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Depressive disorders: Processes leading to neurogeneration and potential novel treatments
Accepted Manuscript Depressive disorders: Processes leading to neurogeneration and potential novel treatments
Gregory M. Brown, Roger S. McIntyre, Joshua Rosenblat, Rüdiger Hardeland PII: DOI: Reference:
S0278-5846(17)30047-7 doi: 10.1016/j.pnpbp.2017.04.023 PNP 9084
To appear in:
Progress in Neuropsychopharmacology & Biological Psychiatry
Received date: Accepted date:
20 January 2017 1 April 2017
Please cite this article as: Gregory M. Brown, Roger S. McIntyre, Joshua Rosenblat, Rüdiger Hardeland , Depressive disorders: Processes leading to neurogeneration and potential novel treatments. The address for the corresponding author was captured as affiliation for all authors. Please check if appropriate. Pnp(2017), doi: 10.1016/ j.pnpbp.2017.04.023
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ACCEPTED MANUSCRIPT Depressive disorders: processes leading to neurogeneration and potential novel treatments Gregory M Browna, Roger S. McIntyreb, Joshua Rosenblatc and Rüdiger Hardelandd M Brown, MD, PhD, FRCPC, FRSC Professor Emeritus, Department of Psychiatry, University of Toronto Centre for Addiction and Mental Health, 100 Stokes St, Toronto, ON M6J 1H4 Mailing address: 100 Bronte Rd., Oakville, Ontario, L6L 6L5 Telephones: 1-905-465-2941 and 52-322-221-1542 [email protected]
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S. McIntyre, M.D., FRCPC Professor of Psychiatry and Pharmacology, University of Toronto Head, Mood Disorders Psychopharmacology Unit University Health Network 399 Bathurst Street, MP 9-325 Toronto, ON M5T 2S8 Canada Telephone: 416-603-5279 Fax: 416-603-5368 [email protected]
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bRoger
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aGregory
Rosenblat MD, Resident of Psychiatry Clinician Scientist Stream, University of Toronto Mood Disorders Psychopharmacology Unit University Health Network 399 Bathurst Street, MP 9-325 Toronto, ON Canada M5T 2S8 Telephone: 416-603-5279 Fax: 416-603-5368 [email protected]
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cJoshua
Hardeland Dr. rer. nat Professor Johann Friedrich Blumenbach Institut für Zoologie und Anthropologie, Universität Göttingen, Buergerstrasse 50 D-37073 Göttingen, GERMANY
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dRüdiger
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Tel.: +49-551-395414 [email protected]
Corresponding author: Dr. Gregory M Brown Mailing address: 100 Bronte Rd., Oakville, Ontario, L6L 6L5 Telephones: 1-905-465-2941 and 52-322-221-1542 [email protected]
ACCEPTED MANUSCRIPT Abstract
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Mood disorders are wide spread with estimates that one in seven of the population are affected at some time in their life(Kessler et al., 2012). Many of those affected with severe depressive disorders have cognitive deficits which may progress to frank neurodegeneration. There are several peripheral markers shown by patients who have cognitive deficits that could represent causative factors and could potentially serve as guides to the prevention or even treatment of neurodegeneration. Circadian rhythm misalignment, immune dysfunction and oxidative stress and circadian rhythm misalignment 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 neurodegeneration 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.
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Keywords:
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depression, cognition, neurodegeneration, mechanisms, inflammation, chronotherapy.
ACCEPTED MANUSCRIPT 1. Introduction 1.1 Depressive disorders
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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 previously 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.
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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 diagnostic criterion(Kaltenboeck et al., 2016). Lifetime prevalence has been estimated at about 1 %.
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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).
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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 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
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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). In addition to being a criterion item, 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 multidimensional 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.
ACCEPTED MANUSCRIPT 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 cognitive disturbances account for more variability in workplace performance 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 improvement in cognitive measures rather than with changed depressive symptom severity.
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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).
