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The roles of dopamine (DA) and norepinephrine (NE) in posttraumatic stress disorder (PTSD) are unclear. The aim of the study was to determine plasma dopamine beta-hydroxylase (DBH) activity and DBH-1021C/T gene polymorphism in combat veterans with (N = 133) or without (N = 34) chronic PTSD. Similar frequencies in genotype or allele distribution were found between veterans with or without PTSD. War veterans with PTSD had lower DBH activity, associated with the DBH-1021C/T variant in DBH genes, than veterans without PTSD. A significantly lower plasma DBH activity was found in combat veterans with PTSD carrying the CC genotype as compared to veterans without PTSD carrying the corresponding genotype. Since both groups were exposed to the same trauma, it is possible that a pre-existing trait difference in regulation of NE function contributed to a differential vulnerability to develop PTSD, or that the regulation of DBH expression was different in response to trauma. The results suggest that that genotype-controlled measurement of plasma DBH activity might be used as a potential biological marker of the response to trauma, and that further studies of DBH and other loci related to DA and NA in PTSD are warranted.

Platelet 5-HT and plasma cortisol concentrations were determined in 59 schizophrenic patients with different time course of illness before and after dexamethasone suppression test (DST). An abnormal DST (nonsuppression) was observed in 51% of patients. In these patients basal cortisol and platelet 5-HT concentrations were higher than in patients with normal DST. After DST, plasma cortisol levels were higher in nonsuppressors with intermittent and intermittent-chronic time course, whereas platelet 5-HT concentrations were increased in nonsuppressors with intermittent-chronic time course. The results suggest that schizophrenic patients have dysregulated hypothalamic-pituitary-adrenal axis as shown by a high rate of DST nonsuppression, and that nonsuppressors showed hypercortisolemia and hyperserotonemia independent of the time course of schizophrenia. No significant association between DST and time course of the illness was found.

The influence of seasons on platelet serotonin (5-HT) concentration was determined in 88 unipolar depressed and 117 schizophrenic male inpatients, and 90 normal male controls. Platelet 5-HT concentrations showed moderate, but insignificant intragroup seasonal variations in healthy controls and in the groups of depressed (psychotic and nonpsychotic) and schizophrenic (positive and negative) patients. In spring, platelet 5-HT concentrations were higher in schizophrenic patients than in normal controls or in depressed patients, while in other seasons platelet 5-HT concentrations were not significantly different between the groups. Higher platelet 5-HT concentrations were detected in psychotic when compared to nonpsychotic depressed patients in summer, fall, and winter. Increased platelet 5-HT concentrations observed in schizophrenic patients with positive symptomes clearly separated these patients from patients with negative schizophrenia, especially in spring, summer, and fall. Our results indicate the necessity to match patients with regard to the season of the sampling, and to divide depressed and schizophrenic patients into subtypes.

Objective Obesity is becoming a fast-growing health problem worldwide. Glycosylation of proteins and their variations significantly affect protein structure and function, thus altering numerous physiological and pathophysiological cellular processes. Since plasma glycans were significantly associated with body mass index (BMI) in both Croatian and Chinese populations, the study evaluated the association between immunoglobulin G (IgG) glycome, which is closer to biological function, and BMI. Method The study included individuals from two Croatian Adriatic islands, Vis and Korcula, and individuals from Northern Scottish Orkney Islands. A hydrophilic interaction chromatography on Waters BEH Glycan chromatography column was used to analyze N -glycans attached to IgG in plasma samples from a total of 3515 individuals. Results A small but significant positive correlation between BMI and the level of neutral glycans without galactoses was detected. After taking into account the influence of age and gender, correlation coefficients indicated that BMI was responsible for up to 2.0% of variation in the level of neutral glycans without galactoses. Furthermore, after adjusting the effects of age and gender, the level of neutral glycans with two terminal galactoses was negatively associated with BMI in analyzed sample groups, suggesting that BMI could be responsible for up to 3.2% of variation in this glycan feature. Conclusion Our study is the first large-scale study to indicate the association of BMI and changes in IgG galactosylation. The observed loss of galactose which is associated with increased BMI might be related to chronic inflammation that accompanies the development of obesity.

Obesity is becoming the epidemic health problem worldwide with a very complex etiology. The interaction between diverse genetic and environmental factors contributes to development of obesity. Among myriad of functions in central and peripheral tissues, brain-derived neurotrophic factor (BDNF) also regulates energy homeostasis, food intake and feeding behavior, and has a role in obesity and increased body mass index (BMI). BDNF Val66Met (rs6265) polymorphism is associated with BMI gain, but both positive associations and non-replications are reported. Since BMI changes over time and since genetic influences on BMI vary with age, the aim of the study was to evaluate association between BDNF Val66Met polymorphism and BMI gain in healthy subjects with middle or old age. The study included a cohort of 339 adult healthy Caucasians of Croatian origin, free of eating and metabolic disorders, evaluated in three time periods in the year 1972, 1982 and 2006, when the subjects were around 40, 50 and 70 years old, respectively. The results revealed a significant effect of smoking on BMI, but a lack of significant association between BDNF Val66Met polymorphism and overweight or obesity, and no significant association between BDNF Val66Met and BMI changes over time. These results did not confirm the major role of BDNF Val66Met in the regulation of BMI changes in adult and old healthy subjects.

Hyperactivity, impulsivity, and inattention are major symptoms occurring in attention-deficit/hyperactivity disorder. This disorder is highly heritable, multifactorial, polygenic, and associated primarily with dysfunctions of dopaminergic, noradrenergic, and serotonergic systems. The present study tested the possible association of the catechol-O-methyltransferase (COMT) Val108/158Met (rs4680) polymorphism with hyperactive–impulsive and inattentive symptoms in male youth. Polymorphism COMT Val108/158Met was analyzed in 807 male unrelated Caucasian young subjects: 231 healthy controls, 195 subjects with moderate hyperactive symptomsand 254 subjects with moderate inattentive symptoms, 111 subjects with severe hyperactive symptoms and 90 subjects with severe inattentive symptoms, all evaluated using Swanson, Nolan, and Pelham Questionnaire IV criteria. The frequency of the COMT genotypes, alleles, and the homozygous Met/Met genotype versus Val carriers (χ2 test with standardized residuals) differed significantly between subjects without and subjects with hyperactive–impulsive and inattentive symptoms. In addition, significantly higher hyperactive–impulsive and inattentive scores were found in subjects with the Met/Met genotype compared to carriers of other COMT genotypes. These significant results were due to the more frequent occurrence of Met/Met genotype or the Met allele in subjects with moderate and severe hyperactive–impulsive and inattentive symptoms compared to matched controls. These results suggest that the Met/Met genotype or the Met allele of the COMT Val108/158Met, contributing to higher dopaminergic activity, are significantly overrepresented in subjects with moderate or severe hyperactive–impulsive and inattentive symptoms, and that this polymorphism is significantly associated with hyperactive-impulsive and inattentive symptoms in young boys and adolescents.

