Schizophrenia Bulletin Advance Access published March 17, 2015

Schizophrenia Bulletin
doi:10.1093/schbul/sbv020

Effects of Endurance Training Combined With Cognitive Remediation

on Everyday Functioning, Symptoms, and Cognition in Multiepisode
Schizophrenia Patients

Downloaded from http://schizophreniabulletin.oxfordjournals.org/ at University of California, San Francisco on March 28, 2015
Berend Malchow*,1, Katriona Keller1,2, Alkomiet Hasan1, Sebastian Dörfler3, Thomas Schneider-Axmann1,
Ursula Hillmer-Vogel2, William G. Honer4, Thomas G. Schulze5, Andree Niklas2, Thomas Wobrock3,6, Andrea Schmitt1,7,
and Peter Falkai1
1
Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University, Munich, Germany; 2Department of Sports Medicine,
University Medical Center Goettingen, Goettingen, Germany; 3Department of Psychiatry and Psychotherapy, University Medical
Center Goettingen, Goettingen, Germany; 4Institute of Mental Health, University of British Columbia, Vancouver, British Columbia,
Canada; 5Institute of Psychiatric Phenomics and Genomics, Ludwig Maximilian University, Munich, Germany; 6Center of Mental
Health, County Hospitals Darmstadt-Dieburg, Groß-Umstadt, Germany; 7Laboratory of Neuroscience (LIM27), Institute of Psychiatry,
University of Sao Paulo, Sao Paulo, Brazil
*To whom correspondence should be addressed; Department of Psychiatry and Psychotherapy, Ludwig Maximilians University,
Nussbaumstraße 7, 80336 Munich, Germany; tel: 49-89-4400-55505, fax: 49-89-440055530, e-mail: berend.malchow@med.uni-
muenchen.de

Aerobic exercise has been shown to improve symptoms in
multiepisode schizophrenia, including cognitive impair-
ments, but results are inconsistent. Therefore, we evalu-
ated the effects of an enriched environment paradigm
consisting of bicycle ergometer training and add-on com-
puter-assisted cognitive remediation (CACR) training. To
our knowledge, this is the first study to evaluate such an
enriched environment paradigm in multiepisode schizo-
phrenia. Twenty-two multiepisode schizophrenia patients
and 22 age- and gender-matched healthy controls under-
went 3 months of endurance training (30 min, 3 times/
wk); CACR training (30 min, 2 times/wk) was added from
week 6. Twenty-one additionally recruited schizophrenia
patients played table soccer (known as “foosball” in the
United States) over the same period and also received
the same CACR training. At baseline and after 6 weeks
and 3 months, we measured the Global Assessment of
Functioning (GAF), Social Adjustment Scale-II (SAS-II),
schizophrenia symptoms (Positive and Negative Syndrome
Scale), and cognitive domains (Verbal Learning Memory
Test [VLMT], Wisconsin Card Sorting Test [WCST],
and Trail Making Test). After 3 months, we observed a
significant improvement in GAF and in SAS-II social/
leisure activities and household functioning adaptation in
the endurance training augmented with cognitive remedia-
tion, but not in the table soccer augmented with cognitive
remediation group. The severity of negative symptoms and
performance in the VLMT and WCST improved signifi-
cantly in the schizophrenia endurance training augmented
with cognitive remediation group from week 6 to the end of
© The Author 2015. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.
All rights reserved. For permissions, please email: journals.permissions@oup.com2015
the 3-month training period. Future studies should inves-
tigate longer intervention periods to show whether endur-
ance training induces stable improvements in everyday
functioning.
Key words: aerobic exercise/endurance training/cognitive
remediation/schizophrenia/everyday functioning
Introduction
Schizophrenia is a severe and debilitating psychiatric
disorder that carries a high personal and socioeconomic
burden.1 Even today, up to 60% of schizophrenia patients
show an unfavorable and multiepisode disease course if
not only symptoms are taken into consideration but also
functioning.2–4 In particular, negative symptoms and cog-
nitive impairments affect the long-term outcome and are
the main contributors to disability.5–8 Despite their clini-
cal impact, however, no effective options are available to
treat them. Both antipsychotic treatment and psychoso-
cial interventions still have limited benefit on negative
symptoms and cognitive impairment.9,10 Beneficial effects
of aerobic exercise on cognition and negative symptoms
as well as brain volumes have been shown also in schizo-
phrenia although the available data differ between stud-
ies.11–15 However, the exercise interventions in these studies
were diverse and ranged from, eg, yoga or circuit training
to the use of ergometers, and duration and frequency of
the training stimulus differed. Most importantly, to our
knowledge, no study has so far evaluated the effects of

