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Abstract

Bipolar disorder (BD) is a severe mental disorder with various hypotheses regarding its pathogenesis. This article provides a summary of numerous studies on the variations in inflammatory cytokine levels in patients with BD and the effects of treatment with antipsychotics, mood stabilizers, and antidepressants on these levels. In addition, patients with autoimmune diseases who use anti-inflammatory monoclonal antibodies experience symptoms, such as depression, anxiety, and insomnia. These pieces of evidence suggest a potential association between immune inflammation and BD and offer new possibilities for therapy. Building upon this relationship, the authors propose an innovative approach for treating BD through individualized and precise therapy using anti-inflammatory monoclonal antibody drugs. To support this proposal, the authors compile information on pharmacological effects and relevant studies, including trials of various anti-inflammatory therapeutic monoclonal antibody drugs (e.g. infliximab, tocilizumab, and canakinumab) for the potential treatment of BD and its associated side effects in psychiatry. The authors categorize these anti-inflammatory monoclonal antibody drugs into levels I–IV through a comprehensive analysis of their advantages and disadvantages. Their potential is examined, and the need for further exploration of their pharmaceutical effects is established.

Keywords

bipolar disorder immune system inflammatory cytokines monoclonal antibody precision therapy

Introduction

Bipolar disorder (BD) is a chronic, episodic disorder characterized by recurrent alternating episodes of mania and depression. It can lead to psychotic symptoms, such as hallucinations and delusions. The onset of the disorder typically occurs at an early age. Research has shown that the suicide rate among patients with BD is more than 20 times higher than that among the general population.¹ The exact cause of BD is still unknown but various studies have linked it to genetic, biorhythmic, biochemical, and environmental factors. Multiple hypotheses exist regarding the development of BD, which involves various pathological mechanisms, including neuronal–glial plasticity, monoamine signaling, inflammatory homeostasis, cellular metabolic pathways, and mitochondrial dysfunction.²

Recent studies have suggested that BD is associated with immune dysfunction. Changes in immune markers, particularly an increase in proinflammatory cytokines, have been observed in the nervous system of individuals with BD.³ In 1981, Horrobin and Lieb⁴ hypothesized that immune dysfunction may be a critical factor in the disease progression of BD and that relapse or remission of BD is driven by the immune system. Since then, many researchers have begun to investigate the relationship between BD and immune dysfunction and focused on inflammatory cytokines. Current studies indicate that inflammatory cytokines in the immune system, such as interleukin (IL), tumor necrosis factor-a (TNF-a), and interferon-γ (IFN-γ), play a crucial role in the pathogenesis of BD.^5,6 Patients with BD have a high prevalence of multisystem inflammatory diseases, which led Leboyer et al.⁷ to conclude that BD is a multisystem inflammatory disease that affects many systems, including mood, cognition, cardiovascular health, metabolism, and sleep. The immune inflammatory hypothesis opens up new possibilities for treating BD, including the discovery of potential drugs and the design of targeted and effective therapeutic regimens.⁸ This review provides an overview of the association between BD and inflammatory cytokines and the latest advancements in monoclonal antibody therapies that target BD-related inflammatory cytokines. Accordingly, we propose precision therapies for BD with monoclonal antibody drugs based on the immune inflammation hypothesis. Studies were included based on the population, intervention, comparison, outcomes, and study design criteria, as shown in the Supplemental Table.

Methods

We performed a forward literature search in ScienceDirect, Springer, PubMed, and China National Knowledge Infrastructure and a backward literature search in the reference lists of retrieved articles published until 31 August 2023. The search strategy included the following intentionally broad terms: (inflammatory factors OR cytokines OR pro-inflammatory molecules OR inflammatory mediators) OR (monoclonal antibodies OR monoclonal antibody therapy OR monoclonal antibody drugs OR monoclonal antibody treatment) AND (bipolar disorder OR manic depression OR manic-depressive illness OR bipolar affective disorder). Duplicate references were excluded. The remaining articles were screened by their titles and abstracts, and the full texts were further inspected to determine if they matched the topic of this narrative review. Papers had to include psychiatry and inflammatory trait research or should have established a link or correlation between psychiatry and inflammatory or immune-related biomarkers. We included all study designs apart from social news reports and conference abstracts. Given the multifaceted nature of the research question, the inclusion criteria were nonsystematic, and papers were included based on the query results or the references cited in the selected articles.⁹

