Depressive symptoms have been reported in schizophrenia patients since the earliest clinical characterizations of the illness and are thought to be highly prevalent representing an important and distinct symptom domain [Reference Chemerinski, Bowie, Anderson and Harvey9]. Depressive symptoms are associated with impairments in social and vocational functioning, poor quality of life and an increased risk of relapse [32,40] also contributing to the alarmingly high rates of suicide [Reference Moller28]. In patients admitted for the first time due to the exacerbation of their psychosis depressive mood as well as loss of self-confidence, feelings of guilt and suicidal thoughts are among the most prevalent symptoms [Reference an der Heiden, Konnecke, Maurer, Ropeter and Hafner6].
However, despite the vast research on depression in schizophrenia patients studies explicitly examining depressive symptoms and their association with other psychopathological symptoms in schizophrenia patients have only rarely been performed so far. Most study reports focus on the assessment of mean scores of depression rating scales often comparing depressed and non-depressed patients yet without going into detail what specific symptoms these so called “depressive” symptoms really are [11,18]. In addition, previous studies vary considerably in terms of the methodology of assessment, the observed interval or the patient status [Reference Siris37] limiting the generalizability of the results. The evaluation and diagnosis of depression in schizophrenia patients is furthermore complicated by the fact that some depressive symptoms such as sleep disturbances, concentration difficulties or attentional deficits overlap with negative symptoms making it hard to differentiate between these symptom domains [Reference Hausmann and Fleischhacker14]. On the other side, some authors found depressive symptoms to be more closely linked to positive than to negative symptoms questioning if the occurrence of depressive symptoms might be a result of living with persistent, severe psychosis [30,34].
Therefore, today the relationship between single depressive symptoms and positive or negative symptoms is still unclear even though a more profound understanding of how these symptoms are interrelated might lead to a better nosologic description of schizophrenia and with it to the development of standardized treatment regimens of the depressive syndrome in schizophrenia [Reference Sax, Strakowski, Keck, Upadhyaya, West and McElroy34]. For this reason, aim of this study was to contribute to the understanding of the role and value of depressive symptoms in schizophrenia by evaluating single depressive symptoms in acutely ill schizophrenia patients and their association with positive and negative symptoms within a naturalistic study.
Data were collected in a multicenter follow-up programme (German Research Network on Schizophrenia) [Reference Wolwer, Buchkremer, Hafner, Klosterkotter, Maier and Moller43] at eleven psychiatric university hospitals and three psychiatric district hospitals in the region surrounding Munich between January 2001 and December 2004. Patients aged between 18 and 65 years and diagnosed according to DSM-IV criteria with schizophrenia, schizophreniform disorder, delusional disorder and schizoaffective disorder were eligible for inclusion. Exclusion criteria were: head injury, severe medical illness such as a malignant disease, alcohol dependency and drug dependency. An informed written consent had to be provided to participate in the study. The study protocol was approved by the local ethics committees [Reference Jager, Riedel, Messer, Laux, Pfeiffer and Naber17].
DSM-IV diagnoses were established by clinical researchers on the basis of the German version of the Structured Clinical Interview for DSM-IV . Depressive symptoms were examined applying the Calgary Depression Scale for Schizophrenia [Reference Addington, Addington and Schissel1]. The CDSS is a 9-item clinician questionnaire (depression, hopelessness, self-depreciation, guilty ideas of reference, pathological guilt, morning depression, early wakening, suicide, observed depression) with a range of the global score of 0–27 points. The CDSS was chosen because it was explicitly developed to examine depressive symptoms in patients with schizophrenia and is not confounded by positive or negative symptoms of schizophrenia psychopathology [Reference Addington, Addington and Maticka-Tyndale4]. A satisfying reliability of the CDSS (Cronbach's α .79) and a concordant validity with the Hamilton Depression Rating Scale (.82) and Beck Depression Inventory II (.79) have been reported [Reference Addington, Addington, Maticka-Tyndale and Joyce2]. To assess symptom severity the clinician rating scale Positive and Negative Syndrome Scale for Schizophrenia (PANSS) [Reference Kay, Opler and Lindenmayer19] was used. All raters had been trained using the applied scales and ratings were performed within the first three days after and biweekly during admission as well as at discharge. Intra-class correlations were calculated based on the PANSS (ANOVA-ICC > 0.8) showing a high inter-rater reliability.