Alterations in serotonin (5-HT) neurochemistry have been implicated in the aetiology of all major neuropsychiatric disorders, ranging from schizophrenia to mood and anxiety-spectrum disorders. This review will focus on the mulifaceted implications of 5-HT-ergic dysfunctions in the pathophysiology of aggressive and suicidal behaviours. After a brief overview of the anatomical distribution of the 5-HT-ergic system in the key brain areas that govern aggression and suicidal behaviours, the implication of 5-HT markers (5-HT receptors, transporter as well as synthetic and metabolic enzymes) in these conditions is discussed. In this regard, particular emphasis is placed on the integration of pharmacological and genetic evidence from animal studies with the findings of human experimental and genetic association studies. Traditional views postulated an inverse relationship between 5-HT and aggression and suicidal behaviours; however, ample evidence has shown that this perspective may be overly simplistic, and that such pathological manifestations may reflect alterations in 5-HT homeostasis due to the interaction of genetic, environmental and gender-related factors, particularly during early critical developmental stages. The development of animal models that may capture the complexity of such interactions promises to afford a powerful tool to elucidate the pathophysiology of impulsive aggression and suicidability, and find new effective therapies for these conditions., peer-reviewed

The study elucidated the association between the COMT Val108/158Met polymorphism and smoking in patients with schizophrenia, patients with alcohol dependence and healthy control subjects. The stepwise logistic regression (odds ratio (OR)=1.56, 95% confidence interval (CI)=1.10–2.23, P=0.014) and the χ2 test (P=0.008) revealed that the COMT Val/Val genotype was significantly associated with smoking in healthy male subjects. Although the hypothesis of the study was that COMT Val108/158Met genotypes will be significantly associated with smoking in schizophrenia and alcohol dependence, our study showed for the first time the lack of significant association between smoking and COMT Val108/158Met polymorphism in schizophrenia, and confirmed no association between smoking and COMT Val108/158Met in alcoholism.

Alcoholism is a chronic psychiatric disorder affecting neural pathways that regulate motivation, stress, reward and arousal. Brain-derived neurotrophic factor (BDNF) regulates mood, response to stress and interacts with neurotransmitters and stress systems involved in reward pathways and addiction. Aim of the study was to evaluate the association between a single nucleotide polymorphism (BDNF Val66Met or rs6265) and alcohol related phenotypes in Caucasian patients. In ethnically homogenous Caucasian subjects of the Croatian origin, the BDNF Val66Met genotype distribution was determined in 549 male and 126 female patients with alcohol dependence and in 655 male and 259 female healthy non-alcoholic control subjects. Based on the structured clinical interview, additional detailed clinical interview, the Brown–Goodwin Scale, the Hamilton Rating Scale for Depression and the Clinical Global Impression scores, alcoholic patients were subdivided into those with or without comorbid depression, aggression, delirium tremens, withdrawal syndrome, early/late onset of alcohol abuse, prior suicidal attempt during lifetime, current suicidal behavior, and severity of alcohol dependence. The results showed no significant association between BDNF Val66Met variants and alcohol dependence and/or any of the alcohol related phenotypes in either Caucasian women, or men, with alcohol dependence. There are few limitations of the study. The overall study sample size was large (N = 1589) but not well-powered to detect differences in BDNF Val66Met genotype distribution between studied groups. Healthy control women were older than female alcoholic patients. Only one BDNF polymorphism (rs6265) was studied. In conclusion, these data do not support the view that BDNF Val66Met polymorphism correlates with the specific alcohol related phenotypes in ethnically homogenous medication-free Caucasian subjects with alcohol dependence.

The noradrenergic system is involved in the etiology and progression of Alzheimer’s disease (AD) but its role is still unclear. Dopamine beta-hydroxylase (DBH) as a catecholamine-synthesizing enzyme plays a central role in noradrenaline (NA) synthesis and turnover. Plasma DBH (pDBH) activity shows wide inheritable interindividual variability that is under genetic control. The aim of this study was to determine pDBH activity, DBH (C-970T ; rs1611115) and DBH (C1603T ; rs6271) gene polymorphisms in 207 patients with AD and in 90 healthy age-matched controls. Plasma DBH activity was lower, particularly in the early stage of AD, compared to values in middle and late stages of the disease, as well as to control values. Two-way ANOVA revealed significant effect of both diagnosis and DBH (C-970T) or DBH (C1603T) genotypes on pDBH activity, but without significant diagnosis x genotype interaction. No association was found between AD and DBH C-970T (OR = 1.08, 95% CI 1.13-4.37 ; p = 0.779) and C1603T (OR = 0.89 ; 95% CI 0.36-2.20 ; p = 0.814) genotypes controlled for age, gender, and ApoE4 allele. The decrease in pDBH activity, found in early phase of AD suggests that alterations in DBH activity represent a compensatory mechanism for the loss of noradrenergic neurons, and that treatment with selective NA reuptake inhibitors may be indicated in early stages of AD to compensate for loss of noradrenergic activity in the locus coeruleus.

Attention-deficit hyperactivity disorder (ADHD) and autism are both heritable, polygenic neurodevelopmental disorders with similar symptoms. Both disorders have onset in childhood and occur more frequently in boys than in girls. Genetic studies have so far focused mostly on candidate genes involved in dopaminergic system, however more non-replications than positive associations were reported. The present study tested the possible association of the variants in dopamine system genes with these disorders in Croatian population. Polymorphisms of the dopamine receptor D4 (DRD4 variable number of tandem repeats), catechol-o-methyltransferase (COMT Val108/158Met), dopamine-beta-hydroxylase (DBH -1021C/T) and monoamine oxidase type B (MAO-B intron 13 polymorphism) were analyzed in unrelated male Caucasian subjects: 128 control subjects, 102 children with ADHD and 80 subjects with autism, diagnosed according to DSM-IV criteria. This study detected significantly reduced frequency of DRD4 L allele in autistic compared to other groups and increased frequency of the COMT Met/Met genotype in autistic and ADHD groups compared to control group. The frequency of the genotypes of DBH -1021C/T and MAO-B intron 13 polymorphisms was similar between subjects with ADHD or autism and healthy subjects. These results suggest that DRD4 L allele and the COMT Met/Met genotype might be associated with ADHD and autism.

Using inductively-coupled plasma mass spectrometry (ICP-MS), we measured the concentrations of thallium and uranium in local water resources from three villages (Ćelije, Draž, and Potnjani) in eastern Croatia, with the aim to determine if they were associated with the levels of these same elements in the serum, urine, and hair collected from the residents of this area. The exposure of the local population to thallium and uranium through drinking water was generally low. ICP-MS was capable of measuring the levels of both of the elements in almost all of the analysed samples. Although there were differences in the concentrations of both elements in water samples and biological specimens taken from the residents, they did not reach the maximum contaminant level in any of the four sample types studied. Although hair was previously reported as an excellent indicator of occupational and environmental exposure to various elements, our study did not confirm it as a reliable biological material for tracing thallium and uranium levels, mainly due to the very low concentrations of these elements, often well below the detection limit. However, our results have shown that the concentration of thallium and uranium in drinking water can be effectively traced in urine samples., Koristeći masenu spektrometriju induktivno spregnute plazme (ICP-MS), izmjerili smo koncentracije talija i urana u lokalnim izvorima vode triju istočnohrvatskih sela (Ćelije, Draž i Potnjani) radi određivanja jesu i povezane s razinama obaju elemenata u serumu, urinu i kosi stanovnika tih triju sela. Izloženost lokalnog stanovništva taliju i uranu preko pitke vode općenito je bila niska. ICP-MS uspješno je izmjerio razine obaju elemenata u gotovo svim analiziranim uzorcima. Iako je bilo razlika u razinama obaju elemenata u uzorcima vode i biološkim uzorcima stanovnika, nijedan nije prešao maksimalnu dopuštenu granicu. Kosa je prethodno opisana kao izvrstan pokazatelj profesionalne ili okolišne izloženosti različitim elementima, no rezultati našeg ispitivanja nisu potvrdili njenu pouzdanost pri mjerenju talija i urana uslijed vrlo niskih koncentracija obaju elemenata, koje su često bile i ispod razine detekcije. Međutim, pokazali su kako uzorci urina mogu poslužiti kao vrlo dobri indikatori prisutnosti talija i urana u pitkoj vodi.

