Search

Ewing Sarcoma (ES) is the second most common primary malignant bone tumor in children and adolescents. microRNAs (miRNAs) are involved in cancer as tumor suppressors or oncogenes. We studied the involvement of miRNAs located on chromosomes 11q and 22q that participate in the most common translocation in ES. Of these, we focused on 3 that belong to the let-7 family. We studied the expression levels of let-7a, and let-7b and detected a significant correlation between low expression of let-7b and increased risk of relapse. let-7 is known to be a negative regulator of the RAS oncogene. Indeed, we detected an inverse association between the expression of let-7 and RAS protein levels and its downstream target p-ERK, following transfection of let-7 mimics and inhibitors. Furthermore, we identified let-7 as a negative regulator of HIF-1α and EWS-FLI-1. Moreover, we were able to show that HIF-1α directly binds to the EWS-FLI-1 promoter. Salirasib treatment in-vitro resulted in the reduction of cell viability, migration ability, and in the decrease of cells in S-phase. A significant reduction in tumor burden and in the expression levels of both HIF-1α and EWS-FLI-1 proteins were observed in mice after treatment. Our results support the hypothesis that let-7 is a tumor suppressor that negatively regulates RAS, also in ES, and that HIF-1α may contribute to the aggressive metastatic behavior of ES. Moreover, the reduction in the tumor burden in a mouse model of ES following Salirasib treatment, suggests therapeutic potential for this RAS inhibitor in ES.

BackgroundNot enough is known about predicting therapeutic response to serotonin-specific reuptake inhibitors, and specifically to fluoxetine. This exploratory study used psychological and biological markers for (retrospective) prediction of treatment-response to fluoxetine in depressed and/or anxious adolescents.MethodsForty-one consecutive adolescent outpatients with a primary diagnosis of severe affective and/or anxiety disorders were assessed and treated with an open-label 8-week trial of fluoxetine. Type D personality was assessed with the 14-item questionnaire, the DS14. In addition, TNFα, IL-6, and IL-1b were measured pre- and post-treatment.ResultsThere was an elevation of Type D personality in patients, compared to the adolescent population rate. Post-treatment, 44% of patients were classified as non-responders; the relative risk of non-response for Type D personality patients was 2.8. Binary logistic regression predicting response vs. non-response showed a contribution of initial TNFα levels as well as Type D personality to non-response.ConclusionsIn this exploratory study, the most significant contributor to non-response was Type D personality. However, the measurement of Type D was not prospective, and thus may be confounded with psychiatric morbidity. The measurement of personality in psychiatric settings may contribute to the understanding of treatment response and have clinical utility.

Several lines of evidence have established the presence of an association between a 3-Mb deletion in chromosome 22q11 and schizophrenia. In this paper we present a complete high-density SNP scan of this segment using DNA pools, and demonstrate significant association between two distinct regions and schizophrenia in an Ashkenazi Jewish population. One of these regions contains the previously identified COMT gene. The pattern of association and linkage disequilibrium (LD) in the second region suggest that DGCR2, which encodes a putative adhesion receptor protein, is the susceptibility gene. We confirmed the association between DGCR2 and schizophrenia through individual genotyping of 1,400 subjects. In a gene expression analysis the risk allele of a coding SNP associated with schizophrenia was found to be associated with a reduced expression of DGCR2. Interestingly, the expression of DGCR2 was also found to be elevated in the dorsolateral prefrontal cortex of schizophrenic patients relative to matched controls. This increase is likely to be explained by exposure to antipsychotic drugs. To test that hypothesis, we looked at rats exposed to antipsychotic medication and found significantly elevated levels of DGCR2 transcripts. The genetic and functional evidences here reported suggest a possible role of the DGCR2 gene in the pathology of schizophrenia and also in the therapeutic effects of antipsychotic drugs.

