Journal of Affective Disorders 133 (2011) 137–149

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Journal of Affective Disorders

j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j a d

Research report

Clinical predictors of response and remission in inpatients with

depressive syndromes☆
Michael Riedel a,k, Hans-Jürgen Möller a, Michael Obermeier a, Mazda Adli g, Michael Bauer c,
Klaus Kronmüller b, Peter Brieger d, Gerd Laux e, Wolfram Bender f, Isabella Heuser h,
Joachim Zeiler i, Wolfgang Gaebel j, Rebecca Schennach-Wolff a,
Verena Henkel a, Florian Seemüller a,⁎
a
Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University Munich, Nussbaumstrasse 7, 80336 Munich, Germany
b
Department of Psychiatry and Psychotherapy, University of Heidelberg, Voßstr. 2, 69115 Heidelberg, Germany
c
Department of Psychiatry and Psychotherapy, Carl Gustav Carus Hospital, Technical University, Fetscherstr. 74, 01307 Dresden, Germany
d
Department of Psychiatry, Psychotherapy and Psychosomatics, Martin-Luther University Halle-Wittenberg, Julius-Kühn-Str.7, 06097 Halle, Germany
e
Department of Psychiatry, Psychotherapy, Psychosomatic Medicine and Neurology, Inn-Salzach-Klinikum. Gabersee 7, 83512 Wasserburg, Germany
f
Department of Psychiatry Psychotherapy, Psychosomatic Medicine and Neurology, Isar-Amper-Klinikum Munich East, Vockestr. 72, 85540 Haar, Germany
g
Department of Psychiatry and Psychotherapy, Campus, Charité Mitte (CCM), Charitéplatz 1, 10117 Berlin, Germany
h
Department of Psychiatry and Psychotherapy, Campus Charité Benjamin Franklin (CFB), Eschenallee 3, 14050 Berlin, Germany
i
Department of Psychiatry Psychotherapy and Psychosomatics, Auguste-Viktoria-Krankenhaus, Rubensstr. 125, 12157 Berlin, Germany
j
Department of Psychiatry and Psychotherapy, University of Düsseldorf, Bergische Landstr.2, 40629 Düsseldorf, Germany
k
Department of Psychiatry, Psychotherapy and Psychosomatics, Vinzenz von Paul Hospital, Rottweil, Germany

a r t i c l e i n f o a b s t r a c t

Article history: Background: Most predictor analyses search for single predictors or rely on data from
Received 2 November 2010 randomized controlled trials. We aimed at detecting a set of clinical baseline variables for
Received in revised form 11 April 2011
prediction of response and remission in 1014 naturalistically treated inpatients with major
Accepted 11 April 2011
depressive episode treated for 53.62 ± 47.5 days.
Available online 8 May 2011
Methods: A three-staged procedure was implemented. First, univariate tests were used for
finding associations with baseline variables. Second, logistic regression and third-CART
Keywords:
analyses were used to determine predictors of response to inpatient treatment.
Response
Results: Presence of suicidality, a higher initial HAMD-21 total score, an episode
Remission
Predictor length b 24 months, fewer previous hospitalizations, and absence of any ICD-10 F4 comorbidity
Major Depression predicted response in 2 different statistical models. Remission was predicted by lower HAMD-
Inpatients 21 baseline score, episode length b 24 months and fewer previous hospitalizations in both
models.
Limitation: Results were assessed by a post-hoc analysis, based on prospectively collected data.
No controlled study design.
Conclusion: Contrary to current beliefs, baseline suicidality might be associated with higher
chances for response. In addition, baseline severity might impact outcome depending on which
criterion (remission or response) used.
© 2011 Elsevier B.V. All rights reserved.

☆ The study was performed within the framework of the German Research Network on Depression, which was funded by the German Federal Ministry for
Education and Research BMBF (01GI0219). The BMBF had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the
report; and in the decision to submit the paper for publication.
⁎ Corresponding author at: Department of psychiatry, Ludwig Maximilians University, Nussbaumstr. 7, 80336 Munich, Germany. Tel.: + 49 89 5160 5511;
fax: + 49 89 5160 5774.
E-mail address: florian.seemueller@med.uni-muenchen.de (F. Seemüller).

