An interventional study of Nature-Based Combined Exercise Program and Indoor Combined Exercise Program in Major Depressive Disorder (MDD), sponsored by University of the Basque Country (UPV/EHU). Not yet recruiting at 1 site in Spain. Open to participants aged 18 Years to 75 Years. Per ClinicalTrials.gov, last updated 2026-11-12.
Sponsored by University of the Basque Country (UPV/EHU) · Not applicable, Interventional, and Treatment
Among 92 studies in Depressive Disorder, Major with a site in Spain — 27 open to participants now, 28 under way, 11 of them phase 3. Depressive Disorder, Major · Spain.
Among the 92 studies in Depressive Disorder, Major with a site in Spain, this one is the 41st largest by planned enrollment of the 77 interventional ones that give a count, is the only one that started in 2027, is one of 19 with no phase, reaches primary completion later than 25 of the 27 other live ones, and was the 90th registered.
3,041 studies on the registry are indexed under Depressive Disorder, Major; 588 are open to participants now.
Browse Depressive Disorder, Major studies →27 of the 92 studies in Depressive Disorder, Major with a site in Spain are open now. Recruiting first, the newest first:
Eli Lilly and Company · Sites in Spain, United States, Australia and 12 more countries
Ages 18–75
Ionclinics & Deionic SL · Sites in Spain
Ages 18+
Fundació Sant Joan de Déu · Sites in Spain
Ages 18+
Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico · Sites in Spain, Germany, Italy
Ages up to 45 · Healthy volunteers
University of the Basque Country (UPV/EHU) · Sites in Spain
Ages 18–65
A study can be open while its sites in Spain have not opened yet or have stopped. Only those recruiting at a site in Spain →
Of the 410 Depressive Disorder, Major studies recruiting now, 92 (22%) set no upper age limit and 292 (71%) stop at 75 or younger; 54 take children under 18; 98 take healthy volunteers.
This study: 18 Years to 75 Years · all sexes · no healthy volunteers.
The full table on the hub →This tab as a report to print or save as PDF → With an account.
92 studies; the count open now beside each. This study's row is marked.
First in 2002; this study’s year is marked. 1 started in 2027.
By drug class, each counting the studies that test any of its medicines:
This study's planned enrollment of 206 is above the median of 79 across 2,530 interventional studies indexed under Depressive Disorder, Major.
Median enrollment 230 across the 77 interventional studies, 275 across the 15 observational. Of the 59 that completed or were terminated, 26 (44%) have results posted.
This tab as a report to print or save as PDF → With an account.
56 of 92 have an industry lead sponsor. The 10 most frequent:
University of the Basque Country (UPV/EHU) is the lead sponsor of 39 studies on the registry; 6 are open to participants now.
University of the Basque Country (UPV/EHU) has 2 studies filed under Depressive Disorder, Major — fewer than ten, so there is no comparison to draw.
10 of the studies in Depressive Disorder, Major with a site in Spain that are under way reach primary completion within a year, 3 of them phase 3. Phase 3 first, then by date:
| Study | Primary completion |
|---|---|
| NCT06559306Phase 3Janssen Research & Development, LLCPhase 3 Study of Adjunctive Treatment With Seltorexant in Adult and Elderly Participants With Major Depressive Disorder and Insomnia Symptoms | 2026-12-30 |
| NCT05850689Phase 3Intra-Cellular Therapies, Inc.Study of Lumateperone as Adjunctive Therapy in the Treatment of Patients With Major Depressive Disorder | 2027-04-05 |
| NCT07076407Phase 3Xenon Pharmaceuticals Inc.A Randomized Study of Azetukalner Versus Placebo in Major Depressive Disorder (X-NOVA3) | 2027-05 |
| NCT07422519Hospital Universitari Vall d'Hebron Research InstituteVirtual Reality-Based Mindfulness as an Adjunct to Treatment as Usual in Treatment-Resistant Depression | 2026-12-15 |
| NCT04084795Parc de Salut MarAugmentation of EMDR With tDCS in the Treatment of Fibromyalgia | 2026-12-31 |
Add all 10 to your calendar (.ics) → With an account.
Among the 92 studies in Depressive Disorder, Major with a site in Spain, from their registry updates:
This tab as a report to print or save as PDF → With an account.
Major depressive disorder (MDD) is a common and disabling mental health condition that can substantially affect emotional well-being, daily functioning, physical health, and quality of life. Although medication and psychotherapy are established treatments, many people continue to experience depressive symptoms and related health problems. Supervised physical exercise has emerged as a promising complementary treatment for depression. However, it remains unclear whether exercising in natural environments provides additional benefits compared with performing a similar exercise program indoors.
The NEST study (Nature-Based Exercise for Major Depressive Disorder) aims to investigate the effects of supervised physical exercise performed in natural versus indoor environments on depressive symptoms in adults with major depressive disorder. The study will also examine whether these exercise programs improve physical fitness, cardiometabolic health, daily functioning, psychological well-being, and quality of life.
NEST is a randomized, controlled, three-arm clinical trial that plans to enroll 206 adults aged 18 to 75 years with major depressive disorder. Participants will be recruited through mental health services in Álava, Spain. Eligible participants will be randomly assigned to one of three groups:
Both exercise groups will participate in a 12-week program consisting of two supervised sessions per week, lasting approximately 80 minutes each. Sessions will combine aerobic interval exercise and resistance training. Exercise intensity will be individually adjusted and monitored by qualified professionals. The main difference between the two exercise groups will be the environment in which the sessions take place.
All participants will undergo assessments before the intervention and after 12 weeks. The primary outcome will be the change in depressive symptom severity, measured using the Montgomery-Åsberg Depression Rating Scale (MADRS).
