disease hypothesis of depression

The age-by-disease interaction hypothesis of late-life depression

Affiliation.

• 1 Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA 15219, USA.
• PMID: 23570886
• PMCID: PMC3549303
• DOI: 10.1016/j.jagp.2013.01.053

The phenomenologic diagnosis of depression is successful in increasing diagnostic reliability, but it is a classification scheme without biologic bases. One subtype of depression for which evidence suggests a unique biologic basis is late-life depression (LLD), with first onset of symptoms after the age of 65. LLD is common and poses a significant burden on affected individuals, caretakers, and society. The pathophysiology of LLD includes disruptions of the neural network underlying mood, which can be conceptualized as the result of dysfunction in multiple underlying biologic processes. Here, we briefly review current LLD hypotheses and then describe the characteristics of molecular brain aging and their overlap with disease processes. Furthermore, we propose a new hypothesis for LLD, the age-by-disease interaction hypothesis, which posits that the clinical presentation of LLD is the integrated output of specific biologic processes that are pushed in LLD-promoting directions by changes in gene expression naturally occurring in the brain during aging. Hence, the brain is led to a physiological state that is more susceptible to LLD, because additional pushes by genetic, environmental, and biochemical factors may now be sufficient to generate dysfunctional states that produce depressive symptoms. We put our propositions together into a decanalization model to aid in illustrating how age-related biologic changes of the brain can shift the repertoire of available functional states in a prodepression direction, and how additional factors can readily lead the system into distinct and stable maladaptive phenotypes, including LLD. This model brings together basic research on neuropsychiatric and neurodegenerative diseases more closely with the investigation of normal aging. Specifically, identifying biologic processes affected during normal aging may inform the development of new interventions for the prevention and treatment of LLD.

Copyright © 2013 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.

Publication types

• Research Support, N.I.H., Extramural
• Aging / genetics*
• Aging / physiology*
• Brain / physiopathology*
• Cost of Illness
• Depression / diagnosis
• Depression / genetics*
• Depression / physiopathology*
• Genetic Predisposition to Disease / genetics*
• Homeostasis / physiology
• Neural Pathways / physiopathology

Grants and funding

• R01 MH093723/MH/NIMH NIH HHS/United States
• R01 MH077159/MH/NIMH NIH HHS/United States
• MH093723/MH/NIMH NIH HHS/United States
• K02 MH084060/MH/NIMH NIH HHS/United States
• UL1 TR000005/TR/NCATS NIH HHS/United States
• MH084060/MH/NIMH NIH HHS/United States

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The inflammatory & neurodegenerative (I&ND) hypothesis of depression: leads for future research and new drug developments in depression

• Original Paper
• Published: 16 December 2008
• Volume 24 , pages 27–53, ( 2009 )

Cite this article

• Michael Maes 1 ,
• Raz Yirmyia 2 ,
• Jens Noraberg 3 , 4 ,
• Stefan Brene 5 ,
• Joe Hibbeln 6 ,
• Giulia Perini 7 ,
• Marta Kubera 8 ,
• Petr Bob 9 ,
• Bernard Lerer 10 &
• Mario Maj 11  

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Despite extensive research, the current theories on serotonergic dysfunctions and cortisol hypersecretion do not provide sufficient explanations for the nature of depression. Rational treatments aimed at causal factors of depression are not available yet. With the currently available antidepressant drugs, which mainly target serotonin, less than two thirds of depressed patients achieve remission. There is now evidence that inflammatory and neurodegenerative (I&ND) processes play an important role in depression and that enhanced neurodegeneration in depression may–at least partly–be caused by inflammatory processes. Multiple inflammatory-cytokines, oxygen radical damage, tryptophan catabolites–and neurodegenerative biomarkers have been established in patients with depression and these findings are corroborated by animal models of depression. A number of vulnerability factors may predispose towards depression by enhancing inflammatory reactions, e.g. lower peptidase activities (dipeptidyl-peptidase IV, DPP IV), lower omega-3 polyunsaturated levels and an increased gut permeability (leaky gut). The cytokine hypothesis considers that external, e.g. psychosocial stressors, and internal stressors, e.g. organic inflammatory disorders or conditions, such as the postpartum period, may trigger depression via inflammatory processes. Most if not all antidepressants have specific anti-inflammatory effects, while restoration of decreased neurogenesis, which may be induced by inflammatory processes, may be related to the therapeutic efficacy of antidepressant treatments. Future research to disentangle the complex etiology of depression calls for a powerful paradigm shift, i.e. by means of a high throughput-high quality screening, including functional genetics and genotyping microarrays; established and novel animal and ex vivo–in vitro models for depression, such as new transgenic mouse models and endophenotype-based animal models, specific cell lines, in vivo and ex vivo electroporation, and organotypic brain slice culture models. This screening will allow to: 1) discover new I&ND biomarkers, both at the level of gene expression and the phenotype; and elucidate the underlying molecular I&ND pathways causing depression; and 2) identify new therapeutic targets in the I&ND pathways; develop new anti-I&ND drugs for these targets; select existing anti-I&ND drugs or substances that could augment the efficacy of antidepressants; and predict therapeutic response by genetic I&ND profiles.

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Michael Maes

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Jens Noraberg

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Maes, M., Yirmyia, R., Noraberg, J. et al. The inflammatory & neurodegenerative (I&ND) hypothesis of depression: leads for future research and new drug developments in depression. Metab Brain Dis 24 , 27–53 (2009). https://doi.org/10.1007/s11011-008-9118-1

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A Story of Depression as a Disease

How we think about depression impacts clinical treatment..

Updated January 3, 2024 | Reviewed by Monica Vilhauer

• What Is Depression?
• Find a therapist to overcome depression
• A model of depression as a disease is incomplete and misleading. It leads to suboptimal treatment choices.
• The "separation distress hypothesis" is an alternative model. It is an integrated, causal model of depression.
• This alternative model leads to psychologically meaningful treatments with higher efficacy than SSRIs.

Is there a difference between these statements: “I have depression ” and "I am depressed?" The first sentence describes something lasting, possibly chronic. The second one describes the state of the person's brain and mind.

As Jonathan Shedler pointed out, the first description provides an illusion of an explanation of why the person is distressed : “Why do I feel this way? Because I have an illness called “depression.”

Can we pause here for a moment? This is not an accident that we talk about depression as a disease. We have been taught to do so. How?

Programming by language happens all the time in our culture. For example, we speak Starbucks: “I’d like a grande-soy-latte, please.”

In Chapter 4 of Ethan Watters’ book [1], McGill University professor Laurence Kirmayer and Keio University Professor Junko Kitanaka shared a remarkable account of how one of the stories of depression was written in Japan [1]. Before the 1990s, there was no word in Japanese for mild-to-moderate depression; and the sales of selective serotonin reuptake inhibitors (SSRIs) were zero, while the sales were approximately 13 billion dollars per year in other countries combined. Then, GlaxoSmithKline, the manufacturer of Paxil, started a massive marketing campaign. Two of their campaign's key messages were that depression was a common disease caused by a chemical imbalance in the brain and that “antidepressants” restored the balance. As a result, the sales of Paxil in Japan reached the level of a billion dollars per year by 2008.

One of the components of this story was the term “antidepressant,” which has been used in the USA since the 1950s. This term is attributed to Max Lurie, a psychiatrist in Cincinnati [2]. He referred to isoniazid , a monoamine oxidase inhibitor (MAOI) as an “antidepressant.” Thereafter, all pills prescribed for depression have been called “antidepressants,” including selective serotonin reuptake inhibitors (SSRIs). In labeling isoniazid as an “antidepressant,” Dr. Lurie did something quite customary in medicine (consider anti-inflammatory or antinausea medications). However, he was influenced by the story that depression was a disease, which led him to use medical terminology.

The prefix “anti” creates an impression of a dichotomous system, where the disease drives the pathological process forward, while an “anti-depressant” drives it back to health.

Here is what I think happens when people hear the term antidepressant : “There is a clear-cut thing, called depression. Depression is a disease, caused by a chemical imbalance in the brain. A cure from this disease is an “antidepressant” – it restores the chemical balance.”

Then, there is a twist:

“When your antidepressant didn’t work, we will consider your depression to be ' treatment-resistant .' Why? Because the anti-depressant was supposed to work. The very name suggests so. The only reason why it didn’t work was that your unruly depression was 'resistant.' Then what? Electro-convulsive therapy (ECT). Still resistant? Ketamine . Resistant still? Surgery.”

Please note that “treatment-resistant depression” was defined in the 1970s as a person’s lack of symptomatic improvement in response to two different courses of “antidepressants” [3]. Therefore, the term “treatment-resistant depression” assumes that anti-depressants are supposed to work. Such a definition is an example of circular logic – you define a drug based on the disease, and then you redefine the disease based on the patient's reaction to the drug.

Now we know that there is no causal theory of serotonin imbalance leading to depressive symptoms [9], and the evidence of the efficacy of SSRIs for depression is weak – it is three times lower than that of psychodynamic psychotherapy [4].

If the tale of depression as a disease is misleading, what are the alternatives? Jonathan Shedler suggested a useful metaphor – a fever. Fever is a non-specific state – it is common in various conditions. Flu, on the other hand, is a disease and we know its etiology (a set of causes) – it is a viral infection. Shedler suggested that depression, like fever, is a non-specific state, not a disease.

We know that Tylenol treats the symptom (fever) but does not cure the flu. Treating symptoms is important [5], as we could die from hyperthermia, but we need to know that the immune system cures the flu, not the Tylenol. Therefore, it would be misleading to describe a lasting flu as “treatment resistant” based on it not responding to Tylenol.

In addition to Shedler’s metaphor of a fever, an integrated, causal model of depression as a state was proposed in 2009 [10], and then further elaborated and refined [6, 9]. This model comes from Affective Neuroscience by the late Jaak Panksepp and his colleague Douglas Watt, as well as Mark Solms, Maggie Zellner, and others [6, 9]. It is called the "separation distress hypothesis." Some of the ideas in this model go back to Sigmund Freud and John Bowlby , but Pansepp and Watt made critical multidisciplinary contributions.

Summarizing the separation distress hypothesis here would not do it justice, as it is reasonably complex (so is the phenomenon it represents). You can find the latest update and systematic review of this model here [9]. The separation distress hypothesis combines innate, developmental, biological, psychological, and environmental factors. It does not reduce the macro phenomenon of depression to a molecular level of serotonin while ignoring all the levels in between. By now we have accumulated considerable evidence from multiple perspectives in support of the separation distress hypothesis [see 9 for a comprehensive review, as well as 6 and 8].

Repeated experiences of neglect, abuse, or abandonment in childhood , maladaptive habits, sleep disturbance, acute traumas at any age, complex trauma, and other factors can all lead to the patient suffering from repeated episodes (states) of depression. As you can see, depression, like fever, is non-specific and there are many possible pathways to it. It is biological and psychological at the same time.

What might the shift to the separation distress hypothesis result in? First, the dominant chemical imbalance story would have to be de-prioritized. An alternative understanding described by Mark Solms and his colleagues is that the feeling of depression means something [6,7]. Solms reminds us that this is not a new idea in medicine. A sensation of acute pain in the leg means that there is possibly a laceration there. Nausea means a possibly upset stomach. These “messages” guide us to what the problem is and where.

One of the meanings of depression, according to Mark Solms, is that our normal need to feel cared for is unmet [6, 7]. We feel painfully alone, unattached, or abandoned. This message is something we can notice, acknowledge, and work with in psychotherapy. Further, there are meaningful psychological reasons why the patient feels depressed, episodically or chronically. There is a way to discover in psychotherapy how this state came about and then work together with the patient to get to a stable resolution of this problem.

Using an etiological approach to depression would allow us to focus on the causal treatment that has shown significantly higher efficacy than SSRIs [4].

It is worthwhile saying that the separation distress hypothesis, like any other theory, has some limitations. For example, it lacks cultural sensitivity. However, I believe that this etiology-based, integrated model is more beneficial in guiding treatment choices for depression than the "chemical imbalance" model.

[1] Watters, E. (2010). Crazy like us: The globalization of the American psyche. Simon and Schuster.

[2] Pereira, V. S., & Hiroaki-Sato, V. A. (2018). A brief history of antidepressant drug development: from tricyclics to beyond ketamine. Acta neuropsychiatrica, 30(6), 307-322.

[3] Murphy JA, Sarris J, Byrne GJ. A review of the conceptualisation and risk factors associated with treatment-resistant depression. Depress Res Treat. 2017;2017:4176825. doi:10.1155/2017/4176825

[4] Shedler, J. (2010). The efficacy of psychodynamic psychotherapy. American psychologist, 65(2), 98.

[5] Solms, M. (2018). The scientific standing of psychoanalysis. BJPsych International, 15(1), 5-8.

[6] Zellner, M. R., Watt, D. F., Solms, M., & Panksepp, J. (2011). Affective neuroscientific and neuropsychoanalytic approaches to two intractable psychiatric problems: why depression feels so bad and what addicts really want. Neuroscience & Biobehavioral Reviews, 35(9), 2000-2008.

[7] Solms, M. L. (2018). The neurobiological underpinnings of psychoanalytic theory and therapy. Frontiers in Behavioral Neuroscience, 12, 402180.

[8] Blomstedt, P., Hariz, M. I., Lees, A., Silberstein, P., Limousin, P., Yelnik, J., & Agid, Y. (2008). Acute severe depression induced by intraoperative stimulation of the substantia nigra: a case report. Parkinsonism & related disorders, 14(3), 253-256.

[9] Watt, D. F. (2023). The separation distress hypothesis of depression–an update and systematic review. Neuropsychoanalysis, 1-57.

[10] Watt, D. F., & Panksepp, J. (2009). Depression: An evolutionarily conserved mechanism to terminate protracted separation distress. A review of aminergic, peptidergic and neural network perspectives. (Target article with invited commentaries). Neuropsychoanalysis, 11(1), 7–51. https://doi.org/10.1080/15294145.2009.10773593

Alexey Tolchinsky, Psy.D. , is a clinical psychologist in private practice in Maryland and a Clinical Fellow of the Neuropsychoanalysis Association.

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• Published: 16 February 2021

On inflammatory hypothesis of depression: what is the role of IL-6 in the middle of the chaos?

• Elnaz Roohi 1 ,
• Nematollah Jaafari 2 &
• Farshad Hashemian 1  

Journal of Neuroinflammation volume  18 , Article number:  45 ( 2021 ) Cite this article

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Many patients with major depressive disorder (MDD) are reported to have higher levels of multiple inflammatory cytokines including interleukin 6 (IL-6). Recent studies both pre-clinical and clinical have advocated for the functional role of IL-6 in development of MDD and suggested a great potential for targeting this cytokine to open new avenues in pharmacotherapy of depression. The purpose of the present narrative review was to provide an integrated account of how IL-6 may contribute to development of depression. All peer-reviewed journal articles published before July 2020 for each area discussed were searched by WOS, PubMed, MEDLINE, Scopus, Google Scholar, for original research, review articles, and book chapters. Publications between 1980 and July 2020 were included. Alterations in IL-6 levels, both within the periphery and the brain, most probably contribute to depression symptomatology in numerous ways. As IL-6 acts on multiple differing target tissues throughout the body, dysregulation of this particular cytokine can precipitate a multitude of events relevant to depression and blocking its effects can prevent further escalation of inflammatory responses, and potentially pave the way for opening new avenues in diagnosis, treatment, and prevention of this debilitating disorder.

Major depressive disorder (MDD) is a leading cause of disability throughout the world with a global prevalence of 2.6–5.9% [ 1 ]. The total estimated number of people living with depression worldwide increased by 49.86% from 1990 to 2017 [ 2 ]. According to worldwide projections, MDD will be the single major cause of burden of all health conditions by 2030 [ 3 ]. MDD is characterized by periods of low mood, altered cognition, considerable functional burden including impaired occupational functioning and psychosocial disability [ 4 ]. Despite available pharmacotherapeutic options, 30–60% of patients with MDD are not responsive to available treatments [ 5 ] and the rate of remission of the disease is often < 50% [ 6 ], while recurrence rates are more than 85% within 10 years of a depressive episode, and average about ≥ 50% within 6 months of assumed clinical remission [ 4 ]. Indeed, there exists no compelling evidence that current treatments are capable of disease modification in MDD patients. Thus, therapeutic deficiency in treatment outcomes reflects the demand for revitalizing psychiatric therapeutics with novel pharmacotherapeutic options that engage non-monoaminergic molecular targets.

A large body of evidence suggests that inflammation has central role in pathogenesis of MDD [ 7 , 8 , 9 , 10 , 11 , 12 , 13 ]. However, the exact mechanisms underlying inflammation-induced depression are not completely elucidated [ 3 ]. Historically, the “monoamine-depletion hypothesis” has been the main proposed pathophysiology [ 14 ]; nevertheless, this hypothesis alone cannot fully account for pathogenesis of MDD [ 15 , 16 ]. In recent years, “inflammatory hypothesis” has been proposed [ 17 ]. However, it is noteworthy that it was probably in the early 1990s that for the first time, possible relationships between the peripheral immune system and major depression was studied [ 18 ]. Maes et al. (1992) established immune cell profile of patients with depression and advocated for the existence of a systemic immune activation during major depressive disorder [ 19 ]. Moreover, correlations between IL-6 activity, acute phase proteins, and hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis were suggested in severe depression [ 20 ].

Most proximally, inflammation is regulated by expression of immune response genes including interleukin (IL)-1B, tumor necrosis factor (TNF), and IL-6 which promote secretion of pro-inflammatory cytokines leading to systemic inflammation. Distally, inflammation is regulated in the brain where socio-environmental cues including possible threat are detected. This neuro-inflammatory link can activate the conserved transcriptional response to adversity (CTRA) before happening of a possible threat or bacterial infection. However, the negative aspect of central regulation of systemic inflammation is that it can give social and foreseen dangers (including those that have not yet occurred or may never actually happen) the ability to activate the CTRA in the absence of actual physical danger. Under normal conditions, CTRA-related inflammatory activity is downregulated by the HPA axis via the production of cortisol. Nevertheless, when prolonged actual or perceived social threat or physical danger is present, glucocorticoid resistance can develop which leads to excessive inflammation that heightens a person’s risk for development of several disorders including MDD, especially if activation of these pathways is prolonged [ 21 ]. As mentioned above, the current understanding of MDD encloses not only alterations in neurotransmitters, but also changes in immune and endocrine functioning as well as neural circuits [ 22 ]. This broadened framework has just started to inform a wide array of novel, personalized therapeutics that are showcasing great promise in a new holistic approach to MDD [ 23 ].

