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Brain-derived neurotrophic factor (BDNF) is implicated in the etiology and treatment response in major depressive disorder (MDD). However, peripheral BDNF concentrations have not been compared across different MDD stages. Bright light therapy (BLT) offers some potential in treatment-resistant depression (TRD), but its effects on BDNF levels are unknown. This study included a cross-sectional analysis of plasma BDNF concentration in females with TRD, unmedicated MDD patients, and healthy controls (HC), and measurements of longitudinal BLT effects on plasma BDNF levels in TRD patients. The present study included 55 drug-naïve, first-episode patients, 25 drug-free recurrent-episode MDD patients, 71 HC participants, and 54 TRD patients. Patients were rated by Hamilton Depression Rating Scale (HAMD)-17 and the Montgomery–Åsberg Depression Rating Scale (MADRS). Patients with TRD received BLT during 4 weeks. The total HAMD-17 and MADRS scores decreased following BLT. All patient groups had lower plasma BDNF than HC, but BDNF levels did not differ between first- and recurrent-episode BDNF patients and TRD patients before or after BLT. However, responders and remitters to BLT had higher post-treatment plasma BDNF concentrations than patients who did not achieve response or remission. The changes in plasma BDNF levels may be candidates for biomarkers of treatment response to BLT in TRD patients.

The aim of this study was to perform a genome-wide expression analysis of whole-blood samples from people with optic neuritis (ON) and to determine differentially expressed mRNAs compared to healthy control subjects. The study included eight people with acute ON and six healthy control subjects. Gene expression was analyzed using DNA microarrays for whole-human-genome analysis, which contain 54,675 25-base pairs. The additional biostatistical analysis included gene ontology analysis and gene set enrichment analysis (GSEA). Quantitative RT-PCR (qPCR) was used to confirm selected differentially expressed genes. In total, 722 differently expressed genes were identified, with 377 exhibiting increased, and 345 decreased, expression. Gene ontology analysis and GSEA revealed that protein phosphorylation and intracellular compartment, apoptosis inhibition, pathways involved in cell cycles, T and B cell functions, and anti-inflammatory central nervous system (CNS) pathways are implicated in ON pathology. qPCR confirmed the differential expression of eight selected genes, with SLPI, CR3, and ITGA4 exhibiting statistically significant results. In conclusion, whole-blood gene expression analysis showed significant differences in the expression profiles of people with ON compared to healthy control subjects. Additionally, pathways involved in T cell regulation and anti-inflammatory pathways within CNS were identified as important in the early phases of MS.

Negative symptoms of schizophrenia, including anhedonia, represent a heavy burden on patients and their relatives. These symptoms are associated with cortical hypodopamynergia and impaired striatal dopamine release in response to reward stimuli. Catechol-O-methyltransferase (COMT) and monoamine oxidase type B (MAO-B) degrade dopamine and affect its neurotransmission. The study determined the association between COMT rs4680 and rs4818, MAO-B rs1799836 and rs6651806 polymorphisms, the severity of negative symptoms, and physical and social anhedonia in schizophrenia. Sex-dependent associations were detected in a research sample of 302 patients with schizophrenia. In female patients with schizophrenia, the presence of the G allele or GG genotype of COMT rs4680 and rs4818, as well as GG haplotype rs4818-rs4680, which were all related to higher COMT activity, was associated with an increase in several dimensions of negative symptoms and anhedonia. In male patients with schizophrenia, carriers of the MAO-B rs1799836 A allele, presumably associated with higher MAO-B activity, had a higher severity of alogia, while carriers of the A allele of the MAO-B rs6651806 had a higher severity of negative symptoms. These findings suggest that higher dopamine degradation, associated with COMT and MAO-B genetic variants, is associated with a sex-specific increase in the severity of negative symptoms in schizophrenia patients.

Catechol-O-methyl transferase (COMT) gene variants are involved in different neuropsychiatric disorders and cognitive impairments, associated with altered dopamine function. This study investigated the genotypic and haplotypic association of COMT rs4680 and rs4618 polymorphisms with the severity of cognitive and other clinical symptoms in 544 male and 385 female subjects with schizophrenia. COMT rs4818 G carriers were more frequent in male patients with mild abstract thinking difficulties, compared to CC homozygotes or C allele carriers. Male carriers of COMT rs4680 A allele had worse abstract thinking (N5) scores than GG carriers, whereas AA homozygotes were more frequent in male subjects with lower scores on the intensity of the somatic concern (G1) item, compared to G carriers. Male carriers of COMT rs4818–rs4680 GA haplotype had the highest scores on the G1 item (somatic concern), whereas GG haplotype carriers had the lowest scores on G2 (anxiety) and G6 (depression) items. COMT GG haplotype was less frequent in female patients with severe disturbance of volition (G13 item) compared to the group with mild symptoms, while CG haplotype was more frequent in female patients with severe then mild symptoms. These findings suggest the sex-specific genotypic and haplotypic association of COMT variants with a severity of cognitive and other clinical symptoms of schizophrenia.

