Predictors of adherence to exercise interventions in people with schizophrenia.

Exercise interventions are nowadays considered as effective add-on treatments in people with schizophrenia but are usually associated with high dropout rates. Therefore, the present study investigated potential predictors of adherence from a large multicenter study, encompassing two types of exercise training, conducted over a 6-month period with individuals with schizophrenia. First, we examined the role of multiple participants' characteristics, including levels of functioning, symptom severity, cognitive performance, quality of life, and physical fitness. Second, we used K-means clustering to identify clinical subgroups of participants that potentially exhibited superior adherence. Last, we explored if adherence could be predicted on the individual level using Random Forest, Logistic Regression, and Ridge Regression. We found that individuals with higher levels of functioning at baseline were more likely to adhere to the exercise interventions, while other factors such as symptom severity, cognitive performance, quality of life or physical fitness seemed to be less influential. Accordingly, the high-functioning group with low symptoms exhibited a greater likelihood of adhering to the interventions compared to the severely ill group. Despite incorporating various algorithms, it was not possible to predict adherence at the individual level. These findings add to the understanding of the factors that influence adherence to exercise interventions. They underscore the predictive importance of daily life functioning while indicating a lack of association between symptom severity and adherence. Future research should focus on developing targeted strategies to improve adherence, particularly for people with schizophrenia who suffer from impairments in daily functioning.Clinical trials registration The study of this manuscript which the manuscript is based was registered in the International Clinical Trials Database, ClinicalTrials.gov (NCT number: NCT03466112, https://clinicaltrials.gov/ct2/show/NCT03466112?term=NCT03466112&draw=2&rank=1 ) and in the German Clinical Trials Register (DRKS-ID: DRKS00009804.

Cognitive and functional deficits are associated with white matter abnormalities in two independent cohorts of patients with schizophrenia.

BACKGROUND: Significant evidence links white matter (WM) microstructural abnormalities to cognitive impairment in schizophrenia (SZ), but the relationship of these abnormalities with functional outcome remains unclear. METHODS: In two independent cohorts (C1, C2), patients with SZ were divided into two subgroups: patients with higher cognitive performance (SZ-HCP-C1, n = 25; SZ-HCP-C2, n = 24) and patients with lower cognitive performance (SZ-LCP-C1, n = 25; SZ-LCP-C2, n = 24). Healthy controls (HC) were included in both cohorts (HC-C1, n = 52; HC-C2, n = 27). We compared fractional anisotropy (FA) of the whole-brain WM skeleton between the three groups (SZ-LCP, SZ-HCP, HC) by a whole-brain exploratory approach and an atlas-defined WM regions-of-interest approach via tract-based spatial statistics. In addition, we explored whether FA values were associated with Global Assessment of Functioning (GAF) scores in the SZ groups. RESULTS: In both cohorts, mean FA values of whole-brain WM skeleton were significantly lower in the SCZ-LCP group than in the SCZ-HCP group. Whereas in C1 the FA of the frontal part of the left inferior fronto-occipital fasciculus (IFOF) was positively correlated with GAF score, in C2 the FA of the temporal part of the left IFOF was positively correlated with GAF score. CONCLUSIONS: We provide robust evidence for WM microstructural abnormalities in SZ. These abnormalities are more prominent in patients with low cognitive performance and are associated with the level of functioning.

Association between aerobic fitness and the functional connectome in patients with schizophrenia.

BACKGROUND: Schizophrenia is accompanied by widespread alterations in static functional connectivity associated with symptom severity and cognitive deficits. Improvements in aerobic fitness have been demonstrated to ameliorate symptomatology and cognition in people with schizophrenia, but the intermediary role of macroscale connectivity patterns remains unknown. OBJECTIVE: Therefore, we aim to explore the relation between aerobic fitness and the functional connectome in individuals with schizophrenia. Further, we investigate clinical and cognitive relevance of the identified fitness-connectivity links. METHODS: Patients diagnosed with schizophrenia were included in this cross-sectional resting-state fMRI analysis. Multilevel Bayesian partial correlations between aerobic fitness and functional connections across the whole brain as well as between static functional connectivity patterns and clinical and cognitive outcome were performed. Preliminary causal inferences were enabled based on mediation analyses. RESULTS: Static functional connectivity between the subcortical nuclei and the cerebellum as well as between temporal seeds mediated the attenuating relation between aerobic fitness and total symptom severity. Functional connections between cerebellar seeds affected the positive link between aerobic fitness and global cognition, while the functional interplay between central and limbic seeds drove the beneficial association between aerobic fitness and emotion recognition. CONCLUSION: The current study provides first insights into the interactions between aerobic fitness, the functional connectome and clinical and cognitive outcome in people with schizophrenia, but causal interpretations are preliminary. Further interventional aerobic exercise studies are needed to replicate the current findings and to enable conclusive causal inferences. TRIAL REGISTRATION: The study which the manuscript is based on is registered in the International Clinical Trials Database (ClinicalTrials.gov identifier [NCT number]: NCT03466112) and in the German Clinical Trials Register (DRKS-ID: DRKS00009804).

