Treatment Resistant major depressive disorder

Pharmacotherapy with Exercise versus Pharmacotherapy Alone in

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Treatment-Resistant Major Depressive Disorder

Major depression is currently one of the most prevalent mental health disorders in the United States. In 2012, an estimated 6.9 percent (16 million) of adults aged 18 and older had at least one major episode of depression (National Institute of Mental Health, 2012). In addition to its prevalence, the World Health Organization reports that major depression is the most burdensome mental health disorder, accounting for 3.7 percent of all United States disability-adjusted life years as well as 8.3 percent of all United States years lived with disability. According to the Centers for Disease Control (2012), populations at greatest risk for major depression include adults aged 45-64 years old, women, African Americans, Hispanics, and non-Hispanic persons of other or multiple races, individuals with less than a high school education, previously married individuals, the unemployed, and those without health insurance coverage.

The diagnosis of major depressive disorder (MDD) is made if an individual exhibits at least five of the following nine DSM-IV criteria nearly every day: a. depressed mood or irritability for the majority of the day, b. anhedonia in most activities, most of the day, c. insomnia or hypersomnia, d. change in activity level, e. fatigue or lethargy, f. feelings of excessive guilt or worthlessness, g. diminished concentration, and h. suicidal ideation (Mayo Clinic, 2014). In addition, these symptoms must be exclusive of other causes such as substance abuse, must impair function of work or personal relationships, and must not follow or accompany manic episodes (Simon & Zieve, 2013).

Depression not only affects one’s mental well-being, but physical well-being as well. Research has shown that MDD can exacerbate illnesses and decrease survival rates. In addition, depression itself is a risk factor for heart disease, obesity, and dementia (Simon & Zieve, 2013). Evidence exists linking immunity dysregulation with depression, thus providing further support that major depression and somatic illnesses are intertwined (Gibney & Drexhage, 2013).

Current Practice Guidelines

The majority of patients with depressive symptoms initially present to their primary care provider (Frank, Huskamp, & Pincus, 2003). Thus, it is imperative that providers identify those at risk and are attuned to signs and symptoms of major depressive disorder. The United States Preventative Services Task Force (USPSTF) assigned a grade B recommendation for screening adults for depression when resources are present to assure accurate diagnosis, treatment, and follow-up care (USPSTF, 2014). While depression is often initially and sometimes largely managed by primary care, the Task Force on Community Preventive Services (2012) recommends a collaborative care approach between specialists based on evidence that this improves symptoms, adherence to treatment, remission, and recovery.

Treatment for major depressive disorder consists of psychotherapy, medication, or both. In particular, cognitive-behavioral therapy has emerged as a safe and effective mode of psychotherapy treatment. Among a variety of antidepressant medications available, selective serotonin reuptake inhibitors (SSRI) remain the most commonly prescribed for depression due to its favorable (yet present) side effect profile (National Alliance on Mental Illness, 2014).

Impact of Nurse Practitioners

Nurse practitioners in the adult-gerontology primary care setting are in an ideal position to screen, diagnose, and manage patients with major depressive disorder. Remaining astute to risk factors and signs and symptoms of major depression can assist in early diagnosis and treatment, thereby minimizing long term affects of the disorder. In addition, it is essential that nurse practitioners educate patients on the pathophysiology of depression in order to eliminate the stigma that often accompanies it, as well as educating them on treatment options, medication side effects, and the plan of care. Nurse practitioners must remain at the forefront of research on treatment options, particularly for individuals with treatment-resistant major depressive disorder, in order to deliver evidence-based clinical practice.

Population of Interest

Depression exists across age groups, ethnicities, race, and gender; the average age of onset is 32 years, with the highest rates occurring in adults aged 49 to 54 years (Simon & Zieve, 2013). As is the case with most medical conditions, diagnosis and treatment must be tailored to the specific population and age group. MDD can greatly affect one’s work productivity, personal relationships, and physical health. Studies have shown that those who suffer from psychiatric disorders, including depression, have higher rates of divorce as well as increased risk of unemployment. Furthermore, while unclear which is the causative factor, depression is linked with higher rates of substance abuse and smoking (Simon & Zieve, 2013). Thus, it is imperative that it is not overlooked or ignored in adulthood, a life stage in which one is cultivating relationships and a family, developing a career, and potentially facing increased risk for the development of chronic illnesses such as diabetes and hypertension.

MDD, also referred to as unipolar affective disorder, is a relapsing and remitting illness that has no known pathophysiology (Cichon et al., 2009). Therefore, treatment aims to relieve symptoms with a goal of remission (Kurian et al., 2009), often employing a combination of psychotherapy and pharmacotherapy. Despite the great potential that these therapies have in improving quality of life, as many as 60 to 70 percent of individuals with MDD have treatment-resistant depression (Trivedi & Daly, 2008). Adding additional medications improves outcomes in some cases, yet results are variable and the side effects, risk of medication interactions, inconvenience, and cost burden make this option quite unfavorable (Fava, 2001).

