Study design and setting
This will take the form of a randomised clinical trial (Fig. 1) to be conducted at health centres in the Albacete Health Area (Spain).
Characteristics of participants
The target population will be subjects aged over 65 years with clinical criteria of a “clinically significant” depressive episode. We intend to use the ICD-10 criteria, which require a minimum of 4 out of 10 symptoms, including at least 2 of the following 3, namely, depressed mood, anhedonia and loss of energy. The 10 symptoms include: depressed mood; loss of interest or pleasure; loss of or increase in weight; insomnia or hypersomnia; agitation or slowing of movements; fatigue or loss of energy; feelings of inadequacy or guilt; poor concentration; poor self-esteem; and recurrent thoughts of death. The duration of the episode must be a minimum of two weeks.
The inclusion criteria will be the following: subjects with the above criteria of mild or moderate depressive episode belonging to the participating health centres. The exclusion criteria will be: physical or mental limitations that bar participation in the study; contraindications for doing physical training (unstable angina, arterial hypertension with systolic blood pressure > 200 or diastolic blood pressure > 110 mmHg, orthostatic hypotension > 20 mmHg accompanied by symptoms, left ventricular outflow tract due to severe/moderate aortic stenosis or obstructive hypertrophic myocardiopathy, supraventricular or ventricular arrhythmias with haemodynamic deterioration not controlled with treatment, decompensated heart failure, third-degree atrioventricular block without pacemaker implantation, and important orthopaedic problems); patients with severe depressive disorder (important interference in social or occupational functioning, psychotic symptoms, active suicidal ideation or situations of personal abandonment); depressive disorders due to a medical or substance-induced disease, depressive disorders in partial or total remission and unspecified depressive disorders; subjects with evidence of a high level of physical activity according to the International Physical Activity Questionnaire (IPAQ); and patients taking antidepressant drugs.
In all participants, initial physical condition will be measured by determining their resting heart rate with a heart-rate monitor and their submaximal heart rate, calculated from the maximum heart rate (220 - age) on an exercise bicycle (70–85% of maximum heart rate at a constant workload and speed for 6 min), electrocardiogram, and flexibility (using the sit and reach test).
Sample size
Based on an estimated positive response in 75% of participants (a reduction of at least 50% in pre-treatment scores on the Montgomery-Asberg Depression Rating Scale/MADRS) in both the intervention (supervised physical exercise) and control groups (antidepressant therapy), an alpha risk of 0.025, a beta risk of 0.20, a non-inferiority margin of 15% (maximum difference of response for it to be deemed not inferior to the experimental treatment) and a percentage loss of 20%, a total of 156 patients will be required in each group (n = 312).
Participants will be consecutively selected at 20 family medicine clinics belonging to 3 health centres.
Interventions
All participants will be observed over a period of 6 months, with assessments being made at baseline and then again at 15 days and 1, 3 and 6 months. In any case where symptoms worsen, with the patient’s clinical profile progressing from mild or moderate to severe depression, the patient will be referred to a mental health department, which will then decide on the course of treatment to be followed. The trial will be deemed to have ended in the following circumstances: completion of the observation period; patient withdrawal; or withdrawal of informed consent.
Patients will be included in the intervention group (physical exercise) or the control group (antidepressant therapy) by simple randomisation generated by a computer software programme. The randomisation sequence will be concealed throughout the recruitment period.
With respect to antidepressant drug therapy, the NICE guideline holds to the general view that there is little difference among the various antidepressants in terms of efficacy. As a result, patients’ physicians will decide on the most suitable drug in every case.
It will be suggested to subjects assigned to the intervention group that they participate in a physical exercise programme consisting of two 1-h sessions per week for a period of 6 months (a total of 48 sessions in groups of 10–12 persons), to be given by sports coaches and held at sports facilities.
The educational content of physical activity, based on the recommendations of the American College of Sports Medicine, will include the following: how to increase physical effort in activities of daily living; how to perform regular exercise adapted to one’s age and individual condition, to help maintain ideal body weight; how to do exercise or aerobic sport; how to warm up; how to perform stretching exercises (musculotendinous stretching); how to conduct a period of cooling-down exercises and relaxation; and how to approach muscle-strengthening and flexibility training.