Aerobic endurance training to improve cognition and enhance recovery in schizophrenia: design and methodology of a multicenter randomized controlled trial.

Even today, patients with schizophrenia often have an unfavorable outcome. Negative symptoms and cognitive deficits are common features in many patients and prevent recovery. In recent years, aerobic endurance training has emerged as a therapeutic approach with positive effects on several domains of patients' health. However, appropriately sized, multicenter randomized controlled trials that would allow better generalization of results are lacking. The exercise study presented here is a multicenter, rater-blind, two-armed, parallel-group randomized clinical trial in patients with clinically stable schizophrenia being conducted at five German tertiary hospitals. The intervention group performs aerobic endurance training on bicycle ergometers three times per week for 40-50 min/session (depending on the intervention week) for a total of 26 weeks, and the control group performs balance and tone training for the same amount of time. Participants are subsequently followed up for 26 weeks. The primary endpoint is all-cause discontinuation; secondary endpoints include psychopathology, cognition, daily functioning, cardiovascular risk factors, and explorative biological measures regarding the underlying mechanisms of exercise. A total of 180 patients will be randomized. With currently 162 randomized participants, our study is the largest trial to date to investigate endurance training in patients with schizophrenia. We hypothesize that aerobic endurance training has beneficial effects on patients' mental and physical health, leading to lower treatment discontinuation rates and improving disease outcomes. The study results will provide a basis for recommending exercise interventions as an add-on therapy in patients with schizophrenia.The study is registered in the International Clinical Trials Database (ClinicalTrials.gov identifier [NCT number]: NCT03466112) and in the German Clinical Trials Register (DRKS-ID: DRKS00009804).

Effects of Three Months of Aerobic Endurance Training on Motor Cortical Excitability in Schizophrenia Patients and Healthy Subjects.

BACKGROUND: Aerobic endurance training has been discussed to induce brain plasticity and improve cognitive functions in healthy subjects and patients with neuropsychiatric disorders. For schizophrenia, a motor cortical inhibitory deficit has been established as one aspect of impaired plasticity, especially involving impairments in GABAergic interneuron networks, but the possibility to restore these deficits via exercise-induced plasticity has not been evaluated yet. METHODS: 17 schizophrenia patients and 16 matched healthy controls underwent 3 months of aerobic endurance training (30 min, 3 times a week) on bicycle ergometers. After 6 weeks, computer-assisted cognitive remediation training (30 min, 2 times a week) was added. Transcranial magnetic stimulation of the left and right hemispheres was performed at baseline and at the end of the intervention. We evaluated the intensity to induce a motor-evoked potential of 1 mV (S1mV), the resting motor threshold (RMT), the cortical silent period (CSP) at an intensity of 120 and 150% of the individual RMT, short-latency interval intracortical inhibition (3 ms), and intracortical facilitation (7 and 15 ms). Depending on the variable and hemisphere, follow-up data was available for 7-15 schizophrenia patients and for 10-12 healthy controls. RESULTS: Repeated measures ANOVA revealed no significant time × group interactions for any of the analyzed variables. A significant increase in S1mV and CSP duration at 150% RMT of the left hemisphere could be observed in both groups over time. CONCLUSION: Regular ergometer training over 3 months increases motor cortical inhibition as displayed by an increase in CSP. The increase in S1mV may also indicate a higher degree of inhibition after the intervention. We could not establish a difference between schizophrenia patients and healthy controls. Due to the limited sample size, our results have to be considered as preliminary and need to be replicated in future trials.

