Exercise as an add-on strategy for the treatment of major depressive disorder: a systematic review

CNS Spectrumshttp://journals.cambridge.org/CNS

Additional services for CNS Spectrums:

Email alerts: Click hereSubscriptions: Click hereCommercial reprints: Click hereTerms of use : Click here

Exercise as an add-on strategy for the treatment of major depressivedisorder: a systematic review

Gioia Mura, Maria Francesca Moro, Scott B. Patten and Mauro G. Carta

CNS Spectrums / FirstView Article / March 2014, pp 1 - 13DOI: 10.1017/S1092852913000953, Published online: 03 March 2014

Link to this article: http://journals.cambridge.org/abstract_S1092852913000953

How to cite this article:Gioia Mura, Maria Francesca Moro, Scott B. Patten and Mauro G. Carta Exercise as an add-on strategy for the treatmentof major depressive disorder: a systematic review . CNS Spectrums, Available on CJO 2014 doi:10.1017/S1092852913000953

Request Permissions : Click here

Downloaded from http://journals.cambridge.org/CNS, IP address: 79.32.86.179 on 11 Mar 2014

CNS Spectrums, page 1 of 13. & Cambridge University Press 2013doi:10.1017/S1092852913000953

SYSTEMATIC REVIEW

Exercise as an add-on strategy for the treatment ofmajor depressive disorder: a systematic review

Gioia Mura,1* Maria Francesca Moro,1 Scott B. Patten,2 and Mauro G. Carta1

1 Department of Public Health, Molecular and Clinical Medicine, University of Cagliari, Cagliari, Italy2 Departments of Community Health Science and Psychiatry, University of Calgary, Calgary, Alberta, Canada

Antidepressants are currently the treatment of choice for major depressive disorder (MDD). Nevertheless, a highpercentage of patients do not respond to a first-line antidepressant drug, and combination treatments andaugmentation strategies increase the risk of side effects. Moreover, a significant proportion of patients are treatment-resistant. In the last 30 years, a number of studies have sought to establish whether exercise could be regarded as analternative to antidepressants, but so far no specific analysis has examined the efficacy of exercise as an adjunctivetreatment in combination with antidepressants. We carried out a systematic review to evaluate the effectiveness ofexercise as an adjunctive treatment with antidepressants on depression.

A search of relevant papers was carried out in PubMed/Medline, Google Scholar, and Scopus with the followingkeywords: ‘‘exercise,’’ ‘‘physical activity,’’ ‘‘physical fitness,’’ ‘‘depressive disorder,’’ ‘‘depression,’’ ‘‘depressive symp-toms,’’ ‘‘add-on,’’ ‘‘augmentation,’’ ‘‘adjunction,’’ and ‘‘combined therapy.’’ Twenty-two full-text articles were retrievedby the search. Among the 13 papers that fulfilled our inclusion criteria, we found methodological weaknesses in themajority. However, the included studies showed a strong effectiveness of exercise combined with antidepressants.

Further analyses and higher quality studies are needed; nevertheless, as we have focused on a particular intervention(exercise in adjunction to antidepressants) that better reflects clinical practice, we can hypothesize that this strategycould be appropriately and safely translated into real-world practice.

Received 24 September 2013; Accepted 20 October 2013

Key words: Adjunction therapy, Antidepressants, depression, depressive disorder, exercise, physical activity.

Clinical Implications’ Antidepressants are currently the accepted treatment of

choice for major depressive disorder, but a fair percentage

of patients do not achieve remission with first-line drugs,

requiring combination/augmentation treatments that

increase the risk of side effects and discontinuation.

’ A number of studies carried out in the past showed that

exercise may reduce depressive symptoms, but systematic

reviews and meta-analysis findings, while generally positive,

continued to be inconclusive and debated, and focused on

the efficacy of exercise as a sole treatment for depression.

’ A systematic analysis of the literature suggests that exercise

should be regarded as an adjunctive strategy with

antidepressants, rather than a stand-alone treatment per se,

reflecting more closely daily clinical practice.

Background

Major depressive disorder (MDD) is currently ranked11th among the leading causes of disease burden and isranked as the second leading cause of years lived withdisability globally.1 It is projected over the next 20 yearsto be the second leading cause of disability worldwideand the leading cause of disability in high-incomenations.2 Antidepressants are currently the acceptedtreatment of choice for MDD3 and are among the mostcommonly prescribed drugs in Western countries, witha point prevalence of yearly use of 6% in the community

*Address for correspondence: Dott.ssa Gioia Mura, Centro diPsichiatria di Consultazione e Psicosomatica AOU Cagliari,Via G. Porcell 4, 09100 Cagliari, Italy.(Email: [email protected])

Authors thank Nasrin Beheshty for translating from Persian thepaper of Rashidi et al. Moreover, we would like to thank all the authorswho have agreed to get in touch with us and answer our questions.

in France,4 4.7% in Italy,5 4.9% in the UK,6 and 10.1%in U.S. households.7

Newer antidepressants, such as selective serotoninreuptake inhibitors (SSRIs) and serotonin–norepinephr-ine reuptake inhibitors (SNRIs), have become thefirst-line treatment for MDD because of a lower risk ofsevere side effects, higher tolerability and safety of use,and an efficacy similar to that of older antidepressantdrugs8; nevertheless, only 47% of patients respond, andonly 33% of patients achieve remission in first-line oftreatment with citalopram, one of the most frequently usedSSRIs.9 In the sequenced treatment alternatives to relievedepression (STAR*D) trial, the cumulative remission rateof treatment-resistant unipolar major depression, after4 treatment levels, increased to 67%,10 meaning that fewerthan 50% of treatment-resistant patients do not achieveremission. Combination therapies or augmentation strate-gies (with lithium salts, triiodothyronine, bupropion,lamotrigine, psychostimulants, and atypical antipsychoticdrugs) significantly increase the risk of drug–drug interac-tions, side effects, and drop-outs, and around one-third oftreatment-resistant patients continue to be resistant.11–13

All of these issues emphasize the need for nonphar-macologic, complementary, and adjunctive therapies,which should be both effective and safe for depressedpatients, and free of drug–drug interactions. Exercise ispotentially one such therapy.

In the last 30 years, a number of studies have shownthat physical activity may reduce depressive symptomsin healthy populations,14–17 in patients diagnosed withMDD,18–22 and those affected by depressive comorbidityin association with physical conditions, such asParkinson’s disease,23 Alzheimer’s disease,24 multiplesclerosis,25 cardiovascular diseases,26 cancer,27 andmetabolic syndrome–related disorders.28

Depression negatively impacts quality of life (QoL), adimension concerning patients’ overall perspectives abouttheir physical, social, and psychological status.29 Physicalactivity has been shown to improve the perceived physicalQoL in depressed patients,30–32 and high doses of exercisehave been found to be related to larger improvements bothin mental and physical aspects of QoL.33

It has been hypothesized that exercise could act ondepression through a number of biological mechanismssimilar to those reported for antidepressant drugs, such asan increase in the level of endorphin and serotonin, anenhancement of the neurotransmission mediated bynorepinephrine, a decrease in the level of cortisol, and apromotion of neuropeptides related to neurotrophism,such as brain derived neurotrophic factor (BDNF), VGF,insulin-like growth factor 1 (IGF-1), and vascular endothe-lial growth factor (VEGF).34 Moreover, exercise exerts abeneficial effect on depressive symptoms by providing thepossibility of diversion from negative thinking, a sense ofpurpose, and enhancement of social contact.35 In this

sense, it seems reasonable to state that exercise can beconsidered a biopsychosocial treatment for MDD.36

While a number of literature reviews and meta-analyseshave been published recently on the efficacy of exercise ondepressive disorder,31,35,37–51 to the best of our knowledgeno specific analysis has been conducted on the efficacy ofexercise as an adjunctive treatment in patients who areundergoing antidepressant therapy. Moreover, the majorityof the reviews that have been published sought to determinewhether exercise could be regarded as an alternative toantidepressants, which is unlikely. Because antidepressantsare a core treatment for MDD, and because they are oftennot fully effective, an adjunctive role for exercise indepression treatment is likely to be its most important role.

