Daniel S. Quintana

Depression, Comorbid Anxiety Disorders, and Heart Rate Variability in Physically Healthy, Unmedicated Patients: Implications for Cardiovascular Risk

Context There is evidence that heart rate variability (HRV) is reduced in major depressive disorder (MDD), although there is debate about whether this effect is caused by medication or the disorder per se. MDD is associated with a two to fourfold increase in the risk of cardiac mortality, and HRV is a robust predictor of cardiac mortality; determining a direct link between HRV and not only MDD, but common comorbid anxiety disorders, will point to psychiatric indicators for cardiovascular risk reduction. Objective To determine in physically healthy, unmedicated patients whether (1) HRV is reduced in MDD relative to controls, and (2) HRV reductions are driven by MDD alone, comorbid generalized anxiety disorder (GAD, characterized by anxious anticipation), or comorbid panic and posttraumatic stress disorders (PD/PTSD, characterized by anxious arousal). Design, Setting, and Patients A case-control study in 2006 and 2007 on 73 MDD patients, including 24 without anxiety comorbidity, 24 with GAD, and 14 with PD/PTSD. Seventy-three MDD and 94 healthy age- and sex-matched control participants were recruited from the general community. Participants had no history of drug addiction, alcoholism, brain injury, loss of consciousness, stroke, neurological disorder, or serious medical conditions. There were no significant differences between the four groups in age, gender, BMI, or alcohol use. Main Outcome Measures HRV was calculated from electrocardiography under a standardized short-term resting state condition. Results HRV was reduced in MDD relative to controls, an effect associated with a medium effect size. MDD participants with comorbid generalized anxiety disorder displayed the greatest reductions in HRV relative to controls, an effect associated with a large effect size. Conclusions Unmedicated, physically healthy MDD patients with and without comorbid anxiety had reduced HRV. Those with comorbid GAD showed the greatest reductions. Implications for cardiovascular risk reduction strategies in otherwise healthy patients with psychiatric illness are discussed.

Anxiety Disorders are Associated with Reduced Heart Rate Variability: A Meta-Analysis

Background: Anxiety disorders increase risk of future cardiovascular disease (CVD) and mortality, even after controlling for confounds including smoking, lifestyle, and socioeconomic status, and irrespective of a history of medical disorders. While impaired vagal function, indicated by reductions in heart rate variability (HRV), may be one mechanism linking anxiety disorders to CVD, prior studies have reported inconsistent findings highlighting the need for meta-analysis. Method: Studies comparing resting-state HRV recordings in patients with an anxiety disorder as a primary diagnosis and healthy controls were considered for meta-analysis. Results: Meta-analyses were based on 36 articles, including 2086 patients with an anxiety disorder and 2294 controls. Overall, anxiety disorders were characterized by lower HRV [high frequency (HF): Hedges’ g = −0.29. 95% CI: −0.41 to −0.17, p < 0.001; time domain: Hedges’ g = −0.45, 95% CI: −0.57 to −0.33, p < 0.001] than controls. Panic disorder (n = 447), post-traumatic stress disorder (n = 192), generalized anxiety disorder (n = 68), and social anxiety disorder (n = 90), but not obsessive–compulsive disorder (n = 40), displayed reductions in HF HRV relative to controls (all ps < 0.001). Conclusion: Anxiety disorders are associated with reduced HRV, findings associated with a small-to-moderate effect size. Findings have important implications for future physical health and well-being of patients, highlighting a need for comprehensive cardiovascular risk reduction.

The relationship between mental and physical health: insights from the study of heart rate variability.

Here we review our recent body of work on the impact of mood and comorbid anxiety disorders, alcohol dependence, and their treatments on heart rate variability (HRV), a psychophysiological marker of mental and physical wellbeing. We have shown that otherwise healthy, unmedicated patients with these disorders display reduced resting-state HRV, and that pharmacological treatments do not ameliorate these reductions. Other studies highlight that tricyclic medications and the serotonin and noradrenaline reuptake inhibitors in particular may have adverse cardiovascular consequences. Reduced HRV has important functional significance for motivation to engage social situations, social approach behaviours, self-regulation and psychological flexibility in the face of stressors. Over the longer-term, reduced HRV leads to immune dysfunction and inflammation, cardiovascular disease and mortality, attributable to the downstream effects of a poorly functioning cholinergic anti-inflammatory reflex. We place our research in the context of the broader literature base and propose a working model for the effects of mood disorders, comorbid conditions, and their treatments to help guide future research activities. Further research is urgently needed on the long-term effects of autonomic dysregulation in otherwise healthy psychiatric patients, and appropriate interventions to halt the progression of a host of conditions associated with morbidity and mortality.

