Suzanne Vrshek-Schallhorn

The cortisol awakening response predicts major depression: predictive stability over a 4-year follow-up and effect of depression history.

BACKGROUND The cortisol awakening response (CAR) has been shown to predict major depressive episodes (MDEs) over a 1-year period. It is unknown whether this effect: (a) is stable over longer periods of time; (b) is independent of prospective stressful life events; and (c) differentially predicts first onsets or recurrences of MDEs. METHOD A total of 270 older adolescents (mean age 17.06 years at cortisol measurement) from the larger prospective Northwestern-UCLA Youth Emotion Project completed baseline diagnostic and life stress interviews, questionnaires, and a 3-day cortisol sampling protocol measuring the CAR and diurnal rhythm, as well as up to four annual follow-up interviews of diagnoses and life stress. RESULTS Non-proportional person-month survival analyses revealed that higher levels of the baseline CAR significantly predict MDEs for 2.5 years following cortisol measurement. However, the strength of prediction of depressive episodes significantly decays over time, with the CAR no longer significantly predicting MDEs after 2.5 years. Elevations in the CAR did not significantly increase vulnerability to prospective major stressful life events. They did, however, predict MDE recurrences more strongly than first onsets. CONCLUSIONS These results suggest that a high CAR represents a time-limited risk factor for onsets of MDEs, which increases risk for depression independently of future major stressful life events. Possible explanations for the stronger effect of the CAR for predicting MDE recurrences than first onsets are discussed.

Elevated Responding to Safe Conditions as a Specific Risk Factor for Anxiety Versus Depressive Disorders: Evidence From a Longitudinal Investigation

The current study evaluated the degree to which startle reflexes (SRs) in safe conditions versus danger conditions were predictive of the onset of anxiety disorders. Specificity of these effects to anxiety disorders was evaluated in comparison to unipolar depressive disorders and with consideration of level of neuroticism. A startle paradigm was administered at baseline to 132 nondisordered adolescents as part of a longitudinal study examining risk factors for emotional disorders. Participants underwent a repetition of eight safe-danger sequences and were told that delivery of an aversive stimulus leading to a muscle contraction of the arm would occur only in the late part of danger conditions. One aversive stimulus occurred midway in the safe-danger sequences. Participants were assessed for the onset of anxiety and unipolar depressive disorders annually over the next 3 to 4 years. Larger SR magnitude during safe conditions following delivery of the aversive stimulus predicted the subsequent first onset of anxiety disorders. Moreover, prediction of the onset of anxiety disorders remained significant above and beyond the effects of comorbid unipolar depression, neuroticism, and subjective ratings of intensity of the aversive stimulus. In sum, elevated responding to safe conditions following an aversive stimulus appears to be a specific, prospective risk factor for the first onset of anxiety disorders.

Variations in the Catechol O-methyltransferase Polymorphism and Prefrontally Guided Behaviors in Adolescents

BACKGROUND The catechol-O-methyltransferase (COMT) gene codes for an enzyme that degrades prefrontal cortex (PFC) synaptic dopamine. Of two identified alleles (Met and Val), the Met allele results in COMT activity that is up to 4 times less pronounced than that conferred by the Val allele, resulting in greater PFC dopamine concentrations. Met-Met homozygotes perform better than individuals who possess the Val allele on PFC-mediated cognitive tasks. These genotypic variations and their associations with executive functions have been described in adults and prepubescent children, but there is a paucity of research assessing these relations in adolescent samples. METHODS In this study, 70 children aged 9-17 were genotyped for COMT and completed measures of working memory, attention, fine motor coordination, and motor speed. RESULTS COMT genotype modulated all but the motor speed measures. The Val-Met genotype was optimal for performance in this adolescent sample. CONCLUSIONS Results are discussed within the context of developmental changes in the dopaminergic system during adolescence.

