Enlargement in Schizophrenia: Is There Really
Ventricular a
Gender Effect?
To the Editor.\p=m-\Andreasenet al1 claim that the finding of increased ventricular-brain ratio (VBR) in schizophrenia is associated primarily with male and not female patients. Although the authors contend that using a larger sample has allowed them to determine something about female patients with schizophrenia, we note that their finding involves unusual female control data. We are particularly concerned about the interpretation of these data because it is the basis of a
far-reaching hypothesis regarding reported gender differences in the clinical manifestations of schizophrenia. In the study, the female controls are unusual in that they had larger mean
VBRs than male controls. The authors acknowledged that this had a substantial influence on the gender effect in their analyses. They felt reassured because they found a similar relationship in another study. However, to our knowledge, in well over 40 years of investigation, no other published study of normal populations, regardless of age, using postmortem sam¬
ples, pneumoencephalograms, or com¬
tomographic or magnetic res¬ puted onance
imaging scans, has reported finding larger mean ventricular vol¬
VBRs in female vs male nor¬ mal subjects. From the first modern postmortem study of normal subjects2 ume or
through
a more
recent
study using
than 400 subjects,3 lateral ven¬ tricular volume has been reported to be larger in men. The normal control data from a recent postmortem study of schizophrenia4 also showed larger ventricular volume in male than in female subjects. Similar observations have been made in numerous normal more
control populations used in comput¬ ed tomographic and magnetic resonace imaging studies. Another puz¬ zling aspect to the data presented in the article by Andreasen et al1 is that the right VBR is greater than the left. This finding is also at odds with re¬ ports from numerous studies of nor¬ mals and patients using various tech¬ niques that have all reported that left tends to be greater than right. In view of the many other studies of patients with schizophrenia that do not claim gender effects on ventricu¬ lar enlargement, as well as a study of monozygotic twins discordant for schizophrenia5 that found that as with male twins, ill female twins had the larger ventricles in a pair, we won¬ dered whether, in the study by An¬ dreasen et al,1 the control group rath¬ er than the patients account for the gender effect. We used several ap¬ proaches to test this hypothesis. Us¬ ing the data provided in their Table 1, we found that female patients have significantly larger ventricles than male controls (two-tailed t test,
P=.0086). Further,
a
f test
comparing
female with male patients showed no significant differences (P>.44). There¬ fore, the data, in fact, suggest that fe¬ male patients have as much enlarge¬ ment of ventricles as male patients. In trying to determine what might be unusual about the female controls, we reviewed the distributions depicted in Fig 4 of their article. While only 10.5% of female patients had VBRs greater than 9, there were twice that many (22.5%) in the female normals. A review of prior studies of ventric¬ ular size shows no such outliers in the distributions of ventricular size in nor¬ mal females. Therefore, it seems quite likely that it is the control population, especially the outliers, that causes this
effect.
We are at a loss to explain the atyp¬ ical results of the control data in this study. However, using all the other
Downloaded From: by a Tulane University User on 01/12/2019
in contrast to the au¬ thors' conclusions, we feel that the data from this sample show the fe¬ male patients to have virtually the same extent of lateral ventricular en¬ largement as the males. Based on this study, the authors sug¬ gest that, given the phenomenological differences in the manifestations of schizophrenia between men and women,6 the reported gender differ¬ ences in ventricular enlargement may be due to different types of illness or different etiologic factors. It is impor¬ tant to remember that, clinically, there
comparisons,
are more common
diagnostic psycho¬
characteristics between male and female patients than there are differences. We suggest that a less elaborate explanation might account for gender differences in the clinical syndromes. For example, a similar in¬ sult, perhaps sustained early in de¬ velopment, might later be influenced
pathologic
differently (eg, hormonally, psycho¬ logically, culturally, etc) in male and female subjects, accounting for phenomenological differences. JEFFREY R. ZIGUN, MD
Department of Psychiatry
Medical College of Wisconsin 8701 Watertown Plank Rd Milwaukee, WI 53226 DAVID G. DANIEL, MD JOEL E. KLEINMAN, MD, PHD DANIEL R. WEINBERGER, MD Washington, DC 1. Andreasen NC, Swayze VW II, Flaum M, Yates WR, Arndt S, McChesney C. Ventricular enlargement in schizophrenia evaluated with
computed tomographic scanning: effects of gender, age, and stage of illness. Arch Gen Psychiatry. 1990;47:1008-1015. 2. Last RJ, Thompsett DH. Casts of the cerebral ventricles. Br J Surg. 1953;40:525-543.
