VBR in schizophrenia: relationship to family history of psychosis and season of birth

SCHIZOPHRENIA RESEARCH ELSEVIER

Schizophrenia Research 20 (1996) 275 285

VBR in schizophrenia: relationship to family history of psychosis and season of birth 1 John R. DeQuardo *, Mona Goldman, Rajiv Tandon Schizophrenia Program, University of Michigan Medical Center, 1500 E. Medical Center Dr., Ann Arbor, M148109-0116, USA Received 18 September 1995; revision 6 December 1995; accepted 29 December 1995

Abstract

Ventricular enlargement has been consistently demonstrated in schizophrenia using both CT and MRI. Despite this, the structural changes that underlie increased ventricle-brain ratio (VBR) and its relationship to environmental factors (intrauterine viral exposure, obstetric complications, etc.) and family history of schizophrenia remain poorly defined. Increased VBR has been shown in some studies to correlate with an absence of family history of schizophrenia and with Winter-Spring birth. In an attempt to obtain a clearer picture of the contribution of environmental and genetic factors to VBR, we studied 54 patients with DSM IILR schizophrenia. VBR was determined from head CT scans via computerized planimetry. Family history of psychosis and non-psychotic mood disorder was determined with the family informant method. Season of birth was encoded in several ways, including season, trimester and dichotomously. Patients without a family history of psychosis had significantly larger VBR than patients with such a history; family history of mood disorder was not related to VBR. Season of birth was not predictive of VBR. Family history of psychosis and season of birth were not related to each other. These results are in line with prior work demonstrating an association between increased VBR and sporadic (non-familial) schizophrenia. We did not find a relationship between VBR and season of birth, which suggests that risk of perinatal viral exposure and other seasonal environmental factors may not account for the ventricular enlargement in non-familial schizophrenia observed in our sample.

Keywords: Schizophrenia; Ventricle-brain ratio; Family history; Season

1. Introduction

A variety of investigative strategies have been utilized to understand the neurobiological sub-

* Corresponding author. Tel: + 1 313-936-4860. Presented in part at the Society of Biological Psychiatry Annual Meeting, Miami, 1995, and the 5th International Congress on Schizophrenia Research, Warm Springs, Virginia, 1995. 0920-9964/96/$15.00 © 1996 Elsevier Science B.V. All rights reserved S S D I 0920-9964(95)00003-5

strate of schizophrenic illness. In vivo structural brain imaging began with pneumoencephalography in the 1920s (Jacobi and Winkler, 1927), but the neuroimaging 'golden age' began with the first CT scan study which documented lateral ventricle enlargement in patients with chronic schizophrenia (Johnstone et al., 1976). Since that time dozens of studies, utilizing both CT (Shelton and Weinberger, 1986) and M R I (Coffman and Nasrallah, 1986), have documented lateral yen-

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tricle enlargement, most often by studying the ventricle-brain ratio (VBR). Although increased VBR is one of the most consistently demonstrated neurobiologic abnormalities in schizophrenia, found in up to one-half of patients (Reveley, 1985), its etiology, clinical correlates, and course of development have eluded precise definition. Despite evidence that there exists a strong genetic component to the etiology of schizophrenia, the modes of transmission and environmental modifiers of the genetic predisposition are unclear. In an effort to explain the heterogeneity of the illness and to investigate the role of genetic and environmental risks for schizophrenia, Murray et al. (1985) postulated the familial-sporadic dichotomization of the illness. They suggested that ventricular enlargement was a marker for nongenetic (sporadic) schizophrenia, and indicated a role for environmental risk factors (intrauterine viral exposure, obstetric complications, head trauma, etc.) in the genesis of the disorder. Alternatively, the presence of a strong family history of schizophrenia presumably produced the illness in the absence of significant environmental risks and associated lateral ventricle enlargement. It is very likely that genetic and environmental factors interact, a point that has been cogently elaborated by Cannon et al. (1994), but here again, increased VBR was postulated to occur only in genetically predisposed individuals exposed to pathogenic environmental influences. Efforts to examine the familial-sporadic hypothesis have been undertaken by studying the relationship between VBR and family history of psychotic illness. To date, this design has produced discrepant results, with increased VBR being associated with an absence of family history of schizophrenia (Vita et al., 1994), the presence of a positive family history (Nasrallah et al., 1983), and unrelated to the presence of the illness in the patients' families (Reddy et al., 1990). Numerous methodologic factors have been suggested to explain the discrepancy in this literature, including differences in image analysis technique, family history definition, and diagnostic criteria employed. Despite this lack of clarity, the majority of studies with significant findings have documented an association between

