Meta-analysis of symptom factors in schizophrenia

SCHIZOPHRENIA RESEARCH ELSEVIER

Schizophrenia Research 31 (1998) 113 120

Meta-analysis of symptom factors in schizophrenia Bret S. Grube a,b,c, Robert M. Bilder b,d,e,,, Robert S. G o l d m a n b a Queens Ho,spital Center, Department o f Psychiatry, Division o f Psychology, 82-68 164th Street, Jamaica, New York, NYl1432, USA b Psvehiat O, Research, Hillside Hospital Division o f Long Island Jewish Medical Center, 75-59 263rd Street, Glen Oaks, New York, N Y l lO04, USA Saint John's UniversiO', Department o f Psychology, 8000 Utopia Parkway, Jamaica, New York, N Y 11439, USA a Nathan S. KIhw InstituteJbr Psychiatric Research, 140 Old Orangeburg Road, Orangeburg, New York, NY10962. USA D¢Tmrtment (4f Ps)'chiato~, Albert Einstein College o f Medicine, 1300 Morris Park Avenue, Bronx, New York, NY10461, USA

Received 20 August 1997; accepted 5 December 1997

Abstract

Factor and correlational analyses have been used to characterize symptom dimensions in schizophrenia, though they have yielded divergent models. This study used meta-analysis of published work to determine the number and composition of symptom dimensions. Principal components analysis of data from 10 empirical studies (pooled n= 896) yielded three factors, "positive', 'negative' and 'conceptual disorganization'. The findings suggest that a threefactor solution is a relatively stable outcome of studies assessing these symptoms in chronic patients, and that some symptoms (alogia, attentional impairment) are less likely to load uniquely on a single factor. © 1998 Elsevier Science B.V. All rights reserved. K~:vwords. Meta-analysis; Symptoms of schizophrenia

I. Introduction

Schizophrenia is a syndrome characterized by heterogeneous s y m p t o m presentations (Strauss et al., 1974). Ever since Crow's (Crow, 1980) Type l/Type II model helped to popularize the positive and negative symptom distinction, investigators have used multivariate statistical techniques, such as factor analysis, in attempts to distinguish more * Corresponding author. Present address: Psychiatry Research, Hillside Hospital, 75-59 263rd Street, Glen Oaks. New York, NY 11004, USA. Tel: (718) 470-8173: Fax: (718) 343-1659: e-maih [email protected] 0920-9964/98/$19.00 !~')1998 Elsevier Science B.V. All rights reserved. PII: S0920-9964(98)00011-5

homogeneous symptom dimensions. Andreasen and Olsen (1982) first used principal components factor analysis (PCA) to explore symptom dimensions, and found support for the positive negative distinction in symptoms of schizophrenia. Other investigators found that the positive and negative dimensions may not best account for the heterogeneity of symptom presentation. Most investigators have found three relatively homogeneous factors or clusters, which represent three independent symptom dimensions in schizophrenia (e.g., Andreasen et al., 1995; Arndt et al., 1991, 1995; Bell et al., 1994; Bilder et al., 1985; Brekke et al., 1994; G u r et al., 1991; Kulhara and

