Edited by: Michele Fornaro, Columbia University, New York State Psychiatric Institute, United States
Reviewed by: Stefano Novello, Università degli Studi di Napoli Federico II, Italy; Andrea Fusco, Università degli Studi di Napoli Federico II, Italy
This article was submitted to Mood and Anxiety Disorders, a section of the journal Frontiers in Psychiatry
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Depression is considered a leading cause of disability worldwide and a major contributor to the overall global burden of disease (
Moreover, the treatment with antidepressant medication is accompanied with poor compliance (
The WHO (
The beneficial effect of physical exercise in the treatment of depression has previously been examined in several meta-analyses. Due to a large heterogeneity of included studies in terms of study quality, diagnosis of depression, mode of exercise, included subjects and duration, the effect sizes given as standardized mean difference (SMD) range between small effects in favor of exercise [−0.34 (
Even though the antidepressant effects of exercise for the treatment of depression are well-understood, the moderating effect of training prescriptors (e.g., exercise frequency, intensity, duration of sessions, number of sessions) and the difference between neuromuscular vs. endurance training remains elusive to date. A differentiation between neuromuscular and endurance exercise seems beneficial as patients do have different exercise preferences and both exercise modes cause different adaptations on behavioral and molecular level (
The present meta-analysis was performed along the PRISMA guidelines (
In addition, recent reviews and cited articles about exercise and depression were screened and potentially eligible articles were added to the library. Duplicates were identified and excluded. The remaining studies were gradually screened using the titles, abstracts and full-texts of the potentially eligible articles (Figure
Flow chart of the different phases of study screening and selection.
Eligible studies had to meet the following inclusion criteria based on the PICOS approach ( - (P) Participants had to be ≥ 18 years of age and were either diagnosed using the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for MDD, a diagnosis of MDD with the International Classification of Diseases (ICD-10), 10th revision, a diagnosis of MDD using the Research Diagnostic criteria (RDC), a diagnosis for depression using the Structured Clinical Interview for Depression (SCID), the 21-item Beck Depression Inventory II (BDI-II), the Geriatric Depression Scale (GDS), or the 9-item Patient Health Questionnaire (PHQ-9). - (I) The (randomized) controlled trials should investigate exercise in the sense that improvement or maintenance of at least one component of physical fitness was the objective. Physical exercise sessions had to be supervised by coaches, medical students or similar experts. The exercise interventions could either be aerobic exercises, strength exercises, functional exercise training, yoga or tai chi. The participants completed at least 10 physical exercise sessions. - (C) There must be a control group (CON), which did not follow a physical exercise intervention like aerobic exercise, strength exercise, yoga exercise, stretching, or relaxation exercise. The control group can either be a control group with behavioral therapy, light therapy, medication therapy, a placebo-group, or an inactive control group. - (O) At least one outcome for the depression score had to be evaluated in the study. That could either be the Beck Depression Score (BDI) or BDI-II, Hamilton Rating Scale for Depression (HAM-D, HRSD, HDRS), Montgomery-Åsberg Depression Rating Scale (MADRS), Center for Epidemiological Studies Depression Scale (CES-D), the Geriatric Depression Scale (GDS), or the 9-item Patient Health Questionnaire (PHQ-9). Depressive symptoms must be measured or reported pre- and post-intervention. - (S) Studies had to be (randomized) controlled interventions with pre- and post-testing and an intervention duration of at least 10 days and 10 sessions, respectively.
Studies were excluded when they met one of the following criteria: (1) children or adolescents <18 years old. (2) Participants without a diagnosis of depression. (3) Participants with chronic illnesses or further diseases apart from MDD (e.g., diabetes). (4) Inappropriate physical exercise interventions or interventions without physical exercise (e.g., mindfulness-based stress reduction therapy). (5) Exercise interventions with non- supervised sessions. (6) Invalid target outcomes (see inclusion criteria). (6) No adequate control condition or control group.