In the entire multicenter study 474 patients were enrolled. Forty-six patients had to drop out for different reasons with another 28 patients excluded due to incomplete admission ratings and 122 patients due to missing CDSS values. Patients excluded form this analysis did not significantly differ from the patients included in terms of gender (P = 0.1984), age (=0.0626), diagnosis (P = 0.073) as well as baseline psychopathology (PANSS total score P = 0).
Therefore, the sample available for analysis comprised 278 (163 male, 115 female) subjects. The mean age was 34.77 years (±11.07) and the mean duration of illness 7.68 years (±9.14). 84% of the patients were diagnosed with schizophrenia, 12% with a schizoaffective disorder and 4% with a brief psychotic disorder and in 11 patients a comorbid depressive episode was diagnosed. The mean number of hospitalisations was 3.94 (±5.68). The duration of current hospitalisation was 68.78 days (±49.65) and the mean age at first treatment 27.03 years (±8.82). Patients were treated under naturalistic conditions (multiple answers possible): 51% of the patients received first-generation antipsychotic, 79% of patients second-generation antipsychotic treatment and 41% of the patients were treated with first – as well as second – generation antipsychotics. Tranquilizers were administered in 66% of patients and mood stabilizers in 12%. Thirty-three percent of the patients were also treated with antidepressants.
2.4. Statistical analysis
A stepwise approach was conducted to examine depressive symptoms in patients suffering from schizophrenia spectrum disorder. In a first step, depressive symptoms were evaluated and described regarding their severity and frequency in acutely ill patients at the time-point of admission. In a second step, in order to examine the presence of depressive symptoms in relation to the patients’ further psychopathological symptoms, depressive symptoms were compared to positive, negative and general psychopathological symptoms using univariate Wilcoxon-tests. In a third step, to evaluate the correlation between depressive symptoms and the patients’ positive, negative and general psychopathological symptoms correlation analyses were calculated using polychoric correlation. With this technique the correlation between two ordinal-scaled variables is expressed by the correlation of the corresponding latent interval-scaled variables. It is recommended if ordinal variables have less than 7 levels [Reference Bartholomew, Steele, Galbraith and Moustaki8]. And in a forth step, factor analysis using principal axis method was computed in order to identify latent structures underlying the data and to identify potential overlap between the different psychopathological symptoms. Parallel plots were used in order to determine a reasonable number of factors. This technique compares the eigenvalues of the original data with the eigenvalues of its random permutations. The method was shown to be superior to the simple eigenvalue-greater-than-one rule. Factor analysis was performed using a correlation matrix, the oblique rotation was based on the assumption that only weak correlations exist between the instrument factors (VARIMAX rotation). To attain a clear arrangement of the results loadings with an absolute value greater than 0.4 are presented in bold. Present results refer to the time-point of admission. All statistical analyses were performed using the statistical software environment R 2.11.1 .
3.1. Baseline psychopathology
At admission, the mean CDSS total score was 6.41 (±4.71) points and the mean PANSS total score 74.01 (±19.46), the mean PANSS positive subscore 18.99 (±6.49), the mean PANSS negative subscore 18.41 (±7.45) and the mean PANSS general psychopathology subscore 36.62 (±10.08) points. For the CDSS score at admission, see Fig. 1.
