Background and Current Overview of Major Depressive Disorder Research
Major depressive disorder (MDD) is a prevalent and disabling psychiatric disease that is characterised by a constellation of symptoms that adversely affect the quality of life and functioning (Hung & Lin,2015). MDD has an estimated lifetime prevalence of 10 –15% with a global prevalence rate of 4.7% in the general population (Lepine,2011; Ferrari,2015). It is universally classified among the most burdensome disorders and is associated with high rates of mortality and morbidity (Cuijpers, 2014; Chesney et al,2014). According to the World Health Organization (2017), MDD will become the leading cause of disability worldwide by the year 2030. Furthermore, the high rate of inadequate treatment of the disorder remains a serious concern.
Approximately one-third of depressed patients fail to respond to conventional monoamine-based therapies such as SSRIs and remission rates utilising anti-depressant medication are less than 30% (Pigott et al, 2010). A limitation of these treatments is that the side effects mimic the very symptoms that they are trying to address making an assessment of efficacy hard to establish (Fried & Neese, 2014). Factors such as early life stress, comorbidities, predisposed genetic risk and low social support can all impact on treatment resistance (Schneidman et al, 2005). Meta-analyses of clinical trials suggest that antidepressants are only marginally efficacious compared to placebos (Pigott et al, 2010). The limited efficacy and delay in onset of initiation of these medications are particularly concerning for a patient population at elevated risk for suicide.
MDD is highly heterogeneous, for example, 227 unique symptom profiles exist for MDD diagnosis using DSM-5 criteria (Fried, 2015). The severity of MDD is routinely estimated in clinical settings using DSM criteria and established behavioural questionnaires, such as the Beck Depression Inventory or Hamilton Scale (Bech,2006). These questionnaires, using a Likert scale format, add up severity scores for many disparate symptoms to create a sum-score. These sum scores act as a threshold limit and if the score exceeds this somewhat arbitrary limit, then the presenting individual is put into a dichotomous classification of either depressed or not depressed, while seemingly discarding the symptoms that are originally presented. However, depression is not a unitary, monolithic construct and is recognised to be a multi-componential disorder with wide heterogeneity amongst the population. These include diffuse changes in motivation, cognition, attention, memory, and mood; as well as contrasting features such as disturbed or increased appetite, hypersomnia/insomnia and physiological changes including cardiovascular and metabolic change (Harrison & Krishinadas, 2016).
Furthermore, MD scores add up very wide-ranging symptoms along with contradictory opposites (Insomnia vs hypersomnia, weight gain vs loss of appetite) making precise measurement and inter-rater reliability limited. While these questionnaires are illustrative in identifying individuals that may potentially have a neuropsychiatric disorder, they lack validity and clinical utility in directing personalised treatment paths.
Monoamine based Hypothesis of Depression
Traditional theories of depression such as the monoamine hypothesis which posits that MD is caused by under-activity of monoamine transmitters such as norepinephrine, dopamine, and serotonin leading to functional deficits in biosynthesis and brain circuitry that could be amended by anti-depressants such as SSRIs to restore the imbalance of these transmitters at both the pre and postsynaptic level. However, the findings supporting this hypothesis have been mixed (Reas & Grilo,2008). While certain studies have shown positive correlations between deficiency of these monoamine neurotransmitters and depressive symptoms there is also inconsistent results regarding altered metabolism of these neurotransmitters.; Antidepressants such as SSRIs have therapeutic lag in action, partially contributed to auto receptor sensitisation and adjustment to increased serotonin levels, that can take 4- 6 weeks before effect. Interestingly, this therapeutic effect has inhibitory effects as opposed to the enhancement of monoamine transmission (Ritter et al,2015). Furthermore, these antidepressants produce their effects via actions that are not directly related to monoamine transmission and, in general, reuptake inhibitor-based treatments such as SSRIs have low efficacy in this disease population (Harmer et al,2017). In contrast to this, pharmacological manipulation of monoamine transmission has yielded positive results in a small subset of MD individuals leading to a reduction in the severity of symptoms (). Thus, monoamine transmission may be a partial contributor to the etiology of MD but equivocating results from a clinical and therapeutic standpoint requires research to move away from this theory and develop new frameworks to treat this disease.
Thanks to rapid progress in neuroscience and, in particular, neuroimmunology, a paradigm shift has occurred from neurotransmitter theory of psychiatric disorders to MDD being a naturally occurring non-adaptive neuroimmunology system disorder. Longitudinal, epidemiological and clinical studies are beginning to clarify a clear role for neuroinflammation as a risk factor for MDD. While this research is still in its infancy and anti-inflammatory drugs may not act as a universal panacea for depression, it provides a potential new avenue to create a downstream of stratification of biologically rational subgroups via potentially different etiopathology of MD, diagnosed on the basis of objective biological assays, which could translate to potential therapeutics that could address this highly unmet medical need.
