Blood Biomarkers of Antipsychotic-Induced Metabolic Syndrome: Comparison
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Please note this is a comparison between Version 2 by Conner Chen and Version 1 by Natalia A. Shnayder.

A biomarker is a characteristic that is objectively measured and evaluated to detect disease in patients. Traditionally, laboratory diagnoses of Metabolic syndrome (MetS) and assessments of cardiovascular risk (CVR) include analyses of blood (serum or plasma) biomarkers, i.e., total cholesterol (TC), TG, HDL-Ctriglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), insulin and C-peptide.

  • metabolic syndrome
  • antipsychotic-induced metabolic syndrome
  • personalized psychiatry
  • psychometabolomics

1. Blood (Serum and Plasma) Biomarkers of Antipsychotic-Induced Metabolic Syndrome

A biomarker is a characteristic that is objectively measured and evaluated to detect disease in patients. Biomarkers act as prognostic tools for classifying and assessing disease progression. They are used to monitor clinical response and positive effects of old (classical) and new therapeutic strategies [17][1].
Traditionally, laboratory diagnoses of metabolic syndrome (MetS) and assessments of CVR include analyses of blood (serum or plasma) biomarkers, i.e., total cholesterol (TC), TG, HDL-Ctriglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), insulin and C-peptide [18][2].
The mechanisms of MetS development continue to be studied, with many studies indicating that it is closely associated with inflammation [19][3], insulin resistance [20][4], vascular endothelial dysfunction [21][5], renal dysfunction [22][6], oxidative stress [23][7] and liver dysfunction [24][8]. It is promising and reasonable to use panels of biomarkers for diagnosing MetS. WIt can be analyzed studies not only of traditional biomarkers, but also of some new biomarkers associated with inflammatory response and subsequent CVR. MetS has long been associated with dyslipidemia [25][9].
Metabolic overload causes oxidative stress, a condition where the balance between the production and inactivation of reactive oxygen species (ROS) is disturbed. These substances play an important role in many physiological systems, but under conditions of increased oxidative stress, they contribute to cellular dysfunction [26][10]. Oxidative stress may play an important role in MetS-related manifestations (atherosclerosis, arterial hypertension (AH), diabetes mellitus (DM) [27][11]. Oxidative stress may be an early event in the pathology of these chronic diseases, and not just a consequence or concomitant process [28][12]. MetS is accompanied by a chronic, indolent inflammatory state, or meta-inflammation, that is, metabolically induced inflammation [29][13], or even para-inflammation [30][14]. Some evidence [31][15] suggests that inflammation explains some of CVR, but this does not rule out other mechanisms. It is also worth emphasizing that oxidative stress and mild inflammation are quite closely related pathogenetically [32][16].
In this study, we considered eight groups of 38 biomarkers: carbohydrates, acids, hormones, other organic compounds, proteins, lipids, enzymes and vitamins.

2. Carbohydrates

Glucose

Elevated fasting glucose (>100 mg/dL) or pharmacotherapy for elevated glucose is one of the MetS criteria [1,2,3][17][18][19]. Most patients with MetS have elevated plasma glucose levels. Fasting plasma glucose levels in the range of 100–125 mg/dL or 2-h postprandial levels of 140–199 mg/dL characterize prediabetes, while diabetes mellitus (DM) is defined as fasting glucose >126 mg/dL or postprandial levels > 200 mg/dL [33][20].
Insulin resistance is the main cause of hyperglycemia in patients with MetS; however, compensatory hyperinsulinemia can lead to normal glucose levels in insulin resistance. When pancreatic beta cell function decreases, compensatory mechanisms fail. Hyperglycemia develops as a later complication and is not the first sign of MetS. Chronic hyperglycemia often leads to microvascular diseases such as chronic kidney disease (CKD) and DM. Diabetic neuropathy may be partially associated with microvascular disease [34][21]. Microvascular diseases can further accelerate the development of congestive heart failure (HF) and contribute to atherogenesis [35][22].
There is evidence of a possible common mechanism for the development of DM and schizophrenia (Sch). More than 38 reports link poor fetal growth with impaired glucose metabolism later in life [36][23]. Most studies have demonstrated an inverse relationship between birth weight and plasma glucose and insulin levels, type 2 DM (DM2) and insulin resistance. Low birth weight (due to intrauterine development delay or prematurity) is associated with subsequent neurological and psychiatric problems, including Sch, in children and adolescents [37][24]. However, the mechanisms underlying these associations have not been sufficiently studied. Nevertheless, acute starvation of the mother in the first trimester of pregnancy during the Dutch famine winter of 1944 led to a two-fold increase in the risk of developing Sch in offspring [38][25].
Also, the development of MetS may be associated not only with the development of Sch, but also with the use of antipsychotics (APs) in the treatment thereof. In a blind, randomized, controlled trial involving 157 patients with Sch treated with clozapine, olanzapine, risperidone or haloperidol for 14 weeks, the following results were reported: clozapine, olanzapine, and haloperidol were found to be associated with an increase in glucose levels, while both clozapine and olanzapine are also associated with an increase of serum level of cholesterol [39][26]. There is also emerging evidence that glucose disturbances may occur shortly after the beginning of the administration of Aps, and that these disturbances may be reversible upon discontinuation of APs, indicating a direct effect of APs on the function of the pancreas [40][27].

