Exercise training improves depressive symptoms in people with multiple sclerosis: Results of a meta-analysis

Journal of Psychosomatic Research 76 (2014) 465–471

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Journal of Psychosomatic Research

Exercise training improves depressive symptoms in people with multiple sclerosis: Results of a meta-analysis Ipek Ensari, Robert W. Motl ⁎, Lara A. Pilutti University of Illinois Urbana-Champaign, Department of Kinesiology and Community Health, Urbana, IL, USA

a r t i c l e

i n f o

Article history: Received 17 December 2013 Received in revised form 21 March 2014 Accepted 22 March 2014 Keywords: Multiple sclerosis Exercise Depressive symptoms Depression Meta-analysis

a b s t r a c t Objective: There is a high prevalence, yet under-treatment of depressive disorder and symptoms by conventional therapy in people with multiple sclerosis (MS). We conducted a meta-analysis examining the overall effect of exercise training on depressive symptoms in MS. Methods: We searched PubMed for randomized controlled trials (RCT) of exercise training and depression as an outcome in samples with MS. There were 13 RCTs that met inclusion criteria and yielded data for effect size (ES) generation (Cohen's d). An overall ES was calculated using a random effects model and expressed as Hedge's g. Results: The weighted mean ES was small, but statistically significant (Hedge's g = 0.36, SE = 0.09, 95% CI = 0.18– 0.54, z = 3.92, p b .001) indicating the exercise training resulted in an improvement in depressive symptoms compared to control. The overall effect was not heterogeneous (Q = 16.46, df = 12, p = 0.17, I2 = 27.08); and post-hoc, exploratory analyses only identified depression symptom scale as a potential moderator variable (p = 0.04). Conclusion: The cumulative evidence indicates that exercise training can yield a small, yet statistically significant and reliable reduction in depressive symptoms for people with MS. © 2014 Elsevier Inc. All rights reserved.

Introduction Multiple sclerosis (MS) is a disease of the central nervous system that often results in depressive disorder (i.e., clinical diagnosis and classification of depression based on an interview and diagnostic criteria) and depressive symptoms (i.e., symptoms such as sadness, hopelessness, and self-blame that are indicative of possible depressive disorder) [1,2]. Indeed, an estimated 50% of patients with MS will develop a depressive disorder over the lifetime of the disease course [3]. One recent survey reported that approximately 47% of the 4178 respondents from the United Kingdom MS Registry had elevated depressive symptoms based on a Hospital Anxiety and Depression Scale (HADS) score of 8 or more [4]. That same study further reported an approximately 1 standard deviation difference in mean HADS depression scores between persons with MS and a United Kingdom population reference group [4]. This is problematic as depressive disorders and symptoms have been associated with cognitive impairment [5], reduced quality of life [6], and poor compliance with disease-modifying therapies [7] in MS. We further note that, upon detection, depression is often not treated adequately or treated at all [7]. Cochrane reviews provide evidence of only modest benefits for antidepressant medication [8] and cognitive behavior therapy (CBT) [9] in MS, but side effects of medications are ⁎ Corresponding author at: Department of Kinesiology and Community Health, University of Illinois, 233 Freer Hall, Urbana, IL 61801, USA. Tel.: + 1 217 265 0886; fax: +1 217 244 7332. E-mail address: [email protected] (R.W. Motl).

http://dx.doi.org/10.1016/j.jpsychores.2014.03.014 0022-3999/© 2014 Elsevier Inc. All rights reserved.

