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Physical activity in the treatment-resistant depression and non-remitted depression: a systematic review of randomized controlled trials
F1000Research
Abstract
Background The objective of this systematic review was to analyze the effects of physical activity (PA) intervention as an adjuvant strategy to pharmacological treatment in people with treatment-resistant depression (TRD) and non-remitted depression (NRD). Methods A search strategy was realized from five databases: PubMed, Cochrane Central Register of Controlled Trials, Scopus, SPORTDiscus, and Web of Science. The Physiotherapy Evidence Database and Oxford’s Evidence Levels were used to classify the quality appraisal. Results Of the 10777 records, 11 randomized controlled studies attained the inclusion criteria. The more significant outcome for this analysis was the improvement of depression by PA or exercise in TRD and NRD. According to the FITT (Frequency, Intensity, Time, and Type) principle, there was some variability in the PA intervention, and except for one article, they all were classified as excellent in terms of quality description. Conclusions This review highlights the potential of PA intervention as an adjuvant program to improve different traits of TRD and NRD. The remission of depression seems to be higher after PA intervention, showing improvements in quality of life, sleep quality, executive function, and vitality.
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Objective
To identify the optimal dose and modality of exercise for treating major depressive disorder, compared with psychotherapy, antidepressants, and control conditions.
Design
Systematic review and network meta-analysis.
Methods
Screening, data extraction, coding, and risk of bias assessment were performed independently and in duplicate. Bayesian arm based, multilevel network meta-analyses were performed for the primary analyses. Quality of the evidence for each arm was graded using the confidence in network meta-analysis (CINeMA) online tool.
Data sources
Cochrane Library, Medline, Embase, SPORTDiscus, and PsycINFO databases.
Eligibility criteria for selecting studies
Any randomised trial with exercise arms for participants meeting clinical cut-offs for major depression.
Results
218 unique studies with a total of 495 arms and 14 170 participants were included. Compared with active controls (eg, usual care, placebo tablet), moderate reductions in depression were found for walking or jogging (n=1210, κ=51, Hedges’ g −0.62, 95% credible interval −0.80 to −0.45), yoga (n=1047, κ=33, g −0.55, −0.73 to −0.36), strength training (n=643, κ=22, g −0.49, −0.69 to −0.29), mixed aerobic exercises (n=1286, κ=51, g −0.43, −0.61 to −0.24), and tai chi or qigong (n=343, κ=12, g −0.42, −0.65 to −0.21). The effects of exercise were proportional to the intensity prescribed. Strength training and yoga appeared to be the most acceptable modalities. Results appeared robust to publication bias, but only one study met the Cochrane criteria for low risk of bias. As a result, confidence in accordance with CINeMA was low for walking or jogging and very low for other treatments.
Conclusions
Exercise is an effective treatment for depression, with walking or jogging, yoga, and strength training more effective than other exercises, particularly when intense. Yoga and strength training were well tolerated compared with other treatments. Exercise appeared equally effective for people with and without comorbidities and with different baseline levels of depression. To mitigate expectancy effects, future studies could aim to blind participants and staff. These forms of exercise could be considered alongside psychotherapy and antidepressants as core treatments for depression.
Systematic review registration
PROSPERO CRD42018118040.
Importance:
Depression is the leading cause of mental health-related disease burden and may be reduced by physical activity, but the dose-response relationship between activity and depression is uncertain.
Objective:
To systematically review and meta-analyze the dose-response association between physical activity and incident depression from published prospective studies of adults.
Data sources:
PubMed, SCOPUS, Web of Science, PsycINFO, and the reference lists of systematic reviews retrieved by a systematic search up to December 11, 2020, with no language limits. The date of the search was November 12, 2020.
Study selection:
We included prospective cohort studies reporting physical activity at 3 or more exposure levels and risk estimates for depression with 3000 or more adults and 3 years or longer of follow-up.
Data extraction and synthesis:
Data extraction was completed independently by 2 extractors and cross-checked for errors. A 2-stage random-effects dose-response meta-analysis was used to synthesize data. Study-specific associations were estimated using generalized least-squares regression and the pooled association was estimated by combining the study-specific coefficients using restricted maximum likelihood.
Main outcomes and measures:
The outcome of interest was depression, including (1) presence of major depressive disorder indicated by self-report of physician diagnosis, registry data, or diagnostic interviews and (2) elevated depressive symptoms established using validated cutoffs for a depressive screening instrument.
Results:
Fifteen studies comprising 191 130 participants and 2 110 588 person-years were included. An inverse curvilinear dose-response association between physical activity and depression was observed, with steeper association gradients at lower activity volumes; heterogeneity was large and significant (I2 = 74%; P < .001). Relative to adults not reporting any activity, those accumulating half the recommended volume of physical activity (4.4 marginal metabolic equivalent task hours per week [mMET-h/wk]) had 18% (95% CI, 13%-23%) lower risk of depression. Adults accumulating the recommended volume of 8.8 mMET hours per week had 25% (95% CI, 18%-32%) lower risk with diminishing potential benefits and higher uncertainty observed beyond that exposure level. There were diminishing additional potential benefits and greater uncertainty at higher volumes of physical activity. Based on an estimate of exposure prevalences among included cohorts, if less active adults had achieved the current physical activity recommendations, 11.5% (95% CI, 7.7%-15.4%) of depression cases could have been prevented.
