Effects of high aerobic intensity training in patients with schizophrenia—A controlled trial

Background: Patients with schizophrenia have a high risk of cardiovascular disease (CVD). High aerobic intensity training (HIT) improve peak oxygen uptake (VO2peak), net mechanical efficiency of walking and risk factors for CVD but has not been investigated in patients with schizophrenia. Aims: To investigate effects from HIT on VO2peak, net mechanical efficiency of walking and risk factors for CVD in patients with schizophrenia. Methods: 25 inpatients (F20-29, ICD-10) were allocated to either HIT or playing computer games (CG), 3 days per week for 8 weeks. HIT consisted of 4 × 4-min intervals with 3-min break periods, at 85-95% and 70% of peak heart rate, respectively. Results: 12 and seven patients completed HIT and CG, respectively. The baseline VO2peak in both groups combined (n = 19) was 36.8 ± 8.2 ml/kg/min and 3.12 ± 0.55 1/min. The HIT group improved VO2peak by 12% from 3.17 ± 0.59 to 3.56 ± 0.68 1/min (P < 0.001), more than the CG group (P = 0.014). Net mechanical efficiency of walking improved by 12% in the HIT group from 19.8 ± 3.0% to 22.2 ± 4.5% (P = 0.005), more than the CG group (P = 0.031). The psychiatric symptoms, expressed as the Positive and Negative Syndrome Scale (PANSS) and the Calgary Depression Scale for Schizophrenia (CDSS), did not improve in either group. Conclusions: VO2peak and net mechanical efficiency of walking improved significantly by 8 weeks of HIT. HIT should be included in rehabilitation in order to improve physical capacity and contribute risk reduction of CVD.

P atients suffering from schizophrenia have an illnessrelated vulnerability to adopt deleterious lifestyles in addition to a congestion of cardiovascular and metabolic risk factors from antipsychotics and a genetic vulnerability for developing cardiovascular disease (CVD) (1). The combination of these factors causes impaired physical fi tness, weight gain, obesity, hyperglycemia, type 2 diabetes, hyperlipidemia and ultimately increased risk of CVD (2, 3). Although these risk factors are related to the physical fi tness level and are improvable with aerobic endurance training, there has not been much attention to the contribution of poor physical fi tness to the risk of CVD in schizophrenia. Reduced physical fi tness also compromises the ability to perform lifestyle physical activity that is necessary for social rehabilitation and integration into the community. Effective aerobic endurance training has the potential to reduce the high risk of CVD, and improve functional ability and quality of life for patients with schizophrenia, as have been reported in other populations with reduced physical fi tness (4). Positive psychological effects on mental health and well-being are also reported in patients with schizophrenia (5).
Physical fi tness, measured as peak oxygen uptake (VO 2peak ), appears to have more infl uence on risk of CVD compared with the physical activity level (6). Relatively small improvement in VO 2peak is associated with a fair-sized decrement in risk of all-cause mortality and CVD (7). This effect might be induced by an improvement in major risk factors for CVD (8), but physically active people have reduced cardiovascular mortality even when CVD risk factors are present (9).
High aerobic intensity training (HIT) performed as 4 ϫ 4-min intervals are found to be an effective training method to improve VO 2peak for healthy individuals, patients with CVD and metabolic syndrome (10 -13). Studies on patients with schizophrenia have usually The CG group spent the same amount of time, 36 min three times per week, training to improve their ability in the computer game, Tetris (THQ Inc. Calabasas Hills, CA) using an Xbox Video Game Systems (Microsoft Corporation, Redmond, USA).
Patients performed the training sessions three times per week for 8 weeks. In both groups, training sessions were lead and monitored by the same exercise physiologist. Adherence to at least 19 training sessions (80%) during the 8-week period was required to be included in the effect analyses.