often problematic and accessibility of therapists represents a major barrier for CBT. Based on a consensus statement released by the American Academy of Neurology [10], there is insufficient evidence regarding the efficacy of antidepressant treatment and/or individual and group therapies for managing depression in persons with MS. Such observations collectively underscore the importance of considering other treatment options for depression in MS. Exercise training, defined as a planned, structured regimen of regular physical activity deliberately performed to improve one or more component of physical fitness (i.e., aerobic capacity or muscle strength and endurance) [11], represents a promising option for managing depressive disorder and symptoms in MS. This possibility is based, in part, on the broader body of research on exercise training for managing clinical depression and depressive symptoms in the non-MS population. For example, one meta-analysis documented the effect of supervised exercise training on depressive symptoms in healthy adults without clinical depression, and reported a mean effect size (ES) of 0.37 favoring exercise training compared with control [12]. Another meta-analysis examined the effect of exercise training on depression (both clinician diagnosed depressive disorder and depressive symptoms) in clinically depressed patients, and reported a mean ES of 0.61 favoring exercise training compared with control [13]. Such meta-analyses support exercise training for reducing depressive symptoms in both healthy adults without clinical depression and those with clinical depression. There have been multiple randomized controlled trials (RCTs) of exercise training and depression in persons with MS. This body of research has recently been summarized in a literature review [14]. The

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researchers reported a total of 11 RCTs that examined the efficacy of exercise training on depressive symptoms as a secondary outcome measure in people with MS; there were no RCTs with clinician diagnosis of depressive disorders as an outcome. The researchers concluded that there was no overall distinct or clear pattern of results regarding the effect of exercise training on depression or depressive symptoms. This lack of a conclusion likely reflects that the 11 RCTs were neither designed nor powered for detecting a change in depressive symptoms with exercise training in persons with MS (i.e., the studies often had non-significant results, perhaps based on small samples, that yielded an uncertain conclusion based on vote counting of positive, negative, and null results). The lack of a conclusion based on a literature review can be overcome through a meta-analysis; this has not yet been done for depression in MS, but has been done for other outcomes wherein literature reviews were inconclusive (e.g. [15,16]). Such a quantitative synthesis would provide a clearer picture regarding the overall existence and magnitude of a significant and possibly reliable effect of exercise training on depression in MS. The meta-analysis might further identify features of the studies (e.g., mode of exercise) and participants (e.g., disability level) that potentially moderate the effect of exercise on depressive symptoms. Both issues are important for the design of subsequent RCTs in this area. We performed a meta-analysis examining the overall magnitude of effect for exercise training compared with control for improving depressive symptoms in people with MS. We further examined the features of the participants and studies as possible moderator variables. Such an analysis is important for informing clinical practice and the design of subsequent research. If exercise is an effective behavioral approach for reducing depressive symptoms, then it can be integrated into mood management interventions targeting people with MS. This is important considering the prevalence, impact, and modest efficacy of existing approaches [10] in managing clinical depression and depressive symptoms in MS. The resulting overall ES and any variation based on moderators could further be adopted for informing the design of future research, in particular for properly powering RCTs. Methods

Identification

“multiple sclerosis” AND “exercise” n = 631

Screening

Limited to human subjects n = 552

Eligibility

Potentially relevant studies on depression and exercise training in MS n = 25

Included

This meta-analysis was conducted consistent with the Meta-analysis of Observational Studies in Epidemiology (MOOSE) framework [17], and a visual description of our step-by-step methods is provided in Fig. 1. We conducted a search of the electronic database PubMed using

