Currently available antidepressants primarily target monoaminergic systems via effects on either monoamine reuptake inhibition, receptor modulation, or monoamine oxidase inhibition [
1]. Available evidence indicates that antidepressants are highly effective for a subset of individuals with major depressive disorder (MDD) and minimally effective for a larger proportion of affected individuals [
2‐
4]. The foregoing therapeutic deficiency in treatment outcomes, as well as the relatively high rates of discontinuation (i.e., 43–61%) due to treatment-emergent adverse events [
5], underscores the need for genuinely novel treatments that primarily engage non-monoaminergic molecular targets. In addition to suboptimal symptomatic/functional outcomes with existing antidepressants, there is no compelling evidence that existing therapies are capable of disease modification in MDD.
Several non-mutually exclusive effector systems are implicated in the pathoetiology of MDD including, but not limited to, dysregulation of the innate immune inflammatory system [
6‐
10]. The innate immune inflammatory system provides immediate defense against pathogens introduced to the body (e.g., resulting from injury or infection) and as a repair system for damaged tissue. Notwithstanding the evolutionary benefits of the inflammatory response in the presence of physical threat, its overactivity in response to everyday social stressors is thought to result in depressive symptomology [
11]. A detailed review of the role of inflammation in depression, including the neurochemical mechanisms by which the immune system affects mood and behavior, is outlined from an evolutionary perspective elsewhere [
12]. Components of the innate immune response include the action of several cytokines, chemokines, cellular adhesion molecules, and acute phase reactants. Of the foregoing categories of inflammatory protein systems, alteration in interleukin-6 (IL-6) levels has been identified as one of the most reproducible abnormalities in MDD [
13].
In addition to being an intrinsic abnormality in adults with MDD, for many individuals with MDD, alterations in the immune inflammatory system are a secondary phenomenon to either the behavioral disturbances observed in depression (e.g., sleep disturbance), comorbidity (e.g., obesity), and/or iatrogenic effects (e.g., weight-gain-promoting psychotropic agents) [
11]. Notwithstanding the potential confounding effects of other contributing factors, alterations in immune inflammatory systems in adults with MDD are also reported in individuals without comorbidities and who are medication-naïve [
14]. Moreover, the observation of alterations in messenger RNA transcripts in unaffected relatives of probands with mood disorders provides further evidence that disturbances in inflammatory system are a trait abnormality in adults with MDD [
15].
Interleukin-6
Interleukin-6 is a pleiotropic cytokine synthesized and released in response to inflammatory signaling, with both pro- and anti-inflammatory properties. As a pro-inflammatory cytokine, IL-6 is a potent transcriptional stimulus for the production of acute-phase proteins [e.g., C-reactive protein (CRP)] [
16,
17], recruitment of leukocytes, and augmentation of the production of other pro-inflammatory chemokines [
18]. IL-6 is also reported to play a role in anti-inflammatory processes, including the activation and enhanced production of anti-inflammatory molecules (e.g., macrophage type 2, IL-1 receptor antagonist) [
19,
20].
The production and method of signaling of IL-6 has been reviewed in detail elsewhere [
21]. The rationale for targeting IL-6 is further augmented by the established interconnectedness of IL-6, as well as other cytokine systems, in effector systems relevant to the pathoetiology and phenomenology of MDD. For example, it is well established that inflammatory cytokines modulate amino acid synthesis, release, and availability (e.g., glutamate), as well as playing a critical role in cellular respiration in oxidative processes. Moreover, cytokine systems implicated as abnormal in MDD are in interplay with the hypothalamic–pituitary–adrenal (HPA) axis and are significantly modulated by circadian rhythms, as well as gut enterotype. Taken together, the foregoing set of effector systems (e.g., glutamate dysregulation, oxidative stress, glucocorticoid signaling alterations, circadian dysrhythmicity, and gut dysbiosis) are all implicated as pathoetiologically relevant in MDD [
22,
23].
