Table 3.
Randomized controlled trials of exercise as an adjunct to pharmacotherapy for major depressive disorder (exercise combined with pharmacotherapy as a treatment arm or all subjects on stable dose of pharmacotherapy)
| Trial | Depression diagnosis criteria and type | Sample | Interventions | Study Duration | Treatment arms (n) | Outcomes |
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|---|---|---|---|---|---|---|---|---|
| Adherence | Drop-outs n(%) | Remission Rate % | ||||||
| Blumenthal et al., 199950 | DSM-IV DIS Major |
Males and females, ≥50y/o, HAM-D17 ≥13 Exclusion: current antidepressant use, use of other medications that would preclude random assignment of exercise (e.g., quinidine, metoprolol), alcohol or substance abuse, medical contraindications to ex (e.g., orthopedic or cardiopulmonary disease), primary diagnosis other than depression (e.g., bipolar, psychosis), acute suicidal risk, psych initiated in past yr, established exercise program n=156 57±6.5y/o 27.6% males |
Outpatient setting AEx: 10min warm-up, 30mins walking or jogging at 70–85% HRR, and 5min cool-down Pharm: Sertraline (50–200mg/d) titrated as needed after meeting with study psychiatrist(s) |
16 weeks AEx: 3d/wk/16wks (48 supervised group sessions) Pharm: 6 sessions (study onset and Week 2, 6, 10, 14, 16) |
AEx (n=55) | 89.6% | 14(26.4%) | 60.4% |
| AEx + Pharm (n=55) | AEx: 91.7% Pharm: 95% |
11(20.0%) | 65.5% | |||||
| Pharm (n=48) | ~95% | 7(14.6%) | 68.8% | |||||
| Pilu et al., 200755 | DSM-IV-SCID Major; comorbid GAD, SP, PD included |
Females, 40–60y/o; non-responders (HAM-D >13) to ≥1 antidepressant after 2mos Exclusion: psychotic disorders, comorbid psychiatric disorders (excluding, GAD, SP, and PD), contraindications to PA; diagnosis of neurological or orthopedic disorders n=30 Age: NR 0(0%) males |
Outpatient setting PA: 5min warm-up, 50mins physiological strengthening with multiple machines available for arms, leg and postural muscles (intensity NR), 5min cool-down Pharm: Varied medication types, dosages, and number taken |
8 months PA: 2d/wk/8mos (64 supervised group sessions) Pharm: Session information NR |
PA + Pharm (n=10) | NR | NR | Remission: NR Change in HAM-D: 60.5% reduction |
| Pharm (n=20) | NR | NR | Remission: NR Change in HAM-D: 13.4% reduction |
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| Mota-Pereira al., 201156 | DSM-IV Major; treatment resistant |
Males and females, 18–60y/o, met depression criteria, non-responder to pharm for >9 and <15mos treatment, physical fitness confirmed by physician, normal ECG Exclusion: psychiatric and relevant clinical co-morbidities, psychotic symptoms, acute suicidal risk, receiving psych, change in pharm <6wks prior to study, participating in regular AEx n=33 Range: 26–60y/o 34.5% males |
Outpatient setting AEx: 30–45mins walking at >3METs on treadmill and overground Pharm: Varied medication types and dosages at therapeutic level, but did not change during study period |
12 weeks AEx: 5d/wk/12wks (60 sessions; supervised 1d/wk and unsupervised 4d/wk) Pharm: 1d/wk/12wks meeting with study staff for 30–45mins |
AEx + Pharm (n=22) | 91.0% | 3(13.6%) | Remission: 26% Response: 21% |
| Pharm (n=11) | NR | 1(9.1%) | Remission: 0% Response: 0% |
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| Danielsson et al., 201457 | DSM-IV-MINI Major |
Males and females, 18–65y/o, met depression criteria, taking 1–2 antidepressants and followed by physician Exclusion: psychotic disorder, substance abuse, previous manic episode, acute suicide risk, untreated heart condition, current exercise program of moderate to high intensity or mind-body activities, pregnancy n=62 Age: NR 22.6% males |
