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Male gender is associated with deficit schizophrenia: a meta-analysis
Schizophrenia Research 47 (2001) 141±147
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Male gender is associated with de®cit schizophrenia: a meta-analysis Marc-Andre Roy*, Michel Maziade, Annie LabbeÂ, Chantal MeÂrette Centre de recherche Universite Laval Robert-Giffard and the deÂpartement de Psychiatrie de la faculte de MeÂdecine de l'Universite Laval, Robert-Giffard, 2601 de la CanardieÁre, Beauport, QueÂbec, Canada G1J 2G3 Received 30 June 1999; accepted 15 November 1999
Abstract An association between de®cit schizophrenia and male gender could be expected, since male schizophrenic subjects have been repeatedly found more severe than females on several dimensions of severity. Surprisingly, very few studies have con®rmed such an association. We performed a more de®nitive test of this association using a meta-analysis. A pooled odds ratio was computed based on the 23 studies that reported the gender ratio in de®cit vs. non-de®cit schizophrenia. We tested for the heterogeneity of the association and examined the potential impact of the sampling method, the method used to assess the de®cit syndrome, the breadth of diagnoses included and the mean duration of illness. A highly signi®cant association between male gender and de®cit schizophrenia was observed (pooled odds ratio 1.75). There was no de®nitive evidence that differences across studies in sampling methods, breadth of diagnoses included, mean duration of illness and methods to assess the de®cit syndrome affected the strength of the association. However, the studies using the `Proxy De®cit Syndrome' method to assess the de®cit syndrome yielded qualitatively weaker evidence. This signi®cant association between male gender and de®cit schizophrenia may re¯ect the in¯uence of a gender related factor (e.g. sexual hormones) or gender differences in the liability to different etiologies of schizophrenia. The role of gender as a potential confounder must be closely examined in studies comparing de®cit and non-de®cit SZ. q 2001 Elsevier Science B.V. All rights reserved. Keywords: Confounding; De®cit syndrome; Etiology; Gender; (Schizophrenia)
1. Introduction Carpenter et al (Carpenter et al., 1988; Kirkpatrick et al., 1989) de®ned de®cit schizophrenia (SZ) by the presence of at least two out of six negative symptoms for at least 12 months. In addition, these symptoms could not be explained by anxiety, psychosis, neuroleptic side-effects, concurrent depression or other causes. A very high degree of temporal stability of * Corresponding author. Tel.: 11-418-663-5741; fax: 11-418-663-9540. E-mail address: [email protected] (M.-A. Roy).
this distinction has been documented in at least two studies (Fenton and McGlashan, 1994; Amador et al., 1999), and it has been found not to be confounded by neuroleptic side-effects (Bustillo et al., 1995). Among several differences that have been observed between de®cit and non-de®cit SZ, the poorer outcome and the poorer premorbid adjustment in de®cit SZ are probably the best replicated (see Roy et al., in press, for a review). Since male SZ subjects have been repeatedly found to have a poorer outcome and poorer premorbid adjustment than their female counterparts (Castle and Murray, 1991; Hafner and An Der Helden, 1997), an association
0920-9964/01/$ - see front matter q 2001 Elsevier Science B.V. All rights reserved. PII: S 0920-996 4(99)00231-5
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between de®cit SZ and male gender could be speculated. Surprisingly, in a recent review on the validity of de®cit vs. non-de®cit SZ subtypes (Roy et al., in press), we found no consistent evidence across studies for such an association, although several studies reported an overproportion of males in de®cit SZ that did not reach statistical signi®cance in most instances. Consequently, it is possible that these studies did not have suf®cient statistical power individually to yield signi®cant evidence for such an association. The present paper used meta-analytic techniques to determine whether pooling these studies would yield signi®cant gender ratio differences in de®cit vs. non-de®cit SZ. 2. Methods 2.1. Selection criteria Articles reporting gender ratio in de®cit vs. nonde®cit SZ subgroups were identi®ed through medline searches, bibliographies of published articles and contacts with one of the developers of these subtypes (Dr Brian Kirkpatrick). The use of Carpenter et al.'s criteria (Carpenter et al., 1988; Kirkpatrick et al., 1989) to de®ne de®cit vs. non-de®cit subtypes was required to include any study in the meta-analysis. 2.2. Statistical analyses For each study, an odds ratio (OR) was computed. Then, each of the studies was considered as a stratum, and a pooled OR was computed using a Mantel± Haenszel test. This test yielded a pooled estimate of the association between male gender and de®cit SZ. The corresponding 95% con®dence interval (C.I.) was provided, and a x 2 was computed to test the null hypothesis that these ORs were not different from unity. A two-sided P-value of 0.05 was used as the threshold of statistical signi®cance for all tests reported in this article. We veri®ed whether the strength of the association between male gender and de®cit SZ varied across studies using a Breslow±Day test of heterogeneity. 2.3. Methodological issues To detect the in¯uence of speci®c methodological
