Table 1.

Aerobic exercise studies in major depressive disorder, including study design, methodology, and clinical outcome

Year	Publication	Study design and diagnosis	Sample size, n		Intervention	Control	Measurement of CRF and PA	Intervention duration /follow-up	Outcome
			IG	CG
2019	Asthon et al. 2020 [52]	Exploratory subanalysis of an RCT (145 of 181 who reported data on PA) Bipolar depression	(A) 50 (B) 46	49	(A) N-acetylcysteine alone (B) N-acetylcysteine with a combination of nutraceuticals	Placebo	MADRS at week 16 IPAQ-SF at week 4 MADRS at week 16 And others	16 weeks	PA was unrelated to change in depression symptoms across study duration In patients receiving combination treatment, total PA significantly predicted changes in bipolar depression symptoms
2019	Gujral et al. 2019 [97]	RCT, double blind Pilot study Major depressive episode	7	8	Venlafaxine XR AND supervised exercise Sessions: individualized, 3x/week, 1 h Moderate intensity (60–75% of age-based HR for ~ 45 min on a treadmill and/or cycle ergometer) Supervised: yes	Venlafaxine XR	CRF: submaximal VO2 test PA: Body Media Sensewear armband, triaxial accelerometer	12 weeks	No significant changes in fitness in the exercise group Significant reduction of depressive symptoms in both groups Association between improvement in fitness and increased cortical thickness in the anterior cingulate cortex
2018	Gerber et al. 2019 [98]	Secondary analysis of RCT MDD	53 Randomization: n.a		(A) Sprint interval training: 25 repetitions of 30 s high-intensity burst at 80% of max. power output, followed by 30 s of total rest (B) Continuous aerobic exercise training: 20 min continuous aerobic exercise on a bicycle ergometer with an intensity level of 60% of the maximal power output Both sessions: 3x/week, 35 min Intensity: prescribed individually to each participant Supervised by an experienced exercise coach	n.a	CRF: VO2max, bicycle ergometer Fitness Questionnaire, not specified	4 weeks	Improvements in VO2max were associated with fewer depressive symptoms, better mental wellbeing, and better sleep post-intervention Improvements in perceived fitness were associated with less depression symptoms and better sleep higher mental wellbeing post-intervention Improvements in VO2max and perceived fitness were associated with favorable changes in depressive symptoms, mental wellbeing, and sleep
2018	Minghetti et al. 2018 [48]	RCT MDD	(A) 30 (B) 29		(A) Continuous aerobic exercise training [108]: 20 min continuous exercise at a power output corresponding to 60% of the maximal power output (B) Sprint interval training (SIT): 25 repetitions of 30 s high-intensity bursts at 80% of maximal power output followed by 30 s of total rest (remaining seated on the bicycle) Sessions: 3x/week, 35 min Supervised by an experienced exercise coach Medication was counterbalanced in both intervention arms	n.a	CRF: exhausting incremental exercise test, bicycle ergometer Beck Depression Inventory-II	4 weeks	BDI-II scores substantially decreased in both groups, while submaximal and maximal variables improved in both groups Short-term SIT leads to similar results as CAT in patients with MDD
2018	Patten et al. 2019 [44]	Pilot Study Depressive symptoms	18	18	Free membership in fitness center for 12 weeks AND Six 30-min individually tailored sessions with an exercise counselor; included aerobic exercise, strength training, stretching, and recommendations to exercise regularly Exercise at the fitness center and at home were both encouraged, but no supervised exercise was provided	Free membership in fitness center for 12 weeks but no additional intervention	CRF: 6–12-min submaximal cardiorespiratory test, cycle ergometer PA: evaluation of trunk flexibility, resting heart rate, blood pressure and body composition measured by bioelectrical impedance Questionnaires: Stage of change for exercise, IPAQ, Beck Depression Inventory-II	12 weeks	No group differences were found in IPAQ or BDI-II scores at week 12. Increases from baseline in IPAQ moderate/vigorous activity minutes were associated with decreases in BDI-II scores at week 12
