By: Maryam Abro


Major depressive disorder (MDD) generally known as clinical depression is very common and seriously challenging for the health care system due to its recurrent and treatment-resistant characteristics (Morres et al., 2019) and one of the leading causes of years lived with disability (YLD) (James et al., 2018 as cited in Pitsillou et al., 2020). MDD is a common disease and affects people of different ages and social backgrounds (Moussavi et al., 2007). It is estimated that depression affects 322 million people worldwide and the number of people living with depression increased by 18.4% between the years 2005 and 2015 (WHO, 2017).

MDD is no longer considered as a discrete disease with simple cause and symptom and believed to be “multidimensional” (Clark et al., 2017 as cited in Pitsillou et al., 2020). MDD is characterized by an assortment of “physiological”, “psychological” and “cognitive symptoms” and it is diagnosed based on a collection of specific symptoms as there are no objective diagnostic tests (Cullen, Klimes-Dougan, Kumara, & Schulz, 2009). The clinical description of depression is mood disturbance for example sad, low, or irritable mood or a persistent loss of interest or pleasure, and must be manifested with additional biological, cognitive, and emotional symptoms such as sleep disturbance, poor concentration, and feeling of worthlessness (Curry, & Hersh, 2014). According to the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), MDD is categorized by peculiar changes in “affective”, “cognitive” and “neurovegetative” domain with symptoms lasting for at least 2 weeks. Moreover, five or more symptoms need to exist in the same event and at the minimum one of the signs as depressed mood or “anhedonia” and other symptoms being unexplained substantial weight change, fatigue or weakness, feelings of guilt or insignificance, difficulty concentrating and frequent suicidal thoughts (AMA, 2013 as cited in Pitsillou et al., 2020). Individuals with MDD become socially isolated and report decreased enjoyment in social connections (Bora & Berk, 2016) and are at greater risk of suicide. Suicide is the third leading cause of death in 10 to 24 years old and 50% of the time the cause is related to MDD (Cullen et al., 2009).

MDD is more common in adolescents than in younger children (Curry, & Hersh, 2014) and the prevalence in women is double as compared to men. MDD follows a recurrent course and on average individuals experience five to nine Major Depressive Episodes (MDEs) and with each recurrence, the time between episodes becomes shorter and shorter (Pizzagali, Whitton, & Webb, 2018). Depression damages health to a greater extent than any other disease (Moussavi et al., 2007) and is “highly comorbid with other mental disorders, most prominently anxiety disorders (59%), impulse control disorders (32%), and substance use disorders (24%), and collectively almost 75% of adults with lifetime MDD report at least one other lifetime DSM disorder” (NCS Replication; Kessler et al., 2011 as cited in Pizzagali et al., 2018). Several studies have suggested that MDD is connected with neurocognitive damage mainly in attention and “executive function” and severity of depressive symptoms are directly related with cognitive difficulties (Bora et al.,2013; Lee et al.,2012; Snyder, 2013; Trivedi and Greer, 2014; Wagner et al.,2012; McDermott and Ebmeier, 2009 as cited in Bora & Berk, 2016). Furthermore, MDD is also linked with other illnesses such as cardiovascular disease, diabetes, arthritis, asthma, and chronic pain (Baxter, Charlson, Somerville, & Whiteford, 2011 as cited in Pizzagali et al., 2018). Due to comorbidity with other mental and physical illnesses, the individuals suffering from MDD have a greater risk of premature mortality and generally have approximately 10–15 years shorter life expectancy (Gerber, Holsboer-Trachsler, Pühse, & Brand, 2016).

The traditional treatment for MDD is pharmacotherapy, psychotherapy or a combination of both (Gerber et al., 2016). In severe cases of depression, electroconvulsive therapy (ECT) can also be used (Pandarakalam, 2018 as cited in Pitsillou et al., 2020). Selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), norepinephrine-dopamine reuptake inhibitors (NDRIs), tricyclic antidepressants (TCAs), or monoamine oxidase inhibitors (MAOIs) are some of the standard medication used for treatment of MDD (Gelenberg et al., 2010).  These drugs act on the monoamine system and increase the availability of serotonin (5-HT), norepinephrine and dopamine in the brain (Pitsillou et al., 2020).

