High Risk For Schizophrenia Research Articles

Causal associations of intelligence with schizophrenia and bipolar disorder: A Mendelian randomization analysis.

Intelligence is inversely associated with schizophrenia (SCZ) and bipolar disorder (BD); it remains unclear whether low intelligence is a cause or consequence. We investigated causal associations of intelligence with SCZ or BD risk and a shared risk between SCZ and BD and SCZ-specific risk. To estimate putative causal associations, we performed multi-single nucleotide polymorphism (SNP) Mendelian randomization (MR) using generalized summary-data-based MR (GSMR). Summary-level datasets from five GWASs (intelligence, SCZ vs. control [CON], BD vs. CON, SCZ+BD vs. CON, and SCZ vs. BD; sample sizes of up to 269,867) were utilized. A strong bidirectional association between risks for SCZ and BD was observed (odds ratio; ORSCZ→BD=1.47, p=2.89×10-41, ORBD→SCZ=1.44, p=1.85×10-52). Low intelligence was bidirectionally associated with a high risk for SCZ, with a stronger effect of intelligence on SCZ risk (ORlower intelligence → SCZ=1.62, p=3.23×10-14) than the reverse (ORSCZ→lower intelligence=1.06, p=3.70×10-23). Furthermore, low intelligence affected a shared risk between SCZ and BD (OR lower intelligence → SCZ+BD=1.23, p=3.41×10-5) and SCZ-specific risk (ORlower intelligence → SCZvsBD=1.64, p=9.72×10-10); the shared risk (ORSCZ+BD→lower intelligence=1.04, p=3.09×10-14) but not SCZ-specific risk (ORSCZvsBD→lower intelligence=1.00, p=0.88) weakly affected low intelligence. Conversely, there was no significant causal association between intelligence and BD risk (p>0.05). These findings support observational studies showing that patients with SCZ display impairment in premorbid intelligence and intelligence decline. Moreover, a shared factor between SCZ and BD might contribute to impairment in premorbid intelligence and intelligence decline but SCZ-specific factors might be affected by impairment in premorbid intelligence. We suggest that patients with these genetic factors should be categorized as having a cognitive disorder SCZ or BD subtype.

Reduced Physical Activity and Sleep in 11-Year Old Children with a Familial High Risk of Schizophrenia or Bipolar Disorder the Danish High Risk and Resilience Study - VIA 11

Reduced Physical Activity and Sleep in 11-Year Old Children with a Familial High Risk of Schizophrenia or Bipolar Disorder the Danish High Risk and Resilience Study - VIA 11

Psychotic experiences in seven-year-old children with familial high risk of schizophrenia or bipolar disorder in: The Danish High Risk and Resilience Study – VIA 7; A population-based cohort study

We aimed to examine the prevalence of psychotic experiences (PEs) in children with familial high risk of schizophrenia (FHR-SZ) or bipolar disorder (FHR-BP) and, in exploratory analyses, to examine the possible associations between PEs and mental disorders as well as level of functioning.A cohort of seven-year-old children with FHR-SZ (N = 199), FHR-BP (N = 118) and controls (N = 196) was recruited through Danish nationwide registers. Lifetime PEs were assessed through interviews using the psychosis section of the ‘Schedule for Affective Disorders and Schizophrenia for School-Age Children - Present and Lifetime Version’ (K-SADS-PL). Lifetime DSM-IV diagnoses were ascertained through K-SADS-PL and the level of functioning of the children through ‘Children's Global Assessment Scale’.Both children with FHR-SZ (OR = 2.9, 95% CI = 1.4–6.2, p = 0.005) and FHR-BP (OR = 2.9, 95% CI = 1.3–6.7, p = 0.011) had an increased risk of having experienced “severe” PEs compared with controls. In the overall cohort PEs were associated with any lifetime mental disorder, Attention-Deficit/Hyperactivity Disorder, anxiety disorders and a lower level of functioning.The findings of a higher proportion of high risk children reporting PEs could represent an early manifestation of later more severe psychopathology or simply an unspecific transitory symptom. Future follow-up studies of this cohort will explore the predictive value of the occurrence of PEs at age seven.