0165-0327/$ – see front matter © 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.jad.2011.04.007
138 M. Riedel et al. / Journal of Affective Disorders 133 (2011) 137–149
1. Introduction
A substantial number of depressed patients do not achieve
remission and only some achieve response with the initial
treatment. For example, in STAR*D only 28% of the initial
sample of the 2876 included depressed patients achieved
remission and 47% were responders with citalopram.
The longer the search for an effective antidepressant
treatment in the individual is, the higher the risk for
chronicity, the overall costs and the worse the functional
outcome. A patient could be detected early as an antidepres-
sant nonresponder and consequently be referred to other
biological highly effective treatments such as ECT (Khalid
et al., 2008), or referred to adjunct psychotherapy right from
the start (Pampallona et al., 2004). By this means the difficult
challenge of optimizing treatment of depression could be
facilitated.
One way to classify predictors is to distinguish between
biological and clinical predictors, meaning either predictors
which can be measured with a distinct laboratory test or
predictors which simply can be observed or asked for. In the
last few years research for biological variables predicting
response to antidepressants such as genetic polymorphisms
or fMRI patterns has gained more and more attention.
However, the methods are expensive and only available in
specialty care settings, and the results are not yet conclusive
(Juckel et al., 2007; Pogarell et al., 2007).
By contrast, clinical predictors are inexpensive and easy
to assess. Most clinical predictors have been predominantly
investigated on outpatients enrolled in RCTs and focussed
either on response or remission. In addition, most studies
looked into single predictors for either response or remis-
sion. Generalizability of predictors derived from RCTs is
limited because of a strong selection bias via inclusion
and exclusion criteria. In addition, single predictors only
explain small percentages of the total variance. Consequent-
ly, it appears to be more appropriate to search for a set
or group of possible predictors. With rare exceptions
(Hennings et al., 2009; Kupfer and Spiker, 1981; Serretti
et al., 2007), no adequately powered previous studies have
searched for baseline features predicting which patients will
achieve remission as opposed to those who will respond to
treatment.
We therefore analysed data from a large prospective
naturalistic multicenter trial on 1014 depressed inpatients
without control group, but with broad inclusion and exclusion
criteria, including suicidal patients, patients with bipolar
disorder and psychotic depression.
Our study aim was the prediction of response/remission for
global inpatient treatment outcome. Specifically, we searched
for a combination of baseline variables predicting outcome of
inpatient treatment for response and remission in a represen-
tative “real-world” sample of depressed inpatients.
We used a three-staged screening procedure. In the first
step, we screened for simple associations of collected baseline
variables with either response or remission. In a second step,
we employed multivariate logistic regression models to select
the most valid predictors. In a third step as proposed by Small
et al. (Small et al., 1995) we validated the established
predictors with a second and different statistical method
Classification and regression trees (CART-analyses).
2. Methods
2.1. Sample and data collection
The main objective and details of the study protocol are
described in detail elsewhere (Seemuller et al., 2010). In brief,
data from a large prospective, naturalistic, multicenter study
(N = 1014) were analyzed. The study was part of the German
research network, funded by the German Federal Ministry of
Education and Research (BMBF). Subjects were recruited
from several German psychiatric university or research
hospitals (2 in Munich, 2 in Berlin, Tübingen, Düsseldorf,
Halle) and psychiatric district hospitals (Munich, Garbersee, 3
in Berlin).
Inclusion criteria were age between 18 and 65 and signed
written informed consent. Patients had to meet ICD-10
diagnostic criteria for any major depressive episode (ICD-10:
F31.3x–5x, F32, F33, F34, F38, F39) or for a depressive disorder
not otherwise specified (ICD-10). Moreover, for confirmation of
the diagnosis of a depressive spectrum disorder according to
DSM-IV as well as for the detection of relevant axis I and axis II
comorbidities, the Structured Clinical Interview for DSM-IV
(SCID-I and SCID-II) was used (Wittchen et al., 1997). Socio-
demographic and clinical variables, as well as potential suicide-
related events, were collected using the scale of clinical and
sociodemographic variables in psychiatry (BADO) (Cording
et al., 1995); psychopathological symptoms were assessed
using the Hamilton Depression Rating Scale (HAMD-21)
(Hamilton, 1967). Ratings were assessed at baseline and
every other week until discharge. Patients were included in
the analysis if at least two assessments were available.
2.2. Treatment
Patients were treated at the discretion of the psychiatrist
in charge under consideration of the international clinical
guidelines for the treatment of depression (APA-, WSFBP)
(American Psychiatric, 2000; Bauer et al., 2007). In addition,
the medication class, their active compounds, the dosage and
the treatment duration were recorded. Furthermore, the
duration and type of other biological treatments such as
electroconvulsive therapy (ECT), sleep deprivation, transcra-
nial magnetic stimulation (TMS) and psychotherapy were
carefully recorded.
2.3. Search for previous studies reporting predictors
A detailed PubMed literature search for previous studies of
the PubMed database (1966–2011, last update on 11.03.2011)
was done using the following keywords: major depression,
response or remission, predictor or prediction. Originally 685
results in PubMed were revealed. The limitation to “clinical
trials” resulted in 193 references. All references were reviewed
by the senior author of the manuscript applying the following
criteria:
a) Predefined outcomes should be response or remission
or both; b) trials should investigate more than one single
predictor; c) predictors for antidepressant pharmacological
treatment; d) no placebo control group; e) the investigated
sample should comprise N50 adult subjects, and f) should
focus on short-term outcome (up to 3 months).
 M. Riedel et al. / Journal of Affective Disorders 133 (2011) 137–149 139

Summary of previously found predictors for response/remission (N = negative association, P = positive association, – = no association, blank space = variable was not assessed, Rem = remission, Resp = response,
The search revealed 10 studies in inpatients and outpatients

hospitalizations
with the 14 following possibly relevant clinical predictors for
either response or remission which also were available in our

Suicidality Prior
database: family history, age, lower educational level, age of

N
N
N
N
onset, length of index episode, comorbid personality disorder,
psychosocial functioning, psychotic features, panic/anxiety
disorder, substance abuse, other comorbid ICD-10 psychiatric
disorder, illness severity, suicidality, and number of prior

–
–

–
P
hospitalizations (Table 1).

Severity

N
–

–
–
P
3. Statistical analyses

Comorbid
axis I/II
Patients were included in the analysis if in addition to the

N
–
–

–
–
baseline assessment at least one post-baseline assessment

Flux = Fluoxetine, Ami = Amitriptyline, NAT = naturalistic treatment, CIT = Citaloprame, Fluv = Fluvoxamine, o.l. = open label, *univariate comparisons were included).

anxiety abuse
was available. Discharged patients (patients with at least one

Subs.
second HAMD-21 assessment) and dropouts were included in

–
–
–
–
the analysis on an intention to treat basis.

Panic/
Response to inpatient treatment was defined as ≥ 50%

N
–

–
HAMD-21 score reduction of the baseline score at final visit.

Psychotic
Features
In accordance with Pfeiffer and Riedel (Pfeiffer et al., 1997;
Riedel et al., 2010) remission was defined as a HAMD-21

N
–

–
–
–
–
score of 7 or less at final visit. Early improvement was defined

personality Psychosocial
Functioning
as 20% HAMD-21 baseline reduction after two weeks of
inpatient treatment. We analyzed both outcome events at

Low
discharge, for two reasons. First we implied that clinicians

N
–

–
–
would judge the mental state at that time point as stable, in
order to allow discharge, and secondly to allow better
disorder
comparability with results from RCTs.
Any

N
–
–

–
–
–
Data are presented as percentages for categorical variables P
episode

and as means and standard deviations for continuous variables.

Longer
index

For predictor analysis we conducted a three-staged procedure.