Due to the serious impact of MDD on quality of life and the challenges faced in those that are treatment-resistant, the use of non-pharmacological augmentation strategies is attractive. Exercise is a proven mood enhancer due to its effects on neurotransmitter regulation, secretion of endorphins, and hippocampus neurogenesis (Trivedi & Greer, 2009). In addition, exercise is cardioprotective, decreases risk of developing diabetes and hypertension, and combats obesity (Powers et al., 2002). The benefits of exercise, combined with its minimal cost, low risk profile, and easy implementation, have piqued the interest of researchers in exploring its impact on treat-resistant MDD. In adults diagnosed with major depressive disorder, is the combination of antidepressant pharmacotherapy and exercise more effective than pharmacotherapy alone in improving depressive symptoms and quality of life?

Literature Search

The nursing section of the UCLA Biomedical Library website was accessed to perform a search of various databases in order to answer the PICO question: In adults diagnosed with major depressive disorder, is the combination of antidepressant pharmacotherapy and exercise more effective than pharmacotherapy alone in improving depressive symptoms and quality of life?

The search began in CINAHL using the terms “exercise” AND “adults” AND “depression” which resulted in 432 entries. Entries were narrowed to articles published within the last ten years, yielding 107 articles. Several articles were pertinent to the PICO question, including one systematic review. While the articles in the systematic review were outdated, it was valuable in identifying authors who published more recent articles on the topic of focus.

Next, PubMed was accessed to search “exercise for depression,” yielding an overwhelming 11,074 articles. The search was modified to include only randomized control trials (RCT), full text articles published within the last ten years, and human species, thereby decreasing the yield to 3,304. In order to find the most relevant articles without the risk of filtering out quality ones, the list was sorted by relevance. Several of the top one hundred articles were obtained for review.

Lastly, Web of Science was accessed and an initial filter of “year 2004-2014 was placed. The search term “exercise for depression” resulted in 4,120 entries. The search was modified to include only articles (document type), human species, and search results within the term “antidepressants.” From the final yield of 188 articles, a few were retained for review.

Articles chosen were ultimately based on their comparison of antidepressant therapy alone versus antidepressant therapy with concurrent exercise in treating those with treatment-resistant MDD. Studies that did not focus on adults aged 18-65 years as well as studies that looked at other depression subtypes were excluded.

Critical Appraisal of the Evidence

Mota-Pereira et al. (2011) sought to determine the impact of a moderate intensity exercise program as an adjuvant to pharmacotherapy in treatment-resistant MDD patients [see TOE]. Results of this study provide strong evidence supporting the use of exercise in treating individuals with treatment-resistant MDD. The randomized, investigator-blinded, and parallel assignment approach limits potential for bias. In addition, the use of the Hamilton Depression Scale (HAM-D17), Beck depression inventory, Global Assessment of Functioning (GAF), and Clinical Global Impression Scale (CGI-S) for outcome measurements bolsters validity.

However, several limitations must be noted. The sample size is very small and researchers randomized participants in a 2:1 ratio of intervention to control group respectively, raising the question of statistical significance. Researchers did not assess for medication adherence thus creating the possibility of a confounding variable. In addition, except for one walk per week, participants exercised independently without supervision; thus, the exercise intensity may not have been consistent across the intervention group. Researchers acknowledged that the study took place from September to March so seasonal affects on depression may have played a role as well. Lastly, the program ended after 12 weeks so the long-term efficacy of exercise cannot be extrapolated.

Trivedi et al. (2011) conducted a similar study to test the efficacy of aerobic exercise at two intensity levels as an augmentation treatment for treatment-resistant MDD patients [see TOE]. While both exercise groups had significant improvements in remission, the higher dosage had a stronger effect. Of particular note, the study found that gender and family history of mental illness appeared to be treatment moderators, as females with a family history of mental illness gained greater benefit from the lower-intensity exercise. In addition, the low-dose exercise group had significantly better adherence rates than the high-dose exercise group.

This RCT utilized blinded physicians and personnel to collect data which limited potential for bias. In addition, all exercise was monitored by personnel, thus ensuring consistency among the intervention group. Measurements via the standard Inventory of Depressive Symptomatology provide validity. However, it should be noted that the majority of participants were white females so the findings may not be applicable to the general population. In addition, like the study by Mota-Pereira et al. (2011), further research is needed to determine effects beyond the 12-week study period.

Dannielsson, Papoulias, Petersson, Carlsson, & Waern (2014) compared the effects of exercise versus basic body awareness therapy (BBAT) as adjuvant therapy for treatment-resistant MDD [see TOE]. Their findings suggest that exercise added to pharmacological treatment has a significantly positive influence on depression severity as well as cardiovascular fitness. In particular, the study reveals that improvement lies in a structured exercise regimen in collaboration with trained professionals, and that simple advisement regarding physical activity is insufficient.