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B. Malchow et al
aerobic exercise on general and everyday functioning in
schizophrenia patients. In schizophrenia patients, cogni-
tive remediation (CR) and computer-assisted cognitive
remediation (CACR) have been shown to exert moderate
effects on cognitive domains, clinical symptoms, and psy-
chosocial functioning.16–20 However, functional outcome
was further improved when CACR has been combined
with other forms of psychiatric rehabilitation.16,18
On the basis of the studies mentioned above, one could
hypothesize that exercise and endurance training com-
bined with CR may potentially improve these important
domains of everyday life and thus help improve outcome.
To test the hypothesis that an enriched environment
interventions consisting of endurance training and CR can
improve everyday and cognitive functioning in schizophre-
nia, we investigated the effects of bicycle ergometer training
with add-on CACR training (endurance training augmented
with CR) in multiepisode schizophrenia patients and healthy
controls. To our knowledge, this is the first study to combine
these 2 approaches. In addition, as a control for the effects
of endurance training augmented with CR, we recruited a
second group of schizophrenia patients who played table
soccer (known as “foosball” in the United States) instead of
training on the bicycles; this group received the same CACR
training (table soccer augmented with CR).
Fig. 1. CONSORT scheme of the trial participants.
Page 2 of 12
Methods
Participants
Sixty-four schizophrenia patients from the
Department of Psychiatry and Psychotherapy at the
University Medical Center Goettingen participated
in this single-center trial between 2010 and 2013 (fig-
ure 1). The primary outcome criteria of this trial was
change in hippocampus volumes following the inter-
vention and these results have been published else-
where. 15 The results presented here are based on the
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clinical, neurocognitive, and functional outcome vari-
ables of this trial. The inclusion criteria were a diag-
nosis of schizophrenia according to the International
Statistical Classification of Diseases and Related
Health Problems, 10th revision (ICD-10) criteria21 and
confirmed by the MINI Plus Interview, 22 age between
18 and 60 years, and a history of at least 2 confirmed
psychotic episodes. Symptom severity was measured by
the Positive and Negative Syndrome Scale (PANSS). 23
Antipsychotic medication was kept stable for 2 weeks
before inclusion in the study and during the whole
study period. Patients with clinically relevant psy-
chiatric comorbidity (including current abuse of or
dependence on illicit drugs or alcohol assessed by

drug urine testing), verbal IQ < 85, clinically relevant
unstable medical conditions, involuntary hospitaliza-
tion, or pregnancy were excluded. We also enrolled 36
healthy controls matched for age, gender, and hand-
edness with no current (confirmed by MINI Plus
Interview) or past mental illness. See table 1 and fig-
ure 1 for baseline characteristics and the CONSORT
chart as well as supplementary methods for detailed
allocation procedures and study discontinuation.
The local ethics committee approved the study pro-
tocol, which was in accordance with the Declaration of
Helsinki. All participants provided written informed con-
sent prior to inclusion in the study. The trial was regis-
tered at www.clinicaltrials.gov (NCT01776112).
Baseline Assessment and Efficacy Measures
We performed psychopathological, functional, and
cognitive assessments at baseline and after 6 weeks and
3 months with the following scales: Global Assessment
of Functioning (GAF) to assess global everyday func-
tioning24,25, Social Adjustment Scale-II (SAS-II)26 to
assess patients’ functional adaptation before and after
the intervention, Clinical Global Impression Severity
(CGI-S)27 index to measure the severity of the illness,
PANSS23 to measure psychopathology, and Calgary
Depression Scale for Schizophrenia28 to assess depres-
sive symptoms. The neuropsychological tests were
selected to represent diverse cognitive domains that
were previously shown to be most consistently cor-
related with functional skills.29,30 Cognitive testing
included the Verbal Learning Memory Test (VLMT),31
Wisconsin Card Sorting Test (WCST),32 and the Trail
Making Tests (TMT-a and TMT-B)33 (for details, see
supplementary methods).
Enriched Environment Intervention
Exercise Testing. Endurance capacity was tested before
and after the full endurance training augmented with CR
or table soccer augmented with CR interventions on a
bicycle ergometer as described before.11,15 For details, see
supplementary methods.
Endurance Training and Table Soccer. We used the same
intervention protocol as published previously.11,15 The
intervention lasted 3 months for both the schizophrenia
and healthy control groups and consisted of 3 sessions
per week of 30 minutes duration each (supplementary fig-
ure 1 and methods).
Cognitive Remediation
After 6 weeks of endurance training or table soccer, all
participants commenced standardized cognitive training
with the computer-assisted training program COGPACK
(software version 8.19 D/8.30 DE; Marker Software,
Endurance and Cognitive Training in Schizophrenia
http://www.cogpack.de/). Patients and healthy controls
completed the memory and attention tasks 2 times per
week for 6 weeks. Each session lasted for 30 minutes and
took place after the endurance training or table soccer
session.
Power Analysis
Sixty-five participants were included in the final analysis.
Assuming a type I error probability of α = .05, a power
of 1 − β = .8, three groups, 3 measurement time points,
Downloaded from http://schizophreniabulletin.oxfordjournals.org/ at University of California, San Francisco on March 28, 2015
and a correlation between the measurements of r = .4,
medium effects of f > 0.31 for the within-subject fac-
tor time, between-subject factor group, and interactions
between time and group can be detected. This sensitivity
analysis was performed with G*power 3.1.3,34 presuming
the type I error probability, the targeted power and the
available sample size.
Statistical Analysis
The significance level was α = .05, and all tests were 2
tailed. Statistical analyses were performed with SPSS
statistics 22. The independent factor was study group
(schizophrenia endurance training augmented with
CR, schizophrenia table soccer augmented with CR,
healthy control endurance training augmented with
CR). Dependent variables were functional scores
(GAF, SAS-II), neurocognitive performance (VLMT:
short- and long-term memory, duration of TMT-A and
TMT-B, number correct on WCST), and psychopatho-
logical scores (PANSS positive, negative, and total, CGI).
Intervening variables were age, duration of school edu-
cation, gender, antipsychotic medication expressed as
chlorpromazine (CPZ) equivalents,35,36 and use of antide-
pressants and benzodiazepines.
As preliminary analyses, Kolmogorov–Smirnov tests
were used to analyze whether there were significant devia-
tions from the normality assumption; this was the case
for SAS-II variables and WCST score. Spearman correla-
tions were performed between dependent variables and
age, duration of school education, and CPZ equivalents.
The influence of gender and antidepressant and benzodi-
azepine use was evaluated by 1-way ANOVA or nonpara-
metric Mann-Whitney U test. If intervening variables
showed a significant effect, further analyses were adjusted
for these variables.
Repeated measures analyses of covariance were con-
ducted as main analyses, with within-subject factor
time of measurement, between-subject factor group,
and intervening variables identified from the initial
analyses. In case of significance, subsequent analyses
were performed between time points and groups. As
there were baseline differences between the groups for
body weight, CGI, and CPZ equivalents, all these anal-
yses were adjusted for weight and additionally for CGI
and CPZ equivalents for analyses not including healthy
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B. Malchow et al

