Hair Cortisol and Health-Related Quality of Life in Children with Mental Disorder

Introduction Children living with mental disorder are at risk for lower health-related quality of life (HRQoL) compared to their peers. While evidence suggests that cortisol dysregulation is implicated in the onset of mental disorder, the extent to which cortisol is associated with HRQoL is largely unknown. Further, it remains unknown how comorbid physical illness may alter this relationship. This study examined whether the presence of a comorbid physical illness moderated the association between hair cortisol concentration (HCC) and HRQoL among children with mental disorder. Methods One-hundred children (4-17 years) receiving care from a pediatric hospital were recruited. The Mini International Neuropsychiatric Interview was used to measure mental disorder and the KIDSCREEN-27 to assess HRQoL. Cortisol extracted from children's hair was assayed using high-sensitivity ELISA. Multiple regression analyses tested the association between HCC and HRQoL. Results Presence of a physical illness was found to moderate the relationship between HCC and HRQoL in the domain of peers and social support [comorbidity: β = −0.57 (−0.97, −0.17); no comorbidity: β = 0.22 (−0.11, 0.55)]. Conclusion The association between HCC and HRQoL in children with mental disorder is moderated by the presence of a physical illness, such that in children with comorbid physical and mental disorder, elevated HCC is associated with lower HRQoL. Approaches that reduce stress in these children may help promote optimal well-being. More research investigating physiological stress and psychosocial outcomes in children with mental disorder, particularly those with comorbid physical illness, is needed.

Using Psychedelics With Therapeutic Intent Is Associated With Lower Shame and Complex Trauma Symptoms in Adults With Histories of Child Maltreatment

Background Child maltreatment negatively affects the formation of internal schemata of self and other during development, leading to negative adaptations in self-concept and social cognition. Clinical reports suggest the efficacy of psychedelics in treating the psychopathological sequelae of child maltreatment. Altering maladaptive schemata of self and other implicated in negative self-concept and impaired social cognition may be a central mechanism for reducing posttraumatic stress symptoms. Aims This study aims to assess whether psychedelic use moderates the relationships between child maltreatment and self-concept, social cognition, and posttraumatic stress symptoms. Method An online survey was completed by 166 participants and included measures of maltreatment exposure and severity, history of intentional therapeutic psychedelic use, posttraumatic stress symptoms, internalized shame, and facial emotion recognition. Results Child maltreatment significantly correlated with posttraumatic stress symptoms ( r = .26 and r = .20, p < .01) and internalized shame ( r = .18, p < .05). Of all maltreatment subtypes, emotional abuse and neglect most strongly correlated with complex trauma symptoms ( r = .32, p < .001) and internalized shame ( r = .31, p < .001). Participants with a history of intentional therapeutic psychedelic use reported significantly lower complex trauma symptoms ( d = 0.33, p < .05) and internalized shame ( d = 0.35, p < .05) despite similar histories of maltreatment. Differences in complex trauma symptoms ( d = 0.66, p < .01) and internalized shame ( d = 0.80, p < .001) were largest for participants with a history of more than 5 occasions of intentional therapeutic psychedelic use. A history of more than 5 occasions of intentional therapeutic psychedelic use significantly moderated the relationship between emotional abuse and neglect and complex trauma symptoms (p < .01). No associations were found between maltreatment or psychedelic use and facial emotion recognition. Conclusion These findings demonstrate that using psychedelic drugs with therapeutic intent is associated with lower levels of complex trauma symptoms and internalized shame in individuals with histories of child maltreatment. Psychedelic use may have therapeutic benefit in treating the posttraumatic sequelae of child maltreatment.

Chronic Pain is Associated With Reduced Sympathetic Nervous System Reactivity During Simple and Complex Walking Tasks: Potential Cerebral Mechanisms

Background Autonomic dysregulation may lead to blunted sympathetic reactivity in chronic pain states. Autonomic responses are controlled by the central autonomic network (CAN). Little research has examined sympathetic reactivity and associations with brain CAN structures in the presence of chronic pain; thus, the present study aims to investigate how chronic pain influences sympathetic reactivity and associations with CAN brain region volumes. Methods Sympathetic reactivity was measured as change in skin conductance level (ΔSCL) between a resting reference period and walking periods for typical and complex walking tasks (obstacle and dual-task). Participants included 31 people with (n = 19) and without (n = 12) chronic musculoskeletal pain. Structural 3 T MRI was used to determine gray matter volume associations with ΔSCL in regions of the CAN (i.e., brainstem, amygdala, insula, and anterior cingulate cortex). Results ΔSCL varied across walking tasks (main effect p = 0.036), with lower ΔSCL in chronic pain participants compared to controls across trials 2 and 3 under the obstacle walking condition. ΔSCL during typical walking was associated with multiple CAN gray matter volumes, including brainstem, bilateral insula, amygdala, and right caudal anterior cingulate cortex (p’s < 0.05). The difference in ΔSCL from typical-to-obstacle walking were associated with volumes of the midbrain segment of the brainstem and anterior segment of the circular sulcus of the insula (p’s < 0.05), with no other significant associations. The difference in ΔSCL from typical-to-dual task walking was associated with the bilateral caudal anterior cingulate cortex, and left rostral cingulate cortex (p’s < 0.05). Conclusions Sympathetic reactivity is blunted during typical and complex walking tasks in persons with chronic pain. Additionally, blunted sympathetic reactivity is associated with CAN brain structure, with direction of association dependent on brain region. These results support the idea that chronic pain may negatively impact typical autonomic responses needed for walking performance via its potential impact on the brain.

