Effects of exercise on depression and anxiety in persons living with HIV: A meta-analysis

Effects of exercise on depression and anxiety in persons living with HIV: A meta-analysis

Journal of Psychosomatic Research 126 (2019) 109823 Contents lists available at ScienceDirect Journal of Psychosomatic Research journal homepage: ww...

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Journal of Psychosomatic Research 126 (2019) 109823

Contents lists available at ScienceDirect

Journal of Psychosomatic Research journal homepage: www.elsevier.com/locate/jpsychores

Review article

Effects of exercise on depression and anxiety in persons living with HIV: A meta-analysis

T

Andreas Heissela, , Philipp Zecha, Michael A. Rappa, Felipe B. Schuchb, Jimmy B. Lawrencea, Maria Kangasc, Stephan Heinzeld ⁎

a

Social and Preventive Medicine, Department Exercise and Health Sciences, University of Potsdam, Germany Departamento de métodos e técnicas desportivas, Universidade Federal de Santa Maria, Brazil c Centre for Emotional Health, Department of Psychology, Macquarie University, Sydney, Australia d Clinical Psychology and Psychotherapy, Department of Education and Psychology, Freie Universität Berlin, Germany b

ARTICLE INFO

ABSTRACT

Keywords: HIV Exercise Depression Anxiety Meta-analysis Supervision

Objective: The purpose of this systematic review and meta-analysis was to examine the effects of exercise on depression and anxiety in people living with HIV (PLWH), and to evaluate, through subgroup analysis, the effects of exercise type, frequency, supervision by exercise professionals, study quality, and control group conditions on these outcomes. Method: A literature search was conducted through four electronic databases from inception to February 2019. Considered for inclusion were randomized controlled trials (RCTs) investigating exercise interventions and depression or anxiety as outcomes in people living with HIV (≥ 18 years of age). Ten studies were included (n = 479 participants, 49.67% females at baseline), and the standardized mean difference (SMD) and heterogeneity were calculated using random-effect models. An additional pre-post meta-analysis was also conducted. Results: A large effect in favor of exercise when compared to controls was found for depression (SMD = −0.84, 95%CI = [−1.57, −0.11], p = 0.02) and anxiety (SMD = −1.23, 95%CI = [−2.42, −0.04], p = 0.04). Subgroup analyses for depression revealed large effects on depression for aerobic exercise only (SMD = −0.96, 95%CI = [−1.63, −0.30], p = 0.004), a frequency of ≥3 exercise sessions per week (SMD = −1.39, 95%CI = [−2.24, −0.54], p < 0.001), professionally supervised exercise (SMD = −1.40, 95%CI = [−2.46, −0.17], p = 0.03]), and high-quality studies (SMD = −1.31, 95%CI = [−2.46, −0.17], p = 0.02). Conclusion: Exercise seems to decrease depressive symptoms and anxiety in PLWH, but other larger and highquality studies are needed to verify these effects.

1. Introduction In 2016, the number of individuals living with the human immunodeficiency virus (HIV) as reported by the World Health Organization (WHO) was estimated to range between 30.8 and 42.9 million people worldwide [1]. People living with HIV (PLWH) face challenges related to social inclusion, uncertainty, and worrying about their future, which are linked, to some extent, to mental and physical impairments associated with HIV, including depressive and anxiety disorders [2,3]. Although highly active antiretroviral therapy (HAART) has extended the lifespan of individuals with HIV, it is not without its risks. Notably, studies have shown that HAART increases the risk of

cardiovascular, kidney, and neurological diseases, as well as metabolic risk factors [4–6]. Moreover, sleep problems and depression in PLWH have been associated with higher disability [7]. The prevalence of PLWH experiencing depression and anxiety has been reported to be two- to fourfold higher than in non-infected individuals [8]. Among other things, both HIV itself and HAART contribute to this elevated prevalence of depression when compared to HIV-negative individuals. Depression has been shown to decrease quality of life (QOL) and negatively affect the HIV disease progression [9], and can lead to a higher risk of suicide in PLWH than in HIVnegative individuals [10,11]. Therefore, the improvement of mental health and QOL in PLWH has become a priority in HIV research [12]. Cluster of differentiation 4 (CD4) cell count and viral load play a key

⁎ Corresponding author at: Social and Preventive Medicine, Department Exercise and Health Sciences, University of Potsdam, Am Neuen Palais 10, Potsdam 14469, Germany. E-mail address: [email protected] (A. Heissel).

https://doi.org/10.1016/j.jpsychores.2019.109823 Received 26 February 2019; Received in revised form 30 August 2019; Accepted 31 August 2019 0022-3999/ © 2019 Elsevier Inc. All rights reserved.

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role for PLWH and help estimate individuals' overall health status. There is evidence for a relationship between CD4 cell count and decreased mental health and well-being. A lower CD4 cell count in PLWH could be an indicator of untreated depression [13]. In other words, chronic depression could negatively affect the disease process and lead to a decreased CD4 cell count and an increased viral load [9,14]. Furthermore, a meta-analysis by Gonzales et al. [15] showed that depression was significantly associated with non-adherence to HIV-treatments. While adherence to HIV medication treatment is essential for a stable viral load, mental health status is not adequately treated by medication alone. Research has shown that psychotherapy treatments such as cognitive behavioral therapy (CBT) increase adherence to HAART and improve depressive symptoms [16]. However, most countries lack adequate resources for psychotherapy [17]. Physical activity, defined as any bodily movement produced by skeletal muscles and which requires energy expenditure [18] has become a topic of great interest for mental health promotion, since people with higher levels of physical activity are less likely to develop depression [19] and anxiety [20]. Moreover, exercise, a structured subset of physical activity, has proven to be an effective low-threshold treatment in individuals suffering from depression and other mental disorders [21,22]. Additionally, people with HIV spend more time in sedentary behavior and less in physical activity when compared to other chronic populations [23,24]. In recent years, a growing number of systematic and meta-analytic reviews have investigated the effects of exercise in PLWH [23–30]. Although the antidepressant effects of exercise have been demonstrated in people with mental disorders, previous reviews of exercise in PLWH have focused mainly on physiological outcomes [25–30], with minimal attention given to mental health outcomes. In a recent Cochrane review in which the authors investigated the effectiveness of aerobic exercise for PLWH [31], only two studies were included which reported the impact of exercise on depressive symptoms. Although in another recent study [32] the aim was to evaluate the effects of various types of interventions on depression for PLWH in Africa, only one study was included based on an exercise intervention. Additionally, in a separate recent systematic review [33], although the aim was to evaluate the effects of exercise and mental health outcomes for PLWH (which included depression and anxiety outcomes), the results were restricted to a qualitative analysis of studies evaluating aerobic and/or resistance exercise; yet, the authors did not conduct a meta-analysis on any mental health outcomes. A further shortcoming yet to be addressed in previous meta-analytic reviews on this topic includes investigating the impact of other forms of physical exercise (beyond aerobic and resistance exercise), such as yoga, on mental health outcomes in PLWH. Additionally, none of the meta-analytic reviews to date have evaluated whether the effects of exercise for PLWH are influenced by training frequency or professional supervision, and whether the exercise intervention condition was compared to a structured versus non-structured control condition. Accordingly, the objective of the present systematic and meta-analytic review is to address these gaps and limitations in this field. In particular, the aims of this review are twofold: 1) to investigate the effect of exercise (including other forms of exercise, e.g., yoga, tai chi) on depression and anxiety in PLWH; and 2) to investigate whether the effects of exercise are moderated by exercise type, training frequency, supervision by exercise professionals, study quality, and different control group conditions (structured and non-structured control groups).

