Physical Exercise Interventions Targeting Cognitive Functioning and the Cognitive Domains in Nondementia Samples: A Systematic Review of Meta-Analyses.

OBJECTIVE: We investigated whether physical exercise interventions improve cognitive functioning in nondementia populations. METHODS: We conducted a systematic review of meta-analyses including only randomized controlled trials (RCTs). Two reviewers completed a systematic search of PubMed, Embase, PsychInfo, and Cochrane Controlled Register of Trials. Study characteristics, effect size data, and heterogeneity estimates were extracted and presented in tabular form. Methodological quality was assessed by 2 reviewers using the AMSTAR-2 checklist. The validity of results was considered based on AMSTAR-2 scores and study characteristics. RESULTS: We included 11 meta-analyses: 6 focused on disease-free older adults and 5 on mild cognitive impairment (MCI) excluding dementia. These meta-analyses summarized 97 unique RCTs. Methodological quality ranged from critically low to high. For overall cognitive functioning, which was the outcome of 6 meta-analyses, 1 showed improvement due to exercise interventions in disease-free older adults (g = 0.29, P < .01), while 2 reported nonsignificant effects. In patients with MCI, 3 meta-analyses reported significant benefits of exercise interventions on overall cognitive functioning (g = 0.25-0.57, P < .01). For cognitive domains such as attention and memory, there was limited evidence of beneficial effects of exercise demonstrated in either disease-free or MCI samples. CONCLUSIONS: Exercise may improve overall cognitive functioning in disease-free older adults, but there is too little high-quality evidence to conclude whether this is achieved through improvement in any of the specific cognitive domains assessed. There is clearer evidence that exercise may improve cognitive functioning in MCI, but again there is limited evidence across most cognitive domains.

Exercise interventions for the prevention of depression: a systematic review of meta-analyses.

BACKGROUND: Exercise may be a promising target for depression interventions. However, evidence for a beneficial effect of exercise interventions on the prevention of depression differs substantially across different studies. METHODS: A systematic search was performed up to July 2018 using PubMed, Embase, PsycINFO, and Cochrane. Articles were included if a meta-analysis of randomized controlled trials was performed that examined the effect of exercise interventions on the onset of depression or depressive symptoms in the general population. Meta-analyses focusing on treatment of diagnosed depression were excluded. Two authors independently screened the articles and graded the quality of included meta-analyses using AMSTAR 2. RESULTS: Eight meta-analyses were included that showed little overlap in 134 included studies. All meta-analyses reported on depressive symptoms rather than onset of depression. Five of these were rated as moderate quality and three of low quality. Six meta-analyses found significant effects, and two found non-significant effects of exercise interventions in reducing depressive symptoms in children, adolescents, adults and the elderly (effect sizes ranging from - 0.10 to - 0.81). Scarce evidence did not allow to draw conclusions about the role of sex and characteristics of exercise on depression. However, some findings suggest that low intensity exercise was as effective as high intensity exercise. Heterogeneity among primary studies was high, likely caused by differences in study quality and exercise characteristics. CONCLUSIONS: The evidence from this study suggests that exercise interventions have a beneficial effect on depressive symptoms in the general population across a wide age-range.

The association of depression and anxiety with cardiac autonomic activity: The role of confounding effects of antidepressants.

