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Original Article |

Brain Volumes in Relatives of Patients With Schizophrenia:  A Meta-analysis FREE

Heleen B. M. Boos, MS; André Aleman, PhD; Wiepke Cahn, MD, PhD; Hilleke Hulshoff Pol, PhD; René S. Kahn, MD, PhD
[+] Author Affiliations

Author Affiliations: Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht (Ms Boos and Drs Cahn, Hulshoff Pol, and Kahn), and BCN NeuroImaging Center, University Medical Center Groningen, Groningen (Dr Aleman), the Netherlands.


Arch Gen Psychiatry. 2007;64(3):297-304. doi:10.1001/archpsyc.64.3.297.
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Published online

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.

Figures in this Article

Structural brain abnormalities are well established in schizophrenia. Several meta-analyses1,2 have reported smaller brain volumes in schizophrenia, with more pronounced reductions in the hippocampus and amygdala. However, the nature of these brain changes is still unresolved. For instance, whether these changes are a result of the use of antipsychotic medication is a matter of debate.36 Similarly, it is unclear to what extent these abnormalities are related to the vulnerability for developing the illness. Both issues can be (partially) addressed by studying brain structures in relatives of patients with schizophrenia. Clearly, the vulnerability for developing schizophrenia is highly genetic: studies7 in families of patients with schizophrenia have shown that the origin of the disorder has an estimated heritability of 80%, including interaction between the genes and environment. Thus, the presence of brain changes in relatives of patients would suggest these to be related to the shared genetic risk of developing schizophrenia. Moreover, brain volume differences in relatives cannot be the result of antipsychotic medication. Therefore, examining brain volumes in nonpsychotic first-degree relatives of schizophrenic patients can clarify some of the causes of the brain abnormalities observed in probands.

In recent years, several studies have measured brain volumes in nonpsychotic relatives of schizophrenic patients compared with those of healthy subjects. Most of these studies816 showed smaller total brain volumes in relatives, but others1719 did not. Similarly, larger ventricular volume has been reported in several studies,14,16,1922 but 2 other studies did not find this.12,23 Furthermore, medial temporal lobe structures were reportedly smaller in several studies,9,17,19,2427 but this finding has not been universally replicated.8,11,16,20,28 Thus, although brain abnormalities have been found in first-degree relatives of schizophrenic patients, the findings are inconsistent. Moreover, effect sizes in the individual studies have not been quantitatively reviewed and integrated.

The aim of the present meta-analysis was to determine the magnitude and extent of brain volume differences in first-degree relatives of schizophrenic patients. We attempted to integrate the findings from magnetic resonance imaging (MRI) studies in relatives of patients with schizophrenia. To this end, we examined volumes of global brain structures and smaller structures in nonpsychotic first-degree relatives of patients with schizophrenia compared with those of healthy control subjects. In an additional analysis, we compared brain volumes of patients with those of the unaffected relatives.

DATA SOURCES

The MRI studies that examined differences in brain volumes in first-degree relatives of patients with schizophrenia compared with healthy control subjects were obtained through computerized databases, including MEDLINE. The keywords used in the computerized search were brainabnormalit(s), relative(s), and schizophre(s). The terms relative(s), sib(s), parent(s), and schizophre(s) were also combined with brain volume(s), gray matter, white matter, ventricle(s), and hippocampus. Titles and abstracts of the articles were examined to see whether or not they could be included. Additional studies were obtained by a hand search of journals published in 2005 that most frequently publish articles on structural brain imaging in schizophrenia to find articles that had not yet been included in computerized databases. The journals included the following: Archives of General Psychiatry, The American Journal of Psychiatry, Biological Psychiatry, Schizophrenia Research, Psychiatry Research: Neuroimaging, American Journal of Medical Genetics, and Neurobiology of Disease. Bibliographies of included articles were used for a further search. Finally, abstracts from conferences on schizophrenia presented in 2005 were taken into account.

STUDY SELECTION

Forty-three studies were identified as potential candidates for the meta-analysis. Studies were included if (1) they were MRI studies of brain structures published before July 2005 or they were not yet published but were presented as an abstract at the International Congress on Schizophrenia Research in 2005, (2) they compared first-degree relatives of patients with schizophrenia with a healthy control group (having no history and family history of psychosis), (3) they were published in the English language, and (4) they reported sufficient data to obtain the effect size: means, standard deviations, exact P values, or exact F values for a 2-group comparison. Studies in which some of the relatives had an ill family member diagnosed as having schizoaffective disorder (instead of schizophrenia) were also included in this analysis.

Fifteen studies were excluded from the meta-analysis because they did not show relevant data to enable us to compute the Cohen d values.2942 Five studies were excluded because they did not report brain volumes of relatives of schizophrenic patients compared with healthy control subjects.4347 Twenty-five studies were identified as suitable for our meta-analysis and included 1065 independent first-degree relatives of patients, 679 patients with schizophrenia, and 1100 control subjects. The 25 studies that were identified as suitable reported brain volumes of different types of first-degree relatives; namely, siblings,9,12,13,1618,20,22,23,48 monozygotic twins,10,11,14,16,25,27,49 dizygotic twins,11,14,25,27,49 parents,15,17,18,21,28,48,50,51 and offspring.24 Four studies did not specify first-degree relatives.8,19,21,26 Together, the 25 studies reported volumes of 56 brain structures. Some of these structures were not evaluated by more than 3 studies, and in this case, these structures were not examined in the analysis. Table 1 lists the included articles and the brain structures that were analyzed.

Table Graphic Jump LocationTable 1. Summary of 25 Studies in Meta-analysis and Included Brain Volumes
DATA EXTRACTION

This meta-analysis was performed to examine measurements of volumes in global brain structures and smaller structures in the medial temporal lobe in nonpsychotic first-degree relatives of schizophrenic patients and healthy control subjects. The structures that were suitable for analysis included total brain, intracranial, lateral ventricle, third-ventricle, gray matter, white matter, amygdala-hippocampal, hippocampal, and cerebrospinal fluid volume. If sufficient data were present, an analysis was performed to examine the effect of the side of the brain and differences in volumes between patients and relatives.

The key to meta-analysis is defining an effect size statistic capable of representing the quantitative findings of a set of research studies in a standardized form that permits meaningful comparison and analyses across the studies.52 Therefore, for each study in this meta-analysis, the effect size statistic Cohen d was calculated. The Cohen d is the difference between the mean of the experimental group and the mean of the comparison group divided by the pooled standard deviation. In this analysis, the mean volume of a specific brain structure for relatives of patients with schizophrenia was subtracted from the mean volume for comparison subjects and divided by the pooled standard deviation of both. When means and standard deviations were not available, d values were calculated from exact P values, t values, or F values. Data extraction and computation of the effect sizes were performed independently by 2 of the authors (H.B.M.B. and A.A.). In cases of discrepancies, a consensus was reached by means of discussion. After computing individual effect sizes for each study, meta-analytic methods were applied to obtain a combined effect size, which indicated the magnitude of the association across all studies.53 Individual effect sizes were inverse variance weighted to correct for upwardly biased estimation of the effect in small sample sizes.53,54 Additionally, a homogeneity statistic, Q, was calculated to test whether the studies could be assumed to share a common population effect size. A significant Q statistic indicates heterogeneity of the individual study effect sizes, which poses a limitation to a reliable interpretation of the results. If significant heterogeneity is found, a moderator analysis can be performed to investigate the potential moderating factors.54 A t test was subsequently performed on the null hypothesis that the d value is 0.00, which we report together with the associated P value. According to Cohen,55 d values of 0.2 show small effects. Values between 0.4 and 0.6 are moderate effects, and d values of 0.8 or higher are large effects. All analyses were performed with a random-effects model using comprehensive meta-analysis.56 A random-effects model assumes that the true effect size estimated by different studies varies among studies because of differences in samples or paradigms and that these true effect sizes have a normal distribution (ie, heterogeneity exists).57

To examine the possibility of publication bias, we computed a fail-safe number of studies.54,58 Publication bias implies that studies with no effect may not be published, posing a threat to the stability of the obtained effect size. The fail-safe number of studies indicates the number of unpublished studies with null effects that must reside in file drawers to reduce the observed effect size to a negligible level. The statistic can be calculated with the use of the formula given by Orwin58 and Lipsey and Wilson52

k × [(ESk-ESc) − 1].

In this formula, k is the number of studies, ESk, the mean weighted effect size; and ESc, the criterion effect size (which we set at a d value of 0.10).

