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Psychiatry Research 117 (2003) 4756

Depressive episodes in stable schizophrenia: critical evaluation of the DSM-IV and ICD-10 diagnostic criteria
Rodrigo A. Bressana,b,*, Ana C. Chavesa, Lyn S. Pilowskyb, Itiro Shirakawaa, Jair J. Maria
b a Schizophrenia Program, Department of Psychiatry, Federal University of Sao Paulo-UNIFESP, Sao Paulo, SP, Brazil Section of Neurochemical Imaging and Psychiatry, Division of Psychological Medicine, Institute of Psychiatry, 1 Windsor Walk, Denmark Hill, London SE5 8AF, UK

Received 17 May 2002; received in revised form 17 October 2002; accepted 12 November 2002

Abstract Depressive episodes are a common and potentially severe occurrence in schizophrenia but are poorly recognised by psychiatrists. Coherent diagnostic criteria are necessary to improve diagnosis and treatment of these conditions. To evaluate the usefulness of the ICD-10 category of post-schizophrenic depression (PSD) and the DSM-IV category of postpsychotic depressive disorder of schizophrenia (PDDS), 80 clinically stable schizophrenic outpatients were evaluated with two independent measures of depression, a dimensional measure and a categorical measure. One rater applied the DSM-IV criteria for major depressive episodes (MDE), and the other applied the Calgary Depression Scale for Schizophrenia, the Positive and Negative Syndrome Scale, and the Extrapyramidal Symptoms Rating Scale. Thirteen patients (16.3%) met criteria for MDE. All of them met the DSM-IV PDDS research criteria, but only two patients matched the ICD-10 PSD criteria, which require that the episode occurred in the 12 months after the last psychotic episode. There was no significant difference in the incidence of depressive episodes within 12 months after an acute psychotic episode and outside this time period. The data suggest that depressive episodes in schizophrenia are not restricted to the first year following the psychotic episode. Useful criteria for depressive episodes in schizophrenia should avoid a temporal relation with the psychotic episode. 2002 Elsevier Science Ireland Ltd. All rights reserved.
Keywords: Schizophrenia; Depression; Postpsychotic depression; Diagnosis; Diagnostic classification

1. Introduction Depression is a frequently occurring symptom in schizophrenia. Studies performing factor analysis of symptoms in large samples of patients consider depression one of the psychopathological domains of schizophrenia in addition to positive,
*Corresponding author. Tel: q44-20-7848-0807; fax: q4420-7848-0051. E-mail address: r.bressan@iop.kcl.ac.uk (R.A. Bressan).

negative, excitement and cognitive domains (Lindenmayer et al., 1994; White et al., 1997; Peralta and Cuesta, 2001). A 10-year follow-up of schizophrenic patients considered depression an independent and stable dimension of schizophrenia with a unique longitudinal course (Marengo et al., 2000). Depressive symptoms can occur in every phase of schizophrenia (for review, see Bartels and Drake, 1988). Depression is commonly described

0165-1781/03/$ - see front matter 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 1 6 5 - 1 7 8 1 0 2 . 0 0 2 9 8 - 6

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among the prodromal symptoms that precede the psychotic episode (Herz and Melville, 1980). Depressive symptoms tend to increase during the acute psychotic episode and tend to remit in parallel with the psychotic symptoms (McGlashan and Carpenter, 1976; Knights and Hirsch, 1981; Goldman et al., 1992; Nakaya et al., 1997). After the resolution of the psychotic episode, during the clinical stability phase, depressive symptoms can remit independently of increases in positive symptoms (Birchwood et al., 2000). In these situations depressive symptoms may be enduring and accompanied by cognitive and vegetative symptoms that may fulfil syndromal definition for major depressive episode in addition to schizophrenia (Siris, 2000). Depressive symptoms in schizophrenia have often been studied cross-sectionally during the post-psychotic period or longitudinally during the acute phase of psychosis. Depressive symptoms occurring during the acute psychotic episode do not constitute a separate syndrome since they tend to respond to antipsychotic treatment together with positive and negative symptoms, and do not need specific interventions. On the other hand, depressive symptoms occurring during the stability phase can characterise a separate syndrome, a depressive episode that requires specific pharmacological (Siris, 2000) and psychotherapeutic treatment (Birchwood and Iqbal, 1998). Depression as a syndrome is considered one of the illnesses that induces more disability in the general population, according to the World Health Report (World Health Organisation, 2000). In schizophrenia, depressive symptoms have been associated with various negative aspects of the clinical outcome, including cognitive impairment (Brebion et al., 1997), deterioration in psychosocial functioning (Glazer et al., 1981), increased risk of relapse (Herz, 1985), longer periods of hospitalisation (Johnson, 1981), poorer response to medication, chronicity (Himmelhoch et al., 1981) and increased risk of suicide (Roy, 1982; Drake et al., 1984). Most of the studies evaluating prognosis used depression as a symptom dimension, and it is expected that patients experiencing a major depressive episode would be even more likely to have a poor clinical outcome.