Randomized controlled trials n = 13

the key words exercise and multiple sclerosis for the articles published between 1960 and November 2013. Depression or depressive symptoms were not used as key words to avoid missing any potentially relevant studies during the search process, as depression is not a primary outcome measure in exercise training studies in MS [14]. This search initially retrieved 631 articles. The search results were limited to human subjects and this resulted in 552 articles. We searched through the 552 articles to identify potentially relevant articles. We further conducted a manual search of reference lists of retrieved literature reviews [11, 13,15–22] and the personal files of all authors. We conducted a followup search using EBSCO Host, Web of Science, and Scopus, and located no additional relevant studies. We included RCTs (i.e., studies that compared exercise training vs. no-treatment control and stated randomly assigning participants into conditions) that administered reliable and valid measures of depressive symptoms (e.g., HADS, CES-D) [23–30] as an outcome assessment prepost intervention. We did not include RCTs that administered global, mental health status questionnaires (e.g. SF-36). The same measures of depressive symptoms often have been included in other metaanalyses of exercise and depression outside of MS [12]. Studies that used physical therapy (i.e., class of therapeutic approaches including exercise, message, electrotherapy, assistive devices, and patient education) as the intervention were excluded so that we could focus solely on the effects of exercise training. This resulted in 25 articles that were reviewed in detail, and 12 were excluded that did not include a depressive symptom outcome measure, an appropriate exercise training intervention (i.e. not physiotherapy/rehabilitation program), and/or did not meet the criteria for an RCT [31–42]. This resulted in 13 RCTs [43–55] that were included in the meta-analysis (see descriptions in Tables 1 and 2). We computed effect sizes (ESs) expressed as Cohen's d [56]. To do this, we computed the mean change from before to after the intervention of the exercise training group and subtracted the mean change of the control group. The resulting difference in mean change between the groups was then divided by the pooled baseline standard deviation (SD) for the experimental and control groups. If the authors did not provide these values, we contacted them via email for further information on the mean scores and the SDs per condition. The ESs were calculated so that a positive ES indicated an improvement in mean depression scores after exercise training, whereas a negative ES indicated a worsening of mean depression scores in the exercise training group compared with control. Separate ESs were calculated per dependent variable

Exclusions due to: not exclusive to MS, no measurement of depressive symptoms, no chronic exercise training, reviews, not RCT n = 527

Exclusions due to: outcome measures not including depressive symptoms, inappropriate mode of exercise training (i.e. physiotherapy), not randomized or cross-over design n = 12

Fig. 1. Flow chart describing the methods for the meta-analysis literature search.

I. Ensari et al. / Journal of Psychosomatic Research 76 (2014) 465–471

467

Table 1 Study characteristics, including the exercise paradigm and measure of depression, for each study included in the meta-analysis Study

PEDro score

Sample SIZE

Number of effects

Average effect size

95% confidence interval

Ahmadi et al. [43] Briken et al. [44] Cakit et al. [45] Dalgas et al. [46] Dettmers et al. [47] Hebert et al. [48] Learmonth et al. [49] Oken et al. [50] Petejan et al. [51] Romberg et al. [52] Schulz et al. [53] Skjerbaek et al. [54] Sutherland et al. [55]

6 6 5 6 6 7 6 5 5 5 6 6 6

31 42 33 31 31 38 32 37 46 95 28 11 22

2 3 2 1 1 1 2 4 3 1 2 1 1

0.56 0.87 0.06 0.67 −0.25 0.09 0.34 0.16 0.56 −0.07 0.65 0.64 0.51

(−0.06–1.19) (0.54–0.76) (−0.19–0.27) (−0.06–1.39) (−1.15–0.65) (−0.68–0.86) (0.26–0.31) (0.03–0.31) (0.46–0.67) (−0.48–0.33) (0.51–0.80) (−0.18–1.46) (−0.34–1.36)

(i.e., some studies had multiple depression outcomes) as well as per type of exercise (i.e., some studies had more than one type of exercise training modality or condition). The analysis itself took place using a single ES per study (i.e., an average ES when there was more than one ES computed by the software). This was necessary as multiple ESs from the same study are not independent [56]. The lack of independence biases the standard error (SE) for judging the significance of the overall ES and multiple ESs from one study bias the overall ES disproportionately compared with the studies that have a single ES [57]. The ESs along with the associated standard error (SE) were entered into the Comprehensive Meta-analysis software (Version 2.0, Biostat, Englewood, New Jersey). We used a random-effects model for computing the overall or mean ES as this model assumes that the samples come from populations with different ESs and the true effect differs between studies [58]. We further computed 95% confidence interval (CI) around the mean ES. An overall Q value and I2 value were calculated to test for homogeneity of variance among ESs. The Q value is a measure of variance among the ESs and a statistically significant (p b .05) sum of the squares of each ES about the weighted mean (Q) indicates heterogeneity. The I2 value represents the magnitude of the heterogeneity where a larger number indicates larger heterogeneity. We further performed post-hoc, exploratory moderator analyses based on the categorical variables of depressive symptom category (defined as none/mild or moderate based on the cut-off score for moderate depression per scale, [23–25,27–30]) and scale (i.e. BDI, MDI, POMS, HADS, IDS and/or CES-D), EDSS (defined as low or high disability using a step score of 4 as the cut-off point), exercise mode (categorized as aerobic vs nonaerobic), number of exercise conditions (categorized as combined vs single modality), exercise duration (categorized as 12 or fewer weeks vs longer than 12 weeks in duration), and exercise frequency (categorized as fewer than 3 sessions per week vs 3 or more sessions per week). These were identified based on clinical Table 2 PEDro item scores for the studies included in the meta-analysis PEDro item number Study