ventricular enlargement and an absence of family history of schizophrenia (see Table 1), suggesting a prominent environmental 'second hit' as being important (and perhaps necessary) in producing the illness in those with less of a genetic vulnerability to developing schizophrenia as reflected by the absence of a family history of schizophrenia. An increase in birth rate of individuals who later develop schizophrenia has been documented to occur in the Winter and early Spring months (Bradbury and Miller, 1985). The connection to the etiology of schizophrenia was thought to reflect exposure to seasonal environmental factors, including perinatal viral exposure, obstetric complications, and nutritional deficiency (Torrey, 1987). If these individuals are at greater environmental risk, the familial-sporadic model would predict an increase in VBR in patients born during this time of year and possibly a decrease in genetic risk (absence of family history of schizophrenia). Several studies have documented an increase in lateral ventricle size and third ventricle size in patients born during Winter and early Spring, although this has not been confirmed in others (see Table 2). Additionally, a relative paucity of family history of schizophrenia in patients born in the Winter-Spring period has been documented by several investigators (Kinney and Jacobsen, 1978; Shur, 1982; Zipursky and Schultz, 1987). Thus, these two lines of research provide converging support for the notion that the genetic and environmental factors underlying the development of schizophrenia exist on separate although intersecting risk spectra, and may in part explain the heterogeneity in the course and clinical manifestations of the illness (Bilder et al., 1988; DeQuardo et al., 1994). It is against this background that the present study was conducted. We sought to investigate the interaction between genetic risk for schizophrenia (as reflected by family history of psychosis) and environmental insults (as indicated by season of birth) in the production of neuroanatomic abnormalities in this illness. Three hypotheses are proposed: (1) ventricular enlargement will be greater in patients without a family history of psychosis; (2) patients born during Winter-Spring months

John R. DeQuardo et al./Schizophrenia Research 20 (1996) 275-285

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Table 1 Review of studies on the relationship between family history and ventricular enlargement Author

Number of pts FHx +

Number of pts F H x -

Definition of family history positive

Findings

Campbell etal., 1979 a

18

17

Tanaka et al., 1981

16

24

1st degree relative with 'major functional psychosis' 'Hereditary factors'

Nasrallah et al., 1983

8

47

1st degree relative hospitalized for schizophrenia

Oxenstierna et al., 1984 b

8

12

1st or 2nd degree relative with 'schizophrenic psychosis'

Reveley et al., 1984

7

14

Boronow et al., 1985 b

?

?

Farmer et al., 1985

8

31

Owens et al., 1985

?

?

1st or 2nd degree relative with 'major psychiatric illness' Psychiatric illness in family member 1st degree relative with schizophrenia Family history of schizophrenia (lst or 2nd degree relationship not stated )

FHx not related to linear measure of ventricular enlargement Linear indices of ventricle enlargement not related to FHx in pts < 50 years Patients with VBR > 2 SD above control mean more likely to be FHx + Greater rating of atrophy (includes linear measures of lateral and 3rd ventricles) in F H x - patients Ventricle volume greater in F H x patients FHx not related to VBR or 3rd ventricle width FHx not related to VBR

Pearlson et al., 1985

6

13

26

25

Williams et al., 1985 b

?

?

Pandurangi et al., 1986

3

17

Turner et al., 1986

?

?

Farmer et al., 1987

6

29

22

25

Romani et al., 1987

8

12

Zipursky and Schultz, 1987

8

24

Nimgaonkar et al., 1988a

6 35

19-48

Reveley and Chitkara, 1985 b

Reveley and Reveley, 1987

Nimgaonkar et al., 1988b

22

29

1st degree relative with schizophrenia 1st or 2nd degree relative with 'major psychiatric illness'

1st degree relative with 'mental disorder' 1st degree relative hospitalized for schizophrenia 1st or 2nd degree relative with schizophrenia 1st degree relative with schizophrenia 1st or 2nd degree relative hospitalized for 'major psychiatric disorder' or had committed suicide 1st degree relative with schizophrenia or hospitalized for depression

Any relative with a diagnosis of or history consistent with schizophrenia Several different definitions used, diagnoses based on Family History RDC 1st or 2nd degree relative with psychosis, diagnosis based on Family History RDC

Pts with VBR above sample mean had greater likelihood of F H x + ; when VBR was stratified there was a significant curvilinear relationship with FHx FHx not related to VBR F H x - pts had VBR larger than controls, F H x + pts did not; F H x - and F H x + pts did not differ on VBR FHx not related to VBR FHx not related to VBR FHx negatively correlated with VBR FHx not related to VBR F H x - patients had significantly greater VBR; more prominent in twins Linear index of ventricular enlargement greater in F H x - patients. 3rd ventricle width not related to FHx FHx not related to VBR or 3rd ventricle-brain ratio FHx not related to VBR

FHx not related to VBR

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John R. DeQuardo et al./Schizophrenia Research 20 (1996) 275-285

Table 1 (continued) Review of studies on the relationship between family history and ventricular enlargement Author

Number of pts FHx +

Number of pts F H x -

Definition of family history positive

Cazzullo et al., 1989

20

137

1st degree schizophrenia

Kaiya et al., 1989

35

36

Owen et al., 1989b

23

48

Andreasen et al., 1990

?

Reddy et al., 1990

10

22

Schwarzkopf et al., 1991

16

15

Waddington et al., 1992

?

9

Wilms et al., 1992

?

?

Jones et al., 1994b

24

138

Roy et al., 1994b

22

29

Vita et al., 1994

31

198

O'Callaghan et al., 1995

10

33

Vita and Sacchetti, 1995

?

