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Schizophrenia and depression: Challenging the paradigm of two separate diseases—A controlled study of schizophrenia, depression and healthy controls

Schizophrenia and depression: Challenging the paradigm of two separate diseases—A controlled study of schizophrenia, depression and healthy controls

Schizophrenia Research 77 (2005) 11 – 24 www.elsevier.com/locate/schres Schizophrenia and depression: Challenging the paradigm of two separate diseas...

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Schizophrenia Research 77 (2005) 11 – 24 www.elsevier.com/locate/schres

Schizophrenia and depression: Challenging the paradigm of two separate diseases—A controlled study of schizophrenia, depression and healthy controlsB Heinz Ha¨fnerT, Kurt Maurer1, Gqnter Trendler2, Wolfram an der Heiden3, Martin Schmidt4, Regina Ko¨nnecke5 Schizophrenia Research Unit, Central Institute of Mental Health, J5, D-68159 Mannheim, Germany Received 15 December 2004; received in revised form 10 January 2005; accepted 10 January 2005 Available online 2 March 2005

Abstract Background: We studied descriptive and causal associations between schizophrenia, depressive symptoms and episodes of depression. Methods: Untreated psychotic, depressive and negative symptoms were assessed retrospectively from onset until first admission using the IRAOS in a population-based sample of 232 first episodes of schizophrenia. A representative subsample of 130 patients, studied retrospectively until onset and followed up prospectively over 6 months after first admission, were compared with 130 age- and sex-matched healthy population controls and with 130 equally matched first admissions for unipolar depressive episodes. Results: The lifetime prevalence of depressive mood (z2 weeks) at first admission for schizophrenia was 83%. The most frequent initial symptom of schizophrenia was depressive mood, appearing more than 4 years before first admission and followed by negative symptoms and functional impairment. Showing considerable overlap in symptoms and functional impairment at their initial stages, schizophrenia and unipolar depression became clearly distinguishable with the emergence of psychotic symptoms. In the first psychotic episode 71% presented clinically relevant depressive symptoms, 23% fulfilled the ICD-10 criteria for a depressive episode. With remitting psychosis the prevalence of depression, too, decreased. The high

B Revised version of an oral presentation entitled bSchizophrenia and depression—A doubly controlled study of onset and course in first admissions for schizophrenia, depression and in healthy controlsQ given at the 12th Biennial Winter Workshop on Schizophrenia, Davos, February 7–13, 2004. T Corresponding author. Tel.: +49 621 17032951; fax: +49 621 17032955. E-mail addresses: [email protected] (H. Ha¨fner)8 [email protected] (K. Maurer)8 [email protected] (G. Trendler)8 [email protected] (W. an der Heiden)8 [email protected] (M. Schmidt)8 [email protected] (R. Ko¨nnecke). 1 Tel.: +49 621 17032954; fax: +49 621 17032955. 2 Tel.: +49 621 17032956; fax: +49 621 17032955. 3 Tel.: +49 621 17032953; fax: +49 621 17032955. 4 Tel.: +49 621 17032956; fax: +49 621 17032955. 5 Tel.: +49 621 17032957; fax: +49 621 17032955.

0920-9964/$ - see front matter D 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.schres.2005.01.004


H. Ha¨fner et al. / Schizophrenia Research 77 (2005) 11–24

frequency of depressive symptoms at the prepsychotic prodromal stage and their increase and decrease with the psychotic episode suggests that depression in schizophrenia might be expression of an early, mild stage of the same neurobiological process that causes psychosis. Conclusions: The high prevalence of depression in the population and the diversity of its causes prompted us to speculate about a hierarchical model of preformed dimensional patterns of psychopathology. D 2005 Elsevier B.V. All rights reserved. Keywords: Depression; Prodrome; Schizophrenia; Early course; Sequence of stages; Paradigm of hierarchical symptom patterns

1. Introduction Unipolar depression is a frequent comorbidity disorder of schizophrenia. The prevalence figures reported from numerous studies vary a great deal: According to a review by Siris and Bench (2003) prevalence rates range from 6% to 75% with a modal value of 25%. Reasons for this pronounced variance are: 1) whether diagnoses, syndromes or single depressive symptoms are being looked at, 2) whether point or lifetime prevalence rates are used and 3) the illness stage of schizophrenia studied. Schizophrenia and unipolar depression share some of their risk factors and precursors. 1) Unipolar depression shows genetic overlap in the offspring of parents suffering from schizophrenia (Kendler et al., 1993, 1996; Maier et al., 1993, 2002). In the New York High-Risk Study Erlenmeyer-Kimling et al. (1991) found that 18% of the offspring (N=73) of mothers with schizophrenia developed schizophrenia and 7% affective psychosis by age 26 years. Molecular-genetic research has identified one gene (G30/G72 in 13q candidate region) which seems to be involved in both schizophrenia and bipolar disorder (Maier et al., 2005). 2) Pre-, peri- and postnatal complications of brain development are risk factors for both disorders, but more prevalent and more severe in schizophrenia than depression (Jones et al., 1994, 1998; Elkis et al., 1995; Marcelis et al., 1998; Van Os et al., 1999c). 3) Structural brain abnormalities constitute risk factors for both schizophrenia and depression: mild loss of brain volume mainly in the prefrontal and temporal cortex and the hippocampus area (Jones et al., 1994; Elkis et al., 1995; Hirayasu et al., 1998; Weinberger, 1999; Heckers et al., 2002).

4) Psychosocial stress is a well-established precipitant of depressive illness and of psychotic relapses in schizophrenia, but not sufficiently replicated as a precipitant of first-episode schizophrenia (Dohrenwend et al., 1995; Bebbington et al., 1993). 5) Certain personality traits, such as neuroticism (Maier et al., 1994; Van Os et al., 2002), and subtle impairment in social, interpersonal and cognitive abilities in childhood and adolescence are precursors of both schizophrenia and depression (Done et al., 1994a,b; Van Os et al., 1999c; Jones and Done, 1997). The effect sizes of all these risk factors, except psychosocial stress, in persons with depression occupy an intermediate position between those in probands with schizophrenia and healthy subjects. The dimensional structure of the full symptoms of schizophrenia comprises besides Liddle’s (1987a,b; Liddle and Barnes, 1990) three factors–positive (reality distortion), negative (psychomotor poverty) and disorganisation–depression as a fourth factor (Kitamura et al., 1995; McGorry et al., 1998; Van Os et al., 1999a,b; Lo¨ffler and Ha¨fner, 1999). Verdoux et al. (1998) and Van Os et al. (1999c) have shown that psychosis is a dimension continuously distributed in the general population, ranging from one single psychotic symptom in healthy individuals to full-blown psychosis in need of treatment. The dimension bdepressed moodQ, also continuously distributed in the general population, is highly significantly associated with the psychosis dimension only in schizophrenic psychosis. Less severe psychopathology on the depression dimension–subthreshold depressed mood and single depressive symptoms in mentally healthy individuals–seem to be widespread in the population and independent of the psychosis dimension.

