Ulk4 regulates GABAergic signaling and anxiety-related behavior

Excitation/inhibition imbalance has been proposed as a fundamental mechanism in the pathogenesis of neuropsychiatric and neurodevelopmental disorders, in which copy number variations of the Unc-51 like kinase 4 (ULK4) gene encoding a putative Serine/Threonine kinase have been reported in approximately 1/1000 of patients suffering pleiotropic clinical conditions of schizophrenia, depression, autistic spectrum disorder (ASD), developmental delay, language delay, intellectual disability, or behavioral disorder. The current study characterized behavior of heterozygous Ulk4(+/tm1a) mice, demonstrating that Ulk4(+/tm1a) mice displayed no schizophrenia-like behavior in acoustic startle reactivity and prepulse inhibition tests or depressive-like behavior in the Porsolt swim or tail suspension tests. However, Ulk4(+/tm1a) mice exhibited an anxiety-like behavioral phenotype in several tests. Previously identified hypo-anxious (Atp1a2, Ptn, and Mdk) and hyper-anxious (Gria1, Syngap1, and Npy2r) genes were found to be dysregulated accordingly in Ulk4 mutants. Ulk4 was found to be expressed in GABAergic neurons and the Gad67⁺ interneurons were significantly reduced in the hippocampus and basolateral amygdala of Ulk4(+/tm1a) mice. Transcriptome analyses revealed a marked reduction of GABAergic neuronal subtypes, including Pvalb, Sst, Cck, Npy, and Nos3, as well as significant upregulation of GABA receptors, including Gabra1, Gabra3, Gabra4, Gabra5, and Gabrb3. This is the first evidence that Ulk4 plays a major role in regulating GABAergic signaling and anxiety-like behavior, which may have implications for the development of novel anxiolytic treatments

Most Antidepressant Use in Primary Care Is Justified; Results of the Netherlands Study of Depression and Anxiety

BACKGROUND: Depression is a common illness, often treated in primary care. Many studies have reported undertreatment with antidepressants in primary care. Recently, some studies also reported overtreatment with antidepressants. The present study was designed to assess whether treatment with antidepressants in primary care is in accordance with current guidelines, with a special focus on overtreatment. METHODOLOGY: We used baseline data of primary care respondents from the Netherlands Study of Depression and Anxiety (NESDA) (n = 1610). Seventy-nine patients with treatment in secondary care were excluded. We assessed justification for treatment with antidepressant according to the Dutch primary care guidelines for depression and for anxiety disorders. Use of antidepressants was based on drug-container inspection or, if unavailable, on self-report. Results were recalculated to the original population of primary care patients from which the participants in NESDA were selected (n = 10,677). PRINCIPAL FINDINGS: Of 1531 included primary care patients, 199 (13%) used an antidepressant, of whom 188 (94.5%) (possibly) justified. After recalculating these numbers to the original population (n = 10,677), we found 908 (95% CI 823 to 994) antidepressant users. Forty-nine (95% CI 20 to 78) of them (5.4%) had no current justification for an antidepressant, but 27 of them (54.5%) had a justified reason for an antidepressant at some earlier point in their life. CONCLUSIONS: We found that overtreatment with antidepressants in primary care is not a frequent problem. Too long continuation of treatment seems to explain the largest proportion of overtreatment as opposed to inappropriate initiation of treatment

Association between substance use and psychosocial characteristics among adolescents of the Seychelles

BACKGROUND: We examined the associations between substance use (cigarette smoking, alcohol drinking, and cannabis use) and psychosocial characteristics at the individual and family levels among adolescents of the Seychelles, a rapidly developing small island state in the African region. METHODS: A school survey was conducted in a representative sample of 1432 students aged 11-17 years from all secondary schools. Data came from a self-administered anonymous questionnaire conducted along a standard methodology (Global School-based Health Survey, GSHS). Risk behaviors and psychosocial characteristics were dichotomized. Association analyses were adjusted for a possible classroom effect. RESULTS: The prevalence of cigarette smoking, alcohol drinking and cannabis use was higher in boys than in girls and increased with age. Age-adjusted and multivariate analyses showed that several individual level characteristics (e.g. suicidal ideation and truancy) and family level characteristics (e.g. poor parental monitoring) were associated with substance use among students. CONCLUSIONS: Our results suggest that health promotion programs should simultaneously address multiple risk behaviors and take into account a wide range of psychosocial characteristics of the students at the individual and family levels

Identification and Characterization of Mechanism of Action of P61-E7, a Novel Phosphine Catalysis-Based Inhibitor of Geranylgeranyltransferase-I

Small molecule inhibitors of protein geranylgeranyltransferase-I (GGTase-I) provide a promising type of anticancer drugs. Here, we first report the identification of a novel tetrahydropyridine scaffold compound, P61-E7, and define effects of this compound on pancreatic cancer cells. P61-E7 was identified from a library of allenoate-derived compounds made through phosphine-catalyzed annulation reactions. P61-E7 inhibits protein geranylgeranylation and blocks membrane association of geranylgeranylated proteins. P61-E7 is effective at inhibiting both cell proliferation and cell cycle progression, and it induces high p21CIP1/WAF1 level in human cancer cells. P61-E7 also increases p27Kip1 protein level and inhibits phosphorylation of p27Kip1 on Thr187. We also report that P61-E7 treatment of Panc-1 cells causes cell rounding, disrupts actin cytoskeleton organization, abolishes focal adhesion assembly and inhibits anchorage independent growth. Because the cellular effects observed pointed to the involvement of RhoA, a geranylgeranylated small GTPase protein shown to influence a number of cellular processes including actin stress fiber organization, cell adhesion and cell proliferation, we have evaluated the significance of the inhibition of RhoA geranylgeranylation on the cellular effects of inhibitors of GGTase-I (GGTIs). Stable expression of farnesylated RhoA mutant (RhoA-F) results in partial resistance to the anti-proliferative effect of P61-E7 and prevents induction of p21CIP1/WAF1 and p27Kip1 by P61-E7 in Panc-1 cells. Moreover, stable expression of RhoA-F rescues Panc-1 cells from cell rounding and inhibition of focal adhesion formation caused by P61-E7. Taken together, these findings suggest that P61-E7 is a promising GGTI compound and that RhoA is an important target of P61-E7 in Panc-1 pancreatic cancer cells

