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Negative symptoms are associated with poor clinical and psychosocial outcome in schizophrenia. Their prevalence and identification in first-episode patients remains controversial. In a large cohort of patients in the early stage of schizophrenia, schizophreniform or schizoaffective disorder, we investigated, over the different phases of the OPTiMiSE trial (baseline, 4, 10 and 22 weeks of treatment), the prevalence of negative symptoms of moderate severity, unconfounded by depression and extrapyramidal symptoms at baseline. Moreover, we assessed symptomatic remission, attrition rate and psychosocial functioning in subjects with short-term (4 weeks) persistent unconfounded negative symptoms (PNS) and in those with negative symptoms that did not persist at follow-up and/or were confounded at baseline (N-PNS). Negative symptoms of moderate severity were observed in 59% of subjects at baseline. They were associated with worse psychosocial functioning and longer duration of psychosis at intake in the study. Eleven percent of subjects had PNS unconfounded at baseline and 7.9% had PNS unconfounded at both baseline and end of 4-week treatment. Psychosocial functioning was comparable in PNS and N-PNS subjects at baseline but it was significantly worse in the former group after 4-weeks. PNS subjects showed lower remission and higher attrition rates at the end of all treatment phases. Fifty-six percent of subjects completing phase 3 (clozapine treatment) had PNS, and 60% of them were non-remitters at the end of this phase. The presence of short-term PNS during the first phases of psychosis was associated with poor clinical outcome and resistance to antipsychotic treatment, including clozapine., Competing Interests: Declaration of Competing Interest C. Arango has been a consultant to or has received honoraria or grants from Acadia, Angelini, Gedeon Richter, Janssen Cilag, Lundbeck, Otsuka, Roche, Sage, Sanofi, Servier, Shire, Schering Plough, Sumitomo Dainippon Pharma, Sunovion and Takeda. R. Buchanan has served on an advisory board for Avanir, GW Pharma Ltd., Minerva, and Roche; and served on a DSMB for Roche. C.M. Díaz-Caneja has received honorary fees from Sanofi-Aventis and Abbvie, and grant support from Instituto de Salud Carlos III (Spanish Ministry of Science, Innovation and Universities). S. Galderisi has been a consultant and/or advisor to or has received honoraria or grants from: Millennium Pharmaceuticals, Innova Pharma-Recordati Group, Janssen Pharmaceutica NV, Sunovion Pharmarmaceuticals, Janssen–Cilag Polska Sp. zo. o., Gedeon Richter-Recordati, Pierre Fabre, Otsuka, Angelini. B. Glenthøj is the leader of a Lundbeck Foundation center of Excellence for Clinical Intervention and Neuropsychiatric Schizophrenia Research (CINS), which is partially financed by an independent grant from the Lundbeck Foundation based on international review and partially financed by the Mental Health Services in the Capital Region of Denmark, the University of Copenhagen, and other foundations. Her group has also received a research grant from Lundbeck A/S for another independent investigator-initiated study. All grants are the property of the Mental Health Services in the Capital Region of Denmark and administrated by them. She has no other conflicts to disclose. S. Leucht has received honoraria as a consultant/advisor and/or for lectures from LB Pharma, Otsuka, Lundbeck, Boehringer Ingelheim, LTS Lohmann, Janssen, Johnson&Johnson, TEVA, MSD, Sandoz, SanofiAventis, Angelini, Recordati, Sunovion, Geodon Richter. A. Mucci received honoraria, advisory board or consulting fees from the following companies: Amgen Dompé, Angelini-Acraf, Astra Zeneca, Bristol-Myers Squibb, Gedeon Richter Bulgaria, Innova-Pharma, Janssen Pharmaceuticals, Lundbeck, Otsuka, Pfizer and Pierre Fabre. R. Rodriguez-Jimenez has been a consultant for, spoken in activities of, or received grants from: Instituto de Salud Carlos III, Fondo de Investigación Sanitaria (FIS), Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid Regional Government(S2010/ BMD-2422 AGES), JanssenCilag, Lundbeck, Otsuka, Pfizer, Ferrer, Juste, Takeda, Exeltis, Angelini. All other authors have no conflicts of interest to declare., (Copyright © 2020. Published by Elsevier B.V.)

Structural brain abnormalities and cognitive deficits have been reported in patients with schizophrenia and to a lesser extent in their first-degree relatives (FDRs). Here we investigated whether brain abnormalities in nonpsychotic relatives differ per type of FDR and how these abnormalities are related to intelligent quotient (IQ). Nine hundred eighty individuals from 5 schizophrenia family cohorts (330 FDRs, 432 controls, 218 patients) were included. Effect sizes were calculated to compare brain measures of FDRs and patients with controls, and between each type of FDR. Analyses were repeated with a correction for IQ, having a nonpsychotic diagnosis, and intracranial volume (ICV). FDRs had significantly smaller ICV, surface area, total brain, cortical gray matter, cerebral white matter, cerebellar gray and white matter, thalamus, putamen, amygdala, and accumbens volumes as compared with controls (ds < -0.19, q < 0.05 corrected). Offspring showed the largest effect sizes relative to the other FDRs; however, none of the effects in the different relative types survived correction for multiple comparisons. After IQ correction, all effects disappeared in the FDRs after correction for multiple comparisons. The findings in FDRs were not explained by having a nonpsychotic disorder and were only partly explained by ICV. FDRs show brain abnormalities that are strongly covarying with IQ. On the basis of consistent evidence of genetic overlap between schizophrenia, IQ, and brain measures, we suggest that the brain abnormalities in FDRs are at least partly explained by genes predisposing to both schizophrenia risk and IQ., (© The Author(s) 2018. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Identifying factors that influence the functional outcome is an important goal in schizophrenia research. The 22q11.2 deletion syndrome (22q11DS) is a unique genetic model with high risk (20-25%) for schizophrenia. This study aimed to identify potentially targetable domains of neurocognitive functioning associated with functional outcome in adults with 22q11DS., Methods: We used comprehensive neurocognitive test data available for 99 adults with 22q11DS (n = 43 with schizophrenia) and principal component analysis to derive four domains of neurocognition (Verbal Memory, Visual and Logical Memory, Motor Performance, and Executive Performance). We then investigated the association of these neurocognitive domains with adaptive functioning using Vineland Adaptive Behavior Scales data and a linear regression model that accounted for the effects of schizophrenia status and overall intellectual level., Results: The regression model explained 46.8% of the variance in functional outcome (p &lt; 0.0001). Executive Performance was significantly associated with functional outcome (p = 0.048). Age and schizophrenia were also significant factors. The effects of Executive Performance on functioning did not significantly differ between those with and without psychotic illness., Conclusion: The findings provide the impetus for further studies to examine the potential of directed (early) interventions targeting Executive Performance to improve long-term adaptive functional outcome in individuals with, or at high risk for, schizophrenia. Moreover, the neurocognitive test profiles may benefit caregivers and clinicians by providing insight into the relative strengths and weaknesses of individuals with 22q11DS, with and without psychotic illness.