Table 1. Demographic and Clinical Variables

Healthy Controls
Schizophrenia Endurance Schizophrenia Table
Endurance Training Training Soccer Group Comparisona

n m SD n m SD n m SD F df P

Age (y) 22 37.3 11.7 23 37.7 11.1 21 35.8 14.4 0.1 2, 63 .87
Height baseline (cm) 22 179.0 10.1 23 175.7 9.7 21 176.8 8.5 0.7 2, 63 .49
Weight baseline (kg) 22 94.8 21.3 23 79.8 14.1 21 85.9 16.1 4.2 2, 63 .020
Waist (cm) 22 102.0 15.2 23 89.5 12.7 21 92.6 17.8 4.0 2, 63 .022
Duration of school education (y) 22 11.9 1.6 23 12.0 1.4 21 11.6 2.0 0.4 2, 63 .69

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Total duration of education (y) 22 15.4 3.7 23 16.6 3.9 20 15.0 3.6 1.1 2, 62 .34
Smoking (cigarettes/d) baseline 22 7.0 10.4 23 3.2 7.3 21 4.9 7.8 χ2 = 1.8 2 .42b
Blood pressure (sys) baseline 22 125.1 18.6 23 134.0 14.2 21 133.5 14.0 2.3 2, 62 .11
Blood pressure (dia) baseline 22 74.7 12.4 23 76.9 9.9 21 81.1 10.4 1.8 2, 62 .17
Pulse baseline 22 83.2 15.3 23 73.7 12.7 21 84.0 13.9 3.8 2, 62 .028
Disease duration (y) 22 10.2 8.1 21 11.7 10.6 0.3 1, 41 .61
Number of hospitalizations 22 4.2 3.3 20 4.8 6.5 0.1 1, 41 .72
Physical Working Capacity (PWC) at 20 1.1 0.3 23 1.3 0.4 20 1.1 0.3 4.4 2, 60 .017
heartrate 130 (W) per kg
PANSS positive score baseline 22 14.1 7.6 21 13.6 4.8 0.1 1, 41 .81
PANSS negative score baseline 22 20.1 9.1 21 18.7 8.9 0.3 1, 41 .62
PANSS general score baseline 22 32.5 18.1 21 39.8 14.6 2.1 1, 41 .15
PANSS total score baseline 22 66.7 32.0 21 72.1 26.5 0.4 1, 41 .55
CDSS baseline 22 4.1 6.0 20 4.0 4.0 0.0 1, 40 .93
CGI severity baseline 22 4.7 0.8 21 3.8 0.8 Z = −3.2 1 .002c
GAF baseline 22 56.8 13.5 21 62.6 11.3 2.3 1, 41 .13
Short-term memory (STM) 22 13.3 4.0 23 13.7 2.9 21 12.0 3.0 1.7 2, 63 .19
score baseline
Long-term memory (LTM) 22 21.9 5.6 23 23.8 4.5 21 20.9 7.7 1.3 2, 63 .27
score baseline
Trail Making Test Version A 22 30.6 13.1 23 28.8 6.2 21 34.1 8.6 1.7 2, 63 .20
(TMT-A) time (s) baseline
Trail Making Test Version B 22 66.3 27.1 23 61.6 28.2 21 81.1 27.1 3.0 2, 63 .058
(TMT-B) time (s) baseline
Wisconsin Card Sorting Test (WCST) 22 34.5 6.8 23 35.7 5.1 21 34.7 7.1 Z = −0.3 2 .77
total correct score baseline
CPZ equivalents daily dosage baseline 22 912.8 791.6 21 351.9 322.6 Z = −2.8 1 .004c
CPZ equivalents cumulative dosage 22 76130.6 63347.4 21 29066.4 27610.8 Z = −3.0 1 .002c
baseline − 3 months