aspects on the strength of the association, we compared the pooled ORs in studies grouped according to four methodological aspects, i.e. the sampling strategy used, the method used to assess the de®cit syndrome, the breadth of the diagnoses included and the level of chronicity of the sample. The sampling strategies in use included (Table 1): (1) convenience sampling (i.e. cases recruited from a clinical or research facility) and (2) systematic sampling (i.e. cases systematically sampled from a catchment area). Systematic sampling, although more dif®cult to achieve, is less prone than convenience sampling to selection biases that could affect the strength of the association between two variables. Pooled ORs were computed separately for each of these two groups of studies and were then compared using the Breslow±Day test. Three methods have been used to assess the de®cit syndrome. The ®rst method is the Schedule for the De®cit Syndrome (SDS; Kirkpatrick et al., 1989), which is a semi-structured interview that systematically assesses the presence, severity and duration of negative symptoms, in addition to whether the negative symptoms are primary or secondary. This interview is meant to be completed with information from medical records, from signi®cant others and from health professionals to derive a global judgment on the presence of a de®cit syndrome. The SDS is generally considered the `gold standard' to assess the de®cit syndrome. The second method is the Proxy De®cit Syndrome (PDS; Kirkpatrick et al., 1993), which classi®es SZ subjects into de®cit or non-de®cit subgroups, based on a speci®c pro®le on the Brief Psychiatric Rating Scale, i.e. low scores on anxiety, guilt feelings, depressive mood and hostility, and high scores on affective blunting, which were found to predict a de®cit syndrome on the SDS (Kirkpatrick et al., 1993). The PDS was developed to be used when the SDS was not available. The evidence for its validity of the PDS rests on a relatively high degree of concordance with the SDS (Kirkpatrick et al., 1993) and on the fact that de®cit SZ de®ned either by SDS or PDS share several features (Kirkpatrick et al., 1998). The third method, that we will thereafter term the `detailed review', relies on extensive data from research interviews and detailed reviews of medical records without speci®cally using the SDS. Pooled ORs were
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Table 1 Characteristics of the 23 studies included in the meta-analysis Authors
Number of subjects
Proportion Proportion Odds ratio males (%) de®cit (95% (%) con®dence interval)
P-value a (twosided)
Type of sampling b
Method to assess the de®cit syndrome c
Only SZ included
Mean duration of illness less than 10 years
Carpenter et al. (1988) Buchanan et al. (1990) Kirkpatrick and Buchanan (1990) Harris et al. (1991) Tamminga et al. (1992) Buchanan et al. (1993) Kirkpatrick et al. (1993) Fenton and McGlashan (1994) Buchanan et al. (1994) Turetsky et al. (1995) Kirkpatrick et al. (1996a) Kirkpatrick et al. (1996b) Kirkpatrick et al. (1996c) Dollfus et al. (1996) Ross et al. (1996) Spaletta et al. (1997) Bustillo et al. (1997) Waltrip et al. (1997) Buchanan et al. (1997) Turetsky et al. (1998) Thibaut et al. (1998) Kirkpatrick et al, (in press a) Kirkpatrick et al, (in press b)
79 34 58 37 11 41 100 187 39 70 154 91 88 71 43 58 45 64 76 64 34 188 133
57.0 82.4 74.1 70.3 63.6 63.4 69.0 52.4 82.1 62.9 66.9 68.1 63.6 50.7 60.5 63.8 80.0 76.6 76.3 64.1 61.8 46.3 67.7
0.01 1.00 0.52 0.50 1.00 0.52 0.31 0.61 1.00 0.01 0.60 0.45 0.82 0.20 0.48 1.00 1.00 1.00 0.03 0.42 1.00 0.22 0.01
Conv Conv Conv Conv Conv Conv Conv Conv Conv Conv Conv Conv Sys Conv Conv Conv Conv Conv Conv Conv Conv Sys Sys
DR SDS SDS SDS SDS SDS SDS DR SDS DR PDS SDS PDS SDS SDS SDS SDS SDS SDS DR SDS PDS DR
No Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes No Yes Yes Yes Yes Yes No Yes Yes No Yes
Yes No No No No No No No No Yes No No Yes No No No No No No Yes No No No
a b c
19.0 50.0 27.6 46.0 36.4 41.5 24.0 24.6 46.2 30.0 34.4 27.5 36.4 31.0 25.6 31.0 37.8 23.4 26.3 32.8 41.2 22.3 16.5
6.5 1.0 1.7 1.8 2.3 1.7 2.0 1.2 1.2 5.3 1.2 1.7 1.1 2.1 2.1 1.2 1.3 1.3 8.3 1.6 1.2 1.6 5.9
(1.4±31.2) (0.2±5.8) (0.4±7.2) (0.4±7.5) (0.1±33.9) (0.5±6.4) (0.7±5.9) (0.6±2.4) (0.2±6.1) (1.4±20.4) (0.6±2.5) (0.6±4.8) (0.5±2.8) (0.8±6.0) (0.5±9.3) (0.4±3.9) (0.3±5.9) (0.3±5.4) (1.0±67.0) (0.5±5.1) (0.3±4.9) (0.8±3.1) (1.3±26.4)
Fisher's exact test. Conv, convenience sampling; Sys, systematic sampling. DR, detailed review method; SDS, Schedule for the De®cit Syndrome; PDS, Proxy De®cit Syndrome.
computed for each of these three groups of studies and were then compared using the Breslow±Day test. Concerning the breadth of the diagnoses, most of the studies were restricted to SZ patients, but a few studies also included schizoaffective patients. The inclusion of schizoaffective patients could have in¯uenced the gender composition of de®cit vs. non-de®cit SZ. Indeed, there is available evidence for a higher proportion of female patients in schizoaffective disorder than in SZ patients and it is plausible that schizoaffective patients would be less likely than SZ patients to develop a de®cit syndrome. Therefore, a pooled OR was computed for the studies restricted to SZ patients and then for the studies including other diagnoses as well, and these two groups of studies were compared using the Breslow±Day test. Finally, there is available evidence for an increasing frequency of the de®cit syndrome over the ®rst 5 years of illness (Fenton and McGlashan, 1994; Kirkpatrick et al., 1996c). Therefore, the level of chronicity could have in¯uenced the gender composition of de®cit vs. non-de®cit SZ if male and female patients
differed in terms of duration of illness, which was impossible to assess since none of the studies reviewed provided the mean duration of illness according to gender. Given the plausibility of a confounding effect of gender, we computed a pooled OR ®rst for samples with a mean duration of illness shorter than 10 years and then for the samples with a mean duration of illness longer than 10 years. These two groups of studies were also compared using the Breslow±Day test.
