Anti-cytokine agents for anhedonia: targeting inflammation and the immune system to treat dimensional disturbances in depression

Abstract

The etiology of mood disorders is mechanistically heterogeneous, underscoring the need for a dimensional approach to identify and develop targeted treatments in psychiatry. Accumulating evidence implicates inflammation as an important contributor to the pathophysiology of depression and presents the immune system as a viable therapeutic target that may be more proximate to the pathogenic nexus of brain-based disorders in specific subpopulations. Anhedonia is a transdiagnostic (e.g. Parkinson’s disease, diabetes mellitus, rheumatic diseases), yet specific, and clinically relevant symptom dimension subserved by well-characterized neurobiological and neurophysiological substrates of the positive valence systems (PVS). Brain circuits, nodes, and networks, as well as cellular and molecular pathways (e.g. dopaminergic transmission; excitotoxicity; synaptic plasticity), subserving anhedonia are preferentially affected by inflammatory processes. To our knowledge, no published randomized, controlled clinical trial in populations with mood disorders has, to date, primarily sought to determine the effects of an anti-inflammatory agent on PVS functions or pathophysiology. Three ongoing clinical trials aim to investigate the effects of anti-TNF-alpha biologic infliximab on measures of anhedonia [ClinicalTrials.gov identifier: NCT02363738], motivational behavior and circuitry [ClinicalTrials.gov identifier: NCT03006393], and glutamatergic changes in the basal ganglia [ClinicalTrials.gov identifier: NCT03004443] in clinical populations with unipolar or bipolar depression. Positive results would further instantiate the relevance of inflammatory processes and the immune system in the pathophysiology of mood disorders and provide the impetus to develop scalable treatments targeting inflammation and the immune system to mitigate transdiagnostic, dimensional disturbances in brain-based disorders.

Keywords

anhedonia anti-inflammatory agents inflammation infliximab Major Depressive Disorder Bipolar Depression

Introduction

In 2017, the World Health Organization identified depression as the leading cause of disability worldwide, affecting approximately 4.4% of the total global population and increasing annually in prevalence.¹ Hitherto, no curative treatments have been identified or developed for the treatment of depression. While available treatments have established symptom-mitigating efficacy in clinical populations, approximately one-third of patients fail to respond to conventional antidepressant therapies and continue to experience clinically significant, recurrent, and progressive deficits in psychosocial, cognitive, and general functioning.² All pharmacological agents currently approved for depression by the US Food and Drug Administration (FDA) target monoaminergic systems, underscoring the need for novel conceptual frameworks that better characterize the mechanistically heterogeneous etiology of depression to develop targeted and disease-modifying treatments in mood disorders. Herein, we outline accumulating data implicating disturbances in the immune system as an important contributor to the pathophysiology of depression and a possible target for treating domain-based pathologies in depression.

Inflammation and its relevance to the phenomenology, etiology, and pathophysiology of depression

In replicated preclinical and clinical studies, transient sickness behavior and depressive symptoms (or depressive-like behaviors) are observed with immune activation.^3–7 For example, the administration of bacterial lipopolysaccharide (LPS) in rodents induces the expression of pro-inflammatory cytokines [e.g. tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta] and transient behavioral changes (e.g. decreased locomotor activity and feeding, greater social withdrawal, and increased slow-wave sleep and pain sensitivity) that peak within 2–6 h of LPS administration.^8,9 While transient sickness behaviors resolve gradually, depressive-like behaviors, such as anhedonia (e.g. reduced sucrose preference) and helplessness (e.g. greater immobility on the forced swim and tail suspension tests), peak 24 h after LPS administration after feeding and locomotor activity have normalized.^8–10 Similarly, individuals receiving pro-inflammatory immunotherapy for malignant melanoma or hepatitis C exhibit acute flu-like neurovegetative and somatic symptoms (e.g. lethargy, loss of appetite, myalgia), which emerge within 6–8 h and typically resolve within 1–3 weeks; neuropsychiatric symptoms (e.g. cognitive impairment, irritability, apathy) develop after a few weeks of treatment.^4,11–14 Up to half of patients receiving chronic interferon (IFN)-alpha therapy meet diagnostic criteria for major depressive disorder (MDD).^14–17

Epidemiologically, chronic immune dysregulation is associated with higher depression incidence. For example, a recent population-based, case-control study (n = 103,307) reported a dose-dependent relationship between the frequency and severity of influenza infections and depression incidence.¹⁸ Approximately 15–22% of individuals with chronic inflammatory conditions (e.g. rheumatoid arthritis, systemic lupus erythematosus) present with clinically significant depressive symptoms.^19,20 Similarly, individuals with mood disorders are more likely to have or develop metabolic and inflammatory comorbidities (e.g. diabetes mellitus, metabolic syndrome, central obesity, hypertension, cardiovascular disease, autoimmune disorders) when compared with the general population.^21–25 Diabetes mellitus and mood disorders are bidirectionally associated with a synergy index of 2.2.²⁶ Populations with an immune-mediated disease (e.g. inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis) also have a higher incidence of major depressive, anxiety, and bipolar disorders.²⁵ Chronic, aberrant activation of the immune system (e.g. increased natural killer cytotoxicity, pro-inflammatory cytokine expression) with psychological stressors has also been hypothesized to subserve the elevated risk for coronary artery disease in populations with mood disorders.²⁷ Moreover, the recognition of mood disorders as an independent risk factor for cardiovascular disease, commensurate with the level of risk conferred by chronic inflammatory disease or human immunodeficiency virus infection, suggests a convergence in the etiology of mood disorders and cardiovascular disease and implicates alterations in inflammatory pathways and networks.²⁸

However, not all patients receiving chronic immunotherapy develop clinically significant depressive symptoms and progress to declare a psychiatric illness, underscoring the need to identify relevant risk factors and vulnerable subpopulations. Among adults receiving IFN-alpha therapy for cancer or hepatitis C, treatment-related and clinical risk factors include: longer treatment duration and higher dose; greater baseline depressive symptom severity; the presence of previous psychiatric diagnoses or sleep disorders; family history of a mood disorder; low social support; and older age.^11,13,29,30 In addition, greater pituitary–adrenal axis reactivity in response to IFN-alpha, higher baseline cytokine levels [e.g. IL-6, soluble IL-6 receptor (IL-6R), IL-2R, IL-10, soluble TNF receptor (sTNFR) 1], lower baseline anti-inflammatory polyunsaturated fatty acid levels, and functional polymorphism in immune [e.g. serotonin transporter (SERT), IL-6] and apolipoprotein E genes may contribute risk.^29,30 Peripheral changes in neopterin, kynurenine (KYN), and KYN-to-tryptophan (TRP) ratio, as well as brain-derived neurotrophic factor (BDNF), correlate with the severity of emergent depressive symptoms, implicating mechanisms of neuroplasticity, oxidative stress, and inflammatory pathways.^5,31