Relationship between BD and different inflammatory cytokines

Cytokines, which are proteins or glycoproteins secreted by immune cells in response to noxious stimuli, play a crucial role in mediating the interaction between immune and neuroendocrine systems.¹⁰ Inflammatory mediator theory, which was proposed in 1988, links cytokines to the inflammatory reaction. This theory suggests that a large number of cytokines released by immune cells form a complex inflammatory cascade that ultimately leads to an inflammatory reaction. Although many cytokines are involved in the inflammatory process, they have different roles. Based on the roles of cytokines in the inflammatory process, they can be categorized as proinflammatory and anti-inflammatory. Proinflammatory cytokines include IL-1β, TNF-α, IL-6, IL-8, IFN-γ, IL-17, IL-18, and IL-33, and anti-inflammatory cytokines include IL-4, IL-10, and IL-1 receptor antagonist (IL-1RA). When the levels of these cytokines are normal, they help restore damage and resist pathogens, but when their levels are abnormal, they may contribute to the development of diseases and the onset of pathological changes. For example, oversecretion of proinflammatory cytokines promotes tryptophan depletion and serotonin catabolism, activates aberrant neuroimmune mechanisms involved in specific neural circuits related to mood regulation, and leads to the dysfunction of noradrenergic and 5-hydroxytryptophanergic neurotransmission in the brain, which is mostly reflected in patients with depressive symptoms.¹¹ Moreover, in the presence of high inflammation, microglia are abnormally activated, and abnormal pathologic neural protrusion pruning and impaired neuroplasticity may occur and eventually induce the onset of BD.^12,13

Systematic studies have been conducted on the applications of Mendelian randomization and have suggested a causal relationship among a proinflammatory state, elevated C-reactive protein (CRP), and the risk of developing BD.^14,15 The hypothalamic–pituitary–adrenal (HPA) axis, for example, plays an important role in the connection between inflammation and BD.^16,17 Proinflammatory cytokines (TNF-α, IL-6, etc.) considerably upregulate HPA activity, thereby increasing systemic cortisol levels.¹⁸ In inflammation, chronic hypercortisolemia downregulates glucocorticoid receptor synthesis, translocation, and sensitivity in the pituitary and hypothalamus, effectively inhibiting the negative feedback loop of the HPA axis.¹⁹ The loss of the negative feedback loop ultimately contributes to BD symptoms, such as mood disorders and cognitive impairment.¹⁷ Furthermore, inflammation may affect brain structures and lead to a dysregulated stress response, potentially causing emotion dysregulation disorders.⁹ For instance, a systematic review has shown that immune markers are linked to functional and structural magnetic resonance imaging alterations in BD, particularly in brain areas involved in affective and somatomotor processing.²⁰ A study that reviewed diffusion tensor imaging found immune system activation, especially within peripheral proinflammatory cytokines (IL-1β, TNF-α, IL-8, and IFN-γ) and CRP, which correlate with white matter microstructural impairments during depressive episodes of BD.²¹ Thus, proinflammatory cytokines are relevant to BD because they may affect brain networks and reveal the pathophysiological mechanisms of BD.

This review aims to explore the relationship between cytokines and BD, to provide a theoretical foundation for the potential use of monoclonal antibodies in the treatment of BD. Table 1 summarizes the results of recent studies on inflammatory cytokine levels in patients with BD to help evaluate the correlation between inflammatory reaction and BD. Overall, most studies showed that the expression levels of proinflammatory cytokines, such as IL-1β, IL-6, TNF-α, IL-8, IL-17, IL-18, and IFN-γ, and anti-inflammatory cytokines IL-10 and IL-1RA are elevated in patients with BD.^5,22–44 Inconsistent results on IL-4 level have been obtained for patients with BD, whereas consistent results have been derived from studies on IL-1β, IL-6, and TNF-α.^{5,6,24,25,27,32–41,45} After BD medication, the expression of proinflammatory cytokines IL-1β, IL-6, and TNF-α decreases, whereas the expression of anti-inflammatory cytokines IL-4 and IL-10 increases.^46–56 The relationship between BD symptomatic improvement after drug treatment and the variation trends of pro/anti-inflammatory cytokine levels suggests a connection between immune inflammation and BD. Although abnormal changes in the levels of inflammatory cytokines are closely related to BD, considerable individual differences still exist. For instance, some studies have reported that there are no significant abnormal changes in inflammatory cytokines among some patients with BD, and studies have suggested that inflammatory cytokines in BD patients may be related to obesity rather than their symptoms.^{34,39,41,44,57} In other words, BD is not inevitability associated with individuals and their inflammatory cytokines. Bishop et al. showed that inflammatory and immune processes are dysregulated in schizophrenia and related psychoses. However, current research is going beyond the univariate analysis of a single inflammatory marker and attempting to identify the relationship between immune inflammation and mental disorders by considering discrete differences in multiple inflammatory markers.⁵⁸ In this case, patients need to be subdivided into subgroups in accordance with the changes in each inflammatory cytokine, and precise individualized treatment must be applied based on the patients’ specific inflammatory cytokines.

Table 1.

Summary of findings related to inflammatory cytokines in patients with BD.