Chi-square Test

n n n χ2 df P

Gender (no. male/no. female) 16/6 16/7 15/6 0.1 2 .97

Hand preference (no. right/no. left) 18/4 19/4 20/1 2.1 2 .36
Marital status (no. partnership/single) 20/1 13/10 15/6 8.6 2 .013
Occupational status (no. employed/no. 8/14 20/3 9/12 13.9 2 .001
unemployed)
Living status (no. own apartment/no. other) 15/7 21/2 14/7 4.7 2 .10
Antidepressants baseline (no. with/no. without) 7/15 3/18 1.9 1 .17
Antidepressants 3 months (no. with/no. without) 8/14 5/16 0.8 1 .37
Benzodiazepine baseline (no. with/no. without) 1/21 3/18 1.2 1 0.27
Benzodiazepine during study course (no. with/ 2/20 3/18 0.3 1 0.59
no. without)

Note: Bold values are significant P values. n, group size; m, mean; no. = number; F, F statistic; χ2 = chi-squrae statistic; P, type I error
probability; PWC, physical working capacity; PANSS, Positive and Negative Syndrome Scale; CGI, Clinical Global Impression; CDSS,
Calgary Depression Scale for Schizophrenia; GAF, Global Assessment of Functioning; CPZ equivalents, chlorpromazine equivalents.
a
Results from ANOVA unless otherwise indicated.
b
Results from Kruskal-Wallis test.
c
Results from Mann-Whitney U test.

