Physical activity in the treatment-resistant depression and non-remitted depression: a systematic review of randomized controlled trials

Identification, selection, and eligibility criteria of studies

For the assessment and selection of the scientific articles, the following PICOS (Participant, Intervention, Comparator, Outcome, Study design) question was utilized:

Two authors (S.M-M and J.E-O) were responsible for retrieving selected articles having in mind the following inclusion criteria: (a) Treatment-resistant or non-remitted depression, (b) physical activity or exercise, (c) clinical trials or experimental trials, (d) studies published in English, (e) scientific studies but not such as a book, magazines, online websites, reports, guidelines or recommendations or thesis. Scientific studies were excluded if they did not accomplish the eligibility PICOS questions. The following exclusion criteria were: (a) suffered depression and responded to treatment, (b) included PA interventions combined with other strategies, (c) the intervention was not adaptations of PA (d) had less than 18 of age, (e) there was not a comparison between pre-and post-intervention, and (f) it was not an RCT.

Data sources and search strategy

A systematic literature search was conducted in June 2024 using the following online databases: PubMed, Cochrane Central Register of Controlled Trials, Scopus, SPORTDiscus, and Web of Science. The search was developed by synonyms of treatment resistant and physical activity or exercise and was performed by the followings search strategies: In PubMed (“major depression” OR “depression disorder” OR “depressive disorder” OR “treatment resistant depression” OR “non-remitted major depressive” OR “poorly responsive depressive” OR “treatment-resistant patients” OR “treatment-resistant major depressive”) AND (“physical activity” OR exercise); in Cochrane, Web of Science and SPORTDiscus “major depression” or “depression disorder” or “depressive disorder” or “treatment resistant depression” or “nonremitted major depressive” or “poorly responsive depressive” or “treatment-resistant patients” or “treatment-resistant major depressive”) and (“physical activity” or exercise); and in Scopus “major depression” OR “depression disorder” OR “depressive disorder” OR “treatment resistant depression” OR “nonremitted major depressive” OR “poorly responsive depressive” OR “treatment-resistant patients” OR “treatment-resistant major depressive” AND ““physical AND activity” OR “exercise””.

Data screening and extraction

After duplicates were removed, the articles were revised by two independent authors (S.M-M and J.E-O) according to the title and abstract by the search strategy. After excluding studies based on title and abstract, any articles that remained questionable were analyzed more thoroughly by reading the full text. The chosen articles were read and assessed using eligibility criteria. In case of discrepancies, a consensus would be reached among the authors. The following articles were revised using Rayyan Intelligent Systematic Review Software: the software was developed specifically to expedite the initial screening of abstracts and titles using a semi-automation process. Likewise, in the publications, details of the investigation appear to show the screening by eligibility criteria.

Outcome parameters

The more significant outcome for this analysis was the improvement of depression by PA or exercise in TRD and NRD.

Quality appraisal

For assessing included scientific articles, the Physiotherapy Evidence Database (PEDro) scale (de Morton, 2009) and Oxford’s Evidence Levels were used (Howick et al., 2009). The PEDro scale rates RCT on a scale from 0 (low quality) to 11 (high quality) related to scientific rigor (de Morton, 2009). Each measure is rated “yes” or “no”. Given that the assessors are rarely blinded and that it is impossible to blind the participants and investigators in supervised PA interventions, the items related to blinding (5–7) were removed from the scale. For this reason, the maximum result on the modified PEDro 8-point scale was 7 (highest score), as the first item is not included in the total score. The qualitative ratings were adjusted to those used in previous exercise-related systematic reviews as follows: 6–7 = “excellent”; 5 = “good”; 4 = “moderate”; and 0–3 = “poor”. Oxford’s Evidence levels range from 1 to 5, with 1a being systematic reviews of high-quality RCT, 1b individual RCT with a narrow confidence interval, 2a systematic review of cohort studies, 2b individual cohort study, 3a systematic review of a case-control study, 3b individual case-control study, 4 case-series, and 5 being expert opinions (Howick et al., 2009). Two researchers (S.M-M and J.E-O) inspected the methodology of each study independently. Disagreements regarding the appraisal of methodological quality were resolved through discussion between the reviewers.

Selection of studies

The database searches identified 10777 references (see Extended data, (Etxaniz-Oses et al., 2023)). 3189 from PubMed, 1219 in Cochrane, 5698 in Web of Science, 567 in Scopus, and 104 in SPORTDiscus. After eliminating duplicates (n=3973) a total of 6804 articles were removed by title, abstract, study design, population, or type of intervention. Consequently, 20 articles were assessed for eligibility, and the assessment was done in full text. Finally, 11 articles were included in the systematic review. These were published between 2002 and 2017, showing the importance of PA in TRD and NRD (Supplementary data).

Principal results and characteristics of studies

Physical activity as a predictor of various factors of mental illness as well as producing benefits in depression was the highlight of the articles (Carta et al., 2008; Greer et al., 2014, 2016; Mather et al., 2002; Mota-Pereira et al., 2011; Rethorst et al., 2013a, 2013b, 2016; Toups et al., 2011, 2017; Trivedi, Greer, Blair, Church, Carmody, Grannemann, Galper, Dunn, Earnest, Sunderajan, & Henley, 2011).

