A mega-analysis of genome-wide association studies for major depressive disorder.

Prior genome-wide association studies (GWAS) of major depressive disorder (MDD) have met with limited success. We sought to increase statistical power to detect disease loci by conducting a GWAS mega-analysis for MDD. In the MDD discovery phase, we analyzed more than 1.2 million autosomal and X chromosome single-nucleotide polymorphisms (SNPs) in 18 759 independent and unrelated subjects of recent European ancestry (9240 MDD cases and 9519 controls). In the MDD replication phase, we evaluated 554 SNPs in independent samples (6783 MDD cases and 50 695 controls). We also conducted a cross-disorder meta-analysis using 819 autosomal SNPs with P<0.0001 for either MDD or the Psychiatric GWAS Consortium bipolar disorder (BIP) mega-analysis (9238 MDD cases/8039 controls and 6998 BIP cases/7775 controls). No SNPs achieved genome-wide significance in the MDD discovery phase, the MDD replication phase or in pre-planned secondary analyses (by sex, recurrent MDD, recurrent early-onset MDD, age of onset, pre-pubertal onset MDD or typical-like MDD from a latent class analyses of the MDD criteria). In the MDD-bipolar cross-disorder analysis, 15 SNPs exceeded genome-wide significance (P<5 × 10(-8)), and all were in a 248 kb interval of high LD on 3p21.1 (chr3:52 425 083-53 822 102, minimum P=5.9 × 10(-9) at rs2535629). Although this is the largest genome-wide analysis of MDD yet conducted, its high prevalence means that the sample is still underpowered to detect genetic effects typical for complex traits. Therefore, we were unable to identify robust and replicable findings. We discuss what this means for genetic research for MDD. The 3p21.1 MDD-BIP finding should be interpreted with caution as the most significant SNP did not replicate in MDD samples, and genotyping in independent samples will be needed to resolve its status.

Prevalence of and associated factors for adult attention deficit hyperactivity disorder in young Swiss men.

OBJECTIVE: The present study aimed to measure the prevalence of adult attention deficit hyperactivity disorder (ADHD) in a large, representative sample of young Swiss men and to assess factors associated with this disorder. METHODS: Our sample consisted of 5656 Swiss men (mean age 20 years) who participated in the Cohort Study on Substance Use Risk Factors (C-SURF). ADHD was assessed with the World Health Organization (WHO) adult ADHD Self Report Screener (ASRS). Logistic regression analyses were conducted to assess the association between ADHD and several socio-demographic, clinical and familial factors. RESULTS: The prevalence of ADHD was 4.0%, being higher in older and French-speaking conscripts. A higher prevalence also was identified among men whose mothers had completed primary or high school/university and those with a family history of alcohol or psychiatric problems. Additionally, adults with ADHD demonstrated impairment in their professional life, as well as considerable mental health impairment. CONCLUSION: Our results demonstrate that ADHD is common among young Swiss men. The impairments in function and mental health we observed highlight the need for further support and interventions to reduce burden in affected individuals. Interventions that incorporate the whole family also seem crucial.

Total IgE and eotaxin (CCL11) contents in tears of patients suffering from seasonal allergic conjunctivitis.

BACKGROUND: To prospectively investigate patients with seasonal allergic conjunctivitis (SAC) during the pollen season and test associations between tears total IgE, eotaxin concentrations, and SAC severity. METHODS: Enrolled patients presented ocular symptoms and clinical signs of SAC at the time of presentation. Ocular itching, hyperaemia, chemosis, eyelid swelling, and tearing were scored, and the sum of these scores was defined as the clinical score. Conjunctival papillae were separately graded. We measured eotaxin concentration in tears by an enzyme-linked immunosorbent assay (ELISA) and total tear IgE by Lacrytest strip. RESULTS: Among thirty patients (30 eyes), 11 showed neither tear IgE nor tear eotaxin, while 15 out of 19 patients with positive IgE values presented a positive amount of eotaxin in their tears (Fisher's test: p < 0.001). The mean eotaxin concentration was 641 ± 154 (SEM) pg/ml. In patients with no amount of tear IgE, we observed a lower conjunctival papilla grade than in patients whose tears contained some amount of IgE (trend test: p = 0.032). In the 15 patients whose tear eotaxin concentration was null, tear IgE concentration was 5.3 ± 3.5 arbitrary units; in the other 15 patients whose eotaxin was positive, IgE reached 21 ± 4.3 arbitrary U (Mann-Whitney: p < 0.001). We measured 127 ± 47 pg/ml eotaxin in patients with no history of SAC but newly diagnosed as suffering from SAC, and 852 ± 218 pg/ml eotaxin in patients with a known SAC (p = 0.008). In contrast, tear IgE concentrations of both groups did not differ statistically significantly (p = 0.947). CONCLUSIONS: If IgE and eotaxin secreted in tears are major contributors in SAC pathogenesis, they however act at different steps of the process.