Conclusions and relevance:
This systematic review and meta-analysis of associations between physical activity and depression suggests significant mental health benefits from being physically active, even at levels below the public health recommendations. Health practitioners should therefore encourage any increase in physical activity to improve mental health.
It has been well established in epidemiological studies and randomized controlled trials that habitual exercise is beneficial for brain health, such as cognition and mental health. Generally, it may be reasonable to say that the physiological benefits of acute exercise can prevent brain disorders in late life if such exercise is habitually/chronically conducted. However, the mechanisms of improvement in brain function via chronic exercise remain incompletely understood because such mechanisms are assumed to be multifactorial, such as the adaptation of repeated acute exercise. This review postulates that cerebral metabolism may be an important physiological factor that determines brain function. Among metabolites, the provision of lactate to meet elevated neural activity and regulate the cerebrovascular system and redox states in response to exercise may be responsible for exercise-enhanced brain health. Here, we summarize the current knowledge regarding the influence of exercise on brain health, particularly cognitive performance, with the underlying mechanisms by means of lactate. Regarding the influence of chronic exercise on brain function, the relevance of exercise intensity and modality, particularly high-intensity interval exercise, is acknowledged to induce “metabolic myokine” (i.e., lactate) for brain health.
The Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement, published in 2009, was designed to help systematic reviewers transparently report why the review was done, what the authors did, and what they found. Over the past decade, advances in systematic review methodology and terminology have necessitated an update to the guideline. The PRISMA 2020 statement replaces the 2009 statement and includes new reporting guidance that reflects advances in methods to identify, select, appraise, and synthesise studies. The structure and presentation of the items have been modified to facilitate implementation. In this article, we present the PRISMA 2020 27-item checklist, an expanded checklist that details reporting recommendations for each item, the PRISMA 2020 abstract checklist, and the revised flow diagrams for original and updated reviews.
Objectives
To describe new WHO 2020 guidelines on physical activity and sedentary behaviour.
Methods
The guidelines were developed in accordance with WHO protocols. An expert Guideline Development Group reviewed evidence to assess associations between physical activity and sedentary behaviour for an agreed set of health outcomes and population groups. The assessment used and systematically updated recent relevant systematic reviews; new primary reviews addressed additional health outcomes or subpopulations.
Results
The new guidelines address children, adolescents, adults, older adults and include new specific recommendations for pregnant and postpartum women and people living with chronic conditions or disability. All adults should undertake 150–300 min of moderate-intensity, or 75–150 min of vigorous-intensity physical activity, or some equivalent combination of moderate-intensity and vigorous-intensity aerobic physical activity, per week. Among children and adolescents, an average of 60 min/day of moderate-to-vigorous intensity aerobic physical activity across the week provides health benefits. The guidelines recommend regular muscle-strengthening activity for all age groups. Additionally, reducing sedentary behaviours is recommended across all age groups and abilities, although evidence was insufficient to quantify a sedentary behaviour threshold.
Conclusion
These 2020 WHO guidelines update previous WHO recommendations released in 2010. They reaffirm messages that some physical activity is better than none, that more physical activity is better for optimal health outcomes and provide a new recommendation on reducing sedentary behaviours. These guidelines highlight the importance of regularly undertaking both aerobic and muscle strengthening activities and for the first time, there are specific recommendations for specific populations including for pregnant and postpartum women and people living with chronic conditions or disability. These guidelines should be used to inform national health policies aligned with the WHO Global Action Plan on Physical Activity 2018–2030 and to strengthen surveillance systems that track progress towards national and global targets.
Objectives:
Major depressive disorder (MDD) is one of the most disabling mental illnesses and it has a significant impact on society. This review aims to provide updated scientific evidence about the epidemiology of MDD.
Methods:
A systematic literature review of the PubMed and MEDLINE databases was performed to identify articles on the prevalence of MDD and its correlates. The search was restricted to manuscripts published between January 2001 and December 2018.
Results:
Sixty-three articles were included in the review. The lifetime prevalence of MDD ranged from 2 to 21%, with the highest rates found in some European countries and the lowest in some Asian countries. The main sociodemographic correlates were separated/divorced marital status and female gender. Child abuse, intimate partner violence, and comorbidity with other physical and mental disorders also were consistently associated with MDD across the reviewed studies.
Conclusions:
MDD is a highly prevalent condition worldwide. There are remarkable interregional differences in the disorder’s prevalence, as well as in certain sociodemographic correlates. MDD is also highly comorbid with physical and mental health problems.