DATA SYNTHESIS

The structures that were analyzed, the number of studies included, and the number of subjects in which the structures were measured are reported in Table 1. The composite effect sizes (Cohen d, associated confidence intervals, Q statistics, and P values) of all studies for the different structures are reported in Table 2. Only those structures for which the volumes were explored in more than 3 individual studies were analyzed. In applicable studies, brain volumes of patients were also compared with those of relatives.

Table Graphic Jump LocationTable 2. Brain Structures Included in Meta-analysis and Results

As presented in Table 2, the results of our meta-analysis indicate brain volume differences between first-degree relatives of patients with schizophrenia and healthy control subjects. The largest effect was found for hippocampal volume, with smaller volumes in relatives compared with healthy subjects (Figure 1). In this analysis, 9 studies were included, with a group size of 421 relatives of patients with schizophrenia and 603 healthy control subjects. One of the studies that measured hippocampal volumes controlled for intracranial volume and 8 studies for whole brain volume. The combined-effect Cohen d of the 9 studies was 0.31 (P<.001). Excluding the studies that controlled for intracranial volume did not change the results, and analyzing studies (n = 12) that measured hippocampal together with amygdala volume even showed a combined-effect Cohen d of 0.52 (P = .005). The largest effect was found in left hippocampal volume (d = 0.47; P = .04; right hippocampal volume: d = 0.23; P = .04). When we measured hippocampal volume in relatives compared with control subjects, the fail-safe number was 18, large enough to lend credence to our findings.

Place holder to copy figure label and caption
Figure 1.

Mean total hippocampal volume. Error bars indicate 95% confidence interval.

Graphic Jump Location

Small effects were found in cerebral gray matter (smaller in relatives vs healthy control subjects; d = 0.18; P = .04; fail-safe number = 7) (Figure 2) and third-ventricle volume (larger in relatives than in healthy control subjects; d = 0.21; P = .02; fail-safe number = 8) (Figure 3). The analysis of gray matter volume included 7 studies, with a group size of 249 relatives and 285 healthy control subjects. The analysis of third-ventricle volume included 7 studies with 414 relatives and 418 healthy controls. Analyses of volumes of the total brain, intracranial space, lateral ventricles, and white matter did not show significant effects. However, the analysis of total brain and white matter volume showed a trend toward significance (total brain: d = 0.28; P = .06; white matter: d = 0.40; P = .07; both smaller in relatives compared with healthy subjects).

Place holder to copy figure label and caption
Figure 2.

Mean cerebral gray matter volume. Error bars indicate 95% confidence interval.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

Mean third-ventricle volume. Error bars indicate 95% confidence interval.

Graphic Jump Location

Seventeen studies also included a sample of patients (679 patients with schizophrenia and 790 nonpsychotic relatives). Nine studies evaluated the hippocampus among 335 patients and 511 relatives, showing a moderate effect (d = 0.43; P = .001; 95% confidence interval, 0.17-0.68) with patients having smaller hippocampal volumes than relatives. This result showed significant heterogeneity (Q = 22.28; P = .004). However, one study was an outlier, reporting a large decrease in hippocampal volume.46 When we excluded this study, the heterogeneity was not significant (d = 0.29; P<.001; Q = 2.67; P = .91). The fail-safe number of studies for this analysis was 29, large enough to lend credence to our findings.

In the analysis that compared first-degree relatives with healthy control subjects, most Q values were nonsignificant (Table 2) except for those in the analyses of amygdala-hippocampal complex volume, white matter volume, total brain volume, and cerebrospinal fluid volume. This significant Q value indicates heterogeneity of the individual study effect sizes and thus limits reliable interpretation of these results.

This meta-analysis integrated the results of 25 MRI studies that compared brain volumes of 1065 nonpsychotic first-degree relatives of patients with schizophrenia with those of 1100 healthy control subjects. The results indicate that brain volumes in relatives of patients with schizophrenia differ from those of healthy control subjects, with effect sizes in the small to moderate range. The largest effect is found in hippocampal volume (d = 0.31), with relatives of patients having smaller volumes than healthy control subjects. In addition, total gray matter volume (d = 0.18) and third-ventricle (d = 0.21) volume are smaller in relatives compared with healthy control subjects. Although total brain and white matter volume did not differ significantly in relatives compared with healthy controls, both structures showed a trend toward significance (P = .06 and P = .07, respectively). The analysis that compared patients with schizophrenia with first-degree relatives showed smaller hippocampal volumes in the patients (d = 0.43). In addition, 3 studies that were excluded from this meta-analysis examined hippocampal volumes in first-degree relatives compared with healthy control subjects. Two studies also showed smaller volumes in relatives compared with healthy controls.32,36 However, Harris et al33 did not find this.

The results of this meta-analysis suggest that brain abnormalities in schizophrenia are related (in part) to the risk of developing the disease and that these brain changes may therefore predate the clinical onset of the disorder. Moreover, they argue against the notion that the brain abnormalities in schizophrenia are solely caused by antipsychotics. These conclusions are bolstered by the finding that the brain structures affected in relatives are the same as those reported to be abnormal in patients.2 The findings are supported by 2 studies59,60 that reported reduced gray matter volumes in similar brain structures of individuals at high risk for schizophrenia. Both studies reported that those relatives who later develop psychotic symptoms have a more severe reduction before the onset of these symptoms.

The finding of hippocampal volume reduction in relatives of schizophrenic patients also dovetails with the results of recent meta-analyses regarding cognitive functioning in relatives.61,62 In these articles, lower performance in relatives of patients compared with healthy control subjects was reported on several cognitive domains, including verbal and declarative memory, executive functioning, and attention. Interestingly, Sitskoorn et al62 found that the largest effect size was obtained for verbal memory (d = 0.54), being significantly worse in relatives of patients than in healthy subjects. However, the performance of relatives on these cognitive tasks was less impaired than has been reported in patients with schizophrenia.63,64 Indeed, decreased verbal memory is one of the most robust neuropsychological findings in schizophrenia.60 Deficits in verbal memory have generally been associated with smaller (left) hippocampal volume,65 as is also the case in patients with schizophrenia66,67 and their relatives.17,26 In the present meta-analysis, the effect size was considerably larger for the left than for the right hippocampus. This finding is consistent with findings from lesion and functional MRI studies in healthy subjects, suggesting more involvement of the left hippocampus in encoding and recognition of verbal as opposed to visual or pictorial material.68 The suggestion of smaller left hippocampal volume as a vulnerability indicator for schizophrenia, put forward by Seidman et al,17 is also consistent with these observations.

The findings of this meta-analysis suggest that a common genetic vulnerability to developing schizophrenia is reflected in brain morphologic findings. McDonald et al69 demonstrated that the genetic risk of schizophrenia is associated with an extensive system of gray matter deficits and white matter abnormalities. However, only a few studies have identified specific genes in relation to brain volume abnormalities in schizophrenia. Szeszko et al70 studied 19 patients with schizophrenia and 25 healthy control subjects and reported a role for brain-derived neurotropic factor in determining hippocampal volume. More relevant to the finding of the current meta-analysis, Callicott et al71 examined the effects of the DISC1 gene on the risk of schizophrenia and its impact on the hippocampus. They found that DISC1 increased the risk of developing the disease and was also associated with structural and functional alterations in the hippocampus.

However, smaller hippocampal volumes in relatives of patients with schizophrenia could also have been caused by environmental factors. Obstetric complications such as hypoxia are known to result in smaller brain volumes, affecting the hippocampus profoundly.21,72,73 Smaller hippocampal volumes have also been associated with brain injury65,74,75 and stress65,76 and have been found not only in schizophrenia but also in several other psychiatric disorders, such as major depression, posttraumatic stress disorder, obsessive-compulsive disorder, and borderline personality disorder.65 An important function of the hippocampus and amygdala is the regulation of the hypothalamic-pituitary-adrenal axis, which plays a role in stress processing. This regulation may be altered because of a genetic predisposition. In depression, the hypothalamic-pituitary-adrenal axis is strongly activated and the adrenal cortex hypersecretes glucocorticoids such as cortisol. Although less pronounced, considerable hypothalamic-pituitary-adrenal activation is also found in schizophrenia.77 On the basis of earlier animal experiments, overexposure to cortisol during prolonged periods of stress is expected to damage the brain, particularly the hippocampus. Sapolsky et al77 provided evidence in rats that chronic stress, with the concomitant increase in corticoid levels, causes loss of neurons in the hippocampus and subsequent deficits in memory function and cognition. In patients with depression, this glucocorticoid cascade has also been presumed to result in decreased hippocampal volume,78 possibly explained by apoptosis.79 Both apoptosis and neurogenesis have been shown to occur in the hippocampus.80 Thus, smaller hippocampal volumes in patients with schizophrenia and their first-degree relatives might also be the result of stress-related processes in the brain.81

