Endocannabinoids and Stress-Related Neurospsychiatric Disorders: A Systematic Review and Meta-Analysis of Basal Concentrations and Response to Acute Psychosocial Stress.

Background: Dysregulation of the endocannabinoid (eCB) system is implicated in various stress-related neuropsychiatric disorders (SRDs), including anxiety, depression, and post-traumatic stress disorder (PTSD). In this systematic review and meta-analysis, our objectives were to characterize circulating anandamide (AEA) and 2-arachidonoylglycerol (2-AG) concentrations at rest and in response to acute laboratory-based psychosocial stress in individuals with SRDs and without (controls). Our primary aims were to assess the effects of acute psychosocial stress on eCB concentrations in controls (Aim 1), compare baseline (prestress) eCB concentrations between individuals with SRDs and controls (Aim 2), and explore differential eCB responses to acute psychosocial stress in individuals with SRDs compared with controls (Aim 3). Methods: On June 8, 2023, a comprehensive review of the MEDLINE (PubMed) database was conducted to identify original articles meeting inclusion criteria. A total of 1072, 1341, and 400 articles were screened for inclusion in Aims 1, 2, and 3, respectively. Results: Aim 1, comprised of seven studies in controls, revealed that most studies reported stress-related increases in AEA (86%, with 43% reporting statistical significance) and 2-AG (83%, though none were statistically significant except for one study in saliva). However, meta-analyses did not support these patterns (p's>0.05). Aim 2, with 20 studies, revealed that most studies reported higher baseline concentrations of both AEA (63%, with 16% reporting statistical significance) and 2-AG (60%, with 10% reporting statistical significance) in individuals with SRDs compared with controls. Meta-analyses confirmed these findings (p's<0.05). Aim 3, which included three studies, had only one study that reported statistically different stress-related changes in 2-AG (but not AEA) between individuals with PTSD (decrease) and controls (increase), which was supported by the meta-analysis (p<0.001). Meta-analyses showed heterogeneity across studies and aims (I2=14-97%). Conclusion: Despite substantial heterogeneity in study characteristics, samples, and methodologies, consistent patterns emerged, including elevated baseline AEA and 2-AG in individuals with SRDs compared with controls, as well as smaller stress-related increases in 2-AG in individuals with SRDs compared with controls. To consider eCBs as reliable biomarkers and potential intervention targets for SRDs, standardized research approaches are needed to clarify the complex relationships between eCBs, SRDs, and psychosocial stress.

Preferences for virtual versus in-person mental and physical healthcare in Canada: a descriptive study from a cohort of youth and their parents enriched for severe mental illness.

BACKGROUND: Virtual care may improve access to healthcare and may be well suited to digitally connected youth, but experts caution that privacy and technology barriers could perpetuate access inequities. Success of virtual care will depend on its alignment with patient preferences. However, information on preferences for virtual and in-person healthcare is missing, especially for youth. We sought to quantify preferences for and barriers to virtual versus in-person mental and physical healthcare in youth and their parents, including in vulnerable segments of the population such as families with a parent with severe mental illness (SMI). METHODS: Participants were 219 youth and 326 parents from the Families Overcoming Risks and Building Opportunities for Wellbeing cohort from Canada, of which 61% of youth had at least one parent with SMI. Participants were interviewed about healthcare preferences and access to privacy/technology between October 2021 and December 2022. RESULTS: Overall, youth reported a preference for in-person mental (66.6%) and physical healthcare (74.7%) versus virtual care or no preference, and to a somewhat lesser degree, so did their parents (48.0% and 53.9%). Half of participants reported privacy/technology barriers to virtual care, with privacy being the most common barrier. Preferences and barriers varied as a function of parent SMI status, socioeconomic status and rural residence. CONCLUSIONS: The majority of youth and parents in this study prefer in-person healthcare, and the preference is stronger in youth and in vulnerable segments of the population. Lack of privacy may be a greater barrier to virtual care than access to technology.

Depressive symptoms in youth before and during the COVID-19 pandemic: longitudinal investigation of patterns dependent on age, sex, and family history of mental illness.