3.2. Depressive symptoms in acutely ill patients with schizophrenia spectrum disorder
The most frequent depressive symptoms in acutely ill schizophrenia patients were as follows: depressed mood (80%), observed depression (62%), hopelessness (54%), self-depreciation (50%), suicide (37%), guilty ideas of reference (36%), early wakening (33%), pathological guilt (29%), morning depression (28%). Generally, a score of > 6 points in the CDSS total score is believed to identify patients suffering from clinically relevant depressive symptoms [Reference Addington, Addington and Maticka-Tyndale3] revealing that 108 patients (39%) in the present study suffered from depressive symptoms at admission. When comparing patients achieving the threshold for clinically relevant symptoms and those scoring ≤ 6 on the CDSS we found the ones with clinically relevant symptoms to suffer significantly more often from a schizoaffective disorder (P = 0.0438) and to be less likely first-episode patients (P = 0.0409), see Table 1.
The level of significance was P < 0.05 (in bold).
3.3. Psychopathological profile of depressed/non-depressed patients
The depressed and non-depressed patients were compared regarding their mean scores on the PANSS items at admission, Fig. 2. In terms of positive symptoms, the depressed patients were found to suffer from more hallucinations (P < 0.01), whereas the non-depressed patients scored significantly higher on the item “grandiosity” (P < 0.01). When comparing the items of the PANSS negative subscore the depressed patients scored significantly higher on all negative items except the item “difficulty in abstract thinking”. 6 out of the 16 PANSS general psychopathology did not significantly differ between the depressed and non-depressed patients (“mannerisms and posturing”, “uncooperativeness”, “unusual thought content”, “disorientation”, “poor attention”, “poor impulse control”). The most significant difference between the two patient cohorts was found in the items “depression”, “anxiety”, “guilt feelings” and “active social avoidance” with depressed patients scoring higher than the non-depressed subgroup.
3.4. Correlation between depressive and positive, negative and global psychopathological symptoms
Results of the correlation analyses are shown in Fig. 3. The positive items of the PANSS showed a generally low to only moderate correlation with the depressive items of the CDSS. The strongest negative correlation was found between the PANSS item “grandiosity” and the CDSS items “depressed mood”, “hopelessness”, “self-depreciation”, “morning depression” and “observed depression”. Also, for the PANSS negative and CDSS items a rather weak, but positive correlation could be observed with the strongest correlation between items “passive/apathetic social withdrawal” and “observed depression”, “depression” and “hopelessness”. A higher level of a positive correlation was found between depressive and single items of the PANSS general psychopathology subscale. Here the strongest correlation could be found between the PANSS item “guilt” and the CDSS items “pathological guilt”, “guilty ideas of reference” and “self-depreciation”. Moderate to strong correlations were furthermore observed regarding the PANSS items “depression” and “active social avoidance” with the CDSS items “depressed mood”, “hopelessness”, “self-depreciation” and “observed depression”.
3.5. Factor analysis of depressive and positive, negative and global psychopathological symptoms
Based on parallel plots five factors were supposed to be extracted from the CDSS and the PANSS. The loadings of the single items are shown in Table 2. Generally, two factors were characterized by negative and positive items of the PANSS, whereas three factors were formed by CDSS items. The items of the PANSS general subscale did not build up a specific factor themselves. The first factor (“negative symptom factor”) was characterized by loadings of almost all negative items (except item “stereotyped thinking” [N7]) as well as items of the PANSS general subscale. The items of the PANSS positive subscale all loaded on the second factor (“psychotic factor”) as well as the negative items “difficulty in abstract thinking” (N5) and “stereotyped thinking” (N7) and the PANSS general items “unusual thought content” (G9), “poor attention” (G11) and “lack of judgement and insight” (G12). The third factor (“depression factor”) was build up by CDSS items on depression, hopelessness and suicidality, the fourth factor (“depressive guilt factor”) with items “self-depreciation”, “guilty ideas of reference” and “pathological guilt” and the fifth factor (“psycho-vegetative factor”) with items “morning depression” and “early wakening”. The variance accounted for by the five factors was 52%.
a These respective PANSS general psychopathology items were excluded from the factor analysis due to ratings of 1 (=not existent) in > 75% of the patients.
