Journal of Affective Disorders 168 (2014) 98–106

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Research report

Exercise or basic body awareness therapy as add-on treatment for major depression: A controlled study Louise Danielsson a,b,n, Ilias Papoulias c, Eva-Lisa Petersson d,e, Jane Carlsson a,b, Margda Waern b,f a Institute of Neuroscience and Physiology, Department of Clinical Neurosciences and Rehabilitation, Sahlgrenska Academy, University of Gothenburg, Box 455, 405 30 Gothenburg, Sweden b University of Gothenburg Centre for Person-Centred Care (GPCC), Sweden c Sahlgrenska University Hospital, Sweden d Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden e Närhälsan Research and Development Primary Health Care, Region Västra Götaland, Gothenburg, Sweden f Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, Sahlgrenska Academy, University of Gothenburg, Sweden

art ic l e i nf o

a b s t r a c t

Article history: Received 14 May 2014 Received in revised form 27 June 2014 Accepted 28 June 2014 Available online 5 July 2014

Background: While physical exercise as adjunctive treatment for major depression has received considerable attention in recent years, the evidence is conflicting. This study evaluates the effects of two different add-on treatments: exercise and basic body awareness therapy. Methods: Randomized controlled trial with two intervention groups and one control, including 62 adults on antidepressant medication, who fulfilled criteria for current major depression as determined by the Mini International Neuropsychiatric Interview. Interventions (10 weeks) were aerobic exercise or basic body awareness therapy (BBAT), compared to a single consultation with advice on physical activity. Primary outcome was depression severity, rated by a blinded assessor using the Montgomery Asberg Rating Scale (MADRS). Secondary outcomes were global function, cardiovascular fitness, self-rated depression, anxiety and body awareness. Results: Improvements in MADRS score (mean change ¼  10.3, 95% CI (  13.5 to  7.1), p ¼0.038) and cardiovascular fitness (mean change¼ 2.4 ml oxygen/kg/min, 95% CI (1.5 to 3.3), p¼0.017) were observed in the exercise group. Per-protocol analysis confirmed the effects of exercise, and indicated that BBAT has an effect on self-rated depression. Limitations: The small sample size and the challenge of missing data. Participants' positive expectations regarding the exercise intervention need to be considered. Conclusions: Exercise in a physical therapy setting seems to have effect on depression severity and fitness, in major depression. Our findings suggest that physical therapy can be a viable clinical strategy to inspire and guide persons with major depression to exercise. More research is needed to clarify the effects of basic body awareness therapy. & 2014 Elsevier B.V. All rights reserved.

Keywords: Randomized controlled trial Person-centred care Physical therapy Major depression

1. Introduction The complexity of managing major depression, demonstrated by a rate of about one third of patients responding insufficiently to available treatments, calls for the development and refinement of alternative and adjunctive treatment options (Rush et al., 2006; Trivedi et al., 2005; Malhi et al., 2013). As such, physical exercise has gained considerable attention, although recent findings from n Corresponding author at: Institute of Neuroscience and Physiology, Department of Clinical Neurosciences and Rehabilitation, University of Gothenburg, Box 455, 405 30 Gothenburg, Sweden. Tel.: þ 46 702 31 99 07. E-mail address: [email protected] (L. Danielsson).

http://dx.doi.org/10.1016/j.jad.2014.06.049 0165-0327/& 2014 Elsevier B.V. All rights reserved.

systematic reviews point to few methodologically robust studies and small or at best, moderate effect sizes (Krogh et al., 2011; Cooney et al., 2014; Danielsson et al., 2013). Working mechanisms are unclear, but theories are proposed on regulation of neurotransmitters, hippocampal cell growth and neuroimmunological mechanisms as well as psychological mediators such as increased self-efficacy and behavioral activation (Trivedi and Greer, 2009). Exercise is now suggested as adjuvant treatment in guidelines for depression, for example in Great Britain (Pilling et al., 2009) and in the United States (Rethorst and Trivedi, 2013). Exercise for depression generally refers to aerobic exercise of a moderate to high intensity such as cycling, jogging, brisk walking or other cardiovascular training (Perraton et al., 2010). Parallel to