Preclinical and clinical evidence also indicates that IL-6 is associated with deficits in cognitive function [
23]. Moreover, it has been well established that amongst mixed populations with MDD, cognitive deficits are prevalent, persistent, and are a principal determinant of psychosocial outcome as well as workplace disability [
24,
25]. The putative role of IL-6 in mediating cognitive function in adults with mood disorders provides a further rationale for conceptualizing IL-6 as a possible convergent substrate subserving multiple domains of psychopathology in mood disorders.
Furthermore, several lines of evidence highlight the robust correlation between elevated peripheral IL-6 concentrations and symptom severity of MDD [
6,
8]. It is additionally reported that pretreatment peripheral IL-6 levels are predictive of suboptimal treatment response to conventional antidepressant therapy [
7,
26]. Central [i.e., cerebrospinal fluid (CSF)] IL-6 concentration is also reported to be elevated in clinical populations with MDD, further suggesting that IL-6 may be a relevant proximate mediator of disease processes in MDD [
27].
Convergent lines of evidence indicate that both peripheral and central IL-6 levels are also significantly elevated in adults exhibiting self-harm (i.e., suicide attempt) [
8,
28]. For example, Lindqvist et al. [
8] reported that CSF IL-6 levels were significantly higher in individuals with MDD (mean = 3.76 pg/mL) and in individuals who attempted violent suicide (mean = 5.25 pg/mL) when compared to healthy controls (mean = 0.64 pg/mL). In a separate study, Janelidze et al. [
28] reported significantly higher levels of peripheral IL-6 in individuals with MDD with history of suicide attempt when compared to individuals with MDD without history of suicide attempt (
p = 0.048) and healthy controls (
p = 0.009). The foregoing observations implicate a putatively mediational role of elevated central and peripheral IL-6 concentrations in both affective valence and possibly cognitive function (e.g., impulsivity).
The potent transcriptional effect of IL-6 on CRP, a nonspecific marker of inflammatory activation, has implications for biosignature characterization of MDD insofar as alterations in CRP are a highly replicated abnormality in clinical populations [
29]. Moreover, alterations in peripheral CRP levels are associated with treatment response outcomes with some antidepressants [
30].
Interventional research indicates that interferon-α (IFN-α) therapy is highly associated with the emergence and/or amplification of depressive symptoms. Risk for treatment-emergent depressive symptoms with cytokine-based therapies has been highly associated with a single nucleotide polymorphism (SNP) at the IL-6 gene [
31]. For example, subjects with the GG/GC genotype were reported to have developed greater depressive symptoms compared to those with the CC genotype at the IL-6 gene promotor region, where the G allele is associated with higher transcriptional activity resulting in higher plasma IL-6 compared to the C allele.
In a separate study, peripherally administered IFN-α was reported to activate central nervous system (CNS) inflammatory responses, as indicated by increased CSF IL-6 and IFN-α levels. Results of the foregoing study indicated that the increase in CSF IL-6 levels significantly correlated with a decrease in the concentration of serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) [
32]. The foregoing collection of convergent findings implicates dysregulation of IL-6 as a critical pathogenetic molecular substrate and possible target in adults with MDD.
Sirukumab is a human monoclonal antibody that targets soluble IL-6 with high affinity and specificity [
33]. Sirukumab targets the IL-6 signaling pathway, inhibiting both the pro- and anti-inflammatory effects of the pleiotropic cytokine IL-6. Interventional studies with sirukumab have been conducted across a variety of inflammatory disorders, including cutaneous or systemic lupus erythematosus (CLE/SLE) and rheumatoid arthritis (RA) [
33‐
38]. Results from studies with sirukumab in clinical populations with inflammatory disorders provide evidence of beneficial effects on patient-reported outcomes (PROs), including measures of global functioning and quality of life. Herein, we review studies from both preclinical and clinical research that provide an empirical basis for hypothesizing that sirukumab is a possible symptom-mitigating and disease-modifying treatment. The application of sirukumab to MDD is chosen as an exemplar of its brain-based potential application, with recognition that there could be applications transdiagnostically in psychiatry.