These hypotheses regarding putative genetic and environmental factors underlying hippocampal damage in relatives of schizophrenic patients can be integrated by taking gene-environment interactions into account. Gene-environment interactions may result from genetically mediated differences in the sensitivity to environmental factors or environmentally mediated influences on gene expression. Evidence of genetically mediated differences in environmental factor sensitivity shows that slightly elevated rates of obstetric complications are found not only in patients with schizophrenia but also in their nonpsychotic first-degree relatives.82,83 As reported by Cannon et al,83 most of these relatives exposed to obstetric complications did not develop schizophrenia, and thus these factors are incapable of causing schizophrenia on their own. Obstetric complications may act additively or interactively with genetic factors in influencing liability to schizophrenia. Van Erp et al9 examined siblings of patients with schizophrenia and found that hippocampal volumes differed stepwise with each increase in genetic predisposition to schizophrenia and that hippocampal volumes of patients exposed to fetal hypoxia were smaller than those who were unexposed, whereas no such relationship was observed within the healthy control subjects. They suggested that carrying susceptibility genes for schizophrenia makes one vulnerable to perinatal damage, especially in the hippocampus.

Some limitations of this meta-analysis should be noted. First, as with all meta-analyses, the results depend on the quality of the individual studies. The adjustment of cerebral structures for whole brain or intracranial volume has been thought to facilitate differences in effects among the studies. However, the results of a moderator variable analysis failed to confirm this hypothesis. Therefore, it is unlikely that the observed differences in volume are due to differences in adjustment.

Second, structures other than those that have been evaluated in this meta-analysis may also be affected in relatives of patients with schizophrenia. The results of smaller hippocampal volumes in relatives compared with healthy control subjects might reflect broader abnormalities in the temporal lobes or even other structures, but because of the small amount of studies that measured these structures, this could not be investigated in our analysis.

Third, the results may have been influenced by publication bias. However, in the present meta-analysis, this is unlikely given a fail-safe number of studies statistic, which indicates the number of studies with null effects that must reside in file drawers before results of the obtained effect sizes are reduced to a negligible level.

Fourth, only a few studies that were included in the meta-analysis and measured brain volumes of siblings specified whether they had used independent samples or multiple siblings per family. Although this may bring in a confounding factor, because of the small number of studies in the meta-analysis, all sibling studies that were available and met the criteria were included.

Fifth, differences in age and sex were not examined. Age and sex are known to affect brain volumes83; however, the studies included in this meta-analysis did not provide enough data to examine the effects of age and sex. Except for hippocampal volume, differences between left and right brain structures were not measured. The statistical test to determine the latter results requires left and right regional volumes, and these data were not generally provided by the original studies. Thus, the possibility that some of the effects found in this meta-analysis were caused by confounding factors such as sex and age cannot be ruled out. In addition, some studies11,48 suggest that white matter reduction reflects an increased risk of developing schizophrenia. Although the present meta-analysis did not find significant decreases, the analysis resulted in significant heterogeneity, which hampers a reliable interpretation and may have influenced the results. More and larger studies are needed to show whether in nonpsychotic relatives total brain and white matter volume differ from healthy control subjects. Longitudinal studies on brain volumes of relatives of schizophrenic patients could also be helpful in diminishing problems of individual study characteristics and reducing heterogeneity issues. In addition, different methods have been proposed for estimating heterogeneity and publication bias. For example, other meta-analyses have included funnel plots (plots of effect estimates against sample size) to index publication bias84 and the I2 statistic to measure the proportion of inconsistency in individual studies that cannot be explained by chance. The latter approach was argued to be a better index of heterogeneity than the Q statistic, especially for collections of studies with either small or large sample sizes (measuring inconsistency in meta-analyses).85 Notably, most studies included in our analyses were of intermediate sample size. Finally, some studies included in this meta-analysis not only studied first-degree relatives but also included some second-degree relatives.19,21,50 These studies did not examine hippocampal and gray matter volume. However, in the analysis of third-ventricle volume, second-degree relatives were included but the exact amount was not reported in the studies. Excluding the 3 studies that examined some second-degree relatives did not alter the results of our meta-analysis.

In summary, our results provide support for the hypothesis that nonpsychotic first-degree relatives of patients with schizophrenia show structural brain abnormalities, particularly in the left hippocampus. These brain abnormalities are similar to the areas that are affected in patients with schizophrenia and parallel the findings of neuropsychological impairments (especially in verbal memory) in both patients and relatives. Although these findings reflect a vulnerability to developing schizophrenia, it is still unclear how and to what extent genes and/or environment are involved. Future studies should focus on the search for susceptibility genes in relation to brain abnormalities by using linkage and association methods.

Correspondence: Heleen B. M. Boos, MS, Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, Room A.00.113, University Medical Center Utrecht, PO Box 85500, 3508 GA Utrecht, the Netherlands (h.b.m.boos@umcutrecht.nl).

Submitted for Publication: December 21, 2005; final revision received June 23, 2006; accepted July 18, 2006.

Financial Disclosure: None reported.

Previous Presentation: This study was presented as a poster at The Thirteenth Biennial Winter Workshop on Schizophrenia Research; February 4-10, 2005; Davos, Switzerland.

