PTSD, Immune System, and Inflammation.

Posttraumatic stress disorder (PTSD) is a severe trauma and stress-related disorder associated with different somatic comorbidities, especially cardiovascular and metabolic disorders, and with chronic low-grade inflammation. Altered balance of the hypothalamic-pituitary-adrenal (HPA) axis, cytokines and chemokines, C-reactive protein, oxidative stress markers, kynurenine pathways, and gut microbiota might be involved in the alterations of certain brain regions regulating fear conditioning and memory processes, that are all altered in PTSD. In addition to the HPA axis, the gut microbiota maintains the balance and interaction of the immune, CNS, and endocrine pathways forming the gut-brain axis. Disbalance in the HPA axis, gut-brain axis, oxidative stress pathways and kynurenine pathways, altered immune signaling and disrupted homeostasis, as well as the association of the PTSD with the inflammation and disrupted cognition support the search for novel strategies for treatment of PTSD. Besides potential anti-inflammatory treatment, dietary interventions or the use of beneficial bacteria, such as probiotics, can potentially improve the composition and the function of the bacterial community in the gut. Therefore, bacterial supplements and controlled dietary changes, with exercise, might have beneficial effects on the psychological and cognitive functions in patients with PTSD. These new treatments should be aimed to attenuate inflammatory processes and consequently to reduce PTSD symptoms but also to improve cognition and reduce cardio-metabolic disorders associated so frequently with PTSD.

The Association of the Polymorphisms in the FUT8-Related Locus with the Plasma Glycosylation in Post-Traumatic Stress Disorder.

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.

Platelet serotonin concentration and trait aggression in veterans with post-traumatic stress disorder: a preliminary study.

Animal and human studies suggest that aggressive behavior may be modulated by brain serotonergic system. Serotonergic (5-HT) dysfunction is associated with post-traumatic stress disorder (PTSD), but also with increased aggression and impulsivity, hallmarks of PTSD. The aim of the study was to investigate the association of platelet 5-HT concentration and various types of aggression and impulsivity in veterans with PTSD. A group of 42 male combat-related PTSD subjects entered the study. Four different aggression facets were measured by the Buss and Perry's Aggression Questionnaire (BPAQ). Verbal and physical types of impulsive aggressive behavior were measured by the subscales of the Zuzul's Aggressiveness Inventory A-87. Impulsivity was determined using Eysenck's IVE questionnaire. PTSD severity was evaluated by Watson's PTSD questionnaire. Platelet serotonin concentration was determined spectrofluorimetrically. Confounding variables were: age, body mass, alcohol use, comorbid depression, and tobacco use. Platelet 5-HT concentration and PTSD severity were independently associated only with impulsive types of aggression, as higher platelet 5-HT concentration and more severe PTSD were related to more impulsive aggression. These results strongly recommend distinguishing between specific types of aggression facets, and advise the importance of theory-based concepts of aggression facets when evaluating the biological correlates of aggression.

Theranostic Biomarkers for Schizophrenia.

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.

Occurrence of post-injection delirium/sedation syndrome after application of olanzapine long-acting injection during one year period.

INTRODUCTION: The aim was to report the occurrence of after application of olanzapine long-acting injection (OLAI) in patients with schizophrenia during one year period. SUBJECTS AND METHODS: During one year period, OLAI was applied to 30 patients with schizophrenia (18 men, 12 women) who were non-adherent to previous treatment with oral olanzapine. Patients were 20-58 years of age (39 years old on average), diagnosed with SCID based on DSM-IV-TR criteria. Patients received OLAI in dosage between 210-405 mg (287±62 (mean ± SD)) every 2-4 weeks. RESULTS: Out of 30 patients that received OLAI, 29 patients improved significantly without side-effects, and one patient developed post-injection delirium/sedation syndrome (PDSS). The patient's somatic condition stabilized and treatment with OLAI was discontinued due to the PDSS. CONCLUSION: The occurrence of PDSS is not common and when it occurs, in our experience, it was reversible.

The association of brain-derived neurotrophic factor with the diagnosis and treatment response in depression.

