Charles L. Raison

Inflammation and Its Discontents: The Role of Cytokines in the Pathophysiology of Major Depression

Recognition that inflammation may represent a common mechanism of disease has been extended to include neuropsychiatric disorders including major depression. Patients with major depression have been found to exhibit increased peripheral blood inflammatory biomarkers, including inflammatory cytokines, which have been shown to access the brain and interact with virtually every pathophysiologic domain known to be involved in depression, including neurotransmitter metabolism, neuroendocrine function, and neural plasticity. Indeed, activation of inflammatory pathways within the brain is believed to contribute to a confluence of decreased neurotrophic support and altered glutamate release/reuptake, as well as oxidative stress, leading to excitotoxicity and loss of glial elements, consistent with neuropathologic findings that characterize depressive disorders. Further instantiating the link between inflammation and depression are data demonstrating that psychosocial stress, a well-known precipitant of mood disorders, is capable of stimulating inflammatory signaling molecules, including nuclear factor kappa B, in part, through activation of sympathetic nervous system outflow pathways. Interestingly, depressed patients with increased inflammatory biomarkers have been found to be more likely to exhibit treatment resistance, and in several studies, antidepressant therapy has been associated with decreased inflammatory responses. Finally, preliminary data from patients with inflammatory disorders, as well as medically healthy depressed patients, suggest that inhibiting proinflammatory cytokines or their signaling pathways may improve depressed mood and increase treatment response to conventional antidepressant medication. Translational implications of these findings include the unique opportunity to identify relevant patient populations, apply immune-targeted therapies, and monitor therapeutic efficacy at the level of the immune system in addition to behavior.

A Randomized Controlled Trial of the Tumor Necrosis Factor Antagonist Infliximab for Treatment-Resistant Depression: The Role of Baseline Inflammatory Biomarkers

CONTEXT Increased concentrations of inflammatory biomarkers predict antidepressant nonresponse, and inflammatory cytokines can sabotage and circumvent the mechanisms of action of conventional antidepressants. OBJECTIVES To determine whether inhibition of the inflammatory cytokine tumor necrosis factor (TNF) reduces depressive symptoms in patients with treatment-resistant depression and whether an increase in baseline plasma inflammatory biomarkers, including high-sensitivity C-reactive protein (hs-CRP), TNF, and its soluble receptors, predicts treatment response. DESIGN Double-blind, placebo-controlled, randomized clinical trial. SETTING Outpatient infusion center at Emory University in Atlanta, Georgia. PARTICIPANTS A total of 60 medically stable outpatients with major depression who were either on a consistent antidepressant regimen (n = 37) or medication-free (n = 23) for 4 weeks or more and who were moderately resistant to treatment as determined by the Massachusetts General Hospital Staging method. INTERVENTIONS Three infusions of the TNF antagonist infliximab (5 mg/kg) (n = 30) or placebo (n = 30) at baseline and weeks 2 and 6 of a 12-week trial. MAIN OUTCOME MEASURES The 17-item Hamilton Scale for Depression (HAM-D) scores. RESULTS No overall difference in change of HAM-D scores between treatment groups across time was found. However, there was a significant interaction between treatment, time, and log baseline hs-CRP concentration (P = .01), with change in HAM-D scores (baseline to week 12) favoring infliximab-treated patients at a baseline hs-CRP concentration greater than 5 mg/L and favoring placebo-treated patients at a baseline hs-CRP concentration of 5 mg/L or less. Exploratory analyses focusing on patients with a baseline hs-CRP concentration greater than 5 mg/L revealed a treatment response (≥50% reduction in HAM-D score at any point during treatment) of 62% (8 of 13 patients) in infliximab-treated patients vs 33% (3 of 9 patients) in placebo-treated patients (P = .19). Baseline concentrations of TNF and its soluble receptors were significantly higher in infliximab-treated responders vs nonresponders (P < .05), and infliximab-treated responders exhibited significantly greater decreases in hs-CRP from baseline to week 12 compared with placebo-treated responders (P < .01). Dropouts and adverse events were limited and did not differ between groups. CONCLUSIONS This proof-of-concept study suggests that TNF antagonism does not have generalized efficacy in treatment-resistant depression but may improve depressive symptoms in patients with high baseline inflammatory biomarkers. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00463580.