BACKGROUND: Depression and anxiety may unfavorably impact on cardiac autonomic dysregulation. However, it is unclear whether this relationship results from a causal effect or may be attributable to confounding factors. We tested the relationship between depression and anxiety with heart rate (HR) and heart rate variability (HRV) across a 9-year follow-up (FU) period and investigated possible confounding by antidepressant use and genetic pleiotropy. METHODS: Data (no. of observations = 6,994, 65% female) were obtained from the longitudinal Netherlands Study of Depression and Anxiety, with repeated waves of data collection of HR, HRV, depression, anxiety, and antidepressant use. Summary statistics from meta-analyses of genome-wide association studies were used to derive polygenic risk scores of depression, HR, and HRV. RESULTS: Across the 9-year FU, generalized estimating equations analyses showed that the relationship between cardiac autonomic dysregulation and depression/anxiety rendered nonsignificant after adjusting for antidepressant use. A robust association was found between antidepressant use (especially tricyclic antidepressants, selective serotonin, and noradrenalin reuptake inhibitors) and unfavorable cardiac autonomic activity across all waves. However, no evidence was found for a genetic correlation of depression with HR and HRV, indicating that confounding by genetic pleiotropy is minimal. CONCLUSIONS: Our results indicate that the association between depression/anxiety and cardiac autonomic dysregulation does not result from a causal pathway or genetic pleiotropy, and these traits might therefore not be inevitably linked. Previously reported associations were likely confounded by the use of certain classes of antidepressants.

Associations of immunometabolic risk factors with symptoms of depression and anxiety: The role of cardiac vagal activity.

OBJECTIVES: This study examined 1) the cross-sectional relationships between symptoms of depression/anxiety and immunometabolic risk factors, and 2) whether these relationships might be explained in part by cardiac vagal activity. METHODS: Data were drawn from the Adult Health and Behavior registries (n = 1785), comprised of community dwelling adults (52.8% women, aged 30-54). Depressive symptoms were measured with the Center for Epidemiological Studies Depression Scale (CES-D) and the Beck Depression Inventory-II (BDI-II), and anxious symptoms with the Trait Anxiety scale of the State-Trait Anxiety Inventory (STAI-T). Immunometabolic risk factors included fasting levels of triglycerides, high-density lipoproteins, glucose, and insulin, as well as blood pressure, waist circumference, body mass index, C-reactive protein, and interleukin-6. Measures of cardiac autonomic activity were high- and low-frequency indicators of heart rate variability (HRV), standard deviation of normal-to-normal R-R intervals, and the mean of absolute and successive differences in R-R intervals. RESULTS: Higher BDI-II scores, in contrast to CES-D and STAI-T scores, were associated with increased immunometabolic risk and decreased HRV, especially HRV likely reflecting cardiac vagal activity. Decreased HRV was also associated with increased immunometabolic risk. Structural equation models indicated that BDI-II scores may relate to immunometabolic risk via cardiac vagal activity (indirect effect: ß = .012, p = .046) or to vagal activity via immunometabolic risk (indirect effect: ß = -.015, p = .021). CONCLUSIONS: Depressive symptoms, as measured by the BDI-II, but not anxious symptoms, were related to elevated levels of immunometabolic risk factors and low cardiac vagal activity. The latter may exhibit bidirectional influences on one another in a meditational framework. Future longitudinal, intervention, an nonhuman animal work is needed to elucidate the precise and mechanistic pathways linking depressive symptoms to immune, metabolic, and autonomic parameters of physiology that predispose to cardiovascular disease risk.

Differential Autonomic Nervous System Reactivity in Depression and Anxiety During Stress Depending on Type of Stressor.