Excess weight and obesity are common health problems with multifactorial and polygenic causes. Abdominal or visceral obesity is associated with a higher risk of obesity related complications. The aim of the study was to evaluate differentially expressed genes in visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) of 10 overweight women undergoing elective laparoscopic cholecystectomy. Following expression profiling using microarrays, a set of 294 genes that exhibited differential expression between VAT and SAT was further analyzed to test the functional correlation of gene sets using the Gene Set Enrichment Analysis method. To confirm the functional pathways involved in differential expression between SAT and VAT, additional pathway analysis was done using the GeneGo MetaCore software and the Ingenuity Pathway Analysis. Ten differentially expressed genes were selected according to the microarray data, with seven exhibiting significant differential expression in the RT-PCR experiments. The data from this preliminary study suggest enrichment of inflammation and oxidative stress related pathways in VAT, while insulin homeostasis pathways as well as pathways pertaining to several growth factors are enriched in SAT.

Background: The aim of this study was to determine the relationship between body mass index, biochemical parameters, and 5-hydroxytryptamine (5-HT) genetic polymorphisms and prostate dysfunction in an elderly general male population. Results: One hundred and seventeen elderly male subjects [60 men without symptoms of prostate hyperplasia, 42 men with untreated benign prostatic hyperplasia (BPH), and 15 men with prostate cancer (PCa)] treated with finasteride or flutamide were included. Multiple comparisons showed significant difference in age, T-score, concentration of phosphorus, calcium, C-reactive protein, and prostate-specific antigen (PSA) between the groups. T-score was the lowest and phosphorus concentration was the highest in the PCa group. Highest PSA, proteins, calcium, and Hekal's formula score were found in the BPH group. Patients with PCa were more frequent GG+GA carriers of 5-HT1B 1997A/G gene polymorphism (p=0.035). Univariate regression analysis showed association of PCa-treated subjects with age (p=0.010) and 5-HT1B genetic polymorphism (p=0.018). Antiandrogen therapy affects T-score (p=0.017), serum phosphorus (p=0.008), glucose (p=0.036), and total proteins (p=0.050). Multivariate-stepwise logistic regression analysis showed the significant association of treated PCa with age (p=0.028) and inorganic phosphorus (p=0.005), and a marginal association with ultrasonographic T-score (p=0.052). Conclusions: Antiandrogen therapy might induce bone mineral loss in elderly PCa patients. Preliminary data imply that the genetic variants of the 5-HT1B receptor might be associated with PCa.

Obesity in children and adolescents is a worldwide health problem, characterized by various somatic, psychosocial and psychiatric complications, and is often associated with adult obesity and related complications. Brain-derived neurotrophic factor (BDNF) is a neurotrophin with important roles in feeding behavior, food intake regulation, energy metabolism and weight control. A common polymorphism of the BDNF genotype (Val66Met) has been associated with various forms of eating disorders, alterations in body mass index (BMI) values and obesity in adult populations. The aim of this study was to determine the association between the gene variants of the BDNF Val66Met polymorphism and obesity in 300 healthy Caucasian children and adolescents of the same ethnic background of Croatian origin, subdivided according to the BMI percentile, but without any form of eating disorders. The frequency of the Met/Met, Met/Val and Val/Val genotypes, Met and Val alleles, and Met carriers (the combined Met/Met and Met/Val genotypes versus the homozygous Val/Val genotype) differed significantly between underweight, normal weight, overweight and obese children, and the presence of one or two Met alleles contributed to this significant effect. These results showed for the first time the significant association between the presence of one or two Met alleles and obesity in ethnically homogenous groups of healthy Caucasian children and adolescents. These data confirmed the major role of BDNF in energy metabolism, food regulation and BMI.

Aim To elucidate the involvement of noradrenergic system in the mechanism by which diazepam suppresses basal hypothalamic-pituitary-adrenal (HPA) axis activity. Methods Plasma corticosterone and adrenocorticotropic hormone (ACTH) levels were determined in female rats treated with diazepam alone, as well as with diazepam in combination with clonidine (α2-adrenoreceptor agonist), yohimbine (α2-adrenoreceptor antagonist), alpha-methyl-p-tyrosine (α-MPT, an inhibitor of catecholamine synthesis), or reserpine (a catecholamine depleting drug) and yohimbine. Results Diazepam administered in a dose of 2.0 mg/kg suppressed basal HPA axis activity, ie, decreased plasma corticosterone and ACTH levels. Pretreatment with clonidine or yohimbine failed to affect basal plasma corticosterone and ACTH concentrations, but abolished diazepam-induced inhibition of the HPA axis activity. Pretreatment with α-MPT, or with a combination of reserpine and yohimbine, increased plasma corticosterone and ACTH levels and prevented diazepam-induced inhibition of the HPA axis activity. Conclusion The results suggest that α2-adrenoreceptors activity, as well as intact presynaptic noradrenergic function, are required for the suppressive effect of diazepam on the HPA axis activity.

Type 2 diabetes (T2D) and Alzheimer's disease (AD) are two progressive disorders with high prevalence worldwide. Polymorphisms in tumor necrosis factor-alpha (TNF-α) and apolipoprotein E (ApoE) genes might be associated with both T2D and AD, representing possible genetic markers for the development of the AD in subjects with T2D. The aim was to determine ApoE and G-308A TNF-α gene polymorphisms in unrelated Croatian Caucasians: 207 patients with sporadic AD, 196 T2D patients and 456 healthy controls. Patients with AD had higher frequency of ApoE4 allele compared to T2D patients and controls. The significant association, observed between ApoE2 allele and T2D, disappeared after the data were adjusted for age and sex. The genotype or allele frequencies of G-308A TNF-α gene polymorphism were similar among the patients with AD, T2D and healthy controls. In conclusion, these results do not support the hypothesis that the A allele of G-308A TNF-α gene polymorphism is associated either with AD or T2D. Our data confirm the association between the ApoE4 allele and AD, and point out the E2 allele of ApoE gene as the possible risk factor for T2D.

Rationale Atypical antipsychotics are frequently prescribed for psychotic and mood disorders in youth, and for symptoms of depression, aggression, irritability and suicidal tendencies, which are associated with subsequent development of borderline personality disorders (BPD). ----- Objectives This study evaluated the effects of 24-weeks of add-on treatment with quetiapine to selective serotonin reuptake inhibitors (SSRIs) in young people with pronounced symptoms of depression, aggression, irritability and suicidal tendencies. ----- Methods In an open-label 24-weeks trial, 22 SSRI-treatment resistant patients (age range 9-18 years) with developing BPD were treated with quetiapine (75-600 mg/day) in combination with SSRIs. Symptoms of depression, aggression, irritability and suicidal tendencies were rated with the Overt Aggression Scale Modified (OAS-M), Kutcher Adolescent Depression Scale (KADS-6) and Children Global Assessment Scale (C-GAS) before and after 4-24 weeks of treatment. ----- Results Quetiapine induced significant (p

Objective: Psychotic symptoms frequently occur in veterans with combat-related posttraumatic stress disorder (PTSD). Brain-derived neurotrophic factor (BDNF) plays a major role in neurodevelopment, neuro-regeneration, neurotransmission, learning, regulation of mood and stress responses. The Met allele of the functional polymorphism, BDNF Val66Met, is associated with psychotic disorders. This study intended to assess whether the Met allele is overrepresented in unrelated Caucasian male veterans with psychotic PTSD compared to veteran controls. Method: The BDNF Val66Met variants were genotyped in 576 veterans: 206 veterans without PTSD and 370 veterans with PTSD subdivided into groups with or without psychotic features. Results: Veterans with psychotic PTSD were more frequently carriers of one or two Met alleles of the BDNF Val66Met polymorphism than veterans with PTSD without psychotic features and veterans without PTSD. Conclusions: The study shows that veterans with psychotic PTSD carried more Met alleles of the BDNF Val66Met than non-psychotic veterans with PTSD or veterans without PTSD. The results might add further support to the hypothesis that psychotic PTSD is a more severe subtype of PTSD.

