Effects of exercise on sleep and nocturnal arousal in patients with unipolar depression

Background
Unipolar depression is a debilitating disease and one of the leading causes of global disease burden.
Unipolar depression is bidirectionally associated with insomnia and attenuated heart rate variability.
Insomnia has a negative effect on disease trajectory across all treatment phases in depression.
Attenuated heart rate variability is one of the pathophysiological mechanisms explaining the increased
risk of cardiovascular disease in patients with depression. Approximately one-third of the patients do
not remit when treated with guideline therapies for depression, i.e., psychotherapy and
pharmacotherapy. Moreover, insomnia is one of the most frequent residual symptoms in those who
respond or remit. Lastly, guideline therapies do not seem to improve heart rate variability. Therefore,
adjuvant therapies to improve depressive and insomnia symptoms and heart rate variability are need.
Exercise is a promising auxiliary treatment based on previous research, but multiple knowledge gaps
remain.
Aims
This Ph.D. project aimed to address important knowledge gaps. The first aim was to summarize the
existing research concerning the effects of aerobic, resistance, and mind-body exercise on sleep quality
in patients with unipolar depression. The second aim was to quantify the effect of a single bout of
moderate-intensity aerobic exercise performed in the afternoon on sleep outcomes in patients with
unipolar depression. The third aim was to quantify the effect of a single bout of moderate-intensity
aerobic exercise performed in the afternoon on mood and adverse effects. The fourth and last aim was
to quantify the effect of a single bout of moderate-intensity aerobic exercise performed in the
afternoon on nocturnal and pre-sleep arousal.
Methods
A systematic review with network meta-analysis and a randomized controlled trial were conducted
within this Ph.D. project. The systematic review (PROSPERO CRD42019115705) was conducted
according to the PRISMA network meta-analysis extension and AMSTAR2 guidelines. A systematic
search was conducted in multiple electronic bibliographic databases (PubMed, EMBASE, Cochrane
Library, PsycINFO, Sportdiscus, CINHAL, OpenGrey, ProQuest Dissertations & Theses A&I,
Clinicaltrials.gov, and WHO International Clinical Trials Registry) from their inception until February
12th, 2020. Randomized controlled trials investigating the effects of regular aerobic, resistance, or
mind-body exercise on self- or observer-reported sleep quality in patients with depression were
included. Network meta-analysis was conducted, and the network geometry, forest plots, and league
tables were reported.
The trial (NCT03673397) was a two-arm parallel-group, randomized, outcome assessor-blinded,
controlled, superiority trial. It was conducted and reported in compliance with SPIRIT, GRAPH, FAIR,
CONSORT, GCP, and GDPR guidelines and directives. The trial took place in the OBERWAID clinic.
Patients between 18 and 65 years of age with a primary diagnosis of unipolar depression were
included. The intervention was a single 30-minute bout of moderate aerobic exercise. The control
group sat and read for 30 minutes. The primary outcome was sleep efficiency measured by
polysomnography. Secondary outcomes were other polysomnographic variables, subjective sleep
quality, daytime sleepiness, mood states, adverse events, pre-sleep arousal, as well as pre-sleep and
nocturnal heart rate variability.
Results
Publication 1: The effects of aerobic, resistance, and meditative movement exercise on sleep in
individuals with depression: protocol for a systematic review and network meta-analysis
This publication provides a thorough account of the purpose and methodology of the systematic
revie and network meta-analysis. The report adhered to the Preferred Reporting Items for Systematic
Review and Meta-analysis Protocols (PRISMA-P) guideline.