Secondary assessments will examine clinical functioning, quality of life, cardiorespiratory fitness, muscle strength, body composition, physical activity, cardiometabolic risk factors, and selected inflammatory and neurotrophic biomarkers. The study will also explore participants' experiences of the exercise programs.
Exercise will be provided as an addition to usual mental healthcare rather than as a replacement for prescribed treatments. The findings may help determine whether natural environments offer additional therapeutic benefits and inform the development of accessible, supervised exercise programs for people living with major depressive disorder.
BACKGROUND AND SCIENTIFIC RATIONALE
Major depressive disorder (MDD) is a prevalent and disabling psychiatric condition associated with persistent depressive mood, loss of interest or pleasure, impaired daily functioning, and reduced quality of life. In addition to its psychological and social consequences, MDD is associated with an increased burden of physical health problems, including cardiovascular disease, metabolic disorders, reduced physical fitness, and premature mortality.
Depression is increasingly recognized as a condition involving interactions among psychological, behavioral, neurobiological, inflammatory, and metabolic processes. People living with MDD frequently experience reduced physical activity, increased sedentary behavior, sleep disturbances, reduced cardiorespiratory fitness, and alterations in body composition and cardiometabolic health. These factors may interact with depressive symptoms and contribute to a cycle of declining physical and psychological well-being.
Current clinical treatments for MDD include pharmacotherapy, psychotherapy, or their combination. Although these treatments are effective for many patients, incomplete symptom improvement, adverse effects, barriers to access, and difficulties maintaining treatment adherence highlight the need for additional therapeutic strategies.
Structured physical exercise has emerged as a promising complementary intervention for depression. Supervised exercise programs may reduce depressive symptoms while improving cardiovascular health, physical fitness, metabolic regulation, muscle strength, and functional capacity. Exercise may also influence biological processes involved in depression, including systemic inflammation, neuroplasticity, and neurotrophic signaling.
However, the context in which exercise is performed may also influence its effects. Exercise in natural environments, sometimes referred to as "green exercise," combines the physiological effects of physical activity with exposure to natural surroundings. Natural environments may provide additional opportunities for psychological restoration, stress reduction, emotional regulation, and positive experiences during physical activity.
Although research suggests that exposure to natural environments may benefit mental health, evidence remains limited regarding whether structured exercise performed outdoors in natural settings produces greater improvements in clinically assessed depressive symptoms than comparable exercise performed indoors.
The NEST randomized clinical trial has been designed to address this question in adults diagnosed with major depressive disorder.
STUDY RATIONALE
NEST evaluates whether the environment in which supervised exercise is performed influences its therapeutic effects in people with MDD.
The study compares two structured exercise programs with similar training components, frequency, and duration, differing primarily in their environmental context: natural green spaces versus indoor facilities.
A third group receiving usual mental healthcare serves as a control condition.
This design will allow the investigation of two complementary questions:
First, whether adding a supervised exercise program to usual mental healthcare improves depressive symptoms compared with usual care.
Second, whether performing a comparable exercise program in natural environments provides additional benefits compared with exercising indoors.
The study also investigates changes in physical health, functional capacity, psychological well-being, and selected biological markers that may help characterize the response to exercise.
By integrating clinical, physiological, behavioral, and biological assessments, NEST aims to contribute to a broader understanding of exercise as a complementary treatment for MDD.
STUDY OBJECTIVES
3.1. Primary Objective
To evaluate the effects of a 12-week supervised combined exercise program performed in natural environments versus indoor environments, compared with a usual-care control group, on depressive symptom severity in adults with major depressive disorder.
The primary outcome is the change in Montgomery-Åsberg Depression Rating Scale (MADRS) score from baseline to the end of the 12-week intervention.
3.2. Secondary Objectives
The secondary objectives are:
STUDY HYPOTHESES
The primary hypothesis is that supervised combined exercise, added to usual mental healthcare, will improve depressive symptoms in adults with MDD compared with usual care alone.
A central secondary hypothesis is that exercise performed in natural environments will produce greater improvements in depressive symptoms than a comparable exercise program performed indoors.
Additional hypotheses are that supervised exercise will improve cardiorespiratory fitness, muscle strength, functional capacity, body composition, cardiometabolic health, and quality of life.
Exploratory hypotheses concern changes in inflammatory and neurotrophic biomarkers, including high-sensitivity C-reactive protein, interleukin-6, tumor necrosis factor-alpha, and brain-derived neurotrophic factor.
The study will also explore whether improvements in physical fitness are associated with reductions in depressive symptom severity.
STUDY DESIGN
NEST is a prospective, randomized, controlled, three-arm, parallel-group clinical trial.
The trial will use an open-label design because participants and exercise professionals cannot be blinded to the environment in which the exercise sessions take place.
Whenever feasible, clinical and physical assessments will be conducted by personnel who are independent of the professionals delivering the exercise intervention.
The study is designed as a pragmatic add-on trial. Participants will continue receiving usual mental healthcare, and the exercise programs will be provided as complementary interventions rather than replacements for established psychiatric treatment.
The three study groups are:
The anticipated sample size is 206 participants.
Study assessments will be performed at two main time points:
T0: Baseline assessment before the intervention.
T1: Post-intervention assessment after 12 weeks.
The study will be conducted in Vitoria-Gasteiz, Álava, Spain, through collaboration among mental health services, the Psychiatric Hospital of Álava, and the University of the Basque Country.
STUDY POPULATION AND RECRUITMENT
The study population will consist of adults aged 18 to 75 years with a diagnosis of major depressive disorder according to DSM-5-TR criteria, confirmed by a psychiatrist.