Background: The sense of self-agency, i.e., experiencing oneself as the cause of one's own actions, is impaired in patients with schizophrenia. Normally, inferences of self-agency are enhanced when actual outcomes match with pre-activated outcome information, where this pre-activation can result from explicitly set goals (i.e., goal-based route) or implicitly primed outcome information (i.e., prime-based route). Previous research suggests that patients show specific impairments in the prime-based route, implicating that they do not rely on matches between implicitly available outcome information and actual action-outcomes when inferring self-agency. The question remains: Why? Here, we examine whether neurocognitive functioning and self-serving bias (SSB) may explain abnormalities in patients' agency inferences., Methods: Thirty-six patients and 36 healthy controls performed a commonly used agency inference task to measure goal- and prime-based self-agency inferences. Neurocognitive functioning was assessed with the Brief Assessment of Cognition in Schizophrenia (BACS) and the SSB was assessed with the Internal Personal and Situational Attributions Questionnaire., Results: Results showed a substantial smaller effect of primed outcome information on agency experiences in patients compared with healthy controls. Whereas patients and controls differed on BACS and marginally on SSB scores, these differences were not related to patients' impairments in prime-based agency inferences., Conclusions: Patients showed impairments in prime-based agency inferences, thereby replicating previous studies. This finding could not be explained by cognitive dysfunction or SSB. Results are discussed in the context of the recent surge to understand and examine deficits in agency experiences in schizophrenia., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Experiencing self-agency over one's own action outcomes is essential for social functioning. Recent research revealed that patients with schizophrenia do not use implicitly available information about their action-outcomes (i.e., prime-based agency inference) to arrive at self-agency experiences. Here, we examined whether this is related to symptoms and/or familial risk to develop the disease. Fifty-four patients, 54 controls, and 19 unaffected (and unrelated) siblings performed an agency inference task, in which experienced agency was measured over action-outcomes that matched or mismatched outcome-primes that were presented before action performance. The Positive and Negative Syndrome Scale (PANSS) and Comprehensive Assessment of Symptoms and History (CASH) were administered to assess psychopathology. Impairments in prime-based inferences did not differ between patients with symptoms of over- and underattribution. However, patients with agency underattribution symptoms reported significantly lower overall self-agency experiences. Siblings displayed stronger prime-based agency inferences than patients, but weaker prime-based inferences than healthy controls. However, these differences were not statistically significant. Findings suggest that impairments in prime-based agency inferences may be a trait characteristic of schizophrenia. Moreover, this study may stimulate further research on the familial basis and the clinical relevance of impairments in implicit agency inferences., (Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.)

Background: Schizophrenia is characterized by positive and negative symptoms, but recently anomalous self-experiences, e.g. exaggerated self-consciousness (hyperreflectivity), receive more attention as an important symptom domain in schizophrenia patients. The semi-structured interview, the Examination of Anomalous Self-Experience (EASE) [Psychopathology 2005;38:236-258], examines experiences of a disturbed sense of self in a sophisticated but time-consuming manner. Therefore, we proposed the Self-Experience Lifetime Frequency scale (SELF), an instrument intended to screen for self-disturbance phenomena. Here we compared scores of patients, their siblings and healthy controls on the SELF. Methods and Sampling: The SELF is composed of a validated screener for symptoms of depersonalization complemented by questions covering several other domains of self-disturbance. A total of 426 patients with a psychotic disorder, 526 of their unaffected siblings, and 297 healthy controls completed the SELF. Patients' scores on the 12 items of the SELF were subjected to an explorative principal axis factor analysis (PAF); composite scores on factor components were compared between the three participant groups., Results: The PAF revealed two components, explaining 43.9 and 9.5% of variance, respectively. The first component represents a disturbance of self-awareness; the second component reflects (milder forms of) diminished self-affection or depersonalization. The two components of the SELF revealed good internal consistency (component 1, α = 0.88; component 2, α = 0.79; x03C1; = 0.85). Patients showed significantly higher scores on both factor components in comparison with both siblings and controls. No significant differences were found between siblings and controls., Conclusions: The findings of the current study suggest that the SELF comprises two components of self-disturbance. Patients reported more (severe) symptoms of self-disturbance on both components, suggesting that it is feasible to screen for self-disturbance phenomena in patients with psychotic disorders with the SELF. Screening for symptoms of self-disturbance is important since these symptoms are associated with suffering and, moreover, these phenomena may mark the transition from intact to aberrant reality testing., (© 2016 S. Karger AG, Basel.)

Phase 1 of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study enrolled a sample of 1493 chronic schizophrenia patients. The European First Episode Schizophrenia Trial (EUFEST) enrolled 498 patients. We have combined these two samples to study the effects of hostility on study discontinuation as well as to examine correlates and predictors of hostility. Individual data from 1154 patients with complete data were used for analyses. Survival analysis demonstrated that higher hostility was associated with earlier all-cause treatment discontinuation. Furthermore, regression analysis indicated that increased hostility was associated with more severe positive symptoms, lower adherence to pharmacological treatment, younger age, impaired insight, and more drug or alcohol consumption. The clinical implications of the results point to the importance of establishing therapeutic alliance while managing patient's symptoms of hostility with antipsychotics such as olanzapine combined with psychosocial interventions to improve insight and reduce substance use., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

Schizophrenia is a chronic psychiatric disorder with a heterogeneous genetic and neurobiological background that influences early brain development, and is expressed as a combination of psychotic symptoms - such as hallucinations, delusions and disorganization - and motivational and cognitive dysfunctions. The mean lifetime prevalence of the disorder is just below 1%, but large regional differences in prevalence rates are evident owing to disparities in urbanicity and patterns of immigration. Although gross brain pathology is not a characteristic of schizophrenia, the disorder involves subtle pathological changes in specific neural cell populations and in cell-cell communication. Schizophrenia, as a cognitive and behavioural disorder, is ultimately about how the brain processes information. Indeed, neuroimaging studies have shown that information processing is functionally abnormal in patients with first-episode and chronic schizophrenia. Although pharmacological treatments for schizophrenia can relieve psychotic symptoms, such drugs generally do not lead to substantial improvements in social, cognitive and occupational functioning. Psychosocial interventions such as cognitive-behavioural therapy, cognitive remediation and supported education and employment have added treatment value, but are inconsistently applied. Given that schizophrenia starts many years before a diagnosis is typically made, the identification of individuals at risk and those in the early phases of the disorder, and the exploration of preventive approaches are crucial.

Corollary discharge (CD) refers to "copies" of motor signals sent to sensory areas, allowing prediction of future sensory states. They enable the putative mechanisms supporting the distinction between self-generated and externally generated sensations. Accordingly, many authors have suggested that disturbed CD engenders psychotic symptoms of schizophrenia, which are characterized by agency distortions. CD also supports perceived visual stability across saccadic eye movements and is used to predict the postsaccadic retinal coordinates of visual stimuli, a process called remapping. We tested whether schizophrenia patients (SZP) show remapping disturbances as evidenced by systematic transsaccadic mislocalizations of visual targets. SZP and healthy controls (HC) performed a task in which a saccadic target disappeared upon saccade initiation and, after a brief delay, reappeared at a horizontally displaced position. HC judged the direction of this displacement accurately, despite spatial errors in saccade landing site, indicating that their comparison of the actual to predicted postsaccadic target location relied on accurate CD. SZP performed worse and relied more on saccade landing site as a proxy for the presaccadic target, consistent with disturbed CD. This remapping failure was strongest in patients with more severe psychotic symptoms, consistent with the theoretical link between disturbed CD and phenomenological experiences in schizophrenia., (Copyright © 2015 the American Physiological Society.)

Importance: Although schizophrenia is characterized by impairments in intelligence and the loss of brain volume, the relationship between changes in IQ and brain measures is not clear., Objective: To investigate the association between IQ and brain measures in patients with schizophrenia across time., Design, Setting, and Participants: Case-control longitudinal study at the Department of Psychiatry at the University Medical Center Utrecht, Utrecht, the Netherlands, comparing patients with schizophrenia and healthy control participants between September 22, 2004, and April 17, 2008. Magnetic resonance imaging of the brain and IQ scores were obtained at baseline and the 3-year follow-up. Participants included 84 patients with schizophrenia (mean illness duration, 4.35 years) and 116 age-matched healthy control participants., Main Outcomes and Measures: Associations between changes in IQ and the total brain, cerebral gray matter, cerebral white matter, lateral ventricular, third ventricles, cortical, and subcortical volumes; cortical thickness; and cortical surface area., Results: Cerebral gray matter volume (P = .006) and cortical volume (P = .03) and thickness (P = .02) decreased more in patients with schizophrenia across time compared with control participants. Patients showed additional loss in cortical volume and thickness of the right supramarginal, posterior superior temporal, left supramarginal, left postcentral, and occipital regions (P values were between <.001 and .03 after clusterwise correction). Although IQ increased similarly in patients with schizophrenia and control participants, changes in IQ were negatively correlated with changes in lateral ventricular volume (P = .05) and positively correlated with changes in cortical volume (P = .007) and thickness (P = .004) only in patients with schizophrenia. Positive correlations between changes in IQ and cortical volume and thickness were found globally and in widespread regions across frontal, temporal, and parietal cortices (P values were between <.001 and .03 after clusterwise correction). These findings were independent of symptom severity at follow-up, cannabis use, and the use of cumulative antipsychotic medications during the 3 years of follow-up., Conclusions and Relevance: Progressive brain tissue loss in schizophrenia is related to relative cognitive decline during the early course of illness.

