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ObjectivesTo report the neuropsychiatric features and frequency of NMDA receptor (NMDAR) and other neuronal immunoglobulin G antibodies in patients with first episode psychosis (FEP) and to assess the performance of reported warning signs and criteria for autoimmune psychosis (AP).MethodsThis was a prospective observational study of patients with FEP assessed for neuropsychiatric symptoms, serum and CSF neuronal antibodies (brain immunohistochemistry, cell-based assays, live neurons), and warning signs and criteria of AP. Previous autoimmune FEP series were reviewed.ResultsOne hundred five patients were included; their median age was 30 (range 14–75) years, and 44 (42%) were female. None had neuronal antibodies. Two of 105 (2%) had CSF pleocytosis, 4 of 100 (4%) had brain MRI abnormalities, and 3 of 73 (4%) EEG alterations. Thirty-four (32%) and 39 (37%) patients fulfilled 2 sets of warning signs of AP, and 21 (20%) fulfilled criteria of possible or probable AP, yet none developed AP. The cause of FEP was psychiatric in 101 (96%) and nonpsychiatric in 4 (4%). During this study, 3 patients with psychosis caused by anti-NMDAR encephalitis were transferred to our center; 2 did not meet criteria for possible AP. Of 1,159 reported patients with FEP, only 7 (1%) had CSF studies; 36 (3%) had serum NMDAR antibodies (without definite diagnosis of AP), and 4 had CSF NMDAR antibodies (3 classic anti-NMDAR encephalitis and 1 with isolated psychiatric features).ConclusionsNMDAR antibodies were not found in patients with FEP unless they had anti-NMDAR encephalitis. Warning signs and criteria for AP have limited utility when neurologic symptoms are absent or paraclinical tests are normal. A diagnostic algorithm for autoimmune FEP is provided.

Some 70–80% of subjects with psychotic risk syndrome (PRS) have lifetime comorbidity, with depressive disorders being the most common. A high proportion of patients with PRS present nonspecific symptoms which can be confounding factors for diagnosis. Depressive and negative symptoms may be difficult to distinguish and it is important to differentiate them. The aim of this study is to assess the presence of depressive disorder in a child and adolescent sample of PRS and to examine the presence of negative symptoms and detect possible confounding characteristics between them and depressive symptoms. This is a naturalistic multi-site study with subjects who met PRS criteria. A sample of 89 PRS adolescent patients was included. Major depressive disorder (MDD) is the most prevalent comorbid disorder (34.83%). The sample was divided into patients who met criteria for MDD (PRS-MDD, n = 31) and those who did not have this disorder (PRS-ND, n = 44). We obtained significant differences in the attenuated negative symptoms (ANS) between PRS-MDD and PRS-ND (68.18 vs. 90.32%, respectively, p = 0.021). Subjects with MDD presented a higher score in ANS and Hamilton Depression Rating Scale (HDRS). Moreover, we obtained a correlation between negative symptomatology and HDRS score with a higher score on HDRS in subjects with higher negative symptom scores (r = 0.533, p

IMPORTANCE The ENIGMA clinical high risk (CHR) for psychosis initiative, the largest pooled neuroimaging sample of individuals at CHR to date, aims to discover robust neurobiological markers of psychosis risk.OBJECTIVE To investigate baseline structural neuroimaging differences between individuals at CHR and healthy controls as well as between participants at CHR who later developed a psychotic disorder (CHR-PS+) and those who did not (CHR-PS-).DESIGN, SETTING, AND PARTICIPANTS In this case-control study, baseline T1-weighted magnetic resonance imaging (MRI) data were pooled from 31 international sites participating in the ENIGMA Clinical High Risk for Psychosis Working Group. CHR status was assessed using the Comprehensive Assessment of At-Risk Mental States or Structured Interview for Prodromal Syndromes. MRI scans were processed using harmonized protocols and analyzed within a mega-analysis and meta-analysis framework from January to October 2020.MAIN OUTCOMES AND MEASURES Measures of regional cortical thickness (CT), surface area, and subcortical volumes were extracted from T1-weighted MRI scans. Independent variables were group (CHR group vs control group) and conversion status (CHR-PS+ group vs CHR-PS- group vs control group).RESULTS Of the 3169 included participants, 1428 (45.1%) were female, and the mean (SD; range) age was 21.1 (4.9; 9.5-39.9) years. This study included 1792 individuals at CHR and 1377 healthy controls. Using longitudinal clinical information, 253 in the CHR-PS+ group, 1234 in the CHR-PS- group, and 305 at CHR without follow-up data were identified. Compared with healthy controls, individuals at CHR exhibited widespread lower CT measures (mean [range] Cohen d = -0.13 [-0.17 to -0.09]), but not surface area or subcortical volume. Lower CT measures in the fusiform, superior temporal, and paracentral regions were associated with psychosis conversion (mean Cohen d = -0.22; 95% CI, -0.35 to 0.10). Among healthy controls, compared with those in the CHR-PS+ group, age showed a stronger negative association with left fusiform CT measures (F = 9.8; P < .001; q < .001) and left paracentral CT measures (F = 5.9; P = .005; q = .02). Effect sizes representing lower CT associated with psychosis conversion resembled patterns of CT differences observed in ENIGMA studies of schizophrenia (rho = 0.35; 95% CI, 0.12 to 0.55; P = .004) and individuals with 22q11.2 microdeletion syndrome and a psychotic disorder diagnosis (rho = 0.43; 95% CI, 0.20 to 0.61; P = .001).CONCLUSIONS AND RELEVANCE This study provides evidence for widespread subtle, lower CT measures in individuals at CHR. The pattern of CT measure differences in those in the CHR-PS+ group was similar to those reported in other large-scale investigations of psychosis. Additionally, a subset of these regions displayed abnormal age associations. Widespread disruptions in CT coupled with abnormal age associations in those at CHR may point to disruptions in postnatal brain developmental processes.Question How are brain morphometric features associated with later psychosis conversion in individuals at clinical high risk (CHR) for developing psychosis?Findings In this case-control study including 3169 participants, lower cortical thickness, but not cortical surface area or subcortical volume, was more pronounced in individuals at CHR in a manner highly consistent with thinner cortex in individuals with established psychosis. Regions that displayed lower cortical thickness in individuals at CHR who later developed a psychotic disorder additionally displayed abnormal associations with age.Meaning In this study, CHR status and later transition to psychosis was robustly associated with lower cortical thickness; abnormal age associations and specificity to cortical thickness may point to aberrant postnatal brain development in individuals at CHR, including pruning and myelination.This case-control study investigates baseline structural magnetic resonance imaging (MRI) differences between individuals at clinical high risk and healthy controls as well as between participants at clinical high risk who later developed a psychotic disorder and those who did not.

Background Offspring of patients diagnosed with bipolar disorder and schizophrenia (Off-BDSZ) have a high genetic risk of developing a mental illness. The aim of this project is to develop and investigate the efficacy of an intervention aimed at this population, based on the concept of cognitive reserve. Methods This is a multicenter randomized trial with an experimental test–retest design study with control group. Two groups will be included: a community comparison group (CC) and a Off-BDSZ group. A total of 108 Off-BDSZ and 65 CC aged between 6 and 25 years will be recruited. Off-BDSZ participants will be randomized to receive either Cognitive Reserve EnhAncement ThErapy (CREATE) (n = 54), or a supportive approach (n = 54). The CC group will be assessed at baseline. The duration of the intervention will be 3 months, with 12 weekly group sessions. The primary outcome will be the improvement in CR measured according to change in the Cognitive Reserve Assessment Scale in Health (CRASH) and Cognitive Reserve scale for Adolescents (CORE-A). All participants will be blindly evaluated using clinical, cognitive and neuroimaging measures at baseline, at three months (after the psychological intervention), and at twelve-month follow-up after treatment completion. Discussion The results will provide insight into whether the CREATE-Offspring version may enhance cognitive reserve (CR) in child, adolescent and young adult Off-BDSZ as well as advance knowledge about changes in clinical manifestations, neuropsychological performance and brain structure and function associated with improving CR. This novel and cost-effective intervention represents an advance in the framework of preventive interventions in mental health. Trial registration Clinicaltrials.gov, NCT03722082 . Registered on 26 October 2018.