Testing
The test started with a 10-min warm-up at approximately 50 -60% of VO 2peak . Patients then walked for 6 min on the treadmill at an inclination and speed corresponding to 60 Watt (22, 23). We obtained the measurements of pulmonary gas exchange and heart rate between 5 and 5 ½ min walking, using the Cortex Metamax II portable metabolic test system (Cortex Biophysik GmbH, Leipzig, Germany) and the Polar S610i heart rate monitor, respectively. Net mechanical effi ciency of walking is defi ned as the percentage of the work input (kilocalories) that is converted into work output. The equation for this calculation is described elsewhere (22,23).
After testing net mechanical effi ciency of walking the patient immediately proceeded with the VO 2peak testing protocol. The speed or the inclination was increased every minute to a level that brought the patient to exhaustion in 3 -6 min. VO 2peak was accepted when VO 2 leveled off, despite further increases in speed and when respiratory exchange ratio (RER) was above 1.10 (24). The highest heart rate recorded during the last minute of the test was determined as HR peak .
The patients took the pre and post-test fasting blood samples in the morning and we calculated low-density lipoprotein (LDL)-cholesterol using the Friedewald equation (25).
Possible changes in positive and negative symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS) (26). The test was performed by two psychiatric nurses, trained in using PANSS, working in the ward and had a personal knowledge of the patient. The Calgary Depression Scale for Schizophrenia (CDSS) was used to assess depressive symptoms (27). The 36-item short form (SF-36) was used to assess the physical health and mental health aspect of health-related quality of life (HRQOL) (28). The SF-36 is a 36-item self-report instrument.
Patients were given 10-min to learn the Tetris computer game before testing. Thereafter patients had three attempts, and the best of three trials were used in the results. We measured performance as total number of lines achieved during a game, We accomplished this test for the CG, but not for HIT patients. Testing was not done blinded to allocation. investigated low-intensity exercise corresponding to Ͻ 70% peak heart rate (HR peak ) (14 -17). Only a few studies have applied direct measurements of oxygen uptake (18 -20), but the exact level of VO 2peak are not described.
A major concern over the cardiovascular health in people with schizophrenia is their ability to engage in and participate in physical training. In addition, inherent diffi culties in recruitment to randomized controlled trials and distrust in methodological issues such as randomization has been described (15, 21).

Aims
The objectives of the study were to investigate effects from HIT, compared with physical inactivity in the form of playing computer games (CG), in patients suffering from schizophrenia. The primary outcome was changes in VO 2peak and net mechanical effi ciency of walking. The secondary outcome was effects on other CVD risk factors and symptoms of schizophrenia. We hypothesized that Ͼ 80% adherence to 24 training sessions with HIT during 8 weeks would improve the primary outcome variables more than the same amount of time spend on CG.

Materials and Methods
All inpatients at three wards in a University hospital that fulfi lled the inclusion criteria were evaluated for eligibility for the study by the medical doctor. In total 38 patients were evaluated, one did not meet the inclusion criteria, fi ve did not want to participate and seven did not participate for other reasons. The fi rst 16 consecutive patients were included in the HIT group and the next nine consecutive patients were included in the CG group. The inclusion criteria were ICD-10 schizophrenia, schizotypal and delusional disorders (F20 -F29). Patients were on stable antipsychotic medication for 6 weeks prior to inclusion. Exclusion criteria were coronary artery disease, chronic obstructive pulmonary disease, unstable pharmacological treatment during the intervention period, and not being able to perform physical treadmill testing and exercise.

Interventions
The HIT group trained 4 ϫ 4-min interval training on a treadmill (Tung Keng Enterprise CO., Ltd, Taiwan) at 85 -95% HR peak interspersed with 3 min of active resting periods at a work load corresponding to 70% HR peak between each interval, previously shown to be highly effective (10 -13). Patients performed the intervals walking or running with a minimum of 5% inclination. Heart rate was assessed continuously during exercise, using a Polar S610i heart rate monitor (Polar Electro, Finland). The exercise physiologist ensured that the patients performed intervals at the scheduled intensity. P Ͻ 0.001), but no change was apparent in the CG group. In both groups combined ( n ϭ 19), VO 2peak was 36.8 Ϯ 8.2 ml/kg/min and 3.12 Ϯ 0.55 l/min at baseline.
The HIT group improved net mechanical effi ciency of walking more than the CG group ( P ϭ 0.031, Table 3). The net mechanical effi ciency of walking improved from pre-to post-test in the HIT group (12%, P ϭ 0.005), but no change was apparent in the CG group. In both groups combined ( n ϭ 19), the net mechanical effi ciency of walking was 19.6 Ϯ 2.9% at baseline.
No signifi cant changes were observed between or within the two groups in PANSS, CDSS and SF-36 ( Table 5). The CG group improved their performance in Tetris, measured as total number of lines achieved, from 10 Ϯ 11 lines at pre-test to 83 Ϯ 41 lines at post-test ( P ϭ 0.003).