2017	Rethorst et al. 2017 [40]	Randomized, secondary analysis MDD			Two exercise doses:  (A) 4 kcal/kg/week  (B) 16 kcal/kg/week Exercise intensity was self-selected and monitored with an HR monitor Supervised: yes (complete dose in week 1, two in week 2, and 1 in week 3–12; rest unsupervised)			12 weeks	Predictors of remission were higher levels of brain-derived neurotrophic factor (BDNF) and Interleukin-1B, greater depressive symptom severity, and higher post-exercise positive affect. Predictors of treatment non-response were low cardiorespiratory fitness, lower levels of IL-6 and BDNF, and lower post-exercise positive affect. Models including these predictors resulted in predictive values greater than 70% (true predicted remitters/all predicted remitters) with specificities greater than 25% (true predicted remitters/all remitters)
2015	Carneiro et al. 2015 [41]	RCT; only women Clinical depression	13	13	Aerobic exercise group: indoor/outdoor natural circuit workouts AND Pharmacotherapy Sessions: 45–50 min/week; 3x/week Intensity: based on baseline fitness. First month: at least 65% of %HRmax; second month: to 70%; third month: 80%. Diverse Supervised: yes Motivational strategies (e.g., multidisciplinary teams; Facebook page; outings in the sunlight and in pleasant settings; etc.)	Pharmacotherapy only	Physical functioning:  Distance walked in 6 min  Number of times they could sit and stand from a chair in 30 s  A seated medicine ball throw	4 months	Decrease in BDI-II and DASS-21 total score scales in exercise group. Relative to DASS-21, a significant decrease in anxiety and stress is found Improvement in relation to physical functioning parameters in exercise group Anthropometric parameters only significant different between groups in fat mass percentage No differences between groups in weight, body mass index, waist circumference, and self-esteem
2015	Doose et al. 2015 [42]	RCT Unipolar depression	30	16	Walking/running aerobic exercise program at a local sports club Sessions 3x/week, 60 min, outside Intensity: self-selected exercise intensity according to perceived exertion Supervised by teams of coaches and medical students	Wait list	CRF: Fitness Index, VO2max as estimated or UKK 2 km Walk Test	8 weeks	Large reduction of depressive symptoms in HRSD-17 scores. BDI-II, FI scores, and VO2 max did not change significantly
2015	Kerling et al. 2015 [92]	Randomized Pilot trial Inpatient Moderate to severe depression	22	20	Exercise training 3x/week, 45 min: 25 min bicycle and 20 min cross trainer, stepper, arm ergometer, treadmill, etc. as preferred Moderate intensity: 50% of maximum workload from incremental test; above the VAT and below anaerobic lactate threshold Supervised by physicians, group format	Treatment as usual	CRF: VO2peak, VAT, Watts, lactate on bicycle ergometer MetS	6 weeks	Cardiorespiratory fitness (VO2peak, VAT, Watts), waist circumference and HDL cholesterol significantly improved in exercise group. Treatment response (expressed as ≥ 50% MADRS reduction) was more frequent in the exercise group
2014	Danielsson et al. 2014 [47]	RCT MDD			(A) Aerobic exercise: Training in the rehab center (e.g., cross trainer, jumping ropes, stationary bikes, etc.) Intensity: intervals with higher perceived intensity (B) Basic body awareness therapy: body scanning and stretch-release movements, postural stability, movement flow, and free breathing Both programs: 2 sessions/week, 1 h during which 5–8 participants trained at the same time Supervised by experienced physical therapists	Single consultation with advice on PA	CRF: VO2max, submaximal bicycle test	10 weeks	Improvements in MADRS score and cardiovascular fitness in the exercise group. Per-protocol analysis confirmed the effects of exercise and indicated that BBAT has an effect on self-rated depression
2014	Krogh et al. 2014 [84]	RCT MDD	41	38	Aerobic exercise intervention on stationary bikes Sessions: 3x/week, 45 min Intensity: 80% of their maximal heart rate Supervised: yes	Attention CG	CRF: VO2max, bicycle cardiopulmonary exercise test	12 weeks	Post-intervention the mean VO2max increased with 3.90 ml/kg/min in the aerobic exercise group and 0.95 ml/kg/min in the control group The hippocampal volume, BDNF, VEGF, or IGF-1 did not differ between the two groups Positive association found post hoc between change in hippocampal volume and verbal memory and change in hippocampal volume and depressive symptoms
