The effect of tumor necrosis factor antagonists on mood and mental health-associated quality of life: Novel hypothesis-driven treatments for bipolar depression?

doi:10.1016/j.neuro.2009.03.004

NeuroToxicology

Volume 30, Issue 4, July 2009, Pages 497-521

https://doi.org/10.1016/j.neuro.2009.03.004 Get rights and content

Abstract

Bipolar disorder (BD) is associated with high rates of morbidity, comorbidity, disability, economic and human capital costs as well as premature mortality. Although, the past decade has witnessed substantial progress in the treatment of BD, high rates of non-recovery, inter-episodic symptomatology, and episode recurrence remain an ongoing deficiency. Conventional treatments for BD are capable of alleviating ‘surface-based’ symptomatology yet no agent is disease-modifying. Translational research initiatives provide evidence that mood disorder symptomatology is subserved by disturbances in interacting immuno-inflammatory, metabolic, and neuroendocrine networks. Numerous studies document elevated pro-inflammatory circulating cytokines [e.g. interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-α)], in individuals with BD as compared to healthy volunteers. Elevated peripheral levels of TNF-α and its receptors (i.e. TNF-R1 and TNF-R2) are a frequent findings across depressive and manic states and may persist into euthymia. As such, TNF-α may constitute a trait marker of BD. Other markers of inflammation including acute phase reactants (e.g. C-reactive protein) and vascular adhesion molecules (e.g. intercellular adhesion molecule-1) are also altered in BD. Herein, we review supporting evidence for the hypothesis that disturbances in inflammatory homeostasis, as marked by elevated TNF-α levels, are salient to the pathophysiology of BD and provide a platform for novel drug discovery. In this review, we propose that TNF-α modulation is a target for disease-modifying treatment of BD. To support this hypothesis, we review evidence from clinical trials evaluating the efficacy of TNF-α antagonists (i.e. adalimumab, etanercept, and infliximab) on depressive symptoms and mental health-associated quality of life measures.

Section snippets

Pro- and anti-inflammatory cytokines

Pro-inflammatory activation refers to the synthesis, secretion, and action of pro-inflammatory cytokines, chemokines, acutephase reactants and cellular adhesion molecules (Raison et al., 2006). Cytokines are secreted regulator proteins that influence the survival, proliferation, differentiation, and effector function of tissue cells. Inflammatory cytokines coordinate the activities of many cell types leading to innate and acquired immune responses. Cytokines have many sites of production but

Cytokines in the central nervous system

Historically, the central nervous system (CNS) has been viewed as an ‘immuno-privileged’ site; it is now well established that the CNS synthesizes and is a target of immune effector systems (Brietzke and Kapczinski, 2008). The role of inflammatory cytokines therefore is not limited to the peripheral system; cytokines act on and are produced by brain tissues (Brietzke and Kapczinski, 2008, Manji et al., 2003). Glial cells are the primary sources of inflammatory mediators (e.g. cytokines) that

Bipolar disorder is marked by cellular, neuronal, and glial abnormalities which may be the consequence of an aberrant immuno-inflammatory system

The explanatory insufficiency of the monoaminergic model is underscored by results documenting disparate cellular, neuronal, and glial abnormalities in BD. Alterations in neuronal plasticity, cellular resilience, and cytoarchitecture, along with regional abnormalities in neuronal and glial density and morphology provide support for the involvement of multi-systemic biological networks (Carlson et al., 2006, Manji and Lenox, 2000, Manji et al., 2003, Rajkowska, 2002). Reduction in glial cell

Individuals with bipolar disorder are differentially affected by inflammatory-mediated medical comorbidity

Several lines of evidence provide support for the hypothesis that BD may be the consequence of an aberrant immuno-inflammatory system. Epidemiological and clinical studies have provided convergent evidence that individuals with BD are differentially affected by inflammatory-mediated medical comorbidity (McIntyre et al., 2006a, McIntyre et al., 2006b, McIntyre et al., 2007b). For example, rates of overweight/obesity, abdominal obesity, type 2 diabetes mellitus, metabolic syndrome, and

