New evidence-coupled with advances in molecular biology-has afforded an unparalleled opportunity to move toward identifying potential new treatments for schizophrenia.
TABLE1. Summary of evidence for immune system dysfunction in schizophrenia
TABLE 2. Advantages and disadvantages of adjunctive monoclonal antibody immunotherapy in schizophrenia
Man cannot discover new oceans unless he has the courage to lose sight of the shore.
“In a stunning discovery that overturns decades of textbook teaching, researchers have determined that the brain is directly connected to the immune system by vessels previously thought not to exist.”1
A hallmark of the CNS is the absence of a classic lymphatic drainage system. Although the CNS is under constant immune surveillance, the mechanisms governing the movement of immune cells in and out of the CNS are not well understood. Two recent independent studies found functional lymphatic vessels lining the dural sinuses of dissected mouse brain meninges.2,3 The dural sinuses drain blood from both internal and external veins in the brain into the internal jugular veins. The identified structures expressed molecular hallmarks of lymphatic endothelial cells, carried both fluid and immune cells from the cerebrospinal fluid (CSF), and were connected to the deep cervical lymph nodes.2,3
In one of the studies, the authors subsequently examined autopsy specimens of human dura. They identified a potentially similar lymphatic structure in human dura, but further studies are needed to assess and characterize the location and organization of meningeal lymphatics in the human CNS.2
The presence of a functional and classic lymphatic system in the CNS suggests that a reassessment of basic assumptions in neuroimmunology is needed. If the presence of these vessels is confirmed in humans, it may follow that dysfunction of meningeal lymphatic vessels contributes to the pathophysiology of a variety of CNS disorders associated with immune dysfunction, including multiple sclerosis, Alzheimer disease, schizophrenia, and mood disorders. This paradigm-shifting finding holds the potential to alter how we perceive brain-immune interactions and would enable a more mechanistic approach to the study of the neuroimmunology of these disorders.
Immune system abnormalities in schizophrenia
The investigation of immune system abnormalities in schizophrenia, though ongoing for decades, has recently become a popular area of research. This interest has been at least partially stimulated by our increased understanding of the interactions that occur between the immune system and the brain in other chronic medical disorders, and has been furthered by this recent seminal finding in neuroscience.
Schizophrenia is associated with immune system dysfunction throughout the lifespan (Table 1). Advances in genetics have led to the identification of associations between genes involved in the regulation of the immune system and an increased risk of schizophrenia.4 Prenatal maternal infection, with a variety of infectious agents, is a replicated risk factor for the development of schizophrenia in the offspring.5
The association between schizophrenia and infections appears to be bidirectional: hospital contact for infection during childhood or adolescence is associated with an increased risk of schizophrenia in adulthood, and schizophrenia is also a risk factor for infections.6,7 Some patients with schizophrenia have evidence of immune abnormalities in the blood, CSF, and CNS, including numbers of immune cells, levels of inflammatory markers, and antibody titers.8 The prevalence of certain comorbid infections appears to be increased in acutely ill patients with schizophrenia.9 Schizophrenia is also associated with increased mortality from infectious diseases, including pneumonia and influenza.10
Several trials have found that treatment with NSAIDs and agents with anti-inflammatory properties-including aspirin, celecoxib, estrogen, minocycline, and N-acetylcysteine-as an adjunct to antipsychotic therapy, was associated with significant improvement in psychopathology in patients with schizophrenia.11,12 In 2 studies, baseline blood levels of cytokines predicted the response to adjunctive NSAID treatment.13,14 Essentially, patients who were more “inflamed” at baseline were more likely to improve with NSAIDs. Taken together, these findings suggest we need to more extensively evaluate the hypothesis that immune dysfunction may be involved in the pathophysiology of schizophrenia.
This evidence-coupled with advances in molecular biology-has afforded an unparalleled opportunity to investigate this hypothesis and to move toward identifying potential new treatments to alleviate symptoms and improve quality of life in patients with schizophrenia: namely, monoclonal antibody immunotherapy. Currently, several humanized monoclonal antibodies are FDA- approved for the treatment of autoimmune disorders and cancers. These antibodies act by directly neutralizing cytokines or binding cytokine receptors.
Cytokines are key signaling molecules of the immune system that exert effects in the periphery and brain. They are produced by immune and non-immune cells and exert their effects by binding specific receptors on a variety of target cells. Cytokines regulate acute and chronic inflammation, a complex but vital biological response that affects all organ systems. They also help coordinate the function of the innate immune system and its components as well as a host of other physiological processes throughout the body.
