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Diagnosing Schizophrenia in the Initial Prodromal Phase
Joachim Klosterkötter, MD;
Martin Hellmich, SMD;
Eckhard M. Steinmeyer, PhD;
Frauke Schultze-Lutter, MSc
Arch Gen Psychiatry. 2001;58:158-164.
ABSTRACT
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Background In schizophrenia research, early detection in the initial prodrome before
first psychotic episodes is a major topic. Therefore, the prognostic accuracy
of initial prodromal symptoms was examined prospectively.
Methods The study sample was composed of patients referred to outpatient departments
of German psychiatric university departments, because of diagnostic problems,
between 1987 and 1991. They were examined with the Bonn Scale for the Assessment
of Basic Symptoms and the Ninth Version of the Present State Examination to
detect an incipient schizophrenic disorder. Of 385 patients showing no schizophrenia-characteristic
symptoms, between 1995 and 1998, 110 with and 50 without initial prodromal
symptoms were followed up and reexamined with the same instruments for a transition
to schizophrenia.
Results During a mean follow-up period of 9.6 years, 79 (49.4%) of the 160 patients
had transited to schizophrenia. The absence of prodromal symptoms excluded
a subsequent schizophrenia with a probability of 96% (sensitivity: 0.98; false-negative
predictions: 1.3%), whereas their presence predicted schizophrenia with a
probability of 70% (specificity: 0.59; false-positive predictions: 20%). Certain
disturbances, such as thought interference, disturbances of receptive language,
or visual distortions, predicted schizophrenia, even with a probability up
to 91% (specificity: 0.85-0.91; false-positive predictions: 1.9%-7.5%).
Conclusions The Bonn Scale for the Assessment of Basic Symptoms operationalization
of prodromal symptoms performed well in the early detection of schizophrenia.
It therefore might be useful for the prediction of the disorder, especially
if it is further refined to select those items with particularly high prognostic
accuracy.
INTRODUCTION
IN THE 1960s, based on longitudinal studies of schizophrenia,1 the German researcher Gerd Huber described subtle,
often only self-perceivable deficits, which were reported not only for the
postpsychotic stages in which the patients were examined, but also, retrospectively,
for the early course, as "basic symptoms."2, 3, 4
In the Bonn Scale for the Assessment of Basic Symptoms (BSABS),5
operational definitions of these prepsychotic deviations are given, along
with typical statements of patients and examples of questions, which allow
their assessment in a fully or semistructured interview. Besides specific
questions, general guiding questions for symptom categories are advised. Based
on the patient's description of a complaint, the interviewer decides whether
the symptom in question is rated as "present," "questionably present," or
"absent." The BSABS has been published in different languages6, 7, 8, 9
(a short English version can be requested from the authors). Furthermore,
the BSABS was partially incorporated in other instruments. In 1991, it provided
the main source for prodromal symptoms of the Instrument for the Retrospective
Assessment of the Onset of Schizophrenia,10
which was used in a large retrospective epidemiological study of the clinical
course of schizophrenia before the first hospitalization.10, 11, 12, 13
Recently, prodromal symptoms as defined by the BSABS were included in 2 early
detection instruments of leading work groups in this field: the Comprehensive
Assessment of At-Risk Mental States14 and the
Scale of Prodromal Symptoms.15 The authors of
the Comprehensive Assessment of At-Risk Mental States16
put special emphasis on Huber's distinction between reversible outpost syndromes
and continuously progressing prodromes as an important modification of the
common concept of prodromes in medicine: because prodromal symptoms can resolve,
this means that it does not guarantee transition to a first psychotic episode,
but may instead indicate an increased risk of this transition. Thereby, the
problem of false-positive predictions17 is especially
important, and an examination of the traditional prodrome concept in prospective
studies becomes critical.
Therefore, in the Cologne Early Recognition (CER) Project, patients
suspected to be in an initial prodromal phase were studied prospectively for
the first time. The study aimed at an examination of the prognostic accuracy
of initial prodromal symptoms as assessed with the BSABS to determine if they
can indeed predict the subsequent development of psychosis.