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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 outcomes (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).
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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 approaches e.g. social rhythm therapy, and where appropriate, sedative hypnotic agents may assist in some persons as sleep disruption is a wellknown anti-cognitive behaviour. Targeting comorbid conditions that 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 dysfunction with relatively few demonstrating direct independent effects on cognitive functions. A surfeit of other psychotropic agents e.g. stimulants, 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
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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).
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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).
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A recent positron emission tomography (PET) brain study of 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 neurotransmitter systems in some of the areas identified in MDD by MRI(Frodl and Amico, 2014; Lener and Iosifescu, 2015). Moreover circulating inflammatory and antioxidant markers are associated with changes on MRI and MRS(Frodl and Amico, 2014; Lindqvist et al., 2014; Young et al., 2014). Postmortem 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,
ACCEPTED MANUSCRIPT enzymatic antioxidant activities and inflammatory cytokines together with lower plasma concentrations of antioxidants. 4. Circadian Rhythm Misalignment and Melatonin alterations INSERT TABLE 1 ABOUT HERE
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Most body functions have a 24 hour 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.
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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 hours(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 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.
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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 discriminates between the forms of depressive disorders is of utmost importance. 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; Virginia Soria et al., 2010),
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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(Rüdiger Hardeland, 2014). 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).
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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 malfunction 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 relationship.
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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 disruptions 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 deprivation, 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 supplemented 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 hr 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 regulation 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,
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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 minutes 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 hr rhythm of cortisol would be altered by desynchronized body rhythms(Nicolaides et al., 2014).
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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 hours 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).
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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 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.
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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 melatonin 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).
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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 neurodegeneration and not by depression although they may result in depressive features. Alzheimer‟s disease is occasionally preceded by depression. Although it is not yet established whether the rhythm dysregulation 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 aggravated 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
ACCEPTED MANUSCRIPT INSERT TABLE 2 ABOUT HERE 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).
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On the background of these relationships between circadian dysfunction and, at least, subtypes of depressive disorders, several treatment 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 interventions without or with rather mild side effects, it may be recommended 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 increasingly done in other polymorphism studies. Technological progress may allow these techniques to become an important diagnostic tool. 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.
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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 pharmacological effects, melatonin is usually very well tolerated and side effects or contraindications have to be only considered under certain specific conditions.
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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., n.d.; 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 recommended 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 information 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,
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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 suppressant 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 those patients that exhibit a shortened rhythm as seen in a subpopulation 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 metaanalysis 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 monotherapy and adjunctive therapy(Tuunainen et al., 2004). A retrorespective 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.
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If light therapy or BB glasses are capable of augmenting the efficacy of other forms of chronotherapy as well as of antidepressant pharmacotherapy, 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 disorders still await respective studies on sufficiently large cohorts.
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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 (Nacetylserotonin O-methyltransferase) were reported to be associated with MDD(V Soria et al., 2010) 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).
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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 pupillary miosis, changes that impair circadian photoreception by melanopsin (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).
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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 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).
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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
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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 presumably 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 phase of administration. The disregard of these fundamental chronobiological 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 resetting 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 possibility 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.
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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 combination 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 chronobiological 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
ACCEPTED MANUSCRIPT 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.
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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 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 possible 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(R Hardeland, 2014) 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; R Hardeland, 2014; Montastruc et al., 2014; Voican et al., 2014).
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However, the antidepressant actions of agomelatine differ considerably 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 5HT2C 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 suggested 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., 2008; 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
ACCEPTED MANUSCRIPT 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.
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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 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 preclinical data indicate that melatonin attenuates mitochondrial dysfunction and can downregulate NADPH oxidase activation, but the relevance 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 antioxidant. The known immune stimulatory actions comprise more upregulations 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.
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6. Immunologic Alterations and signs of oxidative stress INSERT TABLE 3 ABOUT HERE
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Immune dysfunction is strongly associated with numerous psychiatric 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, comparing 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.
