EFFORT-D is a randomized controlled trial, designed along the Consort-statement guidelines [33
], in which outpatients as well as hospitalised depressed patients will be included and randomized in two groups: a control group or an intervention group (see flow chart in
Figure ). The control group outpatients receive usual care (i.e. anti-depressive medication and/or cognitive and/or interpersonal therapy). The control group inpatients have their usual treatment program (consisting of pharmacotherapy and/or sociotherapy, psychotherapy, psycho-education and indicated nonverbal therapies) and are allowed to exercise at low intensity as part of their daily program.
The intervention group receives 6 months supervised exercise therapy for 1 h a week and is instructed to train unsupervised for 1 h a week during this period (combined about 40 exercise sessions during the intervention period). Both training sessions follow an individualised intervention protocol and are in addition to the usual care program.
Included and randomised patients in the intervention group are invited to take part in Running Therapy (RT). Patients will only be referred to Nordic Walking (NW) in case of clear medical contra-indications against RT, such as muscular-skeleton problems, or if patients have a strong dislike for running which obstructs participation and compliance. The study will run for 27 months, with an 18 months inclusion period during which patients are recruited and randomized. There are four measurements for each patient: at baseline (T0), halfway the 6 month intervention period (T3), at the end of the intervention period (T6), and at follow up, 12 months after baseline (T12). In Table the timetable is shown.
The study population consists of adult patients diagnosed by a clinician with a depression or bipolar disorder with depressive mood, who are or will be treated in GGZ Centraal Mental Hospitals or Symfora-Meander Hospital. Patients aged between 18-65, with a DSM-IV diagnoses of unipolar, bipolar depression or seasonal depression not responding to light therapy (10 sessions of 1 h), a baseline Hamilton Rating Scale of Depression (HRSD) score ≥14 and (will be) treated for depression, are included.
Criteria for exclusion are: a depression as part of a psychotic disorder, schizophrenia, schizoaffective disorder or obsessive compulsive disorder, anxiety disorder as primary diagnosis, patients in long stay facilities (including day-care) or with complex pathology and treatment resistant depression (inpatients, treated by protocol more than 6 months with no remission); patients with significant cardiovascular disease or other medical conditions as contra-indication for exercise therapy, walking and/or running such as joint and hip pathology; alcohol/drugs dependence as a primary diagnosis, pregnancy, high suicide risk with treatment on a closed ward, or already being physically active on a regular basis (2-3 times a week on a high-intensity).
Following earlier RCTs [34
] it is expected that patients in the usual care group (controls) will respond with a mean reduction in HRSD of six points. Adding exercise to usual care is expected to result in a decline of at least eight points in HRSD score (thus two extra points). To detect this difference, with an α (two-tailed) of 5% and a power (1-β) of 80%, using two equal groups and a standard deviation of 5 points, 100 patients are needed in each group. Taking 30% drop-out into account, 140 patients have to be included in each group.
Procedures and study instruments
Names of eligible patients with their registration number of the electronic patient file (EPD) are provided by the diagnosing psychiatrists to the research assistant, who will make a first check on inclusion and exclusion criteria, informs the participants and asks them to join the study. Written informed consent will be obtained according to prevailing legal requirements before the start of the study. Eligible patients, HDRS ≥ 14 as primary outcome measure, perform the Åstrand submaximal cycling test, physical measures and fill out the questionnaire, after which the participants are randomized. All outcome parameters measured during baseline will be repeated three, six and 12 months after baseline, except for the blood samples (only at T0 and T6). Height is measured according to protocol (Seca 214, Hamburg, Germany) and a bio-impedance scale is used to measure weight and body composition (Omron HBF-510, Omron Healthcare Europe BV, The Netherlands). Waist circumference is measured twice with a tape measure (Seca 201, Hamburg, Germany) at the midpoint between the lower border of the ribs and the upper border of the pelvis. Systolic and diastolic blood pressure are registered twice at rest, using an electronic blood pressure meter (Omron M6 comfort, Omron Healthcare Europe BV, The Netherlands) with an adequate cuff size. Grip-strength is tested according to protocol using a hydraulic hand dynamometer (Jamar J00105, Sammons Preston Rolyan, Bolingbrook, USA). The submaximal Åstrand test [35
] will be performed on a stationary bicycle ergometer (Examiner, Lode BV, The Netherlands) and the mean heart rate of the last 2 min of the test will be used to estimate the VO2
max. Heart rate during this test is registered by a heart rate monitor (Polar RS 800, Electro Oy, Finland).
At each measurement moment the participant will be asked to fill out a digital questionnaire containing the following instruments:
Demographics and personal life events
Socio-demographic data are collected using standard questions on age, sex, marital status, ethnicity and household composition. Socio-economic variables include highest education and income. Personal history is evaluated by the Life Events Questionnaire (LEQ), a 12-item inventory-type questionnaire in which subjects mark the exposure to negative life events such as unemployment, separation from a partner and death of a close family member which have occurred in the past year [36
Mental and physical health and its consequences
The Hamilton Rating Scale of Depression (HRSD) measures depression with a 17-item list performed by trained interviewers [37
]., using the Dutch translation of the version of Bech et al. [38
], in which the items of depressive symptoms are extensively operationalised and this version is often used in international research [39
The Inventory of Depressive Symptomatology - Self-Reported (IDS-SR) measures the severity of depression with a 30-item self-report list [40
]. It has good responsiveness to change and is more sensitive for atypical depressive criteria than the HRSD. History of depression is evaluated by a single question into the number and duration of depressive episodes for which treatment was necessary.