Discussion
The primary fi nding is that the patients suffering from schizophrenia were able to participate in high aerobic intensity training and improve their VO 2peak . The HIT group improved VO 2peak by 12%. The size of the improvement in VO 2peak is in line with effects of 8 weeks of training in healthy controls and in patients with CVD (10 -12, 29). It seems fair to conclude that, in line with what has been shown for healthy subjects, patients suffering from schizophrenia also benefi t from 8 weeks with HIT.
The ability to improve VO 2peak is highly related to the ability to adhere to the exercise training, which is considered challenging for patients suffering from schizophrenia. The patients included in the present study were inpatients that suffered from severe schizophrenia, the majority of

Statistics
We suggested a change in VO 2peak from pre-to post-test of 4 Ϯ 3 ml/kg/min for use in the sample size estimation; 18 patients was needed in the study for 80% power to detect a between group difference at P Ͻ 0.05. Data are expressed as mean and standard deviation (s). Difference in changes from pre-to post-test between groups is expressed as mean difference and 95% confi dence intervals (CI). Paired samples t -test was performed to determine changes from pre-to post-intervention. Independent sample t -test was performed to test differences at baseline and changes from pre-to post-test between the two groups. The signifi cance level ( α ) was set at P Ͻ 0.05 (two-tailed).

Results
During the training period, six of the 25 included patients did not complete the study and are not included in the results: one HIT and one CG patient were discharged from the hospital before completion and one HIT patient was lost because of ankle pains during running. One CG patient disappeared. In addition, two of the HIT patients were excluded because they completed less than 80% of the training sessions. The patients that discontinued the study were not signifi cantly different in any of the measured baseline variables, compared with the patients that completed the study. Patients in the HIT ( n ϭ 12) and CG ( n ϭ 7) groups performed 85 Ϯ 9% and 83 Ϯ 6% of the scheduled training sessions, respectively. Characteristics of the patients are presented in Table 1.
After 8 weeks of training, the HIT group improved VO 2peak more than the CG group (Table 2). VO 2peak increased in the HIT group from pre-to post-test (12%, 13% and 15% decrements in risk of all-cause mortality and CVD, respectively. These benefi ts may result from an improvement in CVD risk factors, but could also be related to other indirect protective mechanisms. The present study found an improvement of 4.2 ml/kg/min after 8 weeks with HIT, and theoretically a considerable reduction in the CVD risk. VO 2peak values are seldom reported in patients suffering from schizophrenia. Carlsson et al. (18,19) measured oxygen uptake (VO 2 ) in people with schizophrenia in the late 1960s. Carlsson et al. (18) presented VO 2 values that did not seem to reach VO 2peak in all patients and are therefore considerable lower than the current VO 2peak fi ndings. A recent 3-month intervention study found ϩ 5% and Ϫ 3% change in VO 2peak in the exercise group and non-exercise group, respectively (20). The exact level of VO 2peak was not reported.
Participation in HIT was associated with improved net mechanical effi ciency of walking, compared with the CG. The HIT group improved net mechanical effi ciency of walking from 19.8 Ϯ 3.1% to 21.9 Ϯ 4.4%, whereas no signifi cant change was observed within the CG group. This is in line with studies reporting improved work the patients had several years of hospitalization and some were described as treatment resistant. In spite of the severity of their illness, they managed to participate in HIT and improve VO 2peak within a short period. This effectiveness could have important implications for the long-term treatment and prevention of low VO 2peak .
In both groups combined, the VO 2peak at inclusion was low and can be considered close to normative VO 2peak for sedentary people of the same age but well below normative values for active healthy people that participate in occasional aerobic exercise Յ 2 times per week (30, 31). Low VO 2peak is associated with higher risk of cardiovascular morbidity, obesity, high blood pressure, high total-and LDL-cholesterol levels, and reduced glycemic control. A resent meta-analysis defi ned 28 ml/kg/min (7.9 MET) as a critical level, as those with lower than 28 ml/kg/min had substantial higher rates of all-cause mortality and CVD events compared with those with higher VO 2peak (7). Fortunately, only a modest level of improvement in VO 2peak appears to confer a signifi cant protective effect from CVD risk factors. Kodama et al. (7) found that every 3.5 ml/kg/min increase in VO 2peak was associated with s , standard deviation; VO 2peak , peak oxygen uptake; HR, heart rate; V E , total pulmonary ventilation; RER, respiratory exchange ratio; CI, confi dence interval. * * * P Ͻ 0.001, changes from pre-to post-test. † P Ͻ 0.05, † † P Ͻ 0.01 differences in changes from pre-to post-test between groups. The poor VO 2peak and net mechanical effi ciency of walking described in this study might have adverse effects that could hamper rehabilitation and reintegration into the community, reduce compliance to other treatment regimens, increase stigmatization and discrimination, have harmful effects on quality of life and physical functioning, and increase fi nancial burden (4, 34). Poor VO 2peak and net mechanical effi ciency of walking involves that lifestyle physical activity, such as walking and household chores will demand a higher percentage of the patients VO 2peak , making lifestyle physical activity less pleasant. Improved endurance performance is shown to improve functional status in other populations (4). Effective HIT might help the patients to better function in general and cope better with their illness.
The baseline BMI score in all patients was 28.3 kg/m 2 , which is classifi ed as overweight with increased health risk. Blood pressure, triglyceride, hs-CRP, total cholesterol and glucose were within normal values. During economy both in students and in patients with postinfarction heart failure after participation in walking and running interventions (10, 12). Walking is an important part of daily function and interventions that improve net mechanical effi ciency of walking might have great impact in the performance on daily tasks and physical activity in general.
The baseline value for net mechanical effi ciency of walking in all patients ( n ϭ 19) was 19.6%. This is similar to values found in patients with coronary artery disease (19.2%) and lower than in healthy controls (24.7%) (32). It could be assumed that patients with schizophrenia walk with mechanical ineffi ciency. Psychomotor slowing has been recognized as a feature in people with schizophrenia and probably contributes to walking mechanical ineffi ciency (33). However, it also seems connected to inactivity, as we found that net mechanical efficiency of walking could be improved after participation in HIT.  This was an effi cacy trial, and explored if HIT could work under ideal circumstances. The patients that adhere to less than 80% of the training sessions were excluded. The results can be generalized only to patients who adhere to the HIT. Additionally, the 8-week intervention period is a short period.

