HTR1A, HTR1B, HTR2A, HTR2C and HTR6 Gene Polymorphisms and Extrapyramidal Side Effects in Haloperidol-Treated Patients with Schizophrenia.

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

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.

Serotonin risk factors for the development of hypertension in pregnancy.

PURPOSE: To determine platelet serotonin (5-HT) concentrations and genotype and allele frequencies of serotonergic type 2A receptor gene (HTR2A) and 5-HT transporter gene (SLC6A4) in women with pre-eclampsia, gestational hypertension without proteinuria (PIH) and in control normotensive pregnant women. METHODS: The study included 96 control women, 131 women with PIH and 84 women with pre-eclampsia (ICD-10 criteria) in the last trimester of pregnancy. Variants of the HTR2A T102C (rs6313) and SLC6A4 (5-HTTLPR and rs25531) were determined by the PCR and real-time PCR procedures. Platelet 5-HT concentrations were analyzed by the spectrofluorimetric method. RESULTS: The frequency of the 5HTTLPR and of HTR2A T102C genotypes or alleles was similar between three groups of pregnant women and was not associated with low platelet 5-HT concentrations observed in pregnant women with PIH or pre-eclampsia. CONCLUSIONS: The results confirm alterations in the peripheral 5-HT system in pregnancy-induced hypertension. Low platelet 5-HT concentration is a common feature of both PIH and pre-eclampsia. The results did not support the hypothesis that hypertension in pregnancy is a trait associated with polymorphic variants of the HTR2A and SLC6A4 or that they have a role in the predisposition to hypertensive disorders in pregnancy. The further studies are necessary to elucidate the role of 5-HT and genetic factors in the development of hypertensive disorders in pregnancy.

Neurotransmitter measures in the cerebrospinal fluid of patients with Alzheimer's disease: a review.

BACKGROUND: Alzheimer's disease (AD) is a severe neurodegenerative disorder characterized by progressive cognitive and functional decline, as well as by a variety of neuropsychiatric and psychological symptoms and behavioral dysfunctions. Various studies proposed the role of different neurotransmitter systems not only in AD-related cognitive, but also psychotic symptoms and behavioral and emotional deficits. Due to the close proximity, pathological neurochemical changes in brain occurring in AD are likely to be reflected in the cerebrospinal fluid (CSF). The purpose of this review is to provide a summary of the CSF neurotransmitter correlates of AD in order to get further insights into the potential role of altered neurotransmitters in the pathophysiology of AD and to offer novel AD biomarkers. METHODS: PubMed and MEDLINE data bases were searched for English-language articles by using "Alzheimer's disease", "CSF" and "neurotransmitter" as primary terms. No time or article type constraints were applied. Moreover, the lists of references were searched manually for additional articles. RESULTS: Changes in various correlates of cholinergic, monoaminergic and amino acid neurotransmitter systems, as well as neuropeptides, have been observed in CSF of AD patients. However, as the results of these studies have been controversial, the importance of CSF neurotransmitter parameters as potential biomarkers in AD remains quite unclear. The observed discrepancies could be bypassed by implementation of new sensitive methods, such as novel proteomics approaches that include protein separation techniques, mass spectroscopy and targeted multiplex panels of specific analytes. CONCLUSION: Although no individual CSF neurotransmitter correlate was demonstrated as suitable biomarker of AD, a combined profile of several CSF neurochemical parameters might show enhanced sensitivity and specificity and thus contribute to earlier and more accurate diagnosis of AD, crucial for application of effective treatments.

Update on the core and developing cerebrospinal fluid biomarkers for Alzheimer disease.

Alzheimer disease (AD) is a complex neurodegenerative disorder, whose prevalence will dramatically rise by 2050. Despite numerous clinical trials investigating this disease, there is still no effective treatment. Many trials showed negative or inconclusive results, possibly because they recruited only patients with severe disease, who had not undergone disease-modifying therapies in preclinical stages of AD before severe degeneration occurred. Detection of AD in asymptomatic at risk individuals (and a few presymptomatic individuals who carry an autosomal dominant monogenic AD mutation) remains impractical in many of clinical situations and is possible only with reliable biomarkers. In addition to early diagnosis of AD, biomarkers should serve for monitoring disease progression and response to therapy. To date, the most promising biomarkers are cerebrospinal fluid (CSF) and neuroimaging biomarkers. Core CSF biomarkers (amyloid ß1-42, total tau, and phosphorylated tau) showed a high diagnostic accuracy but were still unreliable for preclinical detection of AD. Hence, there is an urgent need for detection and validation of novel CSF biomarkers that would enable early diagnosis of AD in asymptomatic individuals. This article reviews recent research advances on biomarkers for AD, focusing mainly on the CSF biomarkers. In addition to core CSF biomarkers, the potential usefulness of novel CSF biomarkers is discussed.