Inflammation-Associated Depression; Current Evidence
Human and animal studies implicate systemic inflammation as a partial contributor to the pathogenesis of depression. This inflammatory theory is characterised by the complex interplay of expression of peripheral cell-mediated activated cytokines, induction of oxidative and nitrosative stress (OS&NS) microglial activation, mitochondrial dysfunction and decreased neurogenesis (Morris,2015). Cytokines are signaling molecules produced in response to inflammation mediating the immune response on activation of the peripheral immune system. Numerous animal studies have reported the consistently increased concentration of pro-inflammatory cytokines interleukin (IL) 1B, IL-6 and tumor necrosis factor (TNFα). These characteristic serum alterations have been confirmed in various meta-analyses and are involved in communication pathways between the peripheral immune system and the central nervous system (CNS) (Dowlati, 2010; Howren,2009; Liu &Mak, 2012; Haapakowski,2015) Immune responses are triggered when receptors of innate immune cells recognise hardwired features of threatening stimuli. This is termed patterned associated molecular patterns (PAMPs) and pattern recognition receptors such as Toll-like receptors recognise these components of threatening microbes and activate inflammatory response (Slavich,2014). Additionally, stimulation of the immune system either through inducing a bacterial infection or through injection of lipopolysaccharide, a potent inflammatory stimulator, can result in neuroinflammation and act as a model for understanding the relationship of inflammation in depression (Zhang et al,2014, Biesmans et al,2015). Monocyte chemoattractant protein-1 (MHCP), a co-factor in the recruitment of monocyte trafficking to the brain, has been shown to prime microglia to produce IL-1 and TNFα in response to LPS in murine models (Silmani et al,2014).
Further converging evidence lies in clinical studies that demonstrate dysregulated upregulation of several inflammatory markers such as IL-1, acute phase protein C-reactive protein, TNFα, interferon-gamma (INF-γ) and monocyte chemoattractant protein in individuals with MD compared to healthy controls (Raison,2009; Young;2014). A systematic review and meta-analysis of 18,527 participants also reported higher concentrations of CRP and IL-6 which were associated with an increased susceptibility of developing MD. Importantly, this effect remained significant after controlling for confounding factors such as age and socioeconomic status. (Valkanova,2013). Furthermore, anti-inflammatory treatments have been demonstrated to have ameliorative effects on depressive symptoms and higher baseline gene expression of Il-1B and TNFα predicts antidepressant resistance (Cattaneo,2013). This reinforces corroborating evidence that these cytokines might serve as predictive biomarkers.
Systemic inflammation rapidly impairs mood, motivation, and cognition including a stereotyped constellation of symptoms collectively known as “sickness behaviours”. Sickness behaviour has been defined in the literature as a highly organised evolutionary strategy that aims to conserve vital resources to specifically fight disease-causing organisms such as infections or tissue injury to ultimately promote survival (Dantzer,2007). These behavioural symptoms have indistinguishable overlap with MDD symptomologies such as anhedonia and fatigue. Cognitive alterations are particularly prominent features of both depression and sickness behaviour . From a theoretical perspective, this converging evidence has postulated MD evolving out of sickness behaviour and that, at least in a proportion of individuals with depression, have inherited a vulnerability to MD when sickness behaviour and chronic inflammation continues unabated.
Similar to fear being an evolutionary adaptive response to threatening stimuli in the environment and anxiety being the manifestation of aberrant fear circuitry, MDD may be the behavioural output may indicate a malfunction or increased activation in sickness behaviour orientated immune-based defenses (Dantzer &Capuron,2017). A corollary to this theory lies in the foundational criteria of MD diagnosis in the DSM criteria that state that depression is deemed clinically significant following at least a two-week period of continued symptomologies such as anhedonia and social avoidance. Although a criticism of DSM criteria is that it was originally based on general consensus amongst clinicians absent of any scientifically valid evidence.
The mechanism linking inflammation to Major Depressive Disorder
Activation of peripheral cytokines induces the transient recruitment of cytokines via activated endothelial cells and microglia. Microglia are mononuclear phagocytes that are the main cellular effectors of innate immunity in the brain. Microglia express pattern recognition receptors including the toll-like receptor family (Olson & Miller,2004). Microglia serve several physiological functions and form a significant part of the communication route between the peripheral immune system and the central nervous system and when activated displays similar functions as peripheral macrophages in the blood. Their main function is to survey for injury within the CNS and is heavily involved in the active process of homeostasis. These processes include phagocytosis of damaged neurons, synaptic development and plasticity, and production of pro-inflammatory cytokines, chemokines, and prostaglandins which are important mediators of inflammation. Additionally, they have critical adaptive processes; changing from a generalised “surveillance” mode to a rapidly activated response mode during injury and initial onset of disease pathology. They can adopt either a neurotoxic or neuroprotective state and this is contingent upon the nature of the residing microenvironment. The combinations of signaling factors in the brain necessary to maintain microglia phenotypes remain largely unknown (Gosselin et al,2017). Similar macrophages found in the blood originally come from bone marrow whereas microglia populated in the brain at birth from the yolk sac. However, they are hard to differentiate when inflammatory processes occur.
Monocyte trafficking to the brain
When inflammation occurs, an extensive migration of monocyte trafficking into the brain takes place. The brain previously thought of as an immuno-privileged site due to the tight restriction of the blood-brain barrier, has now been shown to be permeable through circumventricular organs where the BBB is incomplete and structural disintegration (Carson et al,2006; Louveau et al,2015). Cytokines can activate primary afferent neurons (eg, vagal nerve) and cytokines, released by macrophage-like cells in response to an immune threat, diffuse through the brain’s circumventricular organs. The increased microglial population could be accounted for by cellular infiltration from the periphery and monocytes adopting a microglial morphology when residing in a CNS environment. The migration of monocytes into the CNS is often accompanied by an increased flux of serum proteins which are transferred to the cerebrospinal fluid (CSF). Pathological changes in the CSF were observed in a subgroup of around 25-30% of patients suffering from MD and analysis of CSF is considered the gold standard in assessing inflammatory markers (Leonard,2006).