Reliable diagnosis of depressive episodes in schizophrenia is a prerequisite to appropriate intervention, since it determines recognition of affected individuals and appropriate treatment. The two most frequently used diagnostic classifications in psychiatry, DSM-IV (American Psychiatric Association, 1994) and ICD-10 (World Health Organisation, 1992), have some compatibility problems (Andrews et al., 1999), and the criteria for depression in schizophrenia are one example. Table 1 summarises the DSM-IV and the ICD-10 categories for depression in schizophrenia. The ICD-10 has a specific diagnostic criterion for depression in schizophrenia called post-schizophrenic depression (PSD), but the DSM-IV does not have any category in the main classification. The diagnostic criteria for depression in schizophrenia of the DSM-IV are still among the Criteria Sets and Axes Provided for Further Study, called postpsychotic depressive disorder of schizophrenia (PDDS). Both criteria are based on the criteria for depressive episodes with some modifications. Both include an item to avoid the diagnosis of a depressive episode during the acute psychotic episode. The DSM-IV criteria include an item to exclude depressive symptoms that are better accounted for as medication side effects or negative symptoms. The main incompatibility between the criteria is the fact that the ICD-10 PSD criteria limit the diagnosis of depressive episode to the 12 months following the psychotic episode, while the DSMIV PPDS criteria do not have time limitations. The aim of this study is to check the suitability of the ICD-10 and DSM-IV diagnostic criteria for a depressive episode in schizophrenic patients. Since the diagnostic criteria for depression in schizophrenia apply only to non-acutely psychotic patients, we have included only clinically stable schizophrenic patients. To better evaluate depression, we applied two independent measures, one to evaluate depressive episode as a syndrome (categorical) and the other to evaluate depressive symptoms (dimensional). 2. Method 2.1. Patient sample Ethical approval was obtained from the Federal Paulo (UNIFESP) ethical comUniversity of Sao

R.A. Bressan et al. / Psychiatry Research 117 (2003) 4756 Table 1 Diagnostic criteria for depressive episodes in schizophrenia DSM IVCriteria sets and axes provided for further study Research criteria for Postpsychotic Depressive Disorder of Schizophrenia (PDDS) Criteria are met for Major Depressive Episode (MDE): must include Criterion A1: depressed mood; do not include symptoms that are better accounted for as medication side effects or negative symptoms of Schizophrenia; The MDE is superimposed on and occurs only during the residual phase of Schizophrenia; The MDE is not due to the direct physiological effects of a substance or general medication condition. ICD 10 F20.4Post-schizophrenic depression (PSD) The patient has had a schizophrenic illness meeting the general criteria for schizophrenia (ICD 10 F20) within the past 12 months; Some schizophrenic symptoms are still present; The depressive symptoms are prominent and distressing, fulfilling at least criteria for depressive episode (F.32.-), and have been present for at least 2 weeks. If the patient no longer has any schizophrenic symptoms, as depressive episode should be diagnosed (F.32.-).