N
N
N
N
First, apart from usual descriptive statistics, Fisher tests, t-tests
Age of
Onset

and Wilcoxon tests were also applied as appropriate to screen

N
–

–
–
–
–
for associations of baseline variables with response or remis-
educat.
Lower

sion to inpatient treatment.

Next, two different methods were used to select the most
N

–
–
important predictors of response to inpatient treatment for
Gender

response and remission, respectively: 1. logistic regression and (fem.)

–

–
–
–
–
P

2. classification and regression tree (CART) analysis. We used

Patients Family Age

response and remission as the dependent variables for logistic

N

–
–
–
–
regression models as well as for the CART analyses. Before
history

predictors entered logistic regression analysis, variance infla-

–
–
–
–
tion factors (VIF) were calculated to check for multicolinearity
Outpat.

Outpat.

Outpat.

(Table 3). Starting with a logistic regression model including all

Inpat.

Inpat.

Inpat.

Inpat.

Inpat.

Inpat.

Inpat.

possible predictors, (all variables with a p-value less than 0.2 in

the univariate tests) a forward-backward method based on the
FLUX.

FLUV
SER/

lowest Akaike Information Criterion (AIC) was used to identify

Trial

NAT

NAT

NAT

NAT
AMI

AMI

RCT
IMI

CIT
o.l.

o.l.

o.l.

o.l.

o.l.

the relevant predictors to inpatient treatment. The final model

Outcome

was computed with only these predictors and validated using a

Resp

Resp

Resp
Resp

Resp

Resp

Resp
Rem
Rem

Rem

Rem

Rem

10-fold cross-validation with AUC as criterion. For the

computation of the AUC every single estimated probability of
the logistic model is used as possible cut-off point for
inpatients

N = 1014
N = 143

N = 205
N = 623

N = 100
N = 329

N = 790

N = 116

Hennings et al., 2009* N = 842

Sample

N = 50

prediction.
In accordance with a previous paper (Seemuller et al.,
2009) CART analysis with the same predictors was used to
Hirschfeld et al., 1998

Seemuller et al., 2011

Zubenko et al., 1994

O'LEARY et al., 2000

Cassano et al. 2004

Serretti et al., 2007

verify the results. The CART analysis results in a hierarchical

Trivedi et al., 2006
Prusoff et al. 1977

Sauer et al. 1986

interpretation of the associations between predictors and

response/remission. Based on the complete data set, the one
variable is selected which splits the data best into two sub-
Table 1

Study

sets, which are more homogeneous with respect to response/

remission than the complete data set. The criterion for the
 140
Table 2
Patient sociodemographics, clinical variables and associations with response or remission at discharge. Numbers and percentages were given for discrete predictors and means and corresponding standard deviation were
given for continuous predictors. ⁎ Effect sizes for categorical variables: Cramer's V. For metrical variables: Cohen's d, Somatic symptoms: HAMD item 12 = “somatic symptoms”, HAMD item 13 = “somatic symptoms general”,

M. Riedel et al. / Journal of Affective Disorders 133 (2011) 137–149

HAMD item 14 = “genital symptoms”, psychotic symptoms: HAMD item 19 = “depersonalisation and derealisation”, HAMD item 20 = “paranoid symptoms”.

Demograph. variables All patients Non-responder Responder Effect size* p-value Non-remitter Remitter Effect size* p-value