H. Ha¨fner et al. / Schizophrenia Research 77 (2005) 11–24

In a 3-year prospective study based on a Dutch population sample from the NEMESIS Study Krabbendam et al. (2004a,b) and Hanssen et al. (2004) found that in probands not suffering from psychosis at baseline psychotic experiences were associated with a 3.99% risk of developing broadly defined psychosis by 3-year follow-up. In the absence of psychotic experiences and depression the risk for developing psychosis was 0.5%. For probands reporting both depressive mood and single psychotic symptoms at baseline the risk for psychosis was as high as 21.71%. Considering the various common risk factors and the association between psychosis-proneness and the depression dimension as a risk factor for schizophrenia in the population at large, it seems very likely that depression and schizophrenia do not merely represent comorbidity, but might share some of their aetiology (Hirsch et al., 1989; Crow, 1990; Taylor, 1992). It is not yet possible to test the validity of this hypothesis directly on the level of causal neurobiological mechanisms. But we will try to gain evidence for or against it by testing some subhypotheses. We studied the frequency of clear-cut depressive symptoms in schizophrenia at the prodromal stage, in the psychotic episode and in the psychosis-free interval. The hypotheses that we tested on this data run: 1) The frequency of depressive symptoms (lifetime, period and point prevalences) in schizophrenia is lower than in depressive illness, but higher than in healthy controls. 2) Depressive symptoms, followed by negative symptoms and functional impairment, emerge before the onset of psychotic symptoms. As the illness progresses–deterioration is operationalised by increase in psychotic symptoms– depressive symptoms, too, become more prevalent and like psychotic symptoms show a maximum at the climax of the episode. With waning psychotic symptoms in the remitting episode a short period of post-psychotic depression occurs. 3) In both schizophrenia and depression patients become socially impaired before the climax of the first episode, depressed patients less so than patients suffering from schizophrenia, but more so than healthy controls. Ideally these hypotheses are tested in prospective studies of representative at-risk populations. However, due to the low annual incidence rate and the frequently unspecific type of onset of schizophrenia,


that approach is impractical. Course-related testing is additionally marred by a shortcoming that cannot be corrected for ethical reasons: Antipsychotic and antidepressive medications modify symptoms in a highly uncontrollable way. For this reason the results gained on treated illness will be of limited validity. In contrast, data on the illness course prior to first admission are largely uninfluenced by antidepressive and antipsychotic medications. Nevertheless, on causal associations, these data collected retrospectively using the IRAOS (Ha¨fner et al. 1992, 1999a, 2003)–although they are based on a clear-cut temporal structure–provide merely pointers rather than hard evidence.

2. Materials and methods The ABC Schizophrenia Study sample was recruited from consecutive first admissions with a diagnosis of schizophrenia (ICD-9: 295, 297, 298.3, 298.4) in age range 12–59 years in a 2-year period from a semirural, semiurban population of about 1.5 million (Mannheim, Heidelberg, Rhine-Neckar District, Eastern Palatinate) to any of the ten mental health institutions (mental hospitals, psychiatric and child-psychiatric university departments) serving that population. A subsample of 130 first admissions from a section of the catchment area (Mannheim, Ludwigshafen, Eastern Palatinate) was the basis for a controlled, retrospective analysis of the early illness course and a prospective follow-up conducted 6 months after first admission. Of the 276 persons who fulfilled the inclusion criteria and were interviewed using the PSE (Wing et al., 1974) and the SANS (Andreasen, 1983) upon hospital admission 16% had experienced episodes of psychotic symptoms of at least 14 days duration before first admission. As a result, 232 cases (=84% of the sample) with first illness episodes of schizophrenia were included in the analysis. For evaluating the PSE data we used a computeraided diagnostic system, CATEGO, which produces automatic psychiatric diagnoses. These instruments had also been adopted in the WHO schizophrenia studies, and we were provided with this data for comparative purposes.


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Table 1 Demographic characteristics of the samples studied Schizophrenia sample n=130 %

Depression sample n=130 %

Normal controls n=130 %

Gender Men Women

50.8 49.2

50.8 49.2

50.8 49.2

Marital status Single Married Stable partnership Separated Divorced Widowed

62.3 18.5 7.7 3.8 6.2 1.5

49.2 29.7 14.9 3.1 2.3 0.8

31.5 36.9 30.0 – 1.5 –

4.6 25.4

6.9 25.6

9.3 39.2
















Educational level University degree General certificate of education— A level (Abitur) General certificate of secondary education (Realschlule) Elementary school (Hauptschule) Certificate from a specialized institution of higher learning (Fachoberschule) Dropped out without certificate In education

Within 2–5 weeks of first admission and, hence, mostly after remission of psychosis to avoid memory distortion, a second interview session took place where the patients were administered the IRAOS interview. To offset memory failures the IRAOS was also done with a key informant, and a modified version was applied to all available documents (medical records, etc.) (for a detailed description of sample and assessment instruments see Ha¨fner et al., 1993). For the controlled study of the early illness course a representative subsample (n=130) was drawn from a defined section of the ABC study area (Mannheim, Eastern Palatinate). Population controls, randomly drawn from the population registers of the study area, were matched to each patient in the schizophrenia sample by age and sex.

A control group of patients with depression (n=130), also matched by age and sex, was recruited from among consecutive first admissions with ICD-10 diagnoses F32, F33, F34.1 and F43.2. Because of the different age of risk, it took considerably longer to recruit the depressed group. Especially young depressed males required for matching to the great number of young males in the schizophrenia group were difficult to find. Bipolar disorder was not included in the study, because the diagnosis cannot be given with certainty in the first episode. The demographic characteristics of the three study groups are given in Table 1. The mean age difference of the matched pairs (age at first admission) was 0.58 years (sd 2.4 years). As for each patient with schizophrenia a patient with depression and a healthy population control were interviewed, there were 50.8% men and 49.2% women in each group. The composition of the depression sample including diagnoses or subtypes is given in Table 2. The high proportions of severe depression (F32.2, 32.30, 32.31) (65.4%) and psychotic depression (16.9%) are primarily accounted for by the criterion bfirst admissionQ used for matching. Adjusted in age and sex to the schizophrenia sample, the depression group shows an overrepresentation of severe cases. This means that the sample of depressed patients does not permit us to draw valid conclusions on depression in general. But our sample representing a rather severe section from the spectrum of depressive illness is well-suited to testing the hypotheses formulated at the outset, because any major influences of external variables (e.g. age and sex) on the design variables are excluded. In addition, a depression sample biased towards more severe psychopathology is better suited Table 2 Diagnostic composition (ICD-10 diagnoses) of the depression sample as based on symptoms assessed by the IRAOS Mild depression (F32.1; n=7) and other types of depressives episodes (F32.8; n=2) Moderate depression (F32.10, 32.11) Severe depression (F32.2, 32.30, 32.31) Severe depression with psychotic symptoms (F32.30, 32.31) Severe depression with mood-incongruent psychotic symptoms (F32.31)

6.9% (n=9) 27.7% (n=36) 65.4% (n=85) 16.9% (n=22) 14.6% (n=19)

130 first admissions with a clinical diagnosis of a moderate or a severe depressive episode (ICD-10: F32, 33, 34.1, 43.2).