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mittee. All patients signed a consent form after being informed of the aims of the study. Two independent raters evaluated 80 consecutive outpatients with a diagnosis of schizophrenia for at least two years (DSM-IV), from four mental health Paulo (Brazil). clinics in the city of Sao Patients were recruited consecutively after their regular appointments with mental health professionals; only three patients refused the interview. Patients were required to fulfil the following criteria for clinical stability of illness: (a) last acute psychotic episode must have taken place more than two months before the interview; (b) within this period, changes in the dose of antipsychotic medication must have been below 5 mg of haloperidol or equivalent dosages of other antipsychotic medications. Exclusion criteria: use of medications or clinical pathologies that could be associated with depression; dependence on or abuse of alcohol or other illegal drugs. 2.2. Assessments Both raters were fully trained in the use of the

instruments. The first rater applied a questionnaire on socio-demographic data, psychiatric history and Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I y P) (First et al., 1995) for Schizophrenia and for Major Depressive Episode (MDE) criteria. The second rater, blind to the result of the first interview, applied the Calgary Depression Scale for Schizophrenia (CDSS) (Addington et al., 1994), the Positive and Negative Syndrome Scale (PANSS) (Kay et al., 1987) and the Extrapyramidal Symptom Rating Scale (ESRS) (Chouinard et al., 1980). The CDSS was specifically developed to assess depression in schizophrenia and prevent overlap with negative and extrapyramidal symptoms (Addington et al., 1994). It was adapted for use in Brazil with good reliability (Bressan et al., 1997) and validity (Bressan et al., 1998). Patients were classified according to DSM-IV criteria for MDE, which requires the presence of at least five of nine items, one of which had to be depressed mood. Patients with three or four items, including depressed mood, were classified as Minor Depression according to the DSM-IV Criteria Sets and Axes Provided for Further Study.

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2.3. Statistical analysis Statistical analysis was carried out using the SPSS-10.0 for Windows software. ANOVA was performed for comparisons of clinical and demographic variables between patients with DSM-IV Major Depressive Episode, DSM-IV Minor Depression and without Depression. The Kruskal Wallis test was used to compare CDSS scores and time since the last psychotic episode between the same three groups. The MannWhitney U test was used to compare CDSS scores between patients with major depression and without major depression. Fishers Exact Test was used to evaluate the frequency of MDE in the 12 months since the last acute psychotic episode and after this period. 3. Results Eighty patients were included in the study, 36 females (45%) and 44 males (55%). The mean age was 38 years (S.D.s11) and the mean disease duration was 15 years (S.D.s8, range 236). Eighteen patients met DSM-IV criteria for MDE, five of whom presented marked diminished interest or pleasure, but did not present depressed mood. These five patients had significantly lower CDSS scores (means2.5, S.D.s1.9) than patients who presented depressed mood (means5, S.D.s1.4) (Us8000, 2 d.f., P-0.05). The symptom marked diminished interest overlaps with negative and extrapyramidal symptoms; therefore these patients were not considered depressed in this study (MDE patients). In this study only the remaining 13 (16.3%) were considered as actually depressed (MDE patients) and used to test the accuracy of the diagnostic criteria. Nine patients (11.2%) met DSM-IV criteria for Minor Depression. Clinical and demographic characteristics were similar in each group apart from the CDSS and PANSS General Psychopathology scores, which were significantly different (Table 2). Only two of 13 MDE patients met the ICD-10 criteria for post-schizophrenic depression, and the remaining 11 were classified as depressive episode not otherwise specified (NOS) (Table 3). These 11 patients did not fulfil the ICD-10 criteria because they developed the major depressive epi-

sode more than 12 months after their last psychotic episode. The 13 MDE patients met the DSM-IV postpsychotic depression criteria provided for further study, but they would be classified as depressive episode NOS in the current version of the DSM-IV. The nine patients with Minor Depression were classified as depressive disorder NOS in both ICD-10 and in DSM-IV. The time since the last psychotic episode ranged between 2 months and 15 years (means33.8 months, S.D.s39.8). Non-depressed patients had the last psychotic episode at 32.6 months (S.D.s 40.4), MDE patients at 32.1 months (S.D.s39.8) and Minor Depression patients at 44.8 months (S.D.s41.2) before the assessment. There were no significant differences in time since the last psychotic episode between these three groups (x2s1.43, 2 d.f., Ps0.49), or between depressed and non-depressed groups (Us517.0, 1 d.f., Ps 0.48). Patients assessed more than 12 months after the last psychotic episode had the same chance of developing a depressive episode as patients assessed earlier than 12 months (x2s0.95, 1 d.f., Ps0.50) (Table 4). CDSS scores found in these two groups did not differ significantly (Us744.0, 1 d.f., Ps0.80). 4. Discussion Examination of the literature suggests that this is the first study specifically evaluating the concept of postpsychotic depression using operationally defined criteria for stability of the disease and two independent measures of depression. We found a high rate of depressive episodes occurring during the stable phase of schizophrenia (16.3%) similar to previous findings (Baynes et al., 2000). Despite this, the majority of these patients did not match any specific diagnostic category in the ICD-10 or the current DSM-IV classification (Table 4). 4.1. Methodological considerations According to Robins and Guze (1970), five steps should be performed to validate a construct such as psychiatric diagnostic criteria: content validity (clinical description of the disorder), con-

