The immune system is a complex, dynamic regulatory network that affects many aspects of human health. Immune dysregulation has been implicated in various psychiatric diseases, including schizophrenia, major depressive disorder (MDD), bipolar disorder, and posttraumatic stress disorder (PTSD).1–3 These psychiatric diseases also seem to be comorbid with inflammatory diseases or disease processes. Depression is more likely in people with autoimmune disease, such as autoimmune thyroiditis4 and atopic dermatitis.5 A history of depression is associated with an increased likelihood of having autoimmune disease across various bodily sites, including blood, gastrointestinal and endocrine systems, and skin.6 Infectious agents were hypothesized to cause schizophrenia and bipolar disorder as early as 1845, with numerous variables related to exposure to infectious disease and inappropriate immune responses found in these populations.7 A records review for those hospitalized for acute psychosis found a greatly increased likelihood of having a urinary tract infection at the time of admission, again suggesting some association between acute infection and psychosis.8–10 Autoantibodies targeted at neurological processes are found across various psychotic disorders and strongly implicated as pathological processes, at least in a subset of disorders.11 Furthermore, autoimmune encephalitis can cause psychotic features and, recently, a proposal has been made to create a new diagnostic category of autoimmune psychosis, as the clinical presentation is distinct enough from known autoimmune encephalitis to warrant this category.12 Thus, the interactions between immune processes and psychiatric illness are broad and may be causal, but there is still much to be understood about how immune processes can affect the expression of psychiatric illnesses and how immune markers may inform the search for clinically relevant biomarkers.
Understanding Immune Changes in Psychiatric Disease
Early work identified both hypoactive immune activity characterized as immunosuppression, as well as hyperactivity in those with mood disorders, primarily depression.13 Subsequent work has regularly found increased proinflammatory cytokines, including interleukin (IL)-1beta, tumor necrosis factor (TNF)-alpha, and IL-6, in those with depression; however, as is discussed later in this article, those markers are now believed to be non-specific to depression. Extensive research has found numerous links between immune-related processes and schizophrenia and bipolar disorder, including in white cell counts and quantifiable antibodies as well as cytokine abnormalities, but a direct causal link is still absent.7 Continued work over the years has found associations between depression and cytokine abnormalities in both clinical and preclinical studies.14–16 This led the field toward exploring depression as a “proinflammatory” state and work to test clinical treatments to intervene in those pathways. Interestingly, one clinical study that looked to specifically inhibit the action of TNF-alpha with infliximab and test its efficacy as an antidepressant did not produce the strong results that many were expecting.17 This study undermined the initial concept that simply by reducing inflammation, one would achieve a clear antidepressant response. A broader examination of the use of anti-inflammatory agents as adjuncts found some evidence to support their use for certain psychiatric disorders, particularly when considering the risk/benefit profile. Specifically, a systematic review supported use of polyunsaturated fatty acids in MDD. Furthermore, they highlighted the findings from the infliximab study, noting that greater efficacy was seen in the MDD group with higher inflammation indicated by increased C-reactive protein (CRP).17,18 Some evidence supports use of cyclooxygenase-2 inhibitors in schizophrenia, although the risks need to be strongly considered. The second-generation tetracycline antibiotic minocycline, which shows anti-inflammatory effects thought to be separate from its microbial properties, also had evidence for improving symptoms of schizophrenia, but the risk profile prevents it from being a first-line add-on therapy.18 Thus, even with these possibly efficacious adjunctive medications, there are still important questions to be asked regarding their most effective clinical use.
Recent evidence suggests additional defects in anti-inflammatory markers that indicate further dysfunction in the immune system in the context of depression,19 and specific evidence of both increased proinflammatory proteins and decreased anti-inflammatory proteins found in the cortex of people who are depressed and have died by suicide,20 and changes in peripheral cytokines that play an anti-inflammatory role.21 Evidence obtained in various bodily components—brain, blood, and cerebrospinal fluid—support the hypothesis that inflammation is related to the expression of psychiatric illness, but it is incorrect to assume that findings in each compartment are equivalent. Specialized barrier properties of the brain specifically segregate blood-based processes from brain-based processes,22 and inflammatory regulation in the brain is still an area of intense research focus.23 It is also important to note that cross-sectional measurement of immune markers does not convey the true nature of the immune dysfunction and many of the studies in psychiatry have historically only examined this in a case-control dichotomy. Thus, there is still a great bit of work to be done in understanding how inflammation may affect the expression of psychiatric illness and how immune markers may guide diagnosis and treatment selection.