Lawrie  SMAbukmeil  SS Brain abnormality in schizophrenia: a systematic and quantitative review of volumetric magnetic resonance imaging studies. Br J Psychiatry 1998;172110- 120
PubMed Link to Article
Wright  ICRabe-Hesketh  SWoodruff  PWDavid  ASMurray  RMBullmore  ET Meta-analysis of regional brain volumes in schizophrenia. Am J Psychiatry 2000;15716- 25
PubMed
Cahn  WHulshoff Pol  HELems  EBvan Haren  NESchnack  HGvan der Linden  JASchothorst  PFVan Engeland  HKahn  RS Brain volume changes in first-episode schizophrenia: a 1-year follow-up study. Arch Gen Psychiatry 2002;591002- 1010
PubMed Link to Article
Gur  REMaany  VMozley  PDSwanson  CBilker  WGur  RC Subcortical MRI volumes in neuroleptic-naive and treated patients with schizophrenia. Am J Psychiatry 1998;1551711- 1717
PubMed
Keshavan  MSBagwell  WWHaas  GLSweeney  JASchooler  NRPettegrew  JW Changes in caudate volume with neuroleptic treatment. Lancet 1994;3441434
PubMed Link to Article
Lieberman  JChakos  MWu  HAlvir  JHoffman  ERobinson  DBilder  R Longitudinal study of brain morphology in first episode schizophrenia. Biol Psychiatry 2001;49487- 499
PubMed Link to Article
Cardno  AGJones  LAMurphy  KCSanders  RDAsherson  POwen  MJMcGuffin  P Dimensions of psychosis in affected sibling pairs. Schizophr Bull 1999;25841- 850
PubMed Link to Article
Wood  SJYucel  MVelakoulis  DPhillips  LJYung  ARBrewer  WMcGorry  PDPantelis  C Hippocampal and anterior cingulate morphology in subjects at ultra-high-risk for psychosis: the role of family history of psychotic illness. Schizophr Res 2005;75295- 301
PubMed Link to Article
van Erp  TGSaleh  PARosso  IMHuttunen  MLonnqvist  JPirkola  TSalonen  OValanne  LPoutanen  VPStandertskjold-Nordenstam  CGCannon  TD Contributions of genetic risk and fetal hypoxia to hippocampal volume in patients with schizophrenia or schizoaffective disorder, their unaffected siblings, and healthy unrelated volunteers. Am J Psychiatry 2002;1591514- 1520
PubMed Link to Article
Noga  JTBartley  AJJones  DWTorrey  EFWeinberger  DR Cortical gyral anatomy and gross brain dimensions in monozygotic twins discordant for schizophrenia. Schizophr Res 1996;2227- 40
PubMed Link to Article
Hulshoff Pol  HEBrans  RGvan Haren  NESchnack  HGLangen  MBaare  WFvan Oel  CJKahn  RS Gray and white matter volume abnormalities in monozygotic and same-gender dizygotic twins discordant for schizophrenia. Biol Psychiatry 2004;55126- 130
PubMed Link to Article
Gogtay  NSporn  AClasen  LSGreenstein  DGiedd  JNLenane  MGochman  PAZijdenbos  ARapoprt  JL Structural brain MRI abnormalities in healthy siblings of patients with childhood-onset schizophrenia. Am J Psychiatry 2003;160569- 571
PubMed Link to Article
Cannon  TDvan Erp  TGRosso  IMHuttunen  MLonnqvist  JPirkola  TSalonen  OValanne  LPoutanen  VPStanderksjold-Nordenstam  CG Fetal hypoxia and structural brain abnormalities in schizophrenic patients, their siblings, and controls. Arch Gen Psychiatry 2002;5935- 41
PubMed Link to Article
Baare  WFvan Oel  CJHulshoff Pol  HESchnack  HGDurston  SSitskoorn  MMKahn  RS Volumes of brain structures in twins discordant for schizophrenia. Arch Gen Psychiatry 2001;5833- 40
PubMed Link to Article
Boos  HBCahn  WAppels  MCSitskoorn  MMHulshoff Pol  HESchnack  HGPalmer  SJKahn  RS Brain volumes in parents of patients with schizophrenia. Schizophr Bull 2005;31382
van Haren  NEPicchioni  MMMcDonald  CMarshall  NDavis  NRibchester  THulshoff Pol  HESharma  TSham  PKahn  RSMurray  R A controlled study of brain structure in monozygotic twins concordant and discordant for schizophrenia. Biol Psychiatry 2004;56454- 461
PubMed Link to Article
Seidman  LJFaraone  SVGoldstein  JMKremen  WSHorton  NJMakris  NToomey  RKennedy  DCaviness  VSTsuang  MT Left hippocampal volume as a vulnerability indicator for schizophrenia: a magnetic resonance imaging morphometric study of nonpsychotic first-degree relatives. Arch Gen Psychiatry 2002;59839- 849
PubMed Link to Article
Marcelis  MSuckling  JWoodruff  PHofman  PBullmore  Evan Os  J Searching for a structural endophenotype in psychosis using computational morphometry. Psychiatry Res 2003;122153- 167
PubMed Link to Article
Lawrie  SMWhalley  HCAbukmeil  SSKestelman  JNDonnelly  LMiller  PBest  JJOwens  DGJohnstone  EC Brain structure, genetic liability, and psychotic symptoms in subjects at high risk of developing schizophrenia. Biol Psychiatry 2001;49811- 823
PubMed Link to Article
Staal  WGHulshoff Pol  HESchnack  Hvan der Schot  ACKahn  RS Partial volume decrease of the thalamus in relatives of patients with schizophrenia. Am J Psychiatry 1998;1551784- 1786
PubMed
McDonald  CGrech  AToulopoulou  TSchulze  KChapple  BSham  PWalshe  MSharma  TSigmundsson  TChitnis  XMurray  RM Brain volumes in familial and non-familial schizophrenic probands and their unaffected relatives. Am J Med Genet 2002;114616- 625
PubMed Link to Article
Seidman  LJFaraone  SVGoldstein  JMGoodman  JMKremen  WSMatsuda  GHoge  EAKennedy  DMakris  NCaviness  VSTsuang  MT Reduced subcortical brain volumes in nonpsychotic siblings of schizophrenic patients: a pilot magnetic resonance imaging study. Am J Med Genet 1997;74507- 514
PubMed Link to Article
Cannon  TDvan Erp  TGHuttunen  MLonnqvist  JSalonen  OValanne  LPoutanen  VPStanderksjold-Nordenstam  CGGur  REYan  M Regional gray matter, white matter, and cerebrospinal fluid distributions in schizophrenic patients, their siblings, and controls. Arch Gen Psychiatry 1998;551084- 1091
PubMed Link to Article
Keshavan  MSDick  EMankowski  IHarenski  KMontrose  DMDiwadkar  VDeBellis  M Decreased left amygdala and hippocampal volumes in young offspring at risk for schizophrenia. Schizophr Res 2002;58173- 183
PubMed Link to Article
Narr  KLvan Erp  TGCannon  TDWoods  RPThompson  PMJang  SBlanton  RPoutanen  VPHuttunen  MLonnqvist  JStanderksjold-Nordenstam  CGKaprio  JMazziotta  JCToga  AW A twin study of genetic contributions to hippocampal morphology in schizophrenia. Neurobiol Dis 2002;1183- 95
PubMed Link to Article
O'Driscoll  GAFlorencio  PSGagnon  DWolff  AVBenkelfat  CMikula  LLal  SEvans  AC Amygdala-hippocampal volume and verbal memory in first-degree relatives of schizophrenic patients. Psychiatry Res 2001;10775- 85
PubMed Link to Article
van Erp  TGSaleh  PAHuttunen  MLonnqvist  JKaprio  JSalonen  OValanne  LPoutanen  VPStandertskjold-Nordenstam  CGCannon  TD Hippocampal volumes in schizophrenic twins. Arch Gen Psychiatry 2004;61346- 353
PubMed Link to Article
Schulze  KMcDonald  CFrangou  SSham  PGrech  AToulopoulou  TWalshe  MSharma  TSigmundsson  TTaylor  MMurray  RM Hippocampal volume in familial and nonfamilial schizophrenic probands and their unaffected relatives. Biol Psychiatry 2003;53562- 570
PubMed Link to Article
Toulopoulou  TGrech  AMorris  GSchulze  KMcDonald  CChapple  BRabe-Hesketh  SMurray  RM The relationship between volumetric brain changes and cognitive function: a family study on schizophrenia. Biol Psychiatry 2004;56447- 453
PubMed Link to Article
Silverman  JMSmith  CJGou  SLMohs  ECSiever  LJDavis  KL Lateral ventricular enlargement in schizophrenic probands and their siblings with schizophrenia-related disorders. Biol Psychiatry 1998;4397- 106
PubMed Link to Article
Posthuma  DBaaré  WFCHulshoff Pol  HEKahn  RSBoomsma  DIde Geus  AJC Genetic correlations between brain volumes and the WAIS-III dimensions of verbal comprehension, working memory, perceptual organization, and processing speed. Twin Res 2003;6131- 139
PubMed Link to Article
Waldo  MCAdler  LELeonard  SOlincy  ARoss  RGHarris  JGFreedman  R Familial transmission of risk factors in the first-degree relatives of schizophrenic people. Biol Psychiatry 2000;47231- 239
PubMed Link to Article
Harris  JGYoung  DARojas  DCCajade-Law  AScherzinger  ANawroz  SAdler  LECullum  CMSimon  JFreedman  R Increased hippocampal volume in schizophrenics' parents with ancestral history of schizophrenia. Schizophr Res 2002;5511- 17
PubMed Link to Article
Chapple  BGrech  ASham  PToulopoulou  TWalshe  MSchulze  KMorgan  RMurray  RMMcDonald  C Normal cerebral asymmetry in familial and non-familial schizophrenic probands and their unaffected relatives. Schizophr Res 2004;6733- 40
PubMed Link to Article
Cannon  TDThompson  PMvan Erp  TGMToga  AWPoutanen  VHuttunen  MLonnqvist  JStanderskjold-Nordenstam  CNarr  KLKhaledy  MZoumalan  CIDail  RKaprio  J Cortex mapping reveals regionally specific patterns of genetic and disease-specific gray-matter deficits in twins discordant for schizophrenia. Proc Natl Acad Sci U S A 2002;993228- 3233
PubMed Link to Article
Job  DEWhalley  HCMcConnell  SGlabus  MJohnstone  ECLawrie  SM Voxel-based morphometry of grey matter densities in subjects at high risk of schizophrenia. Schizophr Res 2003;641- 13
PubMed Link to Article
Keshavan  MSJayakumar  PNDiwadkar  VASingh  A Cavum septi pellucidi in first-episode patients and young relatives at risk for schizophrenia. CNS Spectr 2002;7155- 158
PubMed
Wright  ICSham  PMurray  RMWeinburger  DRBullmore  ET Genetic contributions to regional variability in human brain structure: methods and preliminary results. Neuroimage 2002;17256- 271
PubMed Link to Article
McNeil  TFCantor-Graae  EWeinberger  DR Relationship of obstetric complications and differences in size of brain structures in monozygotic twin pairs discordant for schizophrenia. Am J Psychiatry 2000;157203- 212
PubMed Link to Article
Cannon  TDMarco  E Structural brain abnormalities as indicators of vulnerability to schizophrenia. Schizophr Bull 1994;2089- 102