The complex role of the serotonin system in respiratory function and inflammatory diseases such as asthma is unclear. Our study investigated platelet serotonin (5-HT) levels and platelet monoamine oxidase B (MAO-B) activity, as well as associations with HTR2A (rs6314; rs6313), HTR2C (rs3813929; rs518147), and MAOB (rs1799836; rs6651806) gene polymorphisms in 120 healthy individuals and 120 asthma patients of different severity and phenotypes. Platelet 5-HT concentration was significantly lower, while platelet MAO-B activity was considerably higher in asthma patients; however, they did not differ between patients with different asthma severity or phenotypes. Only the healthy subjects, but not the asthma patients, carrying the MAOB rs1799836 TT genotype had significantly lower platelet MAO-B activity than the C allele carriers. No significant differences in the frequency of the genotypes, alleles, or haplotypes for any of the investigated HTR2A, HTR2C and MAOB gene polymorphisms have been observed between asthma patients and healthy subjects or between patients with various asthma phenotypes. However, the carriers of the HTR2C rs518147 CC genotype or C allele were significantly less frequent in severe asthma patients than in the G allele carriers. Further studies are necessary to elucidate the involvement of the serotonergic system in asthma pathophysiology.

The molecular underpinnings of post-traumatic stress disorder (PTSD) are still unclear due to the complex interactions of genetic, psychological, and environmental factors. Glycosylation is a common post-translational modification of proteins, and different pathophysiological states, such as inflammation, autoimmune diseases, and mental disorders including PTSD, show altered N-glycome. Fucosyltransferase 8 (FUT8) is the enzyme that catalyzes the addition of core fucose on glycoproteins, and mutations in the FUT8 gene are associated with defects in glycosylation and functional abnormalities. This is the first study that investigated the associations of plasma N-glycan levels with FUT8-related rs6573604, rs11621121, rs10483776, and rs4073416 polymorphisms and their haplotypes in 541 PTSD patients and control participants. The results demonstrated that the rs6573604 T allele was more frequent in the PTSD than in the control participants. Significant associations of plasma N-glycan levels with PTSD and FUT8-related polymorphisms were observed. We also detected associations of rs11621121 and rs10483776 polymorphisms and their haplotypes with plasma levels of specific N-glycan species in both the control and PTSD groups. In carriers of different rs6573604 and rs4073416 genotypes and alleles, differences in plasma N-glycan levels were only found in the control group. These molecular findings suggest a possible regulatory role of FUT8-related polymorphisms in glycosylation, the alternations of which could partially explain the development and clinical manifestation of PTSD.

In the last decade, increasing evidence has emerged linking alterations in the brain-derived neurotrophic factor (BDNF) expression with the development of Alzheimer’s disease (AD). Because of the important role of BDNF in cognition and its association with AD pathogenesis, the aim of this study was to evaluate the potential difference in plasma BDNF concentrations between subjects with mild cognitive impairment (MCI; N = 209) and AD patients (N = 295) and to determine the possible association between BDNF plasma levels and the degree of cognitive decline in these individuals. The results showed a significantly higher (p < 0.001) concentration of plasma BDNF in subjects with AD (1.16; 0.13–21.34) compared with individuals with MCI (0.68; 0.02–19.14). The results of the present study additionally indicated a negative correlation between cognitive functions and BDNF plasma concentrations, suggesting higher BDNF levels in subjects with more pronounced cognitive decline. The correlation analysis revealed a significant negative correlation between BDNF plasma levels and both Mini-Mental State Examination (p < 0.001) and Clock Drawing test (p < 0.001) scores. In conclusion, the results of our study point towards elevated plasma BDNF levels in AD patients compared with MCI subjects, which may be due to the body’s attempt to counteract the early and middle stages of neurodegeneration.

Neutrophil–lymphocyte ratio (NLR), platelet–lymphocyte ratio (PLR), monocyte–lymphocyte ratio (MLR) and systemic immune-inflammation index (SII index) are increasingly used as indicators of inflammation in different conditions, including schizophrenia. However, their relationship with negative symptoms, including anhedonia, is largely unknown. Included were 200 patients with schizophrenia and 134 healthy controls (HC), assessed for physical anhedonia (PA), using the Revised Physical Anhedonia Scale (RPAS), and social anhedonia (SA) by the Revised Social Anhedonia Scale (RSAS). Patients were rated by the Positive and Negative Syndrome Scale (PANSS), the Clinical Assessment Interview for Negative Symptoms (CAINS) and the Brief Negative Symptom Scale (BNSS). Most of the negative symptoms were in a weak to moderate positive correlations with blood cell inflammatory ratios, namely, between NLR and MLR with PANSS negative scale, CAINS, and BNSS, and in male patients, between PLR and PANSS negative scale and CAINS. Fewer correlations were detected in females, but also in a positive direction. An exception was SA, given the negative correlation between its severity and the SII index in females, and its presence and higher PLR in males. While different negative symptoms were associated with subclinical inflammation, the relationship between SA and lower inflammatory markers deserves further exploration.

