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1.  Biological Insights From 108 Schizophrenia-Associated Genetic Loci 
Ripke, Stephan | Neale, Benjamin M | Corvin, Aiden | Walters, James TR | Farh, Kai-How | Holmans, Peter A | Lee, Phil | Bulik-Sullivan, Brendan | Collier, David A | Huang, Hailiang | Pers, Tune H | Agartz, Ingrid | Agerbo, Esben | Albus, Margot | Alexander, Madeline | Amin, Farooq | Bacanu, Silviu A | Begemann, Martin | Belliveau, Richard A | Bene, Judit | Bergen, Sarah E | Bevilacqua, Elizabeth | Bigdeli, Tim B | Black, Donald W | Bruggeman, Richard | Buccola, Nancy G | Buckner, Randy L | Byerley, William | Cahn, Wiepke | Cai, Guiqing | Campion, Dominique | Cantor, Rita M | Carr, Vaughan J | Carrera, Noa | Catts, Stanley V | Chambert, Kimberley D | Chan, Raymond CK | Chan, Ronald YL | Chen, Eric YH | Cheng, Wei | Cheung, Eric FC | Chong, Siow Ann | Cloninger, C Robert | Cohen, David | Cohen, Nadine | Cormican, Paul | Craddock, Nick | Crowley, James J | Curtis, David | Davidson, Michael | Davis, Kenneth L | Degenhardt, Franziska | Del Favero, Jurgen | Demontis, Ditte | Dikeos, Dimitris | Dinan, Timothy | Djurovic, Srdjan | Donohoe, Gary | Drapeau, Elodie | Duan, Jubao | Dudbridge, Frank | Durmishi, Naser | Eichhammer, Peter | Eriksson, Johan | Escott-Price, Valentina | Essioux, Laurent | Fanous, Ayman H | Farrell, Martilias S | Frank, Josef | Franke, Lude | Freedman, Robert | Freimer, Nelson B | Friedl, Marion | Friedman, Joseph I | Fromer, Menachem | Genovese, Giulio | Georgieva, Lyudmila | Giegling, Ina | Giusti-Rodríguez, Paola | Godard, Stephanie | Goldstein, Jacqueline I | Golimbet, Vera | Gopal, Srihari | Gratten, Jacob | de Haan, Lieuwe | Hammer, Christian | Hamshere, Marian L | Hansen, Mark | Hansen, Thomas | Haroutunian, Vahram | Hartmann, Annette M | Henskens, Frans A | Herms, Stefan | Hirschhorn, Joel N | Hoffmann, Per | Hofman, Andrea | Hollegaard, Mads V | Hougaard, David M | Ikeda, Masashi | Joa, Inge | Julià, Antonio | Kahn, René S | Kalaydjieva, Luba | Karachanak-Yankova, Sena | Karjalainen, Juha | Kavanagh, David | Keller, Matthew C | Kennedy, James L | Khrunin, Andrey | Kim, Yunjung | Klovins, Janis | Knowles, James A | Konte, Bettina | Kucinskas, Vaidutis | Kucinskiene, Zita Ausrele | Kuzelova-Ptackova, Hana | Kähler, Anna K | Laurent, Claudine | Lee, Jimmy | Lee, S Hong | Legge, Sophie E | Lerer, Bernard | Li, Miaoxin | Li, Tao | Liang, Kung-Yee | Lieberman, Jeffrey | Limborska, Svetlana | Loughland, Carmel M | Lubinski, Jan | Lönnqvist, Jouko | Macek, Milan | Magnusson, Patrik KE | Maher, Brion S | Maier, Wolfgang | Mallet, Jacques | Marsal, Sara | Mattheisen, Manuel | Mattingsdal, Morten | McCarley, Robert W | McDonald, Colm | McIntosh, Andrew M | Meier, Sandra | Meijer, Carin J | Melegh, Bela | Melle, Ingrid | Mesholam-Gately, Raquelle I | Metspalu, Andres | Michie, Patricia T | Milani, Lili | Milanova, Vihra | Mokrab, Younes | Morris, Derek W | Mors, Ole | Murphy, Kieran C | Murray, Robin M | Myin-Germeys, Inez | Müller-Myhsok, Bertram | Nelis, Mari | Nenadic, Igor | Nertney, Deborah A | Nestadt, Gerald | Nicodemus, Kristin K | Nikitina-Zake, Liene | Nisenbaum, Laura | Nordin, Annelie | O’Callaghan, Eadbhard | O’Dushlaine, Colm | O’Neill, F Anthony | Oh, Sang-Yun | Olincy, Ann | Olsen, Line | Van Os, Jim | Pantelis, Christos | Papadimitriou, George N | Papiol, Sergi | Parkhomenko, Elena | Pato, Michele T | Paunio, Tiina | Pejovic-Milovancevic, Milica | Perkins, Diana O | Pietiläinen, Olli | Pimm, Jonathan | Pocklington, Andrew J | Powell, John | Price, Alkes | Pulver, Ann E | Purcell, Shaun M | Quested, Digby | Rasmussen, Henrik B | Reichenberg, Abraham | Reimers, Mark A | Richards, Alexander L | Roffman, Joshua L | Roussos, Panos | Ruderfer, Douglas M | Salomaa, Veikko | Sanders, Alan R | Schall, Ulrich | Schubert, Christian R | Schulze, Thomas G | Schwab, Sibylle G | Scolnick, Edward M | Scott, Rodney J | Seidman, Larry J | Shi, Jianxin | Sigurdsson, Engilbert | Silagadze, Teimuraz | Silverman, Jeremy M | Sim, Kang | Slominsky, Petr | Smoller, Jordan W | So, Hon-Cheong | Spencer, Chris C A | Stahl, Eli A | Stefansson, Hreinn | Steinberg, Stacy | Stogmann, Elisabeth | Straub, Richard E | Strengman, Eric | Strohmaier, Jana | Stroup, T Scott | Subramaniam, Mythily | Suvisaari, Jaana | Svrakic, Dragan M | Szatkiewicz, Jin P | Söderman, Erik | Thirumalai, Srinivas | Toncheva, Draga | Tosato, Sarah | Veijola, Juha | Waddington, John | Walsh, Dermot | Wang, Dai | Wang, Qiang | Webb, Bradley T | Weiser, Mark | Wildenauer, Dieter B | Williams, Nigel M | Williams, Stephanie | Witt, Stephanie H | Wolen, Aaron R | Wong, Emily HM | Wormley, Brandon K | Xi, Hualin Simon | Zai, Clement C | Zheng, Xuebin | Zimprich, Fritz | Wray, Naomi R | Stefansson, Kari | Visscher, Peter M | Adolfsson, Rolf | Andreassen, Ole A | Blackwood, Douglas HR | Bramon, Elvira | Buxbaum, Joseph D | Børglum, Anders D | Cichon, Sven | Darvasi, Ariel | Domenici, Enrico | Ehrenreich, Hannelore | Esko, Tõnu | Gejman, Pablo V | Gill, Michael | Gurling, Hugh | Hultman, Christina M | Iwata, Nakao | Jablensky, Assen V | Jönsson, Erik G | Kendler, Kenneth S | Kirov, George | Knight, Jo | Lencz, Todd | Levinson, Douglas F | Li, Qingqin S | Liu, Jianjun | Malhotra, Anil K | McCarroll, Steven A | McQuillin, Andrew | Moran, Jennifer L | Mortensen, Preben B | Mowry, Bryan J | Nöthen, Markus M | Ophoff, Roel A | Owen, Michael J | Palotie, Aarno | Pato, Carlos N | Petryshen, Tracey L | Posthuma, Danielle | Rietschel, Marcella | Riley, Brien P | Rujescu, Dan | Sham, Pak C | Sklar, Pamela | St Clair, David | Weinberger, Daniel R | Wendland, Jens R | Werge, Thomas | Daly, Mark J | Sullivan, Patrick F | O’Donovan, Michael C
Nature  2014;511(7510):421-427.