Most of the tryptophan we ingest is metabolised along the kynurenine pathway, and only a tiny amount (1%) is converted into serotonin (Dantzer,2017). Glucocorticoids and proinflammatory cytokines enhance the conversion of tryptophan to kynurenine. This Kynurenine pathway, which includes the biosynthesis of serotonin from tryptophan, as well as getting further converted to the sleep hormone melatonin is a crucial pathway in the pathophysiology of MDD. Indoleamine 2,3 dioxygenase (IDO) is a key enzyme involved in neurometabolic processes is expressed in macrophages, can be activated by cytokines including IFNγ and TNFα. These pro-inflammatory cytokines are capable of upregulating IDO1, theoretically depriving microorganisms of tryptophan leading to disturbed neural biochemistry. Within the microglia, kynurenine is metabolized into quinolinic acid, which is an agonist of glutamatergic NMDA receptors. Therefore, there is a serotonergic deficiency and glutamatergic overdrive in proinflammatory states that paves the way toward a likely depressive syndrome
MDD positively correlates with a deficiency in serotonergic neurotransmission and increased NMDA activation (Liu,2017). This kynurenine pathway can be further converted into kynurenine metabolites that have both NMDA agonist and antagonist actions. Quinolinic acid is an NMDA agonist, mainly produced by microglial cells, that exerts strong neurotoxic effects that, through sustained receptor stimulation and excess glutamate release and enhanced oxidative stress, leads to excitotoxicity in the CNS. This excess quinolinic acid production and NMDA receptor overexpression has profound effects on the brain and has been associated with depressive symptomology in neuropsychiatric disorders such as bipolar disorder and structural changes in the striatum, hippocampus and prefrontal cortex (Meir,2016, Dantzer et al,2015, Savitz, 2015). Increased density of quinolinic acid positive microglial has been observed in the ACC of depressed patients.
Moreover, increases in quinolinic acid have been found to correlate with IL-6 levels in individuals who have attempted suicide (Dantzer,2017; Ganaca,2016). Kynurenic acid is an NMDA antagonist, has putatively been linked with neuroprotective properties (Ates,2013). In contrast to this linkage is that it also is implicated with robust antagonist effects on acetylcholine receptors, a potent neurotransmitter involved in enhancing cortical sensitivity to external stimulus and decreased the presynaptic release of glutamate (Alburqurque,2013). These neurophysiological disturbances have been strongly associated in the development of schizophrenia.
Co-Morbidity of Major Depressive Disorder in Inflammation Disorders
Microglial activity is shown to be heavily involved with multiple pathological conditions, such as psychological stress, pathological aging, and neurodevelopmental and lysosomal disorders and their activation is central to neuroinflammation (Singhai,2017; Bigger et al,2015). For example, in individuals with Alzheimer’s disease, microglial instability and quiescence seem to accelerate this neurodegenerative pathology in the absence of microglial support (Navarro et al,2018). Other disorders such as autism spectrum disorder (ASD), schizophrenia and Hunter Syndrome are associated with dysfunction of the immune system and microglial activation, with altered levels of cytokines, which in turn might directly affect neuronal function. For example, in autism, neonatal cytokines and overall skewed cytokine profiles have been observed in children with ASD and microglial activation in Hunter syndrome, a rare congenital lysosomal disorder with progressive neurodegeneration, appear to play a key role in neuroinflammation (Krakowiak et al,2017, Bigger et al,2014). Interestingly. these effects seem to vary depending on the age of onset indicating that immunomodulatory factors such as increased cytokines and microglial activation have influential functional properties in brain development and neurobehavioral phenotypes on an age-related continuum.
Cytokines such as IFN-α are also used to treat autoimmune disorders and evidence corroborates that up to 70% of patients with autoimmune diseases, such as rheumatoid arthritis (RA) or systemic lupus erythematosus, experience MDD. In particular, empirical support shows that RA is closely associated to MD with a prevalence reported to be 13-42% with the risk of developing MDD being at its apex in the first 5 years after formal diagnosis (Isik,2007). Further characterizations of these associations have been demonstrated in the literature via qualitative studies MD contributes significantly to the impaired Health-related quality of life and decreased employment rates or loss of work productivity. Moreover, administration of either anti-1L-6 or anti- TNFα therapies have been shown to rapidly improve HRQOL, preceding improvements in joint inflammation. Consistent with this finding is fMRI imaging showing rapidly altered brain activation in response to a painful peripheral stimulus following anti- TNFα injections within a 24-hour period (Matcham et al,2013). Altered clock genes regulating sleep patterns in this cohort have been noted which may exacerbate depressive symptoms (Gast,2013).
Further empirical support for a meditative role of inflammation in depression comes from studies of patients with co-morbid illnesses such as chronic hepatitis C infection who are treated with IFN-α, a form of cytokines which activates the immune system and acts as anti-viral agents. Consistent results have shown that 30-50% of these individuals develop MD episodes in the absence of any previously documented medical history of depressive illness (Lucaciu,2013). Additional symptoms such as mania were also reported. Importantly, these effects can be prevented by administration of antidepressants. Chronic stimulation of IFN-α treatment exhibits time-dependent behavioral sequelae that have important implications for conceptualizing depressive state behavioral patterns. For example, following administration immediate changes in mood, motivation and fatigue are observed. However, symptoms such as subjective reports of depression and anxiety are not demonstrated until months following chronic IFN-α therapeutic administration (Capuron & Miller,2004). This study, along with supporting animal models, suggest that IFN-α immunotherapy induces an elevated state of inflammation that leads to the emergence of MD symptomology.
