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Depressive Factors and Their Relationships With Other Symptom Domains in Schizophrenia, Schizoaffective Disorder, and Psychotic Depression by M.atihias J. Miiller, Armin Szegedi, Hermann Wetzel, and Otto Benkert Abstract chotic features. The fuzzy boundaries between diagnostic groups are partly due to the nosological nonspecificity of frequently coexisting positive, negative, and affective symptoms (Mundt et al. 1989; Gerbaldo et al. 1995; Maziade et al. 1995; Toomey et al. 1998). Within nosological groups, the overlap of certain symptom domains (e.g., depressive and negative symptoms) additionally obscures the picture (Prosser et al. 1987; Whiteford et al. 1987; Siris et al. 1988; Lewine 1990; Barnes and McPhillips 1995; Collins et al. 1996). To disentangle these sometimes confounded symptoms (Kitamura and Suga 1991) and to investigate the mutual relationship of empirically derived symptom domains could help establish meaningful diagnostic categories and differential treatment implications (Sax et al. 1996). As with negative symptoms, which have been disregarded for a very long time, the negligence of affective symptoms in schizophrenia, foremost depression, in schizophrenia is apparently over-simplistic. There is growing evidence suggesting that depressive symptoms and related mood disturbances are an integral part of schizophrenic disorders (Hirsch 1982; Siris 1995). Several previous studies have investigated the relationship between negative and depressive symptoms, but most of them treated depression as a homogenous construct. A sophisticated analysis in patients not restricted to the diagnosis of schizophrenia suggested that depressive and negative symptoms are frequently strongly associated but should nevertheless be regarded as distinct concepts (Kitamura and Suga 1991). However, akinetic symptoms due to treatment with conventional neuroleptics were not taken into account in this study, despite the possible overlap of akinesia with either depressive or negative symptomatology (Van Putten and May 1978; Harrow et al. 1994). When considering the relationship between depressive and positive symptoms in psychotic disorders, only a few Relationships among different symptom domains were investigated in patients with acute exacerbation of schizophrenia with depressive symptoms, psychotic depression, or schizoaffective disorder, depressive subtype. Scores for depression and depressive factors were correlated with positive, negative, and extrapyramidal symptoms within diagnostic categories. No between-group differences in the relationship of different symptom domains could be found, and no substantial relationship between depression and positive symptoms could be revealed in any diagnostic subgroup. Only the retardation factor of depression showed a significant overlap with negative symptoms; depressive core symptoms did not. Core symptoms of depression were independent from other symptoms in all investigated diagnostic groups. Depression seems to represent a heterogeneous symptom domain with unique relationships of components to positive and negative symptoms across nosological borders. A more differentiated assessment, analysis, and treatment of depressive symptoms is therefore recommended for patients with combined depressive and psychotic symptoms. Keywords: Schizophrenia, major depression, schizoaffective disorder, symptom domains. Schizophrenia Bulletin, 27(l):19-28, 2001. The heterogeneity of symptomatology within the group of schizophrenias is still a major obstacle for defining clinically useful subgroups of these disorders. Furthermore, the problem expands to the nosological borders of schizophrenia on the one hand and other major psychiatric disorders on the other. It is not only difficult to define subgroups of schizophrenia; it is also comparably troublesome to find a clear distinction between the group of schizophrenic disorders, the depressive subtype of schizoaffective disorder, and major depression with psy- Send reprint requests to Dr. M.J. Miiller, Dept. of Psychiatry, University of Mainz, Untere Zahlbacher Str. 8, D-55131 Mainz, Germany; e-mail: [email protected]. 