Cytokines are implicated in pathogenesis of MDD [ 24 , 25 , 26 , 27 , 28 , 29 , 30 ]. Risk factors of developing MDD include familial, developmental, psychological, and medical risk factors as well as molecular factors associated with genetics, epigenetics, gene expression, and also those related to the endocrine and the immune system [ 31 , 32 ]. All these risk factors have been shown to be related with changes in cytokine production or signaling. In other words, cytokines are involved in almost every predisposing or precipitating risk factor associated with MDD [ 24 ]. Indeed, there is accumulating evidence in favor of involvement of pro-inflammatory cytokines in pathophysiology of depression [ 24 , 29 , 33 , 34 , 35 , 36 ]. Various studies reported higher levels of multiple inflammatory markers including IL-6 in patients with MDD [ 37 , 38 , 39 , 40 , 41 ]. Of all pro-inflammatory cytokines, changes in IL-6 serum levels have been reported as one of the most reproducible abnormalities in MDD [ 38 ].

The aim of the present narrative review is to elucidate the fundamentals, implications, challenges of cytokine research specifically IL-6 in major depressive disorder. This comprises of the following:

-) A Brief overview of cytokines

-) Cytokine categories according to immunological function.

-) IL-6 as a pleiotropic cytokine.

-) Brief overview of chemokines and their role in Depression.

-) Challenges of cytokine research in psychiatry.

-) IL-6 alterations in depression.

-) Effects of IL-6 on neurotransmitters’ synthesis, signaling, metabolism, and function.

-) Effects of IL-6 levels on brain morphology in depression.

-) Blockade of IL-6 and its receptor in the periphery as a potential therapeutic option in MDD.

-) Possible role of IL-6 together with gut microbiota in pathogenesis of depression.

-) Elevated levels of IL-6 in patients with COVID-19 infection.

The present article is a narrative review. All peer-reviewed journal articles published before July 2020 for each area discussed were searched by WOS, PubMed, MEDLINE, Scopus, Google Scholar, for original research, review articles, and book chapters. We selected articles on the basis of being comprehensive, innovative, and informative for an in-depth understanding and a critical debate on the topic. Publications between 1973 and 2020 were included.

A brief overview of cytokines

Cytokines are a broad category of released proteins that act as signaling molecules to regulate inflammation and cellular activities [ 24 , 42 ]. They are produced by different immune cells (e.g., macrophages, lymphocytes, mast cells), parenchymal cells, endothelial and epithelial cells, fibroblasts, adipocytes, and stromal cells within the periphery [ 24 , 43 ]. Additionally, they are produced by microglia, astrocytes, and neurons in the brain [ 44 ]. Cytokines from the periphery (peripherally produced cytokines) can exert influences on inflammatory processes in the brain [ 45 , 46 ]. Indeed, they can enter blood-brain barrier (BBB) and affect the brain via humoral (accessing the brain through leaky secretions of the BBB such as choroid plexus), neural (through stimulation of primary afferent nerve fibers in the vagus nerve), and cellular (through stimulation of microglia by pre-inflammatory cytokines to produce monocyte chemottractant protein-1 and recruit monocytes to the brain) pathways [ 47 ]. Most cytokines function in their immediate microenvironment. Few of them are involved in paracrine signaling which indeed is fundamental to the control of an inflammatory response within a given tissue or organ and the activation of a coordinated immune response that involves multiple cell types [ 48 ]. Apart from navigating the immune system to defend the body from pathogens, cytokines have a modifying effect on neurotransmission [ 49 ].

It’s also noteworthy that the same cytokines can be produced by multiple cell types. For example, white blood cells, endothelium, fat cells, and other cells can produce TNF-α [ 50 ]. Additionally, one single cell can release different cytokines. For instance, T Helper type 2 (T H 2) cells can produce IL-3, IL-4, IL-5, IL-6, and IL-13 [ 24 ]. Cytokines can have pleiotropic, redundant, synergistic, and antagonistic effects [ 51 ]. The phenomenon that a single cytokine can act on several different cell types is called pleiotropy [ 51 ]. For instance, IL-10 can activate T H 2 cells and B cells, yet inhibit macrophages and T helper type 1 (T H 1) cells. Thus, being immunostimulatory as well as being immunosuppressive [ 52 ]. Cytokines are redundant in their activity, i.e., similar functions can be exerted by different cytokines. For instance, interferon (IFN)-γ, IL-2, and TNF-α enhance cellular immunity and production of cytotoxic cell contacts [ 53 ]. Cytokines can also act synergistically, i.e., they can have combined effects when acting together. For instance, IL-3 and IL-4 amplify each other’s effects to induce growth, differentiation, and activation of mast cells in a synergistic manner [ 24 ]. Another phenomenon in cytokines signaling is antagonism. An example of cytokine antagonism is that cytokines of the IL-1 superfamily can antagonize IL-18 effects [ 54 ].

Cytokine categories according to immunological function

Four categories of cytokines are usually referred to in psychoimmunological literature. (1) T H 1 cytokines (IL-2, IL-12, IFN-γ) which induce cytotoxic cell contacts. (2) T H 2 cytokines (IL-4, (IL-5, IL-13) which lead to production of antibodies. (3) Pro-inflammatory cytokines (IL-1, IL-6, IL-8, IL-17, IL-21, IL-22, IFN-α, TNF-α) which further the progress of inflammation. (4) Anti-inflammatory cytokines (IL-10, transforming growth factor-beta (TGF)-β which are influenced by regulatory T cells and impede inflammatory process from escalating [ 24 ]. However, these categories are not distinct and it must be considered that cytokines can exert various effects on different cells and therefore, they may have pro- and also anti-inflammatory properties. For instance, IFN-α which has been listed as a pro-inflammatory cytokine can also have anti-inflammatory properties [ 55 ].

IL-6 as a pleiotropic cytokine

IL-6 was first identified as a differentiation factor for B cells which stimulates production of antibodies by activated B cells. Apart from regulation of acute inflammation, IL-6 is known to induce differentiation of B cells, and activation and population expansion of T cells [ 56 ]. Within the peripheral and central nervous system (CNS), IL-6 can act as a neuronal growth factor inducing neurite development and nerve regeneration [ 57 ]. IL-6 receptor (IL-6R) consists of the IL-6-binding chain which has two forms of transmembrane IL-6R and soluble IL-6R (sIL-6R) [ 58 ] and a gp130 signal-transducing chain [ 59 ]. Following binding to its receptor (IL-6R), IL-6 initiates to exert its multiple functions.

It is quite interesting that IL-6 exerts both pro- and anti-inflammatory properties [ 60 , 61 ]. Indeed, its signaling is complex and can lead to both inflammatory and anti-inflammatory cascades depending upon the presence of either IL-6 receptor (IL-6R) or the membrane bound gp130 signal transducer and these are expressed at very different frequencies within specific cell type in the body [ 5 ]. Trans-signaling of IL-6, in which the soluble form of the IL-6 receptor (sIL-6R) is shed from the membrane bound receptors, is known to be pro-inflammatory [ 62 ]. The sIL-6R binds to IL-6 and is transported to any cell type on which gp130 is expressed [ 63 ]. While most soluble receptors (e.g., soluble receptor for TNFα) result in antagonistic action by competing for the ligand, the sIL-6R is agonistic and increases the types of cells through which IL-6 can signal. Additionally, IL-6 engages in classical signaling which is anti-inflammatory [ 63 ] and occurs through binding of IL-6 to the membrane bound cell surface receptor. Classical signaling of IL-6 solely occurs on some subsets of T cells, neutrophils and monocytes megakaryocytes, and hepatocytes [ 64 ]. In both classical and trans-signaling, the IL-6/IL-6R/gp130 complex uses two pathways to activate intracellular signaling namely the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway and the mitogen-activated protein kinase (MAPK) pathway [ 5 ].

Indeed, IL-6 has been mostly regarded as having pro-inflammatory properties; however, it has many anti-inflammatory functions which are necessary for resolution of inflammation [ 65 ]. For instance, IL-6 inhibits activity of the transcription factor named nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and expression of the chemokine receptor on dendritic cells which is needed for recruiting these cells to lymphoid tissues; thus, involving in resolution of inflammation [ 66 ]. Research findings showed that IL-6 has a crucial role in regulation of T helper17 (Th17)/regulatory T (Treg) cells [ 67 ]. In the presence of TGF-β, IL-6 is a vital signal for differentiation of naive T cells into Th17 cells which in turn are implicated in induction of autoimmune diseases [ 68 , 69 ], and result in local tissue injury in chronic inflammatory disorders [ 70 ]. On the contrary, IL-6 can strongly inhibit the TGF-β-induced differentiation of Treg cells which in turn results in inhibition of autoimmunity and protects against tissue damage [ 71 ]. Functional dichotomy of IL-6 indicates that it may be responsible for maintaining the balance between pro- and anti-inflammatory responses, while having tissue-specific properties at the periphery and in the CNS [ 72 ].

Brief overview of chemokines and their role in depression

Chemokines are small chemotactic cytokines that are identified to have significant roles in migration of immune cells, induction of direct chemotaxis, and propagation of inflammatory responses [ 73 ]. They are classified into four sub-families based on their structural criteria (i.e., the number and spacing of their two N-terminals, disulfide bonding participating cysteine residues). These four subfamilies include CXC, CC, C, and CX3C [ 74 ]. Furthermore, they can be categorized according to their biological activity, namely, the maintenance of homeostasis and the induction of inflammation. There are also chemokines which have dual functionality [ 75 ].

These small chemotactic cytokines are known to be secreted in response to inflammatory cytokines; thereafter, selectively recruiting lymphocytes, monocytes, and neutrophil-inducing chemotaxis by activating G-protein-coupled receptors (GPCRs) [ 76 ]. A growing body of evidence suggests that chemotactic cytokines are implicated in neurobiological processes relevant to psychiatric disorders such as synaptic transmission and plasticity, neuroglia communication, and neurogenesis [ 77 ]. Indeed, disruption of any of the mentioned functions which may take place by activation of the inflammatory response system has consistently been found to be relevant in pathogenesis of depression [ 73 ].

There are indeed both pre-clinical and clinical evidence in support of linking alterations in the chemokine network to depressive behavior [ 73 ]. In an animal model of depression, namely prenatal stressed rats, levels of CCL2, and CXCL12 chemokines were found to be upregulated in the hippocampus and prefrontal cortex, which was indeed suggestive of excessive microglial activation [ 78 ]. Additionally, Trojan et al. (2017) investigated the modulatory properties of chronic administration of anti-depressants on the chemokines. According to their results, chronic administration of anti-depressants has been shown to normalize the prenatal stress-induced behavioral disturbances together with the observed alterations in CXCL12 and their receptor. Indeed, they concluded that alterations of CXCL12 and their receptor and at less extend changes in CX3CL1–CX3CR1 expression will probably be normalized following chronic treatment with anti-depressants [ 79 ].

Moreover, several clinical studies found correlations between elevated levels of circulating inflammatory chemokines and depressive symptoms in patients with major depressive disorder [ 73 , 80 , 81 , 82 , 83 ]. According to the results of a comprehensive meta-analysis, peripheral concentrations of a number of chemokines including CCL2, CCL3, CCL4, CCL11, CXCL4, CXCL7, and CXCL8 can potentially discriminate between individuals with depression and those without [ 84 ]. Additionally, Ślusarczyk et al. (2016) provided a comprehensive account of the role of chemokines in processes underlying depressive disorder [ 85 ].

Challenges of cytokine research in psychiatry

There are some difficulties faced by researchers in conducting cytokine research in psychiatry. The major problem seems to be heterogeneity of the obtained results. In other words, research outcomes are conflicting and challenging to interpret [ 24 ]. Moreover, research in this area is largely based on measurement of cytokine levels in the periphery and it is not completely clear how serum or plasma levels of cytokines reflect the situation in the brain [ 47 ]. Compellingly, results of studies that examined both peripheral and CFS levels of IL-6 found no correlations between the mentioned measures; thus, suggesting that peripheral levels of IL-6 may not directly reflect central IL-6 levels [ 86 , 87 ].

It is also noteworthy that some environmental, social, biological, and medical factors may influence peripheral cytokine changes. For instance, one of the characteristics of obesity is chronic inflammation with the increased circulating levels of cytokines [ 88 , 89 ]. Indeed, adipose tissue is reported to build up and activate lymphocytes and macrophages that secrete inflammatory factors [ 89 , 90 ]. Interestingly, obese people show behavioral symptoms such as MDD and cognitive dysfunction at an increased rate in comparison with the general population [ 91 , 92 ]. Therefore, one may argue that alterations in cytokine levels are somehow unspecific [ 24 ]. Additionally, there is a considerable overlap in cytokine values between patients in the acute phase of depression, patients in remission, and patients who are recovered [ 24 ]. Although the use of cytokines as potential biomarkers of depression has been discussed frequently in various studies, cytokine changes have been reported in other psychiatric disorders as well. For instance, increased levels of pro-inflammatory cytokines have been reported in generalized anxiety disorder [ 93 , 94 , 95 ], obsessive-compulsive disorder [ 96 ], posttraumatic stress disorder [ 97 , 98 ], and sleep disorder [ 99 ].

Moreover, cytokine levels change during pharmacotherapy of depression. Indeed, it has been suggested that treatment with anti-depressants can potentially lead to alteration in peripheral levels of cytokines. According to the results of a meta-analysis, anti-depressants, overall, cause decrease in peripheral levels of IL-6, IL-10, and TNF-α [ 100 ]. However, anti-psychotics which are used in psychotic depression, especially those with the highest risk of weight gain (e.g., clozapine and olanzapine), cause significant increase in the blood levels of pro-inflammatory cytokine [ 101 ]. Additionally, mood stabilizers such as lithium and carbamazepine have also been linked with an increase in the peripheral levels of cytokines [ 102 ]. In sum, as cytokine signaling often exhibits pleiotropic, redundant, synergistic, and antagonistic effects, it seems to be advisable to consider all cytokines that work together or against each other and therefore, take into account the whole range of cytokines instead of a single one.

On the role of interleukin-6 in depression

Il-6 alterations in depression.

A growing body of evidence suggests that IL-6 has a crucial role in pathogenesis of depression [ 3 ] and is the most consistently increased cytokine in blood samples of MDD patients [ 38 , 103 ]. The first promising evidence for the role of IL-6 in occurrence of depression is most probably provided by a longitudinal study in which children with higher circulating levels of IL-6 at age 9 were found to be at a 10% greater risk of developing MDD by age 18, compared to the general population or children with low IL-6 levels. Indeed, the researchers concluded that inflammation and high IL-6 levels possibly predate the occurrence of depression [ 104 ]. Another evidence for potential role of IL-6 in depression is that peripheral levels of IL-6 were found to be positively correlated with symptom severity in anti-depressant non-responders [ 105 ].

Stress-based preclinical models of depression showed that IL-6 levels are increased following the onset of depression-associated behaviors. Rodents who were exposed to chronic mild stress exhibited anhedonia and elevated circulating levels of pro-inflammatory cytokines including IL-6 [ 106 , 107 ]. Moreover, in another study on male Wistar rats, serum levels of pro-inflammatory cytokines including IL-6 were reported to be higher in acute and restraint stress compared to non-stressed rats [ 108 ]. It is also noteworthy that some studies reported no significant alteration in peripheral levels of IL-6 in chronic mild stress models of depression [ 109 ]. Nevertheless, they reported elevated CNS levels of other inflammatory markers which probably reflects a time-dependent shift from peripheral to central cytokine activation or potential transport of the peripheral cytokines into CNS [ 109 ]. Another promising evidence was provided by studies on IL-6 knockout mice. Indeed, they were reported to be resistant to the development of depression-like phenotype following long-term light deprivation in the constant darkness, proposing a functional role for IL-6 in stress susceptibility [ 110 ]. Moreover, Ślusarczyk et al. (2015) found evidence for the role of prenatal stress as a priming factor that could exhibit effects on microglial cells and consequently lead to depressive-like disturbances in adult rat offspring. According to their results, the release of pro-inflammatory cytokines including IL-6 is enhanced in microglia obtained from prenatally stressed animals compared to control animals [ 78 ].

In fact, not every individual exposed to prolonged or acute stress develops a psychiatric disorder [ 111 ]. According to previous research, vulnerability to repeated social defeat stress is predicted by differences in IL-6 levels in the innate peripheral immune system [ 112 ]. Following induction of social defeat stress, two thirds of mice were reported to show depression-like behavior measured by social avoidance, anhedonia, circadian system disruptions, and metabolic changes [ 113 ] together with elevated activation of pro-inflammatory cytokines such as IL-6 [ 112 ]. Indeed, higher degrees of elevation in peripheral IL-6 levels of susceptible mice were reported in comparison with resilient mice. Moreover, it was found that this increase occurs within 20 min of the first social defeat. Interestingly, mice that later became susceptible had higher number of leukocytes and those leukocytes produced more levels of IL-6 following stimulation via LPS ex vivo [ 112 ]. Additionally, studies with non-social stress-based models found evidence for the functional role of IL-6 in the development of stress susceptibility. In these models, animals were exposed to a controllable or uncontrollable stress (e.g., shock), and their ability to actively escape a subsequent stressor was measured. According to the results, 20% of animals who were exposed to uncontrollable stress were found susceptible and developed learned helplessness and the rest were found to be resilient. Interestingly, susceptible animals showed elevated levels of peripheral IL-6 together with anhedonia in contrast to resilient animals [ 114 ].

Clinical studies have also revealed that patients with MDD have increased levels of plasma and serum concentrations of pro-inflammatory cytokines including IL-6 in comparison with healthy controls [ 24 , 100 , 115 , 116 ]. It should be noted that three meta-analyses verified increased peripheral IL-6 levels in MDD patients compared to healthy volunteers [ 38 , 116 , 117 ]. Nevertheless, there are also studies reporting no significant differences in IL-6 levels in MDD patients compared to healthy volunteers [ 118 ]. However, one may argue that different subtypes of depression and certain depressive symptoms should be taken into account. For instance, Rudolf et al. (2014) compared IL-6 levels among patients with atypical and typical depression and healthy controls. According to their results, IL-6 levels were significantly increased in patients with atypical depression and not in typical MDD patients compared to healthy controls [ 119 ]. Additionally, Rush et al. (2016) studied peripheral levels of IL-6 and TGF-β in 55 melancholic depressed patients. They were found to have significantly higher baseline IL-6 levels compared to healthy controls. Moreover, these elevated levels of IL-6 did not normalize following electroconvulsive therapy (ECT) [ 120 ]. A recent systematic review conformed Rush et al.’s results. In the mentioned review, authors found that peripheral IL-6 levels are increased in patients with melancholic depression in comparison with controls [ 121 ]. Moreover, Maes et al. (1997) examined serum levels of IL-6 and IL-1 receptor antagonist in patients with chronic, treatment resistant depression both before and after subchronic treatment with anti-depressants. According to their results, subchronic treatment with anti-depressants had no significant impact on serum levels of IL-6; nevertheless, it decreased serum soluble IL-6R levels significantly [ 122 ].

