Our results showed significant improvements in the negative, general, and overall score for the symptoms of psychosis at 16 weeks in the aerobic, strength, and mixed training groups, with moderate to large effect sizes. The mean difference in PANSS-T scores nearly reached the level of the minimal clinically important difference, estimated as a 16% to 24% change from baseline [27]. These findings are consistent with several meta-analyses that showed that PA (i.e., aerobic or mixed exercise) significantly reduced the negative [16,18,26] and total [16,18] score symptoms for schizophrenia.
To date, only two studies have examined the impact of an isolated strength training program on patients with schizophrenia [23,24]. The pilot study by Heggelund et al. [23], which consisted of an 8-week intervention (training 3 days per week) with a single exercise (4×4 repetitions at 85-90% of the 1 repetition maximum, performed with a leg press apparatus), did not report improvements in the negative symptoms. However, this study only included one exercise type completed for short durations, had a small sample size, and had methodological limitations (it was not randomized, assessment was not blinded, the statistical analysis did not study time × group interactions, and the data were not analyzed on an intention-to treat basis).
The most recent study by Silva et al. [24] compared the effects of 20 weeks of strength and mixed training programs (2 days per week) on psychotic symptoms. Although the authors did not find between-group differences in the PANSS-N, the intragroup analysis revealed significant improvements in the strength training group. Nevertheless, this study was also limited by some methodological issues (the sample size was small and not calculated a priori, no allocation concealment was reported, and there was no intention-to treat analysis).
Therefore, our results fill a gap in literature because we consistently demonstrated that a strength training program alone was also an effective treatment for the negative and general symptoms of schizophrenia. Indeed, this type of exercise has already obtained good results in diseases such as anxiety and depression [25] and has been shown to increase cognitive efficiency in older adults [37] and patients with early dementia [38].
Our findings showed that there were significant improvements in the positive symptoms at 16 weeks in the aerobic and strength intervention groups (with small to moderate effect sizes) and showed a positive trend in the mixed intervention group. These findings agree with other studies that analyzed the effects of aerobic interventions on positive symptoms. For example, Firth et al. [16] conducted a meta-analysis of exercise interventions in schizophrenia patients and, after performing a sensitivity analysis to exclude low-intensity exercise interventions, reported significant reductions in the PANSS-P scores, with a pooled standardized mean difference (SMD) of −0.54 (95% CI −0.95 to −0.13). The most recent meta-analysis [26], which included 17 RCTs, conducted a subgroup analysis that differentiated between aerobic interventions (12 RCTs) and non-aerobic interventions (5 RCTs). In this study, aerobic exercise reduced positive symptoms (SMD = −0.27; [95% CI −0.46 to −0.09]; P = 0.004), while non-aerobic interventions did not reduce these symptoms (SMD = −0.03; [95% CI −0.29 to 0.23]; P = 0.82). Nonetheless, it must be noted that, rather than training strength, most non-aerobic intervention studies used other types of low-intensity non-aerobic exercises such as yoga [39].
Contrary to our expectations, in this current work the intragroup analysis failed to show significant improvements at 16 weeks in the mixed training intervention group, and only showed a slight (non-significant) trend. Unlike other mixed intervention studies [21] that performed a per-protocol analysis and found significant improvements in the positive symptoms, we performed an intention-to-treat data analysis. Although the challenges of this type of analysis include possible loss to follow-up and varying compliance levels, this type of analysis maintains the original group composition achieved by randomization (avoiding potential bias due to exclusion of patients) and pragmatically estimates the benefit of the intervention by estimating how it might perform in a real clinical setting [40].
In another vein, the fact that our results did not reach statistical significance in the mixed group could perhaps be explained both by the higher attrition rates and the lower compliance of the patients of this group. Hence, even though our 3 exercise interventions were delivered considering 2 major factors known to increase adherence and compliance in schizophrenic patients, i.e., supervision [10] and a group training setting [16], the percentages of dropouts were higher and the attendance rates were lower in the mixed intervention group (aerobic = 17.9% and 88%; strength = 13.8% and 88%; and mixed = 34.5% and 79%, respectively).
While the mechanisms by which the different exercise interventions may have influenced the positive and negative symptoms of our patients extends beyond the scope of this study, several mechanisms have been proposed in the scientific literature. The most frequently cited are neuroprotective mechanisms such as decreased inflammation, increased neurogenesis and neuroplasticity via brain-derived neurotrophic factor, and remyelination of white matter tracts [41].
A recent large-scale meta-analysis confirmed that SMI patients have a significantly increased risk of CVD and CVD-related mortality and that elevated BMI in these patients, often related to antipsychotic drug use, among other factors, requires urgent clinical attention [6]. In particular, weight gain induced by second-generation antipsychotic drugs is a well-documented and prevalent side effect of antipsychotic treatment [42]. Thus, physical exercise is particularly recommended in this population and is included in clinical guidelines for these patients. In agreement with the literature, most of the patients in our study had baseline BMIs corresponding to excess weight (38%) or obesity (46%). In addition, all our patients were on stable antipsychotic medication, with doses that can be considered ‘high’ [43] corresponding to an equivalent of approximately 850 mg/d of chlorpromazine.