19 Schizophrenia Bulletin, Vol. 27, No. 1, 2001 M.J. Miilleretal. empirical reports, with inconclusive findings, are available so far. A negative correlation was found in patients with acute schizophrenia (Dollfus et al. 1993), whereas a positive relationship between positive and depressive symptoms was found during the chronic course of schizophrenia (Barnes et al. 1989; Norman and Malla 1994). Sax et al. (1996) investigated patients with either schizophrenia and substantial concurrent depression (« = 17) or psychotic depression (n = 25). They revealed an association of depressive and positive symptoms as measured by the Hamilton Depression Rating Scale (HAMD) (Hamilton 1960) and the Scale for the Assessment of Positive Symptoms (SAPS, Andreasen 1982) in only patients with schizophrenia, not patients with psychotic depression. The authors suggested that different levels of depression severity could account for this difference in correlations. However, it has been previously shown (Goldman 1992) that depression as assessed by the HAMD cannot be assumed to be homogenous in psychotic patients. Furthermore, the HAMD sum score might not be an appropriate index of depression severity (Gibbons et al. 1993). Our confirmatory factor analysis (CFA) studies using the Bech-Rafaelsen Melancholia Scale (BRMES, Bech et al. 1979) yielded a three-dimensional structure comprising dimensions of "retardation," "depressive core symptoms," and "accessory depressive symptoms" (Miiller and Wetzel 1998). The three-factor model (table 1) provided the best empirical data fit in patients with acute schizophrenia, although the BRMES had shown unidimensionality in major depression without psychotic features (Maier and Philipp 1985). Therefore, this heterogeneity of depression in psychotic disorders should be taken into account when analyzing correlations with negative and positive symptoms, as differential relationships between latent depressive factors and negative symptoms could emerge. Moreover, different diagnostic groups presenting with concurrent depressive and psychotic symptoms could differ in the structure and composition of depressive factors. Such differences may influence the relationship of depression with other symptom domains. We investigated the relationship between depressive symptoms and other symptom domains (i.e., positive and negative symptoms as assessed by the Positive and Negative Syndrome Scale [PANSS, Kay et al. 1987] as well as akinetic symptoms measured with the Extrapyramidal Symptom Rating Scale [ESRS, Chouinard et al. 1980]). For this purpose, we utilized data from a previously published study (Miiller-Siecheneder et al. 1998). The patients were included according to an operationally defined criterion of concurrent substantial depressive and psychotic symptoms. Three diagnostic groups of patients representing major depression with psychotic features, schizoaffective disorder, and schizophrenia with substantial depression could be separated according to nosological criteria (DSM-III-R, American Psychological Association 1987). In a preceding methodological study, we successfully replicated the aforementioned threedimensional model of depression in this sample (Miiller et al. 1999fo). In the present analysis, we focused on transnosological differences in depressive subfactors and on relationships of depression with positive, negative, and extrapyramidal symptoms. Materials and Methods Patients. The present analysis used baseline data from patients participating in a multicenter clinical trial in 14 psy- Table 1. Three-dimensional factor model of the BRMES BRMES item 1 2 3 4 5 6 7 8 9 10 11 Motor retardation Verbal retardation Intellectual retardation Psychic anxiety Suicidality Depressed mood Self-depreciation Emotional retardation General insomnia Tiredness and pains Work and activities Factor 1 Retardation Factor 2 Depressive core symptoms Factor 3 Accessory depressive symptoms X X X X X X X X X X X Note.—BRMES = Bech-Rafaelsen Melancholia Scale. Muller and Wetzel 1998; Muller et al. 1999b 1 20 Depressive Factors Schizophrenia Bulletin, Vol. 27, No. 1, 2001 chiatric departments in Germany and Austria. The study was conducted in accordance with the current version of the Declaration of Helsinki, and the protocol was approved by local ethics committees. All patients had given their written informed consent; patients under legal guardianship were not enrolled. Some results of the trial have been recently published (Miiller-Siecheneder et al. 1998). Patients were included if they presented with coexisting substantial depressive and psychotic symptoms. The patients' diagnoses were based on structured clinical interviews (the Structured