The methodological quality of all eligible trials was assessed using the PEDro (Physiotherapy Evidence Database) scale. The PEDro scale contains 11 dichotomous (yes or no) items, in which the criteria 2–9 rate randomization and internal validity and the criteria 10–11 rate the presence of statistical replicable results. Criterion 1 relates to the external validity but will not be used to calculate the PEDro score.
Studies were rated independently by two non-blinded reviewers (LN and EL) and they needed to obtain consensus on every item. Discordant study ratings were discussed point to point by the two reviewers (LN and EL) to come to a decision. To represent a high-quality study, the PEDro score had to be ≥6 on the scale from 0 to 10.
The intervention was the mean change in depressive symptoms from baseline to post-intervention measures in the exercise groups compared to the control groups. Stratification to sex, medication and severity was not doable due to the small resulting subgrouping and overall power of the calculations. The standardized outcome was calculated as the standardized mean differences (SMD) and presented as means together with 90% confidence intervals (CI). If included studies contain more than one outcome measure meeting our criteria (mean change pre-and post in depressive symptoms), we prioritized the common scales BDI/BDI-II or HAMD to further minimize heterogeneity of our findings [e.g., (
The following data were extracted by two researchers (LN and EL) and transferred to an excel spread sheet: sample (number of participants in the intervention group and in the control group), exercise (type of exercise, number of sessions, duration of one session, weekly frequency, intensity of the sessions), outcome [pre- and post-test means and standard deviations (SD)]. Exercise intensity was described in the studies in several ways. For the sake of comparability, the different measured values (i.e., maximum oxygen uptake, heart rate reserve or Borg Scale) were categorized in the following intensity groups to make the comparison of underlying exercise intensities more suitable: low intensity (40% of maximal heart rate), low to moderate intensity (50%), moderate intensity (60%), moderate to high intensity (70%), and high intensity (80%). The exercise intensity in trials with Tai Chi or Yoga exercise interventions was not described thus we assumed low to moderate intensity.
Further relevant study information concerning reference (author and date of publication), study- design, number of participants, mean age, interventional characteristics (experimental and control group) as well as training characteristics and outcome measures were additionally described in Table
Study overview of neuromuscular exercise interventions.
1 | ( |
Randomized, controlled trial | Sedentary women with a BDI-II score over 14, aged 18–50 years, |
INT ( |
(a) INT, croup based yoga sessions with 5 min of pranayama (breathing exercise), 5 min warm-up, 40 min of asana (yoga poses) practice and 10 min of savasana (meditation/relaxation). No intensity described, assumption to be low to moderate intensity |
12 weeks, 2 sessions/week (24 training sessions); each session lasted 60 min | BDI-II |
2 | ( |
Randomized, controlled trial | Women with diagnosed depression (Research Diagnostic criteria), aged 18–35 years |
INT ( |
(a) INT, aerobic exercise prescription on the other over- view |
8 weeks, 4 sessions/week (32 training sessions); no general exercise duration | BDI and HRSD |
3 | ( |
Randomized, controlled trial | Pregnant women with diagnostic criteria for depression on SCID, <40 years old, |
INT ( |
(a) INT, yoga/tai- chi group sessions with a duration of 20 min. No intensity described, assumption that Tai- Chi lessons have moderate intensity |
12 weeks, 1 session/week (12 training sessions); each session lasted 20 min | CES-D |
4 | ( |
Comparative, controlled trial with an open- labeled design | Out-patients, fulfilled DSM-IV criteria for MDD, |
INT ( |
(a) INT, yoga only, not in the meta- analysis involved |
First 2 weeks daily train- ing, next 2 weeks weekly interval (16 training ses- sions); each session lasted 60 min | HRSD |
