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Donta ST, Clauw DJ, Engel, Jr CC, et al. Cognitive Behavioral Therapy and Aerobic Exercise for Gulf War Veterans' Illnesses: A Randomized Controlled Trial. JAMA. 2003;289(11):1396–1404. doi:10.1001/jama.289.11.1396
Author Affiliations: VA Medical Center, Boston, Mass (Drs Donta, Sogg, Thakore, and Mori); University of Michigan Medical Center, Ann Arbor (Drs Clauw and Williams); Walter Reed Army Medical Center and Uniformed Services University, Bethesda, Md (Drs Engel and Smith); Cooperative Studies Program Coordinating Center (Mr Guarino and Dr Peduzzi), VA Connecticut Healthcare System (Dr Kerns), West Haven, Conn; Indiana University, Bloomington (Dr Skinner); Portland VA Medical Center and Oregon Health and Science University, Portland (Dr Barkhuizen); VA Medical and Regional Office Center, White River Junction, Vt (Dr Taylor); VA Medical Center, Bedford, Mass (Dr Kazis); VA Puget Sound Healthcare System, Seattle Division, Seattle, Wash (Drs Hunt, Dougherty, and Richardson); New Mexico VA Health Care System, Albuquerque (Drs Kunkel and Salisbury); San Juan VA Medical Center, San Juan, Puerto Rico (Drs Rodriguez and Alicea); Audie L. Murphy Memorial Veterans Hospital, San Antonio, Tex (Dr Chiliade); Naval Health Research Center, San Diego, Calif (Drs Ryan and Gray); New York Harbor VA Healthcare System, Brooklyn Campus, New York, NY (Drs Lutwick and Norwood); Birmingham VA Medical Center, Birmingham, Ala (Drs Everson and Blackburn); John Cochran VA Medical Center, St Louis, Mo (Dr Martin); San Francisco VA Medical Center, San Francisco, Calif (Dr Griffiss); Fargo VA Medical and Regional Office Center, Fargo, ND (Drs Cooper and Renner); H. H. McGuire VA Medical Center, Richmond, Va (Drs Schmitt and McMurtry); VA New Jersey Health Care System, East Orange (Dr Park); Philadelphia VA Medical Center, Philadelphia, Pa (Dr Pullman-Mooar); Dayton VA Medical Center, Dayton, Ohio (Drs Bernstein and Hershberger); and Medical University of South Carolina, Charleston (Dr Feussner).
Context Gulf War veterans' illnesses (GWVI), multisymptom illnesses characterized
by persistent pain, fatigue, and cognitive symptoms, have been reported by
many Gulf War veterans. There are currently no effective therapies available
to treat GWVI.
Objective To compare the effectiveness of cognitive behavioral therapy (CBT),
exercise, and the combination of both for improving physical functioning and
reducing the symptoms of GWVI.
Design, Setting, and Patients Randomized controlled 2 × 2 factorial trial conducted from April
1999 to September 2001 among 1092 Gulf War veterans who reported at least
2 of 3 symptom types (fatigue, pain, and cognitive) for more than 6 months
and at the time of screening. Treatment assignment was unmasked except for
a masked assessor of study outcomes at each clinical site (18 Department of
Veterans Affairs [VA] and 2 Department of Defense [DOD] medical centers).
Interventions Veterans were randomly assigned to receive usual care (n = 271), consisting
of any and all care received from inside or outside the VA or DOD health care
systems; CBT plus usual care (n = 286); exercise plus usual care (n = 269);
or CBT plus exercise plus usual care (n = 266). Exercise sessions were 60
minutes and CBT sessions were 60 to 90 minutes; both met weekly for 12 weeks.
Main Outcome Measures The primary end point was a 7-point or greater increase (improvement)
on the Physical Component Summary scale of the Veterans Short Form 36-Item
Health Survey at 12 months. Secondary outcomes were standardized measures
of pain, fatigue, cognitive symptoms, distress, and mental health functioning.
Participants were evaluated at baseline and at 3, 6, and 12 months.