Page 4 of 12

controls. If the normality assumption was violated,
Friedman and Wilcoxon tests were used to analyze time
effects and Kruskal-Wallis and Mann-Whitney U tests
to analyze group differences.
For the dependent variables, we calculated the dif-
ferences between 3 months and baseline and analyzed
whether the change in assessment of functioning corre-
lated with the changes in psychopathological symptoms
and neuropsychological test results.
Because of the explorative character of the study, results
are presented primarily without Bonferroni adjustment
of the type I error probability. Such an adjustment would
have significantly decreased the test power, ie, the probabil-
ity of revealing existing mean differences would be too low.
However, we specify if a significant difference from a sub-
ordinate comparison persists after Bonferroni correction.
Results
Baseline Measures and Medication Impact
Although the 2 schizophrenia groups did not differ in terms
of duration of illness or symptoms, CGI baseline scores
indicate a less severe illness in the schizophrenia table soc-
cer augmented with CR group (Z = −3.2, P = .002) and
lower daily (Z = −2.8, P = .004) and cumulative (Z = −3.0,
P = .002) CPZ equivalent doses. Antidepressant and ben-
zodiazepine use did not differ between the groups and had
no effect on endurance capacity, changes in symptoms,
or everyday functioning. The WCST total correct score
was lower in patients with antidepressant use at baseline
(Z = −2.6, P = .009) but increased after 3 months (χ2 = 7.5,
P = .023). In patients using benzodiazepines, WCST total
correct score after 3 months was reduced (Z = −2.2,
P = .030). Endurance training augmented with CR patients
showed higher body weight (F = 3.7; df = 2, 62; P = .031)
and waist circumference (F = 3.6; df = 2, 62; P = .033) than
the other 2 groups (table 1).
Change in Everyday Functioning
There were no significant differences in GAF scores at
baseline (table 1). In the longitudinal analysis, the GAF
score showed significant time effects (F = 5.0; df = 2, 37;
P = .012) and time × group interactions (F = 3.7; df = 2,
37; P = .033). After 3 months, schizophrenia endurance
training augmented with CR patients showed significant
increases in GAF score compared with baseline (+16.6%,
P = .001, remained significant after Bonferroni correction
for the number of subgroup comparisons) and 6 weeks
(+9.1%, P = .041). There were no GAF increases over time
in table soccer augmented with CR patients (figure 2).
Social Adjustment
Because there were significant deviations from the nor-
mality assumption, nonparametric tests were used
for SAS-II analysis. At baseline, endurance training
Endurance and Cognitive Training in Schizophrenia
augmented with CR compared with table soccer aug-
mented with CR patients showed higher SAS-II general
(Z = −2.6, P = .017) and social/leisure activities scores
(Z = −2.1, P = .049). SAS-II general score decreased after
3 months compared with baseline (Z = −3.0, P = .003,
remained significant after Bonferroni correction) in
endurance training augmented with CR patients, indicat-
ing improvement in social functioning. After 3 months,
in endurance training augmented with CR patients,
SAS-II subscale scores social/leisure activities (Z = −2.5,
P = .012) and household functioning (Z = −2.1, P = .035)
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decreased compared with baseline (figures 3a–3d). The
table soccer augmented with CR group showed no sig-
nificant decreases over time, indicating no improvement
of social functioning.
Change in Symptoms
There were no significant PANSS score group differ-
ences at baseline (table 1). After 3 months, time effects
for PANSS total score (F = 4.2; df = 2, 37; P = .022) and
PANSS negative subscore (F = 5.3; df = 2, 37; P = .009)
were found. Significant time × group interactions
were observed for PANSS positive (F = 3.5; df = 2, 37;
P = .042) and negative (F = 3.5; df = 2, 37; P = .041) sub-
score. PANSS negative subscore decreased after 3 months
compared with 6 weeks (−14.3%, P = .017) and baseline
(−14.7%, P = .022) in the endurance training augmented
with CR group (figure 3e). The table soccer augmented
with CR group showed a decrease in PANSS positive
subscore (6 weeks vs baseline: −7.7%, P = .046; 3 months
vs baseline: −10.1%, P = .035) and in PANSS total score
(3 months vs baseline: −7.8%, P = .037).
Change in Memory
The short-term memory (STM) score of the VLMT
did not differ significantly between the groups at base-
line. The STM score showed significant time effects
(F = 4.6; df = 2, 53; P = .015) and time × group interac-
tions (F = 2.7; df = 4, 108; P = .034). STM scores were
increased in the endurance training augmented with
CR patients (3 months vs 6 weeks: +10.2%, P = .030),
in the table soccer augmented with CR group (6 weeks
vs baseline: +17.7% P = .021), and in healthy controls
(3 months vs 6 weeks: +11.0% P = .022, 3 months vs
baseline: +17.2% P = .013) (figure 4a).
The LTM score of the VLMT did not differ signifi-
cantly between groups at baseline. It showed a significant
time effect (F = 11.0; df = 2, 53; P < .0005). LTM scores
were increased in the endurance training augmented with
CR patients (3 months vs 6 weeks: +12.7%, P = .030),
but not in the table soccer augmented with CR group. In
healthy controls, the LTM score increased by 14.8% after
3 months compared with 6 weeks and by 13.7% com-
pared with baseline (P < .0005 each) (figure 4b).
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Fig. 2. In the endurance training augmented with cognitive remediation group, the Global Assessment of Functioning (GAF) had
improved significantly after 6 weeks and 3 months of training. In contrast, in the table soccer augmented with cognitive remediation group,
GAF had not improved after the training period. Improvement in GAF correlated with the Social Adjustment Scale-II (SAS-II) household
subscore, but not with the SAS-II work subscore. In the table soccer augmented with cognitive remediation group, GAF correlated
only with the SAS-II general score. In the endurance training augmented with cognitive remediation group, the SAS-II work subscore
correlated with cognitive measures like the Verbal Learning Memory Test (VLMT) and Trail Making Test B (TMT-B). In the table soccer
augmented with cognitive remediation group, the SAS-II work subscore correlated with the VLMT short-term memory score.