2014	Oertel-Knöchel et al., 2014 [37]	?? MDD and SZ	(A) 16 (B) 17	18	(A) CT combined with aerobic physical exercise: boxing, circuit training Intensity: 60–70% of individual HRmax (calculated from HRmax from ECG) Supervised by a trained physical exercise instructor (B) CT combined with relaxation training (no yoga or PMR, just breathing, “enjoy exercises”) Both 3x/week, 75 min: 30 min CT and 45 min training CT and relaxation conducted by an exercise instructor	Waiting list CG	Complete physical examination, ECG, blood investigation Validated questionnaires	4 weeks	Increase in cognitive performance in visual learning, working memory and speed of processing Increase in subjective quality of life between pre- and post-testing Significant reduction in depressive symptoms and state anxiety The effects in SZ patients compared with MDD patients were stronger for cognitive performance, whereas there were stronger effects in MDD patients than in SZ patients in individual psychopathology values
2012	Krogh et al. 2012 [93]	Outpatient RCT MDD	56	59	Aerobic exercise 3x/week: cycle ergometer Intensity: first 4 weeks: at least 65% of maximal capacity (VO2max), progressing to 70% and 80% during the second and third month, respectively Supervised by a physiotherapist	Stretching, low intensity	CRF: estimated VO2max, bicycle cardiopulmonary exercise test	12 weeks	After the intervention, the mean difference between groups was 20.78 points on the HAM-D17 At follow-up, higher VO2max and visuospatial memory on Rey’s Complex Figure Test and lower blood glucose levels and waist circumference in aerobic exercise group compared with stretching exercise group
2010	Oeland et al. 2010 [94]	Controlled clinical study Panic disorder, generalized anxiety disorder, mild and moderate depression, mild and moderate recurrent depressive disorder	27	21	Group exercise: aerobic training (30 min) as circuit training Intensity: high intensity, at least 65–75% of maximum aerobic capacity AND Non-aerobic weightlifting with five basic exercises for muscles in legs, chest, abdomen, and lower and upper back: 8–10 repetitions with an intensity of 10 RM AND The instructor encouraged the participants to exercise once a week on their own initiative, at least 30 min; they were free to choose intensity and type of exercise 2x/week, 90 min Supervised: yes	Yes, but n.a	Aerobic capacity: submaximal bicycle ergometer test Muscle strength: Senior Fitness Test Questionnaires	20 weeks 12 weeks’ follow-up	Increase of physical activity and VO2max in intervention group VO2max increase was maintained after a 12-week follow-up period
2009	Krogh et al. 2009 [49]	RCT, outpatient Unipolar depression	(A) 55 (B) 55	55	(A) Strength group: circuit training with 6 machine exercises for large muscle groups Intensity: Initially 12 repetitions of 50% of RM 2 or 3 times per exercise. As the patients progressed, the numbers of repetitions were reduced to 10 and 8, and RM was increased to 75% (B) Aerobic group program: 10 different aerobic exercises for large muscle groups: cycling, running, stepping, etc Intensity: During the first 8 sessions, each exercise was done twice for 2 min at an intensity level of 70% of maximal heart rate and followed by a 2-min rest. This gradually increased to a level during the last 8 sessions at which each exercise was done for 3 min at an intensity level of 89%, with a 1-min rest Sessions: 2x/week, 1.5 h Supervised by a physiotherapist	Relaxation group	CRF: VO2max, bicycle ergometry; RM	4 months 6 months’ follow-up	Increase of strength measured by 1 RM in strength training group compared to relaxation group at month 4 Increase of VO2max in aerobic group compared to relaxation group at month 4 No statistically significant effect on cognitive abilities
2009	Hoffman et al. 2008 [95]	RCT MDD	(A) 51 (B) 53 (C) 49	49	(A) Supervised aerobic exercise: 3x/week; individual training ranges equivalent to 70–85% HR reserve, calculated from the HRmax achieved during initial treadmill test (B) Home-based aerobic exercise: one initial training and 2 follow-up sessions with an exercise physiologist A and B: individual training ranges equivalent to 70–85% HR reserve, calculated from the HRmax achieved during initial treadmill test (C) Sertraline	Placebo pill	Aerobic capacity: VO2peak, graded treadmill exercise testing	16 weeks	Higher levels of VO2peak and longer treadmill times in supervised exercise patients than in those who exercised at home No differences in neuropsychological tests between groups Better performance on tests of executive function but not on tests of verbal memory or verbal fluency/working memory in exercise group