Outpatient setting PA: 5min warm-up, 45min interval training program at 13–14 (low) and 16–17 (high) on Borg RPE with multiple machines (cross-trainer, stationary bikes, step-up boards, rowing machine, treadmill, jumping ropes, balls, free weights, and cable machine), 5min cool-down BBAT: 50mins of body awareness activities, 10mins of verbal reflection Pharm: Taking 1–2 antidepressants. Type, dosage, and titration NR. Advice: 1 session for advice and support for low to moderate PA |
10 weeks PA and BBAT: Week 1–2: 1d/wk/2wks Week 3–10: 2d/wk/8wks (18 supervised sessions; First two sessions were individual; remainder of sessions were group) Advice: 1 individual meeting |
PA + Pharm (n=22) |
85% | 4(18.2%) | Remission: 32% Response: 9% |
| BBAT + Pharm (n=20) |
75% | 6(30.0%) | Remission: 25% Response: 0% |
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| Advice + Pharm (n=20) | 90% | 6(30.0%) | Remission: 15% Response: 10% |
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| Belvederi Murri et al., 201558 | MINI by psychiatrist Major |
Males and females, 65–85y/o, HAM-D17 ≥18, sedentary but health status compatible with exercise Exclusion: other Axis I disorder(s), substance or alcohol misuse, cognitive impairment, physical illness that would prevent exercise (orthopedic, cardiovascular, and neurologic) n=121 75±6y/o 28.9% males |
Outpatient setting P-AEx: 10min warm-up, 40mins of cycling at 60–85% PHR, 5–10min cool-down NP-AEx: 60mins of activity at ≤70% PHR Pharm: Sertraline (≥50mg/d) prescribed and titrated by psychiatrist |
24 weeks P- and NP-AEx: 3d/wk/24wks (72 supervised group sessions) Pharm: Session information NR |
P-AEx + Pharm (n=42) |
P-AEx: ~70% Pharm: 93% |
4(9.5%) | 81.0% |
| NP-AEx + Pharm (n=37) |
NP-AEx: ~70% Pharm: 84% |
5(13.5%) | 73.0% | |||||
| Pharm (n=42) | Pharm: 74% | 6(14.3%) | 45.0% | |||||
| Carneiro et al., 201559 | ICD-10; psychiatrist confirmed ICD-10 codes: F32.1, F33.1, F43.1 Major, dysthymia |
Females, 18–65y/o, sedentary, met depression criteria, have physical fitness to participate in exercise, normal ECG Exclusion: psychotic comorbidities, participation in other clinical trials, medical history indicating medical constraints, taking beta-blockers, planned or current pregnancy, alcohol/drug abuse/dependence, receiving additional complementary therapies (psych), pharm changes in past 6wks or change during study, attend <60% of study sessions n=26 50.2±12.1y/o 0% males |
Outpatient setting AEx: 5min warm-up, 30mins of various activities (games, circuit workouts with resistance bands, jump ropes, fitness balls, brisk walking, and dancing) at 65–80 % MHR, 5min stretching cool-down Pharm: SSRIs and anxiolytics/hypnotics, if needed, at constant individualized dosages |
16 weeks AEx: 3d/wk/16wks (48 supervised group sessions) Pharm: Session information with psychiatrist over 16wks NR |
AEx + Pharm (n=13) | 82% | 4(31.0%) | Remission: NR Change in BDI: 23.4% reduction |
| Pharm (n=13) | NR | 3(23.0%) | Remission: NR Change in BDI: 7.1% increase |
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| Legrand & Neff, 201660 | DSM-IV Major |
Males and females, admitted to inpatient facility, started medication <2wks prior to enrollment, BDI-II ≥29, ability to run or walk briskly, Exclusion: medical contraindication for exercise, psychotic features, receiving beta-blocking drugs or other therapy (sleep deprivation, ECT) n=35 45.3±13.2y/o 31.4% males |