Clinical Interview for DSM-III-R, Spitzer et al. 1990), but inclusion criteria were operationally defined as a total score of at least 60 points on the PANSS, a score of at least 4 points on at least two items of the PANSS positive symptoms subscale, a total score of at least 15 points on the BRMES, and a score of at least 3 points on the BRMES depression item. Included were 123 consecutively admitted patients (aged 18-65 years) with depressive and psychotic symptoms. Thirty-eight patients had major depression with psychotic features (MDE, DSM-III-R 296.24/34), 19 patients had a nonresidual schizophrenia or schizophreniform disorder with features of a major depression without fulfilling syndromal MDE criteria (SCHIZ, DSM-III-R 295.X), and 66 patients had a schizoaffective disorder (DSM-III-R 295.7) of depressive (SAD, n = 64) or bipolar (« = 2) subtype. The two patients presenting with schizoaffective disorder, bipolar type, were excluded from all analyses. Axis II disorder comorbidity (n = 17, 14%) and pretreatment with antipsychotics (n = 73, 59%), antidepressants (n = 53,43%), or benzodiazepines (n = 29, 24%) showed no differences between groups according to DSM-III-R Axis I diagnosis. Symptom Assessments. Psychopathometric baseline data of 119 patients were available for the present analysis (table 2). All participating patients underwent at least a 3-day washout period, during which no antipsychotic or antidepressant drugs were allowed. After 3 days, the baseline data were assessed. All diagnostic assessments and ratings were carried out by experienced clinicians. One rater did all the ratings on a single patient. Rater training was performed before the study; indexes of interrater reliability were not calculated. The assessment comprised the PANSS (Kay et al. 1987), the BRMES (Bech et al. 1979), and the ESRS (Chouinard et al. 1980). The PANSS consists of three subscales measuring positive symptoms (POS, 7 items), neg- Table 2. Sample characteristics at baseline MDE group (n = 37) SAD group (n = 63) % female Age, mean (SD) 44.7% 47.4(12.3) 75.0% 44.8(10.9) 52.6% 38.7 (10.3) (9.7') 3.8 POS, mean (SD) 20.3 (3.3) 21.2(4.1) 26.1 (3.8) 15.5 NEG, mean (SD) GEN, mean (SD) TOTAL, mean (SD) BRMES, mean (SD) BRMES F1, mean (SD) BRMES F2, mean (SD) 27.9 (5.7) 55.9 (7.9) 104.2(13.8) 26.9 (4.2) 9.3 (2.2) 9.8 (2.4) 27.0 (5.8) 51.7(8.2) 99.8(15.0) 25.6 (4.5) 9.2 (2.4) 8.8 (2.2) 28.8 (5.5) 55.6 (7.8) 110.5(13.8) 25.4 (3.7) 9.3 (2.7) 7.9 (2.2) 0.8 4.0 4.2 1.3 0.05 4.4 0.44 0.027 0.018 0.28 0.95 0.015 BRMES F3, mean (SD) ESRS, mean (SD) % ESRS = 0 4 7.9(1.6) 4.5 (6.2) 37.8% 7.7(1.6) 7.9 (9.5) 28.6% 8.2(1.4) 7.6(13.4) 36.8% 0.8 0.47 0.24 0.58 Characteristic SCHIZ group (n = 19) '2,116 1.43 (1.1 1 ) P 0.0064 0.025 < 0.001 Single comparisons (P<0.05) MDE < SAD* SCHIZ < MDE SCHIZ < SAD MDE < SCHIZ SAD < SCHIZ — SAD < MDE SAD < SCHIZ — — SCHIZ < MDE SAD < MDE — — — Note.— BRMES = Bech-Rafaelsen Melancholia Scale; ESRS = Extrapyramidal Symptom Rating Scale (Parkinsonism and akinesia); F1 = Factor 1, retardation; F2 = Factor 2, depressive core symptoms; F3 = Factor 3, accessory depressive symptoms; GEN = PANSS general psychopathology subscale; MDE = major depression with psychotic features; NEG = PANSS negative subscale; PANSS = Positive and Negative Syndrome Scale; POS = PANSS positive subscale; SAD = schizoaffective disorder, depressive subtype; SCHIZ = nonresidual schizophrenia with depressive symptoms; SD = standard deviation; TOTAL = PANSS total score. 3 4 Nonparametric comparison by Kruskal-Wallis ANOVA revealed x 2 = 2.3, df = 2, p = 0.31. Proportion of patients without extrapyramidal symptoms (ESRS score = 0) at the baseline assessment. 21 Schizophrenia Bulletin, Vol. 27, No. 1, 2001 M.J. Miilleretal. ative symptoms (NEG, 7 items), and general psychopathological symptoms (16 items). All 30 items are rated on a seven-point scale from 1 (absent) to 7 (extreme), following well-defined anchor points. The BRMES measures symptoms of depression with high interrater reliability (Bech et al. 1979). Its 11 items are rated from 0 (absent) to 4 (severe). Content, concurrent, and external validity of the BRMES with reference to other observer ratings has been repeatedly reported (Maier et al. 1988; Smolka and Stieglitz 1999). In a previous methodological study on the dimensionality of the BRMES in 132 patients with acute schizophrenia, we could show that a three-dimensional model was most appropriate. The