ImportanceThe ENIGMA clinical high risk for psychosis (CHR) initiative, the largest pooled CHR-neuroimaging sample to date, aims to discover robust neurobiological markers of psychosis risk in a sample with known heterogeneous outcomes.ObjectiveWe investigated baseline structural neuroimaging differences between CHR subjects and healthy controls (HC), and between CHR participants who later developed a psychotic disorder (CHR-PS+) and those who did not (CHR-PS-). We assessed associations with age by group and conversion status, and similarities between the patterns of effect size maps for psychosis conversion and those found in other large-scale psychosis studies.Design, Setting, and ParticipantsBaseline T1-weighted MRI data were pooled from 31 international sites participating in the ENIGMA CHR Working Group. MRI scans were processed using harmonized protocols and analyzed within a mega- and meta-analysis framework from January-October 2020.Main Outcome(s) and Measure(s)Measures of regional cortical thickness (CT), surface area (SA), and subcortical volumes were extracted from T1-weighted MRI scans. Independent variables were group (CHR, HC) and conversion status (CHR-PS+, CHR-PS-, HC).ResultsThe final dataset consisted of 3,169 participants (CHR=1,792, HC=1,377, age range: 9.5 to 39.8 years, 45% female). Using longitudinal clinical information, we identified CHR-PS+ (N=253) and CHR-PS- (N=1,234). CHR exhibited widespread thinner cortex compared to HC (average d=-0.125, range: -0.09 to -0.17), but not SA or subcortical volume. Thinner cortex in the fusiform, superior temporal, and paracentral regions was associated with psychosis conversion (average d=-0.22). Age showed a stronger negative association with left fusiform and left paracentral CT in HC, compared to CHR-PS+. Regional CT psychosis conversion effect sizes resembled patterns of CT alterations observed in other ENIGMA studies of psychosis.Conclusions and RelevanceWe provide evidence for widespread subtle CT reductions in CHR. The pattern of regions displaying greater CT alterations in CHR-PS+ were similar to those reported in other large-scale investigations of psychosis. Additionally, a subset of these regions displayed abnormal age associations. Widespread CT disruptions coupled with abnormal age associations in CHR may point to disruptions in postnatal brain developmental processes.Key PointsQuestionHow do baseline brain morphometric features relate to later psychosis conversion in individuals at clinical high risk (CHR)?FindingsIn the largest coordinated international analysis to date, reduced baseline cortical thickness, but not cortical surface area or subcortical volume, was more pronounced in CHR, in a manner highly consistent with thinner cortex in established psychosis. Regions that displayed greater cortical thinning in future psychosis converters additionally displayed abnormal associations with age.MeaningCHR status and later transition to psychosis is robustly associated with reduced cortical thickness. Abnormal age associations and specificity to cortical thickness may point to aberrant postnatal brain development in CHR, including pruning and myelination.

Contains fulltext : 235728.pdf (Publisher’s version ) (Closed access) Gray matter and cortical thickness reductions have been documented in individuals at clinical high-risk for psychosis and may be more pronounced in those who transition to psychosis. However, these findings rely on small samples and are inconsistent across studies. In this review and meta-analysis we aimed to investigate neuroanatomical correlates of clinical high-risk for psychosis and potential predictors of transition, using a novel meta-analytic method (Seed-based d Mapping with Permutation of Subject Images) and cortical mask, combining data from surface-based and voxel-based morphometry studies. Individuals at clinical high-risk for psychosis who later transitioned to psychosis were compared to those who did not and to controls, and included three statistical maps. Overall, individuals at clinical high-risk for psychosis did not differ from controls, however, within the clinical high-risk for psychosis group, transition to psychosis was associated with less cortical gray matter in the right temporal lobe (Hedges' g = -0.377), anterior cingulate and paracingulate (Hedges' g = -0.391). These findings have the potential to help refine prognostic and etiopathological research in early psychosis.

Although psychosocial stress is consistently described as a casual factor for psychosis, the role of recent stressful life events (SLEs) is inconclusive. Studies with subjects with psychosis risk syndrome (PRS), fail to show a large number of SLEs but suggest greater stress sensitivity in these populations. We evaluate the presence of recent SLEs and stress sensitivity, and their relationship with symptoms and functionality in a sample consisting exclusively of help-seeking children and adolescents. Seventy-two 10- to 17-year-old help-seeking subjects who met PRS criteria and forty-two healthy control (HC) subjects participated in a naturalistic multi-site study. Measures of stress included the Stressful Life Events Schedule (SLES) and the G4 item of the Scale for Prodromal Syndromes (SOPS) scale. Child and adolescent PRS subjects presented greater number of SLEs during the previous year, greater total accumulated stress, greater sensitivity to stress, and more impaired tolerance to normal stress than did HC subjects. Stress measures showed a relationship with positive and negative attenuated symptoms, clinical variables and functionality. Our results support the role of stress in the PRS status. It reinforces the suggested differences for clinical presentation of PRS in terms of age, highlighting the importance of gathering data on the under-18 population.

Shared vulnerability in offspring of individuals with schizophrenia (SzO) and bipolar disorder (BpO) might manifest early during development through common temperament traits. Temperament dimensions in child and adolescent BpO (N = 80), SzO (N = 34) and the offspring of community controls (CcO) (N = 101) were assessed using the Revised Dimensions of Temperament Survey. The association between temperament dimensions and lifetime psychopathology (including threshold and subthreshold DSM-IV-TR diagnoses) and current socio-academic adjustment was assessed using logistic regression. Fully adjusted models showed that both BpO and SzO scored significantly lower in the positive mood dimension and in the adaptability factor than CcO, with small-medium effect sizes (Cohen's d ~ 0.3-0.5). BpO also scored lower in the activity factor and the activity dimensions than CcO (Cohen's d ~ 0.3). Lower scores in the positive mood dimension were associated with increased risk of impaired adjustment both in BpO [OR 2.30, 95% CI (1.18-4.46)] and in SzO [OR 2.87, 95% CI (1.07-7.66)]. In BpO, lower scores in positive mood were also associated with increased likelihood of internalizing [OR 1.84, 95% CI (1.28-2.64)] and externalizing disorders [OR 1.48, 95% CI (1.01-2.18)]; in SzO, higher scores in activity and flexibility were associated with increased likelihood of internalizing [OR 2.31, 95% CI (1.22-4.38)] and externalizing disorders [OR 3.28, 95% CI (1.2-9)], respectively. Early difficulties in emotion regulation might represent a shared vulnerability phenotype in BpO and SzO. The identification of extreme temperament traits could help to characterize subgroups at greater risk of psychopathology and impaired adjustment, in which targeted interventions are warranted.

Cognitive reserve (CR) is the premorbid brain capacity to cope with neural damage. People with good CR can tolerate higher levels of pathological brain injuries before displaying clinical symptoms than others. This study aimed to analyze CR in a sample of patients diagnosed with first-episode psychosis (FEP) during childhood or adolescence, comparing them to a community control group (CC) and assessing the predictive value of CR regarding psychosocial functioning, clinical symptoms and neuropsychological variables at the 5-year follow-up. 57 patients diagnosed with FEP during childhood or adolescence and 37 controls completed clinical, neuropsychological, and psychosocial functioning assessments at baseline and 5-year follow-up. CR was assessed in both groups at baseline. The FEP group showed lower CR scores than the CC group. Higher CR in the FEP group was associated with fewer psychotic negative symptoms, total psychotic symptoms and depressive symptoms, higher psychosocial functioning, and less impaired memory and attention at the 5-year follow-up. CR is associated with long-term clinical, neuropsychological and psychosocial functioning outcomes in patients diagnosed with FEP during childhood or adolescence.