Clinical Correlates of the NR3C1 Gene Methylation at Various Stages of Psychosis.

BackgroundDysregulation of epigenetic processes might account for alterations of the hypothalamic-pituitary-adrenal axis observed in patients with schizophrenia. Therefore, in this study, we aimed to investigate methylation of the glucocorticoid receptor (NR3C1) gene in patients with schizophrenia-spectrum disorders, individuals at familial high risk of schizophrenia (FHR-P), and healthy controls with respect to clinical manifestation and a history of psychosocial stressors.MethodsWe recruited 40 first-episode psychosis patients, 45 acutely relapsed schizophrenia (SCZ-AR) patients, 39 FHR-P individuals, and 56 healthy controls. The level of methylation at 9 CpG sites of the NR3C1 gene was determined using pyrosequencing.ResultsThe level of NR3C1 methylation was significantly lower in first-episode psychosis patients and significantly higher in SCZ-AR patients compared with other subgroups of participants. Individuals with FHR-P and healthy controls had similar levels of NR3C1 methylation. A history of adverse childhood experiences was associated with significantly lower NR3C1 methylation in all subgroups of participants. Higher methylation of the NR3C1 gene was related to worse performance of attention and immediate memory as well as lower level of general functioning in patients with psychosis.ConclusionsPatients with schizophrenia-spectrum disorders show altered levels of NR3C1 methylation that are significantly lower in first-episode psychosis patients and significantly higher in SCZ-AR patients. Higher methylation of the NR3C1 gene might be related to cognitive impairment observed in this clinical population. The association between a history of adverse childhood experiences and lower NR3C1 methylation is not specific to patients with psychosis. Longitudinal studies are needed to establish causal mechanisms underlying these observations.

Decision making and its associations to neurocognitive functions, psychopathology, and the home environment in seven-year-old children at familial high risk of schizophrenia or bipolar disorder: The Danish High Risk and Resilience Study VIA 7

Background: Slower and suboptimal decision making has been identified in adults with schizophrenia and bipolar disorder. Owing to the limited evidence on decision making in first-degree relatives, we aimed to investigate, whether alterations in decision making are present in young children at familial high risk of bipolar disorder or schizophrenia.Methods: In this population-based cohort study we assessed decision making in 197 children at familial high risk of schizophrenia (FHR-SZ), 115 children at familial high risk of bipolar disorder (FHR-BP), and 190 controls aged seven using the Cambridge Gambling Task. Potential associations to neurocognition, psychopathology, and the home environment were investigated.Results: Children at FHR-SZ or FHR-BP displayed intact decision making. Quality of decision making showed significant but weak cross-sectional associations to neurocognition and adequacy of the home environment. Associations to aspects of executive functions and the home environment differed across groups.Limitations: Due to the cross-sectional nature of this study, the predictive value of efficient and inefficient decision making remains to be investigated in planned follow-up studies of this cohort.Conclusions: Young children at FHR-SZ or FHR-BP do not differ from controls in decision making efficacy, which does not appear to be an early risk marker of bipolar disorder or schizophrenia. Decision making is weakly associated to neurocognition and the home environment, but not to general intelligence or psychopathology.

Associations between gut microbiota and Alzheimer\u2019s disease, major depressive disorder, and schizophrenia