PATIENTS AND METHODS
PATIENTS
The study sample was taken from 695 patients who were examined for prodromal
symptoms at outpatient departments of 5 German psychiatric university departments
between 1987 and 1991. Before their referral, all patients had sought help
for various complaints from various clinicians. The referrals were because
of difficulties that had arisen in the diagnostic and therapeutic procedure.
Thus, patients were presented at the specialized outpatient departments for
diagnostic clarification of a possibly incipient schizophrenic disorder. Patients
were examined with the BSABS and the Ninth Version of the Present State Examination
(PSE9).18 The assessment of these 2 instruments
served as inclusion criteria of the study.
At this examination, some patients already met DSM-III-R criteria of schizophrenia,19 delusional
or psychotic disorder not elsewhere classified. These subjects (n = 189) as
well as those with a confirmed diagnosis of a substance-induced disorder (n
= 47), organic mental disorder (n = 34), or mental retardation (n = 12) were
excluded from the study. An additional exclusion criterion was being older
than 50 years at first examination (n = 28).
In all remaining 385 subjects, no characteristic symptoms according
to DSM-III-R and, after revision, DSM-IV criterion of schizophrenia,20
respectively, had been found, neither at first examination nor at any time
before. Therefore, the subjects could not yet be diagnosed as having the first
episodes of illness, although a large number (n = 253) had reported potential
prodromal symptoms. These patients returned to the care of their referring
clinicians, and only a small number (n = 15) kept in sporadic contact with
the respective outpatient department. Thus, when the follow-up began in 1995,
patients had to be contacted anew and convinced to participate in the study.
Thereby, various problems arose: 113 subjects either refused to participate
or did not respond even after the third letter, 41 had died of causes unknown
to us, and 71 could not be traced or had moved abroad. The remaining 160 patients
(41.6%) could be followed up until the conclusion of the study in 1998 (Table 1).
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Table 1. General Data of Sample (N = 160)
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At first examination, all 385 patients received tentative diagnoses—according
to the prominent clinical picture—mainly of the field of the former
"neuroses," Axis I disorders, and personality
disorders21
(Table 2).
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Table 2. Comparison of General Data Between the Followed-up and Not
Followed-up Group at First Examination*
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Despite these clinical pictures, 110 patients had reported disturbances
at first examination meeting the description of prodromal symptoms according
to BSABS criteria (Table 3).
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Table 3. Comparison of General Data of the Followed-up Sample With
Regard to Prodromal Symptoms at First Examination Being Present or Absent
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There was no difference in the distribution of sex, age, or tentative
diagnosis either between patients who were followed up and those who were
not, or between patients who were followed up and displayed prodromal symptoms
and those who did not (Table 2 and Table 3).
According to the study's hypothesis, it was assumed that the 110 followed-up
patients with prodromal symptoms at first examination actually had been in
an initial prodromal state. Comparing them with the 50 patients without initial
prodromal symptoms regarding a subsequent development of schizophrenia should
clarify whether disturbances, as assessed with the BSABS, can indeed predict
later first psychotic episodes with sufficient accuracy and, if they do, which
disturbances show the best prognostic accuracy.
INSTRUMENTS
Whereas the same instruments, BSABS and PSE9, were applied at first
examination and follow-up, diagnoses were given according to criteria valid
at the respective time at both assessment times: DSM-III-R criteria were used at first examination and DSM-IV criteria at follow-up. Regarding schizophrenic disorders, the PSE9
covers all characteristic symptoms relevant for DSM-IV
diagnosis; for evaluation of potential prodromal symptoms, a shortened 66-item
version of the BSABS was used. For this version, a hierarchical cluster analysis
of items on a large inpatient sample of various diagnoses and normal controls
had recently led to a clinically plausible 5-cluster solution that broadly
confirmed Huber's original categories22: cluster
1, thought, language, perception, and motor disturbances (35 items); cluster
2, impaired bodily sensations (13 items); cluster 3, impaired tolerance to
normal stress (5 items); cluster 4, disorders of emotion and affect, including
impaired thought, energy, concentration, and memory (7 items); and cluster
5, increased emotional reactivity, impaired ability to maintain or initiate
social contacts, and disturbances in nonverbal expression (6 items).