3. Acids

3.1. Sialic Acid

Many acute-phase inflammatory proteins (e.g., haptoglobin, alpha-glycoprotein, fibrinogen, transferrin and complement) are glycoproteins with sialic acid (Sia) as the terminal sugar of the oligosaccharide chain, so serum Sia concentration can be considered a biomarker of acute-phase inflammation response [41][28]. Serum Sia is a possible CVR. The overall level of Sia is also increased in DM2 [42][29]. Elevated serum and urinary Sia concentrations are strongly associated with the presence of microvascular complications in patients with DM2 [43][30]. Thus, elevated levels strongly correlate with the presence of MetS [44][31].
In the general population, a positive correlation has been found between Sia levels and C-reactive protein (CRP) levels [45][32]. In one study, the authors concluded that this biomarker identifies overweight persons with an inflammatory phenotype who are at high risk of developing MetS [46][33]. Large-scale epidemiological studies have found a positive correlation between plasma levels of Sia and the risk of coronary CHDheart disease (CHD),. There is evidence that aberrant sialylation of LDL, LDL receptors and blood cells is involved in the pathological process of atherosclerosis.
Sia regulates the immune response by binding to the immunoglobulin-like lectin-binding Sia (Siglecs). The Sia-Siglecs axis is involved in immune inflammation in atherosclerosis [47][34]. Polysialic acid (polySia) is a unique Sia polymer that spatiotemporally modifies the neural cell adhesion molecule (NCAM) in the embryonic brain. PolySia is an important molecule associated with Sch, regulating intercellular communication through an anti-adhesive effect. PolySia regulates multimolecules such as brain-derived neurotrophic factor (BDNF) and fibroblast growth factor-2 (FGF2) and dopamine. Recently, several studies have reported that PolySia is pathogenetically associated with Sch and other psychiatric disorders [48][35].
There have been isolated studies that have measured the concentration of Sia acid in patients with Sch; however, due to the small sample size, the findings do not have the required level of reliability [49][36], and further research is needed on the association of increased serum Sia in patients with Sch, as well as in patients with Sch and MetS, i.e., antipsychotic-induced MetS (AIMetS).