BackgroundGrowing evidence has shown that alterations in the gut microbiota composition were associated with a variety of neuropsychiatric conditions. However, whether such associations reflect causality remains unknown. We aimed to reveal the causal relationships among gut microbiota, metabolites, and neuropsychiatric disorders including Alzheimer’s disease (AD), major depressive disorder (MDD), and schizophrenia (SCZ).MethodsA two-sample bi-directional Mendelian randomization analysis was performed by using genetic variants from genome-wide association studies as instrumental variables for gut microbiota, metabolites, AD, MDD, and SCZ, respectively.ResultsWe found suggestive associations of host-genetic-driven increase in Blautia (OR, 0.88; 95%CI, 0.79–0.99; P = 0.028) and elevated γ-aminobutyric acid (GABA) (0.96; 0.92–1.00; P = 0.034), a downstream product of Blautia-dependent arginine metabolism, with a lower risk of AD. Genetically increased Enterobacteriaceae family and Enterobacteriales order were potentially associated with a higher risk of SCZ (1.09; 1.00–1.18; P = 0.048), while Gammaproteobacteria class (0.90; 0.83–0.98; P = 0.011) was related to a lower risk for SCZ. Gut production of serotonin was potentially associated with an increased risk of SCZ (1.07; 1.00–1.15; P = 0.047). Furthermore, genetically increased Bacilli class was related to a higher risk of MDD (1.07; 1.02–1.12; P = 0.010). In the other direction, neuropsychiatric disorders altered gut microbiota composition.ConclusionsThese data for the first time provide evidence of potential causal links between gut microbiome and AD, MDD, and SCZ. GABA and serotonin may play an important role in gut microbiota-host crosstalk in AD and SCZ, respectively. Further investigations in understanding the underlying mechanisms of associations between gut microbiota and AD, MDD, and SCZ are required.

Diadochokinetic speech in individuals at clinical high risk for schizophrenia

Past work has shown that individuals at clinical high risk (CHR) for developing psychosis have difficulty with motor coordination (e.g., Mittal etal., 2013). Here we ask whether these motor disruptions also affect their ability to produce speech, resulting in more variable speech productions. CHR participants and matched controls completed a diadochokinetic speech task, in which they first repeated syllables (i.e., papap…, tatat…, kakak…) and then alternated between different syllables (i.e., pataka....) as quickly and accurately as possible. We detect and localize the acoustic syllables /pa/, /ta/ and /ka/ automatically using a deep learning algorithm that was specially designed for the detection of `acoustic objects', discrete events in the acoustic signal (Segal et al., 2019). We predict that, due to less stable control of their articulators, CHR individuals will show increased acoustic variability and more overlap between different sound categories relative to healthy controls.

Disrupted Sleep and Circadian Rhythms in Schizophrenia and Their Interaction With Dopamine Signaling.

Sleep and circadian rhythm disruption (SCRD) is a common feature of schizophrenia, and is associated with symptom severity and patient quality of life. It is commonly manifested as disturbances to the sleep/wake cycle, with sleep abnormalities occurring in up to 80% of patients, making it one of the most common symptoms of this disorder. Severe circadian misalignment has also been reported, including non-24 h periods and phase advances and delays. In parallel, there are alterations to physiological circadian parameters such as body temperature and rhythmic hormone production. At the molecular level, alterations in the rhythmic expression of core clock genes indicate a dysfunctional circadian clock. Furthermore, genetic association studies have demonstrated that mutations in several clock genes are associated with a higher risk of schizophrenia. Collectively, the evidence strongly suggests that sleep and circadian disruption is not only a symptom of schizophrenia but also plays an important causal role in this disorder. The alterations in dopamine signaling that occur in schizophrenia are likely to be central to this role. Dopamine is well-documented to be involved in the regulation of the sleep/wake cycle, in which it acts to promote wakefulness, such that elevated dopamine levels can disturb sleep. There is also evidence for the influence of dopamine on the circadian clock, such as through entrainment of the master clock in the suprachiasmatic nuclei (SCN), and dopamine signaling itself is under circadian control. Therefore dopamine is closely linked with sleep and the circadian system; it appears that they have a complex, bidirectional relationship in the pathogenesis of schizophrenia, such that disturbances to one exacerbate abnormalities in the other. This review will provide an overview of the evidence for a role of SCRD in schizophrenia, and examine the interplay of this with altered dopamine signaling. We will assess the evidence to suggest common underlying mechanisms in the regulation of sleep/circadian rhythms and the pathophysiology of schizophrenia. Improvements in sleep are associated with improvements in symptoms, along with quality of life measures such as cognitive ability and employability. Therefore the circadian system holds valuable potential as a new therapeutic target for this disorder.