Recent evidence support the hypothesis that exposure to stress or trauma during early childhood may disturb the formation of functional brain pathways, in particular, of the limbic circuits. We examined the effects of exposure to early life trauma (juvenile stress) on emotional and cognitive aspects of behavior in adulthood as well as on dehydroepiandrosterone (DHEA) and its sulfate ester (DHEAS) levels in relevant brain regions. Quantitative assessment of the effects of exposure to juvenile stress was made 1 month post-stress, and obtained by measuring: emotional (utilizing an open field and a startle response tests) and cognitive (Morris water-maze task) functions, as well as neurosteroids concentration (DHEA and its sulfate ester, DHEAS) in the hypothalamus and entorhinal cortex. We report here that an exposure to juvenile stress led to elevated levels of anxiety 1 month post-stress. Moreover, in a spatial learning task, the juvenile stress group performed poorer than the control group. Finally, an exposure to juvenile stress increased DHEAS but not DHEA concentrations both in the hypothalamus and the entorhinal cortex. These findings indicate that an exposure to juvenile stress has long-lasting effects on behavior and DHEAS levels in the hypothalamus and the entorhinal cortex. These effects may be of relevance to our understanding of early life stress-related disorders such as PTSD and major depression.

A variety of psychiatric illnesses, including schizophrenia and bipolar disorder, have been reported in patients with microdeletion on chromosome 22q11-a region which includes the catechol-O-methyltransferase (COMT) gene. The variety of psychiatric manifestations in patients with the 22q11 microdeletion and the role of COMT in the degradation of catecholamine neurotransmitters may thus suggest a general involvement of the COMT gene in psychiatric diseases. We have previously reported on a significant association between a COMT haplotype and schizophrenia. In this study, we attempt to test for association between bipolar disorder and the polymorphisms implicated in schizophrenia. The association between COMT and bipolar disorder was tested by examining the allele and haplotype found to be associated with schizophrenia. A significant association between bipolar disorder and COMT polymorphisms was found. The estimated relative risk is greater in women, a result consistent with our previous findings in schizophrenia. We suggest that polymorphisms in the COMT gene may influence susceptibility to both diseases--and probably also a wider range of behavioral traits.

ResumenSe presenta un caso en el que se produjo retención intensa de orina durante una exacerbatión psicótica aguda de esquizofrenia paranoide. La disfunción de la micción se manifesto durante el tratamiento continuo con dosis iguales de haloperidol, y se resolvió por completo con la remisión de los síntomas psicóticos. Era evidente una correlatión temporal clara entre el estado mental de la paciente, la puntuación de la Escala de Evaluatión Psiquiátrica Breve (BPRS) y el grado de retención de orina, que se evaluó midiendo cuantitativamente los residuos de orina diarios totales después de la micción. No pudimos relacionar la retención de orina con ningún trastorno médico general manifiesto o el tratamiento de haloperidol. Los datos presentados indican que la retención de orina en los pacientes esquizofrénicos podría ser el resultado final de diversos mecanismos relacionados con la psicosis.

This study evaluates the comorbidity of epilepsy as a variable supporting a viral hypothesis in Autism. Data covering a 30-year period (1960-1989), including general population live births, autistic births, and incidence of viral encephalitis and viral meningitis, were collected for Israel. 290 autistic births were evaluated. The annual birth pattern of subjects with comorbid epilepsy fit the seasonality of viral meningitis. These findings support the role of viral C.N.S. infections in the causality of this disorder.

BACKGROUND: Suicide-related ideation and behaviors (SRIB) are associated with both alcohol disorders and major depressive disorder (MDD). The objective of this study was to evaluate the relationship of alcohol dependence (AD) and major depression to the risk for lifetime SRIB. METHODS: Data from a community-based sample of 1,237 adult Israeli lifetime drinkers assessed with reliable diagnostic measures were analyzed using logistic regression. RESULTS: Lifetime SRIB was reported in 4.7% and was more prevalent among participants with AD (9.0%) than among those without AD (4.1%); p-value = 0.01. Although both AD and major depression were associated with SRIB (AD: OR 2.2, 95% CI 1.1 to 4.4; MDD: OR 11.4, 95% CI = 6.4 to 20.4), joint analysis showed that AD without MDD increased risk for SRIB as compared to those without AD or MDD (OR 3.1, 95% CI 1.1 to 9.1), but AD did not increase risk among those with MDD (OR 1.1, 95% CI 0.4 to 2.7). Among those with AD, the severity of subclinical depressive symptoms was associated with increased SRIB. CONCLUSIONS: These findings show that AD increases risk for SRIB among individuals without a history of major depression. Suicidal tendencies may be undetected and underdiagnosed in this group because of the absence of major depression and therefore left untreated. These findings should be considered when adopting suicide prevention or treatment strategies for this high-risk subpopulation. Language: en

