High Genetic Risk For Schizophrenia Research Articles

PB 22 Association between genetic risk for schizophrenia and deactivation of the right temporo-parietal junction during working memory encoding – An imaging genetics study

Introduction Schizophrenia is a complex genetic disorder, whose highly polygenic architecture has only partly been elucidated. Recent genome-wide association studies (GWAS) have provided evidence for a growing number of common genetic risk variants. However, the impact of these risk genes on brain function remain poorly understood. In the current imaging genetics study, we investigated the correlation between brain activation during a visuospatial working memory task and genetic risk for schizophrenia. Methods 98 right-handed individuals without personal or family history of psychiatric disorders underwent fMRI during the performance of a visuospatial change detection task. During encoding, an array of three red rectangular bars, which varied in orientation, was presented for 33 ms. After a delay period, a second array was presented for 3000 ms (retrieval). This array was identical to the first array in 50% of trials. Data analysis in Brain Voyager QX 2.8 included standard data preprocessing and a multiscale curvature driven cortex based alignment procedure to minimize macro-anatomical variability between subjects. Subsequently, functional data were analyzed using a random-effects multi-subject general linear model. Participants were genotyped using a custom Illumina HumanCoreExome-24 BeadChip array. Polygenic scores (PGS) for schizophrenia were calculated based on Psychiatric Genetic Consortium data (PGC2). Results We observed a significant negative correlation between BOLD activation in the right temporo-parietal junction (TPJ) and PGS for schizophrenia during the encoding phase. Closer inspection indicated that the right TPJ – part of the ventral attention network – was reliably deactivated across all particpants during the encoding phase. However, participants with higher PGS showed stronger deactivation. Conclusions Previous studies reported stronger deactivation of the right TPJ during working memory encoding with increasing cognitive demand. Therefore, our results indicate that participants with a higher genetic risk for schizophrenia had to commit more cognitive resources to encode information into working memory. This finding is also well in line with converging evidence for a primary disturbance of working memory encoding in schizophrenia.

Attenuated psychotic symptoms in children and adolescent offspring of patients with schizophrenia

ObjectiveTo compare the offspring of patients with SZ (SZoff) with those of a community control group (CC-off) to determine the variables associated with attenuated psychotic symptoms (APS), general symptomatology and functioning that may help to differentiate those at genetic risk for SZ. Methods41 SZ-off and 107 CC-off aged 6–17years were included. The Structured Interview for Prodromal Symptoms (SIPS), scored on the Scale of Prodromal Symptoms (SOPS), was administered by a child psychiatrist blinded to parental diagnoses, together with other clinical and functional scales. ResultsThe SZ-off group presented higher scores in positive (p=0.000), negative (p=0.012), and disorganized (p=0.009) subscale scores, as well as in the total score (p=0.001) on the SOPS when compared with the CC-off group. Other scales indicated significant emotional (p=0.028), behavioral (p=0.000) and peer-related problems (p=0.025), lower performance at school (p=0.025) and increased dysfunction score (p=0.005) in the SZ-off group. Logistic regression analysis revealed lower socioeconomic statuses (OR: 0.92, 95%CI: 0.87–0.97) and higher SOPS positive subscale scores (OR: 2.41, 95%CI: 1.31–4.42) in the SZ-off group. ConclusionsSZ-off presented significantly more APS and higher mean scores in psychopathological scales than CC-off, together with increased dysfunction scores. These early warning signs and follow-up for those at genetic high risk for schizophrenia will provide useful information about symptom progression, facilitating early intervention to improve short and long-term outcomes in youths with a positive family history.