9

?

relative

Findings

with

DSM llI schizophrenia in family member 1st degree relative with schizophrenia, diagnosis based on Family History RDC Family history of schizophrenia based on Family History RDC (1st or 2nd degree relationship not stated) 1st or 2nd degree relative with a diagnosis of schizophrenia; based on DSM III-R best-estimate diagnosis 1st or 2nd degree relative hospitalized for affective disorder or schizophrenia; diagnoses based on Family History RDC Any relative with a diagnosis of schizophrenia 1st degree relative with psychotic or affective disorder Family history of schizophrenia or schizoaffective disorder based on Family History RDC (1 st or 2nd degree relationship not stated) 1st degree relative with schizophrenia, diagnosis based on Family History RDC 1st degree relative with schizophrenia 1st degree relative with schizophrenia, diagnosis based on Family History RDC 1st degree relative with schizophrenia

F H x - patients had trend toward higher ratings of 'diffuse atrophy' (combined VBR and cortical atrophy) FHx not related to VBR or 3rd ventricle brain ratio F H x + and F H x - pts had VBR greater than controls, but did not differ from each other FHx not related to VBR

FHx not related to VBR

F H x - pts had higher ratings of lateral ventricle enlargement; FHx not related to ratings of 3rd ventricle enlargement FHx not related to ventricle volume FHx not related to VBR Trend for F H x - pts to have larger total lateral ventricle volume and larger maximum 3rd ventricle area FHx not volume

related

to

ventricle

VBR greater in F H x - male patients only FHx not related to ventricle volume Trend for F H x larger VBR

pts to have

aDiagnostic criteria for patient inclusion not specified. bPatients with schizoaffective disorder and/or other psychoses also included.

will m a n i f e s t g r e a t e r v e n t r i c u l a r e n l a r g e m e n t t h a n t h o s e b o r n d u r i n g o t h e r p a r t s o f t h e year; a n d (3) p a t i e n t s b o r n d u r i n g the W i n t e r - S p r i n g p e r i o d will h a v e a l o w e r i n c i d e n c e o f f a m i l y h i s t o r y o f psychosis.

2. Methods F i f t y - f o u r i n p a t i e n t s a d m i t t e d to t h e U n i v e r s i t y of Michigan Schizophrenia Program for evaluation and treatment of an acute psychotic episode patti-

John R. DeQuardo et al./Schizophrenia Research 20 (1996) 275-285

279

Table 2 Review of studies on the relationship between season of birth and ventricularenlargement Author

N

Zipursky and Schultz, 1987

32 Trimesters,with year starting in Dec. and in Jan. 30 Winterbirth: Jan.-Mar.: non-winter birth: Aug.-Oct. 42 Winter birth: Dec. Mar. vs. remainder of year 206 Winter birth: Dec.-Apr. vs. remainder of year 42 Winter: Jan. Mar.; Spring: Apr.-June; Summer: Jul~Sept.; Fall: Oct. Dec.

Degreefet al., 1988 Wilms et al.. 1992 Sacchetti et al., 1992 d'Amato et al., 1994

Definitionof season of birth

cipated in this study. Each individual gave informed consent to participate in the research protocol. Demographic data from interviews with the patient and family, and from medical records, included age, gender, education, age of first hospitalization, duration of illness, and history of substance abuse. Patients were evaluated by a faculty psychiatrist who utilized patient and family interviews, results of structured interviews (SADS; Endicott and Spitzer, 1978), social work history and all available records to determine diagnosis; each patient met both DSM III-R (American Psychiatric Association, 1987) and RDC (Spitzer et al., 1978) criteria for schizophrenia. All patients were free of medical and neurological disease (based on screening history, physical exam and laboratory assessment), history of corticosteroid treatment, recent substance abuse, and treatment with electroconvulsive therapy. Patients were nutritionally intact and well hydrated throughout the course of the study. Each person was assessed globally and in terms of positive symptoms (total of hallucinatory behavior, unusual thought content, suspiciousness, and conceptual disorganization items) via the Brief Psychiatric Rating Scale (BPRS) (Overall and Gotham, 1962) and in terms of negative symptoms via the Scale for Assessment of Negative Symptoms (SANS) sum of global scores (Andreasen, 1983). Ratings were carried out at baseline (at least two weeks medicationfree) and after four weeks of clinically determined antipsychotic medication treatment, by a psychiatrist who was blind to neuropsychological test results, family history, and head CT scan data.

Findings Winter Spring birth associated with increased VBR VBR not related to season of birth VBR not related to season of birth Ventricle enlargement more common in Winterborn pts 3rd ventricle width greater in Winter-born pts; VBR not related to season of birth

Head CT scans were performed on each patient (GE 9800 scanner, G E Medical Systems, Milwaukee, WI), with a matrix size of 512 by 512 and slice thickness of 10ram. Lateral ventricle brain ratio (LVBR) and third ventricle-brain ratio (3VBR) were measured on the cut that demonstrated these structures at their largest. Measurements were performed by digitizing the films using computer-based video image acquisition software and displaying them on a computer monitor. The program used to calculate area ('Image' software program, developed at NIMH, Bethesda, MD) allows the operator to magnify the image size and enhance contrast selectively. Lateral and third ventricle areas were hand-traced using the computer mouse, and two measurements were performed on each cut, the mean of which was used for analysis. Total brain area was measured by maximizing the image contrast between brain and bone, and having the computer determine the area of the non-bone structures within the skull; this measurement was exclusively computerdetermined. LVBR and 3VBR were calculated by dividing the ventricle area by the total brain area for each slice. This procedure produced measures of maximum LVBR and 3VBR which were used in subsequent statistical analyses. The investigator measuring LVBR and 3VBR was blind to clinical ratings, family history, and neuropsychological test data. Family history of psychosis ( F H P ) and nonpsychotic mood disorder ( F H M ) were determined via the family informant method (Andreasen et al., 1986) from interviews with patients and family

