Investigating the relationship between Toll-like receptor activity, low-grade inflammation, cognitive deficits, and antipsychotic drug dose in schizophrenia patients: a moderation analysis

Patlola, S. R., Hallahan, B., McManus, R., Kenyon, M., McDonald, C., Morris, D., Kelly, J., Donohoe, G., & McKernan, D. P. (2026). Investigating the relationship between Toll-like receptor activity, low-grade inflammation, cognitive deficits, and antipsychotic drug dose in schizophrenia patients: a moderation analysis. Psychological Medicine, 56, e63, 1–10 https://doi.org/10.1017/S0033291726103596

Abstract

Background Schizophrenia (SZ) is a debilitating psychiatric disorder where patients experience cognitive decline. Antipsychotic drugs alleviate positive symptoms but do not improve cognitive performance. We previously demonstrated that Toll-like receptors (TLRs), involved in cytokine production, can predict cognitive deficits in SZ patients. In this study, we aim to investigate the potential moderating effects of antipsychotic drugs on the associations between cytokines, TLRs, and cognition. Methods In total, 280 participants (201 controls and 79 cases of SZ) were recruited in Ireland. Venous blood from the participants was stimulated with TLR ligands. Levels of cytokines were measured from plasma and post-blood stimulation. The participants were administered a battery of cognitive tasks using the Cambridge Neuropsychological Test Automated Battery and Wechsler Adult Intelligence Scale-IIIR. Olanzapine equivalents were calculated using the defined daily dose method. Results The results indicate that antipsychotic drug dose does not predict TLR activity or cognition, indicating that antipsychotic drug dose does not have a direct effect on cognition or TLR activity. However, the relationship between TLR4 activity and visual learning and memory is moderated by the antipsychotic drug dose (B = −0.065; p < 0.001), where increasing doses have a decreasing impact on their relationship. Conclusions Our data indicate that the dose of antipsychotic drugs alone cannot predict changes in cognitive performance and TLR4-activity. It also suggests that antipsychotic drug doses significantly affect TLR activity and its relationship with cognition. These effects are more pronounced on some domains than others. These findings open up new avenues for understanding the complex interplay between antipsychotic drugs, TLRs, and cognitive deficits in SZ.

Funder

University of Galway
European Research Council

Publisher

Cambridge University Press

Rights

CC BY

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