Cognitive Impairment Among Children At-Risk for Schizophrenia

Journal of Psychiatric Research 50 (2014) 92e99

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Journal of Psychiatric Research

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Cognitive impairment among children at-risk for schizophrenia

Hannah Dickson a,*, Alexis E. Cullen a, Abraham Reichenberg b,c,d,e, Sheilagh Hodgins f, Desmond D. Campbell g, Robin G. Morris h, Kristin R. Laurens a,i,j,* a Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, King’s College London, United Kingdom b Department of Psychosis Studies, Institute of Psychiatry, King’s College London, United Kingdom c Department of Psychiatry, Ichan School of Medicine at Mount Sinai, New York, NY, USA d Department of Preventive Medicine, Ichan School of Medicine at Mount Sinai, New York, NY, USA e Freidman Brain Institute, Ichan School of Medicine at Mount Sinai, New York, NY, USA f Département de Psychiatrie, Université de Montréal, Montréal, Canada g Department of Psychiatry, University of Hong Kong, Hong Kong h Department of Psychology, Institute of Psychiatry, Kings College London, United Kingdom i Research Unit for Schizophrenia Epidemiology, School of Psychiatry, University of New South Wales, Sydney, Australia j Schizophrenia Research Institute, Sydney, Australia article info abstract

Article history: Adults with schizophrenia present cognitive impairments, as do individuals at ultra-high risk for the Received 23 May 2013 disorder, youth with relatives with schizophrenia spectrum disorders, and children with antecedents of Received in revised form schizophrenia. The present study aimed to determine if impairments in childhood differed depending on 13 September 2013 the definition of risk and/or on the degree of relatedness to an affected individual, and if impairments Accepted 3 December 2013 were explained by IQ. Four groups of children aged 9e12 years were studied: (1) 13 children with 1 first-degree or 2 second-degree affected relatives (high familial loading: FHxH); (2) 14 with 1 affected Keywords: second-degree relative (lower familial loading: FHxL); (3) 32 with well-replicated antecedents of Intelligence Psychosis schizophrenia (ASz); and (4) 45 typically-developing (TD) children with neither a positive family history H fi Risk factors nor antecedents. Compared to TD children, both FHx and ASz children exhibited signi cantly poorer H Genetic liability verbal comprehension, scholastic achievement, and verbal working memory, while FHx children Developmental psychopathology additionally displayed significantly lower full-scale IQ, and verbal memory and executive function im- Psychotic-like experiences pairments. After adjusting statistical analyses for IQ, group differences were attenuated. Relative to TD children, FHxL children showed no significant differences in performance. The results imply that im- pairments in verbal comprehension, scholastic achievement, and verbal working memory may index vulnerability for schizophrenia among children with affected relatives with the disorder and among those with multiple antecedents of the disorder who have no affected relatives. More accurate identi- fication of children at-risk for schizophrenia and the specificdeficits that they present provides op- portunities for interventions such as cognitive remediation that may impact the development of the illness. Ó 2013 Elsevier Ltd. All rights reserved.

Cognitive impairments in schizophrenia are apparent across background of generalised cognitive deficit, as indexed by mea- illness stages, including premorbidly among high-risk individuals sures of general intelligence (IQ) (Forbes et al., 2006; Mesholam- (Dickson et al., 2012; Matheson et al., 2011). Patients with chronic Gately et al., 2009; Reichenberg and Harvey, 2007). Typically, schizophrenia, as well as those experiencing their first-episode of cognitive performance among individuals with schizophrenia is psychosis, frequently present with severe cognitive impairments. between 1 and 2 standard deviations (SD) below that of age- These impairments span memory, learning, executive function, matched healthy individuals, and is lower than expected based attention, and processing speed, and are evident against a on maternal level of education (Keefe et al., 2005; Keefe and Fenton, 2007). * Corresponding authors. Department of Forensic and Neurodevelopmental Sci- Neurocognitive impairments are also present among non-ill ences, Box P023, Institute of Psychiatry, King’s College London, De Crespigny Park, relatives of persons with schizophrenia, both in adults who have London SE5 8AF, United Kingdom. Tel.: þ44 (0)20 7848 0964; fax: þ44 (0)20 7848 most likely passed through the risk period for development of 0754. E-mail addresses: [email protected] (H. Dickson), [email protected]. schizophrenia, and in younger relatives who might yet develop uk (K.R. Laurens). illness. Adults with an affected first-degree relative present