Effects of IL-6 on neurotransmitters’ synthesis, signaling, metabolism, and function

The effects of cytokines on neurotransmitters have been studied extensively [ 49 , 123 ]. Cytokines and their signaling pathways (e.g., p38 mitogen activated protein kinase) are reported to exhibit significant impacts on metabolism of multiple neurotransmitters such as serotonin, dopamine, and glutamate; thus, influencing their synthesis, release, and reuptake [ 49 ]. Indeed, cytokines can decrease synthesis of serotonin via activating the enzyme indoleamine 2,3 dioxygenase (IDO) which breaks the precursor of serotonin (i.e., tryptophan) to kynurenine (KYN) instead of metabolizing tryptophan to serotonin; thus, leading to serotonin depletion [ 3 ]. The process of serotonin depletion has been long associated with major depression [ 124 , 125 ]. Moreover, cytokines can modulate serotonin signaling via elevating the expression and function of monoamine transporters. These transporters are known to re-uptake serotonin [ 126 , 127 ].

IL-6 is known to influence neurotransmission by modulating the behavioral output of the brain; however, the exact mechanism is unknown. A previous study showed that IL-6 directly controls the levels of serotonin transporter (SERT) and therefore influences serotonin reuptake. Indeed, the researchers concluded that IL6-induced modulation of serotonergic neurotransmission through the signal transducer and activator of transcription 3 (STAT3) signaling pathway contributes to the role of IL6 in depression [ 128 ]. The activity of SERT forms serotonergic transmission which is implicated in depressive behavioral changes and pathophysiology of the disease [ 129 ]. By intensifying dopaminergic and serotonergic turnover in hippocampus and frontal cortex, IL-6 influences neurotransmission of catecholamines [ 130 ]. It seems that noradrenaline is not affected by IL-6; however, noradrenaline itself can induce expression of IL-6 in glial cells [ 131 ]. IL-6 together with other pro-inflammatory cytokines can activate kinurenine pathway which is involved in glutamatergic neurotransmission [ 132 ].

Effects of IL-6 levels on brain morphology in depression

Previous studies showed that elevated levels of pro-inflammatory cytokines such as IL-6 may affect neurogenesis [ 133 ] and neural plasticity [ 134 ]. Imaging studies have shown that specific brain regions such as basal ganglia (which is involved in motor activity and motivation), the dorsal anterior cingulate cortex (ACC) (which has a central role in generation of anxiety), and the subgenual ACC (which is known to be involved in the development of depression) are influenced by cytokines [ 135 , 136 ]. Additionally, high IL-6 expression levels demonstrated neuropathologic manifestations including neurodegeneration [ 137 , 138 ].

There are many studies in which positron emission tomography (PET) has been applied to test translocator protein (TSPO) binding, a marker of neuroinflammation, in order to study neuroinflammatory hypothesis of depression [ 139 , 140 , 141 , 142 , 143 ]. According to their results, neuroinflammation was present in various regions of the brain (e.g., neocortical grey matter, frontal cortex, prefrontal cortex, anterior cingulate cortex, insula, temporal cortex) as well as the hippocampus [ 139 , 140 , 141 , 142 , 143 ].

In a recent study, Kakeda et al. (2018) evaluated possible relationship between serum levels of IL-1β, IL-6, IFN-γ, and TNFα and brain morphology in terms of brain cortical thinning and hippocampal subfield volumes during the first depressive episode in drug-naïve patients with MDD using a whole-brain SBM analysis. They found a significant inverse correlation between prefrontal cortex (PFC) thickness and serum IL-6 level in MDD patients. Indeed, high serum levels of IL-6 were correlated with reduced left subiculum and right CA1, CA3, CA4, GC-DG, subiculum, and whole hippocampus volumes in MDD patients. Additionally, thickness of the superior frontal and medial orbitofrontal cortices in patients with depression was significantly decreased compared to healthy controls. Since PFC contains high concentrations of IL-6 receptors, IL-6 mediated neurotoxicity might happen under conditions in which high serum IL-6 levels are present (i.e., early stages of MDD). Consequently, the authors advocated that the neuroinflammatory status in the early stage of MDD is associated with changes in the brain gray matter and IL-6 probably plays a key role in the morphological changes observed in the PFC during early stages of the disease. It is also noteworthy that serum IL-6 was the only cytokine among the tested cytokines that showed significant differences between the patients and controls in their study. Indeed, serum IL-6 levels were found to be significantly higher in MDD patients than in healthy controls [ 144 ]. In another study, Frodl et al. (2012) investigated possible effects of changes in the glucocorticoid and inflammatory systems on hippocampal volumes in patients with MDD. According to their results, MDD patients showed increased IL-6 levels and smaller hippocampal volumes compared to healthy controls. Positive effects of messenger RNA (mRNA) expression of glucocorticoid-inducible genes and further inverse effects of IL-6 concentration, on hippocampal volumes were also reported. Thus, they concluded that increased expression of IL-6 can probably predict decreased hippocampal volume [ 145 ].

As already mentioned, there is considerable amount of evidence regarding the central role of the highly plastic, stress-sensitive hippocampal region in pathogenesis of depression [ 146 ]. Indeed, grey-matter structures, including the hippocampus are vulnerable to atrophy in depression [ 147 , 148 ]. Hippocampal volume reductions are most probably the result of remodeling of key cellular elements, involving retraction of dendrites, loss of glial cells, and decreased neurogenesis in the dentate gyros [ 149 ]. Factors underlying this cellular remodeling are known to be stress-induced increased levels of glucocorticoids, which are implicated in decreased neurogenesis [ 150 ]. Moreover, increased activity of the HPA axis resulting in decreased levels of glucocorticoids combined with resistance to glucocorticoid-induced negative feedback control is commonly observed in depression [ 151 ]. This dysregulation of glucocorticoid secretion along with the increased activity of excitatory neurotransmitters can potentially lead to cellular remodeling (which can be reversible) and hippocampal neurons cell death in patients with depression [ 152 ]. Since hippocampus has been identified to have a role in negative feedback inhibition of glucocorticoids, remodeling or neuronal damage may lead to less efficient inhibitory control of the corticotrophin-releasing hormone, resulting in elevated amounts of circulating glucocorticoids and further damage of the hippocampal neurons [ 153 ]. Taken together, it seems that further studies are required to elucidate the physiological mechanisms in which IL-6 might exert changes in the brain grey matter. A brief overview of the effects of cytokines including IL-6 on brain morphology is shown in Fig. 1 .

Effects of cytokines including IL-6 on brain morphology

Blockade of IL-6 and its receptor in the periphery as a potential therapeutic option in MDD

Growing body of evidence suggests that abnormalities in the immune system are most probably relevant to pathogenesis and potential novel treatment of psychiatric disorders. Previous studies showed that alterations in the peripheral IL-6 levels might contribute to depressive-like behavior in animal studies [ 3 , 112 , 114 , 154 ]. Moreover, IL-6 knockout mice showed resistance to development of depressive-like behavior [ 155 ] which gives further evidence for possible role of IL-6 pathogenesis of depression. High peripheral levels of IL-6 are even more apparent in patients with treatment-resistant depression. Additionally, correlations have been found between decrease in IL-6 levels and alleviation of depressive symptoms in patients who were responsive to the pharmacotherapy [ 156 ]. Moreover, results of a study on 222 stroke patients indicated significant associations between IL-6 periphery levels and development of MDD within 2 weeks and at 1 year following stroke. Furthermore, significant correlations were found between statin use and IL-6 on the presence of a depressive disorder at the 1st year. Indeed, preventive effects of treatment with statins (which are known to possess anti-inflammatory properties and potently reduce the cytokine-mediated IL-6 release [ 157 ]) against post-stroke depression was confirmed [ 158 ]. Thus, suppression of IL-6 activity could possibly lead to clinical recovery and may be considered as a novel pharmacotherapeutic option. Utilizing IL-6 receptor antibodies (for instance, Tocilizumab) or IL-6 antibodies (for instance, Sirukumab or Siltuximab) for reduction of IL-6 activity seems to be a novel strategy.

Blockade of IL-6 receptor by the humanized anti-IL-6 antibody, Tocilizumab has been used in treatment of rheumatoid arthritis (RA) [ 159 , 160 , 161 , 162 , 163 ] and systemic juvenile idiopathic arthritis [ 164 , 165 , 166 ]. Extensive clinical studies have established both short-term and long-term efficacy and safety of Tocilizumab [±conventional disease-modifying anti-rheumatic drugs (DMARDs)] in adults with moderate to severe RA. Additionally, Tocilizumab was shown to be effective as a monotherapy in patients with systemic juvenile idiopathic arthritis and also in patients whose disease has been refractory to other therapies [ 164 ]. Moreover, the safety profile of tocilizumab was reported to be consistent over time and also consistent with safety profile of other immunomodulatory agents [ 162 ]. It is also important to note that oral tocilizumab has been shown to inhibit experimental autoimmune encephalitis by elevating Th2 anti-inflammatory cytokines and decreasing pro-inflammatory Th1 cytokines [ 167 ]. With regard to crucial role of IL-6 in regulating metabolic homeostasis, side effects such as significant weight gain followed by hypertrygliceridemia and hypercholesterolemia may be observed in patients treated with tocilizumab [ 168 ]. Blockade of IL-6 trans-signaling, while classical IL-6R signaling stays intact seems to be crucial for the goal of maintaining gut mucosal integrity and epithelial regeneration [ 65 ]. Indeed, few randomized clinical trials were conducted on anti-depressant properties of tocilizumab. According to the results of a recent meta-analysis of anti-depressant activity of anti-cytokine therapies, treatment with tocilizumab showed statistically significant improvements in depressive symptoms [ 169 ].

Another promising human monoclonal antibody against Il-6, namely Sirukumab has been reported to be a safe and well-tolerated agent, capable of modulating the immune response in healthy populations as well as in patients with inflammatory disorders (e.g., rheumatoid arthritis). It targets the IL-6 signaling pathway by inhibition of both the pro- and anti-inflammatory effects of IL-6 [ 170 ]. Effects of Sirukumab on cytokine networks provide a well-founded rationale for its potential use in pharmacotherapy of psychiatric disorders promising possible advantages across varying domains of the biobehavioral research criteria [ 171 ]. In a phase 2, double-blind, placebo-controlled trial, the efficacy of Sirukumab and Siltuximab on depressive symptoms was studied in patients with rheumatoid arthritis or multicentric Castleman’s disease respectively. Compared with placebo, both IL-6 neutralizing antibodies were found to make significantly greater improvements on depressive symptoms in the patients [ 172 ]. Results of a recent mega-analysis of 18 randomized, placebo-controlled clinical trials of efficacy of immunomodulatory drugs on depressive symptoms in patients with inflammatory disorders demonstrated promising results ( N = 10,743 participants). According to their findings, anti-IL-6 antibodies (sirukumab and siltuximab) had large and statistically significant effect sizes on core depressive symptoms before correction for physical health outcomes. Additionally, their effects remained significant in non-responders for the primary disease states evaluated [ 173 ]. Although further research is needed in this area, potential application of anti-IL-6 antibodies could possibly open new avenues in pharmacotherapy of MDD.

Possible role of IL-6 together with gut microbiota in pathogenesis of depression

The human intestine harbors nearly 100 trillion bacteria [ 174 ] consisting assemblages of microorganisms associated with various niches in and on the body with long-term implications to health [ 175 ]. Evidence is emerging regarding correlations of microbial activities with progressive structural and functional processes in the brain of both animal models and humans [ 175 ]. There is a large body of evidence for the role of gut microbiota composition in pathogenesis of depression [ 176 , 177 , 178 , 179 , 180 ]. Moreover, there is growing body of literature for the influence of the gut microbiome on cytokine signaling [ 181 , 182 ].

The dominant gut microbial phyla are known to be Firmicutes and Bacteroideteds [ 183 , 184 ]. The Firmicutes / Bacteroideteds ratio is of great relevance in signaling human gut microbiota status [ 185 ]. For instance, increased levels of Firmicutes / Bacteroideteds ratio have been reported in patients suffering from irritable bowel syndrome (IBD) and seem to have some correlations with development of depression and anxiety [ 186 , 187 ]. Additionally, Firmicutes / Bacteroideteds ratio is associated with overall alterations in bacterial profiles at different life stages [ 185 ]. In a novel study, researchers reported decreased Firmicutes / Bacteroideteds ratio in mice following social defeat stress; thus, proposing possible role of Firmicutes / Bacteroideteds in depressive-like behavior. Furthermore, administration of anti-mouse IL-6 receptor antibody (MR16-1) attenuated the decreased ratio of Firmicutes / Bacteroideteds in susceptible mice. Thus, the researchers concluded that anti-mouse IL-6 receptor antibody may have anti-depressant-like effects by normalizing the Firmicutes / Bacteroideteds ratio via modulation of the immune system [ 3 ].

Decreased number of Oscillospira was detected in patients with depression [ 180 ] which suggests for possible role of Oscillospira in pathogenesis of depression. Two animal studies yielded same results. A recent study investigated therapeutic effects of finasteride on depressive-like behavior in rats together with 1 month of treatment withdrawal. Withdrawal from finasteride was associated with increased depressive-like behavioral responses. Therapeutic use of finasteride was linked with elevations in the phylum Bacteroidetes and in the family Prevotellaceae, and withdrawal was found to be correlated with decreases in the family Ruminococcaceae and the genera Oscillospira and Lachnospira [ 188 ]. In another study, socially stressed mice developing depression-like symptoms showed increases at the genus level of fecal Oscillospira . Interestingly, IV administration of anti-mouse IL-6 receptor antibody (MR16-1) normalized depression-like behavior and resulted in significant decrease in Oscillospira levels towards pre-stressor levels [ 3 ]. Moreover, increased number of Sutterella was reported in fecal samples [ 189 ] and intestinal biopsy samples of children with Autism spectrum disorder [ 190 ]. Additionally, elevated number of Staphylococcus and Sutterella were found in mice following social defeat stress. It is likely that Staphylococcus and Sutterella play a role in the depressive-like behavior via infection-induced inflammation. Interestingly, administration of anti-mouse IL-6 receptor antibody resulted in attenuation of elevated number of Staphylococcus and Sutterella following social defeat stress in mice [ 3 ].

These findings advocate that peripheral IL-6 may have a significant role in pathogenesis of MDD and blockade of IL-6 receptor in the periphery may exhibit rapid-onset effects by attenuating the altered composition of gut microbiota. Taking into account the role of gut-microbiota in immunomodulation, it is highly probable that gut-microbiota-brain- axis plays a role in anti-depressant actions of treatment with anti-IL-6 receptor [ 3 ]. A brief overview of the role of IL-6 together with gut microbiota in pathogenesis of depression is shown in Fig. 2 .

A brief overview of the role of IL-6 together with gut microbiota in pathogenesis of depression

Elevated levels of IL-6 in patients with COVID-19 infection

The world-wide effect of the coronavirus disease 2019 (COVID-19) pandemic is enormous and is not solely limited to the increased mortality and morbidity rates, but also extends into the mental health of the global population [ 191 ]. Considerable amount of clinical data is emerging regarding the manifestation of depression in patients during [ 192 , 193 , 194 ] and post-COVID 19 infection [ 192 , 193 , 194 , 195 ]. It is estimated that about 48% of confirmed COVID-19 cases displayed overt psychological symptoms such as depression and often expressed feelings of regret, loneliness, helplessness, and irritation [ 196 ].

There is growing body of literature regarding dual role of IL-6 in COVID-19 infection and depression [ 192 ]. Normal plasma levels of IL-6 in adults range between 1 and 10 pg/ml; whereas in a systemic inflammation this amount increases to several ng/ml [ 197 ] and even higher concentrations were reported in COVID-19 patients [ 198 ]. Indeed, cytokine release syndrome (CRS) is common in COVID-19 patients and increased levels of serum IL-6 have been identified to be significantly associated with acute respiratory distress syndrome (ARDS), respiratory failure, and poor disease outcome in numerous studies [ 192 , 199 , 200 , 201 ]. Studies suggest that new onset depression is most probably caused by inflammation initiated during the active phase of the infection leading to a cytokine surge [ 202 ]. Indeed, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infects primarily human monocytes and dendritic cells causing dendritic cell dysfunction, leading to T cell apoptosis and exhaustion; thus, contributing to the immunopathology [ 203 ]. Alpert et al. (2020) described two cases of COVID-19 patients with elevated amounts of IL-6 (25 pg/mL and 26.7 pg/mL respectively) who were diagnosed with major depressive disorder (according to the Diagnostic and Statistical Manual of Mental Disorder, 5th Edition (DSM-5)) during COVID 19 infection. Both patients’ depressive symptoms subsided about 6 weeks after initiation of anti-depressant pharmacotherapy and normalization of the inflammatory cytokines [ 192 ]. The authors concluded that lower cytokine activity ameliorates depressive symptoms as normalization of IL-6 plasma levels decreased depression with or without anti-depressants [ 192 ]. Moreover, Benedett et al. (2020) studied effects of treatment with cytokine-blocking agents on the psychopathological status of the patients with COVID-19 infection. Their results were in favor of the protective effects of treatment with cytokine-blocking agents in early phases of COVID-19 against the later onset of depression [ 204 ].

It is indeed crucial to maintain a multidisciplinary approach in management of the psychological effects of this debilitating pandemic. Treatment strategies addressing the immunopathology of SARS-CoV-2 infection will be promising during the acute phase of the disease [ 192 , 205 ]. Currently, there are few studies considering psychological and neuropsychiatric implications of COVID-19; however, it is very likely to expect an increased incidence of mental pathologies both during and post-COVID-19 infection.

Preclinical and clinical studies present strong evidence that inflammation is altered in a subset of patients with MDD and there is mounting body of literature for the role of pro-inflammatory cytokines namely IL-6 in pathophysiology of depression. Nevertheless, there still exists gap in our understanding of the mechanisms by which IL-6 signaling and its molecular components could possibly contribute to depression manifestation. A number of humanized monoclonal antibodies are undergoing clinical trials for potential pharmacotherapy of mood disorders. Biologics including IL-6 receptor antibodies or IL-6 antibodies are currently approved to treat inflammatory disorders such as RA and are undergoing clinical trials as a novel target for MDD treatment. However, these novel therapeutic targets may also raise the possibility of potential side effects. By investigating the interface of peripheral cytokines, namely IL-6 and brain cellular processes contributing to depression, one might be able to develop novel therapeutic options for treatment of mood disorders by sequestering and preventing this peripherally derived inflammatory marker from acting upon mood circuits in the CNS. In sum, therapeutic deficiency in treatment outcomes reflects the growing demand for revitalizing psychiatric therapeutics with novel options that could potentially open new avenues in treatment of this debilitating disorder and enhancement of patients’ quality of life.

