Exercise reduces depression and inflammation but intensity matters
Introduction
Major depression is a common and potentially fatal disorder that represents the leading cause of disability worldwide (Moussavi et al., 2007). The prevailing treatment for depression is a class of drugs known as selective serotonin re-uptake inhibitors (SSRIs) (Nutt et al., 1999); however, SSRIs are only fully effective for one third of depressed patients (Fava & Davidson, 1996). This underscores the critical need for new therapeutic approaches. Inflammation has been identified as a potential contributor to the development of depression (Miller & Raison, 2016), suggesting that anti-inflammatory therapeutics, such as regular physical exercise (Cotman, Berchtold, & Christie, 2007; Gleeson et al., 2011), may be effective at preventing and managing depressive symptoms. However, the optimal intensity of exercise has not been established and this information is critical when determining a prescription. The present study examined the effect of two predominant exercise training protocols: moderate continuous training (MCT) and high-intensity interval training (HIT), on depressive symptoms and pro-inflammatory cytokines in sedentary university students who are known to be at a high risk of developing depression (Ibrahim, Kelly, Adams, & Glazebrook, 2013).
Acute and chronic increases of pro-inflammatory cytokines cause a range of sickness behaviors that overlap with the symptoms of major depression including anhedonia, decreased activity, and social withdrawal (Dantzer, O'Connor, Freund, Johnson, & Kelley, 2008; Reichenberg et al., 2001; Shakhar & Shakhar, 2015; Suarez, Lewis, Krishnan, & Young, 2004; Wright, Strike, Brydon, & Steptoe, 2005). The two key pro-inflammatory cytokines implicated in sickness behavior and its associated depressive symptoms are tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1β) (Dantzer et al., 2008; Dantzer, 2001; Bluthe et al., 1994). When these cytokines are peripherally injected into the blood (Bluthe et al., 1994), they enter the brain, activate microglia, and amplify cytokine activity (Frank, Baratta, Sprunger, Watkins, & Maier, 2007). This causes changes to neurotransmitter metabolism, neuroendocrine function, and behavioral symptoms that are common in individuals with major depression, suggesting that they may contribute to the etiology of the disorder (Bluthe et al., 1994; Dantzer et al., 2008; Frank et al., 2007; Miller, Maletic, & Raison, 2009). Another pro-inflammatory cytokine associated with depressive symptoms is interleukin-6 (IL-6), which is elevated in individuals with SSRI-resistant depression (O’Brien, Scully, Fitzgerald, Scott, & Dinan, 2007). However, peripherally injecting IL-6 into the blood does not induce depressive symptoms (Brebner, Hayley, Zacharko, Merali, & Anisman, 2000). Unlike TNF-α and IL-1β, IL-6 is produced by skeletal muscle (Pedersen & Febbraio, 2008) and is elevated up to 100 times compared to baseline levels following strenuous exercise (Fischer, 2006). This acute increase in IL-6 from exercise has been shown to inhibit the production of TNF-α (Starkie, Ostrowski, Jauffred, Febbraio, & Pedersen, 2003), suggesting that it may have anti-inflammatory properties in the context of exercise (Gleeson et al., 2011; Pedersen and Febbraio, 2008). Critically, this may be a potential mechanism through which exercise may reduce depressive symptoms. Another inflammatory marker, C-reactive protein (CRP) is produced by hepatocytes in response to increases in IL-6, along with TNF-α, and IL-1β (Rattazzi et al., 2003). CRP is elevated in individuals with higher levels of perceived psychological stress (McDade, Hawkley, & Cacioppo, 2006) and lower levels of positive emotional well-being (Ironson, Banerjee, Fitch, & Krause, 2018), suggesting that it may play a role in the development of depressive symptoms from chronic stress.
Although pharmacotherapeutic approaches designed to reduce these pro-inflammatory cytokines (e.g., TNF-α antagonist etanercept) may help prevent and manage depression (Tyring et al., 2006), cytokine antagonist pharmaceutical drugs may not be suitable for individuals who are otherwise healthy. Instead, regular physical exercise (and its anti-inflammatory properties) may be a viable non-pharmacotherapeutic alternative for reducing depressive symptoms caused by inflammation. Indeed, prior randomized controlled trials have established that exercise can reduce depression (Mead et al., 2009; Nabkasorn et al., 2006) and anxiety (Wipfli, Rethorst, & Landers, 2008) in healthy populations. In clinical populations with chronic inflammatory diseases, regular aerobic exercise reduces depression (Perna et al., 2010) and inflammation (Goldhammer et al., 2005). In clinically depressed individuals, aerobic exercise reduces depressive symptoms (Mead et al., 2009; Rethorst et al., 2013), especially in those with high levels of TNF-α (Rethorst et al., 2013).