Objective

We carried out a systematic review of the literature toestablish the current state of knowledge on the efficacyof exercise as an adjunctive treatment to antidepressantdrug therapy.

Method

Identification of the studies

The search for relevant articles was carried out in PubMed/Medline, Google Scholar, and Scopus with the followingkeywords: ‘‘exercise,’’ ‘‘physical activity,’’ ‘‘physical fitness,’’‘‘depressive disorder,’’ ‘‘depression,’’ ‘‘depressive symp-toms,’’ ‘‘add-on,’’ and ‘‘adjunction.’’ We included articlesin all languages that were published from January 1980 toApril 2013. The search was expanded to examine thebibliographies of the selected papers. In the cases when weneeded further information, the authors of the articleswere contacted and asked to clarify methodologicalconcerns or to provide unpublished data.

Inclusion criteria

Studies were included in this review if they wererandomized or non-randomized controlled trials, in whichexercise as adjunctive with antidepressants was comparedto standard treatments (including antidepressant drugs),no treatment, or placebo-control condition, in people ofall ages with depression (diagnosed by any method) asdefined by the authors. We excluded observational andcohort studies, those that compared different types ofexercise without a ‘‘non-exercising’’ control group, thosethat measured outcomes immediately before and after asingle bout of exercise, samples with psychiatric andmedical comorbidity, and samples constituted of athletes.

Quality of studies

We assessed the risk of bias of studies by noting theconcealment of allocation, the use of intention-to-treat

2 G. MURA ET AL.

(ITT) analysis, and blinding. Concealment was consideredadequate if there was central randomization at a siteremote from the study, computerized allocation in alocked file, sealed and opaque sequentially numberedenvelopes, or other methods of ensuring adequateconcealment. Concealment was considered inadequateif an open list or table of random numbers, open computersystem, drawing of non-opaque envelopes, or unclearprocedures were employed. Trials were defined as usingITT analysis if authors clearly declared that results werebased on ITT analysis. For blinding, we distinguishedbetween trials in which the main outcome was measured bya blinded assessor, and those in which the main outcomewas measured either by the participants themselves orby a non-blinded assessor. Moreover, we considered theduration of the trial, if the sample included 20 subjects ormore, and whether the study performed a follow-upassessment. We also considered the quality of assess-ment (ie, structured interview, observer-administered,or self-report questionnaire), both at the baseline and atthe end-point of the trial.

Outcome measures

We considered the measure of depression declared byauthors as the primary outcome measure. For a secondaryoutcome, we considered only quality of life assessment.

Data synthesis

Due to methodological heterogeneity of the studiesidentified, a meta-analysis was not conducted. Datasynthesis was accomplished by detailed consideration ofeach study’s characteristics and findings.

Results

Twenty-one full-text articles were retrieved by thesearch on PubMed. One paper was found throughthe supplementary search on Scopus; no additionalarticles were found either on Google Scholar orthrough searching the citation lists of the retrievedstudies.

Nine papers were excluded because they did notfulfill our criteria. Figure 1 shows the process ofinclusion of studies for review.

We found 11 randomized, clinical trials that fulfilledour inclusion criteria52–62 and 2 non-randomizedtrials.63,64 The main characteristics of the includedstudies are shown in Table 1.

Of the studies, 2 were conducted in the USA,52,57 2 inthe UK,56,62 2 in Brazil,61,64 and 1 each in Germany,53

Norway,54 Denmark,55 Portugal,58 Italy,59 Iran,60 andSpain.63 All of the included papers but the Iranian one60

were published in English.

231 records identifiedthrough database searching

116 records after duplicates removed

115 records screened 94 records excluded

22 full-text articles assessedfor eligibility

9 full-text articles excluded:

No control group “no exercising”Mixed diagnosisCounseling-based intervention

13 articles included forqualitative review

IDE

NT

IFIC

AT

ION

SC

RE

EN

ING

ELE

GIB

ILIT

YIN

CLU

DE

D

612

FIGURE 1. Process of inclusion of studies for qualitative review.

EXERCISE AS ADD-ON FOR MDD 3

TABLE 1. Main characteristics of included studies

TRIAL N TREATMENT CONTROL DURATION BLINDING ASSESSMENT RCT RESULTS

Blumenthal et al. 1999 156 1. Aerobic exercise2. Aerobic exercise plus Sertraline

Sertraline 16 weeks observer HAM-D 17 BDI yes HAM-D p5 0.39BDI p5 0.40

De la Cerda et al. 2011 82 Aerobic exercise1 Fluoxetine Fluoxetine 8 weeks no BDI no p, 0.001Deslandes et al. 2010 20 Aerobic exercise1 antidepressants Antidepressants 12 months no HAM-D 17 BDI SF36 no HAM-D p, 0.001

BDI p, 0.001SF36 p, 0.001

Knubben et al. 2007 38 Aerobic exercise1 antidepressants Stretching/relaxation1 antidepressants

10 days observer BRMS CES-D yes p5 0.01p5 0.01

Martinsen et al. 1985 43 Aerobic exercise (37.5%**) Occupational therapy (73.7%**) 9 weeks observer BDI yes p, 0.05Martiny et al. 2012 75 Exercise1 Duloxetine Chronotherapy1 Duloxetine 9 weeks observer HAM-D17 yes Chronoterapy vs exercisep5 0.013Mather et al. 2002 86 Anaerobic supervised

exercise1 AntidepressantsHealth educ.talks1 Antidepressants

10 weeks1 follow-up34 w

observer HAM-D17 yes p5 0.05

Matthews et al. 2011 424 23.8%* Aerobic/anaerobic exercise (23%**) Health talks/stretching (24.6%**) 12 months observer CES-D yes p5 0.852Mota-Pereira et al. 2011 33 Home-based aerobic1 Antidepressants Antidepressants 12 weeks observer HAM-D17 BDI yes p5 0.014

p5 0.016Pilu et al. 2007 30 Supervised aerobic1 Antidepressants Antidepressants 8 months no HAM-D yes p, 0.0001Rashidi et al. 2013 35 Aerobic exercise1 Antidepressants Stretching1 Antidepressants 2 months observer BDI yes Significant reduction in BDI score of

intervention group compared to controlsSchuch et al. 2011 26 Aerobic exercise 1 Antidepressants Antidepressants 2 weeks1 discharge

assessmentobserver HAM-D 17 WHOQOL-Bref yes HAM-D p5 0.192

WHOQOL-Brefp5 0.004Psychol. Domain

Veale et al. 1992 83 Aerobic exercise (45%**) No treatment (34%**) 12 months observer BDI CIS yes BDI p, 0.005CIS p, 0.005

BDI: Beck Depression Inventory; BRMS: Bech-Rafaelsen Melancholy Scale; CES-D: Centre for Epidemiologic Studies Depression; CIS: Clinical Interview Schedule; HAM-D: Hamilton Rating Scale for Depression; RCT: randomized controlled trial; SF 36: Short FormHealth Survey-36; WHOQOL-Bref: World Health Organization Quality of Life-Bref*Percentage of depressed patients in the sample. **Percentage of participants undergoing antidepressant therapy.

4G.

MURA

ETAL.

Samples

The number of participants in the studies ranged widelyfrom 20 to 424, with a total number of 1131 and a meanper study of 87. Considering only the studies in whichthe whole sample was taking antidepressants, the numberof participants notably decreased (total: n5581, mean perstudy n551).

Three of the trials recruited voluntary participantsthrough flyers, media advertisements, and letters sent tolocal physicians and mental health facilities.52,55,56 Fourtrials focused on depressed inpatients recruited inpsychiatric wards,53,54,60,61 and 4 on depressed out-patients.58,59,63,64 Matthews et al57 recruited partici-pants through telephone screens and direct mails.