Inflammatory cytokines	Manic episode	Depressive episode	Mixed seizure	Remission period	Unclassified
IL-1β	Elevated^6,32	Elevated^6,32	Elevated³²	–	Elevated^15,32,33 No change³⁴
IL-1RA	Elevated³³	Elevated³³	–	–	Elevated^5,31 No change²⁷
IL-4	Elevated³² No change⁴¹	Elevated³²	Elevated³²	No change⁴¹	Decreased⁴⁵ Elevated²⁷
IL-6	Elevated^35,59	Elevated^37–37	Elevated^35,38	Elevated³⁸	Elevated^5,24,25,34
sIL-6R	–	–	–	No change³⁹	Elevated^5,24,25
IL-8	Elevated⁴⁰	Elevated^37,40	–	–	Elevated⁴⁰ No change^5,27
IL-10	Elevated²⁹	–	–	Elevated³⁰	No change²⁷
IL-17	Elevated⁶⁰	–	–	Decreased⁶¹	Elevated⁶²
IL-18	Elevated⁵⁹	Elevated³⁵	–	–	–
IL-33	Elevated⁶³	–	–	–	–
TNF-α	Elevated^34,35,40	Elevated^34–36,40	Elevated³⁵	Elevated³⁰ No change³⁴	Elevated^5,24,25,27
sTNFR1	Elevated^28,42 No change⁴⁴	Elevated^42,43 No change⁴⁴	–	Elevated^28,39	Elevated^25,27
sTNFR2	Elevated²⁸	Elevated⁴³	–	Elevated²⁸	Elevated²⁴ No change^27,64
IFN-γ	–	–	–	–	Elevated²⁴ No change²⁷

‘–’ indicates that no relevant study was found. This table summarizes the changes in various inflammatory cytokines based on a large number of papers and other academic materials. The changes in these cytokines are divided into different episode periods to guide precise treatment.

IFN-γ, interferon-γ; IL-1β, interleukin-1β; IL-1RA, interleukin-1 receptor antagonist; sIL-6R, soluble IL-6 receptor; sTNFR1, soluble necrosis factor receptor 1; sTNFR2, soluble necrosis factor receptor 2; TNF-α, tumor necrosis factor-α.

BD and proinflammatory cytokines

IL-6

The soluble IL-6 receptor (sIL-6R), a soluble receptor for IL-6, enhances the information transduction of IL-6 by binding IL-6. Therefore, sIL-6R levels can reflect IL-6 levels to some extent.²⁶ Several studies have shown that sIL-6R levels are elevated in patients with BD; they indirectly reveal increased IL-6 levels.^24,27 IL-6 exerts a neuroprotective effect at low concentrations and promotes neurodegenerative processes at high concentrations.⁶⁵ IL-6 is implicated in neurogenesis and synaptic plasticity regulation and mediates hippocampal-dependent learning and memory formation, so it plays specific functions in cognitive processes.⁶⁶ The inflammatory microenvironment in the brain induced by IL-6 may progressively damage the hippocampus and other neural circuits involved in cognitive function.⁶⁷ High levels of IL-6 are associated with cognitive impairment due to neurological damage and further alter the patient’s cognitive patterns, possibly contributing to mood disorders, such as BD.

IL-1β

The proinflammatory cytokine IL-1β is primarily secreted by monocytes and macrophages during the formation of antigen–antibody complexes. As a crucial member of the IL-1 family, IL-1β can impair spatial learning and contextual memory in the hippocampus by inhibiting its long-term potentiation effects.⁶⁴ IL-1β can contribute to the decline in cognitive function caused by inflammatory reactions by affecting neurogenesis in the hippocampus.⁶⁸ Viviani et al. demonstrated that IL-1β increases N-methyl-d-aspartate receptors (NMDAR), leading to an uncontrolled rise in calcium inward flow through NMDAR channels. This condition ultimately results in excitotoxicity and impaired neuroplasticity.⁶⁹

TNF-α

The proinflammatory cytokine TNF-α can also inhibit the long-term enhancement of the hippocampus and impair its spatial learning and contextual memory.⁷⁰ In addition to its involvement in the body’s inflammatory reaction and immune response, TNF-α promotes the production of other proinflammatory cytokines that can lead to tissue damage. TNF-α is toxic to neuronal cells because it initiates apoptotic mechanisms through the activation of apoptotic proteases, which result in demyelinating changes in neuronal cells, by participating in neuronal apoptosis, which reduces frontal lobe volume and activity.^71–73 Soluble necrosis factor receptor 1 (sTNFR1) and soluble necrosis factor receptor 2 (sTNFR2), as soluble receptors for TNF-α, can transduce their signals into intracellular signals and may reflect the activity of TNF-α to some extent.²⁸ The levels of sTNFR1 and sTNFR2 are considerably elevated in patients with BD and correlated with the duration of BD, further suggesting that inflammatory mechanisms may be involved in the pathophysiology of BD.^5,24,28