The use of classification and regression trees to predict the likelihood of seasonal influenza.

Background Individual signs and symptoms are of limited value for the diagnosis of influenza. Objective To develop a decision tree for the diagnosis of influenza based on a classification and regression tree (CART) analysis. Methods Data from two previous similar cohort studies were assembled into a single dataset. The data were randomly divided into a development set (70%) and a validation set (30%). We used CART analysis to develop three models that maximize the number of patients who do not require diagnostic testing prior to treatment decisions. The validation set was used to evaluate overfitting of the model to the training set. Results Model 1 has seven terminal nodes based on temperature, the onset of symptoms and the presence of chills, cough and myalgia. Model 2 was a simpler tree with only two splits based on temperature and the presence of chills. Model 3 was developed with temperature as a dichotomous variable (≥38°C) and had only two splits based on the presence of fever and myalgia. The area under the receiver operating characteristic curves (AUROCC) for the development and validation sets, respectively, were 0.82 and 0.80 for Model 1, 0.75 and 0.76 for Model 2 and 0.76 and 0.77 for Model 3. Model 2 classified 67% of patients in the validation group into a high- or low-risk group compared with only 38% for Model 1 and 54% for Model 3. Conclusions A simple decision tree (Model 2) classified two-thirds of patients as low or high risk and had an AUROCC of 0.76. After further validation in an independent population, this CART model could support clinical decision making regarding influenza, with low-risk patients requiring no further evaluation for influenza and high-risk patients being candidates for empiric symptomatic or drug therapy.

Use of High Doses of Quetiapine in Bipolar Disorder Episodes are not Linked to High Activity of Cytochrome P4503A4 and/or Cytochrome P4502D6.

The use of quetiapine for treatment of bipolar disorders at a higher dosage than the licensed range is not unusual in clinical practice. Quetiapine is predominantly metabolised by cytochrome P450 3A4 (CYP3A4) and to a lesser extent by CYP2D6. The large interindividual variability of those isozyme activities could contribute to the variability observed in quetiapine dosage. The aim of the present study is to evaluate if the use of high dosages of quetiapine in some patients, as compared to patients treated with a dosage in the licensed range (up to 800 mg/day), could be explained by a high activity of CYP3A4 and/or of CYP2D6. CYP3A4 activities were determined using the midazolam metabolic ratio in 21 bipolar and schizoaffective bipolar patients genotyped for CYP2D6. 9 patients were treated with a high quetiapine dosage (mean ± SD, median; range: 1467 ± 625, 1200; 1000-3000 mg/day) and 11 with a normal quetiapine dosage (433 ± 274, 350; 100-800 mg/day). One patient in the high dose and one patient in the normal dose groups were genotyped as CYP2D6 ultrarapid metabolizers. CYP3A4 activities were not significantly different between the two groups (midazolam metabolic ratio: 9.4 ± 8.2; 6.2; 1.7-26.8 vs 3.9 ± 2.3; 3.8; 1.5-7.6, in the normal dose group as compared to the high dose group, respectively, NS). The use of high quetiapine dosage for the patients included in the present study cannot be explained by variations in pharmacokinetics parameters such as a high activity of CYP3A4 and/or of CYP2D6.