Availability of data and materials

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Abbreviations

Anterior cingulate cortex

Acute respiratory distress syndrome

Blood-brain barrier

Central nervous system

Coronavirus disease 2019

Cytokine release syndrome

Conserved transcriptional response to adversity

Disease-modifying anti-rheumatic drugs

Diagnostic and Statistical Manual of Mental Disorder, 5th Edition

Electroconvulsive therapy

Glycoprotein 130

G-protein-coupled receptors

Hypothalamic-pituitary-adrenal

Indoleamine 2,3 dioxygenase

Interleukin

IL-6 receptor

Janus kinase/signal transducer and activator of transcription

• Major depressive disorder

Mitogen-activated protein kinase

Messenger RNA

Nuclear factor kappa-light-chain-enhancer of activated B cells

Prefrontal cortex

Rheumatoid arthritis

severe acute respiratory syndrome coronavirus 2

Serotonin transporter

Signal transducer and activator of transcription 3

Soluble IL-6R

Transforming growth factor

T helper type 2

T helper type 1

T helper cell

Tumor necrosis factor

Translocator protein

Regulatory T cells

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Roohi, E., Jaafari, N. & Hashemian, F. On inflammatory hypothesis of depression: what is the role of IL-6 in the middle of the chaos?. J Neuroinflammation 18 , 45 (2021). https://doi.org/10.1186/s12974-021-02100-7

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April 9, 2024, heart disease, depression linked by inflammation: study.

Coronary artery disease and major depression may be genetically linked via inflammatory pathways to an increased risk for cardiomyopathy, a degenerative heart muscle disease, researchers at Vanderbilt University Medical Center and Massachusetts General Hospital have found.

Their report, published April 5 in the journal Nature Mental Health , suggests that drugs prescribed for coronary artery disease and depression, when used in combination, potentially may reduce inflammation and prevent the development of cardiomyopathy.

“This work suggests that chronic low-level inflammation may be a significant contributor to both depression and cardiovascular disease,” said the paper’s corresponding author, Lea Davis , PhD, associate professor of Medicine in the Division of Genetic Medicine and Vanderbilt Genetics Institute.

The connection between depression and other serious health conditions is well known. As many as 44% of patients with coronary artery disease (CAD), the most common form of cardiovascular disease, also have a diagnosis of major depression. Yet the biological relationship between the two conditions remains poorly understood.

A possible connection is inflammation. Changes in the levels of inflammatory markers have been observed in both conditions, suggesting that there may be a common biological pathway linking neuroinflammation in depression with atherosclerotic inflammation in CAD.

In the current study, the researchers used a technique called transcriptome-wide association scans to map single nucleotide polymorphisms (genetic variations) involved in regulating the expression of genes associated with both CAD and depression.

The technique identified 185 genes that were significantly associated with both depression and CAD, and which were “enriched” for biological roles in inflammation and cardiomyopathy. This suggests that predisposition to both depression and CAD, which the researchers called (major) depressive CAD, or (m)dCAD, may further predispose individuals to cardiomyopathy.

However, when the researchers scanned large electronic health record databases at VUMC, Mass General, and the National Institutes of Health’s All of Us Research Program, they found the actual incidence of cardiomyopathy in patients with the enriched genes for (m)dCAD was lower than in patients with CAD alone.

One possible explanation is that medications prescribed for CAD and depression, such as statins and antidepressants, may prevent development of cardiomyopathy by reducing inflammation, the researchers concluded.

“More research is needed to investigate optimal treatment mechanisms,” Davis added, “but at a minimum this work suggests that patient heart and brain health should be considered together when developing management plans to treat depression or cardiovascular disease.”

Kritika Singh, PhD, the paper’s first author, is a former graduate student in the Davis lab who is now a postdoctoral Innovation Fellow at Novartis in Cambridge, Massachusetts.

Other VUMC co-authors are Tyne Miller-Fleming, PhD, Peter Straub, MS, Nancy Cox, PhD, founding director of the Vanderbilt Genetics Institute, and institute members Quinn Wells, MD, PharmD, MSCI, associate professor of Medicine in the Division of the Cardiovascular Medicine, and Emily Hodges, PhD, assistant professor of Biochemistry.

The research was supported by National Institutes of Health grants R56MH120736, R01H118233, 1F31MH124306, and 1R01HL140074, and an American Heart Association Fellowship.

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Heart disease and depression may be genetically linked by inflammation

by Vanderbilt University Medical Center

Coronary artery disease and major depression may be genetically linked via inflammatory pathways to an increased risk for cardiomyopathy, a degenerative heart muscle disease, researchers at Vanderbilt University Medical Center and Massachusetts General Hospital have found.

Their report, published April 5 in the journal Nature Mental Health , suggests that drugs prescribed for coronary artery disease and depression, when used in combination, potentially may reduce inflammation and prevent the development of cardiomyopathy.

"This work suggests that chronic low-level inflammation may be a significant contributor to both depression and cardiovascular disease," said the paper's corresponding author, Lea Davis, Ph.D., associate professor of Medicine in the Division of Genetic Medicine and Vanderbilt Genetics Institute.

The connection between depression and other serious health conditions is well known. As many as 44% of patients with coronary artery disease (CAD), the most common form of cardiovascular disease, also have a diagnosis of major depression . Yet the biological relationship between the two conditions remains poorly understood.

A possible connection is inflammation. Changes in the levels of inflammatory markers have been observed in both conditions, suggesting that there may be a common biological pathway linking neuroinflammation in depression with atherosclerotic inflammation in CAD.

In the current study, the researchers used a technique called transcriptome-wide association scans to map single nucleotide polymorphisms (genetic variations) involved in regulating the expression of genes associated with both CAD and depression.

The technique identified 185 genes that were significantly associated with both depression and CAD, and which were "enriched" for biological roles in inflammation and cardiomyopathy. This suggests that predisposition to both depression and CAD, which the researchers called (major) depressive CAD, or (m)dCAD, may further predispose individuals to cardiomyopathy.

However, when the researchers scanned large electronic health record databases at VUMC, Mass General, and the National Institutes of Health's All of Us Research Program, they found the actual incidence of cardiomyopathy in patients with the enriched genes for (m)dCAD was lower than in patients with CAD alone.

One possible explanation is that medications prescribed for CAD and depression, such as statins and antidepressants, may prevent development of cardiomyopathy by reducing inflammation, the researchers concluded.

"More research is needed to investigate optimal treatment mechanisms," Davis added, "but at a minimum this work suggests that patient heart and brain health should be considered together when developing management plans to treat depression or cardiovascular disease."

Kritika Singh, Ph.D., the paper's first author, is a former graduate student in the Davis lab who is now a postdoctoral Innovation Fellow at Novartis in Cambridge, Massachusetts.

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• Open access
• Published: 09 April 2024

Association of major depression, schizophrenia and bipolar disorder with thyroid cancer: a bidirectional two-sample mendelian randomized study

• Rongliang Qiu 1 , 2 ,
• Huihui Lin 3 ,
• Hongzhan Jiang 3 ,
• Jiali Shen 3 ,
• Jiaxi He 4 &
• Jinbo Fu 1 , 2  

BMC Psychiatry volume  24 , Article number:  261 ( 2024 ) Cite this article

96 Accesses

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Metrics details

Major depressive disease (MDD), schizophrenia (SCZ), and bipolar disorder (BD) are common psychiatric disorders, and their relationship with thyroid cancer has been of great interest. This study aimed to investigate the potential causal effects of MDD, SCZ, BD, and thyroid cancer.

We used publicly available summary statistics from large-scale genome-wide association studies to select genetic variant loci associated with MDD, SCZ, BD, and thyroid cancer as instrumental variables (IVs), which were quality controlled and clustered. Additionally, we used three Mendelian randomization (MR) methods, inverse variance weighted (IVW), MR–Egger regression and weighted median estimator (WME) methods, to estimate the bidirectional causal relationship between psychiatric disorders and thyroid cancer. In addition, we performed heterogeneity and multivariate tests to verify the validity of the IVs.

We used two-sample bidirectional MR analysis to determine whether there was a positive causal association between MDD and thyroid cancer risk. The results of the IVW analysis (OR = 3.956 95% CI = 1.177–13.299; P  = 0.026) and the WME method (OR = 5.563 95% CI = 0.998–31.008; P  = 0.050) confirmed that MDD may increase the risk of thyroid cancer. Additionally, our study revealed a correlation between genetic susceptibility to SCZ and thyroid cancer (OR = 1.532 95% CI = 1.123–2.088; P  = 0.007). The results of the WME method analysis based on the median estimate (OR = 1.599 95% CI = 1.014–2.521; P  = 0.043) also suggested that SCZ may increase the risk of thyroid cancer. Furthermore, our study did not find a causal relationship between BD and thyroid cancer incidence. In addition, the results of reverse MR analysis showed no significant causal relationships between thyroid cancer and MDD, SCZ, or BD ( P  > 0.05), ruling out the possibility of reverse causality.

Conclusions

This MR method analysis provides new evidence that MDD and SCZ may be positively associated with thyroid cancer risk while also revealing a correlation between BD and thyroid cancer. These results may have important implications for public health policy and clinical practice. Future studies will help elucidate the biological mechanisms of these associations and potential confounders.

Peer Review reports

Cancer is recognized as a disease that poses a serious threat to human health, and it has been reported that in the United States alone, more than 609,360 people are expected to lose their lives to cancer in 2022 [ 1 ]. However, the mechanisms underlying the development of most cancers are still not fully understood, which has led to delays in the diagnosis and treatment of cancers, contributing to the increasing incidence and mortality of cancer worldwide. Thyroid cancer is one of the most common endocrine tumours, and its incidence has been steadily increasing worldwide over the last three decades due to the widespread use of diagnostic imaging techniques and ultrasound-guided fine needle aspiration (US-FNA) [ 2 , 3 ]. Despite the continued increase in the incidence of thyroid cancer, its mortality trend has remained relatively stable. Risk factors for thyroid cancer include metabolic syndrome (including diabetes mellitus, hypertension, obesity, etc.), poor lifestyle habits, and environmental pollution, but these factors do not fully explain the mechanism of thyroid cancer development. Therefore, identifying other potentially modifiable risk factors, such as psychiatric disorders, is important for the prevention and treatment of thyroid cancer.

Major depressive disease (MDD), schizophrenia (SCZ), and bipolar disorder (BD) are all serious psychiatric disorders that overlap genetically and clinically, suggesting that they may share common aetiological mechanisms [ 4 ]. The results of a study suggest that quantitative changes in plasma lipids affect several individual characteristics, including those affected by serious psychiatric disorders (MDD, SCZ and BD) [ 5 ]. Moreover, clinical studies have shown that patients with MDD, SCZ and BD have altered Homer1a levels in specific regions and cell types of the brain. A growing body of research confirms the close connection between these three disorders [ 6 ]. MDD is ranked by the World Health Organization as one of the most burdensome diseases in the world; it seriously damages people’s physical and mental health and is associated with a variety of endocrine disorders, such as hypothyroidism and hyperthyroidism [ 7 , 8 , 9 , 10 , 11 ]. Studies have shown that patients with hyperthyroidism and hypothyroidism differ in the presentation of depressive symptoms and disorders [ 12 , 13 ]. Specifically, hyperthyroidism was associated with more depressive symptoms (e.g., insomnia and weight loss) [ 14 ], whereas hypothyroidism was associated with fewer depressive symptoms (e.g., energy deficit and fatigue) [ 15 ]. In addition, individuals with hyperthyroidism have a higher incidence of MDD [ 13 ]. The relationship between depression and cancer has long been of interest, and some observational studies have suggested that depression may be an important risk factor for cancer [ 16 ]. A cross-sectional study from Korea revealed a 5.6% incidence of depression in thyroid cancer patients [ 17 ]. Another study from Germany showed that cancer patients were five times more likely to be depressed than was the general population, and thyroid cancer patients with a detectable high burden of depressive symptoms were 9.3 times more likely to be depressed than was the general population [ 18 ]. However, despite observational studies revealing a correlation between MDD and thyroid cancer, the relationship between MDD and thyroid cancer has not been systematically explored.

SCZ is a chronic psychiatric disorder accompanied by inconsistent behavioural and cognitive symptoms and has profound effects on both individuals and society. More than 50% of those diagnosed have intermittent and chronic psychiatric problems [ 19 ]. This results in a particularly high risk of disengagement from the labour market, with employment rates ranging from 10 to 30%, unemployment rates as high as 89–95%, and a 15–20 year reduction in life expectancy [ 20 , 21 ]. There is growing evidence that thyroid function may be altered in patients with SCZ, but the results of observational studies have been inconsistent [ 22 , 23 ]. In addition, the role of the thyroid gland in the pathophysiology of SCZ is poorly understood, and the relationship between thyroid disorders and SCZ is unclear.

SCZ and BD are considered part of the psychiatric continuum and share similar clinical features. BD is a chronic, disabling illness and a major contributor to the global burden of disease. BD can cause mood swings ranging from depression to mania. Patients exhibit fluctuations during the course of the illness, with some patients experiencing episodes only every few years, while others experience episodes almost continuously. A large body of evidence confirms the association between abnormal thyroid hormone levels and different psychopathological conditions, triggering neuropsychiatric symptoms [ 24 ]. However, observational studies may find an association between psychiatric disorders and thyroid disorders, but confounding factors and reverse causality cannot be excluded.

To explore the causal association between psychiatric disorders (MDD, SCZ and BD) and thyroid cancer risk, we used a two-sample bidirectional Mendelian randomization (MR) study. MR studies [ 25 ] use genetic variation as an instrumental variable closely related to the exposure of interest to explore the causal effect between the exposure and the outcome, thereby improving the reliability of causal inference. Because of the random segregation of alleles at the meiotic stage and the stochastic nature of germline genetic variation at fertilization, MR analyses can avoid confounding factors and reverse causation. In this study, we utilized a two-sample bidirectional MR approach to explore the associations between MDD, SCZ, BD, and thyroid cancer based on statistically pooled data from a genome-wide association study (GWAS). This study aimed to gain insights into the potential link between psychiatric disorders and thyroid cancer and to provide new perspectives and insights for the prevention and treatment of thyroid cancer.

This study is an analysis of previously collected and published public data, including statistical aggregations related to MDD, SCZ, BD, and thyroid cancer, from large public GWASs. Due to the source and nature of the data, no additional ethical review or informed consent was required for this study. Two-sample bidirectional MR analyses were used to assess the causal relationship between psychiatric disorders (MDD, SCZ, BD) and thyroid cancer. We chose psychiatric disorders (MDD, SCZ, BD) as the exposure factor and thyroid cancer as the outcome indicator. Moreover, we conducted a reverse two-sample MR analysis with thyroid cancer as an exposure factor and psychiatric disorders (MDD, SCZ, BD) as an outcome indicator. A flow chart of the MR research design constructed according to this paper is shown in Fig.  1 .

Flowchart of the design of a Mendelian randomized study of the causal association between psychiatric disorders and thyroid cancer. Blue solid lines represent associations between instrumental variables (SNPs) and exposure and between exposure and outcome. The red solid line represents reverse causality. psychiatric disorders include major depression, schizophrenia, and bipolar disorder

Data sources for patients with major depression, schizophrenia, bipolar disorder, or thyroid cancer

The summary-level dataset used for GWASs for MDD in this study was obtained from a meta-analysis of GWAS data conducted by Howard et al. [ 26 ]. It comprises three large-scale GWASs, the Psychiatric Genomics Consortium (PGC), the UK Biobank, and 23andme. Of the three GWASs, only the UK Biobank and the PGC publish summary statistics on genetic variation. The dataset included 500,199 European subjects, including 170,756 cases and 329,443 controls. In the UK Biobank, Howard et al. used a broad definition of depression and asked participants if they reported neurological, anxiety, tension, or depression symptoms to their general practitioner or psychiatrist. At the PGC, Wray et al. diagnosed depression in participants according to international consensus diagnostic criteria (DSM-IV, ICD-9, or ICD-10). See Table  1 for details.

Statistical summary data for SCZ and BD were obtained from the most recent PGC’s GWAS summary statistics. The data for SCZ [ 27 ] are based on a major meta-analysis of multiple groups, including Europeans, East Asians, African Americans, and Latinos, including 76,755 cases and 243,649 control participants. BD [ 28 ] was based on a summary analysis of European ancestry and included 20,352 cases and 31,358 control participants. See Table  1 for detailed information.

To perform two-sample bidirectional analyses, we used independent genome-wide significant single nucleotide polymorphisms (SNPs) as exposure indicators for MDD (50 SNPs), SCZ (217 SNPs), and BD (16 SNPs). The F-statistics of the above SNPs are all greater than 10, indicating that they are strongly correlated instrumental variables (IVs). The detailed information is specified in the Supplementary Material: Tables  1 , 2 and 3 .

Data on genetic variants associated with thyroid cancer were obtained by Deutsches the Krebsforschungszentrum (DKFZ) through GWAS [ 29 ] and included 1080 European participants, including 649 in the case group and 431 in the control group, as detailed in Table  1 . For the bivariate analyses, we used independent genome-wide significant SNPs as indicators of exposure to thyroid cancer (347 SNPs). All 347 SNPs had F-statistics greater than 10, indicating that they were strongly correlated IVs. Specific SNP information is provided in the Supplementary Material: Table  4 .

Selection of genetic instrumental variables

This study was conducted in strict accordance with the quality control steps. First, we selected exposure-related GWAS data and screened SNP loci with genome-wide significance ( p  < 5 × 10 − 8 ) for pooled aggregation. Second, to avoid linkage disequilibrium (LD) from affecting the results, we performed a clustering process by setting the parameter (r 2 ) threshold (r 2  < 0.001 and region width = 10,000 kb) to assess LD among SNPs to ensure independence. SNPs need to fulfil three basic assumptions to serve as IVs for exposure factors, and the fulfilment of these assumptions will enhance the testing power and estimation accuracy of IVs: (1) the association assumption: genetic variants are associated with exposure; (2) the independence assumption: genetic variants are independent of confounders between exposure and outcome; and (3) the exclusivity assumption: genetic variants affect the outcome only through exposure [ 30 ]. Next, we extracted summary statistics of eligible SNPs from the outcome GWAS; finally, we determined that the SNPs included in the dataset met the instrumental variable requirements. The palindromic sequences were excluded to ensure that the effects of SNPs on exposure and outcome were from the same allele. This series of steps finalized the identification of SNPs that served as genetic IVs for this study.

