The Potential of Immune Biomarkers to Advance Personalized Medicine Approaches for Schizophrenia

Abstract

Molecular profiling studies have helped increase the understanding of the immune processes thought to be involved in the etiology and pathophysiology of psychiatric disorders such as schizophrenia. Current therapeutic interventions with first- and second-generation antipsychotics are suboptimal. Poor response rates and debilitating side effects often lead to poor treatment compliance. This highlights the pressing need to identify more effective treatments as well as objective biomarker based tests, which can help predict treatment response and identify diagnostic subpopulations. Such tests could enable early detection of patients who will benefit from particular therapeutic interventions. In this review, we discuss studies relating to dysfunctions of the immune system in patients with schizophrenia and the effects of antipsychotic medication on the molecular components of these systems. Immune system dysfunction may in part be related to genetic risk factors for schizophrenia, but there is substantial evidence that a wide range of environmental factors ranging from exposure to infectious agents such as influenza and Toxoplasma gondii to HPA axis dysfunction play an important role in the etiopathogenesis of schizophrenia. Ongoing research efforts, testing therapeutic efficacy of anti-inflammatory agents used as add-on medications are also discussed. From a therapeutic perspective, these represent the initial steps toward novel treatment approaches and more effective patient care in the field of mental health.

Ethical Implications of the Mild Encephalitis Hypothesis of Schizophrenia

“…Inflammation could be the missing link between stress and psychosis (15). Stress deteriorates the body’s ability to fight infections, triggers autoimmune activity (32), and increases the production of pro-inflammatory cytokines (15, 16, 31, 33). Pro-inflammatory cytokines are key regulators of inflammation, whereas anti-inflammatory cytokines can inhibit the production of their pro-inflammatory counterparts.…”

“…A meta-analysis of 26 randomized, placebo-controlled double-blind studies describes significant effects for aspirin, estrogens, and N -acetylcysteine (NAC, cough syrup) with low to moderate effect sizes (18). Estrogens seem to be effective only in female patients (16, 18); presumably, its effects are hormonal. No statistically significant effects are found for minocycline (antibiotic agent), and omega-3 poly-unsaturated fatty acids (omega-3 PUFAs) (18, 20, 21).…”

“…However, most of these drugs not only exert anti-inflammatory effects, but have further effects that might additionally or alternatively explain their efficacy in schizophrenia: (1) influences on the transmission of dopamine (estrogens, NAC), glutamate (NAC) or serotonin (omega-3-PUFAs), (2) effects on the gut microbiota (minocycline), (3) influence on the body’s stress system (aspirin), (4) neuroprotection (omega-3-PUFAs), (5) enhanced neurogenesis (omega-3-PUFAs), and (6) influence on the composition of cell membranes (omega-3-PUFAs) (16, 18, 21, 51). …”

“…Add-on of this treatment regimen was found to be most effective in first-episode psychosis and influenced by the initial inflammatory status of the patient. Therefore, anti-inflammatory medication could be a cause-targeted therapeutic strategy in early phases of the disease to stop its progression (16, 21). …”

“…According to this hypothesis, a significant subgroup of patients with schizophrenia suffer from a mild, but chronic form of encephalitis which can have quite different etiologies ranging from viral infections, traumas to autoimmune diseases. At least in a subgroup of schizophrenia patients, inflammatory processes occur in the beginning or during the course of the disease (16–20). Therefore, anti-inflammatory drugs might be effective.…”