However, a complication within associations between co-morbidity and depressive symptomology is that it is hard to fully determine is if comorbidity might exist co-independently, MDD might be as a direct result of onset of disease or comorbid illness might be associated with a predisposition to MDD without being causally related to it (Valderas et al,2009). Inflammation and specific biomarkers may act as a common denominator indexing the complex interplay between specific illnesses and onset of depressive symptoms although, currently, this relationship has not been fully elucidated.
Brain regions involved in Stress related inflammation and onset of Major Depressive Disorder
MDD has been related to a variety of alterations in brain structure and formation (Ferre et al,2015). Of note, meta-analyses have pinpointed alterations in grey matter density and volume reductions in brain regions such as the anterior cingulate cortex (ACC), amygdala, insula, hippocampus, and prefrontal cortex (Harrison,2017). The cortical and subcortical regions are termed the limbic circuitry critical to complex motivational behavior, emotion, learning and memory and, along with vagal nerve projections, provide a neural substrate for interoceptive awareness and subjective experience of feelings (Harrison &Critchley,2013). Stress-induced microglia activation and monocyte trafficking to the brain underlie the development of anxiety and depression (Wohleb et al,2014).
Cytokines initiate a cascade of reactions throughout the body including the brain. These brain-specific reactions include lower serotonin biosynthesis and augmented glutamatergic actions, possibly influencing the impact of inflammation on mood regulation. A large proportion of studies indicate that the initial onset of MD is often preceded by a potent stressful event such as interpersonal stress or social rejection (Stroud et al,2008). Pro-inflammatory cytokines are potent stimulators of the hypothalamic-pituitary-adrenal (HPA) axis and hyperactivity or dysregulation, most likely due to impaired feedback inhibition, is a reliable indicator involved in MDD (Miller,2009). HPA axis results in activation of corticotropin release factor (CRF) being released from the hypothalamus, which in turn leads to ACTH being released from the pituitary gland, and then glucocorticoids (GC) being released by the adrenal cortex (Herman et al,2017).
Glucocorticoids have been linked with neuroinflammatory priming (Frank et al,2015). Acute and chronic stress is associated with increased availability of proinflammatory cytokines and glucocorticoids as well as by repeated activation of the neuroendocrine and autonomic systems and promotes a “transcriptional fingerprint” on peripheral leukocytes by up-regulating pro-inflammatory transcriptional control pathways, such as nuclear factor kappa B (NF-κB,) NF-κB, has been found to be an essential mediator at the blood-brain interface that communicates peripheral inflammatory signals to the CNS. Noteworthy, signaling NF-κB, is activated by IL-1β and other cytokines both in peripheral immune cells and in the CNS making it a potential therapeutic target (Koo,2010).
Studies have highlighted that repeated stress exposure, demonstrated through social defeat models of MDD in murine models. induces glucocorticoid (GC) insensitivity in innate immune cells preventing GC- induced suppression of inflammation. Stress has also shown to increase the number of macrophages and expression of cytokine mRNA along with the release of IL-6 and TNFα in blood plasma (Wohleb et al,2014).
Empirical evidence suggests aberrant functioning of the brains reward circuitry is impaired in MD and, in particular, is associated with blunted reward learning and deficits in reward prediction errors (RPE). Thus; self-regulation is dampened, causing a disruption in their attentional focus and creating memory biases toward negative life events (Rutledge et al,2017). Inflammation has also been linked to acute reductions in ventral striatal reactivity to cues predicting rewards. Both experimental and clinical evidence shows that stress-induced neurobiological dysfunction is associated with altered behavioural responses. For instance, IL-B increases the metabolism of serotonin and noradrenalin within the hypothalamus, prefrontal cortex, hippocampus, and amygdala. Elevation of these pro-inflammatory cytokines lead to dendritic atrophy and apoptosis in the hippocampus (Lucassen et al,2014). Additionally, the hippocampus is particularly vulnerable to the neurotoxic effects of cortisol. Similarly, administration of the proinflammatory cytokine IFN-α is associated with reduced levels of serotonin in the prefrontal cortex (Asnis et al, 2003). Positive results in studies that found resistance to antidepressant treatment was associated with abnormalities in the HPA axis negative feedback response and restoration of HPA axis to baseline levels was associated with remission in depressed patients (Harrison,2017). Positive results in studies that found resistance to antidepressant treatment were associated with abnormalities in the HPA axis and restoration to baseline levels was associated with remission in MD cohorts (Harrison,217).