Change in Processing Speed
At baseline, there were no overall group effects for TMT-A
and TMT-B from 3 group comparisons. However, the
table soccer augmented with CR group took longer than
the healthy controls to complete the TMT-A (P = .037)
and TMT-B (P = .039), indicating a poorer performance
in visual attention and task switching. The duration of
TMT-A showed significant time effects (F = 9.5; df = 2,
53; P < .0005) and time × group interactions (F = 2.5;
df = 4, 108; P = .045). TMT-A duration decreased in
table soccer augmented with CR patients (3 months
vs 6 weeks: −15.8%, P = .003; 3 months vs baseline:
−18.1%, P = .007) and in healthy controls (3 months vs 6
weeks: −20.3%, P = .020; 3 months vs baseline: −15.7%,
P = .001).
TMT-B duration also showed a significant time effect
(F = 20.1; df = 2, 53; P < .0005). It decreased in table soc-
cer augmented with CR patients (3 months vs 6 weeks:
−27.4%, P = .001; 3 months vs baseline: −25.1%, P = .035)
and in healthy controls (3 months vs 6 weeks: −23.8%,
P = .016; 3 months vs baseline: −22.0%, P = .001).
Schizophrenia endurance training augmented with
CR patients showed no significant change in TMT-A or
Page 6 of 12
TMT-B (figure 4c). However, after adjustment for base-
line values or 6-week values, respectively, there were no
significant group differences for TMT-A or TMT-B per-
formance (see supplementary material).
Change in Cognitive Flexibility
Because it deviated significantly from normality
assumption, WCST total correct score was analyzed
with nonparametric methods. There were no group
differences at baseline. Schizophrenia endurance train-
ing augmented with CR patients showed an increase
(3 months vs 6 weeks: Z = −2.6, P = .008), indicat-
ing an improved cognitive flexibility performance.
Healthy controls as well showed an increase after
3 months compared with 6 weeks (3 months vs 6 weeks:
Z = −2.5, P = .011), while table soccer augmented with
CR patients showed no significant improvement over
time (figure 4d).
Correlations
The GAF improvement (difference 3 months minus
baseline) in endurance training augmented with CR
 Endurance and Cognitive Training in Schizophrenia

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Fig. 3. Assessment of functioning and psychopathology in schizophrenia patients in the endurance training augmented with cognitive
remediation and table soccer augmented with cognitive remediation groups. (a) Social Adjustment Scale-II (SAS-II) work, (b) SAS-II
household, (c) SAS-II social/leisure activities, (d) SAS-II general adaptation, (e) Positive and Negative Syndrome Scale (PANSS) negative
score, and (f) PANSS positive score. Bars represent means ± 95% CI at baseline, after 6 weeks (only e and f), and after 3 months.
*P < .05; **P < .01.

patients correlated with the reduction of PANSS positive In the schizophrenia endurance training augmented
(ρ = −0.44, P = .040) and negative (ρ = −0.49, P = .021) with CR group, the GAF improvement correlated with
symptoms (supplementary figures 2a and 2b). the improvement in SAS-II general (ρ = −0.56, P = .012),
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B. Malchow et al

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Fig. 4. Neuropsychological test results in participants in the endurance training augmented with cognitive remediation groups
(schizophrenia patients, healthy controls) and in the table soccer augmented with cognitive remediation group (schizophrenia patients).
Bars represent means ± 95% CI at baseline, after 6 weeks, and after 3 months. *P < .05; **P < .01. (a) Verbal Learning Memory Test
(VLMT) short-term memory. (b) VLMT long-term memory scores. (c) Time needed for Trail Making Test B (TMT-B). (d) Wisconsin
Card Sorting Test (WCST).

household functioning (ρ = −0.64, P = .003), and social/
leisure activities scores (ρ = −0.58, P = .010) but showed
only a trend for a correlation with the work score. In table
soccer augmented with CR patients, the difference in the
GAF correlated significantly only with the SAS-II gen-
eral subscore (ρ = −0.53, P = .023) (see supplementary
figures 2c–2f).
In endurance training augmented with CR patients,
the difference in SAS-II work subscore correlated with
the change in STM score (ρ = −0.48, P = .042) and with
improvement in TMT-B duration (ρ = 0.59, P = .010) (see
supplementary figures 3a and 3b).
Discussion
We were able to confirm our hypothesis that enriched
environment interventions consisting of aerobic exercise
Page 8 of 12
and CR improve everyday and cognitive functioning in
schizophrenia: Endurance training alone and the com-
bination of endurance training and CR significantly
improved general, social, and vocational function-
ing measured by GAF as well as cognitive functioning.
General and specific psychopathology, however, did not
improve when 3 months of intervention were compared
with baseline. The positive effects were specific to the
endurance training augmented with CR group and were
not observed in patients playing table soccer augmented
with CR. Our findings indicate that exercise-enriched
environment paradigms would be potentially beneficial
in the treatment of schizophrenia patients. The improve-
ment in the GAF from “moderate symptoms or moderate
difficulty in social, occupational, or school functioning”
(51–60 points) to “mild symptoms or some difficulty
in social, occupational, or school functioning” (61–70