BD and anti-inflammatory cytokines

IL-4

The anti-inflammatory cytokine IL-4, produced by a subpopulation of Th2 cells and mast cells among others, has multiple effects. However, its biological mechanisms of action are complex and modulate various pathophysiologic processes. A study revealed that IL-4 levels in patients with BD are negatively correlated with the Hamilton Depression Scale and the Bipolar Rating Scale.⁴⁵ In addition, the IL-4 levels of patients with BD are lower than those of normal individuals, implying that IL-4 plays a regulatory role in maintaining cellular and humoral immune homeostasis in patients.⁴⁵ Another study reported elevated levels of IL-4 in patients with BD; these elevated levels are believed to increase the activation of the downstream inflammatory signaling pathway nuclear factor-κB (NF-κB) and enhance the monocyte infiltration of neurons.³²

IL-10

IL-10 is a cytokine with anti-inflammatory properties. It is derived from multiple cells and has multiple functions. It can suppress nonspecific and specific immunity by inhibiting the function of immune cells, thereby exerting anti-inflammatory properties.⁷⁴ Several studies showed that patients with type I BD have considerably elevated levels of serum IL-10, which suggests that the body may produce IL-10 as a compensatory mechanism to combat inflammation.^29,30

Interleukin-1 receptor antagonist

The IL-1RA, an antagonist of the IL-1 receptor, is typically found in peripheral blood in a soluble form. Its role is to counteract the proinflammatory effects of IL-1 by binding to the IL-1 receptor, exerting anti-inflammatory effects. Consequently, it is also recognized as an anti-inflammatory cytokine. A meta-analysis demonstrated that patients with BD have high levels of IL-1RA.⁵ Another study conducted on elderly patients with euthymic BD revealed elevated serum IL-1RA levels and posited that IL-1RA is associated with cognitive function deterioration.³¹

Changes in inflammatory cytokine levels after BD treatment

In existing BD treatments, the use of antipsychotics, mood stabilizers, and antidepressants is effective in ameliorating depressive and manic symptoms and attenuating inflammatory reactions in patients with BD. Among the common combinations of antipsychotics and mood stabilizers, the combination of ziprasidone and valproate has been shown to decrease the levels of IL-1β and TNF-α while increasing the levels of IL-4.^46,47 The combination of quetiapine and valproate increases the levels of IL-4 and IL-10 while decreasing the levels of TNF-α and IL-1β.^48,49 Another combination, quetiapine and lithium carbonate, decreases TNF-α, IL-1β, and IL-6 while increasing IL-4 and IL-10.^50–52 The combination of lithium carbonate and valproate decreases IL-6 and TNF-α levels while increasing IL-10.^53,54 In addition, the combination of aripiprazole and olanzapine can effectively decrease IL-1β and TNF-α levels in patients with BD with manic episodes.⁵⁵ The combination of citalopram and sodium valproate alleviates clinical symptoms in patients with depressive episodes of recurrent BD, which is potentially associated with decreased levels of IL-1β and IL-6.⁵⁶ Different therapeutic agents for BD improve patients’ depressive and manic symptoms through various pharmacologic effects. Moreover, existing literature suggests that all these agents affect the levels of inflammatory cytokines. This strong evidence implies an intrinsic link between BD and immune inflammation.

Inflammatory cytokine-based anti-inflammatory drug therapy for BD

Nonsteroidal anti-inflammatory drugs (NSAIDs), N-acetylcysteine, infliximab, pioglitazone, and minocycline have been extensively studied in clinical trials to validate their effectiveness in treating BD.⁷⁵ These trials have demonstrated the efficacy of anti-inflammatory treatments for BD to a certain extent but have highlighted certain issues with existing drugs. For instance, NSAIDs and N-acetylcysteine exert adverse gastrointestinal effects or give rise to cardiovascular disease risks according to clinical trials.^76,77 Clinical trials on pioglitazone and minocycline were limited to certain high-baseline subgroups, short durations, small sample sizes, or case studies that confirmed some degree of effectiveness of anti-inflammatory drugs in depressive or manic symptoms but large sample sizes and long-term studies have failed to find notable differences in the treatment of depressive and manic symptoms.^78–81

In summary, current anti-inflammatory drugs clinically used for the treatment of BD have the following problems: broad drug targets, insufficient drug targeting, and lack of precision medication. These problems lead to limited therapeutic efficacy and increased adverse effects. Considering the relationship between inflammatory cytokines and BD, some scholars hypothesized that tocilizumab, a monoclonal antibody IL-6 antagonist, can be a potential treatment option for BD.^75,82 Therefore, we propose to target BD-related inflammatory cytokines and advance the research on monoclonal antibody anti-inflammatory drug therapy for BD based on these cytokines.

Monoclonal antibodies are antibodies that are cloned from a single B cell. They exhibit high homogeneity and can target a specific antigenic epitope with high specificity. Furthermore, they have a clear mechanism of action and few toxic side effects. Currently, monoclonal antibodies are widely used in targeted therapy for autoimmune diseases, tumors, and other diseases.⁸³ In this review of inflammatory cytokines as therapeutic targets, we introduce monoclonal antibodies against the cytokines associated with BD and investigate their potential efficacy, side effects, and risk of adverse reactions in the treatment of BD. The relevant findings are summarized in Table 2.