3. Results We identi®ed 23 studies (listed in Table 1) that met our selection criteria. In two additional studies (Wagman et al., 1987; Nibuya et al., 1995), de®cit and non-de®cit SZ were paired for gender, and in three additional studies (Thaker et al., 1989; Loas et al., 1996; Buchanan et al., 1998), gender ratios were not provided, which prevented the inclusion of these ®ve studies. The 23 studies meeting our selection
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criteria involved a total of 1765 patients. The global proportion of de®cit patients was 28.7%, and varied between 16.5 and 50% across studies. The global proportion of male subjects was 63.5% and varied between 46.3 and 82.4%. Only four studies yielded ORs that signi®cantly differed from unity. In each of these studies, the ORs were larger than 5 (Carpenter et al., 1988; Turetsky et al., 1995; Buchanan et al., 1997; Kirkpatrick et al., 2000). The 19 other studies resulted in ORs that were not signi®cantly different from unity and were smaller than 2.3 but equal to or larger than 1. The global pooled OR for the 23 selected studies was 1.75 (x 2 22.26, 1 df, P 0.000002; 95% C.I. 1.39±2.21), indicating a highly signi®cant association between male gender and de®cit SZ. No evidence for heterogeneity of the OR was found using the Breslow±Day test [x 2 15.87, 22 degrees of freedom (df ), P 0.82]. 3.1. Strati®cation according to the sampling method We examined whether the type of sampling used could have affected the strength of the association between male gender and de®cit SZ. The three studies that used systematic sampling yielded a pooled OR of 1.78, which was signi®cantly different from unity (x 2 5.11, 1 df, P 0.024; 95% C.I. 1.08±2.94), while the 20 studies using convenience sampling yielded an OR of 1.74, which was also signi®cantly different from unity (x 2 17.16, 1 df, P 0.00004; 95% C.I. 1.34±2.27). There was no evidence of any differences in the magnitude of the pooled OR between these two groups of studies (x 2 0.04, 1 df, P 0.86). 3.2. Strati®cation according to the method used to assess the de®cit syndrome We examined whether the method used to assess the de®cit syndrome could have affected the strength of the association between male gender and de®cit SZ. First, the 15 studies using the SDS yielded a pooled OR of 1.74, which was signi®cantly different from unity ( x 2 9.43, 1 df, P 0.002; 95% C.I. 1.22±2.47). Second, the three studies using the PDS yielded a pooled OR of 1.33, which was not signi®cantly different from
unity (x 2 1.60, 1 df, P 0.21; 95% C.I. 0.86± 2.05). Third, the ®ve studies using the `detailed review' method yielded a pooled OR of 2.36, which was signi®cantly different from unity (x 2 14.07, 1 df, P 0.0002; 95% C.I. 1.51± 3.69). There were no signi®cant differences in the magnitude of the association between de®cit SZ and male gender in the studies using (1) the SDS vs. the PDS, (x 2 0.32, 1 df, P 0.57), (2) the SDS vs. the detailed review method (x 2 0.85, 1 df, P 0.36) or (3) the PDS vs. the detailed review method (x 2 1.81, 1 df, P 0.18). 3.3. Strati®cation according to the breadth of diagnoses included We examined whether the breadth of diagnoses included could have affected the strength of the association between male gender and de®cit SZ. First, the 19 studies restricted to SZ patients yielded a pooled OR of 1.68, which was signi®cantly different from unity (x 2 14.45, 1 df, P 0.0001; 95% C.I. 1.29± 2.19). Second, the four studies including schizoaffective patients as well yielded a pooled OR of 2.02, which was signi®cantly different from unity (x 2 8.24, 1 df, P 0.004; 95% C.I. 1.25±3.26). There was no evidence of any differences in the magnitude of the pooled OR between these two groups of studies (x 2 0.49, 1 df, P 0.49). 3.4. Strati®cation according to the duration of illness We examined whether the mean duration of illness of the patients included could have affected the strength of the association between male gender and de®cit SZ. First, the four studies with a mean duration of illness of less than 10 years yielded a pooled OR of 2.31, which was signi®cantly different from unity (x 2 8.98, 1 df, P 0.003; 95% C.I. 1.34±4.00). Second, the 19 studies with a mean duration of illness of more than 10 years yielded a pooled OR of 1.65, which was signi®cantly different from unity (x 2 1.65, 1 df, P 0.0002; 95% C.I. 1.27±2.13). There was no evidence of any differences in the magnitude of the pooled OR between these two groups of studies (x 2 1.17, 1 df, P 0.28).