The dimensional structure of psychopathology in 22q11.2 Deletion Syndrome

Background22q11.2 Deletion Syndrome (22q11.2DS) is one of the strongest known genetic risk factors for developing schizophrenia. Individuals with 22q11.2DS have high rates of neurodevelopmental disorders in childhood, while in adulthood ∼25% develop schizophrenia. Similar to the general population, high rates of comorbidity are common in 22q11.2DS. Employing a dimensional approach where psychopathology is examined at the symptom-level as complementary to diagnostic categories in a population at such high genetic risk for schizophrenia can help gain a better understanding of how psychopathology is structured as well as its genetic underpinnings. This is the first study to examine the dimensional structure of a wide spectrum of psychopathology in the context of a homogeneous genetic etiology like 22q11.2DS. MethodsWe evaluated 331 individuals with 22q11.2DS, mean age (SD) = 16.9(8.7); 51% males, who underwent prospective comprehensive phenotyping. We sought to replicate previous findings by examining a bi-factor model that derives a general factor of psychopathology in addition to more specific dimensions of psychopathology (i.e., internalizing, externalizing and thought disorder). ResultsPsychopathology in 22q11.2DS was divided into one ‘general psychopathology’ factor and four specific dimensions (i.e., ‘anxiety’, ‘mood’, ‘ADHD’ and ‘psychosis’). The ‘psychosis’ symptoms loaded strongly on the ‘general psychopathology’ factor. ConclusionsThe similarity of the symptom structure of psychopathology between 22q11.2DS and community and clinical populations without the deletion indicate that 22q11.2DS can provide a model to explore alternative approaches to our current nosology. Our findings add to a growing literature indicating the need to reorganize current diagnostic classification systems.

Higher Genetic Risk For Schizophrenia Is Associated With Living In Urban And Populated Areas

Background The prevalence of schizophrenia is higher in urban areas than in rural areas. The association between urbanization and schizophrenia has been reported before in relation to place of birth, place of upbringing and place of residence. Two major hypotheses have been proposed to explain this phenomenon: (1) the causation hypothesis, where the stress of city life and undefined factors in the urban environment would increase the risk of this disease, and (2) the selection hypothesis, where individuals with genetic liability for schizophrenia would move into urban areas. On the other hand, genetic factors have been shown to have a higher impact on the country v.s city living as people grow older (>40y), while the impact of family background decreases. Heritability estimates reported for full ACE models were 12.7%, 22% and 41.2% for those under 20, 20-40 and over 40, respectively. Our aim was to test the alternative hypothesis that adults with higher genetic risk for schizophrenia are more likely to move to and live in urbanized and populated areas than those with lower risk. Methods Our sample was comprised of 15,253 participants in 7,007 families (63.4% women) over 40 years old (M = 54.43, SD = 10.86) living in Australia. The participants reported their postcode as part of the protocols of several studies on health and wellbeing conducted from QIMR. Participants were genotyped genome-wide and imputed to 1000G v.3. We used three measures of urbanicity; (i) subjects’ zip code were categorized into urban, suburban or rural zones; we also computed (ii) distance to the closest city centre and (iii) the population density of the postcode district. Polygenic risk scores (PRS) for schizophrenia based on summary statistics from the Psychiatric Genomics Consortium (PGC-2) were computed with PLINK 1.90 (version 3) for eight different P-value thresholds. We used linear mixed models to predict the three urbanicity measures from the schizophrenia PRS, controlling for age, sex, genetic principal components, GWAS chip and genetic relationship matrix. Predictions were calculated using GCTA (Genome-wide Complex Trait Analysis, version 1.22). Results Genetic risk for schizophrenia was associated with the place where the participants lived in the expected direction, with increased effects as the risk scores included more SNPs. P-values for PRS at thresholds Discussion Our results suggest that people with a higher genetic risk for schizophrenia may prefer to live in more urban and populated areas. Importantly, this study does not use a case-control sample but a non-selected sample where the genetic risk for schizophrenia was estimated. This study proposes that greater genetic predisposition to schizophrenia is at least one mechanism explaining why this illness is more prevalent in city environments. Future research should test if this effect is replicated in other countries. Financial Support: NHMRC Grant 1103603

White Matter Integrity in Genetic High-Risk Individuals and First-Episode Schizophrenia Patients: Similarities and Disassociations.

White matter (WM) neuroimaging studies have shown varied findings at different stages of schizophrenia (SZ). Understanding these variations may elucidate distinct markers of genetic vulnerability and conversion to psychosis. To examine the similarities and differences in WM connectivity between those at-risk for and in early stages of SZ, a cross-sectional diffusion tensor imaging study of 48 individuals diagnosed with first-episode SZ (FE-SZ), 37 nonpsychotic individuals at a high genetic risk of SZ (GHR-SZ), and 67 healthy controls (HC) was conducted. Decreased fractional anisotropy (FA) in the corpus callosum (CC), anterior cingulum (AC), and uncinate fasciculus (UF) was observed in both the GHR-SZ and FE-SZ groups, while decreased FAs in the superior longitudinal fasciculus (SLF) and the fornix were only seen in the FE-SZ participants. Additionally, both GHR-SZ and FE-SZ showed worse executive performance than HC. The left SLF III FA was significantly positively correlated with hallucinations, and right SLF II was positively correlated with thought disorder. The presence of shared WM deficits in both FE-SZ and GHR-SZ individuals may reflect the genetic liability to SZ, while the disparate FA changes in the FE-SZ group may represent symptom-generating circuitry that mediates perceptual and cognitive disturbances of SZ and ultimately culminates in the onset of psychotic episodes.