L. Danielsson et al. / Journal of Affective Disorders 168 (2014) 98–106

this line of research, studies investigating meditative movement practices such as yoga, Tai chi or mindfulness meditation suggest beneficial effects (Tsang et al., 2013; Payne and Crane-Godreau, 2013; Cramer et al., 2013; Ravindran and Da Silva, 2013). In such lower intensity training, focus is on the body-mind interaction and an accepting attitude to one's experiences. Exercise and basic body awareness therapy (BBAT) are two treatment methods commonly employed by physical therapists in Scandinavian mental health settings (Mattsson, 1998). Whereas exercise means structured physical activity to maintain or increase physical fitness (Caspersen et al., 1985), BBAT addresses the interplay of body and mind by exploring slow movements with awareness of postural stability, breathing and flow of movements (Catalan-Matamoros et al., 2011; Mattsson, 1998). Several studies show promising results for BBAT interventions for persons with eating disorders, schizophrenia, chronic fatigue and long-term musculoskeletal pain (Mannerkorpi and Arndorw, 2004; Malmgren-Olsson et al., 2001; Johnsen and Råheim, 2010; Hedlund and Gyllensten, 2010; Gyllensten et al., 2003, 2009; Catalan-Matamoros et al., 2011), and in psychiatric patients with mixed diagnoses (Mattsson et al., 1995; Gyllensten et al., 2003, 2009). Further, depressive symptomatology was shown to decrease in patients with irritable bowel syndrome following BBAT (Eriksson et

99

al., 2007). However, BBAT has not yet been evaluated in a study sample of patients with major depression. Drawing on previous research on exercise and meditative movement practices as well as clinical experiences from physical therapy practice, our objectives were to conduct a study evaluating 1) exercise and 2) basic body awareness therapy, as add-on treatments for persons with major depression.

2. Methods 2.1. Study design A single-site, three-armed randomized controlled design was used. 2.2. Study population Participants, presented in Table 1, were 62 adults aged 18–65, with major depression according to DSM-IV criteria, diagnosed by a psychiatric trainee using the Mini International Neuropsychiatric Interview (MINI) (Sheehan et al., 1998). To take part in the study,

Table 1 Demographic and baseline data of study participants in a randomized controlled trial of exercise and basic body awareness therapy (BBAT) as augmentation treatment for major depression.

Age, mean (SD) Sex, n (%) Women Men Marital status, n (%) Married or co-habiting Single Occupational status, n (%) Full-time Part-time Full sick leave/disability pension Any anxiety disorder b , n (%) Panic disorder with or without agoraphobia Agoraphobia without panic disorder Social phobia Generalized anxiety disorder Antidepressants, duration, n (%) 6 w–3 months 3–9 months 4 9 months Antidepressant drug, type, n (%) Tricyclics (clomipramine) SSRIs (e.g sertraline, fluoxetine) SNRI (venlafaxine) Other agents (e.g mirtazapine, bupropion) Imipramine equivalent dose, mean g/day (SD) Prescription for sedatives/hypnotics (n) Depression severity MADRS, mean (SD) MADRS-S, mean (SD) Anxiety symptoms BAI, mean (SD) Functional capacity GAF symptom, mean (SD) GAF function, mean (SD) Body awareness SBC, mean (SD) Cardiovascular fitness Maximal oxygen uptake ml/min/kg, mean (SD) Body mass index Kg/m2 (SD)

Exercise group (n¼22)

BBAT group (n¼20)

Advice group (n¼20)

p-valuea

44.7 (12.5)

45.4 (13.5)

46.3 (13.9)

0.93 0.82

16 (73) 6 (27)

16 (80) 4 (20)

16 (80) 4 (20)

11 (50) 11 (50)

11 (55) 9 (45)

9 (45) 11 (55)

7 (32) 4 (18) 11 (50) 11 (50) 6 (27) 5 (23) 4 (18) 2 (9)

8 4 8 9 2 4 4 3

(40) (20) (40) (45) (10) (20) (20) (15)

10 (50) 2 (10) 8 (40) 11 (55) 6 (30) 5 (25) 6 (30) 2 (10)

3 (14) 7 (32) 12 (54)

1 (5) 7 (35) 12 (60)

1 (5) 8 (40) 11 (55)

1 16 4 1 149.4 (70.7) 4

0 13 5 2 145.3 (56.0) 5

0 17 2 1 129.4 (56.1) 4

0.45 0.86

24.6 (4.1) 24.1 (6.2)

23.9 (5.0) 25.3 (6.2)

23.4 (5.0) 23.7 (6.7)

0.68 0.71

19.1 (12.8)

20.8 (6.9)

20.8 (10.1)

0.82

53.7 (3.5) 57.3 (4.2)

54.6 (3.5) 56.8 (5.6)

55.3 (3.9) 58.4 (4.6)

0.38 0.71

21.6 (8.4)

22.8 (7.5)

20.0 (6.0)

0.30

23.4 (5.1)

23.5 (3.4)

24.4 (5.8)

0.77

24.2 (4.6)

25.9 (4.8)

25.1 (3.8)

0.48

0.86

0.76

0.56

0.66

0.65

Abbreviations: SD ¼ Standard Deviation, SSRI ¼Selective Serotonin Reuptake Inhibitors, SNRI¼ Serotonin Norepinephrine Reuptake Inhibitors, MADRS ¼ Montgomery Asberg Rating Scale, GAF ¼ Global Assessment of Functioning, BAI¼ Beck's Anxiety Inventory, SBC ¼ Scale of Body Connection. a b

Analysis of variances (ANOVA) was used for comparison of continuous variables, chi-square test was used for categorical variables. Significance level was 0.05. Some subjects fulfill criteria for several anxiety diagnoses.