three dimensions of retardation, depressive core symptoms, and accessory depressive symptoms were established by CFA. This three-dimensional model was originally derived from an exploratory factor analysis and was shown to be superior to one-, two-, and fourdimensional models. The three-dimensional model was successfully replicated for the total group of patients of the present study (n = 121) with a goodness-of-fit index of 0.91 for the total sample. A comparison of parameters of the same model derived from the two independent samples revealed a highly satisfactory agreement (comparative fit index = 0.87) (Miiller and Wetzel 1998; Miiller et al., 19996). Furthermore, the correlation pattern of the 11 BRMES items was very similar in the three nosological subgroups of patients with MDE, SCHIZ, or SAD (Miiller et al. 1999a). Table 1 shows the threedimensional model of the BRMES corroborated in two studies (Miiller and Wetzel 1998; Miiller et al. 1999ft). Summary scores for the three factors were derived by summing up the corresponding item scores and were used in the present evaluation of the relationship between symptom domains. Extrapyramidal symptoms were rated with the ESRS (Chouinard et al. 1980), comprising a Parkinsonism selfrating questionnaire and scales for the objective assessment of Parkinsonism and akinesia, of dystonia, and of dyskinesia. The present analysis is restricted to the sum score consisting mainly of Parkinsonism and akinesia symptoms. computed. As parametric and nonparametric coefficients did not show any substantial differences, only Pearson's correlations were reported. Power calculations revealed that in samples with a size of n - 20, 40, and 65, a significant correlation coefficient (p < 0.05) of r > 0.58, 0.42, and 0.35, respectively, can be revealed with a power of about 0.80 (Dallal 1985). The global level of significance was set at a = 0.05. The Bonferroni procedure was used for adjustment of multiple testing (adjusted level of significance a' = 0.05). Results Sample characteristics are presented in table 2. There were significant differences in gender and age between the groups, with a significantly higher proportion of women with SAD than with MDE (p < 0.05). The patients with SCHIZ were younger than patients of the other two groups (p < 0.05). Despite the fact that substantial positive and depressive symptoms were inclusion criteria for the study independent from nosological diagnosis, there were notable differences between the nosological groups with respect to psychopathology. Patients with SCHIZ had significantly higher scores on global psychopathology severity as measured by the PANSS (p < 0.05). Nonspecific, general psychopathology (GEN) was higher in patients with MDE compared to SAD (p < 0.05). Moreover, patients with MDE presented with significantly higher scores on the core depression subscore of the BRMES scores (p < 0.05), whereas retardation and accessory depressive symptoms, as well as BRMES total scores, were comparable between groups. Negative symptoms (PANSS negative subscale) did not differ significantly between groups and were rather high on average, whereas extrapyramidal symptoms assessed by the ESRS were nearly entirely constituted by akinetic symptoms (Parkinsonism) and were comparably low in all nosological subgroups. Additionally, the proportion of patients without extrapyramidal symptoms at baseline assessment (according to an ESRS total score of zero, 32.2% of the total group) was not significantly different between nosological groups. The correlation coefficients for the four domains of positive, negative, depressive, and extrapyramidal symptoms are reported in table 3 separately for the three diagnostic groups. The upper part of the table shows the relationships of PANSS positive and negative subscales as well as BRMES and ESRS total scores. In all three diagnostic groups, only nonsignificant (p > 0.05) correlation coefficients were revealed for the association of positive symptoms with negative, depressive, and extrapyramidal symptoms. With respect to the diagnostic groups, the interrelations were of very similar magnitude and in the Statistical Analyses. Means and standard deviations are presented in table 2. Global group differences in continuous parameters were analyzed by one-way analysis of variance (ANOVA) comparing groups of patients with MDE, SCHIZ, and SAD. For single comparisons between groups, unpaired t