Antipsychotics (APs) are treatment of choice for schizophrenia spectrum disorders (SSD); however, they are associated with a higher risk of antipsychotic-induced metabolic syndrome (AIMetS) [1]. Metabolic syndrome (MetS) is a cluster of pathological conditions, including central (abdominal) obesity, high blood pressure (BP), fasting hyperglycaemia, triglyceridaemia, and decreased serum high-density lipoprotein cholesterol (HDL-C) [2]. Increased MetS prevalence in many countries [3] leads to higher mortality rates [4] and the economic burden [5]. According to the International Diabetes Federation (IDF), 20–25% of the world adult population has MetS, and the probability of premature mortality in MetS patients is three times higher than wiyhout the syndrome1.

AIMetS prevalence is high and ranges from 37 to 63%, including its main components: weight gain / waist circumference, dyslipidemia, insulin resistance / type 2 diabetes mellitus, and arterial hypertension [6]. AIMetS plays a crucial role in increased risk of premature mortality in SSD patients, mainly of cardiovascular diseases [7]. Negative metabolic AP effects affect more than half of psychiatric patients, children and adolescents being the highest-risk groups, which is a serious obstacle to long-term treatment of socially significant diseases, including SSDs [8][9].

Since prolonged use of APs (more than 3 months) can contribute to AIMetS, international clinical guidelines underline the need for initial physical and laboratory examination of naive patients (prior to AP prescription), as well as subsequent monitoring of clinical and laboratory (biochemical, hormonal) markers for the early detection and treatment of this adverse drug reaction (ADR) [10]. Expanding knowledge about the individual tolerance of well-established typical / atypical APs and the search for new AIMetS biomarkers can help improve the safety of SSD pharmacotherapy and minimise the risk of a drug-induced metabolic disorder [11][12].

The AIMetS mechanisms are not yet clear enough, therefore psychiatrists have access to only a few mitigating (reduced AP dosage or discontinued active SSD therapy with the AP that caused this condition) or alternative actions (optimised lifestyle and diet of an SSD patient) for correcting this AP-induced ADR [13]. This highlights the importance of finding new ways to predict and timely diagnose AIMetS, using, among others, epigenetic biomarkers that predict the risk of adverse reactions following psychopharmacotherapy with a higher sensitivity than classical approaches do [14]. Such promising epigenetic biomarkers include circulating small non-coding ribonucleic acids (microRNAs) [15–17] that play an important role in the regulation of various physiological and pathological processes.

The aim is to evaluate the potential of circulating microRNAs as epigenetic biomarkers for the prediction and early diagnosis of AIMetS.

The analysed fundamental and clinical studies concentrated on circulating microRNAs as epigenetic biomarkers of the main MetS and AIMetS mechanisms, which was included in the Google Scholar, PubMed, Scopus, eLibrary.ru databases for 2014–2024. Search keywords: "метаболический синдром", "антипсихотик", "антипсихотик-индуцированный метаболический синдром", "эпигенетический биомаркер", "микроРНК", "metabolic syndrome", "antipsychotic", "antipsychotic-induced metabolic syndrome", "epigenetic biomarker", "microRNAs". Inclusion criteria: access type – open access to the full-text publication in the Russian or English language; publication type – original article, systematic review, meta-analysis, and Cochrane review. Exclusion criteria: duplicate publications, dissertations, and thesis abstracts published under the copyright.

The analysed publications assessed changes in the expression levels of circulating microRNAs (plasma, serum, exosomes, mononuclears).

According to the new IDF2 definition (2023), to diagnose MetS, a patient must have central obesity (increased waist circumference (Table 1, published on the journal website3) compared with ethnic norms) plus any two of the following markers: serum triglycerides (TG) >150 mg/dL (1.7 mmol/L) or specific treatment of triglyceridemia; serum HDL-C <40 mg/dL (1.03 mmol/L) in men and <50 mg/dL (1.29 mmol/L) in women or specific treatment of this lipid metabolism disorder; increased systolic blood pressure ≥130 mmHg, increased diastolic blood pressure ≥85 mmHg or treatment of previously diagnosed hypertension; fasting plasma glucose >100 mg/dL (5.6 mmol/L) or previously diagnosed type 2 diabetes mellitus (if >100 mg/dL (5.6 mmol/L), a glucose tolerance test is strongly recommended). In 2023, the IDF experts also developed additional clinical and laboratory (biochemical, hormonal) MetS markers (Table 2, published on the journal website4; the Table also adapted materials from [14][18][19].