The increasing number of older adults has seen a corresponding growth in those affected by neurovascular diseases, including stroke and dementia. Since cures are currently unavailable, major efforts in improving brain health need to focus on prevention, with emphasis on modifiable risk factors such as promoting physical activity. Moderate‐intensity continuous training (MICT) paradigms have been shown to confer vascular benefits translating into improved musculoskeletal, cardiopulmonary and cerebrovascular function. However, the time commitment associated with MICT is a potential barrier to participation, and high‐intensity interval training (HIIT) has since emerged as a more time‐efficient mode of exercise that can promote similar if not indeed superior improvements in cardiorespiratory fitness for a given training volume and further promote vascular adaptation. However, randomised controlled trials (RCTs) investigating the impact of HIIT on the brain are surprisingly limited. The present review outlines how the HIIT paradigm has evolved from a historical perspective and describes the established physiological changes including its mechanistic bases. Given the dearth of RCTs, the vascular benefits of MICT are discussed with a focus on the translational neuroprotective benefits including their mechanistic bases that could be further potentiated through HIIT. Safety implications are highlighted and components of an optimal HIIT intervention are discussed including practical recommendations. Finally, statistical effect sizes have been calculated to allow prospective research to be appropriately powered and optimise the potential for detecting treatment effects. Future RCTs that focus on the potential clinical benefits of HIIT are encouraged given the prevalence of cognitive decline in an ever‐ageing population. image
Skeletal muscle is an essential regulator of energy homeostasis and a potent coordinator of exercise-induced adaptations in other organs including the liver, fat or the brain. Skeletal muscle-initiated crosstalk with other tissues is accomplished though the secretion of myokines, protein hormones which can exert autocrine, paracrine and long-distance endocrine effects. In addition, the enhanced release or uptake of metabolites from and into contracting muscle cells, respectively, likewise can act as a powerful mediator of tissue interactions, in particular in regard to the central nervous system. The present review will discuss the current stage of knowledge regarding how exercise and the muscle secretome improve a broad range of brain functions related to vascularization, neuroplasticity, memory, sleep and mood. Even though the molecular and cellular mechanisms underlying the communication between muscle and brain is still poorly understood, physical activity represents one of the most effective strategies to reduce the prevalence and incidence of depression, cognitive, metabolic or degenerative neuronal disorders, and thus warrants further study.
Objectives
To assess the benefits and harms of exercise in patients with depression.
Design
Systematic review
Data sources
Bibliographical databases were searched until 20 June 2017.
Eligibility criteria and outcomes
Eligible trials were randomised clinical trials assessing the effect of exercise in participants diagnosed with depression. Primary outcomes were depression severity, lack of remission and serious adverse events (eg, suicide) assessed at the end of the intervention. Secondary outcomes were quality of life and adverse events such as injuries, as well as assessment of depression severity and lack of remission during follow-up after the intervention.
Results
Thirty-five trials enrolling 2498 participants were included. The effect of exercise versus control on depression severity was −0.66 standardised mean difference (SMD) (95% CI −0.86 to −0.46; p<0.001; grading of recommendations assessment, development and evaluation (GRADE): very low quality). Restricting this analysis to the four trials that seemed less affected of bias, the effect vanished into −0.11 SMD (−0.41 to 0.18; p=0.45; GRADE: low quality). Exercise decreased the relative risk of no remission to 0.78 (0.68 to 0.90; p<0.001; GRADE: very low quality). Restricting this analysis to the two trials that seemed less affected of bias, the effect vanished into 0.95 (0.74 to 1.23; p=0.78). Trial sequential analysis excluded random error when all trials were analysed, but not if focusing on trials less affected of bias. Subgroup analyses found that trial size and intervention duration were inversely associated with effect size for both depression severity and lack of remission. There was no significant effect of exercise on secondary outcomes.
Conclusions
Trials with less risk of bias suggested no antidepressant effects of exercise and there were no significant effects of exercise on quality of life, depression severity or lack of remission during follow-up. Data for serious adverse events and adverse events were scarce not allowing conclusions for these outcomes.
Systematic review registration
The protocol was published in the journal Systematic Reviews: 2015; 4:40.
Objective:
To evaluate the effects of 20 weeks of resistance and concurrent training on psychotic and depressive symptoms, quality of life outcomes, and serum IGF-1, IGFBP-3, and brain-derived neurotrophic factor (BDNF) concentrations in patients with schizophrenia.
Methods:
In this blind, randomized controlled clinical trial, 34 patients with schizophrenia were assigned to one of three groups: control (CTRL, n=13), resistance exercise (RESEX, n=12), or concurrent exercise (CONCEX, n=9). Symptoms, quality of life, strength, and other variables were assessed.
Results:
A significant time-by-group interaction was found for the RESEX and CONCEX groups on the Positive and Negative Syndrome Scale (PANSS) total score for disease symptoms (p = 0.007), positive symptoms (p = 0.003), and on the arm extension one-repetition maximum (1RM) test (p = 0.016). In addition, significant improvements on negative symptoms (p = 0.027), on the role-physical domain of the Short Form-36 Health Survey (p = 0.019), and on the chest press 1RM test (p = 0.040) were observed in the RESEX group. No changes were observed for the other variables investigated.
