How handling extreme C-reactive protein (CRP) values and regularization influences CRP and depression criteria associations in network analyses.

Increasingly, it has been recognized that analysis at the symptom, rather than diagnostic, level will drive progress in the field of immunopsychiatry. Network analysis offers a useful tool in this pursuit with the ability to identify associations between immune markers and individual symptoms, independent of all other variables modeled. However, investigation into how methodological decisions (i.e., including vs. excluding participants with C-reactive protein (CRP) >10 mg/L, regularized vs. nonregularized networks) influence results is necessary to establish best practices for the use of network analysis in immunopsychiatry. In a sample of 3,464 adult participants from the 2015-2016 National Health and Nutrition Examination Survey dataset, this study found consistent support for associations between CRP and fatigue and changes in appetite and some support for additional CRP-criterion associations. Methodologically, results consistently demonstrated that including individuals with CRP >10 mg/L and estimating nonregularized networks provided better estimates of these associations. Thus, we recommend considering the use of nonregularized networks in immunopsychiatry and inclusion of cases with CRP values >10 mg/L when testing the association between CRP and depression criteria, unless contraindicated by the research question being tested. Additionally, results most consistently suggest that CRP is uniquely related to fatigue and changes in appetite, supporting their inclusion in an immunometabolic phenotype of depression. Finally, these associations suggest that fatigue and changes in appetite might be particularly receptive to anti-inflammatory treatments. However, future research with more nuanced measures is necessary to parse out whether appetite increases or decreases drive this association. Further, longitudinal research is an important next step to test how these relationships manifest over time.

Acetyl-l-carnitine deficiency in patients with major depressive disorder.

The lack of biomarkers to identify target populations greatly limits the promise of precision medicine for major depressive disorder (MDD), a primary cause of ill health and disability. The endogenously produced molecule acetyl-l-carnitine (LAC) is critical for hippocampal function and several behavioral domains. In rodents with depressive-like traits, LAC levels are markedly decreased and signal abnormal hippocampal glutamatergic function and dendritic plasticity. LAC supplementation induces rapid and lasting antidepressant-like effects via epigenetic mechanisms of histone acetylation. This mechanistic model led us to evaluate LAC levels in humans. We found that LAC levels, and not those of free carnitine, were decreased in patients with MDD compared with age- and sex-matched healthy controls in two independent study centers. Secondary exploratory analyses showed that the degree of LAC deficiency reflected both the severity and age of onset of MDD. Moreover, these analyses showed that the decrease in LAC was larger in patients with a history of treatment-resistant depression (TRD), among whom childhood trauma and, specifically, a history of emotional neglect and being female, predicted the decreased LAC. These findings suggest that LAC may serve as a candidate biomarker to help diagnose a clinical endophenotype of MDD characterized by decreased LAC, greater severity, and earlier onset as well as a history of childhood trauma in patients with TRD. Together with studies in rodents, these translational findings support further exploration of LAC as a therapeutic target that may help to define individualized treatments in biologically based depression subtype consistent with the spirit of precision medicine.

Executive dysfunction in depression in adolescence: the role of inflammation and higher body mass.

BACKGROUND: There is substantial evidence that many depressed individuals experience impaired executive functioning. Understanding the causes of executive dysfunction in depression is clinically important because cognitive impairment is a substantial contributor to functional impairment. This study investigated whether elevated levels of an inflammatory cytokine [interleukin-6 (IL-6)] and/or higher body mass index (BMI) concurrently and/or prospectively accounted for the relationship between depressive symptoms and impaired executive functioning in adolescents. METHODS: A diverse, community sample of adolescents (N = 288; mean age = 16.33; 51.4% female; 59.0% African-American) completed assessments of height and weight, IL-6, depressive symptoms, and self-report/behavioral measures of executive functioning (selective attention, switching attention) and future orientation annually over 3 years. Adolescents experiencing acute illness or medical conditions that affect inflammation were excluded from analyses. Path analysis within a structural equation modeling framework simultaneously examined the concurrent and prospective relationships between BMI, IL-6, depressive symptoms, and the measures of cognitive functioning across three timepoints. RESULTS: Across all timepoints, higher BMI was prospectively associated with higher levels of IL-6 and depressive symptoms, while higher levels of IL-6 were associated with worse performance on three behavioral and self-report measures of cognitive functioning. Higher depressive symptoms also were prospectively associated with elevated IL-6 and both higher depressive symptoms and a higher BMI predicted worse future executive functioning via increased IL-6. CONCLUSIONS: More severe depressive symptoms and increased BMI may disrupt executive functioning via elevated IL-6.