2007	Legrand and Heuze 2007 [43]	Pilot study, randomized Depression	(A) 8 (B) 8	7	(A) High-frequency exercise: 3–5 sessions/week, within their THR on a motorized treadmill, a stationary bicycle, or a rowing ergometer (B) High-frequency exercise AND group-based intervention: 3–5 sessions/week AND group support: e.g., collective training sessions, asking participants to wear group T-shirts, encouraging participants to chat and to cheer each other on Supervision by first author of the study	Low-frequency exercise: 30 min/week of one aerobic exercise	Reaction to group intervention: participants’ scores of perceived cohesions Questionnaire sur l’Ambiance du Groupe	8 weeks	Lower depression scores in high-frequency aerobic exercise group than in CG at week 4 and 8 Alleviation in depressive symptoms was not found to be greater in those participants who received a group-based intervention
2002	Penninx et al. 2002 [112]	RCT, single blind Knee arthritis plus depression	(A) 112 low dep: 34 high (B) 115 low; 28 high	113 (36 high-dep)	(A) Resistance exercise: facility-based program, 3x/week, 1 h AND a 15-month home-based program. Repetitions of various upper and lower body exercises with dumbbells and cuff weights Supervised: yes (B) Aerobic exercise: indoor track; walking at an intensity equivalent to 50–70% of the HRR (determined from a screening exercise treadmill test). In months 4–6, the exercise leader visited participants four times and called them six times to offer assistance and support in the development of a walking exercise program in their home environment	Health education	Self-reported disability, 6-min walking speed, knee pain	3 months 15 months’ home-based follow-up	Significant decrease of depressive symptoms in aerobic exercise group compared to control group No such effect was observed for resistance exercise Reduction of depressive symptoms in both participants: with initially high and low depressive symptomatology Significant decrease of disability and pain and increase of walking speed in aerobic and resistance exercise group
1999	Blumenthal et al. 1999 [96]	RCT MDD	(A) 53 (B) 48 (C) 55		(A) Aerobic exercise session: 10 min warm up, 30 min continuous walking or jogging, 5 min cool down (B) Medication: antidepressants: Sertraline hydrochloride (C) Exercise + medications combined Sessions 3x/week Intensity: 70–85% of HRR calculated from HRmax Supervised: yes	n.a	Symptom-limited graded exercise treadmill test under continuous electrocardiographic recording	16 weeks	No statistical difference in groups on HAM-D or BDI scores Patients in the exercise and combination groups showed significant improvements in aerobic capacity, whereas patients in the medication group did not
1989	Martinsen et al. 1989 [45]	RCT Inpatient Depression	51	47	Aerobic exercise: Brisk walks and jogging Intensity: corresponding to approximately 70% of maximum aerobic capacity 3x/week, 1 h, 5–10 persons/group Supervision by an experienced instructor	Non-aerobic, low intensity, muscular strength training	CRF: VO2max, submaximal bicycle ergometer test	8 weeks	Significant increase of VO2max in the aerobic group No change in the non-aerobic group Significant reduction of depression scores in both scores during the study Correlation between increase in physical fitness and reduction in depression scores was low

BBAT basic body awareness therapy, BDI-II Beck Depression Inventory-II, BDNF brain-derived neurotrophic factor, CAT continuous aerobic exercise training, CG control group, CRF cardiorespiratory fitness, CT cognitive training, DASS-21 Depression Anxiety and Stress Scale-21, ECG electrocardiogram, FI-Score fitness Index Score, HAM-D17 Hamilton Depression Scale-17, HR_max heart rate maximum, HRR heart rate reserve, HRSD-17 Hamilton Rating Scale for Depression-17, IG Intervention Group, IGF-1 insulin-like growth factor 1, IPAQ International Physical Activity Questionnaire, IPAQ-SF International Physical Activity Questionnaire–Short Form, MADRS Montgomery Asberg Depression Rating Scale, MDD Major depressive disorder, MetS Metabolic Syndrome, n.a. not applicable, PA Physical activity, PMR Progressive muscle relaxation, RCT randomized controlled trial, RM Repetition maximum, SIT sprint interval training, THR target heart rate, UKK 2 km Urho Kaleka Kekkonen 2-km Walk Test, VAT Ventilatory anaerobic threshold, VEGF vascular endothelial growth factor, VO2_max maximal oxygen uptake, VO2_peak peak oxygen uptake