Cytokine Imbalance as a Biomarker of Treatment-Resistant Schizophrenia

Abstract

Treatment-resistant schizophrenia (TRS) is an important and unresolved problem in biological and clinical psychiatry. Approximately 30% of cases of schizophrenia (Sch) are TRS, which may be due to the fact that some patients with TRS may suffer from pathogenetically “non-dopamine” Sch, in the development of which neuroinflammation is supposed to play an important role. The purpose of this narrative review is an attempt to summarize the data characterizing the patterns of production of pro-inflammatory and anti-inflammatory cytokines during the development of therapeutic resistance to APs and their pathogenetic and prognostic significance of cytokine imbalance as TRS biomarkers. This narrative review demonstrates that the problem of evaluating the contribution of pro-inflammatory and anti-inflammatory cytokines to maintaining or changing the cytokine balance can become a new key in unlocking the mystery of “non-dopamine” Sch and developing new therapeutic strategies for the treatment of TRS and psychosis in the setting of acute and chronic neuroinflammation. In addition, the inconsistency of the results of previous studies on the role of pro-inflammatory and anti-inflammatory cytokines indicates that the TRS biomarker, most likely, is not the serum level of one or more cytokines, but the cytokine balance. We have confirmed the hypothesis that cytokine imbalance is one of the most important TRS biomarkers. This hypothesis is partially supported by the variable response to immunomodulators in patients with TRS, which were prescribed without taking into account the cytokine balance of the relation between serum levels of the most important pro-inflammatory and anti-inflammatory cytokines for TRS.

Canonical and Non-Canonical Antipsychotics’ Dopamine-Related Mechanisms of Present and Next Generation Molecules: A Systematic Review on Translational Highlights for Treatment Response and Treatment-Resistant Schizophrenia

“…On the other hand, multiple cytokines exhibit an immunosuppression function: IL-4 increases Th2-mediated cytotoxicity and promotes switching from T-helper to Th2, also modulates macrophage and microglial cell action [ 451 , 452 ], IL-6 modulates the sensitivity of neurons to neurotransmitters [ 453 , 454 , 455 ], and IL-10 activates JAK1 and STAT3 and induces expression of immunosuppressor genes [ 442 , 456 , 457 , 458 , 459 ]. In addition, TRS patients could have non-dopaminergic mechanisms underlying the disorder, and non-canonical druggable mechanisms could even include neuroinflammatory processes [ 460 ].…”

The Role of D-Serine and D-Aspartate in the Pathogenesis and Therapy of Treatment-Resistant Schizophrenia

“…However, the use of first and new-generation APs does not solve the problem of TRS in more than 30% of cases and sometimes leads to the development of serious ADRs, especially in chronic psychopharmacotherapy [ 9 ]. Thus, if psychiatrists avoid such TRS disease-modifying therapy due to a lack of knowledge or willingness to use new Sch treatments that are not supported by pharmaceutical companies and not yet approved by the FDA, they may jeopardize patient recovery due to their own laziness or selfishness [ 118 ].…”

“…However, the issue of achieving a balance between the effectiveness and safety of APs remains open [ 8 ]. Other neurochemical hypotheses for the development of Sch continue to be explored as they may provide clues to discover a disease-modifying therapy for mental disorders [ 9 ].…”

“…The response to APs of the first and new generations ( Figure 1 ) [ 9 ] is variable, and it is still difficult to predict whether the therapy will be effective or not [ 10 ].…”

Oxidative Stress Index and Peripheral Biomarkers for Schizophrenia: A Revisited Approach.

“…Psychiatric diseases such as schizophrenia are exacerbated by discrepancies in the production of cytokines or activation. From the commencement of their initial attack of psychosis (FEP), schizophrenia sufferers as well as their closest relatives have aberrant cytokine levels [6][7][8][9][10][11][12][13][14][15][16][17]. During in ammation, the leukocytes, lymphocytes, and macrophages discharge in ammatory mediators such as cytokines to manage cell communication by binding to the cells' receptors, triggering the cell to alter its function [18] and causing structural and functional deformities in schizophrenia [19].…”