Bearableness of depression is measured with a visual analogue scale (VAS) ranging from 0 (very unbearable) to 100 (very well bearable). Anxiety is measured by the Beck Anxiety Inventory (BAI), a 21-item multiple-choice self report inventory that measures the severity of generalized anxiety and panic symptoms in adults and adolescents [41
Pain complaints are evaluated with the Graded Chronic Pain Scale (GCPS) [42
], a 7-item scale measuring aspects of pain, physical ability and social interference, resulting in a 5-class hierarchical scale ranging from 0 (no pain problem) to IV (high disability/severely limiting). Next to the GCPS, bearableness of pain is evaluated with a VAS-scale ranging from 0 (very unbearable) to 100 (very well bearable).
Other secondary outcomes are disability during the last 30-days associated with both physical and mental problems and is measured by a shortened version of the World Health Organisation - Disability Assessment Schedule II (WHO-DAS-II) [43
], resulting in a disability score ranging from 0-100 with a higher score reflecting greater disability. Quality of life data are collected using the EQ5D [44
], a standardized instrument for describing and valuing health related quality of life.
Subjective health is evaluated by a visual analogue scale ranging from 0 (the worst imaginable health condition) to 100 (the best imaginable health condition).
Health care use and work productivity are evaluated by the Trimbos/iMTA Questionnaire for Costs associated with Psychiatric Illness (TIC-P), a 29-item list which focuses on establishing costs related to loss of productivity at work and health care utilization [45
Variables expected to modify the effect of the intervention
Personality, as a possible effect modifier, is measured at baseline by the NEO-PI-R, a 60-item validated questionnaire measuring the five domains of personality including neuroticism, extraversion, agreeableness, conscientiousness and openness to experience [46
Confounders: Lifestyle behaviours
Self-reported level of physical activity is assessed by means of the validated Short QUestionnaire to ASsess Health enhancing physical activity (SQUASH), a 12-item questionnaire which evaluates the frequency and duration of physical activities in the domains of work, domestic and leisure time [47
]. Tobacco and alcohol intake is measured with a standard single question on the frequency of use per day.
Additional measures in the intervention group
The Profile of Mood States (POMS) registers participants' mood after a running session for in total three times during the intervention period (at the beginning, halfway and at the end). The Dutch shortened version of the POMS [48
] consists of 32 items divided over seven subscales including tension, depression, anger, fatigue, vigour, positive and negative affect.
At regular intervals participants score their exertion on a Borg-scale ranging from 6 (very, very light) to 20 (very, very severe) [49
]. At the end of the intervention period, or when participants dropped out of the RT or NW therapy, a short questionnaire is administered evaluating their satisfaction and experience with the intervention.
Randomisation, blinding and treatment allocation
Randomisation takes place at every location separately. This way, every location will have an equal distribution of participants between the intervention and control group. The SPSS random generator (SPSS version 14.0) [50
] will be used to allocate patients. Ten closed envelopes with allocation numbers are presented to the participants. They choose an envelope, after which the research assistant tells the patients in which arm of the study they are included. Evaluators of the main outcome measure (HRSD) are blinded for group allocation and are trained regularly for inter-rater reliability. All other measures will be evaluated by a research assistant, who is not blinded for group allocation.
The exercise sessions will take place twice a week (40 sessions in total): once a week a supervised group session is offered and once a week the patient does an individual training, with clear instructions beforehand and an evaluation at the beginning of the next supervised session. Each supervised session, in which the trainers are working according to a standardized protocol, lasts one hour, of which 30 min are spent running (RT)/Nordic walking (NW). The remaining time is spent on warming-up and cooling-down. Each patient follows an individualised intervention protocol with a gradually increasing training intensity. The goal is to achieve a 30 min period of continuous running in the last sessions (two times a week 30 min continuous aerobic exercise at least 60% of the maximal heart rate). The NW program follows a comparable progressive schedule with increased time spent Nordic walking with high intensity.
Intensity in RT as in NW is monitored by the instructor during every supervised session by counting the heart rate and three times during the intervention period by electronic registration (Polar RS 400, Electro Oy, Finland). The control group receives usual care for depression in accordance with the revised Dutch guideline [51
] and are advised to exercise regularly. Hospitalised and day-care patients in the control group are supposed not to participate in organised high intensity aerobic exercise during the intervention period. Only low-intensity activity psycho-motor therapy is allowed.
Compliance and withdrawal
In order to improve compliance during the intervention period, a protocol will be followed concerning missed exercise therapy sessions by participants. This protocol includes: 1) active approach by the exercise instructor in case of no show, and 2) encouragement of other participants to contact each other in case of no show. Participants can withdraw at any time for any reason without any consequences. Also, the investigator can decide to withdraw a participant from the study for urgent medical reasons. Participants who withdraw from the intervention will be asked the reason(s) for drop-out but will be retained in the study for the intention to treat analysis.
Comparability of the intervention and control groups will be examined for the baseline measurements. If necessary, analyses will be adjusted for baseline differences. The primary analysis of the data set will be according to the 'intention to treat' principle. A secondary 'per protocol' analysis will be done taking into account the level of compliance and the amount of exercise during the intervention period. Usual daily physical activity, tobacco smoking and alcohol intake will be treated as confounders.
Differences in remission rates (and other categorical outcomes) between the experimental groups are examined by contingency table Chi-square statistics. Differences in mean scores on continuous outcomes (e.g. HRSD) between the intervention groups are examined by analysis-of-variance.
Ethical principles and safety
The study has been designed and will be carried out in accordance with the principles of the Helsinki Declaration (Edinburgh, Scotland Amendment, October 2000). The study protocol has been approved by the Medical ethical committee for mental health (Metigg Kamer Noord).