tests were used in case of significant ANOVA results. Group differences in gender were examined by x2 tests. Correlations were analyzed by means of Pearson product moment coefficient (r) after inspection of all possible bivariate scatterplots. Additionally, nonparametric Spearman rank correlation coefficients (rs) were 22 Depressive Factors Schizophrenia Bulletin, Vol. 27, No. 1, 2001 Table 3. Correlation between symptom domains in patients with different diagnoses POS SAD — — BRMES NEG POS MDE SCHIZ MDE SAD SCHIZ — 0.23 0.20 0.27 0.31 — — — 0.54* — 0.64* 0.90* 0.70* NEG BRMES MDE SAD ESRS SCHIZ MDE SAD SCHIZ 0.23 0.31 -0.23 -0.29 -0.25 0.52* 0.70* 0.33 0.41* 0.20 — — 0.33 0.07 0.10 0.75* 0.68* 0.27 0.23 0.29 BRMES F1 0.27 0.03 0.27 0.59* BRMES F2 0.25 0.21 0.03 0.31 0.21 -0.17 0.79* 0.76* 0.43 0.14 -0.02 -0.33 BRMES F3 0.08 0.31 0.25 0.14 0.22 0.37 0.49* 0.65* 0.64* 0.29 -0.12 0.21 Note.— BRMES = Bech-Rafaelsen Melancholia Scale; ESRS = Extrapyramidal Symptoms Rating Scale (Parkinsonism and akinesia); F1 = Factor 1, retardation; F2 = Factor 2, depressive core symptoms; F3 = Factor 3, accessory depressive symptoms; MDE = major depression with psychotic features (n = 37); NEG = PANSS negative subscale; PANSS = Positive and Negative Syndrome Scale; POS = PANSS positive subscale; SAD = schizoatfective disorder, depressive subtype (n = 63); SCHIZ = nonresidual schizophrenia with depressive symptoms (n = 19). *ps0.0027(s0.05/18) same direction. Relationships between positive and extrapyramidal symptoms were consistently negative, whereas positive and depressive symptoms showed a low but positive interrelationship. Moreover, negative symptoms showed a consistent pattern of positive, nonsignificant correlations with positive symptoms across the three diagnostic groups as well as positive relations with ESRS total scores, reaching significance in the group of SAD patients (p < 0.05). Negative symptoms were statistically significantly related to the BRMES total score in all subgroups (p < 0.05). The lower part of table 2 provides further information on the relationship between negative and depressive symptoms. It was found that only the retardation subfactor of the BRMES (factor 1) showed substantial and significant (p < 0.05) correlations with the PANSS negative subscore. Again, all three diagnostic subgroups showed a similar correlation pattern. Neither depressive core symptoms (BRMES factor 2) nor accessory depressive symptoms (BRMES factor 3) showed a substantial overlap with PANSS negative symptoms (p > 0.05, figure 1). None of the depression subfactors showed a significant correlation with either positive or extrapyramidal symptomatology. With respect to interrelations among the depressive subfactors, no considerable dissimilarities were yielded between nosological groups (table 4). Within the three diagnostic groups, the BRMES factors were almost unrelated, in accordance with an underlying latent factor model considering orthogonal dimensions. Core depression was significantly related to accessory depressive symptoms only in the SAD group (p < 0.05). When descriptively comparing the correlation coefficients between groups (Fisher's z transformation), no significant differences between corresponding correlation coefficients emerged. Additionally, no significant differences between female and male patients were found with respect to the interrelation of BRMES depression factors in the SAD group. Discussion Relationships Between Symptom Domains in Different Diagnostic Groups. In a study of acutely exacerbated patients with functionally defined concurrent depressive and psychotic symptoms, the correlation pattern between different symptom domains was very similar in patients Table 4. Correlation between BRMES factors in patients with different diagnoses Factor 3 Factor 2 Factor 1 Retardation Factor 2 Depressive core symptoms Factor 3 Accessory depressive symptoms MDE SAD SCHIZ MDE SAD SCHIZ 0.29 0.26 -0.27 0.01 0.20 0.24 0.37* 0.30 0.08 Note.