Gut Microbiome and involvement in Major Depressive Disorder
The gut- microbiota- brain axis and the bidirectional communication between these areas has emerged as an important area for MDD research as it may have strong effects on the onset and maintenance of symptomatology. Changes within the gut environment that result in activation of resident immune cells can lead to an increase in production of immune mediators such as TNFα which can compromise epithelial barrier integrity and lead to gut epithelial barrier leakage commonly referred to as a “leaky gut” (Foster et al,2017). A “leaky gut” may promote local and systemic immune responses and promote translocation of cytokines. Numerous factors can affect gut permeability such as alcohol and excess smoking and gut microbiota dysbiosis (Mu,2017). Dysbiosis, a term, for impaired gut microbiota, leads to inflammation of the gastrointestinal tract which is mediated through the release of elevated blood levels of cytokines such as TNFα and monocyte chemoattractant protein. These cytokines can concomitantly have destructive properties on the integrity of both the BBB and the gut microbiome enhancing monocyte trafficking promoting microglial based inflammation (Yarlagadda et al,2009). The composition of the gut microbiome is readily changeable by diet, pathogen infection, and ingestion of probiotics and antibiotics. Putative studies are now looking to establish if antidepressant effects could be delivered indirectly by dietary supplements with anti-inflammatory action or act as adjuvant therapies in conjunction with antidepressants to improve overall efficacy. Epidemiological evidence demonstrates that dietary consumption of rich omega- 3 fatty acids reduces the risk of MDD, bipolar disorder and post-partum depression (Mc Namara,2015). Contradictorily, other studies have shown mixed results and are limited by self-report measures of Omega-3 consumption. (Hastings, 2017; Gong et al,2017). Similarly, studies have found that patients suffering from chronic inflammation responded positively to the ingestion of probiotics, as they decreased the production of TNFα thus suppressing overall inflammation (Hakansson et al,2011).
Coalescing these lines of evidence seems to suggest that the hypothetical mechanism of depression and anxiety-like behaviour is that they body adapts a Immunological hypervigilant surveillance state, characterised by aberrant microglial activity and cascading downstream effects following an initial acute stressor and/or physiological illness which plays the role of the perceived threat to homeostasis by triggering “false alarm” responses, that self-maintain this physiologically miasmic state that then, after prolonged exposure, acclimatises then operationalises, or at least periodically invokes, this dysregulated immunological state throughout an individual’s life. An important caveat in these findings is that a large proportion of MDD patients do not show elevated inflammatory markers so, at least in a subset of individuals with MDD, inflammation levels are disease nonspecific and as it is not a prerequisite to onset (Miller,2009). Also, studies with positive associations with inflammation and depression the inflammatory response system varied amongst studies (Raison,2016). Brain circuitry implicated in MDD also has overlapping relationships with other neuropsychiatric disorders and physiological illnesses which further confounds and mitigates establishing stable and precise estimates of brain disease associations that is tailored to depressive illness. inflammation may act as a shared mechanism in these disorders.
While animal models are an informative tool to generate theories about the underpinnings of depression by mimicking behavioural dimensions seen in MD, they are limited by experimental simplification, lack of reliability and disproportionate use of male rodents. These models, while informative, not yet resulted in truly specific novel medications, although additional factors such as clinical trial designs and FDA approval also hinder this development (Nessler & Krishnan,2011). Rodents also lack a dorsolateral prefrontal cortex; a brain region crucial for cognitive control which is strongly implicated in MD. This suggests an incomplete framework in ascertaining the complex interplay of inflammation and onset of depression in neural circuitry. These limitations have important implications for the utility of these preclinical murine models as it may not fully account for gender differences or higher order executive functioning processes in the pathophysiology of depression. For example, research has shown that women are twice as likely to experience depression with earlier onset and severity (Richards,2016).
Furthermore, Women are three times as likely to have atypical depression, with hypersomnia and weight gain and a large-scale gene expression meta-analysis of transcriptional profiles in brain regions such as the dorsolateral prefrontal cortex, subgenual anterior cingulate cortex, and amygdala demonstrated overall transcriptional profile of MDD was opposite in men and women (Parker,2002; Seney,2018). These findings point to distinct gender differences and molecular phenotypes amongst men and women which should be a consideration in furthering stratified research. However, a recent meta-analysis conducted by the UK biobank on the genetic differences between gender showed no statistically significant correlations even after correction for multiple testing (Hall,2018). However, gender imbalances, poor statistical significance and insufficient lack of independent replication were noted. The role of gender in the manifestation of gender-specific depressive subtypes has yet to be fully clarified.
Bacterial Induction of inflammation
Experimental induction of inflammation, such as LPS or other bacteria that stimulates inflammatory processes, may help quantify an inflammatory profile, it is not generalisable to real-world studies. Furthermore, a major factor hindering the further identification of neurobehavioral phenotypes and reproducible biomarkers relating to MDD is the large heterogeneity of presentation. This is further complicated by the possibility that multiple mechanisms may be present and acting in accordance or against each other. So, while behavioural symptoms may be similar in clusters of individuals, they may be promulgated by different mechanisms. Distinct microglial genetic signatures are lost when you take the cells out of the brain indicating that the milieu of the brains microenvironment is incredibly important to these cells. Additionally, microglia in humans change in response to the disease in very different ways than microglia from mice. This suggests that the majority of our models for microglia and neurological disorders have a large pitfall that we need to overcome for finer grained translatability.
The criticism that the nebulous idea of depression being reconceptualised as “sickness behaviour” and thus this line of research is the proverbial emperor’s new clothes is a valid one. The relationship between depression and inflammation, especially in comorbid diseases, can be largely confounded by the possible likelihood that the symptoms of the disease in of itself is contributing to mood changes or, in non-medically ill patients. Is simply co-occurring with poor health choices. For example, confounding factors such as smoking, which is strongly implicated in the MD cohort, has been known to deplete serotonin as well as induce inflammation which leads to a circular speculation as to whether inflammation is a hallmark feature of depression or correlations such as poor diet is artificially creating “depression” in individuals with increased inflammation and disturbed neural metabolism. However, depression does not merge out of nothingness and considerable evidence points towards a causative role for inflammation. MD is an intricately complex disorder with potentially overlapping shared mechanisms in etiology that may, directly or indirectly, modulate persistent depressive symptoms. While inflammation may only partially explain a small proportion of variance in this population, it is vital that we work towards establishing disease-specific biomarkers that can guide treatment in contrast to broad-based diagnostic descriptions that are not clinically beneficial by themselves. Numerous authors in the field have asserted that scientific inquiry could be advanced by amalgamating distinct scientific disciplines and adopting a more multidisciplinary collaboration or transdiagnostic approach to disentangling the pathophysiology of Mood disorders (Newby et al,2015). In particular, establishing subgroups that are distinguishable on the basis of clinical symptomology as well as immunological markers may help establish biologically rational subgroups and neurobehavioral phenotypes.