Perceived parental attitudes and the levels quality of life in children and adolescents at high risk for schizophrenia

Objective: The aims of this study were to compare the levels quality of life and perceived parental attitude in children and adolescents at high risk for schizophrenia with offspring of parents without any psychiatric disorder, and to investigate the factors affecting parental attitudes perceived by children and quality of life of children. Meth-ods: The psychiatric assessments of parents with schizophrenia who have been followed up in the Community Mental Health Center and that of healthy parents were done by a psychiatrist. Diagnostic interview with the children, within the age range of 7-16 years, was conducted by a child psychiatrist. Children and adolescents were asked to fill out self-report scales relevant to perceived parental attitudes and quality of life. Results: The levels of emotional and social functioning and the levels of parental acceptance/interest were significantly lower in the high risk group when compared to the control group. Children in the high risk group defined their parents as 'negligent' at a higher rate than the control group. There was a significant effect of sociodemographic variables such as parental educa-tion level and paternal vocational status on the quality of life scores. When compared to children of fathers with schizophrenia, children of mothers with schizophrenia had much lower quality of life scores. The duration of parental illness and the duration of hospitalization were negatively correlated with the quality of life of children. Discussion: Our study demonstrated that offspring of parents with schizophrenia had a high risk of being neglected by their parents, and a decline in their quality of life, especially in the social and emotional aspects. Preventive interventions including development of positive relationships with their parents, are crucial for children at genetic high risk for schizophrenia.

Reconsidering Clinical Staging Model: A Case of Genetic High Risk for Schizophrenia

The clinical staging model is considered a useful and practical method not only in dealing with the early stage of psychosis overcoming the debate about diagnostic boundaries but also in emerging mood disorder. However, its one limitation is that it cannot discriminate the heterogeneity of individuals at clinical high risk for psychosis, but lumps them all together. Even a healthy offspring of schizophrenia can eventually show clinical symptoms and progress to schizophrenia under the influence of genetic vulnerability and environmental stress even after the peak age of onset of schizophrenia. Therefore, individuals with genetic liability of schizophrenia may require a more intensive intervention than recommended by the staging model based on current clinical status.

Dissection of major depressive disorder using polygenic risk scores for schizophrenia in two independent cohorts.

Major depressive disorder (MDD) is known for its substantial clinical and suspected causal heterogeneity. It is characterized by low mood, psychomotor slowing and increased levels of the personality trait neuroticism; factors also associated with schizophrenia (SCZ). It is possible that some cases of MDD may have a substantial genetic loading for SCZ. The presence of SCZ-like MDD subgroups would be indicated by an interaction between MDD status and polygenic risk of SCZ on cognitive, personality and mood measures. Here, we hypothesized that higher SCZ polygenic risk would define larger MDD case–control differences in cognitive ability, and smaller differences in distress and neuroticism. Polygenic risk scores (PRSs) for SCZ and their association with cognitive variables, neuroticism, mood and psychological distress were estimated in a large population-based cohort (Generation Scotland: Scottish Family Health Study, GS:SFHS). The individuals were divided into those with, and without, depression (n=2587 and n=16 764, respectively) to test for the interactions between MDD status and schizophrenia risk. Replication was sought in UK Biobank (UKB; n=6049 and n=27 476 cases and controls, respectively). In both the cohorts, we found significant interactions between SCZ-PRS and MDD status for measures of psychological distress (βGS=−0.04, PGS=0.014 and βUKB=−0.09, PUKB⩽0.001 for GS:SFHS and UKB, respectively) and neuroticism (βGS=−0.04, PGS=0.002 and βUKB=−0.06, PUKB=0.023). In both the cohorts, there was a reduction of case–control differences on a background of higher genetic risk of SCZ. These findings suggest that depression on a background of high genetic risk for SCZ may show attenuated associations with distress and neuroticism. This may represent a causally distinct form of MDD more closely related to SCZ.

