Associations of NLRP3 and CARD8 gene polymorphisms with alcohol dependence and commonly related psychiatric disorders: a preliminary study.

We investigated two functional polymorphisms in NLRP3 inflammasome genes (NLRP3 rs35829419 and CARD8 rs2043211) and their association with alcohol dependence and related anxiety, depression, obsession-compulsion, or aggression in 88 hospitalised alcohol-dependent patients, 99 abstinent alcohol-dependent participants, and 94 controls, all male Caucasian. Alcohol dependence-related psychiatric disorders were assessed with the Zung Depression and Anxiety scale, Buss-Durkee Hostility Inventory, Alcohol Use Disorders Identification Test, Brief Social Phobia Scale, Obsessive Compulsive Drinking Scale, and Yale-Brown Obsessive-Compulsive Scale. For genotyping we used the allele-specific quantitative polymerase chain reaction-based methods. The three groups differed significantly in CARD8 rs2043211 distribution (P=0.049; chi-squared=9.557; df=4). The NLPR3 rs35829419 polymorphism was not significantly associated with alcohol dependence. In hospitalised alcohol-dependent patients the investigated polymorphisms were not associated with scores indicating alcohol consumption or comorbid symptoms. In abstinent alcohol-dependent subjects homozygotes for the polymorphic CARD8 allele presented with the highest scores on the Zung Anxiety Scale (p=0.048; df=2; F=3.140). Among controls, CARD8 genotype was associated with high scores on the Obsessive Compulsive Drinking Scale (P=0.027; df=2; F=3.744). In conclusion, our results reveal that CARD8 rs2043211 may play some role in susceptibility to alcohol dependence, expression of anxiety symptoms in abstinent alcohol-dependent subjects, and in obsessive compulsive drinking in healthy controls. However, further studies with larger cohorts are required to confirm these preliminary findings.

Genetic polymorphisms in dopaminergic system and treatment-resistant schizophrenia.

BACKGROUND: Dopaminergic system plays an important role in antipsychotic response. Functional single nucleotide polymorphisms (SNPs) can change dopamine receptor expression or dopamine disposition and thus influence response to antipsychotic treatment. SUBJECTS AND METHODS: 138 schizophrenia patients were stratified in the treatment-resistant and treatment-responsive group. Control group consisted of 94 healthy blood donors. All subjects were genotyped for the following SNPs: DRD1 (rs4532, rs5326), DRD2 (rs1801028, rs1799732), DRD3 (rs6280) and COMT (rs165815, rs4680). Association between the genotypes and clinical symptoms were tested using ANCOVA with current antipsychotic dose as a confounder. Differences in allele frequencies between treatment-responsive and treatment-resistant schizophrenic patients were assessed using χ(2) tests. RESULTS: No statistically significant associations were observed between any of the investigated genotypes and clinical scores and occurrence of the treatment-resistant schizophrenia. CONCLUSIONS: Genetic variability in dopaminergic system does not have a major role in clinical symptoms and occurrence of treatment-resistant schizophrenia among Slovenian patients.

Adenosine Hypothesis of Antipsychotic Drugs Revisited: Pharmacogenomics Variation in Nonacute Schizophrenia.

The existing antipsychotic therapy is based on dopamine hyperfunction and glutamate hypofunction hypotheses of schizophrenia. Adenosine receptors (ADORA) have a neuromodulatory role and can control dopaminergic and glutamatergic systems. To elucidate the effect of ADORA polymorphisms on psychopathological symptoms and adverse effects in patients with schizophrenia on long-term antipsychotic treatment, we examined 127 nonacute schizophrenia outpatients in a cross-sectional study using the Positive and Negative Symptoms Scale, Simpson-Angus Scale, Barnes Akathisia Rating Scale, and Abnormal Involuntary Movement Scale. All patients were genotyped for 18 polymorphisms in ADORA1, ADORA2A, and ADORA3. We found an association between ADORA1 rs3766566 and psychopathological symptoms (p = 0.006), in particular, with positive psychopathological symptoms (p = 0.010) and general psychopathological symptoms (p = 0.023), between ADORA2A rs2298383 and general psychopathological symptoms (p = 0.046), and between ADORA2A rs5751876 and akathisia (p = 0.015). Haplotype analysis showed an association between ADORA1 CTCAACG haplotype and overall psychopathological symptoms (p = 0.019), positive psychopathological symptoms (p = 0.021), and akathisia (p = 0.028). ADORA2A TCCTC haplotype was associated with parkinsonism (p = 0.014). ADORA3 CACTAC was associated with akathisia (p = 0.042), whereas CACTAT was associated with akathisia (p = 0.045) and tardive dyskinesia (p = 0.023). The results of this first comprehensive study on ADORA polymorphisms in patients with nonacute schizophrenia receiving long-term antipsychotic therapy suggest an important neuromodulatory role of ADORA receptors in both psychopathological symptoms and adverse effects of antipsychotics.