BACKGROUND: Cross-sectional studies report high levels of depressive symptoms during the COVID-19 pandemic, especially in youth and females. However, longitudinal research comparing depressive symptoms before and during the pandemic is lacking. Little is known about how the pandemic affected individuals with familial history of mental illness. The present study examines the impact of the pandemic on youth depressive symptoms, including offspring of parents with major mood and psychotic disorders. METHODS: Between March 2018 and February 2020, we measured depressive symptoms in 412 youth aged 5-25 years. We measured depressive symptoms again in 371 (90%) of these youth between April 2020 and May 2022. Two thirds (249) participants had a biological parent with a major mood or psychotic disorder. We tested the effect of the pandemic by comparing depression symptoms before and after March 2020. We examined age, sex, and family history as potential moderators. RESULTS: We found an overall small increase in youth depressive symptoms (b = 0.07, 95% CI -0.01 to 0.15, p = 0.062). This was driven by an increase in female youth without familial history of mental illness (b = 0.35, 95% CI 0.14 to 0.56, p = 0.001). There was no change in depressive symptoms among offspring of parents with mental illness or males. CONCLUSIONS: Our results provide reassurance about the wellbeing of children of parents with mental illness during a period of restricted access to resources outside the family. Rather than increasing symptoms in established risk groups, the pandemic led to a redistribution of depression burden towards segments of the youth population that were previously considered to be low-risk.

Relation of hippocampal volume and SGK1 gene expression to treatment remission in major depression is moderated by childhood maltreatment: A CAN-BIND-1 report.

Preclinical research implicates stress-induced upregulation of the enzyme, serum- and glucocorticoid-regulated kinase 1 (SGK1), in reduced hippocampal volume. In the current study, we tested the hypothesis that greater SGK1 mRNA expression in humans would be associated with lower hippocampal volume, but only among those with a history of prolonged stress exposure, operationalized as childhood maltreatment (physical, sexual, and/or emotional abuse). Further, we examined whether baseline levels of SGK1 and hippocampal volume, or changes in these markers over the course of antidepressant treatment, would predict treatment outcomes in adults with major depression [MDD]. We assessed SGK1 mRNA expression from peripheral blood, and left and right hippocampal volume at baseline, as well as change in these markers over the first 8 weeks of a 16-week open-label trial of escitalopram as part of the Canadian Biomarker Integration Network in Depression program (MDD [n = 161] and healthy comparison participants [n = 91]). Childhood maltreatment was assessed via contextual interview with standardized ratings. In the full sample at baseline, greater SGK1 expression was associated with lower hippocampal volume, but only among those with more severe childhood maltreatment. In individuals with MDD, decreases in SGK1 expression predicted lower remission rates at week 16, again only among those with more severe maltreatment. Decreases in hippocampal volume predicted lower week 16 remission for those with low childhood maltreatment. These results suggest that both glucocorticoid-related neurobiological mechanisms of the stress response and history of childhood stress exposure may be critical to understanding differential treatment outcomes in MDD. ClinicalTrials.gov: NCT01655706 Canadian Biomarker Integration Network for Depression Study.

Anxious arousal predicts within-person changes in hippocampal volume in adults with a history of childhood maltreatment: A CAN-BIND4 report.

Childhood maltreatment (CM) is a strong transdiagnostic risk factor for future psychopathology. This risk is theorized to emerge partly because of glucocorticoid-mediated atrophy in the hippocampus, which leaves this area sensitive to further volume loss even through adulthood in the face of future stress and the emergence of psychopathology. This proof-of-principle study examines which specific dimensions of internalizing psychopathology in the context of a CM history are associated with decreases in hippocampal volume over a 6-month period. This study included 80 community-recruited adults (ages 18-66 years, 61.3% women) oversampled for a lifetime history of internalizing psychopathology. At baseline and a naturalistic 6-month follow-up, the symptom dimensions of the tripartite model (anxious arousal, anhedonic depression, and general distress) were assessed by self-report. Hippocampal volume was derived through T1-weighted magnetic resonance imaging scanning segmented via the volBrain HIPS pipeline. CM severity was determined via a semistructured, contextual interview with independent ratings. We found that higher levels of anxious arousal predicted decreases in hippocampal volume over time in those with greater severity of CM but were associated at a trend with increases in hippocampal volume over time in those with lower severity of maltreatment. Findings were specific to anxious arousal and the CA1 subregion of the hippocampus. These novel results suggest that for individuals with a history of CM, transdiagnostic interventions that target and reduce psychological and physiological arousal may result in the preservation of hippocampal structure and, thus, improvements in cognitive and emotional regulation in the face of stress. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Resilience to substance use disorder following childhood maltreatment: association with peripheral biomarkers of endocannabinoid function and neural indices of emotion regulation.

