Effects of Endurance Training Combined With Cognitive Remediation on Everyday Functioning, Symptoms, and Cognition in Multiepisode Schizophrenia Patients

Abstract

Aerobic exercise has been shown to improve symptoms in multiepisode schizophrenia, including cognitive impairments, but results are inconsistent. Therefore, we evaluated the effects of an enriched environment paradigm consisting of bicycle ergometer training and add-on computer-assisted cognitive remediation (CACR) training. To our knowledge, this is the first study to evaluate such an enriched environment paradigm in multiepisode schizophrenia. Twenty-two multiepisode schizophrenia patients and 22 age- and gender-matched healthy controls underwent 3 months of endurance training (30min, 3 times/wk); CACR training (30min, 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 remediation, but not in the table soccer augmented with cognitive remediation group. The severity of negative symptoms and performance in the VLMT and WCST improved significantly in the schizophrenia endurance training augmented with cognitive remediation group from week 6 to the end of the 3-month training period. Future studies should investigate longer intervention periods to show whether endurance training induces stable improvements in 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 cognitive impairments affect the long-term outcome and are the main contributors to disability.^5–8 Despite their clinical impact, however, no effective options are available to treat them. Both antipsychotic treatment and psychosocial 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 schizophrenia although the available data differ between studies.^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 aerobic exercise on general and everyday functioning in schizophrenia patients. In schizophrenia patients, cognitive remediation (CR) and computer-assisted cognitive remediation (CACR) have been shown to exert moderate effects on cognitive domains, clinical symptoms, and psychosocial 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 combined 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 schizophrenia, 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).

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 (figure 1). The primary outcome criteria of this trial was change in hippocampus volumes following the intervention and these results have been published elsewhere.¹⁵ The results presented here are based on the clinical, neurocognitive, and functional outcome variables of this trial. The inclusion criteria were a diagnosis 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 psychiatric 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 hospitalization, or pregnancy were excluded. We also enrolled 36 healthy controls matched for age, gender, and handedness with no current (confirmed by MINI Plus Interview) or past mental illness. See table 1 and figure 1 for baseline characteristics and the CONSORT chart as well as supplementary methods for detailed allocation procedures and study discontinuation.

Fig. 1.

CONSORT scheme of the trial participants.

Table 1.

Demographic and Clinical Variables

	Schizophrenia Endurance Training			Healthy Controls Endurance Training			Schizophrenia Table 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
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 heartrate 130 (W) per kg	20	1.1	0.3	23	1.3	0.4	20	1.1	0.3	4.4	2, 60	.017
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	.002 c
GAF baseline	22	56.8	13.5				21	62.6	11.3	2.3	1, 41	.13
Short-term memory (STM) score baseline	22	13.3	4.0	23	13.7	2.9	21	12.0	3.0	1.7	2, 63	.19
Long-term memory (LTM) score baseline	22	21.9	5.6	23	23.8	4.5	21	20.9	7.7	1.3	2, 63	.27
Trail Making Test Version A (TMT-A) time (s) baseline	22	30.6	13.1	23	28.8	6.2	21	34.1	8.6	1.7	2, 63	.20
Trail Making Test Version B (TMT-B) time (s) baseline	22	66.3	27.1	23	61.6	28.2	21	81.1	27.1	3.0	2, 63	.058
Wisconsin Card Sorting Test (WCST) total correct score baseline	22	34.5	6.8	23	35.7	5.1	21	34.7	7.1	Z = −0.3	2	.77
CPZ equivalents daily dosage baseline	22	912.8	791.6				21	351.9	322.6	Z = −2.8	1	.004 c
CPZ equivalents cumulative dosage baseline − 3 months	22	76130.6	63347.4				21	29066.4	27610.8	Z = −3.0	1	.002 c

				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. unemployed)	8/14	20/3	9/12	13.9	2	.001
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/ no. without)	2/20		3/18	0.3	1	0.59

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.

^aResults from ANOVA unless otherwise indicated.

^bResults from Kruskal-Wallis test.

^cResults from Mann-Whitney U test.

The local ethics committee approved the study protocol, which was in accordance with the Declaration of Helsinki. All participants provided written informed consent prior to inclusion in the study. The trial was registered 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 functioning^24,25, 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 depressive symptoms. The neuropsychological tests were selected to represent diverse cognitive domains that were previously shown to be most consistently correlated 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 figure 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, 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, and a correlation between the measurements of r = .4, medium effects of f > 0.31 for the within-subject factor 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 psychopathological scores (PANSS positive, negative, and total, CGI). Intervening variables were age, duration of school education, gender, antipsychotic medication expressed as chlorpromazine (CPZ) equivalents,^35,36 and use of antidepressants and benzodiazepines.

