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.

The Associations between COMT and MAO-B Genetic Variants with Negative Symptoms in Patients with Schizophrenia.

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.

A Load to Find Clinically Useful Biomarkers for Depression.

Depression is heterogeneous and complex disease with diverse symptoms. Its neurobiological underpinning is still not completely understood. For now, there are still no validated, easy obtainable, clinically useful noninvasive biomarker(s) or biomarker panel that will be able to confirm a diagnosis of depression, its subtypes and improve diagnostic procedures. Future multimodal preclinical and clinical research that involves (epi)genetic, molecular, cellular, imaging, and other studies is necessary to advance our understanding of the role of monoamines, GABA, HPA axis, neurotrophins, metabolome, and glycome in the pathogenesis of depression and their potential as diagnostic, prognostic, and treatment response biomarkers. These studies should be focused to include the first-episode depression and antidepressant drug-naïve patients with large sample sizes to reduce variability in different biological and clinical parameters. At present, metabolomics study revealed with high precision that a neurometabolite panel consisting of plasma metabolite biomarkers (GABA, dopamine, tyramine, kynurenine) might represent clinically useful biomarkers of MDD.

Remission Is not Associated with DRD2 rs1800497 and DAT1 rs28363170 Genetic Variants in Male Schizophrenic Patients after 6-months Monotherapy with Olanzapine.

BACKGROUND: Symptomatic remission is an achievable goal in the treatment of schizophrenia. The type of antipsychotic medication and particular genetic variants of the dopaminergic system might be associated with remission. Potential pharmacogenetic markers of the treatment response to antipsychotic medication are missing. This study assessed the possible association between dopamine receptor type 2 (DRD2 rs1800497) and dopamine transporter (DAT1 rs28363170) gene variants with symptomatic remission in schizophrenia. SUBJECTS AND METHODS: Olanzapine (5-20 mg/d) monotherapy was administered for 6 months to 150 male Caucasian subjects with schizophrenia. Remission was evaluated according to "Remission in Schizophrenia Working Group" criteria. Genotyping was performed by PCR-RFLP. RESULTS: Symptomatic remission was found in 31% of patients. DRD2 rs1800497 and DAT1 rs28363170 gene variants were not significantly associated with symptomatic remission. The limitations are a relatively small sample size of patients with schizophrenia (N=150), especially of group with symptomatic remission (N=45). However, the study had moderate but adequate sample sizes for most of the comparisons. Only two dopaminergic polymorphisms were analyzed, and plasma concentration of olanzapine was not determined. CONCLUSION: These results revealed a lack of association between DRD2 rs1800497 and DAT1 rs28363170 genetic variants and symptomatic remission in male patients treated with olanzapine, suggesting that these genetic variants could not be used to predict symptomatic remission to olanzapine monotherapy. Negative results should be further confirmed or rejected in the larger samples, including haplotype analyses, to detect clinically useful and easy obtainable pharmacogenetic markers that might predict therapeutic response or remission in schizophrenia.

Genetic Markers in Psychiatry.

Psychiatric disorders such as addiction (substance use and addictive disorders), depression, eating disorders, schizophrenia, and post-traumatic stress disorder (PTSD) are severe, complex, multifactorial mental disorders that carry a high social impact, enormous public health costs, and various comorbidities as well as premature morbidity. Their neurobiological foundation is still not clear. Therefore, it is difficult to uncover new set of genes and possible genetic markers of these disorders since the understanding of the molecular imbalance leading to these disorders is not complete. The integrative approach is needed which will combine genomics and epigenomics; evaluate epigenetic influence on genes and their influence on neuropeptides, neurotransmitters, and hormones; examine gene × gene and gene × environment interplay; and identify abnormalities contributing to development of these disorders. Therefore, novel genetic approaches based on systems biology focused on improvement of the identification of the biological underpinnings might offer genetic markers of addiction, depression, eating disorders, schizophrenia, and PTSD. These markers might be used for early prediction, detection of the risk to develop these disorders, novel subtypes of the diseases and tailored, personalized approach to therapy.

The Association between Serotonin Transporter Polymorphism, Platelet Serotonin Concentration and Insomnia in Non-Depressed Veterans with Posttraumatic Stress Disorder.

BACKGROUND: The role of serotonin transporter and its functional gene polymorphism (5-HTTLPR, serotonin transporter linked polymorphic region) was investigated in sleep disturbances in various mental disorders, with conflicting findings. Here, the association of particular sleep disturbances with 5-HTTLPR genotypes and platelet serotonin (5-HT) concentration was determined simultaneously in veterans with posttraumatic stress disorder (PTSD), who were subdivided into those with or without comorbid depression. SUBJECTS AND METHODS: Croatian male, medication-free war veterans with PTSD (N=325), subdivided into those with or without comorbid depression, and subdivided further according to the various sleep disturbances, were evaluated using the Structured Clinical Interview, the Hamilton Rating Scale for Depression and the Clinician Administered PTSD Scale. Genotyping and platelet 5-HT concentration measurements were conducted using PCR and spectrofluorimetric methods, respectively. RESULTS: Nominally higher frequency of the 5-HTTLPR LL genotype compared to S carriers (p=0.026; χ2 test) and significantly higher platelet 5-HT concentration (p=0.001; one-way ANOVA) were detected in non-depressed veterans with PTSD with early insomnia, compared to matched veterans without early insomnia. CONCLUSIONS: Over-representation of the LL genotype of the 5-HTTLPR and higher platelet 5-HT concentrations were detected in veterans with PTSD who did not develop comorbid depression but had severe early insomnia. These results suggest that 5-HTTLPR genotypes and platelet 5-HT concentration are associated with early insomnia in non-depressed veterans with PTSD. Limitations of the study were the cross-sectional nature of the study, biallelic assessment of the 5-HTTLPR, and a lack of use of the specific sleep measurement scales. These results should be replicated in larger samples, validated on different populations, using specific sleep measurement scales and triallelic 5-HTTLPR assessment.