Two trials also admitted bipolar patients in thedepressive phase.53,55 Three trials were focused ontreatment-resistant depressed patients56,58,59 and 3 onparticipants with severe depression.53,54,61 The remain-ing trials were carried out on patients diagnosed withmild to moderate depression.

Eight trials achieved psychiatric diagnosis of depres-sion through Diagnostic and Statistical Manual ofMental Disorders (DSM) diagnostic criteria forMDD,52–55,58,59,61,64 and 2 trials used InternationalClassification of Diseases (ICD) criteria.56,63 Matthewset al57 assessed participants’ depressive symptomswith the Centre for Epidemiologic Studies Depression(CES-D), and Veale et al62 used the clinical interviewschedule (CIS). Rashidi et al60 did not specify diagnosticcriteria.

In 10 trials, the whole sample was formed byparticipants who were undergoing antidepressanttherapy.52,53,55,56,58–61,63,64 The percentages of thoseon antidepressant drug treatment in the remaining trialsranged from around 24% to over 50% (mean 33.43%).

Intervention groups

Nine studies used an aerobic exercise interven-tion,53,54,58–64 1 used anaerobic exercise,56 and 1 hadan intervention based on mixed aerobic/anaerobicexercise.57 One study had 2 active treatments, withsupervised aerobic exercise and supervised aerobicexercise plus sertraline.52 Another study had 2 interven-tion groups, which compared exercise plus duloxetine towake/light therapy (chronotherapy) plus duloxetine.55

Control groups

Among the trials in which the whole sample underwenttreatment with antidepressants, 4 studies compared theintervention with a control group undergoing onlyantidepressants52,58,59,61; 2 used stretching, flexibility, orrelaxation plus antidepressants53,60; 1 used chronotherapyplus antidepressants55; and 1 used health educational

talks plus antidepressants control group.56 Amongthose studies with a subsample undergoing antidepressantdrug treatment, 1 had an occupational therapy controlgroup,54 1 used health talks and stretching,57 and one hada no-treatment control group.62

Duration

The duration of the trials varied from 10 days to 1 year;the mean duration was 19.3 weeks. A 34-week follow-upassessment was performed in 1 study.56

Quality assessment

Treatment allocation was adequately conceived in 4studies out of 13.53,55–57 Intention to treat analysis wasperformed in 4 studies out of 13.52,53,55,56 Due to theobvious nature of group exercising, none of the studieshad a double-blind design; 10 studies assessed the mainoutcome using blinded assessors.52,53,55–62

The main outcome was a significant reduction com-pared to baseline of Hamilton rating scale for Depression-17 items (HAMD-17) score in 4 studies,55,56,59,61 of BDIscore in 3 studies,54,60,63 and of the CES-D score in 1study.57 In 5 studies, the assessment of participants wasperformed both with an observer-administered and aself-administered questionnaire.52,53,58,62,64 Two studiesevaluated quality of life by World Health OrganizationQuality of Life-Bref (WHOQOL-Bref)61 or short formhealth survey-36 items (SF-36).64 For 2 trials,58,59 furtherpapers were available30,65 that examined quality of lifeby WHOQOL-Brief30 and WHOQOL-Brief and SF-3665 ofthe same trials.

Further information retrieved by the authors

We asked some authors to clarify some methodologicalconcerns that we had regarding their trials. Pilu et al59

and Rashidi et al60 were asked about blinding, intentionto treat analysis, and drop-out rates; Rashidi et al werealso asked about the statistical difference between thetreatment and control groups. Matthews et al57 wereasked about the separate data concerning only patientsundergoing antidepressants.

Trials in Which the Entire Sample Was UndergoingAntidepressant Treatment

Exercise plus antidepressants versus antidepressants alone

Among the 4 randomized controlled trials (RCTs) thatcompared add-on aerobic exercise with antidepressantswith antidepressants alone,52,58,59,61 3 showed a significantdifference between treatment and control group out-come58,59,61 and were focused on particular samples; 2examined the efficacy of combined therapy (antidepressants

EXERCISE AS ADD-ON FOR MDD 5

plus aerobic exercise) in participants affected bytreatment-resistant depression58,59; and 1 utilized the sameintervention on patients with severe depression.61 Twonon-randomized trials also reported positive results.63,64

Mota-Pereira et al58 carried out a trial on 33 patients(males and females aged 18–60 years) who were affectedby treatment-resistant MDD and who were takingappropriate combined therapy, in doses consideredappropriate, for more than 9 months and less than 15months. Participants were randomized to the treatment(5 weekly sessions of aerobic exercise, 1 supervised and 4unsupervised, consisting of 30–45min/day walks, as anadjunction to the usual antidepressant treatment) or acontrol group (usual antidepressant treatment alone) for12 weeks. At the end of the trial, the treatment groupshowed lower HAMD-17 and Beck Depression Inventory(BDI) rates compared to the control group. While in thecontrol group, none of the participants showed response(defined as a decrease from baseline to endpoint of $50%on the HAMD-17 total score) or remission (defined as anendpoint HAMD-17 total score #7), in the treatmentgroup, there was a 21% rate of response and a 26% rate ofremission, although these data were not significant.Another paper that analyzed data on QoL of the sametrial65 reported positive findings on the physical domainof SF-36 and on the social domain of WHOQOL-Brief.

Pilu et al59 performed a randomized trial on a smallsample of 30 female patients affected by MDD, aged40–60 years, who were undergoing but not responding toantidepressant therapy. Participants were randomized in a2:1 fashion either to the treatment (2 weekly supervisedaerobic exercise sessions of 1 hour each plus their usualantidepressant) or the control group (antidepressantalone) for 8 months. Only the treatment group showedsignificant reduction in HAMD-17 scores. Another paperthat analyzed data from the same trial30 found thatexercise also improved the perceived physical domain ofquality of life: the score of WHO-QOL-Brief scale in thephysical domain significantly improved in the exerciseplus antidepressants group, as compared to the controlgroup. The perceived QoL in the other domains did notchange during the treatment in either group.

Schuch et al61 published the preliminary results of arandomized controlled trial of aerobic exercise added toantidepressants, compared to antidepressants alone, on26 inpatients affected by severe depression as diagnosedusing the mini international neuropsychiatric interview(MINI) (according to DSM-IV criteria). Patients in theexercise group exercised to 16 kcal/kg/week during 3sessions/week (ie, ‘‘public health dose’’) in associationwith conventional treatment; in order to improvecompliance, patients could choose the exercise (sta-tionary bicycle, a treadmill, or an elliptical machine) andthe intensity, with the sole objective to complete thetotal calories estimated. Both the exercise and control

groups achieved statistically significant improvementsin HAMD-17 at 2 weeks and at discharge compared tobaseline mean scores. Between groups, there was adifference favorable to the exercise group at discharge.Similarly, both groups showed improvements in physicaland psychological domains of the WHO-QOL Brief atthe second week of hospitalization, with significantdifferences favoring the exercise group at discharge onthe psychological domain and as well as a trend on thephysical domain.

Blumenthal et al52 conducted a 16-week RCT on 156male and female participants with mild to moderateMDD, aged $50 years, who were assigned to a programof aerobic exercise, antidepressant (sertraline), or com-bined exercise and medication. Bipolar disorder andcurrent use of antidepressants at baseline were exclusioncriteria. Depression assessment was done with HAMD-17and BDI. Treatments did not differ in improving depres-sion; nevertheless, some differences were found dependingon the severity of depression at baseline, ie, themedication group exhibited a more rapid initial response.Interestingly, participants with mild depression at baselineresponded more quickly to the combination treatmentthan did moderately to severely depressed participants.