Female 602 183 (30.4%) 419 (69.6%) 0.02 0.6401 311 (51.66%) 291 (48.34%) 0.01 0.6892
Age 45.12 (± 11.87) 44.52 (± 12.05) 45.37 (± 11.8) 0.07 0.3173 45.17 (± 11.99) 45.06 (± 11.76) 0.01 0.8827
Partnership
Without partner 448 156 (30.47%) 356 (69.53%) 0.02 0.6713 269 (52.54%) 243 (47.46%) 0.03 0.3655
With partner 512 130 (29.02%) 318 (70.98%) 222 (49.55%) 226 (50.45%)
Job situation
In job 590 161 (27.29%) 429 (72.71%) 0.08 0.0853 282 (47.8%) 308 (52.2%) 0.11 0.0045
Jobless 123 40 (32.52%) 83 (67.48%) 61 (49.59%) 62 (50.41%)
Retire 141 51 (36.17%) 90 (63.83%) 89 (63.12%) 52 (36.88%)
Age at first treatment
Age at first treatment N 18 842 248 (29.45%) 594 (70.55%) 0.04 0.2362 424 (50.36%) 418 (49.64%) 0.1566
Age at first treatment b 18 44 17 (38.64%) 27 (61.36%) 26 (59.09%) 18 (40.90%)
Age at first treatment 37.93 (± 12.77) 36.28 (± 12.83) 38.63 (± 12.69) 0.18 0.0128 37.37 (± 13.15) 38.5 (± 12.35) 0.09 0.1906
Family history
Affective disorder 90 30 (33.33%) 60 (66.66%) 0.03 0.3965 58 (64.44%) 32 (35.56%) 0.09 0.0077
Schizophrenia 40 13 (32.50%) 27 (67.50%) 0.01 0.7232 21 (52.50%) 19 (47.50%) 0.01 0.8730
Alcohol/drug abuse/addiction 49 23 (46.94%) 26 (53.06%) 0.09 0.0092 31 (63.27%) 18 (36.73%) 0.06 0.0804
Suicide 13 3 (23.08%) 10 (76.92%) 0.02 0.7655 6 (46.15%) 7 (53.85%) 0.01 0.7854
CNS disorder 93 20 (21.51%) 73 (45.49%) 0.06 0.0928 43 (46.24%) 50 (53.86%) 0.03 0.3821
Other psych. abnormality 326 97 (29.75%) 229 (70.25%) 0.00 0.8807 167 (51.23%) 159 (48.77%) 0.00 0.9454
Number of comorbid psychiatric disorders
No 871 250 (28.70%) 621 (71.30%) 0.07 0.0279 436 (50.06%) 435 (49.94%) 0.07 0.0446
N1 89 36 (40.45%) 53 (59.55%) 55 (61.80%) 34 (38.50%)
Mental and behavioural disorders due to psychoactive substance use
No 860 254 (29.53%) 606 (70.47%) 0.02 0.6443 437 (50.81%) 423 (49.19%) 0.02 0.5976
Yes 100 32 (32%) 68 (68%) 54 (54%) 46 (46%)
Neurotic, stress-related and somatoform disorders (ICD-10: F4)
No 853 237 (27.78%) 616 (72.22%) 0.12 0.0002 422 (49.47%) 431 (50.53%) 0.09 0.0039
Yes 107 49 (45.79%) 58 (54.21%) 69 (64.49%) 38 (35.51%)
Any personality disorder
No 525 135 (25.71%) 390 (74.29%) 0.05 0.1361 254 (48.38%) 271 (51.62%) 0.06 0.1203
Yes 280 86 (30.71%) 194 (69.29%) 152 (54.29%) 128 (45.71%)
Specific personality disorder
Not avoidant 689 178 (25.83%) 511 (74.17%) 0.09 0.011 333 (48.33%) 356 (51.67%%) 0.11 0.0036
Avoidant 117 44 (37.61%) 73 (62.39%) 74 (63.25%) 43 (36.75%)
 Not dependent 757 206 (27.21%) 551 (72.79%) 0.03 0.4119 382 (50.46%) 385 (49.54%) 0.00 1
Dependent 49 16 (32.65%) 33 (67.35%) 25 (51.02%) 24 (48.98%)
Not obsessive 697 193 (27.69%) 504 (72.31%) 0.01 0.9083 354 (50.79%) 343 (49.21%) 0.01 0.6818
Obsessive 109 29 (26.61%) 80 (73.39%) 53 (48.62%) 56 (51.38%)
Not self-defeating 782 214 (27.37%) 568 (72.63%) 0.02 0.4943 394 (50.38%) 388 (49.62%) 0.01 0.8366
Self-defeating 24 8 (33.33) 16 (66.67%) 13 (54.17%) 11 (45.83%)
Not depressive 732 199 (27.19%) 533 (72.81%) 0.03 0.4955 368 (50.27%) 364 (49.73%) 0.01 0.7157
Depressive 74 23 (31.08%) 51 (68.92%) 39 (52.70%) 35 (47.30%)
Not paranoid 768 208 (27.08%) 560 (72.92%) 0.05 0.1955 387 (50.39%) 381 (49.61%) 0.01 0.8685
Paranoid 38 14 (36.84%) 24 (63.16%) 20 (52.63%) 18 (47.37%)
Not schizotypal 801 222 (27.72%) 579 (72.28%) 0.05 0.3302 406 (50.69%) 395 (49.31%) 0.05 0.2130
Schizotypal 5 0 (0%) 5 (100%) 1 (20%) 4 (80%)
Not schizoid 788 212 (26.90%) 576 (73.10%) 0.09 0.0133 396 (50.25%) 382 (49.78%) 0.03 0.4760
Schizoid 18 10 (55.56%) 8 (44.44%) 11 (61.11%) 7 (38.89%)
Not histronic 794 221 (27.83%) 573 (72.17%) 0.05 0.1958 404 (50.88%) 390 (49.12%) 0.06 0.0871
Histronic 12 1 (8.33%) 11 (91.67%) 3 (25%) 9 (75%)

M. Riedel et al. / Journal of Affective Disorders 133 (2011) 137–149

Not narcissistic 791 215 (27.18%) 576 (72.82%) 0.06 0.1394 399 (50.44%) 392 (49.56%) 0.01 1
Narcissistic 15 7 (46.67%) 8 (53.33%) 8 (53.33%) 7 (46.67%)
Not borderline 754 211 (27.98%) 543 (72.02%) 0.04 0.3374 382 (50.66%) 382 (49.34%) 0.01 0.7751
Borderline 52 11 (21.15%) 41 (78.85%) 25 (48.08%) 27 (51.92%)
Not antisocial 797 218 (27.35%) 579 (72.65%) 0.04 0.2694 402 (50.44%) 395 (49.56%) 0.01 1
Antisocial 9 4 (44.44%) 5 (55.56%) 5 (55.56%) 4 (44.44%)
ICD-10 depression severity
Mild 24 9 (37.5%) 15 (62.5%) 0.07 0.2844 13 (54.17%) 11 (45.8%) 0.09 0.1048
Moderate 271 80 (29.52%) 191 (70.48%) 117 (43.17%) 154 (56.83%)
Severe 228 57 (25%) 171 (75%) 119 (52.19%) 109 (47.81%)
Bipolar 62 20 (32.26%) 42 (67.74%) 0.01 0.6679 31 (50%) 31 (50%) 0.01 0.8959
Suicidality (HAMD item 3) 132 35 (26.52%) 97 (73.48%) 0.03 0.4131 65 (49.24%) 67 (50.76%) 0.02 0.6407
Lenght of index episode
b24 months 842 237 (28.15%) 605 (71.85%) 0.11 0.001 419 (49.76%) 423 (52.24%) 0.03 0.00008
N24 months 80 34 (42.5%) 46 (57.5%) 50 (62.50%) 30 (37.50%)
Length of illness (years) 7.13 (± 9.11) 8.42 (± 8.94) 6.58 (± 9.13) 0.2 0.00001 7.98 (± 9.37) 6.27 (± 8.76) 0.19 0.00003
Duration hospitalization 56.55 (± 47.16) 61.08 (± 60.76) 54.63 (± 39.92) 0.14 0.0997 60.66 (± 54.51) 52.25 (± 37.56) 0.18 0.0053
GAF score 47.98 (± 11.55) 48.04 (± 11.07) 47.96 (± 11.75) 0.01 0.6279 47.73 (± 11.2) 48.26 (± 11.92) 0.05 0.7127
Previous hospitalizations
No 490 119 (24.29%) 371 (75.71%) 0.12 0.00002 223 (45.51%) 267 (54.49%) 0.12 0
Yes 470 167 (35.53%) 303 (64.47%) 268 (57.02%) 202 (42.98%)
HAMD-21 24.79 (± 6.91) 23.29 (± 6.92) 25.43 (± 6.82) 0.31 0 25.72 (± 6.65) 23.81 (± 7.06) 0.28 0
Somatic symptoms (HAMD items 12,13,14) 3.39 (± 1.49) 3.26 (± 1.47) 3.44 (± 1.49) 0.12 0.0769 3.26 (± 1.47) 3.44 (± 1.49) 0.12 0.0769
Psychotic symptoms (HAMD items 19, 20) 1.67 (± 1.31) 1.46 (± 1.31) 1.76 (± 1.29) 0.23 0.0012 1.67 (± 1.31) 1.67 (± 1.3) 0 0.9841
Antidepressant switch 1.3 (± 0.85) 1.36 (± 0.99) 1.28 (± 0.78) 0.1 0.2269 1.4 (± 0.95) 1.2 (± 0.72) 0.24 0.0006
Early improver 650 136 (20.92%) 514 (79.08%) 0.28 0 283 (43.54%) 367 (56.46%) 0.22 0