1

2

3

4

5

6

7

8

9

10

11

Ahmadi et al. [43] Briken et al. [44] Cakit et al. [45] Dalgas et al. [46] Dettmers et al. [47] Hebert et al. [48] Learmonth et al. [49] Oken et al. [50] Petejan et al. [51] Romberg et al. [52] Schulz et al. [53] Skjerbaek et al. [54] Sutherland et al. [55]

1 1 1 1 1 1 1 1 1 1 1 1 1

1 1 1 1 1 1 1 1 1 1 1 1 1

0 1 0 1 1 1 0 0 0 0 0 1 0

1 1 1 1 1 1 1 1 1 1 1 0 1

0 0 0 0 0 0 0 0 0 0 0 0 0

0 0 0 0 0 0 0 0 0 0 0 0 0

0 0 1 0 0 0 1 1 0 0 0 1 0

1 1 0 1 1 1 0 0 1 0 1 1 1

1 0 0 0 0 1 1 0 0 1 1 0 1

1 1 1 1 1 1 1 1 1 1 1 1 1

1 1 1 1 1 1 1 1 1 1 1 1 1

relevance and experience with understanding prominent characteristics of exercise training interventions. The effect of the categorical moderators was based on the significance of the QB statistic. The QB statistic indicated the statistical significance of the difference between levels of the moderator variables. The quality of studies included in the meta-analysis was established using an 11-item Physiotherapy Evidence Database (PEDro) scale [59,60] for RCTs. All three authors coded each of the studies and any discrepancies were discussed and resolved resulting in the reported PEDro scores. Scores on the PEDro range between 0 and 10, with higher scores indicating higher quality of methodology and has been used previously in reviews of exercise training in MS [20,61]. As dictated by the literature on the guidelines on PEDro scoring [59], item 1 is not included in computing the overall score, therefore resulting in a score out of 10, instead of 11. All studies inevitably received a score of 0 on items 5 and 6 (i.e. blinding of subjects and the therapists to the conditions, respectively), based on the obvious difficulty of blinding to exercise training.

Results The overall methodological quality of the studies along with the sample size and number, average, and the 95% CIsper study are provided in Table 1. Regarding methodological quality, 9 of the 13 studies received a score of 6 or higher on the PEDro scale; individual PEDro item scores for each study are provided in Table 2. The score of 6 has been previously determined as the cut-off point for a high quality study (i.e. Level I evidence) [59]. Table 3 provides the sample size, demographic and clinical sample characteristics, depression symptom scale, baseline score, associated scale cut-off score, and exercise characteristics per study; depression was not a primary outcome in any of the studies and this is not included as a study descriptor in Table 3. Regarding baseline scores on the measures of depressive symptoms, only samples in 2 of the studies had mean scores above the threshold for moderate depressive symptomatology. There were no studies of depression that included a diagnostic interview and interpretive manual for confirming a depressive disorder and examining remission as an outcome. Overall, 24 ESs were retrieved from the 13 published studies that included 477 people with MS. Fig. 2 provides a visual description of the average ES per study. The distribution of ESs had minimal skewness (g1 = −0.42, SE = 0.62) and kurtosis (g2 = −0.90, SE = 1.20). 11 of the 13 ESs from the studies were greater than zero (i.e., 85%). The funnel plot of the average ESs from the 13 studies suggested against publication bias. The overall weighted mean ES was 0.36 (SE = 0.09, 95% CI = 0.18–0.54, z = 3.92, p b .001). This reflects a statistically significant and small effect in favor of exercise training for improving depressive symptoms compared with the control condition. The weighted mean ES was not heterogeneous (Q = 16.46, df = 12, p = 0.17, I2 = 27.08). We still conducted exploratory, post-hoc analyses using categorical moderator variables as a further examination of heterogeneity in the overall ES. Point estimates, SEs, and significance values for the QB statistic are provided in Table 4. The additional analyses only identified depression symptom scale as a possible moderator variable; however, this categorical variable yielded a very small effect (p =0.04) and it should be interpreted with caution. We estimated the possible clinical importance of the overall ES by determining the success/failure rate of exercise training on reducing depressive symptoms compared with no exercise training based on the binomial ES. We converted the overall mean ES of 0.36 into a correlation coefficient (r = 0.18). The chance of treatment success was determined as (0.5 + r/2)100, and the chance of treatment failure was determined as (0.5 − r/2)100. This resulted in 59% chance of treatment success (i.e., a reduction in depressive symptoms) and 41% chance of treatment failure for exercise training on improving depressive symptoms.