Income, income inequality and schizophrenia in China: a population-based multilevel analysis

BackgroundPrevious studies have suggested that socio-environmental factors interact with genetic risk in the genesis of schizophrenia. This study aimed to investigate the relationship between income, income inequality and schizophrenia and...

M193. CHANGES IN THEORY OF MIND DETECTED IN SCHIZOPHRENIA SPECTRUM DISORDERS- A LITERATURE REVIEW

BackgroundTheory of mind (ToM) is a core feature of the social functioning because it influences the way an individual perceive other people’s mental states, and because responses to social cues are shaped by one’s ToM. Patients diagnosed with schizophrenia spectrum disorders (SSD) often present cognitive symptoms as part of their clinical manifestations, and there is a controversy about the relation of ToM deficiencies and more general cognitive features of schizophrenia and related disorders [1]. In order to find data that may clarify if ToM deficiencies are part of the schizophrenia cognitive dimension, or if they precede the onset of psychosis and simply coexist with other symptoms met in this type of disorders, a literature analysis was conducted.MethodsThis review included papers published between January 2000 and August 2019 in the main electronic databases (PubMed, Cochrane, EMBASE, CINAHL). Keywords used for database search were “schizophrenia spectrum disorders”, “schizophrenia”, “schizoaffective disorder”, “delusional disorder”, or “schizophreniform disorder” and “theory of mind”. There was included no age limit, and no exclusion criteria referred to the duration of the disorder.ResultsA number of 93 papers resulted after the primary search, but only 17 remained after de-duplication and application of inclusion/exclusion criteria. A study with young adults diagnosed with first episode of schizophrenia and matched controls (n=128) suggested that ToM deficits are partly independent of other cognitive functions [1]. Another study (n=1630 children 11–12 years old) reported specific alterations in ToM may be associated with specific types of psychotic experiences, and exaggerated type of ToM may index risk for developing psychosis and paranoid delusions in particular [2]. Adolescents who were genetically at high risk for schizophrenia had social skills impairments but no ToM deficits in a study [3]. Also, there is evidence for ToM deficits in the healthy relatives of schizophrenics, patients with delusional disorder, and individual with high schizotypy scores [4]. The hyper-connectivity in SSD has been confirmed on functional magnetic resonance imaging and default connectivity is correlated to and predictive of theory of mind performance [5]. A significant number of papers (n=10) did not formulate any clear argument to support the independent versus secondary status of the ToM deficits in relation to the SSD cognitive dimension.DiscussionToM deficiencies are important elements that have been associated with the social skills and functioning in patients with SSD, although it is not clear if these elements exist independently from other cognitive symptoms. Relatives of patients with SSD may present ToM deficits, and data exist about the correlation between ToM abnormalities and several positive symptoms of the SSD. However, more well designed trials are needed in order to confirm the association between ToM impairments and SSD.ReferencesLindgren M, Torniainen-Holm M, Heiskanen I, et al. Theory of mind in a first-episode psychosis population using the Hinting Task. Psychiatry Res 2018;263:185–192.Clemmensen L, van Os J, Skovgaard AM, et al. Hyper-Theory-of-Mind in children with psychotic experiences. PLoS ONE 2014;9(11):e113082.Gibson CM, Penn DL, Prinstein MJ, et al. Social skills and social cognition in adolescents at genetic risk for psychosis. Schizophr Res 2010;122(1–3):179–184.Bora M. Theory of mind in schizophrenia spectrum disorders. Turkish Journal of Psychiatry 2009;20(3):269–81.Mothersill O, Tangney N, Morris DW, et al. Further evidence of alerted default network connectivity and association with theory of mind ability in schizophrenia. Schizophr Res 2017;184:52–58.

