Brain volumes in relatives of patients with schizophrenia: a meta-analysis.

CONTEXT Smaller brain volumes have consistently been found in patients with schizophrenia, particularly in gray matter and medial temporal lobe structures. Although several studies have investigated brain volumes in nonpsychotic relatives of patients with schizophrenia, results have been inconsistent. OBJECTIVE To determine the magnitude and extent of brain volume differences in first-degree relatives of schizophrenic patients. DATA SOURCES A systematic search was conducted to identify relevant studies. Computer searches of the MEDLINE database were performed for English-language articles published before July 2005. Relevant abstracts published in 2005 were also selected. STUDY SELECTION Magnetic resonance imaging studies that examined differences in brain volumes between first-degree relatives of patients with schizophrenia and healthy control subjects were obtained through computerized databases, including MEDLINE. Studies had to report sufficient data for computation of effect sizes. DATA EXTRACTION For each study, the Cohen d was calculated. Data extraction and calculation of the effect size were performed by 2 authors (H.B.M.B. and A.A.) who reached a consensus in cases of uncertainty and discrepancies. All analyses were performed using the random-effects model. DATA SYNTHESIS Twenty-five studies were identified as suitable for analysis and included 1065 independent first-degree relatives of patients, 679 patients with schizophrenia, and 1100 healthy control subjects. The largest difference between relatives and healthy control subjects was found in hippocampal volume, with relatives having smaller volumes than controls (d = 0.31; 95% confidence interval [CI], 0.13-0.49; 9 effect sizes). Gray matter was smaller (d = 0.18; 95% CI, 0.02-0.33; 7 effect sizes) and third-ventricle volume was larger (d = 0.21; 95% CI, 0.03-0.40; 7 effect sizes) in relatives compared with healthy control subjects. CONCLUSION Brain abnormalities are present in nonpsychotic first-degree relatives of patients with schizophrenia and are most pronounced in the hippocampus.

[1]  N. Laird,et al.  Meta-analysis in clinical trials. , 1986, Controlled clinical trials.

[2]  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.

[3]  S. Lawrie,et al.  Voxel-based morphometry of grey matter reductions in subjects at high risk of schizophrenia and the impact of specific templates , 2002 .

[4]  Sophia Frangou,et al.  Hippocampal volume reduction in schizophrenia: effects of genetic risk and pregnancy and birth complications , 1999, Biological Psychiatry.

[5]  Dennis Velakoulis,et al.  Hippocampal and anterior cingulate morphology in subjects at ultra-high-risk for psychosis: the role of family history of psychotic illness , 2005, Schizophrenia Research.

[6]  Oili Salonen,et al.  Contributions of genetic risk and fetal hypoxia to hippocampal volume in patients with schizophrenia or schizoaffective disorder, their unaffected siblings, and healthy unrelated volunteers. , 2002, The American journal of psychiatry.

[7]  Arthur W Toga,et al.  Genetic Contributions to Altered Callosal Morphology in Schizophrenia , 2002, The Journal of Neuroscience.

[8]  Tyrone D. Cannon,et al.  Hippocampal volumes in schizophrenic twins , 2003, Schizophrenia Research.

[9]  A. Meyer-Lindenberg,et al.  Variation in DISC1 affects hippocampal structure and function and increases risk for schizophrenia. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[10]  Karen F. Berman,et al.  Relations between neuropsychological performance and brain morphological and physiological measures in monozygotic twins discordant for schizophrenia , 1994, Psychiatry Research: Neuroimaging.

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

[12]  M. Keshavan,et al.  Cavum Septi Pellucidi in First-Episode Patients and Young Relatives at Risk for Schizophrenia , 2002, CNS Spectrums.

[13]  E. Bramon,et al.  Association of genetic risks for schizophrenia and bipolar disorder with specific and generic brain structural endophenotypes. , 2004, Archives of general psychiatry.