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In a meta-analysis pooling together the results of twenty-nine 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-) 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 Creactive 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 consistently 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.
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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).
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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 neutralizing ROS. Replicated evidence has demonstrated increased ROS and decreased antioxidants in both MDD and BD, leading to pathologic neurodegeneration in key brain regions subserving mood and cognition(Aboul-Fotouh, 2013; Berk et al., 2011; Black et al., 2015; Palta et al., 2014). More specifically, depressive disorders have been associated 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, glutathione (gamma-glutamyl-cysteinyl-glycine; GSH), superoxide dismutase (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 with current conventional therapies, there has been great interest in new targets to specifically and effectively alleviate cognitive dysfunction in mood disorders. Immune dysfunction has presented as one potential target of interest as pro-inflammatory markers have been independently associated with poorer
ACCEPTED MANUSCRIPT cognitive function in mood disorders(Carvalho et al., 2014; Goldsmith et al., 2016a; Rosenblat et al., 2015).
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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 cognitive 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 summarized herein.
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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 monoamine 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).
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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 neurodegeneration 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.(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 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 production, 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-
ACCEPTED MANUSCRIPT 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 INSER TABLE 4 ABOUT HERE
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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 additional treatment options in treatment resistant populations. Several clinical trials have already been conducted evaluating the antidepressant effects of antiinflammatory agents in a variety of populations, including but not limited to MDD, bipolar depression and sub-syndromal 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 (omega3s) and curcumin, have also been investigated(Bergman et al., 2013; Bloch and Hannestad, 2012; Lopresti et al., 2014).
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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 = 4,258) and four RCTs investigating cytokine inhibitors (n = 2,004)(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.
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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-3s (n=140), NAC (n=76) and pioglitazone (n=44) in the treatment of BD were identified. The overall effect size (SMD) of adjunctive anti-inflammatories on depressive symptom severity was 0.40 (P=0.002), indicative of a moderate and statistically significant 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 particular 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
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suggested that stratification using inflammatory 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 inflammatory 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 evaluated 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 potentially move the field of psychiatry forward to a more personalized medicine approach while simultaneously providing significant insight into the pathophysiology of depression.
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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-3s 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 antioxidant 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., 2016; 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 (250mg twice daily), high-dose curcumin extract (500mg twice daily), or combined low-dose curcumin extract plus saffron (15mg 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.
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Several RCTs have been conducted evaluating the effect of omega-3s 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 studies have been negative(Keck Jr. 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. Interestingly, 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 stratification 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 promise in the treatment of depression in BD and MDD. Several RCTs are currently underway as the field of immuno-psychiatry rapidly progresses. 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
ACCEPTED MANUSCRIPT 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
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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.
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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.
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We know that MDD and especially recurrent MDD causes measurable cognitive problems that are accompanied by immune dysregulation 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 antiinflammatory 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.
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Funding
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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.