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the participants should be on one, or two antidepressant drugs, of any dosage, prescribed and followed up by their ordinary physician. Additional medication with sedatives was allowed. The participants reported their ongoing medication to the researchers during the recruitment phase. In order to compare the different antidepressant drugs, we applied the strategy described by Bollini et al. (1999). We standardized the recommended therapeutic doses (according to Swedish guidelines) with respect to the recommended dose of imipramine (150 mg/day), the first antidepressant introduced into clinical practice. This generated for each drug an equivalence factor by which each participant's dose was multiplied, resulting in imipramine equivalent doses, reported as group means in Table 1. As this study was designed to evaluate augmentation treatments, we did not interfere with the patients' medication. The majority of participants were on selective serotonin reuptake inhibitors, see Table 1 for more details. When entering the trial, participants reported their medication to the researchers. They were instructed to continue their antidepressant treatment as prescribed during the entire study period and to report any changes to the researchers. Further, they were asked at follow up if the medication had been altered, or any other treatment had been added. Criteria for exclusion included ongoing substance use disorder, psychotic disorder, previous manic episodes or imminent suicide risk as determined by the MINI, as well as pregnancy, untreated heart condition or ongoing regular exercise of moderate to high intensity or mind-body activities. Patients enrolled in multidisciplinary teams in specialized mental health care settings were excluded; in Sweden, these teams tend to provide treatments similar to the study interventions. To screen for somatic comorbidity for which intensive exercise might be contraindicated, such as some cardiovascular diseases, we included a standardized screening tool in our screening

questionnaire (see Appendix 1) called the Revised Physical Activity Readiness Questionnaire, recommended by the European Association of Cardiovascular Prevention and Rehabilitation (Borjesson et al., 2011). For two participants, their answers (strong dizziness and heredity for cardiovascular disorder in one case, and a congenital heart condition in the other) resulted in an additional consultation with their physicians. Study participation was approved in both cases. Eight participants were on medication for hypertension and all of these were normotensive. 2.3. Recruitment and randomization procedure During 2012 and 2013, we recruited participants using advertisements in two local morning newspapers. One hundred and thirty-five volunteers expressed interest in the study and contacted the research group by phone or e-mail. In addition, we received six referrals from collaborating health professionals at a primary care health clinic. The initial telephone screening, see Appendix 1, was conducted to check for eligibility and general health status, and to provide verbal and written information about the study. Volunteers who matched screening criteria were assessed for eligibility by a psychiatric trainee using the MINI (Sheehan et al., 1998). These interviews took place at a primary care rehabilitation centre in Gothenburg, as did all measurements and subsequent interventions. Eligible participants signed a written consent form and were then enrolled in the study, see Fig. 1 for participant flow. After baseline measurements, individuals were randomized to one of the three study arms (exercise, BBAT or advice) using sealed, opaque envelopes prepared by a person not involved in the study. This person created blocks of six envelopes, randomly sorted, each block containing two of each group

Fig. 1. Flow chart of study participants in a randomized controlled trial of exercise and basic body awareness therapy (BBAT) in major depression. ITT ¼ intention-to-treat, PP ¼per-protocol.

L. Danielsson et al. / Journal of Affective Disorders 168 (2014) 98–106

assignment. During randomization, each block was distributed before the next one was opened. In this way, the group sizes would not differ by more than two participants. Due to the nature of the interventions, it was impossible to blind participants to their assignment. However, throughout the study, the participants were unaware of the study hypothesis and had only been informed that the study aimed at comparing three different approaches to physical activity.

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Thus, we regarded this minimal intervention as enhanced standard care. The encounter aimed at inspiring the participants to regular low- to moderate physical activity. A brochure with community-based free of charge physical activities was given to those who were interested. The participants were able to contact the physical therapist during the study period for additional support. After completion of the follow-up measurements, those who were randomized to the advice arm were offered an active intervention of their choice, either exercise or BBAT.