Impact of polygenic schizophrenia-related risk and hippocampal volumes on the onset of psychosis.

Alterations in hippocampal volume are a known marker for first-episode psychosis (FEP) as well as for the clinical high-risk state. The Polygenic Schizophrenia-related Risk Score (PSRS), derived from a large case–control study, indicates the polygenic predisposition for schizophrenia in our clinical sample. A total of 65 at-risk mental state (ARMS) and FEP patients underwent structural magnetic resonance imaging. We used automatic segmentation of hippocampal volumes using the FSL-FIRST software and an odds-ratio-weighted PSRS based on the publicly available top single-nucleotide polymorphisms from the Psychiatric Genomics Consortium genome-wide association study (GWAS). We observed a negative association between the PSRS and hippocampal volumes (β=−0.42, P=0.01, 95% confidence interval (CI)=(−0.72 to −0.12)) across FEP and ARMS patients. Moreover, a higher PSRS was significantly associated with a higher probability of an individual being assigned to the FEP group relative to the ARMS group (β=0.64, P=0.03, 95% CI=(0.08–1.29)). These findings provide evidence that a subset of schizophrenia risk variants is negatively associated with hippocampal volumes, and higher values of this PSRS are significantly associated with FEP compared with the ARMS. This implies that FEP patients have a higher genetic risk for schizophrenia than the total cohort of ARMS patients. The identification of associations between genetic risk variants and structural brain alterations will increase our understanding of the neurobiology underlying the transition to psychosis.

PM474. Brain metabolite differences in subjects with high genetic risk of schizophrenia using 1H magnetic resonance spectroscopy

PM474. Brain metabolite differences in subjects with high genetic risk of schizophrenia using 1H magnetic resonance spectroscopy

Association of Genetic Risk for Schizophrenia With Nonparticipation Over Time in a Population-Based Cohort Study.

Progress has recently been made in understanding the genetic basis of schizophrenia and other psychiatric disorders. Longitudinal studies are complicated by participant dropout, which could be related to the presence of psychiatric problems and associated genetic risk. We tested whether common genetic variants implicated in schizophrenia were associated with study nonparticipation among 7,867 children and 7,850 mothers from the Avon Longitudinal Study of Parents and Children (ALSPAC; 1991–2007), a longitudinal population cohort study. Higher polygenic risk scores for schizophrenia were consistently associated with noncompletion of questionnaires by study mothers and children and nonattendance at data collection throughout childhood and adolescence (ages 1–15 years). These associations persisted after adjustment for other potential correlates of nonparticipation. Results suggest that persons at higher genetic risk for schizophrenia are likely to be underrepresented in cohort studies, which will underestimate risk of this and related psychiatric, cognitive, and behavioral phenotypes in the population. Statistical power to detect associations with these phenotypes will be reduced, while analyses of schizophrenia-related phenotypes as outcomes may be biased by the nonrandom missingness of these phenotypes, even if multiple imputation is used. Similarly, in complete-case analyses, collider bias may affect associations between genetic risk and other factors associated with missingness.

Dysfunction and Dysconnection in Cortical-Striatal Networks during Sustained Attention: Genetic Risk for Schizophrenia or Bipolar Disorder and its Impact on Brain Network Function.

Abnormalities in the brain’s attention network may represent early identifiable neurobiological impairments in individuals at increased risk for schizophrenia or bipolar disorder. Here, we provide evidence of dysfunctional regional and network function in adolescents at higher genetic risk for schizophrenia or bipolar disorder [henceforth higher risk (HGR)]. During fMRI, participants engaged in a sustained attention task with variable demands. The task alternated between attention (120 s), visual control (passive viewing; 120 s), and rest (20 s) epochs. Low and high demand attention conditions were created using the rapid presentation of two- or three-digit numbers. Subjects were required to detect repeated presentation of numbers. We demonstrate that the recruitment of cortical and striatal regions are disordered in HGR: relative to typical controls (TC), HGR showed lower recruitment of the dorsal prefrontal cortex, but higher recruitment of the superior parietal cortex. This imbalance was more dramatic in the basal ganglia. There, a group by task demand interaction was observed, such that increased attention demand led to increased engagement in TC, but disengagement in HGR. These activation studies were complemented by network analyses using dynamic causal modeling. Competing model architectures were assessed across a network of cortical–striatal regions, distinguished at a second level using random-effects Bayesian model selection. In the winning architecture, HGR were characterized by significant reductions in coupling across both frontal–striatal and frontal–parietal pathways. The effective connectivity analyses indicate emergent network dysconnection, consistent with findings in patients with schizophrenia. Emergent patterns of regional dysfunction and dysconnection in cortical–striatal pathways may provide functional biological signatures in the adolescent risk-state for psychiatric illness.