This work did not receive any specific grant from funding agencies in the public, commercial, or not-forprofit sectors. References
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ACCEPTED MANUSCRIPT 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 HPA regulation occurs with a recent focus on the cortisol awakening response There are variable melatonin findings perhaps because light exposure varies Desynchronization of rhythms is pro-neurodegenerative in animals
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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
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Table 3 Immunologic alterations and oxidative stress
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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 Table 4 Potential treatments based on immunologic changes Anti-inflammatory agents, especially celecoxib reduce depression Anti-inflammatory agents, especially NAC reduce depression in BP Monoclonal antibody based cytokine inhibitor Infliximab have an antidepressant action in those with elevated CRP and TNF-α Curcumin and curcumin/saffron combination have antidepressive action especially In those with atypical depression
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An Omega-3 study reported that those with high inflammation have a marked remission rate with EPA (eicosapentaenoic acid)
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Immune modulating agents may only benefit those with immune dysfunction
ACCEPTED MANUSCRIPT Highlights
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Screening methods for cognitive alterations in depression are discussed There is strong evidence for neurodegenerative changes in depressive illness Circadian dysfunction is discussed with regard to genetics, entrainment and treatment Role and treatment of immunologic changes in producing cognitive changes
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Gregory M. Brown, Roger S. McIntyre, Joshua Rosenblat, Rüdiger Hardeland PII: DOI: Reference:
S0278-5846(17)30047-7 doi: 10.1016/j.pnpbp.2017.04.023 PNP 9084
To appear in:
Progress in Neuropsychopharmacology & Biological Psychiatry
Received date: Accepted date:
20 January 2017 1 April 2017
Please cite this article as: Gregory M. Brown, Roger S. McIntyre, Joshua Rosenblat, Rüdiger Hardeland , Depressive disorders: Processes leading to neurogeneration and potential novel treatments. The address for the corresponding author was captured as affiliation for all authors. Please check if appropriate. Pnp(2017), doi: 10.1016/ j.pnpbp.2017.04.023
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ACCEPTED MANUSCRIPT Depressive disorders: processes leading to neurogeneration and potential novel treatments Gregory M Browna, Roger S. McIntyreb, Joshua Rosenblatc and Rüdiger Hardelandd M Brown, MD, PhD, FRCPC, FRSC Professor Emeritus, Department of Psychiatry, University of Toronto Centre for Addiction and Mental Health, 100 Stokes St, Toronto, ON M6J 1H4 Mailing address: 100 Bronte Rd., Oakville, Ontario, L6L 6L5 Telephones: 1-905-465-2941 and 52-322-221-1542 [email protected]
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S. McIntyre, M.D., FRCPC Professor of Psychiatry and Pharmacology, University of Toronto Head, Mood Disorders Psychopharmacology Unit University Health Network 399 Bathurst Street, MP 9-325 Toronto, ON M5T 2S8 Canada Telephone: 416-603-5279 Fax: 416-603-5368 [email protected]
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bRoger
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aGregory
Rosenblat MD, Resident of Psychiatry Clinician Scientist Stream, University of Toronto Mood Disorders Psychopharmacology Unit University Health Network 399 Bathurst Street, MP 9-325 Toronto, ON Canada M5T 2S8 Telephone: 416-603-5279 Fax: 416-603-5368 [email protected]
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cJoshua
Hardeland Dr. rer. nat Professor Johann Friedrich Blumenbach Institut für Zoologie und Anthropologie, Universität Göttingen, Buergerstrasse 50 D-37073 Göttingen, GERMANY
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dRüdiger
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Tel.: +49-551-395414 [email protected]
Corresponding author: Dr. Gregory M Brown Mailing address: 100 Bronte Rd., Oakville, Ontario, L6L 6L5 Telephones: 1-905-465-2941 and 52-322-221-1542 [email protected]
ACCEPTED MANUSCRIPT Abstract
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Mood disorders are wide spread with estimates that one in seven of the population are affected at some time in their life(Kessler et al., 2012). Many of those affected with severe depressive disorders have cognitive deficits which may progress to frank neurodegeneration. There are several peripheral markers shown by patients who have cognitive deficits that could represent causative factors and could potentially serve as guides to the prevention or even treatment of neurodegeneration. Circadian rhythm misalignment, immune dysfunction and oxidative stress and circadian rhythm misalignment 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 neurodegeneration 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.
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Keywords:
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depression, cognition, neurodegeneration, mechanisms, inflammation, chronotherapy.
ACCEPTED MANUSCRIPT 1. Introduction 1.1 Depressive disorders
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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 previously 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.
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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 diagnostic criterion(Kaltenboeck et al., 2016). Lifetime prevalence has been estimated at about 1 %.
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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).
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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 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
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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). In addition to being a criterion item, 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 multidimensional 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.
ACCEPTED MANUSCRIPT 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 cognitive disturbances account for more variability in workplace performance 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 improvement in cognitive measures rather than with changed depressive symptom severity.