Background Recent studies have observed high rates of psychopathology in child and adolescent offspring of patients with schizophrenia (SZoff). Attention Deficit Hyperactivity Disorder (ADHD) is the most prevalent psychopathology in SZoff (Sanchez-Gistau, et al., 2015). The high prevalence of ADHD observed in SZoff can conceal the vulnerability characteristics specific to schizophrenia. The aim of this study is to analyze the clinical characteristics of a sample of child and adolescent SZoff diagnosed with ADHD (SZoff-ADHD) compared to a sample of children with ADHD without a family history of psychotic disorders and a sample of healthy controls. We hypothesize that SZoff-ADHD will show more psychopathology and more prodromal psychotic symptoms than the other two groups. Methods we studied a sample of 22 SZoff-ADHD children, 15 children with ADHD with no familiar history of psychotic disorders and 40 healthy controls (HC) between 6 and 17 years old and we conducted a complete clinical assessment which included: Kiddie Schedule for Affective Disorders and Schizophrenia (K-SADS), Young Mania Rating Scale (YMRS), Hamilton Depression Rating Scale (HDRS), Structured interview for Prodromal Symptoms (SOPS) and Global Assessment Functioning (GAF). In order to detect significant differences between groups, multilevel mixed-effect logistic regression models (categorical variables) or multilevel mixed-effect linear regression models (continuous variables) were performed with group as the fixed factor and the fact of having a sibling in the same study (identified by the family number) as the random variable. Results significant differences between groups were found in socio-economic status which was lower in the SZoff-ADHD group than in the other two groups (F=15.886; p Regarding clinical assessments, the SZoff-ADHD group showed a higher percentage of conduct disorders (F=3.720; p=0.039) than the ADHD group. No significant differences were observed in other psychopathological diagnoses. Furthermore the SZoff-ADHD group also obtained higher scores than the HC group on the following scales: YMRS, positive, negative, general and total sub-scales of the SOPS and lower scores in the GAF. The ADHD group obtained significantly higher scores than the HC group in the sub-scale of SOPS general prodromal symptoms and lower scores on the GAF. Significant differences were detected between SZoff-ADHD and ADHD in the YMRS and the positive and negative sub-scales of the SOPS where the SZoff-ADHD group showed higher scores than the ADHD group. Discussion Compared with the HC group, the SZoff-ADHD displayed more manic, prodromal psychotic symptoms and worse psychosocial functioning. The ADHD group showed an intermediate pattern between the SZoff-ADHD and the HC group, with more general prodromal symptoms and lower psychosocial functioning than the HC group but lower scores than the SZoff-ADHD in the psychotic prodromal symptoms interview.

Background Cognitive Reserve (CR) is defined as the ability of the brain to cope and deal with physiological or pathological brain injuries. In the field of psychiatry, higher levels of CR have been associated with lower levels of psychotic symptoms, higher psycho-social functioning and higher cognitive performance, suggesting that CR should be considered as a protective factor (Barnett et al., 2006; Amoretti et al., 2016). This study aims to compare CR levels in a sample of adolescents and young adult offspring of patients with schizophrenia or bipolar disorder who are at high risk of developing these disorders (HR) and compared them with a group of healthy controls (HC). We also assess the utility of CR in predicting clinical and cognitive variables. Methods Participants were 85 HR and 45 HC. A CR proxy was calculated based on premorbid IQ, socio-occupational attainment and social activities. Clinical assessment included: the Structured Interview for Prodromal Symptoms (SOPS), the Young Mania Rating Scale (YMRS) and the Hamilton Depression Rating Scale (HDRS). Neuropsychological assessment included: Working Memory, Processing Speed, Verbal Memory, attention and executive functioning. A factorial analysis was conducted in order to obtain a single CR measure. Differences between groups in CR were assessed via MANCOVA and linear regressions were conducted to check the effectiveness of CR in predicting clinical and neuropsychological variables. Results No significant differences were observed in age or gender between HR and HC groups. Socioeconomic status was lower in HR subjects (F=8.100, p=0.005).CR was significantly lower in the HR group than in the HC group (F=17.522; p Discussion HR subjects have lower CR than controls. CR is associated with clinical and neuropsychological variables. To our knowledge no previous studies have assessed CR in high risk samples. Nevertheless, studies conducted in adult first episode psychotic samples have shown an association between CR and the severity of symptoms.

Background Having one parent diagnosed with a severe mental disorder is considered one of the main risk factors for developing that disorder in adulthood and it also increases the risk of a wide range of mental disorders in the offspring from early childhood and adolescence. The aim of this study is to analyze the prevalence of several psychopathological diagnoses, the presence of prodromal symptoms and global functioning in schizophrenia offspring (SZoff) or bipolar offspring (BDoff) compared to community control offspring (CCoff) at baseline and 2-year follow-up. Methods 41 SZoff, 97 BDoff and 107 CCoff between 7 and 17 years were included. Clinical assessment consisted of a clinical evaluation using the following instruments: structured interview KSADS-PL or SCID-I, semi-structured Interview for Prodromal Syndromes (SIPS) and the Children’s Global Assessment Scale (CGAS). To test between-group differences in DSM-IV diagnoses multilevel mixed-effect logistic regression models (categorical variables) or linear (continuous variables) regression models were conducted with group (SZoff, BDoff and CCoff), time (baseline or 2-year follow-up), interaction time x group, age, gender and socio-economic status as fixed variables. Results Significant differences between groups were found in any lifetime axis I disorder (F=8.720; p Discussion Screening patients’ children is clinically relevant since, as a group, they have an elevated risk of developing a psychiatric disorder and of experiencing their first symptoms during childhood and adolescence.

Although various types of hallucinations are reported at high rates during childhood, the research focusing on visual hallucinations is relatively scarce.1 Visual hallucinations have often been linked to biological causes and have been considered uncommon in psychiatric samples. However, recent studies suggest that almost 30% of visual hallucinations occur in the context of psychosis.1 The risk of psychopathology is often a cause of concern when children report visual hallucinations, especially when associated with poor functioning. A detailed history must be taken to determine whether reported hallucinations are a phenomenon of typical development (for example, imaginary friends, or hypnopompic or hypnogogic hallucinations), a symptom of trauma or anxiety, or have another etiology. In the presence of confirmed distressing complex hallucinations, clinicians should clarify whether they are neurological in origin or are a symptom of an established psychiatric disorder.