PubMed Link to Article
Bridle  NPantelis  CWood  SJCoppola  RVelakoulis  DMcStephen  MTierney  PLe  TLTorrey  EFWeinberger  D Thalamic and caudate volumes in monozygotic twins discordant for schizophrenia. Aust N Z J Psychiatry 2002;36347- 354
PubMed Link to Article
Turetsky  BIMoberg  PJArnold  SEDoty  RLGur  RE Low olfactory bulb volume in first-degree relatives of patients with schizophrenia. Am J Psychiatry 2003;160703- 708
PubMed Link to Article
Phillips  LJVelakoulis  DPantelis  CWood  SYuen  HPYung  ARDesmond  PBrewer  WMcGorry  PD Non-reduction in hippocampal volume is associated with higher risk of psychosis. Schizophr Res 2002;58145- 158
PubMed Link to Article
Stefanis  NFrangou  SYakeley  JSharma  TO'Connell  PMorgan  KSigmundsson  TTaylor  MMurray  R Hippocampal volume reduction in schizophrenia: effects of genetic risk and pregnancy and birth complications. Biol Psychiatry 1999;46697- 702
PubMed Link to Article
Thompson  PMVidal  CGiedd  JNGochman  PBlumenthal  JNicolson  RToga  AWRapoport  JL Mapping adolescent brain change reveals dynamic wave of accelerated gray matter loss in very early-onset schizophrenia. Proc Natl Acad Sci U S A 2001;9811650- 11655
PubMed Link to Article
Suddath  RLChristison  GWTorrey  EFCasanova  MFWeinberger  DR Anatomical abnormalities in the brains of monozygotic twins discordant for schizophrenia. N Engl J Med 1990;322789- 794
PubMed Link to Article
Falkai  PHoner  WGAlfter  DSchneider-Axmann  TBussfeld  PCordes  JBlank  BSchönell  HSteinmetz  HMaier  WTepest  R The temporal lobe in schizophrenia from uni- and multiply affected families. Neurosci Lett 2002;32525- 28
PubMed Link to Article
Narr  KLCannon  TDWoods  RPThompson  PMKim  SAsunction  Dvan Erp  TGPoutanen  VPHuttunen  MLonnqvist  JStanderksjold-Nordenstam  CGKaprio  JMazziotta  JCToga  AW Genetic contributions to altered callosal morphology in schizophrenia. J Neurosci 2002;223720- 3729
PubMed
Sharma  TLancaster  ESigmundsson  TLewis  STakei  NGurling  HBarta  PPearlson  GMurray  R Lack of normal pattern of cerebral asymmetry in familial schizophrenic patients and their relatives—The Maudsley Family Study. Schizophr Res 1999;40111- 120
PubMed Link to Article
Falkai  PTepest  RHoner  WGDani  IAhle  GPfeiffer  UVogeley  KSchulze  TGRietschel  MCordes  JSchonell  HGaebel  WKuhn  KUMaier  WTraber  FBlock  WSchild  HHSchneider-Axmann  T Shape changes in prefrontal, but not parieto-occipital regions: brains of schizophrenic patients come closer to a circle in coronal and sagittal view. Psychiatry Res 2004;132261- 271
PubMed Link to Article
Seidman  LJFaraone  SVGoldstein  JMGoodman  JMKremen  WSToomey  RTourville  JKennedy  DMakris  NCaviness  VSTsuang  M Thalamic and amygdala-hippocampal volume reductions in first-degree relatives of patients with schizophrenia: an MRI-based morphometric analysis. Biol Psychiatry 1999;46941- 954
PubMed Link to Article
Lipsey  MWWilson  DB The way in which intervention studies have “personality” and why it is important to do meta-analysis. Eval Health Prof 2001;24236- 245
PubMed Link to Article
Hedges  LVOlkin  I Statistical Methods for Meta-analysis.  New York, NY Academic Press1985;
Rosenthal  R Meta-analytic Procedures for Social Research.  London, England Sage Publications1991;
Cohen  J Statistical Power Analysis for the Behavioral Sciences.  Hillsdale, NY Lawrence Erlbaum Associates1988;
Borenstein  MRothstein  H Comprehensive meta-analysis. Borenstein  MRothstein  HedsA Computer Program for Research Synthesis. Englewood, NY BioStat Inc 1999;
DerSimonian  RLaird  N Meta-analysis in clinical trials. Control Clin Trials 1986;7177- 188
PubMed Link to Article
Orwin  RG A fail-safe N for effect size in meta-analysis. J Educ Stat 1983;8157- 159
Link to Article
Pantelis  CVelakoulis  DMcGorry  PDWood  SJSuckling  JPhillips  LJYung  ARBullmore  ETBrewer  WSoulsby  BDesmond  PMcGuire  PK Neuroanatomical abnormalities before and after onset of psychosis: a cross-sectional and longitudinal MRI comparison. Lancet 2003;361281- 288
PubMed Link to Article
Job  DEWhalley  HCJohnstone  ECLawrie  SM Grey matter changes over time in high risk subjects developing schizophrenia. Neuroimage 2005;251023- 1030
PubMed Link to Article
Toulopoulou  TMorris  RGRabe-Hesketh  SMurray  RM Selectivity of verbal memory deficit in schizophrenic patients and their relatives. Am J Med Genet B Neuropsychiatr Genet 2003;1161- 7
PubMed Link to Article
Sitskoorn  MMAleman  AEbisch  SJAppels  MCKahn  RS Cognitive deficits in relatives of patients with schizophrenia: a meta-analysis. Schizophr Res 2004;71285- 295
PubMed Link to Article
Aleman  AHijman  Rde Haan  EHKahn  RS Memory impairment in schizophrenia: a meta-analysis. Am J Psychiatry 1999;1561358- 1366
PubMed
Zakzanis  KKTroyer  AKRich  JBHeinrichs  W Component analysis of verbal fluency in patients with schizophrenia. Neuropsychiatry Neuropsychol Behav Neurol 2000;13239- 245
PubMed
Geuze  EVermetten  EBremner  JD MR-based in vivo hippocampal volumetrics, 2: findings in neuropsychiatric disorders. Mol Psychiatry 2005;10160- 184
PubMed Link to Article
Goldberg  TETorrey  EFBerman  KFWeinberger  DR Relations between neuropsychological performance and brain morphological and physiological measures in monozygotic twins discordant for schizophrenia. Psychiatry Res 1994;5551- 61
PubMed Link to Article
Gur  RECowell  PTuretsky  BIGallacher  FCannon  TBilker  WGur  RC A follow-up magnetic resonance imaging study of schizophrenia: relationship of neuroanatomical changes to clinical and neurobehavioral measures. Arch Gen Psychiatry 1998;55145- 152
PubMed Link to Article
Powell  HWKoepp  MJSymms  MRBoulby  PASalek-Haddadi  AThompson  PJDuncan  JSRichardson  MP Material-specific lateralization of memory encoding in the medial temporal lobe: blocked versus event-related design. Neuroimage 2005;27231- 239
PubMed Link to Article
McDonald  CBullmore  ETSham  PCChitnis  XWickham  HBramon  EMurray  RM Association of genetic risks for schizophrenia and bipolar disorder with specific and generic brain structural endophenotypes. Arch Gen Psychiatry 2004;61974- 984
PubMed Link to Article
Szeszko  PRLipsky  RMentschel  CRobinson  DGunduz-Bruce  HSevy  SAshtari  MNapolitano  BBilder  RMKane  JMGoldman  DMalhotra  AK Brain-derived neurotrophic factor val66met polymorphism and volume of the hippocampal formation. Mol Psychiatry 2005;10631- 636
PubMed Link to Article
Callicott  JHStraub  REPezawas  LEgan  MFMattay  VSHariri  ARVerchinski  BAMeyer-Lindenberg  ABalkissoon  RKolachana  BGoldberg  TEWeinberger  DR Variation in DISC1 affects hippocampal structure and function and increases risk for schizophrenia. Proc Natl Acad Sci U S A 2005;1028627- 8632
PubMed Link to Article
Cannon  TDMednick  SAParnas  JSchulsinger  FPraestholm  JVestergaard  A Developmental brain abnormalities in the offspring of schizophrenic mothers, I: contributions of genetic and perinatal factors. Arch Gen Psychiatry 1993;50551- 564
PubMed Link to Article
Kelly  JMurray  RM What risk factors tell us about the causes of schizophrenia and related psychoses. Curr Psychiatry Rep 2000;2378- 385
PubMed Link to Article
Buckley  PStack  JPMadigan  CO'Callaghan  ELarkin  CRedmond  OEnnis  JTWaddington  JL Magnetic resonance imaging of schizophrenia-like psychoses associated with cerebral trauma: clinicopathological correlates. Am J Psychiatry 1993;150146- 148
PubMed
McAllister  TW Traumatic brain injury and psychosis: what is the connection? Semin Clin Neuropsychiatry 1998;3211- 223
PubMed
Smith  GNLang  DJKopala  LCLapointe  JSFalkai  PHoner  WG Developmental abnormalities of the hippocampus in first-episode schizophrenia. Biol Psychiatry 2003;53555- 561
PubMed Link to Article
Sapolsky  RMKrey  LCMcEwen  BS The neuroendocrinology of stress and aging: the glucocorticoid cascade hypothesis. Endocr Rev 1986;7284- 301
PubMed Link to Article
Sapolsky  RMMcEwan  BS Stress, glucocorticoids, and their role in degenerative changes in the aging hippocampus. Crook  TBartens  RTFerris  SGershon  SedsTreatment Development Strategies for Alzheimer's Disease. Madison, Conn Mark Powley Associates1986;151- 171
Swaab  DFBao  AMLucassen  PJ The stress system in the human brain in depression and neurodegeneration. Ageing Res Rev 2005;4141- 194
PubMed Link to Article
Eriksson  PSPerfilieva  EBjork-Eriksson  TAlborn  AMNordborg  CPeterson  DAGage  FH Neurogenesis in the adult human hippocampus. Nat Med 1998;41313- 1317
PubMed Link to Article
McEwen  BS The neurobiology of stress: from serendipity to clinical relevance. Brain Res 2000;886172- 189
PubMed Link to Article
Sacker  ADone  DJCrow  TJ Obstetric complications in children born to parents with schizophrenia: a meta-analysis of case-control studies. Psychol Med 1996;26279- 287
PubMed Link to Article
Cannon  TDRosso  IMHollister  JMBearden  CESanchez  LEHadley  T A prospective cohort study of genetic and perinatal influences in the etiology of schizophrenia. Schizophr Bull 2000;26351- 366
PubMed Link to Article
Cannon  TDHuttunen  MOLonnqvist  JTuulio-Henriksson  APirkola  TGlahn  DFinkelstein  JHietanen  MKaprio  JKoskenvuo  M The inheritance of neuropsychological dysfunction in twins discordant for schizophrenia. Am J Hum Genet 2000;67369- 382
PubMed Link to Article
Gur  RCMozley  PDResnick  SMGottlieb  GLKohn  MZimmerman  RHerman  GAtlas  SGrossman  RBerretta  D Gender differences in age effect on brain atrophy measured by magnetic resonance imaging. Proc Natl Acad Sci U S A 1991;882845- 2849
PubMed Link to Article