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Chandiramani, 1990; Kulhara et al., 1986; Liddle, 1987; Liddle and Barnes, 1990; Malla et al., 1993; Miller et al., 1993; Minas et al., 1992; Silver et al., 1993; Thompson and Meltzer, 1993). There is a substantial convergence of results across these studies, even though they used samples with divergent subject characteristics and different methods of data analysis. There has been controversy over the number of factors, however, and especially over the symptom loadings on the factors. Some investigators have found four factors, with different symptom-loading patterns (e.g., Andreasen and Grove, 1986; Andreasen and Olsen, 1982; Peralta et al., 1992, 1994; Shtasel et al., 1992). Even in studies with three-factor findings, some symptoms consistently loaded on the same factor (e.g., hallucinations and delusions on 'positive', affective flattening and avolition on 'negative'), while other symptoms varied with respect to the factor on which they loaded (e.g., alogia, attentional impairment sometimes on negative, sometimes on 'conceptual disorganization'). Although some of these differences may be due to the item content of the scales used to measure symptoms, much of the variability may reflect measurement error due to small sample sizes relative to the number of symptom variables examined. To address this problem, we conducted a metaanalysis of correlational and factor-analytic studies of symptoms in schizophrenia. Meta-analysis is typically used to combine results of a series of studies by computing a mean size of effect across studies (Rosenthal, 1991), and has the advantage of incorporating data from multiple studies, thereby increasing the total number and diversity of subjects included in the analysis. These assets have led to meta-analysis being used increasingly as a means of resolving differences in findings across individual studies, although it has seldom been used with factoranalytic studies. The goal of the current study was to metaanalyze existing empirical studies of symptoms in schizophrenia, and to generate a single model best characterizing the dimensionality of symptoms. We chose PCA over confirmatory factor analysis (CFA) because our goal was to provide an empiri-

cal description of the relationships among symptoms, not to compare the adequacy of fit of competing theoretical models or to confirm a particular model as in CFA. We pooled data from studies of symptoms in schizophrenia and performed PCA of these data. Because of the large number of subjects involved in the meta-analysis, PCA should yield a more stable factor solution than any of the individual studies that comprise the meta-analysis, and should help to resolve questions about the number of dimensions, and which symptoms form these dimensions. The improvement in construct validity of symptom dimensions provided by a more stable model should, in turn, benefit investigations of pathophysiology, treatment and other external correlates of symptoms.

2. Methods

2.1. Selection oJstudies We selected studies of positive and negative symptoms in schizophrenia that used the Scale for the Assessment of Negative Symptoms (SANS: Andreasen, 1983) to measure 'negative' symptoms (i.e., affective flattening, alogia, avolition, anhedonia and attentional impairment) and the Schedule for Affective Disorders and Schizophrenia (SADS: Endicott and Spitzer, 1978) or the Scale for the Assessment of Positive Symptoms (SAPS: Andreasen, 1984) to measure 'positive' symptoms (i.e., hallucinations, delusions, positive formal thought disorder and bizarre behavior). lntercorrelations among all global symptom ratings were published in four of 10 empirical studies that satisfied these criteria (Andreasen and Olsen, 1982; Bilder et al., 1985; Kulhara et al., 1986; Walker et al., 1988). A number of investigators reported analyses without the raw correlation matrices; we requested these from the authors, and data were provided by Arndt et al. (1991), Gur et al. (1991), A.K. Malla and R.M.G. Norman (1994. Syndromes of schizophrenia: global symptom data. Unpublished raw data), Minas et al. (1992), Peralta et al. (1992) and Silver et al. (1993). Some studies were excluded because there were not enough symptoms from the SANS, SADS

B.S. Grube et al. / Schizophrenia Research 31 (1998) 113~ 120

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Table 1 Subject and study characteristics of meta-analysis and findings of original studies Author(s), year

Subject characteristics

Comments

Andreasen and Olsen, 1982

n = 52 (27 males); inpatients

Bilder et al., 1985

n - 3 2 (16 males): inpatients

Kulhara et al., 1986

Minas et al., 1992

n =98 (51 males); inpatients and outpatients n - 51 ( 39 males); inpatients n - 2 0 7 ( 134 males); patients pooled from three studies n = 107a (74 males); inpatients and outpatients n = 4 l b (28 males); inpatients

Peralta et al., 1992

n = 115 (79 males): inpatients

Malla et al., 1993

n = 155c ( 118 males); inpatients and outpatients n = 38d (24 males): inpatients

Original principal components analysis (PCA) yielded four factors: positive and negative symptoms formed opposite ends of a large 'bipolar" factor Original PCA yielded three factors: positive, negative and conceptual disorganization Original PCA yielded three factors: positive, negative and conceptual disorganization PCA was not performed in the original study Original PCA yielded three factors: positive, negative and conceptual disorganization Original PCA yielded three factors: positive, negative and conceptual disorganization Original multidimensional scaling analysis yielded three dimensions: positive, negative and conceptual disorganization Original PCA yielded three factors: positive, negative and conceptual disorganization Original principal axis factoring yielded three factors: positive, negative and conceptual disorganization Original PCA yielded three factors: positive, negative and conceptual disorganization