The role of lipids in the aetiology and progress of Alzheimer's disease (AD) is still unclear High lipid levels could be one of the risk factors for AD, but no association or even protective effects of high cholesterol levels in the development of the AD were also found. The aim of the study was to determine serum levels of total cholesterol, high-density-lipoprotein cholesterol (HDL-C), low-density-lipoprotein cholesterol (LDL-C) and triglycerides (TG) in female patients with AD and in healthy elderly controls. The 50 patients met the diagnostic criteria of probable AD according to the NINDS-ADRDA and DSM-IV criteria. Cognitive impairment was evaluated using the Mini Mental State Examination (MMSE). Patients were subdivided into two groups of 19 patients in the middle (MMSE 10-19) and 31 patients in the late (MMSE 0-9) phase ofAD. Psychotic and non-psychotic features, evaluated by means of Neuropsychiatric Inventory, were presented in 13 and 37patients with AD, respectively. Control group consisted of 58 subjects without cognitive impairment (MMSE27) and with lipid levels within normal range. Serum lipid levels were determined by the enzymatic colour tests and by the enzymatic clearance assay. Significantly lower lipid levels were found in patients with AD, than in controls. Patients in the late phase of AD had significantly lower entire lipid profile than controls and significantly lower cholesterol and LDL-C levels than patients in the middle stage ofAD. There was no difference in lipid levels between patients with and without psychotic features. The significant positive correlations were found between MMSE scores and cholesterol, LDL-C levels and age in all AD patients. The results support the presumption that lipid profile might be connected with the aetiology and progress of AD and showed the association between low serum cholesterol and LDL-C levels and cognitive decline in patients with AD. Further studies are needed to confirm the relationship between lipid levels and cognition, and to validate the lipid profile as a biological marker for the progress of AD.

One of the candidate genes for suicide is also a gene in the pathway for catecholamine degradation encoding an enzyme catechol-O-methyl-transferase (COMT). It harbors a common functional polymorphism, a G to A nucleotide transition resulting in amino acid substitution from valine (Val) to methionine (Met) at position 158 (COMT Val(108/158) Met; rs4680), that has been associated with psychiatric disorders characterized with an increased risk of suicidal behavior. We have performed the first study on Caucasian population examining the association between completed suicide and the COMT Val(108/158) Met polymorphism. The study population consisted of 356 suicide victims and 198 control subjects. Significant difference in COMT Val(108/158) Met variants' (genotypes, alleles and Val carriers) distribution was found only in male groups, between controls and suicide victims (P = 0.018, P = 0.031, P = 0.005), and between controls and violent suicide victims (P = 0.026, P = 0.042, P = 0.010). The r value from the standardized residuals showed that the Met/Met genotype (r = 2.03) in the control group contributed to these significant differences. In contrast to male subjects, no significant differences in the frequency of the COMT Val(108/158) Met variants were detected between female control and female suicide groups; however, the power of calculation (range 0.161-0.680) was below the desired 0.800. In addition, the logistic regression analysis confirmed these significant differences. In conclusion, our results showed the overpresentation of the Met/Met genotype in male control subjects compared with male suicide victims, suggesting that this genotype of the COMT Val(108/158) Met might be a protective factor against suicide.

Serotonin is a monoamine that could be found in plans, animals and human body. The homeostasis of serotonin is maintained by the series of interdependent processes that include synthesis, storage, transport and removal/degradation. In the human body serotonin is synthesized in two independent compartments that are separated by brain-blood barrier. The majority of serotonin is synthesized in enterochromaffin cells of the gastrointestinal tract, released in the blood stream and stored in blood platelets. About 5% of serotonin is synthesized in the brain within serotonergic neurons. As a neurotransmitter serotonin plays an important role in the regulation of physiological functions like body temperature, sleep, vomiting, sexuality, appetite, behaviour and cognitive functions such as learning and memory. The dysfunction of the serotonergic system has been implicated in the aetiology of a variety of psychiatric (depression, schizophrenia, alcoholism) and neurological (migraine, Alzheimer’s disease, epilepsy) disorders. Recent genetic association studies of the neuropsychiatric disorders have focused on functional polymorphisms i.e. DNA sequence variations that alter the expression and/or functioning of the gene product in the loci encoding different genes. Some of them are genes for tryptophan hydroxylase, serotonin transporter and serotonergic receptors.

Several abnormalities, including lower histamine levels in brain, elevated serum histamine and degeneration of histaminergic neurons in tuberomammillary nucleus, were described in the histaminergic system of patients with Alzheimer's disease (AD). Histamine is a central neurotransmitter with several functions in brain including regulation of memory, cognition, locomotion, and is degraded in part by histamine N-methyltransferase (HNMT). A common Thr105Ile polymorphism within HNMT gene results in decreased enzyme activity. The Thr105Ile polymorphism was associated with Parkinson's disease, essential tremor, attention-deficit hyperactivity disorder (ADHD), asthma and alcoholism, thus we tested possible association of HNMT functional polymorphism with AD. We have tested 256 AD cases and 1190 healthy controls of Croatian origin. Thr105Ile polymorphism was determined by TaqMan RT-PCR Genotyping Assay and EcoRV digestion. Prevalence of functional HNMT polymorphism among all tested groups was similar and frequency of less active Ile105 variant was 11.5% among AD patients and 13.4% for healthy controls (p = 0.26, X2 = 1.25). Our results indicate lack of the association of HNMT Thr105Ile functional polymorphism with Alzheimer's disease.

A functional catechol-o-methyltransferase (COMT Val158/108Met) polymorphism, a valine (Val) to methionine (Met) substitution, has been associated with cognitive processing in the normal brain, older age, mild cognitive impairment and in various dementias. COMT is involved in the breakdown of dopamine and other catecholamines, especially in the frontal cortex; hence the carriers of Met allele, with the lower enzymatic activity, are expected to perform better on particular neuro-cognitive tests. The study included 46 patients with dementia and 65 healthy older subjects. The neurological status was assessed, using the Mini Mental Status Examination (MMSE), and the batery of different neurological tests. In DNA samples COMT polymorphism was genotyped. Patients with dementia exhibited significant genotype-induced differences in scores for MMSE, Visual Association Test (VAT) duration of numbers test, VAT time of response to numbers test, VAT average response to numbers test and WPLCR/PPLR unanswered. Carriers of Met/Met genotype had significantly lower scores of MMSE, significantly longer time to respond to VAT duration of numbers test, VAT time of response to numbers test and VAT average response to numbers test, and significantly greater number of unanswered questions to WPLCR/PPLR when compared to Met/Val or Val/Val genotypes. Our preliminary data showed significantly impaired performance in several neuro-cognitive tests in carriers of Met/Met genotype in patients with dementia compared to either Met/Val or Val/Val genotype carriers. Although Met/Met genotype with more dopamine available in the frontal cortex should be associated with better neuro-cognitive test results than Met/Val or Val/Val genotype, our data on patients with dementia did not confirm this hypothesis. Further study on larger sample of patients is needed to clarify the role of COMT polymorphism in cognitive functions.

The possibility of identifying novel biomarkers for neurodegenerative diseases has been greatly enhanced with recent advances in genomics and proteomics. Novel technologies have the potential to hasten the development of new biomarkers useful as predictors of disease etiology and outcome, as well as responsiveness to therapy. Disease-modifying new therapies are very much needed in modern approaches to treatment of neurodegenerative diseases. Current progress in the field encounters a degree of skepticism about the reliability of genomic and proteomic data and its relevance for clinical applications. Standard operating procedures covering sample collection, methodology and statistical analysis need to be fully developed and strictly adhered to in order to assure reproducible and clinically relevant results. Previous studies involving patients with neurodegenerative diseases show promise in using genomic and proteomic approaches for development of new biomarkers. Confirmation of any novel biomarker in multiple independent patient cohorts and correlation of the improvement in biomarker endpoint with clinical improvement in longitudinal patient studies remains crucial for future successful application. We propose that a combination of approaches in biomarker discovery may in the end lead to identification of promising candidates at DNA, RNA, protein and small molecule level.