3.2. Uric Acid

Uric acid is a product of the metabolic breakdown of purine nucleotides. The enzyme xanthine oxidase produces uric acid from xanthine and hypoxanthine, which, in turn, are derived from other purines [50][37]. Uric acid is a powerful antioxidant [51][38]. An increase in the level of this biomarker is observed in obesity, and a relationship with MetS is also evident [52][39]. A longitudinal study showed that elevated serum levels of uric acid is a strong biomarker of MetS [53][40], and that elevated uric acid is also correlated with several cardiovascular risk factors [54][41]. Uric acid also tends to worsen insulin resistance and exacerbate hyperlipidemia and fatty liver [55][42]. It has been suggested that acute uric acid elevation is a protective factor, while chronic uric acid elevation is a risk factor, but there is still no consensus on this issue [56][43]. Uric acid is not an independent biomarker for predicting MetS, and the question of whether this relationship is causal remains to be explored [57][44]. It is worth noting that in one study in men with Sch treated with haloperidol, plasma uric acid levels were significantly lower than in the control group. Additionally, after discontinuation of haloperidol, plasma uric acid levels further decreased in patients with Sch. There was also a trend toward a decrease in uric acid levels in patients with relapse compared with clinically stable patients [58][45]. In a meta-analysis of all case-control studies investigating serum and plasma uric acid levels in subjects with Sch compared to those in healthy subjects, uric acid levels were reduced in subjects having recently experienced their first episode of psychosis, but in the remaining cases, there were no statistically significant differences in uric acid levels between patients with Sch and healthy controls. These data support the clinical evidence that the first psychotic episode is accompanied by an increased response to oxidative stress [59][46]. Thus, it can be assumed that the complex pathogenetic mechanisms of uric acid involvement in Sch and MetS need to be considered and further investigated for more accurate use as a potential marker of AIMetS.

4. Hormones

4.1. Adiponectin

Adiponectin is a hormone that is synthesized and secreted by white adipose tissue, mainly adipocytes of the visceral region. Its secretion is stimulated by insulin [60][47]. Adiponectin is involved in the regulation of glucose levels and fatty acid breakdown [61][48]. Adiponectin concentration is inversely associated with insulin resistance, DM2 and dyslipidemia [62][49], and an inverse association with MetS has also been confirmed in various studies conducted in different countries [63][50].
Since adiponectin has anti-inflammatory and anti-atherogenic effects, it is also inversely related to a number of risk factors for cardiac ischemia in obese and overweight people [64,65][51][52]. The anti-inflammatory effects of adiponectin were confirmed by the facts that adiponectin is inversely proportional to the level of C-reactive protein (CRP), interleukin (IL)-6 and IL-10, and that it suppresses the production of tumor necrosis factor alpha (TNF-a) by macrophages [66][53]. A prospective study confirmed the role of adiponectin in the development of cardiometabolic disorders in obese patients [67][54]. Also, scientists are considering screening MetS using adiponectin [68][55]. High levels of adiponectin correlate with increased insulin sensitivity and glucose tolerance [69][56].
Clinical and preclinical data have shown that the inability to stimulate the production of adiponectin is associated with metabolic disorders caused by APs. Sch itself is not associated with lower blood levels of adiponectin [70][57]. In schizophrenic patients with MetS, blood levels of adiponectin are lower compared to patients without MetS, and blood levels of adiponectin decrease as MetS components increase [71][58]. In patients with Sch taking APs, the level of adiponectin in the blood is also lower than in healthy people [70][57]. It was found that blood levels of adiponectin increased after a year of administration of risperidone in previously untreated patients with psychotic disorders [72][59]. Blood levels of adiponectin were also found to increase in patients with Sch treated with risperidone for 3 and 12 months, respectively [73][60].
In patients with Sch taking olanzapine for more than 3 months, there is a decrease in the level of adiponectin in the blood [73,74][60][61]. In patients with Sch receiving clozapine for a long time, the level of adiponectin in the blood is lower than in healthy people [75][62]. In patients with Sch treated with clozapine for at least 3 months, blood levels of adiponectin are negatively associated with weight gain and metabolic biomarkers after chronic administration of clozapine [76][63].
Thus, it is necessary to take into account changes in the concentration of adiponectin in the blood of patients with Sch, as well as for those receiving and not receiving APs treatment, since not all APs are able to induce MetS, and a decrease in adiponectin is not always observed when taking Aps. This issue requires further study and research.

4.2. Aldosterone

Aldosterone is a mineralocorticoid hormone that is involved in the regulation of sodium balance. It is elevated in patients with MetS [77][64]. An increase in aldosterone may exacerbate the development of MetS-related AH [78][65]. Also, aldosterone excess may predispose or exacerbate metabolic and cardiovascular complications in patients with obstructive sleep apnea syndrome [79][66].
There is also evidence of an increase in renin activity and plasma aldosterone levels during treatment with haloperidol as a dopamine antagonist; however, it should be noted that MetS was not studied in these patients [80][67].

