Toward a dynamic immunopsychiatry.

In this article, we briefly clarify several points regarding immunopsychiatry. In particular, we argue that higher density data and a greater focus on temporal dynamics are both important, and that studies incorporating these features have the potential to greatly advance the field. We also respond to recent comments made on our original article on this topic (Moriarity and Slavich, 2023), including the contention that our perspective on immunopsychiatry is reductionistic. To the contrary, we believe that strong immunopsychiatry studies are highly integrative and include data from multiple major levels of analysis to form a more complete picture of how processes that are relevant for mental health and behavior emerge and dynamically change over time in relation to one another.

The future is dynamic: A call for intensive longitudinal data in immunopsychiatry.

The long-term value of immunopsychiatry will be based on its ability to translate basic science into effective clinical interventions. In this article, we discuss a key obstacle to achieving this important translational goal-namely, the preponderance of studies that are cross-sectional, or that have months-to-years long follow-up periods. Immunopsychiatric processes such as stress, inflammation, and depression symptoms are inherently dynamic and fluctuate over hours, days, and weeks. This fact suggests that higher-density data collection with only days between measurements is necessary to capture-with adequate resolution-the actual dynamics of these systems, determine optimal time lags with which to observe associations between variables of interest, and maximize the translational potential of these data. To illustrate these points, we use pilot data from our own intensive longitudinal immunopsychiatric study. We then conclude by making several recommendations for future research. By learning how to better use existing data for dynamically informative studies as well as collecting intensive longitudinal data, we believe immunopsychiatry will be much better positioned to advance our causal understanding of the interplay between the immune system and health.

Incorporating causal inference perspectives into psychoneuroimmunology: A simulation study highlighting concerns about controlling for adiposity in immunopsychiatry.

Psychoneuroimmunology and immunopsychiatry are quickly approaching a critical point where the clinical translatability of their evidence base will be tested. To maximize chances for translational success, we believe researchers must adopt causal inference techniques that augment the causal relevance of estimates given theorized causal structures. To illustrate the utility of incorporating causal inference perspectives into psychoneuroimmunology, we applied directed acyclic graphs and a combination of empirical and simulated data to demonstrate the consequences of controlling for adiposity when testing the association between inflammation and depression under the plausible causal structure of increases in adipose tissue leading to greater inflammation that in turn promotes depression. Effect size estimates were pulled from a dataset combining the Midlife in the United States 2 (MIDUS-2) and MIDUS Refresher datasets. Data were extracted and used to simulate data reflecting an adiposity â†’ inflammation â†’ depression causal structure. Next, a Monte Carlo simulation study with 1,000 iterations and three sample size scenarios (Ns = 100, 250, and 500) was conducted testing whether controlling for adiposity when estimating the relation between inflammation and depression influenced the precision of this estimate. Across all simulation scenarios, controlling for adiposity reduced precision of the inflammation â†’ depression estimate, suggesting that researchers primarily interested in quantifying inflammation â†’ depression associations should not control for adiposity. This work thus underscores the importance of incorporating causal inference approaches into psychoneuroimmunological research.

Multi-omics approaches in psychoneuroimmunology and health research: Conceptual considerations and methodological recommendations.

The field of psychoneuroimmunology (PNI) has grown substantially in both relevance and prominence over the past 40 years. Notwithstanding its impressive trajectory, a majority of PNI studies are still based on a relatively small number of analytes. To advance this work, we suggest that PNI, and health research in general, can benefit greatly from adopting a multi-omics approach, which involves integrating data across multiple biological levels (e.g., the genome, proteome, transcriptome, metabolome, lipidome, and microbiome/metagenome) to more comprehensively profile biological functions and relate these profiles to clinical and behavioral outcomes. To assist investigators in this endeavor, we provide an overview of multi-omics research, highlight recent landmark multi-omics studies investigating human health and disease risk, and discuss how multi-omics can be applied to better elucidate links between psychological, nervous system, and immune system activity. In doing so, we describe how to design high-quality multi-omics studies, decide which biological samples (e.g., blood, stool, urine, saliva, solid tissue) are most relevant, incorporate behavioral and wearable sensing data into multi-omics research, and understand key data quality, integration, analysis, and interpretation issues. PNI researchers are addressing some of the most interesting and important questions at the intersection of psychology, neuroscience, and immunology. Applying a multi-omics approach to this work will greatly expand the horizon of what is possible in PNI and has the potential to revolutionize our understanding of mind-body medicine.

Unconsidered issues of measurement noninvariance in biological psychiatry: A focus on biological phenotypes of psychopathology.