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4. Discussion 4.1. Methodological issues This meta analysis provides strong empirical support for an association between male gender and de®cit SZ. In addition, although a few studies yielded ORs that appeared qualitatively larger than that of other studies (i.e. ORs .5), we found no de®nitive evidence for signi®cant heterogeneity across studies in the strength of this association despite the use of ®ve complementary strategies. First, the Breslow± Day test yielded no evidence of heterogeneity. Second, the strength of the association was remarkably similar in studies using systematic or those using convenience sampling. Third, we found no de®nitive evidence for differences in the strength of the association according to the method used to assess the de®cit syndrome, although the group of studies using the PDS was the only one that did not yield a statistically signi®cant association between male gender and de®cit SZ. Fourth, we found no evidence of any differences in the strength of the association according to the breadth of diagnoses included. Fifth, there were no signi®cant differences in the strength of the association in the sample with a mean duration of illness of less vs. more than 10 years. Two plausible explanations can be given for the negative results in the studies using the PDS. First, since only three studies used the PDS, the power of these pooled studies may have been insuf®cient to detect a signi®cant association. This interpretation is supported by the lack of signi®cant differences in the magnitude of the association between male gender and de®cit SZ across the groups of studies de®ned according to the method used to assess the de®cit syndrome (i.e. SDS, PDS or detailed review). Second, the relatively weaker association between male gender and the de®cit syndrome in studies using the PDS may be due to this instrument being less accurate than the SDS, the latter being generally considered the `gold standard'. Although a relatively high degree of concordance between the PDS and the SDS has been found (Kirkpatrick et al., 1993), their degree of nonconcordance may still be suf®cient to slightly decrease the statistical power to detect an association between male gender and de®cit SZ. The issue of a publication bias (i.e. a differential
145
reporting of studies ®nding vs. those not ®nding an association between gender and de®cit SZ) could be raised. Indeed, it has been shown that studies that report a statistically signi®cant association are more likely to be published than studies that do not (Easterbrook et al., 1991). We believe, however, that such a bias is very unlikely in our meta-analysis since the gender ratio in de®cit vs. non-de®cit SZ was never the main research question in any investigation on the de®cit syndrome. 4.2. Implications The strength of the presently observed association between male gender and the de®cit syndrome and its robustness to different methodological issues suggest that this association is genuine. At least two plausible interpretations can be proposed. First, this association between male gender and de®cit SZ could re¯ect gender-related factors in¯uencing severity without being etiologic per se. According to this interpretation, the presence of a de®cit syndrome would be an indicator of a greater severity of SZ. Such a plausible sex-related factor could be estrogens, which have been proposed to play a protective role by decreasing the risk for SZ and the severity of SZ in premenopausal women (Seeman and Lang, 1990). A second interpretation would be that SZ include etiologically distinct subgroups of patients, and that these subgroups have a different gender composition (Sham et al., 1994). For example, males may be more liable than females to develop a severe/neurodevelopmental form of SZ, characterized by a family history of SZ and/or a history of obstetrical complications, while males and females would be equally liable to a less severe and later onset form of SZ, characterized by a genetic liability for affective disorders (Murray et al., 1992). The present results suggest that gender may be an important confounder in studies comparing de®cit vs. non-de®cit SZ. For example, gender meets the three criteria of a confounding variable (Kleinbaum et al., 1982; Hennekens and Buring, 1987; Rhodes et al., 1999) for comparisons between de®cit and non-de®cit SZ on premorbid adjustment. First, as shown in the present meta-analysis, there is a greater proportion of males in de®cit SZ. Second, a poorer premorbid adjustment in male SZ subjects has been repeatedly
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found (Lewis, 1992). Third, gender is not simply a step in a causal pathway linking the de®cit syndrome and poorer premorbid adjustment, i.e. the de®cit syndrome does not in¯uence some sex related factor, which would in turn in¯uence premorbid adjustment (for a recent and complete discussion on confounding, see Rhodes et al., 1999). Given this possible confounding effect of gender, it is essential to control for gender in studies comparing de®cit and non-de®cit SZ on variables on which male and female SZ subjects could differ (e.g. severity of symptoms, age of onset, neurostructural abnormalities, etc.; Lewis, 1992). In other words, if a difference between de®cit and non-de®cit SZ is genuine, it should be present in de®cit vs. non-de®cit SZ male subjects as well as in female de®cit vs. non-de®cit SZ subjects. As discussed in Rhodes et al. (1999), an association between an independent variable (e.g. the de®cit vs. non-de®cit subgrouping) and a dependent variable (e.g. premorbid adjustment) can still be distorted by a confounder (e.g. gender), even if none of these variables is related to each other at a statistically signi®cant level in a given study. Therefore, controlling for gender is needed even for studies that do not yield statistically signi®cant gender ratio differences between de®cit and non-de®cit SZ. Acknowledgements Supported by grants from Medical Research Council of Canada, Health and Welfare Canada, EJLB Foundation and Fonds de la recherche en sante du QueÂbec (FRSQ). Marc-Andre Roy and Chantal MeÂrette are supported by FRSQ scientist awards. References Amador, X.F., Kirkpatrick, B., Buchanan, R.W., Carpenter, W.T., Marcinko, L., Yale, S.A., 1999. Stability of the diagnosis of de®cit syndrome in schizophrenia. Am. J. Psychiatry 156, 637±639. Buchanan, R.W., Kirkpatrick, B., Heinrichs, D.W., Carpenter, W.T.J., 1990. Clinical correlates of the de®cit syndrome of schizophrenia. Am. J. Psychiatry 147, 290±294. Buchanan, R.W., Breier, A., Kirkpatrick, B., Elkashef, A., Munson, R.C., Gellad, F., Carpenter, W.T.J., 1993. Structural abnormalities in de®cit and nonde®cit schizophrenia. Am. J. Psychiatry 150, 59±65. Buchanan, R.W., Strauss, M.E., Kirkpatrick, B., Holsein, C., Breier,