Participants will be shown how to increase their levels of physical activity in daily life, with the idea that at least 30 min of average to moderately intense activity should be performed throughout the entire follow-up period on an almost daily basis. The physical exercise programme will include: aerobic exercises (goal: a minimum of 30 min of aerobic activity of moderate intensity five days per week); muscle-strengthening exercises (goal: a minimum of two non-consecutive days per week, with 10–15 repetitions of each exercise at a moderate-to-high level of intensity); flexibility exercises (goal: at least twice per week for at least 10 min); and balance-strengthening exercises (goal: at least three times per week).
The educational intervention will be conducted from a behavioural standpoint, aimed at achieving patients’ understanding and acceptance, and bringing about a shift towards improvement in their habits. The following will be required: a baseline for adopting and maintaining lifestyle changes; patients’ commitment to and an active role in the process; and a linear design, with consecutive phases of learning adapted to needs.
Study variable
The principal outcome variable will be a reduction in depressive symptoms: a fall in the pre-treatment 10-item Montgomery-Asberg Depression Rating Scale (MADRS) and 15-item Geriatric Depression Scale (GDS) scores, with these scales being administered at baseline and subsequently at 15 days and 1, 3 and 6 months.
At baseline, the following variables will be assessed in all participants: health problems (as classified by the International Classification of Primary Care/ICPC-2); drug use (Anatomical Therapeutic Classification); toxic habits (consumption of tobacco, grams of alcohol/week and other substances); history of depressive disorders and use of antidepressant drugs; and socio-demographic characteristics (gender, age, educational level, social class based on occupation, and marital status).
At baseline and again after 15 days, 1, 3 and 6 months, the following variables will be assessed in all participants: level of physical activity (with the patient being classified as inactive, active or partially active, using the IPAQ); self-perceived health status, using the EQ-5D questionnaire (evaluating the dimensions of mobility, self-care, usual activities, pain/discomfort and anxiety/depression, as well as a visual analogue scale of self-reported health, scored from 0 to 100); anthropometric measurements (weight, height, body mass index and waist circumference); blood pressure using an automatic digital blood pressure arm monitor; and presence of adverse events.
The following variables will be obtained in the intervention group: participants’ attendance at physical-exercise programme sessions and possible reasons for withdrawal; degree of satisfaction and acceptance of the educational programme (scale of 1 to 5 points, ranging from “very dissatisfied” to “very satisfied”); and compliance with exercise recommendations using a simple tool based on self-recording of daily physical activity (this record will be used to assess the frequency, intensity, duration and type of exercise performed).
In patients who receive treatment with antidepressant drugs, the following will be assessed: type of antidepressant (N06A Group Anatomical Therapeutic Classification); changes in treatment across the follow-up period; adherence (Morisky-Green questionnaire); and treatment satisfaction (Satisfaction with Antidepressant Treatment Questionnaire - Cuestionario de Evaluación de la Satisfacción con el Antidepressant treatment/ESTA).
The cost-effectiveness analysis will take into account the direct costs of both the exercise and antidepressant-treatment programmes, including staff expenses, medication, follow-up visits and monitoring.
Statistical analysis
All statistical analyses will be performed on a blinded basis so as to ensure that the respective subjects’ group affiliations remain unknown to the assessor. After the preliminary stages of debugging, exploratory analysis, and variable categorisation or transformation have been completed, variables of interest, stratification of variables and potential confounding at baseline in the two groups will be compared, and the homogeneity of the study variables’ baseline values will be checked. An intention-to-treat analysis will be used to calculate the following parameters with their corresponding confidence intervals: absolute increase in benefit; relative increase in benefit; and number needed to treat.
The trend in the parameters of interest in the two groups will be described and compared (comparison of proportions and means in independent groups). An analysis by subgroup will be performed according to different variables, including sex, intensity of physical activity, adherence to recommendations, etc.
Finally, the effect of the intervention in terms of reducing depressive symptoms will be estimated using a logistic regression model, with statistical adjustment between possible confounding and interaction terms. The model will be interpreted on the basis of the statistical significance of the coefficients and the value of the odds ratios of the explanatory variables.