5 | ( |
Randomized, controlled trial | Older adults over 65 years, with a GDS- score > 5, |
INT ( |
(a) INT, physical exercises including a warm-up, cardio- vascular exercises (walking with waving or clapping hands), muscle strength exercises (triceps brachii, biceps brachii, quadriceps femoris, iliopsoas) with a rated Borg Scale score between 12 and 14 and a cool-down |
12 weeks, 3 sessions/week (36 training sessions); each session lasted 50 min | GDS-15 |
6 | ( |
Randomized, controlled trial | Older adults over 60 years, fulfilled DSM- IV criteria for MDD, |
INT ( |
(a) INT, 2 h of Tai Chi Chi; TCC employs “meditation through movement” No intensity described, assumption to be moderate intensity |
10 weeks, 1 session/week (10 training sessions); each session lasted 120 min | HRSD |
7 | ( |
Randomized, controlled trial | Outpatient with a GDS- score > 10, aged over 53 years, |
INT ( |
(a) INT, exercise classes with predominantly weight- bearing exercise performed to music. There was a warm-up period of 5–10 min and a cool-down period at the end. No intensity described |
10 weeks, 2 sessions/week (20 training sessions); each session lasted 45 min | HRSD and GDS |
8 | ( |
Randomized, naturalistic con- trolled trial | Women, aged 40–60 years, fulfilled DSM- IV criteria for MDD, |
INT ( |
(a) INT, each session included a warm up (5 min), physiological strengthening with machines (50 min) and a cool-down (5 min). The exercise machines allowed different exercises for arms, legs and postural muscles and were changed every 4 min. There is no specific exercise intensity described. Further- more, they received pharmacological therapy |
32 weeks, 2 ses- sions/week (64 training sessions); each session lasted 60 min | HAM-D |
9 | ( |
Randomized, controlled pilot trial | Aged over 18 years, diagnosis of MDD, |
INT ( |
(a) INT, 90- min practice sessions comprised of classical yoga breathing techniques, mindful body postures and final deep relaxation pose. No exercise intensity described, assumption that hatha yoga is low intensity exercise |
8 weeks, 2 sessions/week (16 training sessions); each session lasted 90 min | BDI |
10 | ( |
Randomized, controlled trial | Aged 60 years or older, fulfilled DSM- IV criteria for MDD, |
INT ( |
(a) INT, a high intensity (80% of one repetition maximum) progressive resistance training for the large muscle groups with 3 sets of 8 repetitions on each machine. The exercises included chest press, lat pulldown, leg press, knee extension and knee flexion. (b) CON, control subjects engaged in a health education program of lectures and videos | 10 weeks, 3 sessions/week (30 training sessions); each session lasted 50 min | BDI |
11 | ( |
Randomized, controlled trial | Aged 60–85 years, fulfilled DSM-IV criteria for MDD, |
INT ( |
(c) INT, a high intensity (80% of one repetition maximum) progres- sive resistance training for the large muscle groups with 3 sets of 8 repetitions. Exercise machines included chest press, lat pulldown, leg press, knee extension and knee flexion |
8 weeks, 3 sessions/week (24 training sessions); each session lasted 65 min | HRSD and GDS |
Study overview of endurance exercise interventions.
1 | ( |
Randomized, controlled trial, 3 arms | Older adults ≥50 years, fulfilled DSM- IV criteria for MDD, |
INT ( |
(a) INT, aerobic exercise sessions with a 10-min warm- up, 30 min walking or jogging with 70–85% of HRR and 5 min cool-down exercises; furthermore, patients received sertraline dosage of 50 mg up to 200 mg daily |
16 weeks, 3 ses- sions/week (48 training sessions); each session lasted 45 min | HAMD-D and BDI |
2 | ( |
Randomized, parallel group, pla- cebo-con- trolled trial | Outpatients, fulfilled DSM-IV criteria for MDD, aged over 40 years, |
INT ( |
(a) INT, aerobic exercise sessions with a 10-min warm- up, 30 min walking or jogging with 70–85% of HRR and 5 min cool-down exercises. |
16 weeks, 3 ses- sions/week (48 training sessions); each session lasted 45 min | HAM-D |
3 | ( |
Randomized, controlled trial, 2 arms | Women aged 18–65 years, with ICD-10 diagnosis for depres- sion, |
INT ( |