4.3. Chemerin

Chemerin is an adipokine that has chemoattractant activity. This adipokine is secreted as an inactive pro-protein [81][68]. Chemerin and its receptors are mainly expressed in adipose tissue. Chemerin, as an adipokine, was found to be involved in the pathophysiology of MetS. Plasma concentrations of chemerin were closely associated with body mass index (BMI), TG and blood pressure (BP) [82][69]. Recent studies have demonstrated high plasma levels of chemerin in patients with incipient MetS, which indicates the involvement of this adipokine in the pathogenesis of MetS and its role as an early metabolic biomarker [83][70]. Also, chemerin is considered a biomarker of atherosclerosis in MetS, and an elevated level thereof is considered an independent predictive biomarker of cardiac ischemia in patients with MetS [84][71]. Chemerin and adiponectin may be reciprocally involved in the development of MetS [85][72]. Clinical data consistently indicate that circulating chemerin levels are elevated in patients with obesity, DM and cardiovascular disease (CVD) [86][73].
In a rat study, in addition to inducing hyperphagia and weight gain associated with increased AMP-activated protein kinase activity and decreased H1 receptor expression in the arcuate nucleus, the administration of olanzapine also increased hypothalamic chemerin, presumably in response to weight gain [87][74].

4.4. Ghrelin

Ghrelin is a peptide of 28 amino acids which is involved in the regulation of appetite, as well as energy balance [88][75]. It is produced predominantly by enteroendocrine cells of the gastric fundus [89][76], and has a wide range of effects on various tissues and organs of the human body, including stimulation of the secretion of lactotrophs and corticotrophs, effects on the function of the gastrointestinal tract and pancreas, regulation of insulin secretion, regulation of glucose and lipid metabolism, influence on behavior and sleep, and regulation of the functions of the cardiovascular system [90][77]. Ghrelin characteristically increases food intake and body weight due to its orexigenic, adipogenic and somatotropic properties [91][78].
Blood (plasma) levels of ghrelin decrease in obesity and increase in anorexia nervosa in humans [92][79]. A progressive decline in basal ghrelin levels is associated with an increase in BMI [93][80]. Low ghrelin concentrations are also associated with higher MetS prevalence [94][81]. The total levels of ghrelin in plasma in obese patients with MetS are lower compared to those in non-obese patients. Recently, no significant difference in ghrelin concentrations was found between postmenopausal women with and without MetS [95][82].
An analysis of five prospective and three cross-sectional studies suggested that the concentration of ghrelin in the blood in the treatment of APs is biphasic and depends on the duration of treatment, i.e., it decreases in the early stages and increases in the late periods [96][83].

4.5. Insulin

Insulin is a protein hormone. It is produced in the beta cells of the islets of Langerhans of the pancreas. It has a multifaceted effect on metabolism in almost all tissues. The main action of insulin is the regulation of carbohydrate metabolism, in particular, the utilization of glucose in the body [97][84]. The level of insulin in the blood increases by 30–70% in Sch patients with chronic administration of clozapine or olanzapine [98][85]. It has also been reported that olanzapine-treated patients have significantly higher mean insulin levels than those treated with conventional APs, despite having the same BMI, suggesting a possible effect of olanzapine on pancreatic insulin secretion [99][86]. Because hyperinsulinemia appears to be concentration-dependent in both clozapine-treated and olanzapine-treated patients, lowering the doses of these drugs may reduce hyperinsulinemia in affected patients [100][87]. Insulin is a hormone that can cause weight gain by directly affecting adipose tissue and appetite through hypoglycemia. Reducing the dose of clozapine or olanzapine may lead to weight loss in patients with AP-induced obesity by reducing the severity of hyperinsulinemia [101][88].