Statistical analysis

After coordinating the GWAS effect alleles for MDD, SCZ, BD, and thyroid cancer, we selected three MR approaches. The inverse variance weighted (IVW) test, MR–Egger regression, and weighted median estimator (WME) were used to assess the causal relationship between psychiatric disorders and thyroid cancer risk. The main method of analysis was IVW, while WME and MR–Egger regression were used as complementary methods to IVW estimation, as they provide more reliable estimates under more relaxed conditions [ 31 ]. The Cochran’s Q test was used to estimate the heterogeneity of the causal effects of individual gene variants. If horizontal pleiotropy or heterogeneity is detected, fixed-effects IVW analysis should be chosen, and vice versa for random-effects IVW analysis [ 32 , 33 ]. The IVW method does not take into account the presence of an intercept term and uses the variance of the outcome as the fitting weight. In contrast, the MR–Egger regression method, which is an MR method for assessing the causal effect of genetic variation on the relationship between exposure and outcome, takes into account the presence of an intercept term [ 34 ]. This method corrects for polytropic bias and detects directed polytropy but is susceptible to instrumental variable assumptions. When the Egger intercept of a linear regression is close to zero, it indicates the absence of directional pleiotropy, thus satisfying the exclusivity assumption. The weighted median method is a method that combines data from multiple genetic variants into a single causal estimate and requires that more than 50% of the weights come from valid IVs to obtain a reliable estimate of the causal effect [ 31 ]. To ensure the reliability of the MR estimates, we also detected outliers that may affect our MR estimates by looking at forest plots, funnel plots, scatter plots, and leave-one-out methods.

To test the first hypothesis of correlation, we also assessed the strength of the relationship between IVs and phenotype using the F-statistic (F = beta 2 / se 2 , with beta being the allele effect value and SD being the standard deviation), with F > 10 indicating the presence of strongly correlated IVs [ 35 ].

All of the above MR-related statistical analyses were implemented using TwoSampleMR in R 4.1.1 software.

Three sets of genetic instruments were constructed for the forwards MR study after a series of quality control steps. First, we merged the exposure (MDD)- and outcome (thyroid cancer)-related datasets, and after removing 2 palindromic sequences (rs4936276 and rs4730387), we ultimately included 26 SNPs for analysis. The second set of genetic tools was constructed after the same quality control steps, combining the exposure (SCZ) and outcome (thyroid cancer) datasets and deleting six palindromic sequences (rs12363019, rs217310, rs2470951, rs2944821, rs7709645, rs9925915) before finally including 111 SNPs that were analysed. A third set of genetic instruments was constructed following the same quality control steps, combining exposure (BD) and outcome (thyroid cancer), and after deleting 2 palindromes sequences (rs10455979, rs5758065), and finally included 9 SNPs for analysis. The F-statistics of the above SNPs were greater than 10, indicating that they were strongly correlated with each other (Supplementary Material: Tables  1 , 2 and 3 ).

Three sets of genetic instruments were constructed in the reverse MR study after a series of quality control steps. First, we combined exposure (thyroid cancer) and outcome (MDD)-related datasets, resulting in the inclusion of 331 SNPs for analysis. The second set of genetic instruments was constructed following the same quality control steps, combining the exposure (thyroid cancer) and outcome (SCZ) datasets, resulting in the inclusion of 338 SNPs for analysis. A third set of genetic instruments was constructed following the same quality control steps, combining the exposure (thyroid cancer) and outcome (BD) data and ultimately including 338 SNPs for analysis. The F values of the above IVs were all > 10, indicating reliable results without weak bias.

Mendelian randomization analysis

In our study, we explored the causal relationship between psychiatric disorders (MDD, SCZ, and BD) and thyroid cancer using psychiatric disorders as exposure factors. The results of the IVW analysis showed a significant association between MDD and the risk of thyroid cancer (OR = 3.956 95% CI = 1.177–13.299; P  = 0.026), confirming the possibility of an increased risk of thyroid cancer due to MDD. These findings were reinforced by the results obtained by the WME method (OR = 5.563 95% CI = 0.998–31.008; P  = 0.050), which were consistent with those of the IVW method. However, the results of the MR–Egger regression (OR = 76.975 95% CI = 0.008-766576.333; P  = 0.364) showed that the difference in the effect of MDD and thyroid cancer was not statistically significant (Table  2 ), which may be due to the high false-positive rate of false-negative results from this method. Nevertheless, the IVW and WME methods suggest that MDD may increase the risk of thyroid cancer.

In addition, we found that genetic susceptibility to SCZ was correlated with thyroid cancer (OR = 1.532 95% CI = 1.123–2.088; P  = 0.007). The results of the WME method analysis based on the median estimate (OR = 1.599 95% CI = 1.014–2.521; P  = 0.043) also support that SCZ may increase the risk of thyroid cancer (Table  2 ).

However, no causal relationship between BD and thyroid cancer was found in any of the MR analyses. In addition, we performed reverse MR analysis, which showed no evidence of a causal relationship between genetic susceptibility to thyroid cancer and psychiatric disorders (MDD, SCZ, and BD), ruling out the possibility of reverse causation (Supplementary Material: Table  5 ).

Sensitivity analysis

For sensitivity analysis, we first tested for heterogeneity of results using Cochran’s Q for IVW and MR–Egger regression. The results showed that the p values of the analyses were greater than 0.05, which indicated that there was no significant heterogeneity in our study. Similarly, the MR–Egger intercept method results also showed no horizontal pleiotropy (all p values greater than 0.05). We also constructed funnel plots and leave-one-out plots. The funnel plot was roughly symmetrical, indicating a relatively low risk of bias and high reliability of the results. A leave-one-out plot was generated to reject SNPs one by one, and the analysis showed that the causal relationship between psychiatric disorders and thyroid cancer was largely not driven by a single SNP. We also examined scatter plots, in which each point represents an instrumental variable. Each horizontal solid line in the forest plot reflects a single SNP estimated using the Wald ratio method. Leave-one-out, scatter, funnel, and forest plots can be found in the supplementary materials.

In the inverse sensitivity analyses, Cochran’s Q test revealed heterogeneity between the effects of thyroid cancer on MDD, SCZ, and BD. Therefore, IVW analysis under a random effects model was chosen to balance the heterogeneity of the results. However, it is noteworthy that no heterogeneity was found in thyroid cancer patients with MDD or SCZ. p values for the MR–Egger intercept method were all greater than 0.05, suggesting that there was no horizontal pleiotropy in the results. Leave-one-out, scatter, funnel, and forest plots can be found in the supplementary materials.

With the increasing prevalence of psychiatric disorders and thyroid cancer, there is an increasing overlap between them, prompting us to delve deeper into their relationship. This study is the first two-sample bidirectional MR study of psychiatric disorders (MDD, SCZ, BD) and thyroid cancer. Our MR study showed a significant causal association between MDD and SCZ and thyroid cancer, whereas no such association was found between BD and thyroid cancer. Reverse MR analysis ruled out the possibility of reverse causation.

MR studies have the advantage of effectively avoiding confounding bias. Because SNPs are randomly assigned at conception, MR is also able to exclude reverse causality effects relative to observational studies, thus enhancing the credibility of causal inferences. We suggest the following possible mechanisms for the positive causal relationship between MDD and thyroid cancer: First, MDD may lead to abnormal functioning of the hypothalamic–pituitary–thyroid (HPT) axis, which in turn affects thyroid hormone levels and thyroid-stimulating hormone (TSH) secretion. TSH is a key factor in promoting thyroid cell proliferation, and abnormal TSH levels may increase the risk of thyroid nodules and cancer. Patients with early-stage MDD may suffer from thyroid and metabolic dysfunction [ 36 ]. Data from the study showed that 26.2% of depressed patients had abnormal thyroid function, 18.3% of whom had MDD, and 62.4% of the study population was female [ 37 ]. The results of a multicentre study by the European Antidepressant Study Group showed that the prevalence of hypothyroidism and hyperthyroidism in patients with MDD was 13.2% and 1.6%, respectively [ 38 ]. These results imply that MDD may regulate thyroid hormone levels through the HPT axis, thereby affecting thyroid function and structure. Abnormal HPT axis function has been the focus of research on neuroendocrine mechanisms in patients with psychiatric disorders, and our findings provide insight into the relationship between genetic susceptibility to MDD and thyroid cancer. Second, MDD leads to elevated peripheral inflammatory marker levels [ 39 , 40 ], which induce chronic inflammation and gene mutations in the thyroid gland. These peripheral inflammatory markers include interleukins (ILs), tumour necrosis factor (TNF), and C-reactive protein (CRP), which can affect thyroid tissues through blood circulation or neuroendocrine pathways. Chronic inflammation can mediate tumour development, and the two are interconnected through endogenous and exogenous pathways. Chronic inflammation of the thyroid gland may contribute to genetic defects through the secretion of high levels of mutagenic agents (e.g., reactive oxygen species and nitric oxide) [ 41 ]. Finally, MDD may be associated with type C personality, which is characterized by abnormal emotional expression and abnormal emotion regulation that may affect the immune system and endocrine function [ 42 , 43 , 44 ]. Some scholars [ 43 ] regard negative emotions as an independent risk factor for the occurrence of thyroid cancer and believe that the persistence or recurrence of depression and anxiety is a stress factor for the human body and that stress causes changes in the cerebral cortex and hypothalamus, which can directly or indirectly suppress the immune system and interfere with the endocrine function of the body [ 44 ], thus affecting the normal synthesis and release of thyroid hormones and triggering thyroid nodules and increasing the likelihood of thyroid cancer.

There may be different aetiologies regarding the genetic susceptibility of patients with SCZ to an increased risk of thyroid cancer. Beginning in the late 19th century, when hypothyroidism was connected with psychiatric disorders, an increasing number of clinical studies have shown a strong independent association between SCZ and hypothyroidism [ 45 ]. A recent community-based cross-sectional study comparing patients with SCZ ( n  = 1252) and healthy controls matched for age, sex, socioeconomic status and ancestry ( n  = 3756) revealed that the incidence of hypothyroidism in patients with SCZ increased after treatment but not before diagnosis [ 22 ]. Similarly, in observational studies, patients with SCZ are more likely to have abnormal thyroid function after initiating treatment with antipsychotics [ 46 , 47 ]. Thus, the use of antipsychotics may lead to abnormalities in thyroid function, although it is not clear whether the HPT axis can be directly affected. A systematic review and meta-analysis summarizing 19 studies suggested that TSH levels may be reduced at the onset of psychosis and elevated in patients with multiple episodes of psychosis [ 48 ]. Studies have shown that dopamine or dopamine agonists inhibit TSH secretion, and a possible explanation for the elevated TSH levels lies in the fact that antidopaminergic drugs used to treat SCZ inhibit dopamine neurotransmission, which may cause elevated TSH levels [ 49 ]. Thus, there may be a causal relationship between hypothyroidism or elevated TSH levels and the manifestations of SCZ. Thyroid hormones not only play a role in the dopaminergic system but also in the regulation of serotonergic, glutamatergic, and GABAergic networks [ 50 ]. During neurodevelopment, thyroid hormones play a critical role, and their deficiency may severely impair the development of neural tissues, leading to abnormalities and damage in the cerebellar cortex and cerebral cortex [ 51 ]. In the adult brain, thyroid hormone interacts with glial cells to regulate immune responses and neurotransmitter release and to control neuronal metabolism.

However, our study did not find conclusive evidence to support a causal role between genetic susceptibility to BD and thyroid cancer risk. To date, the association between affective disorders and thyroid cancer has not been widely reported. Although previous epidemiologic studies using case–control methods have suggested an association between BD and abnormal thyroid function [ 52 , 53 , 54 ], this topic has yet to be thoroughly investigated. One large meta-analysis reported that thyroid hormones may affect neurodevelopment by modulating the brain’s serotonin system [ 43 ]. The current preferred mood stabilizer for maintenance treatment of BD is lithium, although lithium alters thyroid functional status [ 55 ]. However, little is known about the pathophysiologic role of thyroid hormones in BD, and genetically, our study did not find a direct relationship between BD and thyroid cancer. However, further validation with larger datasets is needed in the future.

Our study has important implications for understanding the potential link between psychiatric disorders and thyroid cancer, as well as providing new ideas and strategies for the prevention and treatment of these common psychiatric disorders. For example, we can reduce the risk of thyroid cancer by screening and treating psychiatric disorders or improve the clinical management of psychiatric disorders by monitoring and regulating thyroid hormone levels. Specifically, we could conduct thyroid function testing and interventions in patients with psychiatric disorders, along with psychological assessment and treatment in patients with thyroid cancer. This integrated approach is expected to mitigate, to some extent, the adverse effects of psychiatric disorders and thyroid cancer on patients’ quality of life and socioeconomic status. In addition, our study provides clues and research directions for in-depth exploration of the potential relationships between MDD and thyroid cancer and between SCZ and thyroid cancer. More experimental and clinical studies are needed in the future to validate our findings and reveal the molecular cellular mechanisms underlying the causal relationship between psychiatric disorders and thyroid cancer.

In conclusion, our study is the first two-sample bidirectional MR study on the causal relationship between psychiatric disorders and thyroid cancer. Although our study provides useful insights for obtaining a deeper understanding of the relationship between psychiatric disorders and thyroid cancer, there are several limitations to consider. First, we used European population-based GWAS data to select IVs and obtain exposure data, which may limit the generalizability and applicability of our results. Second, our IVs were based on the use of a single nucleotide polymorphism-based design, which may not fully capture genetic variability in exposure or outcome. Finally, due to the limitations of the dataset, the number of thyroid cancer patients in the study was relatively small, which may have led to bias.

In summary, our study provides some suggestive evidence that MDD and SCZ are positively associated with thyroid cancer. This finding may have implications for health care policies regarding psychiatric disorders and thyroid cancer. Considering the high prevalence of psychiatric disorders and thyroid cancer in the general population, revealing the causal relationship between psychiatric disorders and thyroid cancer is important for public health policies for early prevention and timely prevention.

Data availability

Major depression：https://gwas.mrcieu.ac.uk/datasets/ieu-b-102/;Schizophrenia;https://gwas.mrcieu.ac.uk/datasets/ieu-b-5099/; Bipolar disorder:https://gwas.mrcieu.ac.uk/datasets/ieu-b-41/; Thyroid caencer:https://gwas.mrcieu.ac.uk/datasets/ieu-a-1082/;

Abbreviations

• Major depressive disease

schizophrenia

bipolar disorder

• Mendelian randomization

instrumental variables

inverse variance weighted

ultrasound-guided Fine Needle Aspiration

genome-wide association study

Psychiatric Genomics Consortium

single nucleotide polymorphisms

Deutsches the Krebsforschungszentrum

linkage disequilibrium

Weighted Median Estimator

hypothalamic–pituitary–thyroid

thyroid-stimulating hormone

interleukins

tumour necrosis factor

C-reactive protein

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Acknowledgements

This analysis benefited from the valuable data sets provided by various researchers and the summary statistics of multiple GWAS shared by the research community. We thank them for their contributions.

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School of Nursing, Fujian University of Traditional Chinese Medicine, Fuzhou, 350122, China

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Conception and design: QRL, FJB. Development of methodology: JHZ, LHH. Analysis and interpretation of data: SJL, HJX. Writing of the manuscript: QRL, LHH. Study supervision: FJB.

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Qiu, R., Lin, H., Jiang, H. et al. Association of major depression, schizophrenia and bipolar disorder with thyroid cancer: a bidirectional two-sample mendelian randomized study. BMC Psychiatry 24 , 261 (2024). https://doi.org/10.1186/s12888-024-05682-7

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Genetics Factors in Major Depression Disease

Depressive disorders (DDs) are one of the most widespread forms of psychiatric pathology. According to the World Health Organization, about 350 million people in the world are affected by this condition. Family and twin studies have demonstrated that the contribution of genetic factors to the risk of the onset of DDs is quite large. Various methodological approaches (analysis of candidate genes, genome-wide association analysis, genome-wide sequencing) have been used, and a large number of the associations between genes and different clinical DD variants and DD subphenotypes have been published. However, in most cases, these associations have not been confirmed in replication studies, and only a small number of genes have been proven to be associated with DD development risk. To ascertain the role of genetic factors in DD pathogenesis, further investigations of the relevant conditions are required. Special consideration should be given to the polygenic characteristics noted in whole-genome studies of the heritability of the disorder without a pronounced effect of the major gene. These observations accentuate the relevance of the analysis of gene-interaction roles in DD development and progression. It is important that association studies of the inherited variants of the genome should be supported by analysis of dynamic changes during DD progression. Epigenetic changes that cause modifications of a gene's functional state without changing its coding sequence are of primary interest. However, the opportunities for studying changes in the epigenome, transcriptome, and proteome during DD are limited by the nature of the disease and the need for brain tissue analysis, which is possible only postmortem . Therefore, any association studies between DD pathogenesis and epigenetic factors must be supplemented through the use of different animal models of depression. A threefold approach comprising the combination of gene association studies, assessment of the epigenetic state in DD patients, and analysis of different “omic” changes in animal depression models will make it possible to evaluate the contribution of genetic, epigenetic, and environmental factors to the development of different forms of depression and to help develop ways to decrease the risk of depression and improve the treatment of DD.

Introduction

Depressive disorders (DDs) comprise one of the most widespread forms of psychiatric pathology. According to the World Health Organization, about 350 million people are affected by a DD. The worldwide prevalence of DDs varies from 3% in Japan to 16.9% in the USA; in most countries, this prevalence ranges from 8 to 12% ( 1 ). It is predicted that, by 2020, DDs will be the second-leading cause of disability throughout the world after ischemic heart disease ( 2 ).

DD entails a number of unfavorable consequences with medical and sociological relevance, and affects significantly the quality of life and adaptive ability. Long-term and severe depression mixed with chronic somatic or neurological conditions might lead to attempted suicide.

Despite the great medical and social significance of DDs, there is no clear conceptualization to explain the causes and mechanisms of DD development. Several theories have been suggested to explain the onset of depression and have been confirmed by biochemical, immunological, and physiological studies. Parallel to well-known “monoamine,” “cytokine,” and “stress-induced” (hypothalamus–pituitary–adrenal (HPA) axis and stress theories) depression models, the phenomena of altered brain neural plasticity and neurogenesis and circadian rhythm desynchronosis (the chronobiological model) have been proposed to explain the onset of depression.

Family and twin studies have provided strong evidence for the contribution of genetic factors to the risk of depression. For instance, a meta-analysis of twin research data shows that the heritability rate for depression is 37% (95% CI: 31%−42%), and data from family studies show a two- to threefold increase in the risk of depression in first-degree offspring of patients with depression ( 3 ). Heritability has also been shown to be especially influential in severe forms of depression ( 4 , 5 ). The illness severity depends on whether DDs are inherited maternally or paternally ( 6 , 7 ).

