When Heart Beats Differently in Depression: Review of Nonlinear Heart Rate Variability Measures.

BACKGROUND: Disturbed heart dynamics in depression seriously increases mortality risk. Heart rate variability (HRV) is a rich source of information for studying this dynamics. This paper is a meta-analytic review with methodological commentary of the application of nonlinear analysis of HRV and its possibility to address cardiovascular diseases in depression. OBJECTIVE: This paper aimed to appeal for the introduction of cardiological screening to patients with depression, because it is still far from established practice. The other (main) objective of the paper was to show that nonlinear methods in HRV analysis give better results than standard ones. METHODS: We systematically searched on the web for papers on nonlinear analyses of HRV in depression, in line with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) 2020 framework recommendations. We scrutinized the chosen publications and performed random-effects meta-analysis, using the esci module in jamovi software where standardized effect sizes (ESs) are corrected to yield the proof of the practical utility of their results. RESULTS: In all, 26 publications on the connection of nonlinear HRV measures and depression meeting our inclusion criteria were selected, examining a total of 1537 patients diagnosed with depression and 1041 healthy controls (N=2578). The overall ES (unbiased) was 1.03 (95% CI 0.703-1.35; diamond ratio 3.60). We performed 3 more meta-analytic comparisons, demonstrating the overall effectiveness of 3 groups of nonlinear analysis: detrended fluctuation analysis (overall ES 0.364, 95% CI 0.237-0.491), entropy-based measures (overall ES 1.05, 95% CI 0.572-1.52), and all other nonlinear measures (overall ES 0.702, 95% CI 0.422-0.982). The effectiveness of the applied methods of electrocardiogram analysis was compared and discussed in the light of detection and prevention of depression-related cardiovascular risk. CONCLUSIONS: We compared the ESs of nonlinear and conventional time and spectral methods (found in the literature) and demonstrated that those of the former are larger, which recommends their use for the early screening of cardiovascular abnormalities in patients with depression to prevent possible deleterious events.

Nonlinear analysis of EEG complexity in episode and remission phase of recurrent depression.

OBJECTIVES: Biomarkers of major depressive disorder (MDD), its phases and forms have long been sought. Objectives were to examine whether the complexity of EEG activity, measured by Higuchi's fractal dimension (HFD) and sample entropy (SampEn), differs between healthy subjects, patients in remission, and in episode phase of the recurrent depression and whether the changes are differentially distributed between hemispheres and cortical regions. METHODS: Resting state EEG with eyes closed was recorded from 22 patients suffering from recurrent depression (11 in remission, 11 in the episode), and 20 age and sex-matched healthy control subjects. Artifact-free EEG epochs were analyzed by in-house developed programs running HFD and SampEn algorithms. RESULTS: Depressed patients had higher HFD and SampEn complexity compared to healthy subjects. The complexity was higher in patients who were in remission than in those in the acute episode. Altered complexity was present in the frontal and centro-parietal regions when compared to control group. The complexity in frontal and parietal regions differed between the two phases of depressive disorder. CONCLUSIONS: Complexity measures of EEG distinguish between the healthy controls, patients in remission and episode. Further studies are needed to establish whether these measures carry a potential to aid clinically relevant decisions about depression.

PTSD and depressive symptoms are linked to DHEAS via personality.

BACKGROUND: Research results on dehydroepiandrosterone sulfate ester (DHEAS) in post-traumatic stress disorder (PTSD) are inconsistent. We hypothesized that personality traits could be the confounders of DHEAS levels and disease symptoms, which could in part explain the discrepancy in findings. METHOD: This study was a part of a broader project in which simultaneous psychological and biological investigations were carried out in hospital conditions. 380 male subjects were categorized in four groups: A) current PTSD (n = 132), B) lifetime PTSD (n = 66), C) trauma controls (n = 101), and D) healthy controls (n = 81), matched by age. RESULTS: The level of DHEAS is significantly lower in the current PTSD group than in trauma controls. All groups significantly differ in personality traits Disintegration and Neuroticism (current PTSD group having the highest scores). DHEAS is related to both PTSD and depressive symptoms; however, Structural Equation Model (SEM) shows that the relations are indirect, realized via their confounder - personality trait Disintegration. CONCLUSIONS: According to our project results, DHEAS is the second putative biomarker for trauma-related disorders that fails to fulfil this expectation. It appears to be more directly related to personality than to the disease symptoms (the first one being basal cortisol). Our data promote personality as a biologically based construct with seemingly important role in understanding the mental health status.