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www.elsevier.com/locate/schres
Male gender is associated with de®cit schizophrenia: a meta-analysis Marc-Andre Roy*, Michel Maziade, Annie LabbeÂ, Chantal MeÂrette Centre de recherche Universite Laval Robert-Giffard and the deÂpartement de Psychiatrie de la faculte de MeÂdecine de l'Universite Laval, Robert-Giffard, 2601 de la CanardieÁre, Beauport, QueÂbec, Canada G1J 2G3 Received 30 June 1999; accepted 15 November 1999
Abstract An association between de®cit schizophrenia and male gender could be expected, since male schizophrenic subjects have been repeatedly found more severe than females on several dimensions of severity. Surprisingly, very few studies have con®rmed such an association. We performed a more de®nitive test of this association using a meta-analysis. A pooled odds ratio was computed based on the 23 studies that reported the gender ratio in de®cit vs. non-de®cit schizophrenia. We tested for the heterogeneity of the association and examined the potential impact of the sampling method, the method used to assess the de®cit syndrome, the breadth of diagnoses included and the mean duration of illness. A highly signi®cant association between male gender and de®cit schizophrenia was observed (pooled odds ratio 1.75). There was no de®nitive evidence that differences across studies in sampling methods, breadth of diagnoses included, mean duration of illness and methods to assess the de®cit syndrome affected the strength of the association. However, the studies using the `Proxy De®cit Syndrome' method to assess the de®cit syndrome yielded qualitatively weaker evidence. This signi®cant association between male gender and de®cit schizophrenia may re¯ect the in¯uence of a gender related factor (e.g. sexual hormones) or gender differences in the liability to different etiologies of schizophrenia. The role of gender as a potential confounder must be closely examined in studies comparing de®cit and non-de®cit SZ. q 2001 Elsevier Science B.V. All rights reserved. Keywords: Confounding; De®cit syndrome; Etiology; Gender; (Schizophrenia)
1. Introduction Carpenter et al (Carpenter et al., 1988; Kirkpatrick et al., 1989) de®ned de®cit schizophrenia (SZ) by the presence of at least two out of six negative symptoms for at least 12 months. In addition, these symptoms could not be explained by anxiety, psychosis, neuroleptic side-effects, concurrent depression or other causes. A very high degree of temporal stability of * Corresponding author. Tel.: 11-418-663-5741; fax: 11-418-663-9540. E-mail address: [email protected] (M.-A. Roy).
this distinction has been documented in at least two studies (Fenton and McGlashan, 1994; Amador et al., 1999), and it has been found not to be confounded by neuroleptic side-effects (Bustillo et al., 1995). Among several differences that have been observed between de®cit and non-de®cit SZ, the poorer outcome and the poorer premorbid adjustment in de®cit SZ are probably the best replicated (see Roy et al., in press, for a review). Since male SZ subjects have been repeatedly found to have a poorer outcome and poorer premorbid adjustment than their female counterparts (Castle and Murray, 1991; Hafner and An Der Helden, 1997), an association
0920-9964/01/$ - see front matter q 2001 Elsevier Science B.V. All rights reserved. PII: S 0920-996 4(99)00231-5
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between de®cit SZ and male gender could be speculated. Surprisingly, in a recent review on the validity of de®cit vs. non-de®cit SZ subtypes (Roy et al., in press), we found no consistent evidence across studies for such an association, although several studies reported an overproportion of males in de®cit SZ that did not reach statistical signi®cance in most instances. Consequently, it is possible that these studies did not have suf®cient statistical power individually to yield signi®cant evidence for such an association. The present paper used meta-analytic techniques to determine whether pooling these studies would yield signi®cant gender ratio differences in de®cit vs. non-de®cit SZ. 2. Methods 2.1. Selection criteria Articles reporting gender ratio in de®cit vs. nonde®cit SZ subgroups were identi®ed through medline searches, bibliographies of published articles and contacts with one of the developers of these subtypes (Dr Brian Kirkpatrick). The use of Carpenter et al.'s criteria (Carpenter et al., 1988; Kirkpatrick et al., 1989) to de®ne de®cit vs. non-de®cit subtypes was required to include any study in the meta-analysis. 2.2. Statistical analyses For each study, an odds ratio (OR) was computed. Then, each of the studies was considered as a stratum, and a pooled OR was computed using a Mantel± Haenszel test. This test yielded a pooled estimate of the association between male gender and de®cit SZ. The corresponding 95% con®dence interval (C.I.) was provided, and a x 2 was computed to test the null hypothesis that these ORs were not different from unity. A two-sided P-value of 0.05 was used as the threshold of statistical signi®cance for all tests reported in this article. We veri®ed whether the strength of the association between male gender and de®cit SZ varied across studies using a Breslow±Day test of heterogeneity. 2.3. Methodological issues To detect the in¯uence of speci®c methodological