0022-3956/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jpsychires.2013.12.003 H. Dickson et al. / Journal of Psychiatric Research 50 (2014) 92e99 93 impairments on measures of IQ, attention, memory, and executive schizophrenia could provide important information about alter- functioning (for review: Reichenberg and Harvey, 2007). The defi- native trajectories of risk for illness than that conferred by family cits are, however, less pronounced than those presented by history of illness. Based on this approach, one recent study reported schizophrenia patients. Low IQ and deficits in specific cognitive that young adolescents with psychotic-like experiences (PLEs) at functions have also been reported among non-ill first and/or clinical interview displayed slower processing speed and poorer second-degree relatives aged less than 30 years (for review: Agnew- non-verbal working memory relative to healthy adolescents Blais and Seidman, 2013) and among children/adolescents with an without PLEs (Kelleher et al., 2012). ill parent (for reviews of the extensive early literature on these Extending this strategy, our group developed an alternative, studies, see: Agnew-Blais and Seidman, 2013; Erlenmeyer-Kimling, novel approach which uses multiple well-replicated risk markers 2000; Kremen et al., 1994; Niemi et al., 2003). Findings from these for later development of schizophrenia. A large community sample prospective longitudinal studies of offspring of parents with of children aged 9e12 years and their primary caregiver completed schizophrenia indicate that low IQ, poor scholastic achievement, questionnaires in order to identify children presenting a triad of verbal ability, attention, verbal memory, and working memory antecedents of schizophrenia (ASz) (Laurens et al., 2007, 2011), assessed during childhood are associated with later development of incorporating: (1) PLEs; (2) social, emotional, and/or behavioural schizophrenia (Erlenmeyer-Kimling et al., 2000; Sorensen et al., problems in the clinical range; and (3) early speech and/or motor 2006; Seidman et al., 2013). developmental delays/abnormalities. Previous investigations have Evidence indicates that among non-ill adult relatives of in- shown that ASz children, compared to typically-developing chil- dividuals with schizophrenia, the degree of neurocognitive dren, are characterised by features qualitatively similar to those impairment is associated with familial loading for the disorder: the observed among adults with schizophrenia, including: (1) poorer higher the genetic loading, the greater the level of impairment on performance on standardised intelligence and neuropsychological neurocognitive measures (Faraone et al., 2000; Gur et al., 2007; tests of executive function and memory (Cullen et al., 2010); (2) Tsuang et al., 2006; Tuulio-Henriksson et al., 2003; Zilles et al., poorer facial emotion recognition (Dickson et al., in press); (3) 2009). Similarly, among youth aged 10e25 years with a positive elevated levels of social withdrawal (Matheson et al., 2013); (4) family history, those with an affected first-degree relative showed dyskinetic movement abnormalities (MacManus et al., 2012); (5) greater impairment than those with an affected second-degree reduction in the amplitude of the error-related negativity event- relative (Keshavan et al., 2010). related potential component generated in the anterior cingulate Neurocognitive impairments are also observed among in- that indexes internal monitoring of behaviour (Laurens et al., 2010); dividuals meeting ultra-high-risk (UHR) criteria for psychosis (i.e., and (6) structural brain abnormalities encompassing the temporal either attenuated psychotic symptoms, brief, limited intermittent lobe (Cullen et al., 2013). psychotic symptoms, or genetic risk [family history] plus functional Thus, preliminary evidence indicates that, like individuals with a decline). Help-seeking UHR youth present poorer verbal memory, first-degree affected relative, children presenting antecedents of processing speed, attention, working memory, and executive schizophrenia display neurocognitive impairment. It is not known, functioning than healthy comparison groups (for reviews: however, whether these impairments tap corresponding domains Addington and Barbato, 2012; Fusar-Poli et al., 2012). The magni- of similar severity, nor whether these impairments represent dif- tude of these neurocognitive impairments appear to be as severe as ficulties in specific cognitive domains or a general cognitive deficit those reported among individuals with a family history of schizo- represented by lower than average IQ. Further, among those who phrenia (FHx) (Agnew-Blais and Seidman, 2013). are at risk by virtue of family history, the severity and breadth of To date, three studies have directly compared performance of impairments vary by closeness of the affected relatives but could FHx and UHR individuals on a comprehensive neurocognitive test differ by age. These differences, if confirmed, may index differences battery (Mukkala et al., 2011; Myles-Worsley et al., 2007; Seidman in specific aetiological factors. et al., 2010). Seidman and colleagues reported specific impairments The present study examined neurocognitive impairments in on measures of verbal comprehension, processing speed, and ver- children defined as being at-risk for schizophrenia either by the bal fluency among the FHx group (both first and second-degree presence of affected relatives or by the presence of multiple relatives) compared to healthy individuals, while those meeting antecedents of the disorder. The aims were to determine whether UHR criteria performed more poorly than the comparison group on impairments differed depending on the definition of risk and/or tests of processing speed, verbal learning, and memory. Direct on the degree of relatedness to an affected individual. We also comparisons of performance revealed significant differences be- sought to explore the extent to which impairments were tween FHx and UHR youth only on tests of verbal memory, with explained by IQ. We therefore compared performance on a broad UHR individuals exhibiting significantly greater impairment array of neurocognitive tests among four groups of children aged (Seidman et al., 2010). Another investigation found that among 9e12 years, namely those with (1) at least one first-degree or youth aged 14e19 years, those with at least one first- or two two second-degree affected relatives (i.e., high family loading: second-degree affected relatives with the disorder displayed FHxH); (2) one affected second-degree relative (i.e., lower family impaired verbal memory, verbal working memory, attention, and loading: FHxL); (3) ASz; and (4) typically-developing (TD) chil- motor function, while those meeting UHR criteria were impaired on dren. We anticipated that all three high-risk groups of children, spatial working memory and perceptual organisation only (Myles- FHxH,FHxL, and ASz, would display poorer neurocognitive per- Worsley et al., 2007). By contrast, a recent study reported no dif- formance in IQ, scholastic achievement, memory, and executive ferences in neurocognitive functioning between young adult function than TD children, and that the specificimpairments offspring of parents with schizophrenia and UHR individuals rela- would differ across the risk groups (Myles-Worsley et al., 2007; tive to a healthy comparison group (Mukkala et al., 2011). Seidman et al., 2010). We also expected that children with a Thus, both FHx and UHR individuals show evidence of impair- higher degree of family loading for schizophrenia (FHxH)would ments in cognitive functioning relative to healthy individuals. exhibit more severe neurocognitive impairments than those in Moreover, cognitive impairments are present prior to the typical whom the degree of family loading was presumed to be lower age of onset of schizophrenia, suggesting that neurocognitive im- (FHxL). The study also determined the extent to which IQ ex- pairments index vulnerability for schizophrenia. Examining neu- plains differences in neurocognitive performance among children rocognitive functioning among children presenting antecedents of defined as FHxH,FHxL,andASz. 94 H. Dickson et al. / Journal of Psychiatric Research 50 (2014) 92e99