[14]  T. Sigmundsson,et al.  Hippocampal volume in familial and nonfamilial schizophrenic probands and their unaffected relatives , 2003, Biological Psychiatry.

[15]  R. Gur,et al.  Gender differences in age effect on brain atrophy measured by magnetic resonance imaging. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[16]  V S Caviness,et al.  Reduced subcortical brain volumes in nonpsychotic siblings of schizophrenic patients: a pilot magnetic resonance imaging study. , 1997, American journal of medical genetics.

[17]  René S. Kahn,et al.  Cognitive deficits in relatives of patients with schizophrenia: a meta-analysis , 2004, Schizophrenia Research.

[18]  R. Freedman,et al.  Familial transmission of risk factors in the first-degree relatives of schizophrenic people , 2000, Biological Psychiatry.

[19]  Tyrone D. Cannon,et al.  A prospective cohort study of genetic and perinatal influences in the etiology of schizophrenia. , 2000, Schizophrenia bulletin.

[20]  M. Keshavan,et al.  Decreased left amygdala and hippocampal volumes in young offspring at risk for schizophrenia , 2002, Schizophrenia Research.

[21]  J. Rapoport,et al.  Mapping adolescent brain change reveals dynamic wave of accelerated gray matter loss in very early-onset schizophrenia , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[22]  A Sacker,et al.  Obstetric complications in children born to parents with schizophrenia: a meta-analysis of case–control studies , 1996, Psychological Medicine.

[23]  A. Troyer,et al.  Component analysis of verbal fluency in patients with schizophrenia. , 2000, Neuropsychiatry, neuropsychology, and behavioral neurology.

[24]  Theo G. M. van Erp,et al.  A Twin Study of Genetic Contributions to Hippocampal Morphology in Schizophrenia , 2002, Neurobiology of Disease.

[25]  S. Lawrie,et al.  Voxel-based morphometry of grey matter densities in subjects at high risk of schizophrenia , 2003, Schizophrenia Research.

[26]  Nicolette Marshall,et al.  A controlled study of brain structure in monozygotic twins concordant and discordant for schizophrenia , 2004, Biological Psychiatry.

[27]  F. Gage,et al.  Neurogenesis in the adult human hippocampus , 1998, Nature Medicine.

[28]  M. Rietschel,et al.  Shape changes in prefrontal, but not parieto-occipital regions: brains of schizophrenic patients come closer to a circle in coronal and sagittal view , 2004, Psychiatry Research: Neuroimaging.

[29]  Dorret I Boomsma,et al.  Genetic correlations between brain volumes and the WAIS-III dimensions of verbal comprehension, working memory, perceptual organization, and processing speed. , 2003, Twin research : the official journal of the International Society for Twin Studies.

[30]  R. Coppola,et al.  Thalamic and Caudate Volumes in Monozygotic Twins Discordant for Schizophrenia , 2001, The Australian and New Zealand journal of psychiatry.

[31]  Deanna Greenstein,et al.  Structural brain MRI abnormalities in healthy siblings of patients with childhood-onset schizophrenia. , 2003, The American journal of psychiatry.

[32]  Tyrone D. Cannon,et al.  Structural brain abnormalities as indicators of vulnerability to schizophrenia. , 1994, Schizophrenia bulletin.

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

[34]  John S. Duncan,et al.  Material-specific lateralization of memory encoding in the medial temporal lobe: Blocked versus event-related design , 2005, NeuroImage.

[35]  C. Pantelis,et al.  Non-reduction in hippocampal volume is associated with higher risk of psychosis , 2002, Schizophrenia Research.

[36]  W. Honer,et al.  Developmental abnormalities of the hippocampus in First-Episode schizophrenia , 2003, Biological Psychiatry.

[37]  E. T. Bullmore,et al.  Genetic Contributions to Regional Variability in Human Brain Structure: Methods and Preliminary Results , 2002, NeuroImage.