First report of an outbreak of pneumonia caused by Streptococcus pneumoniae serotype 6A.

Five patients in a geropsychiatric unit of a psychiatric hospital became abruptly ill with pneumonia caused by Streptococcus pneumoniae serotype 6A. Four other residents were colonized with the same serotype, which has previously not been reported in association with pneumonia outbreaks. Furthermore, serotype 6A is not included in all vaccine types, which may be important for the choice of vaccine in some settings. All isolates showed identical pulsed-field gel electrophoresis restriction patterns.

Vitamin E and essential polyunsaturated fatty acids supplementation in schizophrenia patients treated with haloperidol.

OBJECTIVES: Previously, oxidative damage has been associated with severity of clinical symptoms and supplementation with antioxidants and essential polyunsaturated fatty acids (EPUFAs) was proposed to have beneficial effects in schizophrenia. We evaluated the effects of supplementation with EPUFAs and vitamin E in patients treated with haloperidol depot injection. DESIGN: This was a double-blind randomized placebo-controlled study with four arms (Placebo, vitamin E, EPUFAs, and vitamin E + EPUFAs). Biomarkers of oxidative stress, neurochemistry, psychopathology, and extrapyramidal symptoms were assessed at baseline and after 4 months. RESULTS: In EPUFAs group of patients, reduced glutathione concentration was increased compared to placebo. Concentration of oxidized glutathione was decreased in patients receiving vitamin E. In addition, compared to placebo a non-significant trend of increased activity of catalase and superoxide dismutase was observed in all three treatment groups. Patients receiving vitamin E experienced less motor retardation. No difference in extrapyramidal symptoms was found. DISCUSSION: Our study indicates that supplementation with vitamin E and EPUFAs may improve the antioxidative defense, especially glutathione system, while there is no major effect on symptoms severity. Supplemental treatment with EPUFAs and vitamin E in schizophrenia patients treated with haloperidol is potentially beneficial and a larger independent study appears warranted.

Personalized treatment of schizophrenia in everyday clinical practice: reality or fiction?

Each day clinical practice tries to follow the idea and principles of personalized medicine. Besides predicting an individual's sensibility or predisposition for developing schizophrenia, pharmacogenetic and pharmacogenomic approaches attempt to define and acknowledge important indicators of clinical response to antipsychotics namely their efficacy and adverse effects. The main focus of our article were not facts regarding the role CYP450 liver enzymes have in this; our purpose is introducing other, new genetic and epigenetic factors which could introduce important biomarkers in diagnostics of the disease itself, the efficacy and tolerance for antipsychotics. There is still a huge gap between gathering and collecting information and using them for the personalized treatment of schizophrenia. From the genetic point of view personalized treatment of schizophrenia is the field we need to focus on and successfully incorporate it our everyday clinical practice in the future.

Influence of 5-HT1A and 5-HTTLPR genetic variants on the schizophrenia symptoms and occurrence of treatment-resistant schizophrenia.

This study aimed to explore the influence of two genetic polymorphisms of the 5-hydroxytryptamine 1A receptor (5-HT1A) and solute carrier family 6, member 4 (SLC6A4) genes on the clinical symptoms and treatment resistance in Slovenian patients with schizophrenia. A total of 138 patients with schizophrenia were evaluated using the Positive and Negative Syndrome Scale, Brief Psychiatric Rating Scale, Clinical Global Impression, and Global Assessment of Functioning. Based on the selected criteria, 94 patients were included in the treatment-responsive and 44 in the treatment-resistant group. All subjects and 94 controls were genotyped for the 5-HT1A rs6295 and 5-HTTLPR polymorphisms. There were no statistically significant differences in the frequencies of these polymorphisms between the patients with schizophrenia and the control group and between the treatment-resistant and treatment-responsive group of schizophrenia patients. Polymorphisms rs6295 and 5-HTTLPR had an influence on the Global Assessment of Functioning scale score, while 5-HTTLPR also had an influence on the total score of the negative subscale within the Positive and Negative Syndrome Scale. Although we found no effect on progression toward the treatment-resistant schizophrenia, our data suggest that the rs6295 and 5-HTTLPR polymorphisms can influence some clinical symptoms in schizophrenia.

Genetic variability testing of neurodevelopmental genes in schizophrenic patients.