Endurance training in patients with schizophrenia and healthy controls: differences and similarities.

The aims were to examine the feasibility of and adaptations to endurance training in persons diagnosed with schizophrenia and to address the question whether the principles and beneficial effects of endurance training established in the healthy population apply also to patients with schizophrenia. In this controlled interventional study, 22 patients with schizophrenia and 22 healthy controls performed a standardized aerobic endurance training on bicycle ergometers over 12 weeks. Another group of 21 patients with schizophrenia played table soccer. Endurance capacity was measured with incremental cycle ergometry before and after the intervention and 3 months later. A specific set of outcome parameters was defined. The training stimuli can be assumed to be similar in both endurance groups. Endurance capacity improved significantly in the endurance groups, but not in the table soccer group. Patients and healthy controls showed comparable adaptations to endurance training, as assessed by physical working capacity and maximal achieved power. Differences were found in changes of performance at a lactate concentration of 3 mmol/l. Endurance training was feasible and effective in both groups. The principles and types of training that are usually applied to healthy controls need to be verified in patients with schizophrenia. Nevertheless, patients benefited from endurance training in terms of improvement of endurance capacity and reduction in the baseline deficit in comparison with healthy controls. Therefore, endurance training should be implemented in future therapy programs. These programs need to pay special attention to the differences between patients with schizophrenia and healthy controls.

Effects of Exercise on Structural and Functional Brain Patterns in Schizophrenia-Data From a Multicenter Randomized-Controlled Study.

BACKGROUND AND HYPOTHESIS: Aerobic exercise interventions in people with schizophrenia have been demonstrated to improve clinical outcomes, but findings regarding the underlying neural mechanisms are limited and mainly focus on the hippocampal formation. Therefore, we conducted a global exploratory analysis of structural and functional neural adaptations after exercise and explored their clinical implications. STUDY DESIGN: In this randomized controlled trial, structural and functional MRI data were available for 91 patients with schizophrenia who performed either aerobic exercise on a bicycle ergometer or underwent a flexibility, strengthening, and balance training as control group. We analyzed clinical and neuroimaging data before and after 6 months of regular exercise. Bayesian linear mixed models and Bayesian logistic regressions were calculated to evaluate effects of exercise on multiple neural outcomes and their potential clinical relevance. STUDY RESULTS: Our results indicated that aerobic exercise in people with schizophrenia led to structural and functional adaptations mainly within the default-mode network, the cortico-striato-pallido-thalamo-cortical loop, and the cerebello-thalamo-cortical pathway. We further observed that volume increases in the right posterior cingulate gyrus as a central node of the default-mode network were linked to improvements in disorder severity. CONCLUSIONS: These exploratory findings suggest a positive impact of aerobic exercise on 3 cerebral networks that are involved in the pathophysiology of schizophrenia. CLINICAL TRIALS REGISTRATION: The underlying study of this manuscript was registered in the International Clinical Trials Database, ClinicalTrials.gov (NCT number: NCT03466112, https://clinicaltrials.gov/ct2/show/NCT03466112?term=NCT03466112&draw=2&rank=1) and in the German Clinical Trials Register (DRKS-ID: DRKS00009804).

Personalized training as a promoter for physical activity in people with depressive disorder-a randomized controlled trial in Germany.