(a) INT, aerobic exercise sessions with a 10- min warm up, 30 min of aerobics with 65–75% of maximal heart rate and 5 min cool- down |
16 weeks, 3 session/week (48 training sessions); each session lasted 45–50 min | BDI-II |
4 | ( |
Not random- ized, con- trolled trial | Women, aged 20–64 years, with ICD-10 diagnosis for depres- sion, |
INT ( |
(a) INT, progressive program of cardiovascular exercise with a warm-up, low- impact aerobics gymnastics, fun dance and walking and a cool- down. Exercise inten- sity is not described but we assumed that low-impact exercises have moderate exercise intensity. Further- more, the patients received 20 mg of Fluoxetine |
8 weeks, 3 sessions/ week (24 training sessions); session duration increased from 45 to 60 min | BDI |
5 | ( |
Single-site, three- armed, randomized controlled trial | Adults, aged 18–65 years, fulfilled DSM- IV criteria for MDD, |
INT ( |
(a) INT, aerobic exercise sessions with a warm- up phase of 5–10 min, 45 min of interval training (inten- sity 16–17 on the Borg Scale) and 5 min cool- down phase with stretching exercise |
8 weeks, 2 sessions/ week (16 training sessions); each session lasted 60 min | MADRS |
6 | ( |
Pragmatic, randomized, controlled trial | Adults, slightly over- weight, aged 18–65 years, with ICD-10 diagnosis of depression, |
INT ( |
(a) INT, sessions with 10–15 min warm-up, 30–40 min walk- ing/running (average Borg Scale Score 11.6) and 10–15 min cool-down. Participants could self- select the exercise intensity. |
8 weeks, 3 ses- sions/week (24 training sessions); each session lasted 60 min | BDI-II |
7 | ( |
Randomized, controlled trial | Women with diagnosed de- pression (Research Diag- nostic criteria), aged 18–35 years, |
INT ( |
(a) INT, 5–10 min warm-up, walking or running with 80% of maximal work capacity on an indoor track, 5–10 min cool- down |
8 weeks, 4 ses- sions/week (32 training sessions); no general exercise duration | HRSD and BDI |
8 | ( |
Randomized, controlled, quasi- experi- mental trial | Female students, diagnosed with MDD, aged 18–25 years, |
INT ( |
(a) INT, 10 min warm-up, three sets of six min running with moderate intensity (60–65% of maximal heart rate) and 3 min relax- ing between the sets. Each week, 1 min had been added to the run- ning time of each set |
8 weeks, 3 ses- sions/week (24 training sessions); session duration in- creased from 40 to 60 min | BDI |
9 | ( |
Randomized, controlled trial | Adults, fulfilled the ICD- 10 criteria for MDD, aged 18–64 years, |
INT ( |
(a) INT, 10 min warm-up, an interval- training exercise regimen (upper and lower extremity exercise training) with 3 bouts of 5- min workout with an intensity of 40–59% HRR. After the 5- min workouts, participants exercised at a reduced intensity of 20–39% HRR for 5 min, making together 30 min of aero- bic interval training | 3 weeks, 5 ses- sions/week (15 training sessions); each session lasted 40 min | BDI and MADRS |
10 | ( |
Randomized, controlled trial | Inpatients in the Hannover Medical School, fulfilled DSM-IV criteria for MDD, |
INT ( |
(a) INT, exercise training with 25 min workout phase on a bicycle ergometer and 20 min with personal preference (cross-trainer, stepper, arm ergometer, treadmill, recumbent or rowing ergome- ter) with an intensity of 50% of maximum oxygen uptake |
6 weeks, 3 ses- sions/week (18 training sessions); each session lasted 45 min | BDI-II and MADRS |
11 | ( |
An open-ran- domized, con- trolled trial | Adults, inpatients with a current antidepressant drug therapy, fulfilled DSM-IV criteria for MDD, |
INT ( |
(a) INT, aerobic exercise group; the intervention consisted of 30 min of daily brisk walking or jogging with an exercise intensity of 65–75% of age- predicted maximal heart rate |
10 days, one ses- sion/ day (10 train- ing sessions); each session lasted 45 min | BDI-II |
12 | ( |
Randomized, controlled trial | Inpatients, aged 18–60 years, fulfilled DSM-IV criteria for MDD, |
INT ( |
(a) INT, a program of systematic aerobic exercise consisting of 1-h training with an intensity of 50–70% of maximal work capacity |
9 weeks, 3 sessions/week (27 training sessions); each session lasted 60 min | BDI |