Participants will be recruited from the Mental Health Network of Álava, including outpatient mental health services and the Psychiatric Hospital of Álava.
Potentially eligible individuals will be identified during routine psychiatric care by members of the clinical research team.
Patients who meet preliminary eligibility criteria will receive verbal and written information about the study, including its objectives, procedures, potential benefits, possible risks, and voluntary nature.
Written informed consent will be obtained before any study-specific procedures are performed.
Eligible participants will complete baseline assessments before randomization.
Participants may continue receiving prescribed psychiatric treatment throughout the study. Changes in psychopharmacological treatment will be recorded and considered in the analysis where appropriate.
RANDOMIZATION AND ALLOCATION
Following eligibility confirmation, informed consent, and baseline assessments, participants will be randomly assigned to one of the three study groups.
Randomization will be performed using the randomization platform of the Bioaraba Health Research Institute.
The allocation process will assign participants to the nature-based exercise group, indoor exercise group, or usual-care control group.
The randomized design is intended to reduce selection bias and support comparisons among the three study conditions.
Because of the nature of the interventions, participants and professionals delivering the exercise sessions will be aware of group assignment.
Standardized assessment procedures and predefined statistical analyses will be used to reduce potential measurement and analytical bias.
EXERCISE INTERVENTIONS
8.1. General Structure
Participants assigned to either exercise group will complete a supervised, structured, combined exercise program lasting 12 weeks.
The program will involve:
Both exercise programs will follow the same general training structure. Their principal difference will be the environment in which the sessions are conducted.
The exercise intervention will be supervised by professionals with qualifications in Physical Activity and Sport Sciences and experience in exercise programming.
8.2. Nature-Based Exercise Group
Participants allocated to the nature-based exercise group will perform supervised exercise sessions in natural green spaces within the Green Belt of Vitoria-Gasteiz.
The program will combine aerobic interval training and circuit-based resistance exercise.
Natural settings may include peri-urban parks and green areas suitable for structured exercise.
The environmental characteristics of the exercise locations will be documented to support interpretation and reproducibility.
Basic environmental conditions, including temperature, precipitation, season, and type of natural setting, will be recorded descriptively during the intervention.
The nature-based exercise group will continue receiving usual mental healthcare throughout the study.
8.3. Indoor Exercise Group
Participants allocated to the indoor exercise group will perform a comparable supervised exercise program in indoor facilities at the Psychiatric Hospital of Álava.
The program will use the same general exercise components, session frequency, duration, and progression principles as the nature-based exercise group.
The purpose of this comparison is to investigate whether the natural environment contributes additional benefits beyond those associated with supervised exercise itself.
Participants in this group will also continue receiving usual mental healthcare.
8.4. Usual-Care Control Group
Participants assigned to the control group will continue receiving usual care provided by mental health services.
They will also receive general recommendations concerning physical activity and healthy lifestyle habits.
According to the study protocol, control participants will take part in occupational activities with a duration and frequency comparable to the exercise sessions.
The control group will not receive either of the structured exercise programs under investigation.
EXERCISE SESSION STRUCTURE
Each supervised exercise session will last approximately 80 minutes and will include three phases.
9.1. Warm-Up
Duration: approximately 15 minutes.
The warm-up will include joint mobility exercises and progressive muscular activation to prepare participants for the main exercise session.
9.2. Main Exercise Phase
The main phase will combine aerobic interval exercise and circuit-based resistance training.
Aerobic training will use a low-volume high-intensity interval training approach (LV-HIIT).
The interval structure will involve approximately one minute of higher-intensity exercise alternated with two minutes of active recovery.
The program will initially include three intervals, progressing to five intervals as participants adapt.
Resistance training will involve a circuit of ten exercises addressing fundamental movement patterns, including knee-dominant and hip-dominant movements, pushing, pulling, core exercises, and low-impact movements.
Exercises will alternate between upper-body and lower-body muscle groups.
Each exercise will be performed for approximately 45 seconds, followed by 15 seconds of recovery.
Participants will initially complete one circuit round, progressing to two rounds according to individual tolerance and adaptation.
9.3. Cool-Down
Duration: approximately 15 minutes.
The session will conclude with passive stretching and progressive recovery activities.
EXERCISE INTENSITY PRESCRIPTION AND MONITORING
Exercise intensity will be individualized using information obtained during baseline cardiopulmonary exercise testing.
The first and second ventilatory thresholds (VT1 and VT2) will be used to identify exercise intensity domains:
R1: Light-to-moderate intensity, below VT1.
R2: Moderate-to-high intensity, between VT1 and VT2.
R3: High-to-severe intensity, above VT2 and up to peak heart rate.
Exercise intensity will be monitored using heart rate measurements and the Borg Rating of Perceived Exertion scale.
Blood pressure will be assessed at the beginning and end of exercise sessions.
Exercise professionals will adapt training intensity according to participants' clinical condition, functional capacity, perceived exertion, and individual tolerance.
Attendance, heart rate, perceived exertion, and affective responses to exercise will be recorded during the program.
The Feeling Scale will be administered before and after sessions to assess affective responses.
INTERVENTION ADHERENCE AND SAFETY
Adherence will be assessed using attendance records from supervised exercise sessions.
The percentage of completed sessions will be calculated for each participant.
Strategies intended to support adherence will include professional supervision, individualized exercise prescription, motivational support, and telephone contact following missed sessions.
Potential adverse events occurring during exercise sessions or in temporal association with the intervention will be recorded and assessed by the research team.
Relevant clinical events will be evaluated according to their severity and possible relationship with exercise.
Exercise sessions may be interrupted or discontinued when clinically indicated.
Participants will remain under the care of their usual mental health professionals throughout the study.