As preliminary analyses, Kolmogorov–Smirnov tests were used to analyze whether there were significant deviations from the normality assumption; this was the case for SAS-II variables and WCST score. Spearman correlations were performed between dependent variables and age, duration of school education, and CPZ equivalents. The influence of gender and antidepressant and benzodiazepine use was evaluated by 1-way ANOVA or nonparametric Mann-Whitney U test. If intervening variables showed a significant effect, further analyses were adjusted for these variables.

Repeated measures analyses of covariance were conducted 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 analyses were adjusted for weight and additionally for CGI and CPZ equivalents for analyses not including healthy 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 differences between 3 months and baseline and analyzed whether the change in assessment of functioning correlated 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 probability of revealing existing mean differences would be too low. However, we specify if a significant difference from a subordinate 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 soccer 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 benzodiazepine 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).

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.

Social Adjustment

Because there were significant deviations from the normality assumption, nonparametric tests were used for SAS-II analysis. At baseline, endurance training augmented with CR compared with table soccer augmented 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, indicating 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) decreased compared with baseline (figures 3a–3d). The table soccer augmented with CR group showed no significant decreases over time, indicating no improvement of social functioning.

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.

Change in Symptoms

There were no significant PANSS score group differences 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) subscore. 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 baseline. The STM score showed significant time effects (F = 4.6; df = 2, 53; P = .015) and time × group interactions (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).

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).

The LTM score of the VLMT did not differ significantly 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% compared with baseline (P < .0005 each) (figure 4b).

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 soccer 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 TMT-B (figure 4c). However, after adjustment for baseline values or 6-week values, respectively, there were no significant group differences for TMT-A or TMT-B performance (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 training augmented with CR patients showed an increase (3 months vs 6 weeks: Z = −2.6, P = .008), indicating 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 patients correlated with the reduction of PANSS positive (ρ = −0.44, P = .040) and negative (ρ = −0.49, P = .021) symptoms (supplementary figures 2a and 2b).

In the schizophrenia endurance training augmented with CR group, the GAF improvement correlated with the improvement in SAS-II general (ρ = −0.56, P = .012), 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 general 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 and CR improve everyday and cognitive functioning in schizophrenia: Endurance training alone and the combination of endurance training and CR significantly improved general, social, and vocational functioning 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 improvement 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 psychiatric 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 significant improvement in general social adaptation skills and the social/leisure activities adaptation and household functioning adaptation subscores in the endurance training augmented with CR group, but not in the table soccer augmented with CR group. In the work adaptation subscore, 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 schizophrenia 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 adaptation subscores, but not with the SAS-II work score. Therefore, we assume that improvements in social everyday functioning in the schizophrenia endurance training augmented with CR group drove the enhancement in GAF score. In line with our findings, Vancampfort and colleagues⁴⁰ found a moderate association in schizophrenia 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 associated also with improved levels of schizophrenia symptoms. Indeed, the severity of negative symptoms had improved significantly in the schizophrenia endurance training augmented with CR group at 3 months compared 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 symptoms. 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 × 25min/wk) but a longer and more frequent cognitive training (3 × 30min/wk) for a total of 4 weeks. Scheewe et al⁴³ calculated a 5-factor PANSS and, after a combination of endurance and resistance training (2 × 1 h/wk for 26 weeks), found a trend-level decrease in PANSS negative 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 studies^11,43–46; this discrepancy may be due to sample selection and the different exercise regimens in terms of frequency and duration of exercise and the specific training 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 analyses of covariance and additionally adjusting for baseline and separately for 6-week values as covariates (supplementary 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 CR appears to have a limited effect on general psychopathology 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 significantly when the 3-month score was compared with baseline. 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 training 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 schizophrenia 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 significantly in the schizophrenia endurance training augmented with CR group, but again, like the other cognitive 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 significant increase in the WCST total correct score, despite the CACR therapy in the second 6 weeks of the experimental 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 training augmented with CR group, patients in the table soccer augmented with CR group numerically improved their TMT-A and TMT-B completion time during the intervention. However, analysis on TMT differences controlled 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 augmented 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 participating in table soccer augmented with CR sessions. Finally, the primary outcome of the whole trial was change in hippocampal volumes following the intervention (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 functioning in multiepisode schizophrenia patients. Deficits improved from medium to mild as assessed with the GAF. Negative symptoms, short- and long-term verbal memory and cognitive flexibility also improved with endurance and cognitive training. It can be hypothesized that a 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 randomized controlled clinical studies with larger cohorts.

Supplementary Material

Supplementary material is available at http://schizophreniabulletin.oxfordjournals.org.

Funding

We would like to express our sincere thanks to the family of Mrs Ricarda Maucher for their generous financial support. 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.).