Development of a maleic acid-based material to selectively solid-phase extract basic compounds from environmental samples.

This study presents a novel mixed-mode weak cation-exchange (WCX) material. This material was prepared by means of the functionalization of a mesoporous divinylbenzene (DVB) resin with maleic acid (maleic acid-DVB), which yielded a high carboxylic moiety content resulting in WCX interactions as well as suitable specific surface area for reversed-phase interactions. After the optimization of the solid-phase extraction (SPE) protocol to enhance the selectivity of the sorbent, this material was evaluated as a novel WCX sorbent in the SPE of a group of drugs from environmental water samples. The method is based on SPE followed by liquid chromatography (LC) coupled to high resolution mass spectrometry (HRMS) with an Orbitrap analyzer, and was validated and applied for the determination of basic drugs in river, effluent and influent wastewater samples. Maleic acid-DVB sorbent yielded suitable recovery rates (57% to 89%) and an acceptable matrix effect (<32%) thanks to the effective washing step included when these environmental waters were loaded through the novel resin. The method was applied to different environmental water samples and some basic drugs were suitably quantified in these environmental samples.

From self-induced to perceived errors - A generalized over-monitoring activity in obsessive-compulsive disorder.

Well-functioning error monitoring of the inner and outer environments is essential for adaptively altering behavior, while malfunction characterizes conditions such as obsessive-compulsive disorder (OCD). The underlying brain processing is manifested as Error-Related Negativity (ERN) signal elicited following error comission, and Perceived Error Related Theta Activity (PERTA) signal elicited following detection of discrepancy in the environment. Yet, while enhanced ERN was repeatedly demonstrated in OCD patients and was found to be potentiated among their unaffected first degree relatives, no comparable observations were reported with regard to PERTA. We recorded EEG activity while OCD patients, OCD patients' siblings (Family), and healthy controls (HC) performed computerized tasks. For the examination of ERN we used the Stroop task and for the examination of PERTA we presented correct and incorrect mathematical equations. Increased ERN (0-120 ms post response) was observed in both the OCD and Family groups, but only the OCD patients' signal significantly differed from that of HC's. Similarly, modified PERTA activity was observed in both the OCD and Family groups in the N1 peak (65-125 ms post perceived error), but only for the OCD group this activity significantly differed from that of HC. Both ERN and PERTA's N1 are fast occurring peaks, which suggests that OCD is associate with a constantly over-activated detection system that monitors the inner and outer environment and reacts promptly following detection of a mistake. Furthermore, the modified but non-significantly different activity of the Family group suggests that the pathological condition evolves in vulnerable individuals with neuronal predisposition.

Clinical factors predicting treatment resistant depression: affirmative results from the European multicenter study.

OBJECTIVES: Clinical variables were investigated in the 'treatment resistant depression (TRD)- III' sample to replicate earlier findings by the European research consortium 'Group for the Study of Resistant Depression' (GSRD) and enable cross-sample prediction of treatment outcome in TRD. EXPERIMENTAL PROCEDURES: TRD was defined by a Montgomery and Åsberg Depression Rating Scale (MADRS) score ≥22 after at least two antidepressive trials. Response was defined by a decline in MADRS score by ≥50% and below a threshold of 22. Logistic regression was applied to replicate predictors for TRD among 16 clinical variables in 916 patients. Elastic net regression was applied for prediction of treatment outcome. RESULTS: Symptom severity (odds ratio (OR) = 3.31), psychotic symptoms (OR = 2.52), suicidal risk (OR = 1.74), generalized anxiety disorder (OR = 1.68), inpatient status (OR = 1.65), higher number of antidepressants administered previously (OR = 1.23), and lifetime depressive episodes (OR = 1.15) as well as longer duration of the current episode (OR = 1.022) increased the risk of TRD. Prediction of TRD reached an accuracy of 0.86 in the independent validation set, TRD-I. CONCLUSION: Symptom severity, suicidal risk, higher number of lifetime depressive episodes, and comorbid anxiety disorder were replicated as the most prominent risk factors for TRD. Significant predictors in TRD-III enabled robust prediction of treatment outcome in TRD-I.

Manifesto for a European research network into Problematic Usage of the Internet.