(http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID= CRD42016035798) and refers to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [35]. 2.1. Included studies and types of interventions Studies were considered for inclusion if they: 1) were RCTs and exercise interventions were compared to any concurrent structured control condition (defined as any assigned activity except exercise) and/or non-structured control condition (defined as no assignment, as usual daily activity or on a waiting list), 2) included at least one exercise intervention ≥1 time per week, 3) investigated depression and/ or anxiety symptoms pre- to post-intervention using a validated measure, 4) were published in English or German, 5) included adult participants ≥18 years old, and 6) included people with an HIV-positive status. For the purposes of this review, exercise was defined as any “planned, structured and repetitive bodily movement done to improve or maintain one or more components of physical fitness” [18]. According to this definition, beyond traditional forms of exercise such as aerobic exercise or strength training, other forms of exercise modes such as yoga or tai chi were also included, as they qualify as effective exercise treatments [36,37]. To examine the differences in effects between PLWH who exercised compared to those who did not (i.e., non-exercisers), the control group was defined as performing no exercise at all. Control groups exercising at different intensity levels or performing any type of exercise were strictly excluded to prevent falsification of the results regarding the comparison of non-exercising and exercising participants because moderate-intensity exercise can have similar effects on mental health when compared to more intense exercise. Therefore, comparing exercise versus exercise may lead to an underestimation of the effect size [38]. For trials which included more than one intensity of exercise, we used the exercise arm with the greatest clinical effect in the review. Similarly, when trials provided more than one type of exercise, we used the type of exercise with the greatest clinical effect. However, because this may overestimate the effect of exercise, we used the exercise arm which provides the biggest ‘dose’ of exercise, and performed a sensitivity analysis to explore the effect of using the smallest ‘dose’. Control groups were separated into structured and non-structured control conditions. Any activity except exercise, e.g. heat therapy, reading a book, were defined as structured control conditions, and non-structured control conditions were defined as not being involved in any organized form of activity and free of any form of intervention, e.g. continuing daily activity or being on a waiting list. A trial was considered an RCT if the allocation of participants was reported as randomized, and the eligibility criteria had to be specified. 2.2. Outcomes The primary outcome was the post-intervention results for depression, and the secondary outcome was anxiety. In cases where a study investigated depression or anxiety with more than one assessment tool [39], separate meta-analyses were conducted. In this review, the specific focus was on evaluating the effects of exercise on depression and anxiety symptoms. Thus, ‘depression’ and ‘anxiety’ was defined in terms of symptom severity, not in terms of a clinical diagnosis of a depressive or anxiety disorder. Studies that only used broad measures of mental health and health-related quality of life (HRQOL) were excluded, as they were deemed too generic. Any study that used a validated quantitative self-report measure assessing depression and anxiety symptoms was considered for inclusion (e.g. State-Trait Anxiety Inventory (STAI), Beck Depression Inventory (BDI), General Health Questionnaire (GHQ), Profile of Mood State-Depression/Anxiety (POMS-D/A), Hospital Anxiety and Depression Scale-Depression/Anxiety (HADS-D/A), Centre for Epidemiological Studies-Depression Scale (CES-D)).

2. Methods We conducted a systematic review and meta-analysis focusing on randomized controlled trials (RCTs) according to the Cochrane Collaboration protocol [34]. The procedure was previously registered on the international prospective register of systematic reviews (PROSPERO). 2

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2.3. Search strategy

as a high-quality study [41,42].

The literature search was conducted by two reviewers (PZ and JL) who first independently screened each title for potential relevance as set by the eligibility criteria described above. If an article met the titlescreening process, the abstracts were then fully screened. For potentially eligible studies, full-text papers were obtained and assessed by the same two independent reviewers. In the case of disagreement, both authors discussed their differences until they reached an agreement. If this was not possible, a third author (AH) was consulted for the final decision. To identify relevant published trials, as well as existing systematic reviews, the following electronic databases were searched to include studies published up to February 2019: Pubmed, Physiotherapy Evidence Database (PEDro), PsycNet, and the Cochrane Central Register of Controlled Trials (CENTRAL). Search parameters and syntax were adapted to the requirements of each database. Combined MeSH terms and text words were related to HIV, exercise, and depression/ anxiety. In addition, systematic reviews and cohort studies were crossreferenced. To identify unpublished or on-going studies, clinicaltrials. gov was searched. Reference lists and tables of contents in relevant publications, reviews, and books were also screened. The search strategies represent the method used for all databases using the Boolean operators AND/OR and can be found in detail in the Appendix (Table A.1).