Childhood maltreatment (CM) is a risk factor for substance use disorders (SUD) in adulthood. Understanding the mechanisms by which people are susceptible or resilient to developing SUD after exposure to CM is important for improving intervention. This case-control study investigated the impact of prospectively assessed CM on biomarkers of endocannabinoid function and emotion regulation in relation to the susceptibility or resilience to developing SUD. Four groups were defined across the dimensions of CM and lifetime SUD (N = 101 in total). After screening, participants completed two experimental sessions on separate days, aimed at assessing the behavioral, physiological, and neural mechanisms involved in emotion regulation. In the first session, participants engaged in tasks assessing biochemical (i.e., cortisol, endocannabinoids), behavioral, and psychophysiological indices of stress and affective reactivity. During the second session, the behavioral and brain mechanisms associated with emotion regulation and negative affect were investigated using magnetic resonance imaging. CM-exposed adults who did not develop SUD, operationally defined as resilient to developing SUD, had higher peripheral levels of the endocannabinoid anandamide at baseline and during stress exposure, compared to controls. Similarly, this group had increased activity in salience and emotion regulation regions in task-based measures of emotion regulation compared to controls, and CM-exposed adults with lifetime SUD. At rest, the resilient group also showed significantly greater negative connectivity between ventromedial prefrontal cortex and anterior insula compared to controls and CM-exposed adults with lifetime SUD. Collectively, these peripheral and central findings point to mechanisms of potential resilience to developing SUD after documented CM exposure.

The Differential Relation of Emotional, Physical, and Sexual Abuse Histories to Antidepressant Treatment Remission and Persistence of Anhedonia in Major Depression: A CAN-BIND-1 Report.

OBJECTIVE: Childhood maltreatment is a potent enviromarker of risk for poor response to antidepressant medication (ADM). However, childhood maltreatment is a heterogeneous construct that includes distinct exposures that have distinct neurobiological and psychological correlates. The purpose of the current study is to examine the differential associations of emotional, physical, and sexual maltreatment to ADM outcome and to examine the unique role of anhedonia in driving poor response in patients with specific maltreatment histories. METHODS: In a multicentre clinical trial of major depression, 164 individuals were assessed for childhood emotional, physical, and sexual maltreatment with a contextual interview with independent, standardized ratings. All individuals received 8 weeks of escitalopram, with nonresponders subsequently also receiving augmentation with aripiprazole, with outcomes measured with depression rating scales and an anhedonia scale. RESULTS: Greater severity of emotional maltreatment perpetrated by the mother was a significant and direct predictor of lower odds of week 16 remission (odds ratio [OR] = 1.68, P = 0.02). In contrast, the relations of paternal-perpetrated emotional maltreatment and physical maltreatment to week 16 remission were indirect, mediated through greater severity of anhedonia at week 8. CONCLUSIONS: We identify emotional maltreatment as a specific early exposure that places patients at the greatest risk for nonremission following pharmacological treatment. Further, we suggest that anhedonia is a key symptom domain driving nonremission in patients with particular maltreatment histories.

Cortisol reactivity to stress predicts behavioral responsivity to reward moderation by sex, depression, and anhedonia.

Depression is associated with blunted reactivity to acute stress, as well as blunted responsivity to rewards. However, the extent to which responses to stress are associated with responses to reward in individuals meeting criteria for a depressive disorder is unknown. The goal of this study was to examine the relation of responses to stress and reward, and to determine if this relation is moderated by depression diagnosis, anhedonia, and sex. Participants included 114 adults (68 depressed, 46 non-depressed; 75% women) recruited from the community. Stress reactivity was operationalized as the total salivary cortisol output to the Trier Social Stress Test (TSST; Kirschbaum et al., 1993). Response bias to monetary reward was assessed following the TSST recovery period with a probabilistic reward task (PRT; Pizzagalli et al., 2005). In men only, total cortisol output during the TSST was more strongly positively associated with response bias to reward across the three blocks of the PRT. In addition, among depressed participants with high levels of anhedonia, higher cortisol output during the TSST was significantly associated with higher overall response bias to reward. We suggest that in men, the stress and reward systems may both respond quickly, and resolve rapidly, in the face of acute stress. Further, in depression, our findings suggest that anhedonia may represent a specific phenotype in which the stress and reward systems are particularly tuned together.

Randomized controlled trial of bikram yoga and aerobic exercise for depression in women: Efficacy and stress-based mechanisms.