4.6. Leptin

Leptin (LEP) is a proteohormone involved in the modulation of appetite, regulation of energy balance and weight [102][89]. A loss of LEP leads to obesity [103][90]. In particular, LEP acts on the hypothalamus to reduce food intake and increase energy expenditure [104][91]. During periods of energy balance (maintenance of body weight), blood LEP concentrations reflect the total amount of fat in the human body [105][92]. LEP is involved in peripheral insulin resistance, impairs the action of insulin on insulin-responsive cells and may induce insulin resistance by affecting insulin secretion. In the human liver, leptin has been shown to attenuate the number of insulin-induced actions that ultimately lead to insulin resistance [106][93]. Subjects with MetS have higher LEP levels compared to individuals without MetS [107][94]. Various authors have stated that plasma LEP is a significant predictor of MetS risk [108][95].
Clozapine and a number of other APs have been shown to increase serum levels of leptin, which may cause AP-induced weight gain. The single nucleotide variant (SNV) rs7799039 (G2548A) in the promoter region of the LEP gene was found to be associated with the obesity phenotype. This SNV affects LEP expression and increases the level of LEP secretion by adipose tissue adipocytes. This SNV was found to be associated with AP-induced weight gain after 10 weeks of risperidone or chlorpromazine administration in Chinese patients with Sch. In addition, the homozygous AA genotype may be a genetic biomarker of AIMetS [109][96].

4.7. Omentin

Human omentin is a 313 amino acid peptide [110][97] originally identified in omental fat. It is reduced in obese patients [111][98], and is downregulated in association with metabolic disorders with obesity [112][99]. Circulating omentin levels are negatively correlated with metabolic risk factors. Omentin has been suggested as a biomarker for MetS [113][100] and has also been reported as a biomarker for endothelial dysfunction in patients with MetS [114][101].
In a study comparing plasma concentrations of omentin in patients with Sch and healthy individuals, it was found that omentin levels were significantly lower in patients with Sch. It was also found that omentin concentration was negatively correlated with the severity of the disease, which suggests that fasting omentin levels are lower in patients with more severe pathologies [115][102].

4.8. Parathyroid Hormone

Elevated plasma levels of parathyroid hormone (PTH) [116][103] have been associated with MetS and each of its individual components [117][104]. PTH elevation is considered a compensatory mechanism for low 25(OH)D. In most cases, PTH, but not vitamin D, is associated with MetS [118][105]. The role of PTH as a link between PTH levels and biomarkers of inflammation in the adult population of the USA has been confirmed [119][106]. High PTH levels are associated with a higher risk of cardiorenal MetS [120][107]. However, some authors argue that serum 25(OH)D, but not PTH, was significantly related to the levels of MetS and several of its component [121][108].
In a prospective study of patients with psychiatric disorders who took APs, a trend of decreasing PTH after a week of taking Aps was found. In that study, the lack of significance of the indicators was due to the small sample [122][109].

4.9. Testosterone

There is evidence that testosterone is involved in stimulating glucose uptake, glycolysis, stimulating glucose utilization and mitochondrial oxidative phosphorylation. Testosterone is also involved in the homeostasis of lipids in tissues such as the liver, adipose tissue and skeletal muscle [123][110]. Testosterone levels decrease with MetS [124][111]. Intervention studies have shown beneficial effects of testosterone on MetS components [125][112] and improved body composition [126][113].
In a cross-sectional study of 190 patients with Sch taking APs, it was found that the decrease in testosterone levels in patients at high risk of MetS was statistically significant, and the five metabolic indices proposed in the study were negatively correlated with testosterone levels. Thus, testosterone has been proposed as a MetS biomarker in Sch [127][114].
Also, in a prospective study of testosterone levels in 78 male patients taking APs, at week 3 of the study, with Sch, a negative effect of APs, elevated prolactin levels and a higher BMI on blood testosterone levels was revealed. At week 8, serum testosterone concentrations were also significantly reduced [128][115].

4.10. Thyroid-Stimulating Hormone

An increase in thyroid-stimulating hormone (TSH) levels has been associated with less favorable lipid concentrations [129][116]. In addition, a slightly elevated serum TSH concentration is associated with increased incidence of obesity [130][117]. Many publications have noted that higher concentrations of TSH are associated with MetS [131][118]. However, the CVR may be high, even with normal TSH [132][119]. In another publication, higher TSH levels and subclinical hypothyroidism are associated with an increased likelihood of prevalence, but not incidence, of MetS [133][120].
A strong negative correlation was found between negative symptoms on the Positive and Negative Syndrome Scale (PANSS) and TSH levels [134][121]. In addition, changes in TG levels are associated with the use of APs [135][122]. In patients with Sch and MetS, TG levels were significantly higher compared with patients with MetS Sch and patients with MetS in a general hospital [136][123]. However, a study of 151 patients with Sch receiving long-acting injectable APs demonstrated no change in TSH in patients with or without MetS [137][124].