Summary
Schizophrenia is a highly heritable disorder. Genetic risk is conferred by a large number of alleles, including common alleles of small effect that might be detected by genome-wide association studies. Here, we report a multi-stage schizophrenia genome-wide association study of up to 36,989 cases and 113,075 controls. We identify 128 independent associations spanning 108 conservatively defined loci that meet genome-wide significance, 83 of which have not been previously reported. Associations were enriched among genes expressed in brain providing biological plausibility for the findings. Many findings have the potential to provide entirely novel insights into aetiology, but associations at DRD2 and multiple genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses. Independent of genes expressed in brain, associations were enriched among genes expressed in tissues that play important roles in immunity, providing support for the hypothesized link between the immune system and schizophrenia.
doi:10.1038/nature13595
PMCID: PMC4112379  PMID: 25056061
2.  Familial Liability to Psychosis Is Associated With Attenuated Dopamine Stress Signaling in Ventromedial Prefrontal Cortex 
Schizophrenia Bulletin  2013;40(1):66-77.
Objective: Patients diagnosed with a psychotic disorder and their first-degree relatives display increased reactivity to stress. Theory predicts that experience of psychosocial stress is associated both with ventromedial prefrontal and mesolimbic dopamine neurotransmission. However, while there is evidence of aberrant striatal dopamine processing in psychotic disorder, the role of the prefrontal cortex remains under-researched. This study aimed at investigating stress-induced in vivo dopamine release in ventromedial prefrontal cortex (vmPFC) of individuals at familial risk for psychosis. Method: Fourteen healthy first-degree relatives of patients with a diagnosis of psychotic disorder and 10 control subjects underwent a single dynamic positron emission tomography (PET) scanning session after intravenous administration of 183.2 (SD = 7.6) MBq [18F]fallypride. Psychosocial stress was initiated at 100min postinjection using a computerized mental arithmetic task with social evaluative threat components. PET data were analyzed using the linearized simplified reference region model. Regression analyses were performed to compare the spatial extent of task-related ligand displacement between control subjects and relatives and to find how it related to self-rated experiences of psychosocial stress and psychosis. Results: First-degree relatives displayed hyporeactive dopamine signaling in the vmPFC in response to stress. Increased levels of subjectively rated stress were associated with increased intensity of psychotic experiences. This effect was particularly pronounced in first-degree relatives. Conclusion: Although previous studies have hypothesized a role for prefrontal dopamine dysfunction in psychosis, this study, to our knowledge, is the first in vivo human imaging study showing attenuated (ie, hyporeactive) dopamine stress neuromodulation in vmPFC of individuals at familial risk for psychosis.
doi:10.1093/schbul/sbs187
PMCID: PMC3885294  PMID: 23363687
schizophrenia; positron emission tomography; neuromodulation; relatives; mesolimbic; salience
3.  Testing an mHealth Momentary Assessment Routine Outcome Monitoring Application: A Focus on Restoration of Daily Life Positive Mood States 
PLoS ONE  2014;9(12):e115254.
Background
Routine Outcome Monitoring (ROM) is used as a means to enrich the process of treatment with feedback on patient outcomes, facilitating patient involvement and shared decision making. While traditional ROM measures focus on retrospective accounts of symptoms, novel mHealth technology makes it possible to collect real life, in-the-moment ambulatory data that allow for an ecologically valid assessment of personalized and contextualized emotional and behavioural adjustment in the flow daily life (mROM).
Method
In a sample of 34 patients with major depressive disorder, treated with antidepressants, the combined effect of treatment and natural course was examined over a period of 18 weeks with Ecological Momentary Assessment (EMA). EMA consisted of repeated, within-subject, mini-measurements of experience (eg positive affect, negative affect, medication side effects) and context (eg stressors, situations, activities) at 10 unselected semi-random moments per day, for a period of six days, repeated three times over the 18-week period (baseline, week 6 and week 18).
Results
EMA measures of emotional and behavioural adjustment were sensitive to the effects of treatment and natural course over the 18-week period, particularly EMA measures focussing on positive mood states and the ability to use natural rewards (impact of positive events on positive mood states), with standardized effect sizes of 0.4–0.5. EMA measures of activities, social interaction, stress-sensitivity and negative mood states were also sensitive to change over time.
Conclusion
This study supports the use of mROM as a means to involve the patient in the process of needs assessment and treatment. EMA data are meaningful to the patient, as they reflect daily life circumstances. Assessment of treatment response with mROM data allows for an interpretation of the effect of treatment at the level of daily life emotional and social adjustment – as an index of health, obviating the need for an exclusive focus on traditional measures of ‘sickness’.
doi:10.1371/journal.pone.0115254
PMCID: PMC4267819  PMID: 25513813
4.  Hyper-Theory-of-Mind in Children with Psychotic Experiences 
PLoS ONE  2014;9(11):e113082.
Background
Alterations in Theory-of-Mind (ToM) are associated with psychotic disorder. In addition, studies in children have documented that alterations in ToM are associated with Psychotic Experiences (PE). Our aim was to examine associations between an exaggerated type of ToM (HyperToM) and PE in children. Children with this type of alteration in ToM infer mental states when none are obviously suggested, and predict behaviour on the basis of these erroneous beliefs. Individuals with HyperToM do not appear to have a conceptual deficit (i.e. lack of representational abilities), but rather they apply their theory of the minds of others in an incorrect or biased way.