PRIMARY OUTCOME: DEPRESSIVE SYMPTOM SEVERITY
The primary outcome will be the change in depressive symptom severity from baseline to 12 weeks, measured using the Montgomery-Åsberg Depression Rating Scale (MADRS).
MADRS is a clinician-rated instrument designed to assess the severity of depressive symptoms.
The scale consists of ten items addressing:
Each item is scored from 0 to 6, producing a total score ranging from 0 to 60.
Higher scores indicate greater depressive symptom severity.
MADRS will be administered at baseline (T0) and after the 12-week intervention (T1).
The primary analysis will compare post-intervention depressive symptom severity among the three randomized groups while adjusting for baseline MADRS scores.
Clinical response will also be explored, defined as a reduction of at least 50% from baseline MADRS score.
Remission will be evaluated using an established clinically appropriate MADRS threshold, as specified in the study analysis procedures.
SECONDARY CLINICAL AND FUNCTIONAL OUTCOMES
13.1. Functional Disability
Functional disability will be assessed using the Sheehan Disability Scale.
The instrument evaluates the impact of psychiatric symptoms on three areas of functioning:
Each domain is scored from 0 to 10, with a total score ranging from 0 to 30.
Higher scores indicate greater functional impairment.
13.2. Clinical Global Impression
Overall clinical severity will be assessed using the Clinical Global Impression scale.
This clinician-rated measure will provide complementary information on participants' global psychiatric condition.
13.3. Psychiatric and Clinical Characteristics
Clinical information will include psychiatric history, age at illness onset, duration of illness, previous psychiatric admissions, relevant medical conditions, and current psychopharmacological treatment.
Changes in medication during the intervention period will be recorded.
These variables may be considered in descriptive analyses and sensitivity analyses.
CARDIORESPIRATORY FITNESS
Cardiorespiratory fitness will be assessed through cardiopulmonary exercise testing (CPET).
CPET provides objective information about the integrated capacity of the cardiovascular, respiratory, and muscular systems to respond to progressive exercise.
Peak oxygen uptake (VO2peak) will be assessed as an indicator of cardiorespiratory fitness.
Ventilatory thresholds will also be determined to support individualized exercise prescription.
Assessments will be performed at baseline and after the 12-week intervention.
Changes in cardiorespiratory fitness will be compared among the three randomized groups.
The study will also explore whether improvements in cardiorespiratory fitness are associated with reductions in depressive symptom severity.
MUSCLE STRENGTH AND PHYSICAL FUNCTIONING
Muscle strength and functional performance will be assessed using standardized procedures described in the study protocol.
These assessments will characterize physical functioning and evaluate changes associated with the exercise interventions.
Muscle strength is of particular interest because depression may be associated with reduced physical activity, deconditioning, and impaired functional capacity.
Changes in strength and functional performance will be evaluated between baseline and post-intervention assessments.
BODY COMPOSITION AND ANTHROPOMETRIC CHARACTERISTICS
Anthropometric and body composition assessments will be conducted to characterize participants' physical health.
Measurements will include body mass, height, body mass index, and body composition parameters.
These assessments will help determine whether the exercise programs influence adiposity and other body composition characteristics.
Measurements will be obtained at baseline and after the intervention.
CARDIOMETABOLIC HEALTH
The study will assess cardiometabolic parameters associated with cardiovascular and metabolic health.
Blood analyses will include:
Insulin resistance will be estimated using the homeostatic model assessment of insulin resistance (HOMA-IR).
These variables will be used to investigate potential changes in cardiometabolic health following the exercise interventions.
INFLAMMATORY AND NEUROTROPHIC BIOMARKERS
The study will include exploratory analyses of selected circulating biomarkers potentially related to depression and the physiological response to exercise.
Inflammatory biomarkers will include:
The neurotrophic biomarker brain-derived neurotrophic factor (BDNF) will also be assessed.
These biomarkers have been selected because of their potential relevance to inflammatory regulation, neuroplasticity, stress-related processes, and exercise adaptation.
Blood samples will be collected at baseline and after the intervention.
Biomarker analyses will be exploratory and will not be used to establish psychiatric diagnoses or guide individual clinical treatment decisions.
PHYSICAL ACTIVITY AND SEDENTARY BEHAVIOR
Habitual physical activity and sedentary behavior will be assessed using the procedures and instruments specified in the study protocol.
These measurements will provide information on participants' activity patterns outside supervised exercise sessions.
The study will investigate whether participation in the exercise programs is associated with changes in overall physical activity and sedentary time.
These variables may also help characterize behavioral factors associated with clinical and physical health outcomes.
EXPOSURE TO AND CONNECTION WITH NATURAL ENVIRONMENTS
A distinctive component of NEST is the assessment of participants' relationship with natural environments.
The study will collect information on exposure to natural settings and connection with nature using the measures specified in the protocol.
For the nature-based exercise group, environmental characteristics of the exercise setting will also be recorded.
These data will support exploratory analyses of whether environmental exposure and subjective connection with nature are associated with psychological and clinical responses to exercise.
COGNITIVE AND PSYCHOLOGICAL ASSESSMENTS
The study includes cognitive and psychological assessments specified in the research protocol and case report forms.
These assessments will provide complementary information about participants' cognitive functioning and psychological characteristics.
Changes between baseline and post-intervention assessments will be examined where applicable.
HEALTH-RELATED QUALITY OF LIFE AND WELL-BEING
Health-related quality of life will be assessed using the standardized instruments included in the study protocol.
These measures will characterize participants' perceived physical, psychological, and social well-being.
The study will evaluate whether the exercise interventions are associated with improvements in quality of life and whether such changes differ according to the exercise environment.