Beyond splitting: observer-rated defense mechanisms in borderline personality disorder

Defense mechanism is a key concept in the psychoanalytic psychopathology of borderline personality disorder (BPD). Theoretical and empirical elaborations on this question are briefly reviewed and discussed with respect to process assessment of defense mechanisms; we put forward observer-rater methodology as an accurate means of assessing unconscious in-session processes. A sample of 25 patients presenting with BPD were interviewed, as were subjects from a matched control group without psychiatric symptoms (n = 25), using a psychodynamic interview paradigm. These interviews were transcribed and rated using the Defense Mechanisms Rating Scales. The results indicate that, compared to controls, patients with BPD used higher percentages of a action, borderline, disavowal, narcissistic, and hysteric defenses, along with lower levels of mature and obsessional defenses. Overall defensive functioning was significantly lower in the patients with BPD, compared to controls. Narcissistic defenses were related with symptom level. These results are discussed in light of previous studies on defensive functioning of BPD and the literature on psychoanalytic psychopathology. These results have several important clinical implications.

Pretreatment and outcome correlates of past sexual and physical trauma in 118 bipolar I disorder patients with a first episode of psychotic mania.

OBJECTIVES: To assess the prevalence and correlates of childhood and adolescent sexual and/or physical abuse (SPA) in bipolar I disorder (BDI) patients treated for a first episode of psychotic mania. METHODS: The Early Psychosis Prevention and Intervention Centre admitted 786 first-episode psychosis patients between 1998 and 2000. Data were collected from patients' files using a standardized questionnaire. A total of 704 files were available; 43 were excluded because of a nonpsychotic diagnosis at endpoint and 3 due to missing data regarding past stressful events. Among 658 patients with available data, 118 received a final diagnosis of BDI and were entered in this study. RESULTS: A total of 80% of patients had been exposed to stressful life events during childhood and adolescence and 24.9% to SPA; in particular, 29.8% of female patients had been exposed to sexual abuse. Patients who were exposed to SPA had poorer premorbid functioning, higher rates of forensic history, were less likely to live with family during treatment period, and were more likely to disengage from treatment. CONCLUSIONS: SPA is highly prevalent in BDI patients presenting with a first episode of psychotic mania; exposed patients have lower premorbid functional levels and poorer engagement with treatment. The context in which such traumas occur must be explored in order to determine whether early intervention strategies may contribute to diminish their prevalence. Specific psychological interventions must also be developed.

The value of 'positive' clinical signs for weakness, sensory and gait disorders in conversion disorder: a systematic and narrative review.

Experts in the field of conversion disorder have suggested for the upcoming DSM-V edition to put less weight on the associated psychological factors and to emphasise the role of clinical findings. Indeed, a critical step in reaching a diagnosis of conversion disorder is careful bedside neurological examination, aimed at excluding organic signs and identifying 'positive' signs suggestive of a functional disorder. These positive signs are well known to all trained neurologists but their validity is still not established. The aim of this study is to provide current evidence regarding their sensitivity and specificity. We conducted a systematic search on motor, sensory and gait functional signs in Embase, Medline, PsycINfo from 1965 to June 2012. Studies in English, German or French reporting objective data on more than 10 participants in a controlled design were included in a systematic review. Other relevant signs are discussed in a narrative review. Eleven controlled studies (out of 147 eligible articles) describing 14 signs (7 motor, 5 sensory, 2 gait) reported low sensitivity of 8-100% but high specificity of 92-100%. Studies were evidence class III, only two had a blinded design and none reported on inter-rater reliability of the signs. Clinical signs for functional neurological symptoms are numerous but only 14 have been validated; overall they have low sensitivity but high specificity and their use should thus be recommended, especially with the introduction of the new DSM-V criteria.

Quetiapine dosage in bipolar disorder episodes and mixed states

OBJECTIVE: Although the maximal quetiapine doses in the published studies were restricted to 800 mg/day, higher quetiapine doses are not unusual in clinical practice. The aim of the present study was to evaluate the effectiveness, tolerability and clinical reasons associated to the use of high dosage of quetiapine (>800 mg), when used under routine clinical conditions, in a sample of bipolar disorder and schizoaffective bipolar inpatients. METHODS: Charts of all bipolar and schizoaffective adult inpatients, who had received quetiapine for a mood episode between 1999 and 2005 were retrospectively reviewed. These charts also included the assessment of manic and depressive symptoms on admission and at discharge using the Beck-Rafaelsen Mania Scale (MAS) and the Montgomery Asberg depression rating scale (MADRS), respectively. RESULTS: Data of 50 patients were analyzed. The overall F in repeated measures ANOVA revealed a significant MAS scores reduction between admission and discharge. MAS scores reduction did not differ between the high and low quetiapine groups. Similarly, a significant MADRS reduction was found. Again, no differences between the high and the low dose group were found. Logistic regression analysis of the 50 patients revealed only mixed episodes predicted high quetiapine dosage. CONCLUSIONS: The present study confirms quetiapine efficiency and tolerability in the treatment of bipolar episodes, even in doses > to 800 mg and found a link between quetiapine doses and mixed episodes