Table 2.

Potential monoclonal antibody drugs for BD anti-inflammatory therapy.

Monoclonal antibody drugs	Pharmacological effect	Advantages	Disadvantages	Test recommendation level^a
Infliximab^84–89	Binds sTNF-α and membrane-type TNF-α (mTNF-α) and inhibits their binding to TNF receptors, thereby blocking the inflammatory signaling induced by TNF-α.	Clinical application is long enough, and it improves depressive symptoms mainly in patients with BD with elevated TNF-α.	Frequent depression and insomnia are common adverse reactions.	I
Tocilizumab^82,90–93	Blocks the interaction of IL-6 with the IL-6 receptor (sIL-6R) to inhibit the inflammatory reaction.	It has a medium–long clinical application time. It improves the depression and anxiety symptoms of patients with rheumatoid arthritis, the manic symptoms and cognitive impairment of relapsing polychondritis patients, and the overall cognitive function of patients with schizophrenia. No psychiatric symptoms have been observed.	No studies have applied it to patients with BD.	I
Adalimumab^94,95	Specifically binds to sTNF-α and blocks its interaction with the TNF receptor, thereby effectively blocking the inflammatory effects of TNF-α.	Clinical application is long enough, and it improves depressive symptoms in patients with major depression.	No studies have applied it to patients with BD, and frequent mood changes, anxiety, and insomnia are common.	II
Canakinumab^96,97	Specifically binds to IL-1β and blocks its binding to the IL-1 receptor to neutralize its activity.	Amelioration of positive symptoms in schizophrenic patients with elevated IL-1β and no adverse psychiatric symptoms have been observed.	Clinical use is short.	II
Siltuximab^98,99	Binds to human IL-6 with high affinity and specificity, thereby neutralizing it.	Improvement of depression in patients with multicenter Castleman’s disease and lack of adverse psychiatric effects.	Clinical application is relatively short, and no studies have applied it to psychiatric patients.	III
Sarilumab^100–102	Binds to IL-6Rα with high affinity and inhibits IL-6/IL-6Rα complex formation.	Improvement of depressive symptoms in patients with rheumatoid arthritis.	Its clinical application time is relatively short, it has not been applied to psychiatric patients, and frequent insomnia and hypothyroidism are common.	III
Certolizumab pegol^90,103,104	Binds sTNF-α and mTNF-α and blocks TNF-α-mediated inflammatory signaling pathways.	May improve depressive symptoms in patients with psoriasis, and the frequency of anxiety and mood disorders is occasional.	Relatively short time in clinical use and no studies have been conducted on psychiatric patients.	III
Golimumab^90,105	Inhibits inflammation by targeting and neutralizing TNF-α.	Advanced preparation technology.	Its clinical application time is short, it has not been applied to psychiatric patients, and frequent depression and insomnia are common.	IV
Satralizumab^106,107	Binds to IL-6Rs specifically.	Potential to treat depressive symptoms.	Its clinical application is short, no study has applied it to psychiatric patients, and frequent depression is common.	IV

This table compares the advantages and disadvantages of various anti-inflammatory monoclonal antibodies. After comparing and weighing the advantages and disadvantages, we set test recommendation levels based on trial priority. We recommend high trial priority for drugs with obvious advantages and few disadvantages.

Recommendations to prioritize drug trials for BD treatment are given levels. I recommends very high priority, II recommends priority, III recommends low priority, and IV does not recommend priority at all.

BD, bipolar disorder; IFN-γ, interferon-γ; IL-1β, interleukin-1β; IL-1RA, IL-1 receptor antagonist; mTNF-α, membrane tumor necrosis factor-α; sIL-6R, soluble IL-6 receptor; sTNF-α, soluble TNF-α.

Monoclonal antibodies against TNF-α

Anti-TNF-α drugs, such as monoclonal antibodies, exert anti-inflammatory effects through multiple pathways. These pathways include neutralization of soluble and membrane-bound TNF-α, inhibition of T-cell activation and pro-inflammatory cytokine release, induction of antibody- or complement-dependent cytotoxicity, apoptosis of T cells and macrophages, enhancement of the intestinal barrier function, and induction of regulatory T-cell differentiation.¹⁰⁸ Four anti-TNF-α monoclonal antibodies have been approved by the Food and Drug Administration (FDA). They are infliximab, adalimumab, certolizumab pegol, and golimumab; they are commonly used to treat diseases, including rheumatoid arthritis, Crohn’s disease, and psoriasis.⁹⁰

Infliximab

Infliximab, the first anti-TNF-α monoclonal antibody to receive marketing approval, is a human–mouse chimeric antibody consisting of a human Immunoglobulin G1 (IgG1) crystallizable Fragment (Fc) region and a mouse variable Fragment (Fv) region. The antibody, with a murine variable region and a human constant region, binds soluble TNF-α (sTNF-α) and membrane TNF-α (mTNF-α), thereby blocking their binding to TNFR and inhibiting inflammatory signaling triggered by TNF-α.^84,85 Recent anti-inflammatory studies have shown that infliximab is effective in patients with BD.⁸⁶