This study investigated the associations between single nucleotide polymorphisms in the neurodevelopmental Disrupted In Schizophrenia 1 (DISC1 ), neuregulin 1 (NRG1), brain-derived neurotrophic factor (BDNF) and NOTCH4 genes and the clinical symptoms and the occurrence of treatment-resistant schizophrenia in the Slovenian population. We included 138 schizophrenia patients, divided into treatment-responsive and treatment-resistant group and 94 healthy blood donors. All subjects were genotyped for eight polymorphisms (DISC1 rs6675281, DISC1 rs821616, NRG1 rs3735781, NRG1 rs3735782, NRG1 rs10503929, NRG1 rs3924999, BDNF rs6265, NOTCH rs367398) and investigated for associations with clinical variables. NOTCH4 rs367398 AA/AG was significantly associated with worse Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impression (CGI) score. NOTCH4 rs367398 was not statistically significantly associated with the occurrence of treatment-resistant schizophrenia after the correction for multiple testing. Our data indicate that NOTCH4 polymorphism can influence clinical symptoms in Slovenian patients with schizophrenia.

Therapeutic drug monitoring and pharmacogenetics--is this a way towards creative psychopharmacotherapy?

Modern development trends in psychiatry incorporate greater care for patients and above all individualisation of therapeutic approaches. Therapeutic drug monitoring (TDM) for phenotyping and genotyping of drug metabolism are possible determinants of improved treatment efficacy, reduced adverse effects of psychotropic drugs, and enhanced treatment compliance. They render possible individual adjustment of psychopharmacological treatment and thus represent a small, but significant piece in the mosaic of creative psychopharmacotherapy.

Efficacy and tolerability of agomelatine in the treatment of depression.

Depression is a severe and usually recurrent mental disorder which often leads to a significant impairment of everyday functioning, a reduced quality of life, and also great suffering of the patients. The treatment of a depressive disorder is not only limited to acute treatment; it also requires prolonged management. Patient compliance is of utmost importance. Unpleasant adverse effects and their impact on everyday living often lead to a premature discontinuation of antidepressant treatment and result in an unfavorable treatment outcome. The new antidepressant agomelatine, a melatonergic MT1/MT2 agonist and 5-HT2C receptor antagonist, has exhibited good antidepressant efficacy in acute, short-term, and long-term treatment. The adverse effect profile of agomelatine has been proven to be favorable and comparable to placebo, which is very important for good treatment compliance and adherence.

The present global financial and economic crisis poses an additional risk factor for mental health problems on the employees.

BACKGROUND: The global financial and economic crisis starting in 2007 led to a deterioration of several socio-economic determinants of mental health. The aim of this cross-sectional study was to examine the impact of the present economic crisis on the depression and anxiety levels of the employed in the private and public sector in Slovenia. SUBJECTS AND METHODS: Altogether 1592 employees completed an internet based self-reported questionnaire. Data about perceived impact of the economic crisis, several socio-demographic, socioeconomic, and health parameters were collected. Depression symptoms were assessed by the Center for Epidemiological Studies-Depression Scale and anxiety symptoms by the Spielberger State-Inventory. Regression models were used 1) to explore the associations of the economic crisis with the level of depression and anxiety symptoms while controlling for some sociodemographic and work characteristic variables, and 2) to understand the relationship between some potentially important socioeconomic variables and the perception of the economic crisis. RESULTS: Depressive and anxiety scores were significantly increased among 590 (46.6%) employees being affected by the economic crisis. The level of depressive symptoms was significantly associated with perceived impact by the crisis, recent sick leave, reported injuries sustained at work, benzodiazepine and analgesic use, the lack of emotional support, and trust in crisis telephone lines. The level of anxiety symptoms yielded the robust association with the level of depression symptoms, reported injuries sustained on the way to work and education. CONCLUSIONS: The economic crisis poses an additional risk factor for mental health problems which clinicians should internalize and become more aware of them. Symptoms of depression and anxiety can be masked in high-utilizers of medical care with physical complaints or psychoactive drug use.

Glutamatergic gene variants impact the clinical profile of efficacy and side effects of haloperidol.

