Antidepressants and psychotherapy
Treatment frequently includes prescription of antidepressants. However, the effectiveness of such treatment may be limited because of poor compliance and limited effectiveness. A recent analysis of data of the US Food and Drugs Administration, showed relatively small drug-placebo differences in antidepressant efficacy [
2]. Other disadvantages of antidepressants are unpleasant side effects and increased risk of hypertension in depressed patients combined with Diabetes Mellitus type II (DM II) [
3,
4].
A systematic review of randomised controlled trials into effectiveness and cost-effectiveness of brief psychological treatment for depression showed that some forms, especially cognitive-behavioural based approaches, were beneficial in the treatment of outpatients [
5]. A meta-analysis, regarding a mostly adult population, found a favourable outcome for a combination of psychotherapy and pharmacotherapy compared to psychological treatment alone for depression in the short-term [
6]. A recent meta-analysis examined whether the quality of the studies investigating psychotherapy for adult depression was associated with the effect-size found in these studies [
7]. It showed that the effects of psychotherapy for adult depression have been overestimated in meta-analytical studies. The authors stated that the effects of psychotherapy are much smaller than is assumed.
The traditional treatment strategies, medication and psychotherapy, are still not ideal and a new intervention, exercise, focusing on a different psychopathological mechanism of depression is needed.
Exercise
Exercise is a potential alternative low-cost therapy, but more studies are needed to define the place of exercise in a stepped care program for depression [
8]. Exercise is relatively safe and has less negative side effects than antidepressants. Obviously, exercise has also many beneficial effects on physical health [
9,
10], and is expected to have additional advantages in depressed patients who suffer from a combination of mental and physical problems, such as pain complaints or increased risk of cardiac morbidity. Exercise is suitable for most individuals, participating in an exercise program promotes social integration and successful adaptation can increase self-esteem. Finally, exercise may reduce the negative side effects of antidepressants, such as fatigue, thus increasing compliance in medication use.
Scientific evidence for the efficacy of exercise
Recent reviews and meta-analyses suggest that exercise leads to improvements in depressive symptoms [
11,
12]. Following the cumulative evidence from prospective cohort studies and RCTs, exercise has proven
protective benefits for several aspects of mental health in general and for symptoms of depression in particular. However, study results on the
curative effect on a present depression are conflicting. A recent Cochrane meta-analysis [
13], updating an earlier systematic review in 2001 by Lawlor and Hopker [
14], concluded that the statistically weak findings didn't support the efficacy of exercise in the treatment of depression. Methodological weaknesses of the trials were identified, including the lack of treatment concealment, intention to treat analysis and a clinical interview to confirm the diagnosis of depression.
Rethorst et al. [
15] argue that the earlier mentioned meta-analysis of Lawlor and Hopker suffered from incomplete research data and a lack of moderating variable analysis. The meta-analysis by Rethorst et al., with 58 RCTs included, calculated an overall effect size of -0.80 for the effects of exercise on depression. The recommendation of both Lawlor et al. and Rethorst et al. is that further, conclusive research is still needed into the use of exercise for depression. Exercise as an adjunct to recognised treatments, such as psychotherapy and/or medication, should also be studied. Furthermore, follow-up research is needed that examines the sustainability of the effects after exercise therapy has ended.
Very recently, Krogh et al. [
16] performed a systematic review and meta-analysis in which only 13 trials were selected because of the stringent selection criteria used (i.e. recording clinical depression according to any diagnostic system, adequate allocation concealment, blinded outcome and intention to treat analysis). Besides an inverse association between duration of intervention and the magnitude of the association of exercise with depression, the effect size was 0.40 for the pooled effect sizes of 13 studies and 0.19 for the selected three high quality design studies. The authors concluded that large high quality design studies are required. The recommendations from the three meta-analysis cited above are integrated in the design of the EFFORT-D study.