Consistent with most previous work [16,20,21,24], none of our three groups showed significant improvements in body composition at 16 weeks. This agrees with the finding of the meta-analysis by Firth et al. [16], which included studies with different types of exercise programs, that found no significant post-intervention changes in BMI in these patients. While achieving reductions in BMI and BFM are important exercise goals that should not be abandoned, a more realistic goal may be the attenuation of expected weight gain, to which schizophrenic patients are particularly susceptible [16]. Thus, perhaps our finding of no BMI or BFM gain should be considered noteworthy in itself. Moreover, active but obese individuals have a reduced risk for all-cause and CVD mortality compared to individuals who have a normal BMI but are physically inactive [44]. Therefore, as suggested by Vancampfort et al. [45], exercise interventions in schizophrenic patients should be primarily developed to improve physical (cardiorespiratory) fitness, with BMI and weight reduction considered as secondary outcomes.
We measured the change in functional exercise capacity using the 6MWT. This test corresponds more to the demands of everyday activities than the maximal oxygen uptake test and is less likely to evoke nervousness or anxiety [46]. Like our results, the studies by Marzolini et al. [20] and Beebe et al. [47] which implemented 12-week mixed and 16-week aerobic interventions, respectively, did not find significant improvements in the 6MWT. In contrast, Korman et al. [19] did report a significant improvement in 6MWT results in their single-arm study (n = 10) with a 10-week mixed intervention. Of these four studies, our study started from the highest basal levels [> 560 meters vs. 535 [20], 452 [21], and 430 [47]] and therefore had the lowest room for improvement.
As expected, there were only significant intra-group improvements in strength in the strength and mixed training groups. Thus, HGS significantly increased (≥ 3 kg) in both groups. In addition, the 30-s STS test narrowly missed achieving significance in the strength group. Our results agree with other work that also found improvements in strength measured with one-repetition maximum tests after a period of isolated [23,24] or mixed [20,22] strength training -i.e., the most recent well-designed randomized controlled trial by Nygård et al. [22] concluded that twelve weeks of maximal strength training restored patients’ lower extremity force-generating capacity to a level similar to healthy references and improved 30-s STS test performance-. A cross-sectional study concluded that patients with schizophrenia showed lower HGS scores compared to healthy controls, and that HGS scores correlated positively with cognitive functions [48]. A more recent study concluded that higher HGS was associated with greater left and right hippocampal volume and reduced white matter hyperintensities in major depressive disorder (MDD). These authors considered that interventions targeting strength fitness could improve brain health and reduce the neurocognitive abnormalities associated with MDD [49]. Moreover, HGS has been suggested as a risk indicator for cancer mortality [50] and fatal cardiovascular and all-cause mortality events [51]. Furthermore, isolated strength training has been associated with a lower risk of all-cause mortality, regardless of participation in aerobic PA [52].
To the best of our knowledge, this current study is the first RCT to compare the long-term effects of 3 different types of exercise programs on the symptomatology, body composition, and physical fitness of schizophrenic patients. Although none of the 3 programs maintained their significant effects for any variable at the 10-month follow-up, it is remarkable that, without any changes in antipsychotic medication, the variables did not worsen with respect to baseline levels.
This study has limitations that must be considered. First, the patients we enrolled were (a) stable on antipsychotic medication; (b) had PANSS-T scores ≥ 58; and (c) had demonstrated an initial level of motivation to engage in the exercise programs. Therefore, our findings may only be generalizable to individuals with similar characteristics. Second, even though we based our sample size calculations on potential losses of 25%, there were 17 losses to the 10-month follow-up, which meant that our statistical analysis was underpowered by the last time point. Therefore, the long-term effects of these interventions should be interpreted with caution.
Despite the availability of comprehensive and evidence-based treatment guidelines, not all patients benefit from standard care (e.g., medication) [53]. While anti-psychotic medication is effective for the positive symptoms of schizophrenia [54], it is less effective for the treatment of its negative symptoms and cognitive deficits [55]. Unfortunately, these deficits constitute major determinants of poor functioning and disability [56] and negative symptoms are an important predictor of an unfavorable disease course [26]. Thus, adjunctive therapies like physical exercise that can reduce negative symptoms, cognitive deficits, and improve functional outcomes are vital.
Perspective
This study concluded that 3 weekly sessions of a moderate to vigorous progressive exercise program for 16 weeks improved the symptomatology of schizophrenic patients, regardless the type of exercise they performed (aerobic, strength, or mixed). Additionally, the greatest improvements in strength were achieved with interventions that included strength training exercises. However, their positive effects declined to baseline levels at the 10-month follow-up, suggesting that PA programs should be maintained for longer. Future studies should be deigned to elucidate strategies to keep patients with schizophrenia physically active over time.