Animal models of ‘cytokine-induced sickness behavior’ resemble the phenotypic presentation of depressive symptoms in humans

Animal models of ‘cytokine-induced sickness behavior’ resemble the phenotypic presentation of depressive symptoms in humans. Experimental injection of pro-inflammatory cytokines, primarily those involved in innate immune function (e.g. TNF-α, IL-1β, IL-6), into rodents induces ‘sickness behavior’, a syndrome phenotypically similar to depressive symptoms that include anorexia, sleep disturbance, neurocognitive impairment, fatigue, and reduced self-care behaviour (Dantzer, 2004). Preclinical

Pro-inflammatory activation in both healthy and medically as well as psychiatrically ill individuals is associated with disturbances in affective, cognitive, and somatic function

In human subjects, the injection of endotoxin (i.e. Salmonella typhi vaccine, a stimulator of the inflammatory system particularly the secretion of TNF-α, IL-1β, IL-6) into healthy volunteers is associated with an induction of depressive symptoms and cognitive disturbance (Reichenberg et al., 2001). The clinical use of cytokine therapy has been demonstrated to induce and/or intensify affective symptomatology (Reichenberg et al., 2005, Asnis and De La, 2005). For example, interferon alpha

Converging evidence points towards pro-inflammatory cytokine elevations in bipolar disorder, most notably in TNF-α as compared to unaffected populations

Converging evidence points towards elevated concentrations of TNF-α in BD as a molecular target for novel treatment development (Brietzke and Kapczinski, 2008). Abnormally high circulating TNF-α levels are consistently reported during depressive (O’Brien et al., 2006, Ortiz-Dominguez et al., 2007) and manic states (O’Brien et al., 2006, Kim et al., 2007, Ortiz-Dominguez et al., 2007) with no significant difference between the two affective states (O’Brien et al., 2006, Ortiz-Dominguez et al.,

Psychotropic agents used to treat bipolar disorder have the capacity to alter pro-inflammatory cytokines and attenuate or restore inflammatory homeostasis

In keeping with the view that a neurotoxic process occurs in mood syndromes, numerous investigations have explored the effect of disparate conventional pharmacological treatments for BD on the production of pro-inflammatory cytokines as well as their gene expression (Rybakowski, 2000, Pollmacher et al., 2000). For example, lithium and antipsychotic treatment have been demonstrated to reduce gene expression of TNF-α, IL-1β, and IL-6, and restore inflammatory homeostasis (Boufidou et al., 2004,

Allostasis in bipolar disorder: a disease of cumulative allostatic states

Although the causal factors that subserve dysregulation of the immuno-inflammatory network in BD are unknown, several interacting networks, including the hypothalamic–pituitary–adrenal-axis (HPA-axis), neurotransmitter metabolism, growth factors, arachidonic acid, insulin-like growth factor 1 (IGF-1), and as well as insulin signaling are proposed. (Kapczinski et al., 2008, Cassidy et al., 1998, Diehl and Gershon, 1992).

Allostasis is broadly defined as the capacity of a system to achieve

Hypothalamic–pituitary–adrenal-axis

Abnormalities in the HPA-axis are well documented in BD and are marked by elevated levels of cortisol and ‘dexamethasone suppression test’ non-suppression (Swann et al., 1992, Watson et al., 2004). Recent reports provide support for T-cell relative resistance to glucocorticoids and altered glucocorticoid-signaling cascades in BD (Knijff et al., 2006, Spiliotaki et al., 2006). Moreover, TNF-α is associated with increases in cortisol production in human adult adrenocortical cell cultures (Stolte

Brain derived neurotrophic factor

Abnormalities in growth factors such as brain derived neurotrophic factor (BDNF), which regulates neurotrophism and neuroplasticity via its effects on neuronal differentiation, proliferation, and structure as well as synaptogenesis are documented in BD (Mattson et al., 2004, Xu et al., 2003). BDNF levels are negatively correlated with the severity of mood symptoms in BD (Hado-Vieira et al., 2007, Shimizu et al., 2003, Cunha et al., 2006, Frey et al., 2006). Recent evidence suggests that TNF-α