PROCEDURE
The mean time interval between first examination and follow-up was 9.6
years (Table 1). After informed
written consent, patients were reexamined by 2 members of our group (J.K.
and F.S-L.) either at the outpatient department or at home. The BSABS and
PSE9 were always applied together, and all interviewers had undergone a thorough
training for their assessment. Before the follow-up, interrater reliabilities
between all 5 interviewers involved in the study for the BSABS and PSE9 subsyndromes
had been tested on 10 remitted inpatients with the DSM-III-R diagnosis of a schizophrenic disorder, and received satisfying bias-corrected 
values23 between 0.72 and 0.78 for pairwise
agreement. Furthermore, interviewers and diagnosticians were blind to the
patients' initial results and diagnoses. Diagnoses were given by 2 senior
psychiatrists well-experienced in DSM-IV, considering
all available results and information about the clinical course, including
clinical records and family reports. A transition to a first psychotic episode
was assumed only if DSM-IV criteria of schizophrenia
were met in the follow-up period. The onset of the prodrome was assumed for
the time patients first noticed subtle changes in themselves that met BSABS
criteria; the onset of frank psychosis was defined as the time that PSE9 criteria
for psychotic symptoms were first noticed.
DATA ANALYSIS
Besides an examination of the general ability of BSABS prodromal symptoms
to predict transition to schizophrenia, the main purpose was to examine potential
prodromal symptoms and certain symptom constellations with regard to their
prognostic accuracy. Quantities typically used to evaluate the prognostic
accuracy of binary variables are sensitivity, specificity, positive predictive
values (PPV), and negative predictive values (NPV) (see Table 4 for definitions),24 whereas
an assessment of the overall prognostic accuracy of ordinal or metric variables
that is not influenced by the choice of cut points is typically assessed by
a geometric approach (the area under the corresponding receiver operating
characteristic [ROC] curve).25
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Table 4. Formal Definitions of Test/Symptom Accuracy Measures, Expressed
in Probabilities (Pr)
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A nonparametric technique of this approach25
for related samples was used to compare the prognostic accuracy of the BSABS
clusters, expressed as the sum of symptoms present. This was done because
it was expected that a number of symptoms would only rarely be present, but
taken together, might show good prognostic accuracy. Each ROC curve was constructed
by varying the threshold used to determine which values of the observed variable
would be considered abnormal (ie, indicating a later transition), and then
plotting the resulting sensitivities against the corresponding false-positive
rates (1-specificity).26
Furthermore, for a general 15% cut point of symptoms of each BSABS subsyndrome
as well as for the single symptoms with binary response, prognostic accuracy
measures were calculated. Besides these 4 quantities (Table 4), the overall percentage of false-positive predictions (FP,
percentage of symptom present, no disease) and false-negative predictions
(FN, percentage of symptom absent, disease) are given that describe the combined
outcomes of diagnosis and test/symptom combinations.26
An advantage of sensitivity and specificity over the predictive values
is their independence from the prevalence of the illness in the sample. In
the absence of general criteria of either minimally acceptable values of diagnostic
accuracy measures26 or the choice of the leading
quantity in symptom selection,27 emphasis was
put on both sensitivity and PPV, and the minimally acceptable value of both
quantities was defined according to 2 studies of diagnostic/prognostic accuracy
of symptoms in schizophrenia.28, 29
Thus, a slightly more liberal value of sensitivity than required for symptoms
of an acute episode ( 0.2529) and a value
of PPV regarded as already high in a retrospective study of DSM-III-R prodromal symptoms (0.7028)
were chosen as selection criteria.
For evaluation of the combined predictive ability of symptoms meeting
these criteria, a logistic model was used. To assess the predictive accuracy
of the derived model in an unbiased manner, the data set was split into a
model development sample and a model validation sample.30
RESULTS
TRANSITION TO SCHIZOPHRENIA
According to DSM-IV criteria (A-E), 79 patients
(49.4%) had developed schizophrenia in the follow-up period, whereas 81 patients
(50.6%) had not. All 79 schizophrenic patients had fulfilled criterion A by
showing bizarre delusions and/or commenting or dialoging auditory hallucinations,
and thus had to be classified as paranoid type. They had all received inpatient
treatment and antipsychotic medication: 48 patients later than 4 weeks after
onset of psychotic symptoms, 31 during the first 4 weeks. In 77 of the 79
transited patients, prodromal symptoms had been found at the first examination
that persisted until outbreak of the illness.