13 | ( |
Randomized, controlled trial | Outpatients, aged 18–60 years, diagnosed for MDD. |
INT ( |
(a) INT, 5 walks per week (1 was supervised on a treadmill) with 5 km/h average speed; Participants were asked to perform the remaining 4 walks with the same intensity. All patients were medicated with antidepressants |
12 weeks, 5 sessions/week (one was supervised); each walk lasted be- tween 30 and 45 min | HAM-D 17 |
14 | ( |
Randomized, controlled trial | Female smokers, aged 18- 55 years, with moderate to severe depressive symp- toms, |
INT ( |
(a) INT, participants exercised on cardiovascular equipment of their choice. Sessions comprised of a 5-min warm-up, 20–30 min of aerobic activity and 5 min cool- down. Exercise was gradually progressed from moderate to vigorous intensity. Participants started with 20 min moderate and 4 min vigorous intensity by adding weekly 2–4 min of vigorous exercise –> by week 12, participants completed 3 sessions with 30 min of vigorous intensity |
12 weeks, 3 sessions/week (36 training sessions); each session lasted 30–40 min | PHQ-9 |
15 | ( |
Randomized, controlled clinical trial | Outpatients, aged 18 to 55 years, fulfilled DSM-IV criteria for MDD, |
INT ( |
(a) INT, exercise session consisted of continuous and intermittent aerobic activ- ity with an intensity of 60% VO2 max at the beginning. Intensity progressively increased up to 85% of VO2max at the end |
4 weeks, 4 sessions/week (16 training sessions); no general exercise duration | BDI and HAM-D |
16 | ( |
Randomized, controlled trial | Aged between 65 and 85% years, sedentary, diagnosis of MDD, |
INT ( |
(a) INT, 10 min warm-up, followed by cycling with an intensity that not exceed 70% of their peak heart rate and a 5–10 min cool-down. Patients reach 50 mg Sertraline within 2 weeks |
24 weeks, 3 sessions/week (72 training sessions); each session lasted 60 min | HRSD |
17 | ( |
Randomized, controlled trial | Depressed patients aged 19–58 years, |
INT ( |
(a) INT, each session consisted of a warm-up routine and stretching exercises, followed by a running programme. Patients continued to receive the usual psychiatric treatment (supportive psychotherapy) |
12 weeks, 3 super- vised sessions/week; no exercise duration pre- scribed | BDI |
The SMDs (with 90% CIs) of the outcome were calculated as a measure of the effectiveness of the treatment and could be either positive or negative. We used the adjusted Hedges' g equation (Equation 1) where m1i is the post- treatment mean of the intervention group and m2i is the post- treatment mean of the control group, divided through the pooled standard deviation si. The adjusted Hedges' g equation was used to take small sample biases into account.
The Cochrane Review Manager Software (Version 5.3) was used to calculate the inverse-variance method according to Deeks and Higgins (
Based on the recommendations of Cohen (
Further, we conducted a multivariate meta-regression analysis to examine the effects of the moderator variables on the study effect sizes. Our potential moderator variables were number of exercise sessions, frequency of exercise sessions, exercise intensity or exercise session duration.
We identified 10,831 articles as potentially relevant throughout the search procedure (Figure
Across the 27 included studies, 17 intervention trials comprised two study arms with an endurance intervention and with a control condition and 10 intervention trials comprised two study arms with neuromuscular interventions and control conditions. In total, 1'452 depressed participants out of the included 27 trials were used for our meta-analysis with meta-regression. 286 participants received neuromuscular exercise (Table
The mean study quality of the endurance intervention trials was 6.2 of the PEDro-scale with a range between 4 and 8 (Table
PEDro scores and sum of the included endurance intervention trials.
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The mean study quality of the neuromuscular intervention trials was 6.6 with a range between 4 and 8 (Table
PEDro scores and sum of the included neuromuscular intervention trials.