Premorbid self-disorders and lifetime diagnosis in the schizophrenia spectrum: a prospective high-risk study.

The notion of a disordered self as a core disturbance of schizophrenia was proposed in many foundational texts. Recent studies, spurred by the development of the Examination of Anomalous Self-Experience (EASE), seem to indicate that self-disorders are a specific manifestation of schizophrenia vulnerability. Follow-up studies of help-seeking, prodromal and first-admission patients have demonstrated the utility of self-disorders for predicting later schizophrenia-spectrum disturbance. We wished to extend these findings by gauging the predictive value of self-disorders in a premorbid, non-clinical population at high risk for schizophrenia. Children from the Copenhagen High-Risk Project with high-genetic risk for schizophrenia (N = 212) were assessed premorbidly (average age = 15), and diagnostically re-evaluated after 10 and 25 years. Since the EASE was not available at the time of premorbid assessment, we hypothesized that a proxy scale drawn from the Minnesota Multiphasic Personality Inventory (MMPI) could distinguish those who later developed a schizophrenia-spectrum disorder (N = 68) from those who remained healthy (N = 64). The Self-Disorder Scale comprised 32 items whose content suggested an aspect of self-disorder as measured by the EASE. Premorbid Self-Disorder Scale scores significantly predicted lifetime schizophrenia-spectrum diagnosis in the high-risk cohort. Although there was considerable item overlap between the new scale and an existing MMPI scale (psychoticism), the overlap did not account for the Self-Disorder Scale's predictive efficacy. The results support the notion of self-disorders as a core vulnerability feature in schizophrenia, detectable premorbidly in those developing later schizophrenia-spectrum disorders.

Brain structure and cognitive development in young children at high genetic risk for schizophrenia

• Structural magnetic resonance imaging scans were acquired from highrisk infants who had mothers with schizophrenia (N=26 at age 1; N=20 at age 2) and from matched typically developing infants (N=52 at age 1; N=40 at age 2) of control mothers. • Infants were matched based on gender, gestational age at birth, and ethnicity. • Image acquisition was performed using a Siemens head-only 3-Tesla scanner during unsedated natural sleep. • T1 weighted image parameters: MP-RAGE, TE of 4.38ms, and flip angle of 7° • T2 weighted image parameters: TSE, TR of 6200ms, TE1 of 20ms, TE2 of 119ms, and flip angle of 150°

Can Psychosis Be Prevented by Treating Adolescent Anxiety

In nonpsychotic adolescents at high genetic risk for schizophrenia (based on family history), researchers have documented greater anxiety levels than

Abnormal effective connectivity in the psychosis high-risk state

In a recently published fMRI study (Dauvermann et al., 2013), nonlinear dynamic causal modeling (DCM) was used to examine condition-specific effective connectivity in subjects at high genetic risk of schizophrenia. The authors concluded that nonlinear DCM could lead to new insights in the development of psychotic symptoms and functional and effective dysconnection at the network level in subjects at high familial risk. In this paper, we place these interesting findings in the context of recent evidence from bilinear DCM studies in subjects at high clinical risk with an at-risk mental state (ARMS) for psychosis by considering their consistency and potential differences with implications for future research in the field of emerging psychosis.

The application of nonlinear Dynamic Causal Modelling for fMRI in subjects at high genetic risk of schizophrenia