aspects on the strength of the association, we compared the pooled ORs in studies grouped according to four methodological aspects, i.e. the sampling strategy used, the method used to assess the de®cit syndrome, the breadth of the diagnoses included and the level of chronicity of the sample. The sampling strategies in use included (Table 1): (1) convenience sampling (i.e. cases recruited from a clinical or research facility) and (2) systematic sampling (i.e. cases systematically sampled from a catchment area). Systematic sampling, although more dif®cult to achieve, is less prone than convenience sampling to selection biases that could affect the strength of the association between two variables. Pooled ORs were computed separately for each of these two groups of studies and were then compared using the Breslow±Day test. Three methods have been used to assess the de®cit syndrome. The ®rst method is the Schedule for the De®cit Syndrome (SDS; Kirkpatrick et al., 1989), which is a semi-structured interview that systematically assesses the presence, severity and duration of negative symptoms, in addition to whether the negative symptoms are primary or secondary. This interview is meant to be completed with information from medical records, from signi®cant others and from health professionals to derive a global judgment on the presence of a de®cit syndrome. The SDS is generally considered the `gold standard' to assess the de®cit syndrome. The second method is the Proxy De®cit Syndrome (PDS; Kirkpatrick et al., 1993), which classi®es SZ subjects into de®cit or non-de®cit subgroups, based on a speci®c pro®le on the Brief Psychiatric Rating Scale, i.e. low scores on anxiety, guilt feelings, depressive mood and hostility, and high scores on affective blunting, which were found to predict a de®cit syndrome on the SDS (Kirkpatrick et al., 1993). The PDS was developed to be used when the SDS was not available. The evidence for its validity of the PDS rests on a relatively high degree of concordance with the SDS (Kirkpatrick et al., 1993) and on the fact that de®cit SZ de®ned either by SDS or PDS share several features (Kirkpatrick et al., 1998). The third method, that we will thereafter term the `detailed review', relies on extensive data from research interviews and detailed reviews of medical records without speci®cally using the SDS. Pooled ORs were
M.-A. Roy et al. / Schizophrenia Research 47 (2001) 141±147
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Table 1 Characteristics of the 23 studies included in the meta-analysis Authors
Number of subjects
Proportion Proportion Odds ratio males (%) de®cit (95% (%) con®dence interval)
P-value a (twosided)
Type of sampling b
Method to assess the de®cit syndrome c
Only SZ included
Mean duration of illness less than 10 years
Carpenter et al. (1988) Buchanan et al. (1990) Kirkpatrick and Buchanan (1990) Harris et al. (1991) Tamminga et al. (1992) Buchanan et al. (1993) Kirkpatrick et al. (1993) Fenton and McGlashan (1994) Buchanan et al. (1994) Turetsky et al. (1995) Kirkpatrick et al. (1996a) Kirkpatrick et al. (1996b) Kirkpatrick et al. (1996c) Dollfus et al. (1996) Ross et al. (1996) Spaletta et al. (1997) Bustillo et al. (1997) Waltrip et al. (1997) Buchanan et al. (1997) Turetsky et al. (1998) Thibaut et al. (1998) Kirkpatrick et al, (in press a) Kirkpatrick et al, (in press b)
79 34 58 37 11 41 100 187 39 70 154 91 88 71 43 58 45 64 76 64 34 188 133
57.0 82.4 74.1 70.3 63.6 63.4 69.0 52.4 82.1 62.9 66.9 68.1 63.6 50.7 60.5 63.8 80.0 76.6 76.3 64.1 61.8 46.3 67.7
0.01 1.00 0.52 0.50 1.00 0.52 0.31 0.61 1.00 0.01 0.60 0.45 0.82 0.20 0.48 1.00 1.00 1.00 0.03 0.42 1.00 0.22 0.01
Conv Conv Conv Conv Conv Conv Conv Conv Conv Conv Conv Conv Sys Conv Conv Conv Conv Conv Conv Conv Conv Sys Sys
DR SDS SDS SDS SDS SDS SDS DR SDS DR PDS SDS PDS SDS SDS SDS SDS SDS SDS DR SDS PDS DR
No Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes No Yes Yes Yes Yes Yes No Yes Yes No Yes
Yes No No No No No No No No Yes No No Yes No No No No No No Yes No No No
a b c
19.0 50.0 27.6 46.0 36.4 41.5 24.0 24.6 46.2 30.0 34.4 27.5 36.4 31.0 25.6 31.0 37.8 23.4 26.3 32.8 41.2 22.3 16.5
6.5 1.0 1.7 1.8 2.3 1.7 2.0 1.2 1.2 5.3 1.2 1.7 1.1 2.1 2.1 1.2 1.3 1.3 8.3 1.6 1.2 1.6 5.9
(1.4±31.2) (0.2±5.8) (0.4±7.2) (0.4±7.5) (0.1±33.9) (0.5±6.4) (0.7±5.9) (0.6±2.4) (0.2±6.1) (1.4±20.4) (0.6±2.5) (0.6±4.8) (0.5±2.8) (0.8±6.0) (0.5±9.3) (0.4±3.9) (0.3±5.9) (0.3±5.4) (1.0±67.0) (0.5±5.1) (0.3±4.9) (0.8±3.1) (1.3±26.4)
Fisher's exact test. Conv, convenience sampling; Sys, systematic sampling. DR, detailed review method; SDS, Schedule for the De®cit Syndrome; PDS, Proxy De®cit Syndrome.
computed for each of these three groups of studies and were then compared using the Breslow±Day test. Concerning the breadth of the diagnoses, most of the studies were restricted to SZ patients, but a few studies also included schizoaffective patients. The inclusion of schizoaffective patients could have in¯uenced the gender composition of de®cit vs. non-de®cit SZ. Indeed, there is available evidence for a higher proportion of female patients in schizoaffective disorder than in SZ patients and it is plausible that schizoaffective patients would be less likely than SZ patients to develop a de®cit syndrome. Therefore, a pooled OR was computed for the studies restricted to SZ patients and then for the studies including other diagnoses as well, and these two groups of studies were compared using the Breslow±Day test. Finally, there is available evidence for an increasing frequency of the de®cit syndrome over the ®rst 5 years of illness (Fenton and McGlashan, 1994; Kirkpatrick et al., 1996c). Therefore, the level of chronicity could have in¯uenced the gender composition of de®cit vs. non-de®cit SZ if male and female patients
differed in terms of duration of illness, which was impossible to assess since none of the studies reviewed provided the mean duration of illness according to gender. Given the plausibility of a confounding effect of gender, we computed a pooled OR ®rst for samples with a mean duration of illness shorter than 10 years and then for the samples with a mean duration of illness longer than 10 years. These two groups of studies were also compared using the Breslow±Day test.