I. Ensari et al. / Journal of Psychosomatic Research 76 (2014) 465–471

4 10 2–3 3–6 6.4–8.1 b5.0 55.2 (8.2) 46.3 (4.1) 11 22 Skierbaek et al. [54] Sutherland et al. [55]

8:3 12:10

3.3 (0.3) 2⁎⁎ 2.2 (1.2) 39.95 (1.8) 43.85 (6.7) 39.5 (9.9) 31:15 61:34 19:9 46 95 28 Peteian et al. [51] Romberg et al. [52] Schulz et al. [53]

⁎ Cut-off score on each scale is based upon the lower limit score for moderate depression levels as published in the literature ([23–25,27–30]). ⁎⁎ Median score. nr = not reported. na = not applicable.

23 45 Arm and leg ergometry Water aerobic exercise

15 26 8 3 5 3–6 45–50 NR 45 Arm and leg cycle ergometry Resistance and aerobic exercise Leg cycle ergometry

8 8–10 20 12 12 6 12 24 3 2–3 5 2 3 2 2 1 50–70 15–45 60 NR 45 55 60 NR Treadmill training/stretching or yoga Leg cycle ergometry, arm ergometry, rowing Leg cycle ergometry, balance, lower extremity exercises Lower extremity progressive resistance training Endurance and resistance training, relaxation Leg cycle ergometry, stretching Resistance, balance, mobility training Leg cycle ergometry or yoga

19 18 19 26 26 20 8 16 NA NA 16 8 NA 26 NA 12.7 (9.7) 16.8 (9.6) 29.2 (15.4) 9.53 (5.27) 9.9 (6.15) 17.9 (7.5) 7.59 (4.15) 10.4 (9.8) 9.3 (4.9) 31.4 (8.4) 15.2 (9.9) 9.3 (1.8) 8.8 (7.8) 12.4 (4.2) 7.2 (6.9) BDI IDS BDI MDI MDI BDI-II HADS CES-D POMS POMS CES-D HADS POMS MDI POMS-SF 2.2 (1.2) 4.9 (0.8) b6.1 3.8 (0.9) 2.7 (0.95) NA 6.02 (0.4) 3.1 (1.8) 35.2 (9.01) 49.8 (8.02) 37.9 (10.4) 48.4 (9.4) 42.8 (8.5) 46.4 (9.8) 51.5 (8.04) 49.05 (9.03) 31 42 33 31 30 26 32 57 Ahmadi et al. [43] Briken et al. [44] Cakit et al. [45] Dalgas et al. [46] Dettmers et al. [47] Hebert et al. [48] Learmonth et al. [49] Oken et al. [50]

F 24:18 23:10 20:11 21:9 22:4 23:9 53:4

Scale cut-off score⁎ Depress symptom score Depressive symptom scale EDSS Age N

Sex (F:M)

Discussion

Reference

Table 3 Sample characteristics at baseline for each study included in the meta-analysis. Standard deviations are provided in parentheses

Mode of exercise

Time (min)