Longitudinal changes of inflammatory biomarkers moderate the relationship between recent stressful life events and prospective symptoms of depression in a diverse sample of urban adolescents.

This study investigated whether longitudinal changes in inflammatory physiology moderated the relationship between recent stressful life events and subsequent depressive symptoms in adolescence. A diverse sample of adolescents representative of an urban community (N = 129; Age at baseline = 12.5 years; 48.8% female; 55.0% African American) completed measures of stressful life events, depressive symptoms, and two annual blood draws (BD1 and BD2). Controlling for inflammatory activity at BD1, depression at BD1, demographics and the time between assessments, increases in interleukin-6 (IL-6; b = 0.878, p = .007) and C-reactive protein (CRP; b = 0.252, p = .024) from BD1 to BD2 interacted with recent stressful life events before BD1 to predict severity of depressive symptoms at BD2. Similar associations were evident for IL-6 (b = 2.074, p = .040) and CRP (b = 0.919, p = .050) when considering acute stressful life events that had occurred within the two weeks before the first blood collection. More frequent stressful life events before BD1 predicted significantly more severe depressive symptoms at BD2, but only for adolescents with moderate (50th percentile) and high (84th percentile) levels of IL-6 and CRP at BD2. In conclusion, adolescents who experienced both recent stressful life events and larger increases in inflammatory activity following these stressors were at increased risk for more severe depressive symptoms after approximately one year. The findings indicate that the interaction of stress and larger changes in inflammatory activity following these stressors are prognostic risk factors for depression severity in adolescents.

A Randomized Dose-Ranging Study of Neuropeptide Y in Patients with Posttraumatic Stress Disorder.

Background: Anxiety and trauma-related disorders are among the most prevalent and disabling medical conditions in the United States, and posttraumatic stress disorder in particular exacts a tremendous public health toll. We examined the tolerability and anxiolytic efficacy of neuropeptide Y administered via an intranasal route in patients with posttraumatic stress disorder. Methods: Twenty-six individuals were randomized in a cross-over, single ascending dose study into 1 of 5 cohorts: 1.4 mg (n=3), 2.8 mg (n=6), 4.6 mg (n=5), 6.8 mg (n=6), and 9.6 mg (n=6). Each individual was dosed with neuropeptide Y or placebo on separate treatment days 1 week apart in random order under double-blind conditions. Assessments were conducted at baseline and following a trauma script symptom provocation procedure subsequent to dosing. Occurrence of adverse events represented the primary tolerability outcome. The difference between treatment conditions on anxiety as measured by the Beck Anxiety Inventory and the State-Trait Anxiety Inventory immediately following the trauma script represented efficacy outcomes. Results: Twenty-four individuals completed both treatment days. Neuropeptide Y was well tolerated up to and including the highest dose. There was a significant interaction between treatment and dose; higher doses of neuropeptide Y were associated with a greater treatment effect, favoring neuropeptide Y over placebo on Beck Anxiety Inventory score (F1,20=4.95, P=.038). There was no significant interaction for State-Trait Anxiety Inventory score. Conclusions: Our study suggests that a single dose of neuropeptide Y is well tolerated up to 9.6 mg and may be associated with anxiolytic effects. Future studies exploring the safety and efficacy of neuropeptide Y in stress-related disorders are warranted. The reported study is registered at: http://clinicaltrials.gov (ID: NCT01533519).

Toward diversification of acute stressors and precision stress research: A stage 2 Registered Report validating a reward-salient stress task in emerging adults.