INTRODUCTION: Recent evidence from the studies evaluating the association between brain-derived neurotrophic factor (BDNF) concentration/levels, BDNF Val66Met (rs6265) polymorphism, and major depressive disorders, referred as depression, and the association between BDNF levels and/or BDNF Val66Met with the treatment response in depression is presented. AREAS COVERED: This mini review focuses on the changes in the peripheral BDNF levels in blood (serum, plasma, platelets) in patients with depression before or after treatment with antidepressant drugs or different therapeutic strategies. In addition, this review describes the recent data on the possible association between different antidepressants/therapeutic strategies and the particular BDNF Val66Met genotypes, evaluating the risk alleles associated with the response in patients with depression. EXPERT OPINION: BDNF has an important role in the pathophysiology and treatment response in depression. Most data reveal that peripheral BDNF levels are lower before than after antidepressant treatment and might be used as potential biomarkers of therapeutic response. Novel therapeutic strategies should target restoring/increasing BDNF levels.

Difference in Methylation and Expression of Brain-Derived Neurotrophic Factor in Alzheimer's Disease and Mild Cognitive Impairment.

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.

Pharmacogenomics of Dementia: Personalizing the Treatment of Cognitive and Neuropsychiatric Symptoms.

Dementia is a syndrome of global and progressive deterioration of cognitive skills, especially memory, learning, abstract thinking, and orientation, usually affecting the elderly. The most common forms are Alzheimer's disease, vascular dementia, and other (frontotemporal, Lewy body disease) dementias. The etiology of these multifactorial disorders involves complex interactions of various environmental and (epi)genetic factors and requires multiple forms of pharmacological intervention, including anti-dementia drugs for cognitive impairment, antidepressants, antipsychotics, anxiolytics and sedatives for behavioral and psychological symptoms of dementia, and other drugs for comorbid disorders. The pharmacotherapy of dementia patients has been characterized by a significant interindividual variability in drug response and the development of adverse drug effects. The therapeutic response to currently available drugs is partially effective in only some individuals, with side effects, drug interactions, intolerance, and non-compliance occurring in the majority of dementia patients. Therefore, understanding the genetic basis of a patient's response to pharmacotherapy might help clinicians select the most effective treatment for dementia while minimizing the likelihood of adverse reactions and drug interactions. Recent advances in pharmacogenomics may contribute to the individualization and optimization of dementia pharmacotherapy by increasing its efficacy and safety via a prediction of clinical outcomes. Thus, it can significantly improve the quality of life in dementia patients.

Genotypic and Haplotypic Association of Catechol-O-Methyltransferase rs4680 and rs4818 Gene Polymorphisms with Particular Clinical Symptoms in Schizophrenia.

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.

Metabolic profiling of Alzheimer's disease: Untargeted metabolomics analysis of plasma samples.

Alzheimer's disease (AD) is often not recognized or is diagnosed very late, which significantly reduces the effectiveness of available pharmacological treatments. Metabolomic analyzes have great potential for improving existing knowledge about the pathogenesis and etiology of AD and represent a novel approach towards discovering biomarkers that could be used for diagnosis, prognosis, and therapy monitoring. In this study, we applied the untargeted metabolomic approach to investigate the changes in biochemical pathways related to AD pathology. We used gas chromatography and liquid chromatography coupled to mass spectrometry (GC-MS and LC-MS, respectively) to identify metabolites whose levels have changed in subjects with AD diagnosis (N = 40) compared to healthy controls (N = 40) and individuals with mild cognitive impairment (MCI, N = 40). The GC-MS identified significant differences between groups in levels of metabolites belonging to the classes of benzene and substituted derivatives, carboxylic acids and derivatives, fatty acyls, hydroxy acids and derivatives, keto acids and derivatives, and organooxygen compounds. Most of the compounds identified by the LC-MS were various fatty acyls, glycerolipids and glycerophospholipids. All of these compounds were decreased in AD patients and in subjects with MCI compared to healthy controls. The results of the study indicate disturbed metabolism of lipids and amino acids and an imbalance of metabolites involved in energy metabolism in individuals diagnosed with AD, compared to healthy controls and MCI subjects.

Relationship between Brain-Derived Neurotrophic Factor and Cognitive Decline in Patients with Mild Cognitive Impairment and Dementia.

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.

Genetic and Epigenetic Association of Hepatocyte Nuclear Factor-1α with Glycosylation in Post-Traumatic Stress Disorder.

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.