points) remained significant after Bonferroni correction
and can be considered to be clinically meaningful (eg, a
GAF ≥ 65 is discussed as cutoff for recovery37).
However, the GAF is criticized for blending psychi-
atric symptoms and global functioning into one single
score.38,39 Therefore, we assessed also social functioning
by using the SAS-II subscores; the results showed a sig-
nificant improvement in general social adaptation skills
and the social/leisure activities adaptation and household
functioning adaptation subscores in the endurance train-
ing augmented with CR group, but not in the table soccer
augmented with CR group. In the work adaptation sub-
score, we found only a trend for differences; however, the
rehabilitation period may not have been long enough to
detect improvements in this domain. In the schizophre-
nia endurance training augmented with CR group, the
improvement in the GAF correlated significantly with
improvement in the SAS-II general adaptation and the
social/leisure activities and household functioning adap-
tation subscores, but not with the SAS-II work score.
Therefore, we assume that improvements in social every-
day functioning in the schizophrenia endurance train-
ing augmented with CR group drove the enhancement
in GAF score. In line with our findings, Vancampfort
and colleagues40 found a moderate association in schizo-
phrenia patients between the GAF score and functional
exercise capacity measured by the 6-minute walk test, a
submaximal test of physical fitness.
Improvement of everyday functioning may be associ-
ated also with improved levels of schizophrenia symp-
toms. Indeed, the severity of negative symptoms had
improved significantly in the schizophrenia endurance
training augmented with CR group at 3 months com-
pared with 6 weeks, but not compared with baseline. One
could speculate that the initial 6-week endurance training
period, which is the time needed to reach physical fitness,41
may be stressful for untrained schizophrenia patients and
consequently not suitable for improving negative symp-
toms. On the other hand, the add-on CACR that was
applied from week 6 until the end of the intervention
may have been able to improve negative symptoms. This
assumption is in line with the findings of Oertel-Knöchel
et al,42 who applied a shorter period of circuit training (3
× 25 min/wk) but a longer and more frequent cognitive
training (3 × 30 min/wk) for a total of 4 weeks. Scheewe
et al43 calculated a 5-factor PANSS and, after a combina-
tion of endurance and resistance training (2 × 1 h/wk for
26 weeks), found a trend-level decrease in PANSS neg-
ative factors although these do not quite equate to the
PANSS negative symptom score.
In the schizophrenia endurance training augmented
with CR group, we did not find a significant reduction of
PANSS total scores, which is in contrast to other exercise
studies11,43–46; this discrepancy may be due to sample selec-
tion and the different exercise regimens in terms of fre-
quency and duration of exercise and the specific training
Endurance and Cognitive Training in Schizophrenia
stimulus applied in the studies. However, Heggelund
et al47 used a more intense endurance training stimulus
over a period of 4 weeks and also found no significant
change in PANSS scores. Using repeated measures analy-
ses of covariance and additionally adjusting for baseline
and separately for 6-week values as covariates (supple-
mentary methods and results) to address for carryover
effects of endurance training, we found an improvement
in PANSS negative symptoms in the endurance training
augmented with CR group.
We conclude that endurance training augmented with
Downloaded from http://schizophreniabulletin.oxfordjournals.org/ at University of California, San Francisco on March 28, 2015
CR appears to have a limited effect on general psychopa-
thology in schizophrenia.
The effects on cognitive performance of adding CACR
to endurance training after week 6 mirrored the picture
of improvement in negative symptoms in the same part of
the study. The hypothesized effect of endurance training
augmented with CR on cognitive functioning, assessed
with the STM composite score, was seen only when the
3-month scores were compared with the 6-week scores,
which means improvement in short-term verbal learning
memory was seen only after exercise was combined with
CR. In contrast to Pajonk et al,11 who studied a smaller
sample, we found no significant increase in the STM
composite score after 3 months compared with baseline,
which may again be due to the sampling of our patients.
Interestingly, the STM also increased significantly in the
table soccer group after 6 weeks compared with baseline
but did not increase significantly after the additional
period of 6 weeks when table soccer was combined with
CR. Again, in this group, STM did not change signifi-
cantly when the 3-month score was compared with base-
line. In summary, we cannot rule out an additional effect
of CACR on STM in the table soccer augmented with CR
group, but any effect does not appear to be prominent,
indicating that the additional use of endurance train-
ing is necessary to enhance the effects of a multimodal
training. To our knowledge, no study has investigated
a possible positive influence of playing table soccer on
cognitive functioning in either healthy controls or schizo-
phrenia patients. We observed a steady improvement in
STM only in the healthy controls, which speaks for intact
neuroplastic capacities in healthy people compared with
schizophrenia patients. The LTM composite score of the
VLMT showed a similar picture, ie, a significant increase
was seen only when comparing scores after 3 months of
endurance training to 6 weeks, but not to baseline. Our
results are in line with other exercise studies that reported