2.5. Data analysis Review Manager 5.3 was used for the data analysis. Different instruments were pooled for data analysis if they measured the same psychological construct for depression and anxiety. For the meta-analysis, the main outcome of the means, standard differences, and number of participants allocated to each group were used. If different measuring units were used in the studies, such as mean ± standard error or mean ± change/difference (post minus pre); these were converted into the common measuring unit of mean ± standard difference. Random-effect models were used when calculating the standardized mean differences (SMD) of the post-treatment measures comparing exercise and other forms of exercise with control groups across all included trials [43]. Subgroup analyses for the different types of exercise, number of sessions, professional supervision, and structured and nonstructured control conditions were performed whenever possible. Highquality studies with a low risk of bias (PEDro score ≥ 5) were analyzed separately [41,42]. In line with the standard analysis procedure in the Cochrane meta-analyses, SMDs were calculated using means, standard differences, and sample sizes post-intervention (post-treatment effect sizes). Due to the possibility that no parallelization pre-intervention between intervention and (structured) control groups was assured in the main outcomes at the starting points, especially in small sample sizes despite randomization or due to high dropout rates, we used an additional method to compare the two methods with one another. Therefore, we conducted additional meta-analyses (pre-post analyses). For the main outcomes, we calculated new means by subtracting the post-intervention means from the pre-intervention means between all groups to determine the differences. Additionally, a pooled standard difference to adjust the differences was used [44], as was the post-intervention sample size. For both groups, these three values were used for statistical calculation in Review Manager 5.3. We interpreted SMD ranges 0.00–0.39 as small, 0.40–0.70 as moderate, and above 0.70 as large [45]. A p value of < 0.05 was considered statistically significant. Heterogeneity was determined by calculating the I2 statistics [46]. We considered three ranges of heterogeneity: a) I2 ≤ 25% for low heterogeneity, b) I2 > 25–75% for moderate heterogeneity, and c) I2 > 75% for considerably high heterogeneity [46]. The conducted pre-post analyses were then compared to the post analyses to identify possible differences [44,47]. Assessing publication bias, Egger's Test was preferred to Begg's Test due to its higher sensitivity [48,49].

2.4. Data extraction Data were extracted by two independent reviewers (PZ and JL) using a standardized data abstraction digital form sheet, and included the following: author, year and country of publication, investigated outcome, exercise method, number of participants (% women), pre-and post-outcome measures at baseline for intervention and control groups, intervention intensity, type of control group, anti-depressants and HAART medication intake, supervision of participants, and peer review or thesis. In the case of missing data or unconvertible measuring units in a study, the authors were contacted via email and the missing data or an adequate conversion of a measuring unit were requested. If two weeks passed with no reply, the author was then kindly reminded of the request. When the corresponding author did not reply, the co-authors were contacted via email as well. When no email address was reported, the author was searched via Google and Research Gate, and contacted if possible. In cases where none of the authors replied to any attempts to make contact, the study was excluded from the quantitative synthesis. In order to determine the risk of bias of the included studies, the Physiotherapy Evidence Database (PEDro) scale was used. The PEDro scale is based upon the Delphi list described by Verhagen et al. [40]. The criteria of the PEDro scale (eligibility criteria (EC)) determine: if the eligibility criteria were specified, 1. whether subjects were randomly allocated to groups, 2. whether the allocation was concealed, 3. whether the groups were similar at baseline regarding the most important prognostic indicator, 4. whether there was blinding of all subjects, 5. whether there was blinding of all therapists who administered the therapy, 6. whether there was blinding of all assessors who measured at least one key outcome, 7. whether the measures of at least one key outcome were obtained from > 85% of the subjects initially allocated to groups, 8. whether all subjects for whom outcome measures were available received the treatment or control condition as allocated or, where this was not the case, data for at least one key outcome were analyzed with an “intention to treat,” 9. whether the results of betweengroup statistical comparisons are reported for at least one key outcome, and 10. whether the study provided both point measures and measures of variability for at least one key outcome. Two reviewers (PZ and JL) independently assessed the risk of bias using the PEDro scale. Discrepancies between the two reviewers were resolved by consulting two other authors (AH and SH). A study with a PEDro score ≥ 5 was graded

3. Results 3.1. Characteristics of excluded studies As shown in Fig. 1, 4850 studies were identified. After four duplicates were removed, 4814 studies were excluded by assessing the title. Nine records needed to be excluded after reading the abstract. Seven records did not investigate depression or anxiety, one study had a nonexercising control group by investigating two different intervention groups, and one study did not assess exercise as an intervention. The full texts of the remaining 23 studies were assessed. Twelve additional studies were then excluded: Eight studies did not measure depression or anxiety [36,50–56], four studies had no exercise intervention or had an exercise intervention that did not meet the inclusion criteria, one study had only two groups differing in their intensity levels of exercise (moderate and high intensity) but no non-exercising control group [57], in one study there was no exercise in the cognitive behavioral stress management intervention [58], one study did not include exercise in the individual or family activity intervention [59], and one study had no exercise included in the positive-affect skills intervention [60]. For further information about the study selection process, see Fig. 1. 3

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Fig. 1. PRISMA flow diagram.

3.2. Characteristics of studies excluded from the quantitative synthesis

3.4. Characteristics of participants

One study was excluded due to missing or incomplete data [61] (see also Appendix Table A.2). The author was contacted twice but the requested data were not made available. Hence, a total of 10 studies were included in the quantitative analysis.

A total of 479 participants for baseline (49.67% females) and 429 participants for post-intervention measures (10.44% withdrawal rate) were investigated. Four studies reported a nil dropout rate [63,65,68,70]. Six studies reported ART medication for all participants [62,64,65,68–70]. One of these six studies that reported ART medication also made a distinction between the antiretroviral medications concerning the drug classification [69]. The other four studies did not report whether participants were on HAART medication [39,63,66,67]. Two studies reported anti-depressant or anti-anxiety medication use [39,69]. In Neidig et al. [39], twelve out of 60 participants used antidepressants (16.70% in the intervention group (IG) and 23.30% in the control group (CG)) and 10% of the 60 participants used anxiolytics (10% in the IG and 10% in the CG) at entry. 16.70% of the participants used antidepressants and 10% of the participants used anti-anxiety agents. Shah et al. [69] only mentioned in the exclusion criteria that participants with untreated depression were excluded. Detailed information about the study characteristics are summarized in Table 1. Six studies investigated participants who were not diagnosed with depressive symptoms [39,62–64,66,67]. In four studies, the authors reported details for depression conditions in the inclusion or exclusion criteria. Participants in the studies of Naoroibam et al. [70] n = 14 (n = 9/22 participants in the intervention group and n = 5/22 participants in the control group) and Daniels et al. [65] n = 8/60 participants were partly diagnosed with depressive symptoms. 20 participants (n = 12/22 participants in the intervention group and n = 8/22 in the control group) in the study by Naoroibam et al. [70] were diagnosed with anxiety symptoms. The study by Kiloor et al. [68] excluded participants with psychiatric illnesses or use of antipsychotic medications.