The randomized controlled design and use of a blinded assessor minimizes risk of bias. In addition, research collaborators remained the same throughout the study, thus strengthening reliability and minimizing risk of inter-rater bias. However, the small sample size raises questions regarding the findings’ statistical significance. In addition, researchers noted that voluntary recruitment may have skewed the pool by attracting individuals who are more optimistic about the benefits of exercise, while those individuals randomized to the BBAT group may have been unenthusiastic and disappointed in their assignment. While there was no significant improvement in functioning, an important aspect of depression remission, it is possible that this may be due to the short ten-week intervention, another limitation of the study.

Schuch, Vasconcelos-Moreno, Borowsky, & Fleck (2011) assessed the effects of exercise as an adjuvant therapy to conventional pharmacotherapy for the treatment of severe depression. Their findings demonstrate the positive impact of physical exercise on depressive symptoms and quality of life. Because this study took place in an inpatient setting, personnel monitored all exercise and medication administration which ensures consistency; in addition, adherence rate was 100 percent. The WHOQOL BREF to measure quality of life as well as the HAM-D17 to measure depressive symptoms provides validity.

The study’s small sample size is limiting. In addition, one patient in the exercise group and three patients in the control group concurrently received electroconvulsant therapy which may be a confounding variable. Lastly, because this study took place in a hospital, its findings may not be applicable to the outpatient setting.

Knubben et al. (2007) evaluated the short-term effects of an endurance training program in patients with MDD, and is unique in its focus on patients who are in the initial treatment stage. The findings demonstrate the benefits of endurance training in relieving depressive symptoms, especially in the period before antidepressant medication begins to provide a therapeutic effect. The Bech-Rafaelsen Melancholy Scale and Center for Epidemiologic Studies Depression scale provide valid measurement tools. In addition, the randomized, parallel arm approach minimizes potential for bias.

The study, however, is limited by a small sample size. In addition, the very brief intervention period raises questions regarding long term effects; researchers acknowledged the possibility that a rebound effect may occur if exercise is halted. Antidepressant medications varied among participants and a confounding variable of sleep deprivation in some participants (as part of the usual treatment) may have affected outcomes. Lastly, because this study took place in an inpatient setting, its findings may not be applicable to the general population.


A review of the literature reveals that adding exercise to traditional antidepressant pharmacotherapy is more effective than pharmacotherapy alone in individuals with treatment-resistant MDD. Every study reviewed identified significant improvements in depressive symptoms when an aerobic exercise augmented antidepressant medication use. While it is evident that exercise is beneficial in adults with MDD, several themes emerged. First, exercise regimens must be personalized with regard to subgroups such as women and those with family history of psychiatric disorders. Therefore, while higher intensity exercise may show more symptom improvement overall, lower dosages may be more feasible and yield better adherence (Trivedi et al., 2011). Second, because many individuals with MDD experience lethargy and lack motivation for even simple everyday tasks, it is crucial that the exercise program has structure as advisement and encouragement to exercise is likely insufficient (Danielsson et al., 2014). Third, while exercise is beneficial throughout the clinical course, its impact may be especially great in the initial weeks of antidepressant therapy as a gap bridge until the medication begins to have take effect (Knubben, et al., 2007).

While the evidence is promising, a number of gaps exist. The articles reviewed had very small sample sizes. In addition, intervention periods in all studies lasted twelve weeks or less and all except one study failed to obtain follow-up data on its participants. Thus, further research utilizing larger samples and longer exercise programs are necessary in order to establish stronger evidence via equivalence analysis, as well as understand the long term implications of exercise on MDD. Furthermore, because it is known that women have twice the rate of MDD (Simon & Zieve, 2013) and may respond differently to exercise programs, further investigation into this subgroup is warranted.

Implications for Practice

Primary care nurse practitioners undoubtedly encounter many patients with MDD and must be well-informed in managing this population. Communication between the provider and patient is essential when creating a plan of care; this is especially true in regards to treatment options for MDD. In collaboration with mental health specialists, structured exercise should be encouraged as augmentation therapy for those with treatment-resistant MDD. However, several factors must be considered in recommending and implementing this intervention. Some patients may have disabilities or conditions that limit their physical abilities to perform aerobic exercises. In addition, as evidenced by Trivedi et al. (2011), women with a family history of psychiatric disorders may have a different response to varied exercise dosages. Furthermore, it is important to understand that many individuals with low socioeconomic status may live in areas where it is unsafe to spend time outdoors and they may lack resources for structured exercise programs.

The nurse practitioner is in an ideal position to educate patients on the benefits of exercise in alleviating depressive symptoms and improving quality of life, as well as to assist patients in finding resources such as the YMCA or local community center, in order to create a viable long-term plan. An individualized approach, with regards to a patient’s physical capability, family psychiatric history, socioeconomic status and access to resources, and personal preferences will ensure adherence, satisfaction, and optimal results.