Background: Substantial evidence exists about emotion processing (EP) impairments in schizophrenia patients. However, whether these deficits are present primarily during psychosis (i.e., state dependent) or an integral part of the disorder (i.e., trait dependent) remains unclear., Methods: EP was assessed with the degraded facial affect recognition task in schizophrenia patients (N=521) and healthy controls (N=312) at baseline (T1) and after a three year follow-up (T2). In schizophrenia patients symptomatic remission was assessed with the Positive and Negative Syndrome Scale (PANSS) remission tool. Patients were divided into four groups: remission T1 and remission T2 (RR); remission T1 and non-remission T2 (RN); non-remission T1 and non-remission T2 (NN) and non-remission T1 and remission T2 (NR). Factorial repeated measures ANCOVA was used to compare EP performance over time between groups. Age, gender and general cognition were included as covariates., Results: Schizophrenia patients performed worse than healthy controls on EP at T1 (p=0.001). The patients that were in symptomatic remission at both time points (the RR group) performed worse than the healthy controls at T2 (p<0.001). Significant group×time interactions were found between RR and RN (p=0.001), and between NR and RN (p=0.04), indicating a differential EP performance over time. No group×time interaction was found between NN and NR., Conclusion: The results show relatively poor EP performance in schizophrenia patients compared to healthy controls. EP performance in schizophrenia patients was associated with symptomatic remission. The results provide support for the hypothesis that EP deficits in schizophrenia are both state and trait dependent., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Schizophrenia is a psychiatric disorder that is associated with impaired functioning of the fronto-striatal network, in particular during reward processing. However, it is unclear whether this dysfunction is related to the illness itself or whether it reflects a genetic vulnerability to develop schizophrenia. Here, we examined reward processing in unaffected siblings of schizophrenia patients using functional magnetic resonance imaging. Brain activity was measured during reward anticipation and reward outcome in 27 unaffected siblings of schizophrenia patients and 29 healthy volunteers using a modified monetary incentive delay task. Task performance was manipulated online so that all subjects won the same amount of money. Despite equal performance, siblings showed reduced activation in the ventral striatum, insula, and supplementary motor area (SMA) during reward anticipation compared to controls. Decreased ventral striatal activation in siblings was correlated with sub-clinical negative symptoms. During the outcome of reward, siblings showed increased activation in the ventral striatum and orbitofrontal cortex compared to controls. Our finding of decreased activity in the ventral striatum during reward anticipation and increased activity in this region during receiving reward may indicate impaired cue processing in siblings. This is consistent with the notion of dopamine dysfunction typically associated with schizophrenia. Since unaffected siblings share on average 50% of their genes with their ill relatives, these deficits may be related to the genetic vulnerability for schizophrenia., (© The Author 2014. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Impaired working memory (WM) is a hallmark of schizophrenia. In addition to classical WM regions such as the dorsolateral prefrontal cortex (DLPFC) and the striatum, dysfunctions in the default-mode network (DMN) contribute to these WM deficits. Unaffected siblings of patients also show WM impairments. However, the nature of the functional deficits underlying these impairments is unclear, mainly because of impaired performance confounding neuroimaging results., Methods: Here, we investigated WM and DMN activity in 23 unaffected siblings of schizophrenia patients and 24 healthy volunteers using fMRI and a Sternberg WM task. WM load was determined prior to scanning to ensure 90% accuracy for all subjects., Results: Siblings showed hyperactivation during the encoding phase of WM in the right medial prefrontal cortex (MPFC) which is the anterior part of the DMN. No differences were found during the maintenance phase. During the retrieval phase, siblings showed hyperactivation in WM regions: DLPFC, inferior parietal cortex and the striatum. Siblings who showed hyperactivity in the MPFC during encoding showed DLPFC and striatum hyperactivation during retrieval., Conclusions: Our finding of hyperactivation in WM and DMN areas indicates that siblings fail to adequately inhibit DMN activity during demanding cognitive tasks and subsequently hyperactivate WM areas. This failure may reflect dopamine hyperactivity in the striatum which prevents adequate DMN suppression needed for effective WM. This study provides support for the notion that aberrant WM and DMN activation patterns may represent candidate endophenotypes for schizophrenia., (© 2013 Elsevier B.V. All rights reserved.)

Schizophrenia is currently classified as a psychotic disorder. This article posits that this emphasis on psychosis is a conceptual fallacy that has greatly contributed to the lack of progress in our understanding of this illness and hence has hampered the development of adequate treatments. Not only have cognitive and intellectual underperformance consistently been shown to be risk factors for schizophrenia, several studies have found that a decline in cognitive functioning precedes the onset of psychosis by almost a decade. Although the question of whether cognitive function continues to decline after psychosis onset is still debated, it is clear that cognitive function in schizophrenia is related to outcome and little influenced by antipsychotic treatment. Thus, our focus on defining (and preventing) the disorder on the basis of psychotic symptoms may be too narrow. Not only should cognition be recognized as the core component of the disorder, our diagnostic efforts should emphasize the changes in cognitive function that occur earlier in development. Putting the focus back on cognition may facilitate finding treatments for the illness before psychosis ever emerges.

