Assessing BDNF as a mediator of the effects of exercise on depression
Introduction
Brain-derived neurotrophic factor (BDNF) is a protein largely found in certain brain regions, such as the hippocampus, cerebral cortex, hypothalamus, and cerebellum, as well as in the peripheral nervous system. BDNF plays a role in neuronal growth and differentiation and in reducing neuro-degeneration and increasing neuroplasticity. Given its role in neuronal growth, studies have shown that decreased levels of BDNF are associated with impairments in memory consolidation, storage, and long-term memory (Cirulli et al., 2004; Roig et al., 2013).
As BDNF and exercise have similar effects on improving cognition (McMorris and Hale, 2012; Smith et al., 2010), BDNF may be the pathway by which exercise exerts its effects (Erickson et al., 2012). A recent meta-analysis aiming to explicate the first component of this pathway--the effect of exercise on BDNF—showed BDNF elevations after a single bout of exercise and after a program of regular exercise (Szuhany et al., 2015). Specifically, results indicated a moderate effect of a acute exercise on an increase in pre-to post-exercise BDNF, which was replicated in a meta-analysis of 55 studies of healthy adults (Dinoff et al., 2017). This pre-to post-exercise BDNF increase was intensified following a program of regular exercise. Resting BDNF also increased following regular exercise, but at a small effect size. Results from this study suggest reliable BDNF increases following both acute and regular exercise.
Concerning the second half of the potential causal pathway between exercise and depression, few studies have examined whether BDNF changes from exercise predict changes in depression symptoms. Few studies in the meta-analysis included participants with psychiatric conditions, and only three included depressed participants (Gustafsson et al., 2009; Laske et al., 2010; Toups et al., 2011). A recent meta-analysis only identified six studies of exercise effects on resting BDNF in patients with MDD (Dinoff et al., 2018). However, within these studies, conflicting results of the effect of BDNF change on depression exist; some suggest BDNF increases in depressed patients as depression improves (Gourgouvelis et al., 2018) and some suggest BDNF is not a factor in depression changes (Toups et al., 2011).
Yet, other research has implicated BDNF in pathways affecting depression. For example, studies have indicated that depressed patients show lower resting levels of serum and plasma BDNF than healthy controls (Bocchio-Chiavetto et al., 2010; Brunoni et al., 2008; Lee et al., 2007). Additionally, meta-analyses and reviews (Russo-Neustadt and Chen, 2005; Sen et al., 2008) have shown that antidepressant treatment significantly increases BDNF from pre-to post-treatment in depressed patients, though the relative degree of increase depends on the specific antidepressant (Zhou et al., 2017).
In the current study, we evaluate the change in BDNF after exercise in depressed outpatients and examine the link between these changes and treatment outcome. Specifically, this was a secondary analysis of possible mediating effects of BDNF in a pilot randomized controlled trial which examined the effects of exercise in combination with psychosocial treatment on depression symptoms (Szuhany and Otto, 2019). In accordance with meta-analytic results, we hypothesized that resting BDNF levels would increase following an exercise program and that the pre-to post-increase in BDNF would intensify over time. We also hypothesized that the increases in resting and pre-to post-exercise BDNF levels would be associated with the degree of improvement in depression symptoms.
Section snippets
Participants
Participants were sedentary adults ages 18–65 with a principal diagnosis of MDD or persistent depressive disorder (PDD) with a current major depressive episode. As this was a secondary analysis, screening procedures and extended psychiatric and medical inclusion and exclusion criteria are presented in greater detail elsewhere (Szuhany and Otto, 2019). Briefly, exclusion criteria were designed for safety (e.g., low to moderate exercise risk; low suicide risk) and generalizability (e.g., no
Patient characteristics
Baseline demographics are described in Table 1. Average resting BDNF levels at baseline were 28690 (±6870) ng/ml and average change score from pre-to post-exercise was 5265 (±10993) ng/ml. There was no significant difference between intervention conditions in total METs of exercise (t(29) = 0.22, p = 0.83, d = 0.08) as reported in the primary paper (Szuhany and Otto, 2019), with both groups demonstrating significant increases in METs of exercise across treatment. Table 2 includes clinical,
Discussion
Recent meta-analytic review (Szuhany et al., 2015) showed reliable moderate effects for increases in pre-to post-exercise BDNF levels following both acute and programs of exercise, but poorly represented individuals with psychiatric disorders. The current study, albeit underpowered, contributes effect size estimates of pre-to post-exercise BDNF changes across an exercise program. Consistent with the meta-analysis, depressed outpatients showed significant increases in BDNF across a single
Role of the funding source
This work was supported by a grant from the National Institute of Mental Health [F31 MH100773]. The funding source did not have any role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the article for publication. BDNF processing was completed by the Albert Einstein College of Medicine with aid from grants: ICTR Einstein-Montefiore CTSA (UL1TR001073) and Diabetes Research Center (DK020541).
CRediT authorship contribution statement
Kristin L. Szuhany: Conceptualization, Methodology, Investigation, Formal analysis, Writing - original draft, Funding acquisition. Michael W. Otto: Conceptualization, Supervision, Funding acquisition, Writing - original draft.
Declaration of competing interest
In addition to Federal grant support, Dr. Otto receives royalties from multiple publishers (including royalties for books on exercise for mood) and receives speaker support from Big Health. Dr. Szuhany declares no conflicts of interest.
Acknowledgements
We would like to acknowledge the contributions of M. Alexandra Kredlow and Josephine Lee for serving as study therapists; Bonnie Brown for drawing blood samples; Elijah Patten, Leslie Unger, Stephen Lo, Emily Carl, Melanie Watkins, and Abraham Eastman for serving as independent evaluators; and Gabrielle Figueroa, Sarah Oppenheimer, Ani Keshishian, Daniel Reichling, and Benjamin Woodward for help with data entry.
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This work was completed as part of Kristin Szuhany's doctoral thesis at Boston University.