Inflammatory Biomarkers in Depression

Inflammatory Biomarkers in Depression: An Opportunity for Novel Therapeutic Interventions

Madeline Li, Joanna K. Soczynska & Sidney H. Kennedy

Current Psychiatry Reports ISSN 1523-3812 Curr Psychiatry Rep DOI 10.1007/ s11920-011-0210-6

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Author's personal copy Curr Psychiatry Rep DOI 10.1007/s11920-011-0210-6

INVITED COMMENTARY

Inflammatory Biomarkers in Depression: An Opportunity for Novel Therapeutic Interventions Madeline Li & Joanna K. Soczynska & Sidney H. Kennedy

# Springer Science+Business Media, LLC 2011

Abstract Currently available antidepressants are effective in less than two thirds of depressed patients, with even lower remission rates in the context of co-morbid medical illness. A rapidly expanding evidence base suggests that maladaptive inflammatory immune responses may be a common pathophysiology underlying depression, particularly in the presence of a general medical condition. The inflammatory hypothesis of depression marks a significant shift away from monoaminebased approaches and is a major step towards developing novel treatments that directly target causal factors of depression. Many antidepressants exert anti-inflammatory effects and there is an emerging literature documenting the efficacy of anti-inflammatory agents as adjunctive treatments for depression. Identification of inflammatory biomarkers in depression will require a re-conceptualization of both the diagnostic phenomenology and the experimental approaches to studying M. Li (*) Psychosocial Oncology and Palliative Care, University Health Network/Princess Margaret Hospital and University of Toronto, 16-749 610 University Avenue, Toronto, ON M5G 2M9, Canada e-mail: [email protected] J. K. Soczynska Institute of Medical Science, University Health Network/Princess Margaret Hospital and University of Toronto, 9M-312A 399 Bathurst Street, Toronto, ON M5T 2S8, Canada S. H. Kennedy Department of Psychiatry, University Health Network/Princess Margaret Hospital and University of Toronto, EN8-222 200 Elizabeth Street, Toronto, ON M5G 2C4, Canada

multi-determined psychiatric disorders. In addition to their application in diagnosis, predicting prognosis, and monitoring severity and response to treatment, inflammatory biomarkers may serve as novel therapeutic targets in the treatment of depression. Keywords Inflammation . Major depressive disorder . Mood disorders . Depression . Cytokines . Therapy . Biomarkers

Introduction Major depressive disorder (MDD) has a lifetime prevalence of approximately 12% to 15% [1] and is second only to cardiovascular disease in disease burden based on disability-adjusted life-years [2]. Major depressive episodes also commonly occur in patients with a broad range of major medical illnesses, including diabetes, cardiovascular disease, and cancer [3]. Despite substantial progress in new drug development, less than 50% of patients achieve remission after an index antidepressant treatment, and even after four systematically applied treatments, about one third of patients fail to achieve remission [4]. Treating episodes of depression in medically ill patients poses additional challenges [5]. Because the majority of antidepressants primarily target monoamine systems, there are grounds to support the exploration of alternative therapeutic targets [6]. These include neuropeptides, amino acid neurotransmitters (eg, glutamate), and neurotrophic and inflammatory factors. The purpose of this commentary is to explore evidence linking inflammatory processes to the pathophysiology of depression and to suggest a putative role for anti-inflammatory agents as antidepressants.

Author's personal copy Curr Psychiatry Rep

The Inflammatory Hypothesis From the award-winning observation in 1927 by Nobel laureate Julius Wagner-Jauregg that malaria inoculation could affect psychiatric functioning, to the “macrophage theory of depression” by Smith [7] in 1991, the role of inflammation in the pathophysiology of depression has been increasingly recognized and is now described as the inflammatory or cytokine hypothesis of depression [8, 9]. Immune dysregulation in patients with MDD is characterized by both immune suppression (eg, decreases in natural killer cell activity and lymphocyte proliferation) and immune activation (eg, immune cell proliferation and increased production of inflammatory markers) [10]. Although acute inflammation and immune activation are components of an adaptive response to physical or psychological stress, chronic inflammation arising from ongoing stress or failure of homeostatic processes is thought to be maladaptive, contributing to the development of illnesses such as MDD. Emerging preclinical literature is beginning to elucidate potential pathophysiologic mechanisms underlying the association between inflammation and MDD, based largely on the actions of cytokines, a family of immunoregulatory signaling molecules secreted by immune cells. Proinflammatory cytokines are key mediators of a constellation of depressive-like signs and symptoms referred to as sickness behavior. Experimental peripheral or central injection of proinflammatory cytokines (eg, interleukin [IL]-1β), induces anhedonia (decreased sucrose consumption), amotivation (reduced self-care, behavioral despair), cognitive impairment, and neurovegetative symptoms (anorexia, sleep disturbance, psychomotor slowing) [11]. Moreover, the clinical use of the proinflammatory cytokine interferon (IFN)-α is associated with the development of a major depressive episode in up to 45% of patients with hepatitis, with symptom onset within days of initiating IFN-α and resolution within weeks of terminating treatment [12]. Whereas neurovegetative symptoms appear early and persist in most patients, the mood and cognitive symptoms appear later in treatment, are more frequent in patients with intrinsic vulnerability such as hypothalamic-pituitaryadrenal axis hyperreactivity, and can be prophylaxed and treated with antidepressants [12]. In depression associated with medical illness, the source of immune activation may be related to infection, tissue destruction, or autoimmune processes—mechanisms that may account for the high comorbidity and bidirectional relationships found in illness-related depression [5]. Recent work has also demonstrated that psychosocial stress, including early adversity, interpersonal conflict, or social isolation, can precipitate increases in cytokines and other inflammatory markers [13, 14]. Psychosocial stress activates the hypothalamic-pituitary-adrenal axis to increase