Inpatient setting AEx: 30mins of daily walking/jogging at 65–75% of APMHR Stretch: 30mins of stretching (60s holds and 60s rests) Pharm: starting medication (SSRIs, SNRIs, and/or dopamine antagonist) <2wks prior to enrollment. Dosage and titration NR. |
10 days AEx: 1x/d/10d (10 supervised outdoor sessions with 92.2% of sessions individual) Stretch: 1x/d/10d (10 supervised indoor sessions with 95.3% of sessions individual) |
AEx + Pharm (n=14) |
AEx: 92.9% attended ≥8 sessions Pharm: NR |
1(17.1%) | Remission: NR Response: 57.1% Change in BDI-II: 47.5% reduction |
| Stretch + Pharm (n=11) | Stretch: 81.8% attended ≥8 sessions Pharm: NR |
2(18.2%) | Remission: NR Response: 9.1% Change in BDI-II: 24.8% reduction |
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| Pharm (n=10) | Pharm: NR | 1(10.0%) | Remission: NR Response: 10.0% Change in BDI-II: 18.0% reduction |
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| Salehi et al., 201661 | DSM-IV Major |
Males and females, 25–40y/o, admitted to inpatient care, BDI ≥30, HAM-D ≥25, no comorbid psychiatric disorders Exclusion: history of epilepsy, physical illness, refused ECT n=60 29.7±5.8y/o 70% males |
Inpatient setting Initial 2wk washout period with pharm Pharm: 40mg/d of citalopram AEx: 40–45mins of cycling at 60–75% of VO2max ECT: 1.5 times seizure threshold dose at 1.0ms pulse width |
4 weeks AEx: 3d/wk/4wks (12 supervised individual sessions) ECT: 3d/wk/4wks (12 supervised individual sessions) |
AEx + ECT + Pharm (n=20) | AEx:100% ECT: 100% Pharm:100% |
NR | 76.5% |
| AEx + Pharm (n=20) | AEx:100% Pharm:100% |
NR | 11.8% | |||||
| ECT + Pharm (n=20) | ECT: 100% Pharm:100% |
NR | 11.8% | |||||
| Siqueira et al., 201662 | DSM-IV Major |
Males and females, met depression criteria, drug free ≥5wks prior to enrollment Exclusion: any contraindication to exercise (disabling medical condition), cardiovascular disease, infection, neurological disorder, drug or alcohol abuse, medical comorbidities, active suicidal ideations, history of any Axis I disorder n=57 38.8±10.7y/o 28.1% males |
Outpatient setting AEx: Duration and activity NR, but progression of intensity from 60–85% of VO2max Pharm: Sertraline (50–100mg/d) titrated as needed |
4 weeks AEx: 4d/wk/4wks (16 supervised individual sessions) Pharm: NR |
AEx + Pharm (n=29) | NR | 9(31.0%) | Remission: NR Change in: HAM-D: 40.7% reduction BDI: 37.7% reduction |
| Pharm (n=28) | NR | 8(28.5%) | Remission: NR Change in: HAM-D: 38.0% reduction BDI: 40.9% reduction |
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| Gujral et al., 201963 | DSM-V, PRIME-MD Major |
Males and females, 20–39y/o and 60–79y/o, sedentary, met criteria for major depressive episode Exclusion: self-reported active lifestyle (3d/wk for >20mins/d), gait or balance impairments, unsafe to participate in moderate AEx, disproval from participant’s physician, uncontrolled hypertension, cardiovascular event in past 12mos, substance use problems in past 3mos, lifetime diagnosis of bipolar disorder or any psychotic disorder, clinically significant cognitive impairment, contraindications to MRI n=15 (10 younger, 5 older) Age: NR Sex: NR |
Outpatient setting Initial 2wk taper off antidepressants AEx: warm-up, 45mins stationary cycling or treadmill at 60–75% APMHR or 13–15 Borg RPE (if taking beta-blocker), cool down (~60mins) Pharm: Venlafaxine XR (dosage NR) |
12 weeks Ex: 3d/wk/12wks (36 supervised sessions) Pharm: biweekly medication management by study clinicians |
