An exploratory study of adolescent response to fluoxetine using psychological and biological predictors.

BACKGROUND: Not 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. METHODS: Forty-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. RESULTS: There 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. CONCLUSIONS: In 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.

The association between let-7, RAS and HIF-1α in Ewing Sarcoma tumor growth.

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.

Alcohol dependence and suicide-related ideation/behaviors in an Israeli household sample, with and without major depression.

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.

Immunomodulatory effect of sertraline in a rat model of rheumatoid arthritis.

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.

Reduced levels of miR-34a in neuroblastoma are not caused by mutations in the TP53 binding site.

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.

Trazodone for the treatment of sexual dysfunction induced by serotonin reuptake inhibitors: a preliminary open-label study.

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 in children and adolescents].

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.

Effect of ADH1B genotype on alcohol consumption in young Israeli Jews.

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 (ADH1B(*)1/1) and protective (ADH1B(*)1/2 or ADH1B(*)2/2) genotypes. Using Maxdrinks as the dependent variable, Poisson's regression was used to test an age x genotype interaction. RESULTS: The ADH1B genotype interacted significantly with age (p=0.01) in a Poisson's model with Maxdrinks as the outcome. Among participants >or=33 years, Maxdrinks was low and unrelated to the ADH1B genotype. Among participants <33 years with ADH1B(*)1/2 or ADH1B(*)2/2, Maxdrinks was also low (mean, 2.6 drinks) but among those with ADH1B(*)1/1, 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 (>or=5 drinks). Environmental influences promoting greater drinking among younger Israelis may particularly affect those with the nonprotective, more common ADH1B genotype.

A complete genetic association scan of the 22q11 deletion region and functional evidence reveal an association between DGCR2 and schizophrenia.

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.

Effects of early-life stress on behavior and neurosteroid levels in the rat hypothalamus and entorhinal cortex.

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.

COMT: a common susceptibility gene in bipolar disorder and schizophrenia.

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.

A highly significant association between a COMT haplotype and schizophrenia.

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=9.5x10-8). The approach presented can be widely implemented for the genetic dissection of other common diseases.