Walker et al., 1988 Arndt et al., 1991 Gur et al., 1991

Silver et al., 1993

Diagnostic procedures

Medication status

DSM-III, schizophrenia

82% of subjects had neuroleptic-treatment histories All but I subject had neuroleptic treatment at time of study

Gur et al., 1991 Minas et al., 1992

RDC, schizophrenia (2 patients schizoaffective) ICD-9, schizophrenia DSM-III, schizophrenia DSM-II1, DSM-III-R, schizophrenia DSM-III-R, schizophrenia DSM-11[, schizophrenia

Peralta et al., 1992 Malla et al., 1993 Silver et al., 1993

DSM-III-R, schizophrenia DSM-II1-R, schizophrenia DSM-III-R, schizophrenia

Andreasen and Olsen, 1982 Bilder et al., 1985 Kulhara et al., 1986 Walker et al., 1988 Arndt et al., 1991

Not reported 86% of subjects had neuroleptic treatment at time of study Most subjects had neuroleptic-treatment histories Subjects had no neuroleptic treatment at time of study Subjects had a mean highest 24 h level of 784 mg of chlorpromazine (CPZ) at time of study Subjects had a CPZ equivalent of 1282 mg at time of study Subjects had a CPZ equivalent of 463 mg at time of study Subjects had a CPZ equivalent of 1201 mg at time of study

aGur et al. (1991) provided data in addition to those reported in the original study.bForty-one schizophrenic patients were a subset of a larger sample of psychotic patients in the study by Minas et al. (1992).CMalla and Norman provided global symptom data in addition to data reported by Malla et al. ( 1993).Two subjects from the Silver et al. (1993) study were dropped because of missing data. o r S A P S t o g e n e r a t e c o m p a r a b l e a n a l y s e s (e.g., n o m e a s u r e o f b i z a r r e b e h a v i o r in s t u d i e s b y L i d d l e , 1987 a n d L i d d l e a n d B a r n e s , 1 9 9 0 ) , b e c a u s e a l t e r n a t e s y m p t o m r a t i n g s c a l e s w e r e u s e d (e.g., K a y et al., 1986; L e w i n e et al., 1 9 8 3 ) , o r b e c a u s e symptom ratings were derived from archival data (e.g., F e n t o n a n d M c G l a s h a n , 1991; L e n z e n w e g e r et al., 1 9 8 9 ) . Sample and study characteristics and a summary

of the original findings of these studies appear in T a b l e I. 2.2. D a t a p r e p a r a t i o n a n d a n a l y s i s The method used to prepare data for metaanalysis followed Rosenthal (1991). For each correlation matrix the r values were converted to Fisher's z-scores. The r-to-z converted matrices

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f r o m the S A N S l o a d e d m o s t heavily on F a c t o r 1; h a l l u c i n a t i o n s a n d delusions l o a d e d m o s t heavily on F a c t o r 2; a n d positive f o r m a l t h o u g h t d i s o r d e r a n d bizarre b e h a v i o r l o a d e d m o s t heavily on F a c t o r 3. In a d d i t i o n to l o a d i n g heavily on F a c t o r 1, a l o g i a a n d a t t e n t i o n a l i m p a i r m e n t (from the S A N S ) l o a d e d m o d e r a t e l y on F a c t o r 3. We also used P C A to re-analyze the original, u n w e i g h t e d c o r r e l a t i o n m a t r i x f r o m each empirical study, and cross-checked the factor solution a g a i n s t m e d i c a t i o n a n d d i a g n o s t i c p r o c e d u r e s used in each study. N o systematic v a r i a t i o n was o b s e r v e d (see Table I).