Due to the increasing number of progressive dementias in the population, numerous studies are being conducted that seek to determine risk factors, biomarkers and pathological mechanisms that could help to differentiate between normal symptoms of aging, mild cognitive impairment (MCI) and dementia. The aim of this study was to investigate the possible association of levels of BDNF and COMT gene expression and methylation in peripheral blood cells with the development of Alzheimer’s disease (AD). Our results revealed higher expression levels of BDNF (p < 0.001) in MCI subjects compared to individuals diagnosed with AD. However, no difference in COMT gene expression (p = 0.366) was detected. DNA methylation of the CpG islands and other sequences with potential effects on gene expression regulation revealed just one region (BDNF_9) in the BDNF gene (p = 0.078) with marginally lower levels of methylation in the AD compared to MCI subjects. Here, we show that the level of BDNF expression in the periphery is decreased in subjects with AD compared to individuals with MCI. The combined results from the gene expression analysis and DNA methylation analysis point to the potential of BDNF as a marker that could help distinguish between MCI and AD patients.

Abstract Antipsychotic drugs target primarily dopaminergic system which makes catechol-O-methyltransferase (COMT) an interesting target in studies searching for treatment response predictors in schizophrenia. The study assessed the association of the COMT rs4680 and rs4818 polymorphisms with therapeutic response to olanzapine, risperidone, clozapine or other antipsychotic medication after 8 weeks of monotherapy in patients with schizophrenia. 521 Caucasian patients with schizophrenia received a monotherapy with olanzapine (10–20 mg/day; N = 190), risperidone (3–6 mg/day; N = 99), or clozapine (100–500 mg/day; N = 102). The fourth group (N = 130) consisted of patients receiving haloperidol (3–15 mg/day), fluphenazine (4–25 mg/day) or quetiapine (50–800 mg/day). Treatment response was defined as a 50% reduction from the baseline positive and negative syndrome scale (PANSS) total and subscale scores, but also as an observed percentage reduction from the initial PANSS0–6 total and subscale scores. Carriers of the COMT rs4680 A allele and carriers of the COMT rs4680–rs4818 C-A haplotype block had greater reduction in the PANSS total scores following olanzapine treatment, compared to carriers of the COMT rs4680 GG genotype and other COMT rs4680–rs4818 haplotypes. The COMT rs4680 A allele, and COMT rs4680–rs4818 C-A haplotype, were significantly associated with therapeutic response in patients treated with olanzapine, but not in patients treated with other antipsychotics.

A decrease in serotonergic transmission throughout the brain is among the earliest pathological changes in Alzheimer’s disease (AD). Serotonergic receptors are also affected in AD. Polymorphisms in genes of serotonin (5HT) receptors have been mostly associated with behavioral and psychological symptoms of dementia (BPSD). In this study, we examined if AD patients carrying different genotypes in 5HTR1B rs13212041, 5HTR2A rs6313 (T102C), 5HTR2C rs3813929 (−759C/T), and 5HTR6 rs1805054 (C267T) polymorphisms have a higher risk of faster disease progression (assessed by neuropsychological testing), are more prone to develop AD-related pathology (reflected by levels of cerebrospinal fluid [CSF] AD biomarkers), or have an association with an apolipoprotein E (APOE) haplotype. This study included 115 patients with AD, 53 patients with mild cognitive impairment (MCI), and 2701 healthy controls. AD biomarkers were determined in the CSF of AD and MCI patients using enzyme-linked immunosorbent assays (ELISA), while polymorphisms were determined using either TaqMan SNP Genotyping Assays or Illumina genotyping platforms. We detected a significant decrease in the CSF amyloid β1–42 (Aβ1–42) and an increase in p-tau181/Aβ1–42 ratio in carriers of the T allele in the 5HTR2C rs3813929 (−759C/T) polymorphism. A significantly higher number of APOE ε4 allele carriers was observed among individuals carrying a TT genotype within the 5HTR2A T102C polymorphism, a C allele within the 5HTR1B rs13212041 polymorphism, and a T allele within the 5HTR6 rs1805054 (C267T) polymorphism. Additionally, individuals carrying the C allele within the 5HTR1B rs13212041 polymorphism were significantly more represented among AD patients and had poorer performances on the Rey–Osterrieth test. Carriers of the T allele within the 5HTR6 rs1805054 had poorer performances on the MMSE and ADAS–Cog. As all four analyzed polymorphisms of serotonin receptor genes showed an association with either genetic, CSF, or neuropsychological biomarkers of AD, they deserve further investigation as potential early genetic biomarkers of AD.