PARTICIPANT EXPERIENCE AND SATISFACTION
Participants' satisfaction with the intervention will be assessed using the procedures established in the study protocol.
Relevant aspects will include satisfaction with the exercise program and the environment in which the intervention was delivered.
The study also includes a qualitative component intended to explore participants' subjective experiences.
This component may provide complementary information about perceived benefits, barriers, motivation, acceptability, and the experience of exercising in natural versus indoor environments.
The qualitative findings will help contextualize the quantitative outcomes and may inform the design of future exercise interventions.
STUDY ASSESSMENT SCHEDULE
Participants will complete assessments at two principal time points:
T0: Baseline, before randomization and initiation of the intervention.
T1: Following completion of the 12-week intervention.
Clinical and psychiatric assessments will be conducted through the participating mental health services.
Physical and functional assessments will be conducted using the facilities and equipment available through the participating institutions, including the University of the Basque Country.
The assessment schedule is designed to characterize changes in depressive symptoms, physical fitness, cardiometabolic health, biological markers, and other relevant outcomes over the intervention period.
SAMPLE SIZE
The planned sample size is 206 participants, distributed across three randomized groups.
The sample size calculation was based on the primary outcome, MADRS, and an analysis of covariance approach.
The protocol assumes a medium effect size (f = 0.25), a statistical power of 90%, and a two-sided significance level of 0.05.
The calculation also considers a clinically relevant between-group difference in depressive symptom severity.
The sample size is intended to provide sufficient statistical power to evaluate differences among the three study conditions.
STATISTICAL ANALYSIS
The primary statistical analysis will follow the intention-to-treat principle, with participants analyzed according to their randomized group assignment.
The primary outcome will be analyzed using analysis of covariance (ANCOVA).
Post-intervention MADRS score will be entered as the dependent variable, study group as the principal factor, and baseline MADRS score as a covariate.
This approach will allow comparison of depressive symptom severity among the three randomized groups while accounting for baseline differences.
Secondary continuous outcomes will be analyzed using analogous approaches, adjusting for baseline values where appropriate.
The analyses will investigate the effects of supervised exercise compared with usual care and explore differences between nature-based and indoor exercise.
Additional exploratory and sensitivity analyses may consider changes in psychopharmacological treatment, baseline expectations, intervention adherence, and other relevant clinical characteristics.
The study will also explore associations between improvements in cardiorespiratory fitness and changes in depressive symptom severity.
Where supported by the data, exploratory analyses may examine potential mediating relationships.
Statistical analyses will be conducted using IBM SPSS Statistics and R.
DATA COLLECTION AND CONFIDENTIALITY
Clinical and research information will initially be recorded using standardized case report forms.
Study data will subsequently be entered into a secure electronic research database.
Participants will be assigned study identification codes to support confidentiality.
The research database will contain pseudonymized information, and access to identifiable data will be restricted to authorized personnel.
Data management will follow applicable European and Spanish data protection requirements.
ETHICAL CONSIDERATIONS
The NEST study received a favorable opinion from the Research Ethics Committee of OSI Araba on August 7, 2026 (reference 2026-038).
Participation will be voluntary.
Potential participants will receive information about the study objectives, procedures, randomization, intervention groups, potential risks, and their right to withdraw.
Written informed consent will be obtained before participation.
Participants will continue receiving their usual mental healthcare throughout the study.
Exercise sessions will be supervised by qualified professionals, and exercise intensity will be adapted to participants' clinical and functional characteristics.
Potential adverse events related to the intervention will be monitored and recorded.
The study will be conducted in accordance with applicable ethical and regulatory requirements.
NEST aims to provide evidence on the effectiveness of supervised combined exercise as a complementary treatment for major depressive disorder.
The comparison of nature-based and indoor exercise will help clarify whether the environmental context of exercise contributes additional therapeutic benefits.
The integration of clinical, physiological, behavioral, and biological outcomes will allow the investigation of potential relationships between improvements in depressive symptoms and changes in physical health.
The findings may contribute to the development of structured, supervised, and potentially accessible exercise programs for people with depression.
The study may also inform future research on nature-based interventions and support the integration of physical activity promotion into mental healthcare.
Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.
Participants receiving psychopharmacological treatment are eligible. Strict stability of psychopharmacological treatment before enrollment is not required, as the trial is conducted under conditions reflecting routine clinical practice.
Exclusion Criteria:
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
The American Psychiatric Association’s manual of mental health diagnoses. DSM-5 (2013, revised as DSM-5-TR in 2022) replaced DSM-IV, and some studies still name the older edition. “Meets DSM criteria for …” means diagnosed by that edition’s diagnostic criteria, usually by a clinician in an interview.
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Short tests of memory and thinking, each scored out of 30. Lower scores suggest more difficulty; criteria give a range, either to include people with memory problems or to leave them out.
A reason a treatment, test or procedure should not be given to a particular person, such as an allergy, another illness or a medicine they take.
DSM diagnostic criteria
The American Psychiatric Association’s manual of mental health diagnoses. DSM-5 (2013, revised as DSM-5-TR in 2022) replaced DSM-IV, and some studies still name the older edition. “Meets DSM criteria for …” means diagnosed by that edition’s diagnostic criteria, usually by a clinician in an interview.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Informed consent
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
MMSE and MoCA
Short tests of memory and thinking, each scored out of 30. Lower scores suggest more difficulty; criteria give a range, either to include people with memory problems or to leave them out.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Contraindication
A reason a treatment, test or procedure should not be given to a particular person, such as an allergy, another illness or a medicine they take.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Participants allocated to this group will complete a 12-week supervised combined exercise program in natural green spaces in Vitoria-Gasteiz, Spain, in addition to continuing their usual mental healthcare. The program will include two approximately 80-minute sessions per week, combining aerobic interval training and resistance exercises. Exercise intensity will be individualized according to baseline fitness assessments and monitored by qualified exercise professionals. Sessions will take place in natural environments, with training progression adapted to participants' physical capacity and clinical condition.