1. Method FHx children had at least one first- or second-degree relative with schizophrenia (n ¼ 25) or schizoaffective disorder (n ¼ 2), 1.1. Sample confirmed by the FIGS (Maxwell, 1992). Initially, a genetic liability score was computed based on the degree of relatedness and the One hundred and four children aged 9e12 years were recruited number of affected relatives (Campbell et al., 2010). With the via two methods described following. Children recruited into the exception of two children with two affected second-degree family study had never experienced a psychotic episode or taken anti- members, the results showed a bimodal distribution distinguishing psychotic medication, and none presented with a neurological FHx children with and without a first-degree affected relative. A disorder, learning difficulties (IQ < 70), or a diagnosis of autism or previous study detected no differences in neurocognitive impair- Asperger’s disorder. ment between adolescents with an affected parent and those with Ethical approval of the study was obtained from the Joint South two affected second-degree relatives with schizophrenia (Myles- London and Maudsley National Health Service Foundation Trust Worsley et al., 2007). Consequently, FHx children were divided and Institute of Psychiatry Research Ethics Committee. Children into two groups. The high familial loading for schizophrenia (FHxH) provided written assent and caregivers provided written consent group was defined to include children with one first-degree and for participation in the study. one second degree relative (n ¼ 4), one first-degree relative only Recruitment of ASz and TD children: Children from 73 primary (n ¼ 7), or two second-degree relatives (n ¼ 2) with schizophrenia schools in greater London and their primary caregivers completed or schizoaffective disorder. The low familial-loading group (FHxL) questionnaires designed to assess replicated antecedents of included children with one second-degree relative with the schizophrenia that have been described previously (Laurens et al., disorder. 2007, 2011). Children presenting antecedents of schizophrenia The final sample comprised four groups: 13 FHxH, 14 FHxL,32 (ASz) met three criteria: (1) a child-reported “certainly-true” ASz, and 45 TD children. One FHxH child and four FHxL children also response on at least one of nine PLE items assessing hallucination- met ASz criteria, but were retained in their respective FHx groups. and delusion-like experiences (Laurens et al., 2012); (2) a score in Table 1 presents demographic comparisons of the four groups. the clinical range (approximately top tenth percentile of U.K. Groups were similar as to age at the time of neurocognitive population norms) on the child-reported emotional symptoms assessment, handedness, and the proportion of males, but differed scale or the caregiver-reported conduct problems, hyperactivity- as to self-ascribed ethnicity, and parents’ occupational status. inattention, or peer relationship problems scales of the Strengths and Difficulties Questionnaire (Goodman, 2001); and (3) a 1.2. Procedure caregiver-report of a delay/abnormality in motor and/or speech development (Laurens et al., 2007). In contrast, TD children were Eligible children and their primary caregivers were invited to defined as those who presented none of the three ASz criteria nor participate in a research study that incorporated a battery of neu- had a first-, second-, or third-degree relative with a schizophrenia rocognitive assessments in addition to biological and psychosocial spectrum disorder, as confirmed using the Family Interview for measures. Genetic Studies which was completed with the child’s primary caregiver (FIGS: Maxwell, 1992). 1.3. Neurocognitive assessments In total, 1504 children and caregivers completed screening questionnaires. Among these, 9.4% of children met ASz triad A brief description of each neurocognitive measure comprising criteria, and 22.9% of children did not present with any of the an- the test battery is provided in Table 2, with subtests spanning the tecedents of schizophrenia. Half of these families (50.2%) indicated neurocognitive domains of general intelligence (IQ), scholastic a willingness to be contacted for further research, of whom 145 achievement, memory, and executive function (EF). were subsequently invited to participate in a research study that Each neurocognitive subtest provided standardised scores based included neurocognitive assessments. Thirteen of these potential on manual-reported, age-adjusted normative data; only the WIAT- participants were excluded: four with insufficient English to com- II UK provided norms for samples of children from the UK. Scores plete assessments, three with neurological disorder, and six with a for each subtest were converted into standardised z-scores based diagnosis of autism or Asperger’s disorder. Of the 54 ASz and 78 TD on TD group (risk group mean minus TD mean, divided by the TD children invited, 32 (59%) and 45 (58%) participated, respectively. standard deviation), so that the TD group had a mean of 0 and a There were no differences observed in the prevalence of ASz triad standard deviation of 1. components among ASz and TD children who participated and who did not participate in the present study, with a single exception. 1.4. Statistical analyses Proportionately fewer of the ASz children in the present study than those who completed only the screening questionnaire obtained Univariate ANOVA and chi-square tests were used to compare SDQ scores for emotional symptoms in the clinical range. groups on demographic variables. The distributions of raw scores Recruitment of FHx children. To identify children with a family and standardised z-scores were assessed for normality and outliers. history of schizophrenia or schizoaffective disorder, the screening Scores on the scholastic achievement domain for two TD children questionnaire included items assessing family mental health diagnosed with dyslexia were excluded, as was the perceptual problems. Approximately 2.1% of the 1504 caregivers completing reasoning score of one ASz child with a diagnosis of dyspraxia. To questionnaires indicated that their child had a relative with a compare scores on the neurocognitive tests of the four groups, schizophrenia spectrum disorder. Additionally, some children aged analysis of covariance (ANCOVA) tests were conducted adjusting for 9e12 years were recruited as relatives of patients receiving treat- ethnicity and parents’ occupational status, with post-hoc Bonfer- ment within the South London and Maudsley National Health roni-Hochberg correction applied (Hochberg, 1988). The size of the Service Foundation Trust. One third (36%) of FHx families recruited group differences is expressed as Cohen’s d effect sizes (Cohen, either through schools or as relatives of patients declined to 1988). To explore the role of general intellectual ability on spe- participate after initial contact. Just over half of the 27 participating cific domains of neurocognitive performance, ANCOVA analyses FHx children were recruited via schools (56%) and the remainder were repeated with the inclusion of full-scale IQ as an additional through contacts with patients. covariate. H. Dickson et al. / Journal of Psychiatric Research 50 (2014) 92e99 95

Table 1 Demographic characteristics for children with high familial loading for schizophrenia (FHxH), children with low familial loading (FHxL), children presenting with multiple antecedents of schizophrenia (ASz), and typically-developing children without antecedents or family history of schizophrenia (TD).

FHxH (n ¼ 13) FHxL (n ¼ 14) ASz (n ¼ 32) TD (n ¼ 45) Statistics

n (%) n (%) n (%) n (%)

Sex (Male) 7 (69) 5 (54) 22 (63) 21 (48) X2 ¼ 5.6, (df ¼ 3), p ¼ 0.1 Lateralitya Fisher’s Exact Test, p ¼ 0.7 Right-hand dominance 12 (92) 12 (86) 25 (77) 39 (87) Mixed- or left-hand dominance 1 (8) 2 (14) 7 (23) 6 (13) Ethnicityb Fisher’s Exact Test, p ¼ 0.001 White 2 (15) 3 (21) 15 (47) 33 (73) Black African and African-Caribbean 7 (54) 3 (43) 9 (28) 7 (16) Other 4 (31) 5 (36) 8 (25) 5 (11) Social Class based on parental occupationc Fisher’s Exact Test, p ¼ 0.001 Professional, managerial and technical occupations 5 (38) 10 (71) 17 (53) 39 (87) All skilled/unskilled manual occupations 8 (62) 4 (29) 15 (47) 6 (13) Mean sd Mean sd Mean sd Mean sd Age on day of assessment 11y, 3m 13m 10y, 7m 13m 10y, 11m 12m 11y, 0m 10m F(3,100) ¼ 1.1, p ¼ 0.4

Notes: y ¼ years, m ¼ months. a Assessed using the Questionnaire of Annett (Annett, 1970). b Ethnic group membership defined according to the 2001 UK Census ethnic group categories defined by the Office of National Statistics (2001) and collapsed into three categories. “Black African and Black African-Caribbean” included children of mixed white-black African/African-Caribbean ethnicity. “Other” included children predominantly of other mixed ethnicities. c Parental occupation coded according to UK Standard Occupational Classification 2000 (Office for National Statistics, 2000) and used to ascertain Social class based on Occupation (Office of Population Censuses and Surveys, 1980).

