The Cytokine Model of Schizophrenia: Emerging Therapeutic Strategies

We discuss the rationale for a trial of a novel biological immunotherapy in schizophrenia (SCZ). Available antipsychotic treatments for SCZ are often limited by partial effectiveness and significant side effects. The search for novel medications is of high priority. All current antipsychotics function primarily by blocking D2-type dopamine receptors. An emerging theory of SCZ 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 SCZ support a convergence between a role for certain cytokines in the pathophysiology of SCZ and major neurochemical postulates of the disorder, including the dopamine and glutamate hypotheses. Several cytokines are elevated in plasma in SCZ, and positron emission tomography studies have shown active inflammation in the brains of patients with psychosis. Treatment studies of anti-inflammatory agents, such as celecoxib and aspirin, in patients with SCZ have provided further support for neuroinflammation in this disorder. The development of approved biological therapies for autoimmune diseases provides new opportunities to target cytokine signaling directly as a novel treatment strategy in SCZ. In addition, advances in imaging, immunology, and psychopharmacology have paved the way for using measures of target engagement of neuroimmune components that would facilitate the identification of patient subgroups who are most likely to benefit from cytokine modulation.