— BRMES = Bech-Rafaelsen Melancholia Scale; MDE = major depression with psychotic features (n = 37); SAD = schizoaffective disorder, depressive subtype (n = 63); SCHIZ = nonresidual schizophrenia with depressive symptoms (n = 19). *pa0.017(s0.05/3) 23 M.J. Miiller et al. Schizophrenia Bulletin, Vol. 27, No. 1, 2001 with different nosological diagnoses. In patients with either schizophrenia, schizoaffective disorder, or psychotic depression diagnosed according to DSM-III-R, positive symptoms (PANSS) were not significantly related to negative (PANSS), depressive (BRMES), or akinetic (ESRS) symptoms. Negative and depressive symptoms were substantially related in the three subgroups of patients, and a slight positive association emerged between negative and extrapyramidal symptoms. These findings strongly support the hypothesis that relations among different symptom domains in patients with both psychotic and depressive symptoms are not substantially different between diagnostic groups when assessed with the same standardized rating instrument. Different nosological categories seem to differ in their particular composition of latent dimensional factors and in the severity of specific symptoms, but not in the presence and relationship of more global symptom domains. Accordingly, global severity of psychopathology as measured by the total scores of the PANSS was higher in SCHIZ patients. The BRMES factor comprising depressive core symptoms (psychic anxiety, suicidality, depressed mood, and self-depreciation) could significantly separate MDE patients from patients with SAD and SCHIZ, although total BRMES scores and scores of the other depressive dimensions (retardation and accessory depressive symptoms) were comparable. The results reflect the ongoing problem in defining nosological borders between different schizophrenic subtypes as well as in establishing a boundary between schizophrenia and related psychotic disorders, mainly schizoaffective disorder and psychotic depression. These results also corroborate a recent factor-analytic study on 221 schizophrenia and 189 nonschizophrenia patients, which proposes that the symptom structure described in schizophrenia is not specific for that diagnosis (Ratakonda et al. 1998). However, that study focused on positive, negative, and disorganized symptoms and did not include depressive or akinetic symptoms. Figure 1. Correlation between negative symptoms and BRMES depression factors in patients with different diagnoses Negative Symptoms (PANSS) • O • O I I o T I I I I I I I I I Depression and Negative Symptoms. A particular issue of the present study was a differentiated evaluation of the relationship between depressive factors and other symptom domains. BRMES total scores were substantially correlated (r > 0.50) with the PANSS negative subscale in all diagnostic groups. The overlap in variance (r2) ranged from 27 percent to 49 percent and is in line with several previous reports using different assessment instruments and investigating patients with various clinical features (Whiteford et al. 1987; Kitamura and Suga 1991; Sax et al. 1996). This result suggests a lack of independence between these two symptom domains. However, when analyzing latent factors of depression, negative symptoms were substantially related exclusively to the retardation factor of the BRMES in all nosological groups, with a 8 m •3 M H Note.— BRMES = Bech-Rafaelsen Melancholia Scale; MDE major depression with psychotic features (n = 37); SAD schizoaffective disorder, depressive subtype (n = 63); SCHIZ nonresidual schizophrenia with depressive symptoms (n = 19). 24 Depressive Factors Schizophrenia Bulletin, Vol. 27, No. 1, 2001 shared variance (r2) of 35 percent to 81 percent, thus providing an explanation for the significant correlation between negative symptoms and BRMES total scores in the three subgroups of patients. Particularly, the BRMES factor of depressive core symptoms was not substantially correlated with negative symptoms in any diagnostic group (r2 < 10%). The correlation of accessory depressive symptoms with negative symptoms also showed low values in all investigated patient groups (r2 < 14%). As previously claimed (Sax et al. 1996), the distinction between depressive and negative symptoms is clinically important in the investigation of underlying biological mechanisms and treatment. Previous studies using the HAMD (e.g., Sax et al. 1996) are likely to have confused negative and depressive symptoms. The HAMD was criticized for its nonspecificity (Goldman 1992), heterogeneity (Gibbons et al. 1993), and deviation from unidimensionality (Maier and Philipp 1985). The BRMES was suggested to be superior in this regard (Maier and Philipp 1985). However, there is still a lack of dimensional homogeneity of the BRMES in psychotic disorders, and a three-dimensional model of depressive symptoms seems to fit empirical data