4.1. Phenomenology, prevalence and severity of depressive symptoms in acutely ill schizophrenia patients
One aim of this study was to examine singles depressive symptoms in acutely ill schizophrenia patients. In the total patient sample, the most frequent depressive symptoms were depressed mood (80%), observed depression (62%), hopelessness (54%) and self-depreciation (50%) which is in line with the only few comparative reports on single depressive symptoms in schizophrenia patients. In a recently published analysis of Majadas et al. on the prevalence of depression and its relationship with other clinical characteristics in stable schizophrenia patients using the CDSS, the authors also found depressed mood and self-depreciation to be among the most common depressive symptoms [Reference Majadas, Olivares, Galan and Diez27]. And an der Heiden et al. examined depression in the long-term course of schizophrenia inpatients with their first admission to hospital reporting that depressive mood, loss of self-confidence, feelings of guilt and suicidal thoughts were among the indicators of the depressive syndrome when applying the Interview for the Retrospective Assessment of the Onset of Schizophrenia [Reference an der Heiden, Konnecke, Maurer, Ropeter and Hafner6].
Generally, depressive symptoms reported in patients with schizophrenia as mentioned before seem similar to those reported in studies examining patients suffering from depression. Seemüller et al. reported for example that depressed mood and feelings of guilt are among the most frequent symptoms in patients suffering from a major depressive disorder [Reference Seemuller, Riedel, Wickelmaier, Adli, Mundt and Marneros35]. Besides, somatic symptoms or symptoms on appetite or weight are highly prevalent in patients with mood disorders [Reference Seemuller, Riedel, Wickelmaier, Adli, Mundt and Marneros35], but are usually not explicitly examined in patients with schizophrenia. Possibly, in patients with schizophrenia somatic symptoms might be less prominent compared to the distinct schizophrenia psychopathology or might be reported less often by the patients due to cognitive dysfunction in comparison to patients with mood disorders.
Generally, in the present study the mean CDSS total score was 6.41 points. Similarly, in a comparative study on citalopram augmentation for subsyndromal depression (=having 2 to 4 out of 9 DSM-IV symptoms of a major depressive episode present for at least 2 weeks) 198 outpatients with schizophrenia and schizoaffective disorder were reported to have a mean CDSS score of 6.462 points in patients receiving citalopram and 7.021 points in placebo-treated patients [Reference Zisook, Kasckow, Golshan, Fellows, Solorzano and Lehman45]. These results finding that a mean CDSS score between 6 and 7 points mirrors subsyndromal depression somewhat question the recommended cut-off of > 6 points believed to identify the presence of a major depressive episode in schizophrenia patients [3,45]. One possible explanation for this discrepancy might lie in the different patient samples and differing sample sizes for in the study proposing the respective cut-off Addington et al. examined only 150 patients shortly after they had experienced a relapse [Reference Addington, Addington and Maticka-Tyndale3]. Future studies should critically re-evaluate present findings concurrently proposing a suitable threshold or instrument in order to adequately identify wearing depressive symptoms in schizophrenia patients.
4.2. What are depressive symptoms in schizophrenia? Association with positive, negative and general psychopathological symptoms
The second aim of our study, besides the description of single depressive symptoms in schizophrenia patients, was to examine the association of these depressive symptoms with schizophrenia psychopathology. To our knowledge this is the first study explicitly examining the CDSS and PANSS on a single item basis using correlation and factor analysis. The traditional results of factor analyses identifying five distinct factors of the PANSS [Reference Hayashi, Igarashi, Yamashina and Suda15] and three factors of the CDSS [Reference Maggini and Raballo26] cannot be compared to present results because first, in the present study the number of factors was limited based on the parallel analysis and second, CDSS and PANSS items were calculated together which significantly influences the item loading of the respective factors.