Figures

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Figure 1.

Mean total hippocampal volume. Error bars indicate 95% confidence interval.

Graphic Jump Location
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Figure 2.

Mean cerebral gray matter volume. Error bars indicate 95% confidence interval.

Graphic Jump Location
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Figure 3.

Mean third-ventricle volume. Error bars indicate 95% confidence interval.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Summary of 25 Studies in Meta-analysis and Included Brain Volumes
Table Graphic Jump LocationTable 2. Brain Structures Included in Meta-analysis and Results

References

Lawrie  SMAbukmeil  SS Brain abnormality in schizophrenia: a systematic and quantitative review of volumetric magnetic resonance imaging studies. Br J Psychiatry 1998;172110- 120
PubMed Link to Article
Wright  ICRabe-Hesketh  SWoodruff  PWDavid  ASMurray  RMBullmore  ET Meta-analysis of regional brain volumes in schizophrenia. Am J Psychiatry 2000;15716- 25
PubMed
Cahn  WHulshoff Pol  HELems  EBvan Haren  NESchnack  HGvan der Linden  JASchothorst  PFVan Engeland  HKahn  RS Brain volume changes in first-episode schizophrenia: a 1-year follow-up study. Arch Gen Psychiatry 2002;591002- 1010
PubMed Link to Article
Gur  REMaany  VMozley  PDSwanson  CBilker  WGur  RC Subcortical MRI volumes in neuroleptic-naive and treated patients with schizophrenia. Am J Psychiatry 1998;1551711- 1717
PubMed
Keshavan  MSBagwell  WWHaas  GLSweeney  JASchooler  NRPettegrew  JW Changes in caudate volume with neuroleptic treatment. Lancet 1994;3441434
PubMed Link to Article
Lieberman  JChakos  MWu  HAlvir  JHoffman  ERobinson  DBilder  R Longitudinal study of brain morphology in first episode schizophrenia. Biol Psychiatry 2001;49487- 499
PubMed Link to Article
Cardno  AGJones  LAMurphy  KCSanders  RDAsherson  POwen  MJMcGuffin  P Dimensions of psychosis in affected sibling pairs. Schizophr Bull 1999;25841- 850
PubMed Link to Article
Wood  SJYucel  MVelakoulis  DPhillips  LJYung  ARBrewer  WMcGorry  PDPantelis  C Hippocampal and anterior cingulate morphology in subjects at ultra-high-risk for psychosis: the role of family history of psychotic illness. Schizophr Res 2005;75295- 301
PubMed Link to Article
van Erp  TGSaleh  PARosso  IMHuttunen  MLonnqvist  JPirkola  TSalonen  OValanne  LPoutanen  VPStandertskjold-Nordenstam  CGCannon  TD Contributions of genetic risk and fetal hypoxia to hippocampal volume in patients with schizophrenia or schizoaffective disorder, their unaffected siblings, and healthy unrelated volunteers. Am J Psychiatry 2002;1591514- 1520
PubMed Link to Article
Noga  JTBartley  AJJones  DWTorrey  EFWeinberger  DR Cortical gyral anatomy and gross brain dimensions in monozygotic twins discordant for schizophrenia. Schizophr Res 1996;2227- 40
PubMed Link to Article
Hulshoff Pol  HEBrans  RGvan Haren  NESchnack  HGLangen  MBaare  WFvan Oel  CJKahn  RS Gray and white matter volume abnormalities in monozygotic and same-gender dizygotic twins discordant for schizophrenia. Biol Psychiatry 2004;55126- 130
PubMed Link to Article
Gogtay  NSporn  AClasen  LSGreenstein  DGiedd  JNLenane  MGochman  PAZijdenbos  ARapoprt  JL Structural brain MRI abnormalities in healthy siblings of patients with childhood-onset schizophrenia. Am J Psychiatry 2003;160569- 571
PubMed Link to Article
Cannon  TDvan Erp  TGRosso  IMHuttunen  MLonnqvist  JPirkola  TSalonen  OValanne  LPoutanen  VPStanderksjold-Nordenstam  CG Fetal hypoxia and structural brain abnormalities in schizophrenic patients, their siblings, and controls. Arch Gen Psychiatry 2002;5935- 41
PubMed Link to Article
Baare  WFvan Oel  CJHulshoff Pol  HESchnack  HGDurston  SSitskoorn  MMKahn  RS Volumes of brain structures in twins discordant for schizophrenia. Arch Gen Psychiatry 2001;5833- 40
PubMed Link to Article
Boos  HBCahn  WAppels  MCSitskoorn  MMHulshoff Pol  HESchnack  HGPalmer  SJKahn  RS Brain volumes in parents of patients with schizophrenia. Schizophr Bull 2005;31382
van Haren  NEPicchioni  MMMcDonald  CMarshall  NDavis  NRibchester  THulshoff Pol  HESharma  TSham  PKahn  RSMurray  R A controlled study of brain structure in monozygotic twins concordant and discordant for schizophrenia. Biol Psychiatry 2004;56454- 461
PubMed Link to Article
Seidman  LJFaraone  SVGoldstein  JMKremen  WSHorton  NJMakris  NToomey  RKennedy  DCaviness  VSTsuang  MT Left hippocampal volume as a vulnerability indicator for schizophrenia: a magnetic resonance imaging morphometric study of nonpsychotic first-degree relatives. Arch Gen Psychiatry 2002;59839- 849
PubMed Link to Article
Marcelis  MSuckling  JWoodruff  PHofman  PBullmore  Evan Os  J Searching for a structural endophenotype in psychosis using computational morphometry. Psychiatry Res 2003;122153- 167
PubMed Link to Article
Lawrie  SMWhalley  HCAbukmeil  SSKestelman  JNDonnelly  LMiller  PBest  JJOwens  DGJohnstone  EC Brain structure, genetic liability, and psychotic symptoms in subjects at high risk of developing schizophrenia. Biol Psychiatry 2001;49811- 823
PubMed Link to Article
Staal  WGHulshoff Pol  HESchnack  Hvan der Schot  ACKahn  RS Partial volume decrease of the thalamus in relatives of patients with schizophrenia. Am J Psychiatry 1998;1551784- 1786
PubMed
McDonald  CGrech  AToulopoulou  TSchulze  KChapple  BSham  PWalshe  MSharma  TSigmundsson  TChitnis  XMurray  RM Brain volumes in familial and non-familial schizophrenic probands and their unaffected relatives. Am J Med Genet 2002;114616- 625
PubMed Link to Article
Seidman  LJFaraone  SVGoldstein  JMGoodman  JMKremen  WSMatsuda  GHoge  EAKennedy  DMakris  NCaviness  VSTsuang  MT Reduced subcortical brain volumes in nonpsychotic siblings of schizophrenic patients: a pilot magnetic resonance imaging study. Am J Med Genet 1997;74507- 514
PubMed Link to Article
Cannon  TDvan Erp  TGHuttunen  MLonnqvist  JSalonen  OValanne  LPoutanen  VPStanderksjold-Nordenstam  CGGur  REYan  M Regional gray matter, white matter, and cerebrospinal fluid distributions in schizophrenic patients, their siblings, and controls. Arch Gen Psychiatry 1998;551084- 1091
PubMed Link to Article
Keshavan  MSDick  EMankowski  IHarenski  KMontrose  DMDiwadkar  VDeBellis  M Decreased left amygdala and hippocampal volumes in young offspring at risk for schizophrenia. Schizophr Res 2002;58173- 183
PubMed Link to Article
Narr  KLvan Erp  TGCannon  TDWoods  RPThompson  PMJang  SBlanton  RPoutanen  VPHuttunen  MLonnqvist  JStanderksjold-Nordenstam  CGKaprio  JMazziotta  JCToga  AW A twin study of genetic contributions to hippocampal morphology in schizophrenia. Neurobiol Dis 2002;1183- 95