OBJECTIVES: It remains unclear whether depressive and anxiety disorders are associated with hyporeactivity or hyperreactivity of the autonomic nervous system (ANS) and whether deviant reactivity occurs in all types of stressors. This study compared ANS reactivity in people with current or remitted depression/anxiety with reactivity in healthy controls during two stress conditions. METHODS: From the Netherlands Study of Depression and Anxiety, data of 804 individuals with current depression/anxiety, 913 individuals with remitted depression/anxiety, and 466 healthy controls (mean age = 44.1 years; 66.4% female) were available. Two conditions were used to evoke stress: a) an n-back task, a cognitively challenging stressor, and 2) a psychiatric interview, evoking personal-emotional stress related to the occurrence of symptoms of depression/anxiety. Indicators of ANS activity were heart rate (HR), root mean square of differences between successive interbeat intervals (RMSSD), respiratory sinus arrhythmia (RSA), and preejection period. RESULTS: As compared with controls, participants with psychopathology had significant hyporeactivity of HR (controls = 4.1 ± 4.2 beats/min; remitted = 3.5 ± 3.5 beats/min; current psychopathology = 3.1 ± 3.4 beats/min), RMSSD (controls = -6.2 ± 14.5 milliseconds; remitted = -5.4 ± 17.8 milliseconds; current psychopathology = -3.5 ± 15.4 milliseconds), and RSA (controls = -9.3 ± 17.0 milliseconds; remitted = -7.4 ± 16.5 milliseconds; current psychopathology = -6.9 ± 15.0 milliseconds) during the n-back task. In contrast, during the psychiatric interview, they showed significant hyperreactivity of HR (controls = 2.7 ± 3.4 beats/min; remitted = 3.5 ± 3.4 beats/min; current psychopathology = 4.0 ± 3.3 beats/min), RMSSD (controls = -3.4 ± 12.2 milliseconds; remitted = -4.1 ± 12.1 milliseconds; current psychopathology = -5.6 ± 11.8 milliseconds), and RSA (controls = -3.8 ± 8.1 milliseconds; remitted = -4.3 ± 7.9 milliseconds; current psychopathology = -5.0 ± 7.9 milliseconds). The lack of group differences in preejection period reactivity suggests that the found effects were driven by altered cardiac vagal reactivity in depression/anxiety. CONCLUSIONS: The direction of altered ANS reactivity in depressed/anxious patients is dependent on the type of stressor, and only the more ecologically valid stressors may evoke hyperreactivity in these patients.

Antidepressants or running therapy: Comparing effects on mental and physical health in patients with depression and anxiety disorders.

BACKGROUND: Antidepressant medication and running therapy are both effective treatments for patients with depressive and anxiety disorders. However, they may work through different pathophysiological mechanisms and could differ in their impact on physical health. This study examined effects of antidepressants versus running therapy on both mental and physical health. METHODS: According to a partially randomized patient preference design, 141 patients with depression and/or anxiety disorder were randomized or offered preferred 16-week treatment: antidepressant medication (escitalopram or sertraline) or group-based running therapy ≥2 per week. Baseline (T0) and post-treatment assessment at week 16 (T16) included mental (diagnosis status and symptom severity) and physical health indicators (metabolic and immune indicators, heart rate (variability), weight, lung function, hand grip strength, fitness). RESULTS: Of the 141 participants (mean age 38.2 years; 58.2 % female), 45 participants received antidepressant medication and 96 underwent running therapy. Intention-to-treat analyses showed that remission rates at T16 were comparable (antidepressants: 44.8 %; running: 43.3 %; p = .881). However, the groups differed significantly on various changes in physical health: weight (d = 0.57; p = .001), waist circumference (d = 0.44; p = .011), systolic (d = 0.45; p = .011) and diastolic (d = 0.53; p = .002) blood pressure, heart rate (d = 0.36; p = .033) and heart rate variability (d = 0.48; p = .006). LIMITATIONS: A minority of the participants was willing to be randomized; the running therapy was larger due to greater preference for this intervention. CONCLUSIONS: While the interventions had comparable effects on mental health, running therapy outperformed antidepressants on physical health, due to both larger improvements in the running therapy group as well as larger deterioration in the antidepressant group. TRIAL REGISTRATION: Trialregister.nl Number of identification: NTR3460.

Familial resemblance in mental health symptoms, social and cognitive vulnerability, and personality: A study of patients with depressive and anxiety disorders and their siblings.