Objective: Previous studies suggest that selective serotonin reuptake inhibitors (SSRIs) modulate immune system functionality. SSRIs are the preferred treatment for major depressive disorder (MDD). A high rate of MDD is observed in rheumatoid arthritis (RA) patients. The aim of this study was to evaluate immunological effects of SSRIs in a rat model of RA. Methods: Adjuvant arthritis was induced in 8-week-old Lewis rats; in the first set of experiments following the induction, 15.3 or 30.6 mg/kg of sertraline was daily injected into the ankle joint of the left rear leg. Clinical disease activity was evaluated and the findings compared with the 3 untreated legs and with control groups given methotrexate (MTX) or vehicle only at the same site. In a second set of experiments, the effect of 5, 25 and 50 mg/kg daily oral sertraline was evaluated in the same rat model. Splenocyte viability and inflammatory mediators were evaluated. Results: The sertraline-treated rats showed a significant reduction in clinical arthritis compared to controls, at all doses given, accompanied by a significant increase in interleukin 10 and a decrease in tumor necrosis factor-α levels and cycloxygenase-2 production, without lymphotoxicity. There was no significant difference from MTX, the first-line treatment for RA patients. Oral sertraline had a significant anti-inflammatory effect at all doses. There was no treatment × time effect. Conclusion: The beneficial effects of sertraline in this rat model of arthritis have clinical implications for its use in humans. Large-scale clinical efficacy trials are needed.

The effects of brief repeated swim stress on the expression of GABAA receptor alpha 1 subunit mRNAs was investigated in the mouse. Adult male mice were exposed to repeated brief (10 min) swim-stress once daily for 7 or 14 days and the levels of GABAA receptor alpha subunit mRNAs were quantified in the hippocampus 24 h after the last session by Northern analysis. Repeated swim stress for 14 days resulted in a 47.3% +/- 6.5 and 39.8% +/- 7.6 decrease in the levels of the 4.8 kb and 4.4 kb GABAA receptor alpha 1 subunit mRNAs, respectively. While there was a trend toward a reduction in the level of GABAA receptor alpha 1 subunit mRNAs following 7 days of repeated swim stress, the latter did not reach statistical significance. In contrast, no significant alterations in the levels of glutamic acid decarboxylase or beta-actin mRNAs were observed at either time point. The reduction in GABAA receptor alpha 1 subunit mRNAs following repeated swim stress may underlie similar alteration(s) in hippocampal GABAA receptor density previously observed following repeated swim stress.

Neuroblastoma (NB) is the most common extracranial solid tumor in children below the age of 5 years. miR-34a, located in chromosome band 1p36, has been recently implicated as a tumor suppressor gene in NB. In addition, it has been shown that miR-34a is activated by TP53 by binding to a TP53 binding site upstream to the mature miR-34a. We studied NB tumors from 57 patients for miR-34a expression levels, 1p status, mutations in the TP53 coding region and mutations of the TP53 binding site. Reduced expression levels of miR-34a were identified in tumors harboring 1p36.3 Loss (P = 0.028). No mutations were identified in the coding region of TP53, or in the TP53 binding site. Thus, mutations in the binding site are not an additional mechanism for the inactivation of miR-34a in NB. Other regulatory mechanisms controlling miR-34a expression and its relationship to TP53 should be further explored. © 2009 Wiley-Liss, Inc.

Introduction Treatment with selective serotonin reuptake inhibitors (SSRIs) may lead to sexual dysfunction in up to 70% of patients. Because the SSRIs are widely used antidepressants, their propensity to cause sexual dysfunction may affect compliance with therapy and ultimately treatment success. To date, the pathophysiological mechanism of sexual dysfunction caused by SSRIs remains incompletely understood, and the management of SSRIs-induced sexual dysfunction remains unsatisfactory. We suggest that medications that antagonize serotonin receptors such as trazodone may improve sexual dysfunction reverting the stimulation of serotonin receptors by SSRIs. Objective The aim of this study was to investigate the efficacy of trazodone administration in the management of SSRI-induced sexual dysfunction. Methods Twenty patients (11 men/9 women) with SSRIs-induced sexual dysfunction were recruited for the study. Trazodone was added to the existing SSRI regimen in open-label fashion for 4 weeks (50 mg for the first week increased to 100 mg until the completion of the study). The improvement in the 4 dimensions of sexual function (desire, erection or lubrication problems in women, ejaculation or orgasm in women, and overall satisfaction by both sexes) was the primary outcome measure of the study. Results Fifteen subjects completed the study. Results indicated improvement in sexual function and overall clinical improvement (depression, anxiety) as well. Specific gender differences indicated improvement in erectile performance in men and lubrication in women. No correlations were noted between clinical improvement of depression or anxiety and improvement in sexual dysfunction. Conclusions The 5-HT2 antagonist, trazodone, may be beneficial in the management of SSRI-induced sexual dysfunction. Large-scale, placebo-controlled, double-blind studies with 5-HT2 antagonists are required to substantiate these preliminary observations.