The Nature of Immune Dysfunction in Psychiatric Disorders
For inflammatory biomarkers to be meaningfully used in the diagnosis and treatment of psychiatric disease, we must gain greater specificity regarding how and when the immune system is engaged in relationship to psychiatric symptoms and disorders. Psychiatry is at its infancy in establishing associated foundational immune dysfunction. Much of the research in the field to date has examined changes in cytokines to demonstrate differences in psychiatric disease compared to normal populations. Such comparisons are hindered by their lack of specificity and consideration of the complexity of immune cell differentiation and cellular productions. A simplified version of this complex cascade is detailed in Figure 1. As described in Figure 1, cytokines can be released from several different cell types, some of which have cell-specific release and others being more promiscuous and released from several cell types. Cytokines may also signal cellular differentiation and then lead to the proliferation of other cell types that can release cytokines in a different context. The presence of a certain cytokine is therefore, in many cases, fairly nonspecific and difficult to interpret. In addition, the consequences of cytokine activity may have wide-ranging effects on the body; for example, affecting genetic expression in an acute fashion and in a more long-term adjustment of immune activity dependent on the immune stimuli.24 Thus, what we may learn from using only cytokine changes in psychiatric disease is likely very narrow.
The multistep cascade resulting from immune stimuli. At each stage, targeted and specific responses are tailored to the stimuli in order for the host to appropriately respond.
A recent review of 43 meta-analyses evaluated the specificity and stability for a broad panel of predominate cytokines in major psychiatric disorders and found a great deal of variability and nonreproducible findings.25 Of the tests comparing inflammation-related factors (IRF) that had been meta-analyzed multiple times, 42% showed inconsistent results between cases and controls and 67% showed inconsistent results when evaluating state-based markers. When examining the specificity of IRFs to psychiatric diseases, IL-2 was significantly low in suicide but high in bipolar disorder (BP), and soluble IL-6 receptor was uniquely high in BP. IL-6 and CRP are the most commonly increased IRFs in four disorders, with nerve growth factor being most commonly decreased in MDD and schizophrenia. When evaluating changes in these IRFs across different states of disease, the results were rather inconsistent. The authors conclude that trait markers, showing difference between disease cases and controls are more reliable, and that the literature is lacking with regards to state markers that associate with symptomatic expression in psychiatric diseases. The presence of heterogeneous disease states within a diagnostic group also presents issues with case/control comparisons such that differing lengths of illness, age at onset, and severity of symptom profiles adds variability to further confound the search for clinical useful state markers.
Immune Markers as Determinants of Pathology
Examining existing data broadly suggests that dysfunctional inflammatory regulation is present in those with psychiatric diseases. A primary function of the immune system is to be adaptive and responsive to the stimuli that are presented; therefore, the immune system becomes customized to the environment in which it is exposed.26 Given the heterogeneity of clinical presentations, variable disease trajectories, and chronicity of symptom severity associated with mental illnesses, the determination of how transient markers of immune response may yield objective markers that will consistently indicate disease-specific pathophysiology is challenging. Many other disease fields have worked diligently to map the immune parameters in which their diseases develop and to find clear markers of disease and progression to provide clinical utility. An example in chronic rhinosinusitis shows how mapping of the intricate inflammatory pathways can reveal new complexity and redefine diagnostic categories.27
Immune activity is expressed in numerous cell types including lymphocytes, monocytes, neutrophils, and natural killer cells. Certain cell types affect differentiation of others, such as dendritic cellular control of T-lymphocyte activation28 and cell-specific action of chemokines on cellular release and response,29 all of which may variably relate to psychopathological symptoms and/or diseases. Furthermore, other biological systems are believed to be affected in depression, and other psychiatric disorders affect the immune system, such as sleep and circadian rhythm changes30 and stress burden.31 Better understanding of immune regulation expands the number of system variables that must be integrated in our understanding, including the contributions of the gut microbiota32,33 and metabolic health.34 Appropriate characterization of the immune response is essential in determining the immune pathophysiology. The field of immunology and the study of immunological diseases have provided helpful clarity in defining biological relationships and giving context to these processes that would be valuable for the field of psychiatry to more fully integrate into the hypothetical models that drive exploration in this area.
