The role of CRP in the causality of schizophrenia has been a subject of interest for many years. It is known that CRP and other acute-phase reactants cause disruption of the BBB and alter its permeability for inflammatory mediators and antibodies
[1][2]. As described above, this compromise in the integrity of the BBB in the backdrop of widespread systemic inflammation has been linked to developing psychotic symptoms
[3][4]. Increased CRP has also been recently linked with a significant decline in multiple cognitive domains, including working memory and learning ability, in individuals of all ages suffering from schizophrenia
[5]. Further reviews were consistent in highlighting a marked cognitive impairment in schizophrenic patients with even low-grade or subclinical inflammation
[6][7]. Interestingly, a study in Finland elucidated the role of elevated maternal CRP levels in increasing the risk of psychosis in the offspring
[8]. In summary, an inverse association of CRP levels and cognitive ability is noted in acute psychosis. However, a clinical trial published in 2019 provided valuable insight into the prognostic value of CRP in six months following the resolution of acute psychosis
[9]. Cognitive abilities improved with time and a noticeable drop in CRP levels was noted in the later periods, continuing the inverse relationship
[9]. The pathophysiology behind increased CRP levels and subsequent cognitive dysfunction is not fully known but some studies have implicated CRP in increasing BBB permeability during acute inflammatory phases and causing neuroinflammation
[10]. Mouse models revealed that CRP has no virtual effect on BBB permeability in smaller amounts but impairs its function and increases paracellular permeability in higher amounts that may be achieved during high systemic inflammation or pro-inflammatory states like psychosis
[10]. Multiple complex molecular pathways have been described to explain CRP-led increased permeability of the BBB and endothelial dysfunction
[10]. Notably, it is widely believed that the disruption of tight junctions is involved in the increased permeation of CRP
[2]. CRP in blood activates the surface Fc-gamma receptors (CD16/32) on endothelial cells and leads to the formation of reaction oxygen species (via p38-mitogen-activated protein kinase mechanism) that causes an alteration in the myosin light chain kinase activity
[2]. This implies that impairment of tight junctions by CRP is most likely achieved via modification of the cytoskeletal structure and induction of abnormal contractility
[2][10]. After entering the CNS, CRP causes a reactive microglial reaction, astrogliosis, and neuroinflammation
[11]. Neuroinflammation in psychiatric conditions is invariably associated with short-term and lasting cognitive deficits
[12]. Therefore, this mechanism may explain how elevated CRP levels (reflecting systemic inflammation) in psychosis may lead to decreased cognitive abilities.
Apart from CRP’s direct role in the disruption of the BBB, its role in the increment of the kynurenine pathway is still unclear. High kynurenic acid levels, as described earlier in this text, act as an antagonist at the NMDA receptor and possibly contribute to psychotic symptoms
[13]. Both CNS and peripheral kynurenine pathways are tightly regulated by the immune status of the body
[14]. With increased BBB permeability in the setting of elevated CRP levels, infiltration of CRP and other cytokines in CNS leads to neuroinflammation and increased activation of astrocytes and microglia
[15]. Tryptophan degeneration and kynurenic acid production are increased and the antagonistic effect on NMDA is more pronounced, leading to psychotic symptoms
[14]. It is also important to consider that some studies have concluded that CRP levels are not associated with the kynurenine pathway or levels of kynurenic acid in CNS
[16][17]. It is important to note that CRP levels have been largely associated with cognitive symptoms in psychosis, while kynurenic acid levels are associated with psychiatric symptoms
[18]. Therefore, it is unclear whether CRP levels and kynurenic acid levels act as two independent markers occurring coincidentally during schizophrenia or have a complex interaction that leads to a possible cause–effect relationship.