Posttraumatic and depressive symptoms in ß-endorphin dynamics.

A disturbed beta-endorphin system can be a part of the post-traumatic stress disorder (PTSD) and depression allostasis. Study subjects (N=392) included those with PTSD and/or (stress-induced) depression, and healthy controls with and without traumas. The aim of the study was to examine the network of relations centered around plasma beta-endorphin. The network included anxiety (as a personality trait), traumatic events, pain, aggressiveness, depressive symptoms, and three clusters of PTSD symptoms: intrusions, avoidance, and hyperarousal. Beta-endorphin was represented by individual mean from 13 time points (BEmean), reflecting the total amount of the peripherally secreted hormone, and the coefficient of variation (BEvar), calculated as the ratio of standard deviation to the mean, reflecting the hormone׳s dynamics. BEvar correlated with all other variables, BEmean had no correlations. Structural equation modeling (SEM) was used to examine all interrelations (including their directions) of BEvar and the state/trait variables in the context of their entirety. The model revealed that hyperarousal and anxiety were the only direct agents of peripheral beta-endorphin fluctuations, mediating the effects of other variables. Traumatic events and intrusions act on BEvar via hyperarousal, while depressive symptoms, avoidance, and pain act via anxiety. Hyperarousal should be emphasized as the main agent not only because its effect on BEvar is larger than that of anxiety, but also because it increases anxiety itself (via avoidance and pain). All influences on BEvar are positive and they indicate long-term (sensitizing) effects (as opposed to direct stimulation, for example, by acute pain, anger, etc.). Relations apart from beta-endorphin are also discussed.

GR gene BclI polymorphysm changes the path, but not the level, of dexamethasone-induced cortisol suppression.

BACKGROUND: The hypothalamo-pituitary-adrenocortical (HPA) axis self-regulation is achieved via cortisol binding to mineralocorticoid (MR) and glucocorticoid receptors (GR). It is often disturbed in mental disorders, particularly in those where traumatic stress has been implicated, such as posttraumatic stress disorder and depression. Although dexamethasone suppression test (DST) is often used as diagnostic aid, the findings still vary. In search of the factors influencing the DST outcome, we examined the glucocorticoid receptor (GR) gene BclI polymorphism. METHODS: A total of 229 male subjects were classified into three BclI groups: two groups with homozygous carriers (of the G allele, N=108, and of the C allele, N=26), and one with heterozygous carriers (N=95). Multiple hierarchical linear regression analysis was done, where the dependent variable was the dexamethasone-induced cortisol suppression, and predictors included receptor variables. The interactions of the count of 'G׳s with the predictors were introduced to single out the effects of the G allele. RESULTS: The means of all studied variables, including suppression, are statistically the same in the three groups. However, the mechanism of suppression involves MRs only in the G allele carriers. LIMITATIONS: The subjects were selected by criteria suited for the aim of the large project whose part is this study, hence the relatively small number of CC carriers. Also, we did not assess MR functional properties that would probably sharpen the results. CONCLUSION: Our finding that MRs participate in cortisol suppression in the G allele carriers suggests that research aimed at refining HPA axis-based therapy might require its adjustment for such patients.

Mineralocorticoid receptor and heat shock protein expression levels in peripheral lymphocytes from war trauma-exposed men with and without PTSD.