There is increasing appreciation that certain biological processes may not be equally related to all psychiatric symptoms in a given diagnostic category. Research on the biological phenotyping of psychopathology has begun examining the etiological and treatment implications of identified biotypes; however, little attention has been paid to a critical methodological implication of these results: measurement noninvariance. Measurement invariance is the ability of an instrument to measure the same construct, the same way, across different people, or across different time points for the same individual. If what a measure quantifies differs across different people (e.g., those with or without a particular biotype) or time points, then it is invalid to directly compare means on that measure. Using a running example of inflammatory phenotypes of depression, we first describe the biological phenotyping of psychopathology. Second, we discuss three types of measurement invariance. Third, we demonstrate how differential biology-symptom associations invariably creates measurement noninvariance using a theoretical example and simulated data (for which code is provided). We also show how this issue can lead to false conclusions about the broader diagnostic construct. Finally, we provide several suggestions for addressing these important issues to help advance the field of biological psychiatry.

Inflammatory phenotype of depression symptom structure: A network perspective.

BACKGROUND: There has been increasing interest in classifying inflammatory phenotypes of depression. Most investigations into inflammatory phenotypes only have tested whether elevated inflammation is associated with elevated levels of depression symptoms, or risk for a diagnosis. This study expanded the definition of phenotype to include the structure of depression symptoms as a function of inflammation. METHODS: Network models of depression symptoms were estimated in a sample of 4157 adults (mean age = 47.6, 51% female) from the 2015-2016 National Health and Nutrition Examination Survey (NHANES). Analyses included comparisons of networks between those with elevated (C-reactive protein (CRP) values ≥ 3.0 mg/L; N = 1696) and non-elevated CRP (N = 2841) as well as moderated network models with CRP group status and raw CRP values moderating the associations between depression symptoms. RESULTS: Differences emerged at all levels of analysis (global, symptom-specific, symptom-symptom associations). Specifically, the elevated CRP group had greater symptom connectivity (stronger total associations between symptoms). Further, difficulty concentrating and psychomotor difficulties had higher expected influence (concordance with other symptoms) in the elevated CRP group. Finally, there was evidence that several symptom-symptom associations were moderated by CRP. CONCLUSIONS: This study provides consistent evidence that the structure of depression symptoms varies as a function of CRP levels. Greater symptom connectivity might contribute to why elevated CRP is associated with treatment-resistant depression. Additionally, differences in symptom structure might highlight different maintenance mechanisms and treatment targets for individuals with compared to those without elevated CRP. Finally, differences in symptom structure as a function of CRP highlight a potential misalignment of standard depression measures (the structure of which are evaluated on groups unselected for CRP levels) and the presentation of depression symptoms in those with elevated CRP.

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.

Goal-striving tendencies moderate the relationship between reward-related brain function and peripheral inflammation.

Inflammation is associated with both lower and higher activity in brain regions that process rewarding stimuli. How can both low and high sensitivity to rewards be associated with higher inflammation? We propose that one potential mechanism underlying these apparently conflicting findings pertains to how people pursue goals in their environment. This prediction is based on evidence that both an inability to disengage from unattainable goals and low interest in and pursuit of important life goals are associated with poor health outcomes, including inflammation. Accordingly, this study examined the relationship between reward-related brain function and peripheral inflammation among individuals with different levels of ambitious goal-striving tendencies. Eighty-three participants completed an ambitious goal-striving tendency measure, an fMRI Monetary Incentive Delay task assessing orbitofrontal cortex (OFC) and nucleus accumbens (NAc) activation during reward anticipation and outcome, and a venous blood draw to assess the inflammatory biomarkers interleukin (IL)-6, IL-8, tumor necrosis factor-alpha, and C-reactive protein, from which we computed an inflammation composite score. We observed a reward anticipation by goal-striving interaction on inflammation, such that high OFC and NAc activation to reward anticipation (but not outcome) were associated with more inflammation, among high goal-striving individuals. By contrast, low NAc activation during reward anticipation (but not outcome) was associated with more inflammation, among low goal-striving individuals. The current study provides further evidence that both blunted and elevated reward function can be associated with inflammation. It also highlights the role that goal-striving tendencies may play in moderating the relationship between neural reward anticipation and inflammation.

Concurrent and Longitudinal Associations of Sex and Race with Inflammatory Biomarkers during Adolescence.

Chronic, systemic inflammation is implicated in physical and mental health; little is known about whether sex and racial differences detected in adulthood are observed during adolescence or about normative changes occurring during adolescence. This longitudinal, United States-based study examined four biomarkers of systemic inflammation [C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and IL-8) in 315 adolescents (51% female; 58% black; baseline age = 16.49 years (SD = 1.56; range: 12.14-21.28)] at three timepoints. Notable results included: general decline in inflammatory biomarkers in older adolescents, lower levels of TNF-α/IL-8 in black adolescents, elevated CRP/IL-6 in females, and especially higher levels of IL-6 in black, female adolescents. Implications are discussed, particularly the potential health implications of elevated IL-6 in black females.

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.