no alterations of this long-term verbal memory subscore
after the same 3-month endurance training paradigm11 or
4 weeks of circuit training combined with CACR.42
The sum of total correct responses in the WCST, which
represents the ability to display flexibility in the face of
changing schedules of reinforcement, improved sig-
nificantly in the schizophrenia endurance training aug-
mented with CR group, but again, like the other cognitive
Page 9 of 12
B. Malchow et al
measures, only when comparing 3 months of intervention
to 6 weeks and not to baseline. Schizophrenia patients
playing table soccer augmented with CR showed no sig-
nificant increase in the WCST total correct score, despite
the CACR therapy in the second 6 weeks of the experi-
mental intervention. So far, no other study investigating
exercise therapy in schizophrenia patients has measured
effects of endurance training on the cognitive flexibility
of working memory. The TMT measures visual attention
and task switching.48 We hypothesize that both domains
are trained by playing table soccer augmented with CR.
Indeed, in contrast to the patients in the endurance train-
ing augmented with CR group, patients in the table soc-
cer augmented with CR group numerically improved
their TMT-A and TMT-B completion time during the
intervention. However, analysis on TMT differences con-
trolled for baseline values or 6-week values, respectively,
revealed no significant group effects.
Some important limitations have to be taken into
account when interpreting the results of this study. We
did not use a randomization procedure to allocate the
schizophrenia patients to the endurance training aug-
mented with CR or table soccer augmented with CR
group, which is an important limitation, possibly leading
to a potential selection bias and to baseline differences
in psychopathology and medication status. During the
second period from 6 weeks to 3 months, we did not
include additional study arms with CR only or with
endurance training only. Therefore, one cannot draw the
conclusion that the effects on cognition and symptoms
are caused by adding CR or endurance training alone.
In addition, treatment conditions could not be blinded
and a crossover design was not feasible because the
potentially longer lasting effects of endurance training
would have required a long washout phase before the
group could have started with the table soccer session.
Moreover, effects of psychopharmacological treatment
cannot be ruled out because doses of antipsychotic
treatment differed between the 2 schizophrenia groups.
We also did not include a healthy control group par-
ticipating in table soccer augmented with CR sessions.
Finally, the primary outcome of the whole trial was
change in hippocampal volumes following the interven-
tion (biological outcome, results published elsewhere).15
The clinical results shown here are therefore based on
secondary outcomes of the trial and the reader should
be aware that the trial was not specifically powered to
access these outcomes.
In summary, a 3-month endurance training program
combined with CR therapy for the last 6 weeks of the
intervention period had positive effects on everyday func-
tioning in multiepisode schizophrenia patients. Deficits
improved from medium to mild as assessed with the GAF.
Negative symptoms, short- and long-term verbal mem-
ory and cognitive flexibility also improved with endur-
ance and cognitive training. It can be hypothesized that a
Page 10 of 12
combination of endurance training and CR therapy is an
effective add-on treatment in multiepisode schizophrenia
and improves everyday functioning in this severe mental
illness. This hypothesis needs to be validated in random-
ized controlled clinical studies with larger cohorts.
Supplementary Material
Supplementary material is available at http://schizophre-
niabulletin.oxfordjournals.org.
Downloaded from http://schizophreniabulletin.oxfordjournals.org/ at University of California, San Francisco on March 28, 2015
Funding
We would like to express our sincere thanks to the family
of Mrs Ricarda Maucher for their generous financial sup-
port. This work was partially supported by the Deutsche
Forschungsgemeinschaft (1950/5-1 to P.F. and T.G.S.).
This work was partially supported by the Dorothea
Schlözer Programme at the Georg-August-University
Göttingen (K.K.).
Acknowledgments
We thank Jacquie Klesing, Board-certified Editor in
the Life Sciences (ELS), for editing assistance with the
manuscript. B.M., K.K., S.D., T.S.-A., U.H.-V., and A.N.
have no conflicts of interest in relation to the subject of
this study. A.H. has been invited to scientific meetings
by Lundbeck, Janssen-Cilag, Pfizer, and Desitin. He is
a member of the advisory board of Roche. W.G.H. is
an unpaid member of the advisory board of In Silico
Biosciences and a paid consultant to Otsuka/Lundbeck,
Roche, Novartis, MDH Consulting, and the Canadian
Agency on Drugs and Technology in Health. A.S. was
an honorary speaker for TAD Pharma and Roche and
has been a member of advisory boards for Roche. T.W.
has received paid speakerships from Alpine Biomed,
AstraZeneca, Bristol Myers Squibb, Eli Lilly, I3G, Janssen
Cilag, Novartis, Lundbeck, Roche, Sanofi-Aventis, and
Pfizer; has accepted travel or hospitality not related to a
speaking engagement from AstraZeneca, Bristol-Myers-
Squibb, Eli Lilly, Janssen Cilag, and Sanofi-Synthelabo;
and has received research grants from AstraZeneca, I3G,
and AOK (a health insurance company). P.F. has been
an honorary speaker for Janssen-Cilag, Astra-Zeneca,
Eli Lilly, Bristol Myers-Squibb, Lundbeck, Pfizer, Bayer
Vital, SmithKline Beecham, Wyeth, and Essex. During
the past 5 years, but not presently, Peter Falkai has been
a member of the advisory boards of Janssen-Cilag,
AstraZeneca, Eli Lilly, and Lundbeck.
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