Frequency (times/wk)

Duration (wk)

468

There have been meta-analyses demonstrating the favorable effect of exercise training on depression in healthy and clinically depressed persons without MS [12,13,62,63]. We are further aware of a recent literature review indicating equivocal effects of exercise training on depression in MS [14]. To that end, we conducted the first metaanalysis of RCTs examining the effects of exercise training on depressive symptoms in people with MS. The evidence suggested that exercise training improved depressive symptoms in the samples of people with MS, and this improvement corresponds to about 1/3 SD improvement (i.e. ES = 0.36) in depression scores compared with control. The overall effect of exercise training on depressive symptoms was statistically significant, but considered small in magnitude. The results of the heterogeneity test suggested that the observed overall ES was likely homogeneous, thereby indicating a lack of significant variation across the 13 RCTs. This was further supported in the exploratory, categorical moderator analyses. The moderator of depressive symptom scale did suggest statistical significance, and this was the only significant moderator variable. The results of the moderator analyses should be interpreted with extreme caution considering the small sample of studies included in the analysis. Collectively, the overall ES and its homogeneity preliminarily suggested that there was a significant, reliable beneficial effect of exercise training across studies, independent of study characteristics (e.g., clinical characteristics of the sample or exercise parameters). The direction and size of the overall ES is consistent with a previous meta-analysis investigating the effect of exercise training on depressive symptoms in the non-MS population [12]. For example, Conn (2010) reported an average ES of 0.37 after conducting a meta-analysis on 38 supervised exercise training studies comparing the effect of exercise training vs. control on depressive symptoms in individuals without a clinical depression diagnosis. This value is very similar to that reported herein thereby indicating that exercise training is as effective in alleviating symptoms of depression in those with MS as it is for the non-MS population without clinical depression. The meta-analysis by Silveira et al. [13], on the other hand, reported a larger, moderate ES of 0.61 based on 10 RCTs involving persons with clinical depressive disorder. This difference in ES magnitude likely reflects the depression status of the samples in the RCTs, such that a larger effect is observed among those with clinically significant levels of depression. This indicates an important direction for future research, namely the importance of examining the effect of exercise training vs. control on depressive symptoms and remission of depressive disorder among those with MS who have major depressive disorder [10]. This will be an important step in improving our understanding of exercise training effects on clinical depression and depressive symptoms in MS, and we expect an even larger ES based on the meta-analyses involving persons with clinicallyrelevant depression without MS [13,63]. We noted limitations of the existing research regarding exercise training and depression in MS. One primary weakness of the existing research was identified when rating the quality of the RCTs. Based on the PEDro scale cut-off score [59], studies in the present meta-analysis had high overall quality (i.e. Level I evidence), with more than half of the studies receiving a score of 6 or higher and a median score of 6 across all studies (See Tables 1 and 2.). Nevertheless, issues regarding blinding of the assessors, participants, and therapists, concealed allocation of participants, and intent-to-treat analyses were the main factors resulting in a loss of points on the PEDro scale (See Table 2). Some of these issues can clearly be overcome in subsequent research. Other issues regarding blinding of the participants and the therapists, on the other hand, are extremely difficult to achieve and therefore all currently included studies received a score of 0 for blinding of participants and the therapist. Consequently, the overall quality scores were inevitably lowered, but the scoring system identified some possible methodological areas for improvement in subsequent RCTs. We note that some literature reviews have opted to eliminate the 2 items regarding participant and therapist

I. Ensari et al. / Journal of Psychosomatic Research 76 (2014) 465–471 Study name

Statistics for each study

469

Hedges's g and 95% CI

Hedges's g

Standard error

Lower limit

Upper limit

Dettmers et al (2009)

-0.250

0.460

-1.152

0.652

Romberg et al (2005)

-0.072

0.205

-0.475

0.330

Cakit et al (2010)

0.056

0.314

-0.559

0.671

Hebert et al (2011)

0.092

0.392

-0.677

0.861

Oken et al (2004)

0.157

0.162

-0.161

0.476

Learmonth et al (2012)