Biomarkers can be used not only to classify and assess the individual risk of developing and progressing mental disorders and comorbid diseases in a patient, but to assess the safety and risk of standard and novel therapeutic strategies [20], including the risk of both primary and secondary MetS in SSD patients (drug-induced), as is the case with AIMetS [8]. In recent years, the pattern of AIMetS laboratory biomarkers has expanded significantly as a result of Russian and foreign fundamental and clinical studies (Table 3).

Considering the study results of these laboratory biomarkers, it is proposed to diagnose three degrees of AIMetS in SSD patients receiving AP for 3 months or more: specific, possible, and probable [14]. Specific AIMetS is marked by: ≥3 MetS clinical criteria (according to the current IDF international criteria or the National Cholesterol Education Program Adult Treatment Panel III (ATP III)/ National Cholesterol Education Program Adult Treatment Panel III-advanced (ATP III-A)5 while taking APs for ≥3 months as a mono- or polytherapy; ≥3 additional AIMetS blood biomarkers (plasma and serum) and ≥3 AIMetS markers of in urine.

Possible AIMetS shows 1 to 3 MetS clinical criteria in accordance with current international criteria (ATP III, ATP III-A or IDF) while taking APs for ≥3 months as a mono- or polytherapy; 1 to 3 blood biomarkers (plasma and serum) or 1 to 3 biomarkers in urine.

Probable AIMetS is marked by the lack of MetS clinical criteria (in accordance with ATP III, ATP III-A or IDF criteria) after ≥ 3 months of taking APs as a mono- or polytherapy; the presence of individual (single) biomarkers of MetS in blood (plasma and serum) and/or single biomarkers in urine.

However, absence of the above clinical and laboratory MetS biomarkers in patients with mental disorders within 3 months of AP therapy does not exclude the risk of AIMetS in the future if AP is continued. Dynamic monitoring of these biomarkers is important in patients with possible AIMetS (once every three months) and with probable AIMetS (once every six months) [14].

Sensitivity and specificity of laboratory (biochemical and hormonal) AIMetS biomarkers can vary in a wide range depending on the environmental factors (geography and climate, nutrition, and sociocultural factors), age and gender of patients with mental disorders, as well as sampling and storage of samples. This encourages researchers to look for new AIMetS biomarkers that would have a better stability profile in blood samples, as well as a good reproducibility of research results in various laboratories. Circulating microRNAs are promising epigenetic biomarkers [15–17] that may contain data on the environment and lifestyle impact on the health of an SSD patient, and also allow monitoring the effectiveness of treatments applied for this mental disorder [27–30].

Advance in epigenomics opened up new possibilities, allowing SSD diagnosis and control and predicting an adverse response to psychopharmacotherapy more accurately, efficiently, and quickly [30][31] than using standard approaches based on the previously proposed clinical and biochemical MetS and AIMetS markers [15][16]. Candidate epigenetic biomarkers are selected from a huge number of molecules produced by cells and tissues in case of MetS and AIMetS during preclinical and clinical studies, including microRNAs and histone posttranslational modifications that can be analysed in a wide range of biological samples (blood plasma, serum, saliva, urine, breast milk, fresh and frozen tissues, formalin-fixed paraffin-embedded tissues, etc.). MicroRNAs are stable and reproducible during sample processing and can be used for MetS and AIMetS prediction and their early diagnosis (identification) in SSD patients, as well as for clarifying natural course and outcome [30].