M57. NEUROCOGNITIVE HETEROGENEITY IN 7-YEAR-OLD CHILDREN AT FAMILIAL HIGH RISK OF SCHIZOPHRENIA OR BIPOLAR DISORDER - THE DANISH HIGH RISK AND RESILIENCE STUDY VIA 7

BackgroundNeurocognitive impairments are widespread in individuals with schizophrenia both premorbid and post illness onset. Although less pronounced, individuals with bipolar disorder also display various neurocognitive deficits. Owing to the impaired neurocognitive functions in first-degree relatives, neurocognitive deficits are considered endophenotypes of both disorders. Importantly, neurocognitive heterogeneity exists in both disorders. Distinct neurocognitive subgroups in young adults with clinical high risk of psychosis or familial risk of bipolar disorder have been identified with an increased risk of conversion to illness and poorer functioning in the most neurocognitively impaired subgroup. However, neurocognitive heterogeneity remains to be investigated in young children at familial high risk of schizophrenia (FHR-SZ) and bipolar disorder (FHR-BP). The aim of this study was to identify relatively homogeneous neurocognitive subgroups in a cohort of children with FHR-SZ or FHR-BP and to investigate the distribution of high risk status across the neurocognitive subgroups. Exploratively, potential differences between these subgroups on functional outcome and polygenic risk were investigated.MethodsNeurocognition was assessed cross-sectionally with a comprehensive test battery in a population-based cohort of 514 children aged 7 with either FHR-SZ (N=197), FHR-BP (N=118) or no familial high risk of these disorders (N=199). A hierarchical cluster analysis of the neurocognitive data was performed using Ward’s method and followed-up by a K-means cluster analysis. The neurocognitive clusters were further compared on measures of current level of functioning and polygenic risk for educational attainment.ResultsThree distinct neurocognitive subgroups were derived from the hierarchical cluster analyses: a 1) significantly impaired, 2) typical, and 3) high functioning subgroup. The three subgroups performed significantly different from each other on the majority of the pairwise comparisons of the neurocognitive functions (Cohen’s d range = 0.33–2.27, p < 0.01). There was a significantly higher percentage of children with FHR-SZ in the significantly impaired subgroup (36%) compared to children with FHR-BP (20%). Importantly, 64% of the children at FHR-SZ and 80% of the children at FHR-BP displayed either typical or high neurocognitive functioning. Finally, the neurocognitive subgroups differed significantly on current level of functioning with the significantly impaired subgroup displaying the lowest level of functioning. Polygenic risk for educational attainment was non-significantly different across neurocognitive subgroups.DiscussionYoung children at familial high risk of severe mental disorders (SMD) are neurocognitively heterogenic with three distinct neurocognitive subgroups of varying severity. A higher percentage of children at FHR-SZ was in the significantly impaired subgroup (36%) compared to children at FHR-BP (20%). In this cross-sectional study, being in the significantly impaired neurocognitive subgroup is associated with poorer daily functioning across risk status and in other, longitudinal studies has proven predictive of transition to illness in young adults at clinical high risk. Therefore, neurocognitive profiling in high-risk offspring may guide future intervention programs targeting the neurocognitively impaired subgroup of young children at familial high risk of SMD using e.g. cognitive remediation or other potentially preemptive or ameliorating interventions.

The behavioral and neurochemical characterization of a Drosophila dysbindin mutant supports the contribution of serotonin to schizophrenia negative symptoms

Mutations in the dystrobrevin binding protein 1 (DTNBP1) gene that encodes for the dysbindin-1 protein, are associated with a higher risk for schizophrenia. Interestingly, individuals carrying high-risk alleles in this gene have been associated with an increased incidence of negative symptoms for the disease, which include anhedonia, avolition and social withdrawal. Here we evaluated behavioral and neurochemical changes in a hypomorphic Drosophila mutant for the orthologue of human Dysbindin-1, dysb1.Mutant dysb1 flies exhibit altered social space parameters, suggesting asocial behavior, accompanied by reduced olfactory performance. Moreover, dysb1 mutant flies show poor performance in basal and startle-induced locomotor activity. We also report a reduction in serotonin brain levels and changes in the expression of the Drosophila serotonin transporter (dSERT) in dysb1 flies. Our data show that the serotonin-releasing amphetamine derivative 4-methylthioamphetamine (4-MTA) modulates social spacing and locomotion in control flies, suggesting that serotonergic circuits modulate these behaviors. 4-MTA was unable to modify the behavioral deficiencies in mutant flies, which is consistent with the idea that the efficiency of pharmacological agents acting at dSERT depends on functional serotonergic circuits.Thus, our data show that the dysb1 mutant exhibits behavioral deficits that mirror some aspects of the endophenotypes associated with the negative symptoms of schizophrenia. We argue that at least part of the behavioral aspects associated with these symptoms could be explained by a serotonergic deficit. The dysb1 mutant presents an opportunity to study the molecular underpinnings of schizophrenia negative symptoms and reveals new potential targets for treatment of the disease.