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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).
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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 outcomes (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).
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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 approaches e.g. social rhythm therapy, and where appropriate, sedative hypnotic agents may assist in some persons as sleep disruption is a wellknown anti-cognitive behaviour. Targeting comorbid conditions that 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 dysfunction with relatively few demonstrating direct independent effects on cognitive functions. A surfeit of other psychotropic agents e.g. stimulants, 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
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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).
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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).
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A recent positron emission tomography (PET) brain study of 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 neurotransmitter systems in some of the areas identified in MDD by MRI(Frodl and Amico, 2014; Lener and Iosifescu, 2015). Moreover circulating inflammatory and antioxidant markers are associated with changes on MRI and MRS(Frodl and Amico, 2014; Lindqvist et al., 2014; Young et al., 2014). Postmortem 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,
ACCEPTED MANUSCRIPT enzymatic antioxidant activities and inflammatory cytokines together with lower plasma concentrations of antioxidants. 4. Circadian Rhythm Misalignment and Melatonin alterations INSERT TABLE 1 ABOUT HERE
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Most body functions have a 24 hour 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.
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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 hours(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 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.
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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 discriminates between the forms of depressive disorders is of utmost importance. 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; Virginia Soria et al., 2010),
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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(Rüdiger Hardeland, 2014). 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).
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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 malfunction 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 relationship.
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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 disruptions 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 deprivation, 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 supplemented 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 hr 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 regulation 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,
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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 minutes 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 hr rhythm of cortisol would be altered by desynchronized body rhythms(Nicolaides et al., 2014).
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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 hours 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).
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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 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.
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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 melatonin 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).
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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 neurodegeneration and not by depression although they may result in depressive features. Alzheimer‟s disease is occasionally preceded by depression. Although it is not yet established whether the rhythm dysregulation 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 aggravated 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
ACCEPTED MANUSCRIPT INSERT TABLE 2 ABOUT HERE 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).
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On the background of these relationships between circadian dysfunction and, at least, subtypes of depressive disorders, several treatment 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 interventions without or with rather mild side effects, it may be recommended 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 increasingly done in other polymorphism studies. Technological progress may allow these techniques to become an important diagnostic tool. 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.
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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 pharmacological effects, melatonin is usually very well tolerated and side effects or contraindications have to be only considered under certain specific conditions.
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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., n.d.; 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 recommended 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 information 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,
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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 suppressant 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 those patients that exhibit a shortened rhythm as seen in a subpopulation 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 metaanalysis 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 monotherapy and adjunctive therapy(Tuunainen et al., 2004). A retrorespective 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.
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If light therapy or BB glasses are capable of augmenting the efficacy of other forms of chronotherapy as well as of antidepressant pharmacotherapy, 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 disorders still await respective studies on sufficiently large cohorts.
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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 (Nacetylserotonin O-methyltransferase) were reported to be associated with MDD(V Soria et al., 2010) 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).
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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 pupillary miosis, changes that impair circadian photoreception by melanopsin (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).
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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 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).
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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
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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 presumably 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 phase of administration. The disregard of these fundamental chronobiological 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 resetting 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 possibility 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.
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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 combination 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 chronobiological 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
ACCEPTED MANUSCRIPT 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.
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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 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 possible 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(R Hardeland, 2014) 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; R Hardeland, 2014; Montastruc et al., 2014; Voican et al., 2014).
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However, the antidepressant actions of agomelatine differ considerably 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 5HT2C 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 suggested 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., 2008; 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
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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 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 preclinical data indicate that melatonin attenuates mitochondrial dysfunction and can downregulate NADPH oxidase activation, but the relevance 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 antioxidant. The known immune stimulatory actions comprise more upregulations 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.
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Immune dysfunction is strongly associated with numerous psychiatric 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, comparing 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.
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In a meta-analysis pooling together the results of twenty-nine 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-) 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 Creactive 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 consistently 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.
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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).
