Major depressive disorder (MDD) is one of the most prevalent mental illnesses in the world, as well as one of the most disabling ( Gutiérrez-Rojas et al., 2020). Considered a multifactorial disease, MDD has a difficult physiopathology ( Cichon et al., 2009). Besides antidepressant symptoms, the population with MDD presents toxic habits, such as smoking, alcohol intake, sedentarism, and/or physical inactivity, which leads to the appearance of different diseases ( i.e., ictus, diabetes, cephalea, obesity, or coronary heart disease) ( Gutiérrez-Rojas et al., 2020). Adding to that, around 60% of people with MDD have a moderate remission; the remainder accomplish the treatment-resistance depression (TRD) or non-remitted depression (NRD) criteria ( Nemeroff, 2007). Although the definitions of TRD and NRD are not clear, in the two cases, the person who receives the treatment does not have a remission, with a poor or unsatisfactory response to at least two adequate ( i.e., optimal dosage and duration) different classes of antidepressants. However, previous research studies have demonstrated a lack of consensus criteria in defining TRD ( Harbi, 2012). On the other hand, NRD refers to patients’ reported partial response as defined by a screening Hamilton Depression Rating Scale (HDRS) score of ≥ 14 ( Trivedi et al., 2006). The treatment for NRD and TRD consists of first and second-generation antidepressants acting over cerebral synapsis, so there is increased bioavailability of amines (serotonin, noradrenaline, and dopamine) ( Cichon et al., 2009). Therefore, in this group of patients, a combination of different pharmacological therapy with antidepressant variety is not sufficient, and they could also need coadjuvant strategies such as physical activity (PA). However, discrepancies have been shown in this sense, with some studies showing no evidence in favor of exercise for patients with MDD ( Krogh et al., 2017), but in others, exercise was associated with a moderate improvement effect over depressive symptoms in people with TRD and NRD ( Carta et al., 2008; Harbi, 2012; Krogh et al., 2017; Mather et al., 2002; Mota-Pereira et al., 2011)

Further, in the latest PA guidelines by the World Health Organization, 150-300 minutes of moderate and/or 75-150 minutes of high-intensity aerobic PA, in conjunction with two days of resistance training recommendations, have been included for people with mental disorders ( Bull et al., 2020).

Therefore, taking into account the recommendations above, the controversial outcomes, and the different exercise protocols related to the FITT principle ( i.e., frequency, intensity, time, and type of exercise) in people with TRD and NRD, the purpose of this systematic review was to analyze the effects of PA intervention as an adjunct strategy to pharmacological treatment in people with TRD and NRD.

The systematic review protocol has been recorded in the PROSPERO database (CRD42022298347). It follows the recommendations suggested by the Preferred Reporting Items for Systematic Review and Meta-analyses ( Page et al., 2021) (see Extended data, ( Etxaniz-Oses et al., 2023)).

The database searches identified 8086 references (see Extended data, ( Etxaniz-Oses et al., 2023)). 2838 from PubMed, 926 in Cochrane, 4232 in Web of Science, 0 in Scopus, and 90 in SPORTDiscus. After eliminating duplicates (n=4383) and those that were not clinical trials (n=866), 2837 clinical trials were analyzed. A total of 2820 articles were removed by title, abstract, study design, or type of intervention. Consequently, 17 articles were assessed for eligibility. Six of those investigations were excluded because of the study design and intervention type. 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). 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 suppmental data included the main characteristic 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) ( Carta et al., 2008; Greer et al., 2014, 2016; Mather et al., 2002; Mota-Pereira et al., 2011; Rethorst et al., 2013a, 2013b, 2016, 2017; 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 traditional training approach was observed in the other articles’ intervention, such as only aerobic continuous exercise (treadmill or cycle-ergometer) ( Carta et al., 2008; Greer et al., 2014, 2016; Mather et al., 2002; 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 special 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, (E txaniz-Oses et al., 2023)). First, there was only one intervention of 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 assessment 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; but psychomotor speed, attention, visual memory, spatial planning, instrumental and expressive roll, and cognitive function improved irrespective of the type or dose of exercise undertaken by participants ( Greer et al., 2014, 2016). The remission of the participants also improved and was achieved a 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).

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.