3.3. Characteristics of studies included in the quantitative synthesis Of the 10 included trials, four studies investigated aerobic exercise (AE) [39,62–64], four investigated aerobic exercise and resistance training (AERT) [65–69], and two studies investigated a yoga intervention (Y) [68,70]. The duration of the interventions ranged from 4 to 12 weeks, the duration of each exercise session ranged from 45 to 75 min, the sessions per week ranged from 2 to 6 times per week. Follow-up data were presented in none of the included studies. Participants were supervised in six trials, and in five of these studies participants were professionally supervised by a yoga trainer [68,70], a personal trainer [39] or a physiotherapist [64,66]. Two studies did not report on supervision [62,63]. In two studies the participants were instructed to exercise privately in their own at home not being supervised [65,69]. Participants in 8 studies performed their exercise intervention stationary. Two studies were conducted in Africa [62,65], three studies in India [66,68,70], two studies in the USA [39,63], and one study in Germany [64]. Five studies assessed structured control groups [62,63,65–67] and five assessed non-structured control groups [39,64,68–70]. No study assessed two different intensity levels for the intervention group. Detailed information about supervision, control group conditions and other study characteristics are available in Table 1. 4

Aweto, 2016, Nigeria

Daniels, 2018, South Africa

Dianatinasab, 2018, Iran

Jaggers, 2014, USA

Kiloor, 2018, India

LaPerriere, 1990, USA

Naoroibam, 2016, India

Neidig, 2003, USA

1

2

3

4

5

6

7

8

Author, Year, Country

5

POMS-D, BDID: depression

HADS-D/A: depression, anxiety

POMS-D/A: depression, anxiety

HADS-D/A: depression, anxiety

POMS-D: depression

GHQ28:depression anxiety

BDI-D: depression

BDI-D: depression

Outcome Parameter

aerobic exercise vs. CG

yoga vs. CG

aerobic exercise vs. CG

aerobic and resistance exercise vs. CG yoga vs. CG

aerobic and resistance exercise vs. CG aerobic and resistance exercise vs. CG

aerobic exercise vs. CG

Method/ Intervention

pre: 60 (13%), post: 48 (8.30%)

pre: 44 (45.50%), post: 44 (45.50%)

60, 48, 20%/yes

44, 44, 0%/ no

17, 17, 0%/ yes

60, 60, 0%/ no

pre: 60 (65%) post: 60 (65%)

pre: 17 (0%), post: 17 (0%)

49, 44, 10.2%/ no

40, 30, 25%/ no

60, 60, 0%/ no

40, 33, 17.5%/ no

n, post (n), WR%/ intention to treat yes/no

pre: 49 (26.50%), post: 44 (NA)

pre: 40 (100%), post: 30 (100%)

pre: 40 (62.50%), post: 33 (69.70%) pre: 60 (100%) post: 60 (100%)

Participants n (% women) pre, post

Table 1 Characteristic of studies included in the meta-analysis.

depression: 10.33 (6.48); 3.50 (1.27); −6.83 (3.88) depression: 6.17 (3.97); 4.85 (2.85); −1.32 (3.41) depression: 4.84 (2.76); 2.69 (1.44); −2.15 (2.10) anxiety: 5.92 (4.46); 3.61 (2.33); −2.31 (3.40) depression: 14.38 (12.15); 6.21 (7.35); −8.17 (9.75) depression: 9.16 (2.15); 4.74 (1.12); −4.42 (1.64) anxiety: 11.29 (2.15); 5.45 (1.34); −5.84 (1.75) depression: 10.90 (1.70); 14 (3.70); 3.1 (2.7) anxiety: 12.80 (2); 12.90 (2.50); 0.10 (2.25) depression: 9.18 (2.95); 7.95 (1.78); −1.23 (2.37) anxiety: 10.82 (3.86); 9.91 (3.35); −0.91 (3.61) POMS-D: depression: 10.90 (11.80); 6.10 (8.90); −4.80 (10.35) BDI-D: depression:

depression: 10.06 (5.96); 8.33 (5.80); −1.73 (5.88) depression: 4.64 (2.79); 2.75 (2.10); −1.89 (2.45) depression: 6.60 (4.25); 7.60 (5.38); 1.00 (4.82) anxiety: 6.30 (4.19); 6.20 (4.29); −0.1 (4.24) depression: 9.39 (9.08); 8.20 (9.30); −1.19 (9.19) depression: 9.19 (2.04); 10.23 (1.93); 1.04 (1.99) anxiety: 11.45 (2.17); 12.48 (2.20); 1.03 (2.19) depression: 10 (1.60); 23.80 (7.90); 13.80 (4.75) anxiety: 11.30 (1.60); 16.30 (3.80); 5 (2.70) depression: 9.55 (3.01); 9.59 (3.03); 0.04 (3.02) anxiety: 10.14 (3.16); 11.45 (3.36); 1.31 (3.26) POMS depression: 10.90 (8.50); 10.90 (11.20); 0 (9.85) BDI depression: 8.90 (5.90); 2

5

3

6

3

60

45

60

60

3

2

3

75

65

N.A.

45

S/Wk

M/S

Intervention

Control

Intervention

Baseline (SD); post (SD); within group difference post minus baseline (SD)

12

4

12

8

6

12

6

6

Wks

180

360

135

300

120

195

N.A.

135

M/Wk

non-structured: wait list, usual activity

non-structured: routine daily activity

structured: assessment only

non-structured: wait list, usual activity

structured: sedentary activities

structured: receiving routine educational and medical service

structured: group counselling for 30 min. Once in two weeks. structured: read the prescribed material

Control group condition

(n) 12/60 antidepressants, (n) 9/60 antianxiety agents/ not mentioned

not mentioned/ on ART

not mentioned/ not mentioned

not mentioned/ on ART

not mentioned/ not mentioned

not mentioned/ not mentioned

not mentioned/ on ART

not mentioned/ on ART

Antidepressant/ ART medication

professionally supervised

professionally supervised

not mentioned

professionally supervised

supervised

professionally supervised

not supervised

not mentioned

Super-vision

peer reviewed

peer reviewed

peer reviewed

peer reviewed

peer reviewed

peer reviewed

peer reviewed

peer reviewed

Peer reviewed/ thesis

(continued on next page)

stationary

stationary

stationary

stationary

stationary

stationary

home based

stationary

Location of exercise intervention

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67, 59, 11.90%/ no pre: 67 (N.A), post: 59 (39%) aerobic and resistance exercise vs. CG BDI-D: depression Shah, 2016, USA 10

Note. Study characteristics presented as author/year of publication, investigated outcome, specific intervention investigated, (n) participants (percentage women) at pre- and post-intervention, withdrawal rate (WR) in percent, intention to treat yes/no, baseline measures mean ± SD intervention group, baseline measure mean ± SD control group, minutes per session (M/S), sessions per week (S/Wk), weeks (Wks), minutes per week (M/Wk), description of control group condition. Standard deviation (SD), antiretroviral therapy (ART), withdrawal rate (WR), State-Trait Anxiety Inventory (STAI), Beck Depression Inventory (BDI), General Health Questionnaire (GHQ), Profile of Mood State-Depression/Anxiety (POMS-D/A), Hospital Anxiety and Depression Scale-Depression/Anxiety (HADS-D/A), intervention group (IG), control group (CG), not available (N.A.).

peer reviewed home based not supervised N.A. N.A.