Stress is one of, if not the, most ubiquitously studied risk factor across the health sciences. This is unlikely to change given that the primary drivers of mortality and disability are chronic, stress-mediated illnesses (often highly comorbid with psychopathology). We argue that an important limitation of stress research is the consistency with which the Trier Social Stress Test is used when the research questions are not specific to social stress. We advocate for precision stress research using qualitatively different stressors to facilitate exploration of how different types of stressors might differentially impact health outcomes, including psychopathology. This registered report validates a reward-salient stress task (a modified Anger Incentive Delay Task) in a sample of 101 emerging adults, over half of whom reported clinically relevant anxiety, hypo/mania, depression, and/or suicidal ideation, who participated in a study between 2020 and 2022. This task involves teaching participants a game where they can win money. Part way through, the "goal frustration" condition changes the rules such that correct responses to trials with anticipatory stimuli indicating the possibility to win money actually lose money on 56% of trials despite visual feedback indicating that responses were successful. Results consistently indicated that the Anger Incentive Delay Task successfully reduced positive emotions and motivation and increased negative emotions. The magnitude of these responses was predicted by individual differences in reward and punishment sensitivity. Given the breadth of psychopathologies that share both (a) stress and (b) reward and punishment sensitivity as risk factors, a reward-salient acute stress task is an important tool for precision psychopathology research. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Chronic inflammation is associated with worsening working memory performance: Preliminary evidence from a diverse, longitudinal cohort of adolescents and young adults.

Many depressed individuals experience cognitive difficulties that persist when depression is in remission. Inflammation is hypothesized to play a role in cognitive dysfunction in depression; however, many aspects of this relationship are not well characterized. The current study examined whether inflammation is associated with specific cognitive deficits in individuals with a history of depression and with progressively worsening working memory over time. Adolescents who participated in a prospective, longitudinal study of adolescent-onset depression were recruited to complete a follow-up cognitive assessment. The sample was comprised of 82 participants (52.4% female; 37.8% white; 42.7% low socioeconomic status) who were aged 22.61 years (SD = 1.50) at the time of the follow-up cognitive assessment. Prior to the follow-up cognitive assessment, they had completed an average of 6.24 (SD = 1.80) prior annual assessments over 6.24 years (SD = 2.08) as part of the parent longitudinal study in which C-reactive protein (CRP), depressive symptoms, and working memory were assessed repeatedly. First, using linear regression, we tested whether individuals exhibiting inflammation (CRP ≥3 mg/L) at multiple timepoints and a history of likely depression (Children's Depression Inventory ≥19) exhibited differentially worse executive functioning, episodic memory, or psychomotor speed. Second, using hierarchical linear modeling, we tested whether the combination of inflammation and likely past depression was associated with poorer working memory over time. Chronic inflammation was associated with worsening working memory over time, but no significant associations were observed in cross-sectional analyses. These preliminary data indicate that chronic inflammation may lead to progressive decline in working memory over time.

Measures of Suicidal Thoughts and Behaviors in Children and Adolescents: A Systematic Review and Recommendations for Use in Clinical and Research Settings.

Empirically supported measures of suicidal thoughts and behaviors (STBs) are needed to serve as reference outcomes for suicide risk screening tools and to monitor severity and treatment progress in children and adolescents with STBs. The present paper systematically reviewed existing measures of STBs in youth and studies evaluating their psychometric properties and clinical utility. Measures were then evaluated on reliability, validity, and clinical utility. Sixteen articles (20 independent samples) were found with psychometric data with youth samples for eight measures. Interview-based measures were found to have the strongest psychometric support and clinical utility. Significant limitations exist for all self-report measures due to inherent characteristics of these measures that cannot be remedied through additional psychometric study. There is an urgent need for the development and validation of new self-report measures of STBs, particularly for preadolescent children, sexual and gender minority youth, and racial/ethnic minority youth.

The Impact of Early and Recent Life Stress on Trajectories of Inflammatory Biomarkers in a Diverse Sample of Adolescents.

Elevated inflammatory activity is one possible pathway through which exposure to childhood adversity engenders risk for physical and psychiatric illnesses. Limited research has investigated the compounding effects of childhood and adolescent stress exposure on changes in circulating levels of inflammatory biomarkers. This study assessed whether childhood adversity interacted with chronic or acute stress during adolescence to affect the temporal trajectories of five inflammatory biomarkers across at least three blood draws in a diverse sample of adolescents (N = 134; observations = 462). Using multilevel modeling, the interaction of childhood adversity, time, and within-person variance of acute stressors significantly predicted trajectories of higher interleukin-10 levels, controlling for demographics, medication use, and body mass index. Adolescents with high levels of childhood adversity who were exposed to a higher frequency of acute stressors compared to their own average rate of stress exposure consistently had higher levels of IL-10 as they got older, but those with average and below frequency of acute stressors had decreasing trajectories of log IL-10 as they matured. The results demonstrate how events early in life shape biological responses to the adolescent environment. This study also highlights the importance of developmental timing on the body's enhanced reactivity to acute and sustained stressors following childhood adversity.