Thus, there is a need to develop a unified theory that links disease processes across molecular, cellular neurocircuitry levels of depression. Stephan et al (2016) have proposed a metacognitive computational theory called dyshomeostasis that converges these multiple associations in depression. Under a Bayesian framework, this metacognitive mechanism that is constantly updating its self-belief at maintaining allostatic homeostasis (it’s belief at maintaining an optimal bodily state), possibly through converging information relayed through mechanisms such as frontal-striatal network and gut microbiome through repeated and prolonged stress exposure, begins to develop a diminished belief at maintain homeostasis due to the widespread deleterious effects of chronic stress exposure that results in fatigue and analogous terms such a learned helplessness and low self-efficacy. While this is beyond the scope of this literature review, model-based studies such as this and Harris concept of “motivational reorientation” In sickness behaviour interesting framework to reconceptualising depression and links to inflammation and impaired circuitry as well as other neuropsychiatric disorders. A salient criticism of phenotype research is the implicit assumption and false ideology, that an unconditionally optimal state of health and conversely optimal brain functioning exists. From an evolutionary perspective, Health is not a static but rather an adaptive concept and analogous to a plane that is rebuilding itself mid-flight throughout the course of an individual’s lifespan and thus there is widely population-based variability with no quantitatively valid blueprint as to what constitutes a standardized phenotype as it is, essentially, a moving target. Further noted by Mitchell (2018) Systematic noise and nonlinearities in development along with environmental influences makes establishing a relationship between genotypes and phenotypes stochastic in nature.
In summary, despite many decades of comprehensive research into uncovering underlying biological mechanisms, no specific and reliable biomarkers have been identified for MDD (Strawbridge, 2017). By disentangling various findings from multiple approaches and forming a coherent framework to understanding the complex pathophysiology to this multi- componential disorder proffers the prospect of clarifying disease-specific circulating inflammatory biomarkers that reliably predict illness development or reoccurrence and treatment response, as well as repurposing existing treatments and novel anti-inflammatory agents as adjuvant therapies, especially in individuals with treatment-resistant MD.
The aim of this project is to measure the net inflammatory potential of serum from severely depressed patients and healthy control subjects to activate microglial cells in the brain. Results from this study could provide exciting new insights into the underlying pathophysiology of MDD and provide a first step in characterising circulating factors responsible for microglial activation. This novel approach could lead to the development of new and much needed diagnostic and therapeutic response biomarkers and novel drug targets.
Cattaneo, A. et al. Candidate genes expression profile associated with antidepressants response in the GENDEP study: differentiating between baseline ‘predictors’ and longitudinal ‘targets’. Neuropsychopharmacology 38, 377–385 (2013).
Dowlati Y, Herrmann N, Swardfager W, Liu H, Sham L, Reim EK, et al. . A meta-analysis of cytokines in major depression. Biol Psychiatry (2010) 67:446–57.
M.B. Howren, D.M. Lamkin, J. Suls. Associations of depression with C-reactive protein, IL-1, and IL-6: a meta-analysis.Psychosomatic Medicine, 71 (2009), pp. 171-186.
Y. Liu, R.C. Ho, A. Mak. Interleukin (IL)-6, tumour necrosis factor alpha (TNF-alpha) and soluble interleukin-2 receptors (sIL-2 R) are elevated in patients with major depressive disorder: a meta-analysis and meta-regression.Journal of Affective Disorders, 139 (2012), pp. 230-
Liu B, Liu J, Wang M, Zhang Y, Li L. From Serotonin to Neuroplasticity: Evolvement of Theories for Major Depressive Disorder. Frontiers in Cellular Neuroscience. 2017;11:305.
R. Haapakoski, et al. Cumulative meta-analysis of interleukins 6 and 1beta, tumour necrosis factor alpha and C-reactive protein in patients with major depressive disorder. Brain Behav. Immun. (2015),
Lampa J, Westman M, Kadetoff D, Agréus AN, Le Maître E, Gillis-Haegerstrand C et al Peripheral inflammatory disease associated with centrally activated IL-1 system in humans and mice. Proc Natl Acad Sci USA 2012; 109: 12728–12733. (microglial-TNF-a-hard to measure)
Koo JW, Russo SJ, Ferguson D, Nestler EJ, Duman RS. Nuclear factor-κB is a critical mediator of stress-impaired neurogenesis and depressive behavior. Proceedings of the National Academy of Sciences of the United States of America. 2010;107(6):2669-2674.
Archer LD, Langford‐Smith KJ, Bigger BW et al. Mucopolysaccharide diseases: a complex interplay between neuroinflammation, microglial activation and adaptive immunity. J Inherit Metab Dis2014; 37:1–12.
Cuijpers, P., Sijbrandij, M., Koole, S. L., Andersson, G., Beekman, A. T. & Reynolds, C. F. (2014) Adding psychotherapy to antidepressant medication in depression and anxiety disorders: A meta-analysis. World Psychiatry 13:56–67.