0.335

0.260

-0.174

0.844

Sutherland et al (2001)

0.510

0.433

-0.339

1.360

Petajan et al (1996)

0.561

0.174

0.219

0.902

Ahmadi et al (2013)

0.561

0.319

-0.063

1.186

Skjerbaek et al (2013)

0.642

0.419

-0.179

1.462

Schulz et al (2004)

0.649

0.296

0.068

1.229

Dalgas et al (2010)

0.667

0.369

-0.056

1.390

Briken et al (2013)

0.869

0.268

0.344

1.394

0.360

0.092

0.180

0.540 -1.50

-0.75

0.00

0.75

1.50

Favorable effect of exercise training Fig. 2. Summary of individual and overall effect sizes.

blinding on the overall PEDro score [61], but we choose to keep them in the computation of the overall scores to stay as authentic to the original scoring guidelines as possible. Another overarching limitation is that depressive outcomes have not been the primary focus for any of the RCTs identified for this meta-analysis. For example, one of the studies [47] specifically excluded persons with major depression from the study, and depressive symptoms were not identified as the primary outcome measures in any study design. This likely results in an underpowered study for detecting an effect of exercise training on depression, and reflects the importance of prescreening for persons with depression or elevated depressive symptoms suggestive of depression. We further note that the scales included in the RCTs were not diagnostic tools for rendering a diagnosis for depressive disorder. None of the studies had conducted clinical interviews with the participants for diagnostic purposes and therefore it is impossible to make any definitive conclusions regarding the effect of exercise training on clinical depressive disorders. This is another limitation of the literature on clinical depression and exercise training. These issues clearly can be overcome in subsequent focal investigations of exercise training and depressive disorders in MS.

Fatigue might have been a confounding factor in our metaanalysis. Indeed, fatigue is a common symptom in MS and has been associated with depressive symptoms in this population [64]. We further note that fatigue is a common manifestation of clinical depressive disorders [65]. We are aware of one non-RCT that identified change in fatigue as a mediator of the effect of exercise training on depressive symptoms in people with MS [35]. To that end, perhaps exercise training is reducing depressive symptoms through a pathway involving fatigue [35]. This should become a focus of future RCTs as well as the identification of other possible mediators and confounding factors such as social interaction during the delivery of exercise training. Another limitation of the RCTs included in this meta-analysis is the sample characteristics and generalizability broadly among those with MS. The participants in these studies were all volunteers who were willing to engage in the exercise training. The sample further had mild-to-moderate disability and mostly relapsing–remitting MS. Such factors suggest that the sample may not be representative of the general MS population, and this is an important limitation regarding the generalizability of our results.

Table 4 Results of the post-hoc moderator analyses. Depressive symptom category and scale, disability status, exercise mode, condition, duration and frequency were examined as categorical moderator variables.*the point estimate for depressive symptom scale indicated slight significance as a moderator variable (p b .05) Moderator variable

Subgroups (# of studies)

Point estimate (SE)

Depressive symptom category

None or mild (9) Moderate or higher (2) BDI (4) IDS (1) MDI (2) HADS (1) CES-D (1) POMS (2) b4 (7) 4 or above (2) Aerobic (9) Nonaerobic (2) Combined (5) Single (7) 12 or fewer (8) N12 (5) b3 (6) 3 or more (7)

0.32 (0.12) 0.22 (0.25) 0.18 (0.18) 0.87 (0.27) 0.62 (0.28) 0.34 (0.26) −0.07 (0.21) 0.55 (0.13) 0.32 (0.12) 0.60 (0.27) 0.36 (0.13) 0.43 (0.21) 0.19 (0.13) 0.45 (0.13) 0.50 (0.12) 0.25 (0.14) 0.40 (0.13) 0.31 (0.14)

Depressive symptom scale

EDSS Exercise mode Number of exercise conditions Exercise frequency (times/week) Exercise frequency (times/week)

Q-value (df)

p-Value

0.14 (1)

0.71

11.45 (5)

0.04*

0.89 (1)

0.34

0.07 (1)

0.80

2.08 (1)