Since 1978, when the first study devoted to identifying possible candidate genes related to DDs was published ( 8 ), many studies have searched for genes involved in the progression of depression worldwide. Based on the available data on the putative neurobiological mechanisms underlying DDs, more than 100 candidate genes have been analyzed to identify the possible associations between their alleles and the risk of depression onset or its symptoms. The studies of DD pathogenesis have yielded conflicting results. Development of DNA microchip technology has made it possible to conduct genome-wide associations studies (GWASs) to look for risk factors of depression onset, independent of the hypotheses to explain depression pathogenesis available at the time. However, GWASs using large sets of samples, including thousands of patients with different forms of DDs and tens of thousands of patients in meta-analyses, have failed to identify any specific loci responsible for predisposition to DDs. These studies have also not unambiguously defined the biological mechanisms underlying the pathogenesis of the pathology of DDs. This failure to identify clearly the genetic associations and underlying mechanisms indicate that depression is a complicated multifactor heterogeneous psychiatric disorder. It is likely that the predisposition to DDs is determined by the coordinated action of many genes and their interaction with each other and with diverse environmental factors. It is also likely that each gene by itself makes a relatively small contribution to the pathogenesis of the disease ( 9 ).

In this review, we discuss the principal theories to explain the development of depression and the genetic evidence in support of these theories. The final section discusses the results of GWASs and the possible contribution of epigenetic factors to the risk of onset of DDs.

Brief characterization of depressive disorder

Depression (lat. depressio —gloominess, oppression) is a psychiatric disorder characterized by a pathologically low mood (hypothymia) and negative esteem about oneself, one's status in the real world, and one's future ( 10 ). In other words, the major depressive disorder is a complex and heterogeneous illness with an etiopathogenesis that is based upon multiple factors that may act at different levels, e.g., psychological, biological, genetic, and social ( 11 ).

Two current reference classifications provide a clinical description of depression: the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) and the International Classification of Diseases, 10th Edition (ICD-10).

According to the DSM-IV, one of the principal forms of depression is major depressive disorder (MDD). For an appropriate diagnosis, five or more of the following 10 DSM-IV symptoms must be exhibited:

• Depressive mood present continuously for a minimum 2-week period prevalent every day and a larger part of the day
• Pronounced elevated emotional psychomotor activity in children and teenagers
• Diminished ability to feel pleasure and rejoice
• Loss or gain of weight against a marked appetite alteration
• Sleep disturbances: insomnia at night and daytime sleepiness
• Objectively registered psychomotor agitation or motor retardation
• Feeling of weakness, loss of energy, marked fatigue even after minimal effort
• Lowered self-esteem and feeling of worthlessness, loss of self-confidence, ungrounded self-accusation to the extent of delirium
• Diminished ability to think or concentrate, mental slowness, lack of resolution
• Thoughts or actions leading to self-injurious or suicidal ideation.

The abovementioned symptoms must be present continuously for at least 2 weeks and cause disturbance of a person's normal vital activities.

In terms of the manifestation of depressive symptoms, the contemporary ICD-10 classification identifies a number of clinical variants of depression, which are classified according to their severity, the presence of psychiatric symptoms, and recurrence of DDs. Episodes of moderate depression (four or more symptoms exhibited; F32.1) and severe depression without psychotic symptoms (commonly with a number of symptoms, usually with lowered self-estimation and suicidal thoughts and attempts; F32.2), and a recurrent (repeated) DD of moderate or severe degree (F33.2–F33.3).

It is important to note that the main classifications of DDs have some differences and that this must be considered when analyzing the experimental data in studies of depression in humans. It is possible that some of the differences in results between studies will be related to the use of different samples of depressed patients who have been diagnosed according to different clinical criteria. Moreover, in our opinion, it is necessary to distinguish exo- and endogenous DD and analyze this type of DD separately. Exogenous, or reactive, depression is usually triggered by some situational stress, as losing a job, the loss of a member of the family, divorce, or relationship difficulties. As opposed to endogenous depression, exogenous is environmentally caused, and associated with anxiety and mood reactivity, and highly sensitive to psychosocial stressors. Endogenous or melancholic depression is a form of DD unrelated to any pronounced exogenous factors (primary severe somatic illness, illness in a close relative, perceived social problems. In exogenous DD can clearly determine the causes of this disease.

Major hypotheses of pathogenesis of depression: from clinical and biochemical data to candidate genes of depression

The monoamine theory.

The monoamine hypothesis of depression, the first theory historically, was proposed by Joseph Schildkraut in the 1960s. This theory was based on the successful use of iproniazid (monoamine oxidase inhibitor) ( 12 – 14 ) and imipramine (reuptake inhibitor of monoamine neuromediators) for depression ( 15 , 16 ). As proposed by this theory, insufficiency of monoamine neuromediators (serotonin, norepinephrine, dopamine) in definite structures of the central nervous system (CNS) may lead to the development of depression. Detailed analysis of the mechanism of action of these preparations and of later designed tricyclic antidepressants and reuptake inhibitors of monoamine neuromediators confirmed the important role of the imbalance and insufficiency of neuromediators in DDs ( 17 – 20 ). According to the monoamine theory, the synthesis, vesicular transport, and receptors of monoamine neuromediators play an important role in the development of DDs. As a result, the first genetic studies focused on identifying and analyzing polymorphisms in genes associated with serotonin, noradrenalin, and dopamine neurotransmission.

Most studies have analyzed SLC6A4 (previously known as SERT ), which encodes the serotonin transporter that is responsible for the reuptake of serotonin (5-HTT) from the synaptic cleft to the presynaptic neuron and thus plays a role in maintenance of the serotonin level in the presynaptic region. Interest in this transporter also arises from the observation that inhibitors of neural serotonin reuptake are used widely in psychiatry for the treatment of depression, anxiety, and other conditions.

The serotonin transporter is encoded by the solute carrier family 6 member 4 gene ( SLC6A4 ) located on chromosome 17q11.1–17q12 ( 21 ). In the promotor region of SLC6A4 , a 5-HTTLPR (5- h ydroxy t ryptamine t ransporter- l inked p olymorphic r egion) polymorphism was shown to be associated with the availability (the long L allele) or absence (the short S allele) of the 44 bp fragment ( 22 ). The L allele bears 16 GC-rich repeated elements of 20–23 bp, whereas the S allele carries 14 similar repeated units that result from the deletion of the region from the 6th to 8th repeated elements ( 23 ). In vitro studies have shown that the S allele is associated with a lower expression level of SLC6A4 mRNA and lower serotonin transporter expression on membranes and, as a consequence, with a lower ability for serotonin reuptake compared with the L allele ( 23 , 24 ). A number of other rare variants of 5-HTTLPR polymorphism, which contained 15, 19, and >20 repeats, were later reported ( 25 ).

In 2006, the single-nucleotide polymorphism (SNP) rs25531 (A → G) near the 5-HTTLPR polymorphism region was revealed by Hu and coauthors. This polymorphism appears to show linkage disequilibrium with 5-HTTLPR, and the G variant is only found in the L allele carriers. The A → G substitution evokes the appearance of the L G allele, the functional analog of the 5-HTTLPR S allele ( 14 , 26 ). This is because the A → G substitution creates a strong AP2–DNA-binding site (TFBS) which, in turn, suppresses the transcription of SLC6A4 in LG allele carriers ( 13 , 14 ). It appears that up to 15% of the individuals included in previous studies as L allele carriers should have been functionally classified as S allele carriers. This error may have distorted the results and created false-positive or false-negative evidence. Moreover, the situation appears to be more complicated and clearly demonstrates possible problems in interpreting the results of association analysis of individual polymorphic markers inside candidate genes.

In 2008, another SNP, rs25532 (C → T) also localized near 5-HTTLPR, was identified in the promotor region of SLC6A4 . This SNP changes the activity of the 5-HTTLPR/rs2553 combination of polymorphisms. For instance, the L AC allele (the combination of the L allele at the 5-HTTLPR polymorphism with the A and C alleles at the rs25531 and rs25532 polymorphisms) is a variant that ensures a high level of SLC6A4 expression ( 27 ). Further studies revealed additional SNPs, with functionally significant changes, such as G56A in exon 2 and 1425V in exon 9. The 1425V mutation is located in the transmembrane area of 5-HTT, which is important for the formation of the secondary structure of this hydrophobic domain.

A polymorphic region comprising three alleles, Stin2.9, Stin2.10, and Stin2.12, was discovered in intron 2 of SLC6A4 . This variable number tandem repeat polymorphism increases the expression in proportion to the number of repeated copies of the 16/17 bp element (12 > 10 > 9), as determined in the embryonic brain and in human JAR cells ( 28 ). Stin2 alleles respond differently to transcription factors YB-1 and CTCF which, in turn, can be regulated by lithium chloride, which is prescribed for the treatment of bipolar disorders ( 28 , 29 ).

The structure of SLC6A4 may be far more complicated. Recent publications have reported that the expression of this gene is modulated by microRNA mir-16 binding sites in the 3′-nontranslating region of the gene ( 30 ). Therefore, polymorphisms localized within or near microRNA binding sites may be able to exert a strong effect on SLC6A4 expression and, consequently, on 5-HTT functions.

It is possible that the abovementioned complexity of SLC5A4 organization may be one reason for the conflicting results obtained by analyses of the association of this gene's polymorphic variants (primarily in the analysis of the L/S polymorphism of the 5-HTTLPR repeat) with the onset of depression. Meta-analyses of these studies allow no final conclusion to be drawn about the role of this polymorphism in the development of depression. For instance, the meta-analysis conducted by Lopez-Leon et al. ( 31 ) disclosed an elevated risk of DDs in S allele carriers, whereas no similar association was found in carriers of other alleles ( 32 – 34 ). The latest meta-analysis of the results of 23 original studies has shown that the S allele raises the risk of DDs; the risk of depression in S allele carriers is increased 1.14-fold (CI: 1.05–1.24). Nevertheless, the high level of heterogeneity of the data included in this meta-analysis should be noted. In all analyzed models, the association p -value does not reach 0.05. This may be due to the inclusion in the meta-analysis of studies of different size samples, including samples comprising fewer than 50 people ( 35 ).

In the context of the monoamine theory of DD development, analysis of a large number of candidate genes has been performed. They are, in particular, receptor genes for dopamine ( DRD3, DRD4 ) and serotonin ( HTR1A, HTR2A, HTR1B, HTR2C ); genes for noradrenalin ( SLC6A2 ) and dopamine ( SLC6A3 ); genes for the enzymes monoamine oxidase A ( MAOA ), tyrosine hydroxylase ( TH ), tryptophan hydroxylase 1 ( TPH1 ), catechol-o-methyl transferase ( COMT ); and the piccolo presynaptic cytomatrix protein ( PCLO ). For each of these genes, polymorphic variants were identified that were associated with point mutations or tandem repeat polymorphisms. These polymorphisms were analyzed in samples from patients of different ethnicity with DD. As for SLC6A4 , different studies have produced conflicting results, and it seems reasonable not to analyze the results of individual studies but to consider only the meta-analyses that have shown the existence of associations between definite variants of the genes and DD development.

One of the first large-scale meta-analyses of genetic case–control research on DDs was conducted in 2008 by Lopez-Leon and coauthors. The final analysis focused on 20 polymorphisms in 18 genes. The pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Among the genes of the monoaminergic system, statistically reliable associations were found for SLC6A4 and SLC6A3 ( 31 ).

In another meta-analysis, Gatt et al. ( 36 ) attempted to identify genes associated with DD and common genes shared by the five severe psychiatric disorders: MDD, anxiety (including panic disorders), schizophrenia, bipolar disorder, the attention deficit–hyperactivity syndrome ( 36 ). Table ​ Table1 1 displays the data for the genes whose products are involved in monoaminergic neurotransmission.

Associations shown in meta-analyses between DDs and polymorphic variants of the genes linked to the exchange of monoamine neuromediators * .

It appears that polymorphic variants of the genes that are in some way associated with the monoamine theory of DD pathogenesis can influence the risk of developing depression. However, this influence is not large and cannot be currently regarded as unambiguously proven because of conflicting results of both individual studies and meta-analyses.

Stress as a cause of depressive disorders

Chronic stress and stressful life events early in life are strong proximal predictors of the onset of depression. Although the response to stress implies stability or maintenance of homeostasis, long-time activation of the stress system can cause harmful or even fatal consequences by elevating the risk of obesity, heart diseases, depression, and other disorders ( 37 ). The Hypothalamic–pituitary–adrenal axis and its three main components—hypothalamic neurosecretory cells, pituitary gland, and adrenal cortex—are responsible for adaptation to changed environmental conditions and for mobilization of the organism's reserves during exposure to stress of different etiologies. The HPA system operates in the following way (Figure ​ (Figure1). 1 ). In response to a stressor, neurons in the hypothalamic paraventricular nuclei secrete corticotropin-releasing hormone (CRH), which exerts its action on the hypophysis to initiate the release into the blood circulation of adrenocorticotropic hormone (ACTH), which stimulates the release of corticosteroids, particularly cortisol, from the adrenal cortex. The final hormonal product of the HPA axis, cortisol, binds to mineralocorticoid receptors (type 1) and glucocorticoid receptors (type 2) to form hormone–receptor complexes, which are then transported into the cell nucleus where they interact with specific DNA regions, the glucocorticoid-response elements, to activate the expression of hormone-dependent genes ( 38 ).

The “stress-induced” theory of DD onset is based on the assumption that hyperactivity of the HPA system may be an important mechanism underlying the development of depression after exposure to stress. A number of examples of abnormal functioning of the HPA system during depression favor this hypothesis. First, stressful events during one's life are the strongest factors that can initiate depression onset ( 39 , 40 ). Second, depressed patients frequently show elevated cortisol levels (the human endogenous glucocorticoid) in plasma, urine, and cerebrospinal fluid and corticotropin (ACTH) level in plasma ( 41 ). Depressed patients also exhibit increased size of the hypophysis and suprarenal glands ( 42 ) or decreased function of corticosteroid receptors ( 43 ). Excessive activation of the HPA axis is observed in 50% of depressed people, and continuous administration of antidepressants helps to attenuate this activation ( 44 ).

A large cohort of genes is likely to be involved in the normal functioning of the HPA axis, but only some of these genes have been actively investigated in the context of DDs. The genes most likely to be involved in DDs are those encoding the targets of cortisol and other glucocorticoid hormones secreted during stress. Polymorphic variants of these genes were analyzed in case-control studies and in some cases, associations between these variants and development of DD were shown. For instance, associations between DD onset and polymorphic sites of the genes coding for the GR ( NR3C1 ) and mineralocorticoid receptor (MCR; NR3C2 ) have been reported ( 45 – 47 ). Moreover, postmortem studies by Klok et al. ( 46 ) have shown that MCR mRNA expression is reduced in the hippocampus in depressed patients ( 46 ).

Associations with DD were also shown for genes CRHR1 and CRHR2 , which encode CRH receptors ( 48 ). Lui et al. ( 48 ) reported significant associations between depression and the SNV rs242939 in the CRHR1 gene. These authors also showed that the haplotype formed by G–G–T alleles of the rs1876828, rs242939, and rs242941 was most often represented in patients with MDD compared with controls ( 48 ). Szczepankiewicz et al. ( 49 ) found associations between DD and the SNVs rs4076452 and rs16940655 of CRHR1 gene ( 49 ). Xiao et al. ( 50 ) also reported associations between the rs242939 polymorphism of CRHR1 gene and recurrent depression ( 50 ).

We note that some of the associations described earlier were included in the meta-analyses by Lopez-Leon et al. ( 31 ) or Gatt et al. ( 36 ). These authors did not find any reliable associations between DDs and polymorphisms in the genes involved in the functioning and regulation of the HPA axis ( 31 , 36 ).

Disturbance of neurogenesis and neuroplasticity

A large body of experimental data has recently provided evidence of a link between the development of depression with disturbance of normal neurogenesis during brain ontogenetic development and decreased neurogenesis of the adult brain. These effects are thought to be caused by metabolism disturbance of neurotrophic factors, primarily the brain-derived neurotrophic factor (BDNF) in nervous tissue ( 51 – 57 ).

BDNF is abundantly expressed in the adult brain's limbic structures. Some data have shown a connection between the BDNF-mediated signaling pathway and the functioning of serotoninergic neurons. For example, BDNF maintains the survivability and differentiation of serotoninergic neurons, and serotoninergic transmission exerts a strong influence on BDNF expression ( 58 – 60 ).

A functional missense polymorphism rs6265 (GI96A) was described in BDNF that is associated with the substitution of methionine (Met) with valine (Val) in codon 66 (Val66Met). The Met allele was shown to cause disturbed maturation of the protein and to be associated with decreased BDNF activity ( 61 ), which might be caused by two different mechanisms: the infective transport of the mutant protein over the regulatory secretory pathway and the defective transport of BDNF mRNA to dendrites ( 62 ). Val66Met is a frequent polymorphism whose frequency of alleles is determined by ethnicity. Met allele frequency is 25–32% in European populations and reaches 40–50% in Asian populations ( 63 ).

Some studies have reported an association of the Val66Met polymorphism in BDNF with DD onset ( 64 – 66 ), but different authors attribute the risk of DD to the effect of different allelic variants. For instance, Frielingsdorf et al. ( 66 ) showed that Met allele homozygotes are at significantly increased risk of MDD ( 66 ), whereas Ribeiro et al. ( 65 ) defined the Val allele as an allele for the risk for depression ( 65 ). This inconsistency motivated the publication of a meta-analysis that combined the results of 14 original studies, but this analysis did not confirm an association between the polymorphic variant in BDNF with DDs ( 63 , 67 ). The effect of this polymorphism may have been observed only in interaction with other polymorphic systems, such as with 5-HTTLPR polymorphisms or after exposure to severe stress ( 68 , 69 ).

The cytokine theory

The brain was earlier thought to be an “immune-privileged” organ that is protected from circulating immune cells by the blood–brain barrier. It is now well known that immune system cells can infiltrate into nervous tissue. Pro- and anti-inflammatory signals can be transmitted to nervous system from peripheral areas. Also, cytokines and their receptors can be produced in the CNS by astrocytes, microglia ( 70 ) and, in some cases, neurons. These molecules are believed to participate in the processes of neuronal development, plasticity, synaptogenesis, and tissue repair.

The hypothesis of bidirectional communication between the immune system and the CNS was suggested in the 1990s. According to this hypothesis, the immune system can interact with the CNS as well as being involved in neuropathological processes. In 1999, Maes M . proposed the inflammatory response system (IRS) model of depression, which claimed that the occurrence of depression depends on activation of the IRS. According to this model, depression can be regarded as a psychoneuroimmunological disease in which peripheral activation of the immune system through the release of anti-inflammatory cytokines can cause the various behavioral, neuroendocrine, and neurochemical changes observed in this disorder ( 71 ). This theory was later extended and is now referred to as the “cytokine theory.”