WOS: 000485217300010, PubMed ID: 31443932, BACKGROUND: Schizophrenia and bipolar disorder share genetic liability, and some structural brain abnormalities are common to both conditions. First-degree relatives of patients with schizophrenia (FDRs-SZ) show similar brain abnormalities to patients, albeit with smaller effect sizes. Imaging findings in first-degree relatives of patients with bipolar disorder (FDRs-BD) have been inconsistent in the past, but recent studies report regionally greater volumes compared with control subjects. METHODS: We performed a meta-analysis of global and subcortical brain measures of 6008 individuals (1228 FDRs-SZ, 852 FDRs-BD, 2246 control subjects, 1016 patients with schizophrenia, 666 patients with bipolar disorder) from 34 schizophrenia and/or bipolar disorder family cohorts with standardized methods. Analyses were repeated with a correction for intracranial volume (ICV) and for the presence of any psychopathology in the relatives and control subjects. RESULTS: FDRs-BD had significantly larger ICV (d = +10.16, q < .05 corrected), whereas FDRs-SZ showed smaller thalamic volumes than control subjects (d = -0.12, q < .05 corrected). ICV explained the enlargements in the brain measures in FDRs-BD. In FDRs-SZ, after correction for ICV, total brain, cortical gray matter, cerebral white matter, cerebellar gray and white matter, and thalamus volumes were significantly smaller; the cortex was thinner (d < -0.09, q < .05 corrected); and third ventricle was larger (d = +0.15, q < .05 corrected). The findings were not explained by psychopathology in the relatives or control subjects. CONCLUSIONS: Despite shared genetic liability, FDRs-SZ and FDRs-BD show a differential pattern of structural brain abnormalities, specifically a divergent effect in ICV. This may imply that the neurodevelopmental trajectories leading to brain anomalies in schizophrenia or bipolar disorder are distinct., Research Council of NorwayResearch Council of Norway [223273]; National Institutes of Health (NIH)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [R01 MH117601, R01 MH116147, R01 MH111671, P41 EB015922, 5T32MH073526, U54EB020403, R03 MH105808]; National Institute on Aging (NIA)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute on Aging (NIA) [T32AG058507]; Canadian Institutes of Health ResearchCanadian Institutes of Health Research (CIHR) [103703, 106469, 341717]; National Centre for Mental Health; 2010 National Alliance for Research on Schizophrenia and Depression (NARSAD) Young Investigator Award [17319]; Dokuz Eylul University Department of Scientific Research Projects FundingDokuz Eylul University [2012.KB.SAG.062]; National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley National Health Service Foundation Trust and King's College London; Ege University School of Medicine Research Foundation [2009-D-00017]; Medical Research CouncilMedical Research Council UK (MRC) [G0901310]; Geestkracht program of the Netherlands Organisation for Health Research and Development [10-000-1002]; National Institute of Mental HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Mental Health (NIMH) [R01 MH 085667]; Nova Scotia Health Research Foundation; Dalhousie Clinical Research Scholarship; 2007 Brain and Behavior Research Foundation Young Investigator Award; Ministry of Health of the Czech RepublicMinistry of Health, Czech Republic [NR8786, NT13891]; Swedish Research CouncilSwedish Research Council [K2007-62X-15077-04-1, K2008-62P-20597-01-3, K2010-62X-15078-07-2, K2012-61X-15078-09-3]; Stockholm County CouncilStockholm County Council; Karolinska InstitutetKarolinska Institutet; Knut and Alice Wallenberg FoundationKnut & Alice Wallenberg Foundation; HUBIN project; Spanish Ministry of Economy and Competitiveness/Instituto de Salud Carlos III [PI070066, PI1100683, PI1500467]; Fundacio Marato TV3 [091630]; ERDF Funds from the European Commission A Way of Making Europe"); Brain and Behaviour Research Foundation (NARSAD Young Investigator Award); Alicia Koplowitz Foundation; Stanley Medical Research Institute; NARSADNARSAD [20244]; Wellcome TrustWellcome Trust [064971, 085475/B/08/Z, 085475/Z/08/Z]; NARSAD Young Investigator AwardNARSAD; European CommunityEuropean Community (EC); NIMH Intramural Research ProgramUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Mental Health (NIMH); NIHR Biomedical Research Centre at University College London Hospital; British Medical Association Margaret Temple Fellowship 2016; German Federal Ministry for Education and ResearchFederal Ministry of Education & Research (BMBF) [O1ZX1314B, O1ZX1314G]; Deutsche ForschungsgemeinschaftGerman Research Foundation (DFG) [1617]; NIMHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Mental Health (NIMH) [R01 MH116147, R01 MH113619]; NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [U01 MH097435, R01 MH084803, R01 EB020062, R01 MH080912, R01 MH052857]; National Science FoundationNational Science Foundation (NSF) [1636893, 1734853]; Australian National Health and Medical Research CouncilNational Health and Medical Research Council of Australia [510135, 1037196, 1063960, 1066177]; ZonMwNetherlands Organization for Health Research and Development [908-02-123]; VIDINetherlands Organization for Scientific Research (NWO) [452-11-014, 917-46-370]; Janssen PharmaceuticaJohnson & Johnson USAJanssen Biotech Inc; Otsuka PharmaceuticalOtsuka Pharmaceutical; Bipolar Disorder Research Network, The researchers and studies included in this article were supported by the Research Council of Norway (Grant No. 223273), National Institutes of Health (NIH) (Grant No. R01 MH117601 [to NJ], Grant Nos. R01 MH116147, R01 MH111671, and P41 EB015922 [to PMT], Grant Nos. 5T32MH073526 and U54EB020403 [to CRKC], and Grant No. R03 MH105808 [to CEB and SCF]) and National Institute on Aging (NIA) (Grant No. T32AG058507 [to CRKC]).; C-SFS: This work was supported by Canadian Institutes of Health Research.; Cardiff: This work was supported by the National Centre for Mental Health, Bipolar Disorder Research Network, 2010 National Alliance for Research on Schizophrenia and Depression (NARSAD) Young Investigator Award (Grant No. 17319).; DEU: This work was supported by Dokuz Eylul University Department of Scientific Research Projects Funding (Grant No. 2012. KB. SAG. 062). This report represents independent research funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley National Health Service Foundation Trust and King's College London. The views expressed are those of the authors and not necessarily those of the National Health Service, NIHR, or Department of Health.; EGEU: This work was supported by the Ege University School of Medicine Research Foundation (Grant No. 2009-D-00017).; EHRS: The Edinburgh High Risk Study was supported by the Medical Research Council.; GROUP: The infrastructure for the GROUP study was supported by the Geestkracht program of the Netherlands Organisation for Health Research and Development (Grant No. 10-000-1002).; ENBD_UT/BPO_FLB: This work was supported by the National Institute of Mental Health (Grant No. R01 MH 085667).; HHR/PHHR: This work was supported by the Canadian Institutes of Health Research (Grant Nos. 103703, 106469, and 341717), Nova Scotia Health Research Foundation, Dalhousie Clinical Research Scholarship (to TH), 2007 Brain and Behavior Research Foundation Young Investigator Award (to TH), and Ministry of Health of the Czech Republic (Grant Nos. NR8786 and NT13891).; HUBIN: This work was supported by the Swedish Research Council (Grant Nos. K2007-62X-15077-04-1, K2008-62P-20597-01-3, K2010-62X-15078-07-2, K2012-61X-15078-09-3), regional agreement on medical training and clinical research between Stockholm County Council and the Karolinska Institutet, Knut and Alice Wallenberg Foundation, and HUBIN project.; IDIBAPS: This work was supported by the Spanish Ministry of Economy and Competitiveness/Instituto de Salud Carlos III (Grant Nos. PI070066, PI1100683, and PI1500467) and Fundacio Marato TV3 (Grant No. 091630), co-financed by ERDF Funds from the European Commission A Way of Making Europe"), Brain and Behaviour Research Foundation (NARSAD Young Investigator Award), and Alicia Koplowitz Foundation.; IoP-BD: The Maudsley Bipolar Twin Study was supported by the Stanley Medical Research Institute and NARSAD.; IoP-SZ: This work was supported by a Wellcome Trust Research Training Fellowship (Grant No. 064971 to MMP), NARSAD Young Investigator Award (to TT), and European Community's Sixth Framework Programme through a Marie Curie Training Network called the European Twin Study Network on Schizophrenia.; Lieber Institute for Brain Development (LIBD): This work was supported by the NIMH Intramural Research Program (to DRW's laboratory). LIBD is a nonprofit research institute located in Baltimore, MD. The work performed at LIBD was performed in accordance with an NIMH material transfer agreement with LIBD.; MFS: The Maudsley Family Study cohort collection was supported by the Wellcome Trust (Grant Nos. 085475/B/08/Z and 085475/Z/08/Z), NIHR Biomedical Research Centre at University College London Hospital, Medical Research Council (Grant No. G0901310), and British Medical Association Margaret Temple Fellowship 2016.; MooDS: This work was supported by the German Federal Ministry for Education and Research grants NGFNplus MooDS (Systematic Investigation of the Molecular Causes of Major Mood Disorders and Schizophrenia) and Integrated Network IntegraMent (Integrated Understanding of Causes and Mechanisms in Mental Disorders) under the auspices of the e: Med program (Grant Nos. O1ZX1314B and O1ZX1314G) and Deutsche Forschungsgemeinschaft (Grant No. 1617 [to AH]).; MSSM: This work was supported by NIMH (Grant Nos. R01 MH116147 and R01 MH113619).; NU: This work was supported by NIH (Grant Nos. U01 MH097435, R01 MH084803, and R01 EB020062) and National Science Foundation (Grant Nos. 1636893 and 1734853).; OLIN: This work was supported by NIH (Grant No. R01 MH080912).; STAR: This work was supported by NIH (Grant No. R01 MH052857).; SydneyBipolarGroup: The Australian cohort collection was supported by the Australian National Health and Medical Research Council Program Grants (Grant No. 510135 [to PBM] and Grant No. 1037196 [to PBM and PRS]) and Project Grants (Grant No. 1063960 [to JMF and PRS] and Grant No. 1066177 [to JMF]).; UMCU: This work was supported by NARSAD (Grant No. 20244 [to MHJH]), ZonMw (Grant No. 908-02-123 [to HEHP]), VIDI (Grant No. 452-11-014 [to NEMvH] and Grant No. 917-46-370 [to HEHP]), and Stanley Medical Research Institute.; CliNG: We thank Anna Fanelli, Kathrin Jakob, and Maria Keil for help with data acquisition.; All authors have contributed to and approved the contents of this manuscript.; GS has received research and travel support from Janssen Pharmaceutica and Otsuka Pharmaceutical and honoraria from Adamed Pharma. NY has been an investigator in clinical studies conducted together with Janssen-Cilag, Corcept Therapeutics, and COMPASS Pathways in the last 3 years. AM-L has received consultant fees from Boehringer Ingelheim, BrainsWay, Elsevier, Lundbeck International Neuroscience Foundation, and Science Advances. CRKC has received partial research support from Biogen, Inc. (Boston, MA) for work unrelated to the topic of this manuscript. The remaining authors report no biomedical financial interests or potential conflicts of interest.