12

N.A.

non-structured: maintain usual daily activity

thesis stationary professionally supervised

not mentioned/ (n) 15/34 participants under ART antidepressants/on ART, drug classification 10 2 60 42, 34, 19%/ no aerobic exercise vs. CG Schlenzig, 1992, Germany 9

STAI: anxiety

pre: 42 (19%), post: 34 (NA)

8.70 (7.10); −0.20 (6.50)

8.60 (6); 5.60 (6.30); −3 (6.15) STAI: 39.30 (9); 42 (11.30); 2.70 (10.15) depression: 13.16 (11.42); 9.55 (11.42); −3.61 (11.42)

STAI: 43.40 (10.60); 44.80 (11.30); 1.4 (10.95) depression: 10.66 (12.08); 10.18 (12.08); −0.48 (12.08)

S/Wk M/S Control Intervention

n, post (n), WR%/ intention to treat yes/no Participants n (% women) pre, post Method/ Intervention Outcome Parameter Author, Year, Country

Table 1 (continued)

Baseline (SD); post (SD); within group difference post minus baseline (SD)

Intervention

Wks

120

M/Wk

Control group condition

nonstructured:routine daily activity

Location of exercise intervention Super-vision Antidepressant/ ART medication

Peer reviewed/ thesis

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The study of Shah et al. [69] explicitly excluded participants with untreated depressive symptoms. 3.5. Outcomes of included studies Nine studies reported the effects of exercise on depression outcomes [39,62,63,65–70], while only five studies reported anxiety outcomes [63,64,66,68,70]. A summary of the outcome measures for these studies are summarized in the Appendix (Table A.3). 3.6. Risk of bias Five studies were graded as having good methodological quality and low risk of bias with a PEDro score ≥ 5 [39,62,63,68,69]. The remaining five studies were rated as low-quality studies (high risk of bias) [64–67,70]. The risk of bias analysis according to the PEDro scale is available in the Appendix, Table A.4. 3.7. Meta-analytic results 3.7.1. Depression Nine studies investigated depression (n = 194 in the exercise group, n = 201 in the control group) and five were of high quality. An overall standardized mean difference SMD = −0.84 (95% CI -1.57 to −0.11) in favor of the exercise group was found in the random-effect model for post-intervention values. There was a significant overall effect (Z = 2.27, p = 0.02) of exercise compared to the control group at posttreatment. Statistical heterogeneity was high (I2 = 91%, X2 = 87.82, df = 8, p < 0.001). Measuring tools used from the included studies were: BDI-D, GHQ-28, POMS-D, HADS-D, see Appendix, Table A.3. Table 2 shows all statistical results of the subgroup analyses for depression. The forest plot of the main analysis of depression is shown in Fig. 2. 3.7.2. Anxiety Five studies investigated anxiety (n = 92 in the exercise group, n = 93 in the control group), two of which were of high quality. An overall standardized mean difference SMD = −1.23 (95% CI -2.42 to −0.04) in favor of the exercise group was found in the random-effect model for post-intervention values. There was a significant overall effect (Z = 2.03, p = 0.04) of exercise compared to the control group at post-treatment. Statistical heterogeneity was high (I2 = 92%, X2 = 48.90, df = 4, p < 0.001). Measuring tools for anxiety used from the included studies were: GHQ-28, POMS-A, HADS-A, STAI, see Appendix, Table A.3. Table 2 shows the results of the meta-analysis for anxiety; no subgroup analysis was conducted due to the low number of studies identified. The forest plot of the main analysis for anxiety is shown in Fig. 3. 3.7.3. Pre-post analyses The SMD difference in the depression post analysis (−0.84) and pre-post analysis (−0.91) was 0.07 favoring the pre-post analysis. A minimal difference in SMD post minus pre-post was found for anxiety (0.04) favoring the pre-post analyses. Thereby no substantial differences between the results and heterogeneity between post and pre-post analyses exist. Post analysis vs. pre-post analysis for the outcomes are presented in Table 3. 3.7.4. Sensitivity analyses Sensitivity analyses where performed after the main analyses. A sensitivity analysis for depression was conducted, excluding the studies of Daniels et al. [65] and Jaggers et al. [67]; a large significant effect was found (SMD = −1.19 (95% CI -1.97 to −0.40), Z = 2.95 p = 0.003, X2 = 0.98, df = 6, p < 0.001, I2 = 89%). The two aforementioned studies were excluded due to the continuously unequal (large differences) baseline measures in the intervention and control 6

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groups ((Daniels et al. [65] IG 6.17 (3.97), CG 4.64 (2.79) at baseline; Jaggers et al. [67]: IG 14.40 (12.20), CG 9.40 (9.10) at baseline). Conducting a second sensitivity analysis for depression (excluding the studies of Shah et al. and Daniels et al. [65,69]), a large significant effect was found (SMD = −1.21 (95% CI -1.97 to −0.45), Z = 3.12 (p < 0.01), X2 = 46.95, df = 6, p < 0.01, I2 = 87%). The reason for excluding these studies was due to the missing information about exercise minutes per session and/or sessions per week, and the circumstance that participants were instructed to perform the instructed exercise at home on their own. Conducting a third sensitivity analysis for depression by excluding the study of LaPerriere [63], a moderate significant effect was found for depression (SMD = −0.76 (95% CI -1.53 to −0.01). Excluding the study of Schlenzig et al. [64], a large significant effect for anxiety was found (SMD = −1.49 (95% CI -2.98 to −0.01).