In 2013, Raison et al.⁸⁷ conducted a double-blind, randomized clinical trial (RCT) that demonstrated infliximab’s potential to improve depressive symptoms in certain patients with BD with high-baseline inflammatory biomarkers. Another double-blind, controlled RCT also revealed that infliximab has high antidepressant efficacy in patients with BD with elevated plasma expression of inflammatory markers, such as TNF-α.⁸⁸ The two studies suggest that infliximab can be effective for patients with BD with elevated levels of TNF-α and indicate that classification using inflammatory biomarkers may help in implementing precise individualized adjunctive therapy for BD patients with varying levels of inflammation.

In 2019, McIntyre et al.⁸⁹ conducted the first study that evaluated the inflammatory evidence on the use of infliximab for adult patients with BD. However, the subjects included in this study needed to meet only one of the various inflammatory characteristics and were not further categorized into subgroups based on the specific inflammatory characteristics. This lack of precise subgrouping may partly explain why the study failed to confirm that adjunctive use of infliximab considerably improves depressive symptoms in patients with BD. However, a post hoc analysis of the study showed that infliximab exhibits high, long-lasting antidepressant efficacy in patients with a history of childhood abuse, particularly physical abuse. This finding further suggests that by precisely subgrouping patients with BD, clinical researchers may be able to identify individuals who can benefit from infliximab.

Overall, infliximab is likely to be an adjuvant drug for individualized precision therapy for the treatment of BD but its efficacy has not been clarified because of the lack of precise RCTs with large sample sizes.

Adalimumab

Adalimumab is the world’s first fully human anti-TNF-α monoclonal antibody to be approved for marketing, and its properties include good efficacy and low immunogenicity. Adalimumab’s mechanism of action is similar to that of infliximab, which specifically binds to sTNF-α and blocks its interaction with TNFR, thus effectively blocking the inflammatory effects of TNF-α.⁹⁴ Recently, Abbasian et al.⁹⁵ conducted a 6-week double-blind RCT, in which 36 patients with major depression were equally assigned to either the adalimumab or placebo group. The results indicated that adjunctive therapy with adalimumab considerably improves patients’ depressive symptoms. However, no clinical studies have examined the direct use of adalimumab for patients with BD.

Certolizumab pegol

Certolizumab pegol is a humanized Fab-engineered antibody fragment with two molecules of polyethylene glycol attached to extend its plasma half-life. It binds to sTNF-α and mTNF-α, effectively blocking the TNF-α-mediated inflammatory signaling pathway.⁹⁰ A recent study found that the use of certolizumab pegol improves depressive symptoms in patients with psoriasis.¹⁰³ A meta-analysis demonstrated high comorbidity between psoriasis and BD.¹⁰⁴ Given that psoriasis and BD roughly share immune inflammatory mechanisms, perhaps these results could indicate the potential efficacy of certolizumab pegol in the treatment of BD. However, clinical studies on the application of certolizumab pegol to patients with BD are still lacking. Furthermore, because of the high comorbidity probability of psoriasis and BD, certolizumab pegol may offer a new approach to cure psoriasis and BD simultaneously.

Golimumab

Golimumab is a fully human anti-TNF-α monoclonal antibody produced by transducing mice with the human IgG motif. The technology used to prepare it is more advanced than the technology for preparing other monoclonal antibodies.⁹⁰ Golimumab inhibits inflammation primarily by targeting and neutralizing TNF-α. Although little clinical experience in golimumab is available, substantial evidence supports its effectiveness and tolerability in patients with rheumatoid arthritis.¹⁰⁵ However, no studies have demonstrated that golimumab can treat symptoms of depression or mania associated with BD.

Monoclonal antibodies against IL-6

Currently, two types of monoclonal antibodies are centered around IL-6 anti-inflammatory therapies: one targets IL-6, and the other targets IL-6R. These monoclonal antibodies can inhibit the inflammation-mediated effects of IL-6 by specifically binding to and blocking its action. To date, four monoclonal antibodies against IL-6 have been approved and are available on the market: tocilizumab, siltuximab, satralizumab, and sarilumab.