Antipsychotic-induced parkinsonism (AIP) is the most common type of extrapyramidal side effect (EPS), caused by the blockage of dopamine receptors. Since dopamine availability might influence the AIP risk, the dopamine transporter (DAT) and serotonin receptors (5-HTRs), which modulate the dopamine release, may be also involved in the AIP development. As some of the individual differences in the susceptibility to AIP might be due to the genetic background, this study aimed to examine the associations of SLC6A3, HTR2C and HTR6 gene polymorphisms with AIP in haloperidol-treated schizophrenia patients. The Extrapyramidal Symptom Rating Scale (ESRS) was used to evaluate AIP as a separate entity. Genotyping was performed using a PCR, following the extraction of blood DNA. The results revealed significant associations between HTR6 rs1805054 polymorphism and haloperidol-induced tremor and rigidity. Additionally, the findings indicated a combined effect of HTR6 T and SLC6A3 9R alleles on AIP, with their combination associated with significantly lower scores of ESRS subscale II for parkinsonism, ESRS-based tremor or hyperkinesia and ESRS subscales VI and VIII. These genetic predictors of AIP could be helpful in better understanding its pathophysiology, recognizing the individuals at risk of developing AIP and offering personalized therapeutic strategies for the patients suffering from this EPS.

Various metals have been associated with the pathogenesis of Alzheimer’s disease (AD), principally heavy metals that are environmental pollutants (such as As, Cd, Hg, and Pb) and essential metals whose homeostasis is disturbed in AD (such as Cu, Fe, and Zn). Although there is evidence of the involvement of these metals in AD, further research is needed on their mechanisms of toxicity. To further assess the involvement of heavy and essential metals in AD pathogenesis, we compared cerebrospinal fluid (CSF) AD biomarkers to macro- and microelements measured in CSF and plasma. We tested if macro- and microelements’ concentrations (heavy metals (As, Cd, Hg, Ni, Pb, and Tl), essential metals (Na, Mg, K, Ca, Fe, Co, Mn, Cu, Zn, and Mo), essential non-metals (B, P, S, and Se), and other non-essential metals (Al, Ba, Li, and Sr)) are associated with CSF AD biomarkers that reflect pathological changes in the AD brain (amyloid β1–42, total tau, phosphorylated tau isoforms, NFL, S100B, VILIP-1, YKL-40, PAPP-A, and albumin). We used inductively coupled plasma mass spectroscopy (ICP-MS) to determine macro- and microelements in CSF and plasma, and enzyme-linked immunosorbent assays (ELISA) to determine protein biomarkers of AD in CSF. This study included 193 participants (124 with AD, 50 with mild cognitive impairment, and 19 healthy controls). Simple correlation, as well as machine learning algorithms (redescription mining and principal component analysis (PCA)), demonstrated that levels of heavy metals (As, Cd, Hg, Ni, Pb, and Tl), essential metals (Ca, Co, Cu, Fe, Mg, Mn, Mo, Na, K, and Zn), and essential non-metals (P, S, and Se) are positively associated with CSF phosphorylated tau isoforms, VILIP-1, S100B, NFL, and YKL-40 in AD.

Post-traumatic stress disorder (PTSD) is a complex trauma-related disorder, the etiology and underlying molecular mechanisms of which are still unclear and probably involve different (epi)genetic and environmental factors. Protein N-glycosylation is a common post-translational modification that has been associated with several pathophysiological states, including inflammation and PTSD. Hepatocyte nuclear factor-1α (HNF1A) is a transcriptional regulator of many genes involved in the inflammatory processes, and it has been identified as master regulator of plasma protein glycosylation. The aim of this study was to determine the association between N-glycan levels in plasma and immunoglobulin G, methylation at four CpG positions in the HNF1A gene, HNF1A antisense RNA 1 (HNF1A-AS1), rs7953249 and HNF1A rs735396 polymorphisms in a total of 555 PTSD and control subjects. We found significant association of rs7953249 and rs735396 polymorphisms, as well as HNF1A gene methylation at the CpG3 site, with highly branched, galactosylated and sialyated plasma N-glycans, mostly in patients with PTSD. HNF1A-AS1 rs7953249 polymorphism was also associated with PTSD; however, none of the polymorphisms were associated with HNF1A gene methylation. These results indicate a possible regulatory role of the investigated HNF1A polymorphisms with respect to the abundance of complex plasma N-glycans previously associated with proinflammatory response, which could contribute to the clinical manifestation of PTSD and its comorbidities.

Post-traumatic stress disorder (PTSD) is a trauma-related disorder. Platelet monoamine oxidase (MAO-B) is a peripheral biomarker associated with various symptoms in different psychopathologies, but its role in PTSD or different symptoms in PTSD is not clear. This study elucidated the association between platelet MAO-B activity and clinical symptoms occurring in PTSD. Platelet MAO-B activity was determined in 1053 male Caucasian subjects: 559 war veterans with PTSD (DSM-5 criteria), 62 combat exposed veterans who did not develop PTSD, and 432 non-combat exposed healthy controls. Clinical symptoms in PTSD were determined using CAPS and PANSS. Platelet MAO-B activity, controlled for the effect of smoking, was significantly increased in PTSD with severe versus mild and moderate traumatic symptoms, and was significantly decreased in PTSD subjects with severe versus mild positive, psychotic, and depressive symptoms. This finding was further confirmed with reduced platelet MAO-B activity in PTSD veterans with severe versus mild individual items of the PANSS-depressed, PANSS-psychotic, and PANSS-positive subscales. Altered platelet MAO-B activity, controlled for the possible confounders, was associated with the development and severity of different symptoms occurring in PTSD. These findings confirmed the role of platelet MAO-B activity as a peripheral marker of various psychopathological symptoms.