further meaningful evidence to this field. Given the moderately high methodological heterogeneity between studies, these findings need to be considered in this context. The studies were conducted in different countries, such as the USA, Africa, Germany, and India. Different prevalence rates for depression in PLWH are reported in China (50.8%) [72], Vietnam [73] (44%), Africa (9% 32%) [74] and India (67.3%) [75]. Also, two studies [63,64] were conducted in the pre-ART era before the year 1995. Depression and anxiety prevalence and levels for PLWH during the pre-ART era were higher. In the study of LaPerriere [63], the values for depression and anxiety in the exercising group (+3.1/ +0.1) did not decrease compared to the non-exercising control group (+13.8/ +5) but was just increasing less. The study of LaPerriere [63] did not report HAART. In the participant description in the paper, it was mentioned that the participants did not know about their HIV status at study entry, which implies that they were not on HAART at all. In the study by Schlenzig [64], 15 of 34 participants were under anti-retroviral medication and the participants presented different HIV-specific disease progressions. The circumstances for developing depression or anxiety are different compared with participants of a study conducted in more recent years with a stable infection and HAART. The two studies in the sub-analysis for depression investigating yoga only were the same as in the sub-analysis for HADS only. The comparison between the (commonly used) postanalyses and the pre-post analyses revealed no differences in the results and heterogeneity indicating that drop-out after randomization especially in small samples sizes did not lead to significant differences in the main outcomes pre- to post intervention. The present findings are in accordance with previous studies demonstrating the beneficial effects of exercise in reducing depressive symptoms [22], which is also evident for PLWH. A large and significant effect (SMD = −1.23) for anxiety was found at post-treatment. However, this finding was based on a conservative number of studies (n = 5); therefore, these results are provisional, as more RCTs are clearly needed in this field. Nonetheless, this effect is also in accordance with previous studies that have shown the anxiolytic effects of exercise [76]. The current findings further indicate that exercise is also beneficial in reducing anxiety symptoms in PLWH.

3.7.5. Publication bias According to Egger's test, a publication bias was found for depression (bias = −8.24, CI 95% 16.41 to −0.06), p = 0.048). However, no publication bias was found for anxiety (bias = −9.66, CI 95% -36.97 to 17.64), p = 0.34. 4. Discussion To our knowledge, this is the first meta-analysis evaluating the effects of exercise (both traditional and non-traditional forms of activity) on depression and anxiety outcomes in PLWH. Notably, the results of the meta-analysis for depression revealed a high and significant effect of exercise on depressive symptoms (SMD = −0.84). When analyzing only low-risk-of-bias studies, this effect was found to be even greater (SMD = −1.31). Importantly, in subgroup analyses testing only exercise trials with three or more sessions per week (SMD = −1.39) and professional supervision (SMD = −1.40), significant and large effects were evident. Although the meta-analysis of O'Brien et al. [31] already found a significant improvement in depression scores favoring the exercisers compared to the non-exercisers, the analysis was limited to two studies (LaPerriere [63] and Smith [71], n = 65; with the study of LaPerriere [63] being conducted in the pre-ART era). We now can add

Table 2 Meta-analytic results – depression, anxiety for post-intervention values. Effect foci

n trials (n participants)

SMD (95% CI)

Z (p)

I2

(Tau2), Chi2, df (p)

Depression Random-effect model

9 (395)

−0.84 [−1.57, −0.11]

2.27 (0.02)

91%

1.11, 87.82, 8 (< 0.001)

Subgroup analysis 1. AE 2. AERT 3. Yoga 4. ≥ 3 sessions/week 5. Professional supervision 6. PEDro score ≥ 5 7. POMS-D - only 8. BDI - only 9. HADS-D - only 10. structured control 11. non-structured control

3 4 2 6 4 5 3 4 2 5 4

−0.96 −0.12 −2.03 −1.39 −1.40 −1.31 −0.60 −0.18 −2.03 −0.62 −1.11

2.86 (0.004)

52% 84% 97% 87% 92% 92% 55% 86% 97% 28.96, 1 (< 0.001) 88% 94%

0.18, 0.47, 3.75, 0.97, 1.45, 1.56, 0.16, 0.53, 3.75, 0.93, 1.55,

Anxiety Random-effect model

5 (185)

92%

1.67, 48.90, 4 (< 0.001)

(98) (193) (104) (232) (182) (217) (109) (200) (104) (184) (211)

[−1.63, [−0.86, [−4.76, [−2.24, [−2.64, [−2.46, [−1.23, [−0.96, [−4.76, [−1.53, [−2.38,

−0.30] 0.62] 0.32 (0.75) 0.70] 1.46 (0.15) −0.54] −0.17] −0.17] 0.02] 0.59] 0.70] 1.46 (0.15) −0.30] 0.15]

−1.23 [−2.42, −0.04]

3.20 2.24 2.24 1.88 0.46 1.46 1.32 1.73

(< 0.001) (0.03) (0.02) (0.06) (0.64) (0.15) (0.19) (0.08)

2.03 (0.04)

4.15, 2 (=0.13) 18.68, 3 (< 0.001) 28.96, 1 (< 0.001) 38.94, 5 (< 0.001) 38.39, 3 (< 0.001) 52.14, 4 (< 0.001) 4.41, 2 (=0.11) 21.00, 3 (=0.001) 28.96, 1 (< 0.001) 32.59, 4 (< 0.001) 50.16, 3 (< 0.001)

Note. Panel includes n trials (n participants), standardized mean difference (SMD), 95% confidence interval (95% CI), Z-score (Z) and significance (p) of exercise vs. control conditions. Statistical heterogeneity (I2) is tested using the Chi2 statistics, including degree of freedom (df) and significance (p) and Tau2. A negative SMD favors the exercise group. Aerobic exercise (AE), aerobic exercise combined with resistance training (AERT), Physiotherapy Evidence Database (PEDro), Beck Depression Inventory (BDI), Profile of Mood State (POMS), Hospital Anxiety and Depression Scale (HADS).

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Fig. 2. Forest plot using random effect model of studies examining the impact of exercise on depression.

Fig. 3. Forest plot using random effect model of studies examining the impact of exercise on anxiety. Table 3 Pre-post comparison of depression and anxiety. Outcome

Studies (n)

Participants (n)

Post-analysis Random effect model

I2

Pre-post analysis Random effect model

I2

Post minus pre-post Diff. random Diff. I2

Depression Anxiety

9 5

395 185

−0.84 [−1.57, −0.11] −1.23 [−2.42, −0.04]

91% 92%

−0.91 [−1.51, −0.32] −1.27 [−2.49, −0.04]

86% 92%

0.07 5% 0.04 0%

Note. Panel includes study outcome, studies (n), participants (n), random effect of post analysis, heterogeneity of post analysis (I2), random effect of pre-post analysis, heterogeneity of pre-post analysis (I2), difference of post minus pre-post analysis of random effect models and heterogeneity (I2).