BACKGROUND: Investigating siblings of probands with affective disorders enables the identification of psychopathology-related risk features. Leveraging data from an older adult sample, as compared to most previous sibling studies, enabled us to study more definitive clinical profiling across the lifespan. We examined prevalence of depressive/anxiety disorders in siblings, proband-sibling resemblance in psychopathology-related features, and whether unaffected siblings showed higher levels of these features than healthy controls. METHODS: The sample (N=929; Mage=50.6) consisted of 256 probands with lifetime depressive and/or anxiety disorders, their 380 siblings, and 293 healthy controls without affected relatives. Fifteen psychopathology-related features were investigated across four domains: mental health symptoms, social vulnerabilities, cognitive vulnerabilities, and personality. RESULTS: Lifetime disorders were present in 50.3% of siblings. Prevalence was 2-3 times higher than Dutch population frequencies. We found small to medium probandsibling resemblance across psychopathology-related features (ρ=0.10-0.32). Unaffected siblings reported poorer interpersonal functioning and more negative life events, childhood trauma, and rumination than healthy controls. LIMITATIONS: Due to the cross-sectional study design, the directionality of effects cannot be determined. No inferences can be made about potential differences in familial resemblance in psychopathology-related features between high- and low-risk families. CONCLUSIONS: Siblings of probands with affective disorders are at higher risk for depressive/anxiety disorders. Even when unaffected, still show higher psychosocial vulnerability than healthy controls. Nevertheless, the only modest proband-sibling resemblance across psychopathology-related features suggests that individual mechanisms differentiate clinical trajectories across the lifespan. Identification of these mechanisms is crucial to improve resilience in subjects with familial risk.

Cortical thickness and resting-state cardiac function across the lifespan: A cross-sectional pooled mega-analysis.

Understanding the association between autonomic nervous system [ANS] function and brain morphology across the lifespan provides important insights into neurovisceral mechanisms underlying health and disease. Resting-state ANS activity, indexed by measures of heart rate [HR] and its variability [HRV] has been associated with brain morphology, particularly cortical thickness [CT]. While findings have been mixed regarding the anatomical distribution and direction of the associations, these inconsistencies may be due to sex and age differences in HR/HRV and CT. Previous studies have been limited by small sample sizes, which impede the assessment of sex differences and aging effects on the association between ANS function and CT. To overcome these limitations, 20 groups worldwide contributed data collected under similar protocols of CT assessment and HR/HRV recording to be pooled in a mega-analysis (N = 1,218 (50.5% female), mean age 36.7 years (range: 12-87)). Findings suggest a decline in HRV as well as CT with increasing age. CT, particularly in the orbitofrontal cortex, explained additional variance in HRV, beyond the effects of aging. This pattern of results may suggest that the decline in HRV with increasing age is related to a decline in orbitofrontal CT. These effects were independent of sex and specific to HRV; with no significant association between CT and HR. Greater CT across the adult lifespan may be vital for the maintenance of healthy cardiac regulation via the ANS-or greater cardiac vagal activity as indirectly reflected in HRV may slow brain atrophy. Findings reveal an important association between CT and cardiac parasympathetic activity with implications for healthy aging and longevity that should be studied further in longitudinal research.

Association Between Depression, Anxiety, and Antidepressant Use With T-Wave Amplitude and QT-Interval.

Objectives: Cardiac repolarization may be affected by psychiatric disorders and/or antidepressant use, but evidence for this is inconclusive. This study examined the relationship between depressive and anxiety disorder and use of antidepressants with T-wave amplitude (TWA) and QT-interval. Methods: Data was obtained from the Netherlands Study of Depression and Anxiety (n = 1,383). Depression/anxiety was diagnosed with the DSM-IV based Composite International Diagnostic Interview. The use of tricyclic antidepressants (TCAs), selective serotonin and noradrenalin reuptake inhibitors (SNRIs), and selective serotonin reuptake inhibitors (SSRIs) was established. T-wave amplitude and QT-interval corrected for heart rate (QTc) were obtained from an ECG measured in a type II axis configuration. Results: Compared to controls, persons with depression or anxiety disorders did not show a significantly different TWA (p = 0.58; Cohen's d = 0.046) or QTc (p = 0.48; Cohen's d = -0.057). In spite of known sympathomimetic effects, TCA use (p = 0.26; Cohen's d = -0.162) and SNRI use (p = 0.70; Cohen's d = -0.055) were not significantly associated with a lower TWA. TCA use (p = 0.12; Cohen's d = 0.225) and SNRI use (p = 0.11; Cohen's d = 0.227) were also not significantly associated with a prolonged QTc. Conclusion: We did not find evidence that either depressive/anxiety disorder or antidepressant use is associated with abnormalities in TWA or QTc. Earlier found sympathomimetic effects of TCAs and SNRIs are not evident in these measures of cardiac repolarization.