De la Cerda et al63 performed a non-randomized,controlled study in which a sample of 82 femaledepressed patients (ICD criteria), aged between 20and 64 years (mean age 32.4 years), were divided into2 age-balanced groups: 1 group receiving fluoxetine20mg/day and aerobic exercise, 1 group receivingongoing fluoxetine 20mg/day alone, for a duration of8 weeks. The aerobic training program consisted of3 sessions per week, of increasing duration from 45 to60minutes, of aerobic gymnastics, fun dance, and walking.Assessment was performed by BDI, and InternationalClassification of Diseases, 10th revision (ICD-10) was usedto confirm diagnosis both at baseline and at the end-pointof the trial. While the majority of patients in thepharmacotherapy/exercise group had decreased BDI andICD-10 severity ratings from moderate to minimal or nodepression, participants in the pharmacotherapy groupdecreased frommoderate to mild depression. Interestingly,the authors noted that the women in the sample belongedto middle–low income social class, and were generallysuffering from loneliness and isolation; thus it could bethat exercising in a group setting functioned as anopportunity for socializing and leisure time. An analogousexperience was experienced by participants in the trial byPilu et al,59 who also belonged to a low-income social class(personal communication, 2013).

Deslandes et al64 published the results of a quasi-experimental study that aimed to identify changes indepressive symptoms, quality of life, and cortical asym-metry produced by aerobic activity on a small sample of20 patients (70% females, 71±3 years) with a diagnosis of

6 G. MURA ET AL.

major depressive disorder according to DSM-IV criteria.Participants were divided into an exercise group (pharma-cological treatment plus aerobic training) and a controlgroup (pharmacological treatment alone). Assessment wasdone by BDI, HAMD-17, Montgomery-Asberg DepressionRating Scale (MADRS) for depression, SF-36 for the QoL,and electroencephalographic measurements (frontal andparietal alpha asymmetry) before treatment and after 1year of treatment. After 1 year, the exercise group showeda statistically significant decrease of depressive symptomscompared to the control group, both according to thedepression questionnaires and in the subscale ‘‘role-physical’’ of SF-36. The control group showed a decreasein cortical activity on the right hemisphere (increase ofalpha power), which was not observed in the exercisegroup. Since the sample was composed of elderly subjects,it is possible that this last result was due to the physicalactivity counteracting the participants’ mental decline.

Exercise plus antidepressants versus stretching/flexibility/

relaxation plus antidepressants

The trial carried out by Knubben et al53 focused on theshort-term (10 days) benefit of physical activity in asmall sample of 38 depressed inpatients who wereundergoing antidepressant therapy. The study assessedthe patients with both an observer-administered ques-tionnaire, the Beck Rafaelsen Melancholy Scale (BRMS),and a self-administered one, the Center for EpidemiologicStudies Depression scale (CES-D). Patients were randomlyassigned to an exercise (daily walking on a treadmill) orplacebo (low-intensity stretching and relaxation exercises)group. The exercise group had a substantially greaterreduction in depression scores (BRMS) than the controlgroup. The subjective evaluation of depression (CES-Dscores) at the end of the study was significantly lower inthe exercise group than the control group.

Rashidi et al69 performed a trial on 35 depressedfemale inpatients who were randomly allocated to atreatment group (which played volleyball, badminton, ordodgeball in teams of 4–5 every day) or a control group(only encouraged to perform warm up and stretchingexercises) for 2 months. At the end of the 60-day period,BDI was filled out by physicians based on the statementsof patients. Both individual and group exercises hadpositive effects on their mental states; nevertheless,the mental health of the treatment group improvedconsiderably more than the control group, but the p-value was not declared in the paper, and the authors didnot respond to our request for further information.

Exercise plus antidepressants versus chronotherapy plus

antidepressants

Martiny et al55 carried out a trial that aimed to estab-lish the effectiveness of wake and light therapy

(ie, chronotherapy), as an adjunction to antidepressants,in inducing a rapid and sustained remission in MDD.In this trial, chronotherapy was compared to exerciseplus antidepressants, which was assumed to be an activecomparator condition to balance treatment expectations.The sample was formed by 75 patients, the majoritysuffering from recurrent, unipolar, long-standingmelancholic depression. Around 84% were receivingantidepressant treatment at inclusion. A small percen-tage of patients was affected by bipolar depression(3 patients with bipolar I disorder and 3 patientswith bipolar II disorder in each group), and 63%of participants were classified as having treatment-resistant depression. Participants were randomlyassigned to a 9-week chronotherapeutic interventionusing wake therapy, bright light therapy, and sleep timestabilization (n5 37) or a 9-week intervention usingdaily exercise (n5 38). During a 1-week run-in phase,all patients began treatment with duloxetine 60mg/day;all other antidepressants were discontinued, while otherpsychopharmacologic drugs were maintained, includingmood stabilizers. The first phase was followed by a1-week intervention phase in which patients in the waketherapy group underwent 3 wake therapies in combina-tion with daily morning light therapy and sleep timestabilization and patients in the exercise group begandaily exercise. This phase was followed by a 7-weekcontinuation phase with daily chronotherapy or dailyexercise. Assessment was performed with HAMD-17.The type of exercise (aerobic or anaerobic) was notdefined in the paper; it was performed both indoor andoutdoor, supervised by a physiotherapist, with a dailyduration of 30minutes, and, interestingly, it could beflexible. In fact, it was intensified in 44.8% of patients(n5 17) and reduced in 2.6% (n5 1), with a meanexercise duration of 63.0minutes/day. While bothtreatments were well tolerated, and both had a clinicallyrelevant antidepressant response, participants assignedto chronotherapy had an immediate and clinicallysignificantly better response (defined as a reductionfrom baseline score on HAMD-17 of $50%) andremission (defined as a score,8 on HAMD-17) com-pared to the exercise group: at the end-point, responsewas obtained in 71.4% of wake therapy patients versus47.3% of exercise patients, and remission was achievedin 45.6% of wake therapy patients versus 23.1% ofexercise patients.

Exercise plus antidepressants versus health educational

talks plus antidepressants

Mather et al56 published a RCT on the effectiveness ofexercise as an adjunct to antidepressant therapy in a sampleof 86 depressed patients aged 53 years or older (medianage: exercise group 63 years, control group 65 years).

EXERCISE AS ADD-ON FOR MDD 7

Participants were randomly assigned to a treatmentgroup (a twice-weekly exercise class, which containedelements of endurance, muscle strengthening, andstretching) or a control group (twice-weekly healtheducation talks) for 10 weeks, and were assessed withHAMD-17 on 3 occasions: baseline, 10 weeks, and34 weeks. Because the study focused on a particularpopulation (ie, a group who had failed to respond toinitial treatment), the general convention in trials ofantidepressant therapy to use a $ 50% reduction inHAMD-17 score as the definition of a response wasmodified by the authors, who assumed that a $30%reduction in HAMD-17 score associated with participationin exercise would be of clinical interest. At 10 weeks, theexercise group achieved a higher response frequencycompared to the control group.

Trials in Which a Part of the Sample UnderwentAntidepressant Treatment

The earliest trial, to our knowledge, that compared add-onexercise with another treatment was the one performed in1985 by Martinsen et al.54 Forty-three inpatients of bothgenders, aged 17–60 years (mean age 40 years), who wereaffected by MDD were randomly assigned to an interven-tion group (1 hour of supervised aerobic exercise 3 times/week for 9 weeks, at 50–70% of maximum aerobiccapacity) or to a control group (occupational therapy).Nine patients of 24 (37.5%) in the intervention group and14 of 19 (73.7%) in the control group were also takingTricyclic Antidepressants (TCAs). Depression was assessedwith the BDI. Mean reductions in BDI scores weresignificantly larger in the exercise group compared tothe control group.

Later, in 1991, Veale et al62 carried out a trial thatshowed the combined results of 2 studies. The first trialaimed to determine whether aerobic exercise, added tothe standard treatment of patients suffering fromdepression, produced additional benefit compared withno extra intervention; the second trial aimed toinvestigate whether the therapeutic component of theexercise program was due to the patients’ improvementin aerobic fitness level. In that second study, patientswere allocated to either an aerobic exercise group or toa low-intensity exercise group. Because of the selectioncriteria of the present review, we consider only thefindings of the first study. Eighty-three depressedoutpatients undergoing standard treatment (ie, medica-tions, psychotherapy, or social interventions) wererandomly assigned in a 3:2 ratio to an interventiongroup (3 sessions per week of aerobic fitness for 12weeks) or to a control group (no extra treatment).Depression assessment used the Clinical InterviewSchedule (CIS) and BDI. There was a randomizationbias, so participants in the control group had higher

depression rates according to the BDI than those in theintervention group (p, 0.05); nevertheless, the per-centages of those taking antidepressants at baselinebetween the groups did not significantly differ (45% inthe intervention and 34% in the control group). Asignificant difference emerged in favor of the exercisinggroup as assessed by CIS mean rates at the end of thetrial, while BDI mean rates did not significantly differ.The percentages of participants taking antidepressanttherapy at the end of the trial were 44% in the treatmentgroup and 24% in the control group.

