15.1: Depression

15.1.1. Prevalence and Burden

Major depressive disorder (MDD) is one of the most common mental illnesses, with point estimates from the Global Burden of Disease Study indicating a mean global prevalence of 3.6% each year between the years 1990 and 2019 (Global Burden of Disease Collaborative Network, 2020). MDD is a leading cause of disability around the world (Friedrich, 2017) that results in a loss of work productivity and increased morbidity (Cuijpers et al., 2014; Walker et al., 2015). MDD is also highly recurrent, with about 35%of individuals experiencing an additional MDD episode within the first year of recovery (Hardeveld et al., 2010). Even after 15 years following recovery, up to 85% of individuals experience another MDD episode. Therefore, it is unsurprising that MDD often exacts profound suffering and places a staggering burden on individuals, families, and society. Indeed, the total estimated economic burden (i.e., indirect and directs costs attributed to depression) of people with MDD was US$210.5 billion in 2010, with ~US$27.7 billion in direct costs due to medical and pharmaceutical services directly related to MDD treatment (Greenberg et al., 2015).

15.1.2. How is Depression Diagnosed?

Current diagnostic practices rely on the Diagnostic and Statistical Manual, Fifth Edition (DSM-5; American Psychiatric Association, 2013) and use specific symptoms as indicators of depression to reach a diagnostic threshold. To constitute a DSM-5 MDD diagnosis, an individual must endorse five of nine symptoms that are present for a minimum of 2 weeks and persist for most of the day, nearly every day (American Psychiatric Association, 2013). In terms of symptoms, individuals must endorse at least one of two core criterion symptoms: depressed or low mood (e.g., feelings of sadness) and/or loss of interest or pleasure in almost all typically or previously enjoyable activities (i.e., anhedonia). An individual must also endorse at least four other symptoms: (a) significant unintentional change in weight or appetite; (b)sleep disturbances (defined as insomnia or hypersomnia); (c) severe psychomotor agitation (e.g., restlessness) or retardation observable by others (e.g., slowed speech or movement patterns); (d) fatigue or low energy; (e) a sense of worthlessness or excessive guilt; (f) impaired ability to think or concentrate and make decisions; or (g) recurrent thoughts of death that include suicidal ideation and/or attempts. Any symptom combination including at least one core criterion symptom and four additional symptoms constitutes a MDD diagnosis. Importantly, these above-mentioned criteria are also used to inform and issue a MDD diagnosis in the United Kingdom (National Collaborating Centre for Mental Health and National Institute for Health and Clinical Excellence, 2010).

15.1.3. Treatments for Depression

Clinical practice guidelines recommend the use of pharmacotherapy (i.e., antidepressant drugs), psychotherapeutic approaches (e.g., cognitive-behavioral therapy [CBT]), or a combination of the two as first-line treatments for MDD (American Psychiatric Association, 2010; American Psychological Association-Depression Guideline Development Panel, 2019; National Collaborating Centre for Mental Health and National Institute for Health and Clinical Excellence, 2010). In terms of pharmacotherapy,antidepressant drugs, namely selective serotonin reuptake inhibitors (SSRIs), are among the most prescribed medications and work by blocking the reuptake of serotonin. Other classes of antidepressant drugs are also prescribed, including serotonin and norepinephrine reuptake inhibitors (SNRIs), and norepinephrine and dopamine reuptake inhibitors (NDRIs); all of which work by inhibiting the reuptake of their targeted neurotransmitter(s), thereby increasing its availability, and altering their levels in the brain.

Despite antidepressant drugs being among the most widely prescribed drugs globally, they are not consistently beneficial. For example, in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, which is the largest depression treatment trial ever conducted and funded by the U.S.National Institute of Mental Health, the effectiveness of antidepressant drug treatments was examined among 4,041 patients with a MDD diagnosis (age range = 18–75 years). In both specialty and primary medical care settings, patients were exposed to a tiered approach consisting of four separate treatment levels. The trial was structured such that patients who were unable to achieve remission—defined as becoming symptom-free following treatment—at one level would then move onto the next treatment level, which could consist of either a switch to a different antidepressant drug or a combination of antidepressant drug with add-on psychotherapy.

STAR*D study results indicated that between 28% and 33% of the patients achieved remission following an initial 14-week treatment with citalopram (Trivedi et al., 2006). After multiple treatment steps, Rush et al. (2006) reported a cumulative remission rate of 67%, which was computed by summating remission rates achieved across all trial stages. As highlighted by Ekkekakis (2021), it is important to note, however, that the actual remission rate is a bit unclear given that a re-analysis of the available data from the trial resulted in a remission rate of 2.7% when appropriately accounting for patients who dropped out or relapsed and remained in the trial at the end of the original trial duration (see Pigott, 2011, 2015). Regardless of the “true” remission rate, many patients were left symptomatic or clinically depressed following the STAR*D trial, which highlights the variable and limited effectiveness of antidepressant drugs in depression treatment. Furthermore, research has shown that even among patients who achieve remission using antidepressant drug treatment, long-term outcomes are uncertain, as estimates indicate that approximately 40% of remitted patients are likely to relapse within a two-year period (Boland & Keller, 2008).