2.4. Interventions 2.5 Measurements 1. Exercise: participants took part in person-centered aerobic exercise for 10 weeks. The program aimed at increased cardiovascular fitness using intervals with higher perceived intensity, corresponding to 16–17 on the Borg Scale for Perceived Exertion (Borg, 1982) and intermittent intervals of lower perceived intensity (13–14 on the Borg Scale). Taking a starting point from two individual sessions, the participant and the physical therapist created, in a collaborative effort, the participant's training program, involving a variety of exercises and gym equipment available at the rehabilitation center. These included cross-trainer, stationary bikes, step-up boards, rowing machine, treadmill, jumping ropes, balls, free weights and cable machines. Participants wore a pulse-watch (Polar RCX3, Polar Electro Sweden) when designing their program. The two individual sessions took place during the initial two weeks of the study period. Thereafter followed an 8-week period with two weekly sessions during which 5–8 participants trained at the same time, guided by the same physical therapist. Each session lasted for one hour, which included a warm-up phase of 5–10 min, 45 min of interval training, and a 5-minutes cool-down phase with stretching exercises. The physical therapist who guided the training had over 20 years of clinical experience of treating patients with mental health problems, in both primary care and hospital settings. 2. BBAT: participants took part in person-centered BBAT for 10 weeks. Taking a starting point from two individual sessions, the participant and the physical therapist explored bodily resources, in a process-oriented manner, by a variety of slow and simple movements. Movements involved body scanning and stretchrelease movements in the supine position, and thereafter postural stability, movement flow and free breathing in sitting and standing. Equipments included yoga mats, meditation cushions, stools, blankets and pillows. The process aimed at enhancing the participant's sense of bodily self and functionality of movements. A further goal was the development of a mindful, accepting attitude. The two individual sessions during the initial two weeks of the study period were followed by an 8-week period with two weekly sessions during which 5–8 participants trained at the same time, guided by the same physical therapist. The duration of each session was one hour, including a 10 min period for verbal reflection at the end, providing an opportunity for each participant to share her or his experiences. The physical therapist working with this group had about eight years experience working with BBAT in psychiatric and primary care settings, and over 20 years of previous experience working with dance and movement group therapies. Both interventions were person-centred in the sense that they were oriented toward the patient as person rather than toward his or her medical diagnosis (Mccormack et al., 2010; Ekman et al., 2011). By exploring and involving the patient's perceived needs, beliefs, experiences and resources, the content of each individual's training evolved in an active and dynamic collaboration between the patient and the physical therapist. 3. Advice on physical activity: participants met on one occasion, individually, with a physical therapist to receive advice and motivational support for physical activity. In Sweden, this type of advice can be provided by staff at most primary health centers.

The primary outcome was change in Montgomery Asberg Depression Rating Scale (MADRS) (28) score over the 10 weeks study period. MADRS is an observer-rated scale with 10 items reflecting key features of depression, each item scoring 0–6 points. The scale is sensitive to change and has strong internal consistency (Cronbach's alpha α ¼0.9) (Carmody et al., 2006). The scale is commonly used in research and clinical practice in psychiatric and primary care settings. Here, the trainee psychiatrist who was blinded to the participants' group assignment assessed depression severity with MADRS at baseline and at 10 weeks. Secondary outcomes were: a) Global function, measured at baseline and at 10 weeks (rated by blinded trainee psychiatrist), using the Global Assessment of Functioning (GAF) (Hall, 1995). b) Self-reported depression symptoms, using the MADRS-S (Svanborg and Asberg, 1994) at baseline, at 5 weeks, and at 10 weeks. This self-report version of the MADRS is frequently used in clinical practice, has acceptable correlation with the observer-rated scale (r ¼0.54) and good internal consistency (α ¼0.84) (Fantino and Moore, 2009). c) Anxiety symptoms, measured using the self-report Beck's Anxiety Inventory (BAI) (Beck et al., 1988) at baseline and at 10 weeks. BAI is a well-established and useful tool for evaluating clinical anxiety, also in major depression (Enns et al., 1998), with high internal consistency (α ¼ 0.92) and good test-retest reliability (0.83) (De Beurs et al., 1997). d) Body awareness, measured using the body awareness domain of the self-rating Scale of Body Connection (SBC) (Price and Thompson, 2007) at baseline and at 10 weeks. The body awareness subscale has good internal validity, both regarding construct validity (goodness-of-fit index of 0.89) and consistency (α ¼0.83) (Price and Thompson, 2007). e) Cardiovascular fitness, measured by estimating maximal oxygen uptake (VO2max), which is a measure of the maximum amount of oxygen that can be utilized in the body during exercise. VO2max was measured using Astrand's submaximal bicycle test (Astrand and Ryhming, 1954), conducted by a physical therapist at baseline and at 10 weeks.

