Assessing BDNF as a mediator of the effects of exercise on depression

https://doi.org/10.1016/j.jpsychires.2020.02.003Get rights and content

Highlights

  • BDNF increases after acute exercise in a sedentary, depressed population.

  • BDNF changes across acute exercise did not intensify during an exercise program.

  • Resting BDNF levels did not change across an exercise program.

  • BDNF changes were not associated with changes in depression symptoms.

  • Future studies may require larger sample sizes given small effect sizes.

Abstract

Brain-derived neurotrophic factor (BDNF) is associated with neuronal growth and reduced BDNF has been implicated in depression. A recent meta-analysis documented reliable effects of exercise on BDNF levels (Szuhany et al., 2015); although, few studies included participants with mental health conditions. In this study, we examine whether increased exercise was associated with enhanced BDNF response in depressed patients, and whether this change mediated clinical benefits. A total of 29 depressed, sedentary participants were randomized to receive either behavioral activation (BA) plus an exercise or stretching prescription. Blood was collected prior to (resting BDNF levels) and following an exercise test (pre-to post-exercise BDNF change) at four points throughout the study. Participants also completed depression and exercise assessments. BDNF increased significantly across all assessment points (p < 0.001, d = 0.83). Changes in BDNF from pre-to post-exercise were at a moderate effect for the interaction of exercise and time which did not reach significance (p = 0.13, d = 0.53), with a similar moderate, non-significant effect for resting BDNF levels (p = 0.20, d = 0.49). Contrary to hypotheses, change in resting BDNF or endpoint change in BDNF was not associated with changes in depression. In an intervention that included active treatment (BA), we could not verify an independent predictive effect for changes in BDNF across the trial. Overall, this study adds to the literature showing reliable effects of acute exercise on increasing BDNF and extends this research to the infrequently studied depressed population, but does not clarify the mechanism behind exercise benefits for depression.

Clinical Trials Registry (clinicaltrials.gov)

NCT02176408, “Efficacy of Adjunctive Exercise for the Behavioral Treatment of Major 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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