The cellular and molecular biosignatures of individuals with depression exhibit the cardinal features of an inflammatory response and implicate disturbances in the immune system and inflammatory pathways [e.g. nuclear factor (NF)-kappaB, caspase-1, NLRP3 inflammasome] in the pathogenesis of mood disorders.^32–35 Case-control studies, as well as prospective and longitudinal clinical staging studies of individuals with or at risk for mood disorders, have reported elevated levels of pro-inflammatory cytokines and their associated receptors [e.g. TNF-alpha, IL-1beta, IL-6, C-reactive protein (CRP), sTNFR1, sTNFR2, soluble IL-2 receptors (sIL-2R)] peripherally and in the cerebrospinal fluid.^5,33,35–39 In addition, the dysregulation of cytokines, adiponectin, and leptin in visceral adipose as part of central obesity has been implicated in the pathogenesis of the metabolic syndrome and associated with greater depressive symptom severity and unfavorable illness course in bipolar disorder, as well as depression-like behavior in animal models.^40–42

While the directionality of the relationship between inflammation and depression is unknown, peripheral immune activation drives inflammation in the central nervous system and alters brain functions.^33,43 Cytokines can cross the blood–brain barrier (BBB) via the circumventricular organs or saturable transporters in the BBB, as well as modulate peripheral afferent nerve fibers (e.g. vagus nerve) with catecholaminergic efferents, resulting in microglial activation.^16,33,44 Activated microglia and astrocytes also drive CC-chemokine ligand (CCL)-2-mediated cellular trafficking of activated immune cells (e.g. monocytes) into the brain.^33,45,46 Neuroimaging studies have noted microglial activation in the prefrontal cortex, anterior cingulate cortex (ACC), and insula among individuals with depression.⁴⁷ Moreover, microglial activation can be experimentally induced in nondepressed healthy controls with peripheral administration of inflammatory stimuli (e.g. endotoxin, lipopolysaccharide).^6,48 In addition, microglial activation is associated with self-reported depressive symptoms and elevated peripheral pro-inflammatory cytokine levels in the foregoing experimental paradigms.^6,48

Functional allelic variants and single nucleotide polymorphisms in immune and inflammatory genes [e.g. TNF-alpha, IL-1beta, cyclooxygenase (COX)-2, phospholipase A2] contribute to depression susceptibility in probands and individuals without family history of mood disorders, correlate with depressive symptom severity in clinical populations with mood disorders, and predict antidepressant response.^17,49–51 Immune reactivity, as proxied by change in serum IL-1beta levels in an experimental paradigm of social stress, has also been reported to correlate with depressive symptoms in a population of postmenopausal women.⁵² Aberrant gene expression profiles in the monocytes of individuals with mood disorders have also implicated cellular signaling, trafficking, and survival genes involved in stress-related inflammatory pathways and glucocorticoid resistance [e.g. TNF, IL-1beta, CCL2, mitogen-activated protein kinase (MAPK)-6].^53–55 Genetic polymorphisms subserving immune complex clearance pathways (e.g. gamma Fc region receptor, integrin alpha M) are also associated with depressive and other neuropsychiatric symptoms in populations with chronic inflammatory conditions.⁵⁶ Taken together, the foregoing observations not only implicate inflammation and dysregulation of the immune system in the phenomenology, etiology, and pathophysiology of depression, but also present the immune system as a possible mechanistic target for developing disease-modifying treatments in mood disorders.

Dimensional disturbances in depression: targeting the positive valence systems

The role of inflammation in the pathophysiology of depression can be further atomized into specific symptom dimensions that are aligned with the Research Domain Criteria (RDoC) and observed across multiple diagnostic categories (e.g. anxiety disorders, schizophrenia). The RDoC matrix was proposed by the National Institute of Mental Health as a novel conceptual framework for brain-based disorders that integrates findings from the biological, behavioral, and cognitive sciences with clinically observed symptoms.^57,58 Within the RDoC framework, transdiagnostic clinical phenomena are operationalized as domains of the negative valence systems, positive valence systems (PVS), cognitive systems, systems of social processes, and arousal and regulatory systems. The RDoC matrix further disentangles mechanistically heterogeneous, symptom-based categories of illness into discrete, validated constructs of neurobiological and quantitative measures of pathology (i.e. ‘units of analysis’) that subserve the foregoing domains, providing targets that are more proximate to the etiology and underlying pathophysiology of brain-based disorders.⁵⁹

Anhedonia is a diagnostic feature of a major depressive episode (MDE) and defined as the diminished ability to experience pleasure or enjoy previously pleasurable activities.⁶⁰ Notwithstanding its conceptualization as a cardinal depressive symptom, anhedonia is a prevalent and pervasive clinical phenomenon, observed transdiagnostically among individuals with or without current, or history of, psychiatric disorders (e.g. schizophrenia, bipolar disorder, substance use disorders).^61–65 In addition, anhedonia is an important determinant of prognosis and quality of life in psychiatric and nonpsychiatric clinical populations (e.g. schizophrenia, Parkinson’s disease, diabetes mellitus, cardiovascular disease).^62,66–72 Anhedonia is also a replicated predictor of antidepressant nonresponse, as observed in the Genome-Based Therapeutic Drugs for Depression (GENDEP) and the Sequenced Treatment Alternatives to Relieve Depression (STAR*D).^73,74

Within the RDoC framework, anhedonia can be conceptualized as a disturbance in the PVS, which comprises constructs related to, and neurobiological substrates subserving, reward- and motivation-related behaviors. The cellular and molecular substrates subserving PVS phenomenology and function are well characterized and include monoaminergic (e.g. dopamine, serotonin) and glutamatergic circuits, nodes, and networks, primarily in the ventral tegmental area, basal ganglia, prefrontal cortex, and ACC.^75–77