3. Results We identi®ed 23 studies (listed in Table 1) that met our selection criteria. In two additional studies (Wagman et al., 1987; Nibuya et al., 1995), de®cit and non-de®cit SZ were paired for gender, and in three additional studies (Thaker et al., 1989; Loas et al., 1996; Buchanan et al., 1998), gender ratios were not provided, which prevented the inclusion of these ®ve studies. The 23 studies meeting our selection
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criteria involved a total of 1765 patients. The global proportion of de®cit patients was 28.7%, and varied between 16.5 and 50% across studies. The global proportion of male subjects was 63.5% and varied between 46.3 and 82.4%. Only four studies yielded ORs that signi®cantly differed from unity. In each of these studies, the ORs were larger than 5 (Carpenter et al., 1988; Turetsky et al., 1995; Buchanan et al., 1997; Kirkpatrick et al., 2000). The 19 other studies resulted in ORs that were not signi®cantly different from unity and were smaller than 2.3 but equal to or larger than 1. The global pooled OR for the 23 selected studies was 1.75 (x 2 22.26, 1 df, P 0.000002; 95% C.I. 1.39±2.21), indicating a highly signi®cant association between male gender and de®cit SZ. No evidence for heterogeneity of the OR was found using the Breslow±Day test [x 2 15.87, 22 degrees of freedom (df ), P 0.82]. 3.1. Strati®cation according to the sampling method We examined whether the type of sampling used could have affected the strength of the association between male gender and de®cit SZ. The three studies that used systematic sampling yielded a pooled OR of 1.78, which was signi®cantly different from unity (x 2 5.11, 1 df, P 0.024; 95% C.I. 1.08±2.94), while the 20 studies using convenience sampling yielded an OR of 1.74, which was also signi®cantly different from unity (x 2 17.16, 1 df, P 0.00004; 95% C.I. 1.34±2.27). There was no evidence of any differences in the magnitude of the pooled OR between these two groups of studies (x 2 0.04, 1 df, P 0.86). 3.2. Strati®cation according to the method used to assess the de®cit syndrome We examined whether the method used to assess the de®cit syndrome could have affected the strength of the association between male gender and de®cit SZ. First, the 15 studies using the SDS yielded a pooled OR of 1.74, which was signi®cantly different from unity ( x 2 9.43, 1 df, P 0.002; 95% C.I. 1.22±2.47). Second, the three studies using the PDS yielded a pooled OR of 1.33, which was not signi®cantly different from
unity (x 2 1.60, 1 df, P 0.21; 95% C.I. 0.86± 2.05). Third, the ®ve studies using the `detailed review' method yielded a pooled OR of 2.36, which was signi®cantly different from unity (x 2 14.07, 1 df, P 0.0002; 95% C.I. 1.51± 3.69). There were no signi®cant differences in the magnitude of the association between de®cit SZ and male gender in the studies using (1) the SDS vs. the PDS, (x 2 0.32, 1 df, P 0.57), (2) the SDS vs. the detailed review method (x 2 0.85, 1 df, P 0.36) or (3) the PDS vs. the detailed review method (x 2 1.81, 1 df, P 0.18). 3.3. Strati®cation according to the breadth of diagnoses included We examined whether the breadth of diagnoses included could have affected the strength of the association between male gender and de®cit SZ. First, the 19 studies restricted to SZ patients yielded a pooled OR of 1.68, which was signi®cantly different from unity (x 2 14.45, 1 df, P 0.0001; 95% C.I. 1.29± 2.19). Second, the four studies including schizoaffective patients as well yielded a pooled OR of 2.02, which was signi®cantly different from unity (x 2 8.24, 1 df, P 0.004; 95% C.I. 1.25±3.26). There was no evidence of any differences in the magnitude of the pooled OR between these two groups of studies (x 2 0.49, 1 df, P 0.49). 3.4. Strati®cation according to the duration of illness We examined whether the mean duration of illness of the patients included could have affected the strength of the association between male gender and de®cit SZ. First, the four studies with a mean duration of illness of less than 10 years yielded a pooled OR of 2.31, which was signi®cantly different from unity (x 2 8.98, 1 df, P 0.003; 95% C.I. 1.34±4.00). Second, the 19 studies with a mean duration of illness of more than 10 years yielded a pooled OR of 1.65, which was signi®cantly different from unity (x 2 1.65, 1 df, P 0.0002; 95% C.I. 1.27±2.13). There was no evidence of any differences in the magnitude of the pooled OR between these two groups of studies (x 2 1.17, 1 df, P 0.28).