peripheral sympathetic tone, which in turn can stimulate proinflammatory cytokine release from circulating immune cells [15]. Peripheral cytokines then access the brain and initiate a mirrored central cytokine expression cascade, which may contribute to the pathophysiology of depression through actions on monoamine levels, increasing neuronal excitotoxicity, reducing brain trophic factors, and impairing autoregulatory endocrine pathways [9]. Converging with the monoamine hypothesis of depression, cytokines can influence neurotransmitter levels directly and indirectly in the central nervous system. Animal studies indicate that cytokines alter serotonin (5HT) turnover in multiple brain regions [16], downregulate 5HT1A receptors [17], and reduce 5HT availability through activation of indoleamine 2,3-dioxygenase (IDO), the enzyme that breaks down the 5HT precursor tryptophan into kynurenine (KYN) [18]. KYN is also converted to kynurenic acid in astrocytes, which inhibits the release of glutamate and, subsequently, dopamine [19]. Cytokines also influence the availability of dopamine through upregulation of the dopamine transporter [20] and stimulation of nitric oxide production, which suppresses dopamine synthesis [21]. Cytokines increase neuronal excitotoxicity and reduce brain trophic factors, both directly by stimulating the release of glutamate from astrocytes and downregulating glutamate transporters [22], and indirectly through KYN conversion to quinolinic acid in microglia. Furthermore, cytokines stimulate the release of reactive oxygen and nitrogen species, which, combined with glutamate and quinolinic acid, can contribute to depression through brain excitotoxicity and suppression of neurogenesis, as well as protective factors such as brain-derived neurotrophic factor [12, 23, 24].

Biomarker Associations with Depression The compelling preclinical evidence for the inflammatory hypothesis is further supported by clinical studies of inflammatory biomarkers in individuals with MDD. Although the correlations between peripheral inflammatory markers and depression have not always been consistent [25], meta-analyses controlling for biobehavioral variables document that MDD is consistently associated with elevations in C-reactive protein, IL-1, IL-1 receptor antagonist, IL-6, and tumor necrosis factor (TNF)-α [26, 27]. In a meta-analysis of inflammatory biomarkers that included measures of cellular immunity, Zorrilla and colleagues [28] concluded that decreased natural killer cell cytotoxicity; decreased mitogen-stimulated lymphocyte proliferation; and increased IL-6, haptoglobin, and prostaglandin E2 are associated with MDD. There is also evidence that IL-1β and IL-6 are elevated in the cerebrospinal fluid of patients with depression [29],


and that cytokine abnormalities may differ in subtypes of MDD. For example, patients with melancholic depression display lower cortisol and ACTH levels, while higher serum IL-1 receptor antagonist/IL-1β ratios are selectively associated with nonmelancholic depression [30]. Moreover, elevated serum levels of IL-6 have been associated with nonresponse to antidepressant treatment [31]. Beyond assessing innate immunity, several other promising avenues of inflammatory biomarker investigation in depression are beginning to emerge. Inflammation in depression may arise from an imbalance among T-cell subsets such as proinflammatory T-helper type 1 (Th1), anti-inflammatory Th2, and regulatory T cells (Tregs), as well as Th17 cells, a newly identified effector T-cell type that functions in autoimmunity [32]. Th17 cells are highly proinflammatory but have yet to be characterized in depressed individuals. The proportion of Tregs is decreased in individuals with MDD [33] and increased in association with antidepressant response [12, 32, 34]. The neurocircuitry targeted by cytokines was explored in a neuroimaging study that demonstrated activation of IL-6 following Salmonella typhi vaccine in healthy individuals was associated with enhanced activity within the subgenual anterior cingulate cortex during mood deterioration [35]. Genetic vulnerability markers such as polymorphisms in cytokine- and inflammation-related genes have been associated with susceptibility to MDD [36, 37], and polymorphisms in the IL-6 and serotonin transporter genes have been associated with IFN-α–induced depression [38–40].