141
142 M. Riedel et al. / Journal of Affective Disorders 133 (2011) 137–149

Table 3
Variance inflation factors for respective predictors entering logistic regression analyses for response and remission as dependent variable. Factors above 5 indicate
multicolinearity.

Previous Length of Neurotic disorders HAMD-21 HAMD item 3 HAMD item Job situation
hospitalizations illness (ICD-10: F4) total 19, 20

Response 1.02 1.02 1.07 1.24 1.17 1.09 –

Remission 1.04 1.01 1.01 1.02 – – 1.05

choice of this variable is the p-value of the corresponding
tests of independency between predictors and response/
remission. Based on the created sub-sets the algorithm is
started again to find a new variable which splits these data
again into two more homogeneous parts. The procedure is
stopped if no suitable variable can be found to split the final
sub-set again, i.e. no test results in a p-value less than 0.01.
The interpretation of the created tree strictly follows the
hierarchical procedure of its creation.
All statistical analyses were made with the statistical
software package R 2.6.1.
4. Patient disposition
1079 patients were enrolled in the study. 65 patients had
to be excluded due to missing baseline data. Dropout rate was
comparably low with 71 patients.
The mean duration of inpatient treatment was 53.62 days
with a range of ±47.5 days. About 67.4% were responders at
the final visit; nearly half of all patients (48.97%) achieved
HAMD-21 remission.
4.1. Sample characteristics and baseline distribution of possible
predictors
Patients had a mean age of 45 ± 12 years. About two thirds
of all patients (N = 1014) were female (62.62%).
To screen for possible predictors of response to inpatient
treatment we looked for associations of response and
remission with different clinical and sociodemographic
values, which are listed in Table 2.
Response to inpatient treatment was significantly positively
associated with age of onset, positive family history of alcohol/
drug abuse/addiction, absence of neurotic, stress-related and
somatoform disorders (ICD-10: F4), absence of avoidant
personality disorder, absence of schizoid personality disorder,
absence of other comorbid psychiatric disorders an index
episodeb 24 months, a shorter length of illness, no previous
hospitalisations, higher HAMD-21 baseline severity, a higher
psychotic symptom score (HAMD-21 items 19 “depersonaliza-
tion” and item 20 “paranoic ideation” (Seemuller et al., 2011))
and higher rates of early improvement (Table 2).
Remission was negatively associated with being retired,
having a positive familial anamnesis for affective disorders,
more than 1 psychiatric comorbidity, presence of neurotic and
stress related somatoform disorders, avoidant personality
disorder, a longer index episode, longer length of illness, longer
inpatient treatment, previous hospitalisations, higher mean
number of antidepressant switches during inpatient treatment
and non early-improvement.
4.2. Treatment
Data concerning medication were available for all patients
of the sample. In short, all patients received antidepressant
medication either as monotherapy or with co-medication.
58% received sedative compounds and 43% were given
hypnotics. Antipsychotic medication was taken by 44% of
patients.
The ten antidepressants most often prescribed with mean
treatment duration time in days (+/−) SD were in declining
order: venlafaxine ((37%); d = 40.4 ± 26.6), mirtazapine
((23%); d = 30.7 ± 23.8), sertraline ((18%); d = 37.7 ± 26.8),
citalopram ((16%); d = 37.1 ± 26.6), trimipramine (N = 91
(13%); d = 37.5 ± 33.3), amitriptyline ((15%); d = 36.5 ±
31.5), reboxetine ((9%); d = 26.8 ± 22.3), doxepine ((7%);
d = 31.3 ± 31.7), paroxetine ((5%); d = 26.0 ± 23.6) and
tranylcypromine ((5%); d = 43.8 ± 28.1).
4.3. Logistic models for prediction of response and remission
Logistic regression analysis revealed the following vari-
ables to be positively and significantly associated with
response to inpatient treatment (Table 4): Fewer prior
hospitalizations, episode duration b 24 months, presence of
suicidal ideation (HAMD item 3 N 3), presence of psychotic

Table 4
Predictors of response found with logistic regression models (AUC: 0.68).

Estimate Std. Error z value Pr(N|z|)

(Intercept) 0 0.3 − 0.01 0.99

Previous hospitalizations − 0.62 0.16 − 4.02 0.00
Length of illness N 24 months − 0.84 0.27 − 3.08 0.00
Suicidality (HAMD item 3) 0.17 0.06 2.56 0.01
Psychotic symptoms 0.17 0.06 2.82 0.00
(HAMD items 19 and 20)
Neurotic disorders (ICD-10: F4) − 0.78 0.22 − 3.51 0.00
HAMD-21 total at baseline 0.03 0.01 2.68 0.01
 M. Riedel et al. / Journal of Affective Disorders 133 (2011) 137–149 143

Table 5
Predictors of remission found with logistic regression models (AUC: 0.63).