Cytokine aberrations in autism spectrum disorder: a systematic review and meta-analysis

The role of non-diagnostic features in the pathophysiology of autism spectrum disorders (ASDs) is unclear. Increasing evidence suggests immune system alterations in ASD may be implicated in the severity of behavioral impairment and other developmental outcomes. The primary objective of this meta-analysis was to investigate if there is a characteristic abnormal cytokine profile in ASD compared with healthy controls (HCs). We identified relevant studies following a search of MEDLINE, EMBASE, PsycINFO, Web of Knowledge and Scopus. A meta-analysis was performed on studies comparing plasma and serum concentrations of cytokines in unmedicated participants with ASD and HCs. Results were reported according to PRISMA statement. Seventeen studies with a total sample size of 743 participants with ASD and 592 HC were included in the analysis. Nineteen cytokines were assessed. Concentrations of interleukin (IL)-1beta (P<0.001), IL-6 (P=0.03), IL-8 (P=0.04), interferon-gamma (P=0.02), eotaxin (P=0.01) and monocyte chemotactic protein-1 (P<0.05) were significantly higher in the participants with ASD compared with the HC group, while concentrations of transforming growth factor-β1 were significantly lower (P<0.001). There were no significant differences between ASD participants and controls for the other 12 cytokines analyzed. The findings of our meta-analysis identified significantly altered concentrations of cytokines in ASD compared to HCs, strengthening evidence of an abnormal cytokine profile in ASD where inflammatory signals dominate.

Heart rate variability is associated with emotion recognition: direct evidence for a relationship between the autonomic nervous system and social cognition.

It is well established that heart rate variability (HRV) plays an important role in social communication. Polyvagal theory suggests that HRV may provide a sensitive marker of ones ability to respond and recognize social cues. The aim of the present study was to directly test this hypothesis. Resting-state HRV was collected and performance on the Reading the Mind in the Eyes Test was assessed in 65 volunteers. HRV was positively associated with performance on this emotion recognition task confirming our hypothesis and these findings were retained after controlling for a variety of confounding variables known to influence HRV - sex, BMI, smoking habits, physical activity levels, depression, anxiety, and stress. Our data suggests that increased HRV may provide a novel marker of ones ability to recognize emotions in humans. Implications for understanding the biological basis of emotion recognition, and social impairment in humans are discussed.

Do delivery routes of intranasally administered oxytocin account for observed effects on social cognition and behavior? A two-level model.

Accumulating evidence demonstrates the important role of oxytocin (OT) in the modulation of social cognition and behavior. This has led many to suggest that the intranasal administration of OT may benefit psychiatric disorders characterized by social dysfunction, such as autism spectrum disorders and schizophrenia. Here, we review nasal anatomy and OT pathways to central and peripheral destinations, along with the impact of OT delivery to these destinations on social behavior and cognition. The primary goal of this review is to describe how these identified pathways may contribute to mechanisms of OT action on social cognition and behavior (that is, modulation of social information processing, anxiolytic effects, increases in approach-behaviors). We propose a two-level model involving three pathways to account for responses observed in both social cognition and behavior after intranasal OT administration and suggest avenues for future research to advance this research field.

Considerations in the assessment of heart rate variability in biobehavioral research

Heart rate variability (HRV) refers to various methods of assessing the beat-to-beat variation in the heart over time, in order to draw inference on the outflow of the autonomic nervous system. Easy access to measuring HRV has led to a plethora of studies within emotion science and psychology assessing autonomic regulation, but significant caveats exist due to the complicated nature of HRV. Firstly, both breathing and blood pressure regulation have their own relationship to social, emotional, and cognitive experiments – if this is the case are we observing heart rate (HR) changes as a consequence of breathing changes? Secondly, experiments often have poor internal and external controls. In this review we highlight the interrelationships between HR and respiration, as well as presenting recommendations for researchers to use when collecting data for HRV assessment. Namely, we highlight the superior utility of within-subjects designs along with the importance of establishing an appropriate baseline and monitoring respiration.

Oxytocin increases heart rate variability in humans at rest: implications for social approach-related motivation and capacity for social engagement.

Context Oxytocin (OT) plays a key regulatory role in human social behaviour. While prior studies have examined the effects of OT on observable social behaviours, studies have seldom examined the effects of OT on psychophysiological markers such as heart rate variability (HRV), which provides an index of individual’s motivation for social behaviour. Furthermore, no studies have examined the impact of OT on HRV under resting conditions, which provides an index of maximal capacity for social engagement. Objective To examine the effects of OT on HRV measures in healthy male participants while at rest. OT was hypothesised to increase HRV, compared to placebo, and that the effects would be greatest for a non-linear measure of HRV (the detrended fluctuation scaling exponent). Methods Twenty-one male participants were recruited for this study. Participants were non-smokers, not on any medications and reported no history of psychiatric illness, neurological disorder, or any other serious medical condition (e.g. diabetes, cardiovascular disease). The study employed a randomised, placebo-controlled, within-subject, crossover, experimental design. Main Outcome Measures HRV was calculated from electrocardiography under a standardized, 10-minute, resting state condition. Results As hypothesised, OT increased HRV and these effects were largest using the detrended fluctuation scaling exponent, a non-linear measure. These changes were observed in the absence of any change in state mood, as measured by the profile of mood states. Importantly, participants were unable to correctly guess which treatment they had been assigned at either of the two assessments. Conclusions Together with the broader literature on OT and HRV, findings suggest that acute administration of OT may facilitate a fundamental psychophysiological feature of social behaviour, increasing capacity for social engagement. Findings also suggest that HRV changes may provide a novel biomarker of response to OT nasal spray that can be incorporated into research on response to treatment.

