Neuroinflammation in first episodes of psychosis

Abstract

Around 3% of the general population suffers a first episode of psychosis (FEP). The population of FEPs represents a unique opportunity to study psychotic disorders in general and schizophrenia in particular, avoiding confounding variables such as antipsychotic treatment, comorbidity and chronicity.

Several hypotheses that involve the immune system and neuroinflammatory processes have been proposed as etiological explanations of psychosis. Most of the available scientific evidence has been found in populations with established schizophrenia. Few studies indicate alterations, often subtle, in inflammatory/immune mediators and oxidative/nitrosative stress in FEPs.

One of the main anti-inflammatory endogenous regulatory systems is the endocannabinoid system (ECS), which has been proposed as a major homeostatic system at various neuropathological scenarios, reducing both neurodegenerative and neuroinflammatory damage. Several studies have linked the ECS in patients with psychotic disorders. Furthermore, exogenous cannabis is one of the major environmental risk factors related to psychosis.

In a first study, 117 FEPs showed systemic inflammatory conditions compared to 106 healthy controls, identifying a significant increase in some intracellular components of the NFKB proinflammatory pathway, together with a significant reduction in the anti-inflammatory components of the 15d-PGJ2/PPARy pathway. The expression of iNOS and COX-2 in PBMC and plasma levels of Homocysteine were identified as the most reliable risk factors, and IκBα and the 15d-PGJ2 as potential protective factors. These results indicate robust phenotypic differences at cellular machinery in PBMC of patients with a FEP. Due to its soluble nature, one notable finding of this study is that the anti-inflammatory mediator 15d- PGJ2 could be used as a plasma biomarker of FEPs.

A second study reinforced the evidence of systemic inflammatory changes after a 6-month follow-up of the sample of FEPs. After 6 months, most of the soluble elements analyzed were significantly altered, suggesting the existence of a greater pro/anti-inflammatory imbalance and potentially more harmful, as showed the lipid peroxidation (TBARS) found. NO2- plasma levels and TBARS and COX-2 expression were the most reliable risk factors, while plasma levels of 15d-PGJ2 functioned as a protective factor. There was an interesting correlation between antipsychotic dose and the change of PGE2 (inverse) and 15d-PGJ2 (direct).There was also an inverse association between the GAF scale and TBARS.

In a third study, a peripheral ECS dysregulation in patients with a FEP was described. After controlling for age, sex, body mass index and cannabis use, the FEP group showed a significantly reduced expression of the main synthesis enzymes (NAPE and DAGL) and increased degradation enzymes (FAAH and MAGL). The subgroup of patients with a history of heavy cannabis users showed lower CB2 receptor, NAPE and DAGL expression compared with the control group. No significant differences were found with non-users/sporadic subgroup.

Although more evidence is needed, this research shows how the determination of several components of the pro/anti-inflammatory pathways and the ECS has an interesting potential as biomarkers risk/protective biomarkers of suffering a FEP.

Despite the limitations, the studies of this thesis have identified conditions of vulnerability to suffer a FEP related to pro/anti-inflammatory pathways and peripheral ECS components in a very well characterized sample of FEPs.

Alrededor del 3% de la población general sufre un primer episodio de psicosis (PEP) a lo largo de su vida. Esta población es única para estudiar los trastornos psicóticos y la esquizofrenia, evitándose las principales variables de confusión.

Varias hipótesis que implican al sistema inmune y procesos neuroinflamatorios se han propuesto como explicaciones etiológicas de la psicosis. La mayoría de estas evidencias se han encontrado en poblaciones con esquizofrenia establecida.

Uno de los principales sistemas antiinflamatorios reguladores endógenos es el sistema endocannabinoide (SEC). Varios estudios lo han relacionado con los trastornos psicóticos. Además consumir cannabis uno de los factores de riesgo ambientales de psicosis más importantes y estudiados.

En un primer estudio con 117 PEPs y 106 controles se evidenciaron condiciones inflamatorias sistémicas en los PEPs, identificando un aumento significativo de componentes de la vía de proinflamatoria principal del NFKB, junto con una disminución de la vía antiinflamatoira del 15d-PGJ2/PPARγ. Un hallazgo notable fue que el mediador antiinflamatorio 15d-PGJ2 podría ser utilizado como biomarcador plasmático de los PEPs.

En un segundo estudio se reforzó la evidencia de alteraciones inflamatorias sistémicas en los PEPs. Tras 6 meses, la gran mayoría de los elementos solubles analizados ya aparecieron alterados de manera significativa, sugiriendo un mayor desequilibrio pro/anti-inflamatorio, potencialmente más dañino.

En un tercer estudio se describió una disregulación periférica del SEC en los PEPs. Después de controlar por factores de confusión, el grupo de PEPs mostró una expresión reducida de las principales enzimas de síntesis (NAPE y DAGL) y un aumento de la degradación (FAAH y MAGL). El subgrupo de pacientes con antecedentes de consumo de cannabis importante mostró una menor expresión del receptor CB2, NAPE y DAGL en comparación con el grupo control, sin diferenciarse del subgrupo de no usuarios/esporádicos.

La determinación de varios componentes de pro/antiinflamatorios y del SEC tiene un interesante potencial como marcadores biológicos y factores de riesgo/protección del PEP.

A pesar de las limitaciones, los estudios que componen esta tesis han identificado condiciones de vulnerabilidad a sufrir un PEP relacionadas con vías pro/antiinflamatorias y el SEC periférico en una muestra muy bien caracterizada.