Pubertal Status and Age are Differentially Associated with Inflammatory Biomarkers in Female and Male Adolescents.

A better understanding of the maturational correlates of inflammatory activity during adolescence is needed to more appropriately study both normal and abnormal development. Inflammation is the immune system's first response to infection, injury, or psychological stress, and it has been shown to be elevated in individuals with both physical and psychological conditions. This study examined unique associations between (1) pubertal status and inflammatory biomarkers, and (2) age and inflammatory biomarkers, and whether these relationships differed by sex in a diverse sample of 155 adolescents (54.2% female, 45.8% male; Mage = 16.22) from a northeastern city in the US. A more advanced pubertal status was uniquely associated with lower levels of tumor necrosis factor alpha (TNF-α) and interleukin-8 (IL-8). Chronological age was uniquely associated with lower IL-8 levels. The association between pubertal status and C-reactive protein (CRP) levels differed by sex: more mature females had higher CRP, whereas pubertal status and CRP were not significantly associated in males. These findings highlight an important relation between pubertal development and inflammatory activity during adolescence.

Reward Sensitivity, Cognitive Response Style, and Inflammatory Response to an Acute Stressor in Adolescents.

Inflammation is gaining support as a biological mediator between stress and many negative outcomes that have heightened risk during adolescence (e.g., mood disorders). Thus, an important line of inquiry is evaluating whether risk factors for mood psychopathology also are associated with heightened inflammatory responses to stress during this developmental period. Two prominent risk factors that interact to predict mood psychopathology are reward sensitivity and perseverative cognitive response styles, which also have been associated with heightened inflammatory proteins. These factors could influence inflammation by synergistically amplifying stress reactivity. Ninety-nine late adolescents (Mage = 18.3 years, range = 15.6-21.9 years) completed measures of reward sensitivity, cognitive response style, and blood draws before and 60-min after a modified Trier Social Stress Task to determine levels of inflammation. Higher reward drive interacted with more perseverative response style ratios (rumination relative to distraction + problem-solving) to predict larger increases in interleukin-6 (a proinflammatory protein). Follow-up analyses found that reward drive interacted with all three components of the ratio to predict change in interleukin-6. Thus, these results suggest that high reward drive and perseverative cognitive response styles are associated with increased inflammatory response to social stress in adolescents, a potential physiological mechanism linking these risk factors to mood psychopathology during this developmental period.

Unique and predictive relationships between components of cognitive vulnerability and symptoms of depression.

BACKGROUND: Cognitive vulnerability theories of depression outline multiple, distinct inferential biases constitutive of cognitive vulnerability to depression. These include attributing negative events to internal, stable, and global factors, assuming that negative events will lead to further negative consequences, and inferring that negative events reflect negative characteristics about the self. Extant research has insufficiently examined these biases as distinct, limiting our understanding of how the individual cognitive vulnerability components interrelate and confer risk for depression symptoms. Thus, we conducted exploratory network analyses to examine the relationships among the five components of negative cognitive style and explore how components may differentially relate to depressive symptoms in adolescents. METHODS: Participants completed measures of negative cognitive style twice over a two-year period. We estimated Graphical Gaussian Models using contemporaneous data and computed a cross-lagged panel network using temporal data from baseline and 2-year follow-up. RESULTS: Results reveal interesting structural dynamics among facets of negative cognitive style and depressive symptoms. For example, results point to biases towards stable and future-oriented inferences as highly influential among negative cognitive style components. The temporal model revealed the internal attributions component to be heavily influenced by depressive symptoms among adolescents, whereas stable and global attributions most influenced future symptoms. CONCLUSIONS: This study presents novel approaches for investigating cognitive style and depression. From this perspective, perhaps more precise predictions can be made about how cognitive risk factors will lead to the development or worsening of psychopathology.

Immunocognitive Model of Depression Secondary to Anxiety in Adolescents.

There is evidence that anxiety precedes the onset of depression and that rumination contributes to this risk pathway in adolescence. This study examined inflammatory biomarkers as mediators in a risk model of depressive symptoms secondary to anxiety symptoms among adolescents who ruminate. A sample of 140 adolescents (52% female, 54% African American, 40% Caucasian, 6% biracial, mean age at T1 = 16.5 years, SD = 1.2 years) provided blood samples on two visits (T1 and T2; mean time between T1 and T2 = 13.5 months, SD = 5.9 months). Self-report anxiety, depression, and rumination measures were given at T1 and the depression measure was given again at a third visit (T3, mean months since T1 = 26.0 months, SD = 9.0 months). Higher anxiety predicted more interleukin-6, but not more C-reactive protein, for adolescents with high levels of rumination. Moderated mediation analyses (N for analysis after removing cases with missing data and outliers = 86) indicated that interleukin-6, but not C-reactive protein, at T2 mediated the relationship between anxiety symptoms at T1 and depressive symptoms at T3, conditional on rumination. Anxiety and rumination interacted such that, as rumination increased, anxiety predicted greater inflammation and depressive symptoms. These results demonstrate that established cognitive vulnerabilities for the development of depressive symptoms secondary to anxiety symptoms in adolescence might indirectly operate though biological mechanisms such as inflammation. In addition to highlighting risk factors and potential treatment targets for depression, this study suggests a potential biological mechanism underlying the effects of psychotherapies that reduce rumination on negative affect (e.g., cognitive behavioral therapy).