Bionomics of Anopheles aquasalis Curry 1932, in Guaraí, state of Rio de Janeiro, southeastern Brazil: I. Seasonal distribution and parity rates

From a total of 12,721 anophelines collected in a lowland area in Guaraí, Rio de Janeiro, from November 1991 to October 1992, 99.7% (12,688) were Anopheles aquasalis. This species occurred throughout the year, but in higher numbers from April to September, when rainfall was low or moderate. The proportion of parous females in June was significantly higher than the annual rate. An. aquasalis was weakly attracted by a light-trap, and no significant differences in abundance were detected between nights with and without moonlight.

Parent-child agreement and prevalence estimates of diagnoses in childhood: direct interview versus family history method.

Diagnostic information on children is typically elicited from both children and their parents. The aims of the present paper were to: (1) compare prevalence estimates according to maternal reports, paternal reports and direct interviews of children [major depressive disorder (MDD), anxiety and attention-deficit and disruptive behavioural disorders]; (2) assess mother-child, father-child and inter-parental agreement for these disorders; (3) determine the association between several child, parent and familial characteristics and the degree of diagnostic agreement or the likelihood of parental reporting; (4) determine the predictive validity of diagnostic information provided by parents and children. Analyses were based on 235 mother-offspring, 189 father-offspring and 128 mother-father pairs. Diagnostic assessment included the Kiddie-schedule for Affective Disorders and Schizophrenia (K-SADS) (offspring) and the Diagnostic Interview for Genetic Studies (DIGS) (parents and offspring at follow-up) interviews. Parental reports were collected using the Family History - Research Diagnostic Criteria (FH-RDC). Analyses revealed: (1) prevalence estimates for internalizing disorders were generally lower according to parental information than according to the K-SADS; (2) mother-child and father-child agreement was poor and within similar ranges; (3) parents with a history of MDD or attention deficit hyperactivity disorder (ADHD) reported these disorders in their children more frequently; (4) in a sub-sample followed-up into adulthood, diagnoses of MDD, separation anxiety and conduct disorder at baseline concurred with the corresponding lifetime diagnosis at age 19 according to the child rather than according to the parents. In conclusion, our findings support large discrepancies of diagnostic information provided by parents and children with generally lower reporting of internalizing disorders by parents, and differential reporting of depression and ADHD by parental disease status. Follow-up data also supports the validity of information provided by adolescent offspring.