Task-Modulated Brain Activity Predicts Antidepressant Responses of Prefrontal Repetitive Transcranial Magnetic Stimulation: A Randomized Sham-Control Study

Background Prolonged intermittent theta-burst stimulation (piTBS) and repetitive transcranial magnetic stimulation (rTMS) are effective antidepressant interventions for major depressive disorder (MDD). Cognition-modulated frontal theta (frontalθ) activity had been identified to predict the antidepressant response to 10-Hz left prefrontal rTMS. However, whether this marker also predicts that of piTBS needs further investigation. Methods The present double-blind randomized trial recruited 105 patients with MDD who showed no response to at least one adequate antidepressant treatment in the current episode. The recruited patients were randomly assigned to one of three groups: group A received piTBS monotherapy; group B received rTMS monotherapy; and group C received sham stimulation. Before a 2-week acute treatment period, electroencephalopgraphy (EEG) and cognition-modulated frontal theta changes (Δfrontalθ) were measured. Depression scores were evaluated at baseline, 1 week, and 2 weeks after the initiation of treatment. Results The Δfrontalθ at baseline was significantly correlated with depression score changes at week 1 (r = −0.383, p = 0.025) and at week 2 for rTMS group (r = −0.419, p = 0.014), but not for the piTBS and sham groups. The area under the receiver operating characteristic curve for Δfrontalθ was 0.800 for the rTMS group (p = 0.003) and was 0.549 for the piTBS group (p = 0.619). Conclusion The predictive value of higher baseline Δfrontalθ for antidepressant efficacy for rTMS not only replicates previous results but also implies that the antidepressant responses to rTMS could be predicted reliably at baseline and both piTBS and rTMS could be effective through different neurobiological mechanisms.

Stress Markers for Mental States and Biotypes of Depression and Anxiety: A Scoping Review and Preliminary Illustrative Analysis

Depression and anxiety disrupt daily function and their effects can be long-lasting and devastating, yet there are no established physiological indicators that can be used to predict onset, diagnose, or target treatments. In this review, we conceptualize depression and anxiety as maladaptive responses to repetitive stress. We provide an overview of the role of chronic stress in depression and anxiety and a review of current knowledge on objective stress indicators of depression and anxiety. We focused on cortisol, heart rate variability and skin conductance that have been well studied in depression and anxiety and implicated in clinical emotional states. A targeted PubMed search was undertaken prioritizing meta-analyses that have linked depression and anxiety to cortisol, heart rate variability and skin conductance. Consistent findings include reduced heart rate variability across depression and anxiety, reduced tonic and phasic skin conductance in depression, and elevated cortisol at different times of day and across the day in depression. We then provide a brief overview of neural circuit disruptions that characterize particular types of depression and anxiety. We also include an illustrative analysis using predictive models to determine how stress markers contribute to specific subgroups of symptoms and how neural circuits add meaningfully to this prediction. For this, we implemented a tree-based multi-class classification model with physiological markers of heart rate variability as predictors and four symptom subtypes, including normative mood, as target variables. We achieved 40% accuracy on the validation set. We then added the neural circuit measures into our predictor set to identify the combination of neural circuit dysfunctions and physiological markers that accurately predict each symptom subtype. Achieving 54% accuracy suggested a strong relationship between those neural-physiological predictors and the mental states that characterize each subtype. Further work to elucidate the complex relationships between physiological markers, neural circuit dysfunction and resulting symptoms would advance our understanding of the pathophysiological pathways underlying depression and anxiety.

Emerging Therapeutics Based on the Amino Acid Neurotransmitter System: An Update on the Pharmaceutical Pipeline for Mood Disorders

Mood disorders represent a pressing public health issue and significant source of disability throughout the world. The classical monoamine hypothesis, while useful in developing improved understanding and clinical treatments, has not fully captured the complex nature underlying mood disorders. Despite these shortcomings, the monoamine hypothesis continues to dominate the conceptual framework when approaching mood disorders. However, recent advances in basic and clinical research have led to a greater appreciation for the role that amino acid neurotransmitters play in the pathophysiology of mood disorders and as potential targets for novel therapies. In this article we review progress of compounds that focus on these systems. We cover both glutamate-targeting drugs such as: esketamine, AVP-786, REL-1017, AXS-05, rapastinel (GLYX-13), AV-101, NRX-101; as well as GABA-targeting drugs such as: brexanolone (SAGE-547), ganaxolone, zuranolone (SAGE-217), and PRAX-114. We focus the review on phase-II and phase-III clinical trials and evaluate the extant data and progress of these compounds.