Findings from numerous studies suggest an association between low cholesterol levels and suicidal behavior in patients with different psychiatric diagnoses. The aims of this case-control study were to test whether cholesterol levels in male suicidal patients (N=20) with borderline personality disorder (BPD) are lower than in male non-suicidal patients (N=20) with BPD and male healthy control group (N=20), and to evaluate the influence of structured individual psychoanalytic psychotherapy on suicidal behavior. The groups were matched for age and body mass index (BMI). Results showed that serum cholesterol levels did not differ significantly between suicidal and non-suicidal BPD patients and healthy controls. The level of psychopathology (measured by Brief Psychiatric Rating Scale and Hamilton Depression Rating Scale) was significantly higher in the group of suicidal patients, which indicates the importance of evaluating particular clinical symptoms in BPD, in order to prevent suicidal behavior. Non-suicidal male patients suffering from BPD received more frequently structured individual psychoanalytic psychotherapy prior to the hospitalization than suicidal group. These results emphasized the role of this type of psychotherapy in preventing suicidal behavior in BPD patients.

A functional catechol-o-methyltransferase (COMT Val158/108Met) polymorphism, a valine (Val) to methionine (Met) substitution, has been associated with cognitive processing in the normal brain, older age, mild cognitive impairment and in various dementias. COMT is involved in the breakdown of dopamine and other catecholamines, especially in the frontal cortex ; hence the carriers of Met allele, with the lower enzymatic activity, are expected to perform better on particular neuro-cognitive tests. The study included 46 patients with dementia and 65 healthy older subjects. The neurological status was assessed, using the Mini Mental Status Examination (MMSE), and the batery of different neurological tests. In DNA samples COMT polymorphism was genotyped. Patients with dementia exhibited significant genotype-induced differences in scores for MMSE, Visual Association Test (VAT) duration of numbers test, VAT time of response to numbers test, VAT average response to numbers test and WPLCR/PPLR unanswered. Carriers of Met/Met genotype had significantly lower scores of MMSE, significantly longer time to respond to VAT duration of numbers test, VAT time of response to numbers test and VAT average response to numbers test, and significantly greater number of unanswered questions to WPLCR/PPLR when compared to Met/Val or Val/Val genotypes. Our preliminary data showed significantly impaired performance in several neuro-cognitive tests in carriers of Met/Met genotype in patients with dementia compared to either Met/Val or Val/Val genotype carriers. Although Met/Met genotype with more dopamine available in the frontal cortex should be associated with better neuro-cognitive test results than Met/Val or Val/Val genotype, our data on patients with dementia did not confirm this hypothesis. Further study on larger sample of patients is needed to clarify the role of COMT polymorphism in cognitive functions.

Objective Alzheimer's disease (AD) is an irreversible, progressive neurodegenerative disorder with a high prevalence. Since behavioral disturbances, such as psychotic symptoms, represent a key feature of AD, genes related to dopamine, serotonin and brain derived neurotrophic factor (BDNF), are considered as candidate genes for AD. BDNF is a neurotrophin that regulates neurodevelopment, neuroplasticity, and neuronal functions. BDNF is involved in the etiopathogenesis of psychiatric and neurodegenerative disorders. A single base pair polymorphism (BDNF Val66Met) was reported to be associated with AD and/or schizophrenia, as well as other psychoses, although some studies failed to replicate these findings. The aim of the study was to evaluate the association between BDNF Val66Met variants and AD, as well as onset of AD or presence of psychotic symptoms in AD. Method BDNF Val66Met was analyzed in 211 patients with AD and in 402 aged healthy control subjects. All subjects were ethnically homogenous Caucasians from Croatia, and were subdivided according to the gender, onset of AD, and presence of psychotic symptoms. A χ 2 test, with Bonferroni correction and standardized residuals were used to evaluate the data. Results Distribution of the BDNF Val66Met genotypes differed significantly between male and female AD patients with or without psychotic symptoms. This difference was due to the significant contribution of the Met/Val genotype and the combined Met/Met and Met/Val genotypes between psychotic and non-psychotic symptoms in male, but not in female patients with AD. The frequency of the gene variants of the BDNF Val66Met did not differ significantly among male and female patients with AD and control subjects, or between male and female patients with early or late onset AD. There were significant sex related differences in age, duration of illness and scores of dementia between patients with AD. Conclusion Our male patients were younger, had shorter duration of illness, and had less severe dementia and higher cognitive performance than female AD patients. The gene variants of the BDNF Val66Met polymorphism were significantly associated with the presence of psychotic symptoms in male, but not in female patients with AD. The results had adequate statistical power to suggest that BDNF Val66Met was not related to susceptibility to AD or the onset of AD, but that presence of one or two Met alleles of BDNF Val66Met polymorphism might present a risk factor for psychosis in AD.

Over a half of all proteins are glycosylated, and their proper glycosylation is essential for normal function. Unfortunately, because of structural complexity of nonlinear branched glycans and the absence of genetic template for their synthesis, the knowledge about glycans is lagging significantly behind the knowledge about proteins or DNA. Using a recently developed quantitative high throughput glycan analysis method we quantified components of the plasma N-glycome in 99 children with attention-deficit hyperactivity disorder (ADHD), 81 child and 5 adults with autism spectrum disorder, and a total of 340 matching healthy controls. No changes in plasma glycome were found to associate with autism spectrum disorder, but several highly significant associations were observed with ADHD. Further structural analysis of plasma glycans revealed that ADHD is associated with increased antennary fucosylation of biantennary glycans and decreased levels of some complex glycans with three or four antennas. The design of this study prevented any functional conclusions about the observed associations, but specific differences in glycosylation appears to be strongly associated with ADHD and warrants further studies in this direction.

Background Brain-derived neurotrophic factor (BDNF) mediates neural plasticity, mood, different behaviours, and stress response. A functional BDNF polymorphism (BDNF Val66Met) was reported to influence the effects of stressful life events or childhood adversity on depression and suicidal behaviour in various psychopathologies. The study evaluated the association between BDNF Val66Met variants and suicide, committed with violent or non-violent methods, in victims with or without stressful childhood experience. Methods BDNF Val66Met polymorphism was genotyped on 560 DNA samples from 359 suicide victims and 201 control subjects collected on autopsy from unrelated Caucasian subjects and subdivided according to gender, method of suicide, and influence of childhood adversity. Results A similar frequency of BDNF Val66Met variants was found between all included suicide victims and the control groups, and also between the male groups. The frequency of the combined Met/Met and Met/Val genotypes and the homozygous Val/Val genotype was significantly different between the female suicide victims and female controls, between the female suicide victims who used violent suicide methods and female controls, and between all included suicide victims with or without stressful life events. The combined Met/Met and Met/Val genotypes contributed to this significance. Limitation A small group of suicide victims with available data on childhood adversity was studied. Conclusions The combined Met/Met and Met/Val genotypes of the BDNF Val66Met variant could be the risk factor for violent suicide in female subjects and for suicide in victims exposed to childhood trauma. These results confirm a major role of BDNF in increased vulnerability to suicide.

Catechol-O-methyl transferase (COMT) is an enzyme involved in the degradation of dopamine. The most commonly examined polymorphism within the COMT gene is Val108/158Met polymorphism, which results in three to fourfold difference in COMT enzyme activity. It is particularely important in prefrontal cortex, since COMT activity is the most important regulator of the prefrontal dopamine function. Given the association between schizophrenia and decreased dopamine activity in the prefrontal cortex, it is not surprising that Val108/158Met polymorphism is among the most extensively investigated polymorphisms in schizophrenia. According to different studies, Val allele may be a small risk factor for schizophrenia. There is also some evidence that Val108/158Met polymorphism influences the age of onset of schizophrenia, cognitive function, severity of psychotic symptoms, as well as efficacy and adverse events of antipsychotics. Heterogenity of patient population has undoubtedly influenced the results of these studies. Interaction of Val108/158Met polymorphism with other genes and environmental factors is an important avenue for future research.