Therapeutic Implications Growing evidence suggests that anti-inflammatory agents may exert antidepressant effects. Two studies have now documented significant improvement in depressive symptoms following adjunctive treatment with celecoxib, a cyclooxygenase-2 inhibitor. In the first study, MDD patients (N=40) who were nonresponders to fluoxetine, 40 mg/d, were randomly assigned to receive celecoxib (200 mg twice daily) or placebo under double-blind conditions for 6 weeks. Combination treatment was associated with significant improvement in depressive symptoms [41]. Muller et al. [42] reported similar findings in a 6-week, randomized, double-blind, placebo-controlled study that evaluated the efficacy of adjunctive celecoxib (400 mg/d) with reboxetine (flexible-dose range, 4–10 mg/d) in MDD patients (N=40). There are also reports that individuals with autoimmune or inflammatory disorders who are treated with a TNF-α inhibitor experience a reduction in depressive symptoms [43–46]. Several cytokine antagonists are currently available, and the challenge will be in rationally and safely selecting which agents to test [47].

Other inflammatory pathway targets include glutamate as well as reactive oxygen and nitrogen species. Early trials of glutamate (N-methyl-D-aspartate) receptor antagonists are already under way, with preliminary evidence supporting the use of ketamine in treatment-resistant depression [48], and of the antioxidant N-acetylcysteine in bipolar depression [49]. Promising translational targets include the IDO and KYN pathways [12] and potentially blocking protein kinase Ctheta, a signaling molecule that both promotes inflammatory Th1 differentiation and, in the presence of TNF-α, inhibits Treg containment of inflammation [50].

Biomarkers on Balance: Future Directions Several challenges in this field need to be addressed [8, 10, 25, 51], including 1) the diagnostic phenomenology or clinical variability within the syndrome of major depression; 2) the impact of biobehavioral variables on biomarker levels [52]; 3) the need to standardize methods of biological sample collection and assay; 4) longitudinal studies to better characterize the associations between symptoms and inflammatory markers; 5) incorporation of genetic, epigenetic, and environmental vulnerability factors; and 6) the development of improved animal models to test pathophysiologic hypotheses. Most crucial and challenging on this list is the clinical paradigm shift in reconceptualizing MDD into pathophysiologic subtypes. This will be facilitated by clinically characterizing subsets of depressed individuals defined by specific immune profiles [10] and minimizing clinical heterogeneity by deconstructing depression into subtypes or symptom clusters. Based on differences in the presentation of MDD and depression associated with medical illness, the latter being associated with fewer core depressive thoughts [53] and more neurovegetative symptoms [54], cytokine-associated depression has been proposed as a new diagnostic entity [25]. Equally important will be an experimental paradigm shift toward increased utilization of the powerful biotechnology available for biomarker testing and biostatistical analysis [8, 55], which will require larger studies of depressed individuals that adopt novel high-throughput approaches such as characterizing the central nervous system transcriptome, proteome, genome, and epigenome. Beyond this, more mechanistic immunologic studies of the relative expression and function of T-cell subsets (eg, Tregs and Th17) will be important in dissecting the pleiotropic and interactive network of cytokine functions. Biological psychiatry research has to date been plagued by the complexity of the multi-determined disorders. Such a multidisciplinary approach will capitalize on the sophisticated computational bioinformatics techniques that are beginning to


be developed [56, 57] and will permit integration of disparate types of data to gain a more comprehensive perspective.

Conclusions There is a tremendous opportunity in the next decade to integrate phenomenologic and pathophysiologic findings by using state-of-the-art technologies to delineate depression subtypes. As residual symptoms are highly prevalent with existing first-line antidepressant treatments, and are overrepresented by somatic complaints [58], novel treatments that directly target neuroinflammatory processes may complement existing treatments. Inflammatory biomarkers are at the vanguard of personalized medicine in depression and may serve as both markers of disease and predictors of outcome. Disclosure Dr. Li received payment for a plenary presentation at the Toronto Psychopharmacology Update 2011 on the topic covered in this commentary. Ms. Soczynska has received travel funds from Janssen and was the recipient of the Eli Lilly Fellowship. S.H. Kennedy has received research funding or honoraria in the past three years from AstraZeneca, Canadian Network for Mood and Anxiety Treatments, Eli Lilly, GlaxoSmithKline, Janssen-Ortho, Lundbeck, Pfizer, St. Jude Medical and Servier.

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