Conclusions:
In this sample of patients with schizophrenia, 20 weeks of resistance or concurrent exercise program improved disease symptoms, strength, and quality of life. ClinicalTrials.gov: NCT01674543.
Background:
Sleep disturbances are persistent residual symptoms following remission of major depressive disorder (MDD) and are associated with an increased risk of MDD recurrence. The purpose of the current study was to examine the effect of exercise augmentation on self-reported sleep quality in participants with non-remitted MDD. Method Participants were randomized to receive selective serotonin reuptake inhibitor (SSRI) augmentation with one of two doses of exercise: 16 kilocalories per kilogram of body weight per week (KKW) or 4 KKW for 12 weeks. Depressive symptoms were assessed using the clinician-rated Inventory of Depressive Symptomatology (IDS-C). The four sleep-related items on the IDS-C (Sleep Onset Insomnia, Mid-Nocturnal Insomnia, Early Morning Insomnia, and Hypersomnia) were used to assess self-reported sleep quality.
Results:
Significant decreases in total insomnia (p < 0.0001) were observed, along with decreases in sleep onset, mid-nocturnal and early-morning insomnia (p's <0.002). Hypersomnia did not change significantly (p = 0.38). Changes in total, mid-nocturnal and early-morning insomnia were independent of changes in depressive symptoms. Higher baseline hypersomnia predicted a greater decrease in depression severity following exercise treatment (p = 0.0057). No significant moderating effect of any baseline sleep on change in depression severity was observed. There were no significant differences between exercise treatment groups on total insomnia or any individual sleep item.
Conclusions:
Exercise augmentation resulted in improvements in self-reported sleep quality in patients with non-remitted MDD. Given the prevalence of insomnia as a residual symptom following MDD treatment and the associated risk of MDD recurrence, exercise augmentation may have an important role in the treatment of MDD.
Patients with major depression respond to antidepressant treatment, but 10%-30% of them do not improve or show a partial response coupled with functional impairment, poor quality of life, suicide ideation and attempts, self-injurious behavior, and a high relapse rate. The aim of this paper is to review the therapeutic options for treating resistant major depressive disorder, as well as evaluating further therapeutic options.
In addition to Google Scholar and Quertle searches, a PubMed search using key words was conducted, and relevant articles published in English peer-reviewed journals (1990-2011) were retrieved. Only those papers that directly addressed treatment options for treatment-resistant depression were retained for extensive review.
Treatment-resistant depression, a complex clinical problem caused by multiple risk factors, is targeted by integrated therapeutic strategies, which include optimization of medications, a combination of antidepressants, switching of antidepressants, and augmentation with non-antidepressants, psychosocial and cultural therapies, and somatic therapies including electroconvulsive therapy, repetitive transcranial magnetic stimulation, magnetic seizure therapy, deep brain stimulation, transcranial direct current stimulation, and vagus nerve stimulation. As a corollary, more than a third of patients with treatment-resistant depression tend to achieve remission and the rest continue to suffer from residual symptoms. The latter group of patients needs further study to identify the most effective therapeutic modalities. Newer biomarker-based antidepressants and other drugs, together with non-drug strategies, are on the horizon to address further the multiple complex issues of treatment-resistant depression.
Treatment-resistant depression continues to challenge mental health care providers, and further relevant research involving newer drugs is warranted to improve the quality of life of patients with the disorder.
We compared the effectiveness of an aerobic and nonaerobic exercise in the treatment of clinical depression in women. A total of 40 women, screened on the Research Diagnostic Criteria for major or minor depressive disorder, were randomly assigned to an 8-week running (aerobic), weight-lifting (nonaerobic), or wait-list control condition. Subjects were reassessed at mid- and posttreatment, and at 1-, 7-, and 12-month follow-ups. Depression was monitored by the Beck Depression Inventory, Lubin’s Depression Adjective Check List, and the Hamilton Rating Scale for Depression; fitness level was assessed using submaximal treadmill testing. Results were remarkably consistent across measures, with both exercise conditions significantly reducing depression compared with the wait-list control condition, and generally appearing indistinguishable from each other. No significant between-group fitness changes were noted. These findings indicate that both types of exercise conditions significantly reduce depression and that these results are not dependent on achieving an aerobic effect.
Depression is a syndrome of stress- and emotion-dysregulation, involving compromised structural integrity of frontal-limbic networks. Meta-analytic evidence indicates that volumetric reductions in the hippocampus, anterior cingulate cortex, prefrontal cortex, striatum, and amygdala, as well as compromised white matter integrity are frequently observed in depressed adults. Exercise has shown promise as an effective treatment for depression, but few studies have attempted to characterize or identify the neural mechanisms of these effects. In this review, we examined the overlap between structural brain abnormalities in depression and the effects of exercise on brain structure in adults, to highlight possible neural mechanisms that may mediate the positive effects of exercise on depressive symptoms. The prefrontal cortex, anterior cingulate cortex, hippocampus, and corpus callosum emerged as structural neural markers that may serve as targets for exercise-based treatments for depression. These findings highlight the need for randomized exercise interventions to test these proposed neurobiological mechanisms of exercise on depression.