Method
Hypotheses were tested in two studies with two independent samples: (i) a general population sample of 1630 Danish children aged 11–12 years, (ii) a population-based sample of 259 Dutch children aged 12–13 years, pertaining to a case-control sampling frame of children with auditory verbal hallucinations. Multinomial regression analyses were carried out to investigate the associations between PE and ToM and HyperToM respectively. Analyses were adjusted for gender and proxy measures of general intelligence.
Results
Low ToM score was significantly associated with PE in sample I (OR = 1.6 95%CI 1.1–2.3 χ2(4) = 12.42 p = 0.010), but not in sample II (OR = 0.9 95%CI 0.5–1.8 χ2(3) = 7.13 p = 0.816). HyperToM was significantly associated with PE both in sample I (OR = 1.8, 95%CI 1.2–2.7 χ2(3) = 10.11 p = 0.006) and II (OR = 4.6, 95%CI 1.3–16.2 χ2(2) = 7.56 p = 0.018). HyperToM was associated particularly with paranoid delusions in both sample I (OR = 2.0, 95%CI: 1.1–3.7% χ2(4) = 9.93 p = 0.021) and II (OR = 6.2 95%CI: 1.7–23.6% χ2(4) = 9.90 p = 0.044).
Conclusion
Specific alterations in ToM may be associated with specific types of psychotic experiences. HyperToM may index risk for developing psychosis and paranoid delusions in particular.
doi:10.1371/journal.pone.0113082
PMCID: PMC4232592  PMID: 25397582
5.  Attenuated Psychosis Syndrome in DSM-5 
Schizophrenia research  2013;150(1):31-35.
Despite advances in the treatment of schizophrenia over the past half-century, the illness is frequently associated with a poor outcome. This is principally related to the late identification and intervention in the course of the illness by which time patients have experienced a substantial amount of socio-occupational decline that can be difficult to reverse. The emphasis has therefore shifted to defining psychosis-risk syndromes and evaluating treatments that can prevent transition to psychosis in these ultra-high risk groups. To consider the appropriateness of adding psychosis risk syndrome to our diagnostic nomenclature, the Psychotic Disorders Workgroup extensively reviewed all available data, consulted a range of experts, and carefully considered the variety of expert and public comments on the topic. It was clear that reliable methods were available to define a syndrome characterized by sub-threshold psychotic symptoms (in severity or duration) and which was associated with a very significant increase in the risk of development of a full-fledged psychotic disorder (schizophrenia spectrum, psychotic mood disorder, other psychotic disorder) within the next year. At the same time, the majority of individuals with “attenuated psychotic symptoms” had one or more other current psychiatric comorbid conditions (usually mood or anxiety disorders, substance use disorder; Fusar-Poli 2012) and exhibited a range of psychiatric outcomes other than conversion to psychosis (significant proportions either fully recover or develop some other psychiatric disorder with a minority developing a psychotic disorder). Whereas the reliability of the diagnosis is well established in academic and research settings, it was found to be less so in community and other clinical settings. Furthermore, the nosological relationship of Attenuated Psychosis Syndrome (APS) to schizotypal personality disorder and other psychiatric conditions was unclear. Further study will hopefully resolve these questions. The Workgroup decided to recommend the inclusion of Attenuated Psychosis Syndrome as a category in the appendix (Section 3) of DSM-5 as a condition for further study.
doi:10.1016/j.schres.2013.05.004
PMCID: PMC3778120  PMID: 23773295
6.  Horizon 2020 Priorities in Clinical Mental Health Research: Results of a Consensus-Based ROAMER Expert Survey 
Within the ROAMER project, which aims to provide a Roadmap for Mental Health Research in Europe, a two-stage Delphi survey among 86 European experts was conducted in order to identify research priorities in clinical mental health research. Expert consensus existed with regard to the importance of three challenges in the field of clinical mental health research: (1) the development of new, safe and effective interventions for mental disorders; (2) understanding the mechanisms of disease in order to be able to develop such new interventions; and (3) defining outcomes (an improved set of outcomes, including alternative outcomes) to use for clinical mental health research evaluation. Proposed actions involved increasing the utilization of tailored approaches (personalized medicine), developing blended eHealth/mHealth decision aids/guidance tools that help the clinician to choose between various treatment modalities, developing specific treatments in order to better target comorbidity and (further) development of biological, psychological and psychopharmacological interventions. The experts indicated that addressing these priorities will result in increased efficacy and impact across Europe; with a high probability of success, given that Europe has important strengths, such as skilled academics and a long research history. Finally, the experts stressed the importance of creating funding and coordinated networking as essential action needed in order to target the variety of challenges in clinical mental health research.
doi:10.3390/ijerph111010915
PMCID: PMC4211014  PMID: 25337940
clinical mental health research; Delphi survey; priorities; Horizon 2020
7.  Novel Evidence That Attributing Affectively Salient Signal to Random Noise Is Associated with Psychosis 
PLoS ONE  2014;9(7):e102520.
We wished to replicate evidence that an experimental paradigm of speech illusions is associated with psychotic experiences. Fifty-four patients with a first episode of psychosis (FEP) and 150 healthy subjects were examined in an experimental paradigm assessing the presence of speech illusion in neutral white noise. Socio-demographic, cognitive function and family history data were collected. The Positive and Negative Syndrome Scale (PANSS) was administered in the patient group and the Structured Interview for Schizotypy-Revised (SIS-R), and the Community Assessment of Psychic Experiences (CAPE) in the control group. Patients had a much higher rate of speech illusions (33.3% versus 8.7%, ORadjusted: 5.1, 95% CI: 2.3–11.5), which was only partly explained by differences in IQ (ORadjusted: 3.4, 95% CI: 1.4–8.3). Differences were particularly marked for signals in random noise that were perceived as affectively salient (ORadjusted: 9.7, 95% CI: 1.8–53.9). Speech illusion tended to be associated with positive symptoms in patients (ORadjusted: 3.3, 95% CI: 0.9–11.6), particularly affectively salient illusions (ORadjusted: 8.3, 95% CI: 0.7–100.3). In controls, speech illusions were not associated with positive schizotypy (ORadjusted: 1.1, 95% CI: 0.3–3.4) or self-reported psychotic experiences (ORadjusted: 1.4, 95% CI: 0.4–4.6). Experimental paradigms indexing the tendency to detect affectively salient signals in noise may be used to identify liability to psychosis.
doi:10.1371/journal.pone.0102520
PMCID: PMC4097069  PMID: 25020079
8.  Towards Horizon 2020: challenges and advances for clinical mental health research – outcome of an expert survey 
Background
The size and increasing burden of disease due to mental disorders in Europe poses substantial challenges to its population and to the health policy of the European Union. This warrants a specific research agenda concerning clinical mental health research as one of the cornerstones of sustainable mental health research and health policy in Europe. The aim of this research was to identify the top priorities needed to address the main challenges in clinical research for mental disorders.