BACKGROUND: The current study presents a randomized controlled 8-week trial of Bikram yoga, aerobic exercise, and waitlist for depression. Bikram yoga was chosen specifically for its standardized nature. Further, we examined changes in three stress-related constructs-perceived stress, rumination, and mindfulness-as mediators of antidepressant effects. METHOD: Fifty-three women (age 18-65; 74% White) with a unipolar depressive disorder were randomly assigned to one of the three conditions. Response was defined as >50% reduction on the Hamilton Rating Scale for Depression (HAM-D). Remission was defined as no longer meeting criteria for depression and a HAM-D ≤ 7. Self-reported perceived stress, rumination, and mindfulness were assessed weekly. RESULTS: In the intention-to-treat sample (n = 53), response rates were significantly higher in the Bikram yoga (61.1%; χ2 = 10.48, p = .001) and aerobic exercise (60.0%; χ2 = 10.44, p = .001) conditions relative to waitlist (6.7%). In the completer sample (n = 42), 73.3% (χ2 = 11.41, p = .001) of women in yoga and 80.0% (χ2 = 13.72, p < .001) in exercise achieved response compared to 8.3% in waitlist. Reductions in rumination significantly mediated HAM-D change for both active treatments, and mindful acceptance was a partial mediator in the exercise condition. LIMITATIONS: The sample was small in size, consisted of women only, and was ethnically homogenous. Inter-rater reliability was not assessed, aerobic exercise was not standardized, and mediators were assessed by self-report. CONCLUSIONS: Bikram yoga showed descriptively similar efficacy to aerobic exercise and both may work, in part, by helping individuals interrupt negative thinking.

Childhood maltreatment and the clinical characteristics of major depressive disorder in adolescence and adulthood.

Childhood maltreatment is widely implicated as the strongest developmental risk factor for depression onset. The current research is novel in examining the fine-grained associations of childhood emotional versus physical versus sexual maltreatment to indices of the severity, course, and presence of anxiety and trauma-related psychopathology in depression. An amalgamation across 6 previous investigations resulted in a sample of 575 adolescents and adults (76% female; age range 12-70, M = 27.88, SD = 13.58). All participants were in a current episode of a unipolar depressive disorder. Retrospective reports of childhood maltreatment were assessed using a rigorous contextual interview with independent, standardized ratings. Higher levels of emotional maltreatment and/or sexual maltreatment emerged as significantly associated with greater depression severity, number of previous episodes, and risk for posttraumatic stress disorder (PTSD), and were significantly more strongly associated with these characteristics than was physical maltreatment. Further, emotional maltreatment perpetrated by mothers was significantly associated with depression severity and history, whereas emotional maltreatment perpetrated by fathers was significantly associated with a greater risk of PTSD. These latter results suggest that prevention and intervention efforts may need to focus on the unique roles of mothers versus fathers on the development of depressive- versus threat-related psychopathology, respectively. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Maternal- versus paternal-perpetrated maltreatment and risk for sexual and peer bullying revictimization in young women with depression.

BACKGROUND: Childhood maltreatment is one of the strongest predictors of sexual and peer bullying re-victimization. However, it is not clear which types of maltreatment are associated with the greatest risk. OBJECTIVE: The current study examined the differential relations of maternal- versus paternal-perpetrated emotional maltreatment, neglect, and physical maltreatment, as well as sexual maltreatment, to sexual victimization and peer bullying victimization outside the home. It was hypothesized that paternal-perpetrated emotional maltreatment would be the strongest predictor of later sexual and peer bullying victimization, and that sexual maltreatment would predict sexual re-victimization. PARTICIPANTS AND SETTING: Participants included data from 263 adolescent and young adult women who had previously taken part in one of three larger studies conducted in an academic research setting investigating the relation between stress and depression. All participants had been recruited from the wider community or clinician referral and met criteria for a unipolar depressive disorder. METHODS: Psychiatric diagnoses were assessed with a structured diagnostic interview. Childhood maltreatment and victimization were assessed retrospectively with a semi-structured contextual interview that includes standardized ratings. RESULTS: Paternal-perpetrated emotional abuse was the only maltreatment type that was independently associated with sexual (OR = 3.09, p = .004) and peer bullying (OR = 1.41, p = .05) re-victimization over other forms of maltreatment and indicators of depression severity. CONCLUSIONS: These findings provide an important foundation for future research examining the mechanisms driving the relation between father's hostility, criticism, and rejection and daughters' revictimization that can ultimately provide targets for prevention in girls at highest risk.

Serotonin and Dopamine Gene Variation and Theory of Mind Decoding Accuracy in Major Depression: A Preliminary Investigation.