Estimate Std. Error z value Pr(N|z|)

(Intercept) 1.2 0.28 4.23 0.00

Previous hospitalizations − 0.45 0.15 − 3.11 0.00
Length of illness N 24 months − 0.65 0.31 − 2.12 0.03
Work: jobless 0.12 0.21 0.55 0.58
Work: retired − 0.46 0.2 − 2.27 0.02
Neurotic disorders (ICD-10: F4) − 0.63 0.23 − 2.73 0.01
HAMD-21 total at baseline − 0.03 0.01 − 3.13 0.00

symptoms, absence of comorbid neurotic and stress-related Receiver operating characteristics (ROC) revealed for the
and somatoform disorders (ICD-10: F 4) and higher initial combination of these predictors an area under the curve
HAMD-21 baseline score (Table 4). For these predictors (AUC) of 0.63 indicating modest predictability.
Receiver Operating Characteristics (ROC) revealed an area
under the curve (AUC) of 0.68 indicating modest 4.4. CART analysis for prediction of response, stable response
predictability. and remission
Remission was also positively associated with fewer prior
hospitalizations, episode duration b 24 months, being not With the exception of psychotic symptoms as predic-
retired, absence of neurotic and stress-related and somato- tor, the same predictors as with the logistic regression
form disorders (ICD-10: F 4) and lower initial HAMD-21 model could be identified with CART analysis for response
baseline score (Table 5). to inpatient treatment (see Fig. 1). The hierarchical

HAMD.total
p < 0.001

< 19 > 19

Prev.hospitalisation Index.episode
p = 0.002 p < 0.001

>24 months <24 months

Neurotic.disorders
p = 0.004

TRUE FALSE TRUE FALSE

HAMD.suicidality
p = 0.002

FALSE TRUE

n = 103 n = 115 n = 57 n = 69 n = 252 n = 364

1 1 1 1 1 1
Responder Non Responder

Responder Non Responder

Responder Non Responder

Responder Non Responder

Responder Non Responder

Responder Non Responder

0.8 0.8 0.8 0.8 0.8 0.8

0.6 0.6 0.6 0.6 0.6 0.6

0.4 0.4 0.4 0.4 0.4 0.4

0.2 0.2 0.2 0.2 0.2 0.2

0 0 0 0 0 0

Fig. 1. Predictors of response found with CART analyses (mincriterion = 0.99).

144 M. Riedel et al. / Journal of Affective Disorders 133 (2011) 137–149

interpretation of the tree can be understood by viewing its 5.1. Limitations

first arm: patients with HAMD-21 of 19 or less at
admission and with previous hospitalizations have a
highly significant lower responder rate (p = 0.002) than
patients with an equally low HAMD-21 value but without
previous hospitalizations.
Out of the 6 predictors found with the logistic models only
3 were associated with remission. These were: the HAMD-21
baseline score, episode duration, and prior hospitalizations;
in addition, the presence of somatic symptoms (HAMD items
12 = "somatic symptoms", item 13 = "somatic symptoms
general", item 14 = "genital symptoms") was detected with
this model (Fig. 2).
5. Discussion
Progress in development of effective treatment as well as
the understanding of why and in whom treatment works or
does not work, strongly depends on identifying predictors of
treatment outcome (Kraemer et al., 2002). Despite quite
consistent results of different multivariate analyses there
remain serious limitations of this analysis.
The strengths of the present analysis are the large sample
size and the simultaneous investigation of a set of predictors
for response and remission on a “real-world population”
resulting in results with high external validity and the
validation with a second different statistical method. How-
ever, the fact that all patients were inpatients, implies that
there was still a selection of patients due to the reasons of
admissions to the hospital This might have affected variables
such as suicidality. Thus the sample is of course not
generalizable to outpatient populations.
The limits on the other hand are that we have not included a
staging method for treatment resistance, as recently proposed
by Fekadu, which might have had an important predictive value
(Fekadu et al., 2009). In addition, psychotic depression might
have been better characterized by including the HAMD item 4
(guilt) or the respective SCID specifier. Due to the naturalistic
design we also not included any control group. Therefore, we
were not able to find predictors for any specific intervention.
The predictors found here may thus also account for sponta-
neous response and remission and only represent predictors for
global outcome to inpatient treatment.

HAMD.total
p < 0.001

< 18 > 18

Index.episode
p = 0.003

>24 months <24 months

Somatic.symptoms
p = 0.002

FALSE TRUE

Prev.hospitalisation
p = 0.004

TRUE FALSE

n = 166 n = 58 n = 48 n = 327 n = 356

1 1 1 1 1
Non Remitter

Non Remitter

Non Remitter

Non Remitter

Non Remitter

0.8 0.8 0.8 0.8 0.8

0.6 0.6 0.6 0.6 0.6

0.4 0.4 0.4 0.4 0.4

Remitter

Remitter

Remitter

Remitter

Remitter

0.2 0.2 0.2 0.2 0.2

0 0 0 0 0

Fig. 2. Predictors of remission found with CART analyses (mincriterion = 0.99).

 M. Riedel et al. / Journal of Affective Disorders 133 (2011) 137–149 145

Early.improving
p < 0.001

Non early improver Early improver

HAMD.total HAMD.total
p < 0.001 p < 0.001

< 18 > 18

< 26 Prev.hospitalisation
> 26
p = 0.005

TRUE FALSE

n = 207 n = 103 n = 39 n = 58 n = 553

1 1 1 1 1
Non Remitter

Non Remitter

Non Remitter

Non Remitter

Non Remitter
0.8 0.8 0.8 0.8 0.8

0.6 0.6 0.6 0.6 0.6

0.4 0.4 0.4 0.4 0.4

Remitter

Remitter

Remitter

Remitter

Remitter
0.2 0.2 0.2 0.2 0.2

0 0 0 0 0

Fig. 3. Predictors of remission including early response (= 20% HAMD baseline reduction after week 2 found with CART analyses (mincriterion = 0.99).

