The role of exercise in the treatment of depression: biological underpinnings and clinical outcomes

Abstract

Globally, depression is a leading cause of disability and has remained so for decades. Antidepressant medications have suboptimal outcomes and are too frequently associated with side effects, highlighting the need for alternative treatment options. Although primarily known for its robust physical health benefits, exercise is increasingly recognized for its mental health and antidepressant benefits. Empirical evidence indicates that exercise is effective in treating individuals with depression; however, the mechanisms by which exercise exerts anti-depressant effects are not fully understood. Acute bouts of exercise have been shown to transiently modulate circulating levels of serotonin and norepinephrine, brain-derived neurotrophic factor, and a variety of immuno-inflammatory mechanisms in clinical cohorts with depression. However, exercise training has not been demonstrated to consistently modulate such mechanisms, and evidence linking these putative mechanisms and reductions in depression is lacking. The complexity of the biological underpinnings of depression coupled with the intricate molecular cascade induced by exercise are significant obstacles in the attempt to disentangle exercise's effects on depression. Notwithstanding our limited understanding of these effects, clinical evidence uniformly argues for the use of exercise to treat depression. Regrettably, exercise remains underutilized despite being an accessible, low-cost alternative/adjunctive intervention that can simultaneously reduce depression and improve overall health. To address the gaps in our understanding of the clinical and molecular effects of exercise on depression, we propose a model that leverages systems biology and multidisciplinary team science with a large-scale public health investment. Until the science matches the scale of complexity and burden posed by depression, our ability to advance knowledge and treatment will continue to be plagued by fragmented, irreproducible mechanistic findings and no guidelines for standards of care.

Figure 1.

Early conceptual model of the effect of exercise on depression. Circles represent the theoretical relative contribution of each mechanism and how each may change from euthymia to depression (and then restored by exercise). White shaded area represents a theoretical level of homeostasis amongst such mechanisms. BDNF, 5-HT/NE, inflammation, and the HPA-axis have each been identified as possible candidate neurobiological mechanisms/pathways involved in depression. In a euthymic state, these implicated mechanisms function appropriately, resulting in homeostasis (white shaded area). While the interaction between these mechanisms and their scaled contributions remains unclear, there is a disruption of homeostasis in depression as abnormalities associated with these mechanisms have been identified: reduced BDNF and 5HT/NE signaling, high levels of inflammation, and HPA-axis dysfunction. Since targeting one specific mechanism or pathway has not been found to completely ameliorate depression, a proposed conceptual approach is to view these mechanisms as a whole working system. Exercise is a viable contender to address multiple aspects of the biological underpinnings of depression. Specifically, aerobic exercise may deliver antidepressant effects via its ability to potentially modulate BDNF, 5HT-NE, inflammation, and HPA-axis function and help restore homeostasis amongst such mechanisms. Resistance exercise may deliver similar benefits, however it remains a scantly studied and underutilized mode of exercise for the treatment of depression.

Figure 2.

Proposed solution to advance the state of the art of the mechanistic understanding of exercise treatment for depression. This proposed next generation research network would utilize the National Institute of Drug Abuse Clinical Trials Network (CTN) and the Molecular Transducers of Physical Activity Consortium (MoTrPAC) as models to advance the science of depression and the interface of exercise and depression. Each node will be an academic medical center with the capability of providing support to obtain, store and analyze biospecimens (i.e., ‘omics analyses). Outlying each node will be clinical treatment sites which will deliver singular exercise treatments (AEx, REx), combination exercise treatments (AEx and REx), or mixed treatments (exercise with nutritional counseling, psychotherapy, pharmacotherapy, or non-invasive brain stimulation). This model provides the infrastructure needed to perform large scale clinical trials while obtaining the biological data needed to elucidate the molecular mechanisms underlying depression, exercise, and the treatment response to exercise-based interventions. Ultimately this model can be leveraged to explore other mental health liabilities, develop novel treatments for such liabilities, and reduce the overall burden of mental health liabilities. Portion of illustration created with Servier Medical Art (smart.servier.com).