Biomarkers of ketamine’s antidepressant effect: a clinical review of genetics, functional connectivity, and neurophysiology

Major depressive disorder (MDD) is one of the leading causes of morbidity and all-cause mortality (including suicide) worldwide, and, unfortunately, first-line monoaminergic antidepressants and evidence-based psychotherapies are not effective for all patients. Subanesthetic doses of the N-methyl-D-aspartate receptor antagonists and glutamate modulators ketamine and S-ketamine have rapid and robust antidepressant efficacy in such treatment-resistant depressed patients (TRD). Yet, as with all antidepressant treatments including electroconvulsive therapy (ECT), not all TRD patients adequately respond, and we are presently unable to a priori predict who will respond or not respond to ketamine. Therefore, antidepressant treatment response biomarkers to ketamine have been a major focus of research for over a decade. In this article, we review the evidence in support of treatment response biomarkers, with a particular focus on genetics, functional magnetic resonance imaging, and neurophysiological studies, i.e. electroencephalography and magnetoencephalography. The studies outlined here lay the groundwork for replication and dissemination.

Sex Differences in Peritraumatic Inflammatory Cytokines and Steroid Hormones Contribute to Prospective Risk for Nonremitting Posttraumatic Stress Disorder

Women are at higher risk for developing posttraumatic stress disorder (PTSD) compared to men, yet little is known about the biological contributors to this sex difference. One possible mechanism is differential immunological and neuroendocrine responses to traumatic stress exposure. In the current prospective study, we aimed to identify whether sex is indirectly associated with the probability of developing nonremitting PTSD through pro-inflammatory markers and whether steroid hormone concentrations influence this effect. Female ( n = 179) and male ( n = 197) trauma survivors were recruited from an emergency department and completed clinical assessment within 24 h and blood samples within ∼three hours of trauma exposure. Pro-inflammatory cytokines (IL-6, IL-1[Formula: see text], TNF, IFNγ), and steroid hormone (estradiol, testosterone, progesterone, cortisol) concentrations were quantified in plasma. Compared to men, women had a higher probability of developing nonremitting PTSD after trauma ( p = 0.04), had lower pro-inflammatory cytokines and testosterone ( p’ s<0.001), and had higher cortisol and progesterone ( p’ s<0.001) concentrations. Estradiol concentrations were not different between the sexes ( p = 0.24). Pro-inflammatory cytokines were a significant mediator in the relationship between sex and probability of developing nonremitting PTSD ( p < 0.05), such that men had higher concentrations of pro-inflammatory cytokines which were associated with lower risk of nonremitting PTSD development. This effect was significantly moderated by estradiol ( p < 0.05), as higher estradiol levels in men were associated with higher pro-inflammatory cytokine concentrations and lower risk for developing nonremitting PTSD. The current results suggest that sex differences in the pro-inflammatory cytokine response to trauma exposure partially mediate the probability of developing nonremitting PTSD, and that the protective ability to mount an pro-inflammatory cytokine response in men may depend on higher estradiol levels in the aftermath of trauma exposure.

Long-term Effects of Maternal Separation on Anxiety-Like Behavior and Neuroendocrine Parameters in Adult Balb/c Mice

Introduction: Disruption of maternal care using maternal separation (MS) models has provided significant evidence of the deleterious long-term effects of early life stress. Several preclinical studies investigating MS showed multiple behavioral and biomolecular alterations. However, there is still conflicting results from MS studies, which represents a challenge for reliability and replicability of those findings. Objective: To address that, this study was conducted to investigate whether MS would affect anxiety-like behaviors using a battery of classical tasks, as well as central and peripheral stress-related biomarkers. Methods: Male Balb/c mice were exposed to MS from postnatal day (PND) 2 to 14 for 180-min per day. Two independent cohorts were performed to evaluate both baseline and anxiety-like behavior responses to MS at PND60. We performed composite scores to evaluate MS effects on anxiety and risk assessment phenotypes. Also, we assessed mRNA gene expression in the medial pre-frontal cortex (mPFC) of glucocorticoid and mineralocorticoid receptors (GR and MR) using real-time PCR and peripheral corticosterone levels (CORT) to investigate possible neurobiological correlates to anxiety behaviors. Results: We found increased anxiety-like behavior and decreased risk assessment and exploratory behaviors in MS mice. The animals exposed to MS also presented a decrease in MR mRNA expression and higher levels of CORT compared to controls. Conclusions: Our findings reinforce the body of evidence suggesting that long-term MS induces effects on anxiety and risk assessment phenotypes following the exposure to a standardized MS protocol. Moreover, MS affected the expression of MR mRNA and induced significant changes on CORT response. This data highlights that the reprograming MS effects on HPA axis could be mediate by MR gene expression in mPFC and chronic overactivity of peripheral CORT levels.