The mean transition time to schizophrenia occurred 4.3 years after the
onset of the initial prodrome in women and after 6.7 years in men (Table 1). The patients who did not develop
schizophrenia showed either the same signs and symptoms as at first examination
or no psychiatric disorder at all; the 33 with prodromal symptoms at first
examination retrospectively reported a full remission of these symptoms, either
within some weeks after first examination or after several fluctuations in
the clinical course. During the follow-up period—in the transited group
only until transition—patients had received nonschizophrenia-specific
treatments with no significant group difference in either type or intensity.
Furthermore, with one exception, no significant difference between the 2 outcome
groups was found regarding the general data as well as the DSM-IV–adapted tentative diagnoses.21
Only the initial diagnosis of a schizotypal personality disorder had a significant
positive correlation with the outcome schizophrenia ( coefficient, 0.19; P<.05).
GENERAL PREDICTIVE ACCURACY OF PRODROMAL SYMPTOMS
The general predictive accuracy of initial BSABS prodromal symptoms
for schizophrenia was examined for the dichotomization "at least 1 BSABS symptom
present" vs "no BSABS symptom present" (Table 5). Whereas 77 of the 79 patients with the development of
schizophrenia had reported at least 1 of the 66 BSABS features at first examination,
only 2 had not (FN: 1.3%); 33 of the 81 patients without subsequent schizophrenia
had also shown at least 1 BSABS feature (FP: 20.6%) (only 48 had not). Thus,
the alternative outcome was correctly predicted by the presence or absence
of at least 1 BSABS prodromal symptom at first examination in 78.1% of patients.
Accordingly, for the prediction of a subsequent schizophrenic development
by prodromal symptoms according to BSABS criteria, a specificity of 0.59,
a sensitivity of 0.98, a PPV of 0.70, and an NPV of 0.96 resulted.
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Table 5. Number of Patients With and Without Prodromal Symptoms at
First Examination With Regard to the Subsequent Development of Schizophrenia
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OVERALL PREDICTIVE ACCURACY OF CLUSTERS
The ROC analyses of the sum scores of the BSABS clusters22
showed that the predictive accuracy of cluster 1 (thought, language, perception,
and motor disturbances) showed a significantly greater predictive discrimination30 in the area under the ROC curve, the concordance index
(c), than any other cluster (Figure 1)
(Table 6).
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Receiver operating characteristics curves for Bonn Scale for the
Assessment of Basic Symptoms clusters (N = 160): cluster 1, thought, language,
perception, and motor disturbances; cluster 2, impaired bodily sensations;
cluster 3, impaired tolerance to normal stress; cluster 4, disorders of emotion
and affect, including impaired thought, energy, concentration, and memory;
cluster 5, increased emotional reactivity, impaired ability to maintain or
initiate social contacts, and disturbances in nonverbal expression.
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Table 6. Statistical Description of the Receiver Operating Characteristics
(ROC) Curves*
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With c equal to 0.81, and a sensitivity of
80%, at a specificity of about 72%, this cluster discriminated between patients
developing schizophrenia and those who did not to a satisfying degree, whereas
the predictive discrimination of the other clusters was similar to tossing
a coin (c: 0.50-0.58) (Table 6) (Figure 1).
PREDICTIVE ACCURACY OF CLUSTERS WITH FIXED CUT POINT
Next, we were interested in the predictive accuracy of the 5 BSABS clusters22 at a fixed cut point. To be able to compare them despite
their varying numbers of included symptoms (ranging from 35 in cluster 1 to
5 in cluster 3), a general cut point of roughly 15% symptoms present was introduced
(Table 7).