Obsessive-compulsive disorder (OCD) in children and adolescents is a common, chronic familial disorder, which is associated with significant distress and disability. OCD is characterized by intrusive, repetitive thoughts or images (obsessions) that increase anxiety, and by ritualistic stereotyped behaviors or mental acts (compulsions) intended to neutralize the anxiety. In recent years there is growing evidence pointing towards the neurobiological basis of the disorder. OCD in children and adolescents is under-diagnosed and under-treated. A few simple screening questions may identify the children and adolescents suspected of having OCD and may lead to early detection and appropriate treatment. Effective, evidence-based treatments for OCD in children and adolescents include cognitive-behavioral therapy and pharmacotherapy with selective serotonin reuptake inhibitors.

Background: The alcohol dehydrogenase 1B (ADH1B) genotype affects the risk for alcoholism, with elevated prevalence of a protective allele in Jews. Alcohol consumption is increasing among younger Israeli Jews, reflecting environmental influences. We investigated whether the relationship of ADH1B genotype with alcohol consumption differed between younger and older adult Israelis. Methods: Israeli community residents aged 22 to 65 participated in a structured interview that included questions on the maximum number of drinks on an occasion (Maxdrinks). The ADH1B genotype was determined for 68 participants and dichotomized into nonprotective (ADH1B1/1) and protective (ADH1B1/2 or ADH1B2/2) genotypes. Using Maxdrinks as the dependent variable, Poisson’s regression was used to test an agegenotype interaction. Results: The ADH1B genotype interacted significantly with age (p 5 0.01) in a Poisson’s model with Maxdrinks as the outcome. Among participants 33 years, Maxdrinks was low and unrelated to the ADH1B genotype. Among participants o33 years with ADH1B1/2 or ADH1B2/2, Maxdrinks was also low (mean, 2.6 drinks) but among those with ADH1B1/1, Maxdrinks was substantially higher (mean, 6.2 drinks). Conclusion: Maximum lifetime drinking among younger adult Israelis without genetic protection exceeded thresholds for risky and unsafe drinking (5 drinks). Environmental influences promoting greater drinking among younger Israelis may particularly affect those with the nonprotective, more common ADH1B genotype.

Introduction Epilepsy is prevalent in people with intellectual disabilities (ID) and autism spectrum disorder (ASD). Valproic acid (VPA) treatment is associated with weight gain, and changes in glucose and lipid metabolism. Objective To study the metabolic features of adults with ID and ASD. Aim: We investigated interactions of body mass index (BMI), fasting blood-glucose (FBG) and total-cholesterol levels with epilepsy and VPA treatment in these populations. Methods Medical charts of 77 adults with ID and 80 adults with ASD were reviewed for epilepsy diagnosis, VPA treatment, BMI, FBG and total-cholesterol. Results People with epilepsy had lower BMI and FBG than people without epilepsy (BMI: 23.18±5.43 vs. 25.61±5.74 kg/m2 respectively, F(1,140) =6.64; p=0.011, FBG: 72.53±11.26 vs. 79.98±14.64 mg/dl respectively, F(1,135) =10.46; p=0.002). Furthermore, in the ID group, there were more obese (BMI >30 kg/m2) adults without epilepsy than adults with epilepsy [11(29.7%) vs. 2(5.7%), respectively, Fisher’s exact test: OR=6.981 (95%CI 1.42-34.31); p=0.0125]. In the ASD group, there were more underweight (BMI People treated with VPA had lower total-cholesterol levels than untreated people (156.56± 26.13 vs. 172.42±33.82 mg/dl, respectively, F(1,150) =7.44; p=0.007), but did not differ in BMI and FBG. Conclusions Adults with ID or ASD and epilepsy had lower BMI and FBG levels than adults with ID or ASD without epilepsy. Surprisingly, adults treated with VPA had unaltered BMI and FBG, and lower total-cholesterol levels than their untreated counterparts.