Tobacco smoking is a global health problem. The association of a functional common polymorphism in the catechol-o-methyltransferase gene (COMT Val158Met) with smoking behavior has been extensively studied, but with divergent findings. In the present study the frequency of COMT genotypes and alleles was evaluated in 578 male and a smaller group of 79 female unrelated, medication-free Caucasian healthy subjects of Croatian origin. Smokers were classified as subjects smoking

Obesity (defined as body mass index (BMI) higher than 30), is a serious and global public health problem, associated with increased morbidity and mortality and it represents a risk factor for developing various somatic and psychiatric disorders. Combat-related posttraumatic stress disorder (PTSD) is frequently associated with increased BMI which leads to overweight and obesity. We therefore evaluated BMI in the ethnically uniform Croatian male participants of the Caucasian origin, combat exposed veterans with or without PTSD, controlled for the effect of trauma, age, smoking, alcohol consumption, physical activity and comorbid psychiatric disorders, and in age matched healthy control subjects. BMI did not differ significantly between veterans with or without PTSD and healthy control subjects, or when participants were subdivided according to the age groups, BMI categories, or the presence of psychiatric disorders. Limitation of the study might be a small number of veterans with or without PTSD. Similar BMI was found in Croatian male veterans with or without PTSD, and age matched healthy control subjects. The data provided evidence of overweight and obesity in large number of veterans but also in healthy control subjects, and indicated that public health organizations should develop more effective strategies to prevent overweight and obesity.

A polymorphism in the serotonin transporter gene (5-HTTLPR) is frequently studied for association with antidepressant treatment response, different personality traits, and psychiatric disorders. Baseline platelet serotonin (5-HT) concentration has been proposed to indicate a good or a poor treatment response to antidepressant drugs and to be associated with particular symptoms in psychiatric disorders. The aim of the study was to elucidate the genotype-phenotype relationship between platelet 5-HT concentration and 5-HTTLPR in healthy subjects. The frequency of 5-HTTLPR genotypes and alleles, as well as platelet 5-HT concentration were evaluated in 434 male and 86 female unrelated healthy medication-free Caucasian subjects of Croatian origin. A two-way ANOVA revealed no significant difference in platelet 5-HT concentration subdivided according to the particular 5-HTTLPR genotype, no significant effect of sex (F=0.122 ; d.f.=1, 514 ; P=0.727), no significant effect of genotype (F=1.000 ; d.f.=2, 514 ; P=0.369), and no significant interaction between sex and genotype (F=2.031 ; d.f.=2, 514 ; P=0.132) on platelet 5-HT concentration. In addition, one-way ANOVAs did not detect significant effects of homozygous S/S genotype (F=1.401 ; d.f.=3, 516 ; P=0.242), or homozygous L/L genotype (F=1.690 ; d.f.=3, 516 ; P=0.168) on platelet 5-HT concentration. Our results showed a lack of significant association between platelet 5-HT concentration and 5-HTTLPR variants, suggesting that there is no functional relationship between 5-HTTLPR alleles and platelet 5-HT concentration in the large groups of healthy control male and female medication-free Caucasian subjects, free of neuro-psychiatric disorders.

Alzheimer's disease (AD) is a progressive, neurodegenerative disorder with unclear etiology. Cognitive impairment in AD might be associated with altered serotonergic system. The aim of the study was to determine platelet serotonin (5-HT) concentrations and platelet monoamine oxidase type B (MAO-B) activity in patients with different severity of AD. Platelet 5-HT concentrations and MAO-B activity were determined spectrofluorimetrically in 74 female patients with AD (NINCDS- ADRDA, DSM-IV-TR criteria), subdivided according to the Mini Mental State Examination (MMSE) scores in three groups with a) 23 patients in early (MMSE scores 18-24), b) 23 patients in middle (MMSE 17-10), and c) 28 patients in late (MMSE 9-0) phase of AD, and in 49 age-matched healthy women. Platelet 5- HT concentrations and MAO-B activity were similar between all patients with AD and healthy subjects, but were significantly lower in patients in the late phase of AD than in other phases of AD, and in healthy controls. The significant correlations were found between MMSE scores and platelet 5-HT concentrations, MAO-B activity and age. Lower platelet 5-HT concentration and MAO-B activity in the late phase of AD suggested that these markers might indicate severity and/or clinical progress of AD.

Aim To compare the frequency of alleles and genotypes in brain-derived neurotrophic factor (BDNF) val66met polymorphism in ethnically homogenous Caucasian (from Croatia) and ethnically homogenous Asian (from South Korea) healthy participants, as inter-population differences in BDNF val66met may be responsible for the divergent findings in genetic and association studies. Methods BDNF val66met was genotyped in 800 (556 Croatian and 244 Korean) healthy participants. Frequencies of alleles and genotypes were evaluated using a χ2 test. Results The frequencies for genotypes (χ2 2 = 114.69; P < 0.001) and alleles (χ2 1 = 120.07; P < 0.001) between Korean and Croatian individuals differed significantly, due to significantly lower (46.3% and 19.5%, P < 0.001) frequency of “Met” allele and significantly higher (53.7% and 80.5%, P < 0.001) frequency of “Val” allele in Croatian than in Korean participants. Conclusion The study found significant ethnic differences in BDNF val66met polymorphism. The most frequent genotype among Korean participants was “Met/Val” and they had similar distribution of “Met” and “Val” alleles. In contrast, the most frequent genotype among Caucasian participants was “Val/Val” and they had different distribution of “Met” and “Val” alleles. These ethnic differences require matching participants for ethnicity in pharmacogenetic studies and in the studies investigating genetic variations in neuropsychiatric disorders.

Anti-anaemic drug ferric-sorbitol citrate showed immunomodulatory effects, activating NF- κ B in peritoneal macrophages, which consequently secrete tumour necrosis factor- α (TNF- α ). TNF- α activates NF- κ B in spleen cells. The aim of this study was to investigate the effect of iron polyisomaltosate, an iron (Fe 3+ ) compound, on serum iron, interleukin-6 (IL-6) and serotonin (5-HT) concentration, neutrophil activity, and NF- κ B activation in peritoneal macrophages and spleen cells in rats. Female Wistar rats were injected i.p. with 7.5 mg iron/kg of iron polyisomaltosate 1.5, 3, 6, 24 and 48 h before sacrifice. Serum iron, 5-HT and IL-6 concentration was determined by colorimetric, spectrofluorimetric and ELISA methods, neutrophil activity by a chemiluminescence assay, and NF- κ B expression/activation by a Dot-Blot method. Iron polyisomaltosate significantly increased serum iron and 5-HT concentrations during the first 6 h, IL-6 levels 3 and 6 h, and diminished respiratory burst of granulocytes 1.5 h after the injection. Iron polyisomaltosate stimulated activation of p65, p50 and RelB subunits of NF- κ B in the peritoneal macrophages after 6 h, and RelB subunit was additionally increased after 24 and 48 h. In the spleen cells iron polyisomaltosate stimulated p65 subunit after 48 h and RelB subunit after 24 h. The results showed time-dependent immunomodulatory effects of iron polyisomaltosate. These effects might be achieved via induction of the intracellular signalling for NF- κ B activation in peritoneal macrophages and later in spleen cells, together with increase of serum 5-HT, and IL-6 but with diminished respiratory burst of granulocytes. Iron polyisomaltosate presumably activated reactive oxygen species resulting in the stimulation of the acute phase reactants in the liver.