5. Other Organic Compounds

Bilirubin

Bilirubin is considered a potentially toxic metabolite of heme catabolism [138][125]. However, it has well-known antioxidant and anti-inflammatory properties, as evidenced by its ability to scavenge peroxyl radicals, inhibit LDL oxidation and repress the expression of cell adhesion molecules, vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion 1 (ICAM-1) in vitro [139][126]. Moderately elevated bilirubin levels are negatively associated with MetS and other diseases mediated by oxidative stress [140][127]. Studies in Asian countries have shown that serum total bilirubin in the upper normal range may provide some protection against MetS and reduce future CVR [141][128]. The fact that highly sensitive CRP (hsCRP) is inversely related to bilirubin also indicates that low bilirubin levels are associated with systemic inflammation [142][129].
In a study of 131 patients with Sch receiving APs, it was found that the level of direct bilirubin is associated with the diagnosis and course of MetS. These results are similar to those of previous studies in the general population, in overweight individuals and in patients with CVD [143][130]. Low levels of direct bilirubin in blood serum are associated with the initial and subsequent diagnosis of MetS, WC and TG criteria at the initial stage, and fasting glucose criteria at follow-up. It was shown that the serum level of indirect bilirubin is statistically significantly associated only with WC criteria at the initial stage. In cases of obesity and MetS, when oxidative stress increases, bilirubin consumption increases, resulting in a decrease in serum bilirubin levels which leads to an increased CVR causing endothelial dysfunction, given the antioxidant properties of bilirubin. The relationship between serum direct bilirubin levels and MetS has also been shown in many previous studies [144][131]. In a sample of 5321 patients, the association between direct bilirubin and the diagnosis of MetS observed during the first and second (after 6 months) visits confirmed this conclusion. Lower levels of direct bilirubin have been associated with more MetS criteria [145][132]. Risk of MetS is increased two to five times in patients with serum direct bilirubin levels in the lower interquartile percentile (0–75th percentile) compared with those in the uppermost percentile (75th–100th percentile), and an increase in total bilirubin by one standard deviation reduces the risk of MetS by 17%. Similarly, a study by Karadag F. et al. showed that MetS diagnosis was significantly lower in the high bilirubin group [144][131].

6. Proteins

6.1. Adipocyte Fatty Acid-Binding Protein

Adipocyte fatty acid-binding protein (A-FABP) is a small lipid-binding protein with a molecular weight of 15 kDa. It is an adipokine [146][133], i.e., it is predominantly produced from adipocytes, but is also produced in macrophages [147][134] and endothelial cells [148][135]. The relationship between the diagnosis of MetS and serum A-FABP had a sensitivity of 40% and a specificity of 99% at a protein level of 16 mg/L [149][136]. Several cross-sectional studies have shown that A-FABP is independently and positively associated with MetS biomarkers, especially those associated with obesity [150][137]. A-FABP is elevated in patients with familial combined hyperlipidemia [151][138] and in patients with non-alcoholic fatty liver disease, which is considered a hepatic manifestation of MetS [152][139]. The level of this protein is also increased in patients with atherosclerosis [153][140] and CVD [154][141]. Elevated A-FABP levels are also associated with left ventricular diastolic dysfunction in MetS comorbid obesity, suggesting that A-FABP is associated with cardiometabolic disorders [155][142]. A high level of A-FABP may be predictive for the development of MetS and CVD [156][143]. A-FABP decreases after weight loss and statine therapy [157][144].

