15.5: Plausible Neurobiological Mechanisms of the Antidepressant Effect

Establishing neurobiological mechanisms of the antidepressant effects of exercise has historically been challenging. Depression is characterized by substantial heterogeneity; estimates indicate that anywhere from 119 (Park et al., 2017) to 681 (Akil et al., 2018) (Akil et al., 2018) to even 1,000 (Fried & Nesse, 2015) unique combinations of depressive symptoms could meet MDD diagnostic criteria. Research attempting to explain the mechanistic effects of exercise on depression often struggle to accommodate for the diverse symptom profiles and presentations across individuals, which makes it difficult to design studies aimed at establishing the mechanisms implicated in the antidepressant effects of exercise. In addition to the heterogeneity, exercise is associated with a wide range of neurobiological effects (see Dishman et al., 2006 for an extensive overview). When considering these factors, it is unsurprising that our general understanding of the mechanisms underlying the antidepressant effects of exercise is unclear. It is likely that exercise improves mood and other specific symptoms in the short-term and reduces depression in the long-term through numerous mechanisms because of its wide range of effects. Indeed, experts have proposed several neurobiological mechanisms (Kandola et al., 2019; Schuch, Deslandes, et al., 2016). In this section, we provide a very brief overview of some of the neurobiological mechanisms that have been assessed in acute and chronic exercise studies. We only focus on neurobiological mechanisms that are hypothesized to be implicated in the pathophysiology of depression and have been studied in relation to changes in depressed mood or depressive symptoms.

15.5.1. Neurobiological Mechanisms Studied in the Context of Acute Exercise

In a series of secondary data analyses, Meyer and colleagues were interested in exploring potential neurobiological mechanisms implicated in the mood-enhancing benefits of acute exercise. In three separate reports, Meyer and colleagues examined whether serum concentrations of brain-derived neurotrophic factor (BDNF; Meyer, Koltyn, et al., 2016b), endocannabinoids and related lipids (Meyer et al., 2019), and cytokines (Perez et al., 2020) could be altered by acute bouts of aerobic exercise and whether alterations were associated with acute changes in mood states. In each of these studies, blood was drawn before and within 10 min after each condition to determine changes in BDNF, endocannabinoids and related lipids, and cytokines. Specific descriptions related to each analysis are outlined below.

In Meyer, Koltyn, et al. (2016b), 24 women with MDD performed 20 min of aerobic exercise at light, moderate, and hard exercise intensities; participants also completed a quiet rest condition. Whileacute exercise significantly improved depressed mood and increased BDNF levels regardless of exercise intensity, these findings do not explain the mechanism, as authors failed to observe a relation between changes in depressed mood and BDNF levels. In Meyer et al. (2019), 17 women with MDD exercised for 20-min at a moderate- (prescribed exercise intensity equivalent to a RPE of 13) or self-selected, preferred-intensity of aerobic exercise (chosen exercise intensity: M_RPE = 12.5; range = 8.5–16). Moderate-intensity aerobic exercise significantly increased endocannabinoid levels (i.e., anandamide) and a related lipid (i.e., oleoylethanolamine). Most notably, changes in anandamide and oleoylethanolamine were associated with changes in mood states, suggesting that endocannabinoids and related lipids may contribute to the mood-enhancing effects of acute exercise in MDD. No such relationships were observed following the self-selected, preferred intensity of aerobic exercise. Differences in findings may be attributed to the substantial variability in how participants selected and performed their preferred exercise intensity, with some individuals exercising at lower intensities than others (see wide range of self-selected intensities above). This suggests that lower intensities of exercise may not be sufficient to induce changes in the endocannabinoid system, or alternatively, other mechanisms might be at play. In 2020, Perez et al. examined whether serum concentrations of interleukins (ILs) 6 and 8 and tumor necrosis factor-α (TNF-α) could be altered by a 20-min bout of aerobic exercise. Participants completed the same experimental conditions as the Meyer, Koltyn, et al. (2016a) study. Perez and colleagues found that hard exercise increased IL-6, IL-8, and TNF-α among 19 women with MDD, while the light and moderate exercise intensities failed to modulate these inflammatory markers. The authors also examined whether changes in each of these inflammatory markers related to changes in depressed mood but failed to find any significant relationships. The authors hypothesized that there is a possibility that acute increases in inflammatory markers following hard exercise could have potential for prompting chronic inflammatory adaptations; however, limited conclusions can be drawn from these studies with longer-term studies needed to test this possibility. Other limitations of these data include the secondary nature of the analyses, as well as the relatively small samples including only women.

In addition to this empirical evidence, Schuch, Deslandes, and colleagues (2016) propose other plausible neurobiological mechanisms that may be modulated by acute exercise, including increased levels of atrial natriuretic peptide, brain natriuretic peptide, copeptin, and growth hormone; however, currently, there is a dearth of evidence to make strong conclusions about neurobiological mechanisms sensitive to change through acute exercise in depression.

15.5.2. Neurobiological Mechanisms Studied in the Context of Chronic Exercise

Chronic exercise studies have examined potential neurobiological mechanisms associated with the antidepressant effects of exercise. These studies have focused on assessing whether changes in specific neurobiological mechanisms are associated with depressive symptom change in response to exercise treatment. To date, chronic exercise studies have focused mostly on oxidative stress markers, BDNF, and inflammatory markers.

In Schuch et al. (2014), the authors conducted a RCT evaluating the effects of exercise as an add-on treatment to treatment-as-usual on thiobarbituric acid-reactive substances (TBARS) and BDNF among 26 severely depressed inpatients. Fifteen individuals were randomized to an exercise plus treatment-as-usual condition, while the other 11 participants were allocated to a treatment-as-usual comparator condition. Participants performing the add-on exercise completed a 16.5 kcal/kg/week dose three times per week throughout their hospitalization stay. Across the hospitalization stay (exercise participants: M_duration = 21.63 days; SD = 4.5; control participants: M_duration = 23.82 days; SD = 5.7), participants in the exercise group performed ~9 total sessions. Serum TBARS levels increased for the exercise group, while no effects were found for serum BDNF levels, indicating that TBARS may be a potential neurobiological mechanism implicated in the antidepressant effects of exercise for participants with depression. It was unclear from this study whether change in TBARS was associated with changes in depressive symptom improvements. Importantly, these patients were also receiving treatment-as-usual which consisted of antidepressant drugs and/or electroconvulsive therapy. It is possible that exercise may impact serum TBARS levels when combined with other forms of treatment. Future studies specifically designed to test whether TBARS is a neurobiological mechanism of the effects of exercise for depression are needed.

Lavebratt and colleagues (2017) examined whether serum IL-6 levels could be altered by 12 weeks of exercise and whether changes corresponded to changes in depressive symptoms. In their study, 116 patients (age range = 18–64 years) completed light (n = 48), moderate (n = 36), and vigorous (n = 32) exercise conditions for three 60-min exercise sessions over 12 weeks. Reductions in IL-6 levels were associated with depressive symptom reductions, indicating that IL-6 may be a potential mechanism of the antidepressant effects of a chronic exercise training program. The authors did not examine other inflammatory markers or mechanisms. It remains unknown whether other mechanisms could also account for the effects.

These studies suggest that there may be a role of specific oxidative stress and inflammatory markers in the antidepressant effects of exercise training. Overall, the available data for neurobiological mechanisms of the antidepressant effects are too premature to make any definitive conclusions.