Results The percentage of veterans with improvement in physical function at
1 year was 11.5% for usual care, 11.7% for exercise alone, 18.4% for CBT plus
exercise, and 18.5% for CBT alone. The adjusted odds ratios (OR) for improvement
in exercise, CBT, and exercise plus CBT vs usual care were 1.07 (95% confidence
interval [CI], 0.63-1.82), 1.72 (95% CI, 0.91-3.23), and 1.84 (95% CI, 0.95-3.55),
respectively. The OR for the overall (marginal) effect of receiving CBT (n
= 552) vs no CBT (n = 535) was 1.71 (95% CI, 1.15-2.53) and for exercise (n
= 531) vs no exercise (n = 556) was 1.07 (95% CI, 0.76-1.50). For secondary
outcomes, exercise alone or in combination with CBT significantly improved
fatigue, distress, cognitive symptoms, and mental health functioning, while
CBT alone significantly improved cognitive symptoms and mental health functioning.
Neither treatment had a significant impact on pain.
Conclusion Our results suggest that CBT and/or exercise can provide modest relief
for some of the symptoms of chronic multisymptom illnesses such as GWVI.
In 1990 and 1991, 700 000 US troops were deployed to the Persian
Gulf in what became known as the Gulf War. Upon their return, many Gulf War
veterans from both the US and other allied forces began to report chronic,
unexplained fatigue, pain, cognitive, and other symptoms.1-3 The
Department of Veterans Affairs (VA) and Department of Defense (DOD) collectively
refer to these symptoms as Gulf War veterans' illnesses (GWVI) because they do not represent a unique illness as implied by
the commonly used term Gulf War syndrome. Many studies
have sought to determine the etiology of these symptoms, but no single cause
or pathogenic mechanism has been identified.4-7
The symptoms of GWVI cannot be distinguished from other chronic multisymptom
illnesses, such as fibromyalgia and chronic fatigue syndrome.1,8,9 Since
2 treatments, cognitive behavioral therapy (CBT) and aerobic exercise, have
been effective in improving the symptoms and functional status of individuals
with other multisymptom illnesses, we hypothesized that these therapies would
also improve the functional status and reduce the symptoms of veterans with
The VA Cooperative Study #470 was a randomized, multicenter, controlled
trial of CBT and/or aerobic exercise in veterans with GWVI.14 The
study was initiated in April 1999 at 18 VA and 2 DOD medical centers and ended
in September 2001. The trial was monitored by the human rights committee at
the coordinating center, the institutional review boards at each participating
site, and an independent data and safety monitoring board (DSMB).
Veterans were eligible for the study if they were deployed to the Gulf
War theater of operations between August 1990 and August 1991 and reported
at least 2 of the following 3 symptoms that began after August 1990, lasted
for more than 6 months, and were present at the time of screening: fatigue
that limited usual activity; musculoskeletal pain involving 2 or more regions
of the body; and cognitive symptoms (memory, concentration, or attention difficulties).
Veterans were excluded from the study for any of the following: a health condition
precluding exercise or CBT; past CBT for treatment of GWVI; concurrent enrollment
in another clinical trial; pregnancy; a clearly defined disease that accounted
for the veteran's symptoms; severe psychiatric illness (any history of psychiatric
hospitalization in the past 2 years, any history of psychoses or use of antipsychotic
medication, alcohol or substance abuse within the past 2 years, or current
suicidal thoughts or a suicide attempt within the past 2 years) as measured
by the Primary Care Evaluation of Mental Disorders (Prime MD)15;
self-reported regular (weekly) activity level raising the metabolic rate to
7 times the resting rate (7 metabolic equivalents [METs]), as determined by
study personnel based on information provided in the study protocol and giving
the energy requirements (in METs) for a wide variety of occupational and recreational
activities; or a score of at least 40 on the Physical Component Summary (PCS)
scale of the Veterans Short Form 36-Item Health Survey (V/SF-36). A score
of 40 is approximately equal to 1 SD below the general US population and 0.5
SD above the population of veterans who use the VA health care system.16 Low PCS scores are indicative of poor physical functioning.
Veterans who satisfied eligibility criteria and gave written informed
consent were randomized to 1 of 4 treatment arms: usual care; CBT alone plus
usual care; exercise alone plus usual care; or CBT plus exercise plus usual
care. Randomization was stratified by medical center using a permuted block
scheme with equal allocation among treatment arms. Because CBT was given in
a group format, eligible participants were randomized in groups of 4 participants,
whenever possible, to 1 of the 4 treatment arms using a permuted block design
with a block size of 8. Randomization was centrally performed by the coordinating
center after verification of eligibility criteria.