Alterations in the number and functional status of mineralocorticoid (MR) and glucocorticoid receptors (GR) may contribute to vulnerability to posttraumatic stress disorder (PTSD). Corticosteroid receptors are chaperoned by heat shock proteins Hsp90 and Hsp70. We examined relations between corticosteroid receptor and heat shock protein expression levels, and related them with war trauma exposure, PTSD and resilience to PTSD. Relative levels of MR, Hsp90 and Hsp70 were determined by immunoblotting in lymphocytes from war trauma-exposed men with current PTSD (current PTSD group, n=113), with life-time PTSD (life-time PTSD group, n=61) and without PTSD (trauma control group, n=88), and from non-traumatized healthy controls (healthy control group, n=85). Between-group differences in MR, Hsp90 and Hsp70 levels and in MR/GR ratio were not observed. The level of MR was correlated with both Hsp90 and Hsp70 levels in trauma control and healthy control groups. On the other hand, GR level was correlated only with Hsp90 level, and this correlation was evident in current PTSD and trauma control groups. In conclusion, PTSD and exposure to trauma are not related to changes in lymphocyte MR, Hsp90 or Hsp70 levels, but may be associated with disturbances in corticosteroid receptors interaction with heat shock proteins.

A preliminary evaluation of leukocyte phospho-glucocorticoid receptor as a potential biomarker of depressogenic vulnerability in healthy adults.

The mechanism of maladaptive chronic stress response involves altered phosphorylation of the glucocorticoid receptor (GR). In this study, we investigated if important depressogenic vulnerability factors, such as neuroticism and self-reports of negative affective states, may be associated with alterations in levels of the GR and GR phosphoisoforms in peripheral blood mononuclear cells (PBMC) of healthy adults. In 21 women and 16 men we evaluated PMBC levels of total GR (tGR), GR phosphorylated at serine 211 (pGR-S211) and serine 226 (pGR-S226) and correlated these data with personality traits and current reports of stress, anxiety and depression. Also, we assessed plasma cortisol levels in all tested subjects. Our results showed that in women nuclear pGR-S226 was positively correlated with neuroticism and current reports of depression, anxiety and stress, while the ratio of nuclear pGR-S211/pGR-S226 was negatively correlated with reports of depression. None of the aforementioned correlations were significant in men. No significant relations between cortisol levels and any of GR parameters were observed. These preliminary findings highlight the value of GR phosphorylation-related research in identifying molecular biomarkers of depressogenic vulnerability, at least in women.

Lymphocyte glucocorticoid receptor expression level and hormone-binding properties differ between war trauma-exposed men with and without PTSD.

OBJECTIVE: Posttraumatic stress disorder (PTSD) has been shown to be associated with altered glucocorticoid receptor (GR) activity. We studied the expression and functional properties of the receptor in peripheral blood mononuclear cells (PBMCs) from non-traumatized healthy individuals (healthy controls; n=85), and war trauma-exposed individuals with current PTSD (n=113), with life-time PTSD (n=61) and without PTSD (trauma controls; n=88). The aim of the study was to distinguish the receptor alterations related to PTSD from those related to trauma itself or to resilience to PTSD. METHODS: Functional status of the receptor was assessed by radioligand binding and lysozyme synthesis inhibition assays. The level of GR gene expression was measured by quantitative PCR and immunoblotting. RESULTS: Current PTSD patients had the lowest, while trauma controls had the highest number of glucocorticoid binding sites (Bmax) in PBMCs. Hormone-binding potential (Bmax/KD ratio) of the receptor was diminished in the current PTSD group in comparison to all other study groups. Correlation between Bmax and KD that normally exists in healthy individuals was decreased in the current PTSD group. Contrasting Bmax data, GR protein level was lower in trauma controls than in participants with current or life-time PTSD. CONCLUSIONS: Current PTSD is characterized by reduced lymphocyte GR hormone-binding potential and by disturbed compensation between Bmax and hormone-binding affinity. Resilience to PTSD is associated with enlarged fraction of the receptor molecules capable of hormone binding, within the total receptor molecule population in PBMCs.

Is there a biological difference between trauma-related depression and PTSD? DST says 'NO'.