Tailoring the therapeutic interventions for behavioral and psychological symptoms of dementia.

INTRODUCTION: Behavioral and psychological symptoms of dementia (BPSD) are symptoms of non-cognitive nature, which frequently develop during the course and different stages of dementia. The diagnosis of BPSD is complex due to symptom variety, and relies on detailed clinical evaluation and medical history. Accurate assessment of BPSD is crucial in order to tailor therapeutic intervention (non-pharmacological and pharmacological) for each individual and monitor patient response to therapy. AREAS COVERED: This review encompasses the epidemiology, classification, assessment and etiology of BPSD, as well as their impact on caregiver distress, and gives an overview of current and emerging non-pharmacological and pharmacological therapeutic options, as well as potential BPSD biomarkers, in order to provide a framework for improving BPSD diagnosis and developing novel, targeted and specific therapeutic strategies for BPSD. EXPERT OPINION: Due to the large heterogeneity of BPSD and of the fact that drugs available only alleviate symptoms, finding an adequate treatment is very challenging and often involves a polytherapeutic approach. Non-pharmacologic interventions have shown promising results in improving BPSD, however further research is needed to confirm their beneficial effects. Thus, the modification of pre-existancing as well as the development of novel pharmacologic and non-pharmacologic solutions should be considered for BPSD therapy.

Reduced plasma BDNF concentration and cognitive decline in veterans with PTSD.

Post-traumatic stress disorder (PTSD) is a trauma and stress related disorder frequently associated with cognitive decline. War veterans with PTSD have a higher risk of developing dementia than healthy subjects. Brain derived neurotrophic factor (BDNF) is an important protein that modulates plasticity, memory consolidation and cognitive processes. Lower circulating BDNF levels were related to memory impairment and cognitive deterioration. The aim of this study was to evaluate cognitive deterioration and plasma BDNF concentration in 120 veterans with combat related PTSD, 120 healthy controls, 47 subjects with mild cognitive impairment (MCI) and 76 patients with Alzheimer's disease (AD), and to assess if plasma BDNF concentration might be used as biomarker of cognitive deterioration. Veterans with PTSD had significantly decreased plasma BDNF concentration and worse cognitive performances (assessed using the Mini Mental State Examination, Clock Drawing test and Montreal Cognitive Assessment scores/categories) than healthy subjects, and similarly reduced plasma BDNF and cognitive decline as MCI subjects. Reduced plasma BDNF was found in cognitively impaired subjects. These results suggest that veterans with PTSD should be closely monitored in order to early detect and predict cognitive worsening and promote interventions that might help restore blood BDNF levels and cognitive functions.

Reduced Platelet MAO-B Activity Is Associated with Psychotic, Positive, and Depressive Symptoms in PTSD.

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.

Plasma lipidomics in subjects with combat posttraumatic stress disorder.

Posttraumatic stress disorder (PTSD) is complex neuropsychiatric disorder triggered by a traumatic event and characterized by the symptoms that represent large burden to patients, as well as to society. Lipidomic approach can be applied as a useful tool for discovery of novel diagnostic, prognostic and therapeutic lipid biomarkers of various disorders, whose etiology is complex and still unknown, including PTSD. Since changes in the levels of lipid metabolites might indicate impairments in various metabolic pathways and cellular processes, the aim of this lipidomic study was to determine altered levels of lipid compounds in PTSD. The study enrolled 235 male patients with combat PTSD and 241 healthy male control subjects. Targeted lipidomic analysis of plasma samples was conducted using reverse-phase liquid chromatography coupled with mass spectrometry. Lipids that have been analyzed belong to the group of ceramides, cholesterol esters, diacylglycerols, lysophosphatidylcholines, lysophosphatidylethanolamines, phosphatidylcholines, phosphatidylethanolamines, sphingomyelins and triglycerides. The levels of fifteen lipid compounds were found to be significantly different between PTSD patients and healthy control subjects, including four phosphatidylcholines, two phosphatidylethanolamines, five sphingomyelins, two cholesterol esters and two ceramides. The lipid metabolites whose levels significantly differed between patients with PTSD and control subjects are associated with various biological processes, including impairments of membrane integrity and function, mitochondrial dysfunction, inflammation and oxidative stress. As these processes might be associated with development and progression of PTSD, altered lipid compounds represent potential biomarkers that could facilitate the diagnosis of PTSD, prediction of the disease, as well as identification of novel treatment approaches in PTSD.