The Internet is now all-pervasive across much of the globe. While it has positive uses (e.g. prompt access to information, rapid news dissemination), many individuals develop Problematic Use of the Internet (PUI), an umbrella term incorporating a range of repetitive impairing behaviours. The Internet can act as a conduit for, and may contribute to, functionally impairing behaviours including excessive and compulsive video gaming, compulsive sexual behaviour, buying, gambling, streaming or social networks use. There is growing public and National health authority concern about the health and societal costs of PUI across the lifespan. Gaming Disorder is being considered for inclusion as a mental disorder in diagnostic classification systems, and was listed in the ICD-11 version released for consideration by Member States (http://www.who.int/classifications/icd/revision/timeline/en/). More research is needed into disorder definitions, validation of clinical tools, prevalence, clinical parameters, brain-based biology, socio-health-economic impact, and empirically validated intervention and policy approaches. Potential cultural differences in the magnitudes and natures of types and patterns of PUI need to be better understood, to inform optimal health policy and service development. To this end, the EU under Horizon 2020 has launched a new four-year European Cooperation in Science and Technology (COST) Action Programme (CA 16207), bringing together scientists and clinicians from across the fields of impulsive, compulsive, and addictive disorders, to advance networked interdisciplinary research into PUI across Europe and beyond, ultimately seeking to inform regulatory policies and clinical practice. This paper describes nine critical and achievable research priorities identified by the Network, needed in order to advance understanding of PUI, with a view towards identifying vulnerable individuals for early intervention. The network shall enable collaborative research networks, shared multinational databases, multicentre studies and joint publications.

Clinical correlates of augmentation/combination treatment strategies in major depressive disorder.

OBJECTIVE: This multicenter, multinational, cross-sectional study aimed to investigate clinical characteristics and treatment outcomes associated with augmentation/combination treatment strategies in major depressive disorder (MDD). METHOD: Sociodemographic, clinical, and treatment features of 1410 adult MDD patients were compared between MDD patients treated with monotherapy and augmentation/combination medication using descriptive statistics, analyses of covariance (ancova), and Spearman's correlation analyses. RESULTS: 60.64% of all participants received augmentation and/or combination strategies with a mean number of 2.18 ± 1.22 simultaneously prescribed psychiatric drugs. We found male gender, older age, Caucasian descent, higher weight, low educational status, absence of occupation, psychotic symptoms, melancholic and atypical features, suicide risk, in-patient treatment, longer duration of hospitalization, some psychiatric comorbidities (panic disorder, agoraphobia, obsessive-compulsive disorder, and bulimia nervosa), comorbid somatic comorbidity in general and concurrent hypertension, thyroid dysfunction, diabetes, and heart disease in particular, higher current and retrospective Montgomery and Åsberg Depression Rating Scale total scores, treatment resistance, and higher antidepressant dosing to be significantly associated with augmentation/combination treatment. These findings were corroborated when examining the number of concurrently administered psychiatric drugs in the statistical analyses. CONCLUSION: Our findings suggest a clear association between augmentation/combination strategies and treatment-resistant/difficult-to-treat MDD conditions characterized by severe symptomatology and high amount of psychiatric and somatic comorbidities.

Obsessive-compulsive disorder in the elderly: A report from the International College of Obsessive-Compulsive Spectrum Disorders (ICOCS).

INTRODUCTION: Obsessive-compulsive disorder (OCD) is a highly disabling condition, with frequent early onset. Adult/adolescent OCD has been extensively investigated, but little is known about prevalence and clinical characterization of geriatric patients with OCD (G-OCD≥65years). The present study aimed to assess prevalence of G-OCD and associated socio-demographic and clinical correlates in a large international sample. METHODS: Data from 416 outpatients, participating in the ICOCS network, were assessed and categorized into 2 groups, age

The wake-promoting drug modafinil stimulates specific hypothalamic circuits to promote adaptive stress responses in an animal model of PTSD.

Pharmacotherapeutic intervention during traumatic memory consolidation has been suggested to alleviate or even prevent the development of posttraumatic stress disorder (PTSD). We recently reported that, in a controlled, prospective animal model, depriving rats of sleep following stress exposure prevents the development of a PTSD-like phenotype. Here, we report that administering the wake-promoting drug modafinil to rats in the aftermath of a stressogenic experience has a similar prophylactic effect, as it significantly reduces the prevalence of PTSD-like phenotype. Moreover, we show that the therapeutic value of modafinil appears to stem from its ability to stimulate a specific circuit within the hypothalamus, which ties together the neuropeptide Y, the orexin system and the HPA axis, to promote adaptive stress responses. The study not only confirms the value of sleep prevention and identifies the mechanism of action of a potential prophylactic treatment after traumatic exposure, but also contributes to understanding mechanisms underlying the shift towards adaptive behavioral response.