M.-A. Roy et al. / Schizophrenia Research 47 (2001) 141±147
4. Discussion 4.1. Methodological issues This meta analysis provides strong empirical support for an association between male gender and de®cit SZ. In addition, although a few studies yielded ORs that appeared qualitatively larger than that of other studies (i.e. ORs .5), we found no de®nitive evidence for signi®cant heterogeneity across studies in the strength of this association despite the use of ®ve complementary strategies. First, the Breslow± Day test yielded no evidence of heterogeneity. Second, the strength of the association was remarkably similar in studies using systematic or those using convenience sampling. Third, we found no de®nitive evidence for differences in the strength of the association according to the method used to assess the de®cit syndrome, although the group of studies using the PDS was the only one that did not yield a statistically signi®cant association between male gender and de®cit SZ. Fourth, we found no evidence of any differences in the strength of the association according to the breadth of diagnoses included. Fifth, there were no signi®cant differences in the strength of the association in the sample with a mean duration of illness of less vs. more than 10 years. Two plausible explanations can be given for the negative results in the studies using the PDS. First, since only three studies used the PDS, the power of these pooled studies may have been insuf®cient to detect a signi®cant association. This interpretation is supported by the lack of signi®cant differences in the magnitude of the association between male gender and de®cit SZ across the groups of studies de®ned according to the method used to assess the de®cit syndrome (i.e. SDS, PDS or detailed review). Second, the relatively weaker association between male gender and the de®cit syndrome in studies using the PDS may be due to this instrument being less accurate than the SDS, the latter being generally considered the `gold standard'. Although a relatively high degree of concordance between the PDS and the SDS has been found (Kirkpatrick et al., 1993), their degree of nonconcordance may still be suf®cient to slightly decrease the statistical power to detect an association between male gender and de®cit SZ. The issue of a publication bias (i.e. a differential
145
reporting of studies ®nding vs. those not ®nding an association between gender and de®cit SZ) could be raised. Indeed, it has been shown that studies that report a statistically signi®cant association are more likely to be published than studies that do not (Easterbrook et al., 1991). We believe, however, that such a bias is very unlikely in our meta-analysis since the gender ratio in de®cit vs. non-de®cit SZ was never the main research question in any investigation on the de®cit syndrome. 4.2. Implications The strength of the presently observed association between male gender and the de®cit syndrome and its robustness to different methodological issues suggest that this association is genuine. At least two plausible interpretations can be proposed. First, this association between male gender and de®cit SZ could re¯ect gender-related factors in¯uencing severity without being etiologic per se. According to this interpretation, the presence of a de®cit syndrome would be an indicator of a greater severity of SZ. Such a plausible sex-related factor could be estrogens, which have been proposed to play a protective role by decreasing the risk for SZ and the severity of SZ in premenopausal women (Seeman and Lang, 1990). A second interpretation would be that SZ include etiologically distinct subgroups of patients, and that these subgroups have a different gender composition (Sham et al., 1994). For example, males may be more liable than females to develop a severe/neurodevelopmental form of SZ, characterized by a family history of SZ and/or a history of obstetrical complications, while males and females would be equally liable to a less severe and later onset form of SZ, characterized by a genetic liability for affective disorders (Murray et al., 1992). The present results suggest that gender may be an important confounder in studies comparing de®cit vs. non-de®cit SZ. For example, gender meets the three criteria of a confounding variable (Kleinbaum et al., 1982; Hennekens and Buring, 1987; Rhodes et al., 1999) for comparisons between de®cit and non-de®cit SZ on premorbid adjustment. First, as shown in the present meta-analysis, there is a greater proportion of males in de®cit SZ. Second, a poorer premorbid adjustment in male SZ subjects has been repeatedly
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found (Lewis, 1992). Third, gender is not simply a step in a causal pathway linking the de®cit syndrome and poorer premorbid adjustment, i.e. the de®cit syndrome does not in¯uence some sex related factor, which would in turn in¯uence premorbid adjustment (for a recent and complete discussion on confounding, see Rhodes et al., 1999). Given this possible confounding effect of gender, it is essential to control for gender in studies comparing de®cit and non-de®cit SZ on variables on which male and female SZ subjects could differ (e.g. severity of symptoms, age of onset, neurostructural abnormalities, etc.; Lewis, 1992). In other words, if a difference between de®cit and non-de®cit SZ is genuine, it should be present in de®cit vs. non-de®cit SZ male subjects as well as in female de®cit vs. non-de®cit SZ subjects. As discussed in Rhodes et al. (1999), an association between an independent variable (e.g. the de®cit vs. non-de®cit subgrouping) and a dependent variable (e.g. premorbid adjustment) can still be distorted by a confounder (e.g. gender), even if none of these variables is related to each other at a statistically signi®cant level in a given study. Therefore, controlling for gender is needed even for studies that do not yield statistically signi®cant gender ratio differences between de®cit and non-de®cit SZ. Acknowledgements Supported by grants from Medical Research Council of Canada, Health and Welfare Canada, EJLB Foundation and Fonds de la recherche en sante du QueÂbec (FRSQ). Marc-Andre Roy and Chantal MeÂrette are supported by FRSQ scientist awards. References Amador, X.F., Kirkpatrick, B., Buchanan, R.W., Carpenter, W.T., Marcinko, L., Yale, S.A., 1999. Stability of the diagnosis of de®cit syndrome in schizophrenia. Am. J. Psychiatry 156, 637±639. Buchanan, R.W., Kirkpatrick, B., Heinrichs, D.W., Carpenter, W.T.J., 1990. Clinical correlates of the de®cit syndrome of schizophrenia. Am. J. Psychiatry 147, 290±294. Buchanan, R.W., Breier, A., Kirkpatrick, B., Elkashef, A., Munson, R.C., Gellad, F., Carpenter, W.T.J., 1993. Structural abnormalities in de®cit and nonde®cit schizophrenia. Am. J. Psychiatry 150, 59±65. Buchanan, R.W., Strauss, M.E., Kirkpatrick, B., Holsein, C., Breier,
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