Cognitive deficits in relatives of patients with schizophrenia: a meta-analysis

BACKGROUND Schizophrenia is characterized by a generalized cognitive impairment with pronounced deficits in the domains of verbal memory, executive functioning and attention. AIM To investigate whether cognitive deficits found in patients with schizophrenia are also found in non-affected relatives. METHOD A meta-analytic review of the published literature on cognitive performance between relatives of schizophrenic patients and healthy controls. RESULTS The meta-analyses yielded nine weighted effect sizes from 37 studies comprising 1639 relatives of schizophrenia patients and 1380 control subjects. The largest differences were found on verbal memory recall (d=0.54, 95% CI=0.43-0.66) and executive functioning (d=0.51, 0.36-0.67). Attentional functioning showed smaller effect sizes (d=0.28, 0.06-0.50). These effect sizes are in the moderate range. CONCLUSION Cognitive deficits found in patients with schizophrenia are also found in non-affected relatives. This finding is consistent with the idea that certain cognitive deficiencies in relatives are caused by familial predisposition to schizophrenia and that these deficiencies might be putative endophenotypes for schizophrenia. However, our results do not address genetic causes directly. Further work is needed to determine whether certain cognitive traits are familial and whether there is co-inheritance of these traits with schizophrenia within families.

[1]  S. Faraone,et al.  Sustained attention deficits as markers of genetic susceptibility to schizophrenia. , 2000, American journal of medical genetics.

[2]  William R. Shadish,et al.  Combining estimates of effect size. , 1994 .

[3]  S. Lawrie,et al.  Neuropsychological change in young people at high risk for schizophrenia: results from the first two neuropsychological assessments of the Edinburgh High Risk Study , 2000, Psychological Medicine.

[4]  D. Yurgelun-Todd,et al.  Patterns of neuropsychological deficits that discriminate schizophrenic individuals from siblings and control subjects. , 1993, The Journal of neuropsychiatry and clinical neurosciences.

[5]  M. Owen,et al.  Sustained and selective attention as measures of genetic liability to schizophrenia , 2001, Schizophrenia Research.

[6]  Larry J Seidman,et al.  Neuropsychologic functioning among the nonpsychotic relatives of schizophrenic patients: the effect of genetic loading , 2000, Biological Psychiatry.

[7]  S. Faraone,et al.  Neuropsychological risk indicators for schizophrenia: a preliminary study of female relatives of schizophrenic and bipolar probands , 1998, Psychiatry Research.

[8]  G. Larrabee,et al.  A review of mild head trauma. Part I: Meta-analytic review of neuropsychological studies. , 1997, Journal of clinical and experimental neuropsychology.

[9]  J. Ragland,et al.  Neuropsychological evidence supporting a neurodevelopmental model of schizophrenia: a longitudinal study , 1997, Schizophrenia Research.

[10]  S. Faraone,et al.  Association of neuropsychological vulnerability markers in relatives of schizophrenic patients , 1998, Schizophrenia Research.

[11]  J. Gruzelier,et al.  Neuropsychology, Psychophysiology And Information Processing , 1991 .

[12]  P. McGuffin,et al.  Genetic basis of schizophrenia , 1995, The Lancet.

[13]  H. Wass,et al.  A Developmental Perspective , 1985 .

[14]  S. Faraone,et al.  Neuropsychological risk indicators for schizophrenia: a review of family studies. , 1994, Schizophrenia bulletin.

[15]  Karl J. Friston,et al.  Brain activations in schizophrenia during a graded memory task studied with functional neuroimaging. , 1998, Archives of general psychiatry.

[16]  B. Cornblatt,et al.  Impaired attention, genetics, and the pathophysiology of schizophrenia. , 1994, Schizophrenia bulletin.

[17]  J. Daléry,et al.  WCST performance and schizotypal features in the first-degree relatives of patients with schizophrenia , 2001, Psychiatry Research.

[18]  W. Maier,et al.  Cognitive functioning and anhedonia in subjects at risk for schizophrenia , 1993, Schizophrenia Research.

[19]  J. Daléry,et al.  Attentional deficits in patients with schizophrenia and in their non-psychotic first-degree relatives , 1999, Psychiatry Research.

[20]  V. Peralta,et al.  Schizophrenic syndrome and Wisconsin Card Sorting Test dimensions , 1995, Psychiatry Research.

[21]  Juan Carlos Espinosa,et al.  Comprehensive Meta-Analysis , 2004 .

[22]  R. Kahn,et al.  Cognitive dysfunctions in parents of schizophrenic patients parallel the deficits found in patients , 2003, Schizophrenia Research.

[23]  Michael F Egan,et al.  Relative risk for cognitive impairments in siblings of patients with schizophrenia , 2001, Biological Psychiatry.

[24]  J van Os,et al.  Single or multiple familial cognitive risk factors in schizophrenia? , 2001, American journal of medical genetics.

[25]  L. DeLisi,et al.  Language processing and memory in ill and well siblings from multiplex families affected with schizophrenia , 1997, Schizophrenia Research.