Cytokines constitute a heterogeneous class of mediator molecules produced as regulators of the immune response by immunocompetent cells such as lymphocytes and microphages. Cytokines can be classified into two groups: proinflammatory and anti-inflammatory cytokines. Proinflammatory cytokines are either immediately or indirectly involved in the inflammatory process: interleukin 1 (IL-1), IL-2, IL-6, and IL-12; interferon γ (IFNγ); and tumor necrosis factor α (TNFα). Anti-inflammatory cytokines include IL-4, IL-10, and IL-13, which suppress the immune response and thereby prevent both cell activation and the production of proinflammatory molecules. Some cytokines, such as IL-8, exert both the pro- and anti-inflammatory functions, according to their concentration.

Immunological changes during depression and psychiatric side effects caused by the use of cytokines in the treatments for hepatitis and cancer provide evidence in favor of this theory. For instance, stressors increase the expression of proinflammatory cytokines such as IL-1β, TNFα, and IL-6) in blood and brain ( 72 , 73 ). DD patients display increased granulocyte and macrophage counts in peripheral blood ( 74 ).

In addition to associations with the depression, associations between inflammatory markers and some symptoms, such as apathy, cognitive dysfunction ( 75 ), and impaired sleep ( 76 ), have been reported. For instance, sleep impairment in depressed patients is associated with increased levels of IL-6 and the soluble forms of intercellular adhesion type 1 molecules in plasma ( 76 ) and with the activation in blood cells of nuclear factor-κB (NF-κB), the principal transcription factor involved in initiation of the inflammatory response ( 77 ). In other studies, about 50% of the patients chronically administered IFNα developed symptoms of depression, which further supports the role of inflammation in DD pathogenesis ( 78 , 79 ).

We note, however, that the average cytokine levels in the plasma are elevated only slightly in DD patients compared with healthy people and that these levels are sometimes close to the physiological norm. In autoimmune or infectious diseases, the cytokine levels increase considerably more. Therefore, DD is not considered as a typical autoimmune disease ( 74 ).

IL1B is located at locus 2q14.1 on chromosome 2. Several SNPs have been reported for this gene, and two—rs1143627 (−31T/C) and rs16944 (−511C/T)—are associated with DD. Some studies have reported an association between rs16944 (−511C/T) and depression onset and with a positive response to treatment with some antidepressant medications ( 80 – 83 ). Borkowska et al. ( 81 ) reported a positive association with recurrent depression ( P = 0.064) for the polymorphic haplotype comprising the rs1143627 SNP C allele and the rs16944 SNP T allele ( 81 ). By contrast, Yu et al. ( 82 ) did not confirm an association of the rs14944 SNP with major depression, although the severity of depression symptoms was elevated in allele C homozygotes ( 82 ). Similarly, Hwang et al. ( 84 ) failed to find any reliable associations of rs16944 SNP with senile depression or the severity of depression symptoms ( 84 ).

The SNPs rs1143627 (−31T/C) and rs16944 (−511C/T) are found in the promoter region of the gene and can affect the expression of this gene, which influences the IL-1β level. Chen et al. ( 85 ) showed that SNP rs1143627 localizes in the TATA box area in the IL1B promoter and that the T allele of this polymorphism is associated with increased production of IL-1β ( 85 ). However, other investigations have failed to find any reliable associations of SNP rs1143627 with IL-1β production in vitro , although one study found an association between elevated IL-1β expression in vivo and the C allele ( 86 ). Data concerning the influence of rs16944 (−511C/T) on IL1B expression are also conflicting. For instance, Hall et al. ( 87 ) showed that this SNP influences the expression directly ( 87 ). On the other hand, some data support the concept that the −511C/T polymorphism influences the expression of the gene only when acting in concert with the −31T/polymorphism ( 85 ).

Therefore, the current data concerning an association of polymorphic variants of the IL1B promoter area do not allow any unambiguous conclusions to be drawn about the role of this gene in the development of depression.

Another actively studied gene, IL6 , encodes the proinflammatory cytokine IL-6 and is located at the 7p15.3 locus. The functional polymorphism rs1800795 (174 G/ C) is located in the gene's promoter region and influences gene expression both at the mRNA and protein levels. The IL-6 level is lower in C allele carriers under conditions of immune system activation ( 88 ). No association of this polymorphism with major depression, depression in children, or postbrain stroke depression has been found ( 89 – 91 ). However, this polymorphism has been reported to affect the progression of depressive symptoms in hepatitis C patients administered the immunomodulators IFNα and ribavirin ( 92 ). Another interesting observation in that study was the interaction between the 5-HTTLPR polymorphism in the serotonin transport gene ( SLC6A4 ) and rs1800795. A “protective” effect of the 5-HTTLPR polymorphism was observed only in the presence of the low-expressing genotype for IL6 ( CC ). Consequently, in the genetics of depression, the transition from the analysis of individual polymorphic variants to the analysis of their combinations including two, three, or more loci seems to be very important.

The circadian rhythm theory

Circadian rhythms oscillate with ~24-h periodicity and are responsible for regulating a wide variety of physiological and behavioral processes. Endogenous cyclic oscillations are regulated in humans and other mammals by the circadian pacemaker—the suprachiasmatic nucleus (SCN) neurons of the anterior hypothalamus ( 93 ). The circadian pacemaker can change its pattern so that the circadian rhythm may be advanced, delayed, or remain constant in various pathological states or when affected by different pharmacological preparations and hormones; for instance, melatonin regulates the function of the biological clock through melatoninergic receptors residing in the hypothalamic SCN ( 94 ). At the cellular level, the “molecular clock” refers to a network of “clock” genes, which are transcriptional regulators organized in a feedback-sustained transcription–translation network. This mechanism helps maintain the rhythmic expression of target genes during a 24-h cycle ( 95 ). The basis of the molecular clock is the negative feedback loop, in which the expression of PER and CRY proteins is inhibited by their interactions with the transcriptional factors CLOCK and BMAL1 and by blocking their binding to E-box regulatory elements in the promoters of the genes for PER and CRY protein family members. Posttranslational modifications of the molecular clock system components by signal molecules such as casein kinase δ/ε and glycogen synthase kinase 3-beta play important roles in the maintenance of circadian rhythms ( 96 ).

Sleep disorders (early awakening, insomnia, and inability to resume sleep after waking) are observed in 80–90% of patients with depression, and insomnia is regarded as a risk factor for the onset of depression ( 97 ). Therefore, disturbance of the normal functioning of circadian system proteins may play a role in DDs. Additional evidence for the role of circadian rhythm genes in DD onset was provided by studies of two familial syndromes of sleep disturbance: familial advanced sleep-phase syndrome and delayed sleep-phase syndrome (DSPS). Both syndromes are caused by mutations in the genes PER2, CKie, PER3 , and CLOCK , which encode circadian system proteins ( 98 ). People with these mutations frequently experience depressive symptoms. In addition, people with a history of depression have elevated expression of the circadian system genes CLOCK, PER1 , and BMAL1 compared with healthy volunteers ( 99 ). Case–control studies have shown associations between depression onset and polymorphic variants of the genes encoding circadian system proteins, including BMAL1, CLOCK, NPAS2, PER3, CRY1 , and TIMELESS . However, none of these genes was confirmed in the meta-analysis ( 100 ).

Other candidate genes

Investigations of the candidate genes selected according to the principles of DD etiopathogenesis theories have identified only five genes whose polymorphic variants are reliably associated with DD onset according to the results of meta-analyses (Table ​ (Table1). 1 ). However, all of these genes have been discussed only in terms of the monoamine theory of depression.

The association research is not confined solely to the DD-related candidate genes studied in terms of DD etiopathogenesis theories. Other genes have also been actively studied, primarily those analyzed for other neurological and psychiatric disorders. Moreover, these studies have revealed a large amount of reliable associations that have passed through testing in large meta-analyzes (Table ​ (Table2). 2 ). These association studies have revealed genes encoding functionally diverse proteins, from chondroitin sulfate biosynthesis enzymes to the key enzyme of the renin–angiotensin system (RAS). On the one hand, this may reflect the limited understanding of DD etiopathogenesis, although the currently known associations suggest new hypotheses. On the other hand, many of the associations revealed are in some way linked to neurogenesis and neuroplasticity processes, and DDs may be regarded as disorders linked to disturbance of neural tissue ontogenesis.

Association shown by meta-analyses between DD and polymorphic variants of genes not linked with the general hypotheses of DD etiopathogenesis.

According to Gatt and coauthors with modifications ( 36 ) .

Associations between DD and polymorphic variants of the genes angiotensin-converting enzyme ( ACE ), apolipoprotein E ( APOE ), and methylenetetrahydrofolate reductase ( MTHFR ) are of special interest. These genes have been discussed in the context of another theory of DD etiopathogenesis—the vascular theory—which postulates that DD occurs because of disturbance in the blood supply to neural tissue. According to this theory, vascular disorders can cause DD as well as other mental illnesses such as schizophrenia and manic–depressive psychosis. It is possible that there is a continuum of these diseases, which are separated by only a thin line; for example, some clinical subtypes of depression are characterized by marked psychotic symptoms (F32.3 in ICD-10). Presumably, there may be a complex link between genetic variants and the occurrence of various pathologies along the continuum. For example, genetically determined vascular disorders provoke increased risk for different mental disorders. Progression of a particular disease (e.g., schizophrenia, depression, manic–depressive psychosis) may be determined by other genetic factors, such as those associated with neuromediator functions.

Genome-wide association analysis of depressive disorder

As noted above, >20 genes have been associated with DD onset and confirmed by meta-analyses. In most cases, these associations involve genes that are not directly linked to the general theories of depression ethnopathogenesis. Association studies appeared to be connected with transition to genome-wide methods of association analysis without any suggestions about the genetic risk factors of depression.

In the first stage of GWASs, families with members that have experienced multiple depression events, severe course of the disorder, or an early age at its clinical onset were analyzed with special interest in patients with rare monogenic forms of depression. The results of these studies are summarized in Table ​ Table3. 3 . These studies have reported associations with extended genomic regions (even as long as full-length chromosomes), and the identification of the candidate genes seems to be provisional. This identification mainly based on the DD candidate genes mapped earlier in these genome regions.

Mapping the loci associated with predisposition to different forms of depression in family studies using SNP panels of DNA markers.

GWASs have been used increasingly in the past decade to identify loci that control complex traits. In this analysis, as many as hundreds of thousands to several millions of SNPs distributed over the whole genome are identified in groups of persons having a particular trait of interest. Analysis of the genotype–phenotype associations makes it possible to establish a link between the allelic variant in some particular region of the genome with the trait studied. The principal difference between GWASs and candidate gene studies using the case–control method is that there is no preliminary hypothesis to explain the contribution of polymorphic variants of genes to the development of a pathology of interest. However, for a study to achieve statistically significant results, its algorithm requires very large samples of both patients and healthy persons. It can be extremely difficult to achieve clinical homogeneity in very large samples, especially when studying psychiatric diseases because there is always a subjectivity factor affecting the diagnostic accuracy in the relevant international classifications with almost no instrumental methods for assessing the patient's condition.

A number of studies have searched for loci associated with MDD or individual symptoms of depression. The results are summarized in Table ​ Table4. 4 . This table focuses mainly on those studies that analyzed primarily the risk of depression as a disease and not the endophenotypes (e.g., clinical onset age, severity of particular symptoms, patients' responses to therapy). As well, Table ​ Table4 4 includes the most statistically significant results from the analyzed articles.

Genome-wide association studies of major depressive disorders (MDDs) and recurrent depressive disorders (RDDs).

The first GWAS of a large representative sample (1738 DD patients, 1802 controls) was reported by Sullivan et al. ( 106 ). In this study, no association with any of SNPs achieved the value of genome wide significance. The maximum significance was found for the rs2715148 ( p = 7.7 × 10 −7 ). Also, in this genomic region near PCLO gene 10 more SNPs were associated with DD with relatively low significance ( p = 10 −5 -10–6). They were mapped to a 167 kb region where PCLO was located ( 106 ). PCLO protein localizes in the cytoplasmic matrix of the presynaptic active zone and plays a significant role in brain monoaminergic neurotransmission. A possible role of this region in depression onset was confirmed by Hek et al. ( 115 ), who showed an association between the rs2522833 SNP in PCLO and DD in a population-based study from the Netherlands ( 115 ). Aragam et al. ( 113 ) found a close statistically significant association between DD development for the rs2715148 SNP ( P = 5.64 × 10 −7 ) in PCLO in women ( 113 ). This study found another SNP in LGSN that was associated with DD occurrence in men (rs9352774, P = 2.26 × 10 −4 ). This gene is actively expressed in the human crystalline lens and encodes a protein related to GS-I and, to a lesser degree, to GS-II glutamine synthetases. This protein may play a role in glutamate exchange in both the retina and the nervous system.

A role of glutamate in DD was found in a GWAS conducted by Rietschel et al. ( 109 ). They found an association between DD and the rs7713917 SNP ( P = 5.87 × 10 −5 ) located in a putative regulatory region of HOMER1 , which encodes proteins involved in glutaminergic processes via interaction with the metabotropic glutamate receptors mGluR1 and mGluR5.

We reiterate that the associations discovered in most GWASs did not attain a genome-wide significance level, primarily because of the genetic architecture of complex traits predisposing to depression. Adjustments of the genome-wide significance level are very rigorous, and we believe that SNP markers with a probability value close to the genome-wide threshold level should also be considered.

Some studies have achieved a genome-wide significance level. Kohli et al. ( 112 ) were the first to report an association between DDs and the rs1545843 SNP in SLC6A15 (solute carrier family 6, neutral amino acid transporter, member 15) in a recessive model of the effect of this polymorphism on the risk of DDs ( 112 ). This gene encodes the neutral amino acid transporter, and different rs1545843 alleles were shown to have different SLC6A15 expression levels in the hippocampus of epileptic patients. The authors presented additional evidence to support the involvement of this association and showed that the presence of the risk allele correlated with lower SLC6A15 expression in the hippocampus, smaller hippocampus volume, and neuronal integrity in vivo . Lower expression of Slc6a15 was also observed in the hippocampus of mice with elevated chronic stress susceptibility.

Kohli et al. ( 112 ) reported abundant data in support of the association between SLC6A15 and DD. However, subsequent GWAS disclosed no significant associations with this gene. The data obtained in GWASs are often not reproducible, and only one gene, PCLO , appeared to be associated with DD in two GWASs.

The Psychiatric Genomics Consortium (PGC) performed a meta-analysis of GWAS data. Unlike the conventional meta-analyses, which summarize the statistical data for each constituent analysis examined, the PGS study brought together and examined individual genotypic and phenotypic data from patients from different research centers. The PGS published the results of its genome-wide comparative analysis of 9240 samples collected from DD patients and 9519 samples from a control group of nine European populations ( 122 ). However, in the PGS analysis, none of SNPs identified in earlier studies achieved a genome-wide significance level. The SNPs with the most significant values were rs11579964 ( P = 1.0 × 10 −7 ), which mapped near CNIH4, NVL , and WDR26 , and rs7647854 ( P = 6.5 × 10 −7 ), which mapped near C3orf70 and EHHADH . A subsequent replicative study conducted using an independent sample (6783 patients with MDD and 50,695 controls) did not confirm the associations mentioned.

Therefore, no locus has been shown to be consistently associated with a DD at a whole-genome significance level. Associations shown in independent samples have also not been reproduced. This lack of significance and reproducibility may reflect the particular features of the GWAS methodology, which has focused on polymorphic sites with a high minor allele frequency (>5%) in the associative analysis. These frequent polymorphic variants themselves are probably not pathogenically essential, but there may be disequilibrium linkages with rare variants of genes associated with DD pathogenesis. These rare variants may be specific for different populations. As a result, any association between the disease and a frequent polymorphic site may be found in one sample and may reflect the disequilibrium linkage of this polymorphic site with a rare, pathogenically significant variant in that sample. However, the pathogenically significant site may be missing in another sample and, as a consequence, no association of frequent polymorphism with DD occurrence will be found. In addition, the important role of rare genomic variants (a frequency <1%) has been reported in association with other mental disorders, such as schizophrenia and autism ( 123 , 124 ).

To overcome these problems, transition from the analysis of polymorphic DNA markers using microarrays to low-coverage DNA sequencing may provide a new direction for research to identify DD-associated genetic variants. The first study of this kind was conducted within the CONVERGE Project ( 125 ) and included genome sequencing with an average coverage of 1.7 × in >9000 Chinese females; 5000 females out of this group were patients with melancholic depression, which is recognized as a more severe form of depression. This study found two loci bearing an association at a 10 −8 significance level: one on the 5′-side of SIRT1 (SNP rs12415800) and the other in an LHPP intron (SNP rs35936514). This association was confirmed in an independent sample of melancholic Chinese women, and the significance values combined for the two samples were 2.53 × 10 −10 for SIRT1 and 6.45 × 10 −12 for LHPP . It is important to note that both associated SNPs occur frequently (e.g., the minimal allele frequencies were 45.3 and 26.2%), yet neither is included in the microarrays used widely for SNP marker typing and, therefore, may have been ignored in earlier GWASs.

Further analysis of the data in this project showed that frequent SNPs accounted for 20–30% of the DD risk dispersion, which suggested that the heritability of DD is evenly distributed over all chromosomes with preferential localization of DD-associated SNPs in both the coding and the 3′-untranslated areas of genes. DD patients showed an elevated frequency of unique mutations in gene coding regions, primarily in the genes actively expressed in nervous tissue ( 126 ).

Importantly, this study included a specific ethnic group (Han Chinese), which is sufficiently homogeneous, and only females, who show a higher heritability level as mentioned above, with a severe form of DD. This design included a more rigorous approach to inclusion of samples and consideration of factors such as the patients' sex, clinical DD variation, clinical onset age, and other factors that can affect the risk of disease and its progression. However, these factors may exert no influence on the risk of DD development; for example, the clinical onset age was recently shown to not affect the association analysis results in the Chinese CONVERGE sample ( 127 ).

Another study also found that ethnicity was important ( 128 ). That study included a combined analysis of the results obtained in the CONVERGE investigation of Chinese and of studies conducted by the PGC in different European populations. These studies found that some SNPs influence the risk of DD onset in both ethnic groups mentioned but, at the same time, detected a set of SNPs specific to each ethnic group. The highest contribution of genetic factors in both ethnic groups was observed in females and in recurrently depressed patients.

Powers et al. ( 116 ) attempted to include environmental factors into GWASs ( 116 ). They included as a factor stress-provoking events when including case–control pairs of patients in the study—a method referred to as propensity score matching . This analysis allowed them to reduce the heterogeneity of the samples with regard to the stress factor and to compare DD patients and healthy controls exposed to similar stressors.