2. Results applied, indicated that FHxL children obtained significantly lower visual memory scores than FHxH children (p ¼ 0.01). On the EF- 2.1. Group comparisons of neurocognitive performance inhibition/switching subtest, FHxH performed significantly more poorly compared to the FHxL (p ¼ 0.02) and TD groups (p ¼ 0.007). Standardised z-scores calculated for each test and for each risk H group relative to the TD group are presented in Figs. 1 and 2. FHx 3. Discussion children exhibited neurocognitive impairments on all measures except visual memory, while ASz children performed at an inter- The present study examined neurocognitive functioning of H L mediate level relative to the FHx and FHx groups. Neurocognitive three groups of children aged 9e12 years putatively at-risk for L performance of FHx children in all domains except visual memory schizophrenia, relative to TD peers. FHxH children exhibited lower fell between that of ASz and TD groups. full scale IQ, verbal IQ, and perceptual reasoning scores, and poorer Tables 3 and 4 present mean scores for performance of each scholastic achievement, verbal memory, verbal working memory, group on the neurocognitive tests, the results of ANCOVAs adjust- category switching and inhibition/switching, FHxL children showed ing for ethnicity and parents’ occupation, and the significant post- no significant differences to TD children, and ASz children pre- hoc group comparisons. Significant overall group differences were sented significantly lower verbal comprehension, and poorer obtained for full-scale IQ, verbal comprehension, scholastic scholastic achievement and verbal working memory. Scores ob- achievement, verbal memory, verbal working memory, EF e cate- tained by the FHxH and ASz children were similar on all tests except gory switching accuracy, and EF e inhibition/switching. EF-category switching accuracy, where FHxH children demon- Post-hoc group comparisons with corrections for multiple strated more a prominent impairment. These results imply that, by H testing indicated that FHx children performed significantly more late childhood, children with one first-degree or two second- poorly than the TD children on full-scale IQ, verbal comprehension, degree relatives with schizophrenia, and children presenting perceptual reasoning, scholastic achievement, verbal memory, well-replicated antecedents of schizophrenia, are characterised by verbal working memory, EF-category switching accuracy, and EF- cognitive impairment. inhibition/switching domains, with large effect size differences. Deficits in verbal comprehension, verbal working memory, and H FHx children also displayed poorer performance on EF-category scholastic achievement were observed among both FHxH and ASz L switching accuracy relative to both FHx and ASz children, and on children compared to the TD children. Poor verbal comprehension L scholastic achievement compared to FHx children. ASz children and verbal working memory have been identified consistently in obtained lower verbal comprehension scores than TD children and children and youth with a first-degree relative with schizophrenia also showed poorer scholastic achievement and verbal working who have not yet passed through the age-range of risk for the L memory. The performance of the FHx children did not differ disorder (Agnew-Blais and Seidman, 2013) and among UHR ado- significantly from that of the TD children on any test. lescents and young adults (Addington and Barbato, 2012; Fusar-Poli et al., 2012). These specific cognitive impairments may represent 2.2. Does IQ explain group differences in neurocognitive generalised risk markers for later psychosis that span genetic (i.e., performance? individuals with a first-degree affected relatives) and clinical high- risk groups. The poor verbal abilities observed among both FHxH When full-scale IQ was entered as an additional covariate in and ASz children are in keeping with a previous investigation ANCOVA models, overall group differences on neurocognitive suggesting that verbal abilities may be one of the first cognitive measures were attenuated, such that only scores for EF- inhibition/ processes to show impairment in children who subsequently switching [F(3, 95) ¼ 2.7, p ¼ 0.05] and visual memory [F(3, develop schizophrenia (Reichenberg et al., 2010). 96) ¼ 2.9, p ¼ 0.04] differed significantly across the four groups. The extent to which poor school performance is associated with Post-hoc group comparisons, with corrections for multiple testing later schizophrenia is currently unclear (Dickson et al., 2012). 96 H. Dickson et al. / Journal of Psychiatric Research 50 (2014) 92e99

Table 2 Details of cognitive assessments.

Cognitive measure Test description

Intelligence (Wechsler Abbreviated Scale of Intelligence; WASI, Wechsler, 1999) Verbal Comprehension - Vocabulary Define orally and visually presented words - Similarities Identify similarities between pairs of words Perceptual Reasoning - Block Design Replicate geometric patterns using two-coloured cubes within a specified time limit - Matrix Reasoning Choose one shape from five to complete a pattern Scholastic Achievement (Wechsler Individual Achievement Test; WIAT-II UK, Wechsler, 2005) - Word Reading Read aloud a word list - Numerical Operations Complete mathematical problems - Spelling Write verbally presented words Memory (Wide Range Assessment of Learning and Memory; WRAML2, Sheslow and Adams, 2003) Verbal Memory Fig. 1. Group z-scores of intelligence and scholastic achievement scores standardised - Story Memory Immediate recall of details from to the typically-developing group mean. two short stories read aloud - Verbal Learning Immediate free recall of word list (four trials) underestimation of specific neurocognitive deficits, since some Visual Memory - Design Memory Immediate recall of five geometric aspects of cognitive ability are correlated with IQ (MacCabe et al., designs 2012). - Picture Memory Identify differences between four The current findings demonstrate that children with differing similar pairs of pictures profiles of risk for schizophrenia exhibit different degrees of neu- - Verbal Working Memory Immediate recall of word lists by animal and non-animal categories rocognitive impairment; those with a higher familial loading for Executive Functioning (Delis-Kaplan Executive Function System; schizophrenia were more cognitively impaired than children with D-KEFS, Delis et al, 2001) lower familial loading, and children presenting with antecedents of Verbal Fluency schizophrenia. These results extend previous findings of greater - Letter Fluency Generate words beginning with F, neurocognitive impairment among youth with a first-degree A, and S in 60 s - Category Fluency Generate animals and boys’ compared to second-degree relative with schizophrenia names in 60 s (Keshavan et al., 2010) to children assessed well before the typical - Category Switching Accuracy Alternatively generate words from period of risk for development of the disorder. fruits and furniture categories in 60 s FHxH children, relative to TD children, additionally showed poor Colour Word interference - Inhibition Name ink colour of colour verbal memory, which is among the most robust impairment words printed in different observed among children and young adults with affected first- colour ink (Stroop, 1935) degree relatives with schizophrenia and UHR individuals - Inhibition/Switching As for Inhibition subtest; or, reading colour word (ignore printed ink colour) Towers Tests - Towers Test Build towers using one to five Achievement score disks in the fewest possible number of moves