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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 neutralizing ROS. Replicated evidence has demonstrated increased ROS and decreased antioxidants in both MDD and BD, leading to pathologic neurodegeneration in key brain regions subserving mood and cognition(Aboul-Fotouh, 2013; Berk et al., 2011; Black et al., 2015; Palta et al., 2014). More specifically, depressive disorders have been associated 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, glutathione (gamma-glutamyl-cysteinyl-glycine; GSH), superoxide dismutase (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 with current conventional therapies, there has been great interest in new targets to specifically and effectively alleviate cognitive dysfunction in mood disorders. Immune dysfunction has presented as one potential target of interest as pro-inflammatory markers have been independently associated with poorer
ACCEPTED MANUSCRIPT cognitive function in mood disorders(Carvalho et al., 2014; Goldsmith et al., 2016a; Rosenblat et al., 2015).
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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 cognitive 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 summarized herein.
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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 monoamine 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).
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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 neurodegeneration 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.(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 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 production, 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-
ACCEPTED MANUSCRIPT 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 INSER TABLE 4 ABOUT HERE
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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 additional treatment options in treatment resistant populations. Several clinical trials have already been conducted evaluating the antidepressant effects of antiinflammatory agents in a variety of populations, including but not limited to MDD, bipolar depression and sub-syndromal 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 (omega3s) and curcumin, have also been investigated(Bergman et al., 2013; Bloch and Hannestad, 2012; Lopresti et al., 2014).
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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 = 4,258) and four RCTs investigating cytokine inhibitors (n = 2,004)(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.
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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-3s (n=140), NAC (n=76) and pioglitazone (n=44) in the treatment of BD were identified. The overall effect size (SMD) of adjunctive anti-inflammatories on depressive symptom severity was 0.40 (P=0.002), indicative of a moderate and statistically significant 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 particular 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
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suggested that stratification using inflammatory 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 inflammatory 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 evaluated 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 potentially move the field of psychiatry forward to a more personalized medicine approach while simultaneously providing significant insight into the pathophysiology of depression.
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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-3s 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 antioxidant 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., 2016; 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 (250mg twice daily), high-dose curcumin extract (500mg twice daily), or combined low-dose curcumin extract plus saffron (15mg 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.
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Several RCTs have been conducted evaluating the effect of omega-3s 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 studies have been negative(Keck Jr. 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. Interestingly, 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 stratification 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 promise in the treatment of depression in BD and MDD. Several RCTs are currently underway as the field of immuno-psychiatry rapidly progresses. 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
ACCEPTED MANUSCRIPT 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
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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.
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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.
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We know that MDD and especially recurrent MDD causes measurable cognitive problems that are accompanied by immune dysregulation 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 antiinflammatory 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.
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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.
This work did not receive any specific grant from funding agencies in the public, commercial, or not-forprofit sectors. References
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ACCEPTED MANUSCRIPT 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 HPA regulation occurs with a recent focus on the cortisol awakening response There are variable melatonin findings perhaps because light exposure varies Desynchronization of rhythms is pro-neurodegenerative in animals
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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
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Table 3 Immunologic alterations and oxidative stress
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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 Table 4 Potential treatments based on immunologic changes Anti-inflammatory agents, especially celecoxib reduce depression Anti-inflammatory agents, especially NAC reduce depression in BP Monoclonal antibody based cytokine inhibitor Infliximab have an antidepressant action in those with elevated CRP and TNF-α Curcumin and curcumin/saffron combination have antidepressive action especially In those with atypical depression
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An Omega-3 study reported that those with high inflammation have a marked remission rate with EPA (eicosapentaenoic acid)
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Immune modulating agents may only benefit those with immune dysfunction
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Screening methods for cognitive alterations in depression are discussed There is strong evidence for neurodegenerative changes in depressive illness Circadian dysfunction is discussed with regard to genetics, entrainment and treatment Role and treatment of immunologic changes in producing cognitive changes
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