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The overall mean PEDro score including all endurance and neuromuscular intervention trials was 6.41 with a range between 4 and 8 (Tables
The funnel plot of the endurance intervention studies (Figure
Funnel plots for publication bias in the included neuromuscular intervention studies
The funnel plot of neuromuscular intervention studies (Figure
The results of our meta-analysis with all included studies (Figure
Analysis of depressive symptom outcomes for exercise interventions vs. control groups. SE, standard error; CI, confidence interval; Std., standardized; IV, independent variable.
Further, we conducted a sensitivity analysis due to the methodological weakness of several studies with the assumption that the effect size could be exaggerated in favor of exercise. The pooled data from all included studies with good methodological quality (studies with a PEDro score ≥ 6) still showed a large significant improvement in favor of exercise interventions compared to the control condition [SMD: −0.83 (90% CI: −1.13 to −0.54);
Sensitivity analysis of depressive symptom outcomes for exercise interventions vs. control groups in studies with good methodological quality. SE, standard error; CI, confidence interval, Std., standardized; IV, independent variable.
The results of the present meta-analysis show moderate to large effects in favor of endurance exercise interventions compared to the control condition [SMD: −0.79 (90% CI: −1.10 to – 0.48);
Depressive symptom outcomes for endurance exercise interventions vs. control groups. SE, standard error; CI, confidence interval; Std., standardized; IV, independent variable.
Very large effects were found in favor of neuromuscular exercise interventions compared to the control condition [SMD: −1.14 (90% CI: −1.50 to −0.78);
A summary of the results of the multivariate meta-regression analysis in endurance interventions is presented in Table
Multivariate meta-regression analysis results in endurance interventions.
Intercept | 2.46 | 2.82 | 0.38 | −3.07; 7.99 |
Duration of sessions | −0.06 | 0.02 | 0.01 | −0.11; −0.01 |
Frequency | −0.24 | 0.18 | 0.18 | −0.60; 0.12 |
Intensity | 0.01 | 0.02 | 0.81 | −0.04; 0.05 |
Number of sessions | 0.01 | 0.01 | 0.50 | −0.01; 0.02 |
A summary of all meta-regression analyses in neuromuscular interventions is presented in Table
Multivariate meta-regression analysis results in neuromuscular interventions.
Intercept | 3.133 | 1.999 | 0.12 | −0.78; 7.05 |
Duration of sessions | −0.009 | 0.011 | 0.44 | −0.03; 0.01 |
Frequency | 0.002 | 0.171 | 0.99 | −0.33; 0.34 |
Intensity | −0.054 | 0.028 | 0.05 | −0.11; −0.00 |
Number of sessions | −0.017 | 0.02 | 0.38 | −0.06; 0.02 |
To the best of our knowledge, this is the first meta-analytical review with meta-regression that examined the differential effects of endurance vs. neuromuscular exercise interventions for the treatment of depression taking exercise training prescriptors and study quality into account. A differentiation between neuromuscular and endurance exercise seems beneficial as patients do have different exercise preferences and both exercise modes cause different adaptations on behavioral and molecular level (
Our meta-analysis suggests a large significant overall effect size of
Our sensitivity analysis differentiating the endurance and neuromuscular exercise intervention effects resulted in a meaningful difference of effect size when considering strong studies based on PEDro score evaluation. Thus, we conclude that neuromuscular exercise interventions can be more effective than endurance exercise interventions in the treatment of depression. Allocation of patients either to endurance or neuromuscular exercise training programs could be conducted based on individual preferences, emphasizing the potential of strength training. The comparison of our results with earlier meta-analyses is however quite difficult. One available meta-analysis of Silveira et al. (
In contrast, Rethorst et al. (
We found significant moderating effects for the training prescriptors “exercise duration” in the way that an extended exercise duration strengthened the antidepressant effect of endurance exercise interventions. We found an antidepressant effect size increase of −0.62 for exercising 10 min longer. Furthermore, we found significant results for the training prescriptor “exercise intensity” in the way that an increased exercise intensity strengthened the antidepressant effect of neuromuscular exercise interventions. Furthermore, we found an effect size increase of −0.54 in favor of neuromuscular exercise for a 10% increase of exercise intensity. Based on these findings, we cautiously suggest that high intensity neuromuscular exercise can be more effective than low intensity neuromuscular exercise in the treatment of depression. Nevertheless, this conclusion is debatable because of different descriptions of the exercise intensity used in the included neuromuscular intervention trials.