Temporal stability and drivers of change in cardiac autonomic nervous system activity.

OBJECTIVES: This study determined temporal stability of ambulatory measured cardiac autonomic activity for different time periods and investigated potential drivers of changes in this activity. METHODS: Data was drawn from baseline (n=2379), 2-year (n=2245), and 6-year (n=1876) follow-up from the Netherlands Study of Depression and Anxiety. Cardiac autonomic activity was measured with heart rate (HR), respiratory sinus arrhythmia (RSA) and pre-ejection period (PEP). Autonomic temporal stability was determined across 2, 4, and 6year intervals. We subsequently examined the association between sociodemographics, lifestyle, mental health, cardiometabolic health, and the use of antidepressant and cardiac medication with change in cardiac autonomic activity. RESULTS: Over 2years, stability was good for HR (ICC=0.703), excellent for RSA (ICC=0.792) and moderate for PEP (ICC=0.576). Stability decreased for a 4- (HR ICC=0.688, RSA ICC=0.652 and PEP ICC=0.387) and 6-year interval (HR ICC=0.633, RSA ICC=0.654 and PEP ICC=0.355). The most important determinants for increase in HR were (increase in) smoking, increase in body mass index (BMI) and (starting) the use of antidepressants. Beta-blocking/antiarrhythmic drug use led to a decrease in HR. Decrease in RSA was associated with age, smoking and (starting) antidepressant use. Decrease in PEP was associated with age and (increase in) BMI. CONCLUSIONS: Cardiac autonomic measures were rather stable over 2years, but stability decreased with increasing time span. Determinants contributing to cardiac autonomic deterioration were older age, (increase in) smoking and BMI, and (starting) the use of antidepressants. (Starting) the use of cardiac medication improved autonomic function.

Basal autonomic activity, stress reactivity, and increases in metabolic syndrome components over time.

CONTEXT: Basal autonomic nervous system (ANS) functioning has been linked to the metabolic syndrome (MetS), but the role of ANS reactivity in response to stress remains unclear. OBJECTIVE: To examine cross-sectionally and longitudinally to what extent ANS basal level and stress reactivity are related to MetS. DESIGN: 2-year and 6-year data from a prospective cohort: the Netherlands Study of Depression and Anxiety. SETTING: Participants were recruited from the general community, primary care, and mental health care organizations. PARTICIPANTS: 1922 respondents (mean age=43.7years). MAIN OUTCOME MEASURES: Indicators of ANS functioning were heart rate (HR), respiratory sinus arrhythmia (RSA) and pre-ejection period (PEP). ANS stress reactivity was measured during a cognitively challenging stressor and a personal-emotional stressor. MetS components included triglycerides, high-density lipoprotein cholesterol, blood pressure, glucose and waist circumference. RESULTS: Cross-sectional analyses indicated that higher basal HR, lower basal values of RSA and PEP, and higher RSA reactivity during cognitive challenge were related to less favorable values of almost all individual MetS components. Longitudinal analyses showed that higher basal HR and shorter basal PEP predicted 4-year increase in many MetS abnormalities. Higher RSA stress reactivity during cognitive challenge predicted 4-year increase in number of MetS components. CONCLUSION: Higher basal sympathetic, lower basal parasympathetic activity, and increased parasympathetic withdrawal during stress are associated with multiple MetS components, and higher basal sympathetic activity predicts an increase in metabolic abnormalities over time. These findings support a role for ANS dysregulation in the risk for MetS and, consequently, the development of cardiovascular disease.