Methods
The research was conducted as an expert survey and expert panel discussion during a scientific workshop.
Results
Eighty-nine experts in clinical research and representing most European countries participated in this survey. Identified top priorities were the need for new intervention studies, understanding the diagnostic and therapeutic implications of mechanisms of disease, and research in the field of somatic-psychiatric comorbidity. The “subjectivity gap” between basic neuroscience research and clinical reality for patients with mental disorders is considered the main challenge in psychiatric research, suggesting that a shift in research paradigms is required.
Conclusion
Innovations in clinical mental health research should bridge the gap between mechanisms underlying novel therapeutic interventions and the patient experience of mental disorder and, if present, somatic comorbidity. Clinical mental health research is relatively underfunded and should receive specific attention in Horizon 2020 funding programs.
doi:10.2147/NDT.S59958
PMCID: PMC4085314  PMID: 25061300
clinical research; mental health; randomized clinical trials; Horizon 2020; expert survey; challenge; research agenda; Europe
9.  How to Boost Positive Interpretations? A Meta-Analysis of the Effectiveness of Cognitive Bias Modification for Interpretation 
PLoS ONE  2014;9(6):e100925.
The current meta-analysis explores the strength of effects of cognitive bias modification training for interpretation bias (CBM-I) on positive (i.e., adaptive) interpretations and mood as well as the training and sample characteristics influencing these effects. Data-bases were searched with the key words “interpret* bias AND training” and “interpret* bias AND modif*”. Reference lists of identified articles were checked and authors of identified articles were contacted for further relevant articles and unpublished data. Studies were reviewed for inclusion with eligibility criteria being that the study (a) aimed to target interpretation biases through any kind of training, (b) assessed mood and/or interpretation bias as outcome measures, (c) allocated individuals to training conditions at random, and (d) recruited adult samples. A meta-analytic multilevel mixed-effects model was employed to assess standardized mean changes in interpretation bias, negative mood, and emotional reactivity. In addition, several training and sample characteristics were explored for their potential to enhance benign training effectiveness. On average, benign CBM-I resulted in an increase in positive interpretation bias (p<.01) and a decrease in negative mood state (p<.001), but did not affect emotional reactivity. These effects were not consistently different from control conditions with no or neutral training. However, within benign training conditions imagery instructions and more training sessions were related to larger cognitive and mood effects, whereas feedback about training performance and inclusion of non-benign training items (instead of including benign items only) boosted cognitive effects only. Finally, training was more effective in women (cognitive and mood effects) and presumably samples with symptomatic emotional dysregulation (cognitive effects). Although the effects of emotional dysregulation and number of training sessions could not well be distinguished, there is an indication that when used with imagery instructions and more training sessions, benign CBM-I can be employed as a useful complementary treatment to usual psychotherapies.
doi:10.1371/journal.pone.0100925
PMCID: PMC4072710  PMID: 24968234
10.  Epigenetic Genes and Emotional Reactivity to Daily Life Events: A Multi-Step Gene-Environment Interaction Study 
PLoS ONE  2014;9(6):e100935.
Recent human and animal studies suggest that epigenetic mechanisms mediate the impact of environment on development of mental disorders. Therefore, we hypothesized that polymorphisms in epigenetic-regulatory genes impact stress-induced emotional changes. A multi-step, multi-sample gene-environment interaction analysis was conducted to test whether 31 single nucleotide polymorphisms (SNPs) in epigenetic-regulatory genes, i.e. three DNA methyltransferase genes DNMT1, DNMT3A, DNMT3B, and methylenetetrahydrofolate reductase (MTHFR), moderate emotional responses to stressful and pleasant stimuli in daily life as measured by Experience Sampling Methodology (ESM). In the first step, main and interactive effects were tested in a sample of 112 healthy individuals. Significant associations in this discovery sample were then investigated in a population-based sample of 434 individuals for replication. SNPs showing significant effects in both the discovery and replication samples were subsequently tested in three other samples of: (i) 85 unaffected siblings of patients with psychosis, (ii) 110 patients with psychotic disorders, and iii) 126 patients with a history of major depressive disorder. Multilevel linear regression analyses showed no significant association between SNPs and negative affect or positive affect. No SNPs moderated the effect of pleasant stimuli on positive affect. Three SNPs of DNMT3A (rs11683424, rs1465764, rs1465825) and 1 SNP of MTHFR (rs1801131) moderated the effect of stressful events on negative affect. Only rs11683424 of DNMT3A showed consistent directions of effect in the majority of the 5 samples. These data provide the first evidence that emotional responses to daily life stressors may be moderated by genetic variation in the genes involved in the epigenetic machinery.
doi:10.1371/journal.pone.0100935
PMCID: PMC4072714  PMID: 24967710
11.  Almost All Antipsychotics Result in Weight Gain: A Meta-Analysis 
PLoS ONE  2014;9(4):e94112.
Introduction
Antipsychotics (AP) induce weight gain. However, reviews and meta-analyses generally are restricted to second generation antipsychotics (SGA) and do not stratify for duration of AP use. It is hypothesised that patients gain more weight if duration of AP use is longer.
Method
A meta-analysis was conducted of clinical trials of AP that reported weight change. Outcome measures were body weight change, change in BMI and clinically relevant weight change (7% weight gain or loss). Duration of AP-use was stratified as follows: ≤6 weeks, 6–16 weeks, 16–38 weeks and >38 weeks. Forest plots stratified by AP as well as by duration of use were generated and results were summarised in figures.
Results
307 articles met inclusion criteria. The majority were AP switch studies. Almost all AP showed a degree of weight gain after prolonged use, except for amisulpride, aripiprazole and ziprasidone, for which prolonged exposure resulted in negligible weight change. The level of weight gain per AP varied from discrete to severe. Contrary to expectations, switch of AP did not result in weight loss for amisulpride, aripiprazole or ziprasidone. In AP-naive patients, weight gain was much more pronounced for all AP.
Conclusion
Given prolonged exposure, virtually all AP are associated with weight gain. The rational of switching AP to achieve weight reduction may be overrated. In AP-naive patients, weight gain is more pronounced.
doi:10.1371/journal.pone.0094112
PMCID: PMC3998960  PMID: 24763306
12.  Histone Deacetylase 2 in the Mouse Hippocampus: Attenuation of Age-Related Increase by Caloric Restriction 
Current Alzheimer research  2013;10(8):868-876.