Introduction:
Measurement of symptoms domains and their response to treatment in relative isolation from diagnosed mental disorders has gained new urgency, as reflected by the National Institute of Mental Health's introduction of the Research Domain Criteria (RDoC). The Snaith Hamilton Pleasure Scale (SHAPS) and the Motivation and Energy Inventory (MEI) are two scales measuring positive valence symptoms. We evaluated the effect of exercise on positive valence symptoms of Major Depressive Disorder (MDD).
Methods:
Subjects in the Treatment with Exercise Augmentation for Depression (TREAD) study completed self-reported SHAPS and MEI during 12 weeks of exercise augmentation for depression. We evaluated the effect of exercise on SHAPS and MEI scores, and whether the changes were related to overall MDD severity measured with the Quick Inventory of Depression Symptomatology (QIDS).
Results:
SHAPS and MEI scores significantly improved with exercise. MEI score change had larger effect size and greater correlation with change in QIDS score. MEI also showed significant moderator and mediator effects of exercise in MDD.
Limitations:
Generalizability to other treatments is limited. This study lacked other bio-behavioral markers that would enhance understanding of the relationship of RDoC and the measures used.
Conclusions:
Positive valence symptoms improve with exercise treatment for depression, and this change correlates well with overall outcome. Motivation and energy may be more clinically relevant to outcome of exercise treatment than anhedonia.
Background:
Functional impairments often remain despite symptomatic improvement with antidepressant treatment, supporting the need for novel treatment approaches. The present study examined the extent to which exercise augmentation improved several domains of psychosocial functioning and quality of life (QoL) among depressed participants.
Methods:
Data were collected from 122 partial responders to antidepressant medication. Participants were randomized to either high- (16 kcal/kg of weight/week [KKW]) or low-dose (4-KKW) exercise. Participants completed a combination of supervised and home-based exercise for 12 weeks. The Short-Form Health Survey, Work and Social Adjustment Scale, Social Adjustment Scale, Quality of Life Enjoyment and Satisfaction Questionnaire, and Satisfaction with Life Scale were collected at 6 and 12 weeks. Participants with data for at least one of the two follow-up time points (n = 106) were analyzed using a linear mixed model to assess change from baseline within groups and the difference between groups for each psychosocial outcome measure. All analyses controlled for covariates, including baseline depressive symptomatology.
Results:
Participants experienced significant improvements in functioning across tested domains, and generally fell within a healthy range of functioning on all measures at Weeks 6 and 12. Although no differences were found between exercise groups, improvements were observed across a variety of psychosocial and QoL domains, even in the low-dose exercise group.
Conclusions:
These findings support exercise augmentation of antidepressant treatment as a viable intervention for treatment-resistant depression to improve function in addition to symptoms.
Effective treatment of Major Depressive Disorder (MDD) will require the development of alternative treatments and the ability for clinicians to match patients with the treatment likely to produce the greatest effect. We examined atypical depression subtype as a predictor of treatment response to aerobic exercise augmentation in persons with non-remitted MDD. Our results revealed a small-to-moderate effect, particularly in a group assigned to high-dose exercise (semi-partial eta-squared =0.0335, p=0.0735), indicating that those with atypical depression tended to have larger treatment response to exercise. Through this hypothesis-generating analysis, we indicate the need for research to examine depression subtype, along with other demographic, clinical and biological factors as predictors of treatment response to exercise.
Objective:
The authors conducted a review of the history and empirical basis of genomewide association studies (GWAS), the rationale for GWAS of psychiatric disorders, results to date, limitations, and plans for GWAS meta-analyses.
Method:
A literature review was carried out, power and other issues discussed, and planned studies assessed.
Results:
Most of the genomic DNA sequence differences between any two people are common (frequency >5%) single nucleotide polymorphisms (SNPs). Because of localized patterns of correlation (linkage disequilibrium), 500,000 to 1,000,000 of these SNPs can test the hypothesis that one or more common variants explain part of the genetic risk for a disease. GWAS technologies can also detect some of the copy number variants (deletions and duplications) in the genome. Systematic study of rare variants will require large-scale resequencing analyses. GWAS methods have detected a remarkable number of robust genetic associations for dozens of common diseases and traits, leading to new pathophysiological hypotheses, although only small proportions of genetic variance have been explained thus far and therapeutic applications will require substantial further effort. Study design issues, power, and limitations are discussed. For psychiatric disorders, there are initial significant findings for common SNPs and for rare copy number variants, and many other studies are in progress.