were w e i g h t e d by the degrees o f f r e e d o m for each study a n d c o m b i n e d to yield a m a t r i x o f s u m m e d z-scores. This m a t r i x o f - - s c o r e s was divided by the s u m m e d degrees o f f r e e d o m a n d then c o n v e r t e d b a c k to c o r r e l a t i o n coefficients to f o r m a c o m p o s i t e m a t r i x o f m e a n r values. This c o m p o s i t e m a t r i x c o m p r i s e d i n t e r c o r r e l a t i o n s a m o n g nine g l o b a l s y m p t o m ratings. We then p e r f o r m e d P C A (with o r t h o g o n a l r o t a t i o n ) o f the c o m p o s i t e matrix, with eigenvalues > 1.0 as criteria for factor extraction.

3. Results T h e c o m p o s i t e c o r r e l a t i o n m a t r i x a p p e a r s in Table 2 ( n u m b e r o f s t u d i e s = 10; n u m b e r o f subjects = 896), a l o n g with the 95% confidence interval for each c o r r e l a t i o n . All S A N S s y m p t o m s h a d positive i n t e r c o r r e l a t i o n s (r values r a n g e d f r o m 0.34 to 0.59). H a l l u c i n a t i o n s a n d delusions also c o r r e l a t e d positively ( r = 0 . 4 0 ) . Positive f o r m a l t h o u g h t d i s o r d e r c o r r e l a t e d positively with bizarre b e h a v i o r ( r = 0 . 3 4 ) and, to a lesser extent, with h a l l u c i n a t i o n s a n d delusions ( r = 0 . 2 5 a n d 0.28, respectively). D e l u s i o n s h a d inverse c o r r e l a t i o n s with all S A N S s y m p t o m s , a l t h o u g h these t e n d e d to be small (r values r a n g e d from - 0 . 0 1 to - 0 . 1 0 ) . P C A o f these d a t a yielded three factors with eigenvalues > 1.0, which a c c o u n t e d for 63% o f the variance. A s s h o w n in Table 3, the five s y m p t o m s

4. Discussion M e t a - a n a l y s i s o f s y m p t o m s in schizophrenia, c o m p r i s i n g a t o t a l o f 896 subjects f r o m l0 studies, yielded a t h r e e - f a c t o r solution. S u p p o r t was f o u n d for three s y m p t o m d i m e n s i o n s in schizophrenia: 'positive', ' n e g a t i v e ' a n d ' c o n c e p t u a l d i s o r g a n i z a tion'. These findings suggest t h a t a t w o - d i m e n sional model, based on positive a n d negative s y m p t o m s , does n o t a d e q u a t e l y a c c o u n t for the variance o b s e r v e d in the s y m p t o m s o f schizophrenia. These findings s h o u l d be c o n s i d e r e d relatively stable due to the high n u m b e r o f subjects involved, a n d highlight the i m p o r t a n c e o f including

Table 2 Composite correlation matrix across studies included in the meta-analysis (above the diagonal) and 95% confidence intervals of correlations (below the diagonal ) Symptom

1

2

3

4

5

6

7

8

9

I. Affective flattening 2. Alogia 3. Avolition 4. Anhedonia 5. Attentional impairment 6. Hallucinations 7. Delusions 8. PFTD a 9. Bizarre behavior

*

0.54

0.48

0.47

0.36

0.04

-0.08

-0.02

0.09

0.53 0.55 0.47 0 . 4 9 0.47 0 . 4 8 0.34 0.38

* 0.42-0.44 0.41-0.43 0.53-0.55

0.43 * 0.58-0.60 0.38 0.40

0.42 0.59 * 0.33 0.35

0.54 0.39 0.34 *

0.02 0.05 0.02 0.12

-0.10 -0.04 -0.01 -0.04

0.17 0.08 -0.02 0.19

0.18 0.12 0.05 0.15

0.03 0 . 0 6 -0.09 -0.07 0.03 0.01 0.07 0 . 1 0

0.01-0.03 0.03 0.06 I).02 0.03 -0.12 0.08 -I).05 -0.03 0.02 0.01 0.15-0.19 0.06 0.09 -0.03 -0.01 0.17-0.20 0.11 0.13 0.04 0.06