Tumor necrosis factor alpha physiology

TNF-α is a 157 amino acid pro-inflammatory cytokine that was identified in 1975 as the factor in serum isolated from endotoxin-treated mice that induced necrosis of a methylcholanthrene-induced murine sarcoma (Carswell et al., 1975). TNF-α is synthesized and secreted by macrophages, lymphocytes, neutrophils, and structural cells including fibroblasts, smooth muscle cells, astrocytes, and microglia. The synthesis and secretion of TNF-α is increased in response to injury, infection, and

Tumor necrosis factor alpha and cognition in bipolar disorder

Cognitive deficits are well documented in BD persisting across affective and euthymic states. Several identified risk factors for cognitive dysfunction include the number of depressive and manic episodes, number of hospitalizations, and duration of illness. Deficits in verbal memory and executive function are the most consistently replicated abnormalities in euthymic BD individuals (Leonard, 2001).

The association between neurocognitive function and pro-inflammatory cytokine activation has not

Tumor necrosis factor antagonists

Binding of TNF antagonists can induce reverse signaling through the membrane-anchored ligand and trigger cell activation, and cytokine suppression or apoptosis (Tracey et al., 2008). Currently there are three Food and Drug Administration approved TNF-α antagonists: adalimumab (Humira), a fully human monoclonal antibody, infliximab (Remicade), a chimeric monoclonal antibody, and etanercept (Enbrel), a soluble receptor construct (Tracey et al., 2008, Segal et al., 2008). Several other TNF-α

Adalimumab (Humira)

Adalimumab is a recombinant human IgG1 monoclonal antibody for TNF-α that consists of 1330 amino acids with a molecular weight of 149 kD. It is supplied in single-use, 1 mL pre-filled glass syringes, and also 2 mL glass vials as a sterile, preservative-free solution for subcutaneous administration. Adalimumab solution is clear and colorless, with a pH of approximately 5.2. The solution contains 40 mg of adalimumab with additional non-active ingredients; 4.93 mg sodium chloride, 069 mg monobasic

Adalimumab, mood symptoms, and quality of life (see Table 4 for review)

The effect of adalimumab maintenance therapy on health-related quality of life as well as depressive symptoms has been evaluated in patients with moderate to severe Crohn's disease in a randomized, double-blind clinical trial. Following open-label adalimumab treatment of 80 mg at baseline and 40 mg at week 2, patients were randomized to adalimumab maintenance treatment at week 4 (40 mg every other week or 40 mg weekly) or placebo (open-label treatment only). Significant improvement in

Etanercept (Enbrel)

Etanercept is a dimeric fusion protein consisting of the extracellular ligand-binding portion of the human 75 kDa (p75) TNF receptor (TNF-R) linked to the Fc portion of the human IgG1. Etanercept is produced by recombinant DNA technology in a Chinese hamster ovary mammalian cell expression system. It consists of 934 amino acids and has a molecular weight of approximately 150 kDa (Tracey et al., 2008).

Etanercept is supplied as a sterile, white, preservative-free, lyophilized powder for parental

Etanercept, mood and cognitive symptoms (see Table 5 for review)

We identified one randomized, double-blind, placebo-controlled trial with etanercept (Tyring et al., 2006) and one open-label effectiveness study that included depression outcomes (Gelfand et al., 2008); the Beck Depression Inventory (BDI) and the Hamilton Depression Rating Scale (HAMD). Secondly, we identified one open-label study with etanercept in individuals with Alzheimer's disease (Tobinick et al., 2006).