The “heterogeneity” of depression poses serious challenges for traditional treatments (Kandola, Ashdown-Franks, Hendrikse, Sabiston, & Stubbs, 2019). The treatment outcome for pharmacotherapy and psychotherapy are not broad and 34% of people with depression tend to be non-responsive to treatment (Cipriani et al., 2018; Cuijpers et al., 2019; Rush et al., 2006 as cited in Kandola et al., 2019). Currently, antidepressants are prescribed on a ‘trial and error’ approach (Serretti, 2018 as cited in Pitsillou et al., 2020) and it is estimated that only 30% to 50% of patients respond to “single-action” or “dual-action” monotherapy and majority of patients require change or increase in medication (Gerber et al., 2016). Furthermore, antidepressants can cause various side effects (Anderson et al., 2012 as cited in Kandola et al., 2019).

The traditional treatments for depression such as pharmacotherapy and psychotherapy will continue a pivotal role in the treatment, however, considerable number of people with depression do not pursue treatment and more than 50% of patients, who even seek treatment do not respond effectively and require additional treatment options, which most of time do not provide remission. Consequently, new and complementary treatment options are urgently need (Gerber et al., 2016; Kandola et al., 2019). Physical activity has proved to be effective alternative option for the treatment of depression (Karg, Dorscht, Kornhuber, & Luttenberger, 2020).

Effects of Exercise

Notwithstanding widespread research on the effectiveness of exercise, the exact mechanisms through which antidepressant effects are produced have not been established. It is believed that exercise produces antidepressant effects through numerous biological and psychosocial avenues (Kandola et al., 2019).

Biological Mechanisms

The neurobiological mechanism theory suggests that physical activity increases cognition and mental health by changes in the structural and functional composition of the brain (Lin, & Kuo, 2013; Dishman, & O’Connor, 2009 as cited in Lubans et al., 2016). Voss et al (2013) described three main categories that are impacted by exercise:

  1. Cells, molecules and circuits;
  2. Biomarkers- gray matter volume, cerebral blood volume, flow;
  3. Peripheral biomarkers- circulating growth factors, inflammatory markers (as cited in Lubans et al., 2016).

Several meta-analyses have discovered the relation between depression and structural abnormalities in the brain such as a decrease in hippocampal, prefrontal, orbitofrontal, and anterior cingulate cortex volumes (Bora et al., 2012; Du et al., 2012; Kempton et al., 2011; Koolschijn et al., 2009; Lai, 2013; Sacher et al., 2012; Schmaal et al., 2015; Zhao et al., 2014 as cited in Kandola et al., 2019). In people with depression, the hippocampus is the commonly affected area in the brain (Schmaal et al., 2015 as cited in Kandola et al., 2019). The hippocampus is associated with emotional processing and stress regulation and these regions are mainly affected by depression (Zheng et al., 2019; Dranovsky and Hen, 2006 as cited in Kandola et al., 2019).  Animal models suggest that depression impairs various cellular processes, including hippocampal neurogenesis (Anacker et al., 2013; Eisch and Petrik, 2012; Hill et al., 2015; Sahay and Hen, 2007 as cited in Kandola et al., 2019) and it is believed that decreased rates of hippocampal neurogenesis are partly accountable for depressed mood (Duman, Heninger, & Nestler, 1997 as cited in Rethorst et al., 2009).

It is believed that antidepressant effects of exercise are related to physiological changes that triggers hippocampal neurogenesis (Ernst et al., 2006 as cited in Rethorst et al., 2009). In animal studies, it has been observed that exercise results in changes in brain-derived neurotropic factor (BDNF), increase in cell proliferation, survival, and differentiation. Further, it stimulates the growth of new capillaries that are vital for the transportation of essential nutrients to neurons and results in an increase in neurochemicals, e.g. brain-derived neurotrophic factor (BDNF), insulin-like growth factor 1 (IGF-1), and vascular endothelial growth factor (VEGF) ( Van Praag, 2008; Kleim, & Cooper, 2002; Cotman, Berchtold, & Christie, 2007 as cited in Lubans et al., 2016).