Behavioral: Nature-Based Combined Exercise Program
Participants allocated to this group will complete a 12-week supervised combined exercise program in indoor facilities at the Psychiatric Hospital of Álava, Spain, in addition to continuing their usual mental healthcare. The program will include two approximately 80-minute sessions per week, combining aerobic interval training and resistance exercises. Exercise intensity, session structure, and progression will be comparable to those of the nature-based exercise group. The main difference between the two exercise programs will be the environment in which the sessions are performed.
Behavioral: Indoor Combined Exercise Program
Participants allocated to the control group will continue receiving their usual mental healthcare, including psychiatric follow-up and prescribed treatments as clinically indicated. They will receive general recommendations concerning physical activity and healthy lifestyle habits and will participate in occupational activities according to the study protocol. They will not receive either of the structured supervised exercise programs being investigated. Participants will complete the same baseline and 12-week outcome assessments as the exercise groups.
Behavioral: Usual Mental Healthcare and Occupational Activities
A 12-week supervised combined exercise program conducted in natural green spaces in Vitoria-Gasteiz, Spain. Participants will attend two sessions per week, each lasting approximately 80 minutes. Sessions will include a 15-minute warm-up, aerobic interval training and circuit-based resistance exercises, followed by a 15-minute cool-down. Aerobic training will use low-volume high-intensity intervals, with approximately one minute of higher-intensity exercise alternating with two minutes of active recovery. Resistance exercises will target major muscle groups and fundamental movement patterns. Training intensity will be individualized using baseline fitness assessments, heart rate, and perceived exertion. Exercise progression will be adapted to each participant's capacity and tolerance. The intervention will be delivered alongside usual mental healthcare.
A 12-week supervised combined exercise program conducted in indoor facilities at the Psychiatric Hospital of Álava, Spain. Participants will attend two sessions per week, each lasting approximately 80 minutes. Sessions will include a 15-minute warm-up, aerobic interval training and circuit-based resistance exercises, followed by a 15-minute cool-down. The aerobic and resistance training components, intensity prescription, monitoring procedures, and progression principles will be comparable to those used in the nature-based exercise group. Training will be individualized according to participants' baseline fitness, heart rate, perceived exertion, and clinical tolerance. The intervention will be delivered alongside usual mental healthcare. Its main distinguishing feature will be the indoor exercise environment.
Participants allocated to the control group will continue receiving usual mental healthcare, including psychiatric follow-up, prescribed pharmacological treatment, and other clinically indicated services. They will receive general recommendations concerning physical activity and healthy lifestyle habits. According to the study protocol, participants will also engage in occupational activities with a frequency and duration comparable to those of the supervised exercise sessions. The control group will not participate in either of the structured combined exercise programs under investigation. Clinical and physical assessments will be conducted at baseline and after 12 weeks.
Change in Depressive Symptom Severity Assessed by the Montgomery-Åsberg Depression Rating Scale (MADRS)
Depressive symptom severity will be assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS), a clinician-rated instrument consisting of 10 items evaluating depressive symptoms. Each item is scored from 0 to 6, resulting in a total score ranging from 0 to 60, with higher scores indicating greater depressive symptom severity. The outcome will be the change in total MADRS score from baseline to 12 weeks. Between-group differences will be evaluated using analysis of covariance, with the post-intervention MADRS score as the dependent variable, randomized group as the factor, and baseline MADRS score as a covariate.
Time frame: Baseline and 12 weeks (post-intervention)
Clinical Response Rate Based on MADRS
Percentage of participants achieving a reduction of at least 50% in total MADRS score from baseline to 12 weeks. A higher percentage indicates a greater clinical response rate.
Time frame: 12 weeks (post-intervention; compared with baseline MADRS score where applicable)
Remission Rate Based on MADRS
Percentage of participants meeting the prespecified remission criterion on the MADRS at 12 weeks. The numerical remission threshold will be established according to the approved study protocol.
Time frame: 12 weeks (post-intervention; compared with baseline MADRS score where applicable)
Change in Functional Disability (Sheehan Disability Scale)
Functional disability will be assessed using the Sheehan Disability Scale (SDS). The scale evaluates impairment in work or studies, social life, and family life. Each domain is scored from 0 to 10, giving a total score from 0 to 30. Higher scores indicate greater functional impairment.
Time frame: Baseline and 12 weeks (post-intervention)
Change in Clinical Global Impression Severity (CGI-S)
Overall psychiatric illness severity will be assessed using the Clinical Global Impression-Severity scale (CGI-S), a clinician-rated measure ranging from 1 (normal, not at all ill) to 7 (among the most extremely ill patients). Higher scores indicate greater illness severity.
Time frame: Baseline and 12 weeks (post-intervention)
Change in Health-Related Quality of Life (SF-36)
Health-related quality of life will be assessed using the 36-Item Short Form Health Survey (SF-36), covering eight dimensions of physical and mental health. Scores will be calculated according to the instrument's standard scoring procedures, with higher scores indicating better health-related quality of life.
Time frame: Baseline and 12 weeks (post-intervention)
Change in Mental Well-Being (WEMWBS)
Mental well-being will be assessed using the Warwick-Edinburgh Mental Well-Being Scale (WEMWBS). The instrument contains 14 positively worded items scored from 1 to 5, giving a total score from 14 to 70. Higher scores indicate greater mental well-being.