2.6. Ethical considerations All participants received verbal and written information about the study followed by a brief communication with the study coordinator for questions or other reflections, prior to giving their consent to participate and signing a consent form. They were also informed about confidentiality and their right to resign at any phase of the study. The interventions were used as augmentation to the patients' ongoing medical treatment, to minimize the risk of worsening their mental health. In addition, the following preventive measures were taken: a) self-reported depressive symptoms were measured half-time through the study's 10 weeks; b) patients were instructed to contact their doctor should they

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experience considerable increase of symptoms or discomfort and c) patients were instructed to report side effects to the group leaders or to the study coordinator during the study. Also, they were asked about side effects at follow-up, recorded in free text. The Regional Ethics Review Board approved the study.

2.7. Statistical analysis For all efficacy variables, we hypothesized that the change from baseline to follow-up would differ significantly between groups. The remission and response rates were also calculated, defining remission as at least 50% improvement of the primary efficacy variable with a post-intervention MADRS score of maximal 10 points and a clinically relevant response without remission as at least 50% improvement (Trivedi et al., 2009). As this was an augmentation study with patients who had not responded to medication, we added a category of “some response”, defined as at least 30% improvement (Mather et al., 2002). The primary analysis was performed using the intention-totreat (ITT) population, including all randomized participants. For missing data, the last observation was carried forward, assuming no change for non-completers. All analyses were also carried out per-protocol (PP). The PP population included all ITT subjects who did not deviate in any major way from the protocol, who adhered to their designated treatment and who completed the post-intervention follow-up. Data are presented using descriptive statistics including the number of observations, means and standard deviations for continuous variables. For the categorical variables, frequencies and percentages are presented and data were analyzed using the chi-square test. Based on plotted histograms confirming that data for all outcomes were regarded as approximately normally distributed, we analyzed continuous data using a univariate general linear model, (ANCOVA), in which treatment was used as a fixed factor and the baseline levels as a covariate in the model. Pairwise comparisons were adjusted for multiple testing using the Bonferroni correction. Data are presented as mean changes (estimated marginal means) with corresponding 95% confidence intervals or standard errors and p-values from the between-groups comparison. The categorical outcome treatment response was analyzed using the chi-square test. For all tests, a p-value below 0.05 was regarded as statistically significant. All analyses were performed using Statistical Package for the Social Sciences (SPSS), version 21.0 (IBM Corp, Armonk, NY, USA).

3. Results 3.1. Participants Sixty-two participants were enrolled in the study and randomized into the three groups, see Fig. 1. Demographics and baseline values for the three groups are presented in Table 1. One-way ANOVA showed no significant differences in baseline values between groups. Thirteen subjects failed to complete the follow-up assessment for the primary outcome. Four of these subjects completed the self-assessments at follow-up (MADRS-S, BAI and SBC), and returned these by mail. Median attendance (maximum 18 sessions) was 14 (range 0–17) sessions in the exercise group and 13 (range 0–18) sessions in the BBAT group. All but two of those randomized to the advice group took part in the single session. Adherence to protocol was defined as participating in 450% of scheduled sessions and not commencing another treatment provided by health care during the study period. Adherence rates were 85% in the exercise group and 75% in the BBAT group. At follow-up, five participants reported a change in antidepressant medication after enrolment. Dosages were increased for one participant in the exercise group, and for two in the control group. Decreased dosages were reported by one participant in the exercise group and one in the BBAT group. Two participants in the advice group were excluded from the PP analysis since they reported that they had taken up regular participation in other treatments during the study period. These treatments were physical therapy exercise and mindfulness cognitive behavioral therapy. Two persons in the BBAT group were excluded due to low attendance (o50% of scheduled sessions). Results from ITT and PP analyses are reported as mean changes and standard errors for all outcomes with p-value from ANCOVA test for between-group differences, see Table 2. 3.2. Primary outcome For observer-rated depression severity, the mean change in MADRS score was  10.3 with a 95% confidence interval ( 13.5 to  7.1) in the exercise group,  5.8 (95% CI  9.2 to  2.5) in the BBAT group and  4.6 (95% CI  7.9 to  1.2) in the advice group. The ANCOVA resulted in a significant difference between groups, p¼ 0.038. In the Bonferroni-adjusted pairwise comparisons, we found that the exercise group improved significantly compared to the advice group, p¼0.048.