Schizophrenia, depression and posttraumatic stress disorder (PTSD) are severe mental disorders and complicated diagnostic entities, due to their phenotypic, biological and genetic heterogeneity, unknown etiology, and poorly understood alterations in biological pathways and biological mechanisms. Disturbed homeostasis between overproduction of oxidant species, overcoming redox regulation and a lack of cellular antioxidant defenses, resulting in free radical-mediated pathology and subsequent neurotoxicity contributes to development of depression, schizophrenia and PTSD, their heterogeneous clinical presentation and resistance to treatment. Metabolomics is a discipline that combines different strategies with the aim to extract, detect, identify and quantify all metabolites that are present in a biological sample and might provide mechanistic insights into the etiology of various psychiatric disorders. Therefore, oxidative stress research combined with metabolomics might offer a novel approach in dissecting psychiatric disorders, since these data-driven but not necessarily hypothesis-driven methods might identify new targets, molecules and pathways responsible for development of schizophrenia, depression or PTSD. Findings from the oxidative research in psychiatry together with metabolomics data might facilitate development of specific and validated prognostic, therapeutic and clinical biomarkers. These methods might reveal bio-signatures of individual patients, leading to individualized treatment approach. In reviewing findings related to oxidative stress and metabolomics in selected psychiatric disorders, we have highlighted how these novel approaches might make a unique contribution to deeper understanding of psychopathological alterations underlying schizophrenia, depression and PTSD. Keywords: Schizophrenia, Depression, Posttraumatic stress disorder, Oxidative stress, Lipid peroxidation, Metabolomics, Biomarkers

Abstract Background Type II diabetes is an important health problem with a complex connection to obesity, leading to a broad range of cardiovascular complications. Insulin therapy often results in weight gain and does not always ensure adequate glycemic control. However, previous studies reported that insulin detemir is an efficient long-acting insulin with a weight sparing effect. The aim of this study was to determine the association of catechol O-methyltransferase (COMT) Val108/158Met and dopamine-beta-hydroxylase (DBH) 1021C/T polymorphisms with the effectiveness of insulin detemir in achieving glucose control and body weight control. Participants and methods: This 52-week observational study included 185 patients with inadequate glycemic control treated with premix insulin analogues, which were replaced with insulin aspart and insulin detemir, and 156 healthy controls. After DNA isolation from blood samples, genotyping of DBH-1021C/T polymorphism (rs1611115) and COMT Val108/158Met polymorphism (rs4680) was performed. Results Our results confirmed that insulin detemir did not lead to weight gain. The most significant finding was that A carriers (the combined AG and AA genotype) of the COMT Val108/158Met achieved significantly better hemoglobin A1c (HbA1c) values compared to patients carrying GG genotype. No association between DBH-1021C/T genotypes and weight and/or glucose control was detected in diabetes patients or in healthy control subjects. Conclusions This study showed that the presence of one or two A allele of the COMT Val108/158Met was associated with improved glycemic response, and with a better response to insulin detemir therapy in patients with type II diabetes, separating them as best candidates for detemir therapy.

Repeated activation of the hypothalamic-pituitary-adrenal axis system, sleep disturbances, and other symptoms related to posttraumatic stress disorder (PTSD) elevate reactive oxygen species, increase inflammation, and accelerate cellular aging, leading to neuroprogression and cognitive decline. However, there is no information about possible involvement of 4-hydroxynonenal (4-HNE), the product of lipid peroxidation associated with stress-associated diseases, in the complex etiology of PTSD. Therefore, the aim of this study was to compare the plasma levels of 4-HNE between war veterans with PTSD (n = 62) and age-, sex- and ethnicity- matched healthy control subjects (n = 58) in order to evaluate the potential of HNE-modified proteins as blood-based biomarker of PTSD. The genuine 4-HNE-Enzyme-Linked Immunosorbent Assay (HNE-ELISA), based on monoclonal antibody specific for HNE-histidine (HNE-His) adducts, was used to determine plasma HNE-protein conjugates. Our results revealed significantly elevated levels of 4-HNE in patients with PTSD. Moreover, the accumulation of plasma 4-HNE seems to increase with aging but in a negative correlation with BMI, showing specific pattern of change for individuals diagnosed with PTSD. These findings suggest that oxidative stress and altered lipid metabolism reflected by increase of 4-HNE might be associated with PTSD. If confirmed with further studies, elevated 4-HNE plasma levels might serve as a potential biomarker of PTSD.