Objective: The objective of this multicenter randomised clinical trial was to examine the effect of exercise versus occupational therapy on mental and physical health in schizophrenia patients., Method: Sixty-three patients with schizophrenia were randomly assigned to 2 h of structured exercise (n = 31) or occupational therapy (n = 32) weekly for 6 months. Symptoms (Positive and Negative Syndrome Scale) and cardiovascular fitness levels (Wpeak and VO2peak ), as assessed with a cardiopulmonary exercise test, were the primary outcome measures. Secondary outcome measures were the Montgomery and Åsberg Depression Rating Scale, Camberwell Assessment of Needs, body mass index, body fat percentage, and metabolic syndrome (MetS)., Results: Intention-to-treat analyses showed exercise therapy had a trend-level effect on depressive symptoms (P = 0.07) and a significant effect on cardiovascular fitness, measured by Wpeak (P < 0.01), compared with occupational therapy. Per protocol analyses showed that exercise therapy reduced symptoms of schizophrenia (P = 0.001), depression (P = 0.012), need of care (P = 0.050), and increased cardiovascular fitness (P < 0.001) compared with occupational therapy. No effect for MetS (factors) was found except a trend reduction in triglycerides (P = 0.08)., Conclusion: Exercise therapy, when performed once to twice a week, improved mental health and cardiovascular fitness and reduced need of care in patients with schizophrenia., (© 2012 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Unlabelled: Studies and meta-analyses investigating the influence of substance use disorder (SUD) (substance abuse or dependence) on psychopathology and neurocognitive function in schizophrenia patients have revealed controversial results. Most studies did only have small samples and did not focus exclusively on first-episode schizophrenia patients., Method: In a post-hoc analysis of the European First Episode Schizophrenia Trial (EUFEST) psychopathology and cognitive performances of patients with (FE-SUD, N=119, consisting of N=88 patients with persisting SUD at baseline and N=31 patients with previous SUD) and without SUD (FE-non-SUD, N=204) were compared at baseline and 6 months follow-up. Neurocognitive assessment included the Rey Auditory Verbal Learning Test (RAVLT); Trail Making Tests A and B (TMT), Purdue Pegboard and Digit-Symbol Coding., Results: In total 31.1% of patients reported SUD, and 22.2% of patients used cannabis. There were no significant differences between patients with and without SUD concerning PANSS scores, extrapyramidal motor symptoms or neurocognitive measures except better performance in psychomotor speed (TMT-A, p=0.033, Cohen's d=0.26) in patients with SUD at 6 months follow-up. Interestingly, SUD patients with ongoing substance use at follow-up showed elevated positive symptoms (PANSS positive score, p=0.008, Cohen's d=0.84) compared to those who abstained. PANSS scores at baseline were increased in patients with an onset of SUD before the age of 16 years. In addition we found a correlation between longer duration of cannabis use and higher cognitive performance as well as reduced symptom improvement and more extrapyramidal motor symptoms in patients with higher frequency of cannabis consumption., Conclusions: FE-SUD and FE-non-SUD show similar psychopathology and neuropsychological performances at baseline and during the first 6 months of antipsychotic treatment., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Background: Cognitive deficits have been recognized as a key feature of schizophrenia, since the first description by Kraepelin. Specifically, lower intelligence is considered a core feature of the disorder and may represent a risk factor for its development. However, whether global intelligence decreases over time in schizophrenia is not known. The aims of this quantitative meta-analysis are to gather, integrate and estimate the overall mean effect size of IQ change over time in schizophrenia as compared to healthy individuals., Methods: A systematic search was conducted to identify relevant studies. Longitudinal studies with at least two intelligence assessments in schizophrenia cohorts were retrieved. Studies had to report sufficient data on IQ-change and include data from healthy comparisons for computation of effect sizes. For each study, the Cohen d was calculated as well as a combined mean effect size., Results: Fourteen studies were identified. Eight studies with a total of 280 patients and 306 healthy controls were suitable to be included. The mean weighted baseline IQ was 97.20 for patients and 109.26 for controls. The mean weighted IQ-change per year was +0.33 for patients and +2.08 for controls. The combined effect size was Cohen's d = -0.48, p = 0.01., Conclusions: A global cognitive deficit is present in patients with schizophrenia expressed as a lower test score increase over repeated testing as compared to healthy subjects possibly due to the lack of practice effects in patients. Thus, schizophrenia is characterized by a relative lack of gain in global cognitive abilities over time., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Negative symptoms that do not improve following antipsychotic treatment represent a challenge for development of effective treatments. Few studies have been carried out so far, especially in first-episode schizophrenia patients, to clarify prevalence, correlates and impact of persistent negative symptoms (PNS) on short- and long-term outcome of the disease. All patients from EUFEST study for whom both baseline and 12-month assessments were available were included (N=345). PNS were defined as the presence of at least one negative symptom of moderate or higher severity, not confounded by depression or parkinsonism, at baseline and after 1 year of treatment. Patients with PNS were compared to those with at least one negative symptom of moderate or higher severity at the baseline, not persisting after 1 year, on demographic, clinical, neurocognitive, global functioning and quality of life measures. PNS not confounded by depression or parkinsonism were present in 6.7% of the sample. The symptom that more often persisted was blunted affect. Patients with PNS differed from those without PNS for a longer duration of untreated psychosis (DUP) and a more frequent discontinuation of study treatment; they also had a poorer psychopathological outcome and a worse global functioning after 1 year of treatment. The presence of PNS was associated to poorer improvement of all psychopathological dimensions and worse global functioning after 1 year of treatment. The longer DUP in subjects with PNS suggests that programs aimed at shortening DUP might reduce the prevalence of PNS and improve prognosis of schizophrenia., (Copyright © 2012 Elsevier B.V. and ECNP. All rights reserved.)

Background: People usually feel they cause their own actions and the consequences of those actions, i.e., they attribute behavior to the proper agent. Research suggests that there are two routes to the experience of self-agency: 1) an explicit route, where one has the intention to obtain a goal (if it occurs, I must have done it) and 2) an implicit route, where information about the goal is unconsciously available and increases the feeling of self-agency. Schizophrenia patients typically experience no behavioral control and exhibit difficulties in distinguishing one's own actions from those of others. The present study investigates differences in both routes to self-agency experiences between schizophrenia patients and controls., Methods: Twenty-three schizophrenia patients and 23 controls performed a task where they performed an action (button press) and subsequently indicated whether or not they were the agent of the consequence of this action (the outcome) on a 9-point scale. The task can be manipulated to measure both the explicit and implicit route (by using priming) to the experience of self-agency., Results: In the explicit condition (participants intended to produce a specific outcome, and this outcome matched their goal), both groups experienced enhanced self-agency. In the implicit condition (the outcome matched the primed outcome), healthy controls showed increased self-agency over the outcome, while patients did not. Potential differences in task motivation and attention did not explain these findings., Conclusions: These findings provide new evidence for the idea that implicit processes leading to feelings of self-agency may be disturbed in schizophrenia., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background: Intellectual deficits are commonly found in schizophrenia patients. These intellectual deficits have been found to be heritable. However, whether the intellectual deficits change over time and, if so, whether the change is related with an increased genetic risk for the disease are not known., Method: We investigated change of intelligence quotient (IQ) in a twin sample of chronically ill schizophrenia patients, the discordant co-twins and healthy controls during a follow-up period of 5 years. A total of 52 twins completed two IQ assessments: nine patients [three monozygotic (MZ) and six dizygotic (DZ)], 10 unaffected co-twins (three MZ and seven DZ) and 33 healthy control twins (21 MZ and 12 DZ)., Results: A significant interaction effect over time was found between IQ measurement and illness (F=4.22, df=1, p<0.05), indicating that change in IQ over time is significantly different between the groups. A stable course in IQ over time was found in the patients with schizophrenia (mean IQ from 109.78 at baseline to 108.44 at follow-up) relative to both the healthy control twins who showed a small increase (from 114.61 at baseline to 119.18 at follow-up) (t=2.06, p<0.05) and the unaffected co-twins (from 111.60 to 117.60, t=-2.32, p<0.05). IQ change in the unaffected co-twins of schizophrenia patients was comparable with that in healthy control twins (t=-0.49, p=0.63)., Conclusions: Patients with schizophrenia in the chronic phase of the disease, but not the discordant co-twins, show a lack of increase in IQ, which is probably due to environmental (non-genetic) factors related to the disease.

Background: Hallucinations have consistently been associated with traumatic experiences during childhood. This association appears strongest between physical and sexual abuse and auditory verbal hallucinations (AVH). It remains unclear whether traumatic experiences mainly colour the content of AVH or whether childhood trauma triggers the vulnerability to experience hallucinations in general. In order to investigate the association between hallucinations, childhood trauma and the emotional content of hallucinations, experienced trauma and phenomenology of AVH were investigated in non-psychotic individuals and in patients with a psychotic disorder who hear voices., Method: A total of 127 non-psychotic individuals with frequent AVH, 124 healthy controls and 100 psychotic patients with AVH were assessed for childhood trauma. Prevalence of childhood trauma was compared between groups and the relation between characteristics of voices, especially emotional valence of content, and childhood trauma was investigated., Results: Both non-psychotic individuals with AVH and patients with a psychotic disorder and AVH experienced more sexual and emotional abuse compared with the healthy controls. No difference in the prevalence of traumatic experiences could be observed between the two groups experiencing AVH. In addition, no type of childhood trauma could distinguish between positive or negative emotional valence of the voices and associated distress. No correlations were found between sexual abuse and emotional abuse and other AVH characteristics., Conclusions: These results suggest that sexual and emotional trauma during childhood render a person more vulnerable to experience AVH in general, which can be either positive voices without associated distress or negative voices as part of a psychotic disorder.