3. Skullerud K. Variations in the size of the human brain. Acta Neurol. 1985;71(suppl):3-94. 4. Crow TJ, Ball J, Bloom SR, Brown R, Bruton CJ, Colter N, Frith CD, Johnstone EC, Owens DGC, Roberts GW. Schizophrenia as an anomaly of development of cerebral asymmetry: a postmortem study and a proposal concerning the genetic basis of the disease. Arch Gen Psychiatry.
1989;46:1145-1150.
5. Suddath RL, Christison GW, Torrey EF, Casanova MF, Weinberger DR. Anatomical abnormalities in the brains of monozygotic twins discord schizophrenia. N EnglJ Med. 1990;322: 789-794. 6. DeLisi LE, Dauphinais ID, Hauser P. Gender differences in the brain: are they relevant to the
pathogenesis of schizophrenia? Compr Psychiatry. 1989;30:197-208.
In Reply.- Zigun et al have raised several issues concerning our article. Their major concerns appear to be the following: (1) the control group may be atypical; and (2) they take exception to a statement attributed to us that
"given the phenomenological
differ-
in the manifestations of schizophrenia between men and women, the reported gender differences in ventricular enlargement may be due to different types of illness or different etiologic factors." ences
Zigun et al do not accurately sum-
marize the contents or conclusions of our article, since many of the issues raised in their letter were already discussed in the article, while the phenomenology of schizophrenia in re-
lation to gender differences was not discussed at all. An Atypical Control Group-\p=m-\Toour knowledge, this study reports on one of the largest samples of carefully screened healthy normal volunteers that has been studied with computed tomography (CT). The total sample size of the controls was 75. They were
community volunteers, carefully screened with a structured psychiat¬ ric interview, medical history, and neurologic examination before the CT
obtained. In addition, all assessed with a comprehensive neuropsychological battery that in¬ cluded the Wechsler Adult Intelligence Scale-Revised. As discussed in the ar¬ ticle, we were surprised to observe that two of the female subjects, both in their twenties, had VBRs of 11.2 and scans that were interpreted visu¬ ally to be "abnormal" for their ages. However, nothing in their psychiatric or medical history or their neuropsy¬ chological testing suggested that these women were abnormal, so we felt ob¬ ligated to include them. As discussed in the article, however, nothing in the reported results would have changed had we excluded them and two other normal individuals who also had ven¬ tricular size that would usually be con¬ sidered to be outside the normal range. The entire issue of the selection of appropriate control groups has been scan was
were
extensively discussed and debated in the literature.1"5 Early CT studies used "samples of convenience" for their control groups. For example, the ear¬ ly study by Weinberger et al6 used the relatives of patients with Huntington's
disease who had normal CT scans. Others have used controls selected from radiology files who were stud¬ ied for complaints such as headache and whose scans were read as nor¬ mal.1·7"9 As discussed in our article, these strategies run the risk of artifi¬ cially truncating distributions by ex¬ cluding individuals from the control sample whose scans are read as ab¬ normal. This could bias results in a variety of ways, including the risk of producing spurious findings of ven¬ tricular enlargement in patients but not controls. A desire to identify the "truest possible" assessment of the dis¬ tribution of ventricular size in nor¬ mals led us to pursue the strategy of collecting a large sample of healthy normal volunteers who were careful¬ ly screened. If our distributions ap¬ pear to be atypical, it may be because they are being compared with a dif¬ ferent literature—based primarily on postmortem studies (with all the prob¬ lems inherent therein), and samples of convenience. The post hoc f tests mentioned by Zigun et al are not a legitimate way to test
a
hypothesis concerning gender
differences. As we reported before, female and male normal controls have no significant differences in ventric¬ ular size (F[l,145]=2.19, P
Ventricular a
Gender Effect?