A variety of psychiatric illnesses, including schizophrenia and bipolar disorder, have been reported in patients with microdeletion on chromosome 22q11-a region which includes the catechol-O-methyltransferase (COMT) gene. The variety of psychiatric manifestations in patients with the 22q11 microdeletion and the role of COMT in the degradation of catecholamine neurotransmitters may thus suggest a general involvement of the COMT gene in psychiatric diseases. We have previously reported on a significant association between a COMT haplotype and schizophrenia. In this study, we attempt to test for association between bipolar disorder and the polymorphisms implicated in schizophrenia. The association between COMT and bipolar disorder was tested by examining the allele and haplotype found to be associated with schizophrenia. A significant association between bipolar disorder and COMT polymorphisms was found. The estimated relative risk is greater in women, a result consistent with our previous findings in schizophrenia. We suggest that polymorphisms in the COMT gene may influence susceptibility to both diseases--and probably also a wider range of behavioral traits.

Several lines of evidence have placed the catechol-O-methyltransferase (COMT) gene in the limelight as a candidate gene for schizophrenia. One of these is its biochemical function in metabolism of catecholamine neurotransmitters; another is the microdeletion, on chromosome 22q11, that includes the COMT gene and causes velocardiofacial syndrome, a syndrome associated with a high rate of psychosis, particularly schizophrenia. The interest in the COMT gene as a candidate risk factor for schizophrenia has led to numerous linkage and association analyses. These, however, have failed to produce any conclusive result. Here we report an efficient approach to gene discovery. The approach consists of ( i ) a large sample size—to our knowledge, the present study is the largest case-control study performed to date in schizophrenia; ( ii ) the use of Ashkenazi Jews, a well defined homogeneous population; and ( iii ) a stepwise procedure in which several single nucleotide polymorphisms (SNPs) are scanned in DNA pools, followed by individual genotyping and haplotype analysis of the relevant SNPs. We found a highly significant association between schizophrenia and a COMT haplotype ( P =9.5×10 −8 ). The approach presented can be widely implemented for the genetic dissection of other common diseases.

Aim: Ewing sarcoma (ES) is the second most common and aggressive primary malignant bone tumor in children and adolescents. The hallmarks of the tumor are specific translocations; the most frequent involves the EWS gene on chromosome 22 and the FLI-1 gene on chromosome 11. Our aim was to identify microRNAs (miRs) and genes involved in the aggressiveness of ES. Out of the miRs located on these chromosomes, 3 belong to the let-7 family. Methods: We evaluated the expression levels of hsa-let-7a and hsa-let-7b by RQ-PCR in 57 primary ES tumors. We measured the protein levels of p-ERK, HIF-1a and EWS-FLI-1 following transfection with let-7a, let-7b or HIF-1a . The effect of a Ras inhibitor was evaluated in vitro and in vivo. Results: In the group of patients with localized disease, a significant correlation with outcome was observed. Progression free survival (PFS) at ten years for patients with high hsa-let-7b expression was 62% versus 29% for those with low hsa-let-7b expression level (p=0.029). Multivariate Cox regression analysis identified expression of let-7b as an independent prognostic factor in ES, with a 4.4 fold increased risk of relapse (p=0.021). hsa-let-7 is known to be a negative regulator of the RAS oncogene. Positive p-ERK immuno-staining was detected in 31 out of the 45 (69%) tumors analyzed, and a significant inverse correlation was identified between hsa-let-7a and p-ERK (p=0.037). One of the target genes of RAS is Hypoxia inducible factor 1 (HIF-1). We detected a high level of HIF-1α protein in ES cell lines, under normoxic conditions, which did not change following induced hypoxia. This implies for a mechanism that mimics hypoxia and probably contributes to the high frequency of metastasis and thereby aggressiveness of this tumor. Following transfection with hsa-let-7a and hsa-let-7b mimics (overexpression) the levels of RAS, p-ERK, HIF-1α and EWS-FLI-1 proteins were significantly reduced (60%, p=0.0019, 52%, p=0.003, 45%, p=0.0028 and 38%, p=0.006, respectively). Silencing of HIF-1α resulted in a decrease of 61% of EWS-FLI-1, suggesting that HIF-1α regulates EWS-FLI-1, and we were able to show that HIF-1α directly binds EWS promoter. This was accompanied by a reduction of 32% (p=0.009) in cell proliferation rate and by a significant decrease of 36% (p=0.0013) in cell migration ability. Using a RAS inhibitor, Salirasib, we observed a significant decrease of HIF-1α and EWS-FLI-1 protein levels in both in-vitro and in-vivo settings. In addition, a significant inhibition of tumor growth was demonstrated in the treated animals. Conclusions: These results imply that Ras and HIF-1α might contribute to the high frequency of metastasis and thereby aggressiveness of ES tumors. The reduction in tumor burden in a mouse model of ES following Salirasib treatment, demonstrates the therapeutic potential of this RAS inhibitor in ES. Citation Format: Michal Hameiri-Grossman, Adi Porat-Klein, Ian J. Cohen, Shifra Ash, Yoel Kloog, Ronit Haklai, Galit Elad-Sfadia, Avraham Weizman, Isaac Yaniv, Smadar Avigad. Ras pathway and HIF-1α contribute to the aggressiveness of Ewing sarcoma. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr A76.