Among 16 year old offspring of adults with schizophrenia, two studies have reported an association between poor scholastic achievement based on end of year school assessment and family history of schizophrenia (Forsyth et al., 2013; Jundong et al., 2012), while there are no investigations of scholastic achievement among UHR individuals. Recent evidence supports an association between low scholastic performance and PLEs during childhood (Bartels- Velthuis et al., 2011; Hameed et al., 2013). Meta-analyses indicate that lower than average IQ characterises children and adolescents who subsequently develop schizophrenia (Dickson et al., 2012; Woodberry et al., 2008). Consistent with this finding, the results of the present study demonstrated that inclusion of full-scale IQ as a covariate in analyses of specific neurocognitive domains attenuated group differences, suggesting that specific cognitive impairments in FHx and ASz children were partly attributable to differences in general intellectual ability. Fig. 2. Group z-scores of memory and executive functioning scores standardised to the However, adjusting for IQ in statistical analyses may lead to an typically-developing group mean. H. Dickson et al. / Journal of Psychiatric Research 50 (2014) 92e99 97

Table 3 Comparisons of general intelligence and scholastic achievement of children with high familial loading for schizophrenia (FHxH), children with low familial loading (FHxL), children with antecedents of schizophrenia (ASz), and typically-developing children without antecedents or family history of schizophrenia (TD).

Subtest variable FHxH (n ¼ 13) FHxL (n ¼ 14) ASz (n ¼ 32) TD (n ¼ 45) ANCOVA adjusted for ethnicity and parents’ occupation

Mean (SD) Mean (SD) Mean (SD) Mean (SD) F (df); p Significant post-hoc tests, Cohen’s d

General Intelligence Full scale IQ 92.8 (13.7) 107.4 (14.3) 103.1 (11.8) 114.9 (15.0) 4.2 (3,98); 0.008 FHxH < TD, d ¼ 1.1 Verbal Comprehension 93.3 (10.8) 109.1 (14.2) 101.9 (12.3) 113.9 (14.6) 4.7 (3,98); 0.004 FHxH < TD, d ¼ 1.3; ASz < TD, d ¼ 0.9 Perceptual Reasoning 93.8 (17.0) 103.5 (12.7) 102.6 (13.5) 113.2 (15.4) 2.6 (3.97); 0.06 FHxH < TD, d ¼ 1.2 Scholastic Achievement 89.6 (12.3) 102.7 (8.3) 94.9 (12.0) 104.4 (11.0) 4.5 (3,93); 0.006 FHxH < TD, d ¼ 1.3; ASz < TD, d ¼ 0.8; FHxH < FHxL; d ¼ 1.3

Notes. Information on scholastic achievement was not available for 2 ASz participants. ANCOVA statistics include F statistic, degrees-of-freedom, and p-value, and are adjusted for ethnicity and parents’ occupation. Only post-hoc tests that were significant after Bonferroni-Hochberg corrections for multiple testing are reported.

(Addington and Barbato, 2012; Agnew-Blais and Seidman, 2013; memory, and EF e inhibition scores in ASz children relative to TD Fusar-Poli et al., 2012). Importantly, verbal memory deficits predict children (Cullen et al., 2010). The differences in results obtained conversion to later psychosis among young offspring of individuals across studies might be due to the small sample in the previous with schizophrenia and UHR youth (Brewer et al., 2005; investigation or inclusion in that ASz group of three children with a Erlenmeyer-Kimling et al., 2000; Lencz et al., 2006; Simon et al., positive family history of schizophrenia (two FHxH and one FHxL). 2012; Woodberry et al., 2010). Previous investigations directly Moreover, in the present study, unlike the previous one, group comparing neurocognition in adolescents and young adults with comparisons controlled for ethnicity and parents’ occupation. The first/second degree FHx relatives and UHR individuals observed prevalence of schizophrenia is higher among people of low socio- verbal memory impairments in the FHx group (Myles-Worsley economic status and of African-Caribbean and black African et al., 2007) or the UHR group only (Seidman et al., 2010). Meth- ethnicity living in the UK (Fearon et al., 2006; Tandon et al., 2008). odological differences between studies make results hard to Similarly, the prevalence ASz is higher among children of African- aggregate; however, our findings, and those of a recent review of Caribbean and black African origin, than among white British cognitive impairment among first-degree family members of children, living in the UK (Laurens et al., 2011, 2008). affected individuals aged 30 years and younger (Agnew-Blais and Strengths of the present study include the novel comparison of Seidman, 2013), indicate that poor verbal memory may represent three groups at-risk for schizophrenia based on differing vulnera- a possible genetic vulnerability indicator for schizophrenia. bility profiles, the examination of children prior to the age typically Further, FHxH children displayed impairment in additional associated with onset of the prodrome, and the broad array of cognitive domains that were not observed in FHxL or ASz groups. neurocognitive tests employed. The small sample size may have Relative to the TD group, FHxH children performed more poorly on limited our ability to detect neurocognitive impairments of small two EF tasks, category switching accuracy and inhibition/switching, effect, and prohibited further examination of the role of con- indicating reduced cognitive flexibility. These findings are consis- founding variables such as ethnicity in explaining group differ- tent with the poor cognitive flexibility widely observed among ences. Nonetheless, already in childhood, those with a first degree first-degree relatives of individuals who have yet to pass the age- or two second-degree relatives with schizophrenia showed range of risk typically associated with the disorder (Agnew-Blais impairment across a range of cognitive domains consistent with and Seidman, 2013). several reviews of cognitive functioning in FHx adolescents and Our previous investigation based on a smaller sample of ASz and young adults (Agnew-Blais and Seidman, 2013; Erlenmeyer- TD children indicated lower full-scale IQ, verbal memory, working Kimling, 2000; Niemi et al., 2003). While indexing family history

Table 4 Comparisons of memory and executive functioning of children with high familial loading for schizophrenia (FHxH), children with low familial loading (FHxL), children with antecedents of schizophrenia (ASz), and typically-developing children without antecedents or family history of schizophrenia (TD).