However, surprisingly little is known about the effects of exercise on inflammation in non-clinical populations who may be at risk of developing depression. To our knowledge, only two studies (Kop, Weinstein, Deuster, Whittaker, & Tracy, 2008; Poole, Hamer, Wawrzyniak, & Steptoe, 2011) have examined exercise, inflammation and depressive symptoms in non-clinical populations. Both studies recruited non-depressed individuals who engaged in regular physical exercise and examined the impact of withdrawing exercise for two weeks on mood (not depression per se) and cytokines levels. Although both studies reported a decrease in mood among the exercisers who had to withdraw from exercising, the cytokines results were less clear. One study found that IL-6 decreased after two weeks of not exercising, possibly due to the reduced release of IL-6 from the skeletal muscle (Poole et al., 2011); they also found no change in TNF-α, or in anti-inflammatory cytokines interleukin 1 receptor antagonist (IL-1ra) or interleukin 10 (IL-10). In contrast, the other study found no effect on IL-6 or CRP after two weeks of not exercising (Kop et al., 2008). Critically, neither study examined the effects of increasing exercise in sedentary individuals to prevent the development of depressive symptoms.
When evaluating whether exercise is a viable approach for reducing depressive symptoms, it is critical to determine the optimal intensity. Although there is evidence for the benefits of moderate-intensity exercise for reducing both depression (Dunn, Trivedi, Kampert, Clark, & Chambliss, 2005) and inflammation (Goldhammer et al., 2005; Thompson et al., 2010), engaging in a new exercise program can be challenging for sedentary individuals. The recent rise in popularity of high-intensity interval training (HIT) may be more appealing due to its shorter time commitment for similar physiological benefits (Gibala et al., 2006). HIT has also been shown to induce greater functional adaptation of the immune system in athletes (Born, Zinner, & Sperlich, 2017). Furthermore, recent work from our group shows that previous sedentary young adults found HIT to be more enjoyable than traditional forms of moderate-intensity continuous training (MCT) after six weeks (Heisz, Tejada, Paolucci, & Muir, 2016). Indeed, with respect to inflammation, greater release of IL-6 induced by more intense protocols like HIT (Fischer, 2006) may inhibit the production of TNF-α to a greater degree (Petersen & Pedersen, 2005; Starkie et al., 2003) for stronger anti-depressive effects than moderate intensity exercise. However, with respect to mood, there have been equivocal results, and some evidence suggests that HIT may be too strenuous to improve the mood of sedentary individuals and instead, may actually decrease it (Oliveira, Slama, Deslandes, Furtado, & Santos, 2013); that said, the effect of HIT on depression has not been assessed.
The present study examined the effect of six weeks of exercise training on mental health and pro-inflammatory cytokines in university students who are known to be at a higher risk of developing depression than the general population (Ibrahim et al., 2013). During their academic term, the students were randomly assigned to one of three groups: 1) moderate-intensity continuous training (MCT) group, 2) high-intensity interval training (HIT) group, or 3) no training control group (CON). Before and after the intervention, we measured changes in resting-state pro-inflammatory cytokines (TNF-α, IL-6, IL-1β, CRP) and depressive symptoms as well as other associated changes in anxiety and perceived psychological stress (Beiter et al., 2015). We hypothesized that students would have higher perceived psychological stress than population norms (Cohen & Janicki-Deverts, 2012), and that this would be accompanied by increases in depression, anxiety and pro-inflammatory cytokines in the controls. MCT was hypothesized to decrease depressive symptoms and pro-inflammatory cytokines relative to CON; however, it was unclear whether HIT would be similarly effective as MCT at decreasing both depressive symptoms and pro-inflammatory cytokines.
Section snippets
Participants
Sixty-one healthy young adults (72% female) were recruited from McMaster University. Participants were students who met the inclusion criteria of: being a young adult aged 18–30 years old, and partaking in no more than one hour of vigorous physical activity per week prior to joining the study. Participants were stratified by sex and randomly assigned to one of three intervention groups: 1) High-intensity interval training (HIT) group, 2) Moderate-intensity continuous training (MCT) group and 3)
Mental health
Fig. 1 displays the change in depression, anxiety and perceived stress scores across the six-week intervention for the three groups. Table 1 presents pre and post intervention scores for each of the mental health variables. Depression decreased following MCT (p = 0.005, Cohen’s d = 0.83) and HIT (p = 0.012; Cohen’s d = 0.73) relative to CON, but the changes following MCT and HIT were not significantly different from each other (p = 0.77) [main effect of group, F(2, 52) = 5.92, p < 0.01;
Discussion
Exercise may help to mitigate symptoms of depression by reducing inflammation. Until now it has been unclear whether the exercise intensity matters. Our results suggest that it does and that moderate-intensity continuous exercise may be an optimal intensity when prescribing exercise as medicine for mental health.