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Table 7. Prognostic Accuracy of Bonn Scale for the Assessment of Basic
Symptoms (BSABS) Clusters at a Cutoff of 15% Symptoms Present*
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The results supported those of the ROC analyses: again, the first cluster
of thought, language, perception, and motor disturbances at a cut point any
5 of 35 items showed the best predictive accuracy regarding the accuracy quantities
in general (Table 7). It had by
far the highest specificity (0.84) and PPV (0.77), and the least FP (8.1%),
as well as the second highest NPV (0.66). Although its sensitivity was the
second lowest (0.56), it still clearly exceeded the minimum value of 0.30
to 0.40 required for diagnostically relevant symptoms of schizophrenia by
Andreasen and Flaum.29 Except for cluster 2
(impaired bodily sensations), all other clusters at a roughly 15% cut point
were present in higher frequency (sensitivity, 0.63-0.92) and had lower FN
(3.8%-18.1%), but all had considerably poorer specificity, PPV, and FP with
only cluster 4 (disorders of emotion and affect), which has been the most
frequent one with the least FN, doing slightly better in NPV (0.68) than cluster
1 (Table 7).
PREDICTIVE ACCURACY OF SINGLE PRODROMAL SYMPTOMS
Ten BSABS prodromal symptoms fulfilled the criteria of sensitivity of
0.25 and greater and a PPV of 0.70 and greater (Table 8). All other symptoms either were not present in a sufficient
number of later schizophrenics (ie, sensitivity <0.25) or were so frequent
among all patients that their PPVs were less than 0.70. For these 10 symptoms,
sensitivity, NPV, and FN were generally acceptable, specificity and PPV were
high, and FP, at less than 10%, was very low (Table 8).
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Table 8. Predictive Accuracy of Prodromal Symptoms That Occur at Least
in a Quarter of Patients Who Later Transited to Schizophrenia (Sensitivity
>0.25) and Have a Good Positive Predictive Value (>0.70)*
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PREDICTIVE ACCURACY OF THE LOGISTIC MODEL OF SELECTED SYMPTOMS
The 10 selected symptoms were entered into a logistic regression analysis
of the model development sample. At iteration 5, the resulting logistic model
had a -2 log likelihood of 74.2 and was highly significant ( 210 = 36.7, P = .0001). It led to
correct predictions in 81.2% of the development and in 76.2% of the validation
sample. Thus, exhibiting an only insignificant difference between the samples
(21 = 0.59, P = .44),
sample artifacts can be assumed to play a minor role in this solution. Regarding
its predictive accuracy, all accuracy quantities were well above 0.70, and
all false predictions were below 15% in the development as well as the validation
sample (Table 9). But whereas false
positives amounted to only 6.3% in the development sample and thus were comparable
with those of single items, they reached a less favorable 12.5% in the validation
sample (Table 9), indicating a
slight bias toward the prediction of schizophrenia.
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Table 9. Predictive Accuracy of the Logistic Model of Prodromal Symptoms,
With Sensitivity at Least 0.25 and PPV at Least 0.70 in Both Samples
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COMMENT
The main results of the CER Project indicated that the absence of BSABS
prodromal symptoms excluded the development of a first psychotic episode,
with a probability of 96%, with the percentage of false negatives being only
1.3%. Yet, for these prodromal symptoms in general, specificity (0.59) and
PPV (0.70) were considerably lower than sensitivity (0.98) and NPV (0.96),
and the percentage of false positives was still 20.6%. Because of its excellent
negative predictive ability, this operationalization of prodromal symptoms
seems applicable to a broad identification of at-risk persons in the general
population. However, the positive predictive ability had to be greater to
be of use for a treatment-related prognosis, which seems to be true for the
subgroup of thought, language, perception, and motor disturbances. They showed
a sensitivity sufficient for a diagnostic criterion of schizophrenia (>0.25),
a high PPV (>0.70), few FPs (<8%), and a good discriminative ability (81.2%
correct classifications).
The CER Project was performed with an identical and independent assessment
at first examination and follow-up, and thus can be regarded as a prospective
study. However, in the years 1995 through 1998, when contact with the patients
was restored, the first examination had taken place more than 4 years previously.
Thus, the study has certain limitations.