Life events (LEs) contribute to the development of psychiatric disorders such as anxiety and depression. Nevertheless, the power of the stress-affective disorders correlation is relatively low, suggesting the existence of moderating and mediating factors (Liu et al., 2000). Caspi et al. (2003), showed a mediating effect for short allele in the 5-HTTLPR gene to be a vulnerability factor for developing affective reaction towards life events. The present study t aimed to examine the intensity of anxiety, depression and suicidal symptoms within a clinical population as a function of the genetic vulnerability and LEs variables, focusing on adolescents. The sample consisted of 146 adolescents, aged from 11 to 18 years, 54 with main diagnosis of depression, 38 with anxiety disorder and 54 healthy control group. A post-hoc analysis yielded that only for the anxiety group, but not for the depressive group, the correlation between early trauma and the suicidal ideation is dependent on genetic vulnerability. As such, only for those who suffer from anxiety disorder who also have two short alleles (ss), the existence of childhood trauma predicts more suicidality that accompany their affective disorder., while for those with two long alleles, or for those with depression, this linkage does not have significance.

Introduction Lower Limb Edema (LLE) is a common finding among admitted psychiatric patients in general and is associated with agitated state. Possible explanations include general medical condition and treatment adverse effects. Objectives To determine association between LLE and the type of psychiatric exacerbations among hospitalized patients. Methods A retrospective study was conducted using medical data from 2529 patients admitted to Geha mental Health Center between 2002 and 2012. Incident cases of LLE and the type of psychiatric exacerbation were included. A logistic regression models were used to estimate the odds ratio (OR) for LLE among patients admitted to psychiatric hospital for manic episode, psychotic episode or depressive episode. Results Lower limb edema was diagnosed in 95 of 2529 admitted patients (3.8%). Edema was found in 38 of 366 cases of manic episode (10.4%), 41 of 1563 cases of psychotic episode (2.6%) and 16 of 600 cases of depressive episode (2.7%).OR of LLE was 4.3 (95% CI, 2.7-6.7) for manic episode vs. psychotic episode and 4.2 (95% CI, 2.3-7.6) for manic episode vs. depressive episode. Applying a multivariate model adjusted for age, sex, number of past admissions, length of hospitalization, substance abuse, cardiovascular and endocrine co-morbidities, pulse, Positive and Negative Syndrome Scale (PANSS) score and blood test results did not substantially altered the risk for LLE associated with manic episode vs. psychotic episode(OR, 4.1 [95% CI, 1.6-9.9]). Conclusions Admission to psychiatric hospital for manic episode was associated with significantly increased risk for LLE.