MicroRNAs are small non–coding single-stranded RNAs (19–25 nucleotides) involved in transcriptional and post-transcriptional regulation of gene expression through specific interactions with target genes [32]. MicroRNAs play an important role in the regulation of various physiological and pathological processes involved in MetS and AIMetS mechanisms, including oxidative stress [33][34], systemic inflammation [35][36], adipocyte differentiation and central obesity [35–37], lipid and glucose metabolism [35][38–50], regulation of appetite changes [51–54][56], changes in: neuropeptide Y (NPY) expression [51][56][57], leptin sensitivity [36][56][57], orexin expression [58][59], testosterone levels [60], thyroid hormones [61] and parathyroid hormone [62] (Table 4). The signature of circulating microRNAs in AIMetS patients receiving AP differs from that in naive patients (before AP prescription) and in healthy people [33–56][58–62].

Over the recent years, an extensively discussed hypothesis is that circulating microRNAs can participate in initiation and modification of the development and severity [36][63][64] for both AIMetS and MetS associated with SSD itself [65-67]. In addition, polymorphic variants in microRNA-coding genes and/or in the binding sites of target genes and microRNAs can alter the expression levels of circulating microRNAs in the blood, which is also associated with MetS and AIMetS risk and severity in patients with mental disorders [68][69].

Circulating microRNAs are promising biomarkers of AIMetS occurrence and severity in SSD patients due to the simple and accessible obtaining of biological samples. Over the past 10 years, Russian and foreign studies have demonstrated that circulating microRNAs and their mediated regulation of the metabolic response to APs can be considered as a basic level of epigenetic control for various pathogenetic AIMetS mechanisms and individual variability in AP safety in general, including the risk of therapeutic resistance to APs [70].

Despite its frequent occurrence in psychopharmacotherapy, the problem of early AIMetS detection is far from being resolved. The first part of this review describes approaches to the spectrum and assessment of the main and additional clinical / laboratory MetS markers in SSD patients in general and AIMetS in particular. Previously used classical biomarkers (biochemical, hormonal) are individually variable and influenced by both environmental factors and sample preparation / storage of biological samples, which affects their ex vivo stability.

Circulating microRNAs are involved in the initiation and modification of the development of all AIMetS manifestations, including oxidative stress, systemic inflammation, adipocyte differentiation, lipid and glucose metabolism, appetite regulation, changes in neuropeptide Y expression, leptin sensitivity, orexin expression, testosterone levels, thyroid hormones, and parathyroid hormone. MicroRNAs are promising as AIMetS prognostic and diagnostic biomarkers, as they are detected in easily accessible samples (blood, saliva, urine), are highly stable in the stored biological samples (including during multiple cycles of freezing and thawing), better reproducibility, and higher sensitivity in individual patients compared with classical biomarkers.

The second part of the review will consider the role of specific circulating microRNAs as epigenetic biomarkers of the main AIMetS domains. The authors will also describe their ideas on the gradation of microRNA signatures in SSD patients depending on AIMetS risk (low, medium, high) and discuss the prospects for their clinical use in the psychiatric practice.

1. The IDF consensus worldwide definition of the metabolic syndrome. IDF; 2006. https://idf.org/media/uploads/2023/05/attachments-30.pdf 2. The IDF consensus worldwide definition of the metabolic syndrome. IDF; 2006. https://idf.org/media/uploads/2023/05/attachments-30.pdf 3. https://doi.org/10.30895/2312-7821-2025-478-tabl1-2 4. https://doi.org/10.30895/2312-7821-2025-478-tabl1-2 5. National Cholesterol Education Program High Blood Cholesterol ATP III Guidelines At-A-Glance: Quick Desk Reference. https://www.nhlbi.nih.gov/files/docs/guidelines/atglance.pdf 6. https://www.biovendor.com/file/5881/PDS_67_HOME_ENG.004.A_EV.pdf?version=202303080807https://www.abcam.com/products/elisa-kits/human-mcp-1-elisa-kit-ab179886.htmlhttps://practical-haemostasis.com/Fibrinolysis/pai_1.htmlhttps://www.athensresearch.com/products/human-proteins/retinol-binding-protein-human-plasma-rbp-4https://www.randox.com/superoxide-dismutase-ransod/