Smoking prevalence for schizophrenic patients is higher than this for general population. More than 60% of schizophrenic patients are current smokers, which contributes to excessive mortality in these patients. The reasons for high frequency of both smoking prevalence and heavy smoking in schizophrenic patients is thought to be at least partially related to enhancement of brain dopaminergic activity, which, in turn, results in behavioral reinforcement due to stimulant effects. Smoking stimulates dopaminergic activity in the brain by inducing its release and inhibiting its degradation. There is also evidence that cigarette smoking can reduce deficits relative to dopamine hypofunction in prefrontal cortex. Recent neuroimaging studies have further contributed the evidence of complex influences of cigarette smoking on brain dopaminergic function. It has been suggested that smoking may be an attempt by schizophrenic patients to alleviate cognitive deficits and to reduce extrapyramidal side-effects induced by antipsychotic medication. Cigarette smoke also increases the activity of CYP 1A2 enzymes, thus decreasing the concentration of many drugs, including clozapine and olanzapine. There is also evidence that smoking is associated with increased clearance of tiotixene, fluphenazine and haloperidol. Given the high frequency of smoking in schizophrenic patients, clinicians need to check smoking status in each patient. Schizophrenic patients who smoke may require higher dosages of antipsychotics than nonsmokers. Conversely, upon smoking cessation, smokers may require a reduction in the dosage of antipsychotics.

The 24th C.I.N.P. meeting was held in Paris, France, from June 20-24, 2004. The opening ceremony and welcome reception was chaired by Professor Herbert Y Meltzer, Vanderbilt University, Nashville, TN, USA, President of C.I.N.P., and a new president was elected (Professor Brian E. Leonard, Ireland). Congress included the rich social program, combined with lectures of invited speakers, speeches and awards. There were 6650 registered participants all over the world. The meeting consisted of 4 plenary lectures (held by Professor FE Bloom, Department of Neuropharmacology, The Scripps Research Institute, La Jolla USA, Professor HY Meltzer, Vanderbilt University, Nashville, TN, USA, Professor CL Masters, The University of Melbourne, and the Mental Health Research Institute of Victoria, Melbourne, Australia, and Professor JP Changeux, CNRS URA 2182 Recepteurs and Cognition, Paris, France), 69 symposia, 5 synthesia, 25 satellite symposia, 2 electronic interactive sessions, 6 meet the expert sessions, 11 sessions that were held under the name breaking scientific news, 6 workshops, 5 joint meetings, and 2 poster sessions with 657 posters. Posters were displayed for 2 days between 12.00 to 18.00 h, and presenters were available between 16.30 and 18.00 h to answer the questions. Abstracts from the congress were published in International Journal of Neuropsychopharmacology, vol 7, Supplement 1, June 2004. The 24th Collegium Internationale Neuro-Psychopharmacologicum (C.I.N.P.) Congress introduced some new exciting data, summarized some new knowledge, and its goal was to connect the preclinical and clinical data and to introduce some news into clinical practice. The smaller part of the congress that I was able to follow was well organized, and very good attended, with diverse topics, covering all aspects of neuropsychopharmacological research. The sponsorship by the pharmaceutical industries was visible only in the selected sponsored symposia.

Epidemiological studies suggest a strong heritability in schizophrenia. Positive family history is the greatest risk factor for developing schizophrenia. However, regarding the genetic factors in schizophrenia, there is a lot of the inconsistency (i.e. non-replication) in the literature of the associations of different genes with schizophrenia. The presence of a single gene is neither sufficient, nor necessary to cause schizophrenia. The understanding of the genetic basis of schizophrenia is complex. Besides different gene polymorphisms, numerous environmental factors, interacting with genes, contribute to susceptibility to schizophrenia. Such factors include the use of street drugs, childhood head injury, maternal infection during pregnancy, paternal age at conception, stressful life events and urban upbringing. While knowing genetic risks, integrative psychiatry may have a role in reducing other modifiable risk factors, including reduction of stress level, stress management strategies, family consultation/education, education against street drugs use, treatment of prodromal symptoms and development of social skills.

Antiepileptic drug lamotrigine, similarly to selective serotonin reuptake inhibitor paroxetine in patients with MDD, decreased platelet 5-HT concentration in patients with bipolar depression. The results suggest that lamotrigine possesses in vivo 5-HT uptake inhibiting property, and this effect might have contributed to its antidepressant activity.

Background/Aim: The relationship between the hypothalamic-pituitary-thyroid (HPT) axis and the serotonergic (5-hydroxytryptamine, 5-HT) system is not clear. The aim of the study was to determine platelet biochemical markers (5-HT concentration and monoamine oxidase B, MAO-B, activity) in hypothyroid patients. Methods: The study included 25 medication-free female hypothyroid patients in postoperative follow-up after total thyroidectomy due to papillary thyroid carcinoma, who had not been treated with synthetic thyroxine (T4) for 4 weeks, and 44 age-matched euthyroid healthy women. The platelet 5-HT concentration, platelet MAO-B activity, total T4 and thyroid-stimulating hormone (TSH) levels were determined using spectrofluorimetric methods, radioimmunoassay and fluoroimmunoassay, respectively. Results: Hypothyroid patients had significantly higher TSH, significantly lower T4 levels and platelet 5-HT concentrations, and unchanged platelet MAO-B activity than healthy subjects. A positive correlation was found between the 5-HT concentration and platelet MAO-B activity, and between the platelet MAO-B activity and T4 in control subjects. Conclusions: Reduced platelet 5-HT concentrations in hypothyroid patients suggests a complex interaction between the 5-HT system and HPT axis activity, which could be related to the frequent occurrence of depressive symptoms in hypothyroid patients. The determination of platelet 5-HT concentrations should be considered a diagnostic tool for the evaluation of depressive symptoms in hypothyroid patients during the hormone withdrawal procedure.

Post mortem brain studies indicate that alterations in serotonergic and catecholaminergic systems might be associated with Alzheimer's disease (AD). The aim of the study was to determine serotonin (5-HT) levels and monoamine oxidase type B (MAO-B) activity in platelets of psychotic and non-psychotic patients with AD, established according to the NINCDS-ADRDA and DSM-IV-TR criteria. Cognitive impairment and psychotic features were evaluated using Mini Mental Status Examination and Neuropsychiatric Inventory. Platelet 5-HT concentration and MAO-B activity were determined spectrofluorimetrically in 116 (51 male, 65 female) healthy subjects and 70 psychotic (10 male, 60 female) and 151 non-psychotic (32 male, 119 female) patients. Psychotic and non-psychotic female and psychotic male patients had significantly lower platelet 5-HT concentration than corresponding sex matched control subjects. Platelet MAO-B activity was significantly increased in both male and female non-psychotic patients compared to the sex matched controls. Non-psychotic female patients had significantly higher platelet MAO-B activity than psychotic female patients. Our data suggest that platelet MAO-B activity, but not platelet 5-HT concentration, could differentiate between psychotic and non-psychotic subtypes of AD.

Lamotrigine is an anticonvulsant drug effective in the treatment of epilepsy and bipolar depression. Preclinical data showed that lamotrigine inhibited monoamine oxidase (MAO) activity in vitro. The aim of the study was to determine the effects of 6-weeks lamotrigine treatment on platelet MAO type B (MAO-B) activity in patient with bipolar depression. The study included 26 female patients with bipolar I disorder in depressive episode (DSM-IV criteria, Hamilton Depression Rating Scale (HAMD) and Young Mania Rating Scale). Platelet MAO-B activity was determined spectrofluorimetrically before and after 6 weeks of the treatment with a relatively low dose of lamotrigine (100 mg/day). Six weeks of treatment with lamotrigine significantly decreased platelet MAO-B activity in bipolar depressed patients. This inhibitory effect was not related to smoking status and was independent of the treatment combinations (lamotrigine alone or in combination with either lithium or antipsychotics). Lamotrigine treatment induced a decrease in total HAMD scores in bipolar depressed patients, which was not significantly correlated with reduction of platelet MAO-B activity. These findings provide in vivo insight of lamotrigine effect on platelet MAO-B activity in patients with bipolar depression. Its in vivo MAO-B inhibiting effect might have contributed in part to its antidepressant activity.