Psychoneuroimmunology Meets Neuropsychopharmacology: Translational Implications of the Impact of Inflammation on Behavior

The potential contribution of chronic inflammation to the development of neuropsychiatric disorders such as major depression has received increasing attention. Elevated biomarkers of inflammation, including inflammatory cytokines and acute-phase proteins, have been found in depressed patients, and administration of inflammatory stimuli has been associated with the development of depressive symptoms. Data also have demonstrated that inflammatory cytokines can interact with multiple pathways known to be involved in the development of depression, including monoamine metabolism, neuroendocrine function, synaptic plasticity, and neurocircuits relevant to mood regulation. Further understanding of mechanisms by which cytokines alter behavior have revealed a host of pharmacologic targets that may be unique to the impact of inflammation on behavior and may be especially relevant to the treatment and prevention of depression in patients with evidence of increased inflammation. Such targets include the inflammatory signaling pathways cyclooxygenase, p38 mitogen-activated protein kinase, and nuclear factor-κB, as well as the metabolic enzyme, indoleamine-2,3-dioxygenase, which breaks down tryptophan into kynurenine. Other targets include the cytokines themselves in addition to chemokines, which attract inflammatory cells from the periphery to the brain. Psychosocial stress, diet, obesity, a leaky gut, and an imbalance between regulatory and pro-inflammatory T cells also contribute to inflammation and may serve as a focus for preventative strategies relevant to both the development of depression and its recurrence. Taken together, identification of mechanisms by which cytokines influence behavior may reveal a panoply of personalized treatment options that target the unique contributions of the immune system to depression.

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

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.

Effect of compassion meditation on neuroendocrine, innate immune and behavioral responses to psychosocial stress

Meditation practices may impact physiological pathways that are modulated by stress and relevant to disease. While much attention has been paid to meditation practices that emphasize calming the mind, improving focused attention, or developing mindfulness, less is known about meditation practices that foster compassion. Accordingly, the current study examined the effect of compassion meditation on innate immune, neuroendocrine and behavioral responses to psychosocial stress and evaluated the degree to which engagement in meditation practice influenced stress reactivity. Sixty-one healthy adults were randomized to 6 weeks of training in compassion meditation (n=33) or participation in a health discussion control group (n=28) followed by exposure to a standardized laboratory stressor (Trier social stress test [TSST]). Physiologic and behavioral responses to the TSST were determined by repeated assessments of plasma concentrations of interleukin (IL)-6 and cortisol as well as total distress scores on the Profile of Mood States (POMS). No main effect of group assignment on TSST responses was found for IL-6, cortisol or POMS scores. However, within the meditation group, increased meditation practice was correlated with decreased TSST-induced IL-6 (r(p)=-0.46, p=0.008) and POMS distress scores (r(p)=-0.43, p=0.014). Moreover, individuals with meditation practice times above the median exhibited lower TSST-induced IL-6 and POMS distress scores compared to individuals below the median, who did not differ from controls. These data suggest that engagement in compassion meditation may reduce stress-induced immune and behavioral responses, although future studies are required to determine whether individuals who engage in compassion meditation techniques are more likely to exhibit reduced stress reactivity.

