MiRNA Differences Related to Treatment-Resistant Schizophrenia

Abstract

Schizophrenia (SZ) is a serious mental disorder that is typically treated with antipsychotic medication. Treatment-resistant schizophrenia (TRS) is the condition where symptoms remain after pharmacological intervention, resulting in long-lasting functional and social impairments. As the identification and treatment of a TRS patient requires previous failed treatments, early mechanisms of detection are needed in order to quicken the access to effective therapy, as well as improve treatment adherence. In this study, we aim to find a microRNA (miRNA) signature for TRS, as well as to shed some light on the molecular pathways potentially involved in this severe condition. To do this, we compared the blood miRNAs of schizophrenia patients that respond to medication and TRS patients, thus obtaining a 16-miRNA TRS profile. Then, we assessed the ability of this signature to separate responders and TRS patients using hierarchical clustering, observing that most of them are grouped correctly (~70% accuracy). We also conducted a network, pathway analysis, and bibliography search to spot molecular pathways potentially altered in TRS. We found that the response to stress seems to be a key factor in TRS and that proteins p53, SIRT1, MDM2, and TRIM28 could be the potential mediators of such responses. Finally, we suggest a molecular pathway potentially regulated by the miRNAs of the TRS profile.

MyBrain-Seq: A Pipeline for MiRNA-Seq Data Analysis in Neuropsychiatric Disorders

“…An early version of myBrain-Seq (v0.1.0) was used in Pérez-Rodríguez et al 2023 to perform all analysis steps up to quantification [ 8 ]. In this study, myBrain-Seq was used to identify 16 differentially expressed miRNAs (DE miRNAs) between the MR and MNR conditions using DESeq2.…”

“…MyBrain-Seq has already been used in a real case study in which we compared schizophrenia patients who responded to medication to treatment-resistant schizophrenia patients to obtain a 16-miRNA treatment-resistant schizophrenia profile [ 8 ]. We were able to reproduce all the findings from the case study up to the functional analysis stage, including the miRNA profile suggested in Pérez-Rodríguez et al 2023, as well as the hierarchical clustering.…”

“…The application of myBrain-Seq to biomedical research is illustrated in a recent study [ 8 ] with the comparison of the miRNA profile of patients with schizophrenia (SZ) and treatment-resistant schizophrenia (TRS). The dataset comprises reads of circulating miRNA of 40 human patients with schizophrenia, of which 19 patients have a normal response to medication (MR; n = 19) and 21 have an insufficient response to medication (MNR; n = 21).…”

“…As epigenetic regulators, they are closely associated with adaptation processes and their expression levels are affected by events such as diet, sleep, stress or medications [ 7 ]. Nowadays, miRNAs are recognized as important etiological factors of neuropsychiatric diseases such as schizophrenia [ 8 , 9 ], depression [ 10 , 11 ] or Alzheimer’s disease [ 12 , 13 ], and thus have potential to be biomarkers and therapeutic targets. As a result, the number of studies using miRNA-Seq has increased in the last decade [ 7 ], leading to the creation of miRNA databases such as the human microRNA disease database (HMDD) [ 14 ], the Central Nervous System microRNA Profiles (CNS microRNA Profiles) [ 15 ] and the Human miRNA Expression Database (miRmine) [ 16 ].…”

“…In this study, we demonstrate the usefulness of myBrain-Seq by showing how it is applied to a real case study in which we compared schizophrenia patients who responded to medication with treatment-resistant schizophrenia patients to obtain a 16-miRNA treatment-resistant schizophrenia profile [ 8 ].…”