The aging process in the hippocampus is associated with aberrant epigenetic marks, such as DNA methylation and histone tail alterations. Recent evidence suggests that caloric restriction (CR) can potentially delay the aging process, while upregulation of antioxidants may also have a beneficial effect in this respect. We have recently observed that CR attenuates age-related changes in the levels of the epigenetic molecules DNA methyltransferase 3a, 5-methylcytidine (5-mC) and 5-hydroxymethylcytosine in the mouse hippocampus while overexpression of the antioxidant Cu/Zn superoxide dismutase 1 (SOD1) does not. However, the impact of aging on the levels of histone-modifying enzymes such as histone deacetylase 2 (HDAC2) in the hippocampus has not been studied in much detail. Here, we investigated immunoreactivity (IR) of HDAC2 in three subregions of the hippocampus (dentate gyrus, CA3 and CA1-2) of mice taken from large cohorts of aging wild-type and transgenic mice overexpressing normal human SOD1, which were kept under normal diet or CR from weaning onwards. Independent from the genotype, aging (between 12 and 24 months) increased levels of HDAC2 IR in the hippocampus. Moreover, CR prevented this age-related increase, particularly in the CA3 and CA1-2 subregions, while SOD1 overexpression did not. Quantitative image analyses showed that HDAC2 IR correlated positively with 5-mC IR while these markers were shown to colocalize in the nucleus of hippocampal cells. Together with recent literature reports, these findings suggest that altered levels of epigenetic regulatory proteins including HDAC2 regulate age-related changes in the mouse hippocampus and that CR may prevent these age-related changes.
PMCID: PMC3966721  PMID: 24093534
Aging; epigenesis; histone deacetylase 2 (HDAC2); caloric restriction; hippocampus
13.  Brain-Derived Neurotrophic Factor/FK506-Binding Protein 5 Genotype by Childhood Trauma Interactions Do Not Impact on Hippocampal Volume and Cognitive Performance 
PLoS ONE  2014;9(3):e92722.
In the development of psychotic symptoms, environmental and genetic factors may both play a role. The reported association between childhood trauma and psychotic symptoms could therefore be moderated by single nucleotide polymorphisms (SNPs) associated with the stress response, such as FK506-binding protein 5 (FKBP5) and brain-derived neurotrophic factor (BDNF). Recent studies investigating childhood trauma by SNP interactions have inconsistently found the hippocampus to be a potential target underlying these interactions. Therefore, more detailed modelling of these effects, using appropriate covariates, is required. We examined whether BDNF/FKBP5 and childhood trauma interactions affected two proxies of hippocampal integrity: (i) hippocampal volume and (ii) cognitive performance on a block design (BD) and delayed auditory verbal task (AVLT). We also investigated whether the putative interaction was different for patients with a psychotic disorder (n = 89) compared to their non-psychotic siblings (n = 95), in order to elicit possible group-specific protective/vulnerability effects. SNPs were rs9296158, rs4713916, rs992105, rs3800373 (FKBP5) and rs6265 (BDNF). In the combined sample, no BDNF/FKBP5 by childhood trauma interactions were apparent for either outcome, and BDNF/FKBP5 by childhood trauma interactions were not different for patients and siblings. The omission of drug use and alcohol consumption sometimes yielded false positives, greatly affected explained error and influenced p-values. The consistent absence of any significant BDNF/FKBP5 by childhood trauma interactions on assessments of hippocampal integrity suggests that the effect of these interactions on psychotic symptoms is not mediated by hippocampal integrity. The importance of appropriate statistical designs and inclusion of relevant covariates should be carefully considered.
doi:10.1371/journal.pone.0092722
PMCID: PMC3962453  PMID: 24658422
14.  Neurofeedback As a Treatment for Major Depressive Disorder – A Pilot Study 
PLoS ONE  2014;9(3):e91837.
Background
There is growing interest in neurofeedback as a treatment for major depressive disorder. Reduction of asymmetry of alpha-activity between left and right prefrontal areas with neurofeedback has been postulated as effective in earlier studies. Unfortunately, methodological shortcomings limit conclusions that can be drawn from these studies. In a pilot-study, we investigated the effectiveness of reduction of asymmetry of alpha-activity with neurofeedback in depressed participants with the use of a stringent methodological approach.
Methods
Nine participants meeting DSM-IV criteria for major depressive disorder were treated with a maximum of 30 neurofeedback-sessions, aimed at reducing asymmetry of alpha-activity, over a 10-week period. No changes in the use of antidepressants were allowed 6 weeks before and during the intervention. Changes in depressive symptomatology were assessed with the Quick Inventory of Depressive Symptoms, self-report version.
Results
We observed response in 1 and remission in 4 out of a total of 9 participants. The effectiveness appeared largest in female participants. The mean asymmetry of alpha-activity decreased significantly over sessions in a quadratic fashion. This decrease was associated with clinical response.
Conclusions
This pilot study suggests that neurofeedback aimed at a reduction of frontal asymmetry of alpha-activity may be effective as a treatment for depression. However, this was an open label pilot study. Non-specific effects of the procedure and/or a beneficial natural course may have confounded the results. Randomized controlled trials will have to establish the efficacy of neurofeedback for depression.
Trial Registration
Nederlands Trial Register NTR1629
doi:10.1371/journal.pone.0091837
PMCID: PMC3958393  PMID: 24642756
15.  Schizophrenia Candidate Gene ERBB4: Covert Routes of Vulnerability to Psychosis Detected at the Population Level 
Schizophrenia Bulletin  2011;39(2):349-357.
Prior genetic and functional evidence established ERBB4 as a probable schizophrenia susceptibility gene that may confer risk via modulating brain information processing dependent on the integrity of frontotemporal brain circuitry. Utilizing retrospective data drawn from the cross-sectional population-based Athens Study of Psychosis Proneness and Incidence of Schizophrenia (ASPIS) (n = 1127), we attempted to independently replicate and further extend previous findings by examining the effects of ERBB4 gene variants on 3 broad population–based psychosis-related phenotypes: verbal working memory (VWM), trait schizotypy, and stress-induced subclinical psychotic experiences (PE). Three common ERBB4 single nucleotide polymorphisms that were previously associated with schizophrenia and impaired frontotemporal-related information processing (rs7598440, rs839523, and rs707284), their haplotypes, and corresponding diplotypes were tested. VWM performance was significantly associated with rs839523 and rs707284 markers even after correction for multiple testing, thus validating reported findings that have implicated ERBB4 gene variation on working memory. No associations were detected between these ERBB4 variants and trait schizotypy. However, we were able to detect a significant effect of rs7598440 marker on PE expressed under stressful environmental conditions. Combined haplotype analysis of the above 3 markers, identified a “yin-yang” pattern of association, confirmed at the diplotype level. While GGG haplotype homozygotes were associated with “protective” effects on VWM performance and PE, AAA “risk” haplotype carriers were associated with worse VWM performance and simultaneously exhibited significantly elevated PE. This dual, possibly pleiotropic, impact on frontotemporal circuitry and increased sensitivity to psychosocial stress may represent subtle manifestations of ERBB4-related vulnerability to psychosis, expressed at the population level.
doi:10.1093/schbul/sbr169
PMCID: PMC3576167  PMID: 22115776
schizotypy; working memory; psychotic symptoms; schizophrenia; stress; polymorphism
16.  Stereotype Awareness, Self-Esteem and Psychopathology in People with Psychosis 
PLoS ONE  2014;9(2):e88586.