Monoclonal antibody immunotherapy has several potential advantages over NSAIDs and other anti-inflammatory agents (Table 2). Perhaps most importantly, NSAIDs have relevant off-target (ie, non- immune) effects. For example, aspirin may modulate NMDA receptors, and celecoxib may affect glucocorticoid receptors.15,16 In contrast, monoclonal antibodies have no off-target effects and instead act only on specific inflammatory cytokines. Therefore, improvements in psychopathology in response to monoclonal antibody immunotherapy would further (and directly) implicate inflammatory pathways in the pathophysiology of schizophrenia. In other words, monoclonal antibodies permit direct testing of the hypothesis that inflammation plays a causal role in schizophrenia symptomatology.
Compared with other anti-inflammatory agents, monoclonal antibodies also have more potent anti- inflammatory properties. NSAIDs are less effective in conditions with significant inflammation (eg, autoimmune disorders), which often require immunosuppressive therapy. In schizophrenia, adjunctive treatment with anti-inflammatory agents has been associated with small to moderate effect sizes for improvements in psychopathology. While this may reflect the fact that immune system involvement occurs in only a subset of patients with schizophrenia, another possibility is that more potent anti-inflammatory agents are needed for more robust effects. This may also help explain why treatment studies that have targeted inflammation in schizophrenia have yielded mixed results.
Another important issue regarding monoclonal antibody immunotherapy is route of administration. Presently, the majority of these agents are administered by intravenous infusion, typically once monthly, although some agents can be given subcutaneously or orally. From a purely research perspective, this is advantageous in terms of obviating issues of medication adherence that may confound findings. However, this treatment approach poses a myriad of logistical issues for patients and clinicians.
Despite these potential advantages, there are other important considerations regarding the clinical utility of monoclonal antibody immunotherapy (Table 2). Serious adverse effects due to profound immunosuppression, including life-threatening infections, demyelinating disorders, ulcers, and malignancy, are possible. Although the adverse effects of NSAIDs are generally more benign, there is an increased risk of gastrointestinal bleeding and cardiovascular mortality with prolonged use of these agents. The high cost of monoclonal antibody immunotherapy (potentially more than $1000 per dose) is another important factor that may limit more widespread use.
In a seminal study, Raison and colleagues17 compared adjunctive infliximab, a monoclonal antibody against the inflammatory cytokine tumor necrosis factor-alpha, with placebo in 60 patients with treatment-resistant depression. Although they did not find an overall difference in the change in depression scores between the treatment groups, there was a significant time by group interaction that favored infliximab-treated patients with elevated baseline levels of the inflammatory marker C-reactive protein.
To date, the results of 2 small studies of cytokine-based immunotherapy in schizophrenia have been published, although several other trials are ongoing. The first is a case series of 2 patients with treatment-resistant schizophrenia who had significant improvement in total psychopathology during adjunctive treatment with interferon gamma-1b.18 The second, an 8-week open-label trial of adjunctive tocilizumab (an anti-interleukin-6 receptor monoclonal antibody) in 6 patients with schizophrenia, which was associated with significant improvements in cognition, was recently published by our group.19
Currently, all FDA-approved antipsychotics for the treatment of schizophrenia are anti-dopaminergic agents. While these medications are effective for many patients, particularly those with positive symptoms, many other patients have some degree of treatment resistance. Thus, there is a great impetus to identify other effective pharmacologic treatments for schizophrenia, especially for negative symptoms and cognitive dysfunction. Doing so will likely require “the courage to lose sight of the shore.”
Overall, there is a compelling rationale for well-designed, carefully conducted trials of monoclonal antibody immunotherapy in schizophrenia. Other important considerations include the timing of therapy during the course of the disorder and the duration of treatment, as well as patient selection. Notably, a trial of monoclonal antibody immunotherapy should be conducted exclusively in “inflamed” patients, as this group may be more likely to respond to this treatment. Such studies, regardless of outcome, will provide valuable insights into the role of the immune system in schizophrenia.
This article was originally posted on 1/7/2016 and has since been updated.
Dr Miller is Associate Professor in the Department of Psychiatry at Georgia Regents University in Augusta, GA, and Schizophrenia Section Editor for Psychiatric Times. He reports no conflicts of interest concerning the subject matter of this article.
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