Nonlinear Dynamic Causal Modelling (DCM) for fMRI provides computational modelling of gating mechanisms at the neuronal population level. It allows for estimations of connection strengths with nonlinear modulation within task-dependent networks. This paper presents an application of nonlinear DCM in subjects at high familial risk of schizophrenia performing the Hayling Sentence Completion Task (HSCT). We analysed scans of 19 healthy controls and 46 subjects at high familial risk of schizophrenia, which included 26 high risk subjects without psychotic symptoms and 20 subjects with psychotic symptoms. The activity-dependent network consists of the intra parietal cortex (IPS), inferior frontal gyrus (IFG), middle temporal gyrus (MTG), anterior cingulate cortex (ACC) and the mediodorsal (MD) thalamus. The connections between the MD thalamus and the IFG were gated by the MD thalamus. We used DCM to investigate altered connection strength of these connections. Bayesian Model Selection (BMS) at the group and family level was used to compare the optimal bilinear and nonlinear models. Bayesian Model Averaging (BMA) was used to assess the connection strengths with the gating from the MD thalamus and the IFG. The nonlinear models provided the better explanation of the data. Furthermore, the BMA analysis showed significantly lower connection strength of the thalamocortical connection with nonlinear modulation from the MD thalamus in high risk subjects with psychotic symptoms and those who subsequently developed schizophrenia. These findings demonstrate that nonlinear DCM provides a method to investigate altered connectivity at the level of neural circuits. The reduced connection strength with thalamic gating may be a neurobiomarker implicated in the development of psychotic symptoms. This study suggests that nonlinear DCM could lead to new insights into functional and effective dysconnection at the network level in subjects at high familial risk.

Altered auditory processing in frontal and left temporal cortex in 22q11.2 deletion syndrome: A group at high genetic risk for schizophrenia

In order to investigate electroencephalographic (EEG) biomarkers of auditory processing for schizophrenia, we studied a group with a well known high-risk profile: patients with 22q11.2 deletion syndrome (22q11 DS) have a 30% risk of developing schizophrenia during adulthood. We performed high-density EEG source imaging to measure auditory gating of the P50 component of the evoked potential and middle to late latency auditory processing in 21 participants with the 22q11.2 deletion and 17 age-matched healthy controls. While we found no indication of altered P50 suppression in 22q11 DS, we observed marked differences for the first N1 component with increased amplitudes on central electrodes, corresponding to increased activations in dorsal anterior cingulate and medial frontal cortex. We also found a left lateralized reduction of activation of primary and secondary auditory cortex during the second N1 (120ms) and the P2 component in 22q11 DS. Our results show that sensory gating and activations until 50ms were preserved in 22q11 DS, while impairments appear at latencies that correspond to higher order auditory processing. While the increased activation of cingulate and medial frontal cortex could reflect developmental changes in 22q11 DS, the reduced activity seen in left auditory cortex might serve as a biomarker for the development of schizophrenia, if confirmed by longitudinal research protocols.

Impact of a microRNA MIR137 susceptibility variant on brain function in people at high genetic risk of schizophrenia or bipolar disorder.

A recent 'mega-analysis' combining genome-wide association study data from over 40,000 individuals identified novel genetic loci associated with schizophrenia (SCZ) at genome-wide significance level. The strongest finding was a locus within an intron of a putative primary transcript for microRNA MIR137. In the current study, we examine the impact of variation at this locus (rs1625579, G/T; where T is the common and presumed risk allele) on brain activation during a sentence completion task that differentiates individuals with SCZ, bipolar disorder (BD), and their relatives from controls. We examined three groups of individuals performing a sentence completion paradigm: (i) individuals at high genetic risk of SCZ (n=44), (ii) individuals at high genetic risk of BD (n=90), and (iii) healthy controls (n=81) in order to test the hypothesis that genotype at rs1625579 would influence brain activation. Genotype groups were assigned as 'RISK-' for GT and GG individuals, and 'RISK+' for TT homozygotes. The main effect of genotype was significantly greater activation in the RISK- individuals in the posterior right medial frontal gyrus, BA 6. There was also a significant genotype(*)group interaction in the left amygdala and left pre/postcentral gyrus. This was due to differences between the controls (where individuals with the RISK- genotype showed greater activation than RISK+ subjects) and the SCZ high-risk group, where the opposite genotype effect was seen. These results suggest that the newly identified SCZ locus may influence brain activation in a manner that is partly dependent on the presence of existing genetic susceptibility for SCZ.

Use of second-person pronouns and schizophrenia

A masked analysis of videotaped assessments of people at high genetic risk of schizophrenia revealed that those who subsequently went on to develop schizophrenia used significantly more second-person pronouns. This was evident before diagnosis, at two separate assessments approximately 18 months apart. This supports the view that people who go on to develop schizophrenia may have an abnormality in the deictic frame of interpersonal communication - that is, the distinction between concepts being self-generated or from elsewhere may be blurred prior to the onset of a diagnosis of schizophrenia.