Introduction: Adopting an active lifestyle is an important goal, but can be difficult to achieve for people with depressive disorders. Current guidelines recommend the integration of physical activity in the multimodal treatment of depressive disorders. However, the possibilities to provide individual support for physical activities are frequently limited. The aim of our study was to examine how physical activity can be increased in a real-world setting by combining physical training and psychological interventions. Materials and methods: In this randomized-controlled interventional study, 31 outpatients diagnosed with moderate to severe depression were recruited from the region of Hannover. The intervention group (n = 16) was offered six weekly individual sessions lasting between 60 and 90 min with a sports scientist, including Motivational Interviewing and accompanied exercise activities. The control group (n = 15) received a written booklet with information on steps toward becoming more active. Moderate-to-vigorous physical activity (MVPA) as the primary outcome was analyzed using activity sensors before and after the 6-week intervention, and 3 months subsequently. Secondary outcomes included the Six-Minute Walk Test (6MWT), Sit-to-Stand test (STS), and mental health assessed with self-rating questionnaires. Results: In the intervention group, MVPA increased significantly between baseline and the first follow-up and remained at an increased level at the second follow-up in comparison to decreased levels in the control group (difference of 15.5 min/day between groups over time, SE = 6.2 min/day, 95%-CI[2.7, 28.3], p = 0.020). The increased activity level was associated with markers of increased fitness (6MWT and STS) in the intervention group. Both groups showed comparable improvements in depressive symptoms, while the number of patients receiving antidepressants increased in the control group and decreased in the intervention group. Two patients dropped out of the intervention group during the trial. Conclusion: The intervention proved to be a feasible and effective aid to promote a physically active lifestyle for patients diagnosed with depression. Furthermore, the higher level of physical activity was maintained for the follow-up period. Given the success of the approach evaluated in this project, individual support for physical activity should be investigated in larger sample sizes and potentially be considered in the multimodal treatment of depression. Clinical trial registration: [https://clinicaltrials.gov/], identifier [DRKS00023257].

Exercise as an add-on treatment in individuals with schizophrenia: Results from a large multicenter randomized controlled trial.

Current treatment methods do not achieve recovery for most individuals with schizophrenia, and symptoms such as negative symptoms and cognitive deficits often persist. Aerobic endurance training has been suggested as a potential add-on treatment targeting both physical and mental health. We performed a large-scale multicenter, rater-blind, parallel-group randomized controlled clinical trial in individuals with stable schizophrenia. Participants underwent a professionally supervised six-month training comprising either aerobic endurance training (AET) or flexibility, strengthening, and balance training (FSBT, control group), follow-up was another six months. The primary endpoint was all-cause discontinuation (ACD); secondary endpoints included effects on psychopathology, cognition, functioning, and cardiovascular risk. In total, 180 participants were randomized. AET was not superior to FSBT in ACD and most secondary outcomes, with dropout rates of 59.55% and 57.14% in the six-month active phase, respectively. However, both groups showed significant improvements in positive, general, and total symptoms, levels of functioning and in cognitive performance. A higher training frequency additionally promoted further memory domains. Participants with higher baseline cognitive abilities were more likely to respond to the interventions. Our results support integrating exercise into schizophrenia treatment, while future studies should aim to develop personalized training recommendations to maximize exercise-induced benefits.

Associations between aerobic fitness, negative symptoms, cognitive deficits and brain structure in schizophrenia-a cross-sectional study.

Negative symptoms and cognitive deficits are common in individuals with schizophrenia, greatly affect their outcome, and have been associated with alterations in cerebral gray and white matter volume (GMV, WMV). In the last decade, aerobic endurance training has emerged as a promising intervention to alleviate these symptoms and improved aerobic fitness has been suggested as a key moderator variable. In the present study, we investigated, whether aerobic fitness is associated with fewer cognitive deficits and negative symptoms and with GMVs and WMVs in individuals with schizophrenia in a cross-sectional design. In the largest study to date on the implications of fitness in individuals with schizophrenia, 111 participants at two centers underwent assessments of negative symptoms, cognitive functioning, and aerobic fitness and 69 underwent additional structural magnetic resonance imaging. Multilevel Bayesian partial correlations were computed to quantify relationships between the variables of interest. The main finding was a positive association of aerobic fitness with right hippocampal GMV and WMVs in parahippocampal and several cerebellar regions. We found limited evidence for an association of aerobic fitness with cognitive functioning and negative symptoms. In summary, our results strengthen the notion that aerobic fitness and hippocampal plasticity are interrelated which holds implications for the design of exercise interventions in individuals with schizophrenia.

Effect of aerobic exercise on cortical thickness in patients with schizophrenia-A dataset.

This is a data article from the original publication "Effect of aerobic exercise combined with cognitive remediation on cortical thickness and prediction of social adaptation in patients with schizophrenia" [1]. Twenty-one patients with schizophrenia and 23 healthy controls underwent aerobic exercise. Another 21 patients with schizophrenia played table soccer instead. The 12-week exercise intervention was combined with computer-assisted cognitive remediation training from week 6 to week 12. Clinical assessments were conducted at baseline and after the 12-week intervention. Magnetic resonance imaging (MRI) scans were acquired at baseline then in weeks 6, 12, and 24. The thickness of the entorhinal, parahippocampal, and lateral and medial prefrontal cortices was assessed with FreeSurfer 6.0. Data are publicy available via https://osf.io/sfgxk/.