Neuronal cell adhesion genes and antidepressant response in three independent samples.

Drug-effect phenotypes in human lymphoblastoid cell lines recently allowed to identify CHL1 (cell adhesion molecule with homology to L1CAM), GAP43 (growth-associated protein 43) and ITGB3 (integrin beta 3) as new candidates for involvement in the antidepressant effect. CHL1 and ITGB3 code for adhesion molecules, while GAP43 codes for a neuron-specific cytosolic protein expressed in neuronal growth cones; all the three gene products are involved in synaptic plasticity. Sixteen polymorphisms in these genes were genotyped in two samples (n=369 and 90) with diagnosis of major depressive episode who were treated with antidepressants in a naturalistic setting. Phenotypes were response, remission and treatment-resistant depression. Logistic regression including appropriate covariates was performed. Genes associated with outcomes were investigated in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) genome-wide study (n=1861) as both individual genes and through a pathway analysis (Reactome and String databases). Gene-based analysis suggested CHL1 rs4003413, GAP43 rs283393 and rs9860828, ITGB3 rs3809865 as the top candidates due to their replication across the largest original sample and the STAR*D cohort. GAP43 molecular pathway was associated with both response and remission in the STAR*D, with ELAVL4 representing the gene with the highest percentage of single nucleotide polymorphisms (SNPs) associated with outcomes. Other promising genes emerging from the pathway analysis were ITGB1 and NRP1. The present study was the first to analyze cell adhesion genes and their molecular pathways in antidepressant response. Genes and biomarkers involved in neuronal adhesion should be considered by further studies aimed to identify predictors of antidepressant response.

PPP3CC gene: a putative modulator of antidepressant response through the B-cell receptor signaling pathway.

Antidepressant pharmacogenetics represents a stimulating, but often discouraging field. The present study proposes a combination of several methodologies across three independent samples. Genes belonging to monoamine, neuroplasticity, circadian rhythm and transcription factor pathways were investigated in two samples (n=369 and 88) with diagnosis of major depression who were treated with antidepressants. Phenotypes were response, remission and treatment-resistant depression. Logistic regression including appropriate covariates was performed. Genes associated with outcomes were investigated in the STAR*D (Sequenced Treatment Alternatives to Relieve Depression) genome-wide study (n=1861). Top genes were further studied through a pathway analysis. In both original samples, markers associated with outcomes were concentrated in the PPP3CC gene. Other interesting findings were particularly in the HTR2A gene in one original sample and the STAR*D. The B-cell receptor signaling pathway proved to be the putative mediator of PPP3CC's effect on antidepressant response (P=0.03). Among innovative candidates, PPP3CC, involved in the regulation of immune system and synaptic plasticity, seems promising for further investigation.

A comparison between print vs. internet methods for a clinical trial recruitment--a pan European OCD study.

Recruitment for clinical studies presents a serious challenge in terms of meeting both time and budget constraints. The internet offers a potentially powerful means for quick and effective recruitment-either as an add-on or as alternative to traditional methods. We developed a Google search based solution which enhances patient recruitment. Recruitment via internet was associated with greater exposure to relevant applicants and better response to treatment as compared to traditional printed ads.

Manifesto for a European research network into obsessive-compulsive and related disorders.

Obsessive-compulsive and related disorders (O-CRDs) are highly disabling psychiatric illnesses of early-onset. They are responsible for considerable morbidity and socioeconomic burden. Existing treatments are usually only partially successful and there is an urgent need to understand the aetiological factors and neurobiological bases of the disorders in order to develop new and more effective strategies for prevention, early detection and effective treatment. Emerging data from the neurosciences supports the reconceptualisation of obsessive-compulsive disorder as a spectrum disorder, related to but different from the anxiety disorders and closely aligned with other less well understood psychiatric disorders characterised by compulsive acts such as body dysmorphic disorder, trichotillomania, skin-picking disorder, hoarding disorder; and possibly extending to tic disorders and other neurodevelopmental disorders such as autism. A new, O-CRDs research network, supported by the Networks Initiative of the European College of Neuropsychopharmacology and comprising leading figures in preclinical and clinical research, has been established. It aims to provide a European perspective on the current debate around internationally-accepted diagnostic criteria and treatment strategies for O-CRDs. Its objectives include; (1) identifying the key outstanding research questions that depend upon cross-centre collaborative investigation, (2) setting a research agenda that is likely to produce an impact on health-outcomes, and (3) strengthening existing projects and collaborative enterprises with these objectives in mind. This paper reviews some of these critical research priorities. By establishing shared multinational databases, collaborative research networks, multicentre studies and joint publications, it is hoped that progress will be achieved.