Cognitive Behavioral Therapy. Cognitive behavioral therapy was delivered in groups of 3 to 8 participants.14 Treatment sessions were 60 to 90 minutes long and
groups met weekly for 12 weeks; participants remained in the same group throughout
the treatment period. The CBT protocol was designed specifically to target
physical function, with the goals of (1) teaching behavioral skills to help
participants experience a safe and gradual improvement in physical functioning
without experiencing a disabling exacerbation of symptoms and (2) teaching
cognitive strategies to help participants learn systematic ways of analyzing
and producing solutions to problems that serve as barriers to functioning.
Components of CBT intervention included time-contingent activity pacing, pleasant
activity scheduling, mnemonic strategies, sleep hygiene, assertiveness skills,
confrontation of negative thinking and affect, and structured problem-solving
skills. Although all of the CBT components were used to increase physical
functioning, CBT did not specifically encourage exercise or its compliance
in this study. All study therapists were licensed doctoral-level psychologists
with previous training in CBT modalities; at most clinical sites, only 1 CBT
therapist conducted treatment sessions. Each therapist received protocol training
before study initiation. Treatment manuals were provided to therapists and
participating veterans to ensure uniformity of the intervention across sites
and to facilitate monitoring of treatment fidelity. The participants' treatment
manual was designed for use either in supervised therapy or as a self-help
Aerobic Exercise. The exercise intervention was designed specifically to increase activity
level by allowing flexibility in selecting the types of exercise and by giving
participants the ability to set the intensity of exercise based on their symptoms.
A submaximal cycle ergometer exercise test was used to determine physical
fitness at baseline and to develop individualized prescriptions for a low-intensity
aerobic exercise program to increase the activity level of veterans assigned
to exercise.14 Participating veterans were
asked to exercise once per week for 1 hour in the presence of the exercise
therapist during the 12-week treatment phase. Exercise therapists were either
certified physical therapists or masters-level exercise physiologists. Therapists
instructed participants about exercise, stretching techniques, and activity
selection using ratings of perceived exertion, target heart rate, and METs.
Participants were also asked to exercise independently 2 to 3 times per week
during the 12-week treatment phase and throughout the follow-up period. Intensity
and duration of exercise were gradually increased as tolerated.
Cognitive Behavioral Therapy Plus Aerobic Exercise. Veterans randomized to combination therapy were assigned to concurrently
receive 12 one-hour weekly sessions of CBT and 12 one-hour weekly sessions of exercise training.
Usual Care. All study participants received usual care consisting of any and all
care received from inside or outside of the VA or DOD health care systems.
This care included a variety of nonsystematic interventions aimed at symptom
relief. The control group received only usual care.
Participants were evaluated at baseline, 3 months, 6 months, and 12
months. Evaluations included completion of the primary and secondary outcome
assessment forms, the Prime MD,15 a physical
examination, a dolorimeter/tenderpoint examination, and a submaximal exercise
The primary study outcome measure was binary and was defined as the
presence or absence of more than a 7-point increase (improvement) at 12 months
relative to baseline on the PCS scale of the V/SF-36. The V/SF-36, a brief
self-administered patient questionnaire assessing health status and health-related
quality of life, is a modification of the well-established Medical Outcomes
Study SF-36, used in ambulatory care veterans standardized to a US population
mean of 50 points with an SD of 10 points.17,18 The
PCS scale was selected because it integrates measures of functional status
that span 8 domains of health that are relevant to GWVI and because there
is no validated disease-specific measure for this illness. The first 5 domains
of PCS are physical (physical functioning, role limitations due to physical
problems, bodily pain, general health, and vitality) and are given greater
weight; the last 3 domains are mental and given smaller weight (social functioning,
role limitations due to emotional problems, and mental health). The common
symptoms of GWVI (pain, fatigue, myalgia, rash, dyspnea, insomnia, various
gastrointestinal symptoms, and sensitivity to odors) span a wide range of
physical manifestations largely covered by the PCS concepts. The 7-point change
was selected because a change greater than 7 points is outside the 95% confidence
interval (CI) for an individual patient score, as estimated from the SD and
score reliability.19 Changes of this magnitude
have also been shown to be clinically relevant in many studies of chronic
12-month follow-up was selected because clinical trials using exercise and
CBT have demonstrated benefits for this duration.10,12,25,26
Secondary outcome measures were assessments of pain,27 fatigue,28 cognitive symptoms,29 distress,
and mental health–related functioning, assessed by standardized instruments
(Table 1). Research assistants
who were masked to treatment assignment administered all primary and secondary
Site investigators were instructed to report all adverse events and
to evaluate each event for its date of onset, relatedness to treatment (based
on the investigator's clinical judgment), and resolution. Adverse events were
defined as serious if they were fatal or life threatening or resulted in inpatient
hospitalization or permanent disability. The DSMB and study chairs independently
reviewed each serious adverse event to determine if further action was necessary.