H. Ha¨fner et al. / Schizophrenia Research 77 (2005) 11–24 Table 3 Number of patients with schizophrenia and depression assessed/lost at 6-month follow-up Follow-up

Patients with schizophrenia

No Yes


Patients with depression No


11 (8.5%) 7 (5.4%) 18 (13.8%)

18 (13.8%) 94 (72.3%) 112 (86.2%)


29 (22.3%) 101 (77.7%) 130 (100.0%)

for comparisons with schizophrenia cases, because the diagnostic criteria for schizophrenia, too, and the inclusion criterion bfirst admissionQ yield samples that comprise more or less severe cases from the total spectrum of psychotic illness and exclude all milder forms to be found on the psychosis dimension. Table 3 shows the proportions of patients lost for various reasons (deceased, not reached, refusing) at follow-up in the schizophrenia and depression groups. At 6 months, 112 probands from the depression group (=86.2% of 130) and 101 from the schizophrenia group (=77.7% of 130) went through a complete follow-up assessment. The following analyses are based on 94 probands from each patient group and 94 matched bhealthyQ controls (=72.3% of the total sample each), for whom there were complete data sets available in all three groups. Due to the matching procedure the sex differences in the samples are uninformative. A comparison across the three groups showed what we had demonstrated in our previous comparisons of the


ABC sample and healthy controls, namely that there is little indication of persons with schizophrenia lagging behind their healthy peers in social-role achievement at age of illness onset (Table 4). And the same holds for the depression group. The result of a somewhat lower proportion of healthy controls with finished school education compared with the two patient groups is accounted for by the fact that a higher proportion of these persons are still in education. Analogously, the slightly higher proportion of persons with schizophrenia with finished occupational training can be explained by the fact that a higher proportion of this group finish their training on a lower level. The lack of difference in the other roles indicates that compared with healthy controls the two patient groups are not yet socially disadvantaged or delayed in their social development to any essential extent at illness onset, except for a weak trend to finishing school or vocational training earlier.

3. Results 3.1. ABC study sample (n=232 first episodes of schizophrenia) Testing Hypothesis 1: frequency of the depressive syndrome in schizophrenia, we calculated the lifetime prevalence of depressive mood at first admission, a core syndrome of depression clearly distinguishable from negative symptoms. Eighty-three percent of the total ABC first-episode sample of schizophrenia and 81% of the cases with a restrictive ICD 295 diagnosis of schizophrenia had suffered from depressive mood

Table 4 Social-role performance in patients with schizophrenia (Sz), depression (Dep) and in normal controls (NC) at first sign of illness Social role

Finished school education Occupational training Employment Own income Own accommodation Marriage/stable partnership

Percentage of probands fulfilling role

Test of significance



Normal controls




65.4 43.9 39.1 43.1 48.5 39.2

69.5 29.2 35.2 50.8 47.7 43.9

61.5 35.7 36.2 46.2 50.0 51.9

McNemar test: n.s.=not significant; opb0.10; *pb0.05; **pb0.01.




n.s. ** n.s. n.s. n.s. n.s.


* n.s. n.s. n.s. n.s. n.s.


n.s. n.s. n.s. *


H. Ha¨fner et al. / Schizophrenia Research 77 (2005) 11–24

for at least 2 weeks before first admission. Depressive symptoms persisting from onset until first admission were more frequent than a recurrent type (39% versus 34%), and a single occurrence was rare (8%). To find out whether depressive mood in the early course is a predictor of symptoms in the first psychotic episode, we compared the 19% of patients without an episode of depressive mood in the early course with the 81% who had experienced at least one episode. We found that depressed patients showed significantly higher scores for depressive, but also for positive, negative and non-specific symptoms in the first episode compared with non-depressed patients (CATEGO total score: 42 for depressed, 30 for non-depressed) (Ha¨fner et al., 1999b). 3.2. Comparison of patients with schizophrenia, depression and of healthy controls (each group n=130) Eighty-one percent of the patients with schizophrenia and 79% of those with depression had not received any psychopharmacological treatment before first admission. The duration of the early illness course from the first sign of the disorder until first admission was 5.3 years in schizophrenia and 7.2 years in depression. Despite the fact that severe depressive episodes are overrepresented in the depression group, this result is an indication of the frequency of long-persisting subclinical prodromal stages or of mild depressive illness that precedes the climax of the first depressive episode. 3.3. Depressive symptoms in the early course of schizophrenia, depression and in healthy controls As depressive symptoms assessed in schizophrenia may be confounded by negative symptoms (Crow, 1980; Knights and Hirsch, 1981; Siris et al., 1988; Siris, 2000; Wassink et al., 1999), we selected four depressive symptoms clearly distinguishable from negative symptoms: depressive mood (z2 weeks), feelings of guilt, lack of self-confidence, suicide attempt and compared the lifetime prevalence rates for these symptoms at first admission between the three groups (Table 5). As expected the lifetime prevalence rates by age at first admission for schizophrenia lie between those for patients with

Table 5 Comparison of 4 depressive IRAOS items in patients with schizophrenia and depression and in bhealthyQ controls—lifetime prevalence by age at first admission because of schizophrenia; both control samples matched by age and sex IRAOS item Patients with Patients with bHealthyQ Cochran’s schizophrenia depression controls Q test (n=130)% (n=130)% (n=130)% Depressive mood Feelings of guilt Lack of selfconfidence Suicide attempt

