6.2. C-Peptide

C-peptide is a by-product of insulin synthesis. It is produced in equal molar amounts relative to insulin, primarily by the kidneys, and has a half-life three to four times that of insulin [158][145]. C-peptide is clinically useful for diagnosing patients with insulin-dependent diseases and may be a biomarker for monitoring MetS in patients with DM2 [159][146]. Since there is one molecule of C-peptide for every insulin molecule, it is a good biomarker for assessing the amount of endogenous insulin. C-peptide levels are higher in patients with MetS [160][147]. The role of C-peptide is considered as a prognostic biomarker of CVR [161][148].
In a longitudinal study of 112 patients with Sch treated with APs for 8 weeks, C-peptide levels increased significantly in all groups (divided by APs received), but not fasting glucose. Also, the concentration of cholesterol and TG was significantly increased in the clozapine and olanzapine groups. In patients treated with clozapine and olanzapine, fasting insulin and C-peptide levels were higher than in patients treated with risperidone and sulpiride. Among the four APs, the increase in mean BMI from high to low was as follows: clozapine, olanzapine, sulpiride, and risperidone [162][149]. Similar conclusions were outlined in another study that evaluated, among other things, the level of C-peptide after 7 months of APs treatment in patients with Sch who had not previously received APs. Seven months of APs treatment reduced clinical symptoms but significantly increased BMI, increased the levels of C-peptide (p-value = 0.03) and leptin (p-value = 0.02) and decreased the level of adiponectin (p-value = 0.01) [163][150].

6.3. Ligand CD40

The CD40 ligand (CD40L), a pro-inflammatory mediator, is expressed on CD4+ T cells and is activated by platelets. CD40L is expressed on vascular cells and is increased by MetS [164][151]. CD40L levels are higher in patients with MetS and cardiac ischemia [165][152]. The CD40L–CD40 interaction is important in the cascade of inflammatory and pro-atherothrombotic reactions [166][153]. This ligand has not yet been studied in patients receiving APs against AIMetS.

6.4. Cystatin C

Cystatin-C (cys-C) is a 15 kDa protein that acts as a negative regulator of proatherogenic cysteine proteases [167][154]. It is also a new biomarker of kidney and cardiovascular function [168][155]. Since patients with MetS are at high risk of developing renal failure [169][156], cys-C has been proposed as a sensitive endogenous serum biomarker for changes in glomerular glomerular filtration rate [170][157]. The level of cys-C is higher in patients with MetS, regardless of creatinine clearance [171][158]. A progressive increase in cys-C levels, depending on the amount of MetS components [172][159], indicates an increased risk of CVD [173][160]. A high level of cys-C may be predictive biomarker of MetS, also in the diagnosis of cardiac ischemia [174][161]. This protein has not yet been studied in patients receiving APs against AIMetS.

6.5. Ferritin

Ferritin is a protein and the main intracellular iron storage mechanism. It is synthesized in hepatocytes [175][162]. Serum ferritin level is a biomarker for assessing the overload of the human body with iron. In addition, elevated ferritin levels are a biomarker of oxidative stress and MetS [176][163]. An increase in serum ferritin is characteristic of some hereditary metabolic diseases, including familial combined hyperlipidemia and familial hypertriglyceridemia [177][164].
In an animal model study where rats were given APs (clozapine and haloperidol) for 12 weeks, female rats were found to store iron in the form of hepatic hemosiderin or ferritin granules, which is reflected in higher serum ferritin levels and hemosiderin in the liver, while male rats treated with clozapine increased the level of hepatic hemosiderin [178][165]. However, another study demonstrated that the concentrations of ferritin in patients with various psychiatric disorders taking APs were inversely proportional to the weight gain induced by risperidone, even after prolonged treatment and despite adequate iron intake. It has also been concluded that low iron stores are associated with poorer response to treatment. Future studies should investigate iron absorption during APs treatment and elucidate the relationship between ferritin levels and AIMetS [179][166].

6.6. Fibrinogen

Fibrinogen is a blood plasma protein. Upon activation of the blood coagulation system, it undergoes enzymatic cleavage by the enzyme thrombin. The resulting fibrin, under the action of active coagulation factor XIII, precipitates in the form of white threads of fibrin-polymer. Together with plasminogen activator inhibitor 1 (PAI-1), high plasma fibrinogen levels contribute to the elevated CVR, characteristic of people with MetS [180][167]. Hyperfibrinogenemia has long been regarded as MetS [181][168]. In contrast to the control group, a correlation between higher levels of fibrinogen and MetS was found in the offspring of patients with AH [182][169].
Patients treated with typical APs had slightly elevated PAI-1 but similar fibrinogen levels compared to patients treated with atypical APs. In addition, the mean plasma levels of fibrinogen and PAI-1 in Sch patients who had taken APs for more than 10 years were slightly higher than those who had taken APs for 10 years or less. Patients taking typical APs and those having used atypical APs for more than 10 years may benefit from periodic assessment of prothrombotic biomarkers for early assessment of the risk AIMetS [183][170].