Table 2 Mean change from baseline to follow-up in efficacy variables for the intention-to-treat (ITT) and per-protocol (PP) population. ITT

Depression severity MADRS score MADRS-S score Functional capacity GAF symptom score GAF function score Anxiety symptoms BAI score Body awareness SBC score Cardiovascular fitness Oxygen uptake (max ml/kg/min)

PP

Exercise n ¼22

BBAT n ¼20

Advice n¼ 20

p-value

Exercise n ¼18

BBAT n¼ 14

Advice n ¼14

p-value

 10.3 7 1.6  7.2 7 1.4

 5.8 7 1.7  4.2 7 1.5

 4.6 7 1.7  1.8 7 1.5

0.038 0.034

 12.8 7 1.6  9.5 7 1.3

 8.4 7 1.8  6.6 7 1.5

 5.17 1.8  1.4 7 1.5

0.012 0.001

6.9 7 1.7 7.5 7 1.7

2.8 7 1.8 2.2 7 1.8

3.8 7 1.8 3.2 7 1.8

0.236 0.075

8.2 7 2.1 9.2 7 2.1

3.9 7 2.3 2.7 7 2.3

4.2 7 2.4 3.2 7 2.4

0.293 0.075

 3.6 7 1.4

 5.0 7 1.5

 3.4 7 1.5

0.715

 5.9 7 1.8

 7.9 7 2.0

 1.6 7 2.0

0.078

1.9 7 1.2

3.6 7 1.3

2.17 1.3

0.603

2.5 7 1.4

4.2 7 1.6

1.8 7 1.6

0.583

2.4 7 0.4

0.8 7 0.5

0.8 7 0.5

0.017

3.0 7 0.5

1.17 0.5

0.5 7 0.5

0.003

Values from analysis of covariance (ANCOVA), presented as estimated marginal means with standard errors. BBAT¼ Basic Body Awareness Therapy.

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remission, the crude estimate of numbers needed to treat (NNT), that is, the number of patients needed to treat in order to prevent one undesirable outcome (non-remission), was 5.0 in the exercise group and 10 in the BBAT group. This means that for exercise, administered as in this study and compared to receiving advice, 5.9 patients need to be treated for one to recover. As a general rule, an NNT of 2–5 indicates an effective therapy, although the number should always be interpreted in light of the clinical context. It we define all responses over 30% as a benefit for the patient, the NNT was 3.5 for exercise and 6.7 for BBAT. 3.4. Adverse events

Fig. 2. Boxplot of the primary outcome presenting group mean changes in MADRS (Montgomery Asberg Depression Rating Scale) score in the per-protocol population, total n¼ 46.

Table 3 Remission and response ratesa in a study examining the effects of exercise and basic body awareness therapy (BBAT) as add-on treatment in major depression. Exercise n¼ 22 BBAT n¼ 20 Advice n¼ 20 Remission Response 50% without remission Some response ( 430% o 50%) Non-response ( o 30%)

7 2 5 8

(32) (9) (23) (36)

5 0 5 10

(25) (0) (25) (50)

3 2 2 13

(15) (10) (10) (65)

a Values are n (%) out of intention-to-treat population. P-value from chi-square test is 0.44.

The results were confirmed in the PP analysis, see Table 2 and Fig. 2. Here, the p-value for the significant difference between the exercise group and the advice group was 0.011. 3.3. Secondary outcomes For self-rated depression, there was a statistically significant difference in mean change across the three groups, favoring exercise; mean change in MADRS-S ¼ 7.2 (95% CI  10.0 to 4.4), p ¼0.036. For the BBAT group, the mean change was 4.2 (  7.1 to  1.3) and for the advice group, the mean change was 1.8(  4.8 to 1.1). Pairwise comparisons showed improvement in the exercise group compared to the advice group, p ¼0.030. Mean changes in cardiovascular fitness for the three groups respectively were: exercise 2.4 (95% CI 1.5 to 3.3), BBAT 0.8 (95% CI 0.2 to 1.7) and advice 0.8 (95% CI  0.2 to 1.7). There was a statistically significant difference between groups, see Table 2. Pairwise comparisons showed improvement in the exercise group compared to advice (p¼ 0.042) and in the exercise group compared to BBAT (p ¼0.041). We found no statistically significant differences between the three groups regarding GAF, self-rated BAI and SBC. Overall, the results were confirmed in the PP analysis, see Table 2. However, regarding the PP analysis of self-rated depression (MADRS-S), the pairwise comparisons revealed improvement both in the exercise group compared to advice (p o0.001) and in the BBAT group compared to advice (p ¼0.048). We analyzed the bivariate correlation (two-tailed) between change in MADRS score and change in cardiovascular fitness in the overall sample, which showed a significant negative correlation (Pearson coefficient r¼  0.37, p¼0.003), that is, a correlation between decreased MADRS score and increased fitness at follow-up. There were no significant differences between the three groups regarding remission and response rates, reported in Table 3. For

Higher MADRS or MADRS-S score was observed in six participants at follow-up. Four of these participants were in the advice group, one was in the exercise group and one was in the BBAT group. In the exercise group, the following side effects were reported: achilles tendinosis (n ¼1), joint pain (n¼ 2); and muscle pain (n ¼1). In the BBAT group, the following side effects were reported: increased emotional distress/anxiety (n ¼4) and joint pain (n¼ 1).