The supplemental data included the main characteristics of the accepted studies in this systematic review. First, it is important to highlight that eight of the 11 chosen articles were from the same research project in the TRD or NRD population (n=275). Therefore, no variability was seen in the population and study design (i.e., two groups comparing different volumes of exercise doses) (Greer et al., 2014, 2016; Rethorst et al., 2013a, 2013b, 2016; Toups et al., 2011, 2017; Trivedi et al., 2011). Nevertheless, the other three articles were not in the same research project (Carta et al., 2008; Mather et al., 2002; Mota-Pereira et al., 2011). Concerning the type of PA assessed, while two articles conducted a novelty concurrent exercise intervention (i.e., including endurance and resistance training in the same session) (Carta et al., 2008; Mather et al., 2002), a endurance training approach was observed in the other articles’ intervention, such as only aerobic continuous exercise (treadmill or cycle-ergometer) (Greer et al., 2014, 2016; Rethorst et al., 2013a, 2013b, 2016; Toups et al., 2011, 2017; Trivedi et al., 2011), or weight-bearing strengthening exercise (Mota-Pereira et al., 2011). None of the control groups performed any particular exercise, but pharmacological treatment (Carta et al., 2008) or health-educational talks (Mather et al., 2002).

In terms of the weekly frequency and time (volume) of PA, variability was shown in the studied articles (see Extended data, (Etxaniz-Oses et al., 2023)). First, there was only one intervention five days per week (Mota-Pereira et al., 2011), while the rest of the articles were performed two days per week. Second, the duration of the session ranges lasting from 45 to 60 minutes. In addition, the period of PA or exercise intervention to analyze the changes ranged from 10 (Mather et al., 2002) to 12 weeks (Greer et al., 2014, 2016; Mota-Pereira et al., 2011; Rethorst et al., 2013a, 2013b, 2016; Toups et al., 2011, 2017; Trivedi et al., 2011); but on the other hand, there was one article with a period of eight months of assessment (Carta et al., 2008), and only one study presented a follow-up assessment after 24 weeks (Mather et al., 2002). All the reviewed studies used moderate intensities for exercise and continuous endurance training controlled by a heart rate monitor (Carta et al., 2008; Greer et al., 2014, 2016; Mota-Pereira et al., 2011; Rethorst et al., 2013a, 2013b, 2016; Toups et al., 2011, 2017) and rate of perceived exertion (Mota-Pereira et al., 2011). However, in two studies, the intensity was not mentioned (Carta et al., 2008; Mather et al., 2002), and another survey carried out endurance training on the treadmill with an absolute exercise intensity of 5 km/h (Mota-Pereira et al., 2011). In this sense, the rest of the articles performed two different exercise doses (i.e., low dose: 4 kcal/kg/week (KKW) equivalent to 75 min/week, and high dose: 16 KKW equivalent to 210 min/week (Greer et al., 2014, 2016; Rethorst et al., 2013a, 2013b, 2016; Toups et al., 2011, 2017; Trivedi et al., 2011).

Overall, after PA intervention, in all but one of the reviewed articles (Rethorst et al., 2016), depression symptoms and functioning parameters improved, both in the TRD and NRD. The Hamilton Rating Scale for Depression (HRSD), Inventory of Depressive Symptoms-Clinical rated (IDS-C), Clinical Global Impression (CGI), and Geriatric Depression Scale (GDS), were the most widely used scales for depression screening (Carta et al., 2008; Mather et al., 2002; Mota-Pereira et al., 2011; Rethorst et al., 2013a, 2013b). In addition, the quality of life assessed with different instruments such as SF-36 and The World Health Organization Quality of Life (WHOQOL) also improved significantly (Greer et al., 2016). Further, sleep quality (Rethorst et al., 2013a), pro-inflammatory levels (Rethorst et al., 2013b), and some biomarkers of depression (Toups et al., 2011) showed better values after PA intervention. In addition, executive function and working memory were improved depending on the exercise volume. Still, psychomotor speed, attention, visual memory, spatial planning, instrumental and expressive roll, and cognitive function improved irrespective of the type or dose of exercise participants undertook (Greer et al., 2014, 2016). The remission of the participants also improved and was achieved in response to antidepressants with the PA as an adjuvant program on the different traits of TRD and NRD. Thus, in one of the RCTs, it was shown that 29.5% of the participants achieved remission (Trivedi et al., 2011), and the remission was analyzed with different scales, such as HRSD, IDS-C, CGI, and GDS (Mather et al., 2002; Mota-Pereira et al., 2011).

Although we understand that the meta-analysis of the results of the different studies may provide objective global information on specific variables, according to the chosen articles, our data are insufficient to perform the statistical procedure required for meta-analysis. Further, the diversity of the primary outcomes makes it even more difficult to combine data derived from the different studies. In this sense, the final decision was influenced by heterogeneity among studies, as well as studies’ quality or the risk of bias.

Table 1 summarizes the PEDro scale and Oxford’s Evidence levels for the included articles in this systematic review. All the articles but one (Carta et al., 2008), were classified as excellent. Inadequate concealed allocation to groups and the lack of similarity in the comparison groups at baseline were the methodological limitation in the article considered a “good” quality description. All papers were RCT, and for this reason, Oxford’s Evidence levels were 1b. All studies performed a comparison of both intra-group (pre- and post-PA-intervention) and inter-group (exercise vs. control group) when it was presented. Further, inclusion and exclusion criteria were defined, and blinding eligibility was presented.