Matthews et al57 carried out a post-hoc analysis of datafrom the Lifestyle Interventions and Independence forElders Pilot (LIFE-P) study, a 12-month single-blind RCTthat compared a moderate intensity physical activityintervention (PA), consisting of a combination of aerobic,strength, flexibility, and balance exercises in 3 phases(individualized, center-based, and finally home-basedexercise program, with group-based counseling sessions),with the successful aging (SA) control, a series of sessionson health topics relevant to older adults followed by5–10minutes of stretching. The participants were 424aged volunteers (mean age 76.77 years). Of the sample,23.8% had depressive symptoms, and 15.8% had elevateddepressive symptom scores (CES-D $14). The percen-tages of participants taking antidepressant medicationswere significantly higher in those with high depressive(42.1% in the PA intervention group, and 55.2% in theSA control group) versus low depressive symptoms(18.9% in the PA intervention group, and 19.8% in theSA control group), but were comparable between the 2intervention arms (23% in the PA group, 24.6% in the SAgroup). There was no significant improvement in CES-Dscore over time as a result of participation in eitherintervention group. No significant changes in CES-Dscores were found in association with either interventionwhen examined in participants with high and lowdepressive symptoms over the duration of the trial.

Discussion

Considered overall, the studies included in the presentreview showed a strong effectiveness of exercisecombined with antidepressants. Nine of the trialsshowed a statistically significant superiority in reducingdepression scores in favor of combined interven-tions,53,54,56,58–60,62–64 and, among the other 4 trials,352,55,61 reported good results for both the interventionand control groups. Whenever we considered only trialswith the whole sample in treatment with antidepres-sants, the findings appear to be significant.

Moreover, 4 of the included studies30,61,64,65 foundan improvement in quality of life, and corroborated theresults of some previous studies on the efficacy ofexercise as a sole treatment for depression.20,66,67

8 G. MURA ET AL.

Also, certain secondary considerations in some trialsshould be highlighted regarding the compliance to theadd-on strategy. Drop-out rates in the selected studiesvaried between 0 and 30%, with 7 trials in which therewere no drop outs at all53,55,56,59–61,63 and another with adrop out percentage under 10%.58 While the remainingstudies’ withdrawal rates did not differ from those of trialswith antidepressants treatment,68,69 this is a significantfact that can be explained by the high acceptability and, insome case, flexibility, of physical activity intervention.

Some authors also reported the number of patientswho did not agree to participate in the proposed trial:Schuch et al,61 while reporting no drop-outs, high-lighted that 14 of the 40 invited patients ‘‘were notinterested’’ in participating in the study, Rashidi et al60

excluded 4 patients in the treatment group who werenot interested in participating in group sports, andMartinsen et al54 reported 6 patients who dropped outof the study at the beginning (4 in the interventiongroup and 2 in the control group), with ‘‘withdrawalsnot related to treatment.’’ Nevertheless, all theseauthors carried out the analyses with the remainingparticipants. Mather et al56 reported that initial scrutinyof the data revealed that 1 patient in the exercise groupout of 87 initially scrutinized participants had not metthe eligibility criteria for the study, so this individual’sresults were removed from the analysis. Furthermore,Matthews et al57 reported that adherence did not differbetween participants with higher depressive symptomscompared with those with lower depressive symptoms,and Mota-Pereira et al58 even highlighted that partici-pants in the exercise group significantly differed fromthose in the control group, as they showed greaterdepression severity (higher HAMD-17 and BDI totalscores) and worse functioning (lower global assessmentof functioning (GAF) and higher clinical global impres-sion - severity scale (CGI-S)). Martiny et al55 reportedthat recruitment was stopped at 75 patients due to timeconstraints and funding limits. Thus, no authors but butSchuch et al61 reported significant rates of selectedpatients who refused to participate in the trials,implying that exercise in adjunction to antidepressantsis an acceptable treatment for the majority of thepatients.

Significantly, some authors proposed physical activityinterventions with characteristics of flexibility andpleasantness: de la Cerda et al63 and Rashidi et al60

utilized varied interventions (ie, different activities ateach of 3 weekly sessions), Martiny et al55 made surethat patients could choose the intensity of exercise, andSchuch et al61 varied the type of activity. Recently, atrial carried out by Callaghan et al70 affirmed thesuperiority of preferred, rather than prescribed, inten-sity exercise in reducing depression severity andimproving QoL. Moreover, Mather et al,56 Pilu et al,59

Rashidi et al,60 Veale et al,62 and de la Cerda et al63 hadparticipants who exercised in groups. Thus, exerciseprovides an opportunity to have leisure time and socialcontacts, which are experiences generally lacking indepressed people and which are not directly addressedby pharmacotherapy.63

One of the major limits of the included studies is theexercise-related placebo effect. Martinsen et al,54 Piluet al,59 de la Cerda et al,63 and Veale et al62 underlinedthat therapeutically effective components in their trialscould be due to the beneficial effect of socialization due toexercise, rather than a therapeutic component of exerciseper se. To minimize this issue, some trials had controlgroups with ‘‘placebo treatments’’ with similar componentsof socialization, without the active form of treatment relatedto physical activity. Stretching, flexibility, and relaxa-tion53,57,60 seem to be an acceptable compromise to addressthis issue; nevertheless, some studies chose control groupsbased on occupational therapy54 or health educationaltalks56,57 that could have introduced uncontrolled variablesin the analysis. Furthermore, Martiny et al55 compared anunproven treatment (chronotherapy) to exercise.

On the other hand, researchers often tend todisregard that depression sometimes spontaneouslyimproves, and such an improvement is not totally dueto placebo response, as the estimated effect size for thechange in depression scores during wait-list control was0.505, which represents an average improvement of 4points on the Hamilton Rating Scale for Depression.71

Moreover, placebo response rates of antidepressanttherapies tend to increase from $30% and $40%,respectively, for monotherapy and adjunctive trials.72

Still, the gold standard for testing the efficacy of a newtreatment for MDD continues to be antidepressants.

Among the studies that were included in the presentreview, a variety of methodological weaknesses coulddevalue the relevance of results. Above all, allocationwas adequately conceived in only 4 studies, andintention to treat analysis also was only conducted in4 studies. Samples were small among studies that showedthe largest effect of treatment, and it could be argued thatthe effect would be smaller in larger samples.

Nevertheless, we have focused on a question that reflectsvery well a natural clinical setting, but which may bedifficult to transfer appropriately to the setting of a clinicaltrial: how effective is exercise in addition to antidepres-sants? Interestingly, all of the included trials that focusedon patients suffering from treatment-resistant depres-sion53,56,58–61 showed a larger improvement in depressionscores in the exercise-plus-antidepressants interventiongroups compared to control groups, thus confirmingprevious findings of a possible role of exercise asan adjuvant treatment for patients with severe MDD.73

While exercise has a high cost-effectiveness74 compared toa first-line antidepressant drug treatment, and it may be

EXERCISE AS ADD-ON FOR MDD 9

not always available, it might be more useful as a step-2treatment for antidepressant medication nonresponders.