4. Discussion Taken together, results suggest that add-on exercise treatment, compared to advice, has a clinically relevant effect on both depression severity and cardiovascular fitness in persons with major depression. Among participants following protocol, results suggest that BBAT has an effect on self-rated depression symptoms compared to advice on physical activity. The main findings corresponded to our expectations paralleling the work of others (Ho et al., 2014; Schuch et al., 2011; Blumenthal et al., 2007; Dunn et al., 2005). We chose a control condition that would potentially feel meaningful and inspiring to the participants, rather than treatment-as-usual or wait-list, since non-active controls are suggested to have a negative influence on study results (Kinser and Robins, 2013). Our finding of significant improvement in the exercise group as compared to the advice group further strengthens the evidence for exercise as an efficient adjuvant in the treatment of major depression. In previous studies, an antidepressant effect of exercise was concluded when comparing to treatment-as-usual or wait-list controls (Mota-Pereira et al., 2011; Schuch et al., 2011) but no effect was found when exercise was compared to active control conditions such as less intensive physical activity (Krogh et al., 2012, 2009; Trivedi et al., 2011). In contrast to these studies, the present study suggests that more intensive activities that increase fitness might play a mediating role in alleviating symptoms. In a recent epidemiological study, poor cardiovascular fitness at the age of 18 predicted the risk for depression later in life (Åberg et al., 2012). Neurobiological models, such as neurogenesis (Trivedi and Greer, 2009) or changes in cortisol responses and growth hormones (Krogh et al., 2010), are potential working mechanisms. Moreover, although not evaluated in the current study, psychological phenomena such as increased coping skills, peer support and enhanced selfesteem are all mechanisms of potential interest for our result. Previous studies have acknowledged supervised and homebased exercise as equally effective (Hoffman et al., 2011; Perraton et al., 2010; Craft et al., 2007). Our findings suggest that merely advising a depressed person to be physically active is insufficient; and that scheduled sessions in active collaboration with a trained professional increases the chance of improvement. Along these lines, recent studies on physical activity show a lack of effect of motivational support only (Chalder et al., 2012), but effects were demonstrated following a jointly created training program based on

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the patient's preferences (Callaghan et al., 2011). Participants in our study reported that they needed scheduled appointments and “someone to be expecting them”, to overcome the lack of drive and motivation. The person-centred approach used here, focusing on building and working a partnership with a starting-point from patient's experiences, can be particularly useful in promoting exercise for depression, similar to what is suggested more generally in relation to health services for depression (Gulley et al., 2011). While the lack of significant improvement in GAF score appears to be related to the small sample size, it might also be explained by the fact that functional progress in major depression takes longer time than the alleviation of symptoms (Papakostas, 2009). The impact of BBAT on the primary outcome was poorer than what we had anticipated. We address here three potential issues. First, although data were not systematically collected regarding participants' reactions to group assignment, a clear majority expressed that they were interested in exercise and admitted that they were less eager to participate in BBAT. Low motivation was noted and discussed in a study on a similar intervention of body psychotherapy in chronic depression (Rohricht et al., 2013). It is likely that the patients' attitude to the complementary treatment strategies impact on outcome, as suggested in a recent overview on meditative movement practices (Payne and Crane-Godreau, 2013). Second, it is possible that the duration of the study period was insufficient. Studies investigating long-term effects of BBAT in psychiatric settings suggest effects in long-term follow-ups that are not seen at postintervention ratings (Mattsson et al., 1995; Gyllensten et al., 2009). Third, although there is little verbal communication during BBAT sessions, we suggest that the group dynamics in this study made some participants feel uncomfortable, as it was brought up as a sideeffect. It is possible that the lower level of group interaction involved in the exercise intervention might be in general more appropriate for persons with major depression.