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members and by a review of the medical and research records. Patients were classified FHP + if they had a first degree relative with a psychotic disorder and F H P - if there were no such family members ( F H P + , n=12; F H P - , n=41). Individuals were designated F H M + if at least one first degree relative had a history of mood disorder (unipolar or bipolar) or had committed suicide, and F H M - if there were no first degree family members with a history of mood disorder ( F H M + , n=14; F H M - , n=39). One patient's family history was unknown as this person was adopted. Winter-Spring season of birth has been defined in several ways in studies investigating seasonal effects on neuroanatomy (see Table 2). We chose to define season of birth using three different strategies: Winter-Spring birth versus the remainder of the year; trimesters; and seasons of the year. Winter-Spring birth was categorized as including patients born December through March (Wilms et al., 1992) and December through April (Sacchetti et al., 1992); these individuals were compared to patients born during the remainder of the year (e.g., non-Winter birth). Similar to Zipursky and Schultz (1987), patients were divided by trimesters based on month of birth (January through April, May through August, and September through December). Lastly, patients were divided based on season (d'Amato et al., 1994): Winter - January through March, Spring April through June, Summer - July through September, and Fall - October through November. The use of multiple definitions of Winter-Spring birth will enable us to assess several seasonal effects on neuroanatomy and potential interactions with genetic risk, and will allow us to discuss the discrepancies present in the literature investigating these relationships. Premorbid intellectual functioning and deterioration were estimated using the formulas developed by Bilder et al. (1988) which are based on the assumption that some WAIS-R subscales are sensitive to organic disease ('don't hold' tests) and others are relatively insensitive ('hold' tests). Information and Vocabulary are two subscales identified as 'hold' subscales by Wechsler (1958); the Digit Symbol subscale was chosen as the 'don't

hold' subscale as it has been shown to be sensitive to cognitive impairment from a number of causes (McFie, 1975; Bilder, 1985). Premorbid intellectual ability was measured as the mean of the agecorrected Vocabulary and Information subscales; intellectual deterioration was calculated as the premorbid score minus the age-corrected Digit Symbol subscale score. Statistical analyses included Spearman's Rankorder correlations and Mann-Whitney U and Kruskal Wallis tests of CT data with clinical, demographic, family history and season of birth data. These non-parametric statistics were used because the distribution of the CT scan data was non-normal. One-way ANOVA was used to assess relationships between season of birth and clinical and demographic data, and the X2 statistic to investigate relationships between season of birth and family history.

3. Results

The neuroanatomic, clinical, and demographic data for the entire sample is presented in Table 3. LVBR was significantly greater in patients with a family history that was negative for psychosis (Z = 2.40, p<0.02), no difference between 3VBR and family history status was found (see Fig. 1). Family history of mood disorder was not related to the neuroanatomic data. Patients with a family history positive for psychosis had lower negative symptom ratings at baseline (t=2.71, p<0.01) and after treatment (t=2.40, p <0.02) than patients with a negative family history; no other symptom assessments or demographic variable differed between these groups. Family history of mood disorder was not associated with symptom or demographic data. Season of birth, no matter how it was defined, was not associated with LVBR or 3VBR, or family history status. Timing of birth was also unrelated to clinical and demographic variables. Twenty-four of the 54 subjects in this study (44%) had comprehensive neuropsychological testing performed as part of their in-patient assessment, and thus premorbid cognitive ability and deterioration could be estimated in these individuals. Patients with a negative family history for

John R. DeQuardo et al./Schizophrenia Research 20 (1996) 275-285 Table 3 Demographic, clinical, and neuroanatomic characteristics of the sample Variable

N

Mean _ SD

Range

LVBR 3VBR Age (years) Age 1st hospitalization Gender

54 54 54 54

0.01 0.15 0.001 0.009 17-67 15-47

Education (years) Pretreatment BPRS (1-7, 18 item) Pretreatment positive Sx Pretreatment SANS Post-treatment BPRS Post-treatment positive Sx Post-treatment SANS FSIQ VIQ PIQ Premorbid scale Deterioration scale Family history - psychosis

54 54

0.08+_0.03 0.004+0.002 29.3+-9.8 25.4 +-7.6 M = 38 (69%) F = 1 6 (31%) 12.6+-2.5 48.0+8.5 15.1+ 3.1 12.6+4.3 35.2+6.8 9.5+2.8 8.6+ 3.6 85.6_+17.2 88.2+-17.4 84.5+16.2 8.7+3.6 2.2+2.4 + = 12 (23%) - = 4 1 (77%) + = 15 (28%)

7-24 3-20 22-58 4-18 1-19 54-130 59-127 52-123 3.5-17 0-8.5

Family history

54 54 54 54 54 24 24 24 24 24

mood

7-22 28-72

- = 3 8 (72%)

psychosis demonstrated a trend toward better premorbid cognitive ability (t = 1.73, p < 0.10); they also had greater deterioration but this did not reach statistical significance. We have previously shown (DeQuardo et al., 1994) that premorbid ability and deterioration are associated with ventricular enlargement in schizophrenia. Premorbid cognitive ability and deterioration were not related to family history of mood disorder or season of birth. Patients who had this information available had significantly lower ratings of positive syrup,1fi o

14 : o .I

-7

.e4. O

O

FH.POS Fig. 1.

