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The Effect of Exercise on Depression
By Susan T. Marcolina, MD, FACP, Dr. Marcolina is a board-certified internist and geriatrician in Issaquah, WA; she reports no consultant, stockholder, speaker's bureau, research, or other financial relationships with companies having ties to this field of study.
Regular daily aerobic exercise has been recommended by the Centers for Disease Control and Prevention (CDC) and the American College of Sports Medicine (ACSM) as a treatment for many types of medical disorders such as cardiovascular disease, hyperlipidemia, diabetes, and osteoarthritis. Additionally, such exercise has a number of psychological benefits that may make it suitable as part of the treatment armamentarium for depression.
Depression affects 5-10% of patients in the primary care setting, and women experience depression at nearly twice the prevalence rate of men.1,2 Of the adults who experience depression, two-thirds do not get the necessary treatment. This untreated depression causes pervasive functional impairment and suffering and is not only a barrier to the effective management of common comorbid illnesses such as diabetes, stroke, and cardiovascular disease but, in fact, is a risk factor for unfavorable outcomes of these diseases.3 Table 1 lists risk factors for depression, which can help clinicians identify high-risk individuals for screening and therapy as indicated.4,5
Gender Differences in Prevalence of Depression
The 2:1 female-to-male prevalence ratio of major depressive disorder (MDD) has been documented in different countries and ethnic groups. National comorbidity data reveal that sex differences in the prevalence of depression begin around age 10 until midlife, after which the prevalence differences disappear.1,6
Diagnostic Criteria in Depression
The most commonly used depression screening tools in adults are the Beck Depression Inventory Scales II, the Zung Self-Rating Depression Scale (http://healthnet.umassmed.edu/mhealth/ZungSelfRatedDepressionScale.pdf), and the Center for Epidemiologic Studies Depression Scale-Revised (CES-D, www.chcr.brown.edu/pcoc/cesdscale.pdf). There are also certain instruments, such as the Edinburgh Postnatal Depression Scale (www.aap.org/practicingsafety/Toolkit_Resources/Module2/EPDS.pdf), which screen for postpartum depression, and the Hopkins Symptom Checklist-25 (www.nelmh.org/downloads/other_info/hopkins_symptom_checklist.pdf), which has been validated in refugee populations. Cognitive impairment, however, limits the use of such screening instruments, particularly in an elderly population. In this situation, interviewer administered instruments such as the Cornell Scale for Depression in Dementia or the Hamilton Rating Scale for Depression (HRSD) should be used.5
Mulrow et al found in a direct comparison of screening instruments used in adults that the two question screen (see Table 2), in conjunction with change from the patient's previous functioning, was as effective a screening tool as many of the longer ones and more efficient to administer.7 An inventory of symptoms outlined in the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) including the presence of sleep disturbance, anhedonia, low self-esteem, and appetite disturbance should be assessed in patients who answer affirmatively to at least one of the two question screen. The presence of two of these four symptoms daily for at least two weeks identifies 97% of patients with major depression.8
Differential Diagnosis of Depression
Symptoms of depression can be caused by commonly used medications such as glucocorticoids, oral contraceptives, propranolol, interferon, and possibly isotretinoin (Accutane®).5,9 Clinical medical illnesses such as hypothyroidism, Cushing's Disease, or vitamin B12 deficiency can present as depression. Appropriate physical examination and confirmatory blood work should establish the underlying diagnosis.
A major depressive disorder can also be an initial manifestation of other psychiatric disorders. Patients with psychotic symptoms or substance abuse are at higher risk for suicide and should have prompt and ongoing psychiatric evaluation.10
Associations between Physical Activity and Depression
Observational studies suggest an inverse association between physical activity and depression.11 Physical inactivity is a common characteristic among depressed persons, partially due to fatigue, lack of energy, and motivation. Exercise has, however, numerous psychological and emotional benefits for depressed exercisers, which include: 1) promotion of self-confidence as small, daily goals are met, 2) distraction from unpleasant thoughts, 3) creation of opportunities to positively interact with others, and 4) incorporation of a healthy coping strategy to deal with depressive symptoms.12
Longitudinal epidemiologic studies such as the NHANES series have shown that a high level of physical activity, even when adopted later in life is associated with a reduced risk of developing depressive symptomatology over time.13
Therapeutic Options for Depression
Pharmacologic treatment consisting of antidepressants alone or in combination with psychotherapy is efficacious and currently is the standard of care for patients with MDD.14 Such regimens may have undesirable side effects or there may be obstacles to the delivery of care such as limited therapist availability and insurance policy restrictions. Selective serotonin reuptake inhibitors (SSRIs) are generally the first line of antidepressant medication therapy, especially for patients with severe MDD. They mitigate symptoms in approximately 50-60% of patients, but have a latency of several weeks for optimal efficacy. Furthermore, only 30-35% of patients achieve remission (a return to baseline mood and functioning). Thus 65-70% of patients achieve only a partial response, which results in residual symptoms and impaired function with an increased likelihood of relapse. Such subsyndromal depressive symptoms that persist after the resolution of major depressive episodes are associated with more medical and psychiatric visits, emergency room use, psychiatric hospitalization, increased public assistance, disability benefits, suicidal ideation, and attempted suicide.15,16
Achieving remission requires the implementation of multiple strategies, including optimization of the dose and duration of antidepressant treatment, switching to a different antidepressant if undesirable side effects occur, or augmentation of a current antidepressant with additional pharmacotherapy, psychotherapy, or perhaps an exercise program. Augmentation strategies are beneficial in partial responders because they maintain current benefits from the initial treatment while additional pharmacologic or nonpharmacologic treatment is employed to achieve remission.17 An individualized exercise program, initiated concomitantly with medication or psychotherapy, may engage the patient more actively in treatment and offset the inherent latency as well as enhance and prolong the remission.