[26]  B. Clementz,et al.  Familial prevalence and coaggregation of schizotypy indicators: a multitrait family study. , 1991, Journal of abnormal psychology.

[27]  J. Rybakowski,et al.  Eye movement and neuropsychological studies in first-degree relatives of schizophrenic patients , 2002, Schizophrenia Research.

[28]  C. Frith,et al.  Disordered functional connectivity in schizophrenia , 1996, Psychological Medicine.

[29]  R. Kahn,et al.  Release From Proactive Inhibition in Schizophrenia and its Potential as a Genotypic Marker , 2002, Journal of clinical and experimental neuropsychology.

[30]  T. Goldberg,et al.  Genetic risk of neuropsychological impairment in schizophrenia: a study of monozygotic twins discordant and concordant for the disorder , 1995, Schizophrenia Research.

[31]  W. Maier,et al.  Wisconsin Card Sorting Test: an indicator of vulnerability to schizophrenia? , 1992, Schizophrenia Research.

[32]  Leslie G. Ungerleider.  Functional Brain Imaging Studies of Cortical Mechanisms for Memory , 1995, Science.

[33]  P. Stratta,et al.  No deficit in Wisconsin Card Sorting Test performance of schizophrenic patients' first-degree relatives , 1997, Schizophrenia Research.

[34]  D. Blackwood,et al.  Neuropsychological and P300 abnormalities in schizophrenics and their relatives , 1993, Psychological Medicine.

[35]  S. Faraone,et al.  Neuropsychological functioning among the nonpsychotic relatives of schizophrenic patients: a diagnostic efficiency analysis. , 1995, Journal of abnormal psychology.

[36]  S. Faraone,et al.  Factor structure of the Wisconsin Card Sorting Test: dimensions of deficit in schizophrenia. , 1998, Neuropsychology.

[37]  R. Murray,et al.  Heritability estimates for psychotic disorders: the Maudsley twin psychosis series. , 1999, Archives of general psychiatry.

[38]  L. Hedges,et al.  Statistical Methods for Meta-Analysis , 1987 .

[39]  D. Weinberger,et al.  Evidence of dysfunction of a prefrontal-limbic network in schizophrenia: a magnetic resonance imaging and regional cerebral blood flow study of discordant monozygotic twins. , 1992, The American journal of psychiatry.

[40]  Mohamed Saoud,et al.  Neuropsychological functioning among non-psychotic siblings and parents of schizophrenic patients , 1999, Psychiatry Research.

[41]  L. Hedges,et al.  The Handbook of Research Synthesis , 1995 .

[42]  E. Johnstone,et al.  Neuropsychological assessment of young people at high genetic risk for developing schizophrenia compared with controls: preliminary findings of the Edinburgh High Risk Study (EHRS) , 1999, Psychological Medicine.

[43]  M. Albus,et al.  Are there gender differences in neuropsychological performance in patients with first-episode schizophrenia? , 1997, Schizophrenia Research.

[44]  E. Tulving,et al.  Frontal lobe damage produces episodic memory impairment , 1995, Journal of the International Neuropsychological Society.

[45]  Nikos Makris,et al.  Left hippocampal volume as a vulnerability indicator for schizophrenia: a magnetic resonance imaging morphometric study of nonpsychotic first-degree relatives. , 2002, Archives of general psychiatry.

[46]  I. Gottesman,et al.  The endophenotype concept in psychiatry: etymology and strategic intentions. , 2003, The American journal of psychiatry.

[47]  Karl J. Friston,et al.  Abnormal neural integration related to cognition in schizophrenia , 1999, Acta psychiatrica Scandinavica. Supplementum.

[48]  M. Egan,et al.  Relative risk of attention deficits in siblings of patients with schizophrenia. , 2000, The American journal of psychiatry.

[49]  S. Faraone,et al.  Verbal learning and memory in relatives of schizophrenics: Preliminary findings , 1995, Biological Psychiatry.

[50]  Alan C. Evans,et al.  Amygdala–hippocampal volume and verbal memory in first-degree relatives of schizophrenic patients , 2001, Psychiatry Research: Neuroimaging.

[51]  Sohee Park,et al.  Spatial working memory deficits in schizophrenia patients and their first degree relatives from Palau, Micronesia. , 2002, American journal of medical genetics.

[52]  F. Bloom,et al.  Psychopharmacology: The Fourth Generation of Progress , 1995 .

[53]  S. Lawrie,et al.  Sustained attention in young people at high risk for schizophrenia , 2002, Psychological Medicine.

[54]  B. Ismail,et al.  Minor physical anomalies in schizophrenia: cognitive, neurological and other clinical correlates. , 2000, Journal of psychiatric research.

[55]  R Kikinis,et al.  Neuropsychological correlates of MRI temporal lobe abnormalities in schizophrenia. , 1993, The American journal of psychiatry.

[56]  R. Näätänen.  Implications of ERP data for psychological theories of attention , 1988, Biological Psychology.

[57]  R. E. Passingham,et al.  Memory and the frontal lobes , 1984, Behavioural Brain Research.