Posttraumatic stress disorder (PTSD) is frequently associated with cognitive disturbances and high prevalence of smoking. This study evaluated cognition in war veterans with PTSD and control subjects, controlled for the effect of smoking and brain derived neurotrophic factor (BDNF) rs6265 and rs56164415 genotypes/alleles. Study included 643 male war veterans with combat related PTSD and 120 healthy controls. Genotyping was done by real time PCR. Cognitive disturbances were evaluated using the Positive and Negative Syndrome Scale (PANSS) cognition subscale and the Rey-Osterrieth Complex Figure (ROCF) test scores. Diagnosis (p < 0.001), BDNF rs56164415 (p = 0.011) and smoking (p = 0.028) were significant predictors of the cognitive decline in subjects with PTSD. BDNF rs56164415 T alleles were more frequently found in subjects with PTSD, smokers and non-smokers, with impaired cognition, i.e., with the higher PANSS cognition subscale scores and with the lower ROCF immediate recall test scores. Presence of one or two BDNF rs56164415 T alleles was related to cognitive decline in PTSD. The T allele carriers with PTSD had advanced cognitive deterioration in smokers and nonsmokers with PTSD, and worse short-term visual memory function. Our findings emphasize the role of the BDNF rs56164415 T allele and smoking in cognitive dysfunction in war veterans with PTSD.

Posttraumatic stress disorder (PTSD) is a trauma and stressor related disorder that may develop after exposure to an event that involved the actual or possible threat of death, violence or serious injury. Its molecular underpinning is still not clear. Brain-derived neurotrophic factor (BDNF) modulates neuronal processes such as the response to stress, but also weight control, energy and glucose homeostasis. Plasma BDNF levels and a functional BDNF Val66Met (rs6265) polymorphism were reported to be associated with PTSD, as well as with increased body mass index (BMI) and dyslipidaemia in healthy subjects and patients with cardio-metabolic diseases, but these results are controversial. The other frequently studied BDNF polymorphism, C270T (rs56164415), has been associated with the development of different neuropsychiatric symptoms/disorders. As far as we are aware, there are no data on the association of BDNF Val66Met and C270T polymorphisms with metabolic indices in PTSD. Due to high rates of obesity and dyslipidaemia in PTSD, the aim of this study was to elucidate the association of BDNF Val66Met and C270T polymorphisms with BMI and lipid levels in veterans with PTSD. We hypothesized that BDNF variants contribute to susceptibility to metabolic disturbances in PTSD. The study included 333 Caucasian males with combat related PTSD, diagnosed according to DSM-5 criteria. Genotyping of the BDNF Val66Met and C270T polymorphisms was performed using the real-time PCR method. Results were analyzed using hierarchical multiple linear regression and the Mann–Whitney test, with p-value corrected to 0.005. The results showed that BDNF Val66Met and BDNF C270T polymorphisms were not significantly associated with BMI, total cholesterol, LDL-cholesterol, HDL-cholesterol or triglycerides. Although the BDNF C270T polymorphism was nominally associated only with HDL-cholesterol in veterans with PTSD, this significance disappeared after controlling for the effect of age. Namely, slightly higher plasma HDL values in T allele carriers, compared to CC homozygotes, were associated with differences in age. Our results, controlled for the critical covariates, revealed that BDNF Val66Met and C270T were not significantly associated with metabolic indices in veterans with PTSD and that these genetic variants do not contribute to susceptibility to metabolic disturbances in PTSD.

There are currently no validated biomarkers which can be used to accurately diagnose Alzheimer’s disease (AD) or to distinguish it from other dementia-causing neuropathologies. Moreover, to date, only symptomatic treatments exist for this progressive neurodegenerative disorder. In the search for new, more reliable biomarkers and potential therapeutic options, epigenetic modifications have emerged as important players in the pathogenesis of AD. The aim of the article was to provide a brief overview of the current knowledge regarding the role of epigenetics (including mitoepigenetics) in AD, and the possibility of applying these advances for future AD therapy. Extensive research has suggested an important role of DNA methylation and hydroxymethylation, histone posttranslational modifications, and non-coding RNA regulation (with the emphasis on microRNAs) in the course and development of AD. Recent studies also indicated mitochondrial DNA (mtDNA) as an interesting biomarker of AD, since dysfunctions in the mitochondria and lower mtDNA copy number have been associated with AD pathophysiology. The current evidence suggests that epigenetic changes can be successfully detected, not only in the central nervous system, but also in the cerebrospinal fluid and on the periphery, contributing further to their potential as both biomarkers and therapeutic targets in AD.

Juvenile delinquency is related to several biological factors, yet very few vulnerability biomarkers have been identified. Previous data suggest that the enzyme monoamine oxidase B (MAO-B) influences several personality traits linked to the propensity to engage in delinquent behavior. Building on this evidence, we assessed whether conduct disorder (CD), juvenile delinquency adjudications, or detention in a correctional facility were associated with either platelet MAO-B activity or the MAOB rs1799836 polymorphism. The study enrolled 289 medication-free male youths, including 182 individuals detained in a correctional facility (with or without a diagnosis of CD). Of the remaining 107 participants, 26 subjects had a diagnosis of CD, and 81 were mentally healthy controls. Platelet MAO-B activity was determined by spectrophotofluorometry, while MAOB rs1799836 was genotyped using qPCR. Platelet MAO-B activity, corrected for age and smoking, was significantly higher in juvenile detainees (p < 0.001), irrespective of CD diagnosis. MAOB rs1799836 was not associated with platelet MAO-B activity or with detention in a correctional facility, CD diagnosis, or delinquent behavior. These data suggest that detention in a juvenile correctional facility increases platelet MAO-B activity in male adolescents. Future studies are needed to determine the mechanisms and functional significance of MAO-B peripheral elevation in juvenile male detainees.