The association study of polymorphisms in DAT, DRD2, and COMT genes and acute extrapyramidal adverse effects in male schizophrenic patients treated with haloperidol.

Extrapyramidal symptoms (EPSs) are common adverse effects of antipsychotics. The development of acute EPSs could depend on the activity of dopaminergic system and its gene variants. The aim of this study was to determine the association between dopaminergic type 2 receptor (DRD2) dopamine transporter (SLC6A3) and catechol-O-methyltransferase (COMT) gene polymorphisms and acute EPSs in 240 male schizophrenic patients treated with haloperidol (15-mg/d) over a period of 2 weeks. Acute EPSs were assessed with Simpson-Angus Scale. Three dopaminergic gene polymorphisms, the DRD2 Taq1A, the SLC6A3 VNTR, and the COMT Val158Met, were determined. Extrapyramidal symptoms occurred in 116 (48.3%) of patients. Statistically significant associations were found for SLC6A3 VNTR and COMT Val158Met polymorphisms and EPS susceptibility. Patients with SLC6A3 9/10 genotype had almost twice the odds to develop EPSs compared with those with all other SLC6A3 genotypes (odds ratio, 1.9; 95% confidence interval, 1.13-3.30), and patients with COMT Val/Met genotype had 1.7 times greater odds to develop EPSs than those with all other COMT genotypes (odds ratio, 1.7; 95% confidence interval, 1.01-2.88). There was no statistically significant association between genotype and allele frequencies of DRD2, SLC6A3, or COMT polymorphisms and the development of particular EPSs.In conclusion, the results of the present study showed for the first time the association between acute haloperidol-induced EPSs and SLC6A3 VNTR and COMT Val158Met polymorphisms. Although the precise biological mechanisms underlying these findings are not yet understood, the results suggest that the dopaminergic gene variations could predict the vulnerability to the development of the acute EPSs in haloperidol-treated schizophrenic patients.

Human plasma glycome in attention-deficit hyperactivity disorder and autism spectrum disorders.

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.

Alzheimer's disease and type 2 diabetes: the association study of polymorphisms in tumor necrosis factor-alpha and apolipoprotein E genes.

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.

The involvement of noradrenergic mechanisms in the suppressive effects of diazepam on the hypothalamic-pituitary-adrenal axis activity in female rats.

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 (α(2)-adrenoreceptor agonist), yohimbine (α(2)-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 α(2)-adrenoreceptors activity, as well as intact presynaptic noradrenergic function, are required for the suppressive effect of diazepam on the HPA axis activity.

Association study of a functional catechol-O-methyltransferase (COMT) Val108/158Met polymorphism and suicide attempts in patients with alcohol dependence.

Alcohol dependence is frequently associated with aggressive and suicidal behaviour. Genetic factors contribute to both behaviours. Candidate genes, related to suicide and aggression, include genes involved in serotonin, norepinephrine and dopamine pathways. The enzyme catechol-O-methyl transferase (COMT) degrades dopamine, epinephrine and norepinephrine. The functional polymorphism (COMT Val108/158Met) affects COMT activity, with the valine (Val) variant associated with higher and the methionine (Met) variant with lower COMT activity. This polymorphism is associated with aggressive and suicidal behaviour, but the literature data on this relationship is contradictory and inconsistent. The hypothesis of this study was that Met allele carriers with alcohol dependence will have a higher frequency of suicide attempts compared to other genotypes. Participants were 312 male and 81 female medication-free patients with alcohol dependence and 487 male and 122 female unrelated, non-suicidal medication-free Caucasian healthy subjects. Our results showed significant (χ2 test with standardized residuals) differences in the frequencies of COMT variants in all alcoholics, alcoholics with different comorbid diagnoses, and in male but not in female alcoholics, with or without suicide attempts. Male alcoholic suicide attempters, compared to male non-attempters, had the higher frequency of Met/Met genotype or Met allele, and significantly (Kruskal-Wallis ANOVA on ranks and Mann-Whitney test) higher aggression and depression scores. These results confirmed the associations between Met allele and aggressive behaviour or violent suicide attempts in various psychiatric diagnoses, and suggested that Met allele of the COMT Val108/158 Met might be used as an independent biomarker of suicidal behaviour across different psychopathologies.

Association study of a functional catechol-o-methyltransferase polymorphism and cognitive function in patients with dementia.

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.