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Table 2 Demographic and clinical characteristics of schizophrenic patients with major depression, with minor depression and without depression Diagnostic group Without depression (ns58) Minor depression (ns9) Major depressive episode (ns13) 38.3 (8.4) 7 y6 5 y8 7.1 (3.9) 15.7 (7.1) 21.8 (7.0) 32.1 (39.8) 1.2 (1.3) 8 y5 Significance

Demographic characteristics Age (years) Sex (femaleymale) Marital status (marriedynot married) Education (years) Psychiatric history Duration of disease (years) Age of onset (years) Time since the last psychotic episode (month) Suicide attempts Suicide attempts (yesyno) Clinical characteristics PANSS positive PANSS negative PANSS general Psychopathology CDSS ESRS Equivalent neuroleptic dosage (mg of chlorpromazine)

37.6 (11.1) 23y35 10y48 7.2 (3.8) 14.5 (8.9) 23.1 (7.2) 32.6 (40.4) 0.7 (1.2) 22y36

43.1 (12.8) 6 y3 1 y8 4.4 (2.3) 14.2 (7.0) 28.7 (11.9) 44.8 (41.2) 0.4 (0.7) 3 y6

N.S. N.S. N.S. N.S. N.S. N.S. N.S. N.S. N.S.

10.2 (3.6) 17.5 (5.7) 22.0 (4.3) 1.2 (1.8) 9.9 (6.7) 362.6 (238.9)

10.7 (2.9) 19.5 (4.5) 24.7 (5.4) 5.0 (1.5)* 11.3 (7.4) 222.2 (169.3)

11.1 (3.3) 17.7 (3.9) 28.1 (6.3)* 7.8 (2.8)* 12.1 (2.8) 403.5 (276.0)

N.S. N.S. * f s8.57, F-0.01 *x2s41.9, P-0.01 N.S. N.S.

Except where otherwise specified, data are presented as mean (S.D.). CDSSsCalgary Depression Scale for Schizophrenia. PANSS Positive, PANSS Negative and PANSS General PsychopathologysPositive, Negative and General Psychopathology subscales of Positive and Negative Syndrome Scale. ESRSsExtrapyramidal Symptom Rating Scale.

current validity (concurrent assessment of laboratory measures or psychopathological symptoms), family history, predictive validity (evolution and treatment response) and discriminant validity (independence of the diagnosis of other possible diagnoses). In the present study we evaluated the concurrent validity of the ICD-10 and DSM-IV criteria for depressive episodes in schizophrenia. In the absence of a gold standard instrument to assess depressive episodes in schizophrenia, the concurrent validity was assessed by evaluating depressive symptoms with CDSS and depressive episodes with the MDE criteria. The CDSS is a reliable and well-validated depression scale specifically developed for schizophrenia, which was highly correlated with the MDE criteria used here

(Bressan et al., 1998). Further studies are necessary to evaluate the predictive values and discriminant validity of the diagnostic criteria for depressive episodes in schizophrenia and better determine its construct validity. The independent measures of depression, dimensionally measured by CDSS and categorically defined by MDE DSM-IV, have demonstrated high correspondence with each other. The CDSS ability to discriminate MDE patients was previously tested by means of receiver operating characteristic (ROC) analysis and was considered very good because of high sensitivity and specificity (Bressan et al., 1998). These findings suggest that although the diagnosis of depressive episodes in schizophrenia has to be carefully addressed because of

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Table 3 ICD 10 and DSM IV classification of patients that fulfilled criteria for minor depression and major or depressive episode including depressed mood (DSM IV) Minor depression (ns9) ICD-10 No depression Post-schizophrenic depression (PSD) Depressive episode not otherwise specified DSM-IV No depression Postpsychotic depressive disorder of schizophrenia (PDDS)* Depressive episode not otherwise specified
*