Pro-inflammatory cytokines affect cellular and molecular substrates that influence brain structures and circuits that subserve PVS pathophysiology. For example, TNF-alpha, IL-1beta, and IFNs can decrease monoaminergic transmission by increasing dopamine, serotonin, and norepinephrine transporter activity and expression via activation of p38 MAPK pathways; decreasing vesicular monoamine transporter-2 expression and function; decreasing enzymatic cofactor tetrahydrobiopterin availability via production of reactive oxygen and nitrogen species; and depleting serotonin precursor tryptophan via activation of indoleamine 2,3-dioxygenase (IDO), which metabolizes TRP to KYN.^32,33,78 Serum levels of KYN and neopterin, as well as KYN-to-TRP ratios, correlate with depressive symptom severity.³¹ Moreover, IDO activation appears to peak synchronously with depressive-like behavior with LPS administration in murine models.⁹ In addition, TNF-alpha promotes insulin resistance, via its effects on insulin receptor substrate, which is associated with increased monoamine turnover (e.g. dopamine) and alterations in brain circuits, nodes, and networks subserving general cognition, as well as reward- and motivation-related behaviors.^79–82

The activation of IDO by pro-inflammatory cytokines also modulates glutamatergic transmission. Activated microglia and infiltrating monocytes and macrophages convert KYN in the brain into neurotoxin quinolinic acid, which activates presynaptic N-methyl-D-aspartate (NMDA) receptors to release glutamate and blocks astrocytic reuptake of synaptic glutamate, decreasing BDNF expression and contributing to excitotoxicity and decreased neurogenesis.^29,83 Increased glutamate levels have been noted in the basal ganglia and dorsal ACC of depressed patients with serum CRP levels of 3 mg/l or greater, relative to those with CRP < 3 mg/l, and correlate with anhedonia.⁸⁴ Oxidative stress also activates astrocytes and stimulates excess glutamate release.^29,83 Pro-inflammatory cytokines also reduce neurogenesis in the dentate gyrus, synaptic plasticity, and dendritic sprouting, ultimately affecting brain structures and functions.^33,85 Physical and psychological stressors also promote glucocorticoid resistance via danger-associated molecular pattern signaling pathways and its effects on the NLRP3 inflammasome.^34,54

Convergent evidence indicates that innate immune activation and inflammatory processes, via their effects on monoaminergic and glutamatergic transmission and metabolism (e.g. via the KYN pathway) preferentially affect dopaminergic circuits and networks subserving PVS phenomenology.^86–88 For example, among 50 unmedicated adults with MDD or bipolar disorder, higher serum CRP levels predicted greater glutamate levels in the basal ganglia.⁸⁹ Glutamate levels in the basal ganglia were associated with measures of anhedonia and psychomotor processing, supporting the notion that inflammatory processes preferentially affect reward circuits and dopaminergic neurons involved in reward- and motivation-, as well as motor activity-related behaviors.^86–89 Peripheral inflammatory challenges have also been associated with decreased responsiveness to monetary reward in the ventral striatum and deficits in reward-related behaviors, as well as psychomotor slowing, in nondepressed subjects, consistent with clinical observations of anhedonia and psychomotor slowing as predominant depressive symptoms in populations with acute infections or receiving chronic IFN-alpha therapy.^86,90,91 In addition, a proof-of-concept study inclusive of 16 healthy, nondepressed participants reported that typhoid vaccinations induced peripheral IL-6 levels, activated the subgenual ACC, and decreased subgenual ACC-ventral striatum functional connectivity; in addition, IL-6 levels moderated the foregoing decrease in reward circuit connectivity.⁹² Similarly, in a resting-state neuroimaging study of 48 unmedicated, depressed subjects, higher serum CRP levels were associated with functional dysconnectivity in corticostriatal reward circuitry and predicted greater anhedonic and psychomotor slowing symptoms.⁸⁷

Observed brain correlates of anhedonia have been reported as part of a connectome-wide association analysis in 172 adults with a mood disorder, schizophrenia, or psychosis risk and 53 adults without any psychiatric conditions.⁹³ Dissociable patterns of hyperconnectivity within the default mode network (DMN), diminished DMN connectivity with the nucleus accumbens and cingulo-opercular network, and increased connectivity between the nucleus accumbens and the cingulo-opercular network were noted, instantiating the transdiagnostic relevance of anhedonia and a convergence in the neurobiological substrates subserving PVS pathophysiology.⁹³ In addition, the antisuicide effects of ketamine have been postulated to be subserved by glutamatergic modulation of brain circuits and networks involved in general cognitive and PVS.⁹⁴

Moreover, a recent multisite study using machine learning capabilities aimed to identify clinically relevant neurophysiological subtypes informed by symptom profiles and resting-state functional neuroimaging data from 333 subjects with MDD and a current MDE and 378 age- and sex-matched subjects without any psychiatric history.⁹⁵ Clinically relevant patterns of functional dysconnectivity in limbic and frontostriatal networks accurately classified 80–93% of subjects’ diagnostic labels in an independent, out-of-sample replication dataset (n = 125 MDD, n = 352 controls).⁹⁵ Of note, hyperconnectivity in thalamic and frontostriatal networks, which correlated with increased anhedonia and psychomotor retardation, emerged as the most robust subtype, implicating anhedonia as a transdiagnostic clinical phenotype with discrete, yet convergent, neurophysiological correlates.

The immune system as a viable therapeutic target in depression

Accumulating evidence indicates that anti-inflammatory agents may be effective for the treatment of depression, at least for a significant proportion of patients presenting with baseline inflammatory activation.⁹⁶ However, available data are limited by heterogeneity in study design, such as the use of different anti-inflammatory agents with various off-target effects [e.g. nonsteroidal anti-inflammatories (NSAIDs) also modulate prostaglandin production, which may be pro-inflammatory in chronic disease states]; the measurement of depressive symptom severity broadly rather than dimensionally, with symptom-specific outcomes (e.g. anhedonia); and the inclusion of patients solely on the basis of clinical diagnoses without study population enrichment for relevant neurobiological or neurophysiological substrates, or evidence of target engagement.^97–100 In contrast, preliminary evidence suggests that biologics (e.g. monoclonal antibodies) that specifically target individual cytokines (e.g. TNF-alpha) are effective in reducing depressive symptoms without off-target effects. For example, a recent meta-analysis (n = 2370) of seven randomized, controlled trials of anticytokine agents (e.g. adalimumab, etanercept, tocilizumab, infliximab) in chronic inflammatory conditions (e.g. rheumatoid arthritis) reported significant antidepressant efficacy of moderate effect size [standardized mean difference (SMD) = 0.40, 95% confidence interval (CI) = 0.22, 0.59].¹⁰⁰