A growing number of studies, both performed onanimal models of depression and on depressed humans,has focused on other possible molecular targets forantidepressant treatment, besides monoamines. Thishas led researchers to postulate the ‘‘neurotrophichypothesis of depression.’’75 According to this hypoth-esis, several alterations in the levels of neurotrophins,particularly of brain-derived neurotrophic factor(BDNF), might produce the structural and neurochem-ical changes that underlie depression. In particular, thelimbic structures, most notably the hippocampus, havebeen shown to be affected by neuronal atrophy76,77 indepressed patients. Both pharmacological and nonphar-macological interventions for depression have beenshown to produce changes in the levels of neurotro-phins. BDNF increases have been reported to follow theadministration of antidepressant drugs,78–82 whichsuggests that BDNF expression may mediate the actionof antidepressants. Moreover, an increase in BDNF hasalso been detected with electroconvulsive therapy(ECT)82,83 and exercise.80,84–87 Interestingly, exercisein adjunction with the antidepressant reboxetine hasbeen shown to quickly increase BDNF levels, whereasreboxetine alone did not.80 A similar add-on strategywith tranylcypromine was shown to increase BDNF andhave a more favorable effect on a rat model of depressivebehavior than did an antidepressant alone.88 Notably,this effect was demonstrated both in young and in agedrats, confirming the possibility of adult neurogenesis.89

It has been recently hypothesized that the increase inserotonin levels induced by antidepressant drugs,specifically SSRIs, may not improve depression per se,but rather enhances neuroplasticity through the mod-ulation of BDNF mRNA, consequently rending theindividual more susceptible to the influence of theenvironment.90 According to this interesting hypoth-esis, researchers showed that in an animal model ofchronic depression, animals that were chronicallytreated with fluoxetine did not display the expectedincrease in BDNF and even worsened in a stressfulenvironment. Thus, the authors suggested that theeffects of antidepressants medications could be enhancedby training patients to cope with harsh environments, forinstance through cognitive behavioral therapy. We believethat there is enough evidence to recommend exercise inadjunction to antidepressants to manage treatment-resistant depression.

A number of reviews and meta-analyses on theefficacy of exercise on depression, which were publishedin the last 30 years, have testified to the researchers’interest in this subject; nevertheless, while generallypositive, findings have continued to be somewhatinconclusive and debated, and the literature has

been criticized because a variety of methodologicallimitations.39,42,44,46,47,49,50,91 Furthermore, directcomparisons between studies were often difficult dueto wide varieties in assessment or diagnosis of depression,level of severity of the disorder, size of the sample, type,frequency and duration of the intervention, and assess-ment of outcome.31

Few of the meta-analyses and systematic reviewscarried out have considered studies of physical activityas additions to antidepressant medications,41,51,73,92,93

and, to the best of our knowledge, no meta-analysis orsystematic review has focused specifically on this topic.Craft and Perna41 converted the overall effect sizes of–0.72, –0.94, and –1.1 of 3 meta-analyses46,94,95 intobinomial effect sizes, reflecting an increase in successrate due to exercise of 67%, 71%, and 74%, respectively.The authors pointed out that clinical guidelinesconsider a 50% reduction in symptoms a treatmentresponse, and argued that, considering clinical criteriamore relevant than statistical significance, there isstrong evidence to advocate the use of exercise as apotentially powerful adjunct to existing treatment(pharmacotherapies and psychological therapies).

Further high-quality research could establish theefficacy of exercise as an adjunction to antidepressantsto treat MDD, and our results should encourage effortsin such a promising direction.

Conclusions

This is the first review to have focused on exercise as anadd-on strategy in the treatment of MDD. Our findingscorroborate some previous observations that were basedon few studies and which were difficult to general-ize.41,51,73,92,93 Given the results of the present article,it seems that exercise might be an effective strategy toenhance the antidepressant effect of medication treat-ments. Moreover, we hypothesize that the main role ofexercise on treatment-resistant depression is in inducingneurogenesis by increasing BDNF expression, as wasdemonstrated by several recent studies.

Further analyses and higher quality studies areneeded; nevertheless, as we have focused on a particularintervention (exercise in adjunction to antidepressants)that perhaps more closely reflects daily clinical practicerather than the structured context of a clinical trial, wehave shown that this strategy could appropriately andsafety translate into a real context, in particular if exercisehas both flexible and acceptable features.

Disclosures

The authors do not have an affiliation with or financialinterest in any organization that might pose a conflict ofinterest.

10 G. MURA ET AL.

REFERENCES :

1. Murray CJ, Vos T, Lozano R, et al. Disability-adjusted life years(DALYs) for 291 diseases and injuries in 21 regions, 1990–2010: asystematic analysis for the Global Burden of Disease Study 2010.Lancet. 2012; 380(9859): 2197–2223.

2. Mathers CD, Loncar D. Projections of global mortality andburden of disease from 2002 to 2030. PLoS Med. 2006; 3(11):2011–2030.

3. Hollon SD, Thase ME, Markowitz JC. Treatment and preventionof depression. Psychol Sci Public Interest. 2002; 3(2): 39–77.

4. Gasquet I, Negre-Pages L, Fourrier A, et al. Psychotropic drug useand mental psychiatric disorders in France; results of the generalpopulation ESEMeD/MHEDEA 2000 epidemiological study.Encephale. 2005; 31(2): 195–206.

5. Carta MG, Aguglia E, Bocchetta A, et al. The use of antidepressantdrugs and the lifetime prevalence of major depressive disorders inItaly. Clin Pract Epidemiol Ment Health. 2010; 6: 94–100.

6. Hamer M, Batty GD, Seldenrijk A, Kivimaki M. Antidepressantmedication use and future risk of cardiovascular disease: theScottish Health Survey. Eur Heart J. 2011; 32(4): 437–442.

7. Olfson M, Marcus SC. National patterns in antidepressantmedication treatment. Arch Gen Psychiatry. 2009; 66(8): 848–856.

8. Gartlehner G, Hansen RA, Thieda P , et al. ComparativeEffectiveness of Second-Generation Antidepressants in thePharmacologic Treatment of Adult Depression. ComparativeEffectiveness Reviews, No. 7. AHRQ Publication No. 07-EHC007-EF. Rockville, MD: Agency for Healthcare Research and Quality;2007. http://www.ncbi.nlm.nih.gov/books/NBK43023/.

9. Trivedi MH, Rush AJ, Wisniewski SR, et al. Evaluation of outcomeswith citalopram for depression using measurement-based care inSTAR*D: implications for clinical practice. Am J Psychiatry. 2006;163: 28–40.

10. Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-termoutcomes in depressed outpatients requiring one or severaltreatment steps: a STAR*D report. Am J Psychiatry. 2006;163(11): 1905–1917.

11. Thase M, Howland R, Friedman E. Treating antidepressantnonresponders with augmentation strategies: an overview.J Clin Psychiatry. 1998; 59(Suppl 5): 5–12.

12. Treatment-resistant depression: no panacea, many uncertainties.Adverse effects are a major factor in treatment choice. Prescrire Int.2011; 20: 128–133. [No authors listed].

13. Al-Harbi KS. Treatment-resistant depression: therapeutic trends,challenges and future directions. Patient Prefer Adherence. 2012; 6:369–388.

14. Blumenthal JA, Emery CF, Madden DJ, et al. Cardiovascular andbehavioral effects of aerobic exercise training in healthy older menand women. J Gerontol. 1989; 44: M147–157.

15. DiLorenzo TM, Bargman EP, Stucky-Ropp R, et al. Long-termeffects of aerobic exercise on psychological outcomes. Prev Med.1999; 28(1): 75–85.

16. Roth DL, Holmes DS. Influence of aerobic exercise training andrelaxation training on physical and psychologic health followingstressful life events. Psychosom Med. 1987; 49: 355–365.

17. King AC, Taylor CB, Haskell WL. Effects of differing intensities andformats of 12 months of exercise training on psychologicaloutcomes in older adults. Health Psychol. 1993; 12(4): 292–300.

18. Klein MH, Greist JH, Gurman AS, Neiberyer DP. A comparativeoutcome study of group psychotherapy vs. exercise treatments fordepression. International Journal of Mental Health. 1985; 13(3–4):148–177.

19. Dunn AL, Trivedi MH, Kempert JB, Clark CG, Chambliss OH.Exercise treatment for depression: efficacy and dose response.Am J Prev Med. 2005; 28(1): 1–8.