Background: There is considerable variation in progressive brain volume changes in schizophrenia. Whether this is related to the clinical heterogeneity that characterizes the illness remains to be determined. This study examines the relationship between change in brain volume over time and individual variation in psychopathology, as measured by five continuous symptom dimensions (i.e. negative, positive, disorganization, mania and depression)., Methods: Global brain volume measurements from 105 schizophrenia patients and 100 healthy comparison subjects, obtained at inclusion and 5-year follow-up, were used in this study. Symptom dimension scores were calculated by factor analysis of clinical symptoms. Using linear regression analyses and independent-samples t-tests, the relationship between symptom dimensions and progressive brain volume changes, corrected for age, gender and intracranial volume, was examined. Antipsychotic medication, outcome and IQ were investigated as potential confounders., Results: In patients, the disorganization dimension was associated with change in total brain (β=-0.295, p=0.003) and cerebellar (β=-0.349, p<0.001) volume. Furthermore, higher levels of disorganization were associated with lower IQ, irrespective of psychiatric status (i.e. patient or control). In healthy comparison subjects, disorganization score was not associated with progressive brain volume changes., Conclusion: Heterogeneity in progressive brain volume changes in schizophrenia is particularly associated with variation in disorganization. Schizophrenia patients with high levels of disorganization exhibit more progressive decrease of global brain volumes and have lower total IQ. We propose that these patients form a phenotypically and biologically homogenous subgroup that may be useful for etiological (e.g., genetic) studies., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background: This study aimed to identify the course of unmet needs by patients with a first episode of schizophrenia and to determine associated variables., Method: We investigated baseline assessments in the European First Episode Schizophrenia Trial (EUFEST) and also follow-up interviews at 6 and 12 months. Latent class growth analysis was used to identify patient groups based on individual differences in the development of unmet needs. Multinomial logistic regression determined the predictors of group membership., Results: Four classes were identified. Three differed in their baseline levels of unmet needs whereas the fourth had a marked decrease in such needs. Main predictors of class membership were prognosis and depression at baseline, and the quality of life and psychosocial intervention at follow-up. Depression at follow-up did not vary among classes., Conclusions: We identified subtypes of patients with different courses of unmet needs. Prognosis of clinical improvement was a better predictor for the decline in unmet needs than was psychopathology. Needs concerning social relationships were particularly persistent in patients who remained high in their unmet needs and who lacked additional psychosocial treatment.

Background: Findings on the impact of cannabis use on the course of schizophrenia are inconsistent and not conclusive., Aims: To study the effect of cannabis use on the course of schizophrenia taking into account the effects of the quantity of cannabis use and important confounders., Methods: Prospective cohort study with assessments of symptoms, confounders and hospitalizations at baseline, 6 month and 12 month follow up., Results: In a representative cohort of 145 male patients with schizophrenia, 68 (46.9%) used cannabis. Mean age at onset of schizophrenia in cannabis using patients was significantly lower than in non-cannabis using patients. No other cross-sectional demographic or clinical differences were observed between users and non-users. In a series of longitudinal analyses, cannabis use was not associated with differences in psychopathology, but relapse in terms of the number of hospitalizations was significantly higher in cannabis using patients compared to non-cannabis using patients., Conclusions: Patients with schizophrenia using cannabis are more frequently hospitalized than non-cannabis using patients but do not differ with respect to psychopathology. Possible explanations for these findings are discussed., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Context: The nosologic dichotomy between schizophrenia and bipolar disorder (BD) as formulated by Kraepelin is currently being questioned, stimulated by the finding that schizophrenia and BD partly share a common genetic origin. Although both disorders are characterized by changes in brain structure, family studies suggest more segregating than overlapping neuroanatomical abnormalities in both disorders., Objectives: To investigate whether patients with schizophrenia and patients with BD display overlapping abnormalities in brain volumes and cortical thickness and whether these are caused by shared genetic or environmental influences., Design: Magnetic resonance imaging findings of monozygotic (MZ) and dizygotic (DZ) twin pairs discordant for schizophrenia, twin pairs concordant and discordant for BD, and healthy twin pairs were compared using structural equation modeling., Setting: The Netherlands Twin Register and University Medical Center Utrecht., Participants: A total of 310 individuals from 158 (152 complete and 6 incomplete) twin pairs were included: 26 pairs discordant for schizophrenia (13 MZ and 13 DZ), 49 pairs with BD (9 MZ and 4 DZ concordant; 14 MZ and 22 DZ discordant), and 83 healthy twin pairs (44 MZ and 39 DZ)., Main Outcome Measures: Estimates of additive genetic and unique environmental associations between schizophrenia and BD with overlapping and nonoverlapping volumes and cortical thickness., Results: Higher genetic liabilities for schizophrenia and BD were associated with smaller white matter volume, thinner right (and left) parahippocampus, thinner right orbitofrontal cortex, and thicker temporoparietal and left superior motor cortices; higher environmental liabilities were associated with thinner right medial occipital cortex. Genetic liability for schizophrenia was associated with thicker right parietal cortex; for BD, with larger intracranial volume., Conclusions: Brain structures reflect overlapping and segregating genetic liabilities for schizophrenia and BD. The overlapping smaller white matter volume and common areas of thinner cortex suggest that both disorders share genetic (neurodevelopmental) roots.

The interrelation between needs for care and quality of life has been described and replicated by several studies. The present work aims to add to the understanding of longitudinal interrelations between needs for care, quality of life, and other outcome measures by analyzing a sample of patients at the onset of schizophrenia. This study relied on data from the EUFEST trial, designed to compare first- and second-generation antipsychotics during 1 year. At baseline, 498 patients have been included. The first (baseline) and the last assessment (12 months after baseline) were used for the analyses. Predictors of quality of life were determined using regression analyses. We tested the complex longitudinal interrelations between baseline and outcome measures with structural equation models. Unmet needs were not definitively confirmed as a predictor of subsequent quality of life, unless unmet needs changing to no needs were separated from unmet needs changing to met needs. Each unmet need that changed to no need enhanced the quality of life (mean score 1-7) by 0.136 scale points. This study suggests that when studying quality of life and needs for treatment, it is crucial to differentiate whether unmet needs disappeared or whether they were met, as the former has a stronger impact on quality of life.

Objective: To compare the effects of haloperidol, amisulpride, olanzapine, quetiapine, and ziprasidone on hostility in first-episode schizophrenia, schizoaffective disorder, or schizophreniform disorder., Method: We used the data acquired in the European First-Episode Schizophrenia Trial, an open, randomized trial (conducted in 14 countries) comparing 5 antipsychotic drugs in 498 patients aged 18-40 years with first-episode schizophrenia, schizoaffective disorder, or schizophreniform disorder. DSM-IV diagnostic criteria were used. Patients were assessed between December 23, 2002 and January 14, 2006. Most subjects joined the study as inpatients and then continued with follow-ups in outpatient clinic visits. The Positive and Negative Syndrome Scale (PANSS) was administered at baseline and at 1, 3, 6, 9, and 12 months after randomization. We analyzed the scores on the PANSS hostility item in a subset of 302 patients showing at least minimal hostility (a score > 1) at baseline. We hypothesized (1) that the treatments would differ in their efficacy for hostility and (2) that olanzapine would be superior to haloperidol. Our primary statistical analysis tested the null hypothesis of no difference among the treatment groups in change in hostility over time. Secondary analysis addressed the question of whether the effects on hostility found in the primary analysis were specific to this item. All our analyses were post hoc., Results: The primary analysis of hostility indicated an effect of differences between treatments (F(4,889) = 4.02, P = .0031). Post hoc treatment-group contrasts for hostility change showed that, at months 1 and 3, olanzapine was significantly superior (P < .05) to haloperidol, quetiapine, and amisulpride in reducing hostility. Secondary analyses demonstrated that these results were at least partly specific to hostility., Conclusions: Both hypotheses were supported. Olanzapine appears to be a superior treatment for hostility in early phases of therapy for first-episode schizophrenia, schizoaffective disorder, and schizophreniform disorder. This efficacy advantage of olanzapine must be weighed against its adverse metabolic effects and propensity to cause weight gain., Trial Registration: ISRCTN Register Identifier: ISRCTN68736636., (© Copyright 2011 Physicians Postgraduate Press, Inc.)