Anhedonia in Schizophrenia: Mini-Review.

The perception of reward exerts a powerful influence on human behavior. While anhedonia might occur in healthy individuals, its prevalence and severity are much higher in psychiatric patients, particularly those with depression and schizophrenia. Anhedonia is a negative symptom, and presumably a trait marker in schizophrenia. Recent research confirmed that anhedonia is a complex construct, consisting of anticipatory, consummatory, and reward learning components. In general, schizophrenia patients show anticipation deficits, and a substantial portion of them have physical (PA) and social anhedonia (SA). The relationship between anhedonia and psychopathology appears bidirectional. While gene-environment interactions affect reward circuity, anhedonia modulates clinical features, such as suicidality and nicotine consumption. Future clinical research employing longitudinal designs may shed more light on the dynamics and treatment of anhedonia in schizophrenia.

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.

Overview of metabolomic aspects in postpartum depression.

Along with the typical biochemical alterations that occur during pregnancy, certain metabolic changes might be associated with the development of several psychiatric disorders, including postpartum depression (PPD), which is the most common type of psychiatric disorder during pregnancy or first postpartum year, and it develops in about 15% of women. Metabolomics is a rapidly developing discipline that deals with the metabolites as the final products of all genetically controlled biochemical pathways, highly influenced by external and internal changes. The aim of this paper was to review the published studies whose results suggest or deny a possible association between the fine regulation of the metabolome and PPD, enabling conclusions about whether metabolomics could be a useful tool in defining the biochemical pathways directly involved in the etiology, diagnosis and course of PPD. Beside numerous hormonal changes, a lot of different metabolic pathways have been discovered to be affected in women with PPD or associated with its development, including alterations in the energy metabolism, tryptophan and amino acid metabolism, steroid metabolism, purine cycle, as well as neurotransmitter metabolism. Additionally, metabolomics helped in defining the association between PPD and the exposure to various endocrine disrupting metabolites during pregnancy. Finally, metabolome reflects different PPD therapies and exposure of fetus or breastfed infants to pharmacotherapy prescribed to a mother suffering from PPD. This review can help in creating the picture about metabolomics' broad application in PPD studies, but it also implies that its potential is still not completely used.

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.

Platelet Serotonin (5-HT) Concentration, Platelet Monoamine Oxidase B (MAO-B) Activity and HTR2A, HTR2C, and MAOB Gene Polymorphisms in Asthma.

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.

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.

Cannabinoid CB2 Receptors in Neurodegenerative Proteinopathies: New Insights and Therapeutic Potential.

Some of the most prevalent neurodegenerative disorders, including Alzheimer's and Parkinson's disease, are proteinopathies characterized by the accumulation of specific protein aggregates in the brain. Such misfolded protein aggregates can trigger modulation of the innate and adaptive immune systems and subsequently lead to chronic neuroinflammation that drives the onset and progression of neurodegenerative diseases. Since there is still no effective disease-modifying treatment, new therapeutic targets for neurodegenerative proteinopathies have been sought. The endocannabinoid system, and in particular the cannabinoid CB2 receptors, have been extensively studied, due to their important role in neuroinflammation, especially in microglial cells. Several studies have shown promising effects of CB2 receptor activation on reducing protein aggregation-based pathology as well as on attenuating inflammation and several dementia-related symptoms. In this review, we discuss the available data on the role of CB2 receptors in neuroinflammation and the potential benefits and limitations of specific agonists of these receptors in the therapy of neurodegenerative proteinopathies.

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.

Serotonin 5-HT2A receptor polymorphisms are associated with irritability and aggression in conduct disorder.

In childhood and adolescence, overt antisocial and aggressive manifestations are typically diagnosed as conduct disorder (CD). Given that the emerging research has pointed to the influence of 5-HT2A receptors in the ontogeny of aggression, we aimed to analyze the association of its genetic polymorphisms with CD. The study included 228 male adolescent subjects (120 with and 108 without CD). CD was diagnosed according to Structured Clinical Interview for DSM-IV criteria, while evaluations of aggressive/dissociative behaviors were performed using psychometric questionnaires including the PCL-YV, OAS-M, KADS, and CBCL. Platelet 5-HT concentration was determined by spectrophotofluorometry. Genotyping of 5-HT2A receptor polymorphisms rs2070040, rs9534511, rs4142900, rs9534512 was performed using TaqMan SNP Genotyping Assays. Subjective irritability, physical aggression toward others, and antisocial behavior were strongly associated with the G allele of rs2070040 and rs4142900, and the C allele of rs9534511 and rs9534512. A significantly increased platelet 5-HT concentration in CD subjects, compared to controls, was lost after the correction according to the smoking status. Our results indicate an association of the studied HTR2A polymorphisms and their haplotypes with irritability and impulsivity traits, which may contribute to the aggressive and antisocial behavior in male adolescents with CD.