Off-label utilization of antipsychotics

Résumé Ce travail s'inscrit dans un programme de recherche centré sur la pharmacovigilance en psychiatrie. Buts de l'étude Les nouveaux antipsychotiques atypiques sont prescrits avec beaucoup de succès, parce qu'ils présentent une sécurité dans leur emploi bien supérieure à celle des antipsychotiques classiques. Cette situation a conduit à une large prescription «off-label» (hors indication admise). Le but de ce travail a été d'étudier la pratique en matière de prescription des psychiatres hospitaliers en ce qui concerne les antipsychotiques en comparant des patients traités pour des psychoses ou d'autres indications officielles aux patients recevant un traitement antipsychotique «off-label». Méthode Dans le cadre d'un programme de pharmacovigilance - pharmacoépidemiologie, tous les médicaments prescrits à 5 jours de référence (entre 1999 et 2001) à l'hôpital psychiatrique universitaire de Lausanne (98 lits) ont été enregistrés, avec des données sur l'âge, le sexe et le diagnostic des patients. Les prescriptions de 202 patients ont été évaluées. Les patients ont été classés dans 3 groupes diagnostiques : (1) patient présentant des troubles psychotiques, (2) patient présentant des épisodes maniaques et des épisodes dépressifs avec des symptômes psychotiques, et (3) patient présentant d'autres troubles. Les groupes (1) et (2) forment une classe de patients recevant un antipsychotique pour une indication officielle, et les prescriptions dans le groupe (3) ont été considérées comme «off-label». Résultats principaux Moins de patients psychotiques ont reçu un antidépresseur (p<0.05) ou des hypnotiques non-benzodiazepine (p<0.001) comparés aux patients des deux autres groupes. Les patients présentant des troubles affectifs recevaient seulement exceptionnellement une combinaison d'un antipsychotique atypique et conventionnel, tandis qu'un nombre inférieur de patients avec des indications « off-label » ont reçu moins .souvent des antipsychotiques atypiques que ceux des deux groupes de comparaison (p<0.05). L'analyse statistique (stepwise logistic regression) a révélé que les patients présentant des troubles psychotiques avaient un risque plus élevé de recevoir un médicament antipsychotique d'une dose moyenne ou élevée, (p<0.001) en comparaison aux deux autres groupes. Conclusion Les nouveaux médicaments antipsychotiques semblent être prescrits avec moins d'hésitation principalement pour des indications admises. Les médecins prescrivent de nouveaux médicaments « off-label » seulement après avoir acquis une certaine expérience dans le domaine des indications approuvées, et ils étaient plus prudents en ce qui concerne la dose en traitant sur la base «off-label». Abstract Objective The new brands of atypical antipsychotics are very successfully prescribed because of their enhanced safety profiles and their larger pharmacological profile in comparison to the conventional antipsychotic. This has led to broad off-label utilisation. The aim of the present survey was to study the prescription practice of hospital psychiatrists with regard to antipsychotic drugs, comparing patients treated for psychoses or other registered indications to patients receiving an off-label antipsychotic treatment. Method As part of a pharmacovigilance/pharmacoepidemiology program, all drugs given on 5 reference days (1999 - 2001) in the 98-bed psychiatric hospital of the University of Lausanne, Switzerland, were recorded along with age, sex and diagnosis. The prescriptions of 202 patients were assessed. Patients were classified in 3 diagnostic groups: (1) patient with psychotic disorders, (2) patients with manic episodes and depressive episodes with psychotic symptoms, and (3) patients with other disorders. Group (1) and (2) formed the class of patients receiving an antipsychotic for a registered indication, and the prescriptions in group (3) were considered as off-label. Main results A lesser number of psychotic patients received antidepressant (p<0.05) and nonbenzodiazepine hypnotics (p<0.001) compared to the patients of the other two groups. The patients with affective disorders received only exceptionally a combination of an atypical and a conventional antipsychotic, whereas a lesser number of patients with off-label indications received less often atypical antipsychotics than those of the two comparison groups (p<0.05). Stepwise logistic regression revealed that patients with psychotic disorder were at higher risk of receiving an antipsychotic medication in medium or high dose (p<0.001), in comparison to the two other groups. Conclusions The new antipsychotic drugs seem to be prescribed with less hesitation mainly for approved indications. Physicians prescribe new drugs on off-label application only after having gained some experience in the field of the approved indications, and were more cautious with regard to dose when treating on an off-label basis.

Former eating disorder impairs 3rd person but not 1st person perspective taking. Does dance training help?

The mental ability to take the perspective of another person may depend on one's own bodily awareness and experience. In the present study, the former was defined as having a history of an eating disorder, and the latter variable was defined as formal experience with dance. The study used a 2 × 2 × 2 factorial design in which reaction times in two mental perspective taking tasks were compared between female dancers and non-dancers with and without a former eating disorder. Participants were asked to imagine two perspectives: i) the position of front-facing and back-facing figures (3rd person perspective taking task) and ii) that these same figures are a self reflection in a mirror (1st person perspective taking task). In both tasks, a particular hand was indicated in the presented figures, and the participants had to decide whether the hand represented their own left or right hand. Overall, responses were slower for front-facing than back-facing figures in the 3rd person perspective taking task, and for back-facing than front-facing figures in the 1st person perspective taking task. Importantly, having a former history of an eating disorder related to a decreased performance in the 3rd person perspective taking task, but only in participants without dance experience. Results from an additional control group (a history of exercise but no dance experience) indicated that dance is particularly beneficial for mental bodily perspective taking. Dance experience, more so than exercise in general, can benefit 3rd person or extrapersonal perspective taking, supporting the favourable impact this exercise has on own body processing