**pb0.01, ***pb0.001. Source: Ha¨fner, 2004.

depression and healthy controls. The differences are highly significant. But it also became clear that depressive symptoms are quite frequent in schizophrenia, too. The rate of attempted suicide at this early illness stage in the depression group (almost 30%) is almost three times that among healthy controls. A further finding was that healthy controls, too, show rather high lifetime prevalence rates of depressive mood and lack of self-confidence. To study the point prevalences of symptoms at onset as a further aspect of Hypothesis 1, we compared the ranks and frequencies of the ten most frequent initial symptoms in schizophrenia and depression respectively, which yielded a total of 13 symptoms (Table 6). Although the values are low, there is a high degree of overlap. Eight (shaded cells in the table) of the 13 symptoms do not differ significantly in frequency. The rank orders, too, show similarities. That means that in both disorders a depressive core syndrome (consisting of depressive mood, loss of self-confidence, worrying, disturbed appetite and/or sleep, anxiety) and a negative syndrome in combination with early indicators of functional impairment (e.g. difficulties of thinking and concentration, loss of energy and social withdrawal) frequently occur at the earliest stage of the prodromal phase in both disorders. The few significant differences between schizophrenia and depression are accounted for by symptoms of low specificity: Patients with schizophrenia are more frequently restless and have fewer episodes of depressive mood. The

H. Ha¨fner et al. / Schizophrenia Research 77 (2005) 11–24


Table 6 Percentages of probands presenting initial symptoms in schizophrenia (Sz) and depression (Dep)—symptoms with rank 1 to 10 in either group


Schizophrenia %

Worrying Headaches, other aches and pains Nervousness, restlessness Anxiety Difficulties of thinking, concentration Depressed mood Loss of self-confidence Social withdrawal, suspiciousness Disturbed appetite, sleep Loss of energy/slowness Loss of libido Oversensitivity Other changes in affect (blunted)

19.2 10.3 21.9 23.2 17.1 20.6 11.9 11.6 15.0 13.5 4.1 3.3 11.1

Depression Rank 4 – 2 1 5 3 8 9 6 7 – – 10

% 14.1 13.2 6.2 15.4 16.5 34.9 14.0 13.3 21.9 8.5 8.5 9.3 0.8

Rank 5 8 – 4 3 1 6 7 2 5 5 9 –

Sz vs. Dep n.s. n.s. *** o

n.s. * n.s. n.s. n.s. n.s. n.s. o


McNemar test: n.s.=not significant; opb0.10; *pb0.05; ***pb0.001.

only characteristic difference is shown by the symptom blunted affect: not yet very prevalent in schizophrenia at this early stage, in depression it occurs at a frequency under 1%. 3.4. Period prevalences of symptoms in the early course of schizophrenia and depression compared with controls The next step in studying the expected and observed frequency of symptoms in the early courses of the two disorders–this analysis is relevant to Hypothesis 1 and 2– is illustrated in Table 7. It shows the period prevalences of the ten most frequent symptoms–a total of 17 symptoms–in the early course of schizophrenia and depression from onset to first admission and in healthy controls for the same period of life. In the last two columns on the right the two patient groups are compared with healthy controls. The highly significant differences in all but two items–dissocial behaviour and oversensitivity (the latter showing a maximum in depression), which are presumably widespread personality traits–between patients and healthy controls indicate that both illnesses at this early stage are already clearly distinguishable from health. A comparison of the prevalence figures and ranks of the ten most frequent initial symptoms between schizophrenia and depression (Table 7) again showed

surprising similarities: six from a total of 17 items (nervousness/restlessness, anxiety, difficulties of thinking and concentration, disturbed appetite and/or sleep, irritability and dissocial behaviour) (cf. shaded cells in the table) occurred at similar frequencies. Most of the items different in frequency showed high rates in the other group, too (depressed mood 100% vs. 85%, social withdrawal 91% vs. 80%). The only exceptions were the two delusional symptoms highly specific to schizophrenia. Judged by their frequency depressive symptoms in the schizophrenia group seem to occupy an intermediate position between the depression group and healthy controls, but to be closer to the depressive group than to healthy controls. This result supports Hypothesis 1. The high degree of overlap between the ten most frequent initial symptoms of schizophrenia and depression and the ten symptoms showing the highest period prevalences from onset to first admission (in schizophrenia 9 of the 10; in depression 8 of the 10 most frequent initial symptoms are among the ten symptoms with the highest period prevalence rates in the early course) strongly suggest that the initial symptoms assessed reflect a core psychopathology of these disorders. To give an idea of the illness course from onset to first admission, i.e. to the climax of the first episode, we compared the beginning and the end state of that


H. Ha¨fner et al. / Schizophrenia Research 77 (2005) 11–24

Table 7 Comparison of the period prevalences of the ten most frequent symptoms in the early course of schizophrenia (Sz), depression (Dep) and among normal controls (NC)—the symptoms were assessed retrospectively at age of first admission; symptoms with rank 1–10 in any of the three groups



Worrying Headaches, other aches and pains Nervousness, restlessness Anxiety Difficulties of thinking, concentration Depressed mood Loss of self-confidence Social withdrawal, suspiciousness Disturbed appetite and/or sleep Loss of energy/slowness Irritability Delusional mood Delusional misinterpretations, delusions of reference Oversensitivity Dissocial behaviour Reduced spare-time activities Reduced interests/citizen role


Normal controls Rank






74.6 49.2 88.3 88.1 93.8 84.9 68.3 79.8 93.8 82.5 65.4 68.3 80.3

9 – 3 4 1.5 5 10.5 8 1.5 6 – 10.5 7

94.6 66.9 81.5 81.5 96.9 100.0 89.2 90.8 98.5 93.8 68.5 4.6 6.2

4 – 10.5 10.5 3 1 7 6 2 5 – – –

26.9 30.8 27.7 26.9 20.8 46.9 35.7 13.8 43.4 15.4 26.2 0.0 0.0

22.3 15.3 63.5 33.9

– – – –

52.3 14.6 89.1 87.7

– – 8 9

25.4 22.3 15.5 3.8

Sz vs. NC

Dep vs. NC

*** ** n.s. n.s. n.s. *** *** * n.s. ** n.s. *** ***

*** ** *** *** *** *** *** *** *** *** *** *** ***

*** *** *** *** *** *** *** *** *** *** *** * **

*** n.s. *** ***

n.s. n.s. *** ***

*** n.s. *** ***

Sz vs. Dep

6.5 4 5 6.5 – 1 3 – 2 – 8 – – 9 10 – –

McNemar test: n.s.=not significant; *pb0.05; **pb0.01; ***pb0.001.

process. Fig. 1 illustrates the course of non-psychotic prodromal symptoms from illness onset to first admission. The increases in the frequencies of the ten most prevalent non-psychotic symptoms in schiz-

Percentage of patients with symptom

Depressive symptoms

100 95 90 85 80 75 70 65 60 55 50 45 40 35 30 25 20 15 10 5 0

*: p < 0.05 **: p < 0.01 ***: p < 0.001


ophrenia and depression are almost parallel. Despite the numerous significant differences, the frequencies and profiles of these symptoms, which emerge at the early prodromal stage in both disorders, do not differ Negative symptoms



Dysphoric symptoms



*** * *** **

Schizophrenia at illness onset

Schizophrenia at first admission

Depression at illness onset

Depression at first admission

Fig. 1. Increase in the frequency of the ten most prevalent non-psychotic symptoms in schizophrenia and depression (a total of 13 symptoms grouped into three clinical categories) as assessed at illness onset (bottom) and at the climax of the first psychotic episode (=first admission) (top).