The first trial enrolled patients with plaque psoriasis (n = 618) who were randomized

Infliximab (Remicade)

Infliximab is a chimeric IgG1k monoclonal antibody for TNF-α with a molecular weight of 150 kDa. It is composed of human constant and murine variable regions of the antibody. Infliximab is supplied as a sterile, white, lyophilized powder for intravenous injection; following reconstitution with 10 mL of sterile water for injection it has a pH of approximately 7.2. Each single-use vile contains 100 mg of infliximab, 50 mg sucrose, 0.5 mg polysorbate 80, 2.2 mg monobasic sodium phosphate, monohydrate,

Infliximab and mood symptoms (see Table 6 for review)

One clinical trial with infliximab was identified on clinicaltrials.gov (NCT00463580) for treatment resistant depression including bipolar and unipolar disorder. Infliximab, single-dose, has been shown to reduce fatigue and depressive scores as well as improve quality of life at 4 weeks in patients with Crohn's disease (Persoons et al., 2005). Specific measures of depression were identified in three open-label studies (Persoons et al., 2005, Tookman et al., 2008, Minderhoud et al., 2007).

In a

Safety and toxicity concerns

The major risk associated with TNF-antagonists is an increased propensity for infections. As a result, treatment should not be initiated in patients who demonstrate evidence of acute or chronic infections. Patients must be monitored closely for clinical presentations suggestive of infection while receiving a TNF-antagonist. Allergic reactions have been reported in approximately 1% of patients; serious allergic reactions are rare. Moreover, although rare, patients treated with TNF-antagonists

Conclusions

Available clinical trials provide preliminary support that TNF-α antagonists offer therapeutic benefit for depressive and cognitive symptoms in non-psychiatric populations. Moreover, improvements in fatigue, vitality and other somatic symptoms are well documented with available TNF-α antagonists. The efficacy of these agents in mood disorders remains to be determined, although it can be reasonably surmised that similar benefits may be observed in primary mood disorder populations. A pressing

Conflict of interest

Joanna K. Soczynska has previously received travel honoraria from “Organon and Wyeth”. Roger S. McIntyre is on the Advisory Board for “Astra Zeneca, Bristol-Myers Squibb, France Foundation, GlaxcoSmithKline, Jaanssen-Ortho, Solvay/Wyeth, Eli Lilly, Organon, Lundbeck, Biovail, Pfizer, and Shire” and is on the Speakers Bureau for Janssen-Ortho, Astra-Zeneca, Eli Lilly, Lundbeck, and Biovail”. Dr. McIntyre is also involved in CME Activities with “Astra Zeneca, Bristol-Myers Squibb, France

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Citation Excerpt :
Endotoxin (0.8 ng/kg), even given in doses insufficient to cause influenza-like sickness symptoms, results in symptoms identical to clinical depression (Reichenberg et al., 2001). Meanwhile, anti-inflammatory drugs such as cyclooxygenase-2 inhibitors (e.g. celecoxib) and TNF blockers (e.g. etanercept, adalimumab and infliximab) may improve depressive or manic symptoms in patients with mood disorders or other psychiatric conditions (Krishnan et al., 2007; Menter et al., 2010; Muller et al., 2006b; Persoons et al., 2005; Soczynska et al., 2009). Administration of endotoxin leads to decreased sucrose preference (akin to human anhedonia), reduced exploratory and social behaviors, reduced food intake, and increased sleep (Dantzer et al., 2008), making it a very convincing animal model for depression.
Mood disorders are chronic, recurrent mental diseases that affect millions of individuals worldwide. Although over the past 40 years the biogenic amine models have provided meaningful links with the clinical phenomena of, and the pharmacological treatments currently employed in, mood disorders, there is still a need to examine the contribution of other systems to the neurobiology and treatment of mood disorders. This article reviews the current literature describing the potential role of nitric oxide (NO) signaling in the pathophysiology and thereby the treatment of mood disorders. The hypothesis has arisen from several observations including (i) altered NO levels in patients with mood disorders; (ii) antidepressant effects of NO signaling blockers in both clinical and pre-clinical studies; (iii) interaction between conventional antidepressants/mood stabilizers and NO signaling modulators in several biochemical and behavioral studies; (iv) biochemical and physiological evidence of interaction between monoaminergic (serotonin, noradrenaline, and dopamine) system and NO signaling; (v) interaction between neurotrophic factors and NO signaling in mood regulation and neuroprotection; and finally (vi) a crucial role for NO signaling in the inflammatory processes involved in pathophysiology of mood disorders. These accumulating lines of evidence have provided a new insight into novel approaches for the treatment of mood disorders.