Besides reduction of depressive symptoms, exercise can be useful for other treatment indications, such as cardiovascular condition, metabolic syndrome, pain modulation and the immune system. Depression is associated with
cardiovascular disease. It is an established risk factor for mortality after acute myocardial infarction. A recent meta-analysis of cohort studies also shows the aetiological and prognostic effects of depression on coronary heart disease (CHD) [
17]: the pooled relative risk of depression on future coronary heart disease was 1.80. Another meta-analysis shows an overall relative risk of dying in depressed subjects of 1.80 compared to non-depressed subjects, with no major differences between men and women [
18]. The increased relative risk on mortality was also found in subclinical forms of depression.
These findings suggest that exercise may also be prescribed to improve the cardiovascular condition and prevent future heart disease. Depressed patients should also be more closely monitored regarding cardiovascular parameters.
The body of evidence showing an association between depression and
obesity and metabolic deregulation is growing. Recent meta-analysis of cross-sectional studies in the general population found a significant positive association between depression and obesity, affecting women more than men. A reciprocal risk relation between obesity and depression [
19,
20], and an U-shaped, non-linear trend in the association between BMI and depression was found [
21]. The Dutch NESDA study [
22] shows an association between severity of depression and unfavourable cholesterol high-hdl/low-ldl concentration [
23]. This tendency for a higher risk of depression on metabolic syndrome, in which various cardiovascular risk factors appear, emphasizes the need of careful screening on this parameters [
24], and exercise could positively influence these parameters.
A recent meta-analysis of studies into cytokines in depressed patients [
25] showed that depression and an
activation of the immune-system do co-exist. Both tumornecrosisfactor-α (TNF-α) and interleukine-6-concentration (IL-6) were significantly raised and C-reactive protein (CRP) was linearly associated with several conventional risk factors and inflammatory markers [
26]. The relevance of CRP however still remains controversial [
27]. Therefore, measurement of CRP blood levels in an intervention exercise study could contribute to a better understanding of the clinical importance in relation to heart condition.
The reciprocal relation between
pain and depression has been reported in several studies where Major Depressive Disorder (MDD) was associated with chronic pain (> 6 months) and nearly 50% of patients had at least one chronic painful physical condition [
28,
29]. The duration of depressive symptoms was found to be prolonged in the presence of chronic pain. The therapeutic prognosis of co-morbid pain and depression is poor and the pain-depression association was found to be stronger in men than in women and in older adults compared to younger. Productivity was decreased when depression and pain existed in a co-morbid pattern [
30].
Quality of life and cost-effectiveness
Systematic evaluation of cost-effectiveness and quality of life, including life-events in the treatment of depression, may contribute to the development of more evidence based care models [
31], for instance by disease management.
A population sample study showed that, in patients with a remitted MDD, the quality of life was lower than in the general population. A higher depressive severity was associated with a lower quality of life. Ten Doesschate et al. argue that, even in depression in remission, attention is needed for the quality of life, and above that, residual symptoms must be treated aggressively to achieve a higher quality of life [
32].
Summarized aims and hypothesis of EFFORT-D
The main objective of the study is to assess the effectiveness of exercise therapy (running therapy (RT) or Nordic walking (NW)), in addition to usual care, on depression in adult patients. We hypothesize that adding exercise therapy to usual care will result in a larger reduction in depressive symptoms (as measured with the Hamilton Rating Scale of Depression, (HRSD)) during a 6 month treatment program as well as at 6 months follow-up, compared to usual care without exercise therapy.
Secondary aims are to assess the effectiveness of exercise therapy (RT or NW) on the following outcome measures: 1) Cardiovascular and metabolic risk parameters as fitness (VO2 max, grip strength), BMI, waist circumference, body composition, blood pressure, fasting blood glucose, cholesterol HDL/LDL ratio and CRP, 2) Co-morbid symptoms of anxiety and pain 3) Quality of life, and 4) Cost-effectiveness.
To assess whether there are subgroups of patients who show a larger or less effect of exercise therapy on depression, subgroup analysis will be conducted differentiated on demographic variables (age, sex) and level and type of depression based on the HRSD, personality traits and level of fitness.