The use of the low-dose dexamethasone suppression test (DST) as a potentially discriminative marker between post-traumatic stress disorder (PTSD) and depression is still under discussion. In order to compare the influence of these psychopathologies on the DST results, we examined suppression in war-traumatized subjects with one or both of these disorders, as well as in healthy controls. Based on our previous findings, we hypothesized that subjects with any disorder would exhibit higher dexamethasone suppression than healthy controls due to traumatic experiences. This study was a part of a broader project in which simultaneous psychological and biological investigations were carried out in hospital conditions on 399 male participants: 57 with PTSD, 28 with depression, 76 with PTSD+depression, and 238 healthy controls. Cortisol was measured in blood samples taken at 0900 h before and after administering 0.5mg of dexamethasone (at 2300 h). Group means ± standard deviation of cortisol suppression were: 79.4±18.5 in the PTSD group, 80.8±11.6 in the depression group, 77.5±24.6 in the group with PTSD+depression, and 66.8±34.6 in healthy controls. The first three groups suppressed significantly more than the fourth. When the number of traumas was introduced as a covariate, the differences disappeared. The hypothesis was confirmed: in respect to DST, the examined trauma-related psychopathologies showed the same pattern: hypersuppression, due to multiple traumatic experiences.

The role of personality and traumatic events in cortisol levels--where does PTSD fit in?

BACKGROUND: Studies of cortisol in post-traumatic stress disorder (PTSD) have yielded mixed results. We hypothesize that personality traits and traumatic experiences could be the confounders of cortisol measures and disease symptoms. METHOD: This study was a part of a broader project in which simultaneous psychological and biological investigations were carried out in hospital conditions on 400 male participants categorized by four groups: (A) 133 with current PTSD, (B) 66 with lifetime PTSD, (C) 102 trauma controls, and (D) 99 healthy controls (matched by age and education). Cortisol and ACTH were measured in blood samples taken hourly from 22:00 h to 09:00 h, with an additional sample at 07:30 h (resting state and morning rise). The next night, dexamethasone (0.5mg) suppression test was performed. RESULTS: No significant differences in basal cortisol and ACTH were found between study groups. The trait Conscientiousness, negatively modulated by Extraversion (assessed by NEO Personality Inventory-Revised) was found to correlate with cortisol (but not with ACTH). Group differences are found on suppression. Structural equation modeling shows excellent fit only when the paths (influences) from Conscientiousness to basal cortisol and from traumatic events to suppression are present. The paths connecting suppression and PTSD symptoms do not contribute. CONCLUSIONS: Two sources of differences of hypothalamo-pituitary-adrenocortical axis functioning are implied, both only indirectly connected to PTSD. It seems that basal cortisol secretion is associated more tightly with personality (introvertively modulated Conscientiousness), while the regulation by glucocorticoid receptor system is sensitized by repeated traumatic situations.

A theoretical study of hypothalamo-pituitary-adrenocortical axis dynamics.

Does the hypothalamo-pituitary-adrenocortical (HPA) axis itself generate oscillations? The affirmative answer to this question is commonly assumed, because a regular daily rhythm of its hormones is observed. We offer another plausible explanation of the origin of this pattern: HPA just responds to an external pacemaker. A qualitative mathematical model is constructed wherein all the terms in the equations are physicochemically interpretable. Linear stability analysis shows that this system does not generate oscillations. Computer simulation yields oscillations that are the system's response to an external pulsing activator, implying that the observed pattern does not have to be an intrinsic property of this system.

Do personality traits predict post-traumatic stress?: a prospective study in civilians experiencing air attacks.

BACKGROUND: Previous studies have suggested an association between personality traits and post-traumatic stress. These studies either focused exclusively on military veterans or assessed personality traits after the traumatic event. This study investigates to what extent personality traits as assessed before the traumatic experience predict post-traumatic stress in civilians experiencing air attacks at the end of the exposure to stressful events and 1 year later. METHOD: The revised version of the NEO Personality Inventory was administered to 70 students in Belgrade, Yugoslavia. In 1999, 1 or 2 years after the assessment, all students were exposed to air attacks for 11 weeks. At the end of the attacks and 1 year later post-traumatic stress was measured on the Impact of Event Scale. RESULTS: Pre-trauma personality predicted 13% of the variance of intrusion scores 1 year after the attacks. There was no significant correlation between personality traits and subsequent avoidance scores at any point of time. CONCLUSIONS: Personality traits that are assessed before a traumatic event can, to a limited extent, predict intrusive symptoms in a non-clinical sample of civilians. Pre-trauma assessments of personality might be less strongly associated with post-traumatic stress than personality traits obtained after the traumatic event.