BACKGROUND: The glutamatergic system may be relevant to the pathophysiology of psychosis and to the effects of antipsychotic treatments. OBJECTIVES: We investigated a set of 62 SNPs located in genes coding for subunits of glutamatergic receptors (GAD1, GRIA1, GRIA3, GRIA4, GRID2, GRIK1, GRIK2, GRIK3, GRIK4, GRIN2B, GRM1 and GRM4), and the transporter of glycine (SLC6A5), as modulators of the effects of haloperidol. METHODS AND RESULTS: We studied a sample of 101 acutely ill psychotic patients. We then validated our result in two independent samples from Slovenia (n=71 and n=118) of schizophrenic patients treated with antipsychotics. We both investigated the antipsychotic effect (Positive and Negative Syndrome Scale) and motor side effect (Extrapyramidal Symptom Rating Scale) at baseline and days 3, 7, 14, 21 and 28. SLC6A5 variant (rs2298826) was found to be associated with a rapid rise of motor side effects at the beginning of the treatment (repeated measures of analysis of variance, P=0.0002), followed by a subsequent adaptation, probably dependent on haloperidol doses down titration. A specific effect was noted for dyskinetic symptoms. Haplotype analysis strengthened the relevance of SLC6A5: the C-A-C haplotype (rs1443548, rs883377, rs1945771) was found to be associated with higher Extrapyramidal symptom rating scale scores (overall P=0.01, haplotype P=0.000001). We successfully replicated this finding in the two independent samples from Slovenia. CONCLUSION: This result further stresses the relevance of the glutamatergic system in modulating the effects of haloperidol treatment, especially with regards to motor side effects.

Efficacy and tolerability of venlafaxine extended release in patients with major depressive disorder.

BACKGROUND: In this study we wanted to determine the efficacy and tolerability of venlafaxine extended release in patients with major depressive disorder. SUBJECTS AND METHODS: 161 patients with major depressive disorder were included in an open-label, multicentre clinical study. All patients were treated with venlafaxine extended release in flexible doses ranging from 75 to 325 mg daily over an 8-week period. Efficacy measurements included the 17-item Hamilton Depression Scale, the Clinical Global Impression-Improvement scale (CGI-I), the Severity of Illness scale (CGI-S), and the Depression and Somatic Symptom Scale (DSSS). All scales were administered at baseline and at weeks 2, 4 and 8. RESULTS: A total of 148 (91.2%) patients completed the study. After 8 weeks of treatment with venlafaxine extended release, response and remission rates were 93% and 45% respectively. At the end of the study, 52.7% of patients were rated on CGI-S with 2 or 1 (not ill/mildly ill) and on CGI-I 81.1% of patients were rated by the physician as much/very much improved. The severity of somatic symptoms such as headache, back pain, chest pain, tenderness of more than a half of body muscles, and fatigue or loss of energy decreased towards the end of the study (p<.0001). Adverse events caused discontinuation in 4.7% of patients. No significant changes of body mass (p=.237), Body Mass Index (p=.281), and heart rate (p=.840) were present, but systolic and diastolic blood pressure significantly decreased (p<.0001) towards the end of the study. CONCLUSION: The data from this study indicate that venlafaxine XR is an efficient and safe therapeutic option for patients with major depressive disorder, with the additional effect of reducing associated painful physical symptoms.

Personalized antipsychotic treatment: the adverse effects perspectives.

Antipsychotics are the lodestar in the treatment of schizophrenia despite the variability of the therapeutic response and drug-induced adverse effects (especially extrapyramidal symptoms, gain weight, and metabolic disturbances). More and more data are supporting the notion that genetic factors - as well as often overlooked personal and environmental factors - that define the inter-individual differences in pharmacokinetic and pharmacodynamic treatment response. At present, there are no practical pharmakogenetic tests that could be used in everyday clinical practice; however, in the field of psychiatry they are expected within a few years. Pharmacogenetic tests will indubitably become an important tool for personalized prescription.

MDR1 gene polymorphisms and response to acute risperidone treatment.

Polymorphic multidrug resistant protein 1 (MDR1) transports drugs against a concentration gradient across the blood-brain barrier and reduces their accumulation in the brain. MDR1 may therefore influence antipsychotic brain availability contributing to inter-individual differences in treatment response and adverse effects, regardless of plasma concentrations. In the present study we investigated the influence of two common MDR1 polymorphisms on the improvement of psychopathological symptoms and occurrence of extrapyramidal side effects (EPS) in Slovenian schizophrenia patients acutely treated with risperidone. A total of 59 clinically well defined patients with first episode schizophrenia spectrum disorders or after tapering their maintenance treatment were genotyped for MDR1 C3435T and G2677T/A. Steady-state plasma concentrations of risperidone active moiety (sum of risperidone and the 9-hydroxyrisperidone) were determined. G2677T/A and C3435T genotypes were not associated to psychopathological symptoms, efficacy of treatment and risk for parkinsonism. Marginal associations with akathisia (p=0.039 and p=0.042, respectively) and dystonia (p=0.013 and p=0.034, respectively) were observed for both G2677T/A and C3435T genotypes. However, higher AIMS and BARS scores were observed only in heterozygous carriers of G2677T/A and C3435T polymorphisms and there was no tendency of gene-dose effect. The present study does not suggest a major influence of MDR1 G2677T/A and C3435T polymorphisms on treatment response during short-term risperidone therapy in patients with schizophrenia or schizoaffective disorder.