Effect of aerobic exercise combined with cognitive remediation on cortical thickness and prediction of social adaptation in patients with schizophrenia.

Aerobic exercise is a promising intervention for patients with schizophrenia, but structural neuroplastic effects on brain regions relevant to the pathophysiology of the disease remain unclear. This study aimed to elucidate longitudinal changes in cortical thickness after aerobic exercise intervention in schizophrenia patients and the relationship of these changes to clinical correlates. We investigated 21 schizophrenia patients and 23 healthy controls who performed aerobic exercise and 21 schizophrenia patients who played table soccer. The 12-week exercise intervention was combined with computer-assisted cognitive remediation training from week 6 to week 12. Magnetic resonance imaging (MRI) scans were acquired at baseline and weeks 6, 12, and 24. The thickness of the entorhinal, parahippocampal, and lateral and medial prefrontal cortices was assessed with FreeSurfer 6.0. The schizophrenia aerobic exercise group showed a significant increase of cortical thickness in the right entorhinal cortex at week 6, and we found a significant correlation between the cortical thickness of the right lateral prefrontal cortex at baseline and improvement of social adaptation at week 12. In the schizophrenia table soccer and healthy control groups, we found no significant longitudinal change in cortical thickness through the intervention and follow-up period and no correlation of cortical thickness at baseline with clinical measures. Our results suggest that aerobic exercise in schizophrenia modulates the thickness of the entorhinal cortex, a structure adjacent to the hippocampus. Greater cortical thickness of the right lateral prefrontal cortex appears to predict better clinical response to an aerobic exercise intervention in patients with schizophrenia.

The impact of endurance training and table soccer on brain metabolites in schizophrenia.

Higher glutamate and glutamine (together: Glx) and lower N-acetyl-aspartate (NAA) levels were reported in schizophrenia. Endurance training normalizes NAA in the hippocampus, but its effects on other metabolites in the brain and the relationship of metabolites to clinical symptoms remain unknown. For 12 weeks, 20 schizophrenia inpatients (14 men, 6 women) and 23 healthy controls (16 men, 7 women) performed endurance training and a control group of 21 schizophrenia inpatients (15 men, 6 women) played table soccer. A computer-assisted cognitive performance training program was introduced after 6 weeks. We assessed cognitive performance, psychopathological symptoms, and everyday functioning at baseline and after 6 and 12 weeks and performed single voxel magnetic resonance spectroscopy of the hippocampus, left dorsolateral prefrontal cortex (DLPFC), and thalamus. We quantified NAA, Glx, total creatine (tCr), calculated NAA/tCr and Glx/tCr and correlated these ratios with physical fitness, clinical and neurocognitive scores, and everyday functioning. At baseline, in both schizophrenia groups NAA/tCr was lower in the left DLPFC and left hippocampus and Glx/tCr was lower in the hippocampus than in the healthy controls. After 6 weeks, NAA/tCr increased in the left DLPFC in both schizophrenia groups. Brain metabolites did not change significantly in the hippocampus or thalamus, but the correlation between NAA/tCr and Glx/tCr normalized in the left DLPFC. Global Assessment of Functioning improvements correlated with NAA/tCr changes in the left DLPFC. In our study, endurance training and table soccer induced normalization of brain metabolite ratios in the brain circuitry associated with neuronal and synaptic elements, including metabolites of the glutamatergic system.

Employers With Metabolic Syndrome and Increased Depression/Anxiety Severity Profit Most From Structured Exercise Intervention for Work Ability and Quality of Life.

