Schizophrenia affects approximately 24 million people around the world and is considered a severe psychiatric disorder characterized by ‘positive symptoms’ (hallucinations and delusions), ‘negative symptoms’ (including avolition and anhedonia), and cognitive deficits (such as deficiencies in perception, memory, and attention) [1
]. Despite extensive research on this disorder, standard treatments including medication and cognitive behavioral therapy have not been shown to be effective, mainly in relation to negative symptoms and cognitive deficits [2
One of the reasons why current treatments are ineffective is that schizophrenia is still sometimes misunderstood because of the complexity of its pathogenesis [3
]. The manifold interactions between the immune system and the nervous system could underlie the development of schizophrenia as part of a complex mechanism. Evidence suggests that an increasing level of a stressing hormone may activate the inflammatory arm of the immune system and, hence, trigger the expression of genes responsible to elicit a chronic and low-grade inflammation state [4
]. The interest in immune/inflammatory changes and their associated oxidative consequences as a potential determinant/key in the pathophysiology of schizophrenia has been recently restored. The latest evidence supports a model which describes that the onset of oxidative stress stimuli and a consequent immune dysfunction may alter cellular homeostasis which, in turn, may determine an aberrant growth of interneurons and, consequently, a psychotic symptomatology [5
]. Within this context, the possible relationship between a psychotic breakdown evolving in schizophrenia and inflammation proteins, such C-reactive protein (CRP), has been investigated [6
]. CRP is thought to assist in complement binding to foreign and damaged cells and to affect the humoral response to disease [7
]. It is also believed to play an important role in innate immunity, as an early defence system against infections [8
], but future research is needed to investigate the relationships between CRP levels and cytokines [9
]. The current evidence, supported by genetic studies, relates this disorder to an imbalance in cytokines and, consequently, to dysregulated triggering of inflammatory processes, with IL-6 being at the center of many of these studies [10
This new evidence regarding the possible relationships between the immune system and schizophrenia, together with the lack of efficacy of standard treatments, means that exercise is now being considered as a possible treatment for this disease. This is because, when combined with the adequate prescription of other treatments, it has beneficial effects on the immune system. In fact, some studies have already been published that show a reduction in the symptomology of patients with schizophrenia thanks to exercise interventions [11
In this article we examine the relationships between schizophrenia, exercise, and the immune system, and specifically look at the current evidence regarding IL-6 as one of the potential mechanisms through which exercise could produce improvements in the symptoms of schizophrenia.
Our search strategy conducted an electronic database search of CINAHL, Scopus, Web of Science, MEDLINE, Embase, the Cochrane Library, and PubMed from inception on 10 May 2018. The keyword search terms used were as follows: ‘schizophrenia’ and ‘exercise’ or ‘physical activity’ and ‘cognitive’ or ‘cognition’ and ‘IL-6′. As we did not find enough information, we carried out two more searches. First of all we used the following keyword search terms: ‘schizophrenia’ and ‘exercise’ or ‘physical activity’ and ‘IL-6′. Secondly, we used the following keyword search terms: ‘schizophrenia’ and ‘cognitive’ or ‘cognition’ and ‘IL-6′. Google Scholar and the reference lists of retrieved articles were also searched in order to identify any additional relevant publications.
The evidence available in the scientific literature strongly corroborates that exercise has numerous beneficial effects on the CNS; it exerts a neuroprotective effect, delays and slows the decline in cognitive performance produced by age, and improves and optimizes different cognitive functions such as learning, memory, and executive functions [12
]. As set out by the EPA guide [20
], the benefits related to exercise seen in healthy people are also observed in patients with schizophrenia, both in terms of symptomatology and in improvements in cognitive function.