The prescription of exercise for the development and maintenance of both mental and physical fitness in women consists of activities to improve cardiorespiratory status (aerobic exercise) and musculoskeletal status (progressive resistance exercise). Aerobic exercise consists of activities that use large muscle groups in continuous rhythmic movements such as walking, hiking, jogging/running, dance, swimming, cycling, and rowing. In addition to aerobic workouts, weight lifting and flexibility exercises are also beneficial. The moderate-intensity physical activity recommended by the CDC and ACSM for 30 minutes most days of the week (5-7 days/week) is defined as an activity with an energy requirement of 3-5 metabolic equivalents, which for most healthy adults is equivalent to a brisk walk at 3-4 mph or stationary cycling at 50-100 watts.
The exercise plan can be matched to individual needs and preferences of patients. Adherence to the plan can be enhanced by ongoing professional support with a certified fitness professional (certified by a national organization such as the ACSM or the American Council on Exercise) during the initial weeks of the implementation of the exercise program on a weekly or twice weekly basis.18
Most healthy women, even if pregnant, can follow these recommendations with regard to improving their mental health. However, pregnancy is associated with profound anatomical and physiological changes; exercise prescriptions given to pregnant women must be customized to their individual clinical situations. There are also several absolute contraindications to aerobic and resistance exercise during pregnancy (see Table 3).19,20
Clinical Studies of Exercise as Monotherapy for Depression
Dunn et al conducted a placebo-controlled, randomized study of 80 adults (ages 20-45) to assess the effects of exercise monotherapy on patients with mild-to-moderate MDD.21 Subjects were randomized to either aerobic exercise at 17.5 kcal/kg/week (a public health dose [PHD] consistent with CDC/ACSM recommendations) vs. 7.0 kcal/kg/week (low dose [LD] equivalent to 20 minutes of exercise 3 days/week) vs. exercise placebo control (3 days/week flexibility exercises for 10 minutes) for 12 weeks in a supervised setting. Study patients in the PHD exercise group had a 47% reduction in the HRSD from baseline compared with a 30% reduction for LD and 29% for control after 12 weeks. This finding suggests the PHD exercise dose exerts a threshold effect for the treatment of MDD. A lower dose of aerobic exercise has an effect comparable to placebo.21
Penninx et al examined data from the Fitness, Arthritis, and Seniors Trial (FAST), which randomized a total of 438 persons 60 years and older (70% female) with known osteoarthritis and depressive symptoms to a health education control, resistance exercise, or aerobic exercise groups and assessed the effects on depressive symptoms (assessed by CES-D) and physical function at baseline and after three, nine, and 18 months.22 Both resistance (upper and lower body exercise repetitions with weights) and aerobic exercise (walking) programs consisted of three facility-based, supervised one-hour sessions weekly for three months followed by a 15-month home-based program.
Participants in the aerobic exercise intervention group reported significantly reduced (by 23%) depression scores over time (P < 0.001) compared to the control. The resistance exercise group decreased scores by 6%, but this was not significant compared to the control group. A separate analysis of subjects with the highest compliance rate with both exercise programs (79% for the resistance exercisers and 41-78% compliance for the aerobic group) showed a 28% reduction in depressive scores for the resistance group and a 24% reduction for the aerobic group compared to controls. The efficacy of resistance and aerobic exercise on physical function outcomes was separately analyzed and adjusted for race, age, sex, education, body mass index, and baseline scores. Patients in the aerobic exercise group had significantly lower disability and pain scores and higher walking speed over time (all P < 0.001) compared to the average differences in scores from controls of -9%, -12%, and +9%, respectively. For the resistance exercise group, patients had similar improvements for disability (P = 0.01) and pain (marginally significant with P = 0.07) but not for walking speed with average differences from controls of -7%, -5%, and 0%, respectively.22
Clinical Studies of Exercise as Augmentation to Depression Treatment
Blumenthal et al in the Standard Medical Intervention and Long-term Exercise (SMILE) study conducted a randomized, prospective, parallel-group study of 156 volunteers aged 50 years and older with DSM-IV criteria for MDD and a minimal HRSD score of 13.23 They were randomly assigned to either supervised aerobic exercise training, pharmacotherapy with sertraline, or a combination of medication and exercise for 16 weeks. The exercise group participants attended three professionally monitored training sessions per week for the study duration and were assigned heart rate (HR) training ranges of 70-85% based the maximal heart rate achieved during a baseline treadmill test. Each session included warm up and cool down exercises with 30 minutes of cycling, walking, or jogging at the target HR intensity. At the end of the study, after adjustment for severity of depression, all of the groups had similar remission rates for MDD (P = 0.67) with 60.4% for exercise group patients, 65.5% in the medication group, and 68.8% in the combination group. A total of 83 patients were diagnosed to be in remission at the end of this study.