20. Singh NA, Stavrinos TM, Scarbek Y, et al. A randomized controlledtrial of high versus low intensity weight training versus generalpractitioner care for clinical depression in older adults. J Gerontol ABiol Sci Med Sci. 2005; 60(6): 768–776.

21. McNeil JK, LeBlanc EM, Joyner M. The effect of exercise ondepressive symptoms in the moderately depressed elderly. PsycholAging. 1991; 6(3): 487–488.

22. Singh NA, Clements KM, Singh MA. The efficacy of exercise as along-term antidepressant in elderly subjects: a randomized,controlled trial. J Gerontol A Biol Sci Med Sci. 2001; 56(8):M497–504.

23. Goodwin VA, Richards SH, Taylor RS, Taylor AH, Campbell JL.The effectiveness of exercise interventions for people withParkinson’s disease: a systematic review and meta-analysis.Mov Disord. 2008; 23(5): 631–640.

24. Williams CL, Tappen RM. Exercise training for depressed olderadults with Alzheimer’s disease. Aging Ment Health. 2008;12(1): 72–80.

25. Motl RW, Pilutti LA. The benefits of exercise training in multiplesclerosis. Nat Rev Neurol. 2012; 8(9): 487–497.

26. Ades PA, Coello CE. Effects of exercise and cardiac rehabilitationon cardiovascular outcomes. Med Clin North Am. 2000; 84(1):251–265; x–xi.

27. Newton RU, Galvao DA. Exercise in prevention and management ofcancer. Curr Treat Options Oncol. 2008; 9(2–3): 135–146.

28. Pedersen BK, Saltin B. Evidence for prescribing exercise as therapyin chronic disease. Scand J Med Sci Sports. 2006; 16(Suppl 1):3–63.

29. Kennedy SH, Eisfeld BS, Cooke RG. Quality of life: an importantdimension in assessing the treatment of depression? J PsychiatryNeurosci. 2001; 26 Suppl: S23–S28.

30. Carta MG, Hardoy MC, Pilu A, et al. Improving physical quality oflife with group physical activity in the adjunctive treatment of majordepressive disorder. Clin Pract Epidemiol Ment Health. 2008; 4:1–14.

31. Blake H. Physical activity and exercise in the treatment ofdepression. Front Psychiatry. 2012; 3: 106.

32. Patten SB, Williams JV, Lavorato DH, Bulloch AG. Recreationalphysical activity ameliorates some of the negative impact of majordepression on health-related quality of life. Front Psychiatry. 2013;4: 22.

33. Martin CK, Church TS, Thompson AM, Earnest CP, Blair SN.Exercise dose and quality of life: a randomized controlled trial. ArchIntern Med. 2009; 169(3): 269–278.

34. Helmich I, Latini A, Sigwalt A, et al. Neurobiological alterationsinduced by exercise and their impact on depressive disorders.Clin Pract Epidemiol Ment Health. 2010; 6: 115–125.

35. Searle A, Calnan M, Lewis G, et al. Patients’ views of physicalactivity as treatment for depression: a qualitative study. Br J GenPract. 2011; 61(585): 149–156.

36. Lopresti AL, Hood SD, Drummond PD. A review of lifestyle factorsthat contribute to important pathways associated with majordepression: diet, sleep and exercise. J Affect Disord. 2013;148(1): 12–27.

37. Blake H, Mo P, Malik S, Thomas S. How effective are physicalactivity interventions for alleviating depressive symptoms inolder people? A systematic review. Clin Rehabil. 2009; 23(10):873–887.

38. Bridle C, Spanjers K, Patel S, Atherton NM, Lamb SE. Effect ofexercise on depression severity in older people: systematic reviewand meta-analysis of randomised controlled trials. Br J Psychiatry.2012; 201(3): 180–185.

39. Brosse AL, Sheets ES, Lett HS, Blumenthal JA. Exercise and thetreatment of clinical depression in adults: recent findings andfuture directions. Sports Med. 2002; 32(12): 741–760.

EXERCISE AS ADD-ON FOR MDD 11

40. Conn VS. Depressive symptom outcomes of physical activityinterventions: meta-analysis findings. Ann Behav Med. 2010;39(2): 128–138.

41. Craft LL, Perna FM. The benefits of exercise for the clinicallydepressed. Prim Care Companion J Clin Psychiatry. 2004; 6(3):104–111.

42. Daley A. Exercise and depression: a review of reviews. J ClinPsychol Med Settings. 2008; 15(2): 140–147.

43. Gill A, Womack R, Safranek S. Clinical inquiries: does exercisealleviate symptoms of depression? J Fam Pract. 2010; 59(9):530–531.

44. Greer TL, Trivedi MH. Exercise in the treatment of depression.Curr Psychiatry Rep. 2009; 11(6): 466–472.

45. Krogh J, Nordentoft M, Sterne JA, Lawlor DA. The effect ofexercise in clinically depressed adults: systematic review and meta-analysis of randomized controlled trials. J Clin Psychiatry. 2011;72(4): 529–538.

46. Lawlor D, Hopker SW. The effectiveness of exercise as anintervention in the management of depression: systematic reviewand meta-regression analysis of randomised controlled trials.BMJ. 2001; 322(7289): 763–767.

47. Mead GE, Morley W, Campbell P, et al. Exercise for depression.Cochrane Database Syst Rev. 2009;(3): CD004366.

48. Perraton LG, Kumar S, Machotka Z. Exercise parameters in thetreatment of clinical depression: a systematic review of randomizedcontrolled trials. J Eval Clin Pract. 2010; 16(3): 597–604.

49. Rethorst CD, Wipfli BM, Landers DM. The antidepressive effects ofexercise: a meta-analysis of randomized trials. Sports Med. 2009;39(6): 491–511.

50. Rimer J, Dwan K, Lawlor DA, et al. Exercise for depression.Cochrane Database Syst Rev. 2012;(7): CD004366.

51. Mura G, Carta MG. Physical activity in depressed elderly:a systematic review. Clin Pract Epidemiol Ment Health. 2013;9: 125–135.

52. Blumenthal JA, Babyak MA, Moore KA, et al. Effects of exercisetraining on older patients with major depression. Arch Intern Med.1999; 159: 2349–2356.

53. Knubben K, Reischies FM, Adli M, et al. A randomised, controlledstudy on the effects of a short-term endurance training programmein patients with major depression. Br J Sports Med. 2007; 41(1):29–33.

54. Martinsen EW, Medhus A, Sandvik L. Effects of aerobic exercise ondepression: a controlled study. BMJ. 1985; 291(6488): 109.

55. Martiny K, Refsgaard E, Lund V, et al. A 9-week randomized trialcomparing a chronotherapeutic intervention (wake and lighttherapy) to exercise in major depressive disorder patients treatedwith duloxetine. J Clin Psychiatry. 2012; 73(9): 1234–1242.

56. Mather AS, Rodriguez C, Guthrie MF, et al. Effects of exercise ondepressive symptoms in older adults with poorly responsivedepressive disorder: randomised controlled trial. Br J Psychiatry.2002; 180: 411–415.

57. Matthews MM, Hsu FC, Walkup MP, et al. Depressive symptoms andphysical performance in the Lifestyle Interventions andIndependence for Elders Pilot (LIFE-P) study. J Am Geriatr Soc.2011; 59(3): 495–500.

58. Mota-Pereira J, Silverio J, Carvalho S, et al. Moderate exerciseimproves depression parameters in treatment-resistant patientswith major depressive disorder. J Psychiatr Res. 2011; 45(8):1005–1011.

59. Pilu A, Sorba M, Hardoy MC, et al. Efficacy of physical activity inthe adjunctive treatment of major depressive disorders: preliminaryresults. Clin Pract Epidem Ment Health. 2007; 3: 8.

60. Rashidi Z, Rashidi A, Rouzbahani R, Rezaei F. Effects of groupexercise on women’s depressive symptoms. Journal of IsfahanMedical School. 2013; 30(212): 1861–1865. [In Persian].