Introduction
Stigma is an important environmental risk factor for a variety of outcomes in schizophrenia. In order to understand and remediate its effects, research is required to assess how stigma experiences are processed at the level of the individual. To this end, stereotype awareness (SA) with respect to people with mental illness and their families was explored in persons with psychotic disorder.
Method
Data from the Dutch Genetic Risk and OUtcome of Psychosis project (GROUP) were analyzed. SA was measured using scales that assess a respondent's perception of common opinions about people with a mental illness and their families.
Results
People with higher level of self-esteem were less aware of stereotypes about patients and families. People with more severe psychopathology reported more awareness of stereotypes about families, not about patients.
Conclusion
Enhancing psychological resources, by increasing self-esteem and the ability to cope with symptoms, can be targeted to diminish stereotype threat and improve stigma resilience. Interventions can be tailored to individual differences to increase their impact. Furthermore, in order to diminish detrimental consequences of negative stereotypes, mental health professionals, health educators and experts by experience can inform the public about mental illness and stigma.
doi:10.1371/journal.pone.0088586
PMCID: PMC3921218  PMID: 24523918
17.  Evidence That a Psychopathology Interactome Has Diagnostic Value, Predicting Clinical Needs: An Experience Sampling Study 
PLoS ONE  2014;9(1):e86652.
Background
For the purpose of diagnosis, psychopathology can be represented as categories of mental disorder, symptom dimensions or symptom networks. Also, psychopathology can be assessed at different levels of temporal resolution (monthly episodes, daily fluctuating symptoms, momentary fluctuating mental states). We tested the diagnostic value, in terms of prediction of treatment needs, of the combination of symptom networks and momentary assessment level.
Method
Fifty-seven patients with a psychotic disorder participated in an ESM study, capturing psychotic experiences, emotions and circumstances at 10 semi-random moments in the flow of daily life over a period of 6 days. Symptoms were assessed by interview with the Positive and Negative Syndrome Scale (PANSS); treatment needs were assessed using the Camberwell Assessment of Need (CAN).
Results
Psychotic symptoms assessed with the PANSS (Clinical Psychotic Symptoms) were strongly associated with psychotic experiences assessed with ESM (Momentary Psychotic Experiences). However, the degree to which Momentary Psychotic Experiences manifested as Clinical Psychotic Symptoms was determined by level of momentary negative affect (higher levels increasing probability of Momentary Psychotic Experiences manifesting as Clinical Psychotic Symptoms), momentary positive affect (higher levels decreasing probability of Clinical Psychotic Symptoms), greater persistence of Momentary Psychotic Experiences (persistence predicting increased probability of Clinical Psychotic Symptoms) and momentary environmental stress associated with events and activities (higher levels increasing probability of Clinical Psychotic Symptoms). Similarly, the degree to which momentary visual or auditory hallucinations manifested as Clinical Psychotic Symptoms was strongly contingent on the level of accompanying momentary paranoid delusional ideation. Momentary Psychotic Experiences were associated with CAN unmet treatment needs, over and above PANSS measures of psychopathology, similarly moderated by momentary interactions with emotions and context.
Conclusion
The results suggest that psychopathology, represented as an interactome at the momentary level of temporal resolution, is informative in diagnosing clinical needs, over and above traditional symptom measures.
doi:10.1371/journal.pone.0086652
PMCID: PMC3900579  PMID: 24466189
18.  Does Assessment Type Matter? A Measurement Invariance Analysis of Online and Paper and Pencil Assessment of the Community Assessment of Psychic Experiences (CAPE) 
PLoS ONE  2014;9(1):e84011.
Background
The psychometric properties of an online test are not necessarily identical to its paper and pencil original. The aim of this study is to test whether the factor structure of the Community Assessment of Psychic Experiences (CAPE) is measurement invariant with respect to online vs. paper and pencil assessment.
Method
The factor structure of CAPE items assessed by paper and pencil (N = 796) was compared with the factor structure of CAPE items assessed by the Internet (N = 21,590) using formal tests for Measurement Invariance (MI). The effect size was calculated by estimating the Signed Item Difference in the Sample (SIDS) index and the Signed Test Difference in the Sample (STDS) for a hypothetical subject who scores 2 standard deviations above average on the latent dimensions.
Results
The more restricted Metric Invariance model showed a significantly worse fit compared to the less restricted Configural Invariance model (χ2(23) = 152.75, p<0.001). However, the SIDS indices appear to be small, with an average of −0.11. A STDS of −4.80 indicates that Internet sample members who score 2 standard deviations above average would be expected to score 4.80 points lower on the CAPE total scale (ranging from 42 to 114 points) than would members of the Paper sample with the same latent trait score.
Conclusions
Our findings did not support measurement invariance with respect to assessment method. Because of the small effect sizes, the measurement differences between the online assessed CAPE and its paper and pencil original can be neglected without major consequences for research purposes. However, a person with a high vulnerability for psychotic symptoms would score 4.80 points lower on the total scale if the CAPE is assessed online compared to paper and pencil assessment. Therefore, for clinical purposes, one should be cautious with online assessment of the CAPE.
doi:10.1371/journal.pone.0084011
PMCID: PMC3898946  PMID: 24465389
19.  Emotional Experience in Negative Symptoms of Schizophrenia—No Evidence for a Generalized Hedonic Deficit 
Schizophrenia Bulletin  2011;39(1):217-225.
Background: Deficits in emotion processing are thought to underlie the key negative symptoms flat affect and anhedonia observed in psychotic disorders. This study investigated emotional experience and social behavior in the realm of daily life in a sample of patients with schizophrenia and schizoaffective disorder, stratified by level of negative symptoms. Methods: Emotional experience and behavior of 149 patients with schizophrenia and schizoaffective disorder and 143 controls were explored using the Experience Sampling Method. Results: Patients reported lower levels of positive and higher levels of negative affect compared with controls. High negative symptom patients reported similar emotional stability and capacity to generate positive affect as controls, whereas low negative symptom patients reported increased instability. All participants displayed roughly comparable emotional responses to the company of other people. However, in comparison with controls, patients showed more social withdrawal and preference to be alone while in company, particularly the high negative symptom group. Conclusions: This study revealed no evidence for a generalized hedonic deficit in patients with psychotic spectrum disorders. Lower rather than higher levels of negative symptoms were associated with a pattern of emotional processing which was different from healthy controls.
doi:10.1093/schbul/sbr137
PMCID: PMC3523912  PMID: 22021660
emotions; psychosis; negative symptomatology; anhedonia; experience sampling method (ESM); daily life
20.  Dynamic Association Between Interpersonal Functioning and Positive Symptom Dimensions of Psychosis Over Time: A Longitudinal Study of Healthy Adolescents 
Schizophrenia Bulletin  2011;39(1):179-185.