0.10 0.13 -0.05 -0.02 0.18 0.20 0.14 0.17

* 0.40 0.40 0.41 * 0.23 0.27 0.27 0.30 0.12 0.15 0.14 0.16

{).25 0.28 * 0.33-0.35

0.14 0.15 0.34 *

apositive formal thought disorder.

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Table 3 Rotated factor solution from principal components analysis Symptom

Factor I

Factor 2

Factor 3

Affective flattening Alogia Avolition Anhedonia Attentional impairment Hallucinations Delusions PFTD" Bizarre behavior

0.77 0.73 0.79 0.79 0.63 0.08 0.09 0.01 0.07

- 0.04 - 0.16 0.06 0.09 -0.04 0.80 0.83 0.29 0.05

- 0.02 0.33 0.00 -0.15 0.35 0.12 0.12 0.75 0.77

Eigenvalue Variance explained

20.9 32.3%

10.8 19.8%

10.0 11.3%

"Positive formal thought disorder. these three symptom dimensions in studies of pathophysiology and treatment of schizophrenia. The three-factor solution found in the metaanalysis confirms earlier three-factor findings (e.g., Andreasen et al., 1995; Arndt et al., 1991, 1995; Bell et al., 1994; Bilder et al., 1985; Brekke et al., 1994; G u r et al., 1991; Kulhara and Chandiramani, 1990; Kulhara et al., 1986; Liddle, 1987; Liddle and Barnes, 1990; Malla et al., 1993; Miller et al., 1993; Silver et al., 1993; T h o m p s o n and Meltzer, 1993). SANS symptoms formed a negative factor; hallucinations and delusions formed a positive factor; and positive formal thought disorder and bizarre behavior formed a conceptual disorganization factor. Support for a three-dimensional model of symptoms in schizophrenia has also emerged from investigations using multidimensional scaling methods (Minas et al., 1992; Klimidis et al., 1993). The results of the current study were based on analyses of s y m p t o m ratings derived from the SANS and SADS or SAPS, and different results may be obtained when analyzing symptoms derived from scales that assess broader domains of psychopathology (e.g., social and/or affective functioning). Strauss et al. (1974) proposed a three-dimensional model of schizophrenia, based on positive symptoms, negative symptoms and disordered personal-social relationships, that was different from the one yielded by the current metaanalysis. Lewine et al. (1983) found three similar dimensions in a study using Rasch models on

different symptom scales. Support for a disordered personal social relationships dimension similar to that proposed by Strauss et al. was found also in confirmatory factor-analytic studies by Lenzenweger et al. ( 1991 ) and Peralta et al. (1994). Since factor-analytic solutions obviously depend on the variables included in analyses, the inclusion of 'social relationships' symptoms in these studies can account for the findings of disordered personal-social relationships dimensions. A notable finding from this meta-analysis is that, in addition to loading heavily on the negative factor, alogia and attentional impairment loaded moderately on the conceptual disorganization factor. These symptoms also varied considerably with respect to their factor loadings across original studies. Alogia and attentional impairment had dual factor loadings in studies by Bilder et al. (1985), G u r et al. (1991) and Bell et al. (1994), while alogia had dual loadings in studies by Andreasen and Grove (1986) and Arndt et al. (1991). Furthermore, Miller et al. (1993) found that attentional impairment is multi-factorial, loading on all three factors in their analysis, and suggested that it might be a non-specific measure that correlates with the general severity of symptoms in schizophrenia. One reason these symptoms varied may be due to divergent subject characteristics across studies, such as sample size, sex, hospitalization status and medication status. Another reason for the polyfactorial nature of