We assessed university students during their academic term. This demographic is known to be at a higher risk of developing depression (Ibrahim et al., 2013) because of their
Financial disclosures
The authors declare no competing financial interests.
Acknowledgements
This research was supported by the Natural Sciences and Engineering Research Council of Canada (NSERC) Discovery Grant 296518 to JJH, and NSERC Canada Graduate Scholarship to EMP. DMEB is the Canada Research Chair in Aging and Immunity. DL is the recipient of a CIHR Canada Graduate Scholarship.
References (60)
- et al.
The prevalence and correlates of depression, anxiety, and stress in a sample of college students
Journal of Affective Disorders
(2015) - et al.
Synergy between tumor necrosis factor α and interleukin-1 in the induction of sickness behavior in mice
Psychoneuroendocrinology
(1994) - et al.
Synergistic effects of interleukin-1β, interleukin-6, and tumor necrosis factor-α: Central monoamine, corticosterone, and behavioral variations
Neuropsychopharmacology
(2000) - et al.
Exercise builds brain health: Key roles of growth factor cascades and inflammation
Trends in Neurosciences
(2007) Cytokine-induced sickness behavior: Where do we stand?
Brain, Behavior, and Immunity
(2001)- et al.
Exercise treatment for depression: Efficacy and dose response
American Journal of Preventive Medicine
(2005) - et al.
Definition and epidemiology of treatment-resistant depression
Psychiatric Clinics of North America
(1996) - et al.
Microglia serve as a neuroimmune substrate for stress-induced potentiation of CNS pro-inflammatory cytokine responses
Brain, Behavior, and Immunity
(2007) - et al.
Exercise training modulates cytokines activity in coronary heart disease patients
International Journal of Cardiology
(2005) - et al.
A systematic review of studies of depression prevalence in university students
Journal of Psychiatric Research
(2013)
Positive emotional well-being, health behaviors, and inflammation measured by C-Reactive protein
Social Science & Medicine
Inflammatory markers and negative mood symptoms following exercise withdrawal
Brain, Behavior, and Immunity
Allostasis and allostatic load: Implications for neuropsychopharmacology
Neuropsychopharmacology
Inflammation and its discontents: The role of cytokines in the pathophysiology of major depression
Biological Psychiatry
Depression, chronic diseases, and decrements in health: results from the World Health Surveys
The Lancet
Mechanisms of action of selective serotonin reuptake inhibitors in the treatment of psychiatric disorders
European Neuropsychopharmacology
Plasma cytokine profiles in depressed patients who fail to respond to selective serotonin reuptake inhibitor therapy
Journal of Psychiatric Research
Enhanced expression of cytokines and chemokines by blood monocytes to in vitro lipopolysaccharide stimulation are associated with hostility and severity of depressive symptoms in healthy women
Psychoneuroendocrinology
Etanercept and clinical outcomes, fatigue, and depression in psoriasis: double-blind placebo-controlled randomised phase III trial
The Lancet
Problems with the differentiation of anxiety and depression
Journal of Psychiatric Research
Acute inflammation and negative mood: Mediation by cytokine activation
Brain, Behavior, and Immunity
Manual for the Beck anxiety inventory
An inventory for measuring clinical anxiety: Psychometric properties
Journal of Consulting and Clinical Psychology
Affect responses to acute bouts of aerobic exercise in fit and unfit participants: An examination of opponent-process theory
Journal of Sport Behavior
The mucosal immune function is not compromised during a period of high-intensity interval training. Is it time to reconsider an old assumption?
Frontiers in Physiology
Endocrinology of the stress response 1
Annual Review of Physiology
Sympathetic nervous activity during exercise
Annual Review of Physiology
Who's stressed? Distributions of psychological stress in the United States in probability samples from 1983, 2006, and 2009
Journal of Applied Social Psychology
From inflammation to sickness and depression: When the immune system subjugates the brain
Nature Reviews Neuroscience
Cited by (221)
Let's Be Practical: Home-based Moderate-intensity Exercise Interventions Are Needed
2024, European Urology FocusClinical value and mechanistic analysis of HIIT on modulating risk and symptoms of depression: A systematic review
2024, International Journal of Clinical and Health PsychologyThe effect of exercise in patients with colorectal cancer surgery: A systematic review
2023, Surgery in Practice and ScienceEffects of physical exercise intervention on depressive and anxious moods of college students: A meta-analysis of randomized controlled trials
2023, Asian Journal of Sport and Exercise Psychology