Background: Schizophrenia is characterized by impaired social cognition, including emotion processing. Behavioral studies have reported impaired performance on various emotion processing tasks, and imaging studies in patients have observed aberrant activity within the underlying neural circuitry. Also, subjects at increased genetic risk of developing schizophrenia, including unaffected siblings of patients, show behavioral impairments in emotion processing. It is unclear, however, whether and how the underlying neural system is disrupted in these subjects. In this study, we investigated whether siblings of patients with schizophrenia show abnormal brain activation during basic emotion processing., Methods: Brain activity was measured using functional magnetic resonance imaging in 24 unaffected siblings of patients with schizophrenia and 25 healthy control subjects while they viewed and rated neutral, positive, and negative pictures. None of the subjects had a psychiatric disorder, and the two groups did not differ in age, gender, or level of own, paternal, or maternal education., Results: Compared with control subjects, siblings showed increased activity within the amygdala, hippocampus, medial prefrontal cortex, posterior and anterior cingulate cortex, and middle temporal gyrus in response to emotionally arousing pictures relative to neutral pictures. No activation differences between the groups were found during the neutral stimuli, indicating that the observed hyperactivity is likely caused by abnormal emotion processing rather than impaired visuoattentional processing., Conclusions: Our findings of hyperactivity in siblings during emotion processing suggest that functional abnormalities within the neural circuitry of emotion processing are related to the genetic risk for developing schizophrenia., (Copyright © 2011 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Sexual dysfunctions (SDs) occur frequently in schizophrenia patients and have a huge impact on quality of life and compliance. They are often associated with antipsychotic medication. Nicotine consumption, negative or depressive symptoms, and physical illness are also discussed as contributing factors. Data on SD in first-episode schizophrenia patients are scarce.As part of the European First Episode Schizophrenia Trial, first-episode schizophrenia patients were randomly assigned to 5 medication groups. We assessed SD by analyzing selected items from the Udvalg for Kliniske Undersugelser at baseline and at 5 following visits.Differences between antipsychotics were small for all SDs, and fairly little change in the prevalence of SDs was seen over the course of the study. A significantly larger increase of amenorrhea and galactorrhea was seen with amisulpride than with the other medications. In men, higher age, more pronounced Positive and Negative Syndrome Scale general psychopathology symptoms, and higher plasma prolactin levels predicted higher rates of erectile and ejaculatory dysfunctions. Positive and Negative Syndrome Scale negative symptoms and higher age were predictors for decreased libido.In women, higher prolactin plasma levels were identified as a predictor of amenorrhea. Positive and Negative Syndrome Scale negative symptoms predicted decreased libido.All evidence taken together underscores the influence of the disease schizophrenia itself on sexual functioning. In addition, there is a strong correlation between the prolactin-increasing properties of amisulpride and menstrual irregularities.

Objective: The ability to use the gaze direction of another person to guide attention is important for social functioning, but behavioral reports on this topic among individuals with schizophrenia are inconclusive. Event Related Potentials (ERPs) can very accurately pinpoint the shifting of attention, and can therefore shed more light on cueing abilities in schizophrenia., Methods: ERPs were measured during two spatial attention tasks in 14 high-functioning, young adult schizophrenic individuals and 19 age- and IQ-matched controls. In one task neutral faces were used as cues, and in the other arrows., Results: Speeded behavioral and ERP responses were found to validly cued targets compared with responses to invalidly cued targets in both groups. However, we found more prolonged cueing effects in the patient group in later stages of processing, indicated by enhanced validity effects of late ERP latencies to gaze cues but not to arrow cues., Conclusions: Our study provides evidence for normal attentional orienting at behavioral level and early cognitive processing, but more prolonged cognitive evaluation of gaze cues in young adults with schizophrenia., Significance: Evidence from this study excludes a specific attentional orienting deficit from being a possible endophenotype for the disorder., (Copyright © 2010 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

Introduction: Head-to-head comparisons of antipsychotics have predominantly included patients with chronic conditions. The aim of the present study was to compare the efficacy and tolerability of ziprasidone and olanzapine in patients with recent-onset schizophrenia., Methods: The study was an 8-week, double-blind, parallel-group, randomized, controlled multicenter trial (NCT00145444). Seventy-six patients with schizophreniform disorder, schizophrenia or schizoaffective disorder (diagnosis < 5 y), and a maximum lifetime antipsychotic treatment < 16 weeks participated in the study. Efficacy of ziprasidone (80-160 mg/d) and olanzapine 10-20 mg was measured using the Positive and Negative Syndrome Scale (PANSS), the Clinical Global Impression (CGI) Scale, the Calgary Depression Scale for Schizophrenia (CDSS), and the Heinrich Quality of Life Scale (HQLS); tolerability assessments included laboratory assessments, body weight, and electroencephalogram., Results: Olanzapine (n = 34) and ziprasidone (n = 39) showed equal efficacy as measured by the PANSS, CDSS, CGI, and HQLS. However, mean weight gain was significantly higher in the olanzapine group (6.8 vs 0.1 kg, P < .001). Ziprasidone was associated with decreasing levels of triglycerides, cholesterol, and transaminases, while these parameters increased in the olanzapine group (all P values < .05). There were no significant differences in fasting glucose and prolactin levels or in cardiac or sexual side effects. Patients on ziprasidone used biperiden for extrapyramidal side effects more frequently (P < .05)., Discussion: The results of this study indicate that ziprasidone and olanzapine have comparable therapeutic efficacy but differ in their side effect profile. However, there is a risk of a type II error with this sample size. Clinically significant weight gain and laboratory abnormalities appear early after initiating treatment and are more prominent with olanzapine, while more patients on ziprasidone received anticholinergic drugs to treat extrapyramidal symptoms.

Introduction: To enhance functional outcome in schizophrenia improvement of cognitive symptoms is crucial., Experimental Procedures: Using a comprehensive test battery, this follow-up examines cognitive effects in patients with recent-onset schizophrenia after a change of medication following insufficient clinical response and intolerance., Results: After eight weeks cognitive outcomes had not improved in the patients having switched from olanzapine to ziprasidone (n=11; mean dose 136 mg) nor in those having switched from ziprasidone to olanzapine (n=10; mean 16 mg), while the symptoms of patients maintaining olanzapine (n=18; mean 10.9 mg) or ziprasidone (n=18; mean 88.9 mg) treatment had not improved further., Discussion: The findings suggest that also in early-stage schizophrenia the antipsychotics tested affect cognitive symptoms similarly., (Copyright © 2010 Elsevier B.V. and ECNP. All rights reserved.)

It is unknown whether the reported brain loss in schizophrenia can be attributed to the effects of tobacco smoking. 96 Patients (54 smokers/42 non-smokers) and 113 control subjects (35/78) were included in a 5-year longitudinal MRI study. Despite the higher prevalence of smoking behavior and the higher number of cigarettes consumed per day in the patients, cigarette smoking did not explain the excessive cerebral (gray matter) volume decreases in the patients. Moreover, smoking was not associated with brain volume change over time in the healthy subjects. However, extremely heavy smoking may contribute to excessive gray matter volume loss in schizophrenia., (Copyright 2010 Elsevier B.V. and ECNP. Published by Elsevier B.V. All rights reserved.)