[38]  D Robinson,et al.  Brain-derived neurotrophic factor Val66met polymorphism and volume of the hippocampal formation , 2005, Molecular Psychiatry.

[39]  Robert G. Orwin,et al.  A Fail-SafeN for Effect Size in Meta-Analysis , 1983 .

[40]  Dimensions of psychosis in affected sibling pairs , 1999 .

[41]  R. Sapolsky,et al.  Stress, glucocorticoids, and aging , 1992, Aging.

[42]  P. Buckley.  Brain Volumes in Relatives of Patients With Schizophrenia: A MetaanalysisBoos HBM, Aleman A, Cahn W, et al (Univ Med Ctr Utrecht, The Netherlands; Univ Med Ctr Groningen, The Netherlands) Arch Gen Psychiatry 64:297–304, 2007§ , 2008 .

[43]  R S Kahn,et al.  Partial volume decrease of the thalamus in relatives of patients with schizophrenia. , 1998, The American journal of psychiatry.

[44]  R. Murray,et al.  Normal cerebral asymmetry in familial and non-familial schizophrenic probands and their unaffected relatives , 2004, Schizophrenia Research.

[45]  R. Orwin.  A fail-safe N for effect size in meta-analysis. , 1983 .

[46]  Hilleke E. Hulshoff Pol,et al.  Changes in First-Episode Schizophrenia A 1-Year Follow-up Study , 2002 .

[47]  R. Gur,et al.  Subcortical MRI volumes in neuroleptic-naive and treated patients with schizophrenia. , 1998, The American journal of psychiatry.

[48]  S. Lawrie,et al.  Brain structure, genetic liability, and psychotic symptoms in subjects at high risk of developing schizophrenia , 2001, Biological Psychiatry.

[49]  Robin M. Murray,et al.  The relationship between volumetric brain changes and cognitive function: A family study on schizophrenia , 2004, Biological Psychiatry.

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

[51]  D. Weinberger,et al.  Anatomical abnormalities in the brains of monozygotic twins discordant for schizophrenia. , 1990, The New England journal of medicine.

[52]  Sophia Rabe-Hesketh,et al.  Selectivity of verbal memory deficit in schizophrenic patients and their relatives , 2003, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[53]  Muriel Walshe,et al.  Brain volumes in familial and non-familial schizophrenic probands and their unaffected relatives. , 2002, American journal of medical genetics.

[54]  S. Lawrie,et al.  Brain abnormality in schizophrenia , 1998, British Journal of Psychiatry.

[55]  B. McEwen,et al.  The neuroendocrinology of stress and aging: the glucocorticoid cascade hypothesis. , 1986, Endocrine reviews.

[56]  R. Murray,et al.  Meta-analysis of regional brain volumes in schizophrenia. , 2000, The American journal of psychiatry.

[57]  B. Turetsky,et al.  Low olfactory bulb volume in first-degree relatives of patients with schizophrenia. , 2003, The American journal of psychiatry.

[58]  Nikos Makris,et al.  Thalamic and amygdala–hippocampal volume reductions in first-degree relatives of patients with schizophrenia: an MRI-based morphometric analysis , 1999, Biological Psychiatry.

[59]  J. Lieberman,et al.  Longitudinal study of brain morphology in first episode schizophrenia , 2001, Biological Psychiatry.

[60]  J. Stack,et al.  Magnetic resonance imaging of schizophrenia-like psychoses associated with cerebral trauma: clinicopathological correlates. , 1993, The American journal of psychiatry.

[61]  Eve C. Johnstone,et al.  Grey matter changes over time in high risk subjects developing schizophrenia , 2005, NeuroImage.

[62]  Daniel R. Weinberger,et al.  Cortical gyral anatomy and gross brain dimensions in monozygotic twins discordant for schizophrenia , 1996, Schizophrenia Research.

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

[64]  McAllister.  Traumatic Brain Injury and Psychosis: What Is the Connection? , 1998, Seminars in clinical neuropsychiatry.