ObjectiveTo describe the sleep disorders in anti–NMDA receptor encephalitis (anti-NMDARe).MethodsPatients recovering from anti-NMDARe were invited to participate in a prospective observational single-center study including comprehensive clinical, video-polysomnography (V-PSG) sleep assessment, and neuropsychological evaluation. Age- and sex-matched healthy participants served as controls.ResultsEighteen patients (89% female, median age 26 years, interquartile range [IQR] 21–29 years) and 21 controls (81% female, median age 23 years, IQR 18–26 years) were included. In the acute stage, 16 (89%) patients reported insomnia and 2 hypersomnia; nightmares occurred in 7. After the acute stage, 14 (78%) had hypersomnia. At study admission (median 183 days after disease onset, IQR 110–242 days), 8 patients still had hypersomnia, 1 had insomnia, and 9 had normal sleep duration. Patients had more daytime sleepiness than controls (higher Barcelona Sleepiness Index, p = 0.02, and Epworth Sleepiness Score, p = 0.04). On V-PSG, sleep efficiency was similar in both groups, but patients more frequently had multiple and longer confusional arousals in non-REM (NREM) sleep (videos provided). In addition, 13 (72%) patients had cognitive deficits; 12 (67%) had psychological, social, or occupational disability; and 33% had depression or mania. Compared with controls, patients had a higher body mass index (median 23.5 [IQR 22.3–30.2] vs 20.5 [19.1–21.1] kg/m2; p = 0.007). Between disease onset and last follow-up, 14 (78%) patients developed hyperphagia, and 6 (33%) developed hypersexuality (2 requiring hospitalization), all associated with sleep dysfunction.ConclusionsSleep disturbances are frequent in anti-NMDARe. They show a temporal pattern (predominantly insomnia at onset; hypersomnia during recovery), are associated with behavioral and cognitive changes, and can occur with confusional arousals during NREM sleep.

Schizophrenia (SZ) and bipolar disorder (BD) are severe mental diseases associated with cognitive impairment, mood disturbance, and psychosis. Both disorders are highly heritable and share a common genetic background. The present study assesses, for the first time, differences in genotype frequencies of polymorphisms located in genes involved in neurodevelopment and synaptic plasticity between genetic high-risk individuals (offspring of patients with SZ or BD; N=100: 31 and 69, respectively) and control subjects (offspring of community controls; N=96). Individuals from both groups had similar ages, around 12 years. A higher percentage of men were included in the genetic high-risk group (58%) compared with the control group (40.6%). A total of 244 validated SNPs located in 35 candidate gene regions were analyzed in 196 participants. Multivariate methods based on logistic regression analysis were performed to assess differences in genotype frequencies. Bonferroni correction was applied for the multiple comparisons performed. Two polymorphisms, CACNA1C rs10848683 and SYNE1 rs214950, showed significant differences. The frequency of heterozygotes for CACNA1C rs10848683 in genetic high-risk individuals was double that in controls (OR=3.15; P=0.00016). For SYNE1 rs214950, higher frequencies of heterozygotes (OR=1.97) and homozygotes for the minor allele (OR=17.89; P=0.00020) were found in the genetic high-risk group than in the control group. In conclusion, polymorphisms in CACNA1C and SYNE1 could confer a greater risk of developing SZ and BD in individuals who are already at high risk because of their family history. This could help identify subjects with a very high genetic risk, in whom early detection and early intervention could lead to better prognosis.

Having one parent diagnosed with a severe mental disorder is considered one of the main risk factors for developing that disorder in adulthood, and it also increases the risk of a wide range of mental disorders in the offspring. The aim of this study is to compare the prevalence of several psychopathological diagnoses, the presence of prodromal symptoms, and global functioning in offspring of parents with schizophrenia or bipolar disorder and in offspring of controls at baseline and 2-year follow-up. This study included 41 offspring of parents with schizophrenia, 90 offspring of parents with bipolar disorder, and 107 offspring of controls (mean age 11.7 ± 3.2 at baseline and 13.9 ± 3.2 at follow-up). The prevalence of psychopathology and comorbidity was higher in offspring of parents with schizophrenia and offspring of parents with bipolar disorder than in offspring of controls at baseline and at 2-year follow-up. Interestingly, mood disorders were more prevalent in offspring of parents with bipolar disorder and disruptive disorders were more prevalent in offspring of parents with schizophrenia. Prodromal symptoms were more frequent in offspring of parents with schizophrenia than in offspring of controls, while the offspring of parents with bipolar disorder showed an intermediate pattern. Finally, global functioning was lower in the offspring of parents with schizophrenia than the offspring of parents with bipolar disorder and the offspring of controls. Screening patients’ children is clinically relevant, since, as a group, they have an elevated risk of developing a psychiatric disorder and of experiencing their first symptoms during childhood and adolescence.

Neuropsychological underperformance is well described in young adults at clinical high risk for psychosis, but the literature is scarce on the cognitive profile of at-risk children and adolescents. The aim of this study is to describe the neuropsychological profile of a child and adolescent sample of patients with psychosis risk syndrome (PRS) compared to healthy controls and to analyze associations between attenuated psychotic symptoms and cognitive impairment. Cross-sectional baseline data analysis from a longitudinal, naturalistic, case–control, two-site study is presented. Eighty-one help-seeking subjects with PRS and 39 healthy controls (HC) aged between 10 and 17 years of age were recruited. PRS was defined by: positive or negative attenuated symptoms, Brief Limited Intermittent Psychotic Symptoms (BLIPS), genetic risk (first- or second-degree relative), or schizotypal personality disorder plus impairment in functioning. A neuropsychological battery was administered to assess general intelligence, verbal and visual memory, visuospatial abilities, speed processing, attention, and executive functions. The PRS group showed lower general neuropsychological performance scores at a multivariate level and lower scores than controls in general intelligence and executive functions. Lower scores on executive function and poorer attention were associated with high scores of positive attenuated psychotic symptoms. No association with attenuated negative symptoms was found. This study provides evidence of cognitive impairment in PRS children and adolescents and shows a relationship between greater cognitive impairment in executive functions and attention tasks and severe attenuated positive symptoms. However, longitudinal studies are needed to clarify the nature of cognitive impairment as a possible vulnerability marker.

During the last 10 years, early intervention in psychosis programs has been implemented by the Public Health System (PHS) in some of the 17 autonomous communities of Spain. Most of these programs have focused on assessment and intervention in patients with first episode psychosis (FEP), with only a minority including participants with an attenuated psychosis syndromes (APS). These are recruited both through self-referrals by help-seeking patients and through strategies actively seeking to recruit APS from within the community. In the existing programs so far, identification of APS is performed with the Structured Interview of Prodromal Symptoms (SIPS) and Scale of Prodromal Symptoms (SOPS), and Comprehensive Assessment of At-Risk Mental Status (CAARMS), translated into Spanish. Intervention approaches are documented in clinical practice guidelines sponsored by PHS authorities. Although there are some common features across the different programs such as first-line psychological treatments, there are other aspects, such as type of psychotherapy delivered or the indication or type of pharmacological treatments, which vary across programs. Thus, there is substantial variability in the assessment and intervention received by patients with APS throughout Spain. Research in patients with attenuated psychotic symptoms has grown exponentially in Spain in recent years, employing clinical, cognitive, hormonal, immunological, and neuroimaging measures, and has added to the collective body of research characterizing the APS and predictors of transition to psychosis. An illustration of a typical APS case with some characteristic features of current Spanish society is also presented.

Background The N-methyl-D-aspartate receptor hypofunction model of schizophrenia suggests that dysfunction of these receptors leads to an excess release of glutamate and could explain the brain structural abnormalities characterizing these patients. However, glutamatergic pathways underlying transition to psychosis are yet unclear. Methods Youth with recent onset psychosis (FEP), within the first 5 years of disease, individuals with high risk for psychosis (HR) –including participants with psychosis risk syndrome meeting SIPS/SOPS criteria and offspring of parents with bipolar disorder or schizophrenia –, and healthy volunteers, were recruited and scanned with a 3T Siemens scanner. Magnetic resonance spectroscopy was performed using a 2x2x2 cm3 voxel (VOI) placed in the middle frontal region. Ratios of glutamate (Glu), and glutamate + glutamine (Glx) were quantified using LCModel. Results 18 adolescents with FEP, 33 HR and 32 healthy controls (HC) were included in the analysis. There were no significant differences between groups in mean age (16.4±2.1 vs 15.7±2.7 vs 16.8±1.9; F=2.0, p=.139), but there were trend-level differences in gender (%females: 33.3% vs 57.6% vs 68.8%; Х2=5.9, p=.052). Multivariate models controlling for gender showed a trend-level effect of group in Glu (F=2.9, p=.062), but not in Glx. Post-hoc pairwise contrasts for Glu revealed significantly higher Glu levels in HR individuals (1.38±0.16) compared to FEP (1.27±0.20) and HC (1.31±0.15). Discussion Our findings support that increased Glu in the prefrontal cortex may index risk of psychosis from the early stages of the disease, during adolescence. Our observations suggest a possible hyperglutamatergia in premorbid stages that may normalize –or even decrease – after illness onset, possibly related to treatment or compensatory mechanisms. While requiring replication in a larger sample and including follow-up through transition in HR individuals, our findings raise the possibility that abnormal glutamatergic metabolism in the prefrontal cortex could be used as a potential biomarker of illness and putative treatment target.

