Review
Neuroimmune mechanisms of cytokine-induced depression: Current theories and novel treatment strategies

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Abstract

The relationships between immune and neural function are an increasingly important area of study for neuropsychiatric disorders, in particular depression. This is exemplified by the growing number of publications on cytokines and depression during the last 10 years, as compared to earlier decades. This review summarizes the current theories and novel treatment strategies for depression, with a focus on cytokine-induced depression. Neuroimmune mechanisms are now viewed as central to the development of depressive symptoms and emerging evidence is beginning to identify the neural circuits involved in cytokine-induced depression. The current diagnostic categories for depression, as defined by the Diagnostic and Statistical Manual of Mental Disorders, however, are not etiologically or biologically derived, and it has been proposed that “depression”, likely reflects multiple pathogeneses leading to varying symptom constellations. As we move toward a better biological understanding of depression-related symptom constellations or syndromes, the term “depression” may prove inadequately broad, and an integration of interdisciplinary literatures will increase in importance. Future research should aim to characterize these depression-related symptom constellations or syndromes better with the goal of optimizing treatment strategies.

Introduction

Cytokines [e.g., interferons (IFN) and interleukins (IL)] are pleitropic, immunomodulatory signaling molecules that have been increasingly implicated in the development of neuropsychiatric disorders, especially major depressive disorder. In 1927 Julius Wagner-Jauregg won the Nobel Prize for the seminal observation that activation of the immune system by an infectious agent (i.e., malaria inoculation) can affect psychiatric functioning. On the basis of this and related discoveries, it was concluded that cytokines signal the brain and can serve as mediators between the immune and central nervous systems. Subsequently, Maes et al., investigated plasma concentrations and in vitro production of several cytokines, including IL-1 and IL-6 which led to the additional conclusion that there is an increase in proinflammatory cytokines in patients with major depression that seems to correlate with severity of illness and measures of hypothalamic–pituitary–adrenal (HPA) axis hyperactivity (Maes et al., 1993, Maes et al., 1995). Since the early 1990s there has been a dramatic increase in the number of papers published on the topic of cytokines and major depression (Fig. 1).

It is debated whether or not cytokine-induced depression is analogous to major depressive disorder or a major depressive episode, as defined by the DSM-IV-TR. A recent study seeking an answer to this question investigated the similarities and differences between cytokine-induced depression and idiopathic major depression in otherwise healthy participants. The authors reported considerable overlap in the depressive symptom profiles between the two groups, with the exception that, compared to medically healthy patients with major depression, patients with IFN-α-induced depression had significantly greater psychomotor retardation and weight loss and significantly less severe feelings of guilt (Capuron et al., 2009). Thus, rather than differentiating between cytokine-induced depression and idiopathic depression, this review focuses on (1) the neuroimmune mechanisms that are central to the development or progression of depressive symptoms across diagnostic categories, and (2) the need for improved diagnostic definitions that are supported by biological as well as psychological data.

Section snippets

Depression (aka sickness, conservation-withdrawal and passive stress-coping behaviors in animal models)

The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) defines a depressive episode as a period of greater than 2 weeks that is characterized by five or more symptoms ranging from depressed mood (sadness, emptiness, tearfulness), anhedonia, feelings of worthlessness or guilt, and suicidal ideation, to changes in weight, appetite, sleep, energy, and psychomotor function, to reduced ability to think or concentrate (DSM-IV-TR, 2000). These symptoms

Cytokines in the central nervous system

Cytokines in the central nervous system: 1) are constitutively expressed, 2) can have functions such as neuroprotection or neurodegeneration, and 3) can be regulated by nonimmune factors, such as neurotransmitters and hormones. Peripheral cytokines can also access the brain and affect function via vagal nerve activation, a leaky or compromised blood–brain barrier, and active transport across the blood–brain barrier, or binding to cell-surface proteins on brain endothelial cells. The most recent

Co-morbid depression is common in patients with medical conditions

There is abundant evidence that depression involves alterations in multiple aspects of immunity that may contribute to the development or exacerbation of a number of medical disorders and also may play a role in the etiology of depressive symptoms. The relationship between medical illness and depression has been particularly well-described in cardiovascular disease (Wirtz et al., 2009, Grippo and Johnson, 2009, Halaris, 2009, Davidson et al., 2009), multiple sclerosis (Gold and Irwin, 2006),

Mechanisms of cytokine-induced depression

Cytokines play an active role in the molecular events influencing synaptic transmission, neuronal plasticity, and depressive behaviors. However, although cytokine-induced depression is well-established (Raison et al., 2009, Anisman, 2009), the specific mechanisms by which activation of the innate immune system and expression of specific depressive symptoms are related remain poorly understood, in part, because of the complex and diverse processes involved. The potential mechanisms leading to

Animal models and hypothesized mechanisms of cytokine-induced depression

As in clinical studies, inflammatory factors and cytokine-specific alterations of monoamine and neuroendocrine function are similarly observed in animal models of depression. Newly developed animal models of depression based on induced inflammation are summarized in Table 2; these animal models accompany and contribute to the studies using previously established models of depression—which remain highly relevant, as these models not only result in the expression of depressive behaviors but also

Novel treatment strategies

The use of anti-inflammatory approaches for the treatment of depression is being examined at both pre-clinical and clinical levels. Many antidepressant medications have specific anti-inflammatory effects (Lim et al., 2009, Carvalho and Pariante, 2008) and significant immunoregulatory activities, such as reducing the number of Th1 cells secreting IFN-γ (Bengtsson et al., 1992, Zhu et al., 1998), increasing the production of IL-6 and IL-10 (Kubera et al., 2000), and inhibiting IFN-γ-induced

Conclusions and future perspectives

This review summarized current theories regarding the relationships between immune activation and neural function, as they relate to the development and expression of depressive symptoms. Collectively, this body of clinical and pre-clinical research supports the theory that inflammation and immune dysregulation can influence neurotransmitter metabolism, neuroendocrine function, synaptic plasticity and growth factor production, thus altering neural circuitry and contributing to depressive

Acknowledgments

We wish to thank the following individuals for their respective contributions to this paper: Lynsey Gebelin and Starr DeGennaro (data compilation for Fig. 1), Gray Whelan (graphic design and illustrations for Fig. 2), and Max Strater (editorial support).

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