Sample size was calculated to detect all 6 pairwise differences between
treatment arms for the primary end point, assuming a 15% improvement with
usual care, 30% with CBT or exercise alone, and 45% with CBT plus exercise.
The target sample size was 1064 veterans for 80% power and a type I error
of .0083 (2-sided and corrected for the 6 comparisons).
A modified intent-to-treat analysis was used for the primary outcome
measure; 5 participants without a calculable PCS score at baseline were excluded
from the analysis per recommendation of the DSMB. Participants who withdrew
from the study or missed the 12-month visit were classified as not improved30 per protocol. A generalized linear mixed model31-33 was used to analyze
treatment efficacy, adjusted for the study design (randomization by site and
by groups of veterans within site), baseline PCS score, and whether veterans
reported a pending disability claim (unbalanced at baseline; P = .009). Statistical significance for the pairwise treatment comparisons
was determined by the Hochberg procedure using an overall type I error of
.05.34 Treatment effects were summarized by
adjusted odds ratios (ORs) and 95% familywise CIs (ie, CIs corrected for the
multiple pairwise comparisons that preserve the overall type I error of .05).
Since there was no interaction between treatment and the primary outcome measure,
a secondary analysis evaluated the marginal effects of exercise and CBT using
the methods described herein.
A modified intent-to-treat analysis also was used for the secondary
outcome measures, including actual PCS scores. Participants without a baseline
value or without any follow-up measurements were excluded from the analysis.
Treatment efficacy was analyzed by mixed models, adjusted for study design
and pending disability claims.35 The outcome
variable in each mixed model was the change at 3, 6, and 12 months relative
to baseline, with the baseline value as a covariate in the model. Mixed models
were fitted by maximum likelihood methods using all available data. A type
I error rate of .025 was used for all tests of significance for secondary
end points, and P values for pairwise treatment comparisons
were determined by the Hochberg procedure.34 Since
there were no significant treatment × time interactions (ie, the treatment
effect was the same for all time points), the marginal effects of each treatment
are presented as least-squares mean differences from baseline (ie, the average
treatment effect over the follow-up period). Sensitivity analyses were conducted
with imputed missing values by multiple imputation using the stated baseline
the results were similar.
We also conducted analyses based on adherence, defined as attending
at least two thirds of the treatment sessions (8 sessions for CBT alone, 8
sessions for exercise alone, and 16 sessions for CBT plus exercise). SAS Version
8.2 (SAS Institute Inc, Cary, NC) was used for all analyses.
Between April 1999 and September 2000, 1092 veterans were enrolled of
2793 screened (Figure 1). The most
frequent reason for exclusion was a PCS score of at least 40. Eight randomized
veterans were later determined to be ineligible but were included in analyses
per DSMB recommendation.
Baseline characteristics were generally comparable among the 4 treatment
arms (Table 2). Overall mean (SD)
V/SF-36 PCS and Mental Component Summary (MCS) scores were 33.7 (7.5) and
37.5 (12.1), respectively. The overall mean PCS score was approximately 1.6
SDs below the US population mean and 0.2 SD below that of veterans who use
the VA health care system, while the overall mean MCS score was about 1.3
SD below the US population and 0.6 SD below that of veterans who use the VA
health care system.16 The mean (SD) age was
40.7 (8.7) years, 15% were female, and 81% presented with all 3 cardinal symptoms
of GWVI at the time of screening; the mean duration of symptoms was 6.7 years.