Reduced heart rate variability in social anxiety disorder: associations with gender and symptom severity.

Background Polyvagal theory emphasizes that autonomic nervous system functioning plays a key role in social behavior and emotion. The theory predicts that psychiatric disorders of social dysfunction are associated with reduced heart rate variability, an index of autonomic control, as well as social inhibition and avoidance. The purpose of this study was to examine whether heart rate variability was reduced in treatment-seeking patients diagnosed with social anxiety disorder, a disorder characterized by social fear and avoidance. Methods Social anxiety patients (n = 53) were recruited prior to receiving psychological therapy. Healthy volunteers were recruited through the University of Sydney and the general community and were matched by gender and age (n = 53). Heart rate variability was assessed during a five-minute recording at rest, with participants completing a range of self-report clinical symptom measures. Results Compared to controls, participants with social anxiety exhibited significant reductions across a number of heart rate variability measures. Reductions in heart rate variability were observed in females with social anxiety, compared to female controls, and in patients taking psychotropic medication compared to non-medicated patients. Finally, within the clinical group, we observed significant associations between reduced heart rate variability and increased social interaction anxiety, psychological distress, and harmful alcohol use. Conclusions The results of this study confirm that social anxiety disorder is associated with reduced heart rate variability. Resting state heart rate variability may therefore be considered a marker for social approach-related motivation and capacity for social engagement. Additionally, heart rate variability may provide a useful biomarker to explain underlying difficulties with social approach, impaired stress regulation, and behavioral inhibition, especially in disorders associated with significant impairments in these domains.

On the validity of using the Polar RS800 heart rate monitor for heart rate variability research

Dear Editor, We read with interest the report of Wallen et al. (2012) concerning the validity of the Polar RS800 heart rate monitor (HRM) as compared to a 5-min supine electrocardiogram (ECG) with respect to the calculation of various indices of heart rate variability (HRV). The Polar system consists of an HRM with bundled software (Polar Pro Trainer 5; PPT) which is used to derive HRV values. Wallen et al. (2012) compare the results from hand-corrected ECG data to this system, and conclude that traditional ECGs should be preferred as ‘‘...the Polar system did not identify errors satisfactorily, or return valid values of HRV for certain groups...’’. It should be noted first that within a research context, inaccuracy of a bundled hardware/software system is somewhat moot. Research groups overwhelmingly utilize the Polar system as a source of RR intervals, which are exported from the PPT software, and corrected if necessary to a normal-to-normal approximation then analysed using separate software. Recent work within this journal, for example, bears this out (e.g., Mateo et al. 2012; Mendonca et al. 2011; Vieira et al. 2012). As Wallen et al. (2012) note, the accuracy of this method is not in question, as previous research (e.g., Weippert et al. 2010) compared the accuracy of ECG-derived and Polar-derived RR intervals and concluded that the RR intervals are sufficiently interchangeable when analysed through identical methods. Wallen et al. (2012) note that recorded RR intervals (as provided from the Polar HRM) are less than ideal for the identification of cardiac dysrhythmia, as a normative ECG waveform is not available. This is undoubtedly the case, but as might be expected from a system designed primarily for tracking HR in a sporting context, the Polar system makes no systematic claims about its ability to identify and eliminate ectopy in groups that may display persistent ectopy at baseline (e.g., the elderly). Thus, the appropriate question is whether Polar-recorded data can optimally produce ECG-comparable measures of HRV, not whether the HRM system is able to identify and deal with cardiac dysrhythmia. Several recent implementations of correction methods applicable to RR series exist (e.g. Barbieri and Brown 2006; Clifford and Tarassenko 2005) but were not attempted by Wallen et al. (2012). The presence and correction of cardiac dysrhythmia (e.g., ectopy, premature atrial contraction) is a well-known source of error in the calculation for HRV, especially in the frequency domain as even one ectopic beat can bias the analysis of a short-term recording (Berntson and Stowell 1998). However, with regard to analytical methods, Wallen et al. (2012) did not provide an explicit methodology for the identification of ectopic beats in their ECG recording beyond visual inspection. The Task Force (1996) paper cited does not specify a methodology beyond stating that interpolation or regression methods may improve the bias conferred by ectopy. The lack of a uniform methodology for the detection of ectopy has the potential for unintended bias in the comparative ECG recording against which the HRM intervals were compared, especially if the assessors are not blind to the overall research question (which was the case in the report by Wallen et al. 2012). Furthermore, Communicated by Susan A. Ward.