FH.NEG

281

toms (t = 2.15, p < 0.04), global psychopathology (t=2.76, p<0.01) and negative symptoms (t= 4.08, p<0.001) at baseline and lower negative symptoms (t = 2.44, p < 0.02) after treatment than those who did not complete neuropsychological testing. They also had significantly less change in positive symptoms (t = 2.18, p < 0.04), global psychopathology (t-2.20, p<0.04) and negative symptoms (t = 2.45, p < 0.02) with treatment than those who did not complete testing. There were no differences in LVBR, 3VBR, family history, season of birth, and demographic variables between those with and without available neuropsychological data.

4. D i s c u s s i o n

Of the three hypotheses stated at the outset, only one was confirmed: patients with a family history negative for psychosis had greater ventricular enlargement than those with a positive family history. Season of birth, no matter how it was operationalized, was not related to ventricle size or family history. The finding of a positive relationship between ventricular enlargement and absence of a family history of psychosis is consistent with the majority of prior studies that have produced significant findings. As can be seen in Table 1, of the 32 studies reported in the literature that have examined family history of schizophrenia (or other psychiatric illness) 12 have produced significant findings, all but one of which has found an association between absence of family history of schizophrenia (or other psychiatric illness) and ventricular enlargement. This body of work has been very difficult to interpret, however, in large part due to the marked variability in study design and criteria used to define the presence or absence of family history. Our finding of a significant association between negative family history of psychosis and increased LVBR and an absence of a relationship between LVBR and family history of mood disorder suggests that environmental factors are more important in the etiology of schizophrenia in patients with lesser genetic loading for the illness. Also, the relationship between genetic risk and neuro-

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John R. DeQuardo et al./Schizophrenia Research 20 (1996) 275~85

anatomic abnormality is limited to genetic risk for psychosis and not psychiatric illness in general. Our finding supports the suggestion of Murray et al. (1985) that environmental factors are more important in the etiology of schizophrenia in the setting of an absence of a positive family history and are also consistent with recent findings in high risk studies suggesting an interaction between genetic loading for schizophrenia and environmental influences in the production of lateral ventricular enlargement (Cannon et al., 1994). This is not to say that these are mutually exclusive factors; it is highly likely that there is an interaction between environmental insults (e.g., intrauterine viral infection, obstetric complications, etc.) and genetic risk present in the majority of patients with schizophrenia. The absence of an association between season of birth and LVBR and between season of birth and family history suggests that seasonal factors are not vital in mediating the interaction between genetic loading for schizophrenia and ventricular enlargement. A viral component in the genesis of schizophrenia is certainly not rendered untenable by this finding, but may be masked by other nonseasonal factors operating in this sample (e.g., poor childhood nutrition). Furthermore, the season of birth definitions used in this study only take into account an individual's risk of being exposed to viral infection (i.e. being born during months in which viral illness is more likely) and not the more clearly documented risk of maternal viral exposure during the second trimester of gestation. Both of these types of viral risk exposure may be relevant ,to the etiology of schizophrenia but may have different implications for brain anatomy and development. :The relatively small sample size may have resulted in lack of sufficient power to detect a relationship between LVBR and season of birth. Contrary to our third hypothesis,' we did not find a relationship between family history of schizophrenia and season of birth. This suggests that Winter-Spring season of birth-associated risks are not the primary environmental etiologic factors involved in the development of schizophrenia. Other, non-seasonal factors, such as obstetric complications or intrauterine viral exposure may be

important risk factors for patients with a lower genetic loading for schizophrenia. This interpretation is consistent with and supported by our finding of an absence of relationship between season of birth and LVBR. A relationship between a family history of schizophrenia and lesser negative symptoms both before and after four weeks of antipsychotic treatment was found in the present study. On the surface this suggests that negative symptoms are associated with greater exposure to environmental risk factors than with genetic risk, and runs counter to previous work suggesting that negative symptoms (if one sees negative symptoms as evidence of more severe psychopathology) have a significant heritable component (McGuffin et al., 1987). It should be noted, however, that negative symptoms are heterogeneous and the various components of negative symptoms have different developmental trajectories (Mukherjee et al., 1991; Tandon et al., 1995). A trend-level association was found between estimated premorbid cognitive functioning and an absence of family history of schizophrenia; this finding may help to expand our previously stated hypothesis regarding the relationship between ventricular enlargement and premorbid functioning in schizophrenia (DeQuardo et al., 1994). We suggest that there are (at least) two developmental trajectories in schizophrenia: (1) poor premorbid ability associated with an absence of ventricular enlargement and functional decline; and (2) relatively normal premorbid ability associated with ventricular enlargement and significant functional decline during the course of the illness. Linking the results of these two studies, patients with a greater genetic loading for schizophrenia may be those individuals who demonstrate poorer premorbid ability, earlier disease onset, less functional decline and normal LVBR; whereas patients with a presumably greater environmental component to the etiology of their illness are those who demonstrate better premorbid functioning, significant functional decline and increased LVBR. The fact that neuropsychological test data was available in only 44% of our sample, and that those individuals for whom this data was missing were significantly more symptomatic than those for whom it was available, limits the certainty