PubMed Link to Article
O'Driscoll  GAFlorencio  PSGagnon  DWolff  AVBenkelfat  CMikula  LLal  SEvans  AC Amygdala-hippocampal volume and verbal memory in first-degree relatives of schizophrenic patients. Psychiatry Res 2001;10775- 85
PubMed Link to Article
van Erp  TGSaleh  PAHuttunen  MLonnqvist  JKaprio  JSalonen  OValanne  LPoutanen  VPStandertskjold-Nordenstam  CGCannon  TD Hippocampal volumes in schizophrenic twins. Arch Gen Psychiatry 2004;61346- 353
PubMed Link to Article
Schulze  KMcDonald  CFrangou  SSham  PGrech  AToulopoulou  TWalshe  MSharma  TSigmundsson  TTaylor  MMurray  RM Hippocampal volume in familial and nonfamilial schizophrenic probands and their unaffected relatives. Biol Psychiatry 2003;53562- 570
PubMed Link to Article
Toulopoulou  TGrech  AMorris  GSchulze  KMcDonald  CChapple  BRabe-Hesketh  SMurray  RM The relationship between volumetric brain changes and cognitive function: a family study on schizophrenia. Biol Psychiatry 2004;56447- 453
PubMed Link to Article
Silverman  JMSmith  CJGou  SLMohs  ECSiever  LJDavis  KL Lateral ventricular enlargement in schizophrenic probands and their siblings with schizophrenia-related disorders. Biol Psychiatry 1998;4397- 106
PubMed Link to Article
Posthuma  DBaaré  WFCHulshoff Pol  HEKahn  RSBoomsma  DIde Geus  AJC Genetic correlations between brain volumes and the WAIS-III dimensions of verbal comprehension, working memory, perceptual organization, and processing speed. Twin Res 2003;6131- 139
PubMed Link to Article
Waldo  MCAdler  LELeonard  SOlincy  ARoss  RGHarris  JGFreedman  R Familial transmission of risk factors in the first-degree relatives of schizophrenic people. Biol Psychiatry 2000;47231- 239
PubMed Link to Article
Harris  JGYoung  DARojas  DCCajade-Law  AScherzinger  ANawroz  SAdler  LECullum  CMSimon  JFreedman  R Increased hippocampal volume in schizophrenics' parents with ancestral history of schizophrenia. Schizophr Res 2002;5511- 17
PubMed Link to Article
Chapple  BGrech  ASham  PToulopoulou  TWalshe  MSchulze  KMorgan  RMurray  RMMcDonald  C Normal cerebral asymmetry in familial and non-familial schizophrenic probands and their unaffected relatives. Schizophr Res 2004;6733- 40
PubMed Link to Article
Cannon  TDThompson  PMvan Erp  TGMToga  AWPoutanen  VHuttunen  MLonnqvist  JStanderskjold-Nordenstam  CNarr  KLKhaledy  MZoumalan  CIDail  RKaprio  J Cortex mapping reveals regionally specific patterns of genetic and disease-specific gray-matter deficits in twins discordant for schizophrenia. Proc Natl Acad Sci U S A 2002;993228- 3233
PubMed Link to Article
Job  DEWhalley  HCMcConnell  SGlabus  MJohnstone  ECLawrie  SM Voxel-based morphometry of grey matter densities in subjects at high risk of schizophrenia. Schizophr Res 2003;641- 13
PubMed Link to Article
Keshavan  MSJayakumar  PNDiwadkar  VASingh  A Cavum septi pellucidi in first-episode patients and young relatives at risk for schizophrenia. CNS Spectr 2002;7155- 158
PubMed
Wright  ICSham  PMurray  RMWeinburger  DRBullmore  ET Genetic contributions to regional variability in human brain structure: methods and preliminary results. Neuroimage 2002;17256- 271
PubMed Link to Article
McNeil  TFCantor-Graae  EWeinberger  DR Relationship of obstetric complications and differences in size of brain structures in monozygotic twin pairs discordant for schizophrenia. Am J Psychiatry 2000;157203- 212
PubMed Link to Article
Cannon  TDMarco  E Structural brain abnormalities as indicators of vulnerability to schizophrenia. Schizophr Bull 1994;2089- 102
PubMed Link to Article
Bridle  NPantelis  CWood  SJCoppola  RVelakoulis  DMcStephen  MTierney  PLe  TLTorrey  EFWeinberger  D Thalamic and caudate volumes in monozygotic twins discordant for schizophrenia. Aust N Z J Psychiatry 2002;36347- 354
PubMed Link to Article
Turetsky  BIMoberg  PJArnold  SEDoty  RLGur  RE Low olfactory bulb volume in first-degree relatives of patients with schizophrenia. Am J Psychiatry 2003;160703- 708
PubMed Link to Article
Phillips  LJVelakoulis  DPantelis  CWood  SYuen  HPYung  ARDesmond  PBrewer  WMcGorry  PD Non-reduction in hippocampal volume is associated with higher risk of psychosis. Schizophr Res 2002;58145- 158
PubMed Link to Article
Stefanis  NFrangou  SYakeley  JSharma  TO'Connell  PMorgan  KSigmundsson  TTaylor  MMurray  R Hippocampal volume reduction in schizophrenia: effects of genetic risk and pregnancy and birth complications. Biol Psychiatry 1999;46697- 702
PubMed Link to Article
Thompson  PMVidal  CGiedd  JNGochman  PBlumenthal  JNicolson  RToga  AWRapoport  JL Mapping adolescent brain change reveals dynamic wave of accelerated gray matter loss in very early-onset schizophrenia. Proc Natl Acad Sci U S A 2001;9811650- 11655
PubMed Link to Article
Suddath  RLChristison  GWTorrey  EFCasanova  MFWeinberger  DR Anatomical abnormalities in the brains of monozygotic twins discordant for schizophrenia. N Engl J Med 1990;322789- 794
PubMed Link to Article
Falkai  PHoner  WGAlfter  DSchneider-Axmann  TBussfeld  PCordes  JBlank  BSchönell  HSteinmetz  HMaier  WTepest  R The temporal lobe in schizophrenia from uni- and multiply affected families. Neurosci Lett 2002;32525- 28
PubMed Link to Article
Narr  KLCannon  TDWoods  RPThompson  PMKim  SAsunction  Dvan Erp  TGPoutanen  VPHuttunen  MLonnqvist  JStanderksjold-Nordenstam  CGKaprio  JMazziotta  JCToga  AW Genetic contributions to altered callosal morphology in schizophrenia. J Neurosci 2002;223720- 3729
PubMed
Sharma  TLancaster  ESigmundsson  TLewis  STakei  NGurling  HBarta  PPearlson  GMurray  R Lack of normal pattern of cerebral asymmetry in familial schizophrenic patients and their relatives—The Maudsley Family Study. Schizophr Res 1999;40111- 120
PubMed Link to Article
Falkai  PTepest  RHoner  WGDani  IAhle  GPfeiffer  UVogeley  KSchulze  TGRietschel  MCordes  JSchonell  HGaebel  WKuhn  KUMaier  WTraber  FBlock  WSchild  HHSchneider-Axmann  T Shape changes in prefrontal, but not parieto-occipital regions: brains of schizophrenic patients come closer to a circle in coronal and sagittal view. Psychiatry Res 2004;132261- 271
PubMed Link to Article
Seidman  LJFaraone  SVGoldstein  JMGoodman  JMKremen  WSToomey  RTourville  JKennedy  DMakris  NCaviness  VSTsuang  M Thalamic and amygdala-hippocampal volume reductions in first-degree relatives of patients with schizophrenia: an MRI-based morphometric analysis. Biol Psychiatry 1999;46941- 954
PubMed Link to Article