Physical co-morbidity among treatment resistant vs. treatment responsive patients with major depressive disorder.

Co-morbid physical illness has been suggested to play an important role among the factors contributing to treatment resistance in patients with major depressive disorder. In the current study we compared the rate of physical co-morbidity, defined by ICD-10, among a large multicenter sample of 702 patients with major depressive disorder. A total of 356 of the participants were defined as treatment resistant depression (TRD) patients-having failed two or more adequate antidepressant trials. No significant difference was found between TRD and non-TRD participants in the prevalence of any ICD-10 category. This finding suggests that although physical conditions such as diabetes, thyroid dysfunction, hypertension, ischemic heart disease, and peptic diseases are often accompanied by co-morbid MDD, they do not necessarily have an impact on the course of MDD or the likelihood to respond to treatment. Marginally higher rates of co-morbid breast cancer, migraine and glaucoma were found among TRD participants. Possible explanations for these findings and their possible relation to TRD are discussed.

A pilot study of the "Continuation of Care" model in "revolving-door" patients.

PURPOSE: The efficiency of continuation of care (COC) treatment by inpatient caregivers as compared to treatment administered by outpatient services for "revolving door" psychiatric patients was tested in this study. Number and days of hospitalization were examined. METHOD: All patients who were hospitalized three times or more during the past 12 months were offered continuing follow-up in the ward, by the same staff, instead of being referred to the outpatient department. Information on number and length of hospitalizations before and after initiation of this care model was retrieved from the hospital computerized database. RESULTS: Of the 36 patients meeting the criteria, 35 patients agreed to participate. The number of hospitalizations in the 18 months following the index hospitalization was 1.79±3.51 as compared to 4.67±1.79 before the index hospitalization (p=0.0002), and the number of days of hospitalization 18 months after was 24±41.65 as compared to 119.71±69.31 before (p<0.0001). CONCLUSION: COC via inpatient follow-up significantly reduces the number and length of hospitalizations in "revolving door" psychiatric patients as compared to the traditional system of follow-up in an outpatient clinic.

Microinfusion of a corticotrophin-releasing hormone receptor 1 antisense oligodeoxynucleotide into the dorsal hippocampus attenuates stress responses at specific times after stress exposure.

Corticotrophin-releasing hormone (CRH) plays a key role in the adjustment of neuroendocrine and behavioural adaptations to stress. Dysregulation in CRH systems has been implicated in a variety of stress-related psychiatric disorders such as post-traumatic stress disorder (PTSD). The present study examined the relationship between stress-induced PTSD-like behavioural response patterns and levels of CRH, CRH receptor (CHR-R)1 and phosphorylated extracellular signal-regulated kinase (pERK1/2) in the rat hippocampus subregions. The effects of pharmacological manipulations on behavioural, physiological and response patterns of brain-derived neurotrophic factor (BDNF) and pERK1/2 expression using a CRH receptor (CRH-R)1-antisense oligodeoxynucleotide (CRH-R1-ASODN) were evaluated. CRH and CRH-R1 mRNA and pERK1/2 protein levels were assessed in the hippocampus subregions 7 days after exposure to predator scent stress (PSS). The effects of CRH-ASODN versus CRH-Scrambled-ODN microinfusion to the dorsal hippocampus either 1 h or 48 h post-exposure on behavioural tests (elevated plus maze and acoustic startle response) were evaluated 7 days later, 14 days after PSS exposure. Localised brain expression of BDNF and ERK1/2 was subsequently assessed. All data were analysed in relation to individual behaviour patterns. A distinct pattern associated with extreme behavioural response (EBR) was revealed in the bioassay of behavioural study subjects, classified according to their individual patterns of behavioural response at 7 days. These EBR individuals displayed significantly higher CRH and CRH-R1 mRNA levels in the CA1 and CA3 areas, mediating down-regulation of pERK1/2 protein levels. Microinfusion of a CRH-R1-ASODN into the dorsal hippocampus 48 h after stress exposure, although not immediately after exposure (1 h), significantly reduced behavioural disruption and was associated with concomitant up-regulation of BDNF and pERK1/2 protein levels compared to CRH-R1-Scrambled -ODN controls. CRH/CRH-R1 is actively involved in the neurobiological response to predator scent stress processes and thus warrants further study as a potential therapeutic avenue for the treatment of anxiety-related disorders.