Bech P. Rating scales in depression: limitations and pitfalls. Dialogues in Clinical Neuroscience. 2006;8(2):207-215.
Lépine J-P, Briley M. The increasing burden of depression. Neuropsychiatric Disease and Treatment. 2011;7(Suppl 1):3-7. doi:10.2147/NDT.S19617.
Valderas JM, Starfield B, Sibbald B, et al. Defining comorbidity: implications for understanding health and health services. Ann Fam Med. 2009;7:357–63.
Pigott HE, Leventhal AM, Alter GS, Boren JJ. Efficacy and effectiveness of antidepressants: current status of research. Psychother Psychosom 2010; 79: 267–279.
Chesney E, Goodwin GM, Fazel S. Risks of all-cause and suicide mortality in mental disorders: a meta-review. World Psychiatry. 2014;13(2):153-160.
Krishnan V, Nestler EJ. Animal Models of Depression: Molecular Perspectives. Current Topics in Behavioral Neurosciences. 2011;7:121-147.
R.K. McNamara. Mitigation of inflammation-induced mood dysregulation by long-chain omega-3 fatty acids.J. Am. Coll. Nutr., 34 (Suppl. 1) (2015), pp. 48-55
Slavich GM, Irwin MR. From Stress to Inflammation and Major Depressive Disorder: A Social Signal Transduction Theory of Depression. Psychological bulletin. 2014;140(3):774-815.
Ferrari AJ, et al. Burden of depressive disorders by country, Sex, Age, and year: findings from the global burden of disease study 2010. PLoS Med. 2013;10(11):e1001547.
M.L. Seney, Z. Huo, K. Cahill, L. French, R. Puralewski, J. Zhang, et al.Opposite molecular signatures of depression in men and women.Biol Psychiatry, 84 (2018), pp. 18-27.
R. Krishnadas, N.A. HarrisonDepression phenotype, inflammation, and the brain: implications for future research.Psychosom Med, 78 (4) (2016), pp. 384-388
Inflammation-Associated Depression: Evidence, Mechanisms and Implications
Volume 31 of Current Topics in Behavioral Neurosciences
J.J. Young, D. Bruno, N. PomaraA review of the relationship between proinflammatory cytokines and major depressive disorder.J. Affect. Disord., 169 (2014), pp. 15-20
Navarro V, Sanchez-Mejias E, Jimenez S, et al. Microglia in Alzheimer’s Disease: Activated, Dysfunctional or Degenerative. Frontiers in Aging Neuroscience. 2018; 10:140.
C.B. Stroud, J. Davila, A. Moyer.The relationship between stress and depression in first onsets versus recurrences: A meta-analytic review. Journal of Abnormal Psychology, 117 (2008), pp. 206-213
Eric J. Nestler, Michel Barrot, Ralph J. DiLeone, Amelia J. Eisch, Stephen J. Gold, Lisa M. Monteggia,
Neurobiology of Depression, Neuron,Volume 34, Issue 1,(2002),pp. 13-25.
Gabay C, Kushner I. Acute-phase proteins and other systemic responses to inflammation. N Engl J Med (1999); 340:448–45
Strasser, Barbara & Sperner-Unterweger, Barbara & Fuchs, Dietmar & M. Gostner, Johanna. (2016). Mechanisms of Inflammation-Associated Depression: Immune Influences on Tryptophan and Phenylalanine Metabolisms. Current topics in behavioral neurosciences.
Foster JA, Rinaman L, Cryan JF. Stress & the gut-brain axis: Regulation by the microbiome. Neurobiology of Stress. 2017;7:124-136.
Dale, M. M., Rang, H. P., & Dale, M. M. (2007). Rang & Dale’s pharmacology. Edinburgh: Churchill Livingstone.
World Health Organization The global burden of disease: 2004 update. 2004.http://www.who.int/entity/healthinfo/global_burden_disease/GBD_report_2004update_full.pdf.
Widner, B., Leblhuber, F., Fuchs, D. Increased neopterin production and tryptophan degradation in advanced Parkinson’s disease. J Neural Transm. 2002; 109: 181–9.
Schneiderman N, Ironson G, Siegel SD. STRESS AND HEALTH: Psychological, Behavioral, and Biological Determinants. Annual review of clinical psychology. 2005;1:607-628.
Fried EI, Nesse RM (2014) The Impact of Individual Depressive Symptoms on Impairment of Psychosocial Functioning. PLoS ONE 9(2).
Harmer CJ, Duman RS, Cowen PJ. How do antidepressants work? New perspectives for refining future treatment approaches. The lancet Psychiatry. 2017;4(5):409-418.
Morris G, Berk M. The many roads to mitochondrial dysfunction in neuroimmune and neuropsychiatric disorders. BMC Medicine. 2015;13:68.
H. Slimani, Y. Zhai, N.G. Yousif, L. Ao, Q. Zeng, D.A. Fullerton, X. MengEnhanced monocyte chemoattractant protein-1 production in aging mice exaggerates cardiac depression during endotoxemia.Crit. Care (London, Engl.), 18 (2014), p. 527
V. Valkanova, K.P. Ebmeier, C.L. AllanCRP, IL-6 and depression: a systematic review and meta-analysis of longitudinal studies.J. Affect. Disord., 150 (2013), pp. 736-744
Carson MJ, Doose JM, Melchior B, Schmid CD, Ploix CC. CNS immune privilege: hiding in plain sight. Immunological reviews. 2006;213:48-65.