Background The onset of a psychotic disorder before age 18 (early-onset psychosis, EOP) is a marker of greater clinical severity and poor outcome. There is a lack of studies examining the efficacy of psychological treatment in this population. The Cognitive-Behavioral Social Skills Training (CBSST) is an evidence-based psychological intervention for patients with schizophrenia. OBJECTIVE: To analyze the efficacy of the adolescent version of CBSTT (CBSST-Adolt) versus an active psychological intervention, administered during the critical period, to improve symptoms and functioning in patients with EOP. Methods Randomized controlled trail (RCT) of the adolescent version of the CBSST-Adol compared to an active control intervention. Interventions: The CBSTT-Adol included the 3 original modules (cognitive abilities, social skills, problem-solving skills) but number of sessions was reduced. It was administered in small groups. The active control intervention (PSYCHOED-Adol) included 3 modules (psychoeducation, relapse prevention, healthy life style) with the same format and number of sessions. The language and examples were adapted for adolescents in both interventions. Inclusion criteria: schizophrenia spectrum disorder (schizophrenia, schizoaffective disorder, psychotic disorder not otherwise specified), diagnosed before 18; being in the critical period of the illness (first 5 years after the onset); being clinically stabilized (outpatients). Exclusion criteria: IQ Results There were no significant differences in sex or age, but in socioeconomic status (p0.05). There was a similar rate of dropouts during the trail in both branches of the study (31% and 29%, p>0.05). Improvements in clinical symptoms (PANSS total, p=0.045; PANSS positive symptoms, p=0.009) and functioning (GAF, p=0.002; GF:Social, p=0.025, CBI, p=0.020) were found at post-treatment in all sample. However, there was no a superior effect of CBSST-Adol compared to PSYCHOED-Adol in any variable. There was only a trend to a higher improving of the Communication and social contact subscale of the Life Skills Profile in the CBSST-Adol intervention (p=0.061). Discussion The results support the efficacy of psychological intervention improving symptoms and functioning in EOP. We find a similar positive effect after the treatment in both CBSTT-Adol and PSYCHOED-Adol interventions. Main limitations: not having a non-active control group and the sample size.

Background Bipolar Disorder (BD) is a major psychiatric illness defined by episodic mood changes, which in approximately 50% of cases is associated with psychotic features. Over the past decades, a large amount of research has identified brain structural and functional alterations in patients with this mental disorder. Some findings have been found to be specific to patients with psychotic symptoms, raising suggestions that this could represent a biological subtype of the disorder. Recent interest has been addressed to Early-Onset Bipolar Disorder (EOBD, onset prior to age 18). Latest reviews in EOBD samples have pointed to abnormalities in the frontal lobe and limbic structures, with some inconsistencies in the reported results possibly caused by differences in the methodology. In addition, no study so far has examined the neural structural correlates of psychotic symptoms in adolescent-onset bipolar disorder (AOBD). The aim of the present study is to examine the impact of psychosis on the neurobiological architecture in a sample of patients with AOBD. To our knowledge, this is the first study comparing gray matter structure between AOBD patients with or without psychotic features. Methods We conducted a cross-sectional study collecting T1-weighted structural magnetic resonance neuroimaging (3T-MRI) data in patients diagnosed with Bipolar Disorder type I or II between 12 and 19 years old (N=46, mean age (SD)=15.89 (1.94), gender=52.2% females). All patients were recruited from child and adolescent mental health services of the Hospital Clinic of Barcelona, Spain. Diagnoses were confirmed with a semi-structured clinical interview (Kiddie-Sads present and lifetime version) by child and adolescent psychiatrists. Images were pre-processed employing FreeSurfer 5.3.0, and data corresponding to Cortical Thickness (CTH) and Subcortical Volumes (SCV) was obtained. Groups were compared according to whether patients had experienced psychotic symptoms at any point during their illness: Non-Psychotic Bipolar Disorder (NPSBD, N=25) and Psychotic Bipolar Disorder (PSBD, N=21). No differences in age (t=0.498, p=0.621) or sex (χ2=0.001, p=0.979). Group effects in relation to both CT and SCV were examined with a general linear model. The main effect of group on CTH and SCV, was performed for the whole brain, performing a correction for multiple comparisons (Montecarlo correction, threshold = 0.05). Results Between-group analyses showed smaller CTH in a cluster in the left medial orbitofrontal cortex (cluster size= 1142.58 mm2) in PSBD relative to NPSBD (x, y, z: 25.63, 89.61, -42.74; p=0.002). In addition, we observed a smaller right hippocampus volume (p=0.025) in PSBD relative to NPSBD. No other statistically significant differences were obtained. Discussion PSBD showed smaller cortical thickness in the left medial orbitofrontal cortex, as well as a volumetric reduction in the right hippocampal volume. Similar results have been reported in a study comparing adolescent patients with psychotic BD and healthy controls. These results add evidence about the role of these two structures in the genesis of psychotic symptoms in a population diagnosed with AOBD. Interestingly, one study has reported a surface area decreased of the orbitofrontal cortex in adolescent patients with a non-bipolar psychotic disorder, which suggests that they may be a common substrate to psychotic symptoms during adolescence regardless of co-occurring affective symptoms. In summary, this study points to the existence of a distinct biological nature between bipolar patients according to psychotic symptoms, underpinned by a different neurobiological architecture. Future research should focus on replication and on examining the clinical value of this finding.

Although second generation long-acting injectable antipsychotics (SG-LAIAs) have been approved and are widely used in adults, there is limited evidence for the use of long-acting formulations in children and adolescents. Thus, we systematically describe the off-label use of SG-LAIAs in clinical practice in adolescent inpatients.All individuals admitted to our Children and Adolescent Inpatient Psychiatry Unit receiving treatment with SG-LAIAs between January 2013 and June 2016 were reviewed. A retrospective analysis of medical records was conducted. Clinical diagnoses were established using DSM-5 criteria.Thirty individuals (53.3% female) out of a total of 1,148 admitted patients (2.6%) were identified. The mean age was 16.3 (SD = 1.3; range: 12.5-17.9).The main diagnoses were psychosis (70%) and disruptive behavior disorders (DBDs) (30%), although comorbidity was frequent (96.6%), especially drug use (55.2%, mostly cannabis). SG-LAIAs used were aripiprazole (40%), risperidone (36.7%), and paliperidone palmitate (23.3%), and the main reasons were a history of low compliance (90%) and/or poor insight (73.3%). A mean improvement of 31.7 (SD = 8.7) between admission and discharge was registered in the Children's Global Assessment Scale (CGAS); no differences were observed between different SG-LAIAs. Although they were generally well tolerated, 23.3% of patients reported mild short-term side effects, which were more frequent with risperidone than with aripiprazole (p = .014).Our clinical experience suggests that SG-LAIAs may be a safe treatment option during adolescence in inpatients with psychotic disorders, as well as with DBD. No differences were found in CGAS improvement scores between the three SGA-LAIAs used, although patients on risperidone reported more side effects than those on aripiprazole. Further research is needed so as to evaluate safety and effectiveness of SG-LAIAs in this population.

Aim Despite the interest in psychosis risk syndrome (PRS) in children and adolescents, information on the syndrome in this population is scarce. Methods Prospective naturalistic multi-site study in which 10- to 17-year-old help-seeking subjects who met PRS criteria (positive or negative attenuated symptoms; brief limited intermittent psychotic symptoms; genetic risk or schizotypal personality disorder plus impairment in functioning) were included, along with 45 age and sex-matched healthy controls (HC). All subjects were clinically and functionally assessed. Results Ninety-one PRS subjects (PRSS) with a mean age of 15.5 ± 1.4 met inclusion criteria (IC). Compared with HC, PRSS presented worse global and academic functioning in the previous year, had experienced more psychiatric and psychological problems, and presented gestational ages outside the normal range. More than 80% of PRSS met ≥2 IC, with 65.9% having one Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition Text Revision diagnosis, and 61.7% of those having ≥2 diagnoses. Some 49.5% of PRSS had a first- or second-degree family history (FH) of psychosis. Patients with first- and second-degree FH do not differ in their clinical expression. Conclusions Children and adolescents with PRS are a patient group with a pattern of neurodevelopmental impairment and clinical complexity similar to patients with schizophrenia spectrum disorders, highlighting the importance of assessing these variables in child and adolescent samples. PRSS with first- and second-degree relatives with FH do not present differences in their clinical presentation, suggesting that including these two groups of patients in the genetic risk criteria would enrich knowledge of these criteria.