Serum lipid levels in patients with Alzheimer's disease.

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 (MMSE >27) 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.

Platelet monoamine oxidase activity in children with attention-deficit/hyperactivity disorder.

Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable developmental disorder characterized by symptoms of impulsivity, hyperactivity and/or inattention, and associated with structural and biochemical abnormalities in cortical and limbic structures innervated by dopamine, noradrenalin and serotonin. The enzyme monoamine oxidase, type B (MAO-B), is expressed in platelets, and metabolizes endogenous amines. Its activity has been proposed to represent a peripheral marker of various traits and forms of psychopathology. This study evaluated platelet MAO activity with a spectrofluorimetric method in 72 boys and 12 girls with predominantly hyperactive, predominantly inattentive, and combined subtype of ADHD (DSM-IV criteria), and in 64 control children. The results showed significantly lower platelet MAO activity in children with hyperactive, inattentive, and combined subtype of ADHD than in control children. There was no significant association between platelet MAO activity and gender or age. The limitation of the study was in the small sample of girls with ADHD (N=12), and in the determination of only one peripheral marker. In line with hypotheses of lower platelet MAO activity in different types of psychopathology, children with different subtypes of ADHD had significantly lower platelet MAO-B activity than control children.

Catechol-O-methyl transferase and schizophrenia.

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.

Platelet serotonin concentration in children with attention-deficit/hyperactivity disorder.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a psychiatric disorder highly prevalent in children. The neurobiology of ADHD is still not clear, but is assumed to be related to disturbances in catecholaminergic and serotonergic (5-hydroxytryptamine, 5-HT) systems. Peripheral indices of central 5-HT function were shown in recent studies to be lower, unaltered, or increased in ADHD. METHODS: The study determined platelet 5-HT concentration in 84 medication-free 9-year-old (range 4-14 years) boys and girls with DSM-IV diagnosis of ADHD, subdivided according to the different symptoms (inattention, hyperactivity, and impulsivity) and clinical ADHD subtypes (predominantly hyperactive, predominantly inattentive, and combined subtype), and in 30 age- and sex-matched healthy controls. RESULTS: Children with ADHD had similar platelet 5-HT concentrations to control children. Platelet 5-HT concentration did not differ between boys and girls, or between children with a hyperactive, inattentive, or combined subtype of ADHD. In children with ADHD there was a significant positive correlation between platelet 5-HT concentration and impulsive symptoms, but not with symptoms of inattention or hyperactivity.Platelet 5-HT concentration wassignificantly higher in impulsive compared to non-impulsive children with ADHD. CONCLUSION: The data provide preliminary evidence that increased platelet 5-HT concentration might be a trait marker predictive of impulsivity in ADHD.

Lipid levels in female patients with affective disorders.

The role of serum lipids [total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG)] in the pathophysiology of mood disorders is not clear. The aim of this study was to determine lipid profiles in patients with affective disorders. The study included medication-free female subjects (41 patients with bipolar disorder, 22 in a manic and 19 in a depressive phase), 34 patients with major depression, and 50 healthy controls. Serum lipid levels were determined using standard laboratory tests. All patients had significantly lower HDL-C values than control subjects. Increased TG levels were found in patients with bipolar disorder compared with healthy subjects. The changes in lipid profiles persisted when data were adjusted for age, smoking and menopausal status. The results revealed no differences in cholesterol and LDL-C levels and body mass index, but significant differences in the ratios of cholesterol/HDL-C and LDL-C/HDL-C (atherogenic index) among groups. Our results suggest that low HDL-C levels and a high atherogenic index might be a hallmark of affective disorders. Since low HDL-C levels could be a risk factor for the development of coronary heart disease, further investigation of lipid metabolism in affective disorders is warranted.

Platelet serotonin concentration and monoamine oxidase activity in hypothyroid patients.

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 (T(4)) for 4 weeks, and 44 age-matched euthyroid healthy women. The platelet 5-HT concentration, platelet MAO-B activity, total T(4) and thyroid-stimulating hormone (TSH) levels were determined using spectrofluorimetric methods, radioimmunoassay and fluoroimmunoassay, respectively. RESULTS: Hypothyroid patients had significantly higher TSH, significantly lower T(4) 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 T(4) 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.

Ethnic differences in brain-derived neurotrophic factor Val66Met polymorphism in Croatian and Korean healthy participants.

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 chi(2) test. RESULTS: The frequencies for genotypes (chi(2)2=114.69; P<0.001) and alleles (chi(2)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.

Smoking and schizophrenia.

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 effect of lamotrigine on platelet monoamine oxidase type B activity in patients with bipolar depression.

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.