Greater baseline inflammatory activation has been observed among patients exhibiting poorer response to conventional antidepressant therapy.^101–103 The foregoing observation highlights the opportunity to use immune system substrates as biomarkers to identify patients who are likely to be treatment resistant and may benefit from novel therapeutic strategies.⁹⁶ For example, baseline plasma adipokine abnormalities predict antidepressant response to ketamine in unipolar or bipolar depression and are postulated to contribute to the antidepressant effects of ketamine.¹⁰⁴ In addition, baseline measures and changes in composite inflammatory biomarkers [i.e. body mass index ⩾ 30 k/m², IL-6, IL-8, high sensitivity (hs)-CRP, TNF-alpha, and leptin] predicted and correlated with antidepressant response to L-methylfolate calcium in MDD.¹⁰⁵ Similarly, composite markers of baseline inflammatory activation predicted greater depressive symptom improvement with eicosapentaenoic acid (EPA), and reduced responsiveness to placebo, when compared to subjects with low baseline inflammatory activation.¹⁰⁶ A corollary of the stratification of treatment response by inflammatory biomarkers is the presence of a U-shaped relationship between inflammation and depression.¹⁰⁷ Only a subpopulation of individuals with depression with baseline inflammatory activation may benefit from anti-inflammatory treatment, underscoring the importance of identifying, screening for, and targeting specific subpopulations that are most likely to benefit from an intervention, as well as highlighting the opportunity to use immune substrates as biomarkers to personalize care and improve outcomes in psychiatry.¹⁰⁷

To our knowledge, the antidepressant efficacy of only one anticytokine agent–infliximab–has been investigated as part of a randomized, controlled clinical trial and published as a primary outcome among adults with mood disorders; etanercept has also been investigated as part of an open-label clinical trial.^107,108 Infliximab is a chimeric monoclonal antibody that targets TNF-alpha, is administered intravenously, and is approved by the FDA and Health Canada for the treatment of several rheumatic disorders (e.g. rheumatoid arthritis, Crohn’s disease, ankylosing spondylitis, psoriatic arthritis, and ulcerative colitis).¹⁰⁹ In a randomized, double-blinded, placebo-controlled trial of infliximab in depressed subjects meeting diagnostic criteria for a current MDE as part of treatment-resistant MDD (n = 51) or bipolar disorder (n = 9), Raison and colleagues reported that infliximab significantly improved depressive symptoms in subjects with baseline inflammatory activation (i.e. hs-CRP levels of >5 mg/l), but not in subjects without baseline inflammatory activation (i.e. hs-CRP ⩽ 5 mg/l); in fact, subjects without baseline inflammatory activation were more likely to benefit from placebo than active treatment.¹⁰⁷ A case report of antidepressant efficacy of TNF-alpha inhibitor etanercept in two geriatric patients with treatment resistant depression reported mixed findings, but did not assay baseline inflammation.¹⁰⁸

Three randomized, double-blinded, placebo-controlled clinical trials investigating the efficacy of infliximab on a measure of anhedonia are currently ongoing (Table 1). One 12-week trial in adults (n = 60) with bipolar I/II depression exhibiting baseline inflammatory activation includes an assessment of the Snaith-Hamilton Pleasure Scale (SHAPS) with three infusions of inflixmab or placebo and is expected to complete in April 2018 [ClinicalTrials.gov identifier: NCT02363738]. Two 2-week trials include adults currently experiencing clinically significant depressive symptoms as part of bipolar or MDD with baseline CRP > 3 mg/l and a single infusion of infliximab or placebo and are expected to complete in March 2021. One study (n = 80) primarily aims to assess the effects of infliximab on motivational circuits and behavior as assessed using an functional magnetic-resonance-imaging-adapted Behavioral Effort-Expenditure for Rewards Task (behEEfRT) [ClinicalTrials.gov identifier: NCT03006393]. A separate study (n = 60) primarily aims to investigate the effects of infliximab on glutamate levels in the basal ganglia as measured by magnetic resonance spectroscopy and additionally includes cerebrospinal fluid biomarkers [ClinicalTrials.gov identifier: NCT03004443]. All three clinical trials include measures of cognition, overall depressive symptom severity, and peripheral biomarkers, among others (Table 1).

Table 1.

Summary of ongoing clinical trials investigating the efficacy of anti-tumor necrosis factor alpha biologic infliximab on a measure of anhedonia.

Study location [ClinicalTrials.gov identifier]	Recruitment status (estimated study completion date)	Study design	Intervention	Participants	Primary outcome measure	Secondary outcome measures
Toronto Western Hospital, University Health Network, Toronto, Canada; VA Palo Alto Health Care System, Stanford University, Palo Alto, USA [NCT02363738]	Completed (April 2018)	Phase II, 12-week randomized, placebo-controlled clinical trial with masking of participant, investigator, outcomes assessor, and care provider	Three infusions of adjunctive infliximab (5 mg/kg) versus saline at weeks 0, 2, 6 (parallel assignment)	Adults (n = 60) ages 18–65 with current MDE as part of BD-I/II exhibiting baseline inflammatory activation (obesity and hypertension/dyslipidemia, diabetes mellitus, inflammatory bowel disorder, rheumatoid arthritis, psoriasis, daily cigarette smoking, or baseline CRP ⩾ 5 mg/l)	MADRS total score (change from baseline to up to week 12)	Anhedonia (SHAPS), plasma cytokine levels, cognitive function (DSST, RAVLT, PDQ-D-20), structural MRI and MRS, quality of life (SF-36), functional disability (SDS, EWPS), suicide risk (CSSRS)
Emory University, Atlanta, USA [NCT03006393]	Recruiting (November 2021)	Phase I, 2-week, randomized, placebo-controlled clinical trial with masking of participant and investigator	Single infusion of infliximab (5 mg/kg) versus saline (parallel assignment)	Adults (n = 80) ages 25–60 with current MDE as part of MDD or BD with baseline CRP > 3 mg/l	fMRI-adapted behEEfRT with two task difficulty level choices (change from baseline to week 2)	Anhedonia (SHAPS, MAP), fatigue (MFI, FSS), overall depressive symptom severity (IDS-SR), emotional states (PANAS-X), suicide risk (CSSRS), cognition (Go/No-Go, RTT, DSST), motor control (FTT), plasma biomarkers (CRP, TNF-alpha, sTNFR1, sTNFR2, IL-1, IL-1RA, IL-6, sIL-6R)
Emory University, Atlanta, USA [NCT03004443]	Recruiting (March 2021)	Phase IV, 2-week, randomized, placebo-controlled clinical trial with masking of participant, investigator, and outcomes assessor	Single infusion of infliximab (5 mg/kg) versus saline (parallel assignment)	Adults (n = 60) ages 25–60 with current MDE as part of MDD or BD with baseline CRP > 3 mg/l	Basal ganglia glutamate, assessed by MRS (change from baseline to day 3 to 14)	Anhedonia (SHAPS, MAP), motivation (EEfRT), motor control (FTT), cognition (RTT, DSST, TMT-A), psychomotor retardation (RSS), fatigue (MFI), overall depressive symptom severity (IDS-SR), plasma and CSF inflammatory markers (CRP, TNF, TNFR2, IL-1RA, IL-6, sIL-6R, IL-10, MCP-1, mRNA)