Previous meta-analyses revealed different results in their analyses. Silveira et al. (
Another meta-analysis (
The present meta-analytical review was conducted according to the PRISMA statement (
The calculated effect sizes were accompanied with a large heterogeneity between the included studies and reasonably narrow confidence intervals. Therefore, our findings provide a comprehensive view of the differential effects of endurance vs. neuromuscular exercise interventions in the treatment of depression.
However, depressive disorders can encompass a plenty of different signs and symptoms which could be also in contrast to each other (DSM-5) such as decreased mood tone, apathy, emotional blunting, hypersomnia, lack of energy, anhedonia, but also irritability, anxiety, hyperphagia, insomnia, and motor activation. A major depressed patient with a melancholic pattern characterized by a marked energy impairment is not likely to benefit from physical exercises more than antidepressant drug administration. Thus, exercise should only be administered as a complementary treatment therapy and not as a substitute for pharmaceutical therapy. In line with this point, a lack of patients' stratification according to severity of symptoms of the underlying studies might provoke a selection bias, as a patient with a high score at HAMD could be less prone to undergo physical exercise in comparison with a patient with less severe depressive symptoms. Moreover, selected studies had to provide adult patients who met criteria for depressive disorder according to DSM IV (validated by SCID), ICD-10, or RDC. On the other hand, BDI-II, GDS, and PHQ-9 are currently used to assess the severity of depressive symptoms, but they are not diagnostic scales. Thus, subgroup analyses on severity of depression and exercise effect was not calculable due to the small resulting sample and used scales. The majority of the included trials show clinical difference between severe, moderate and mild depressions which provoke a lack of stratification which can be clinically relevant too and could be a possible bias. Finally, the control groups have practiced other therapies, also pharmacotherapy, this is a considerable bias with lack of stratification.
Our findings on the influence of different exercise training prescriptors might be biased because of the inclusion of the weaker studies in the analysis. A meta-regression analysis only including the studies with sound methodological quality could lead to different conclusions. Also, the different exercise intensity descriptions in the trials and our transformation to percentage groups to enable adequate comparison may create a limitation to our meta-regression analysis. Further, the blinding of therapist, subject and assessor is impossible in exercise intervention and this may introduce bias. There are also several studies that compared combined exercise and medication treatment to only antidepressant medication treatment. The impact of the antidepressant medication treatment in these studies is unknown and therefore, we do not know how big this potential limitation for our meta-analysis might be.
Our meta-analysis underpins that exercise training is generally an effective complementary treatment option for depressed patients. Interestingly, neuromuscular exercise interventions can be more effective than endurance exercise interventions when only considering stronger trials. This finding underpins the need of allocating patients to neuromuscular training based on scientific evidence and individual preferences, goals and barriers. To confirm this finding, further randomized controlled trials with clear defined strength training interventions are required. To strengthen our findings regarding the moderation of exercise duration in endurance interventions and exercise intensity in neuromuscular interventions, concurrent training parameters in prospective randomized controlled trials are needed.
Overall, further randomized controlled trials of exercise interventions following the PICOS approach and clearly defined training parameters are required, especially with severely depressed patients in order to state more on the potential of neuromuscular and endurance training in patients that might be less prone to complementary exercise-based treatments. However, strength and endurance training with longer duration and intensities, respectively, should be progressively embedded into treatment regimen of depressed patients.
LN and LD wrote the whole review of abstract, introduction, material and methods, results, discussion and made tables and figures. LN and LD did study selection and discussed data extraction. LN and EL did methodological quality assessment and statistical analysis. OF and LZ gave comments and advices. AM and MG gave comments and advices to the final version of the manuscript. All authors approved the final version for submission.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.