First, only 41.6% of the initial sample could be followed up. Therefore,
regarding the overall transition rate of 49.4% (which reached 70% for patients
with initial prodromal symptoms), the question of a selection bias for patients
with severe disturbances at follow-up arises. Since no significant differences
between followed-up patients and those lost to follow-up occurred for presence
of prodromal symptoms, tentative diagnoses, age, or sex, no indication of
an additional selection, a workup, or a verification bias31
at follow-up is given, and the follow-up sample seems fairly representative.
On the other hand, the presence of an initial referral bias31
can be neither negated nor affirmed. The incidence of schizophrenia is too
low to allow prospective population studies of prodromal symptoms, so no certain
knowledge about the representativeness of the referred patients, clearly disturbed
and receiving psychiatric diagnoses, for those at-risk in the general population
is available.
Second, no repeated measures were carried out, as is usually done in
prospective studies. Consequently, possible changes of symptoms or symptom
profiles in the longitudinal course could not be appraised reliably, and survival
analyses to assess time-to-event dependencies could not be carried out. Expressly
with regard to the rather difficult differentiation between statelike prodromal
symptoms and traitlike schizotypy features,32
and considering the fact that the DSM-IV schizotypal
personality disorder had been the only tentative diagnosis correlating with
a later transition to schizophrenia, repeated measures would have been revealing.
In any case, BSABS prodromal symptoms by definition differ from DSM-IV schizotypy features and, even among the schizotypal patients
of the study, had occurred in late adolescence or early adulthood (around
age 20 years). Moreover, the long duration of these disturbances does not
preclude their interpretation as prodromal symptoms; with a mean duration
of 5.6 years, it corresponds well with the findings in retrospective studies11 of an mean 5- to 6-year duration of the initial prodrome.
The reason for the chosen sampling strategy lay in the empirically low
referral rate of patients with initial prodromal symptoms, so that a sample
of sufficient size with the clinical course duration long enough to ensure
the assessment of a subsequent schizophrenia (ie, at least 5 to 6 years) could
be followed up. To our knowledge, only one other prospectively designed study
has so far been published.14 However, in this
study, the number/sample of 20 patients hitherto followed up over 6 months
is still small, and thus, information about the psychosis-predictive accuracy
of the included risk indicators has not yet been published. Whether the referral
rate can be increased in the future will depend on the success of early detection
networks that have been initiated in several countries (eg, Australia, Norway,
United States, England, Finland, and, since 1997, in Cologne). Thus far, in
the early detection centers, attenuated (ie, 6 DSM-IV
schizotypy features) and transient psychotic symptoms were mainly defined
as criteria of an initial prodrome.14 Patients
were already at the end of the initial prodromal stage, or even at the beginning
of the first psychotic episode, when they were included in the service of
the respective center or in early detection and intervention studies. Yet,
the results of the CER Project give, to our knowledge, the first empirical
evidence that early detection in an even earlier state of the prodrome is
possible by detecting disturbances with less obvious relationship to psychotic
symptoms. An early detection strategy based on these symptoms may have a better
chance to prevent the illness and avoid serious problems that arise during
the initial prodromal phase (eg, social deficits that develop early in the
course of the illness).33
AUTHOR INFORMATION
Accepted for publication May 11, 2000.
Funded by grant PSF 27, 0701627 from the German Ministry of Research
and Technology, Alliance Ministry for Development and Research, Berlin (1989-1990),
the Ørnulv-Ødegård Memory Prize from the Saugstad Foundation
(1993-1995), and grant Kl 970 from the German Research Society Research Community,
Bonn (1995-1998) (Dr Klosterkötter).
From the Department of Psychiatry and Psychotherapy (Drs Klosterkötter
and Steinmeyer and Mrs Schultze-Lutter), and the Institute of Medical Statistics,
Informatics, and Epidemiology, University of Cologne, Cologne, Germany (Dr
Hellmich).
Corresponding author: Joachim Klosterkötter, MD, Department
of Psychiatry and Psychotherapy, University of Cologne, Joseph-Stelzmann-Strasse
9, 50924 Cologne, Germany (e-mail: joachim.klosterkoetter{at}medizin.uni-koeln.de)
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