best (Miiller and Wetzel 1998; Miiller et al. 19996). The recently developed Calgary Depression Rating Scale for Schizophrenia (CDSS, Addington et al. 1990; Miiller et al. 1999a) could overcome such deficiencies of traditionally used depression rating instruments in psychotic disorders (Collins 1996). This scale has been reported to show only a weak overlap with negative symptoms in schizophrenia patients (Addington et al. 1994, Addington et al. 1996). It is interesting that three of four symptoms of the BRMES core depression factor (depressed mood, suicidality, and self-depreciation) are covered by the nineitem CDSS. A confounding variable in earlier studies was the propensity of conventional neuroleptics to induce depressionlike symptoms ("akinetic depression," van Putten and May 1978) or signs and symptoms that mimic negative symptoms (Harrow et al. 1994). In the present study, BRMES total score and BRMES subscores were not related to extrapyramidal symptoms, whereas a slight association emerged between negative and extrapyramidal symptoms (r2 = 4% to 17%) (shared variance between 4% and 17%), which reached significance only in patients with SAD. Thus, the relationship between depressive and negative symptoms does not seem confounded by extrapyramidal symptoms in the present study. Additional subgroup analyses in patients with or without baseline extrapyramidal symptoms (ESRS score > or = 0, respectively) revealed no substantial influence of extrapyramidal symptoms on group means or on relationships of the remaining symptom domains (data not shown). As clozapine and other newer antipsychotics have less propensity for inducing extrapyramidal symptoms and seem to show particular antidepressant properties in addition to their antipsychotic efficacy, prospective studies with these drugs using a refined assessment of depression should be carried out. Retrospective statistical analyses, including path analysis (Tollefson et al. 1998), cannot replace prospectively designed studies to untangle overlapping psychopathological assessments. Furthermore, empirically derived and clinically meaningful symptom classifications are more appropriate to test hypotheses of underlying biological mechanisms (e.g., by means of functional imaging and receptor occupancy studies). Depression and Positive Symptoms. Neither the BRMES total score nor any of the depressive factors were substantially related to positive symptoms in any of the diagnostic subgroups. These results could not replicate the findings of Sax et al. (1996) reporting a significant positive correlation between positive and depressive symptoms in schizophrenia spectrum disorder but not in psychotic depression. The authors have claimed that either the higher severity of depression in delusional depression or a different status of depression in both diseases could explain their results. In our study, patients in the MDE and SCHIZ groups had comparable BRMES total scores but differed significantly in the level of depressive core symptoms. Nonetheless, all diagnostic subgroups showed comparable nonsignificant relationships between positive and depressive symptoms. When comparing our study with that of Sax et al. (1996), some differences are apparent. Different assessment scales were used, and the HAMD may be rather unsuitable for specific assessment of depression in people with schizophrenia, as 65 percent of the HAMD items cover symptoms that are not directly mood-related (Snaith 1993). In addition, Sax et al. (1996) investigated only patients without psychopharmacological treatment prior to the study; patients may have received medication within the 72 hours before assessment. In the present study, about 50 percent of patients had received neuroleptics or antidepressants prior to the study, but all underwent washout for 3 days before assessment. It is unclear whether previous medication or washout periods have short- or long-term effects on the relationship of symptom domains. Another study has found a positive association between dysphoric mood and positive symptoms in schizophrenia patients during a period of 12 to 29 months (Norman and Malla 1994), whereas Dollfus et al. (1993) reported a negative association between depressive and positive symptoms during the acute state of schizophrenic illness and a lack of association between the symptom domains at the postacute and residual states. Our study therefore does not corroborate either