Neuropsychiatric Adverse Effects of Interferon-α Recognition and Management

Recombinant preparations of the cytokine interferon (IFN)-α are increasingly used to treat a number of medical conditions, including chronic viral hepatitis and several malignancies. Although frequently effective, IFNαα induces a variety of neuropsychiatric adverse effects, including an acute confusional state that develops rapidly after initiation of high-dose IFNαα, a depressive syndrome that develops more slowly over weeks to months of treatment, and manic conditions most often characterised by extreme irritability and agitation, but also occasionally by euphoria. Acute IFNαα-induced confusional states are typically characterised by disorientation, lethargy, somnolence, psychomotor retardation, difficulties with speaking and writing, parkinsonism and psychotic symptoms. Strategies for managing delirium should be employed, including treatment of contributing medical conditions, use of either typical or atypical antipsychotic agents and avoidance of medications likely to worsen mental status. Significant depressive symptoms occur in 21–58% of patients receiving IFNαα, with symptoms typically manifesting over the first several months of treatment. The most replicated risk factor for developing depression is the presence of mood and anxiety symptoms prior to treatment. Other potential, but less frequently replicated, risk factors include a past history of major depression, being female and increasing IFNα dosage and treatment duration. The available data support two approaches to the pharmacological management of IFNα-induced depression: antidepressant pretreatment or symptomatic treatment once IFNα has been initiated. Pretreatment might be best reserved for patients already receiving antidepressants or for patients who endorse depression or anxiety symptoms of mild or greater severity prior to therapy. Several recent studies demonstrate that antidepressants effectively treat IFNα-induced depression once it has developed, allowing the vast majority of subjects to complete treatment successfully. Recent data suggest that IFNα-induced depression may be composed of two overlapping syndromes: a depression-specific syndrome characterised by mood, anxiety and cognitive complaints, and a neurovegetative syndrome characterised by fatigue, anorexia, pain and psychomotor slowing. Depression-specific symptoms are highly responsive to serotonergic antidepressants, whereas neurovegetative symptoms are significantly less responsive to these agents. These symptoms may be more effectively treated by agents that modulate catecholaminergic functioning, such as combined serotonin-noradrenaline (norepinephrine) antidepressants, bupropion, psychostimulants or modafinil. Additional factors to consider in selecting an antidepressant include potential drug-drug interactions and adverse effect profile. Finally, IFNα appears capable of inducing manic symptoms. Mania, especially when severe, is a clinical emergency. When this occurs, IFNα and antidepressants should be stopped, an emergency psychiatric consultation should be obtained, and treatment with a mood stabiliser should be initiated.

CSF concentrations of brain tryptophan and kynurenines during immune stimulation with IFN-α: Relationship to CNS immune responses and depression

Cytokine-induced activation of indoleamine 2,3-dioxygenase (IDO) catabolizes L-tryptophan (TRP) into L-kynurenine (KYN), which is metabolized to quinolinic acid (QUIN) and kynurenic acid (KA). QUIN and KA are neuroactive and may contribute to the behavioral changes experienced by some patients during exposure to inflammatory stimuli such as interferon (IFN)-α. A relationship between depressive symptoms and peripheral blood TRP, KYN and KA during treatment with IFN-α has been described. However, whether peripheral blood changes in these IDO catabolites are manifest in the brain and whether they are related to central nervous system cytokine responses and/or behavior is unknown. Accordingly, TRP, KYN, QUIN and KA were measured in cerebrospinal fluid (CSF) and blood along with CSF concentrations of relevant cytokines, chemokines and soluble cytokine receptors in 27 patients with hepatitis C after ∼12 weeks of either treatment with IFN-α (n=16) or no treatment (n=11). Depressive symptoms were assessed using the Montgomery–Asberg Depression Rating Scale. IFN-α significantly increased peripheral blood KYN, which was accompanied by marked increases in CSF KYN. Increased CSF KYN was in turn associated with significant increases in CSF QUIN and KA. Despite significant decreases in peripheral blood TRP, IFN-α had no effect on CSF TRP concentrations. Increases in CSF KYN and QUIN were correlated with increased CSF IFN-α, soluble tumor necrosis factor-α receptor 2 and monocyte chemoattractant protein-1 as well as increased depressive symptoms. In conclusion, peripheral administration of IFN-α activated IDO in concert with central cytokine responses, resulting in increased brain KYN and QUIN, which correlated with depressive symptoms.