Theory of mind-the ability to decode and reason about others' mental states-is a universal human skill and forms the basis of social cognition. Theory of mind accuracy is impaired in clinical conditions evidencing social impairment, including major depressive disorder. The current study is a preliminary investigation of the association of polymorphisms of the serotonin transporter (SLC6A4), dopamine transporter (DAT1), dopamine receptor D4 (DRD4), and catechol-O-methyl transferase (COMT) genes with theory of mind decoding in a sample of adults with major depression. Ninety-six young adults (38 depressed, 58 non-depressed) completed the 'Reading the Mind in the Eyes task' and a non-mentalistic control task. Genetic associations were only found for the depressed group. Specifically, superior accuracy in decoding mental states of a positive valence was seen in those homozygous for the long allele of the serotonin transporter gene, 9-allele carriers of DAT1, and long-allele carriers of DRD4. In contrast, superior accuracy in decoding mental states of a negative valence was seen in short-allele carriers of the serotonin transporter gene and 10/10 homozygotes of DAT1. Results are discussed in terms of their implications for integrating social cognitive and neurobiological models of etiology in major depression.

Interactions between childhood maltreatment and brain-derived neurotrophic factor and serotonin transporter polymorphisms on depression symptoms.

This study represents the first replication of the BDNF Val66Met ⁎ 5-HTTLPR ⁎ childhood maltreatment effect on self-reported depression symptoms using a rigorous maltreatment interview. Participants included a community sample of 339 adolescents/young adults (age 12-33; 265 female). In the context of childhood neglect, among BDNF Met-carriers, s-allele carriers of 5-HTTLPR reported significantly higher depression than l/l homozygotes, whereas a differential relation of 5-HTTLPR genotype to depression was not seen among BDNF Val/Val homozygotes.

Childhood emotional and sexual maltreatment moderate the relation of the serotonin transporter gene to stress generation.

Emerging evidence suggests that the tendency to generate stressful life events may be, at least in part, genetically determined. However, the role of the early environment in shaping responses to later stressors is crucial to fully specifying biogenetic models of stress generation. The current study examined the moderating role of childhood emotional, physical, and sexual maltreatment on the relation of the serotonin-transporter-linked promoter region (5-HTTLPR) polymorphism of the serotonin transporter gene to proximal independent, dependent, and dependent-interpersonal life events. This question was tested in a cross-sectional community sample of 297 adolescents and young adults. Childhood maltreatment history and proximal life events were assessed with state-of-the-art interviews that provide independent and standardized ratings of the environmental context. Consistent with the stress generation hypothesis, individuals with the risk s-allele of the serotonin transporter gene reported significantly higher rates of dependent and dependent-interpersonal life events than those homozygous for the l-allele, but only in the context of a history of maternal emotional maltreatment or sexual maltreatment. Neither serotonin transporter gene polymorphisms or childhood maltreatment, or their interaction, were associated with reports of independent life events. The current results demonstrate the importance of considering specificity in the early environmental context when examining the relation of genetic factors to the generation of proximal stress.

Rumination and impaired cortisol recovery following a social stressor in adolescent depression.

Response styles theory promotes rumination as a central cognitive construct driving negative mood and depression, and past research suggests that at least part of the mechanism driving rumination's depressogenic effect is through inhibiting the individual's ability to shift attentional focus away from negative environmental stimuli. In the current study, we hypothesized that high trait rumination would be associated with impaired recovery of the body's biological response to psychological stress. In a community sample of depressed (n = 31) and non-depressed (n = 33) adolescents we assessed rumination and the more adaptive trait of distraction and problem-solving with the Children's Response Styles Questionnaire (CRSQ; Abela 2000), and diagnostic status was confirmed using the Child and Adolescent Schedule of Affective Disorders and Schizophrenia (K-SADS; Kaufman et al. Journal of the American Academy of Child and Adolescent Psychiatry 36:980-988, 1997). Participants completed the Trier Social Stress Test (TSST; Kirschbaum et al. Neuropsychobiology 28:76-81, 1993), and the focus of our analyses was the change in salivary cortisol concentration between peak cortisol output (25 min post-stressor) and a sample taken during the "Recovery" period 65 minutes post-stressor. Consistent with the predictions of response style theory, among the depressed adolescents only, high trait rumination was associated with delayed post-stressor cortisol recovery, whereas high trait distraction and problem-solving was associated with more rapid recovery. In contrast, response styles were not associated with cortisol recovery in the non-depressed group. These findings implicate impaired post-stress cortisol recovery as a potential mechanism underlying the pathological effect of rumination on the development and maintenance of Major Depressive Disorder (MDD).