H. Ha¨fner et al. / Schizophrenia Research 77 (2005) 11–24

with depressive symptoms. In moderate and severe depression, the picture is very much the same, except for a still earlier onset of depressive symptoms. Again it becomes plain that schizophrenia and unipolar depression are very similar at the initial stage (Knights and Hirsch, 1981; Koreen et al., 1993). It is not until psychotic symptoms appear towards the end of the early course of schizophrenia that the two disorders become clearly separable. In depressive illness, apart from the rare cases of psychotic depression, psychopathology is limited to the affective dimension and in most cases no new symptom dimension emerges during the entire course of illness.

much in quantitative terms until the end of the early course. They seem to represent a rather stable core syndrome at least of the early course of these disorders. Positive correlations between depression and psychotic symptoms have also been demonstrated by Norman and Malla (1991), Sax et al. (1996), Zisook et al. (1999) and Baynes et al. (2000). Unlike non-psychotic core symptoms, positive symptoms increase considerably in the early course of schizophrenia, but not so in depression and certainly not in healthy controls (Fig. 2). They make clear what distinguishes the two disorders at a fairly late stage of the early course. Only a few psychotic symptoms, e.g. hallucinations, delusions and thought disorder, which emerge early in a small proportion of episodes involving psychotic depression, show significant increases from onset to first admission.

3.6. When does social impairment lead to social disadvantage? When do the social consequences of schizophrenia visible at first admission actually emerge? In our earlier analyses of the ABC sample (Ha¨fner et al., 1999b) we had shown that at illness onset people with schizophrenia and depression are not yet significantly inferior in their social development to age- and sexmatched controls. A comparison based on the social domains of own income (an indicator of economic independence) and marriage or stable partnership (an indicator of mating ability) between the three groups confirmed the finding (Fig. 4). At onset patients with schizophrenia or depression did not yet differ significantly from healthy

3.5. The temporal dimension of first onset of symptoms in schizophrenia and depression Fig. 3 illustrates the temporal order of symptom emergence: Classified in five clinical categories, the symptoms of the early course of schizophrenia and depression as they appeared for the first time are depicted in a time frame of 72 months preceding first admission. As expected, depressive symptoms were the first to appear. As next negative symptoms and functional impairment as well as unspecific dysphoric symptoms emerged, showing considerable overlap

Percentage of patients with symptom

Thought disorders 80 75 70 65 60 55 50 45 40 35 30 25 20 15 10 5 0



Various delusions


*** *** *** ***

*: p < 0.05 **: p < 0.01 ***: p < 0.001

*** ***










*** *** *** **

Schizophrenia at illness onset

Schizophrenia at first admission

Depression at illness onset

Depression at first admission

Fig. 2. Increase in the frequency of the ten most prevalent psychotic symptoms in schizophrenia and depression (a total of 16 symptoms grouped into three clinical categories) as assessed at illness onset and at the climax of the first psychotic episode (=first admission).


H. Ha¨fner et al. / Schizophrenia Research 77 (2005) 11–24



(ICD-9: 295, 297, 298.3, 298.4) n = 130

(ICD-10, F32, F33, F34.1, 43.2) n = 130

Fig. 3. Timepoint of onset of symptoms (assessed by the IRAOS) by five clinical categories in the early course of schizophrenia and depression before first admission (symptoms present in at least 5% of the samples).

controls in terms of social development. The gap between patients with schizophrenia and controls increased significantly from onset towards first admission. Patients with depression fared quite well in the domain of economic independence, but slightly worse than controls in the partnership role. Depressive symptoms, such as lack of self-confidence, depressed mood and lack of drive, probably impair mating behaviour in persons suffering from moderate or severe depression. In terms of the early social course, moderate or severe depression occupies a position between schizophrenia and health.

To take only a short look at the further course of depressive symptoms in schizophrenia, the point prevalence rates for depression, defined by the depressive syndrome (PSE CATEGO), steeply fall from a maximum of 62.8% in the first episode along with psychotic symptoms to a low mean value of 33.3% 6 months after first admission. The simultaneous remission of all the depressive and the psychotic symptoms provides further evidence in support of the hypothesis that depression and psychosis are associated at least in the early course of schizophrenia. It also becomes clear that these data do not support the hypothesis of a post-psychotic

% probands with role


Own income Depression Own income Controls Marriage Controls

70 60

Marriage Depression


Own income Schizophrenia

40 30

Marriage Schizophrenia

20 Illness onset at age 24.2 years

Psychosis onset at age 28.2 years

First admission at age 29.9 years

Fig. 4. Social development based on: (1) marriage or stable partnership and (2) own income (economic independence) in the early illness course (from onset to first admission) in patients with schizophrenia and depression and in healthy controls (matched samples n=130 each)—ABC Schizophrenia Study.

H. Ha¨fner et al. / Schizophrenia Research 77 (2005) 11–24

depression. Of course they do not rule out the possibility that some depressive syndromes occurring in acute psychotic episodes and persisting for short periods thereafter are developed as a reaction to the traumatic experience of illness (Birchwood et al., 1993; McGorry et al., 1998). Like the depressive syndrome at the prodromal stage of the first episode, depressive mood has been reported by several authors (Herz and Melville, 1980; Hirsch and Jolley, 1989; Malla and Norman, 1994; Tollefson et al., 1999) to constitute a frequent prodrome of psychotic relapses. In a total of 333 psychotic relapses occurring over a 12-year follow-up period in the ABC sample, too, depressive mood was the most frequent symptom (Maurer et al., in press). The predictive power of depressive prodromes in psychotic relapses described by Falloon et al. (1988), Mandel et al. (1982) and Olfson et al. (1999) has been demonstrated in several studies, but not yet conclusively established.

4. Discussion In most cases both schizophrenia and unipolar depression start with a prodromal stage involving depressive symptoms and increasing impairment. Fairly late in the early course the illness transits to schizophrenic psychosis in a number of cases or, provided no psychotic symptoms occur, progresses as unipolar depression or remits. Psychotic depressions and depressive schizo-affective psychoses seem to be located between those two symptom dimensions. Underlying the depressive and the psychotic symptom patterns seem to be different patterns of central neurotransmitter dysfunctioning (dopaminergic and glutamatergic in psychosis, serotoninergic and noradrenalinergic in depression) associated with different therapy responses. Most of the risk factors, however, are common to both symptom dimensions. They are clearly more frequent and more severe in schizophrenia, whereas psychogenic factors more often trigger depression. In psychosis-prone individuals, characterised by occasional psychotic symptoms, depressive symptoms have turned out to be a risk factor for transition to psychosis, as shown by Krabbendam et al. (2004a) in the NEMESIS study cited above.