Protocol for project MIME: Motivation, inflammation, and Mood in Emerging Adults.

Background: Atypical inflammatory biology is gaining evidence as a risk factor for mood psychopathology; however, little work has attempted to integrate inflammation into extant psychosocial frameworks of risk. Recent work using secondary data analysis has investigated the possibility of an immunocognitive model of mood disorders, in which cognitive vulnerabilities (i.e., rumination on positive or negative affect) increase the effect that arousal-related characteristics (e.g., reward sensitivity) have on inflammatory biology in ways that may confer risk for depression and hypo/mania symptoms. Project MIME (Motivation, Inflammation, and Mood in Emerging Adults) was designed to test this model in the context of a novel, reward-salient stressor (the Anger Incentive Delay Task, AIDT). Methods: This NIMH-funded study will result in a dataset of approximately 100 college undergraduates from a large university in Pennsylvania, United States of America. Eligible participants are recruited from an online screener, have to be 18-22 years old, fluent in English, and successfully answer several items designed to test whether participants randomly answer questions on the screener. Eligible participants are invited to an in-person visit in which they completed the AIDT, blood draws pre- and 50 minutes post-AIDT, and self-report questionnaires. Participants also complete a set of online questionnaires two weeks after the in-person visit. Discussion: Consistent with calls from the NIH director, this study seeks to diversify the tools used in stress research by validating a novel reward-salient stressor (in contrast to the field's reliance on social stressors) with respect to affective and immunological stress reactivity. In addition to this methodological goal, Project MIME is the first study specifically designed to test the immunocognitive model of mood psychopathology. Given the integration of several malleable treatment targets (approach behavior, emotion regulation, inflammation) into this model, results from this study could inform comprehensive, flexible intervention strategies for mood disorder prevention and treatment.

Applications of psychoneuroimmunology models of toxic stress in prevention and intervention efforts across early development.

Although evidence supporting psychoneuroimmunology (PNI) models of toxic stress have emerged over the past decade, the PNI field has struggled to integrate these important findings into real-world practical applications. There is great potential for these models to reduce the societal burden of childhood adversity by facilitating early detection and prevention with those children and adolescents at greatest risk for stress-related physical and psychological disorders. But further research is needed to validate and scale developmentally appropriate interventions with specific immune and endocrine mechanism-based targets that are developmentally sensitive. The allostatic load and additive PNI models of toxic stress exposure in youth are summarized. These models highlight the importance of integrating a standardized screening of environmental and interpersonal risk factors with stable and scalable cognitive and biological markers of risk. PNI models of toxic stress illustrate the need for intervention delivery as early as possible to prevent negative health outcomes in youth and comprehensive screening efforts would facilitate the deployment of community and family level interventions. This review discusses practical applications of toxic stress models that are currently under investigation, clarifies key obstacles, such as research gaps and scalability, and provides potential solutions, including cross-disciplinary partnerships.

Self-Critical and Self-Punishment Cognitions Differentiate Those With and Without a History of Nonsuicidal Self-Injury: An Ecological Momentary Assessment Study.

The aim of this study was to examine trait, state, and temporal instability measures of self-critical and self-punishment cognitions to evaluate their respective roles in nonsuicidal self-injury (NSSI). Participants were university students with a history of NSSI (n = 64) and those with no history of NSSI (n = 59). At baseline, participants completed measures assessing history of NSSI behavior, as well as trait measures of self-criticism and self-punishment. After completion of baseline procedures, participants subsequently participated in a 10-day ecological momentary assessment protocol in which self-critical and self-punishment cognitions were assessed in real time three times daily. Employing bivariate and multivariate frameworks, our results demonstrate that both trait and state levels of self-critical and self-punishment cognitions robustly differentiate between young adults with and without a lifetime history of NSSI. The present results also confirm that the temporal instability of these cognitive states also meaningfully differentiate between groups, such that those who exhibit greater fluctuations in these cognitive states are more likely to have a history of NSSI. The current findings suggest that trait, state, and temporal instability of negative self-focused cognitions may be vulnerability factors for engagement in NSSI.

Emotional response inhibition to self-harm stimuli interacts with momentary negative affect to predict nonsuicidal self-injury urges.