BD: bipolar disorder; behEEfRT: behavioral EEfRT; CRP: C-reactive protein; CSF: cerebrospinal fluid; CSSRS: Columbia Suicide Severity Rating Scale; DSST: Digit Symbol Substitution Test; EEfRT: Effort-Expenditure for Rewards Task; EWPS: Endicott Workplace Productivity Scale; FSS: Fatigue Severity Scale; IDS-SR: Inventory of Depressive Symptoms Self-Report; IL: interleukin; IL-1RA: IL-1 receptor agonist; MADRS: Montgomery-Asberg Depression Rating Scale; MAP: Mood and Pleasure Scale; MCP: monocyte chemoattractant protein; MDD: major depressive disorder; MDE: major depressive episode; MFI: Multidimensional Fatigue Inventory; MRI: magnetic resonance imaging; mRNA, messenger ribonucleic acid; MRS: magnetic resonance spectroscopy; PANAS-X: Positive Affect/Negative Affect Scale: now; PDQ-D-20: Perceived Deficits Questionnaire: Depression, 20-item; RAVLT: Rey Auditory Verbal Learning Test; SDS: Sheehan Disability Scale; SF-36: 36-item Short Form health survey; RTT: Reaction Time Task; SHAPS: Snaith-Hamilton Pleasure Scale; sIL-6R: soluble IL-6 receptor; TMT: Trail-Making Test; TNF: tumor necrosis factor; TNFR: TNF receptor; VA, Veterans Affairs.

Conclusion

Taken together, the etiology of mood disorders is mechanistically heterogeneous, underscoring the need for a dimensional approach to identify and develop disease-modifying and potentially curative treatments in psychiatry. Accumulating evidence implicates inflammation as an important contributor to the pathophysiology of depression and presents the immune system as a viable therapeutic target that may be more proximate to the pathogenic nexus of brain-based disorders in specific subpopulations. Cellular and molecular inflammatory and innate immune substrates are valuable biomarkers that can be used in conjunction with specific symptom dimensions to demonstrate target engagement with novel or repurposed therapeutic agents and to differentiate patient populations who are most likely benefit from these treatments.

Anhedonia is a transdiagnostic, yet specific, and clinically relevant symptom dimension subserved by well-characterized neurobiological and neurophysiological substrates that are preferentially affected by inflammatory processes and their effects on cellular and molecular pathways (e.g. dopaminergic transmission; excitotoxicity; synaptic plasticity), as well as brain circuits, nodes, and networks that subserve PVS phenomenology. To our knowledge, no published randomized, controlled clinical trial in populations with mood disorders has hitherto primarily sought to determine the effects of an anti-inflammatory agent on PVS functions and pathophysiology. Notwithstanding, three ongoing clinical trials aim to investigate the effects of anti-TNF-alpha biologic infliximab on measures of anhedonia [ClinicalTrials.gov identifier: NCT02363738], motivational behavior and circuitry [ClinicalTrials.gov identifier: NCT03006393], and glutamatergic changes in the basal ganglia [ClinicalTrials.gov identifier: NCT03004443] in clinical populations with unipolar or bipolar depression. Positive results would further instantiate the relevance of inflammatory processes and the immune system in the phenomenology and etiology of mood disorders and provide the impetus to develop scalable treatments targeting inflammation and the immune system to mitigate transdiagnostic, dimensional disturbances in brain-based disorders.

Footnotes

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of interest statement

The authors declare that there is no conflict of interest.

References

World Health Organization. Depression and other common mental disorders: global health estimates (Internet). Geneva, Switzerland: World Health Organization, http://apps.who.int/iris/bitstream/10665/254610/1/WHO-MSD-MER-2017.2-eng.pdf?ua=1 (accessed 1 September 2018).

Trivedi

Rush

Wisniewski

et al . Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry 2006; 163: 28–40.

Dantzer

O’Connor

Freund

et al . From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci 2008; 9: 46–56.

Dieperink

Willenbring

SB.

Neuropsychiatric symptoms associated with hepatitis C and interferon alpha: a review. Am J Psychiatry 2000; 157: 867–876.

Huckans

Fuller

Wheaton

et al . A longitudinal study evaluating the effects of interferon-alpha therapy on cognitive and psychiatric function in adults with chronic hepatitis C. J Psychosom Res 2015; 78: 184–192.

Hannestad

Gallezot

J-D

Schafbauer

et al . Endotoxin-induced systemic inflammation activates microglia: [11C]PBR28 positron emission tomography in nonhuman primates. Neuroimage 2012; 63: 232–239.

Kelley

O’Connor

Lawson

et al . Aging leads to prolonged duration of inflammation-induced depression-like behavior caused by Bacillus Calmette-Guérin. Brain Behav Immun 2013; 32: 63–69.

Van Dam

Brouns

Louisse

et al . Appearance of interleukin-1 in macrophages and in ramified microglia in the brain of endotoxin-treated rats: a pathway for the induction of non-specific symptoms of sickness? Brain Res 1992; 588: 291–296.

Dantzer

Cytokine-induced sickness behavior: where do we stand?

Brain Behav Immun 2001; 15: 7–24.

10.

Biesmans

Matthews

LJR

Bouwknecht

et al . Systematic analysis of the cytokine and anhedonia response to peripheral lipopolysaccharide administration in rats. Biomed Res Int 2016; 2016: 9085273.

11.

Dieperink

Thuras

et al . A prospective study of neuropsychiatric symptoms associated with interferon-alpha-2b and ribavirin therapy for patients with chronic hepatitis C. Psychosomatics 2003; 44: 104–112.

12.