Migraine and psychiatric comorbidity: a review of clinical findings

Migraine is an extremely common disorder. The underlying mechanisms of this chronic illness interspersed with acute symptoms appear to be increasingly complex. An important aspect of migraine heterogeneity is comorbidity with other neurological diseases, cardiovascular disorders, and psychiatric illnesses. Depressive disorders are among the leading causes of disability worldwide according to WHO estimation. In this review, we have mainly considered the findings from general population studies and studies on clinical samples, in adults and children, focusing on the association between migraine and psychiatric disorders (axis I of the DSM), carried over after the first classification of IHS (1988). Though not easily comparable due to differences in methodology to reach diagnosis, general population studies generally indicate an increased risk of affective and anxiety disorders in patients with migraine, compared to non-migrainous subjects. There would also be a trend towards an association of migraine with bipolar disorder, but not with substance abuse/dependence. With respect to migraine subtypes, comorbidity mainly involves migraine with aura. Patients suffering from migraine, however, show a decreased risk of developing affective and anxiety disorders compared to patients with daily chronic headache. It would also appear that psychiatric disorders prevail in patients with chronic headache and substance use than in patients with simple migraine. The mechanisms underlying migraine psychiatric comorbidity are presently poorly understood, but this topic remains a priority for future research. Psychiatric comorbidity indeed affects migraine evolution, may lead to chronic substance use, and may change treatment strategies, eventually modifying the outcome of this important disorder

Relevance of Stress and Female Sex Hormones for Emotion and Cognition

There are clear sex differences in incidence and onset of stress-related and other psychiatric disorders in humans. Yet, rodent models for psychiatric disorders are predominantly based on male animals. The strongest argument for not using female rodents is their estrous cycle and the fluctuating sex hormones per phase which multiplies the number of animals to be tested. Here, we will discuss studies focused on sex differences in emotionality and cognitive abilities in experimental conditions with and without stress. First, female sex hormones such as estrogens and progesterone affect emotions and cognition, contributing to sex differences in behavior. Second, females respond differently to stress than males which might be related to the phase of the estrous cycle. For example, female rats and mice express less anxiety than males in a novel environment. Proestrus females are less anxious than females in the other estrous phases. Third, males perform in spatial tasks superior to females. However, while stress impairs spatial memory in males, females improve their spatial abilities, depending on the task and kind of stressor. We conclude that the differences in emotion, cognition and responses to stress between males and females over the different phases of the estrous cycle should be used in animal models for stress-related psychiatric disorders

The Rotterdam Study: 2010 objectives and design update

The Rotterdam Study is a prospective cohort study ongoing since 1990 in the city of Rotterdam in The Netherlands. The study targets cardiovascular, endocrine, hepatic, neurological, ophthalmic, psychiatric and respiratory diseases. As of 2008, 14,926 subjects aged 45 years or over comprise the Rotterdam Study cohort. The findings of the Rotterdam Study have been presented in close to a 1,000 research articles and reports (see www.epib.nl/rotterdamstudy). This article gives the rationale of the study and its design. It also presents a summary of the major findings and an update of the objectives and methods

Limited effect of screening for depression with written feedback in outpatients with diabetes mellitus: a randomised controlled trial

Item does not contain fulltextAIMS/HYPOTHESIS: The aim of this study was to test the effectiveness of a screening procedure for depression (SCR) vs care as usual (CAU) in outpatients with diabetes. The primary outcome measured was depression score and the secondary outcomes were mental healthcare consumption, diabetes-distress and HbA(1c). MATERIALS AND METHODS: In a multicentre parallel randomised controlled trial, 223 outpatients with diabetes, who had an elevated depression score, were randomly assigned to SCR (n = 116) or CAU (n = 107), using computer generated numbers. SCR-patients were invited for a Composite International Diagnostic Interview (CIDI) to diagnose depression and/or anxiety (interviewers were not blinded for group assignment). As part of the intervention, patients and their physicians were informed of the outcome of the CIDI in a letter and provided with treatment advice. At baseline and 6 month follow-up, depression and diabetes-distress were measured using the Centre for Epidemiologic Studies Depression Scale (CES-D) and the Problem Areas in Diabetes survey (PAID). HbA(1c) levels were obtained from medical charts. RESULTS: Mean CES-D depression scores decreased from baseline to 6 months in both groups (24 +/- 8 to 21 +/- 8 [CAU] and 26 +/- 7 to 22 +/- 10 [SCR] respectively [p < 0.001]), with no significant differences between groups. Neither diabetes-distress nor HbA(1c) changed significantly within and between groups. The percentage of patients receiving mental healthcare increased in the SCR group from 20% to 28%, compared with 15% to 18% in the CAU group. CONCLUSIONS/INTERPRETATION: Depression screening with written feedback to patient and physician does not improve depression scores and has a limited impact on mental healthcare utilisation, compared with CAU. It appears that more intensive depression management is required to improve depression outcomes in patients with diabetes