Subtest variable FHxH (n ¼ 13) FHxL (n ¼ 14) ASz (n ¼ 32) TD (n ¼ 45) ANCOVA adjusted for ethnicity and parents’ occupation

Mean (SD) Mean (SD) Mean (SD) Mean (SD) F (df); p Significant post-hoc tests, Cohens d

Memory Verbal Memory 17.2 (5.1) 21.6 (3.6) 21.7 (4.6) 23.9 (4.8) 3.1 (3, 97); 0.03 FHxH < TD, d ¼ 0.9 Visual Memory 18.8 (5.0) 15.5 (5.6) 16.7 (4.7) 18.8 (3.5) 2.5 (3, 97); 0.06 Verbal Working Memory 9.1 (2.4) 10.0 (2.0) 9.7 (2.2) 11.5 (2.5) 3.8 (3, 96); 0.01 FHxH < TD, d ¼ 1.0; ASz < TD, d ¼ 0.7 Executive Functioning Verbal Fluency Letter Fluency 10.2 (2.4) 11.5 (3.6) 10.5 (3.2) 11.5 (2.6) 1.5 (3, 97); 0.22 Category Fluency 11.4 (2.2) 12.0 (3.4) 12.2 (2.9) 12.8 (2.8) 0.1 (3, 96); 0.93 Category Switching Accuracy 7.2 (3.4) 10.4 (1.5) 10.2 (2.9) 11.2 (2.8) 4.4 (3, 97); 0.01 FHxH < TD, d ¼ 1.4; FHxH < ASz, d ¼ 1.0; FHxH < FHxL, d ¼ 1.3 Colour Word Interference Inhibition 9.1 (3.5) 10.6 (1.7) 10.7 (2.3) 11.7 (2.3) 1.5 (3, 96); 0.22 Inhibition/Switching 8.8 (2.5) 11.1 (2.2) 10.5 (2.8) 11.2 (2.0) 2.9 (3, 96); 0.04 FHxH < TD, d ¼ 1.2 Towers Test Towers Test Achievement Score 10.3 (2.3) 10.8 (1.8) 10.6 (2.4) 11.2 (2.6) 0.2 (3, 95); 0.90