Major depressive episode (ns13) 2 11 13

9 9

Criteria sets and axes provided for further study-DSM IV.

overlap with other syndromes, when properly assessed, both dimensional and categorical measures of depression have great agreement. The present study was limited by its crosssectional nature and by a relatively small number of patients with significant depression. The sample size (80) was powerful enough to show that among clinically stable schizophrenic patients depressive episodes are not more frequent in the first year after the acute psychotic episode than in other periods. Larger samples would be necessary to confirm the trend found here that depressive episodes are actually more frequent after 12 months have elapsed since the last psychotic episode. In this study, operational criteria defining clinically stable schizophrenia were used to avoid measuring depressive symptoms occurring during an acute psychotic episode, and allowed the identification of MDE, who are the clinically relevant patients in need of appropriate diagnostic criteria for depression (Johnson, 1988). Our findings sug-

gesting that depressive episodes do not occur more frequently within the first 12 months after and acute psychotic episode corroborate Johnsons (1988) follow-up study of 119 patients with schizophrenia. The main limitation of Johnsons results is the fact that many patients were relapsing when they were assessed. Green et al. (1990) demonstrated that relapsing patients present many depressive symptoms, which cannot be considered a depressive episode, but a psychotic relapse. Furthermore, Johnson (1988) used the Hamilton Rating Scale for Depression (Hamilton, 1960), which contains many items that overlap with negative and extrapyramidal symptoms of schizophrenia (Goldman et al., 1992). The high rates of depressive episodes (50%) reported by Johnson (1988) could be either an artefact of negative and extrapyramidal symptoms or a consequence of psychotic relapse. Our study avoided these issues by sampling clinically stable patients and by using a specific scale for depression in schizophrenia. The

Table 4 Frequency of major depressive episodes (MDE) during the 12 months since the last acute psychotic episode and after this period DSM-IV categories Time since the last psychotic episode -12 months Without depression Major depressive episode Total
*

Total

)12 months 48 (81%) 11 (19%) 59 (100%) 67 (84%) 13 (16%)* 80 (100%)

19 (90%) 2 (10%) 21 (100%)

x2s0.947, 1 d.f., Ps0.496.

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CDSS scores presented very low overlap with negative and extrapyramidal symptoms, showing that depressive symptoms can be assessed independently of negative and extrapyramidal symptoms (Bressan et al., 1998). 4.2. ICD-10 and DSM-IV classification of depressive episodes in schizophrenia Minor depression patients did not match any criteria of the diagnostic classifications. The importance of minor depression for schizophrenia is not known and it would be interesting to investigate the possibility of a diagnosis corresponding to dysthymia (chronic mild depression) or chronic demoralisation. Bartels and Drake (1988) have described chronic demoralisation in the context of schizophrenia as a state of chronic and persistent hopelessness and low self-esteem in the absence of vegetative features of depression. Although the authors suggest that these patients are at high risk of suicide, we believe that more prospective follow-up studies with larger samples would be necessary to establish the course and impact of mild depressive symptoms for schizophrenic patients. In our study, 5 out of 18 schizophrenic patients fulfilled the DSM-IV MDE criteria without presenting depressed mood. This occurred because of the overlap between negative and nonspecific symptoms of schizophrenia and MDE symptoms such as marked diminished interest and pleasure in all activities most of the day, sleep disturbances, loss of energy, and diminished ability to think or concentrate (American Psychiatric Association, 1994). The DSM-IV criteria for postpsychotic depressive disorder of schizophrenia require the symptom depressed mood to avoid overlap with negative and extrapyramidal symptoms (Table 1). Our results emphasise the importance of this requirement, since patients who fulfilled the MDE criteria and did not have depressed mood actually presented much lower depressive symptoms in the CDSS than patients who had depressed mood. Addington et al. (1990, 1994) performed a search for depressive symptoms that did not overlap with other symptoms of schizophrenia to develop the CDSS. Diagnostic