61. Schuch FB, Vasconcelos-Moreno MP, Borowsky C, Fleck MP.Exercise and severe depression: preliminary results of an add-onstudy. J Affect Disord. 2011; 133(3): 615–618.

62. Veale D, Le Fevre K, Pantelis C, et al. Aerobic exercise in theadjunctive treatment of depression: a randomized controlled trial.J R Soc Med. 1992; 85(9): 541–544.

63. de la Cerda P, Cervello E, Cocca A, Viciana J. Effect of an aerobictraining program as complementary therapy in patients withmoderate depression. Percept Mot Skills. 2011; 112(3): 761–769.

64. Deslandes AC, Moraes H, Alves H, et al. Effect of aerobic trainingon EEG alpha asymmetry and depressive symptoms in the elderly: a1-year follow-up study. Braz J Med Biol Res. 2010; 43(6): 585–592.

65. Mota-Pereira J, Carvalho S, Silverio J, et al. Moderate physicalexercise and quality of life in patients with treatment-resistantmajor depressive disorder. J Psychiatr Res. 2011; 45(12):1657–1659.

66. Brenes GA, Williamson JD, Messier SP, et al. Treatment of minordepression in older adults: a pilot study comparing sertraline andexercise. Aging Ment Health. 2007; 11(1): 61–68.

67. Singh NA, Clements KM, Fiatarone MA. A randomized controlledtrial of progressive resistance training in depressed elders.J Gerontol A Biol Sci Med Sci. 1997; 52(1): M27–35.

68. Rush AJ, Golden WE, Hall GW, et al Depression in Primary Care,Vol. 1: Detection and Diagnosis. Clinical Practice Guideline,Number 5. Rockville, MD: U.S. Department of Health and HumanServices, Public Health Service, Agency for Health Care Policy andResearch; 1993.

69. Rush AJ, Golden WE, Hall GW, et al. Depression in Primary Care,Vol. 2: Treatment of Major Depression. Rockville, MD: U.S.Department of Health and Human Services, Public Health Service,Agency for Health Care Policy and Research; 1993.

70. Callaghan P, Khalil E, Morres I, Carter I. Pragmatic randomisedcontrolled trial of preferred intensity exercise in women living withdepression. BMC Public Health. 2011; 11: 465.

71. Rutherford BR, Mori S, Sneed JR, Pimontel MA, Roose SP.Contribution of spontaneous improvement to placebo response indepression: a meta-analytic review. J Psychiatr Res. 2012; 46(6):697–702.

72. Iovieno N, Papakostas GI. Correlation between different levels ofplacebo response rate and clinical trial outcome in major depressivedisorder: a meta-analysis. J Clin Psychiatry. 2012; 73(10):1300–1306.

73. Mota-Pereira J, Silverio J, Carvalho S, Ramos J, Ribeiro JC. Physicalexercise and major depressive disorder—where do we stand?Curr Psychopharmacol. 2012; 1(2): 167–177.

74. Chalder M, Wiles NJ, Campbell J, et al. Facilitated physical activityas a treatment for depressed adults: randomised controlled trial.BMJ. 2012; 344: e2758.

75. Neto FL, Borges G, Torres-Sanchez S, Mico JA, Berrocoso E.Neurotrophins role in depression neurobiology: a review of basicand clinical evidence. Curr Neuropharmacol. 2011; 9(4): 530–552.

76. Mendez-David I, Hen R, Gardier AM, David DJ. Adult hippocampalneurogenesis: an actor in the antidepressant-like action. AnnPharm Fr. 2013; 71(3): 143–149.

77. Tanti A, Belzung C. Hippocampal neurogenesis: a biomarker fordepression or antidepressant effects? Methodologicalconsiderations and perspectives for future research. Cell Tissue Res.2013; 354(1): 203–219.

78. De Foubert G, Carney SL, Robinson CS, et al. Fluoxetine-inducedchange in rat brain expression of brain-derived neurotrophic factorvaries depending on length of treatment. Neuroscience. 2004;128(3): 597–604.

79. Coppell AL, Pei Q, Zetterstrom TS. Bi-phasic change in BDNF geneexpression following antidepressant drug treatment.Neuropharmacology. 2003; 44(7): 903–910.

12 G. MURA ET AL.

80. Russo-Neustadt AA, Alejandre H, Garcia C, Ivy AS, Chen MJ.Hippocampal brain-derived neurotrophic factor expressionfollowing treatment with reboxetine, citalopram, and physicalexercise. Neuropsychopharmacology. 2004; 29(12): 2189–2199.

81. Czubak A, Nowakowska E, Kus K, et al. Influences of chronicvenlafaxine, olanzapine and nicotine on the hippocampal andcortical concentrations of brain-derived neurotrophic factor(BDNF). Pharmacol Rep. 2009; 61(6): 1017–1023.

82. Nibuya M, Morinobu S, Duman RS. Regulation of BDNF andtrkB mRNA in rat brain by chronic electroconvulsive seizure andantidepressant drug treatments. J Neurosci. 1995; 15(11): 7539–7547.

83. Altar CA, Whitehead RE, Chen R, Wortwein G, Madsen TM. Effectsof electroconvulsive seizures and antidepressant drugs on brain-derived neurotrophic factor protein in rat brain. Biol Psychiatry.2003; 54(7): 703–709.

84. Neeper SA, Gomez-Pinilla F, Choi J, Cotman CW. Physical activityincreases mRNA for brain-derived neurotrophic factor and nervegrowth factor in rat brain. Brain Res. 1996; 726(1–2): 49–56.

85. Russo-Neustadt A, Beard RC, Cotman CW. Exercise, anti-depressantmedications, and enhanced brain derived neurotrophic factorexpression. Neuropsychopharmacology. 1999; 21(5): 679–682.

86. Adlard PA, Perreau VM, Engesser-Cesar C, Cotman CW. Thetimecourse of induction of brain-derived neurotrophic factormRNA and protein in the rat hippocampus following voluntaryexercise. Neurosci Lett. 2004; 363(1): 43–48.

87. Arunrut T, Alejandre H, Chen M, Cha J, Russo-Neustadt A.Differential behavioral and neurochemical effects of exercise,

reboxetine and citalopram with the forced swim test. Life Sci. 2009;84(17–18): 584–589.

88. Russo-Neustadt A, Ha T, Ramirez R, Kesslak JP. Physical activity-antidepressant treatment combination: impact on brain-derivedneurotrophic factor and behavior in an animal model. Behav BrainRes. 2001; 120(1): 87–95.

89. Garza AA, Ha TG, Garcia C, Chen MJ, Russo-Neustadt AA.Exercise, antidepressant treatment, and BDNF mRNA expression in the aging brain. Pharmacol Biochem Behav. 2004; 77(2):209–220.

90. Branchi I, Santarelli S, Capoccia S, et al. Antidepressant treatmentoutcome depends on the quality of the living environment: a pre-clinical investigation in mice. PLoS One. 2013; 8(4): e62226.

91. Josefsson T, Lindwall M, Archer T. Physical exercise intervention indepressive disorders: meta-analysis and systematic review. Scand JMed Sci Sports. In press. DOI: 10.1111/sms.12050.

92. Silveira H, Moraes H, Oliveira N, et al. Physical exercise andclinically depressed patients: a systematic review and meta-analysis.Neuropsychobiology. 2013; 67(2): 61–68.

93. Danielsson L, Noras AM, Waern M, Carlsson J. Exercise in thetreatment of major depression: a systematic review grading thequality of evidence. Physiother Theory Pract. 2013; 29(8): 573–585.

94. Craft LL, Landers DM. The effect of exercise on clinical depressionand depression resulting from mental illness: a meta-analysis.J Sport Exerc Psychol. 1998; 20(4): 339–357.

95. North TC, McCullagh P, Tran ZV. Effect of exercise on depression.Exerc Sport Sci Rev. 1990; 18: 379–415.

EXERCISE AS ADD-ON FOR MDD 13