In this investigation, only two studies [68,69] explicitly excluded participants with a psychiatric illness, which includes depression and anxiety. For all other included studies, diagnosed depression was not a reason for exclusion. Effectively, the baseline scores of the depression and anxiety measures were under the cut-off values for depression or anxiety in six studies [39,62–64,66,67]. Overall, 42 (8.8%) of the 479 participants at baseline were diagnosed with depression or anxiety. In the review by Chaudhury et al. [77], the prevalence of depression was 36% and of anxiety 16% in PLWH. Also, they reported that the prevalence of depression and anxiety in PLWH ranged from 7.2% to 71.9% and from 4.5% to 82.3%, respectively. Given the fact that the prevalence for depression and anxiety is underrepresented in the included studies compared to the general HIV population, the effect of exercise could also be underestimated.

total sample range of 17 to 67 participants. This wide sampling variability increases the risk of sample bias among the studies and can lead to high statistical heterogeneity. Furthermore, across the ten studies, the participant dropout rate was 10.44% (n = 50). Six of these studies had a high withdrawal rate according to the quality assessment from the PEDro scale (≥ 15% of participants dropped out) [39,62,64,66,67,70]. However, due to the proportionate dropout rates in the intervention and control groups in these trials, the migration bias within the studies of participants who dropped out is minimized. Taken together, this pattern of findings highlights the need for future RCTs in this field to use larger sample sizes that comply with the criteria of highquality studies, including the blinding of assessors and intention-totreat analysis, and involve clinically standardized outcome measures. As outlined in the participants' characteristics, two of the included studies included samples taking anti-depressants or anti-anxiety medications [39,69]. The inclusion of these studies may have partially influenced the current results of the meta-analyses, as medication use in combination with exercise may have a potential synergistic effect in improving well-being. It is unclear, however, whether participants in the remaining eight studies used anti-depressants or anxiolytics, as these studies did not report on medication usage. This merits further investigation in future, larger scale RCTs in this field. Furthermore, it is known that HAART medication affects physiological parameters such as muscle tissue, body composition, cardiovascular parameters, and also

5. Limitations This review was based explicitly on depression and anxiety outcomes. Hence, the findings may not generalize to broader QOL outcomes that are more multidimensional. The results from the current review need to also be interpreted in the context of several limitations. First, the findings from the pre-post analysis may have in part been influenced by the small sample sizes, given that the majority (i.e., 60%) of included trials was comprised of samples < 50, with a combined

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psychological parameters [5,78–80]. Although the medication intake in the studies that reported HARRT use was similar, the risk of medication bias is still possible since different types of HAART were analyzed. The duration of HAART intake and the number of therapy changes may also be different for every HIVpositive participant. These factors may influence the effect of any type of exercise method investigated. Further research in a more homogenous classification for medication intake is needed. In addition, the current meta-analysis excluded any control groups exercising at different intensity levels or performing other forms of exercise. However, we considered the strict differentiation between exercising and non-exercising participants as a strength of this study. The inclusion of an exercising control group would lead to confounded results regarding the comparison of exercising and non-exercising PLWH. This current meta-analysis excluded studies investigating quality of life. It must be mentioned that the MOS-HIV or the SF-36 are primary tools of investigation in several excluded studies, e.g. Mutimura et al. [81], Maharaj et al. [82], Ogalha et al. [83], and Mkandla et al. [84]. These questionnaires also include domains of anxiety and depression as part of the mental health summary score. The current findings are relatively comparable to the findings of Nosrat et al. [33], although they found positive effects of exercise when comparing exercise to control groups. The limitation of Nosrat's review [33] is that the results are not based on meta-analytical findings. In the current meta-analysis, we used validated specific measures for depression and anxiety. Regarding the control group conditions, the meta-analysis for depression showed a higher effect in favor of the intervention group when comparing non-structured vs. structured control conditions (SMD = 1.11 vs. SMD = −0.62), even though both analyses are not significant (p = 0.08 vs. p = 0.19). Furthermore, within a non-structured control condition such as “maintaining daily activity,” it remains unclear what exactly the participants did during this time.

indeed a synergistic effect when exercise is combined with medication use. Third, the effect of age regarding the impact of exercise on depression and anxiety status has not been investigated systematically. Finally, the number of studies investigating exercise beyond the traditional forms of aerobic and resistance training is small, with only two studies identified for PLWH. Hence, it is too early to determine whether the benefits of exercise are equivalent across different forms of physical activity for PLWH. Further research is clearly needed to extend this line of research. With regard to the higher effect in the subgroup analysis of professional supervision (SMD = −1.40 [−2.64, −0.17]), these results are similar to those of Schuch et al.'s [87] meta analyses investigating exercise in the context of depressed patients also finding large and higher effects for exercise led by exercise professionals. Another study in the context of exercise and aging with nearly 500 participants found that the perceived need support from the exercise professional predicts depressive symptoms and satisfaction with life [88]. Therefore, further studies need to control for the effect of the supervision suggesting that e.g. the competence and empathy of the supervisor influences the outcomes positively. Also exercising with a training partner or in a group can have positive effects on the outcomes and therefore should be controlled and might promote an even greater decrease in depressive and anxiety symptoms. 5.2. Implications for practice PLWH have a higher risk of developing depressive or anxiety symptoms when compared to HIV negatives. This meta-analysis showed the benefits of performing exercise for reducing depressive and anxiety symptoms beyond the well investigated benefits for physical health in PLWH. Additionally, exercise is generally a fast reachable and easy accessible option that should be recommended by physicians to PLWH. Moreover, the results further showed that a high frequency of training sessions (3 or more per week) may be beneficial specifically for the reduction of depressive symptoms. Supervision by qualified exercise professionals also led to greater effects for depression. This psycho-social component of the involvement of an exercise professional that might be further increased by exercising within a group or a partner should be considered in the recommendations of physicians and outreach clinics.