The association between BDNF C270T genetic variants and smoking in patients with mental disorders and in healthy controls.

Studies investigating the association between smoking and the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism have reported inconclusive results, while the studies on the association of smoking status with BDNF C270T polymorphism are missing. We aimed to determine the association of smoking and BDNF Val66Met and C270T genetic variants in control subjects and patients with mental disorders. This study included 3502 Caucasian subjects: 918 healthy controls and 2584 patients with mental disorders (519 individuals with posttraumatic stress disorder (PTSD), 419 patients with depression, 996 patients with schizophrenia, and 650 patients with alcohol dependence). The frequency of the BDNF Val66Met and C270T variants were presented in codominant, dominant and recessive models. BDNF C270T, but not BDNF Val66Met polymorphism, was significantly associated with smoking in all groups, since the presence of the C270T T allele was more frequently found in smokers compared to non-smokers. Significant predictors of smoking were sex, age and BDNF C270T genetic variants. However, after detailed analysis of the separate diagnostic entities, the significant association of BDNF C270T polymorphism was confirmed only in healthy subjects, but not in patients with mental disorders; and was not related to number of cigarettes smoked per day. In patients with alcohol dependence, the severity of smoking was significantly associated with BDNF Val66Met variants. This is a first report of the significant association between the BDNF C270T polymorphism and smoking status in the large groups of Caucasian cases/controls.

Alzheimer's dementia: current data review.

The review focuses on current data on Alzhemier's dementia, a clinical syndrom characterised with acquired deterioration of cognitive functioning and emotional capacities, which impaires everyday activity and quality of life. Alzheimer's dementia is the most common type of dementia in clinical surveys. The diagnosis of Alzheimer's dementia is primarily based on symptoms and signs and memory impairment is clinically most significant. Cholinesterase inhibitors -donepezil, rivastigmine and galantamine are considered to be the first line pharmacotherapy for mild to moderate Alzheimer's disease. Currently, no effective pharmacologic interventions have been researched enough to support their use in prevention of Alzheimer's dementia. Studies suggest that healthy lifestyle, ongoing education, regular physical activity, and cholesterol control, play a role in prevention of Alzheimer's dementia.

Metabolic syndrome in patients with depressive disorder--features of comorbidity.

BACKGROUND: Depression is associated with increased physical morbidity and overall mortality. The results of a previous investigation on the relationship of the metabolic syndrome and its single components with coronary heart disease, cardiovascular disease (CVD), and all-cause mortality suggested that the metabolic syndrome is a marker of CVD risk, but not above and beyond the risk associated with its individual components. The aim of this article is to review literature regarding prevalence of metabolic syndrome in patients with depressive disorder, and association between metabolic syndrome and depression. CONTENT ANALYSIS OF LITERATURE: Literature research included structured searches of Medline and other publications on the subject of metabolic syndrome, particularly prevalence of metabolic syndrome in patients with depressive disorder, and association between metabolic syndrome and depression. CONCLUSION: Prevalence of the metabolic syndrome in patients with depression is high and varies among the analysed studies. Some investigations showed association between metabolic syndrome and depression. Further investigations are necessary in order to clarify the association between metabolic syndrome and depression.

Reinforcement of irritability during therapy with benzodiazepines.

BACKGROUND: Often, long-term treatment with benzodiazepines is a subject of discussion due to potential side effects, with dependence on benzodiazepines as the most serous one. After longer period of benzodiazepines tolerance on their anxiolytic effects develops. Discontinuation is usually beneficial as it is followed by improved psychomotor and cognitive functioning, particularly in the elderly. Previous studies confirmed occurrence of physical dependence in high percentage of patients in long term treatment with benzodiazepines at therapeutic dosages. Benzodiazepines are relatively well-tolerated medicines but can induce serious problems of addiction and that is why their use is regulated. The aim of this article is to report a case of a patient who was taking 15 tablets of oxazepam daily for a period of time, during which reinforcement of irritability occurred. CONCLUSION: It is necessary to warn patients who take benzodiazepines in therapy that reinforcement of irritability may occur in case of higher dosage of benzodiazepines, which may be misinterpreted as worsening in mental condition.