Background Identification of biomarkers of transition to psychosis in individuals at ultra-high risk (UHR) has the potential to improve future outcomes (McGorry, 2008). Structural MRI studies with UHR samples have revealed steeper rates of cortical thinning in temporal, prefrontal and cingulate cortices in individuals who later develop psychosis in both baseline and longitudinal comparisons (Fusar-Poli, 2011; Cannon, 2014). However, little is known about how onset of prodromal symptoms during adolescence impacts on changes in cortical thickness (CTH) (Ziermans, 2012). Methods Multicentre cross-sectional case-control study, including youth aged 10–17 years, recruited from two child and adolescent mental health centres. UHR individuals were identified using the Structured Interview for Prodromal Syndromes criteria with some modifications. Healthy controls (HC) were recruited from the same geographical area. Exclusion criteria comprised personal history of psychotic symptoms, IQ.6) for CTH measures. Images were pre-processed employing automated procedures implemented in FreeSurfer 5.3.0, cortical parcellation employed the Desikan-Killiany brain atlas. Analyses: First, mean global and lobar (frontal, parietal, temporal, occipital, insula and cingulate) CTH measurements were computed. Then, within lobes showing group effects, CTH was measured for each parcellation. ANCOVA was performed to test differences between groups in SPSS 22.0, including gender, age, total intracranial volume and site as covariates. Significance was set at p

Background Structural volume loss of cortical gray matter over time in schizophrenia has been widely reported (Vita et al. 2012), and may be more pronounced when the disorder has an onset prior to age 18 (Early Onset Psychosis, EOP; Arango et al. 2008). More recently, studies have focused on measures of cortical morphology. The single study in EOP so far has identified greater loss of cortical thickness (CTH) in patients with schizophrenia over time (van Haren et al. 2011), whereas to our knowledge, no so far study has examined measures of surface area (SA) in EOP following a longitudinal design. We set out to examine measures of both CTH and SA in a sample of EOP at 10-year-follow-up. Methods Patients with EOP were recruited at first episode, matched by sex and age with healthy controls (HC) and re-assessed at 10 years. Subjects were evaluated clinically and structural T1 volumes were acquired using magnetic resonance imaging at baseline and 10-year-follow-up. Images were preprocessed, segmented and analysed with FreeSurfer. Quality control procedure was carried out by two raters. Images were segmented and CTH and SA values were extracted for each parcellation employing Desikan-Killiany Atlas; these were grouped in frontal, occipital, temporal, parietal and cingulate lobes so as to reduce multiple comparisons. When group or group by time effects were detected, parcellations were individually examined. A linear mixed model was built using Stata IC 13.1 to evaluate the effect of group and time on CTH and SA, including hemisphere as fixed effects and correcting by total intracranial volume and setting a critical p-value of .05. Results Thirty-nine subjects completed the follow-up. After removing 9 due to poor quality T1 images (technical problems, excess of movement), 28 subjects were finally included (13 EOP, 15 HC). There were no significant differences in age (EOP=26.9 ± 0.6 vs HC=27.2 ± 0.3 at follow-up) or sex distribution (%female: EOP=43% vs HC=38%) between groups. The distribution of diagnosis in the case group was: schizoaffective disorder (n=5), bipolar disorder with psychotic features (n=3), schizophrenia (n=2) and others (n=3). There was a trend-level group effect in global CTH (p = .07) which was significant in the frontal lobe (p = .014). EOP exhibited less CTH in the caudal middle frontal (p = .016) and pars opercularis (p = .03) and orbitalis (p = .007) of the inferior frontal gyrus. There was an effect of time in the parietal (p = .013) and occipital (p = .004) lobes consisting of thinner CTH at follow-up in both groups. There were no differences in SA between groups. Both showed an increase in total SA (p < .001) and for parietal (p < .001), temporal (p = .009) and occipital (p = .003) regions at follow-up. There a group by time effect in frontal SA, consisting of an increase over time in HC and a decrease in EOP (p = .044), specifically in medial orbito-frontal cortex (p = .039). Discussion Our results have identified: 1) thinner cortices in frontal regions in EOP compared to HC, which seems to be constant over time; and 2) a decreased in SA in frontal areas in EOP along time, contrasting with HC, whose frontal surface increased at follow-up. These findings are consistent with another study (Greenstein et al. 2006) which also reported reduced CTH in frontal areas in EOP during development, while we found no abnormalities in temporal regions (Vita et al. 2012). Despite the small sample size, to our knowledge this is the longest follow-up of an EOP sample employing magnetic resonance imaging so far.

Background High-risk symptoms for psychosis (HRS) and substantial functional impairment occurs early in the course of psychosis (Fusar-Poli et al., 2015). Many patients with HRS are adolescents who are still living at home and are highly reliant on their relatives for support. Objectives: (1) To compare the family burden of caregivers of adolescents with HRS with carers of an age and gender matched healthy control group (HC), (2) to examine the relationships between different family burden aspects and high-risk symptoms for psychosis in the HRS sample. Methods Sample: 68 HRS subjects (15.3 ± 1.7 years, 66% females) and 42 HC subjects (15.5 ± 1.5 years, 66% females) from a prospective longitudinal study including help-seeking subjects who met HRS criteria (Child and Adolescent Psychiatry and Psychology departments of Hospital Clínic and Sant Joan de Déu, Barcelona, Spain). Inclusion criteria: age 10–17 years, meeting criteria for 1) attenuated positive or negative symptoms in the previous 12-months, 2) brief intermittent psychotic symptoms, 3) first or second degree relative with schizophrenia or schizotypical disorder plus impairment of functioning. Exclusion criteria: IQ-9.35, p-5.59, p

Paliperidone palmitate long-acting injection (PPLAI) is an atypical antipsychotic agent currently approved by the European Medicine Agency for the acute and maintenance treatment of schizophrenia in adults. However, there is no information so far on safety and effectiveness in patients under 18 years of age. We report on two clinical cases of adolescents with a psychotic spectrum disorder treated with PPLAI in an inpatient setting. The cases illustrate that PPLAI may hold potential as an effective and acceptably tolerated antipsychotic drug in adolescents with psychotic spectrum disorders. Given the lack of approved long acting injectable antipsychotics in patients under 18 years of age, reports on the effectiveness and safety of such medications in children and adolescent patients are of importance.

Background Studies in child and adolescent offspring of patients with schizophrenia or bipolar disorders may help understand the influence of neurodevelopmental factors on the premorbid phenotype of these disorders. Aims To assess whether a combination of neurodevelopmental factors discriminates between young offspring of patients with schizophrenia (SzO) or bipolar disorder (BpO) and community controls (CcO). To assess the association between these factors and rates of psychiatric diagnoses in high risk (HR) youth. Methods One hundred thirty-three HR offspring (47 SzO and 86 BpO) and 84 CcO, aged 6-17, underwent cross-sectional clinical, neurocognitive, and structural neuroimaging assessment. Information on perinatal events and early childhood development was also obtained. General linear mixed models were performed to assess group discrimination and association with lifetime axis I psychiatric disorders. Results Multivariate analyses revealed that greater neurological soft signs (NSS), less total grey matter volume (GMV) and a higher frequency of obstetric complications discriminated HR offspring from CcO. When comparing each group individually, greater NSS and a higher frequency of obstetric complications discriminated SzO from CcO, and BpO from CcO, while lower intelligence also discriminated SzO from CcO and from BpO. Within HR offspring, lower intelligence and less total GMV were associated with lifetime incidence of psychiatric disorders. Conclusions Both SzO and BpO showed evidence of neurodevelopmental insult, although this may have a greater impact in SzO. Lower intelligence and less total GMV hold potential as biomarkers of risk for psychiatric disorders in HR youth.