Based on the Prime MD,15 45% of veterans had
either a major depressive disorder or dysthymia, 35% had an anxiety disorder,
and 43% had posttraumatic stress disorder; 23% were receiving medication for
a psychiatric disorder. Twenty-four percent had a pending disability claim
(significantly different among treatment arms; P =
.009) and 42% were receiving disability payments.
Between July 1999 and September 2001, a total of 913 participants (84%)
completed the 3-month follow-up visit, 939 (86%) completed the 6-month follow-up
visit, and 998 (91%) completed the 12-month follow-up visit. Of the 94 participants
(8.6%) who did not complete the study, 46 were lost to follow-up, 44 refused
further follow-up, 3 died, and 1 was released from the study prematurely for
safety reasons (Figure 1).
The median number of exercise treatment sessions attended was 6; 68
participants (13%) did not attend any session and 87 (16%) attended all 12
sessions. The median number of CBT treatment sessions attended was 5; 83 participants
(15%) did not attend any CBT session and 39 (7%) attended all 12 sessions.
The number of veterans classified as adherent to treatment (attending at least
two thirds of the treatment sessions) was 102 (38%) for CBT plus exercise,
103 (36%) for CBT alone, and 124 (47%) for exercise alone.
Receipt of nonprotocol treatment was tracked during the 3-month treatment
phase. During this period, 27% of participants assigned to usual care exercised
regularly and approximately 5% received some form of CBT outside of the study.
Among those assigned to CBT alone, 23% exercised regularly; among those assigned
to exercise alone, less than 1% received some form of CBT outside of the study.
A total of 112 serious adverse events were reported: 23 with CBT plus
exercise, 27 with exercise alone, 30 with CBT alone, and 32 with usual care.
Most adverse events were hospitalizations for events unrelated to the study;
however, 3 events were possibly related to the study, 2 with usual care (psychosis
and angina) and 1 with exercise alone (back surgery).
The percentage of veterans who improved more than 7 points on the PCS
at 12 months relative to baseline was 11.5% (31/270) with usual care, 11.7%
(31/265) with exercise alone, 18.4% (49/266) with CBT plus exercise, and 18.5%
(53/286) with CBT alone. Corresponding percentages at 3 months were 9.3%,
12.8%, 16.5%, and 15.0% and at 6 months were 12.2%, 13.6%, 16.2%, and 12.9%,
respectively. Several lower cut points for PCS improvement (4, 5, and 6 points)
were also examined and the findings were similar (data not shown).
Table 3 displays the unadjusted
and adjusted pairwise ORs and 95% familywise CIs for the proportion of participants
who improved at 12 months for all treatment comparisons, along with the raw P values and P values corrected
for multiple comparisons. Although none of the treatment comparisons was statistically
significant after correcting for multiple comparisons, the adjusted ORs for
CBT plus exercise (1.84) and CBT alone (1.72) relative to usual care were
comparable, while the OR for exercise alone was 1.07, indicating that CBT
accounts for most of the combined effect of treatment and that the treatments
did not act synergistically.
Table 4 displays outcomes
by treatment according to adherence. With exercise alone, the percentage of
participants whose PCS score improved was significantly higher (P = .02) among adherent participants (16.9%) compared with nonadherent
participants (7.1%). The associations were similar but not significant for
CBT alone and CBT plus exercise. In contrast, the treatment effect was not
significantly associated with the presence of disability (either receipt of
disability claims or disability claims pending) or psychiatric disorders at
baseline, use of psychiatric medications, or the receipt of nonprotocol exercise
(data not shown).
Because there was little evidence of an interaction between treatment
and the primary outcome measure (P = .99), the overall
or marginal effects of exercise and CBT were evaluated (Table 3). Of the 531 veterans who were assigned to exercise, 80
(15.1%) improved more than 7 points on the PCS compared with 83 (14.9%) of
556 veterans who were not assigned to exercise, with an adjusted OR of 1.07
(95% CI, 0.76-1.50). In contrast, 101 (18.3%) of the 552 veterans who received
CBT improved compared with only 62 (11.6%) of 535 veterans who did not receive
CBT, with an adjusted OR of 1.71 (95% CI, 1.21-2.41), corresponding to a number
needed to treat of about 15.