Attitudes of midwifery students towards teaching breast-self examination.

BACKGROUND: The purpose of this study was to asses the attitude of undergraduate midwifery students towards teaching other women in methods of breast self-examination (BSE). PARTICIPANTS AND METHODS.: The study was performed at the beginning and at the end of students' study at the Faculty of Health Sciences in Ljubljana, Slovenia. It was carried out during the academic year 2002/2003 and involved 28 first and 25 third year undergraduate midwifery students. The data were gathered from questionnaires and processed with the use of descriptive and inferential statistics. RESULTS: All study participants were of the opinion that teaching other women in methods of BSE is of great importance for an early detection of breast cancer (BC) and that this task ought to be one of their duties. There were no significant differences between the two groups when the readiness to upgrade their own knowledge of BSE or when the optimism regarding the progress in breast cancer detection and therapy in the future were concerned. CONCLUSIONS: The readiness of midwifery students to pass the knowledge of BSE to other women could help to increase their breast health awareness and thus improve their willingness and ability to detect early changes, associated with BC.

Electroconvulsive therapy in psychiatric practice: a selective review of the evidence.

Electroconvulsive therapy (ECT) is largely historical but is still in use. Modern psychiatry requires careful selection of patients in whom ECT will be performed. The indications for ECT treatment are limited, and the selection criteria should be strictly followed. The advantages and the disadvantages of the methods are discussed here. Despite the limitations, ECT seems to have real value in selected mental conditions in which it can even be considered a life-saving procedure.

CYP 2D6 polymorphism and antipsychotic therapy.

One of the most challenging problems in clinical psychiatry are inter-individual differences in clinical response to antipsychotic treatment. Several studies were investigating the impact of the polymorphic cytochrome P450 2D6 gene (CYP 2D6) on the psychopathological and extrapyramidal symptoms, but the results were conflicting. There is a lack of clinical studies of the impact of CYP2D6 polymorphism on therapeutic efficacy, especially in the long-term treatment of schizophrenia. The aim of the presentation was to evaluate the impact of CYP2D6 genotype on psychopathological and extrapyramidal symptoms in a group of Slovenian outpatients with schizophrenia or schizoaffective disorder in stable remission, who were receiving long-term maintenance therapy.

Acute antipyschotic efficacy and side effects in schizophrenia: association with serotonin transporter promoter genotypes.

BACKGROUND: The serotonin transporter (5-HTT) plays an important role in serotonergic neurotransmission. In the present study, we investigated the effects of the 44 bp insertion/deletion polymorphism in the promoter region of 5-HTT gene (5-HTTLPR) on symptomatology of psychosis and clinical response to antipsychotic drugs. METHODS: In total 56 patients acutely treated with haloperidol or risperidone either for the first episode of schizophrenia, schizophreniform or schizoaffective disorders, or for the relapse of these psychotic disorders after tapering their maintenance treatment, were genotyped for the 5-HTTLPR L and S alleles and for the new A/G functional variant within the L alelle (La/g). Psychopathological symptoms were assessed with the Brief Psychiatric Rating Scale (BPRS) and with Clinical Global Impression (CGI) twice: at 8-12 days after the first dose of antipsychotic and after 4 weeks. Extrapyramidal side effects were assessed with the Simpson-Angus Extrapyramidal Side Effects Scale (EPS), the Barnes Akathisia Scale (BARS) and the Abnormal Involuntary Movement Scale (AIMS). RESULTS: Age, body mass index (BMI), illness duration, drug type and dosage were considered as covariates when analysing association with genetic variants as they were associated with baseline or final BPRS and CGI scores and/or extrapyramidal side effects. 5-HTTLPR was not associated with baseline and final BPRS and CGI scores or with the CGI% reduction. However, the 5-HTTLPR S allele was associated with a lower improvement in BPRS scores (P=0.022) and this effect was even stronger after pooling subjects with S or Lg containing alleles (P=0.006). We did not observe any effect of 5-HTTLPR on acute antipsychotics side effects. CONCLUSION: Present result supports a contribution of serotonin system to neuroleptics efficacy for the treatment of schizophrenia. The analysis of the La/g functional variant may significantly improve the predictive power of 5-HTTLPR genotyping and represent a step further towards the development of the personalized antipsychotic treatment.