Hypothalamus-pituitary-thyroid (HPT) axis dysfunction has been associated with pathophysiology of major depression. The aim of the study was to determine serum levels of total 3, 5, 3’ -triiodothyronine (T3), total thyroxine (T4) and thyroid-stimulating-hormone (TSH) in patients with major depression and healthy controls. The study included 53 medication-free patients with depression and 49 healthy controls. Exclusion criteria for patients was: other axis-I and axis-II diagnoses, intensive psychotherapy or electroconvulsive therapy, prior clinical and/or laboratory evidence of hypoor hyperthyroidism, alcohol or nicotine dependence, pregnancy, hormone supplement therapy, somatic illnesses (diabetes, renal or hepatic disorders), infections or autoimmune diseases, recent surgical treatment or significantly changed body weight. For controls: the presence of psychiatric disorders and/or thyroid dysfunctions. The diagnosis of major depression was made using structured clinical interview based on DSM-IV criteria. The results showed significantly lower T3 and TSH levels in patients compared to controls. There was no significant difference in T4 values between patients with depression and control subjects. The results showing altered levels of thyroid hormones in depression indicate that further research on thyroid hormone activity can contribute to the better understanding of the biological basis of depression. Based on the high frequency of the subtle neuroendocrine disorders coexisting with depression, the association of thyroid abnormalities and depression should not be underestimated. Future research should identify different behavioral endophenotypes characteristic for depression, which would greatly facilitate delineating the biological phenomena associated with this psychiatric illness.

Epidemiological studies suggest a strong heritability in schizophrenia. Positive family history is the greatest risk factor for developing schizophrenia. However, regarding the genetic factors in schizophrenia, there is a lot of the inconsistency (i.e. non- replication) in the literature of the associations of different genes with schizophrenia. The presence of a single gene is neither sufficient, nor necessary to cause schizophrenia. The understanding of the genetic basis of schizophrenia is complex. Besides different gene polymorphisms, numerous environmental factors, interacting with genes, contribute to susceptibility to schizophrenia. Such factors include the use of street drugs, childhood head injury, maternal infection during pregnancy, paternal age at conception, stressful life events and urban upbringing. While knowing genetic risks, integrative psychiatry may have a role in reducing other modifiable risk factors, including reduction of stress level, stress management strategies, family consultation/education, education against street drugs use, treatment of prodromal symptoms and development of social skills.

Pharmacotherapy of schizophrenia is associated with the stressful side effects. Muscle rigidity causes distress, discomfort and poor compliance. The aim of the study was to determine the relationship between plasma hormones (cortisol and prolactin /PRL/) and muscle rigidity in female schizophrenic patients treated with olanzapine or fluphenazine. In a randomized, double-blind 22-weeks study, 12 patients were treated with olanzapine (5-20 mg/day) and 10 patients received fluphenazine (6-21 mg/day). Treatment with olanzapine moderately decreased, while treatment with fluphenazine significantly increased plasma cortisol levels and muscle rigidity. The marked and moderate increase in plasma PRL levels were found in patients treated with fluphenazine and olanzapine, respectively. The results suggested that olanzapine induced moderate neuroendocrine effects and a reduction in rigidity as compared to fluphenazine treatment.

BACKGROUND: The role of serotonergic system and lipid status in the etiology of mania and its subtypes is not clear. The aims of the study were to determine platelet serotonin (5-HT) concentration, platelet monoamine oxidase (MAO) activity, and serum total cholesterol, high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL) and triglycerides (TG) in patients with psychotic and nonpsychotic subtypes of mania and in healthy control subjects. - - - - - METHODS: The serum lipids, platelet 5-HT and MAO were determined in 40 (17 psychotic, 23 nonpsychotic) drug free male inpatients with type I bipolar affective disorder, current episode mania (DSM-IV criteria), and in 32 healthy male subjects. - - - - - RESULTS: Platelet 5-HT levels in manic patients were similar to the values in healthy controls. Serum cholesterol and LDL values were significantly lower in manic patients than in healthy controls. Patients with psychotic features had increased platelet 5-HT concentrations and decreased levels of cholesterol and LDL as compared to the nonpsychotic manic patients and healthy controls. There was no significant difference in age, body mass index, platelet MAO activity, serum levels of TG and HDL between psychotic and nonpsychotic manic patients and healthy subjects. - - - - - LIMITATION: Data on physical activity, dietary habits and alcohol consumption before hospitalization were not collected. - - - - - CONCLUSION: The results of the present study suggest that biological differences between subtypes of mania might depend upon the presence of the psychotic symptoms. Our data confirm our previous results showing the increased platelet 5-HT concentration in psychotic disorders across the different diagnoses.

Platelet serotonin (5-HT) can be used as a limited, peripheral model for the central 5-HT synaptosomes. Altered platelet 5-HT concentrations have been associated with psychiatric disorders like depression and schizophrenia. The aim of the present study was to compare platelet 5-HT concentrations during long, medium and short period of natural daylight exposure in a large number of medication-free male and female schizophrenic and depressed patients and sex-matched healthy controls. Platelet 5-HT concentration was determined spectrofluorimetrically in 240 (97 female, 143 male) schizophrenic and 258 (153 female, 105 male) nonpsychotic, nonsuicidal depressed medication-free patients and 328 (149 women, 179 men) healthy subjects during periods with short (12) and medium (average 12) hours of the natural daylight. Platelet 5-HT concentration was significantly lower in women compared to men in all groups. Healthy male subjects had significantly higher (p=0.011) platelet 5-HT concentrations during long compared to medium period. There were no significant differences (p>0.05) in platelet 5-HT concentration between different periods in healthy women. The significant increase in platelet 5-HT values were found in female (p=0.01) and male (p=0.029) depressed patients during long compared to short period. There were no significant associations between platelet 5-HT concentrations and different periods in both male and female schizophrenic patients. The results indicate the sex-related differences in the serotonergic system. The alterations of platelet 5-HT concentrations, observed across period with different durations of daylight exposure, point to a direct or indirect effect of light on peripheral 5-HT system that could be related to different sensitivity of the pineal gland to light and/or melatonin influence on 5-HT metabolism.

Background: Combat-related posttraumatic stress disorder (PTSD) is severe form of PTSD, frequently associated with psychotic symptoms. Platelet serotonin (5-hydroxytryptamine, 5-HT) was used as a peripheral 5-HT marker to identify particular symptoms in PTSD. ----- Methods: Platelet 5-HT was determined fluorimetrically in 67 war veterans with combat related PTSD. 36 combat exposed veterans who did not develop PTSD, 35 veterans with PTSD complicated with psychotic features. PTSD diagnosis of current and chronic PTSD, and clinical symptoms of PTSD and psychoses were assessed according to DSM-IV criteria, using the Clinician Administrated PTSD Scale, and Positive and Negative Syndrome Scale (PANSS). ----- Results: Platelet 5-HT concentration was significantly higher in veterans with psychotic PTSD than in veterans with non-psychotic PTSD, veterans without PTSD, or in control subjects. Platelet 5-HT was significantly positively correlated with the positive symptoms in PANSS subscale, and with the symptoms of delusions within PANSS positive subscale. ----- Limitations: The results were obtained on peripheral 5-HT marker, i.e. platelet 5-HT concentration. ----- Conclusions: Since the delusions are the core psychotic symptoms occurring in our psychotic PTSD patients, the result of the increased platelet 5-HT concentration, associated with delusions, indicate that platelet 5-HT might be used as a trait marker of psychotic symptoms in PTSD, but not as a state marker for PTSD. reserved.