Questions remain regarding the site of action of immune effects, whether these are central or peripheral, and on the overall state of the immune system, being hyperactivated or underresponsive. Efforts have been made toward answering these questions, with theoretical work providing a framework to examine the immune-inflammatory response system separate from the compensatory immune-regulatory reflex system with associated symptoms of schizophrenia.35 Evidence shows that in certain contexts, the compensatory immune activity is associated with more positive outcomes and may be more of a protective factor, providing possible targets for clinical intervention or biomarkers to help classify schizophrenia spectrum subtypes by their underlying immune dysfunction. These new targets could include macrophage activation state or quantification of T-cell subsets. Additional evidence suggests that some of these dysfunctions are sex-specific36,37 and given the preponderance of psychiatric diseases that show imbalanced sex-specific distributions, this may be an important step in clarifying immune disruptions within psychiatric disease. It is highly likely that not all who are diagnosed with a particular psychiatric disease will show the same immune dysfunction and that subsets of dysfunction will exist. The use of putative markers in tandem with other key demographic and disease-specific parameters, such as biological sex, exposure to infectious disease, vaccine history, and current medications with effects on inflammatory activity, will likely be integral to their clinical utility.
Excellent progress has been made in the search for biomarkers that cross diagnostic categories, such as the identification of distinct psychosis biotypes that cross the traditional diagnostic categories of schizophrenia, schizoaffective disorder, and bipolar disorder by the Bipolar-Schizophrenia Network on Intermediate Phenotypes consortium.38 Given the commonality of some of these immune differences across psychiatric illnesses, a combined approach to look at common pathway dysfunction across these disorders may yield similar exciting results.
Immune Markers for Treatment Selection
Given that the field is far from understanding how immune dysfunction may play a causal role in psychiatric disease, it is helpful that work has been done to determine which immune markers may assist with treatment optimization and matching patients to treatments. In the field of depression, CRP has shown good evidence to assist in treatment selection. CRP is a marker of general inflammation and is best studied in regard to cardiovascular disease. Participants in the Combining Medications to Enhance Depression Outcomes trial were evaluated to determine if baseline CRP was associated with treatment response. These participants had been randomly assigned to receive either escitalopram plus placebo (selective serotonin reuptake inhibitors [SSRI] monotherapy, n = 51) or bupropion plus escitalopram combination (bupropion-SSRI combination, n = 55). Higher baseline CRP levels were associated with lower depression severity after bupropion-SSRI combination but not with SSRI monotherapy. The overall remission rate for the original trial was 41.5%; the remission rate using CRP threshold-based assignment of SSRI monotherapy for low inflammation and bupropion-SSRI for high inflammation increased the remission rate to 53.1%.39 High baseline CRP in conjunction with normal weight body mass index was found to associate with greater reduction in depressive symptoms and cognitive performance in young patients (age 10–17 years) treated with lurasidone.40 In a study evaluating exercise as a treatment for depression, high baseline TNF-alpha was associated with greater decrease in depressive symptoms and a positive correlation was found between IL-1beta and depression symptom scores.41 These data show promise that widely available immune markers could be used as biomarkers for treatment selection and improve outcomes quickly, in conjunction with continued research into more specific biomarkers and new interventions. Treatments that specifically affect inflammation are being actively studied for depression and many different mechanisms of action are targeted, from kynueurine pathways to broad anti-inflammatory action using aspirin.42 Future research will provide more evidence to support or refute the use of these targets as efficacious antidepressants. A deeper understanding of how the immune system dysregulation in psychiatric disorders will give us additional targets and the precision that is required to manage the pathogenic signal while leaving functionality of this key physiological regulatory system intact.
Extensive data support the hypotheses that dysfunctional immunological activity contributes to the expression of many psychiatric disorders and that targeting immune pathways can improve symptoms in some people. The field is still far from having clear immune-based biomarkers that can guide the identification of subtypes, inform treatment selection, or suggest fundamental pathophysiological causes; however, these may appear in the near future. Continued testing of biomarker candidates will reveal the contexts in which these biomarkers can be implemented in clinical work as well as give further clarification to the research questions yet to be answered.
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