Lipsey  MWWilson  DB The way in which intervention studies have “personality” and why it is important to do meta-analysis. Eval Health Prof 2001;24236- 245
PubMed Link to Article
Hedges  LVOlkin  I Statistical Methods for Meta-analysis.  New York, NY Academic Press1985;
Rosenthal  R Meta-analytic Procedures for Social Research.  London, England Sage Publications1991;
Cohen  J Statistical Power Analysis for the Behavioral Sciences.  Hillsdale, NY Lawrence Erlbaum Associates1988;
Borenstein  MRothstein  H Comprehensive meta-analysis. Borenstein  MRothstein  HedsA Computer Program for Research Synthesis. Englewood, NY BioStat Inc 1999;
DerSimonian  RLaird  N Meta-analysis in clinical trials. Control Clin Trials 1986;7177- 188
PubMed Link to Article
Orwin  RG A fail-safe N for effect size in meta-analysis. J Educ Stat 1983;8157- 159
Link to Article
Pantelis  CVelakoulis  DMcGorry  PDWood  SJSuckling  JPhillips  LJYung  ARBullmore  ETBrewer  WSoulsby  BDesmond  PMcGuire  PK Neuroanatomical abnormalities before and after onset of psychosis: a cross-sectional and longitudinal MRI comparison. Lancet 2003;361281- 288
PubMed Link to Article
Job  DEWhalley  HCJohnstone  ECLawrie  SM Grey matter changes over time in high risk subjects developing schizophrenia. Neuroimage 2005;251023- 1030
PubMed Link to Article
Toulopoulou  TMorris  RGRabe-Hesketh  SMurray  RM Selectivity of verbal memory deficit in schizophrenic patients and their relatives. Am J Med Genet B Neuropsychiatr Genet 2003;1161- 7
PubMed Link to Article
Sitskoorn  MMAleman  AEbisch  SJAppels  MCKahn  RS Cognitive deficits in relatives of patients with schizophrenia: a meta-analysis. Schizophr Res 2004;71285- 295
PubMed Link to Article
Aleman  AHijman  Rde Haan  EHKahn  RS Memory impairment in schizophrenia: a meta-analysis. Am J Psychiatry 1999;1561358- 1366
PubMed
Zakzanis  KKTroyer  AKRich  JBHeinrichs  W Component analysis of verbal fluency in patients with schizophrenia. Neuropsychiatry Neuropsychol Behav Neurol 2000;13239- 245
PubMed
Geuze  EVermetten  EBremner  JD MR-based in vivo hippocampal volumetrics, 2: findings in neuropsychiatric disorders. Mol Psychiatry 2005;10160- 184
PubMed Link to Article
Goldberg  TETorrey  EFBerman  KFWeinberger  DR Relations between neuropsychological performance and brain morphological and physiological measures in monozygotic twins discordant for schizophrenia. Psychiatry Res 1994;5551- 61
PubMed Link to Article
Gur  RECowell  PTuretsky  BIGallacher  FCannon  TBilker  WGur  RC A follow-up magnetic resonance imaging study of schizophrenia: relationship of neuroanatomical changes to clinical and neurobehavioral measures. Arch Gen Psychiatry 1998;55145- 152
PubMed Link to Article
Powell  HWKoepp  MJSymms  MRBoulby  PASalek-Haddadi  AThompson  PJDuncan  JSRichardson  MP Material-specific lateralization of memory encoding in the medial temporal lobe: blocked versus event-related design. Neuroimage 2005;27231- 239
PubMed Link to Article
McDonald  CBullmore  ETSham  PCChitnis  XWickham  HBramon  EMurray  RM Association of genetic risks for schizophrenia and bipolar disorder with specific and generic brain structural endophenotypes. Arch Gen Psychiatry 2004;61974- 984
PubMed Link to Article
Szeszko  PRLipsky  RMentschel  CRobinson  DGunduz-Bruce  HSevy  SAshtari  MNapolitano  BBilder  RMKane  JMGoldman  DMalhotra  AK Brain-derived neurotrophic factor val66met polymorphism and volume of the hippocampal formation. Mol Psychiatry 2005;10631- 636
PubMed Link to Article
Callicott  JHStraub  REPezawas  LEgan  MFMattay  VSHariri  ARVerchinski  BAMeyer-Lindenberg  ABalkissoon  RKolachana  BGoldberg  TEWeinberger  DR Variation in DISC1 affects hippocampal structure and function and increases risk for schizophrenia. Proc Natl Acad Sci U S A 2005;1028627- 8632
PubMed Link to Article
Cannon  TDMednick  SAParnas  JSchulsinger  FPraestholm  JVestergaard  A Developmental brain abnormalities in the offspring of schizophrenic mothers, I: contributions of genetic and perinatal factors. Arch Gen Psychiatry 1993;50551- 564
PubMed Link to Article
Kelly  JMurray  RM What risk factors tell us about the causes of schizophrenia and related psychoses. Curr Psychiatry Rep 2000;2378- 385
PubMed Link to Article
Buckley  PStack  JPMadigan  CO'Callaghan  ELarkin  CRedmond  OEnnis  JTWaddington  JL Magnetic resonance imaging of schizophrenia-like psychoses associated with cerebral trauma: clinicopathological correlates. Am J Psychiatry 1993;150146- 148
PubMed
McAllister  TW Traumatic brain injury and psychosis: what is the connection? Semin Clin Neuropsychiatry 1998;3211- 223
PubMed
Smith  GNLang  DJKopala  LCLapointe  JSFalkai  PHoner  WG Developmental abnormalities of the hippocampus in first-episode schizophrenia. Biol Psychiatry 2003;53555- 561
PubMed Link to Article
Sapolsky  RMKrey  LCMcEwen  BS The neuroendocrinology of stress and aging: the glucocorticoid cascade hypothesis. Endocr Rev 1986;7284- 301
PubMed Link to Article
Sapolsky  RMMcEwan  BS Stress, glucocorticoids, and their role in degenerative changes in the aging hippocampus. Crook  TBartens  RTFerris  SGershon  SedsTreatment Development Strategies for Alzheimer's Disease. Madison, Conn Mark Powley Associates1986;151- 171
Swaab  DFBao  AMLucassen  PJ The stress system in the human brain in depression and neurodegeneration. Ageing Res Rev 2005;4141- 194
PubMed Link to Article
Eriksson  PSPerfilieva  EBjork-Eriksson  TAlborn  AMNordborg  CPeterson  DAGage  FH Neurogenesis in the adult human hippocampus. Nat Med 1998;41313- 1317
PubMed Link to Article
McEwen  BS The neurobiology of stress: from serendipity to clinical relevance. Brain Res 2000;886172- 189
PubMed Link to Article
Sacker  ADone  DJCrow  TJ Obstetric complications in children born to parents with schizophrenia: a meta-analysis of case-control studies. Psychol Med 1996;26279- 287
PubMed Link to Article
Cannon  TDRosso  IMHollister  JMBearden  CESanchez  LEHadley  T A prospective cohort study of genetic and perinatal influences in the etiology of schizophrenia. Schizophr Bull 2000;26351- 366
PubMed Link to Article
Cannon  TDHuttunen  MOLonnqvist  JTuulio-Henriksson  APirkola  TGlahn  DFinkelstein  JHietanen  MKaprio  JKoskenvuo  M The inheritance of neuropsychological dysfunction in twins discordant for schizophrenia. Am J Hum Genet 2000;67369- 382
PubMed Link to Article
Gur  RCMozley  PDResnick  SMGottlieb  GLKohn  MZimmerman  RHerman  GAtlas  SGrossman  RBerretta  D Gender differences in age effect on brain atrophy measured by magnetic resonance imaging. Proc Natl Acad Sci U S A 1991;882845- 2849
PubMed Link to Article

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