John IL DeQuardo et al./Schizophrenia Research 20 (1996) 275-285

of this interpretation. However, this is a potentially important finding that helps tie together genetic, environmental, developmental and neuroanatomic data, and clearly warrants further investigation. The present study has a number of shortcomings, in addition to those mentioned above, that may limit the generalizability of these results. The family informant method used to gather data on the incidence of psychosis and mood disorders in the families of patients enrolled in the study is potentially prone to misclassification error. Such misclassification would attenuate any relationships studied involving family history and therefore reduce the power to detect associations. The ideal method to quantify family history involves structured interviews of all family members with a anchored diagnostic instrument, such as the Structured Clinical Interview for DSM III-R (Spitzer et al., 1988), and controlling for the number of family members and period of risk these individuals have passed through before determining degree of genetic risk. However, this method is very costly and labor intensive, thus the vast majority of studies investigating the family history of schizophrenia have utilized methods similar to ours. The use of LVBR to quantify neuroanatomic abnormality is suboptimal, it allows one to conclude that there is some pathological process involving the brain but does not allow conclusions regarding location, course and amount of pathological involvement. Additionally, relatively small sample size and cross-sectional symptom assessment further limits the certainty with which our conclusions can be stated. In summary, we found a significant relationship between an absence of family history of psychosis and ventricular enlargement in a sample of patients assessed in a university-based schizophrenia program. This, coupled with an absence of correlation between season of birth and LVBR, suggests that non-seasonal environmental factors are important to the etiology of schizophrenia in patients demonstrating lateral ventricle enlargement. The familial-non-familial dichotomization of schizophrenia is not an all or nothing proposition, genetic and environmental risk factors are both clearly involved in the vast majority of patients suffering from schizophrenia. How these categories of risk

283

factors interact to influence neuroanatomy, phenomenology, course, and outcome are vital to our efforts to understand and treat the illness.

Acknowledgment Supported in part by grants to Dr. Rajiv Tandon from ADAMHA (MH 19634), the National Alliance for Research in Schizophrenia and Depression, Chicago, Ill, and the Scottish Rite Schizophrenia Research Program, Lexington, Mass.

References American Psychiatric Association (1987) Diagnostic and Statistical Manual of Mental Disorders (3rd edn., revised) (DSM Ill-R). American Psychiatric Association, Washington, DC. Andreasen, N.C. (1983) Scale for the Assessment of Negative Symptoms (SANS). The University of Iowa, Iowa City. Andreasen, N.C., Rice, J., Endicott, J., Reich, T. and Coryell, W. (1986) The family history approach to diagnosis. How useful is it? Arch. Gen. Psychiatry 43, 421-429. Andreasen, N.C., Swayze, V.W., Flaum, M., Yates, W.R., Arndt, S. and McChesney, C. (1990) Ventricular enlargement in schizophrenia evaluated with computed tomographic scanning. Effects of gender, age, and stage of illness. Arch. Gen. Psychiatry 47, 1008-1015. Bilder, R.M. (1985) Subtyping in Chronic Schizophrenia: Clinical, Neuropsychological, and Structural Indices of Deterioration. University Microfilms, Ann Arbor. Bilder, R.M., Degreef, G., Pandurangi, A.K., Reider, R.O., Sackeim, H.A. and Mukherjee, S. (1988)Neuropsychological deterioration and CT scan findings in chronic schizophrenia. Schizophr. Res. 1, 37 45. Boronow, J., Pickar, D., Ninan, P.T., Roy, A., Hommer, D., Linnoila, M. and Paul, S.M. (1985) Atrophy limited to the third ventricle in chronic schizophrenic patients. Report of a controlled series. Arch. Gen. Psychiatry 42, 266-27l. Bradbury, T.N. and Miller, G.A. (1985) Season of birth in schizophrenia: a review of evidence, methodology and etiology. Psychol. Bull. 98, 569-594. Campbell, R.; Hays, P., Russell, D.B. and Zacks, D.J. (1979) CT scan variants and genetic heterogeneity in schizophrenia. Am. J. Psychiatry 136, 722--723. Cannon, T.D., Mednick, S.A., Parnus, J., Schulsinger, F., Praestholm, J. and Vestergaard, A. (1994) Developmental brain abnormalities in the offspring of schizophrenic mothers 11. Structural brain characteristics of schizophrenia and schizotypal personality disorder. Arch. Gen. Psychiatry 51, 955-962.