[65]  M. Keshavan,et al.  Changes in caudate volume with neuroleptic treatment , 1994, The Lancet.

[66]  R. Kahn,et al.  Genetic Correlations Between Brain Volumes and the WAIS-III Dimensions of Verbal Comprehension, Working Memory, Perceptual Organization, and Processing Speed , 2003, Twin Research.

[67]  L. Siever,et al.  133 Lateral ventricular enlargement in schizophrenic probands and their siblings with schizophrenia-related disorders , 1997, Schizophrenia Research.

[68]  Silvia Moscoso,et al.  Comprehensive meta-analysis of the construct validity of the employment interview , 2002 .

[69]  Bruce S. McEwen,et al.  The neurobiology of stress: from serendipity to clinical relevance. , 2000, Brain research.

[70]  Oili Salonen,et al.  Fetal hypoxia and structural brain abnormalities in schizophrenic patients, their siblings, and controls. , 2002, Archives of general psychiatry.

[71]  D. Swaab,et al.  The stress system in the human brain in depression and neurodegeneration , 2005, Ageing Research Reviews.

[72]  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.

[73]  D. Weinberger,et al.  Relationship of obstetric complications and differences in size of brain structures in monozygotic twin pairs discordant for schizophrenia. , 2000, The American journal of psychiatry.

[74]  R. Murray,et al.  What risk factors tell us about the causes of schizophrenia and related psychoses , 2000, Current psychiatry reports.

[75]  Godfrey Pearlson,et al.  Lack of normal pattern of cerebral asymmetry in familial schizophrenic patients and their relatives — The Maudsley Family Study , 1999, Schizophrenia Research.

[76]  J. Simon,et al.  Increased hippocampal volume in schizophrenics' parents with ancestral history of schizophrenia , 2002, Schizophrenia Research.

[77]  T. Schneider-Axmann,et al.  The temporal lobe in schizophrenia from uni- and multiply affected families , 2002, Neuroscience Letters.

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

[79]  Tyrone D. Cannon,et al.  Developmental brain abnormalities in the offspring of schizophrenic mothers. I. Contributions of genetic and perinatal factors. , 1993, Archives of general psychiatry.

[80]  J. Bremner,et al.  MR-based in vivo hippocampal volumetrics: 2. Findings in neuropsychiatric disorders , 2005, Molecular Psychiatry.

[81]  Tyrone D. Cannon,et al.  A follow-up magnetic resonance imaging study of schizophrenia. Relationship of neuroanatomical changes to clinical and neurobehavioral measures. , 1998, Archives of general psychiatry.

[82]  R. Kahn,et al.  Volumes of brain structures in twins discordant for schizophrenia. , 2001, Archives of general psychiatry.

[83]  Marieke Langen,et al.  Gray and white matter volume abnormalities in monozygotic and same-gender dizygotic twins discordant for schizophrenia , 2004, Biological Psychiatry.

[84]  John Suckling,et al.  Searching for a structural endophenotype in psychosis using computational morphometry , 2003, Psychiatry Research: Neuroimaging.

[85]  O Salonen,et al.  Regional gray matter, white matter, and cerebrospinal fluid distributions in schizophrenic patients, their siblings, and controls. , 1998, Archives of general psychiatry.

[86]  McAllister Tw,et al.  Traumatic Brain Injury and Psychosis: What Is the Connection? , 1998 .

[87]  Gwenn W. Gröndal,et al.  Meta-analytic procedures for social research , 1993 .

[88]  Tyrone D. Cannon,et al.  Cortex mapping reveals regionally specific patterns of genetic and disease-specific gray-matter deficits in twins discordant for schizophrenia , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[89]  John Suckling,et al.  For personal use. Only reproduce with permission from The Lancet Publishing Group. Effect of sunlight and season on serotonin turnover in the brain , 2002 .