Conclusions:
GWAS of large samples have detected associations of common SNPs and of rare copy number variants with psychiatric disorders. More findings are likely, since larger GWAS samples detect larger numbers of common susceptibility variants, with smaller effects. The Psychiatric GWAS Consortium is conducting GWAS meta-analyses for schizophrenia, bipolar disorder, major depressive disorder, autism, and attention deficit hyperactivity disorder. Based on results for other diseases, larger samples will be required. The contribution of GWAS will depend on the true genetic architecture of each disorder.
Cognitive dysfunction has been repeatedly observed in major depressive disorder (MDD), particularly in areas of attention, verbal and nonverbal learning and memory, and executive functioning. Exercise has been shown to improve cognitive outcomes in other populations, including age-associated cognitive decline, but has not to our knowledge been investigated as an augmentation strategy in depression. This study evaluated the effectiveness of exercise augmentation on cognitive performance in persons with MDD and residual symptoms that included cognitive complaints following initial treatment with a selective serotonin reuptake inhibitor (SSRI). Participants enrolled in the Treatment with Exercise Augmentation for Depression (TREAD) study were randomized to receive either a low or high dose exercise regimen. TREAD participants who provided informed consent for the current study completed Cambridge Neuropsychological Test Automated Battery measures assessing Attention, Visual Memory, Executive Function/Set-shifting and Working Memory, and Executive Function/Spatial Planning domains. Data were analyzed for 39 participants completing both baseline and Week 12 cognitive testing. Overall tests indicated a significant task x group x time interaction for the Executive Function/Set-shifting and Working Memory domain. Post hoc tests indicated improvements in high dose exercisers’ spatial working memory, but decreases in spatial working memory and set-shifting outcomes in low dose exercisers. Both groups improved on measures of psychomotor speed, attention, visual memory and spatial planning. This study suggests a dose-response effect of exercise in specific executive function and working memory tasks among depressed persons with a partial response to SSRI and cognitive complaints, with some cognitive functions improving regardless of exercise dose.
A substantial body of evidence supports the role of exercise interventions for people with a mental illness. However, much of this literature is conducted using outpatient and community-based populations. We undertook a systematic review examining the effect of exercise interventions on the health of people hospitalized with depression, schizophrenia, bipolar disorder, or anxiety disorders. Eight studies met our inclusion criteria. Several studies show positive health outcomes from short-term and long-term interventions for people hospitalized due to depression. Although positive, the evidence for inpatients with schizophrenia, bipolar disorder, or anxiety disorders is substantially less. There is an urgent need to address the paucity of literature in this area, in particular the optimal dose and delivery of exercise for people hospitalized as a result of mental illness. Standardization of reporting exercise programme variables, the assessment of mental illness, and the reporting of adverse events must accompany future studies.
Objectives:
There is growing interest in the use of exercise in the treatment of depression. A number of randomized controlled trials (RCTs) have demonstrated a reduction in depressive symptoms with both aerobic and non-aerobic exercise interventions. This has been supported in a number of systematic reviews and meta-analyses. However, the heterogeneous nature of the exercise intervention trials makes determining the appropriate program variables (frequency, intensity, duration and type of exercise) difficult.
Design:
A systematic review was undertaken on all RCTs reporting a significant treatment effect of exercise in the treatment of depression.
Methods:
Studies were analyzed for exercise frequency, intensity, session duration, exercise type, exercise mode, intervention duration, delivery of exercise, level and quality of supervision and compliance. Study quality was assessed using the PEDro scale.
Results:
Five RCTs published since 2007 met the inclusion criteria and were subsequently analyzed. Most programs were performed three times weekly and of moderate intensity. All included trials used aerobic exercise, either treadmill or outdoor walking, stationary cycle or elliptical cross trainer exercise. Intervention duration ranged from four to twelve weeks. Both group and individual programs were shown to be effective in lowering the symptoms of depression. Some level of supervision is recommended.
Conclusions:
There is evidence for the use supervised aerobic exercise, undertaken three times weekly at moderate intensity for a minimum of nine weeks in the treatment of depression. Further research on the manipulation of program variables is warranted.
Exercise is an efficacious treatment for Major Depressive Disorder (MDD) and has independently been shown to have anti-inflammatory effects in non depressed subjects. Patients with MDD have elevated inflammatory cytokines but it is not known if exercise affects inflammation in MDD patients and whether these changes are clinically relevant. In the TReatment with Exercise Augmentation for Depression (TREAD) study, participants who were partial responders to a Selective Serotonin Reuptake Inhibitor (SSRI) were randomized to receive one of two doses of exercise: 16 kilocalories per kilogram of body weight (KKW), or 4 KKW for 12 weeks.
Blood samples were collected before initiation and again at the end of the 12-week exercise intervention. Serum was analyzed using a multiplexed ELISA for Interferon-γ (IFN-γ), Interleukin 1-β (IL-1β), Interleukin-6 (IL-6), and Tumor Necrosis Factor-α (TNF-α).