BACKGROUND: Major depressive disorder and anxiety disorders are associated with less productivity, earlier retirement, and more sick-days at the workplace. These associations also exist for patients with metabolic syndrome. For both, exercise is a generally recommended part of multimodal treatments. However, for individuals with metabolic syndrome, in which depression and anxiety is more prevalent and severe, evidence for the efficacy of exercise interventions is limited. METHODS: Company employees with diagnosed metabolic syndrome (n=314, age: 48 ± 8 yrs) were randomized to a 6-month exercise intervention (150 min per week) or wait-list control. Participants received individual recommendations for exercise activities by personal meetings, telephone, or via a smartphone app. Physical activities were supervised and adapted using activity monitor data transferred to a central database. Work ability (work ability index), depression severity and anxiety severity [hospital anxiety and depression scale (HADS)], and health-related quality of live [short form 36 (SF-36)] were assessed. RESULTS: We included 314 subjects from which 287 finished the intervention. Total work ability, depression- and anxiety severity, and the mental component score of the SF-36 improved after 6 months exercise compared to controls. After baseline stratification for normal (HADS scores 0-7) and increased depression- and anxiety scores (HADS scores 8-21) individuals with increased severity scores had similar age, body composition, blood lipids, and cardiorespiratory fitness compared to those with normal scores, but lower total work ability and component sum scores of health-related quality of life. After 6 months total work ability increased in the exercise group compared to controls with the magnitude of the observed increase being significantly greater for subjects with increased depression- and anxiety severity at baseline compared to those with normal severity scores. CONCLUSIONS: A 6-month exercise intervention for company employees with metabolic syndrome showed strongest effects on self-perceived work ability in individuals with mild to severe depression- and anxiety severity. This suggests exercise programs offered to workers with metabolic syndrome not only reduces individual disease risk but may also reduce healthcare and employers costs arising from metabolic syndrome and mental disease conditions. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, identifier NCT03293264.

The Influence of Continuous Exercising on Chronotropic Incompetence in Multi-Episode Schizophrenia.

People with schizophrenia die on average 15-20 years earlier than age and gender matched controls in the general population. An essential part of this excess mortality in people with schizophrenia is caused by physical illnesses. Among the physical illnesses, cardiovascular disease (CVD) has been identified as the most common natural cause of death in up to 40-45% of the cases. Chronotropic incompetence (CI) is defined as the inability of the heart to increase its beating frequency in proportion to increased physical activity or higher metabolic demand. It is an established independent cardiovascular risk factor for major cardiac events and overall mortality and might explain adaptation intolerance of the cardiovascular system to even minor exercise courses. CI needs objective exercise testing for definitive diagnosis and therefore represents a biological marker indicating the integrity of the cardiovascular system. It was recently described in patients with schizophrenia and might help explain the reduced physical fitness in these patients and the inability of a subgroup of patients to benefit from exercise interventions. In this study, we tried to replicate the occurrence of CI in an independent sample of patients with schizophrenia and evaluated whether CI can be influenced by a continuous endurance training of 12 weeks. Therefore, we re-analyzed the fitness testing data of 43 patients with schizophrenia and 22 aged and gender matched healthy controls. Parameters of aerobic fitness and chronotropic response to exercise were calculated. Patients with schizophrenia were less physically fit than the healthy controls and displayed a significantly higher heart rate at rest. 10 of 43 patients with schizophrenia and no healthy control subject were classified as chronotropically incompetent. Chronotropic response to exercise did not change significantly after 12 weeks of continuous aerobic exercise training. No differences were observed for baseline heart rate and peak heart rate in both subgroups of schizophrenia patients. Aerobic fitness did not improve significantly in the patients with schizophrenia classified as chronotropically incompetent. Our results confirm the occurrence of CI in patients with multi-episode schizophrenia. This should be taken into account when planning an exercise or lifestyle intervention studies in this population. Schizophrenia patients with CI do not seem to benefit as well as schizophrenia patients without CI from aerobic exercise training interventions. Larger, prospective randomized controlled clinical trials with different training interventions are urgently needed to address the topic of schizophrenia patients not responding to exercise and the relationship to the illness itself.

A systematic review of trials investigating strength training in schizophrenia spectrum disorders.

This systematic review analyzed strength training (ST) in patients with schizophrenia. Two independent reviewers searched PubMed and CENTRAL. Only two studies reported on the effects of isolated ST. ST with a single exercise did not improve psychopathology but walking performance. ST for several large muscle groups significantly improved muscle strength and psychopathology. To date, no treatment recommendations can be made for ST. Consistent with recommendations for healthy people combined strength and endurance training can be recommended for schizophrenia. For higher transparency regarding trainings aspects, we recommend for future studies to use the sport science checklist proposed in this paper.