Background: Cross-sectional studies have indicated that alterations in social functioning, particularly interpersonal functioning, are associated with the occurrence of psychotic symptoms and experiences at different levels of the extended psychosis phenotype (ranging from population psychometric expression of liability to overt psychotic disorder). However, more research is needed on the development of this association over time. Methods: Cross-lagged path modeling was used to analyze bidirectional, longitudinal associations between 4 dimensions of subclinical psychotic experiences (persecutory ideation, bizarre experiences, perceptual abnormalities, and magical thinking) and interpersonal functioning in an adolescent general population sample (N = 881 at T1, N = 652 at T2, and N = 512 at T3) assessed 3 times in 3 years. Results: All symptom dimensions showed some association with interpersonal functioning over time, but only bizarre experiences and persecutory ideation were consistently and longitudinally associated with interpersonal functioning. Poorer interpersonal functioning predicted higher levels of bizarre experiences and persecutory ideation at later measurement points (both T1 to T2 and T2 to T3). Conclusions: Poor interpersonal functioning in adolescence may reflect the earliest expression of neurodevelopmental alterations preceding expression of psychotic experiences in a symptom-specific fashion.
doi:10.1093/schbul/sbr115
PMCID: PMC3523924  PMID: 21930645
psychotic disorder; interpersonal relation; social support; longitudinal studies; risk factors; schizophrenic psychology
21.  Common Variant at 16p11.2 Conferring Risk of Psychosis 
Steinberg, Stacy | de Jong, Simone | Mattheisen, Manuel | Costas, Javier | Demontis, Ditte | Jamain, Stéphane | Pietiläinen, Olli P H | Lin, Kuang | Papiol, Sergi | Huttenlocher, Johanna | Sigurdsson, Engilbert | Vassos, Evangelos | Giegling, Ina | Breuer, René | Fraser, Gillian | Walker, Nicholas | Melle, Ingrid | Djurovic, Srdjan | Agartz, Ingrid | Tuulio-Henriksson, Annamari | Suvisaari, Jaana | Lönnqvist, Jouko | Paunio, Tiina | Olsen, Line | Hansen, Thomas | Ingason, Andres | Pirinen, Matti | Strengman, Eric | Hougaard, David M | Ørntoft, Torben | Didriksen, Michael | Hollegaard, Mads V | Nordentoft, Merete | Abramova, Lilia | Kaleda, Vasily | Arrojo, Manuel | Sanjuán, Julio | Arango, Celso | Etain, Bruno | Bellivier, Frank | Méary, Alexandre | Schürhoff, Franck | Szoke, Andrei | Ribolsi, Michele | Magni, Valentina | Siracusano, Alberto | Sperling, Swetlana | Rossner, Moritz | Christiansen, Claus | Kiemeney, Lambertus A | Franke, Barbara | van den Berg, Leonard H | Veldink, Jan | Curran, Sarah | Bolton, Patrick | Poot, Martin | Staal, Wouter | Rehnstrom, Karola | Kilpinen, Helena | Freitag, Christine M | Meyer, Jobst | Magnusson, Pall | Saemundsen, Evald | Martsenkovsky, Igor | Bikshaieva, Iana | Martsenkovska, Inna | Vashchenko, Olesya | Raleva, Marija | Paketchieva, Kamka | Stefanovski, Branislav | Durmishi, Naser | Milovancevic, Milica Pejovic | Tosevski, Dusica Lecic | Silagadze, Teimuraz | Naneishvili, Nino | Mikeladze, Nina | Surguladze, Simon | Vincent, John B | Farmer, Anne | Mitchell, Philip B | Wright, Adam | Schofield, Peter R | Fullerton, Janice M | Montgomery, Grant W | Martin, Nicholas G | Rubino, I Alex | van Winkel, Ruud | Kenis, Gunter | De Hert, Marc | Réthelyi, János M | Bitter, István | Terenius, Lars | Jönsson, Erik G | Bakker, Steven | van Os, Jim | Jablensky, Assen | Leboyer, Marion | Bramon, Elvira | Powell, John | Murray, Robin | Corvin, Aiden | Gill, Michael | Morris, Derek | O’Neill, F Anthony | Kendler, Ken | Riley, Brien | Craddock, Nick | Owen, Michael J | O’Donovan, Michael C | Thorsteinsdottir, Unnur | Kong, Augustine | Ehrenreich, Hannelore | Carracedo, Angel | Golimbet, Vera | Andreassen, Ole A | Børglum, Anders D | Mors, Ole | Mortensen, Preben B | Werge, Thomas | Ophoff, Roel A | Nöthen, Markus M | Rietschel, Marcella | Cichon, Sven | Ruggeri, Mirella | Tosato, Sarah | Palotie, Aarno | St Clair, David | Rujescu, Dan | Collier, David A | Stefansson, Hreinn | Stefansson, Kari
Molecular psychiatry  2012;19(1):10.1038/mp.2012.157.
Epidemiological and genetic data support the notion that schizophrenia and bipolar disorder share genetic risk factors. In our previous genome-wide association (GWA) study, meta-analysis and follow-up (totaling as many as 18,206 cases and 42,536 controls), we identified four loci showing genome-wide significant association with schizophrenia. Here we consider a mixed schizophrenia and bipolar disorder (psychosis) phenotype (addition of 7,469 bipolar disorder cases, 1,535 schizophrenia cases, 333 other psychosis cases, 808 unaffected family members and 46,160 controls). Combined analysis reveals a novel variant at 16p11.2 showing genome-wide significant association (rs4583255[T], OR = 1.08, P = 6.6 × 10−11). The new variant is located within a 593 kb region that substantially increases risk of psychosis when duplicated. In line with the association of the duplication with reduced body mass index (BMI), rs4583255[T] is also associated with lower BMI (P = 0.0039 in the public GIANT consortium dataset; P = 0.00047 in 22,651 additional Icelanders).
doi:10.1038/mp.2012.157
PMCID: PMC3872086  PMID: 23164818
schizophrenia; bipolar disorder; association; 16p11.2; cross-disorder
22.  Replicated Evidence of Absence of Association between Serum S100B and (Risk of) Psychotic Disorder 
PLoS ONE  2013;8(12):e82535.
