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Meta-analysis of Brain Volumes in Unaffected First-Degree Relatives of Patients With Schizophrenia Overemphasizes Hippocampal Deficits—Reply

Meta-analysis of Brain Volumes in Unaffected First-Degree Relatives of Patients With... In reply With this response, we want to clarify and refute most of the issues raised by McDonald et al. Although we regret that a number of minor (mainly typographical) errors have been made in our article, which we will discuss in the following comments, our results and our conclusions stand firmly. The main point by McDonald et al that we overemphasize significant hippocampal volume reduction in first-degree relatives of patients with schizophrenia in our meta-analysis is not warranted on the basis of the available data. We do agree, however, as we stated in our original article, that there is a paucity of research into brain structures other than the hippocampus in relatives and that this deserves more attention in future investigations. First, with regard to the study of Wood et al,1 we agree with McDonald et al that part of this group had an at-risk mental state and those individuals should have been excluded from the meta-analysis. However, if we disregard those individuals and repeat the meta-analysis, the overall results do not change, and the effect size for the hippocampus volume remains highly significant (d = 0.32 [95% confidence interval, 0.14-0.49]; P < .001). Second,McDonald et al raise the issue of overlapping samples in the study from van Haren et al2 and Schulze et al.3 However, the van Haren et al article does not state that (part of) their results had been published elsewhere and it does not make reference to Schulze et al in this regard. Both do refer to the sample described inMcDonald et al,4 but then McDonald et al did not report data on hippocampus volumes. Indeed, van Haren et al report on twins, which were not reported on by Schulze et al. It was therefore not apparent to us that these studies concerned the same samples. Third, the study referred to as Toulopoulou et al5 is an editorial typo in the figure and should read Narr et al6 (the numbers in the figure are correct and correspond to Narr et al6). Indeed, Toulopoulou et al5 was not included in Table 1, nor in the analysis. We do not agree withMcDonald et al that the study from Narr et al6 should not have been included in our meta-analysis. There is no clue in their article, nor in the article by van Erp et al,7 that this should be the same sample. The fact that both drew their participants from a large Scandinavian register does by no means necessarily imply overlap. According to McDonald et al, our meta-analysis overemphasizes hippocampal volume reduction in relatives of patients with schizophrenia. To test the robustness of our claim, we repeated our meta-analysis, without the studies of Schulze et al3 and Narr et al,6 which, according to McDonald et al, have sample overlap with other studies. Even then, however, the mean weighted effect size remains highly significant and not different from the mean effect size we reported in our original article, namely d = 0.29 (95% confidence interval, 0.08-0.52); P = .01. We can therefore, again, safely conclude that significant volume reduction of the hippocampus has been established in relatives of patients with schizophrenia. We agree that hippocampal volume should have been mentioned for Baaré et al8 in Table 1, since this study was also included in our analysis (which is accurately reported in Figure 1). In addition, O’Driscoll et al9 did indeed not analyze the hippocampus proper and were therefore not in our analysis, nor in Figure 1 of our article. We regret the typo we made in Table 1, where it should indeed have been AHC (amygdala-hippocampal) instead of HC (hippocampus). Table 2 of our article shows the different structures that were included in the meta-analysis and corresponding results. McDonald et al argue that we misleadingly reported that the amygdala-hippocampus was assessed in 12 studies. However, we have clearly explained that only those structures for which the volumes were explored in more than 3 individual studies were analyzed and thus given in Table 2. From Table 1, the reader can further easily conclude that the amygdala-hippocampus was only assessed by a few studies. The number 12 refers to the total number of studies that included the amygdala and/or hippocampus. Correspondence: Ms Boos, Department of Psychiatry, University Medical Center Utrecht, Rudolf Magnus Institute of Neuroscience, A.00.331, PO Box 85500, 3508 GA Utrecht, the Netherlands (h.b.m.boos@umcutrecht.nl). Financial Disclosure: None reported. References 1. 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;75 (2-3) 295- 301PubMedGoogle ScholarCrossref 2. 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;56 (6) 454- 461PubMedGoogle ScholarCrossref 3. 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;53 (7) 562- 570PubMedGoogle ScholarCrossref 4. McDonald CGrech AToulopoulou TSchulze KChapple BSham PCWalshe MSharma TSigmundsson TChitnis XMurray RM Brain volumes in familial and non-familial schizophrenic probands and their unaffected relatives. Am J Med Genet 2002;114 (6) 616- 625PubMedGoogle ScholarCrossref 5. 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;116 (1) 1- 7PubMedGoogle ScholarCrossref 6. Narr KL van 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;11 (1) 83- 95PubMedGoogle ScholarCrossref 7. van Erp TGSaleh PAHuttunen MLonnqvist JKaprio JSalonen OValanne LPoutanen VPStandertskjold-Nordenstam CGCannon TD Hippocampal volumes in schizophrenic twins. Arch Gen Psychiatry 2004;61 (4) 346- 353PubMedGoogle ScholarCrossref 8. Baaré WFvan Oel CJHulshoff Pol HESchnack HGDurston SSitskoorn MMKahn RS Volumes of brain structures in twins discordant for schizophrenia. Arch Gen Psychiatry 2001;58 (1) 33- 40PubMedGoogle ScholarCrossref 9. 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;107 (2) 75- 85PubMedGoogle ScholarCrossref http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Archives of General Psychiatry American Medical Association

Meta-analysis of Brain Volumes in Unaffected First-Degree Relatives of Patients With Schizophrenia Overemphasizes Hippocampal Deficits—Reply