Higher baseline levels of TNF-α were associated with greater decrease in depression symptoms over the 12 week exercise period (p = 0.0023). In addition, a significant positive correlation between change in IL-1β and change in depression symptom scores was observed (p=0.0441). There were no significant changes in mean level of any cytokine following the 12-week intervention, and no significant relationship between exercise dose and change in mean cytokine level.
Results suggest that high TNF-α may differentially predict better outcomes with exercise treatment as opposed to antidepressant medications for which high TNF-α is linked to poor response. Our results also confirm findings from studies of antidepressant medications that tie decreasing IL-1β to positive depression treatment outcomes.
Most patients with major depressive disorder (MDD) require second-step treatments to achieve remission. The Treatment with Exercise Augmentation for Depression (TREAD) study was designed to test the efficacy of aerobic exercise as an augmentation treatment for MDD patients who had not remitted with antidepressant treatment.
Eligible participants in this randomized controlled trial were sedentary individuals (men and women aged 18-70 years) diagnosed with DSM-IV nonpsychotic MDD who had not remitted with selective serotonin reuptake inhibitor (SSRI) treatment. Participants were recruited through physician referrals and advertisements. A total of 126 participants were randomized to augmentation treatment with either 16 kcal per kg per week (KKW) or 4 KKW of exercise expenditure for 12 weeks while SSRI treatment was held constant. Supervised sessions were conducted at The Cooper Institute, Dallas, Texas, with additional home-based sessions as needed to fulfill the weekly exercise prescription. The primary outcome was remission (as determined by a score ≤ 12 on the Inventory of Depressive Symptomatology, Clinician-Rated). The study took place between August 2003 and August 2007.
There were significant improvements over time for both groups combined (F₁,₁₂₁ = 39.9, P < .0001), without differential group effect (group effect: F₁,₁₃₄ = 3.2, P = .07; group-by-time effect: F₁,₁₁₉ = 3.8, P = .06). Adjusted remission rates at week 12 were 28.3% versus 15.5% for the 16-KKW and 4-KKW groups, respectively, leading to a number needed to treat (NNT) of 7.8 for 16 KKW versus 4 KKW. Men, regardless of family history of mental illness, and women without a family history of mental illness had higher remission rates by week 12 with higher-dose (women, 39.0%; men, 85.4%) than with lower-dose exercise (women, 5.6%; men, 0.1%) (women: t₉₅ = 2.1, P = .04; men: t₈₈ = 5.4, P < .0001) (NNT: women, 3.0; men, 1.2).
There was a trend for higher remission rates in the higher-dose exercise group (P < .06), with a clinically meaningful NNT of 7.8 in favor of the high exercise dose. Significant differences between groups were found when the moderating effects of gender and family history of mental illness were taken into account and suggest that higher-dose exercise may be better for all men and for women without a family history of mental illness.
clinicaltrials.gov Identifier: NCT00076258.
Brain Derived Neurotrophic Factor (BDNF) has potential as a biomarker of depression treatment because serum BDNF in depressed human subjects is decreased and normalizes with treatment. The relationship between serum BDNF and exercise treatment of depression is not known. The Treatment with Exercise Augmentation for Depression (TREAD) study examined dosed exercise augmentation treatment of partial responders to antidepressants. Serum BDNF in TREAD subjects was analyzed to understand its relationship with exercise training.
Subjects were randomized to high (16 kcal/kg/week or KKW) or low (4 KKW) energy expenditure exercise over 12 weeks. Actual kcal/week expended and IDS-C scores were collected weekly. One hundred four subjects in TREAD provided baseline blood samples; a subset of 70 subjects also provided week 12 samples. Serum BDNF was determined using ELISA. Correlations were examined between change in BDNF and 1) mean kcal/week expended, and 2) change in IDS-C score. Mixed-effects ANOVA examined the effect of baseline BDNF on outcome.
Resting serum BDNF was stable and did not correlate with energy expenditure (p = 0.15) or IDS-C improvement (p = 0.89). Subjects entering the study with higher BDNF improved more rapidly on the IDS-C (p = 0.003).
Serum may not be the most sensitive blood fraction in which to measure BDNF change. Pre-treatment with medication may mask exercise effect on BDNF.
These results suggest that change in serum BDNF does not reflect efficacy of exercise augmentation treatment of MDD. Instead BDNF may function as an augmentation moderator. Pre-treatments that raise BDNF may improve the efficacy of exercise treatment of MDD.
Previous systematic reviews have concluded that exercise programmes are effective in the management of clinical depression. The aim of this review was to analyse the parameters of exercise programmes reported in the primary research, in order to provide clinicians with evidence-based recommendations for exercise prescription for clinical depression.
A systematic review of randomized controlled trials was undertaken. Only trials that reported exercise to be effective in treating depression were included and our review was limited to adults. Appropriate databases and reference lists were searched using established keywords. Data relating to the type, intensity, frequency, duration, mode of exercise and mode of application of exercise was extracted and collated.