Louveau A, Harris TH, Kipnis J. Revisiting the concept of CNS immune privilege. Trends in immunology. 2015;36(10):569-577. .
Leonard BE, Myint A. Changes in the immune system in depression and dementia: causal or coincidental effects? Dialogues in Clinical Neuroscience. 2006;8(2):163-174.
Ganança L, Oquendo MA, Tyrka AR, Cisneros-Trujillo S, Mann JJ, Sublette ME. The Role of Cytokines in the Pathophysiology of Suicidal Behavior. Psychoneuroendocrinology. 2016;63:296-310. .
Ates-Alagoz Z, Adejare A. NMDA Receptor Antagonists for Treatment of Depression. Pharmaceuticals. 2013;6(4):480-499. .
Albuquerque EX, Schwarcz R. Kynurenic acid as an Antagonist of α7 Nicotinic Acetylcholine Receptors in the Brain: Facts and Challenges. Biochemical pharmacology. 2013;85(8):1027-1032.
Singhal G, Baune BT. Microglia: An Interface between the Loss of Neuroplasticity and Depression. Frontiers in Cellular Neuroscience. 2017;11:270.
Gudayol-Ferré E, Peró-Cebollero M, González-Garrido AA, Guàrdia-Olmos J. Changes in brain connectivity related to the treatment of depression measured through fMRI: a systematic review. Frontiers in Human Neuroscience. 2015;9:582. .
Wohleb ES, McKim DB, Sheridan JF, Godbout JP. Monocyte trafficking to the brain with stress and inflammation: a novel axis of immune-to-brain communication that influences mood and behavior. Frontiers in Neuroscience. 2014;8:447.
Herman JP, McKlveen JM, Ghosal S, et al. Regulation of the hypothalamic-pituitary-adrenocortical stress response. Comprehensive Physiology. 2016;6(2):603-621. .
Miller AH, Maletic V, Raison CL. Inflammation and Its Discontents: The Role of Cytokines in the Pathophysiology of Major Depression. Biological psychiatry. 2009;65(9):732-741.
Rutledge RB, Moutoussis M, Smittenaar P, et al. Association of Neural and Emotional Impacts of Reward Prediction Errors With Major Depression. JAMA Psychiatry. 2017;74(8):790–797.
Hastings CN, Sheridan H, Pariante CM, Mondelli V. Does diet matter? The use of polyunsaturated fatty acids (PUFAs) and other dietary supplements in inflammation-associated depression. Curr Top Behav Neurosci. 2017;31:321–338
Gong Z-Y, Yuan Z-Q, Dong Z-W, Peng Y-Z. Glutamine with probiotics attenuates intestinal inflammation and oxidative stress in a rat burn injury model through altered iNOS gene aberrant methylation. American Journal of Translational Research. 2017;9(5):2535-2547.
Miller AH, Raison CL. The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nature reviews Immunology. 2016;16(1):22-34.
Raison CL (2016) The promise and limitations of anti-inflammatory agents for the treatment of major depressive disorder. Current Topics in Behavioral Neurosciences 31: 287–302.
H.D. Critchley, N.A. Harrison.Visceral influences on brain and behavior. Neuron, 77 (2013), pp. 624-638
N.A. Harrison. Brain structures implicated in inflammation-associated depression.Curr. Top. Behav. Neurosci., 31 (2017), pp. 221-248,
Hall LS, Adams MJ, Arnau-Soler A, et al. : Genome-Wide Meta-Analyses Of Stratified Depression In Generation Scotland And UK Biobank. bioRxiv. 2017.
Strawbridge R, Young AH, Cleare AJ. Biomarkers for depression: recent insights, current challenges and future prospects. Neuropsychiatric Disease and Treatment. 2017;13:1245-1262.
Isik, A., Koca, S. S., Ozturk, A., Mermi, O. (2006) Anxiety and depression in patients with rheumatoid arthritis. Clin. Rheumatol. 26,872-878
M. Margaretten, L. Julian, P. Katz, E. Yelin. Depression in patients with rheumatoid arthritis: description, causes and mechanisms.Int J Clin Rheumatol, 6 (6) (2011), pp. 617-623
Lucaciu LA, Dumitrascu DL. Depression and suicide ideation in chronic hepatitis C patients untreated and treated with interferon: prevalence, prevention, and treatment. Annals of Gastroenterology : Quarterly Publication of the Hellenic Society of Gastroenterology. 2015;28(4):440-447.
Capuron L, Miller AH. Cytokines and psychopathology: lessons from interferon-alpha. Biol Psychiatry. 2004;56:819–824.
Lucassen PJ, Pruessner J, Sousa N, et al. Neuropathology of stress. Acta Neuropathologica. 2014;127(1):109-135.
Jill M. Newby, Anna McKinnon, Willem Kuyken, Simon Gilbody, Tim Dalgleish,
Systematic review and meta-analysis of transdiagnostic psychological treatments for anxiety and depressive disorders in adulthood, Clinical Psychology Review, Volume 40,2015,Pages 91-110,
Stephan KE, Manjaly ZM, Mathys CD, et al. Allostatic Self-efficacy: A Metacognitive Theory of Dyshomeostasis-Induced Fatigue and Depression. Frontiers in Human Neuroscience. 2016;10:550.
Parker G, Roy K, Mitchell P, Wilhelm K, Malhi G, Hadzi-Pavlovic D. Atypical depression: a reappraisal. Am J Psychiatry 2002; 159: 1470–1479.