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ReviewThe effect of tumor necrosis factor antagonists on mood and mental health-associated quality of life: Novel hypothesis-driven treatments for bipolar depression?

Abstract

Section snippets

Pro- and anti-inflammatory cytokines

Cytokines in the central nervous system

Bipolar disorder is marked by cellular, neuronal, and glial abnormalities which may be the consequence of an aberrant immuno-inflammatory system

Individuals with bipolar disorder are differentially affected by inflammatory-mediated medical comorbidity

Animal models of ‘cytokine-induced sickness behavior’ resemble the phenotypic presentation of depressive symptoms in humans

Pro-inflammatory activation in both healthy and medically as well as psychiatrically ill individuals is associated with disturbances in affective, cognitive, and somatic function

Converging evidence points towards pro-inflammatory cytokine elevations in bipolar disorder, most notably in TNF-α as compared to unaffected populations

Psychotropic agents used to treat bipolar disorder have the capacity to alter pro-inflammatory cytokines and attenuate or restore inflammatory homeostasis

Allostasis in bipolar disorder: a disease of cumulative allostatic states

Hypothalamic–pituitary–adrenal-axis

Brain derived neurotrophic factor

Tumor necrosis factor alpha physiology

Tumor necrosis factor alpha and cognition in bipolar disorder

Tumor necrosis factor antagonists

Adalimumab (Humira)

Adalimumab, mood symptoms, and quality of life (see Table 4 for review)

Etanercept (Enbrel)

Etanercept, mood and cognitive symptoms (see Table 5 for review)

Infliximab (Remicade)

Infliximab and mood symptoms (see Table 6 for review)

Safety and toxicity concerns

Conclusions

Conflict of interest

Prog Neuropsychopharmacol Biol Psychiatry

J Affect Disord

J Affect Disord

Lancet

Biol Psychiatry

Prog Neuropsychopharmacol Biol Psychiatry

Biol Psychiatry

Prostaglandins Leukot Essent Fatty Acids

Biol Psychiatry

NeuroRx

Biol Psychiatry

Brain Behav Immun

Neurosci Lett

Biochem Biophys Res Commun

Neurosci Lett

Eur J Pharmacol

Prog Neuropsychopharmacol Biol Psychiatry

Compr Psychiatry

J Biol Chem

Brain Res

Life Sci

Value Health

Clin Ther

J Psychiatr Res

Eur Neuropsychopharmacol

Semin Arthritis Rheum

J Affect Disord

Prog Neuropsychopharmacol Biol Psychiatry

J Am Acad Dermatol

Neurosci Biobehav Rev

J Affect Disord

Psychiatry Res

Brain Behav Immun

Prostaglandins Leukot Essent Fatty Acids

Int J Dev Neurosci

Cytokine

J Neuroimmunol

J Psychiatr Res

Biol Psychiatry

Ageing Res Rev

Brain Behav Immun

Cytokines in Alzheimer's disease and vascular dementia

Int J Neurosci

Infliximab for patients with plaque psoriasis and severe psychiatric comorbidity

J Eur Acad Dermatol Venereol

Medical comorbidity in a bipolar outpatient clinical population

Neuropsychopharmacology

Improvement in patient-reported outcomes for patients with ankylosing spondylitis treated with etanercept 50 mg once-weekly and 25 mg twice-weekly

Rheumatology (Oxford)

Evidence that cytokines play a role in rheumatoid arthritis

J Clin Invest

TNFα signaling in depression and anxiety: behavioral consequences of individual receptor targeting

Biol Psychiatry

Modulation of proinflammatory cytokine release in rheumatoid synovial membrane cell cultures. Comparison of monoclonal anti TNF-alpha antibody with the interleukin-1 receptor antagonist

Review
The effect of tumor necrosis factor antagonists on mood and mental health-associated quality of life: Novel hypothesis-driven treatments for bipolar depression?