Background Dysfunctional attitudes such as defeatist performance beliefs (DPB) and asocial beliefs (AB) have been linked to negative symptoms and functional outcome in chronic schizophrenia (Campellone et al., 2016; Grant and Beck, 2010) and in adults with recent onset schizophrenia (Ventura et al., 2014). Adolescents with early-onset psychosis (EOP) are at major risk of having persistent negative symptoms (Puig et al., 2017) but no previous study has examined dysfunctional attitudes in this population. We aimed: (1) to examine if more DPB and AB were present in adolescents with EOP compared with normal controls, and (2) to study the relationships between DPB and AB with symptoms and functioning. Methods Sample: 15 adolescents with EOP (11♀, age=15.33 ± 1.23) and 10 healthy controls (8♀, age=15.60 ± 1.51), participants in a trial about cognitive and behavioral social skills treatment in EOP developing in Hospital Clínic of Barcelona (baseline data). Patients were under antipsychotic meds. Inclusion criteria: having an early-onset schizophrenia spectrum disorder diagnosed between 9–18 years-old (schizophrenia, schizoaffective disorder, psychosis n.o.s.); being within the 5 first years after the disease onset; clinical stability. Exclusion criteria: IQ6.67, p3.02, p

Background A 22 - 31% prevalence of abnormal radiological findings (RF) has been reported among patients with first episode of psychosis (FEP), ranging from clinically non-significant findings to overt neurological pathology. While one study (Borgwardt et al., 2006) found a higher proportion of RF in adult subjects at high risk for psychosis (35%) and FEP patients (40%) than in patients with depression (18%) or healthy controls (12%), another found a similar increase in RF in patients with affective and psychotic disorders (Landin et al, 2016). This suggests that macroscopic brain anomalies may be characteristic of at least a subset of patients in the early stages of psychosis, and these RF may not be specific to schizophrenia, but also to psychosis with affective symptoms. To this day, all published research studies have been done in primarily adult samples. Psychosis with onset before age 18 may be associated with more salient biological features linked with greater genetic load and neurodevelopmental antecedents (Arango, 2014). Aims To assess the prevalence of neuroradiological abnormalities in a population with early-onset psychosis (EOP) in comparison to a sample of community controls, and to evaluate the association of these findings with the type of psychotic disorder of the patients. Methods Design: Naturalistic, observational, retrospective, single-center controlled study. A chart review of individuals admitted to the Inpatient unit of the Dept. of Child and Adolescent Psychiatry and Psychology from January 2013 to December 2016 was done. Patients were 6 to 17 years old, fulfilled DSM-IV-TR criteria for a psychotic disorder (PD), and had a radiology report of a brain MRI. The community control (CC) group had a similar age and gender distribution and no current diagnosis of any psychotic disorder. Any neurological or severe medical condition or head trauma with loss of consciousness were exclusion criteria for both groups. Sociodemographic, clinical, and radiological variables were recorded for both groups. Given the association of abnormal RF with prematurity, perinatal complications and neurodevelopmental disorders, these data were collected and sorted dichotomously. Descriptive statistical analysis consisted of a means and standard deviation for quantitative variables and percentages for qualitative variables. Between-group differences were calculated with chi-square test or Fisher’s test using IBM SPSS v23. Results A total of 191 individuals were included (127 PD vs 64 CC, mean ages: 14.7 ± 1.8 vs 13.8 ± 2.3, t=3.0, p=.01; %females: 55.9.0% vs 60.9%, χ2=.44, p=.50). Main diagnoses in PD were psychosis not otherwise specified (PNOS) (59.1%), schizoaffective disorder (SAD) (12.6%), schizophrenia (SCZ) (11.0%), bipolar disorder (BD) (8.7%) and major depression with psychotic features (MDD) (8.7%). The PD group presented with a significantly higher prevalence of qualitative neuroimaging abnormalities in comparison to CC (21.3% (n=27) vs 6.2% (n=4), χ2=7.1, p=.008). These included arachnoid cysts, dilated perivascular space or white matter intensity anomalies. The prevalence of abnormal RF was 25.3% in PNOS, 21.4% in SCZ, 18.2% in MDD 12.5% in SAD and 9.1% in BD. Discussion A significantly higher prevalence of RF was found in youth with both affective and non-affective psychosis compared to similar-aged controls, concurring with some (Borgwardt et al., 2006; Landin et al., 2016), yet not with other (Sommer et al., 2013) observations in adult samples. These findings may reflect an impact of subtle biological alterations associated with psychosis on brain development, which may be more salient in early-onset cases. Our data highlight the need to continue assessing the significance of abnormal RF in patients with EOP

Recent articles published in CNS Neuroscience and Therapeutics reflect the increasing interest of the scientific community in the therapeutic properties of cannabis[1,2]. However, an aspect that is commonly overlooked is the potential medical side effects of cannabis use, among which severe hyperemesis is an uncommon condition. Cannabinoid hyperemesis syndrome (CHS) occurs in chronic, daily cannabis users and is characterized by cyclic vomiting and compulsive bathing behavior. This clinical manifestation is paradoxical, given the previously identified therapeutic role of cannabis as an antiemetic agent. We report a recent case of CHS associated with organic and psychiatric complications that was diagnosed at our center. A 36-year-old Hispanic woman attended the emergency department of a tertiary hospital presenting with second-degree burns on 20% of her body surface. These had been caused by repeated showers in excessively hot water. She also reported a history of frequent episodes of nausea and vomiting for the previous 24 months, which after several inconclusive assessments had been attributed to anxiety. She denied any medical or surgical history, except diagnosis of gastritis in 2011, treated with omeprazole. She had visited the emergency department on several occasions during the previous 5 years referring anxiety and abdominal pain associated with vomiting and compulsive hot showers which the patient had claimed were aimed at relieving anxiety symptoms, and which were considered to be part of an obsessive–compulsive disorder (OCD). She had been treated with antidepressant and anxiolytic drugs without clear improvement. She admitted to smoking marijuana daily for at least 5 years, while she denied the use of any other illicit substances. The patient was admitted for evaluation and was administered acid-suppressive medications, antiemetics, rehydration, and topical treatment. The patient’s laboratory data at admission were normal, except for hypokalemia and a positive urinary drug screen for cannabis, while the physical examination yielded no additional information. During the length of the patient’s hospital admission, she continued to take hot showers numerous times each day. Taking into account the patient’s clinical presentation and her history of regular cannabis use, she was diagnosed with CHS. The patient was informed of the diagnosis, and of the need to cease her marijuana use. On further questioning, the patient confirmed persistent, daily marijuana use over the past 5 years. Following liaison with her psychiatrist, she was referred to a drug treatment center to address her cannabis use disorder, while her OCD diagnosis was withdrawn and her medication modified. Six months later, she had succeeded in giving up cannabis use entirely, she had not suffered any further episodes of nausea or vomiting, and she showered once daily with mild warm water.

Introduction: A number of observational studies have revealed an earlier onset of psychosis in schizophrenic patients with history of cannabis use. We evaluated whether use of cannabis determines an earlier onset of schizophrenia in a sample of first episode patients in an area with one of Europe’s highest rates of cannabis use. Methods: All first psychotic episode patients admitted in the case register of the Schizophrenia-Clinic Programme between 2002-2007 were assessed. Only those with confirmed diagnosis of schizophrenia (DSM-IV) were included in the analysis. Age at first antipsychotic treatment was used as proxy for age of psychosis onset, acting as dependent variable for the statistical analysis. Cannabis use was evaluated retrospectively considering period of greatest consumption: 46 (39.7%) had never used cannabis, 23 (19.9%) sporadically and 47 (40.5%) daily. Analysis of variance, polinomic lineal tendency analysis and individual post-hoc contrasts were performed. Results: The final sample included 116 subjects. Age of first antipsychotic treatment differed between groups (mean and [SD]: 27.0 [4.94]; 25.7 [4.44] and 24.5 [4.36]; p=0.033) and diminished as cannabis use increased (linear tendency; p=0.009). Post-hoc contrasts revealed that patients who had used cannabis (irrespective of frequency) had significantly lower ages of onset (p=0.033), ranging between 0.17 and 3.70 years (CI 95%). Conclusions: In our sample, cannabis use significantly decreased age of psychosis onset in schizophrenia. Prospective studies with larger samples are necessary to further study this association. References [1] Veen ND, Selten JP, van dT, I, Feller WG, Hoek HW, Kahn RS: Cannabis use and age at onset of schizophrenia. Am J Psychiatry 2004; 161(3):501-506 [2] Smit F, Bolier F, and Cuijpers P. Cannabis and risk of later schizophrenia: a review. Addiction 99, 425-430.2 004. [3] Moore TH, Zammit S, Lingford-Hughes A, Barnes TR, Jones PB, Burke M, and Lewis G. Cannabis use and risk of psychotic or affective mental health outcomes: a systematic review. The Lancet 370, 319-328. 2007.