How is inflammation biology truly associated with depression in patients with stable coronary heart disease?: Insights from the heart and Soul study.

Depression is known to be associated with inflammation among patients with established coronary heart disease (CHD), but it is unclear whether this is due to individual depression symptoms or to the broader construct of depression. We addressed this gap by using moderated non-linear factor analysis (MNLFA) to determine the extent that inflammation is associated with latent depression and/or individual symptoms in this patient group. We evaluated 1,024 outpatients with stable CHD from the baseline cross-sectional data of the Heart and Soul Study. Depression was assessed using the 9-item Patient Health Questionnaire, while inflammation was evaluated via C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and monocyte chemoattractant protein-1 (MCP-1) levels. MNLFA is based on the concept of model parameter moderation with regard to individual characteristics. Using the MNLFA approach, we simultaneously tested for differences in (1) latent depression, (2) individual depression items, and (3) the factor loading of the item on latent depression as a function of inflammatory markers, with and without covariate adjustment. Higher TNF-α levels were associated with both higher levels of a latent depression factor and greater endorsement of an individual symptom (appetite changes). Increased CRP levels were significantly associated with greater appetite changes, lower concentration difficulty, and greater fatigue. Elevated IL-6 levels were only related to greater fatigue, while increased MCP-1 levels were linked to greater sleep disturbance. After adjusting for covariates, some associations became insignificant. Inflammatory markers were not consistent predictors of factor loadings. This study represents the initial step to discussing how inflammation biology is truly related to depression among patients with established CHD.

Longitudinal Measurement Invariance of the ASEBA Youth/Adult Self-Reports Across the Transition From Adolescence to Adulthood.

The ability to quantify within-person changes in mental health is central to the mission of clinical psychology. Typically, this is done using total or mean scores on symptom measures; however, this approach assumes that measures quantify the same construct, the same way, each time the measure is completed. Without this quality, termed longitudinal measurement invariance, an observed difference between timepoints might be partially attributable to changing measurement properties rather than changes in comparable symptom measurements. This concern is amplified in research using different forms of a measure across developmental periods due to potential differences in reporting styles, item-wording, and developmental context. This study provides the strongest support for the longitudinal measurement invariance of the Anxiety Scale, Depression/Affective Problems: Cognitive Subscale, and the Attention Deficit Hyperactivity Disorder (ADHD) Scale; moderate support for the Depression/Affective Problems Scale and the Somatic Scale, and poor support for the Depression/Affective Problems: Somatic Symptoms Subscale of the Dutch Achenbach System of Empirically Based Assessment Youth Self-Report and Adult Self-Report in a sample of 1,309 individuals (N = 1,090 population-based, N = 219 clinic-based/referred to an outpatient clinic before age 11 years) across six waves of data (mean ages = 11 years at Wave 1 and 26 years at Wave 6).

Characterizing the hierarchical depression phenotype in sexually diverse individuals.

INTRODUCTION: Sexual diverse individuals are at high risk for internalizing psychopathologies, such as depression. Understanding how symptom profiles of heterogeneous psychiatric disorders such as depression differ for sexually diverse vs. heterosexual individuals is thus critical to advance precision psychiatry and maximize our ability to effectively treat members of this population. Research has failed to consider the possibility of hierarchical phenotypes, wherein sexual orientation status may be uniquely and simultaneously associated with both depression broadly and with individual symptoms. METHOD: To address these issues, we conducted a moderated nonlinear factor analysis in Wave IV of the Add Health study, using sexual diversity status as a predictor of (a) latent depression, (b) factor loadings, and (c) individual symptoms, with and without controlling for race. RESULTS: Sexual diversity status was positively and simultaneously associated with latent depression, concentration difficulties, and happiness. DISCUSSION: These findings suggest that sexually diverse populations not only face greater depression, broadly defined, but are disproportionately more likely to experience concentration difficulties and be happier compared to heterosexual counterparts. Methodologically, these models indicate that the CES-D is scalar noninvariant as a function of sexual diversity status (i.e., identical scores on the CES-D may represent different manifestations of depression for sexually diverse and heterosexual participants). Studies examining disparities in depression across heterosexual and sexually diverse samples should thus consider depression broadly as well as specific symptoms. Further, it is critical to examine whether these relations function via different mechanisms.

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.