Constant

Castera

Dantzer

et al . Mood alterations during interferon-alfa therapy in patients with chronic hepatitis C: evidence for an overlap between manic/hypomanic and depressive symptoms. J Clin Psychiatry 2005; 66: 1050–1057.

13.

Scheibel

Valentine

O’Brien

et al . Cognitive dysfunction and depression during treatment with interferon-alpha and chemotherapy. J Neuropsychiatry Clin Neurosci 2004; 16: 185–191.

14.

Bonaccorso

Marino

Biondi

et al . Depression induced by treatment with interferon-alpha in patients affected by hepatitis C virus. J Affect Disord 2002; 72: 237–241.

15.

Capuron

Gumnick

Musselman

et al . Neurobehavioral effects of interferon-alpha in cancer patients: phenomenology and paroxetine responsiveness of symptom dimensions. Neuropsychopharmacology 2002; 26: 643–652.

16.

Raison

Borisov

Majer

et al . Activation of central nervous system inflammatory pathways by interferon-alpha: relationship to monoamines and depression. Biol Psychiatry. 2009; 65: 296–303.

17.

Hepgul

Cattaneo

Agarwal

et al . Transcriptomics in interferon-α-treated patients identifies inflammation-, neuroplasticity- and oxidative stress-related signatures as predictors and correlates of depression. Neuropsychopharmacology 2016; 41: 2502–2511.

18.

Bornand

Toovey

Jick

et al . The risk of new onset depression in association with influenza–A population-based observational study. Brain Behav Immun 2016; 53: 131–137.

19.

Mak

Tang

CS-K

Chan

M-F

et al . Damage accrual, cumulative glucocorticoid dose and depression predict anxiety in patients with systemic lupus erythematosus. Clin Rheumatol 2011; 30: 795–803.

20.

RCM

EHY

Chua

ANC

et al . Clinical and psychosocial factors associated with depression and anxiety in Singaporean patients with rheumatoid arthritis. Int J Rheum Dis 2011; 14: 37–47.

21.

Mansur

Brietzke

McIntyre

RS.

Is there a “metabolic-mood syndrome”? A review of the relationship between obesity and mood disorders. Neurosci Biobehav Rev 2015; 52: 89–104.

22.

Centorrino

Mark

Talamo

et al . Health and economic burden of metabolic comorbidity among individuals with bipolar disorder. J Clin Psychopharmacol 2009; 29: 595–600.

23.

Reininghaus

McIntyre

Reininghaus

et al . Tryptophan breakdown is increased in euthymic overweight individuals with bipolar disorder: a preliminary report. Bipolar Disord 2014; 16: 432–440.

24.

Goldstein

Kemp

Soczynska

et al . Inflammation and the phenomenology, pathophysiology, comorbidity, and treatment of bipolar disorder: a systematic review of the literature. J Clin Psychiatry 2009; 70: 1078–1090.

25.

Marrie

Walld

Bolton

et al . Rising incidence of psychiatric disorders before diagnosis of immune-mediated inflammatory disease. Epidemiol Psychiatr Sci 2017; 1–10.

26.

Scott

Von Korff

Alonso

et al . Mental-physical co-morbidity and its relationship with disability: results from the World Mental Health Surveys. Psychol Med 2009; 39: 33–43.

27.

Neo

Chua

et al . Research on psychoneuroimmunology: does stress influence immunity and cause coronary artery disease. Ann Acad Med Singapore 2010; 39: 191–196.

28.

Goldstein

Carnethon

Matthews

et al . Major depressive disorder and bipolar disorder predispose youth to accelerated atherosclerosis and early cardiovascular disease: a scientific statement from the American Heart Association. Circulation 2015; 132: 965–986.

29.

Dantzer

O’Connor

Lawson

et al . Inflammation-associated depression: from serotonin to kynurenine. Psychoneuroendocrinology 2011; 36: 426–436.

30.

Schaefer

Capuron

Friebe

et al . Hepatitis C infection, antiviral treatment and mental health: a European expert consensus statement. J Hepatol 2012; 57: 1379–1390.

31.

Capuron

Neurauter

Musselman

et al . Interferon-alpha–induced changes in tryptophan metabolism. Biol Psychiatry 2003; 54: 906–914.

32.

Miller

Raison

CL.

The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nat Rev Immunol 2016; 16: 22–34.

33.

Miller

Maletic

Raison

CL.

Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol Psychiatry 2009; 65: 732–741.

34.

Guo

Callaway

Ting

JP-Y

. Inflammasomes: mechanism of action, role in disease, and therapeutics. Nat Med 2015; 21: 677–687.

35.

Howren

Lamkin

Suls

Associations of depression with C-reactive protein, IL-1, and IL-6: a meta-analysis. Psychosom Med 2009; 71: 171–186.

36.

Modabbernia

Taslimi

Brietzke

et al . Cytokine alterations in bipolar disorder: a meta-analysis of 30 studies. Biol Psychiatry 2013; 74: 15–25.

37.

Dowlati

Herrmann

Swardfager

et al . A meta-analysis of cytokines in major depression. Biol Psychiatry 2010; 67: 446–457.

38.

Liu

RC-M

Mak

Interleukin (IL)-6, tumour necrosis factor alpha (TNF-α) and soluble interleukin-2 receptors (sIL-2R) are elevated in patients with major depressive disorder: a meta-analysis and meta-regression. J Affect Disord 2012; 139: 230–239.

39.

Huckans

Fuller

Olavarria

et al . Multi-analyte profile analysis of plasma immune proteins: altered expression of peripheral immune factors is associated with neuropsychiatric symptom severity in adults with and without chronic hepatitis C virus infection. Brain Behav 2014; 4: 123–142.

40.

CSH

Zhang

MWB

Mak

et al . Metabolic syndrome in psychiatry: advances in understanding and management. Adv Psychiatr Treat 2014; 20: 101–112.

41.

Yang

Liu

Jiang

et al . The effects of high-fat-diet combined with chronic unpredictable mild stress on depression-like behavior and leptin/LepRb in male rats. Sci Rep 2016; 6: 35239.

42.

Mansur

Rizzo

Santos

et al . Adipokines, metabolic dysfunction and illness course in bipolar disorder. J Psychiatr Res 2016; 74: 63–69.

43.

Haroon

Raison

Miller

AH.

Psychoneuroimmunology meets neuropsychopharmacology: translational implications of the impact of inflammation on behavior. Neuropsychopharmacology 2012; 37: 137–162.

44.

Quan

Banks

WA.

