The Cytokine Model of Schizophrenia: Emerging Therapeutic Strategies

Abstract

We discuss the rationale for a trial of a novel biologic immunotherapy in schizophrenia (SZ). Available antipsychotic treatments for SZ are often limited by partial effectiveness and significant side effects. Thus, the search for novel medications is of high priority. All current antipsychotics function primarily by blocking D2-type dopamine receptors. An emerging theory of SZ postulates disturbances of cytokines and inflammatory mediators (i.e., the cytokine model), possibly originating in part from infectious exposures. Cytokines are one of the most important components of the immune system that orchestrate the response to infectious and other exogenous insults. Preclinical models of SZ support a convergence between a role for certain cytokines in the pathophysiology of SZ and major neurochemical postulates of the disorder, including the dopamine and glutamate hypotheses. Furthermore, several cytokines are elevated in plasma in SZ, and Positron Emission Tomography (PET) studies have shown active inflammation in the brains of individuals with psychosis. Treatment studies of certain anti-inflammatory agents, such as celecoxib and aspirin, in patients with SZ have provided further support for neuroinflammation in this disorder. The recent development of approved biological therapies for autoimmune diseases provides us with new opportunities to directly target cytokine signaling as a novel treatment strategy in SZ. In addition, advances in imaging, immunology, and psychopharmacology have paved the way for utilizing measures of target engagement of neuroimmune components that would facilitate the identification of patient subgroups who are most likely to benefit from cytokine modulation.

Interleukin-1β/Interleukin10 Ratio Produced by Monocytes as a Biomarker of Neuroinflammation in Autism

“…3) Inflammation triggered by innate immunity has been shown to play a role in other neuropsychiatric diseases, such as depression and schizophrenia, especially in the onset and early stages [10][11][12][13].…”

Anti-inflammatory strategies in the treatment of schizophrenia

“…Data from animal models of schizophrenia as well as patients with the illness suggest that aberrant inflammatory mechanisms and inflammatory markers are present in plasma as well as in the brain before, during, and after the onset of psychosis; these have been well reviewed, recently [1][2][3][4]. Clues about possible inflammatory origins include association with history of infection and presence of antibodies against specific organisms, presence of possible autoantibodies in serum and cerebrospinal fluid, changes in the levels of inflammatory cytokines, glial cell activation in the brain, and others (1-4).…”

“…Clues about possible inflammatory origins include association with history of infection and presence of antibodies against specific organisms, presence of possible autoantibodies in serum and cerebrospinal fluid, changes in the levels of inflammatory cytokines, glial cell activation in the brain, and others (1-4). The inflammatory processes may be genetically driven [4] or resultant from prenatal or postnatal exposure to infection [3]. Inflammatory hypotheses converge with rather than supplant existing neurochemical hypotheses, such as the dopaminergic and glutamatergic hypotheses of schizophrenia [3].…”

“…The inflammatory processes may be genetically driven [4] or resultant from prenatal or postnatal exposure to infection [3]. Inflammatory hypotheses converge with rather than supplant existing neurochemical hypotheses, such as the dopaminergic and glutamatergic hypotheses of schizophrenia [3]. If inflammation contributes even partly to the pathophysiology of schizophrenia, then treatments as ordinary as conventional anti-inflammatory drugs may strike at the root of the disease process [3].…”

“…If immunological mechanisms (which are related to anti-inflammatory mechanisms) are involved in schizophrenia, immunological approaches may merit study, whether or not conventional antiinflammatory treatments work [3]. In this regard, infliximab, a TNF-alpha antibody, was found to reduce depression rating scores at 12 weeks in patients with treatment-resistant depression and elevated baseline TNF-a levels [22].…”