A subsequent study by Babyak et al in which six-month follow-up data were available on 133 of the original 156 patients found that participants in the exercise group exhibited lower rates of depression (30%) than participants in the medication (52%) and combined groups (55%) (P = 0.028).24 More detailed study of the 83 patients who had been in remission at four months revealed that only 8% of the remitted patients in the exercise group had relapsed six months later (10 months after study initiation) compared with 38% in the medication group and 31% in the combination group.
Interestingly, the combination of exercise with medication conferred no additional advantage over either separate treatment. This paradoxical effect may be secondary to a bias from the lack of blinding since several patients in the combination group spontaneously reported that the medication interfered with the exercise program.24
Knubben et al conducted a RCT of 38 patients (55% female) hospitalized for treatment of a major depressive episode (according to DSM-IV criteria) who were stratified according to the type of antidepressant medication they received at the time of study enrollment.25 The patients were then randomized to 10 days of endurance exercise intervals (treadmill walking five times for 3 minutes at target HR of 80% predicted maximum alternating with five 3-minute half-speed intervals) vs. placebo control (30 minutes daily of light stretching exercises for major muscle groups). After the intervention, the CES-D scores showed a statistically significant reduction in the endurance training group (41%) compared to the control group (21%) (P = 0.01). There was also a nonsignificant trend toward shorter hospital stays for the training group vs. the placebo group.
Trivedi et al are currently conducting a randomized controlled trial, Treatment with Exercise Augmentation for Depression (TREND), which is designed to evaluate aerobic exercise as an augmenting strategy in patients with unremitted MDD after an adequate treatment course with an SSRI.26 The objective is to compare the efficacy of a 24-week course of SSRI augmented with a public health dose of exercise vs. a low dose of exercise (4 KKW) in bringing about a remission in MDD. The second objective is to compare functioning and quality of life of participants treated with both exercise intensities.
Overall, patients in the clinical studies reported no negative effects of exercise (e.g., muscle pain, stiffness, or fatigue) during the course of the supervised exercise programs, though such effects are possible if the patients do not perform an adequate warm up and cool down or are not judicious about performing exercise in extremes of temperature without adequate clothing, hydration, footwear, or attention to proper form and technique.
The FDA has added a black box warning statement regarding a possible increased risk for suicide for many of the SSRIs, SNRIs, and bupropion.27 Many antidepressants are either classified as Class C category or D (paroxetine) for use in pregnancy.28 A recent large observational, case-control study by Louik et al showed an a association between the use of the SSRI sertraline and fetal omphalocele (a birth defect in which the intestines remain outside the abdominal wall) and septal heart defects, as well as an association between the use of paroxetine and fetal right ventricle cardiac defects. Although the overall absolute risks to the fetus are very small given the rarity of these conditions and the small numbers of exposed affected infants in this study, these are still issues for depressed pregnant women and their doctors to discuss.29
As an augmentation strategy, exercise has many ancillary health benefits, especially when initiated simultaneously with first-line therapy for MDD. Regular exercise has a positive effect on mood as well as overall physical function and general health. An exercise routine can offer patients choice, structure, and a chance to assess progress as treatment proceeds. The use of exercise as a treatment modality avoids the possibility of medication-induced side effects and drug interactions, which can complicate antidepressant therapy, especially for pregnant women.
All patients diagnosed with MDD should be considered for an exercise program either as concomitant treatment with medication or psychotherapy or as an augmentation strategy in patients who do not adequately respond to medication or psychotherapy alone. Because women are more vulnerable to the development of depression throughout much of their lifespan, incorporation of a regular regimen of exercise is an important lifestyle modification that is essential for optimal physical as well as mental health. Since depression is an independent risk factor for several disease states such as coronary artery disease, stroke, and diabetes, patients with MDD who adopt and maintain an exercise regimen are likely to gain multiple health and functional benefits beyond the amelioration of depressive symptoms.
Patient input should be sought with regard to the type of exercise regimen with careful instruction about exercise duration, intensity, and frequency. The progress of each patient should be assessed and documented regularly with regard to compliance, training efficacy, problems, and effect on mood.
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