Depressive prodromal stages not only occur in schizophrenia, but are also frequent in organic, especially degenerative brain disorders, e.g. Alzheimer’s disease (Rabins and Lavrisha, 2003). Speculating about how to explain the association between the two symptom dimensions one is tempted to say farewell to the categorical disease model proposed by Kraepelin (1896) in his early works. Characterised by a low threshold of precipitation and a wide array of heterogeneous causes, the depressive syndrome is one of the most prevalent types of psychopathology in the population (Wittchen et al., 2000). On these premises it is reasonable to presume that the depressive syndrome is a preformed reaction pattern originating in the genetic organisation of the human brain. It is equally justified to speak of a preformed reaction pattern of human personality, which can be triggered in different severity by a variety of fairly mild stressors and dysfunctions. As the underlying dysfunction progresses, a further preformed reaction pattern, such as psychosis, will be triggered, provided the brain has reached a level of maturity required for producing such complex symptoms. This is presumably the case from puberty on. At a considerably less mature stage the brain seems to be incapable of producing the entire spectrum of elaborate psychotic symptoms. Further progression in cerebral dysfunction brings forth more severe reaction patterns such as disorientation and finally dementia. Severe dementia, however, represents a new dimension, because it deprives the preceding milder patterns of psychopathology of their cognitive basis (Fig. 5). Embracing these premises would mean giving up the model of a disease entity proposed by Kraepelin (1896) in his early works and substituting it by a hierarchical model based on a limited number of preformed reaction patterns with a dimensional distribution of severity. The differences in the symptomatologies of the two disorders, difficult to distinguish empirically, are accounted for by the fact that depending on the strength of the causal dysfunction and on illness stage different combinations of these symptom dimensions are involved. The hierarchical disease models are not new. They date back to Jackson (1887), underwent further differentiation in Karl Jaspers’ bAllgemeine Psy-


H. Ha¨fner et al. / Schizophrenia Research 77 (2005) 11–24

Stress overproduction of stress hormones

Mild and limited brain dysfunction


Alzheimer's disease


Psychosis Severe cognitive Impairment Dementia mild


Fig. 5. A hierarchical model of preformed symptom patterns (dimensionally distributed from mild to severe) caused by neurobiological (and psychological) reactions to stress, various types of brain dysfunctions or degenerative brain disorder (represented by the arrows).

chopathologieQ (General Psychopathology) (1913) and were adopted by Emil Kraepelin (1920) after he had critically revised his own disease concept. Kraepelin came to the conclusion that there are bencephalopathic mental statesQ, which can be activated by different causes blike the registers of an organ pulled by an organistQ. The milder ones, he believed, are frequently triggered by more severe ones. He distinguished three levels of increasing severity: 1) the affective, paranoid and hysteric type, 2) the schizophrenic type and 3) the encephalopathic and paroxysmal (epileptic) type. At least in its tendency this late, crudely outlined, not much noticed theory of Kraepelin had trail-blazing qualities. Acknowledgements The ABC study was supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) as part of the Special Research Branch (Sonderforschungsbereich) 258 at the Central Institute of Mental Health until December 1998. From January 1999 to September 2002, it was continued to be funded by the DFG as an independent project. This paper was written within the framework of the German Research Network on Schizophrenia and was funded by the German Federal Ministry for Education and Research BMBF (grant 01GI 0236).

References Andreasen, N.C., 1983. The Scale for the Assessment of Negative Symptoms (SANS). University of Iowa, Iowa City. Baynes, D., Mulholland, C., Cooper, S.J., Montgomery, R.C., MacFlynn, G., Lynch, G., Kelly, C., King, D.J., 2000. Depressive symptoms in stable chronic schizophrenia: prevalence and relationship to psychopathology and treatment. Schizophr. Res. 45, 47 – 56. Bebbington, P., Wilkins, S., Jones, P.B., Foerster, A., Murray, R., Toone, B., Lewis, S., 1993. Life events and psychosis. Initial results from the Camberwell Collaborative Psychosis Study. Br. J. Psychiatry 162, 72 – 79. Birchwood, M., Mason, R., Macmillan, F., Healy, J., 1993. Depression, demoralization and control over psychotic illness: a comparison of depressed and non-depressed patients with a chronic psychosis. Psychol. Med. 23, 387 – 395. Crow, T.J., 1980. Positive and negative schizophrenic symptoms and the role of dopamine. Br. J. Psychiatry 137, 383 – 386. Crow, T.J., 1990. Nature of the genetic contribution to psychotic illness: a continuum viewpoint. Acta Psychiatr. Scand. 81, 401 – 408. Dohrenwend, B.P., Shrout, P.E., Link, B.G., Skodol, A.E., Stueve, A., 1995. Life events and other possible psychosocial risk factors for episodes of schizophrenia and major depression: a case-control study. In: Mazure, C.M. (Ed.), Does Stress Cause Psychiatric Illness? American Psychiatric Press, Washington, DC, pp. 43 – 65. Done, D., Crow, T.J., Johnstone, E.C., Sacker, A., 1994a. Childhood antecedents of schizophrenia and affective illness: social adjustment at ages 7 and 11. Br. Med. J. 309, 699 – 703. Done, D.J., Sacker, A., Crow, T.J., 1994b. Childhood antecedents of schizophrenia and affective illness: intellectual performance at ages 7 and 11. Schizophr. Res. 11, 96 – 97.