Tocilizumab

Tocilizumab, a humanized anti-IL-6R monoclonal antibody, can inhibit the inflammatory reaction by blocking the interaction between IL-6 and the IL-6 receptor (sIL-6R). It is mainly used in the treatment of rheumatoid arthritis and cytokine release syndrome.⁹⁰ Clinical trials conducted by Tiosano et al.⁹¹ revealed that tocilizumab improves depression and anxiety symptoms in patients with rheumatoid arthritis. Liu et al.⁹² found that tocilizumab usage improves manic symptoms and cognitive deficits in patients with relapsing polychondritis. In addition, based on clinical trial results showing that tocilizumab can improve the overall cognitive function of patients with schizophrenia, Miller et al.⁹³ posited that tocilizumab can be advanced as a personalized therapeutic agent for schizophrenia after conducting large-sample-size longitudinal studies on individuals with baseline inflammation. Considering the upregulation of IL-6 expression levels in patients with BD, some scholars suggested that tocilizumab may be a potential therapeutic option for BD.⁸² Meanwhile, IL-6 is associated with rheumatoid arthritis, relapsing polychondritis, schizophrenia, and BD. Previous clinical trials and case reports have indicated that tocilizumab can effectively alleviate symptoms, such as depression, mania, anxiety, and cognitive impairment. Consequently, tocilizumab holds promise as a personalized medication with the potential to be developed for the treatment of cognitive function impairment, mania, and mood symptoms in patients with BD.

Siltuximab

Siltuximab is an anti-IL-6 human–mouse chimeric monoclonal antibody that can bind to IL-6 with high affinity and specificity. By neutralizing IL-6, it reduces the level of unbound IL-6 and prevents it from binding to the receptor, thereby blocking its downstream signaling pathway. It is usually used to treat HIV and HHV-8-negative multicenter Castleman’s disease.⁹⁸ Double-blind RCT results indicate that siltuximab is considerably superior to placebos in improving depressed mood, fatigue, and anhedonia in patients with multicenter Castleman’s disease.⁹⁹ However, no clinical trials have been conducted to evaluate the efficacy of siltuximab in the treatment of patients with BD.

Satralizumab

Satralizumab, a novel recombinant humanized IgG2 monoclonal antibody, is primarily used to treat optic chiropractic inflammation; it inhibits the onset of the neuroinflammatory reaction by specifically binding to IL-6R.¹⁰⁶ Some scholars reported that IL-6R is a promising target for the treatment of depressive symptoms and concluded that satralizumab may have great potential for treating depression.¹⁰⁷ However, further studies are needed to validate this claim.

Sarilumab

Sarilumab is the first fully human monoclonal IgG antibody that directly targets the alpha subunit of the IL-6 receptor complex (IL-6Rα). It binds to IL-6Rα with high affinity, inhibits the formation of the IL-6/IL-6Rα complex, and interrupts the cytokine-mediated inflammatory signaling cascade for the treatment of rheumatoid arthritis.¹⁰⁹ A clinical trial demonstrated a reduction in the incidence of depressive symptoms and an improvement in fatigue symptoms among patients using sarilumab.^100,101 Moreover, an RCT revealed that sarilumab leads to greater improvements in health-related quality of life scores compared with adalimumab in patients with rheumatoid arthritis with high baseline IL-6 levels.¹⁰² However, studies on the effectiveness of sarilumab in treating BD are lacking.

Monoclonal antibodies against IL-1β

IL-1β plays an essential role in the inflammatory reaction. The use of an anti-IL-1β monoclonal antibody can effectively reduce the biological activity of IL-1β and inhibit the inflammatory reaction. To date, the only globally approved and marketed IL-1β monoclonal antibody is canakinumab.

Canakinumab

Canakinumab is a human IgGκ monoclonal antibody that targets IL-1β. By specifically binding to IL-1β and blocking its interaction with the IL-1 receptor, canakinumab neutralizes its activity and inhibits inflammation. Canakinumab is commonly used in the treatment of cryopyrin-associated periodic syndromes, juvenile arthritis, and other diseases.⁹⁶ In a double-blind RCT conducted by Thomas et al.,⁹⁷ patients with schizophrenia or schizotypal affective disorder were included when they had elevated levels of peripheral markers of inflammation, such as IL-1β, at baseline. The results of the trial showed that canakinumab suppresses the inflammatory reaction and considerably improves positive symptoms in such patients. These findings imply that canakinumab has a relatively strong effect on inflammation suppression and positive symptom improvement. Hence, we speculate that canakinumab may be effective for the individualized treatment of mental disorders.

Psychiatric adverse reactions of monoclonal antibodies

In discussions of the treatment of BD with monoclonal antibodies, the therapeutic advantages and limitations in terms of the psychiatric side effects of these antibodies must be acknowledged.^110,111 A notable advantage is the potential to improve depressive symptoms, as indicated by studies on natalizumab.¹¹² One of the limitations is that natalizumab and other monoclonal antibodies can induce suicidal thoughts and behavior by triggering the secretion of proinflammatory cytokines.¹¹³ Compared with other monoclonal antibodies, those that target the immune system are more likely to cause depression and suicide, which are associated with imbalances in inflammatory cytokines.¹¹⁰ The authors posit that monoclonal antibodies targeting the immune system can regulate levels of inflammatory cytokines and can have positive or negative effects.