Nonetheless, many unresolved questions remain about the specific mechanisms through which exercise mediates these beneficial effects on the cognitive system, both generally in healthy people [29
] and especially, in patients with schizophrenia [49
]. However, the evidence suggesting that the immune system plays a predominant role in these effects is mounting. Numerous studies have revealed that exercise has an anti-inflammatory effect that positively affects neuroplasticity [13
]. Related to exercise, several studies have revealed that pro- and anti-inflammatory cytokines must be properly balanced so that the immune system can exert positive or negative effects on brain neuroplasticity, to modulate and consolidate the reorganization of neural networks, and the benefits that exercise has on schizophrenia are because it mediates cerebral structural changes via the immune system [25
When pro- and anti-inflammatory cytokines are adequately balanced, the cytokine IL-6 appears to play a significant role in both pro- and anti-inflammatory responses, depending on the levels of its expression [40
]. Moreover, IL-6 can cross the blood–brain barrier where it can modulate central inflammatory processes and, if its levels are too high, it results in increased neurodegeneration and negatively influences cognitive function [27
]. Furthermore, recently-published reviews indicate that high levels of inflammation and IL-6 are related to the negative symptoms of schizophrenia [29
We now know that the activity generated in the skeletal muscles by exercise is one of the main mechanisms by which the plasma and baseline levels of IL-6 can be modulated [44
]. Although there are doubts about the exact mechanism through which this modulation occurs, several studies have shown that as a consequence of exercise there is an acute increase in the plasma levels of IL-6 [40
]. This increase occurs as a result of the muscle damage caused by exercise and depends on the different parameters of the exercise performed, including its intensity, duration, and the types of muscle contraction involved, with higher levels of IL-6 resulting from exercise which causes homeostasis to destabilize [50
Conversely, regularly performing exercise reduces the peak of these increases in IL-6 levels, thus attenuating this acute effect. This means that the final increases in plasma IL-6 levels are a function of the fitness status of each person and their individual level of adaptation to exercise [50
]. This decreased IL-6 plasma level peak, seen after only one exercise session in individuals who regularly do exercise, is also observed in the basal levels of IL-6, so that people who regularly exercise have lower baseline levels than those who are sedentary [44
Therefore, the acute response to a single dose of exercise leads to an increase in plasma levels of IL-6, but the chronic response to regular exercise produces both a minor increase in this acute response and a decrease of the basal levels of IL-6. Regarding the effects of increased levels of IL-6, although most studies refer to its negative effects [39
] and its pro-inflammatory properties, several studies also suggest that the moderate increases in IL-6 levels provoked by exercise could lead to an anti-inflammatory response by inhibiting the production of other pro-inflammatory cytokines such as IL-1b and TNFα, reducing levels of inflammation and promoting a neuroprotective effect [46
Considering that IL-6 plays a major role in the development and advancement of schizophrenia [29
], it is possible that the behavior of IL-6 levels in response to exercise may explain its beneficial effects on this disease which are evident in many studies. These include improved performance in tasks involving working memory, processing speed, and attentional processes [21
], as well as a protective effect on brain plasticity resulting in improvements in the symptomatology of schizophrenia [11
As a stressor, physical exercise would initially cause an acute response leading to an increase in plasma levels of IL-6. Although this may initially be counterproductive in people with schizophrenia (who usually have high IL-6 and inflammation levels), with regular exercise (and the resulting increased adaptative fitness) a chronic response could be achieved. As a result of this chronic response, both the basal IL-6 levels and the peak levels of IL-6 produced during acute responses would decrease in these patients (Figure 3
). This double-chronic response would favor both an anti-inflammatory response and a decrease in basal IL-6 levels. This would systemically reduce the state of inflammation which characterizes schizophrenia and favor the exercise-mediated neuroprotective effect on the brain which produces the improvements in cognitive function and symptomatology previously described [11
Regarding the most appropriate type of exercise, it is still unknown how the different changes in the parameters of the exercise (intensity, duration, density...) specifically affect the levels of IL-6 [13
]. Despite this ignorance, recent studies have observed that high-intensity exercise (anaerobic exercise or strength exercise) causes a greater increase in IL-6 levels than low intensity exercise [47
], and that eccentric exercise stimulates a greater production of IL-6 than concentric exercise [40
Currently, most studies use aerobic exercise protocols or concurrent protocols (protocols in which both aerobic and anaerobic exercises are used) [13
]. The problem with concurrent protocols is that we cannot know if the effects on IL-6 are due to aerobic exercise or anaerobic exercise.
Because the increase in levels of IL-6 is related to the amount of muscle damage caused by exercise and also because patients with schizophrenia have a state of permanent inflammation, we should stimulate the production of IL-6 progressively with the aim that the consequences of the acute response are not negative.
Therefore, we should start with an aerobic exercise protocol that causes the least possible muscle damage and, consequently, a controlled increase in the levels of IL-6. When patients with schizophrenia adapt to aerobic exercise protocols, we should progressively change to anaerobic exercise protocols (or strength exercise protocols), first with concentric exercise and later with eccentric exercise. With this progression we will achieve that the protocols always provoke a stimulation of IL-6.