H. Ha¨fner et al. / Schizophrenia Research 77 (2005) 11–24 Elkis, H., Friedman, L., Wise, A., Meltzer, H.Y., 1995. Metaanalysis of studies of ventricular enlargement and cortical sulcal prominence in mood disorders. Comparisons with controls or patients with schizophrenia. Arch. Gen. Psychiatry 52, 735 – 746. Erlenmeyer-Kimling, L., Rock, D., Squires-Wheeler, E., Roberts, S., Yang, J., 1991. Early life precursors of psychiatric outcomes in adulthood of subjects at risk for schizophrenia or affective disorders. Psychiatry Res. 39, 239 – 256. Falloon, I., Watt, D.C., Shepherd, M., 1998. A comparative controlled trial of pimozide and fluphenazine decanoate in the continuation therapy of schizophrenia. Psychol. Med. 8, 59 – 70. Ha¨ fner, H., 2004. Schizophrenia: still Kraepelin’s Dimentia Praecox? Epidemiol. Psichiatr. Soc. 13.2, 99 – 112. Ha¨fner, H., Riecher-Ro¨ssler, A., Hambrecht, M., Maurer, K., Meissner, S., Schmidtke, A., Fa¨tkenheuer, B., Lo¨ffler, W., An der Heiden, W., 1992. IRAOS: an instrument for the assessment of onset and early course of schizophrenia. Schizophr. Res. 6, 209 – 223. Ha¨fner, H., Maurer, K., Lo¨ffler, W., Riecher-Ro¨ssler, A., 1993. The influence of age and sex on the onset and early course of schizophrenia. Br. J. Psychiatry 162, 80 – 86. Ha¨fner, H., Lo¨ffler, W., Maurer, K., Riecher-Ro¨ssler, A., Stein, A., 1999a. IRAOS. Interview fqr die retrospektive Erfassung des Erkrankungsbeginns und-verlaufs bei Schizophrenie und anderen Psychosen. Hans Huber Verlag, Bern. Ha¨fner, H., Lo¨ffler, W., Maurer, K., Hambrecht, M., an der Heiden, W., 1999b. Depression, negative symptoms, social stagnation and social decline in the early course of schizophrenia. Acta Psychiatr. Scand. 100, 105 – 118. Ha¨fner, H., Lo¨ffler, W., Maurer, K., Riecher-Ro¨ssler, A., Stein, A., 2003. IRAOS—Interview for the Retrospective Assessment of the Onset and Course of Schizophrenia and Other Psychoses. Hogrefe and Huber, Go¨ttingen. Hanssen, M., Bak, M., Bijl, R., Vollebergh, W., Van Os, J., 2004. Outcome of self-reported psychotic experiences in the general population: a prospective study. In: Hanssen, M. (Ed.), A Continuous Psychosis Phenotype: From Description to Prediction. (South-Limburg Mental Health Research and Teaching Network PHD Series). M.S.S. Hanssen, Maastricht, pp. 95 – 107. Heckers, S., Stone, D., Walsh, J., Shick, J., Koul, P., Benes, F.M., 2002. Differential hippocampal expression of glutamic acid decarboxylase 65 and 67 messenger RNA in bipolar disorder and schizophrenia. Arch. Gen. Psychiatry 59, 521 – 529. Herz, M., Melville, C., 1980. Relapse in schizophrenia. Am. J. Psychiatry 137, 801 – 805. Hirayasu, Y., Shenton, M.E., Salisbury, D.F., Dickey, C.C., Fischer, I.A., Mazzoni, P., Kisler, T., Arakaki, H., Kwon, J.S., Anderson, J.E., Yurgelun-Todd, D., Tohen, M., McCarley, R.W., 1998. Lower left temporal lobe MRI volumes in patients with firstepisode schizophrenia compared with psychotic patients with first-episode affective disorder and normal subjects. Am. J. Psychiatry 155, 1384 – 1391. Hirsch, S.R., Jolley, A.G., 1989. The dysphoric syndrome in schizophrenia and its implications for relapse. Br. J. Psychiatry 155 (Suppl 5), 46 – 50.


Hirsch, S.R., Jolley, A.G., Barnes, T.R.E., Liddle, P.F., Curson, D.A., Patel, A., York, A., Bercu, S., Patel, M., 1989. Dysphoric and depressive symptoms in chronic schizophrenia. Schizophr. Res. 2, 259 – 264. Jackson, H., 1887. Remarks on evolution and dissolution of the nervous system. J. Ment. Sci. 33, 25 – 48. Jones, P., Done, D.J., 1997. From birth to onset: a developmental perspective of schizophrenia in two national birth cohorts. In: KeshaVan, M.S., Murray, R.M. (Eds.), Neurodevelopmental Models of Psychopathology. Cambridge University Press, Cambridge, pp. 119 – 136. Jones, P.B., Harvey, I., Lewis, S.W., Toone, B.K., von Os, J., Williams, M., Murray, R.M., 1994. Cerebral ventricle dimensions as risk factors for schizophrenia and affective psychosis: an epidemiological approach. Psychol. Med. 24, 995 – 1011. Jones, P.B., Rantakallio, P., Hartikainen, A.L., Isohanni, M., Sipila¨, P., 1998. Schizophrenia as a long-term outcome of pregnancy, delivery, and perinatal complications: a 28-year follow-up of the 1996 north Finland general population birth cohort. Am. J. Psychiatry 155, 355 – 364. Kendler, K.S., McGuire, M., Gruenberg, A.M., O’Hare, A., Spellman, M., Walsh, D., 1993. The Roscommon Family Study: I. Methods, diagnosis of probands and risk of schizophrenia in relatives. Arch. Gen. Psychiatry 50, 527 – 540. Kendler, K.S., Karkowski-Shuman, L., Walsh, D., 1996. The risk for psychiatric illness in siblings of schizophrenics: the impact of psychotic and non-psychotic affective illness and alcoholism in parents. Acta Psychiatr. Scand. 94, 49 – 55. Kitamura, T., Okazaki, Y., Fujinawa, A., Yoshino, M., Kasahara, Y., 1995. Symptoms of psychoses. A factor-analytic study. Br. J. Psychiatry 166, 236 – 240. Knights, A., Hirsch, S.R., 1981. dRevealedT depression and drug treatment for schizophrenia. Arch. Gen. Psychiatry 38, 806 – 811. Koreen, A.R., Siris, S.G., Chakos, M., Alvir, J., Mayerhoff, D., Lieberman, J., 1993. Depression in first episode schizophrenia. Am. J. Psychiatry 150, 1643 – 1648. Krabbendam, L., Myin-Germeys, I., Hanssen, M., Bijl, R.V., De Graaf, R., Vollebergh, W., Bak, M., Van Os, J., 2004. Hallucinatory experiences and onset of psychotic disorder: evidence that the risk is mediated by delusion formation. Acta Psychiatr. Scand. 110, 264 – 272. Krabbendam, L., Hanssen, M., Bak, M., Van Os, J., 2004. Psychotic features in the general population. Risk factors for what? In: Gattaz, W.F., Ha¨fner, H. (Eds.), Search for the Causes of Schizophrenia, vol. V. Steinkopff-Verlag, Darmstadt, pp. 54 – 78. Kraepelin, E., 1896. Psychiatrie, 5th edn. Barth, Leipzig. Kraepelin, E., 1920. Die Erscheinungsformen des Irreseins. Z. Gesamte Neurol. Psychiatr. 62, 1 – 29. Liddle, P.F., 1987a. Schizophrenic syndromes, cognitive performance and neurological dysfunction. Psychol. Med. 17, 49 – 57. Liddle, P.F., 1987b. The symptoms of chronic schizophrenia: a reexamination of the positive–negative dichotomy. Br. J. Psychiatry 151, 145 – 151. Liddle, P.F., Barnes, T.R.E., 1990. Syndromes of chronic schizophrenia. Br. J. Psychiatry 157, 558 – 561.