Notes: Data were missing for memory, verbal working memory, and executive functioning for 1 ASz participant, category fluency for 1 FHxH participant, inhibition/switching for 1 TD participant, and achievement score on the Towers test for 1 ASz and TD participant. Scores for inhibition from 1 FHxH participant were excluded as an outlier. ANCOVA statistics include F statistic, degrees-of-freedom, and p-value. Only post-hoc tests that were significant after Bonferroni-Hochberg corrections for multiple testing are reported. 98 H. Dickson et al. / Journal of Psychiatric Research 50 (2014) 92e99 as a continuous measure may theoretically provide more statistical Agnew-Blais J, Seidman LJ. Neurocognition in youth and young adults under age 30 power for detecting associations between liability and neuro- at familial risk for schizophrenia: a quantitative and qualitative review. Cogn Neuropsychiatry 2013;18:1e39. cognitive impairment, a categorical approach to indexing genetic Annett M. A classification of hand preference by association analyses. Br J Psychol liability identified two groups of children at-risk, and yielded 1970;61:303e21. similar results to a previous study that used both categorical and Bartels-Velthuis AA, van de Willige G, Jenner JA, van Os J, Wiersma D. Course of fi fi auditory vocal hallucinations in childhood: 5-year follow-up study. Br J Psy- continuous de nitions of family risk and identi ed similar neuro- chiatry 2011;199:296e302. cognitive impairments among non-ill relatives (Byrne et al., 2003). Brewer WJ, Francey SM, Wood SJ, Jackson HJ, Pantelis C, Phillips LJ, et al. Memory Both children with a first-degree relative or two second-degree impairments identified in people at ultra-high risk for psychosis who later develop first-episode psychosis. Am J Psychiatry 2005;162:71e8. relatives with schizophrenia and those presenting a triad of ante- Byrne M, Clafferty B, Cosway R, Grant E, Hodges A, Whalley H, et al. Neuropsy- cedents showed impairments on neurocognitive tests relative to TD chology, genetic liability, and psychotic symptoms in those at high risk of children. The impairments were explained largely by differences in schizophrenia. J Abnorm Psychol 2003;112:38e48. Campbell DD, Sham P, Knight J, Wickham H, Landau S. Software for generating li- IQ. By contrast, the performance of children with one second- ability distributions for Pedigrees conditional on their observed disease states degree affected relative on these tests was similar to that of TD and covariates. Genet Epidemiol 2010;34:159e70. children. If replicated, these findings may provide clues for iden- Cohen J. Statistical power analysis for the behavioural sciences. 2nd ed. Hillsdale, tifying distinct aetiological factors active within each risk group, NJ: Erlbaum; 1988. Cullen AE, De Brito SA, Gregory SL, Murray RM, Williams SCR, Hodgins S, et al. though verbal comprehension, scholastic achievement, and verbal Temporal lobe volume abnormalities precede the prodrome: a study of working memory domains may confer generalised risk for psy- children presenting antecedents of schizophrenia. Schizophr Bull 2013;39: e chosis across at-risk groups. Intervening to improve cognitive 1318 27. Cullen AE, Dickson H, West SA, Morris RG, Mould GL, Hodgins S, et al. Neuro- performance in children at risk for schizophrenia might alter the cognitive deficits in children aged 9e12 years who present putative anteced- course of the developing illness. For example, among children with ents of schizophrenia. Schizophr Res 2010;121:15e23. e deficits in working memory, a learning-based intervention has Delis DC, Kaplan E, Kramer JH. The Delis Kaplan executive function system: ex- fi aminers manual. The Psychological Corporation: San Antonio; 2001. been shown to largely eliminate the de cit (Holmes et al., 2009). Dickson H, Calkins ME, Kohler CG, Hodgins S, Laurens KR. Misperceptions of facial Evaluating such interventions with different risk groups of children emotions among youth aged 9e14 years who present multiple antecedents of may further understanding of the aetiology of schizophrenia and schizophrenia. Schizophr Bull 2013 [in press]. Dickson H, Laurens KR, Cullen AE, Hodgins S. Meta-analyses of cognitive and motor identify strategies to increase resilience. function in youth aged 16 years and younger who subsequently develop schizophrenia. Psychol Med 2012;42:743e55. fi Role of funding source Erlenmeyer-Kimling L. Neurobehavioral de cits in offspring of schizophrenic parents: liability indicators and predictors of illness. Am J Med Genet 2000;97: 65e71. This work was supported by funding to KRL from a National Erlenmeyer-Kimling L, Rock D, Roberts SA, Janal M, Kestenbaum C, Cornblatt B, et al. Institute for Health Research (NIHR) Career Development Fellow- Attention, memory, and motor skills as childhood predictors of schizophrenia- related psychoses: the New York high-risk project. Am J Psychiatry 2000;157: ship (CDF/08/01/015); a Bial Foundation Research Grant (36/06); a 1416e22. NARSAD Young Investigator Award (2005); and the British Medical Faraone SV, Seidman LJ, Kremen WS, Toomey R, Pepple JR, Tsuang MT. Neuro- Association Margaret Temple Award for schizophrenia research psychologic functioning among the nonpsychotic relatives of schizophrenic patients: the effect of genetic loading. Biol Psychiatry 2000;48:120e6. (2006). HD was supported by a PhD studentship from the NIHR Fearon P, Kirkbride JB, Morgan C, Dazzan P, Morgan K, Lloyd T, et al. Incidence of Specialist Biomedical Research Centre for Mental Health at the schizophrenia and other psychoses in ethnic minority groups: results from the South London and Maudsley NHS Foundation Trust and Institute of MRC AESOP study. Psychol Med 2006;36:1541e50. ’ Forbes NF, Carrick LA, McIntosh AM, Lawrie SM. Working memory in schizophrenia: Psychiatry, King s College London, United Kingdom. a meta-analysis. Psychol Med 2006;39:889e905. Forsyth JK, Ellman LM, Tanskanen A, Mustonen U, Huttunen MO, Suvisaari J, Contributors et al. Genetic risk for schizophrenia, obstetric complications, and adoles- cent school outcome: evidence for gene-environment interaction. Schiz- ophr Bull 2013;39(5):1067e76. KRL and SH designed the study, and KRL and RGM selected the Fusar-Poli P, Deste G, Smieskova R, Barlati S, Yung AR, Howes OD, et al. Cognitive neurocognitive measures. HD and AEC completed the neuropsy- functioning in prodromal psychosis: a meta-analysis. Arch Gen Psychiatry 2012;69:562e71. chological assessments. HD conducted the literature search, sta- Goodman R. Psychometric properties of the strengths and difficulties questionnaire. tistical analyses, and wrote the initial draft of manuscript. AR and J Am Acad Child Adolesc Psychiatry 2001;40:1337e45. DDC provided statistical/analytical advice. All authors contributed Gur RE, Nimgaonkar VW, Almasy L, Calkins ME, Ragland DE, Pogue-Geile MF, et al. fi Neurocognitive endophenotypes in a multiplex multigenerational family study to and have approved the nal manuscript. of schizophrenia. Am J Psychiatry 2007;164:813e9. Hameed MA, Lewis AJ, Sullivan S, Zammit S. Child literacy and psychotic experi- fi Conflict of interest ences in early adolescence: ndings from the ALSPAC study. Schizophr Res 2013;145:88e94. Hochberg Y. A sharper Bonferroni procedure for multiple significance testing. Bio- All authors declare no conflict of interest. metrika 1988;75:800e3. Holmes J, Gathercole SE, Dunning DL. Adaptive training leads to sustained enhancement of poor working memory in children. Dev Sci 2009;12:9e15. Acknowledgements Jundong J, Kuja-Halkola R, Hultman C, Långström N, D’Onofrio BM, Lichtenstein P. Poor school performance in offspring of patients with schizophrenia: what are e The authors thank the children and caregivers who participated the mechanisms? Psychol Med 2012;42:111 23. Keefe RSE, Eesley CE, Poe MP. Defining a cognitive function decrement in schizo- in the study, and the research staff and students who contributed to phrenia. Biol Psychiatry 2005;57:688e91. data collection. HD, SH, and KRL are affiliated with the NIHR Keefe RSE, Fenton WS. How should DSM-V criteria for schizophrenia include e Specialist Biomedical Research Centre for Mental Health at the cognitive impairment? Schizophr Bull 2007;33:912 20. Kelleher I, Murtagh A, Clarke MC, Murphy J, Rawdon C, Cannon M. Neurocognitive South London and Maudsley NHS Foundation Trust and Institute of performance of a community-based sample of young people at putative ultra Psychiatry, King’s College London, United Kingdom. high risk for psychosis: support for the processing speed hypothesis. Cogn Neuropsychiatry 2012:1e17. Keshavan MS, Kulkarni SR, Bhojraj T, Francis A, Diwadkar V, Montrose DM, et al. References Premorbid cognitive deficits in young relatives of schizophrenia patients. Front Hum Neurosci 2010;3:1e14. Addington J, Barbato M. The role of cognitive functioning in the outcome of those at Kremen WS, Seidman LJ, Pepple JR, Lyons MJ, Tsuang MT, Faraone SV. Neuropsy- clinical high risk for developing psychosis. Epidemiol Psychiatr Sci 2012;21: chological risk indicators for schizophrenia: a review of family studies. Schiz- 335e42. ophr Bull 1994;20:103e19. H. Dickson et al. / Journal of Psychiatric Research 50 (2014) 92e99 99