Several meta-analyses, Dowlati et al. (2010); Howren et al. (2009); Köhler et al. (2017); Valkanova et al. (2013), suggested that people with depression have raised levels of pro-inflammatory markers, including Interleukin (IL)-6, IL-1, Tumour necrosis factor-alpha (TNF-α), C-reactive proteins (CRP) and several other IL receptors and receptor antagonists (as cited in Kandola et al., 2019).  Inflammation can interrupt several pathways involved in depression e.g., “dysregulating BDNF” or “neurotransmitter systems” via “kynurenine pathways” (Kiecolt-Glaser et al., 2015; Calabrese et al., 2014; Cervenka et al., 2017; Schwarcz et al., 2012 as cited in Kandola et al., 2019).

Studies have noted reduction in number of “circulating inflammatory factors” such as IL-6, IL-18, CRP, leptin, fibrinogen and angiotensin II due to exercise (Fedewa et al., 2017, 2018; Lin et al., 2015 as cited in Kandola et al., 2019). In a recent Randomized control trials (RCT) on 98 participants with MDD by Euteneuer et al. (2017), an increase in anti-inflammatory marker IL-10 in the plasma was observed in experimental group- undergoing CBT with exercise as add on (as cited in Kandola et al., 2019). Similarly, in another 12-week study, reduction in depression symptoms and serum samples of pro-inflammatory IL-6 was noticed due to exercise (Lavebratt et al., 2017 as cited in Kandola et al., 2019).

Psychosocial and Behavioral Mechanism

People with depression have lower levels of self-esteem that could be potential reason for sense of worthlessness (Keane and Loades, 2017; Orth et al., 2008; Van de Vliet et al., 2002 as cited in Kandola et al., 2019). A negative association exists between weight status and mental health. People who have dissatisfaction with body image have higher risk of depression and show significantly lower scores on physical self-perceptions (Ali et al., 2010; Tang et al., 2010; Jackson et al., 2014; Van deVliet et al., 2002 as cited in Kandola et al., 2019).

Cross-sectional studies suggest that physical activity is linked with higher self-esteem scores, QOL and positive affect due to physical self-perception (Feuerhahn et al., 2014; Sani et al., 2016 as cited in Kandola et al., 2019). Legrand (2014) found that 7-week exercise intervention resulted in increases in physical self-perception, self-esteem, and decreases in depressive symptoms in women with elevated depressive symptoms (as cited in Kandola et al., 2019). Further, physical activity assist contact with the natural environment and could improve mood that affect wider affective states and other signs of well-being (Deci, & Ryan, 2002; Ryff, & Keyes, 1995 as cited in Lubans et al., 2016). Ossip-Klein et al (1989), in a study of clinically depressed women, found that exercise, both aerobic and resistance training, resulted in increased self-esteem and a decrease in depressive symptoms. The authors suggested that an increase in self-esteem may be responsible for decrease in depressive symptoms and contributed to higher self-esteem to improved body image and increased mastery (as cited in Rethorst et al., 2009).

The behavioral mechanism theory contends that changes in mental health outcomes due to physical activity are facilitated by changes in applicable and related behaviors, for example, involvement in exercise may result in better sleep length, sleep effectiveness, sleep latency and reduce sleepiness. Furthermore, partaking in physical activity may also affect self-regulation and coping skills that have potential implications for mental health (Stone, Stevens, & Faulkner, 2013; McNeil et al., 2015; Lang et al., 2013; Gaina et al., 2007 as cited in Lubans et al., 2016). Meta-analytical studies have displayed that exercise increases total sleep, increases slow-wave sleep, and decreases REM sleep resulting in a substantial decrease in Serotonin discharge during REM sleep (Kubitz et al., 1996; Youngstedt, O’ Connor, & Dishman, 1997; McGinty, & Harper, 1976 as cited in Rethorst et al., 2009).