Time frame: Baseline and 12 weeks (post-intervention)
Change in Peak Oxygen Uptake (VO2peak)
Peak oxygen uptake will be measured during a maximal cardiopulmonary exercise test (CPET) performed on a treadmill using a modified Bruce protocol. VO2peak will be expressed in mL/kg/min. Higher values indicate better cardiorespiratory fitness.
Time frame: Baseline and 12 weeks (post-intervention)
Change in Modified Shuttle Walk Test Performance
Functional exercise capacity will be assessed using the Modified Shuttle Walk Test (MSWT), performed over a 10-meter course. Performance will be expressed as total distance covered in meters. Higher values indicate better functional exercise capacity.
Time frame: Baseline and 12 weeks (post-intervention)
Change in Estimated Lower-Body Maximal Strength
Lower-body maximal strength will be assessed using a submaximal velocity-based training protocol to estimate one-repetition maximum (1RM) in the squat and leg press exercises. Estimated 1RM will be expressed in kilograms. Higher values indicate greater maximal strength.
Time frame: Baseline and 12 weeks (post-intervention)
Change in Estimated Upper-Body Maximal Strength
Upper-body maximal strength will be assessed using a submaximal velocity-based training protocol to estimate one-repetition maximum (1RM) in the bench press exercise. Estimated 1RM will be expressed in kilograms. Higher values indicate greater maximal strength.
Time frame: Baseline and 12 weeks (post-intervention)
Change in Handgrip Strength
Isometric handgrip strength will be measured using a hand dynamometer. Three trials will be performed with each hand, and the highest recorded value will be used. Strength will be expressed in kilograms. Higher values indicate greater handgrip strength.
Time frame: Baseline and 12 weeks (post-intervention)
Change in Objectively Measured Moderate-to-Vigorous Physical Activity
Moderate-to-vigorous physical activity will be assessed using an ActiGraph GT3X+ triaxial accelerometer worn on the non-dominant wrist over eight consecutive days. Physical activity will be quantified using the prespecified accelerometer processing procedures and expressed in minutes per day.
Time frame: Baseline and 12 weeks (post-intervention; 8-day monitoring period at each assessment)
Change in Objectively Measured Sedentary Time
Sedentary behavior will be assessed using an ActiGraph GT3X+ triaxial accelerometer worn on the non-dominant wrist over eight consecutive days. Sedentary time will be expressed in minutes per day according to the prespecified data processing criteria.
Time frame: Baseline and 12 weeks (post-intervention; 8-day monitoring period at each assessment)
Change in Self-Reported Physical Activity (IPAQ)
Self-reported physical activity will be assessed using the International Physical Activity Questionnaire (IPAQ). Physical activity will be quantified according to the questionnaire's scoring procedures and expressed in metabolic equivalent minutes per week (MET-min/week). Higher values indicate greater reported physical activity.
Time frame: Baseline and 12 weeks (post-intervention; 8-day monitoring period at each assessment)
Change in Accelerometer-Derived Sleep Duration
Sleep duration will be estimated from wrist-worn ActiGraph GT3X+ accelerometry over eight consecutive days using prespecified sleep identification and processing procedures. Mean sleep duration will be expressed in minutes per night.
Time frame: Baseline and 12 weeks (post-intervention; 8-day monitoring period at each assessment)
Change in Body Mass
Body mass will be measured using a calibrated scale and expressed in kilograms.
Time frame: Baseline and 12 weeks (post-intervention)
Change in Body Fat Percentage
Body fat percentage will be estimated using bioelectrical impedance analysis. Results will be expressed as a percentage of total body mass.
Time frame: Baseline and 12 weeks (post-intervention)
Change in Fat-Free Mass
Fat-free mass will be estimated using bioelectrical impedance analysis and expressed in kilograms.
Time frame: Baseline and 12 weeks (post-intervention)
Change in Waist Circumference
Waist circumference will be measured using a flexible anthropometric measuring tape and expressed in centimeters.
Time frame: Baseline and 12 weeks (post-intervention)
Change in Waist-to-Hip Ratio
Waist-to-hip ratio will be calculated by dividing waist circumference by hip circumference, both measured in the same units. The result is dimensionless.
Time frame: Baseline and 12 weeks (post-intervention)
Change in Resting Systolic Blood Pressure
Resting systolic blood pressure will be measured using an automated upper-arm blood pressure monitor and expressed in mmHg.
Time frame: Baseline and 12 weeks (post-intervention)
Change in Resting Diastolic Blood Pressure
Resting diastolic blood pressure will be measured using an automated upper-arm blood pressure monitor and expressed in mmHg.
Time frame: Baseline and 12 weeks (post-intervention)
Change in Total Cholesterol
Serum total cholesterol concentration will be measured through laboratory blood analysis and expressed in mg/dL.
Time frame: Baseline and 12 weeks (post-intervention)
Change in HDL Cholesterol
High-density lipoprotein cholesterol (HDL-C) concentration will be measured through laboratory blood analysis and expressed in mg/dL.
Time frame: Baseline and 12 weeks (post-intervention)
Change in LDL Cholesterol
Low-density lipoprotein cholesterol (LDL-C) concentration will be assessed through laboratory blood analysis and expressed in mg/dL.
Time frame: Baseline and 12 weeks (post-intervention)
Change in Triglycerides
Serum triglyceride concentration will be measured through laboratory blood analysis and expressed in mg/dL.
Time frame: Baseline and 12 weeks (post-intervention)
Change in Fasting Plasma Glucose
Fasting plasma glucose concentration will be measured through laboratory blood analysis and expressed in mg/dL.
Time frame: Baseline and 12 weeks (post-intervention)
Change in Fasting Insulin
Fasting insulin concentration will be measured through laboratory blood analysis. Results will be expressed in µIU/mL, subject to confirmation of the laboratory reporting units.