Laurens KR, Hobbs MJ, Sunderland M, Green MJ, Mould GL. Psychotic-like experi- Office of National Statistics. Classification e the classification of ethnic groups; ences in a community sample of 8000 children aged 9 to 11 years: an item 2001. response theory analysis. Psychol Med 2012;42:1495e506. Office of Population Census and Surveys. Classification of occupations and coding; Laurens KR, Hodgins S, Maughan B, Murray RM, Rutter ML, Taylor EA. Community 1980. London. screening for psychotic-like experiences and other putative antecedents of Reichenberg A, Caspi A, Harrington H, Houts R, Keefe RSE, Murray RM, et al. Static schizophrenia in children aged 9e12 years. Schizophr Res 2007;90:130e46. and dynamic cognitive deficits in childhood preceding adult schizophrenia: a Laurens KR, Hodgins S, Mould GL, West SA, Schoenberg PLA, Murray RM, et al. 30-year study. Am J Psychiatry 2010;167:160e9. Error-related processing dysfunction in children aged 9 to 12 years presenting Reichenberg A, Harvey PD. Neuropsychological impairments in schizophrenia: putative antecedents of schizophrenia. Biol Psychiatry 2010;67:238e45. integration of performance-based and brain imaging findings. Psychol Bull Laurens KR, Hodgins S, Taylor EA, Murray RM. Is earlier intervention in 2007;133:833e58. schizophrenia possible? Identifying antecedents of schizophrenia in children Seidman LJ, Cherkerzian S, Goldstein JM, Agnew-Blais J, Tsuang MT, Buka SL. aged 9e12 years. In: David AS, McGuffin P, Kapur S, editors. Schizophrenia: the Neuropsychological performance and family history in children at age 7 who final frontier. London: Psychology Press; 2011. develop adult schizophrenia or bipolar psychosis in the New England Family Laurens KR, West SA, Murray RM, Hodgins S. Psychotic-like experiences and Studies. Psychological Medicine 2013;43:119e31. other antecedents of schizophrenia in children aged 9-12 years: a comparison Seidman LJ, Giuliano AJ, Meyer EC, Addington J, Cadenhead KS, Cannon TD, et al. of ethnic and migrant groups in the United Kingdom. Psychol Med 2008;38: Neuropsychology of the prodrome to psychosis in the napls consortium: rela- 1103e11. tionship to family history and conversion to psychosis. Arch Gen Psychiatry Lencz T, Smith CW, McLaughlin D, Auther A, Nakayama E, Hovey L, et al. Generalized 2010;67:578e88. and specific neurocognitive deficits in prodromal schizophrenia. Biol Psychiatry Sheslow D, Adams W. Wide Range Assessment of Memory and Learning e second 2006;59:863e71. edition (WRAML2). Wide range Inc: Delaware; 2003. MacCabe J,H, Brebion A, Reichenberg A, Ganguly T, McKenna PJ, Murray RM, et al. Simon AE, Grädel M, Cattapan-Ludewig K, Gruber K, Ballinari P, Roth B, et al. Superior intellectual ability in schizophrenia: neuropsychological characteris- Cognitive functioning in at-risk mental states for psychosis and 2-year clinical tics. Neuropsychology 2012;26:181e90. outcome. Schizophr Res 2012;142:108e15. MacManus D, Laurens KR, Walker EF, Brasfield JL, Riaz M, Hodgins S. Movement Sorensen HJ, Mortensen EL, Parnas J, Mednick SA. Premorbid neurocognitive abnormalties and psychotic-like experiences in childhood: markers for devel- functioning in schizophrenia spectrum disorder. Schizophr Bull 2006;32: oping schizophrenia? Psychol Med 2012;42:99e109. 578e83. Matheson SL, Shepherd AM, Laurens KR, Carr VJ. A systematic meta-review grading Stroop J. Studies of interference in serial verbal reactions. J Exp Psychol 1935;18: the evidence for non-genetic risk factors and putative antecedents of schizo- 643e62. phrenia. Schizophr Res 2011;133:133e42. Tandon R, Keshavan MS, Nasrallah HA, Schizophrenia. “Just the facts”: what we Matheson SL, Vijayan H, Dickson H, Shepherd AM, Carr VJ, Laurens KR. Systematic know in 2008: part 1: overview. Schizophr Res 2008;100:4e19. meta-analysis of childhood social withdrawal in schizophrenia, and comparison Tsuang H-C, Lin S-H, Liu SK, Hsieh M-H, Hwang TJ, Liu C-M, et al. More severe with data from at-risk children aged 9e14 years. J Psychiatr Res 2013;47:1061e8. sustained attention deficits in nonpsychotic siblings of multiplex schizo- Maxwell ME. Family interview for genetic studies (FIGS). Clincal Neurogenetic phrenia families than in those of simplex ones. Schizophr Res 2006;87: Branch, Intramural Research Program: National Institute of Mental Health; 172e80. 1992. Tuulio-Henriksson A, Arajärvi R, Partonen T, Haukka J, Varilo T, Schreck M, et al. Mesholam-Gately RI, Giuliano AJ, Goff KP, Faraone SV, Seidman L. Neurocognition in Familial loading associates with impairment in visual span among healthy first-episode schizophrenia: a meta-analytic review. Neuropsychology 2009;23: siblings of schizophrenia patients. Biol Psychiatry 2003;54:623e8. 315e536. Wechsler D. Wechsler Abbreviated Scale of General Intelligence (WASI). Harcourt Mukkala S, Ilonen T, Nordström T, Miettunen J, Loukkola J, Barnett JH, et al. Different Assessment: San Antonio; 1999. vulnerability indicators for psychosis and their neuropsychological character- Wechsler D. Wechsler Individual Achievement Test e second edition (WIAT-II). istics in the Northern Finland 1986 birth cohort. J Clin Exp Neuropsychol Harcourt Assessment: San Antonio; 2005. 2011;33:385e94. Woodberry KA, Giuliano AJ, Seidman LJ. Premorbid IQ in schizophrenia: a meta- Myles-Worsley M, Ord LM, Ngiralmau H, Weaver S, Blailes F, Faraone SV. The Palau analytic review. Am J Psychiatry 2008;165:579e87. early psychosis study: neurocognitive functioning in high-risk adolescents. Woodberry KA, Seidman LJ, Giuliano AJ, Verdi MB, Cook WL, McFarlane WR. Schizophr Res 2007;89:299e307. Neuropsychological profiles in individuals at clinical high risk for psycho- Niemi LT, Suvisaari JM, Tuulio-Henriksson A, Lönnqvist JK. Childhood develop- sis: relationship to psychosis and intelligence. Schizophr Res 2010;123: mental abnormalities in schizophrenia: evidence from high-risk studies. 188e98. Schizophr Res 2003;60:239e58. Zilles D, Burke S, Schneider-Axmann T, Falkai P, Gruber O. Diagnosis-specific effect Office for National Statistics. Standard occupational classification: structure and of familial loading on verbal working memory in schizophrenia. Eur Arch descriptions of unit groups. Basingstoke: Palgrave Macmillian; 2000. Psychiatry Clin Neurosci 2009;259:309e15.