To the Editor.\p=m-\Andreasenet al1 claim that the finding of increased ventricular-brain ratio (VBR) in schizophrenia is associated primarily with male and not female patients. Although the authors contend that using a larger sample has allowed them to determine something about female patients with schizophrenia, we note that their finding involves unusual female control data. We are particularly concerned about the interpretation of these data because it is the basis of a
far-reaching hypothesis regarding reported gender differences in the clinical manifestations of schizophrenia. In the study, the female controls are unusual in that they had larger mean
VBRs than male controls. The authors acknowledged that this had a substantial influence on the gender effect in their analyses. They felt reassured because they found a similar relationship in another study. However, to our knowledge, in well over 40 years of investigation, no other published study of normal populations, regardless of age, using postmortem sam¬
ples, pneumoencephalograms, or com¬
tomographic or magnetic res¬ puted onance
imaging scans, has reported finding larger mean ventricular vol¬
VBRs in female vs male nor¬ mal subjects. From the first modern postmortem study of normal subjects2 ume or
through
a more
recent
study using
than 400 subjects,3 lateral ven¬ tricular volume has been reported to be larger in men. The normal control data from a recent postmortem study of schizophrenia4 also showed larger ventricular volume in male than in female subjects. Similar observations have been made in numerous normal more
control populations used in comput¬ ed tomographic and magnetic resonace imaging studies. Another puz¬ zling aspect to the data presented in the article by Andreasen et al1 is that the right VBR is greater than the left. This finding is also at odds with re¬ ports from numerous studies of nor¬ mals and patients using various tech¬ niques that have all reported that left tends to be greater than right. In view of the many other studies of patients with schizophrenia that do not claim gender effects on ventricu¬ lar enlargement, as well as a study of monozygotic twins discordant for schizophrenia5 that found that as with male twins, ill female twins had the larger ventricles in a pair, we won¬ dered whether, in the study by An¬ dreasen et al,1 the control group rath¬ er than the patients account for the gender effect. We used several ap¬ proaches to test this hypothesis. Us¬ ing the data provided in their Table 1, we found that female patients have significantly larger ventricles than male controls (two-tailed t test,
P=.0086). Further,
a
f test
comparing
female with male patients showed no significant differences (P>.44). There¬ fore, the data, in fact, suggest that fe¬ male patients have as much enlarge¬ ment of ventricles as male patients. In trying to determine what might be unusual about the female controls, we reviewed the distributions depicted in Fig 4 of their article. While only 10.5% of female patients had VBRs greater than 9, there were twice that many (22.5%) in the female normals. A review of prior studies of ventric¬ ular size shows no such outliers in the distributions of ventricular size in nor¬ mal females. Therefore, it seems quite likely that it is the control population, especially the outliers, that causes this
effect.
We are at a loss to explain the atyp¬ ical results of the control data in this study. However, using all the other
Downloaded From: by a Tulane University User on 01/12/2019
in contrast to the au¬ thors' conclusions, we feel that the data from this sample show the fe¬ male patients to have virtually the same extent of lateral ventricular en¬ largement as the males. Based on this study, the authors sug¬ gest that, given the phenomenological differences in the manifestations of schizophrenia between men and women,6 the reported gender differ¬ ences in ventricular enlargement may be due to different types of illness or different etiologic factors. It is impor¬ tant to remember that, clinically, there
comparisons,
are more common
diagnostic psycho¬
characteristics between male and female patients than there are differences. We suggest that a less elaborate explanation might account for gender differences in the clinical syndromes. For example, a similar in¬ sult, perhaps sustained early in de¬ velopment, might later be influenced
pathologic
differently (eg, hormonally, psycho¬ logically, culturally, etc) in male and female subjects, accounting for phenomenological differences. JEFFREY R. ZIGUN, MD
Department of Psychiatry
Medical College of Wisconsin 8701 Watertown Plank Rd Milwaukee, WI 53226 DAVID G. DANIEL, MD JOEL E. KLEINMAN, MD, PHD DANIEL R. WEINBERGER, MD Washington, DC 1. Andreasen NC, Swayze VW II, Flaum M, Yates WR, Arndt S, McChesney C. Ventricular enlargement in schizophrenia evaluated with
computed tomographic scanning: effects of gender, age, and stage of illness. Arch Gen Psychiatry. 1990;47:1008-1015. 2. Last RJ, Thompsett DH. Casts of the cerebral ventricles. Br J Surg. 1953;40:525-543.