Brain-derived neurotrophic factor (BDNF) and its tropomyosin-related kinase B (TrkB) receptor might contribute to normal lung functioning and immune responses; however, their role in asthma remains unclear. Plasma BDNF concentrations, as well as BDNF and NTRK2 (TrkB gene) polymorphisms, were investigated in 120 asthma patients and 120 healthy individuals using enzyme-linked immunosorbent assay and polymerase chain reaction, respectively. The genotype and allele frequencies of BDNF Val66Met (rs6265) and NTRK2 rs1439050 polymorphisms did not differ between healthy individuals and asthma patients, nor between patients grouped according to severity or different asthma phenotypes. Although plasma BDNF concentrations were higher among healthy subjects carrying the BDNF Val66Met GG genotype compared to the A allele carriers, such differences were not detected in asthma patients, suggesting the influences of other factors. Plasma BDNF concentration was not affected by NTRK2 rs1439050 polymorphism. Asthma patients had higher plasma BDNF concentrations than control subjects; however, no differences were found between patients subdivided according to asthma severity, or Type-2, allergic, and eosinophilic asthma. Higher plasma BDNF levels were observed in asthma patients with aspirin sensitivity and aspirin-exacerbated respiratory disease. These results suggest that plasma BDNF may serve as a potential peripheral biomarker for asthma, particularly asthma with aspirin sensitivity.

Schizophrenia is a serious, chronic psychiatric disorder requiring lifelong treatment. Extrapyramidal side effects (EPS) are common adverse reactions to antipsychotic medications. In addition to the dopaminergic system, serotonergic mechanisms, including serotonin (5-HT) receptors, might be involved in EPS development. This study aimed to examine molecular associations of HTR1A, HTR1B, HTR2A, HTR2C and HTR6 gene polymorphisms with acute EPS in 229 male schizophrenia patients, following two weeks of haloperidol monotherapy. The Simpson–Angus Rating Scale for Extrapyramidal Side Effects (SAS), Barnes Akathisia Rating Scale (BARS) and Extrapyramidal Symptom Rating Scale (ESRS) were used to evaluate EPS severity. Genotyping was performed using real-time PCR, following extraction of blood DNA. Significant acute EPS appeared in 48.03% of schizophrenia patients. For the rs13212041 HTR1B gene polymorphism, affecting microRNA regulation of HTR1B gene expression, a higher frequency of TT carriers was found among haloperidol-treated patients with akathisia when compared to the group without akathisia symptoms. In comparison to C-allele carriers, patients carrying the TT genotype had higher akathisia severity, as determined by the SAS, BARS and ESRS scales. These molecular findings suggest potential involvement of 5-HT1B receptors in akathisia development following haloperidol treatment, as well as possible epigenetic mechanisms of serotonergic modulation associated with antipsychotic-induced EPS.

Treatment-resistant schizophrenia (TRS) continues to be a challenge. It was related to different factors, including alterations in the activity of brain dopaminergic system, which could be influenced by the dopamine-degrading enzyme, catechol-O-methyltransferase (COMT). Variants of the COMT gene have been extensively studied as risk factors for schizophrenia; however, their association with TRS has been poorly investigated. The aim of the present study was to determine the haplotypic and genotypic association of COMT rs4680 and rs4818 polymorphisms with the presence of TRS. Overall, 931 Caucasian patients diagnosed with schizophrenia (386 females and 545 males) were included, while 270 participants met the criteria for TRS. In males, no significant haplotypic and genotypic associations between COMT rs4680 and rs4818 polymorphisms and TRS were detected. However, genotypic analyses demonstrated higher frequency of COMT rs4680 AA genotype carriers compared to G-allele carriers (p = 0.033) and higher frequency of COMT rs4818 CC genotype carriers than G-allele carriers (p = 0.014) in females with TRS. Haplotype analyses confirmed that the presence of the G allele in females was associated with lower risk of TRS. In women with TRS, the high activity G-G/G-G haplotype was rare, while carriers of other haplotypes were overrepresented (p = 0.009). Such associations of COMT rs4680 and rs4818 high-activity (G variants), as well as G-G/G-G haplotype, with the lower risk of TRS in females, but not in males, suggest significant, but sex-specific influence of COMT variants on the development of treatment-resistance in patients with schizophrenia. However, due to relatively low number of females, those findings require replication in a larger sample.