finding. Nonetheless, 25 Schizophrenia Bulletin, Vol. 27, No. 1, 2001 M.J. Miiller et al. toms and dimensions than traditional investigations. However, we did not analyze the relationship of single symptoms, although such a strategy has been successfully applied (Barnes et al. 1989; Costello 1992; Norman and Malla 1994). Our endeavor may be regarded as intermediate between an entirely symptom-focusing and a completely nosological approach. The high prevalence of depressive symptoms in schizophrenia is increasingly recognized (Siris 1995; Addington et al. 1998). The elevated suicide risk for psychotic patients seems to be related to depressive mood states (Addington and Addington 1992), whereas—at least in chronic schizophrenia—higher scores on negative symptoms were associated with a lower risk for suicide (Fenton et al. 1997). With respect to these data, it seems clinically very important to disentangle depressive and negative symptoms. According to the present results, negative symptoms and depressive core symptoms can be separated across nosological borders. For this purpose, accurate assessment and differentiated analysis are indispensable. When a traditional depression rating scale is used, the partial overlap of some depressive symptoms with negative symptoms has to be taken into account. Depression in psychotic disorders should not be regarded as unidimensional, and there seems to exist a depressive core syndrome independent from positive, negative, and akinetic extrapyramidal symptoms in schizophrenia, in schizoaffective disorder, and in psychotic depression. The findings should encourage further studies on the underlying biological mechanisms, neuropsychological correlates, and specific treatment of symptom domains and factors in patients suffering from that serious combination of psychotic and depressive symptoms, which puts them at the highest potential risk for suicide. our results seem to be intriguing as they were very consistent among three diagnostic subgroups and our evaluation strategy seems to be appropriate for separating negative and depressive symptoms. Limitations and Conclusions. A methodological limitation of the present study is the partly restricted and unequal sample size, due to the inclusion criteria not focusing on equal-sized subgroups. A power analysis revealed that significant nonzero correlations could be revealed with sufficient power in the analyzed subgroups. In addition, the consistency of findings and adjustment for multiple tests substantiate the present results. With respect to the significantly greater number of women with SAD in the present sample, we did not find substantial sex differences in the BRMES factor structure. However, given the generally higher prevalence of depression in women, further studies addressing possible sex differences in the relationship between different symptom domains are needed to clarify this issue. All patients of the present study were newly admitted to the hospital due to an acute exacerbation. Hence, interpretation should not be incautiously extended to the posthospitalization period or to the chronic course of illness. Another problem might be that patients were drug-free for only 3 days. For studying basic psychopathological phenomena, untreated patients are certainly most suitable; however, totally drug-naive patients with acute psychosis and depression are—fortunately, from a clinical viewpoint—the exception in university hospitals. A washout period of 3 days is about as long as could practically and ethically be done. Nevertheless, some drug effects may still have been present due to the different half-lives of different medication in different individuals. Such effects could have contributed to the findings on the relationships between different symptom domains. However, there was no significant difference between the diagnostic groups regarding pretreatment with neuroleptics, antidepressants, or benzodiazepines. Therefore, pretreatment should not have influenced the findings of the present analyses differentially in the three diagnostic groups. When looking at the interrelations of depressive dimensions as assessed by the BRMES, no considerable differences emerged with respect to the nosological groups. The associations were generally low, corroborating a CFA model of three independent latent dimensions (Miiller and Wetzel 1998; Muller et al. 1999b). 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