Static and dynamic cognitive deficits in childhood preceding adult schizophrenia: a 30-year study.
ABSTRACT Premorbid cognitive deficits in schizophrenia are well documented and have been interpreted as supporting a neurodevelopmental etiological model. The authors investigated the following three unresolved questions about premorbid cognitive deficits: What is their developmental course? Do all premorbid cognitive deficits follow the same course? Are premorbid cognitive deficits specific to schizophrenia or shared by other psychiatric disorders?
Participants were members of a representative cohort of 1,037 males and females born between 1972 and 1973 in Dunedin, New Zealand. Cohort members underwent follow-up evaluations at specific intervals from age 3 to 32 years, with a 96% retention rate. Cognitive development was analyzed and compared in children who later developed schizophrenia or recurrent depression as well as in healthy comparison subjects.
Children who developed adult schizophrenia exhibited developmental deficits (i.e., static cognitive impairments that emerge early and remain stable) on tests indexing verbal and visual knowledge acquisition, reasoning, and conceptualization. In addition, these children exhibited developmental lags (i.e., growth that is slower relative to healthy comparison subjects) on tests indexing processing speed, attention, visual-spatial problem solving ability, and working memory. These two premorbid cognitive patterns were not observed in children who later developed recurrent depression.
These findings suggest that the origins of schizophrenia include two interrelated developmental processes evident from childhood to early adolescence (ages 7-13 years). Children who will grow up to develop adult schizophrenia enter primary school struggling with verbal reasoning and lag further behind their peers in working memory, attention, and processing speed as they get older.
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ABSTRACT: IMPORTANCE One approach to understanding the genetic complexity of schizophrenia is to study associated behavioral and biological phenotypes that may be more directly linked to genetic variation. OBJECTIVE To identify single-nucleotide polymorphisms associated with general cognitive ability (g) in people with schizophrenia and control individuals. DESIGN, SETTING, AND PARTICIPANTS Genomewide association study, followed by analyses in unaffected siblings and independent schizophrenia samples, functional magnetic resonance imaging studies of brain physiology in vivo, and RNA sequencing in postmortem brain samples. The discovery cohort and unaffected siblings were participants in the National Institute of Mental Health Clinical Brain Disorders Branch schizophrenia genetics studies. Additional schizophrenia cohorts were from psychiatric treatment settings in the United States, Japan, and Germany. The discovery cohort comprised 339 with schizophrenia and 363 community control participants. Follow-up analyses studied 147 unaffected siblings of the schizophrenia cases and independent schizophrenia samples including a total of an additional 668 participants. Imaging analyses included 87 schizophrenia cases and 397 control individuals. Brain tissue samples were available for 64 cases and 61 control individuals. MAIN OUTCOMES AND MEASURES We studied genomewide association with g, by group, in the discovery cohort. We used selected genotypes to test specific associations in unaffected siblings and independent schizophrenia samples. Imaging analyses focused on activation in the prefrontal cortex during working memory. Brain tissue studies yielded messenger RNA expression levels for RefSeq transcripts. RESULTS The schizophrenia discovery cohort showed genomewide-significant association of g with polymorphisms in sodium channel gene SCN2A, accounting for 10.4% of g variance (rs10174400, P = 9.27 × 10-10). Control individuals showed a trend for g/genotype association with reversed allelic directionality. The genotype-by-group interaction was also genomewide significant (P = 1.75 × 10-9). Siblings showed a genotype association with g parallel to the schizophrenia group and the same interaction pattern. Parallel, but weaker, associations with cognition were found in independent schizophrenia samples. Imaging analyses showed a similar pattern of genotype associations by group and genotype-by-group interaction. Sequencing of RNA in brain revealed reduced expression in 2 of 3 SCN2A alternative transcripts in the patient group, with genotype-by-group interaction, that again paralleled the cognition effects. CONCLUSIONS AND RELEVANCE The findings implicate SCN2A and sodium channel biology in cognitive impairment in schizophrenia cases and unaffected relatives and may facilitate development of cognition-enhancing treatments.JAMA Psychiatry 04/2014; · 12.01 Impact Factor
- American Journal of Psychiatry 01/2014; 171(1):9-12. · 14.72 Impact Factor
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ABSTRACT: Processing speed deficit, ascertained by Digit-Symbol Substitution Test (DSST), is considered as a fundamental impairment in Schizophrenia. Clinical correlates of processing speed abnormalities, especially using the parametric version of DSST is yet to be evaluated comprehensively. In this study, we examined schizophrenia patients (N = 66) and demographically-matched healthy controls (N = 72) using computer-administered parametric DSST (pDSST) with fixed (pDSSTF) as well as random (pDSSTR) conditions & analysed the relationship between pDSST performance and clinical symptoms. Psychopathology was assessed using Scale for Assessment of Positive Symptoms (SAPS)/Negative Symptoms (SANS) with good inter-rater reliability. In comparison with healthy controls, patients demonstrated significantly lesser number of correct responses (CN) in pDSSTF (t = 8.0; p < 0.001) and pDSSTR (t = 7.8; p < 0.001) as well as significantly prolonged reaction time in pDSSTF (t = 7.1; p < 0.001) and pDSSTR (t = 7.0; p < 0.001). The difference in CN between pDSSTF and pDSSTR [ΔCN] was significantly lesser in patients than healthy controls (t = 2.61; p = 0.01). The pDSST reaction time had significant positive correlation with negative syndrome scores as well as bizarre behaviour score. Significantly greater processing speed deficits in pDSST suggest potential relational memory/visual scanning abnormalities in schizophrenia. Furthermore, pDSST deficits demonstrated a significant association with the psychopathology, especially with the various negative symptoms and bizarre behaviour.Asian Journal of Psychiatry 08/2014;