El objetivo de este estudio ha sido comparar la frecuencia de trastornos somáticos en veteranos de guerra y personas no expuestas a la experiencia traumática del campo de batalla, así como determinar si la exposición a factores socio-demográficos en tiempo de guerra pueden predisponer a traumas, alteraciones o trastornos somáticos. El estudio incluye 1.558 pacientes del sur de Croacia: 501 varones veteranos de guerra con Trastorno de Estrés Postraumático (TEPT) y un grupo de control de 825 varones no expuestos a la experiencia de combate. Los veteranos con TEPT, independientemente del tiempo pasado en la guerra, desarrollan más a menudo alteraciones gastrointestinales, cardiovasculares, dermatológicas, locomotoras, pulmonares y metabólicas que los sujetos del grupo control. Los indicadores de alteraciones cardiológicas, locomotoras, entre otros, han sido la edad, el tiempo pasado en combate y el daño allí sufrido. Un largo período en la zona de combate ha sido asociado con arritmias y otras complicaciones de tipo psiquiátrico. El TEPT, como resultado de la exposición a experiencias traumáticas del campo de batalla, incrementa la posibilidad de desarrollo de trastornos somáticos.

The monoaminergic systems are the target of several drugs for the treatment of mood, motor and cognitive disorders as well as neurological conditions. In most cases, advances have occurred through serendipity, except for Parkinson’s disease where the pathophysiology led almost immediately to the introduction of dopamine restoring agents. Extensive neuropharmacological studies first showed that the primary target of antipsychotics, antidepressants, and anxiolytic drugs were specific components of the monoaminergic systems. Later, some dramatic side effects associated with older medicines were shown to disappear with new chemical compounds targeting the origin of the therapeutic benefit more specifically. The increased knowledge regarding the function and interaction of the monoaminergic systems in the brain resulting from in vivo neurochemical and neurophysiological studies indicated new monoaminergic targets that could achieve the efficacy of the older medicines with fewer side-effects. Yet, this accumulated knowledge regarding monoamines did not produce valuable treatments for diseases where no monoaminergic drug has been shown to be effective. Here, we emphasize the new therapeutic and monoaminergic-based strategies for the treatment of psychiatric diseases. We will consider three main groups of diseases, based on the evidence of monoamines involvement (schizophrenia, depression, obesity), the identification of monoamines in the diseases processes (Parkinson’s disease, addiction) and the prospect of the involvement of monoaminergic mechanisms (epilepsy, Alzheimer’s disease, stroke). In most cases, the clinically available monoaminergic drugs induce widespread modifications of amine tone or excitability through neurobiological networks and exemplify the overlap between therapeutic approaches to psychiatric and neurological conditions. More recent developments that have resulted in improved drug specificity and responses will be discussed in this review.

A large body of experimental and clinical evidence has strongly suggested that monoamines play an important role in regulating epileptogenesis, seizure susceptibility, convulsions and comorbid psychiatric disorders commonly seen in people with epilepsy. However, neither the relative significance of individual monoamines nor their interaction has yet been fully clarified due to the complexity of these neurotransmitter systems. In addition, epilepsy is diverse, with many different seizure types and epilepsy syndromes, and the role played by monoamines may vary from one condition to another. In this review, we will focus on the role of serotonin, dopamine, noradrenaline, histamine and melatonin in epilepsy. Recent experimental, clinical and genetic evidence, will be reviewed in consideration of the mutual relationship of monoamines with the other putative neurotransmitters. The complexity of epileptic pathogenesis may explain why the currently available drugs, developed according to the classic drug discovery paradigm of one-molecule-one-target, have turned out to be effective only in a percentage of people with epilepsy. Although no antiepileptic drugs currently target specifically monoaminergic systems, multi-target directed ligands acting on different monoaminergic proteins present on both neurons and glia cells may represent a new approach in the management of seizures and their generation as well as comorbid neuropsychiatric disorders.

Schizophrenia is a highly heritable, chronic, severe, disabling neurodevelopmental brain disorder with a heterogeneous genetic and neurobiological background, which is still poorly understood. To allow better diagnostic procedures and therapeutic strategies in schizophrenia patients, use of easy accessible biomarkers is suggested. The most frequently used biomarkers in schizophrenia are those associated with the neuroimmune and neuroendocrine system, metabolism, different neurotransmitter systems and neurotrophic factors. However, there are still no validated and reliable biomarkers in clinical use for schizophrenia. This review will address potential biomarkers in schizophrenia. It will discuss biomarkers in schizophrenia and propose the use of specific blood-based panels that will include a set of markers associated with immune processes, metabolic disorders, and neuroendocrine/neurotrophin/neurotransmitter alterations. The combination of different markers, or complex multi-marker panels, might help in the discrimination of patients with different underlying pathologies and in the better classification of the more homogenous groups. Therefore, the development of the diagnostic, prognostic and theranostic biomarkers is an urgent and an unmet need in psychiatry, with the aim of improving diagnosis, therapy monitoring, prediction of treatment outcome and focus on the personal medicine approach in order to improve the quality of life in patients with schizophrenia and decrease health costs worldwide.