Autoimmune phenotypes in schizophrenia reveal novel treatment targets

Abstract

Typical and atypical antipsychotics are the first-line treatments for schizophrenia, but these classes of drugs are not universally effective, and they can have serious side effects that impact compliance. Antipsychotic drugs generally target the dopamine pathways with some variation. As research of schizophrenia pathophysiology has shifted away from a strictly dopamine-centric focus, the development of new pharmacotherapies has waned. A field of inquiry with centuries-old roots is gaining traction in psychiatric research circles and may represent a new frontier for drug discovery in schizophrenia. At the forefront of this investigative effort is the immune system and its many components, pathways and phenotypes, which are now known to actively engage the brain. Studies in schizophrenia reveal an intricate association of environmentally-driven immune activation in concert with a disrupted genetic template. A consistent conduit through this gene-environmental milieu is the gut-brain axis, which when dysregulated can generate pathological autoimmunity. In this review, we present epidemiological and biochemical evidence in support of an autoimmune component in schizophrenia and depict gut processes and a dysbiotic microbiome as a source and perpetuator of autoimmune dysfunction in the brain. Within this framework, we review the role of infectious agents, inflammation, gut dysbioses and autoantibody propagation on CNS pathologies such as neurotransmitter receptor hypofunction and complement pathway-mediated synaptic pruning. We then review the new pharmacotherapeutic horizon and novel agents directed to impact these pathological conditions. At the core of this discourse is the understanding that schizophrenia is etiologically and pathophysiologically heterogeneous and thus its treatment requires individualized attention with disease state variants diagnosed with objective biomarkers.

Women who suffer from schizophrenia: Critical issues

“…More recently, a new understanding of the brain-gut connection[ 152 ] has implicated nutritional factors. In addition, there is the probability of shared susceptibility genes between schizophrenia and physical diseases that can decrease health-related quality of life and hasten death, auto-immune disease ( e.g ., Crohn’s disease, multiple sclerosis, systemic lupus erythematosus, type 1 diabetes, and ulcerative colitis) being one such category of illness[ 153 ].…”

Immuno-moodulin: A new anxiogenic factor produced by Annexin-A1 transgenic autoimmune-prone T cells

“…In fact, reports have shown a significant association between AnxA1 gene duplication and autism (Correia et al, 2014) or single nucleotide polymorphism in AnxA1 gene and schizophrenia (Clark et al, 2006) bipolar disorder or depression (Huang et al, 2010). Most intriguingly, all these conditions have been often linked to immune dysfunctions or inflammatory conditions (Muller, 2017;Prata et al, 2017;Severance et al, 2018).…”

Early onset first-episode psychosis during treatment with thalidomide for refractory ulcerative colitis: a case report

“…GI inflammation affects endothelial permeability and provides a means by which gut-derived products might penetrate the blood-brain barrier. These faulty barriers may be particularly important if autoantibodies generated in the inflamed gut would cross a compromised blood–brain barrier [6, 22]. Despite the growing evidence that increased intestinal permeability with subsequent immune activation has a major role in the pathophysiology of various psychiatric disorders [23], to date, the “leaky gut” hypothesis needs further demonstrations.…”