[58]  F M Miezin,et al.  Activation of the hippocampus in normal humans: a functional anatomical study of memory. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[59]  T. Goldberg,et al.  Learning and memory in monozygotic twins discordant for schizophrenia , 1993, Psychological Medicine.

[60]  J. Jolles,et al.  Cognitive performance in relation to MRI temporal lobe volume in schizophrenic patients and healthy control subjects. , 2000, The Journal of neuropsychiatry and clinical neurosciences.

[61]  L. Leach,et al.  Neuropsychological Differential Diagnosis , 1999 .

[62]  R. Kahn,et al.  Memory impairment in schizophrenia: a meta-analysis. , 1999, The American journal of psychiatry.

[63]  I. Gottesman.  Schizophrenia Genesis: The Origins of Madness , 1990 .

[64]  S. Steinhauer,et al.  language comprehension in schizophrenics and their brothers , 1992, Biological Psychiatry.

[65]  N. Docherty,et al.  Immediate memory, attention and communication disturbances in schizophrenia patients and their relatives , 1999, Psychological Medicine.

[66]  Tyrone D. Cannon,et al.  Attentional dysfunctions in neuroleptic-naive and neuroleptic-withdrawn schizophrenic patients and their siblings , 1995, Schizophrenia Research.

[67]  R. Heinrichs,et al.  Neurocognitive deficit in schizophrenia: a quantitative review of the evidence. , 1998, Neuropsychology.

[68]  Jacob Cohen.  Statistical Power Analysis for the Behavioral Sciences , 1969, The SAGE Encyclopedia of Research Design.

[69]  W. Maier,et al.  Attentional abilities and measures of schizotypy: Their variation and covariation in schizophrenic patients, their siblings, and normal control subjects , 1994, Psychiatry Research.

[70]  S. Kéri,et al.  Different trait markers for schizophrenia and bipolar disorder: a neurocognitive approach , 2001, Psychological Medicine.

[71]  C. Waternaux,et al.  Obstetrical complications and trail making deficits discriminate schizophrenics from unaffected siblings and controls , 1994, Schizophrenia Research.

[72]  R. Bilder.  Neuropsychology and neurophysiology in schizophrenia , 1996 .

[73]  M. Nieuwenstein,et al.  Relationship between symptom dimensions and neurocognitive functioning in schizophrenia: a meta-analysis of WCST and CPT studies. Wisconsin Card Sorting Test. Continuous Performance Test. , 2001, Journal of psychiatric research.

[74]  R. Gur,et al.  Neuropsychological deficits in neuroleptic naive patients with first-episode schizophrenia. , 1994, Archives of general psychiatry.

[75]  Tyrone D. Cannon,et al.  Heritability and number of quantitative trait loci of neurocognitive functions in families with schizophrenia. , 2002, American journal of medical genetics.

[76]  L R Squire,et al.  Memory, memory impairment, and the medial temporal lobe. , 1996, Cold Spring Harbor symposia on quantitative biology.

[77]  Tyrone D. Cannon,et al.  The inheritance of neuropsychological dysfunction in twins discordant for schizophrenia. , 2000, American journal of human genetics.

[78]  S. Dollfus,et al.  Executive/attentional cognitive functions in schizophrenic patients and their parents: a preliminary study , 2002, Schizophrenia Research.

[79]  H. Uylings.  Cognition, emotion and autonomic responses: the integrative role of the prefrontal cortex and limbic structures. Proceedings of the 21st International Summer School of Brain Research. Amsterdam, The Netherlands, 23-27 August 1999. , 2000, Progress in brain research.

[80]  D. Boomsma,et al.  Editorial: Genetics of Brain Function and Cognition , 2001, Behavior genetics.

[81]  Karl J. Friston,et al.  Functional topography: multidimensional scaling and functional connectivity in the brain. , 1996, Cerebral cortex.

[82]  D. Stuss.  Assessment of neuropsychological dysfunction in frontal lobe degeneration. , 1993, Dementia.

[83]  W. Maier,et al.  Neuropsychological indicators of the vulnerability to schizophrenia , 1992, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[84]  M. Marie-cardine,et al.  Neuropsychological deficit in siblings discordant for schizophrenia. , 2000, Schizophrenia bulletin.

[85]  D. Weinberger,et al.  From neuropathology to neurodevelopment , 1995, The Lancet.

[86]  J. Daléry,et al.  Executive/attentional performance and measures of schizotypy in patients with schizophrenia and in their nonpsychotic first-degree relatives , 2000, Schizophrenia Research.

[87]  Philip D. Harvey,et al.  Performance of nonpsychotic relatives of schizophrenic patients on cognitive tests , 1994, Psychiatry Research.

[88]  R. Coppola,et al.  Executive subprocesses in working memory: relationship to catechol-O-methyltransferase Val158Met genotype and schizophrenia. , 2003, Archives of general psychiatry.

[89]  M. Lipsey,et al.  The Way in Which Intervention Studies Have “Personality” and why it is Important to Meta-Analysis , 2001, Evaluation & the health professions.