A total of 14 randomized controlled trials were included in this review and from these trials 20 intervention arms were analysed. The majority of trials used an aerobic exercise intervention and were supervised. The most common exercise parameters were 60-80% of maximum heart rate for 30 minutes three times per week for an overall duration of 8 weeks. There is an equal volume of evidence supporting group as opposed to individually completed exercise programmes and no trends were identified which would support one mode of exercise over another.
Currently the primary research on this topic supports the use of aerobic exercise which is supervised in some capacity. The current evidence base supports a prescription of three 30-minute sessions per week of aerobic exercise at 60-80% of maximum heart rate for at least 8 weeks.
Does the PEDro scale measure only one construct ie, the methodological quality of clinical trials? What is the hierarchy of items of the PEDro scale from least to most adhered to? Is there any effect of year of publication of trials on item adherence? Are PEDro scale ordinal scores equivalent to interval data?
Rasch analysis of two independent samples of 100 clinical trials from the PEDro database scored using the PEDro scale.
Both samples of PEDro data showed fit to the Rasch model with no item misfit. The PEDro scale item hierarchy was the same in both samples, ranging from the most adhered to item random allocation, to the least adhered to item therapist blinding. There was no differential item functioning by year of publication. Original PEDro ordinal scores were highly correlated with transformed PEDro interval scores (r = 0.99).
The PEDro scale is a valid measure of the methodological quality of clinical trials. It is valid to sum PEDro scale item scores to obtain a total score that can be treated as interval level measurement and subjected to parametric statistical analysis.
We compared aerobic with nonaerobic forms of exercise in the treatment of clinical depression. Ninety-nine inpatients, who met the DMS-III-R criteria for major depression, dysthymic disorder, or depressive disorder not otherwise specified (NOS), took part in the study. They were randomly assigned to two different physical training conditions, aerobic and nonaerobic. In both conditions, one hour of training was performed three times a week for a period of 8 weeks. There was a significant increase in maximum oxygen uptake (VO2 max) in the aerobic group; there was no change in the nonaerobic group regarding this variable. Depression scores in both groups were significantly reduced during the study, but there was no significant difference between the groups. The correlation between increase in physical fitness and reduction in depression scores was low. The study indicates that the antidepressive effects associated with exercises are not restricted to aerobic forms of training.
Depression is common in later life.
To determine whether exercise is effective as an adjunct to antidepressant therapy in reducing depressive symptoms in older people.
Patients were randomised to attend either exercise classes or health education talks for 10 weeks. Assessments were made "blind" at baseline, and at 10 and 34 weeks. The primary outcome was seen with the 17-item Hamilton Rating Scale for Depression (HRSD). Secondary outcomes were seen with the Geriatric Depression Scale, Clinical Global Impression and Patient Global Impression.
At 10 weeks a significantly higher proportion of the exercise group (55% v. 33%) experienced a greater than 30% decline in depression according to HRSD (OR=2.51, P=0.05, 95% CI 1.00-6.38).
Because exercise was associated with a modest improvement in depressive symptoms at 10 weeks, older people with poorly responsive depressive disorder should be encouraged to attend group exercise activities.
Despite recent advancements in the pharmacological treatment of major depressive disorder (MDD), over half of patients who receive treatment with antidepressant medication do not achieve full remission of symptoms. There is evidence that exercise can reduce depressive symptomatology when used as a treatment for MDD. However, no randomized controlled trials have evaluated exercise as an augmentation strategy for patients with carefully diagnosed MDD who remain symptomatic following an adequate acute phase trial of antidepressant therapy.
TReatment with Exercise Augmentation for Depression (TREAD) is an NIMH-funded, randomized, controlled trial designed to assess the relative efficacy of two doses of aerobic exercise to augment selective serotonin reuptake inhibitor (SSRI) treatment of MDD.
The TREAD study includes 12 weeks of acute phase treatment with a 12-week post-treatment follow-up. In addition to looking at change in depressive symptoms as a primary outcome, it also includes comprehensive assessment of psychosocial function and treatment adherence.
This paper reviews the rationale and design of TREAD and illustrates how we address several key issues in contemporary patient-oriented research on MDD: 1) the use of augmentation strategies in the treatment of depressive disorders in general, 2) the use of non-pharmacological strategies in the treatment of depressive disorders, 3) the considerations of designing a well-controlled trial using two active treatment groups, and 4) the implementation of an adherence program for the use of exercise as a treatment strategy.
The TREAD study is uniquely designed to overcome sources of potential bias and threats to internal and external validity that have limited prior research on the mental health effects of exercise. The study is facilitated by the development of a multidisciplinary research team that includes experts in both depression treatment and exercise physiology, as well as other related fields.
How does the skeletal muscle communicate with the brain in health and disease?
- A Isaac
Physical activity in the treatment-resistance depression and non-remitted depression: a systematic review of randomized controlled trials.
- J Etxaniz-Oses
Prevalence management treatment resistant depression.
- C Nemeroff
Clinical practice and epidemiology in mental health improving physical quality of life with group physical activity in the adjunctive treatment of major depressive disorder.
- M Carta