In other words, because monoclonal antibodies targeting the immune system can effectively affect brain inflammation and cause changes in affective and cognitive systems, such as depression and suicide, after natalizumab use, the treatment of BD with anti-inflammatory monoclonal antibodies exerts opposite effects. Adverse psychiatric reactions can be avoided by closely monitoring these effects and making informed decisions, and BD could even be treated. However, if inflammatory cytokine levels are not carefully monitored during treatment, an increase in proinflammatory cytokines may lead to adverse psychiatric reactions. In conclusion, no contradiction exists between adverse psychiatric reactions and BD treatment potential. Misuse of these antibodies may lead to inflammation in the central nervous system, which may result in depression and suicide. However, when these antibodies are used correctly to suppress inflammation, they could be employed to treat BD. The authors acknowledge the limitation, namely, adverse psychiatric reaction, of monoclonal antibodies and regard it as a problem to be solved in the future.

Conclusion

This review summarizes a large number of existing reports on inflammatory cytokines that support the immune inflammation hypothesis on the pathogenesis of BD, including TNF-α, IL-6, and IL-1β. Based on the sufficient literature evidence from the BD efficacy trials of anti-inflammatory drugs, this review posits that the effectiveness of anti-inflammatory therapy is closely related to the targeting of drugs and the accuracy of personalized medication. Hence, we review three monoclonal antibodies, namely, infliximab, tocilizumab, and canakinumab, that target the three abovementioned inflammatory cytokines. We recommend their use for the precise treatment of cognitive impairment, depression, and mania in BD because of their high targeting ability and few side effects.

Prospect

As modern medicine enters the era of precision medicine, the field of drug research and development and clinical medication is gradually shifting toward individualized precision targeted therapy. Individualized precision therapy has become the development direction of this field and the most effective among different clinical treatments. Given the complex nature of BD’s pathogenesis, which involves various etiological factors and considerable individual variations among patients, precision therapy is necessary. The use of individualized monoclonal antibody-assisted therapy that is customized based on the specific levels of certain inflammatory cytokines shows promise in improving the precision, effectiveness, and safety of BD treatment. This approach offers a valuable strategy for rational drug utilization. However, many problems still need to be verified and solved in the process of realizing this goal (section ‘Limitations’ provides the details). Extensive clinical trials and studies are required to validate the actual effectiveness of monoclonal antibodies in the precise treatment of BD. Notably, adverse reactions to monoclonal antibody drugs are still common, and these include adverse psychosomatic reactions, such as depression, anxiety, and even mania. Therefore, the issue of adverse reactions needs to be thoroughly considered and addressed when monoclonal antibody drugs are actually applied to BD patients. Nevertheless, we believe that in the future, individualized adjuvant use of monoclonal antibodies will broaden the application of precision immunotherapy in BD and will offer patients targeted, efficient, safe treatment options.

Limitations

The review has several limitations that need attention. First, this review has a narrative nature, so it is exposed to the risk of bias and may not comprehensively cover all existing literature due to the lack of systematic methods. Second, conclusive evidence, such as sufficient RCTs and meta-analyses, on the topic is lacking. Third, the underlying pathophysiological mechanisms of specific cytokines in BD remain unclear. Although some studies suggested the potential therapeutic effects of using monoclonal antibodies, they did not consider the issue of population heterogeneity, such as bipolar I and II subtypes. Fourth, the authors focused on the potential therapeutic effects of BD based on similarities in symptoms and did not consider the subjects, sample sizes, and durations of the included studies. Last, some studies on monoclonal antibodies found that these antibodies have no efficacy for patients with BD and may even have side effects, especially when patients are not subdivided into certain biotype subgroups.

Supplemental Material

sj-docx-1-tpp-10.1177_20451253241227772 – Supplemental material for Monoclonal antibody precision therapy targeting inflammation for bipolar disorder: a narrative review

Supplemental material, sj-docx-1-tpp-10.1177_20451253241227772 for Monoclonal antibody precision therapy targeting inflammation for bipolar disorder: a narrative review by Shijin Wu and Yuyang Zhou in Therapeutic Advances in Psychopharmacology

Footnotes

Acknowledgements

The authors would like to express their heartfelt gratitude to Dr Huang Zebin (The Affiliated Brain Hospital of Guangzhou Medical University) for his long-term teaching and guidance in this review. As an excellent psychiatrist and outstanding psychiatry expert, his teaching of clinical knowledge and academic research guidance have played a crucial role in the authors’ personal growth and scientific research. The authors would like to acknowledge the use of Citexs () for improving the grammar and writing structure, as well as proofreading the final draft. However, it is important to note that despite these efforts, artificial intelligence (including Citexs) may still have potential biases, errors, and knowledge gaps. The authors have thoroughly reviewed the manuscript multiple times to address these issues, ensuring the accuracy, effectiveness, and appropriateness of the content. In addition, the authors assure that there is no plagiarism as a result of utilizing artificial intelligence in this manuscript.

Declarations

ORCID iD

Yuyang Zhou

Supplemental material

Supplemental material for this article is available online.

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