The genetic structure of depression appears to be extremely complicated and involves a large number of loci, which cause various phenotypic effects and display complex interlocus interactions. Studies of the genetic structure suggest the need for a transition from the analysis of individual SNPs to that of sets of SNPs and, finally, to include a polygenic risk score, as used in genetics research of schizophrenia ( 129 ).

To address similar problem, a strategy for studying gene networks created by uniting signals from numerous SNPs and subsequent functional analysis of the signaling and metabolic pathways have been used with success. This approach provides for an increase in the power of comparative analysis of weak signals from numerous loci. The study by Song et al. ( 130 ) is an example of such an analysis. On the basis of a GWAS of samples from European cohorts, the authors conducted a search and analysis of DD-linked SNPs and genes with these SNPs to discover signal pathways linking these genes to each other ( 130 ). Five resulting signal paths were found to play a role in DD pathogenesis. Three of them were claimed to be connected in some way with the negative regulation of gene expression (GO:0016481, GO:0045934, GO:0010629) and were related to some DD-associated SNPs: rs3213764 in ATF7IP ; rs2301721 in HOXA7 ; rs6720481 in LRRFIP1 ; rs2229742 in NRIP1 .

Okbay et al. ( 118 ) and Hyde et al. ( 131 ) offered an alternative approach for sampling ( 118 , 131 ). To diagnose DDs, they compiled a questionnaire to be completed by the respondents. Depression was diagnosed on the basis of the respondents' answers to the questionnaire with no clinical diagnosis by a psychiatrist. Although the accuracy of the diagnosis may be questioned, the questionnaire included questions on a wide range of phenotypic traits, and respondents could not associate them with any diagnoses. Data from biobanks or mass genotyping services such as 23 and Me allowed them to markedly increase the sample size. For example, the study by Hyde et al. ( 131 ) included >450,000 individuals, and analysis of their questionnaire data allowed them to diagnose depression in about 120,000 participants ( 131 ). Samples of this size are an order of magnitude greater than those included in the PGC studies or CONVERGE Project, and help to minimize the problems caused by DD diagnostic errors. The authors managed to identify 17 SNP markers in 15 loci whose significance level was >5 × 10 −8 , which reflects the size of the sample analyzed. The DNA markers detected differ from those associated with DD in the PGC studies, although they both analyzed samples of European origin. Therefore, the problem of the reproducibility of results obtained in the GWASs remains to be solved.

A possible way to solve this problem is to conduct a meta-analysis of GWA studies. This analysis was carried out by Wray et al. ( 121 ). This meta-analysis identified 44 independent loci that were statistically significant ( P < 5 × 10 −8 ). Of these loci, 30 are new and 14 were significant in a prior study of MDD or depressive symptoms, and 6 shared loci with schizophrenia. Thus, the increase in sample sizes in the meta-analysis, on the one hand, allows the confirmation of the results obtained earlier with GWAS for the previously described loci associated with MDD. On the other hand, it increases the power of the study, by increasing the sample size, making it possible to identify new loci associated with the MDD.

Several methods were proposed for calculating of genetic risk score (GRS): simple count genetic risk score (SC-GRS), odds ratio weighted genetic risk score (OR-GRS), direct logistic regression genetic risk score (DL-GRS), polygenic genetic risk score (PG-GRS) and explained variance weighted genetic risk score (EV-GRS). Currently, the most widely used method is polygenic risk score (PGRS) ( 132 ). This approach has been used to obtain evidence of a genetic effect even when no single markers are significant, to establish a common genetic basis for related disorders, and to construct risk prediction models ( 133 ). Currently, alternative approaches to statistical analysis of GWASs data are proposed, where the analysis is not of individual DNA markers, but their combinations. Recently, several papers have been published using PGRS for the MDD and other psychiatric disorders ( 134 – 136 ). The possibility of using the PGRS to evaluate the cumulative contribution of several polymorphic variants of genes to the formation of endophenotypes of MDD was demonstrated. Whalley et al. ( 135 ), using the PGRS, divided the MDD into two subtypes, one of which is close to schizophrenia ( 135 ).

Conclusions

Summing up the last quarter-century of investigation of the role of genetic factors in DD onset and progression, we note the polygenicity of inherited diseases with no pronounced effect of the principal gene. This has been made clear by recent studies undertaken in the CONVERGENCE and PGC studies and by analysis of candidate genes, which show that each of the genes implicated probably make a small contribution to DD progression. The important role of intergenic interactions has not been studied to date and will require new methods to analyze the data of association studies by including the contribution of combinations of two or more polymorphic DNA markers.

As noted above, DD typically has a high phenotypic heterogeneity, which may be manifested in differing severity of the main symptoms, and this heterogeneity limits the use of association studies. An approach to analyzing very large samples with minimally rigid assessment criteria for the DD phenotype (an extreme example is the variant identified by the 23andMe company associated with self-diagnostics of DD) is one possibility, but this must be supplemented by analysis of small and clinically highly homologous samples. This kind of analysis may not clear up the uncertainty about the genetics of DD on the whole, but it will make it possible to identify certain genetic variants underlying individual subphenotypes of DD.

A small but growing body of evidence suggests that mitochondrial dysfunction may play a role in the development of MDD. MDD was found to be associated with an increased production of mtROS, which could indicate a dysfunction of mitochondria ( 137 , 138 ). Gardner et al. ( 139 ) found a decrease of mitochondrial ATP production rates and mitochondrial enzyme ratios in the muscle of patients with major depressive disorder and chronic physical conditions compared to controls ( 139 ). As well, decreased levels of an important part of electron transport chain, i.e., CoQ10, were found in the serum and peripheral blood mononuclear cells received from patients with MDD, which may also indicate a dysfunction of mitochondria ( 140 ).

Currently, however, there have been few studies on the role of genetic variants in mitochondrial DNA associated with MDD. A deletion in mtDNA in a child was associated with mitochondrial disease symptoms and with mild-moderate unipolar depression ( 141 ). Sequeira et al. ( 142 ) have analyzed post-mortem brain samples from human subjects and were failed to show associations of the mitochondrial haplogroups and major depression. However rare homoplasmic mutations with possible functional consequences were reveled in major depression cases, in the ATP synthase 8 (ATP8), ATP synthase 6 (ATP6), ND5 and cytochrome b (CYTB) genes, while another subject with depression demonstrated subthreshold heteroplasmy rate at a variant in the displacement loop (D-loop) part of mtDNA ( 142 ). Veronese et al. ( 143 ) found no significant associations between specific mitochondrial haplogroups and depressive symptoms either ( 143 ). Thus, changes in the functioning of mitochondria may be caused both by an abnormality of the mitochondrial DNA, and by variants of nuclear genes that encode mitochondrial proteins. The meta-analysis conducted by Huo et al. (141) identified SCL25A37 as a novel MDD risk gene, and Zhang et al. ( 144 ) have showed that a haplotype T-C consisting of rs12457810 and rs12964485 in the 5'-upstream region of NDUFV2 may be a protective factor for the development of MDD in Han Chinese ( 144 , 145 ).

It is also important to supplement the association studies of inherited genome variants with analysis of dynamic modifications occurring during DD. There is much interest in the epigenetic changes that can modify a gene's functional status without changing its coding sequence. These epigenetic modifications can be caused by the action of different factors and can be stably inherited after disappearance of the factor causing the change. These epigenetic factors primarily involve DNA methylation and histone modification (methylation and acetylation). In recent years, several studies have analyzed changes in DNA methylation in DD. The first genome-wide analysis of methylation profiles in DD was by Sabuncian et al. ( 146 ), who assessed DNA methylation in postmortem frontal cortex material from DD patients and healthy people. In a number of regions, methylation differed reliably between healthy individuals and DD patients ( 146 ). A subsequent replicative investigation confirmed this modification of the methylation status in DD patients of the proline rich membrane anchor 1 gene, PRIMA1 , which codes for the protein responsible for the assembly of acetylcholine esterase into tetramers and its “anchorage” in the neuron cellular membranes ( 147 ). This gene has not been mentioned in association with DD onset. Methylome changes were reported in peripheral blood of twins discordant with regard to DD occurrence. This study also reported on associative studies showing that, in some cases, the changes were related to genes linked to the development of the disorder (e.g., ZBTB20, AGTPB1, TBC1D8 , and CLSTN1 ) ( 148 ). A number of studies have focused on associations between DD and histone methylation or acetylation ( 149 , 150 ). Changes in lysine methylation of histone K27H3 were found postmortem in the BDNF promotor region in the prefrontal and frontal cortex of DD patients, and these changes correlated well with the expression level of BDNF . However, in this review, we do not analyze in detail the role of epigenetic factors in the development of the pathogenesis of DD.

Investigation of changes in the epigenome, transcriptome, and proteome in DD is probably limited by the nature of this disease and the need for brain tissue, which is possible only postmortem . Researchers must work with an extremely limited number of samples from patients, many of whom are on long-term treatment for both DD and somatic conditions. Therefore, to understand fully the entire process involved in DD onset and progression, studies of DD pathogenesis must be supplemented with experiments using different animal models of depression, which would permit an evaluation at different levels of the nervous system organization.

A threefold approach that combines gene-association studies with assessment of the epigenetic status of DD patients and analysis of the changes in animal models of depression, despite the limitations of such models ( 34 ), will enable researchers to identify the contributions of genetic, epigenetic, and environmental factors to different forms of DDs and to develop ways to reduce the risk of depression and to provide adequate treatment.

Author contributions

All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Funding. This study was supported by Russian Science Foundation (RSF) (project no. 16-15-10199).

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Stanford University School of Medicine blog

Imagining virtual reality as a simple tool to treat depression  

Some of the 17 million Americans afflicted with major depressive disorder each year may soon receive a surprising new prescription from their clinician: Have fun on a virtual reality device.

Engaging in activities that make you feel good may seem like overly simplistic advice, especially when directed at people with severe depression. But the science behind this idea, called "behavioral activation," is well established. Multiple studies have found that encouraging people to get outside, exercise, socialize, volunteer or immerse themselves in enjoyable activities in a prescribed, systematic way can help ease the symptoms of depression.

• Virtual reality helps people with hoarding disorder practice decluttering

Now, Stanford researchers have discovered that engaging in these behaviors within a virtual reality system may show just as much efficacy in treating depression as carrying them out in the real world. And for those depressed to a level that makes leaving the house a challenge, it could provide the benefits of getting outside -- and even motivate them to get out.

"People who might otherwise have barriers to getting treatment might be open to using this technology in their own homes," said Kim Bullock, MD , a clinical professor of psychiatry and behavioral sciences.

The study by Bullock's team, published in JMIR Mental Health , followed 26 people with major depressive disorder. Half were assigned traditional behavioral activation, and half used a virtual reality headset to participate in activities ranging from table tennis and mini-golf to touring foreign cities or attending shows. People in both groups saw their depression scores decrease by similar amounts.

"We've found that using virtual reality in an outpatient group of patients was both simple and efficacious in treating symptoms of depression," said Bullock, founder and director of Stanford's Neurobehavioral Clinic and Virtual Reality and Immersive Technologies (VRIT) program. "It can reduce the barriers to getting mental health treatment in a number of ways."

Bullock and her colleagues at the Stanford VRIT program have long studied the diverse ways to treat mental illnesses with virtual reality (VR) platforms, in which users donning headsets are immersed in simulated, three-dimensional environments.

Previous studies have examined how VR can be used to conduct therapy appointments, help people overcome anxieties and phobias, ease pain, learn social skills, and treat eating disorders and hoarding . But few research projects had focused on how to use the technology to treat anything as pervasive as major depressive disorder or other mood disorders 

Depression impacts so many people right now, and we thought VR could have a large impact. Kim Bullock

"Depression impacts so many people right now, and we thought VR could have a large impact," Bullock said. "There can be significant barriers to behavioral activation in some patients -- they might be stuck in a hospital bed, or not have the means to access joyful activities or the motivation to leave their house. We started wondering whether simulated, pleasant activities might be a good first step for some people."

Bullock, along with clinical assistant professor Margot Paul, PsyD , first carried out a small feasibility study to see whether people with depression could use a VR headset with pre-loaded videos to engage in behavioral activation homework assigned by their therapist. After positive feedback from participants, the researchers conducted the randomized, controlled trial to test the efficacy of a more immersive and interactive VR approach. 

The participants in the trial, all adults diagnosed with major depressive disorder who had not recently changed medications, met weekly with a clinical psychologist at Stanford who assigned them behavioral activation homework between sessions -- scheduling and committing to at least four pleasurable activities each week, either in virtual reality or real life. 

Thirteen people in the study received a VR Meta Quest 2 headset as well as a list of potential activity ideas they could engage in using the headset, including games, travel videos, fitness classes, chat programs and education apps. The other 13 people were told to plan and partake in real life activities in a more typical fashion -- by going on outings in their community or socializing with friends. 

After four weeks, both groups saw a significant decrease in their symptoms of depression and their depression rating on a widely used scale. Moreover, many people who had used the VR devices said the virtual activities had helped push them to get out of the house and be more involved in in-person activities.

"One of the most common pieces of feedback we got was that using the VR inspired people to get out and do things in the real world," Paul said. "These virtual activities got their motors running just enough to get out of bed."

• Stanford Medicine uses augmented reality for real-time data visualization during surgery

The only negative feedback pertained to learning how to set up the device, as well as the need for alerts or reminders to keep people accountable for engaging in the behavioral activation. Paul and Bullock have since developed a companion VR behavioral activation app that will help address some of these concerns. 

The team says larger and longer-term studies are needed to find the best ways to administer virtual behavioral activation, as well as which patient populations might be best targeted with the VR treatment. They also think more efforts are needed to inform clinicians -- from therapists and psychologists to primary care doctors -- about how to prescribe VR behavioral activation appropriately.

These virtual activities got their motors running just enough to get out of bed. Margot Paul

But Paul, Bullock and their colleagues at Stanford VRIT believe the cost and ease of many VR platforms -- especially those that use mobile phones inserted into cheap cardboard headsets -- make it an easy treatment to scale up. They also believe the technology's relatability to a younger audience can only bring more openness to treating serious conditions like depression.

"As something that seems cool to young people, it serves not only to enhance but also de-stigmatize mental health treatments," Bullock said.

Illustration: Emily Moskal

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• Pilot study shows ketogenic diet improves severe mental illness
• Psychoactive drug ibogaine effectively treats traumatic brain injury in special ops military vets
• Human Neural Circuitry program seeks to investigate deepest mysteries of brain function, dysfunction
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• Review Article
• Published: 29 December 2015

The role of inflammation in depression: from evolutionary imperative to modern treatment target

• Andrew H. Miller 1 &
• Charles L. Raison 2  

Nature Reviews Immunology volume  16 ,  pages 22–34 ( 2016 ) Cite this article

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• Adaptive immunity
• Inflammation
• Innate immunity

Across evolutionary time, inflammatory responses and depressive symptoms were part of an integrated adaptive response to pathogens that facilitated fighting infection, healing wounds and avoiding subsequent pathogen exposure in the pathogen-rich environments in which humans evolved. In the more sanitary environments of the modern world, the relationship between inflammatory pathways and the brain may drive depression and contribute to non-response to antidepressant medication.

Increased levels of inflammatory cytokines and induction of their signalling pathways as well as activation of different immune cell subsets has been detected in the brain and peripheral blood of a subgroup of patients with depression. C-reactive protein (CRP), tumour necrosis factor, interleukin-1β (IL-1β) and IL-6 appear to be the most reliably elevated inflammatory markers in the peripheral blood of subjects with depression.

Activation of the inflammasome by stress-induced, non-pathogenic stimuli, including damage-associated molecular patterns as well as microbial-associated molecular patterns elaborated from the gut microbiome, may drive peripheral inflammatory responses, which are then transmitted to the brain by trafficking of activated monocytes.

Inflammation impacts several neurotransmitter systems in the brain, including serotonin, dopamine and glutamate pathways, as well as the kynurenine pathway, which generates the neurotoxic metabolite quinolinic acid. Neuroimaging studies have demonstrated that disruption of neurotransmitter pathways is associated with inflammation-induced alterations in brain circuits that mediate motivation and motor activity as well as anxiety, arousal and alarm.

Activation of effector T cells during stress can prevent the development of depressive- and anxiety-like behaviour in mice. These effects may be mediated by the trafficking of effector T cells to the meningeal space where they produce IL-4, which supports anti-inflammatory responses while also stimulating the production of growth factors in the brain that support neural plasticity and resilience.

Studies in depression suggest that inflammatory biomarkers, such as CRP, can be used to enrich samples for anti-inflammatory clinical trials for depression that target inflammation-related symptoms such as anhedonia and anxiety, thereby supporting intelligent trial design. Though still in development, imaging of neuroinflammation will help establish a 'target' in the brain to further facilitate the testing of anti-inflammatory therapies for depression.

Crosstalk between inflammatory pathways and neurocircuits in the brain can lead to behavioural responses, such as avoidance and alarm, that are likely to have provided early humans with an evolutionary advantage in their interactions with pathogens and predators. However, in modern times, such interactions between inflammation and the brain appear to drive the development of depression and may contribute to non-responsiveness to current antidepressant therapies. Recent data have elucidated the mechanisms by which the innate and adaptive immune systems interact with neurotransmitters and neurocircuits to influence the risk for depression. Here, we detail our current understanding of these pathways and discuss the therapeutic potential of targeting the immune system to treat depression.

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Members of the same species.

An adaptive response to illness, often precipitated by infection, that includes social withdrawal, decreased appetite, lethargy, impaired concentration, depressed mood, irritability, muscle aches and pain, and fever. This syndrome is believed to prioritize shifting of energy resources to fighting infection and wound healing.

A lack of interest in usually pleasurable activities that represents a decrease in motivation, which can either represent a decrease in the response to reward or in the willingness to expend effort to obtain reward.

A clinical syndrome of depression characterized by the primary symptoms of depressed mood and anhedonia, and diagnosed using criteria set forth by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition.

A model of depression that entails repeated exposure to a conspecific animal screened for aggressive behaviour. The animals are placed together in the same cage where they are exposed to brief bouts of defeat lasting 5–10 minutes daily typically for 6–10 days.

A heterogeneous population of cells of myeloid origin that rapidly expands during inflammation and can potently suppress T cell responses. They are now being explored as potential therapeutic targets to inhibit immune responses in autoimmune disease or transplant rejection.

A theoretical framework that suggests that cytokines have a primary role in alterations of neurotransmitter metabolism, neuroendocrine function, neuroplasticity, neurocircuitry and behaviour in a subgroup of patients with depression and increased inflammation.

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Miller, A., Raison, C. The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nat Rev Immunol 16 , 22–34 (2016). https://doi.org/10.1038/nri.2015.5

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DOI : https://doi.org/10.1038/nri.2015.5

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