4.2.1. Positive symptoms
Results of the univariate tests comparing the depressed/non-depressed patient subgroups and results of the correlation analysis match the generally negligible correlations between depressive and positive symptoms, which is in line with other reports [Reference Muller, Szegedi, Wetzel and Benkert29]. However, the depressed/non-depressed patients differed significantly in two positive items, namely hallucinations and grandiosity. Hallucinations were found to show a moderately strong correlation to depressive symptoms. Consistent with results of past research patients with hallucinations were found to suffer more likely from pathological guilt and self-depreciation emphasizing the role of emotion in schizophrenia patients [Reference Serper and Berenbaum36]. Smith et al., for example, examined the link between depression and hallucinations in 100 patients suffering from a schizophrenia spectrum disorder and reported that patients with more depressive symptoms had auditory hallucinations of greater severity [Reference Smith, Fowler, Freeman, Bebbington, Bashforth and Garety38]. It has been hypothesized that this might be due to greater use of expressive suppression associated with an increase in the severity of hallucinations [Reference Badcock, Paulik and Maybery7]. In terms of the link between depressive symptoms and grandiosity a negative relationship was found in that sense that patients with ideas of grandiosity were less likely to suffer from depressive symptoms. The fact that in the factor analysis the item grandiosity showed a negative loading on the “depression factor” furthermore underlines this relationship, which is somewhat expected from a clinical point of view. Apart from the item “grandiosity” all positive symptoms loaded on a “positive symptom” factor suggesting a strong affiliation within the positive syndrome and a distinct boundary to the other symptom domains.
4.2.2. Negative symptoms
Similarly, all negative symptoms except the item “stereotyped thinking” loaded on one factor (“negative symptom factor”) mirroring uniformity also for the negative symptom domain. Besides, given that the “negative symptom factor” accounted for most of the data variance there seems to be a stronger relation within the negative symptom domain compared to positive or depressive symptoms. As mentioned before, comparative research regarding the correlation between negative and depressive symptoms does not give clear guidance with some authors reporting a lack of association between depression and negative symptom ratings [24,39] and others finding highly significant correlations [Reference Kitamura and Suga20]. Rocca et al. believe that this discrepancy might be explained by the inconsistent assessment tools and threshold for diagnosis of depressive comorbid disorder applied in previous research [Reference Rocca, Bellino, Calvarese, Marchiaro, Patria and Rasetti33]. Another relevant aspect, however, might be that mostly total scores of depressive and/or negative syndromes have been examined, an approach possibly too rough to detect subtle associations between specific symptoms. Sax et al. for example report of a significant relationship between depressive and negative symptoms limited to negative symptoms of poor motivation, social withdrawal, and anhedonia [Reference Sax, Strakowski, Keck, Upadhyaya, West and McElroy34]. Also, Whiteford et al. found a significant correlation between depressive symptoms and negative symptoms on avolition-apathy and anhedonia-asociality, but not with other negative symptoms [Reference Whiteford, Riney and Csernansky42]. Concurrently, Kulhara et al. suggest a significant correlation between the negative symptom domain and specific depressive symptoms like retardation, lack of energy or slowness, and not with the general depressed mood itself [Reference Kulhara, Avasthi, Chadda, Chandiramani, Mattoo and Kota22]. In agreement with these results, we also found stronger correlations between specific depressive and negative symptoms such as passive social withdrawal or emotional withdrawal. Interestingly, negative items on formal thought disorders such as difficulty in abstract thinking or stereotyped thinking did not significantly differ between depressed/non-depressed patients and showed negligible correlations with depressive symptoms again underlining the hypothesis that there is a partial overlap between depressive and negative symptoms, yet based on generally two distinct symptom domains [Reference Hausmann and Fleischhacker14].