Conclusion
This study indicates that patients with schizophrenia have a level of VO 2peak that is associated with increased risk of CVD. The patients also seem to have poor net mechanical effi ciency of walking and spend excessive energy during walking. HIT can effectively improve VO 2peak and net mechanical effi ciency of walking during 8 weeks in patients that adhere to training. Treatment for schizophrenia should include effi cient aerobic endurance training to contribute risk reduction of inactivity-related comorbidity and poor physical ability.

Declaration of interest :
The authors report no confl icts of interest. The authors alone are responsible for the content and writing of the paper. the intervention period, HDL-cholesterol changed significantly between the groups.
No signifi cant changes in PANSS, CDSS or in SF-36 in either group or between groups were found in the present study. A few exercise studies have applied the same instruments in patients with schizophrenia. In a study by Beebe et al. (15) the patients participated in less strenuous training that continued for twice as long (16 weeks) as in the present study, or a control group that did not exercise. They reported a non-signifi cant tendency of improvement in total PANSS score in the experimental group. Another study found that total PANSS improved somewhat in a cycling exercise group ( Ϫ 9%) and worsened in a non-exercise group ( ϩ 13%) after 3 months (20). A signifi cant reduction in depression has been found after an aerobic exercise intervention in a combined group of patients suffering from schizophrenia and bipolar disorder, which could possibly interfere with the result (14). Another study found a signifi cant reduction in overall psychopathology using the Psychiatric Assessment Scale (PAS), Nurses Global Impressions Scale (NGI) and Symptom Checklist-90 (SCL-90) (16). The intervention included a combination of different types of sport activities, meditation and stress education. Thus, it was not possible to separate effects from aerobic exercise alone. Using qualitative measures, studies have reported mood-elevating effects and reduction in depression and anxiety (14, 34). In conclusion, both the type and duration of the intervention along with the type of instruments used to evaluate potential benefi ts might explain the diverging effects on symptoms of schizophrenia. In patients with chronic schizophrenia already receiving much psychosocial support, it might be difficult to demonstrate improvement in symptoms or in psychosocial function with an 8-week physical training intervention.
A limitation of the study is that we did not conduct a random allocation of subjects to the two groups, but included consecutive patients fi rst to the HIT group and then to the CG group. Some patients with schizophrenia have distrust in randomization, and randomized controlled trials might exclude patients with a high level of symptoms from participating in studies evaluating this type of intervention in schizophrenia (21). To recruit patients, we had to explain very carefully and in detail what they were going to take part in. In this study, a randomized protocol would probably exclude the patients with severe hallucinations or delusions. All patients were able to participate in both interventions and none of them was selected because they fi tted one of the groups more than the other. However, as they were specifi cally asked to participate in a either HIT or CG, their personal preference for that particular intervention might infl uenced their decision. A selection bias cannot be ruled out and thus compromising the external validity.