The overall adjusted mean change in scores relative to baseline (ie,
the average treatment effect over the entire follow-up period) for each secondary
end point are displayed in Table 5.
For the MCS, mean changes were −1.03 for usual care, 0.97 for CBT alone,
2.30 for CBT plus exercise, and 2.33 for exercise alone. All comparisons with
usual care were statistically significant at the .025 level. Similar results
were observed for cognitive symptoms. All 5 measures of fatigue and the measure
of distress (V/SF-36 Mental Health Index) exhibited statistically significant
and comparable effects for exercise alone and CBT plus exercise compared with
usual care. In contrast, only 1 of the 4 measures of pain (affective) showed
significant treatment differences for CBT alone and CBT plus exercise compared
with usual care. None of the treatment comparisons was significant for changes
in PCS score.
For all secondary outcome measures, significant treatment differences
were seen at 3 months and remained constant over the follow-up period. There
was, however, deterioration in each measure over the follow-up period across
all treatment arms. This is demonstrated graphically in Figure 2, which displays the percentage change in the raw mean score
for representative secondary outcome measures at 3, 6, and 12 months relative
to baseline. Most measures improved with exercise and/or CBT, with maximum
improvement at 3 months and deterioration thereafter. In contrast, there was
little or no improvement in scores at 3 months for usual care, with subsequent
worsening over time.
In this cohort of Gulf War veterans with chronic multisymptom illnesses,
a 12-week program of CBT led to a modest improvement in the primary outcome
measure of physical function at 1 year and accounted for nearly all of the
combined effect of both treatments. In contrast, almost no improvement in
physical function was observed with exercise. Those assigned to exercise,
however, demonstrated modest improvements in fatigue, cognitive symptoms,
distress, and mental health functioning compared with usual care, whereas
CBT showed modest improvements only in cognitive symptoms and mental health
functioning. Neither treatment had much of an impact on pain.
The overall findings of this study can be related to differences in
the 2 interventions. Since evidence from prior studies suggests that the effects
of CBT are maximized when it is tailored to address specific targeted outcomes,
our CBT protocol was designed specifically to target physical function. Hence,
many secondary outcome measures that were not specifically targeted by CBT
did not improve.39,40 In contrast,
the exercise intervention was specifically designed to improve activity level
by incorporating the patient's symptoms into the treatment regimen. This may
explain why we observed symptom improvement that did not translate into functional
improvement. Other studies of aerobic exercise in patients with fibromyalgia
and chronic fatigue syndrome have also demonstrated improvements in symptoms
but not physical function.26,41,42
The benefits observed in this study were modest and smaller than those
observed in previous studies of this spectrum of illness.10-13,43,44 There
are several possible reasons for this finding. First, testing these interventions
in a large-scale multicenter trial, rather than in the typical small-scale,
single-site efficacy trial with a highly selected population, may have dampened
the effectiveness of the treatment. For example, CBT was administered in a
group format, rather than individual sessions, by therapists with a wide range
of experience, resulting in highly variable treatment effects across study
sites. Second, participants were relatively noncompliant with both therapies,
attending on average only 50% of the sessions (13%-15% did not attend any
sessions). However, the rate of adherence in this trial is typical of most
studies using these forms of therapy.45-50 Nevertheless,
adherence was strongly predictive of outcome for participants assigned to
exercise alone and marginally related to outcome for the other 2 treatment
arms. Finally, in contrast with nearly all studies of this spectrum of illnesses,
participating veterans were predominantly men who may have exhibited a different
response than women.
This is the first large-scale, multicenter trial comparing the effectiveness
of CBT and exercise in GWVI. Overall, we found that CBT improved physical
function whereas exercise relieved many of the symptoms of GWVI; both therapies
improved cognitive symptoms and mental health functioning but neither therapy
improved pain. Our results are consistent with the reported modest beneficial
effects of these therapies in similar multisymptom illnesses and demonstrate
that such treatments are safe and could be implemented in a large health care
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