Is Depression an Inflammatory Disorder

Studies consistently report that groups of individuals with major depressive disorder (MDD) demonstrate increased levels of a variety of peripheral inflammatory biomarkers when compared with groups of nondepressed individuals. These findings are often interpreted as meaning that MDD, even in medically healthy individuals, may be an inflammatory condition. In this article, we examine evidence for and against this idea by looking more closely into what the actual patterns of inflammatory findings indicate in terms of the relationship between MDD and the immune system. Data are presented in support of the idea that inflammation only contributes to depression in a subset of patients versus the possibility that the depressogenic effect of inflammatory activation is more widespread and varies depending on the degree of vulnerability any given individual evinces in interconnected physiologic systems known to be implicated in the etiology of MDD. Finally, the treatment implications of these various possibilities are discussed.

Activation of Central Nervous System Inflammatory Pathways by Interferon-Alpha: Relationship to Monoamines and Depression

BACKGROUND Interferon (IFN)-alpha has been used to study the effects of innate immune cytokines on the brain and behavior in humans. The degree to which peripheral administration of IFN-alpha accesses the brain and is associated with a central nervous system (CNS) inflammatory response is unknown. Moreover, the relationship among IFN-alpha-associated CNS inflammatory responses, neurotransmitter metabolism, and behavior has yet to be established. METHODS Twenty-four patients with hepatitis C underwent lumbar puncture and blood sampling after approximately 12 weeks of either no treatment (n = 12) or treatment with pegylated IFN-alpha 2b (n = 12). Cerebrospinal fluid (CSF) and blood samples were analyzed for proinflammatory cytokines and their receptors as well as the chemokine, monocyte chemoattractant protein-1 (MCP-1), and IFN-alpha. Cerebrospinal fluid samples were additionally analyzed for monoamine metabolites and corticotropin releasing hormone. Depressive symptoms were assessed using the Montgomery Asberg Depression Rating Scale. RESULTS Interferon-alpha was detected in the CSF of all IFN-alpha-treated patients and only one control subject. Despite no increases in plasma IL-6, IFN-alpha-treated patients exhibited significant elevations in CSF IL-6 and MCP-1, both of which were highly correlated with CSF IFN-alpha concentrations. Of the immunologic and neurotransmitter variables, log-transformed CSF concentrations of the serotonin metabolite, 5-hydroxyindoleacetic acid (5-HIAA), were the strongest predictor of depressive symptoms. Log-transformed CSF concentrations of IL-6, but not IFN-alpha or MCP-1, were negatively correlated with log-transformed CSF 5-HIAA (r(2) = -.25, p < .05). CONCLUSIONS These data indicate that a peripherally administered cytokine can activate a CNS inflammatory response in humans that interacts with monoamine (serotonin) metabolism, which is associated with depression.

Effects of mindful-attention and compassion meditation training on amygdala response to emotional stimuli in an ordinary, non-meditative state

The amygdala has been repeatedly implicated in emotional processing of both positive and negative-valence stimuli. Previous studies suggest that the amygdala response to emotional stimuli is lower when the subject is in a meditative state of mindful-attention, both in beginner meditators after an 8-week meditation intervention and in expert meditators. However, the longitudinal effects of meditation training on amygdala responses have not been reported when participants are in an ordinary, non-meditative state. In this study, we investigated how 8 weeks of training in meditation affects amygdala responses to emotional stimuli in subjects when in a non-meditative state. Healthy adults with no prior meditation experience took part in 8 weeks of either Mindful Attention Training (MAT), Cognitively-Based Compassion Training (CBCT; a program based on Tibetan Buddhist compassion meditation practices), or an active control intervention. Before and after the intervention, participants underwent an fMRI experiment during which they were presented images with positive, negative, and neutral emotional valences from the IAPS database while remaining in an ordinary, non-meditative state. Using a region-of-interest analysis, we found a longitudinal decrease in right amygdala activation in the Mindful Attention group in response to positive images, and in response to images of all valences overall. In the CBCT group, we found a trend increase in right amygdala response to negative images, which was significantly correlated with a decrease in depression score. No effects or trends were observed in the control group. This finding suggests that the effects of meditation training on emotional processing might transfer to non-meditative states. This is consistent with the hypothesis that meditation training may induce learning that is not stimulus- or task-specific, but process-specific, and thereby may result in enduring changes in mental function.