Decreased Gamma-Band Auditory Steady State Response is Associated With Social Functional Impairment in Patients at Clinical High Risk for Schizophrenia

Decreased Gamma-Band Auditory Steady State Response is Associated With Social Functional Impairment in Patients at Clinical High Risk for Schizophrenia

Cognition- and circuit-based dysfunction in a mouse model of 22q11.2 microdeletion syndrome: effects of stress

Genetic microdeletion at the 22q11 locus is associated with very high risk for schizophrenia. The 22q11.2 microdeletion (Df(h22q11)/+) mouse model shows cognitive deficits observed in this disorder, some of which can be linked to dysfunction of the prefrontal cortex (PFC). We used behavioral (n = 10 per genotype), electrophysiological (n = 7 per genotype per group), and neuroanatomical (n = 5 per genotype) techniques to investigate schizophrenia-related pathology of Df(h22q11)/+ mice, which showed a significant decrease in the total number of parvalbumin positive interneurons in the medial PFC. The Df(h22q11)/+ mice when tested on PFC-dependent behavioral tasks, including gambling tasks, perform significantly worse than control animals while exhibiting normal behavior on hippocampus-dependent tasks. They also show a significant decrease in hippocampus-medial Prefrontal cortex (H-PFC) synaptic plasticity (long-term potentiation, LTP). Acute platform stress almost abolished H-PFC LTP in both wild-type and Df(h22q11)/+ mice. H-PFC LTP was restored to prestress levels by clozapine (3 mg/kg i.p.) in stressed Df(h22q11)/+ mice, but the restoration of stress-induced LTP, while significant, was similar between wild-type and Df(h22q11)/+ mice. A medial PFC dysfunction may underlie the negative and cognitive symptoms in human 22q11 deletion carriers, and these results are relevant to the current debate on the utility of clozapine in such subjects.

Odor identification in 7-year-old children at familial high risk of schizophrenia or bipolar disorder - the Danish high risk and resilience study VIA 7

BackgroundOdor identification deficits occur in individuals with schizophrenia and their unaffected first-degree relatives, while deficits are less pronounced in individuals with bipolar disorder. We hypothesized that children at familial high-risk for schizophrenia (FHR-SZ) show odor identification deficits compared to population-based controls and that children at familial high-risk for bipolar disorder (FHR-BP) perform intermediate. MethodsOdor identification was assessed at age 7 in 184 children with FHR-SZ, 106 children with FHR-BP, and 186 population-based controls with the Brief Smell Identification Test. Dimensional and predefined categorical outcomes were used in the analyses. Potential relationships with psychopathological, cognitive, and home environmental variables were conducted using hierarchical and logistic multiple regression analyses. ResultsANOVA revealed no between-group differences in odor identification. Using the recommended cut-off (below 5), we found a significantly greater proportion of boys at FHR-SZ than population-based boys with an abnormal odor identification (p = .013). However, a supplementary analysis using a Danish-based cut-off (below 4) did not support this. All children showed significant, positive associations of odor identification with female gender, social responsiveness, and verbal working memory. Lower social responsiveness predicted abnormal odor identification in boys at FHR-SZ, only using the recommended cut-off. ConclusionsOdor identification efficacy and risk status appear independent in this early developmental phase. Using the recommended threshold, abnormal odor identification is more frequent in young boys at FHR-SZ than in population-based boys and is linked to lower social responsiveness. The validity of these results is questioned by non-significant differences in the rates when using an exploratory Danish-based threshold.