the study sample had been treated for depression 4 9 months and could be regarded as treatment-resistant. Thus, we argue that the LOCF assumption of no change in non-completers is less hazardous. The self-reported medication status both at enrolment and at follow-up is another potential bias to the result. An alternative method of obtaining information about prescriptions could have been through chart review. However, our ethics board approval did not include access to medical records at the various health centers that were attended by the participants in our study. The concept of body awareness is complex and therefore difficult to capture with psychometrics. We searched for adequate and reliable assessment tools, of which we found few. The scale of body connection (SBC) had, in our view, the most suitable items and was rated as one of the most valid assessments in a recent overview (Mehling et al., 2009). However, it must be noted that the instrument has not previously been used in research on major depression. This might explain why our study failed to capture an anticipated improvement of body awareness. It has come to our attention that new assessment tools are under development (Mehling et al., 2012; Rohricht et al., 2013), which will be a welcome addition to the field. Strengths of this study were the randomized controlled design, the thorough eligibility assessment using a well-established, faceto-face, structured diagnostic interview, and the use of a blinded assessor. Moreover, we were able to employ the same research collaborators throughout the study, both regarding enrolment, assessments and interventions. This minimizes the risk for systematic bias due to inter-rating discrepancies. Another argument that supports this study's finding of an effect of exercise per se is our use of a design with two parallel augmentation conditions, similar in attention and social support.

6. Implications and Conclusions 5. Limitations 6.1. Implications for clinical practise and future research The major weakness was the small sample size in this study, which increases the risk of falsely negative results (type II error). In the planning stage, a power analysis showed that a sample size of 30 participants per group would be needed to detect a difference between the groups. As recruitment pace was slower than expected, which had consequences with regard to clinical collaborators and upcoming organizational changes affecting the site of the study, we decided to analyze the data collected within our pre-planned timeframe. Further, given that we recruited volunteers, there is a risk of selective recruitment; i.e. participants might be more interested in physical activity interventions than their peers in the overall population. Thus, our results must be interpreted in that context. Handling missing data in clinical trials is always a challenge, for which there is no ideal approach. The traditional approach of using last observation carried forward (LOCF) is in general preferable to using only observed cases, but has considerable limitations since it projects the assumption that subjects' responses after dropout remain constant (Hamer and Simpson, 2009). Notably, as this was a pre-post design with two measures and the dropout rate was slightly smaller in the exercise group (18% vs. 25% in the BBAT and 20% in the advice group) the use of LOCF can be debatable. We discussed using a mixed model, increasingly used in psychiatric research, as this would allow for an estimation of parameters without imputing missing values. However, these models rely on theory that applies to large samples with low dropout rates and, further, they disregard the issue of non-random missing data (Hamer and Simpson, 2009). In this small sample, we opted for the LOCF analysis. Moreover, as reported in Table 1, about 50% of

Our results point to the impact of person-centred exercise in a physical therapy setting as a beneficial add-on treatment for depression, to date underused in clinical practice. Future research could focus on the transition between exercise as rehabilitation and the long-term maintenance of exercise outside health care facilities, with gradually phased-out support by the physical therapist. Further studies of BBAT are warranted. Awaiting these, BBAT might be introduced as an alternative add-on treatment for motivated patients, or for patients with co-morbid pain or other conditions that preclude exercise. Further studies on adequate sample sizes should also investigate predictors for outcome and mediators, preferably from a biopsychosocial perspective including both biomarkers and psychological concepts related to for example self-efficacy, self-esteem, and sense of coherence. The trans-disciplinary concept of embodiment, combining ideas from phenomenological philosophy with modern cognitive neuroscience (Thompson and Varela, 2001; Michalak et al., 2012), is another interesting angle to explore in relation to physical therapies and major depression. Studies to explicate patients' attitudes to and experiences of each of the active treatments are currently being conducted by our research group. 6.2. Conclusions This study suggests that exercise as add-on therapy, using a person-centred physical therapy approach, has beneficial effects on depression severity and cardiovascular fitness in persons with major depression. In relation to clinical practice, physical therapy

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seems a viable strategy to inspire and involve persons with major depression in physical exercise. Basic body awareness therapy might be an option for some individuals, but this approach needs to be further explored in larger cohorts.

Role of funding source This study was supported by Grants from Närhälsan Research and Development Primary Health Care, Gothenburg, Sweden, Grant no. 22018, and from the Region of Västra Götaland, Gothenburg, Sweden, Grant no. 211341. Financial support was also received from Centre for Person-Centred Care at the University of Gothenburg (GPCC), which is funded by Swedish Research Council, Grant no. 2009-1088.

Conflict of interest All authors declare that they have no conflicts of interest.

Acknowledgments We are grateful to the patients who wanted to take part in this study. We thank dedicated physical therapists Kristina Hedberg Karlberg, Birgitta Kihlbom and Lina Imbert, who enabled the interventions. We also want to thank our clinical collaborators, especially Tone Lindersköld Burell and co-workers, for encouraging this project and providing the localities.

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