AEx + Pharm (n=7) | 91% | 1(14%) | Remission: NR Response: NR Change in MADRS: 74% reduction (unclear if analysis was ITT or per protocol) |
| Pharm (n=8) | NR (States completers were adherent) | 3(38%) | Remission: NR Response: NR Change in MADRS: 64% reduction (unclear if analysis was ITT or per protocol) |
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| Moraes et al., 202064 | DSM-IV confirmation by psychiatrist Major |
Males and females, >60y/o; met criteria for depression, sedentary, HAM-D ≤18, taking antidepressants and anxiolytics (if needed) for ≥ 4wks at therapeutic dosage prior to study Exclusion: low functional capacity, poor mobility, balance impairment, severe visual and/or auditory impairment, cognitive impairment, cerebro- vascular infarction; neurodegenerative disease; cardiovascular problems, clinical and psychiatric comorbidities n=27 Range: 60–81y/o 16.0% males |
Outpatient setting PREx: 3×8–12 reps of 4 exercises (chest press, low rows, leg press, knee extension, and knee flexion) at 70% of 1-RM (~30mins). Progressed when completed max number of reps for each set NP-AEx: 5min warm-up, 20mins of walking or stationary cycling at 60% of VO2max or 70% of MHR, 5min cool-down LO-PA: 5mins of low intensity walking (2.5 km/hr) or stationary cycling (<40 RPM), 1×8 reps of 4 exercises (chest press, low rows, leg press, knee extension, and knee flexion) with minimal load (“one plate”), series of stretching with 10sec holds (30mins total) Pharm: Varying therapeutic dosages of antidepressants (fluoxetine or sertraline) and anxiolytics as needed (diazepam or clonazepam) |
12 weeks PREx, NP-AEx, and LO-PA: 2d/wk/12wks (24 supervised sessions) Pharm: Session information NR |
PREx + Pharm (n=9) |
PREx: ≥75% Pharm: NR |
0(0%) | HAM-D Remission: 44.4% Response: 22.2% BDI Remission: 22.2% Response: 55.6% |
| NP-AEx + Pharm (n=9) |
NP-AEx: ≥75% Pharm: NR |
0(0%) | HAM-D Remission:55.6% Response: 55.6% BDI Remission: 33.3% Response: 22.2% |
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| LO-PA + Pharm (n=9) |
LO-PA: ≥75% Pharm: NR |
2(2.2%) | HAM-D Remission: 0% Response: 0% BDI Remission: 0% Response: 0% |
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AEx = aerobic exercise; min(s) = minute(s); APMHR = age-predicted maximum heart rate; BBAT = basic body awareness therapy; BDI = Beck Depression Inventory; d = day(s); DIS = Diagnostic Interview Schedule; DSM-IV= Diagnostic and Statistical Manual of Mental Disorders, fourth edition; ECG = electrocardiogram; ECT = electroconvulsive therapy; GAD = generalized anxiety disorder; HAM-D = Hamilton Rating Scale of Depression; HRR = heart rate reserve; ICD-10 = International Classification of Diseases, 10th Revision; LO-PA = low intensity physical activity; MADRS = Montgomery Depression Rating Scale; MET = metabolic equivalent; MHR = maximum heart rate; MINI = Mini International Neuropsychiatric Interview; mo(s) = month(s); MRI = magnetic resonance imaging; NP-AEx = non-progressive aerobic exercise; NR = not reported; PA = physical activity; P-AEx = progressive aerobic exercise; PD = panic disorder; Pharm = pharmacotherapy; PHR = peak heart rate; PREx = progressive resistance exercise; PRIME-MD = Primary Care Evaluation of Mental Disorders; Psych = psychotherapy; RPE = rating of perceived exertion; RPM = revolutions per minute; SCID = Structured Clinical Interview of DSM Disorders; SNRIs = serotonin and norepinephrine reuptake inhibitors; SP = social phobia; SSRIs = selective serotonin reuptake inhibitors; VO2max = maximal oxygen uptake; wk(s) = weeks; y/o = years old; 1-RM = one-repetition maximum