284

John 1~ DeQuardo et al./Schizophrenia Research 20 (1996) 275-285

Cazzullo, C.L., Vita, A., Sacchetti, E., Dieci, M., Giobbio, M. and Valvassori, G. (1989) Brain morphology in schizophrenic disorder: prevalence and correlates of diffuse (cortical and subcortical) brain atrophy. Psychiatr. Res. 29, 257-259. Coffman, J.A. and Nasrallah, H.A. (1986) Magnetic resonance brain imaging in schizophrenia. In: Nasrallah, H.A. (Series ed.) Handbook of Schizophrenia, Vol. 1: Nasrallah, H.A. and Weinberger, D.R. (eds) The Neurology of Schizophrenia. Elsevier Medical Publishing, Amsterdam, pp. 251-266. d'Amato, T., Rochet, T., Dalery, J., Chauchat, J.H., Martin, J.P. and Marie-Cardine, M. (1994) Seasonality of birth and ventricular enlargement in chronic schizophrenia. Psychiatry Res. Neuroimaging 55, 65-73. Degreef, G., Mukherjee, S., Gilder, R. and Schnur, D. (1988) Season of birth and CT scan findings in schizophrenic patients. Biol. Psychiatry 24, 461-464. DeQuardo, J.R., Tandon, R., Goldman, R., Meador-Woodnuff, J.H., McGrath-Giroux, M., Brunberg, J.A. and Kim, L. (1994) Ventricular enlargement, neuropsychological status, and premorbid function in schizophrenia. Biol. Psychiatry 35, 517 524. Endicott, J. and Spitzer, R.L. (1978) A diagnostic interview: the Schedule for Affective Disorders and Schizophrenia (SADS). Arch. Gen. Psychiatry 35, 837-844. Farmer, A., McGuffin, P., Jackson, R. and Storey, P. (1985) Classifying schizophrenia. Lancet i, 1333. Farmer, A., Jackson, R., McGuffin, P. and Storey, P. (1987) Cerebral ventricular enlargement in chronic schizophrenia: consistencies and contradictions. Br. J. Psychiatry 150, 324-330. Jacobi, W. and Winkler, H. (1927) Encephalographische studier an chronisch schizophrenen. Arch. Psychiatr. Nervenkr. 84, 208-226. Johnstone, E.C., Crow, T.J., Frith, C.D., Husband, J. and Kreel, L. (1976) Cerebral ventricular size and cognitive impairment in chronic schizophrenia. Lancet ii, 924-926. Jones, P.B., Harvey, I., Lewis, S.W., Toone, B.K., Van Os, J., Williams, M. and Murray, R.M. (1994) Cerebral ventricle dimensions as risk factors for schizophrenia and affective psychosis: an epidemiological approach to analysis. Psychol. Med. 24, 995-1011. Kaiya, H., Uematsu, M., Ofuji, M., Nishida, A., Morikiyo, M. and Adachi S. (1989) Computerised tomography in schizophrenia. Familial versus non-familial forms of illness. Br. J. Psychiatry 155, 444-450. Kinney, D.K. and Jacobsen, B. (1978) Environmental factors in schizophrenia; new adoption study evidence. In: Wynn, L.C., Cromwell, R.L. and Mattysse, S. (eds) The Nature of Schizophrenia: New Approaches to Research and Treatment. John Wiley and Sons, New York, pp. 38-51. McFie, J. (1975) Assessment of Organic Intellectual Impairment. Academic Press, New York. McGuffin, P., Farmer, A. and Gottesman, 1.1. (1987) Is there really a split in schizophrenia. The genetic evidence. Br. J. Psychiatry 150, 581-592. Mukherjee, S., Reddy, R. and Schnur, D.B. (1991) A developmental model of negative syndromes in schizophrenia. In:

Tandon, R. and Greden, J.F. (eds) Negative Schizophrenic Symptoms: Pathophysiology and Clinical Implications. American Psychiatric Press, Washington, DC, pp. 173-185. Murray, R.M., Lewis, S.W. and Reveley, A.M. (1985) Towards an aetiological classification of schizophrenia. Lancet i, 1023-1026. Nasrallah, H.A., Kuperman, S., Hamra, B.J. and McCalleyWhitters, M. (1983) Clinical differences between schizophrenic patients with and without large cerebral ventricles. J. Clin. Psychiatry 44, 407-409. Nimgaonkar, V.L., Wessely, S., Tune, L.E. and Murray, R.M. (1988a) Response to drugs in schizophrenia: the influence of family history, obstetric complications and ventricular enlargement. Psychol. Med. 18, 583-592. Nimgaonkar, V.L., Wessely, S. and Murray, R.M. (1988b) Prevalence of familiality, obstetric complications, and structural brain damage in schizophrenic patients. Br. J. Psychiatry 153, 191-197. O'Callaghan, E.O., Buckley, P., Madigan, C., Redmond, O., Stack, J.P., Kinsella, A., Larkin, C., Ennis, J.T. and Waddington, J.L. (1995) The relationship of minor physical anomalies and other putative indices of developmental disturbance in schizophrenia to abnormalities of cerebral structure on magnetic resonance imaging. Biol. Psychiatry 38, 516-524. Overall, J.E. and Gotham, D.R. (1962) The brief psychiatric rating scale. Psychol. Rep. 10, 799-812. Owen, M.J., Lewis, S.W. and Murray, R.M. (1989) Family history and cerebral ventricular enlargement in schizophrenia. A case control study. Br. J. Psychiatry 154, 629-634. Owens, D.G.C., Johnstone, E.C., Crow, T.J., Frith, C.D., Jagoe, J.R. and Kreel, L. (1985) Lateral ventricular size in schizophrenia: relationship to the disease process and its clinical manifestations. Psychol. Med. 15, 27-41. Oxenstierna, G., Bergstrand, G., Bjerkenstedt, L., Sedvall, G. and Wik, G. (1984) Evidence of disturbed CSF circulation and brain atrophy in cases of schizophrenic psychosis. Br. J. Psychiatry 144, 654-661. Pandurangi, A.K., Dewan, M.J., Boucher, M., Levy, B., Ramachandran, T., Bartell, K., Bick, P.A., Phelps, B.H. and Major, L. (1986) A comprehensive study of chronic schizophrenic patients II: Biological, neuropsychological, and clinical correlates of CT abnormality. Acta Psychiatr. Scand. 73, 161-171. Pearlson, G.D., Garbacz, D.J., Moberg, P.J., Ahn, H.S. and DePaulo, J.R. (1985) Symptomatic, familial, perinatal, and social correlates of computerized axial tomography (CAT) changes in schizophrenics and bipolars. J. Nervous Mental Dis. 173, 42-50. Reddy, R., Mukherjee, S., Schnur, D.B., Chin, J. and Gedreef, G. (1990) History of obstetric complications, family history, and CT scan findings in schizophrenic patients. Schizophr. Res. 3, 311-314. Reveley, M.A. (1985) CT scans in schizophrenia. Br. J. Psychiatry 146, 367-371. Reveley, A.M., Reveley, M.A. and Murray, R.M. (1984) Cerebral ventricular enlargement in non-genetic schizophrenia: a controlled twin study. Br. J. Psychiatry 144, 89-93.