Paroxetine can improve primary visual cortex activity in a high-risk mouse model of schizophrenia

Visual cortex functional deficits can be observed in schizophrenia patients and in individuals at high risk of schizophrenia. However, to date, few studies have investigated methods to improve these functional deficits. This study aimed to investigate the pathological change in the primary visual cortex of a prenatal MK-801-induced high-risk mouse model of schizophrenia (HRMMS) and to test the effect of paroxetine on visual cortex activity. Pregnant mice were given a systemic injection of MK-801, and male offspring that did not present schizophrenia-like behaviors in early adulthood were defined as HRMMS. Some of the HRMMS mice were treated with pharmacological agents beginning at 4 weeks of age. After 4 weeks of treatment with risperidone and/or paroxetine, two-photon calcium imaging was performed to analyze the primary visual cortex activity. The sucrose preference test and the prepulse inhibition (PPI) apparatus test were used to assess the cognitive and behavioral performance. HRMMS mice with or without risperidone treatment had impairments in the primary visual cortex as observed by reduced neuronal calcium activity. Risperidone plus paroxetine and paroxetine alone treatments increased the neuronal calcium activity in the primary visual cortex. Notably, the neuronal calcium activity was higher in mice treated with paroxetine alone. Treatment with paroxetine alone also improved the cognitive and behavioral performance better than treatment with risperidone plus paroxetine. Our pioneering animal model showed that treatment with paroxetine alone improves visual cortex impairments in HRMMS mice better than treatment with risperidone plus paroxetine, indicating that antipsychotics cannot normalize visual cortex impairments.

N400 event-related brain potential as an index of real-world and neurocognitive function in patients at clinical high risk for schizophrenia.

The N400 event-related potential is a neurophysiological index of cognitive processing of real-world knowledge. In healthy populations, N400 amplitude is smaller in response to stimuli that are more related to preceding context. This 'N400 semantic priming effect' is thought to reflect activation of contextually related information in semantic memory (SM). N400 semantic priming deficits have been found in schizophrenia, and in patients at clinical high risk (CHR) for this disorder. Because this abnormality in processing relationships between meaningful stimuli could affect ability to navigate everyday situations, we hypothesized it would be associated with real-world functional impairment in CHR patients. Second, we hypothesized it would correlate with global neurocognitive impairment in this group. We measured N400 semantic priming in 35 CHR patients who viewed prime words each followed by a related or unrelated target word, at stimulus-onset asynchrony (SOA) of 300 or 750 ms. We measured academic/occupational and social function with the global function (GF): Role and Social scales, and cognitive function with the MATRICS Consensus Cognitive Battery (MCCB). Decreased N400 semantic priming at the 300-ms SOA correlated with lower GF:Role scores. Decreased N400 semantic priming at the 750-ms SOA correlated with lower MCCB composite scores. Deficits in activating contextually related concepts in SM over short time intervals may contribute to functional impairment in CHR patients. Furthermore, N400 priming deficits over longer intervals may be a biomarker of global cognitive dysfunction in this population. Longitudinal studies are needed to determine whether these deficits are associated with schizophrenia risk within this population.

P.415 Effect of C1473G polymorphism in tryptophan hydroxylase 2 and lipopolysaccharide on serotonin and protein tyrosine phosphatase 5 in mouse brain