Background Discontinuation of anti-psychotic drugs in schizophrenia patients is a major concern, since it results in relapse and re-hospitalizations. Non-adherence is strongly associated with negative subjective response to antipsychotics which is composed of the subjective experience of negative drug effects and attitude towards the treatment. Objective To assess subjective experience towards specific drug-related adverse effects which leads to a generally negative subjective attitude towards antipsychotics. Methods Attitude and experience were measured in schizophrenia inpatients (n=84) on eight subscales: weight gain, sedation, sexual anhedonia, extra-pyramidal syndrome, affective flattening, excessive sleep, diminished sociability and metabolic syndrome. DAI-30 was used to measure attitude towards drugs, and PANSS to assess psychopathology. Results Weak correlation was found between subjective experience and attitude on most of the sub-scales. The only strong, albeit inverse, correlation between experience and attitude that was found was with regard to affective flattening, experienced by 37% of the sample, and it also predicted negative drug attitude as measured by the DAI-30, RR: 1.87 (95% CI: 1.06-3.3, df=1, x2=4.525, p Conclusion Drug-related affective flattening should be evaluated routinely, since experiencing it may predict negative attitude towards drugs, potentially leading to poor compliance and relapse.

Clozapine has superior efficacy for treating patients with schizophrenia. Its discontinuation could have detrimental consequences. We attempted to identify the clinical parameters that could predict clozapine discontinuation in patients diagnosed as having schizophrenia by conducting a retrospective analysis of all of those who started on clozapine treatment during their hospitalization in our institution between 2002 and 2008 (n = 100). Demographic and clinical parameters were analyzed and compared between the 58 patients who continued and the 42 who discontinued clozapine treatment during a follow-up period of 8.1 years. Twenty of the latter patients (47.6%) discontinued clozapine because of nonadherence and 11 (26.2%) because of side effects. Thirty-three of them (78.6%) stopped taking clozapine during the first year of treatment. The duration of clozapine use correlated significantly with the time to readmission (P

Objective To assess the impact of lithium treatment alone or combined with other medications on TSH levels and WBC count in hospitalized bipolar and non-bipolar children, adolescents and young adults using data extracted from electronic medical records. Method The study investigated serum TSH and WBC count in lithium treated hospitalized youth, aged 12–24 years. The study included 122 BP (N = 67) or non-BP (N = 55) disorder inpatients treated with lithium for mean duration of 173 days. TSH and WBC values were examined at baseline and at the end of the hospitalization. Subjects were divided into two groups for analysis: group 1 was treated with lithium as monotherapy and group 2 was treated with lithium combined with other psychotropic agents (polypharmacy). Results The mean end-point TSH levels were significantly higher (3.16 ± 2.68 vs 1.52 ± 0.92 mU/L, P 3 cells, P Conclusions Lithium treatment is associated with significant increase in thyrotropin levels and WBC counts in youth. Higher-baseline TSH level is associated with higher TSH levels in lithium-treated subjects. Close monitoring of thyroid functions in lithium treated children and adolescents is recommended.

Background Compulsory admission is practiced around the world with legislative variations. The legal status during compulsory hospitalization might be changed to consent or the patient might be discharged against medical advice (AMA), if he no longer poses a risk. Objective In the present study we investigated the outcome of compulsory admitted patients who left the hospital after commitment period despite request by the treating psychiatrist to remain in the hospital (AMA) vs. those who agreed to prolong their hospitalization. Results Of 320 patients with schizophrenia admitted involuntarily, 157 (49%) were discharged without converting to consent and 163 (51%) agreed to stay in the hospital. There was no difference in baseline clinical and demographic characteristics and outcome measures (rate of readmission, legal status of next admission and length of stay in the next admission) between the two groups. Conclusions Prolongation of length of stay in compulsorily psychiatrist-ordered schizophrenia patients did not affect their rate of re-hospitalizations or the length of next admission compared to those who left the hospital immediately after the change in their legal status AMA.

The effect of a single or repeated swim stress on in vivo benzodiazepine receptor binding to various brain regions in adrenalectomized and sham-operated (control) mice was assessed using the benzodiazepine receptor antagonist, [3H]Ro15-1788. In sham-operated mice the binding of [3H]Ro15-1788 to benzodiazepine receptors was reduced in the hippocampus and hypothalamus (single or repeated stress) and cerebral cortex (repeated swim stress) compared to non-stressed mice. In contrast, no alterations in [3H]Ro15-1788 binding were observed in any brain region in adrenalectomized mice after either single or repeated swim stress. These data suggest that an intact hypothalamic-pituitary-adrenal axis is required for the stress-induced decrease in benzodiazepine receptor occupancy measured using the in vivo binding method.