5.2. Predicting outcome in real world patients

1.0

A categorization of predictors that is widely accepted

today is to distinguish between factors that identify on whom
and under what circumstances treatments have different
0.8

effects. Good examples are baseline features that identify who

will achieve remission (Baron and Kenny, 1986; Kraemer
et al., 2002). On the other side are factors that describe why
0.6
Sensitivity

and how treatments have effects. These factors usually rely on

progression parameters which can be measured or observed
during the treatment. Our group could recently replicate
0.4

results showing that early improvement (defined as 20%

HAMD baseline reduction after week 2) might be a valid
predictor for both remission and response with an acceptable
0.2

sensitivity: (80% and 75%) and moderate specificity (43 and

59%) in major depression (Henkel et al., 2009; Szegedi et al.,
2003). Later, Szegedi reported even higher sensitivity figures
0.0

in his meta-analysis on 6907 patients (81% for response and

87% for remission) (Szegedi et al., 2009). 0.0 0.2 0.4 0.6 0.8 1.0
The importance of early improvement is also highlighted 1-Specificity
by the fact that including early improvement as a predictor of
response to inpatient treatment in logistic regression ana- Fig. 4. ROC-curve for the logistic regression model for response to inpatient
lyses raises the AUC value from 0.68 to 0.72 (Figs. 4 and 5). treatment without early improvement (AUC = 0. 68).
146 M. Riedel et al. / Journal of Affective Disorders 133 (2011) 137–149
1.0
0.8
0.6
Sensitivity
0.4
0.2
0.0
0.0 0.2 0.4 0.6 0.8
1-Specificity
Fig. 5. ROC-curve for the logistic regression model for response to inpatient
treatment including early improvement (AUC = 0.72).
Even more interesting are changes in the Classification and
Regression Trees (CART), as they also allow hierarchical
interpretations of selected predictors. For example, for
remission early improvement was found to be the most
decisive variable of all selected predictors (Fig. 3). Early
improvers with a baseline HAMD ≤ 18 and no history of
previous hospitalisation had a more than 80% chance of
remitting after inpatient treatment. By contrast, non-early
improvers with a baseline HAMD ≥ 26 had a more than 80%
chance of non-remission after inpatient treatment. In addi-
tion, predictors like somatic symptoms and length of index
episode were eliminated.
In accordance with our study aim and due to the strong
influence of early improvement, we chose to rely on a
combination of baseline variables not including progression
parameters like early improvement.
5.3. Prior hospitalisations
The most important predictors of non-response/non-
remission of the present analysis were more prior hospitaliza-
tions and episode duration N 24 months. Regarding content,
both are connected to each other and indicate a more chronic
illness course and are, as a matter of course, connected to lower
chances of remission and response.
A higher number of hospitalizations predicting lower
response rates has been known as a predictor for a long time
and has been found in many studies searching for predictors
(Davidson et al., 1991; Goodwin, 1993; Kleindienst et al.,
2005; Moller et al., 1987), but has rarely been investigated
systematically together with a larger set of baseline variables
(Table 1). Only Hennings et al. (2009) included prior
hospitalizations in their univariate analysis on 842 depressed
inpatients and found this to be a strong predictor for worse
response and remission rates in a sample of 842 naturalisti-
cally treated depressed inpatients (Hennings et al., 2009).
“Number of prior hospitalizations” also resembles “number of
prior episodes” with an emphasis on more severe episodes,
which require inpatient treatment. A higher number of prior
episodes have also been very consistently found to predict
worse response and remission rates in placebo controlled
studies (Deykin and DiMascio, 1972; Paykel, 1972; Paykel
et al., 1973; Wittenborn et al., 1973).
5.4. Episode length
An episode length N 24 months is according to DSM-IV
referred to as chronic depression or partial refractory
depression (American Psychiatric, 2000): As it belongs to
the most commonly used exclusion criteria (Zimmerman
et al., 2002), it has seldom been under investigation in RCTs
apart from studies especially focusing on this issue. However,
a longer index episode, as a continuous measure, predicting
worse outcome, is probably one of the most consistent
predictors for worse response rates in recent analyses
1.0 (Table 1).
5.5. Baseline severity
Illness severity as measured by the HAMD-21 total score
was significantly associated with response and remission,
respectively. Interestingly, the direction of association was
contrary, with a high HAMD-21 baseline score predicting a
higher chance of response and a lower HAMD-21 baseline
score predicting a higher chance of remission. With respect to
the literature, the results are conflicting with respect to the
direction of association. High baseline scores were in some
studies associated with lower response rates (Friedman et al.,
1961; Hirschfeld et al., 1998), whereas others found higher
response rates (Henkel et al., 2011). However, other re-
searchers found no correlation of baseline score with
outcome at all (Hennings et al., 2009; Zubenko et al., 1994).
Most likely, different definitions of “response” contribute to
these conflicting results. Those who defined response not as
percentaged reduction of baseline severity but defined a
distinct cut-off score, similar to the remission criterion
(HAMD-21 ≤ 7), also revealed lower response rates the
higher the baseline score (Henkel et al., 2011; Hirschfeld
et al., 1998), as did those who used remission as outcome
(O'Leary et al., 2000; Trivedi et al., 2006).
Thus one possible explanation for this phenomenon might
be that outcomes expressed as percental changes are
methodologically biased in favour of high baseline scores
(with larger percentages when patients improve, even when
this is e.g. regression to the mean), while absolute endpoints
like remission methodologically bias towards lower baseline
scores (since patients simply have to drop less in the same
amount of time). This is also in good accordance with the law
of initial value (LIV) which suggests that the magnitude of
any psychobiological response is dependent on the initial
baseline level (Myrtek and Foerster, 1986).
In conclusion, the reporting of remission rates in relation
to the study entry severity might be the best way to show
efficacy of an antidepressant treatment.
5.6. Neurotic, stress related and somatoform disorders
In both logistic models the presence of any ICD-10 F40-F48
