acute inflammation and negative
mood: mediation by cytokine activation. Brain Behav. Immun. 19, 345–350. http://
dx.doi.org/10.1016/j.bbi.2004.10.003.
Wu, J.C., Kelsoe, J.R., Schachat, C., Bunney, B.G., DeModena, A., Golshan, S., Gillin, J.C.,
Potkin, S.G., Bunney, W.E., 2009. Rapid and sustained antidepressant response with
sleep deprivation and chronotherapy in bipolar disorder. Biol. Psychiatry 66,
298–301.
Young, J.J., Bruno, D., Pomara, N., 2014. A review of the relationship between
proinflammatory cytokines and major depressive disorder. J. Affect. Disord. 169,
15–20. http://dx.doi.org/10.1016/j.jad.2014.07.032.
Zawilska, J.B., Skene, D.J., Arendt, J., 2009. Physiology and pharmacology of melatonin
in relation to biological rhythms. Pharmacol. Rep. 61, 383–410.
Zhang, J., Terreni, L., De Simoni, M.G., Dunn, A.J., 2001. Peripheral interleukin-6
administration increases extracellular concentrations of serotonin and the evoked
release of serotonin in the rat striatum. Neurochem. Int. 38, 303–308.