John P~ DeQuardo et al./Schizophrenia Research 20 (1996) 275-285

Reveley, M.A. and Chitkara, B. (1985) Subgroups in schizophrenia. Lancet i, 1503. Reveley, A.M. and Reveley, M.A. (1987) The relationship of twinning to the familial-sporadic distinction in schizophrenia. J. Psychiatr. Res. 21,515-520. Romani, A., Merello, S., Gozzoli, L., Zerbi, F., Grassi, M. and Cosi, V. (1987) P300 and CT scan in patients with chronic schizophrenia. Br. J. Psychiatry 151,506-513. Roy, M.A., Flaum, M.A., Arndt, S.V., Crowe, R.R. and Andreasen, N.C. (1994) Magnetic resonance imaging in familial versus sporadic cases of schizophrenia. Psychiatry Res. 54, 25-36. Sacchetti, E., Calzeroni, A., Vita, A., Terzi, A., Pollastro, F. and Cazzullo, C.L. (1992) The brain damage hypothesis of the seasonality of births in schizophrenia and major affective disorders: evidence from computerised Tomography. Br. J. Psychiatry 160, 390-397. Schwarzkopf, S.B., Nasrallah, H.A., Olson, S.C., Bogerts, B., McLaughlin, J.A. and Mitra, T. (1991) Family history and brain morphology in schizophrenia: an MRI study. Psychiatry Res. 40, 49 60. Shelton, R.C. and Weinberger, D.R. (1986) X-ray computerized tomography studies in schizophrenia: a review and synthesis. In: Nasrallah, H.A. (Series ed.) Handbook of Schizophrenia, Vol. 1: Nasrallah, H.A. and Weinberger, D.R. (eds) The Neurology of Schizophrenia. Elsevier Medical Publishing, Amsterdam, pp. 207-250. Shut, E. (1982) Season of birth in high and low genetic risk schizophrenics. Br. J. Psychiatry 140, 410-415. Spitzer, R.L., Endicott, J. and Robins, M. (1978) Research diagnostic criteria: rationale and reliability. Arch. Gen. Psychiatry 35, 773-782. Spitzer, R.L., Williams, J.B.W., Gibbon, M. and First, M.D. (1988) Structured Clinical Interview for DSM III-R - Patient Version (SCID-P). Biometric Research Department, New York State Psychiatric Institute, New York. Tanaka, Y., Hazama, R., Kawahara, R. and Kobayashi, K. ( 1981 ) Computerized tomography of the brain in schizophrenic patients. A controlled study. Acta Psychiatr. Scand. 63, 191-197.

285

Tandon, R., Jibson, M.D., Taylor, S.F. and DeQuardo, J.R. (1995) Conceptual models of the relationship between positive and negative symptoms: implications for pathophysiology and treatment. In: Shriqui, C. and Nasrallah, H.A. (eds) Contemporary Issues in the Treatment of Schizophrenia. American Psychiatric Press, Washington, DC, pp. 109-124. Torrey, E.F, (1987) Hypotheses on the seasonality of schizophrenic births. In: Cazzullo, C.L., Invernizzi, G. and Sacchetti, E. (eds) Etiopathogenic Hypotheses of Schizophrenia: The Impact of Epidemiological, Biochemical and Neuromorphological Studies. MPT Press, Lancaster~ pp. 41-48. Turner, S.W., Toone, B.K. and Brett-Jones, J.R. (1986) Computerized tomographic scan changes in early schizophrenia - preliminary findings. Psychol. Med. 16, 219-225. Vita, A., Dieci, M., Giobbio, G.M., Garbarini, M., Morganti, C., Braga, M. and lnvernizzi, G. (1994) A reconsideration of the relationship between cerebral structural abnormalities and family history of schizophrenia. Psychiatry Res. 53, 41-55. Vita, A. and Sacchetti, E. (1995) Developmental brain abnormalities in schizophrenia: contributions of genetic and perinatal factors. Arch. Gen. Psychiatry 52, 157. Waddington, J.L., O'Callaghan, E., Buckley, P., Larkin, C., Redmond, O., Stack, J. and Ennis, J.T. (1992) MR imaging and spectroscopy in schizophrenia in relation to the neurodevelopmental hypothesis. Clin. Neuropharmacol. 118A-119A. Wechsler, D. (1958) The Measurement and Appraisal of Adult Intelligence, 4th edn. Williams and Wilkins, Baltimore. Williams, A.O., Reveley, M.A., Kolakowska, T., Ardern, M. and Mandelbrote, B.M. (1985) Schizophrenia with good and poor outcome II: Cerebral ventricular size and its clinical significance. Br. J. Psychiatry 146, 239-246. Wilms, G., Ongeval, C., Baert, A.L., Claus, A., Bollen, J., De Cuyper, H., Eneman, M., Malfroid, M., Peuskens, J. and Heylen, S. (1992) Ventricular enlargement, clinical correlates and treatment outcome in chronic schizophrenic inpatients. Acta Psychiatr. Scand. 85, 306-312. Zipursky, R.B. and Schultz, C. (1987) Seasonality of birth and CT findings in schizophrenia. Biol. Psychiatry 22, 1288-1292.