Mutations in the dystrobrevin binding protein 1 (DTNBP1) gene that encodes for the dysbindin-1 protein, are associated with a higher risk for schizophrenia. Interestingly, individuals carrying high-risk alleles in this gene have been associated with an increased incidence of negative symptoms for the disease, which include anhedonia, avolition and social withdrawal. Here we evaluated behavioral and neurochemical changes in a hypomorphic Drosophila mutant for the orthologue of human Dysbindin-1, dysb1.Mutant dysb1 flies exhibit altered social space parameters, suggesting asocial behavior, accompanied by reduced olfactory performance. Moreover, dysb1 mutant flies show poor performance in basal and startle-induced locomotor activity. We also report a reduction in serotonin brain levels and changes in the expression of the Drosophila serotonin transporter (dSERT) in dysb1 flies. Our data show that the serotonin-releasing amphetamine derivative 4-methylthioamphetamine (4-MTA) modulates social spacing and locomotion in control flies, suggesting that serotonergic circuits modulate these behaviors. 4-MTA was unable to modify the behavioral deficiencies in mutant flies, which is consistent with the idea that the efficiency of pharmacological agents acting at dSERT depends on functional serotonergic circuits.Thus, our data show that the dysb1 mutant exhibits behavioral deficits that mirror some aspects of the endophenotypes associated with the negative symptoms of schizophrenia. We argue that at least part of the behavioral aspects associated with these symptoms could be explained by a serotonergic deficit. The dysb1 mutant presents an opportunity to study the molecular underpinnings of schizophrenia negative symptoms and reveals new potential targets for treatment of the disease.

GPS mobility as a digital biomarker of negative symptoms in schizophrenia: a case control study

Mobility is an important correlate of physical, cognitive, and mental health in chronic illness, and can be measured passively with mobile phone global positional satellite (GPS) sensors. To date, GPS data have been reported in a few studies of schizophrenia, yet it is unclear whether these data correlate with concurrent momentary reports of location, vary by people with schizophrenia and healthy comparison subjects, or associate with symptom clusters in schizophrenia. A total of 142 participants with schizophrenia (n = 86) or healthy comparison subjects (n = 56) completed 7 days of ecological momentary assessment (EMA) reports of location and behavior, and simultaneous GPS locations were tracked every five minutes. We found that GPS-derived indicators of average distance travelled overall and distance from home, as well as percent of GPS samples at home were highly correlated with EMA reports of location at the day- and week-averaged level. GPS-based mobility indicators were lower in schizophrenia with medium to large effect sizes. Less GPS mobility was related to greater negative symptom severity, particularly diminished motivation, whereas greater GPS mobility was weakly associated with more community functioning. Neurocognition, depression, and positive symptoms were not associated with mobility indicators. Therefore, passive GPS sensing could provide a low-burden proxy measure of important outcomes in schizophrenia, including negative symptoms and possibly of functioning. As such, passive GPS sensing could be used for monitoring and timely interventions for negative symptoms in young persons at high risk for schizophrenia.

Quality of life and self-esteem in 7-year-old children with familial high risk of schizophrenia or bipolar disorder: the Danish High Risk and Resilience Study-VIA 7-a population-based cohort study.

It is well established that children with familial high risk of schizophrenia (FHR-SZ) or bipolar disorder (FHR-BP) have a higher risk of developing mental disorders, however, little is known of to what degree the genetic and environmental vulnerabilities affect the quality of life and self-esteem of these children. We aimed to compare the quality of life and self-esteem between children with FHR-SZ or FHR-BP and controls. We used Danish nationwide registers to retrieve a cohort of 522 7-year-old children with FHR-SZ or FHR-BP and controls. Quality of life was assessed with the 'Health-related Quality of Life Screening Instrument', KIDSCREEN-27, and the scale 'Social Acceptance (Bullying)' from the KIDSCREEN-52. Self-esteem was assessed with the self-report scale 'I think I am'. Assessors were blind to familial risk status of the children. Children with FHR-SZ displayed lower levels of the general quality of life, as well as lower scores on the 'Psychological Well-being' scale and the 'School Environment' scale of the KIDSCREEN-27 compared with controls. Both children with FHR-SZ and FHR-BP reported more bullying victimization compared with controls. Children with FHR-SZ reported lower self-esteem on the total scale of 'I think I am', as well as on the 'Skills and talents', the 'Psychological well-being', and the 'Relationships with others' subscales compared with controls. The findings of lower quality of life and self-esteem in children with FHR-SZ together with more bullying victimization in both familial high-risk groups call for studies on low risk, early intervention strategies towards this group of vulnerable children.