criteria for depressive episodes in schizophrenia would have improved specificity if they included specific symptoms, such as depressive mood, hopelessness, self-depreciation, guilt idea of reference, pathological guilt, morning depression, early wakening and suicide (Addington et al., 1994). The ICD-10 criterion for post-schizophrenic depression misclassified most of the MDE patients because it requires the occurrence of a depressive episode during the first 12 months after the psychotic episode. This study does not support a particular connection in time between depressive episodes and the last psychotic episode. Patients that experienced an acute psychotic episode more than a year before the assessment actually were more likely to be depressed than patients that were in the postpsychotic phase (12 months after the psychotic episode). The present data confirm the suggestion of Siris (1991) that a cut-off of 12 months is arbitrary since patients can develop depressive episodes at any time during the disease independent of the time since the last psychotic episode. 4.3. Postpsychotic depression Depressive symptoms in patients with schizophrenia may have a multifactorial aetiology: they may be part of the core pathology (Knights and Hirsch, 1981) or they may be reactive post-psychotic (Birchwood et al., 2000), pharmacogenic (Galdi, 1983; Bressan et al., 2002) or akinetic (Van Putten and May, 1978). Diagnostic criteria for depressive episode (syndrome) in schizophrenia should not be restricted to any of the possible aetiological factors. Actually, the diagnostic criteria could benefit from a non-aetiological approach, since in clinical practice it is difficult to discriminate the aetiological factors involved. The term post-psychotic depression is classically used in most of the diagnostic classifications. The majority of the studies substantiating these classifications have evaluated depressive symptoms in acutely psychotic patients and followed them up for a variable number of months. The design of these studies may overemphasise the post-psychotic period to the detriment of the following stability periods. One of the best studies using this design

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and specific depression scales found that a large proportion of the patients develop post-psychotic depression (36%) independently of psychotic symptoms in the first year after the psychotic episode (Birchwood et al., 2000). The rates of depressive episodes in the first year after the psychotic episode (36% Birchwood et al., 2000) seem higher than in the stability periods found in this study (16.2%) and previous studies (9% Pogue-Geile, 1989; 13.3% Baynes et al., 2000). However, this study indicates that the majority of the depressed (MDE) stable schizophrenic patients had their last psychotic episode more than 1 year ago and cannot be appropriately diagnosed by the current diagnostic criteria. Although the rates of depressive episodes are higher during the first year after the psychotic episode, the absolute number of depressive episodes during the stability phase must be much higher than after the psychotic episode, since the majority of the schizophrenic patients are in a stable phase. Therefore, our impression is that restricting the diagnosis of depressive episodes to the post-psychotic period may lead to misdiagnosis and undertreatment of a large number of cases. Although clinicians have noted the importance of treatment of depressive episodes in schizophrenia, there are currently no well-defined approaches to the recognition and management of depressive symptoms in schizophrenia (Addington et al., 2002). Nevertheless, specific treatment guidelines for postpsychotic depression have been developed, which include pharmacological and psychosocial strategies to treat the condition (Expert Consensus Guideline Series, 1999). Appropriate diagnosis of depressive episodes in schizophrenia is fundamental to provide the best available treatment to a large number of patients suffering from this condition. Improved diagnosis would also facilitate trials on treatment of depressive symptoms in schizophrenia (Collaborative Working Group on Clinical Trial Evaluations, 1998). 5. Conclusion Depressive episodes in stable schizophrenic patients are a common and potentially severe occurrence in need of appropriate therapeutic inter-

ventions. In this study we found that the diagnostic criteria available in the current version of DSMIV and ICD-10 did not identify depressive episodes in the majority of clinically stable schizophrenic patients. This has research and clinical implications. In the clinic, faithful adherence to the present classification system could lead to misdiagnosis and under-treatment of depressive episodes in schizophrenia. The evidence presented here suggests amendments to the present criteria would better describe comorbid depressive episodes in schizophrenia. These might include incorporation of the DSM-IV research criteria for postpsychotic depressive disorder of schizophrenia into Axis I. Secondly, both ICD-10 and DSM-IV criteria could include specific depressive symptoms that do not overlap with negative and extrapyramidal symptoms. Thirdly, the criteria could include patients independent of the time of the last psychotic episode, but exclude patients experiencing a psychotic relapse. Acknowledgments This study was funded by a grant from the Sao Paulo State Research Foundation (FAPESP). RAB is sponsored by the CAPES (Brazil). LSP is a UK Medical Research Council Senior Clinical Fellow. JJM is a researcher I-A from the Brazilian Research Council CNPq. We thank MDL Mateus, CM Pariante and Prof. I Pilowsky for invaluable help with this work. References
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