Background
S100B is a potential marker of neurological and psychiatric illness. In schizophrenia, increased S100B levels, as well as associations with acute positive and persisting negative symptoms, have been reported. It remains unclear whether S100B elevation, which possibly reflects glial dysfunction, is the consequence of disease or compensatory processes, or whether it is an indicator of familial risk.
Methods
Serum samples were acquired from two large independent family samples (n = 348 and n = 254) in the Netherlands comprising patients with psychotic disorder (n = 140 and n = 82), non-psychotic siblings of patients with psychotic disorder (n = 125 and n = 94) and controls (n = 83 and n = 78). S100B was analyzed with a Liaison automated chemiluminescence system. Associations between familial risk of psychotic disorder and S100B were examined.
Results
Results showed that S100B levels in patients (P) and siblings (S) were not significantly different from controls (C) (dataset 1: P vs. C: B = 0.004, 95% CI −0.005 to 0.013, p = 0.351; S vs. C: B = 0.000, 95% CI −0.009 to 0.008, p = 0.926; and dataset 2: P vs. C: B = 0.008, 95% CI −0.011 to 0.028, p = 0.410; S vs. C: B = 0.002, 95% CI −0.016 to 0.021, p = 0.797). In patients, negative symptoms were positively associated with S100B (B = 0.001, 95% CI 0.000 to 0.002, p = 0.005) in one of the datasets, however with failure of replication in the other. There was no significant association between S100B and positive symptoms or present use or type of antipsychotic medication.
Conclusions
S100B is neither an intermediate phenotype, nor a trait marker for psychotic illness.
doi:10.1371/journal.pone.0082535
PMCID: PMC3866164  PMID: 24358202
23.  Flexible Assertive Community Treatment, Severity of Symptoms and Psychiatric Health Service Use, a Real life Observational Study 
Background:
Introduction of Flexible Assertive Community Treatment (FACT) may be associated with increased remission rates and changes in patterns of care. The present paper reports on differences in psychosocial functioning and health care use between patients in FACT and two groups of patients not currently provided with a specific model of community service.
Methods:
The ongoing "Pharmacotherapy Monitoring and Outcome Survey" provided routine outcome measures of patients using antipsychotics in the north of the Netherlands. Level of psychosocial functioning was assessed using the Health of the Nations Outcome Scales (HoNOS) and matched with psychiatric health care consumption obtained from the Psychiatric Case Register. Patients who never received FACT, patients ever in FACT but not at assessment date, and patients in FACT were identified. Data were subjected to multilevel linear regression analysis.
Results:
Data showed that most patients in FACT also had non-FACT episodes after the start of FACT. Furthermore, patients in FACT displayed higher levels of psychosocial functioning and used more outpatient care than the other two groups.
Conclusions:
Patients in FACT receive more outpatient care and have better psychosocial functioning. However, causal inferences cannot be derived from these data. In addition, membership of a FACT-team in this setting did not last indefinitely.
doi:10.2174/1745017901309010202
PMCID: PMC3866708  PMID: 24358050
Assertive Community Treatment; Health Care; Population Register; Psychiatry; Psychosocial Factors; Severity of Illness.
24.  Evidence That Transition from Health to Psychotic Disorder Can Be Traced to Semi-Ubiquitous Environmental Effects Operating against Background Genetic Risk 
PLoS ONE  2013;8(11):e76690.
Background
In order to assess the importance of environmental and genetic risk on transition from health to psychotic disorder, a prospective study of individuals at average (n = 462) and high genetic risk (n = 810) was conducted.
Method
A three-year cohort study examined the rate of transition to psychotic disorder. Binary measures indexing environmental exposure (combining urban birth, cannabis use, ethnicity and childhood trauma) and proxy genetic risk (high-risk sibling status) were used to model transition.
Results
The majority of high-risk siblings (68%) and healthy comparison subjects (60%) had been exposed to one or more environmental risks. The risk of transition in siblings (n = 9, 1.1%) was higher than the risk in healthy comparison subjects (n = 2, 0.4%; ORadj  = 2.2,95%CI:5–10.3). All transitions (100%) were associated with environmental exposure, compared to 65% of non-transitions (p = 0.014), with the greatest effects for childhood trauma (ORadj  = 34.4,95%CI:4.4–267.4), cannabis use (OR = 4.1,95%CI:1.1, 15.4), minority ethnic group (OR = 3.8,95%CI:1.2,12.8) and urban birth (OR = 3.7,95%CI:0.9,15.4). The proportion of transitions in the population attributable to environmental and genetic risk ranged from 28% for minority ethnic group, 45% for urban birth, 57% for cannabis use, 86% for childhood trauma, and 50% for high-risk sibling status. Nine out of 11 transitions (82%) were exposed to both genetic and environmental risk, compared to only 43% of non-transitions (p = 0.03).
Conclusion
Environmental risk associated with transition to psychotic disorder is semi-ubiquitous regardless of genetic high risk status. Careful prospective documentation suggests most transitions can be attributed to powerful environmental effects that become detectable when analysed against elevated background genetic risk, indicating gene-environment interaction.
doi:10.1371/journal.pone.0076690
PMCID: PMC3819353  PMID: 24223116
25.  Introducing the Event Related Fixed Interval Area (ERFIA) Multilevel Technique: a Method to Analyze the Complete Epoch of Event-Related Potentials at Single Trial Level  
PLoS ONE  2013;8(11):e79905.
In analyzing time-locked event-related potentials (ERPs), many studies have focused on specific peaks and their differences between experimental conditions. In theory, each latency point after a stimulus contains potentially meaningful information, regardless of whether it is peak-related. Based on this assumption, we introduce a new concept which allows for flexible investigation of the whole epoch and does not primarily focus on peaks and their corresponding latencies. For each trial, the entire epoch is partitioned into event-related fixed-interval areas under the curve (ERFIAs). These ERFIAs, obtained at single trial level, act as dependent variables in a multilevel random regression analysis. The ERFIA multilevel method was tested in an existing ERP dataset of 85 healthy subjects, who underwent a rating paradigm of 150 painful and non-painful somatosensory electrical stimuli. We modeled the variability of each consecutive ERFIA with a set of predictor variables among which were stimulus intensity and stimulus number. Furthermore, we corrected for latency variations of the P2 (260 ms). With respect to known relationships between stimulus intensity, habituation, and pain-related somatosensory ERP, the ERFIA method generated highly comparable results to those of commonly used methods. Notably, effects on stimulus intensity and habituation were also observed in non-peak-related latency ranges. Further, cortical processing of actual stimulus intensity depended on the intensity of the previous stimulus, which may reflect pain-memory processing. In conclusion, the ERFIA multilevel method is a promising tool that can be used to study event-related cortical processing.
doi:10.1371/journal.pone.0079905
PMCID: PMC3817110  PMID: 24224018

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