The efficacy of antidepressant drugs to treat depression was also examined in a meta-analysis of six studies that evaluated the impact of antidepressant drugs in randomized placebo-controlled depression treatment trials approved by the U.S. Food and Drug Administration. After aggregating individual patient-level data from 434 patients receiving antidepressant drugs and 284 patients in placebo groups across six separate trials, Fournier et al. (2010) found that antidepressant drug efficacy varied as a function of depressive symptom severity. Only patients exhibiting severe symptoms of depression before enrolling in the trial experienced significant pre-to-post treatment reductions in depressive symptoms compared to those in placebo control groups. Antidepressant drugs were no more efficacious in reducing depressive symptoms compared to placebo control for patients experiencing mild-to-moderate symptom severity before treatment.¹ Despite their limited efficacy, there are also several barriers associated with antidepressant drugs, such as costs and avast side effect profile,including but not limited to nausea, vomiting, diarrhea, dry mouth, constipation, and sexual dysfunction. These side effects are intolerable (Corponi et al., 2020) and a primary contributor for treatment discontinuation and poor patient compliance (Lader et al., 2004).

Various forms of psychotherapy, including CBT and behavioral activation, are broadly used to treat MDD and have shown effectiveness in reducing depression (e.g., Cuijpers et al., 2013). In the largest quantitative review conducted on the topic, Cuijpers et al. (2020) assessed whether psychotherapeutic approaches were effective in reducing depression and whether effects differed across the lifespan. The authors compiled data from 366 randomized controlled trials (RCTs) and found that psychotherapy was generally effective, resulting in moderate-to-large depressive symptom reductions among individuals with clinically diagnosed depression of all ages, with moderate-to-large effect sizes. As with antidepressant drugs, psychotherapy is associated with variable success rates, with many individuals often failing to adequately respond or derive antidepressant benefits to psychological treatments (DeRubeis et al., 2005). Moreover, there are several barriers to accessing psychotherapy for many individuals. Psychotherapy is costly and its effectiveness depends on some of the following: (a)availability and accessibility of mental health professionals (Olfson & Marcus, 2010); (b)characteristics of the mental health professional (Olfson et al., 2009); (c) the delivery of intervention (e.g., internet-delivered versus face-to-face versus group-based); and (d) individual preferences.

15.1.4. Purpose of the Chapter

Given the variable effectiveness and barriers associated with first-line treatments, there is an urgent need to identify alternative strategies or interventions that can be used to treat depression or prevent the occurrence of the disorder altogether. Exercise and physical activity are two lifestyle behaviors that have been touted for decades and even centuries in the management and treatment of depression. For example, ancient physicians and philosophers including Hippocrates (460 BCE–370 BCE), Suśruta (or Sushruta; 600 BCE) and Hua T’o from the Eastern Han Dynasty (25 CE–220 CE) recognized the importance of engaging in regular physical activity to maintain health. In particular, Hippocrates,considered by many to have been the first physician to prescribe exercise for a patient suffering from a mental health condition, believed that “eating alone will not keep a man well; he must also take exercise” (Jones, 1923; p. 229).

In the context of depression, exercise and physical activity did not gain significant traction in the scientific literature until seminal studies by William P. Morgan were published in the late 1960s to early 1970s. For example, Morgan conducted the first observational studies to indicate that patients with depression tended to have lower cardiovascular fitness levels compared to non-depressed healthy counterparts (Morgan, 1968, 1969; Morgan et al., 1970). These early efforts laid the foundation for decades of work to follow and since then, there has been burgeoning research interest in this area (see Figure 15.1), which has resulted in substantial progress toward establishing these two lifestyle behaviors as important strategies to ward off depression.

Figure 15.1. Annual Number of Research Publications on the Exercise and Physical Activity–Depression Relationship from 1970-2020

In this chapter, we examine the research evidence related to exercise and physical activity² as prevention and treatment strategies used for depression. We will first summarize the evidence base of exercise and physical activity in the prevention of depression. Then, we will summarize the current evidence on the influence of exercise as a treatment for depression before offering insight into possible neurobiological mechanisms associated with the exercise-depression relationship. We highlight open questions that need to be explored in future research to help elucidate on the exercise, physical activity, and depression relationship throughout the chapter. Before presenting the evidence base, it is important to gain insight into how MDD and depressive symptoms are measured to understand conclusions that can be drawn from the evidence.

Photo by Pixabay from Pexels

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Reference

¹ Those interested in learning more about research regarding the use of antidepressant drugs in the treatment of depression should refer to review articles and commentaries by Kirsch et al. (2008), Kirsch (2014), Kirsch (2019), Möller (2008), and Turner et al. (2008).

² Physical activity is broadly defined as any bodily movement resulting in energy expenditure, while exercise is a subset of physical activity that is performed for the intention of improving or maintaining one or more aspects of physical fitness (Casperson et al., 1985).