Brain-immune communication pathways. Brain Behav Immun 2007; 21: 727–735.

45.

D’Mello

Swain

MG.

Cerebral microglia recruit monocytes into the brain in response to tumor necrosis factorα signaling during peripheral organ inflammation. J Neurosci 2009; 29: 2089–2102.

46.

Wohleb

Powell

Godbout

et al . Stress-induced recruitment of bone marrow-derived monocytes to the brain promotes anxiety-like behavior. J Neurosci 2013; 33: 13820–13833.

47.

Setiawan

Wilson

Mizrahi

et al . Role of translocator protein density, a marker of neuroinflammation, in the brain during major depressive episodes. JAMA Psychiatry 2015; 72: 268–275.

48.

Sandiego

Gallezot

J-D

Pittman

et al . Imaging robust microglial activation after lipopolysaccharide administration in humans with PET. Proc Natl Acad Sci USA 2015; 112: 12468–12473.

49.

Wong

M-L

Dong

Maestre-Mesa

et al . Polymorphisms in inflammation-related genes are associated with susceptibility to major depression and antidepressant response. Mol Psychiatry 2008; 13: 800–812.

50.

K-P

Huang

S-Y

Peng

C-Y

et al . Phospholipase A2 and cyclooxygenase 2 genes influence the risk of interferon-alpha-induced depression by regulating polyunsaturated fatty acids levels. Biol Psychiatry 2010; 67: 550–557.

51.

Bufalino

Hepgul

Aguglia

et al . The role of immune genes in the association between depression and inflammation: a review of recent clinical studies. Brain Behav Immun 2013; 31: 31–47.

52.

Aschbacher

Epel

Wolkowitz

et al . Maintenance of a positive outlook during acute stress protects against pro-inflammatory reactivity and future depressive symptoms. Brain Behav Immun 2012; 26: 346–352.

53.

Padmos

Hillegers

MHJ

Knijff

et al . A discriminating messenger RNA signature for bipolar disorder formed by an aberrant expression of inflammatory genes in monocytes. Arch Gen Psychiatry 2008; 65: 395–407.

54.

Iwata

Ota

Duman

RS.

The inflammasome: pathways linking psychological stress, depression, and systemic illnesses. Brain Behav Immun 2013; 31: 105–114.

55.

Alcocer-Gómez

De Miguel

Casas-Barquero

et al . NLRP3 inflammasome is activated in mononuclear blood cells from patients with major depressive disorder. Brain Behav Immun 2014; 36: 111–117.

56.

Ong

Thiaghu

et al . Genetic variants that are associated with neuropsychiatric systemic lupus erythematosus. J Rheumatol 2016; 43: 541–551.

57.

Cuthbert

Insel

TR.

Toward the future of psychiatric diagnosis: the seven pillars of RDoC. BMC Med 2013; 11: 126.

58.

Insel

Cuthbert

Garvey

et al . Research domain criteria (RDoC): toward a new classification framework for research on mental disorders. Am J Psychiatry 2010; 167: 748–751.

59.

Insel

TR.

The NIMH Research Domain Criteria (RDoC) Project: precision medicine for psychiatry. Am J Psychiatry 2014; 171: 395–397.

60.

American Psychiatric Association. Diagnostic and statistical manual of mental disorders (DSM-5®). Washington, DC: American Psychiatric Pub, 2013, 991 p. 123–188.

61.

Bedwell

Gooding

Chan

et al . Anhedonia in the age of RDoC. Schizophr Res 2014; 160: 226–227.

62.

Ritsner

Arbitman

Lisker

Anhedonia is an important factor of health-related quality-of-life deficit in schizophrenia and schizoaffective disorder. J Nerv Ment Dis 2011; 199: 845–853.

63.

Garfield

JBB

Lubman

Yücel

Anhedonia in substance use disorders: a systematic review of its nature, course and clinical correlates. Aust N Z J Psychiatry 2014; 48: 36–51.

64.

Rømer Thomsen

Whybrow

Kringelbach

. Reconceptualizing anhedonia: novel perspectives on balancing the pleasure networks in the human brain. Front Behav Neurosci 2015; 9: 49.

65.

Whitton

Treadway

Pizzagalli

DA.

Reward processing dysfunction in major depression, bipolar disorder and schizophrenia. Curr Opin Psychiatry 2015; 28: 7–12.

66.

Carter

Swardfager

Mood and metabolism: anhedonia as a clinical target in type 2 diabetes. Psychoneuroendocrinology 2016; 69: 123–132.

67.

Nefs

Pop

VJM

Denollet

et al . Depressive symptoms and all-cause mortality in people with type 2 diabetes: a focus on potential mechanisms. Br J Psychiatry 2016; 209: 142–149.

68.

Davidson

Burg

Kronish

et al . Association of anhedonia with recurrent major adverse cardiac events and mortality 1 year after acute coronary syndrome. Arch Gen Psychiatry 2010; 67: 480–488.

69.

Matsui

Tachibana

Yamanishi

et al . Clinical correlates of anhedonia in patients with Parkinson’s disease. Clin Neurol Neurosurg 2013; 115: 2524–2527.

70.

Lemke

Brecht

Koester

et al . Effects of the dopamine agonist pramipexole on depression, anhedonia and motor functioning in Parkinson’s disease. J Neurol Sci 2006; 248: 266–270.

71.

Loas

Krystkowiak

Godefroy

Anhedonia in Parkinson’s disease: an overview. J Neuropsychiatry Clin Neurosci 2012; 24: 444–451.

72.

Nagayama

Maeda

Uchiyama

et al . Anhedonia and its correlation with clinical aspects in Parkinson’s disease. J Neurol Sci 2017; 372: 403–407.

73.

Uher

Farmer

Maier

et al . Measuring depression: comparison and integration of three scales in the GENDEP study. Psychol Med 2008; 38: 289–300.

74.

Uher

Perlis

Henigsberg

et al . Depression symptom dimensions as predictors of antidepressant treatment outcome: replicable evidence for interest-activity symptoms. Psychol Med 2012; 42: 967–980.

75.

Russo

Nestler

EJ.

The brain reward circuitry in mood disorders. Nat Rev Neurosci 2013; 14: 609–625.

76.

Nestler

EJ.

Role of the brain’s reward circuitry in depression: transcriptional mechanisms. Int Rev Neurobiol 2015; 124: 151–170.

77.

Haber

SN.

Neuroanatomy of reward: a view from the ventral striatum. In: Gottfried

(ed.) Neurobiology of sensation and reward. Boca Raton (FL): CRC Press/Taylor & Francis, 2012.