H. Ha¨fner et al. / Schizophrenia Research 77 (2005) 11–24

Lo¨ffler, W., Ha¨fner, H., 1999. Dimensionen der schizophrenen Symptomatik. Nervenarzt 70, 416 – 429. Maier, W., Lichtermann, D., Minges, J., Hallmayer, J., Heun, R., Benkert, O., Levinson, D.F., 1993. Continuity and discontinuity of affective disorders and schizophrenia: results of a controlled family study. Arch. Gen. Psychiatry 50, 871 – 883. Maier, W., Minges, J., Lichermann, D., Heun, R., Franke, P., 1994. Personality variations in healthy relatives of schizophrenics. Schizophr. Res. 12, 81 – 88. Maier, W., Lichtermann, D., Franke, P., Heun, R., Falkai, P., Rietschel, M., 2002. The dichotomy of schizophrenia and affective disorders in extended pedigrees. Schizophr. Res. 57, 259 – 266. Maier, W., Ho¨fgen, B., Zobel, A., Rietschel, M., 2005. Genetic models of schizophrenia and bipolar disorder—overlapping inheritance or discrete genotypes? Eur. Arch. Psychiatry Clin. Neurosci (Special Issue, in print). Malla, A.K., Norman, R.M.G., 1994. Prodromal symptoms in schizophrenia. Br. J. Psychiatry 164, 287 – 293. Mandel, M.R., Severe, J.B., Schooler, N.R., Gelenberg, A.J., Mieske, M., 1982. Development and prediction of postpsychotic depression in neuroleptic-treated schizophrenics. Arch. Gen. Psychiatry 39, 197 – 203. Marcelis, M., Van Os, J., Sham, P., Jones, P., Gilvarry, C., Cannon, M., McKenzie, K., Murray, R., 1998. Obstetric complications and familial morbid risk of psychiatric disorders. Am. J. Med. Genet. 81, 29 – 36. Maurer, K., Trendler, G., Schmidt, M., an der Heiden, W., Ko¨nnecke, R., Ho¨ fner, H., in press. Schizophrenie und depression. Nervenarzt. McGorry, P.D., Bell, R.C., Dudgeon, P.L., Jackson, H.J., 1998. The dimensional structure of first episode psychosis: an exploratory factor analysis. Psychol. Med. 28, 935 – 947. Norman, R.M.G., Malla, A.K., 1991. Dysphoric mood and symptomatology in schizophrenia. Psychol. Med. 21, 897 – 903. Olfson, M., Mechanic, D., Boyer, C.A., Hansell, S., Walkup, J., Weiden, P.J., 1999. Assessing clinical predictions of early rehospitalization in schizophrenia. J. of Nerv. Ment. Dis. 187, 721 – 729. Rabins, P.V., Lavrisha, M., 2003. Long-term follow-up and phenomenologic differences distinguish among late-onset schizophrenia, late-life depression, and progressive dementia. Am. J. Geriatr. Psychiatry 11, 589 – 594. Sax, K.W., Strakowski, S.M., Keck, P.E., Upadhyaya, V.H., West, S.A., McElroy, S.L., 1996. Relationships among negative, positive, and depressive symptoms in schizophrenia and psychotic depression. Br. J. Psychiatry 168, 68 – 71. Siris, S.G., 2000. Depression in schizophrenia: perspective in the era of datypicalT antipsychotic agents. Am. J. Psychiatry 157, 1379 – 1389.

Siris, S.G., Bench, C., 2003. Depression and schizophrenia. In: Hirsch, S.R., Weinberger, D.R. (Eds.), Schizophrenia, 2nd edn. Blackwell Publishing, Oxford, pp. 142 – 167. Siris, S.G., Adan, F., Cohen, M., Mandeli, J., Aronson, A., Casey, E., 1988. Postpsychotic depression and negative symptoms: an investigation of syndromal overlap. Am. J. Psychiatry 145, 1532 – 1537. Taylor, M.A., 1992. Are schizophrenia and affective disorders related? A selective literature review. Am. J. Psychiatry 149, 22 – 32. Tollefson, G.D., Andersen, S.W., Tran, P.V., 1999. The course of depressive symptoms in predicting relapse in schizophrenia: a double-blind, randomized comparison of olanzapine and risperidone. Biol. Psychiatry 46, 365 – 373. Van Os, J., Gilvarry, C., Bale, R., Van Horn, E., Tattan, T., White, I., Murray, R.M., 1999a. A comparison of the utility of dimensional and categorical representations of psychosis. Psychol. Med. 29, 595 – 606. Van Os, J., Gilvarry, C., Bale, R., Van Horn, L., White, I., Murray, R.M., 1999b. To what extent does symptomatic improvement result in better outcome in psychotic illness? UK700 Group. Psychol. Med. 29, 1183 – 1195. Van Os, J., Verdoux, H., Maurice-Tison, S., Gay, B., Liraud, F., Salamon, R., Bourgeois, M., 1999. Self-reported psychosis-like symptoms and the continuum of psychosis. Soc. Psychiatry Psychiatr. Epidemiol. 34, 459 – 463. Van Os, J., Janssen, I., Hanssen, M., Bak, M., Myin-Germeys, I., Marcelis, M., Bijl, R., Vollebergh, W., Delespaul, P., 2002. Cognitive epidemiology: psychological and social risk mechanisms for psychosis. In: Ha¨fner, H. (Ed.), Risk and Protective Factors in Schizophrenia. Steinkopff, Darmstadt, pp. 207 – 228. Verdoux, H., Maurice-Tison, S., Gay, B., Van Os, J., Salamon, R., Bourgeois, M.L., 1998. A survey of delusional ideation in primary-care patients. Psychol. Med. 28, 127 – 134. Wassink, T.H., Flaum, M., Nopoulos, P., Andreasen, N.C., 1999. Prevalence of depressive symptoms in the early course of schizophrenia. Am. J. Psychiatry 156, 315 – 316. Weinberger, D.R., 1999. Cell biology of the hippocampal formation in schizophrenia. Biol. Psychiatry 45, 395 – 402. Wing, J.K., Cooper, J.E., Sartorius, N., 1974. Measurement and Classification of Psychiatric Symptoms: An Instruction Manual for the PSE and CATEGO Program. Cambridge University Press, London. Wittchen, H.-U., Mqller, N., Schmidtkunz, B., Winter, S., Pfister, H., 2000. Erscheinungsformen, Ha¨ufigkeit und Versorgung von Depressionen. Fortschr. Med 118 (Sonderheft 1), 4 – 10. Zisook, S., McAdams, L.A., Kuck, J., Harris, M.J., Bailey, A., Patterson, T.L., Judd, L.L., Jeste, D.V., 1999. Depressive symptoms in schizophrenia. Am. J. Psychiatry 156, 1736 – 1743.