5.1. Implications for Research It is noteworthy that there was an equal gender distribution in the included studies, with women comprising 49.7% of the sample average. This indicates that the findings are applicable across both genders. This is particularly relevant given that research has shown that the prevalence rates for anxiety and depression may be higher in women versus men [85,86]. However, given that all of included studies in the current review did not report the depression and anxiety results separately for each gender, unfortunately this precluded conducting subanalyses according to whether or not the effects of exercise for depression and anxiety were influenced by gender. Accordingly, future research is needed to specifically test whether women and men benefit equally from the positive effects of exercise interventions. The outcomes of this review identified some additional gaps that need to be addressed in future research. First, PEDro scale criteria: blinding subjects (n = 0), and blinding researchers/evaluators (n = 0) were not met from any study. Blinding subject and blinding researchers/evaluators are hardly realizable due to the nature of the exercise intervention. Some criteria for high methodological quality were not met by many studies, such as blinding assessors (n = 7), measuring at least one key outcome obtained from > 85% of subjects initially allocated to groups (n = 6), and intention-to-treat analysis (n = 8). Therefore, the methodological quality of studies needs to be improved in future trials. Second, medication intake, especially antidepressants, was not specified in the majority of trials. This information is important to detail in future studies in order to establish whether or not there is

6. Conclusion The present meta-analytic outcomes indicate large effects for the efficacy of exercise interventions in reducing both depression and anxiety symptoms in PLWH. Although these findings are based on a small number of RCTs, these results suggest that exercise seems to be moderately to largely beneficial for reducing depression and anxiety in PLWH. Taken together, the results suggest that highly frequent (3 or more per week), professionally supervised, and aerobic exercise may lead to the greatest improvements in depressive symptoms for PLWH. Dclaration of Competing Interests The authors have no competing interests to report. Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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Appendices Table A.1

Systematic search strategy. Database

Date

Combined terms and text words

Pubmed

13.02.2019

(((((((((HIV[MeSH Terms]) AND physical exercise[MeSH Terms]) OR physical activity[MeSH Terms]) OR yoga[MeSH Terms]) OR tai chi[MeSH Terms]) OR qigong[MeSH Terms]) AND psychological [MeSH Terms] depression[MeSH Terms]) OR dysthymia[MeSH Terms]) OR anxiety[MeSH Terms] HIV, exercise, physical activity, depression, anxiety

Cochrane Cen- 13.02.2019 tral PsycNet 13.02.2019 PEDro Clinicaltrials. gov

13.02.2019 13.02.2019

“HIV” OR “human immunodeficiency virus”) AND (“exercise” OR “physical activity” OR “aerobic” OR “resistance” OR “strength “OR “fitness “OR “yoga “OR “tai chi “OR “qigong“) AND (“depression” OR “psychological” OR “depressive” OR “dysthymic” OR “dysthymia” OR “anxiety”) HIV, exercise, physical activity, depression, anxiety (HIV exercise OR physical activity OR resistance OR aerobic OR yoga OR tai chi OR qigong AND depression OR anxiety or dysthymia)

Note. Scientific databases consulted for the systematic review, with search term combinations and search dates as day, month and year.

Table A.2

Study characteristics of studies excluded from quantitative synthesis.

1

Author, Year, Country

Outcome Parameters

Method /Intervention

Participants

Galantino, ML., 2005 USA

POMS

aerobic exercise vs. tai chi vs. control

(n) = 38, AE n = 13,TC n = 13, CG n = 12

Baseline

Intervention

Intervention

Control

M/ S

S/ Wk

Wks

2

8

M/ Wk

Control group

Reason for exclusion

Supervision

non-structured: usual daily activity

no baseline not menor post tioned measures

Peer reviewed/ thesis peer reviewed

Note. Study characteristics presented as author/year of publication, investigated outcome, specific intervention investigated, (n) participants, baseline measures mean ± SD intervention group, baseline measure mean ± SD control group, minutes per session (M/S), sessions per week (S/Wk), weeks (Wks), minutes per week (M/Wk), description of control group condition. Profile of Mood State (POMS), aerobic exercise (AE), tai chi (TC), control group (CG).

Table A.3

Outcome measures. Studies

Outcome

Measuring tool

Number of studies (%)

(Aweto et al., 2016; Daniels & Van Niekerk 2018; Dianatinasab et al., 2018; Jaggers et al., 2014; Kiloor et al., 2018; LaPerriere et al., 1990; Naoroibam et al. 2016; Neidig et al. 2003; Shah et al., 2016) (Dianatinasab et al. 2018; Kiloor et al., 2018; LaPerriere et al., 1990; Naoroibam et al., 2016, Schlenzig et al., 1992)

Depression

BDI-D, GHQ-28, POMSD, HADS-D (GHQ-28, POMS-A, HADS-A, STAI)

9 (90%)

Anxiety

5 (50%)

Note. Studies: author/year of publication, Outcome: investigated parameter, measuring tool, number of investigating studies (percentage), Beck Depression Inventory-Depression (BDI-D), General Health Questionnaire −28 (GHQ-28), Profile of Mood State-Depression/Anxiety (POMS-D/A), Hospital Anxiety and Depression Scale (HADS), State-Trait Anxiety Inventory (STAI), percentage (%).

Table A.4

Risk of bias analysis according to the PEDro scale. Study

EC

I

II

III

IV

V

VI

VII

VIII

IX

X

Total

Aweto HA. 2016 Daniels AK. 2018 Dianatinasab M. 2016 Jaggers FR. 2014 Kiloor A. 2018 LaPerriere A. 1990 Naoroibam R. 2016 Neidig JL. 2003 Schlenzig C. 1992 Shah KN. 2016

Y Y Y Y Y Y Y Y Y Y

1 1 1 1 1 1 1 1 1 1

1 0 0 0 1 0 0 0 0 1

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

0 1 0 0 1 1 0 0 0 1

0 0 0 0 0 1 0 1 0 0

1 1 1 1 1 1 1 1 1 1

1 1 1 1 1 1 1 1 1 1

5 4 4 3 6 6 4 6 4 7

Note. EC: eligibility criteria, I: allocated randomization of subjects to groups, II: concealed allocation, III: similarities of groups at baseline, IV: blinding of subjects, V: blinding of researchers/evaluators, VI: blinding of assessors, VII: measure of at least one key outcome obtained from > 85% of subjects initially allocated to groups, VIII: intention to treat, IX: statistical comparison of between-group results, X: measured at least one key outcome at two time points, 1: criteria is present, 0: criteria is missing. *EC does not contribute to the total score, Y: Yes, eligibility criteria present.

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