Publication 2: The effects of exercise on sleep in unipolar depression: a systematic review and network
meta-analysis
The network meta-analysis was based on 17 trials with N = 1645 patients randomized to 13 treatments
yielding 35 comparisons. The confidence in the mixed (i.e., direct and indirect) evidence was moderate
(43% of comparisons), low (39% of comparisons), or very low (18% of comparisons). All exercise types
and intensity levels except moderate aerobic exercise improved sleep quality more than passive
control. The effects of active control, mind-body exercise, treatment as usual, and vigorous aerobic
exercise were similar. Vigorous strength exercise yielded a significantly larger effect on sleep quality
than aerobic or mind-body exercise compared to passive control. None of the exercise modes or
intensities was significantly less efficacious than treatment as usual. Adding moderate or vigorous
aerobic exercise to treatment as usual resulted in slightly larger effect sizes, but these differences were
not statistically significant. However, vigorous strength exercise alone or adding mind-body exercise
to treatment as usual resulted in significantly larger effects than treatment as usual alone.
Publication 3: The acute effects of aerobic exercise on sleep in patients with depression: study protocol
for a randomized controlled trial
This publication presents the rationale, hypothesis, and procedures of the randomized controlled trial
in detail. The publication was written in accordance with the Standard Protocol Items
Recommendations for Interventional Trials (SPIRIT) statement.
Publication 4: The acute effects of aerobic exercise on sleep in patients with unipolar depression: a
randomized controlled trial
There was no evidence for an effect of allocation on polysomnographic sleep efficiency. This finding
was confirmed in all sensitivity analyses (i.e., complete case and per-protocol analysis as well as
excluding an influential data point). There was also no evidence that chronotype, expectancy, or credibility altered the effect of allocation. No evidence of a correlation between exercise intensity (i.e.,
rate of perceived exertion and percent of maximal age-predicted heart rate) and sleep efficiency at
follow-up was found. Furthermore, there was no evidence for an effect of allocation on any of the
secondary objective or subjective measures of sleep or daytime sleepiness. However, there was a
strong effect of allocation on mood immediately post-exercise. This effect was consistent across all
subscales, with the intervention group showing decreases in negative and increases in positive mood
states. Although there was a trend toward lower symptom severity in the intervention group compared
to the control group immediately post-exercise, this effect was non-significant.
Publication 5: The acute effects of aerobic exercise on nocturnal and pre-sleep arousal in patients with
unipolar depression: a randomized controlled trial
There was no evidence for an effect of allocation on root mean square of successive differences of
normal-to-normal intervals during the sleep period. All sensitivity analyses confirmed this finding (i.e.,
only using complete data, excluding patients who smoked, used either beta-blockers, any
antidepressant, or only tricyclic antidepressants). Furthermore, no evidence suggested that allocation
altered root mean square of successive differences of normal-to-normal intervals in any sleep stage
(although N1 was not analyzed due to insufficient data). There was also no evidence to suggest that
any of the other heart rate variability parameters were affected by allocation during the sleep period.
Lastly, no evidence indicated that pre-sleep root mean square of successive differences of normal-tonormal
intervals or pre-sleep somatic and cognitive arousal were altered by allocation.
Conclusions
The findings of the network meta-analysis confirm the salubrious effects of regular aerobic, resistance,
and mind-body exercise for patients with depression. None of the investigated exercise types or
intensities lowered subjective sleep quality. Vigorous resistance and mind-body exercise in
combination with treatment as usual elicited the most substantial effects. Therefore, these exercise
modes might be recommended to target sleep quality in patients with depression specifically.
However, the confidence in these findings is low, and thus more research is needed. The results of
publications 4 and 5 confirm previous findings, which found no evidence of an adverse effect of acute
exercise after 02:00 pm on sleep-related outcomes. The absence of evidence was consistent across all
outcomes of sleep, pre-sleep arousal, and heart rate variability. Thus, these findings question the
validity of the exercise timing recommendations in sleep hygiene guidelines. Moreover, a single bout
of moderate-intensity exercise lasting 30 minutes can be recommended to improve the mood of
patients with depression. In summary, regular aerobic, resistance, and mind-body exercise can be
recommended as an adjuvant treatment to improve mood and insomnia symptoms in patients with
depression.