Background: In the pathophysiology of schizophrenia, aberrant connectivity between brain regions may be a central feature. Diffusion tensor imaging (DTI) studies have shown altered fractional anisotropy (FA) in white brain matter in schizophrenia. Focal reductions in myelin have been suggested in patients using magnetization transfer ratio (MTR) imaging but to what extent schizophrenia may be related to changes in MTR measured along entire fiber bundles is still unknown., Methods: DTI and MTR images were acquired with a 1.5-T scanner in 40 schizophrenia patients and compared with those of 40 healthy participants. The mean FA and mean MTR were measured along the genu of the corpus callosum and the left and right uncinate fasciculus., Results: A higher mean MTR of 1% was found in the right uncinate fasciculus in patients compared with healthy participants. A significant negative correlation between age and mean FA in the left uncinate fasciculus was found in schizophrenia patients but not in healthy participants., Conclusions: Decreased FA in the left uncinate fasciculus may be more prominent in patients with longer illness duration. The increased mean MTR in the right uncinate fasciculus could reflect a compensatory role for myelin in these fibers or possibly represent aberrant frontotemporal connectivity.

Effectiveness has become more and more important as a comprehensive outcome measure for (long-term) treatment in schizophrenia. Early predictors to identify patients at a high risk for not succeeding the initiated treatment would be very useful. Discontinuation of the initiated treatment was used as criterion for effectiveness and patients' drug attitude was shown to be predictive for non-adherence or discontinuation of long-term treatment in schizophrenia. Accordingly, the predictive validity of the Drug Attitude Inventory (DAI) for effectiveness should be evaluated. Based on a sub-sample of patients from the EUFEST study for whom DAI assessments were available significant predictors for effectiveness as measured by discontinuation of initiated treatment were identified based on a logistic and a Cox-regression analysis. A Receiver-Operating Characteristic- (ROC-) analysis was conducted for the DAI, prognostic / diagnostic parameters (sensitivity, specificity) were calculated and a cut-off value suggested. In a sample of 228 first-episode patients, the DAI score was the most powerful predictor for effectiveness (p<0.001) besides two other significant predictors (PANSS-positive score and sexual side effects). The ROC-analysis revealed an area under the curve of 0.64 (p<0.001). The suggested cut-off point of about 20 yielded a sensitivity of 70-75% and a specificity of 40-45%. Study results indicate that the Drug Attitude Inventory, filled in by patients early in treatment seems to be a valid predictor for effectiveness as measured by discontinuation of the initiated treatment. DAI scores could also serve as an (differential) indicator for the need of enhanced treatment monitoring. These findings have to be validated in other (first-episode) samples., (2010 Elsevier B.V. and ECNP. All rights reserved.)

Genetic association studies have yielded extensive but frequently inconclusive data about genetic risk factors for schizophrenia. Clinical and genetic heterogeneity are possible factors explaining the inconsistent findings. The objective of this study was to test the association of commonly incriminated candidate genes with two clinically divergent subgroups, non-deficit (SZ-ND) and deficit-schizophrenia (SZ-D), and symptom severity, in order to test for replication of previously reported results. A homogeneous sample of 280 schizophrenia patients and 230 healthy controls of Hungarian, Caucasian descent were genotyped for polymorphisms in schizophrenia candidate genes NRG1, DTNBP1, RGS4, G72/G30, and PIP5K2A. Patients were divided into the diagnostic subgroups of SZ-ND and SZ-D using the Schedule for Deficit Syndrome (SDS), and assessed clinically by the Positive and Negative Symptom Scale (PANSS). SNP8NRG241930 in NRG1 and rs1011313 in DTNBP1 were associated with SZ-ND (P = 0.04 and 0.03, respectively). Polymorphisms in RGS4, G72/G30, and PIP5K2A were neither associated with SZ-ND nor with SZ-D. SNP8NRG241930 showed association with the PANSS cognitive and hostility/excitability factors, rs1011313 with the negative factor and SDS total score, and rs10917670 in RGS4 was associated with the depression factor. Although these results replicate earlier findings about the genetic background of SZ-ND and SZ-D only partially, our data seem to confirm previously reported association of NRG1 with schizophrenia without prominent negative symptoms. It was possible to detect associations of small-to-medium effect size between the investigated candidate genes and symptom severity. Such studies have the potential to unravel the possible connection between genetic and clinical heterogeneity in schizophrenia.

Background: Profile and correlates of cognitive deficits in first episode (FE) schizophrenia patients are still debated. The present study is aimed to clarify in a large sample of FE patients the extent of impairment in key cognitive domains and its relationships with demographic and clinical variables., Method: The European First Episode Schizophrenia Trial collected demographic, clinical and neurocognitive baseline data in 498 FE patients with minimal or no prior exposure to antipsychotics. Two-hundred-twenty healthy subjects (HS) were also evaluated. Neurocognitive assessment included the Rey Auditory Verbal Learning Test; Trail Making A and B, Purdue Pegboard and Digit-Symbol Coding., Results: Patients performed worse than HS on all tests (effect sizes from -0.88 to -1.73). Correlations with psychopathological dimensions were weak and involved reality distortion and disorganization. The duration of untreated psychosis (DUP) was not associated with cognitive impairment. Subjects living alone had a better neurocognitive performance, while the occupation status did not reveal any association with cognition., Conclusions: A moderate/severe impairment of processing speed, motor dexterity, verbal memory and cognitive flexibility was found in the largest sample of FE patients analyzed so far. The impairment was largely independent from psychopathology and not associated with DUP.

Background: Recent studies have shown that schizophrenia is characterized by visual perceptual deficits, especially in the ability to integrate stimulus details into a global percept. Also, several studies have found amplitude attenuation of the visual P1 component of the event-related brain potential (ERP), probably indicating impaired visual feedforward processing in schizophrenia. However, there is little knowledge on the role of feedbackward processing in this group. This question is of importance, as recent studies indicate that feedback processing is critical in stimulus integration., Methods: In the present study we tested whether there is evidence for atypical recurrent processing in a group of 14 young adults with recent-onset schizophrenia (mean age 21.7 years, mean TIQ 92.7) and 17 age and IQ matched control subjects, all males. To achieve this aim, we used a texture segregation task and measured ERP activity concurrently., Results: We found normal amplitudes, but longer latencies of activity related to feedbackward processing in the schizophrenia group. In addition, we found enhanced occipito-temporal activity around 160 ms that is probably the reflection of increased detail processing., Discussion: We show for the first time evidence for abnormal timing in feedback activity related to visual perception in subjects with schizophrenia. It is hypothesized that this latency effect is the functional reflection of abnormal structural connectivity in this group, and might result in increased processing of stimulus detail.

Background: A strategy to improve genetic studies of schizophrenia involves the use of endophenotypes. Information on overlapping genetic contributions among endophenotypes may provide additional power, reveal biological pathways, and have practical implications for genetic research. Several cognitive endophenotypes, including intelligence, are likely to be modulated by overlapping genetic influences., Methods: We quantified potential genetic and environmental correlations among endophenotypes for schizophrenia, including sensorimotor gating, openness, verbal fluency, early visual perception, spatial working memory, and intelligence, using variance component models in 35 patients and 145 relatives from 25 multigenerational Dutch families multiply affected with schizophrenia., Results: Significant correlations were found between spatial working memory and intelligence (.45), verbal fluency and intelligence (.36), verbal fluency and spatial working memory (.20), and early visual perception and spatial working memory (.19). A strong genetic correlation (.75) accounted for 76% of the variance shared between spatial working memory and intelligence. Significant environmental correlations were found between verbal fluency and openness (.50) and between verbal fluency and spatial working memory (.58). Sensorimotor gating and openness showed few genetic or environmental correlations with other endophenotypes., Conclusions: Our results suggest that intelligence strongly overlaps genetically with a known cognitive endophenotype for schizophrenia. Intelligence may thus be a promising endophenotype for genetic research in schizophrenia, even though the underlying genetic mechanism may still be complex. In contrast, sensorimotor gating and openness appear to represent separate genetic entities with simpler inheritance patterns and may therefore augment the detection of separate genetic pathways contributing to schizophrenia.