The impact of COMT gene polymorphisms on suicidality in treatment resistant major depressive disorder--a European multicenter study.

Many association studies have reported associations between the catechol-O-methyltransferase (COMT) gene and psychiatric disorders including major depression (MDD). The COMT gene has further been associated with suicidal behaviour, as well as with treatment response, although with conflicting results. In the present study, we further elucidate the impact of COMT in treatment response in MDD patients with suicide risk and/or a personal history of suicide attempts. Two hundred fifty MDD patients were collected in the context of a European multicentre resistant depression study and treated with antidepressants at adequate doses for at least 4 weeks. Suicidality was assessed using Mini International Neuropsychiatric Interview (MINI) and the Hamilton Rating Scale for Depression (HAM-D). Treatment response was defined as HAM-D ≤ 17 and remission as HAM-D ≤ 7 after 4 weeks of treatment with antidepressants at adequate dose. Genotyping was performed for seven SNPs (rs4680, rs2075507, rs737865, rs6269, rs4633, rs4818 and rs165599) within the COMT gene. With regard to suicide risk and personal history of suicide attempts, neither single marker nor haplotypic association was found with any SNP after multiple testing correction. In non-responders, we found significant single marker and haplotypic association with suicide risk, but not in responders. The same holds true for both remitters and non-remitters, and when testing for association with a personal history of suicide attempts and treatment response phenotypes. In conclusion, we found significant association of COMT SNPs with suicide risk in MDD patients not responding to antidepressant treatment. Larger well-defined cohorts will be required to dissect this further.

Animal models of depression and anxiety: What do they tell us about human condition?

While modern neurobiology methods are necessary they are not sufficient to elucidate etiology and pathophysiology of affective disorders and develop new treatments. Achievement of these goals is contingent on applying cutting edge methods on appropriate disease models. In this review, the authors present four rodent models with good face-, construct-, and predictive-validity: the Flinders Sensitive rat line (FSL); the genetically "anxious" High Anxiety-like Behavior (HAB) line; the serotonin transporter knockout 5-HTT(-/-) rat and mouse lines; and the post-traumatic stress disorder (PTSD) model induced by exposure to predator scent, that they have employed to investigate the nature of depression and anxiety.

Hippocampal microinfusion of oxytocin attenuates the behavioural response to stress by means of dynamic interplay with the glucocorticoid-catecholamine responses.

The neurohypophysial hormone oxytocin acts as a central nervous system neurotransmitter/neuromodulator. We evaluated the effects of oxytocin on behavioural responses to stress, as well as associated biophysiological responses, in a controlled, prospective animal model. The long-term effects of exogenous oxytocin microinjected to the hippocampus of male rats were assessed. Animals were exposed to predator scent stress and treated 1 h or 7 days later with oxytocin or vehicle. Behaviours were assessed with the elevated plus-maze and acoustic startle response tests, 7 days after microinjection and freezing behaviour upon exposure to a trauma-related cue on day 8. These data served for classification into behavioural response groups. Trauma cue response, circulating corticosterone and oxytocin, hippocampal expression of glucocorticoid and mineralocorticoid receptors, and oxytocin receptor mRNA levels were assessed. The interplay between oxytocin, corticosterone and norepinephrine was assessed. Microinfusion of oxytocin both immediately after predator scent stress exposure or 7 days later, after exposure to trauma cue significantly reduced the prevalence rates of extreme responders and reduced trauma cue freezing responses. Post-exposure treatment with oxytocin significantly corrected the corticosterone stress response, decreased glucocorticoid receptor expression and increased mineralocorticoid receptor expression in the hippocampus compared to vehicle treatment. High-dose corticosterone administration together with norepinephrine caused release of plasma oxytocin and hippocampal oxytocin receptor. Oxytocin is actively involved in the neurobiological response to predator scent stress processes and thus warrants further study as a potential therapeutic avenue for the treatment of anxiety-related disorders.