The objective of this study was to investigate the effects of PA intervention in TRD and NRD, describing the different parameters such as psychological, physical, and mental function and quality of life ( 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 et al., 2011). Over review determined 11 articles and identified that 1) PA intervention as an adjuvant program could improve different traits of TRD and NRD, 2) the remission of depression seems to be higher after PA intervention, showing also improvements in quality of life, sleep quality, executive function, or vitality, and 3) according to the FITT (Frequency, Intensity, Time, and Type) principle, there was some variability in the PA intervention, and except for one article ( Carta et al., 2008), they all were classified as excellent in terms of quality description.

A recent meta-analysis has found an interesting association between PA and incident depression, even below the public health recommendations, with an additional benefit when minimum recommendations are met ( Pearce et al., 2022). Thus, in the present systematic review, even though different types of intervention ( i.e., concurrent or endurance training) were performed in the reviewed articles, the depression decreased via HRSD ( Mather et al., 2002; Mota-Pereira et al., 2011), and the quality of life increased ( Carta et al., 2008; Greer et al., 2016), irrespective of PA type. Concerning only resistance intervention in patients with depression, previous studies have compared aerobic vs. nonaerobic exercise training and observed that both groups reduced depression scores, but with no significant difference between groups ( Doyne et al., 1987; Martinsen et al., 1989). Taking into account all the aforementioned, and the recent World Health Organization PA guidelines for people with chronic conditions ( Bull et al., 2020), it might be a good idea to include both resistance and endurance training in the adjuvant PA programs for TRD and NRD population, as it might result in better outcomes as seen in other populations ( Silva et al., 2015; Stanton & Reaburn, 2013). In this sense, the prefrontal cortex, anterior cingulate cortex, hippocampus, and corpus callosum emerge as possible neural markers that benefit from exercise in people with depression ( Gujral et al., 2017). It is time to confirm that during exercise, skeletal muscle releases valuable molecules that activate signals from skeletal muscle to different tissues, including the brain, highlighting that inactivity and loss of muscle mass may render the brain vulnerable to neurological dysfunction and disease ( Delezie & Handschin, 2018; Isaac et al., 2021). Regarding the frequency of weekly sessions, interventions ranged from two to five sessions, but the most frequently used was 2.6 sessions per week. This information was not observed in other systematic reviews, which noted that th three sessions had the highest frequency per week ( Perraton et al., 2010; Stanton & Happell, 2013). Our results could be associated with TRD and NRD patients’ poorer physical condition and chronicity over time compared to those patients with a diagnosis of only depression. The duration of the interventions in the articles was between 10 and 12 weeks in almost all of them ( 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 et al., 2011). However, another article used a longer intervention with an eight-month intervention ( Carta et al., 2008). Other research on patients with depression used interventions for more than eight weeks ( Perraton e t al., 2010). Yet, it may be that an intervention with a duration of 10-12 weeks would be sufficient to improve depression in TRD and NRD. Regarding the intensity of exercise, in the current study, all the reviewed articles performed moderate-intensity training interventions ( 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 et al., 2011), with no studies including high-intensity training. Thus, recent investigations are promoting the relevance of exercise intensity and modality ( i.e., high-intensity interval training) to induce a higher metabolic myokine effect on brain health ( Calverley et al., 2020; Hashimoto et al., 2021).

Three articles carried out a comparison between the control (no exercise intervention) and experimental group ( Carta et al., 2008; Mather et al., 2002; Mota-Pereira et al., 2011); the rest of the articles used a comparison with different doses of exercise ( Greer et al., 2014, 2016; Rethorst et al., 2013a, 2013b, 2016; Toups et al., 2011, 2017; Trivedi et al., 2011). In the articles that compared the control and experimental groups, the experimental groups observed better results than the control groups. In the same way, the groups that performed a high dose of exercise improved more than a low dose of exercise.

The present systematic review of RCTs analyzing the effects of PA intervention in patients with TRD and NRD determined the benefits of PA not only in the decrease of the depression symptoms but also in other variables related to the quality of life, such as sleep quality, executive and cognitive function, and memory. Therefore, regarding clinical practice and considering the results and the quality of the reviews, there is scientific evidence for a patient with TRD or NRD to recommend PA as an adjuvant treatment. However, there is a complex interplay in the type of exercise program or intervention intensity, hence, a need for further investigation.