4.2.3. General psychopathology
As one might expect, due to very similar or even identical items of the CDSS and the PANSS general psychopathology subscore, the most significant association between depressive symptoms and the patient's other psychopathological symptoms was found for specific PANSS general psychopathology items such as “depression” and “guilt”. This strong relationship is furthermore supported by results of the factor analysis finding the PANSS item “depression” loading on the CDSS “depression factor” and the PANSS item “guilt” concurrently loading on the CDSS “depressive guilt factor”. A strong correlation has consistently been reported between the CDSS and the PANSS general psychopathology subscore suggesting that this subscore of the PANSS gives a correct global evaluation of depression in patients with schizophrenia [Reference Majadas, Olivares, Galan and Diez27]. However, what should be kept in mind is that the PANSS general psychopathology subscore has certain limitations (such as not evaluating suicidality) making the specifically developed CDSS the number one choice when assessing depressive symptoms in schizophrenia patients [10,21]. What becomes furthermore apparent is the strong association between guilt and depression in schizophrenia patients which has been reported before [Reference Lake23]. Due to a very strong association between the overall level of depression and the degree of guilty ideas, it has been discussed whether guilty ideas of reference possibly yield predictive value in regard to helping identify individuals likely to develop a future episode of major depression [Reference Zisook, Nyer, Kasckow, Golshan, Lehman and Montross44]. Our results suggest that the symptom of guilt is an integral part of the depressive syndrome in schizophrenia patients supporting its potential role as indicator of a depressive episode in schizophrenia patients – an interesting result requiring replication.
4.3. What can be drawn from this study?
Our results suggest that depressive symptoms are a distinct psychopathological domain in patients suffering from schizophrenia given that the majority of the depressive symptoms loaded on a specific depression factor supporting the recently ongoing discussion on classification schemes in the psychiatric community. Interestingly, Hagele et al. found depressive symptoms to correlate with dysfunction in reward anticipation regardless of the respective diagnostic entity when comparing anticipation of reward between patients with schizophrenia, major depressive disorder, bipolar disorder and alcohol dependence and controls. They conclude that their results strengthen a dimensional approach in psychiatry [Reference Hagele, Schlagenhauf, Rapp, Sterzer, Beck and Bermpohl13]. There has been an ongoing discussion on how to classify and define psychiatric symptoms and diseases given that the current diagnostic procedure is unlikely to represent discrete nosological entities [Reference Linscott, Allardyce and Van25]. Van Os and Kapur, for example, describe how the addition of dimensional indicators applied across diagnostic categories of affective and non-affective psychotic disorder would mirror the evidence for shared genetic causes underlying diagnoses of psychotic disorders [Reference Van Os and Kapur41]. In order to allow for genetic, neuroimaging and cognitive science to be incorporated into future diagnostic schemes and aiming to find new ways of classifying mental disorders a specific program (Research Domain Criteria project) has been founded by the National Institute of Mental Health [12,16]. Such funding projects might allow for future research and clinical practice to be driven by neuroscience-based nosologies and not by symptom clusters as today, resulting in a better understanding and evolving more effective treatment approaches even in such complex diseases such as schizophrenia [12,16].
4.4. Strengths and limitations
The naturalistic study design is both a strength and a limitation. On the one hand such a design does not allow a sufficient control of study results for the effect of different pharmacological treatments, on the other hand a naturalistic design resembles the daily clinical routine allowing to draw reliable clinical implications. Also, due to the liberal inclusion and exclusion criteria, findings of this study on treatment seeking patients might be more generalizable and exhibit higher external validity than results from RCTs.
In acutely ill schizophrenia patients 39% of the patients suffered from mild to moderate depressive symptoms. The most prevalent depressive symptoms were depressed mood, hopelessness and self-depreciation. Negligible correlations were found between depressive and positive symptoms, whereas low to moderate correlations were found between depressive and negative symptoms. The fact that the depressed patients scored significantly higher on almost all negative symptoms suggests a partial overlap between these symptom domains. Still, the factor analysis identified a single factor loading almost all negative symptoms accounting for most of the data variance as well as a psychotic factor and factors of depression suggesting that depressive symptoms are a distinct symptom domain in acutely ill schizophrenia patients.
Disclosure of interest
The authors declare that they have no conflicts of interest concerning this article.