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these symptoms may be that the global ratings of alogia and attentional impairment are impure; that is, they may comprise items that are not homogeneous with respect to the construct. There has been controversy regarding the item content of symptom subscales, and studies using item-level analysis have suggested that some subscales comprise heterogeneous items. In several studies, either the poverty of content of speech item from the alogia subscale, the inappropriate affect item from the affective flattening subscale, or both, emerged on a conceptual disorganization dimension apart from other negative symptoms (e.g., Andreasen et al,, 1995; Arndt et al., 1995; Liddle, 1987; Liddle and Barnes, 1990; Malla et al., 1993; Miller et al., 1993: Minas et al., 1992; Peralta et al., 1992, 1994: Shtasel et al., 1992, Silver et al., 1993). In an earlier study (Andreasen and Grove, 1986), inappropriate affect correlated poorly with the affective flattening subscale and with negative symptoms in general, and Andreasen (1987) subsequently dropped the item from the SANS and included it as a positive global symptom rating. Another persistent finding from item-level analyses was that persecutory delusions, along with delusions of reference and grandiose delusions in some studies, were associated with a dimension apart from other items from the delusions subscales of the SAPS and SADS (e.g., Minas et al., 1992; Shtasel et al., 1992; Malla et al., 1993; Silver et al., 1993; Thompson and Meltzer, 1993). Even a more highly refined global rating, however, or an individual item may remain polyfactorial. For example, attentional impairment may be rated as high for different reasons in different patients, which could result in high loadings for that symptom on different factors. Consider that individuals with schizophrenia have been characterized as more 'distractible', but also as more perseverative and fixed in attention. Distractibility may be manifested clinically as conceptual disorganization, while perseveration may be manifested more as a negative symptom. Indeed, excesses of both random and highly predictable behaviors are observed even within individual patients (Paulus et al., 1996). Similar patterns may occur among the linguistic errors characteristic of schizophrenia (Barr et al., 1989). More detailed examination of impaired language and attentional processes using

increasingly refined scales or other instrumentation, such as neuropsychological, cognitive and linguistic assessments, may be required to more fully understand these constructs and their relations to other symptoms, and ultimately to their unique functional anatomic substrates. One restriction of this study is that some qualities of the data were not incorporated in the metaanalysis. While data from studies included in the meta-analysis were weighted by their respective numbers of subjects, they were not weighted by other parameters, such as magnitude of interrater reliability, rater characteristics (e,g., qualifications, quality of training), subject characteristics, or other aspects of study design. Unfortunately, most studies did not report this information or provided insufficient detail to enable meaningful comparison for inclusion in this study. The large number of subjects included in the meta-analysis, however, should attenuate this problem. This study demonstrated that meta-analysis can be applied successfully to factor-analytic data, and it revealed the instability of certain global symptoms in schizophrenia. This method can also be used for more fine-grained analyses, and metaanalysis can be applied by future investigators to item-level symptom data in schizophrenia. For example, the item content of some negative symptoms and of delusions has been debated, and this method can be used to solve these questions. The results of this study provide strong support for a three-dimensional model of schizophrenia, including a conceptual disorganization dimension, though further research is needed to determine more precisely which symptoms comprise that dimension. This refinement, along with the inclusion of additional symptoms (such as social relations), might best be employed in longitudinal studies, where the stability of symptom covariation can be examined. These studies could ultimately provide more factorially pure dimensions of symptom expression that can be meaningfully related to putative pathophysiologic substrates, and that may be differentially affected by treatments.

Acknowledgment The authors thank Drs Nancy C. Andreasen, Stephan Arndt, Steven Klimidis, Lauren Korfine,

B.S, Grube et a L / Schizophrenia Research 31 (1998) 113-120

Parmanand Kulhara, A s h o k K. Malla, I. Harold Minas, Geoff W. Stuart, Elaine F. Walker and other reviewers for their valuable comments, as well as investigators who contributed data to this study.

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