The current study investigated whether impaired emotional response inhibition to self-harm stimuli is a risk factor for real-time nonsuicidal self-injury (NSSI) urges. Participants were 60 university students with a history of repetitive NSSI. At baseline, participants completed an emotional stop-signal task assessing response inhibition to self-harm stimuli. Participants subsequently completed an ecological momentary assessment protocol in which they reported negative affect, urgency, and NSSI urge intensity three times daily over a ten-day period. Impaired emotional response inhibition to self-harm stimuli did not evidence a main effect on the strength of momentary NSSI urges. However, emotional response inhibition to self-harm images interacted with momentary negative affect to predict the strength of real-time NSSI urges, after adjusting for emotional response inhibition to neutral images. Our findings suggest that emotional response inhibition deficits specifically to self-harm stimuli may pose vulnerability for increased NSSI urge intensity during real-time, state-level negative affect.

The role of reward sensitivity and childhood maltreatment in predicting nonsuicidal self-injury.

OBJECTIVE: Findings from prior research on reward sensitivity in nonsuicidal self-injury (NSSI) have been mixed. Childhood maltreatment is an independent risk factor for NSSI and for hyposensitivity to rewards. This study aimed to disentangle the role of reward sensitivity as a predictor of NSSI for those with an elevated severity of childhood maltreatment. METHOD: In a diverse undergraduate sample (N = 586), trait reward sensitivity (i.e., behavioral approach system subscales) and the severity of maltreatment were assessed as predictors of a lifetime history of NSSI. In a subset of this sample (n = 51), predictors of NSSI urge intensity were measured using ecological momentary assessment. RESULTS: Individuals with elevated maltreatment who reported less positive responsiveness to rewards were more likely to have a lifetime history of NSSI. Those with elevated maltreatment who reported a lower likelihood to approach rewards experienced more intense NSSI urges across the ten-day observation period. However, those with elevated maltreatment who reported a greater likelihood to approach rewards experienced less intense NSSI urges. CONCLUSIONS: The role of reward sensitivity as a cognitive risk factor for NSSI varies depending on childhood maltreatment history. Findings indicate that, for those with elevated maltreatment, hypersensitivity to approaching rewards may decrease risk for NSSI urges.

Trajectories of depressive symptoms through adolescence as predictors of cortical thickness in the orbitofrontal cortex: An examination of sex differences.

Previous research has found associations between orbitofrontal cortex (OFC) structure and symptoms of major depression, though specific aspects of this complex relationship remain unclear. The current study examined sex differences in the influence of individual trajectories of depressive symptoms on cortical thickness (CT) in the OFC during late adolescence. Fifty-four participants enrolled in an ongoing longitudinal study completed assessments of depression symptoms at baseline (Mage = 12.09; SD = 1.06) and at 6-month intervals through adolescence, followed by an MRI assessment (Mage = 17.34; SD = 0.98). Estimates of CT in the OFC were obtained using FreeSurfer. Multilevel modeling (MLM) analyses estimated individuals' symptom trajectories, and identified significant variability in trajectories of depressive symptoms. Trajectory estimates were extracted and included as predictors of CT in multiple regression analyses. Results did not reveal any significant main effect associations between trajectories of depression and CT in the OFC. However, sex moderated the associations between slope of depression and CT in the left OFC; the slope of depressive symptoms demonstrated significant, but opposite, associations with CT in the OFC across sexes, such that greater increases in symptoms across time were associated with reduced CT in males, but increased CT in females.

Bidirectional Associations Between Inflammatory Biomarkers and Depressive Symptoms in Adolescents: Potential Causal Relationships.

There are inconsistent findings in the literature about the directionality and magnitude of the association between inflammation and depressive symptoms. This analysis separates predictors into between-person and within-person components to gain greater clarity about this relationship. Blood samples were collected and depressive symptoms assessed in 140 adolescents (54% female, 59% Black, Mage = 16.1 years) with at least three blood draws and a total of 394 follow-up observations. Multi-level modeling indicated that the within-person effect of tumor necrosis factor alpha (TNF-α) predicted change in total depressive symptoms, suggesting a potential causal relationship. There were no significant within-person effects of total depressive symptoms on change in biomarkers. Exploratory analyses examined associations between inflammatory biomarkers and subsets of depressive symptoms. These findings inform modeling decisions that may explain inconsistencies in the extant literature as well as suggest potential causal relationships between certain proteins with significant within-person effects on depressive symptoms, and vice-versa.