Background: Psychomotor slowing is regarded as an important clinical phenomenon in schizophrenia and simple graphic tasks consistently revealed deficits in the (implicit) planning and execution of motor actions in patients with chronic schizophrenia. The aim of the present study is to test the hypothesis that such deficits are already present in patients with recent-onset schizophrenia., Methods: Psychomotor performance and several aspects of movement planning were analyzed in 36 patients with recent-onset schizophrenia and a group of 33 matched healthy controls. Participants were required to draw patterns varying in complexity in three different figure-copying tasks, match and draw simple symbols in the Digit Symbol Substitution Test (DSST) and connect target circles with varying orientations in a newly developed Line Sequencing Task., Results: Relative to the controls, the patients showed significantly longer initiation times when the patterns in the copying tasks became more complex, suggesting increased difficulty in movement planning. Overall, they were not slowed in the execution stages. In the cognitively more demanding DSST, the patients were significantly slowed in both the initiation and movement phases. Moreover, they selected less optimal movement directions in the Line Sequencing Task., Conclusions: Psychomotor planning deficits are already present in the early stages of schizophrenia and involve deficient planning but intact motor action. Planning difficulties can be detected in motor sequences as well. The results indicate that the cognitive deficit in schizophrenia also affects the implicit planning of very simple movements.

Background: The use of symptom dimensions of schizophrenia as quantitative phenotypes has been proposed as a mean to reduce the heterogeneity of schizophrenia and facilitate genetic research. However, the genetic background of symptom dimensions is not clear., Aim: We aim to investigate whether the symptom dimensions "reality distortion", "psychomotor poverty" and "disorganization" are heritable phenotypes., Method: We performed a Medline search including all papers from 1980 to August 2007. In addition to reviewing the articles, we performed meta-analyses on these studies where possible., Results: We identified 18 relevant papers. Only the studies on affected sibling pairs were suitable for meta-analysis. Data from twin and affected sibling studies are consistent with a genetic contribution to the disorganization dimension. However these studies did not unequivocally support a large genetic contribution to neither the reality distortion symptom dimension nor to the psychomotor poverty symptom dimension. In contrast several molecular genetic studies did report associations of genes with psychomotor poverty., Conclusions: These data suggest that only the disorganization symptom dimension may provide an useful alternative phenotype for genetic research. More research is required to make any definitive conclusions.

Background: Patients with schizophrenia have been found to display abnormalities in social cognition. The aim of the study was to test whether patients with schizophrenia and unaffected first-degree relatives of schizophrenic patients display behavioural signs of social brain dysfunction when making social judgements., Method: Eighteen patients with schizophrenia, 24 first-degree unaffected relatives and 28 healthy comparison subjects completed a task which involves trustworthiness judgements of faces. A second task was completed to measure the general ability to recognize faces., Results: Patients with schizophrenia rated faces as more trustworthy, especially those that were judged to be untrustworthy by healthy comparison subjects. Siblings of schizophrenia patients display the same bias, albeit to a lesser degree., Conclusions: The pattern of more positive trustworthiness judgements parallels the results from studies of patients with abnormalities in brain areas involved in social cognition. Because patients and siblings did not differ significantly from controls in their general ability to recognize faces, these findings cannot be dismissed as abnormalities in face perception by itself.

Unlabelled: The objectives of this study were 1) to examine whether the prevalence of 22q11.2 deletion syndrome (22q11DS) in schizophrenia patients with the Deficit syndrome is higher than the reported approximately 2% for the population of schizophrenia patients as a whole, and 2) to estimate the overall prevalence of 22q11DS among schizophrenia patients by combining all available studies. Our sample, enriched for patients with the Deficit syndrome, had 88% power to detect an estimated prevalence of 5% of 22q11.2 deletions. No 22q11.2 deletions were detected in 311 schizophrenia patients, 146 of whom met criteria for the Deficit syndrome. Our literature research revealed that in eight studies sixteen deletions were identified in 2133 patients with schizophrenia. This corresponds to a prevalence of 0.75% (95%CI: 0.5%-1.2%)., In Conclusion: The prevalence of 22q11.2DS in schizophrenia patients with the Deficit syndrome is not higher than in the population of schizophrenia patients as a whole. The prevalence of 22q11.2DS in schizophrenia patients is lower than the frequently reported prevalence of 2% or more.

Purpose: To describe the early course of psychotic disorders in general and to examine whether certain variables can predict the early course of schizophrenic disorders (DSM-IV: schizophrenia, schizophreniform or schizoaffective disorder)., Subjects and Method: Follow-up and re-diagnosis of a highly representative Dutch incidence cohort (N=181), thirty months after first contact with a physician for a psychotic disorder. Poor course was defined as a continuous psychotic illness or a score of less than 39 on the Global Assessment of Functioning scale., Results: The follow-up rate was 92%. 125 Subjects were diagnosed with a schizophrenic disorder. Poor course was present in 70 of these subjects (56%). Univariable analysis showed that male sex, heavy cannabis use during the follow-up period (sometimes or often more than one joint a day) and long duration of dysfunctioning before psychosis onset (>1 month) were predictors of poor course, while age at onset, ethnicity, socioeconomic status and duration of untreated psychosis (trend, p=0.08) were not. The effect of cannabis was confounded by sex. Multivariable analysis showed that male sex was the sole significant and independent predictor of poor course and explained 13% of the variation. The odds ratio for males, adjusted for duration of pre-psychotic dysfunctioning and cannabis use during the follow-up period, was 3.0 (95% CI, 1.0-8.9). STRENGTHS AND LIMITATIONS: This is the first study to examine the influence of cannabis in an epidemiological, highly representative sample. A limitation was the sample size., Conclusion: Male sex is an independent risk factor for an unfavorable early course in schizophrenia.

Background: Deficits in emotion processing may be one of the most pervasive disturbances in schizophrenia that may contribute to social isolation. In this report we focus on vocal emotion processing. This function bears upon two corner stones of social functioning, language and emotion, which have both been found to be impaired in schizophrenia., Methods: We used meta-analysis to integrate findings of studies published between 1980 and June 2007 on perception of emotional prosody in schizophrenia. 17 studies provided sufficient information to be included. A mean weighted effect size was computed in the random effects model. Publication bias was tested using funnel plots and fail-safe number of studies. Seven studies were included in an analysis on the expression (i.e. production) of emotional prosody in schizophrenia., Results: A significant and stable mean weighted effect size was found for the perception of emotional prosody, d=-1.24, 95% CI=-1.55 to -0.93. The effect was also found in the early stages of the illness. Expression of emotional prosody was also significantly impaired, d=-1.11, 95% CI=-1.78 to -0.43., Conclusions: Results indicate that individuals with schizophrenia are impaired in the perception and expression of emotional prosody, with a large effect size. As a growing body of evidence shows that impaired social cognition in schizophrenia may be an important predictor of social outcome, training programs that aim at the recognition of emotional prosody should be developed.

Although schizophrenia has often been associated with deficits in facial affect recognition, it is debated whether the recognition of specific emotions is affected and if these facial affect-processing deficits are related to symptomatology or other patient characteristics. The purpose of the present study was to explore whether particular patient characteristics are associated with the recognition of specific facial expressions in patients with schizophrenia. Sixty-four patients with a DSM-IV diagnosis of schizophrenia were assessed with a computerized test of degraded facial affect recognition. Linear regression analysis showed that, in particular, negative symptoms and male sex were associated with worse recognition of fearful faces. Furthermore, diagnosis of nonparanoid schizophrenia and later age of onset were associated with worse recognition of neutral faces. Findings are explained in the light of a neuroanatomical dysfunction accounting for both negative symptoms, such as reduced emotional expression and social-emotional dysfunction, for which men seem more vulnerable than women.