0.15

1.94 (1)

0.16

0.23 (1)

0.63

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We believe that the time is right for additional investigations of exercise training in MS, particularly those that compare exercise training with other therapies for reducing depression and depressive symptoms. For example, researchers have compared the efficacy of anti-depressant medication with exercise training in 156 older adults with major depressive disorder (MDD) in a 16-week RCT [66]. The researchers reported that exercise training and antidepressant medication were equally effective in reducing MDD based on a structured clinical interview and depressive symptoms measured by the HAM-D and the BDI, and that there were no additive benefits of combining exercise training and anti-depressant treatment. Another RCT compared anti-depressant medication, home-based exercise training, and supervised exercise training to placebo pill for improving MDD and depressive symptoms in a sample of 202 adults diagnosed with MDD [67]. The researchers reported that all 3 treatments resulted in comparable improvements in post-intervention depression scores on the HAM-D and the structured clinical interview outcome, compared with placebo. There is further evidence in the literature of similar remission rates for exercise training and antidepressant treatments post-intervention and more importantly, protective ability of exercise against remission of depressive disorder [68]. Collectively, these findings provide consistent evidence that exercise training is as effective as antidepressants for treating patients with major depressive disorder, and this points to the importance of conducting similar RCTs with individuals who have MS and clinical depression. Such investigations might further consider comparing exercise training with cognitive behavioral therapy for managing depression in MS. Overall, the findings of this meta-analysis are important as exercise training is a readily modifiable factor with a positive side effect profile; this is compared with pharmacotherapy that requires prescription and can have a negative side effect profile. Accordingly, clinicians might consider suggesting that people with MS engage in exercise training as an approach for potentially preventing [69] and for alleviating symptoms of depression. This recommendation will be further clarified as we await additional RCTs examining exercise training for managing mood disturbances in persons with MS who have clinically-relevant depression. Competing Interest Statement: All authors have completed the Unified Competing Interest form and declare that they have no competing interests to report. Conflict of Interest No authors have any conflict of interest to declare. References [1] Joffe RT, Lippert GP, Gray TA, Sawa G, Horvath Z. Mood disorder and multiple sclerosis. Arch Neurol 1987;44:376–8. [2] Patten SB, Beck CA, Williams JVA, Barbui C, Metz LM. Major depression in multiple sclerosis: a population-based perspective. Neurology 2003;61:1524–7. [3] Sadovnick AD. Depression and multiple sclerosis. Neurology 1996;46:628–32. [4] Jones KH, Ford DV, Jones PA, John A, Middleton RM, Lockhart-Jones H, et al. A large scale study of anxiety and depression in people with multiple sclerosis: a survey via the web portal of the UK MS register. PLoS One 2012;7:e41910. [5] Arnett PA, Higginson CI, Voss WD, Wright B, Bender WI, Wurst JM, et al. Depressed mood in multiple sclerosis: relationship to capacity-demanding memory and attentional functioning. Neuropsychology 1999;13:434–46. [6] D'Alisa S, Miscio G, Baudo S, Simone A, Tesio L, Mauro A. Depression is the main determinant of quality of life in multiple sclerosis: a classification-regression (CART) study. Disabil Rehabil 2006;28:307–14. [7] Mohr D. Treatment of depression for patients with multiple sclerosis in neurology clinics. Mult Scler 2006;12:204–8. [8] Koch MW, Glazenborg A, Uyttenboogaart M, Mostert J, De Keyser J. Pharmacologic treatment of depression in multiple sclerosis. Cochrane Database Syst Rev 2011;2: CD007295. [9] Hind D, O'Cathain A, Cooper CL, Parry GD, Isaac CL, Rose A, et al. The acceptability of computerised cognitive behavioural therapy for the treatment of depression in people with chronic physical disease: a qualitative study of people with multiple sclerosis. Psychol Health 2009;25:699–712. [10] Minden SL, Feinstein A, Kalb RC, Miller D, Mohr DC, Patten SB, et al. Evidence-based guideline: assessment and management of psychiatric disorders in individuals with

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