The Effect of Exercise on Depressive Symptoms in Unmedicated Patients
The Effect of Exercise on Depressive Symptoms in Unmedicated Patients
This trial investigates the biological effect of exercise training on depression.
 Participants will randomly be allocated to either a aerobic exercise group performing
 exercise on stationary bikes or a group performing low-impact exercise such as stretching
 exercises. Both groups will attend sessions three times per week for 3 months. Before and
 after the intervention the investigators will measure the severity of depression using the
 Hamilton depression rating scale (HAM-D17).
The yearly incidence of depression is estimated to be 3-5%, with a lifetime prevalence of 17%
 in western societies.Furthermore, Major depression is associated with increased mortality
 from somatic disorders such as cardiovascular disease, stroke, and endocrinological diseases.
 WHO and others stated that unipolar depressive disorders was the leading cause of disease
 burden in the western world in 2002 accounting for 9,0% of all disability adjusted life
 years. Projecting the current development in disease patterns unipolar depression is expected
 to be the second highest cause of global disease burden in 2030. With remission rates of
 approximately 50% using medical antidepressant therapy, the search for alternative or
 augmentation therapy is a key issue in depressive research.

 In 2001 a meta-analysis concluded that the effect of exercise training could not be
 determined due to lack of good quality research. The authors found that the majority of
 trials were without blinded outcome assessment, lacked intention-to-treat analysis, and most
 had short follow-up. In this context, one of the authors in 2004 launched a pragmatic
 randomized controlled trial investigating the effect of exercise training on depressive
 symptoms - the DEMO trial(10). The 165 included participants were randomized to either
 aerobic, non-aerobic, or relaxation training in a four-month training programme. The primary
 outcome was the Hamilton depression rating scale (HAM-D17) and data collection ended June 1st
 2007. After four month intervention there were no overall effect of exercise on depressive
 symptoms; the estimate at four month between non-aerobic and relaxation training was -0.9
 (95%CI: -3.2 to 1.4) and between aerobic and relaxation training was 0.99 (95%CI: -1.3 to
 3.3). These results do not support any biological effect of exercise on major depression.
 However, the majority (115/165) of patients had received antidepressant medication for more
 than six weeks at baseline thus the lack of a positive result could partly be explained by a
 treatment resistant group. A subgroup analysis of patients not medicated at baseline
 estimated the effect between non-aerobic and relaxation training to -1.7 (95% CI: -6.0 to
 2.5) and between aerobic and relaxation training to 0.3 (95% CI: -3.9 to 4.6). The number of
 patients in this important sub-group, means that any conclusion on non-medicated patients is
 underpowered. In addition the literature suggest that the possible effect of exercise on
 depression is frequency and intensity related. In the DEMO trial the participants only
 trained twice pr. week.

 This result from the DEMO trial is somewhat in contrast with the abundant publications of
 animal research showing that exercise stimulates hippocampal neurogenesis and in theory
 improves depressive symptoms and cognitive skills. The hippocampus is involved in cognitive
 functions such as memory and learning processes as well as regulation of the hypothalamus. In
 depression and neurodegenerative diseases such as Alzheimer and Parkinson Disease, which
 share features like impaired memory and learning abilities, the hippocampus is characterized
 by atrophia. In addition to a decreased hippocampal volume, brain imaging studies have
 observed reduction in volume of prefrontal cortex of depressed patients, though postmortem
 studies have less evident results.

 Prospective studies on healthy adults suggest that exercise has a beneficial effect on
 cognitive functions or reduces an age related decline in these. Research on rodents suggest
 that an increase in memory and learning in relation to exercise is mediated through an
 up-regulation of brain derived neurotrophic factor, which has the ability to stimulate
 synaptic-plasticity.

 Interestingly the exercise induced cell proliferation is inhibited by peripheral blockade of
 either insulin growth factor 1 (IGF-1) or vascular endothelial growth factor (VEGF), which
 could indicate that the exercise induced neurogenesis is dependent of IGF-I/VEGF. The role of
 IGF-I in neurogenesis is supported by studies showing an increase in new hippocampal cells in
 sedentary animals given IGF-I infusion. Fibroblast growth factor 2 (FGF-2) also increases in
 the rat hippocampus in response to exercise, however FGF-2 injections into the adult rat
 hippocampus do not increase neurogenesis. The importance of IGF-I in neurogenesis is
 emphasized by the fact that homozygous IGF1 -/- mice at the age of to months had reduced
 brain weight affecting all major brain areas, especially the volume of the dentate gyrus(33)
 in contrary to BDNF null mutant mice that did not show major hippocampal deficits.

 Furthermore, it has been shown that antidepressant treatment up-regulates sBDNF in humans and
 a relationship between genetic variants of BDNF locus and depression have been implied. On
 this background it could be argued that low BDNF levels contribute to the pathophysiology of
 depression, and that exercise has a beneficial effect on cognitive function in patients with
 depression through an up-regulation of IGF-1, VEGF and BDNF.

 The effect of exercise on hippocampal neurogenesis and cognition have recently been supported
 in a human study measuring cerebral blood volume in the dentate gyrus by magnetic resonance
 imaging.

 On this background the investigators have designed this randomized trial comparing aerobic
 exercise and no treatment in light to moderate depression. This trial will employ adequate
 methods of reducing bias such as centralized randomization, blinded outcome assessment, and
 analysis according to the intent-to-treat principle. In addition the investigators plan to
 include a healthy control group to establish any differences in biological response to
 exercise

 Objectives The primary objective for the DEMOII superiority trial is to assess the beneficial
 and harmful effect of aerobic exercise versus stretching exercise in patients diagnosed with
 moderate depression according to ICD-10. The primary outcome will be an assessment of
 depressive symptoms as measured with the Hamilton Depression Scale (HAM-D17), by outcome
 assessors blinded to intervention group.

 The secondary objective is to measure the effect of exercise on neurogenesis in the
 hippocampal region by cerebral blood volume. The assessors will be blind to participation
 status.

 Tertiary objects is to evaluate cognitive skills, brain derived neurotrophic factor, insulin
 like growth hormone 1, vascular endothelial growth factor, and other variables associated
 with the development of cardiovascular disease (interleukin 6, maximal oxygen uptake, BMI,
 tumour necroses factor alpha and blood pressure).
Inclusion Criteria:

 1. 18 - 60 years

 2. Major depression according to DSM-IV

 3. Living within 30 km of training facilities

 4. Able to read and understand informed consent

 Exclusion Criteria:

 1. Recreational or current drug abuse

 2. Having used antidepressant medication within the last 2 months

 3. Contraindications to physical exercise

 4. Recreational exercise> 1 hour per week

 5. Medication for diabetes, hypertension, or any kidney disease

 6. Suicidal behaviour (ham-d17 item3 > 2)