Time frame: Baseline and 12 weeks (post-intervention)
Change in Glycated Hemoglobin (HbA1c)
Glycated hemoglobin (HbA1c) will be measured through laboratory blood analysis and expressed as a percentage, subject to confirmation of the laboratory reporting format.
Time frame: Baseline and 12 weeks (post-intervention)
Change in Insulin Resistance (HOMA-IR)
Insulin resistance will be estimated using the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), calculated from fasting glucose and insulin concentrations. Higher values indicate greater estimated insulin resistance.
Time frame: Baseline and 12 weeks (post-intervention)
Change in High-Sensitivity C-Reactive Protein (hs-CRP)
High-sensitivity C-reactive protein (hs-CRP) concentration will be measured in serum as an exploratory marker of low-grade systemic inflammation. Concentrations will be expressed in mg/L.
Time frame: Baseline and 12 weeks (post-intervention)
Change in Interleukin-6 (IL-6)
Circulating interleukin-6 (IL-6) concentration will be measured in serum as an exploratory inflammatory biomarker. Concentrations will be expressed in pg/mL.
Time frame: Baseline and 12 weeks (post-intervention)
Change in Tumor Necrosis Factor-Alpha (TNF-alpha)
Circulating tumor necrosis factor-alpha (TNF-alpha) concentration will be measured in serum as an exploratory inflammatory biomarker. Concentrations will be expressed in pg/mL.
Time frame: Baseline and 12 weeks (post-intervention)
Change in Brain-Derived Neurotrophic Factor (BDNF)
Circulating brain-derived neurotrophic factor (BDNF) concentration will be measured in serum as an exploratory neurotrophic biomarker potentially related to neuroplasticity and exercise adaptation. Concentrations will be expressed in the units reported by the laboratory assay.
Time frame: Baseline and 12 weeks (post-intervention)
Change in Inclusion of Nature in Self (INS)
Connection with nature will be assessed using the Inclusion of Nature in Self (INS) scale, a pictorial measure representing the perceived overlap between the self and nature. Higher scores indicate a stronger perceived connection with nature.
Time frame: Baseline and 12 weeks (post-intervention)
Change in Nature Relatedness Scale (NRS) Score
Nature relatedness will be assessed using the Nature Relatedness Scale (NRS), a questionnaire measuring individuals' subjective relationship with the natural world. Scores will be calculated according to the version and scoring procedures specified in the study protocol. Higher scores indicate greater nature relatedness.
Time frame: Baseline and 12 weeks (post-intervention)
Change in Trail Making Test Performance
Cognitive performance will be assessed using the Spanish validated version of the Trail Making Test (TMT), which evaluates processing speed, attention, and cognitive flexibility. Completion time will be recorded in seconds. Longer completion times indicate poorer performance.
Time frame: Baseline and 12 weeks (post-intervention)
Adherence to the Supervised Exercise Program
Adherence will be calculated as the percentage of supervised exercise sessions attended relative to the total number of scheduled sessions during the 12-week intervention. Attendance will be recorded by the exercise professionals. Higher percentages indicate greater intervention adherence.
Time frame: Throughout the 12-week intervention
Participant Satisfaction With the Exercise Intervention
Satisfaction with the exercise intervention will be assessed at the end of the 12-week program using a five-item questionnaire. Each item is rated on a five-point Likert scale, with higher scores indicating greater satisfaction. Items assess overall satisfaction, perceived health benefits, exercise suitability, satisfaction with the exercise environment, and intention to continue physical activity.
Time frame: 12 weeks (post-intervention)
Cumulative Exposure to Natural Environments During Exercise
Cumulative exposure to natural environments will be calculated as the total number of minutes spent performing supervised exercise in natural settings during the 12-week intervention. This measure will be assessed in the nature-based exercise group and used in exploratory analyses of associations with clinical and physiological outcomes.
Time frame: Throughout the 12-week intervention
Participant-Reported Experiences of the Exercise Intervention
Participants' experiences will be explored through semi-structured qualitative interviews conducted with a subsample after the intervention. Interviews will address perceived benefits, barriers and facilitators, motivation, and experiences of exercising in natural versus indoor environments. Interview data will be examined using thematic analysis.
Time frame: 12 weeks (post-intervention)
Plan to share: No — Individual participant data (IPD) will not be routinely shared with external researchers because no formal IPD-sharing plan has been established for this study. The trial involves sensitive psychiatric and health-related information, including depression severity, clinical history, psychopharmacological treatment, physiological measurements, and biological markers. Participant confidentiality and compliance with applicable data protection legislation, including the European Union General Data Protection Regulation (GDPR), will be prioritized. Any future request for access to appropriately de-identified study data may be considered on a case-by-case basis, subject to the scope of participants' informed consent, scientific justification, applicable ethical and institutional approvals, and appropriate data protection safeguards. No unrestricted public release of participant-level data is currently planned.
No publications or documents are linked to this record.
Start is estimated for Jan 2027; primary completion for Dec 2029, 35 months later.
Of 647 non-industry interventional studies with no phase under Depressive Disorder, Major, half reached primary completion within 35 months of starting (the median), counting those still running; a quarter within 19 and three quarters within 55. This study's planned 35 months is close to that.
Counting every sponsor, half of 687 studies reached it within 33 months; a quarter within 17 and three quarters within 55.
How these figures are worked out, and which studies are left out of them.
From the registry record's own update history. This site started tracking changes on Sep 25, 2026; for anything earlier, see the record history on ClinicalTrials.gov ↗
This study is not yet recruiting, as verified in Nov 2026. You cannot join it, but the record below documents what was studied.
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University of the Basque Country (UPV/EHU)