78.

Felger

Lotrich

FE.

Inflammatory cytokines in depression: neurobiological mechanisms and therapeutic implications. Neuroscience 2013; 246: 199–229.

79.

Kleinridders

Cai

Cappellucci

et al . Insulin resistance in brain alters dopamine turnover and causes behavioral disorders. Proc Natl Acad Sci U S A 2015; 112: 3463–3468.

80.

Kullmann

Heni

Veit

et al . The obese brain: association of body mass index and insulin sensitivity with resting state network functional connectivity. Hum Brain Mapp 2012; 33: 1052–1061.

81.

Mansur

Ahmed

Cha

et al . Liraglutide promotes improvements in objective measures of cognitive dysfunction in individuals with mood disorders: a pilot, open-label study. J Affect Disord 2017; 207: 114–120.

82.

Aggarwal

BB.

Signalling pathways of the TNF superfamily: a double-edged sword. Nat Rev Immunol 2003; 3: 745–756.

83.

Dantzer

Walker

AK.

Is there a role for glutamate-mediated excitotoxicity in inflammation-induced depression?

J Neural Transm 2014; 121: 925–932.

84.

Haroon

Woolwine

Chen

et al . IFN-alpha-induced cortical and subcortical glutamate changes assessed by magnetic resonance spectroscopy. Neuropsychopharmacology 2014; 39: 1777–1785.

85.

Berk

Kapczinski

Andreazza

et al . Pathways underlying neuroprogression in bipolar disorder: focus on inflammation, oxidative stress and neurotrophic factors. Neurosci Biobehav Rev 2011; 35: 804–817.

86.

Felger

Treadway

MT.

Inflammation effects on motivation and motor activity: role of dopamine. Neuropsychopharmacology 2017; 42: 216–241.

87.

Felger

Haroon

et al . Inflammation is associated with decreased functional connectivity within corticostriatal reward circuitry in depression. Mol Psychiatry 2016; 21: 1358–1365.

88.

Treadway

Zald

DH.

Reconsidering anhedonia in depression: lessons from translational neuroscience. Neurosci Biobehav Rev 2011; 35: 537–555.

89.

Haroon

Fleischer

Felger

et al . Conceptual convergence: increased inflammation is associated with increased basal ganglia glutamate in patients with major depression. Mol Psychiatry 2016; 21: 1351–1357.

90.

Eisenberger

Berkman

Inagaki

et al . Inflammation-induced anhedonia: endotoxin reduces ventral striatum responses to reward. Biol Psychiatry 2010; 68: 748–754.

91.

Lasselin

Treadway

Lacourt

et al . Lipopolysaccharide alters motivated behavior in a monetary reward task: a randomized trial. Neuropsychopharmacology 2017; 42: 801–810.

92.

Harrison

Brydon

Walker

et al . Inflammation causes mood changes through alterations in subgenual cingulate activity and mesolimbic connectivity. Biol Psychiatry 2009; 66: 407–414.

93.

Sharma

Wolf

Ciric

et al . Common dimensional reward deficits across mood and psychotic disorders: a connectome-wide association study. Am J Psychiatry 2017; 174: 657–666.

94.

Lee

Syeda

Maruschak

et al . A new perspective on the anti-suicide effects with ketamine treatment: a procognitive effect. J Clin Psychopharmacol 2016; 36: 50–56.

95.

Drysdale

Grosenick

Downar

et al . Resting-state connectivity biomarkers define neurophysiological subtypes of depression. Nat Med 2017; 23: 28–38.

96.

Raison

CL.

The promise and limitations of anti-inflammatory agents for the treatment of major depressive disorder. Curr Top Behav Neurosci 2017; 31: 287–302.

97.

Miller

Raison

CL.

Are anti-inflammatory therapies viable treatments for psychiatric disorders? Where the rubber meets the road. JAMA Psychiatry 2015; 72: 527–528.

98.

Rosenblat

Kakar

Berk

et al . Anti-inflammatory agents in the treatment of bipolar depression: a systematic review and meta-analysis. Bipolar Disord 2016; 18: 89–101.

99.

Köhler

Benros

Nordentoft

et al . Effect of anti-inflammatory treatment on depression, depressive symptoms, and adverse effects: a systematic review and meta-analysis of randomized clinical trials. JAMA Psychiatry 2014; 71: 1381–1391.

100.

Kappelmann

Lewis

Dantzer

et al . Antidepressant activity of anti-cytokine treatment: a systematic review and meta-analysis of clinical trials of chronic inflammatory conditions. Mol Psychiatry 2016; 23: 335–343.

101.

Strawbridge

Arnone

Danese

et al . Inflammation and clinical response to treatment in depression: a meta-analysis. Eur Neuropsychopharmacol 2015; 25: 1532–1543.

102.

Benedetti

Poletti

Hoogenboezem

et al . Higher baseline proinflammatory cytokines mark poor antidepressant response in bipolar disorder. J Clin Psychiatry 2017; 78: e986–e993.

103.

Lanquillon

Krieg

Bening-Abu-Shach

et al . Cytokine production and treatment response in major depressive disorder. Neuropsychopharmacology 2000; 22: 370–379.

104.

Machado-Vieira

Gold

Luckenbaugh

et al . The role of adipokines in the rapid antidepressant effects of ketamine. Mol Psychiatry 2017; 22: 127–133.

105.

Shelton

Pencina

Barrentine

et al . Association of obesity and inflammatory marker levels on treatment outcome: results from a double-blind, randomized study of adjunctive L-methylfolate calcium in patients with MDD who are inadequate responders to SSRIs. J Clin Psychiatry 2015; 76: 1635–1641.

106.

Rapaport

Nierenberg

Schettler

et al . Inflammation as a predictive biomarker for response to omega-3 fatty acids in major depressive disorder: a proof-of-concept study. Mol Psychiatry 2016; 21: 71–79.

107.

Raison

Rutherford

Woolwine

et al . A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: the role of baseline inflammatory biomarkers. JAMA Psychiatry 2013; 70: 31–41.

108.

Schmidt

Kirkby

Himmerich

The TNF-alpha inhibitor etanercept as monotherapy in treatment-resistant depression - report of two cases. Psychiatr Danub 2014; 26: 288–290.

109.

Tracey

Klareskog

Sasso

et al . Tumor necrosis factor antagonist mechanisms of action: a comprehensive review. Pharmacol Ther 2008; 117: 244–279.