diagnosis (“Neurotic, stress-related and somatoform
 M. Riedel et al. / Journal of Affective Disorders 133 (2011) 137–149
disorders”) was associated with worse remission and response
rates (World Health Organization, 1992). But CART models
could only replicate this predictor for response to inpatient
treatment. Hidden behind this diffuse rubric are all phobic
disorders (F40.X) as well as anxiety disorders (F41.X) which are
well known for their negative impact on outcome (Table 1). In
fact, 76% of all F4 diagnoses in this sample had a diagnose of
either F40 or F41. Thus the true impact of the F4 rubric on
outcome is likely to be due to anxiety disorders included in this
category. This is in good accordance with a recent STAR*D
report of Fava and coworkers, demonstrating that anxious
depression, as defined by a HAMD-17 subscore, was present in
53% of all cases and predicted longer time to remission, higher
side effect frequency, intensity, and burden, as well as a higher
number of serious adverse events (Fava et al., 2008).
5.7. Suicidal ideation
The last predictor for higher chance of response to
inpatient treatment which emerged in both models was
presence of suicidal ideation at baseline, as measured with
the HAMD-21 item 3 N 3. The predictive capability of severe
suicidality has rarely been investigated as it also belongs to
mandatory exclusion criteria in almost all RCTs. Some studies
suggest that a higher number of prior suicide attempts might
be significantly negatively predictive of a favourable outcome
(Serretti et al., 2007). Only one small study explicitly
investigated suicidality as prognostic marker in 9 depressed
suicidal patients compared to 54 non-suicidal patients and
found no difference in outcome(Malhotra et al., 2004). As
suicidality is one of the most important referral reasons for
inpatient treatment, an enrichment of inpatients, as in our
study, enhances chances for detecting a signal for suicidality
as prognostic marker. To the best of our knowledge, so far no
other study has found a positive association of baseline
suicidality with better response rates. One explanation might
be that suicidality strongly correlates with overall depression
severity and may thus be a surrogate marker for overall
illness severity which, as discussed above, is positively
associated with response and not with remission (Emslie
et al., 2003; Robin and Langley, 1964). In line with this
hypothesis, a modest but highly significant correlation
r = 0.21 (P b 0.0001 spearman correlation) for the HAMD
suicidality item with the HAMD-21 total score (excluding
HAMD-item3) was found. However, inpatient treatment of
suicidal patients includes the liberal use of benzodiazepines
and caring attention towards the suicidal patient, also
possibly leading to a more rapid symptom reduction and
higher response rate at the end of the day (Seemuller et al.,
2010).
Especially in the light of the current discussion of possible
suicidal ideation promoting properties of antidepressants,
this finding further underlines the fact that depressed
patients who exhibit suicidal ideation should not be deprived
of effective antidepressant inpatient treatment (Seemuller
et al., 2009).
6. Conclusion
In summary a combination of predictors can lead to higher
accuracy in predicting treatment outcome of inpatient
147
treatment with major depression, than single predictors
alone. The most important baseline predictors are baseline
severity, number of previous hospitalizations and length of
the current episode. However the explained variance leaves
still much room for improvement. The inclusion of genetic
variables and progression parameters like early improvement
might lead the way for a better understanding of outcome
prediction.
Role of funding source
The study was performed within the framework of the German Research
Network on Depression, which was funded by the German Federal Ministry
for Education and Research BMBF (01GI0219). The BMBF had no further role
in study design; in the collection, analysis and interpretation of data; in the
writing of the report; and in the decision to submit the paper for publication.
Conflict of interest
M. Riedel has received research grants/support or has served as a
consultant for AstraZeneca, Pfizer, Otsuka Pharma, Janssen-Cilag. Hans-
Jürgen Möller has received/is receiving research grants/support from, serves
as a consultant or is on the advisory board for, or is a member of the speaker
bureau for AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Eisai, GlaxoSmithK-
line, Janssen Cilag, Lundbeck, Merck, Novartis, Organon, Pfizer, Sanofi
Aventis, Sepracor, Servier, Wyeth. Peter Brieger has received speakers
honoraria from or is on the advisory board for Astra Zeneca, Pfizer, Lundbeck,
Bristol-Meyers Squib and Servier.
Professor Michael Bauer has received/is receiving research grants/
support from, serves as a consultant or is on the advisory board for, or is a
member of the speaker bureau for Eli Lilly, GlaxoSmithKline, Novartis,
Servier, Astra Zenecka. Isabella Heuser is a member of the Bayer and Schering
advisory Board. Wolfgang Gaebel has received speakers honoraria and
research grants from the following companies: Astra Zeneca; Janssen-Cilag;
Eli Lilly; Servier. He is a member of the Scientific Advisory Board of: Janssen
Cilag; Eli Lilly Deutschland; Lundbeck; Wyeth Pharma. He has received or
currently is receiving research grants from: Janssen-Cilag; Kendle; Eli Lilly;
International clinical research H. Lundbeck; Pfizer. Joachim Zeiler, Verena
Henkel, Mazda Adli, Klaus Kronmüller, Gerd Laux, Wolfram Bender, Rebecca
Schennach-Wolff, Michael Obermeier and Florian Seemüller declare no
conflict of interest.
Acknowledgement
The network study was conducted in 12 psychiatric
hospitals: Berlin Charite Campus Mitte (Andreas Heinz,
Mazda Adli, Katja Wiethoff), Berlin Charité Campus Benjamin
Franklin (Isabella Heuser, Gerd Bischof), Berlin Auguste
Viktoria Klinik (Joachim Zeiler, Robert Fisher, Cornelia
Fähser), Berlin St. Hedwig (Florian Standfest), Berlin St.
Joseph (Dorothea Schloth), Düsseldorf (Wolfgang Gaebel,
Joachim Cordes, Arian Mobascher), Gabersee (Gerd Laux, Sissi
Artmann), Haar (Wolfram Bender, Nicole Theyson), Halle
(Andreas Marneros, Dörthe Strube, Yvonne Reinelt, Peter
Brieger), Heidelberg (Christoph Mundt, Klaus Kronmüller,
Daniela Victor), München LMU (Hans-Jürgen Möller, Ulrich
Hegerl, Roland Mergel, Michael Riedel, Florian Seemüller,
Florian Wickelmaier, Markus Jäger, Thomas Baghai, Ingrid
Borski, Constanze Schorr, Roland Bottlender), and München
MPI (Florian Holsboer, Matthias Majer, Marcus Ising).
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