3. Skullerud K. Variations in the size of the human brain. Acta Neurol. 1985;71(suppl):3-94. 4. Crow TJ, Ball J, Bloom SR, Brown R, Bruton CJ, Colter N, Frith CD, Johnstone EC, Owens DGC, Roberts GW. Schizophrenia as an anomaly of development of cerebral asymmetry: a postmortem study and a proposal concerning the genetic basis of the disease. Arch Gen Psychiatry.
1989;46:1145-1150.
5. Suddath RL, Christison GW, Torrey EF, Casanova MF, Weinberger DR. Anatomical abnormalities in the brains of monozygotic twins discord schizophrenia. N EnglJ Med. 1990;322: 789-794. 6. DeLisi LE, Dauphinais ID, Hauser P. Gender differences in the brain: are they relevant to the
pathogenesis of schizophrenia? Compr Psychiatry. 1989;30:197-208.
In Reply.- Zigun et al have raised several issues concerning our article. Their major concerns appear to be the following: (1) the control group may be atypical; and (2) they take exception to a statement attributed to us that
"given the phenomenological
differ-
in the manifestations of schizophrenia between men and women, the reported gender differences in ventricular enlargement may be due to different types of illness or different etiologic factors." ences
Zigun et al do not accurately sum-
marize the contents or conclusions of our article, since many of the issues raised in their letter were already discussed in the article, while the phenomenology of schizophrenia in re-
lation to gender differences was not discussed at all. An Atypical Control Group-\p=m-\Toour knowledge, this study reports on one of the largest samples of carefully screened healthy normal volunteers that has been studied with computed tomography (CT). The total sample size of the controls was 75. They were
community volunteers, carefully screened with a structured psychiat¬ ric interview, medical history, and neurologic examination before the CT
obtained. In addition, all assessed with a comprehensive neuropsychological battery that in¬ cluded the Wechsler Adult Intelligence Scale-Revised. As discussed in the ar¬ ticle, we were surprised to observe that two of the female subjects, both in their twenties, had VBRs of 11.2 and scans that were interpreted visu¬ ally to be "abnormal" for their ages. However, nothing in their psychiatric or medical history or their neuropsy¬ chological testing suggested that these women were abnormal, so we felt ob¬ ligated to include them. As discussed in the article, however, nothing in the reported results would have changed had we excluded them and two other normal individuals who also had ven¬ tricular size that would usually be con¬ sidered to be outside the normal range. The entire issue of the selection of appropriate control groups has been scan was
were
extensively discussed and debated in the literature.1"5 Early CT studies used "samples of convenience" for their control groups. For example, the ear¬ ly study by Weinberger et al6 used the relatives of patients with Huntington's
disease who had normal CT scans. Others have used controls selected from radiology files who were stud¬ ied for complaints such as headache and whose scans were read as nor¬ mal.1·7"9 As discussed in our article, these strategies run the risk of artifi¬ cially truncating distributions by ex¬ cluding individuals from the control sample whose scans are read as ab¬ normal. This could bias results in a variety of ways, including the risk of producing spurious findings of ven¬ tricular enlargement in patients but not controls. A desire to identify the "truest possible" assessment of the dis¬ tribution of ventricular size in nor¬ mals led us to pursue the strategy of collecting a large sample of healthy normal volunteers who were careful¬ ly screened. If our distributions ap¬ pear to be atypical, it may be because they are being compared with a dif¬ ferent literature—based primarily on postmortem studies (with all the prob¬ lems inherent therein), and samples of convenience. The post hoc f tests mentioned by Zigun et al are not a legitimate way to test
a
hypothesis concerning gender
differences. As we reported before, female and male normal controls have no significant differences in ventric¬ ular size (F[l,145]=2.19, P