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References (9)

Publisher
American Medical Association
Copyright
Copyright © 2008 American Medical Association. All Rights Reserved.
ISSN
0003-990X
eISSN
1598-3636
DOI
10.1001/archpsyc.65.5.604
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Abstract

In reply With this response, we want to clarify and refute most of the issues raised by McDonald et al. Although we regret that a number of minor (mainly typographical) errors have been made in our article, which we will discuss in the following comments, our results and our conclusions stand firmly. The main point by McDonald et al that we overemphasize significant hippocampal volume reduction in first-degree relatives of patients with schizophrenia in our meta-analysis is not warranted on the basis of the available data. We do agree, however, as we stated in our original article, that there is a paucity of research into brain structures other than the hippocampus in relatives and that this deserves more attention in future investigations. First, with regard to the study of Wood et al,1 we agree with McDonald et al that part of this group had an at-risk mental state and those individuals should have been excluded from the meta-analysis. However, if we disregard those individuals and repeat the meta-analysis, the overall results do not change, and the effect size for the hippocampus volume remains highly significant (d = 0.32 [95% confidence interval, 0.14-0.49]; P < .001). Second,McDonald et al raise the issue of overlapping samples in the study from van Haren et al2 and Schulze et al.3 However, the van Haren et al article does not state that (part of) their results had been published elsewhere and it does not make reference to Schulze et al in this regard. Both do refer to the sample described inMcDonald et al,4 but then McDonald et al did not report data on hippocampus volumes. Indeed, van Haren et al report on twins, which were not reported on by Schulze et al. It was therefore not apparent to us that these studies concerned the same samples. Third, the study referred to as Toulopoulou et al5 is an editorial typo in the figure and should read Narr et al6 (the numbers in the figure are correct and correspond to Narr et al6). Indeed, Toulopoulou et al5 was not included in Table 1, nor in the analysis. We do not agree withMcDonald et al that the study from Narr et al6 should not have been included in our meta-analysis. There is no clue in their article, nor in the article by van Erp et al,7 that this should be the same sample. The fact that both drew their participants from a large Scandinavian register does by no means necessarily imply overlap. According to McDonald et al, our meta-analysis overemphasizes hippocampal volume reduction in relatives of patients with schizophrenia. To test the robustness of our claim, we repeated our meta-analysis, without the studies of Schulze et al3 and Narr et al,6 which, according to McDonald et al, have sample overlap with other studies. Even then, however, the mean weighted effect size remains highly significant and not different from the mean effect size we reported in our original article, namely d = 0.29 (95% confidence interval, 0.08-0.52); P = .01. We can therefore, again, safely conclude that significant volume reduction of the hippocampus has been established in relatives of patients with schizophrenia. We agree that hippocampal volume should have been mentioned for Baaré et al8 in Table 1, since this study was also included in our analysis (which is accurately reported in Figure 1). In addition, O’Driscoll et al9 did indeed not analyze the hippocampus proper and were therefore not in our analysis, nor in Figure 1 of our article. We regret the typo we made in Table 1, where it should indeed have been AHC (amygdala-hippocampal) instead of HC (hippocampus). Table 2 of our article shows the different structures that were included in the meta-analysis and corresponding results. McDonald et al argue that we misleadingly reported that the amygdala-hippocampus was assessed in 12 studies. However, we have clearly explained that only those structures for which the volumes were explored in more than 3 individual studies were analyzed and thus given in Table 2. From Table 1, the reader can further easily conclude that the amygdala-hippocampus was only assessed by a few studies. The number 12 refers to the total number of studies that included the amygdala and/or hippocampus. Correspondence: Ms Boos, Department of Psychiatry, University Medical Center Utrecht, Rudolf Magnus Institute of Neuroscience, A.00.331, PO Box 85500, 3508 GA Utrecht, the Netherlands (h.b.m.boos@umcutrecht.nl). Financial Disclosure: None reported. References 1. 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;75 (2-3) 295- 301PubMedGoogle ScholarCrossref 2. 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;56 (6) 454- 461PubMedGoogle ScholarCrossref 3. 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;53 (7) 562- 570PubMedGoogle ScholarCrossref 4. McDonald CGrech AToulopoulou TSchulze KChapple BSham PCWalshe MSharma TSigmundsson TChitnis XMurray RM Brain volumes in familial and non-familial schizophrenic probands and their unaffected relatives. Am J Med Genet 2002;114 (6) 616- 625PubMedGoogle ScholarCrossref 5. 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;116 (1) 1- 7PubMedGoogle ScholarCrossref 6. Narr KL van 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;11 (1) 83- 95PubMedGoogle ScholarCrossref 7. van Erp TGSaleh PAHuttunen MLonnqvist JKaprio JSalonen OValanne LPoutanen VPStandertskjold-Nordenstam CGCannon TD Hippocampal volumes in schizophrenic twins. Arch Gen Psychiatry 2004;61 (4) 346- 353PubMedGoogle ScholarCrossref 8. Baaré WFvan Oel CJHulshoff Pol HESchnack HGDurston SSitskoorn MMKahn RS Volumes of brain structures in twins discordant for schizophrenia. Arch Gen Psychiatry 2001;58 (1) 33- 40PubMedGoogle ScholarCrossref 9. 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;107 (2) 75- 85PubMedGoogle ScholarCrossref

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Archives of General Psychiatry – American Medical Association

Published: May 1, 2008

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