6.7. Fibroblast Growth Factor-21

Fibroblast growth factor (FGF)-21 is a polypeptide produced predominantly in liver tissues [184][171]. It has beneficial effects on glucose and lipid metabolism and has high insulin sensitivity [185][172]. Serum levels of FGF-21 were significantly higher in overweight/obese individuals than in normal or underweight individuals. The level of FGF-21 was positively correlated with obesity, fasting insulin and TG and negatively with LDL-C. An association between FGF-21 and MetS has been found in adults [186][173] but not in children [187][174]. Elevated levels of FGF-21 are associated with carotid atherosclerosis, regardless of established risk factors, including adverse lipid profiles and CRP [188][175].
It is currently proposed that the FGF system is involved in a variety of processes that are likely associated with Sch, and that manipulation of FGF and its receptors results in Sch-associated phenotypes in rodents. It has also been hypothesized that genetic variations in growth factors (FGF and other factors such as BDNF) increase the risk of developing psychiatric disorders. Because these growth factors play a role in the development of the nervous system, they can lead to the subtle changes in brain structure seen in Sch. WIt can be known that disruption of FGF signaling can affect dopamine signaling, neuronal proliferation and differentiation in the cerebral cortex. Dopamine disturbances and (prefrontal) cortical dysfunction are associated with Sch and may exacerbate each other. The FGF gene encoding a protein of the same name has been proposed as a candidate gene for Sch and other major mental disorders [189][176].

6.8. Monocyte Chemoattractant Protein-1

Monocyte chemoattractant protein-1 (MCP-1) is considered a key cytokine in the recruitment of monocytes from the blood to early atherosclerotic lesions and plays an important role in atherosclerosis, secreted by adipocytes [190][177]. MCP-1 levels are higher in patients with MetS and are associated with mild systemic inflammatory response [191][178]. Elevated MCP-1 levels have also been observed in patients with DM2 with MetS [192][179].
In a study in China, MCP-1 and IL-8 concentrations were significantly higher in patients with Sch than in controls. In addition, the serum concentrations of MCP-1 and IL-8 in patients were positively correlated with the severity of AIMetS symptoms [193][180].

6.9. Plasminogen Activator Inhibitor-1

Plasminogen activator inhibitor 1 (PAI-1) is a protein of the blood coagulation system. It is a member of the proteins of the serine protease inhibitor superfamily (serpins) [194][181]. PAI-1 is the main and fast-acting inhibitor of the fibrinolytic system [195][182] which is sometimes called the prothrombotic adipokine [196][183]. Elevated plasma PAI-1 is a common feature in MetS patients [197][184] and is directly related to disease severity [198][185]. Moderate-intensity exercise [199][186] and weight loss with a low-calorie diet reduces PAI-1 levels [200][187].

6.10. Retinol-Binding Protein 4

Retinol-binding protein 4 (RBP-4) is a protein that specifically transports retinol in the blood. It is predominantly produced in the liver but is also produced in increased amounts by adipocytes in obesity, which contributes to impaired insulin action [201][188]. In a cross-sectional study, it was found that levels of RBP-4 gradually increased with an increase in the number of MetS components [202][189]. Moreover, elevated plasma levels of RBP-4 have been associated with an unfavorable profile of markers of oxidative stress and inflammation [203][190]. RBP-4 correlates with waist-to-hip ratio or areas of visceral fat [204][191], and can be used as a predictive biomarker for MetS [205][192]. A marked decrease in RBP-4 levels after bariatric surgery correlates with a decrease in visceral fat mass and the degree of change in MetS severity [206][193].

6.11. Tumor Necrosis Factor Alpha

Tumor necrosis factor alpha (TNF-α) is a pro-inflammatory cytokine that modifies adipose tissue function, influences adipogenesis and is involved in complications associated with obesity [207][194]. TNF-α levels are elevated in patients with MetS [208][195].
Increased levels of TNF-α (p-value < 0.005) were also found in patients with Sch with an average and high risk of AIMetS compared with a control group [209][196].

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