Prospective Associations Between the Cortisol Awakening Response and First Onsets of Anxiety Disorders Over a Six-Year Follow-up – 2013 Curt Richter Award Winner

Cross-sectional associations have been found between anxiety disorders (ADs) and hypothalamic-pituitary-adrenal (HPA) axis functioning, as measured by levels of salivary cortisol, but prospective data are lacking, as are studies examining specific ADs. We have previously shown that one aspect of the diurnal rhythm of cortisol, the cortisol awakening response (CAR), prospectively predicts both new onsets and recurrences of major depressive disorder (MDD). Here we sought to examine whether it also predicts ADs. Participants (N=232) were drawn from the larger Northwestern-UCLA Youth Emotion Project, a two-site, longitudinal study of older adolescents, which aims to identify common and specific risk factors for mood and anxiety disorders. After baseline interviews for mental health diagnoses, a subset of adolescents completed a three-day cortisol sampling protocol measuring the CAR and other diurnal rhythm indices. Participants with past or current anxiety disorders at the time of cortisol measurement were excluded and Cox regression (survival analysis) was used to predict first onsets of ADs over the subsequent six years. AD onsets (N=25), the largest subset of which were social anxiety disorder (SAD) onsets (N=11), were observed over six annual follow up diagnostic interviews. Even when statistically adjusting for past and prospective MDD onsets and other covariates, a higher CAR significantly predicted increased first onsets of ADs (HR=2.20, p<.05). A higher CAR was also a strong and significant predictor of the subset of SAD onsets (HR=5.37, p<.005). Implications for the etiology of ADs, with a focus on SAD, are discussed.

Severe and nonsevere events in first onsets versus recurrences of depression: evidence for stress sensitization.

Overall, research has evidenced support for Posts (1992) model, which asserts that the 1st episode of depression is more likely to be associated with severe life events than are subsequent episodes. In spite of this, there are significant gaps in the understanding of the stress-depression association. This study aimed to address three gaps by (a) identifying the explanatory model underlying the association (stress sensitization vs. stress autonomy), (b) elucidating how the role of stress changes with successive episodes, and (c) examining the role of nonsevere events. The impact and occurrence of severe and nonsevere events in a 5-year longitudinal study of late-adolescent women were examined using Cox regression models. Overall, we found support for the stress sensitization model over the stress autonomy model. Specifically, the impact of nonsevere (but not severe) events was greater in individuals with a history of depression compared with those with no history of depression. In addition, the occurrence of severe (but not nonsevere) events was greater for 1st onsets than recurrences. These effects were modified by event independence. The results were discussed in terms of the underlying mechanisms of the stress-depression association and future directions for research were elaborated.

Refining the Candidate Environment Interpersonal Stress, the Serotonin Transporter Polymorphism, and Gene-Environment Interactions in Major Depression

Meta-analytic evidence has supported a gene-environment interaction between life stress and the serotonin transporter–linked polymorphism (5-HTTLPR) on depression, but few studies have examined factors that influence detection of this effect, despite years of inconsistent results. We propose that the candidate environment (akin to a candidate gene) is key. Theory and evidence have implicated major stressful life events (SLEs)—particularly major interpersonal SLEs—as well as chronic family stress. A total of 400 participants from the Youth Emotion Project (which began with 627 high school juniors oversampled for high neuroticism) completed up to five annual diagnostic and stress interviews and provided DNA samples. A significant gene-environment effect for major SLEs and S-carrier genotype was accounted for significantly by major interpersonal SLEs but not significantly by major noninterpersonal SLEs. S-carrier genotype and chronic family stress also significantly interacted. Identifying such candidate environments may facilitate future gene-environment research in depression and psychopathology more broadly.

Testing a Hierarchical Model of Neuroticism and Its Cognitive Facets Latent Structure and Prospective Prediction of First Onsets of Anxiety and Unipolar Mood Disorders During 3 Years in Late Adolescence

Neuroticism and several other traits have been proposed to confer vulnerability for unipolar mood disorders (UMDs) and anxiety disorders (ADs). However, it is unclear whether the associations of these vulnerabilities with these disorders are attributable to a latent variable common to all vulnerabilities, more narrow latent variables, or both. In addition, some researchers have suggested that neuroticism predicts UMDs, ADs, and substance use disorders (SUDs) with comparable strength, whereas other researchers have hypothesized that neuroticism is more strongly related to UMDs and ADs. We tested hypotheses about the factor structure of several vulnerabilities and the prospective associations of these latent variables with initial onsets of UMDs, ADs, and SUDs during a 3-year period in 547 participants recruited as high school juniors. Although a general neuroticism factor predicted SUDs, it predicted UMDs and ADs more strongly and especially predicted comorbid UMDs and ADs. There was also mixed support for specific associations involving more narrow latent vulnerabilities.

Chronic and episodic interpersonal stress as statistically unique predictors of depression in two samples of emerging adults

Few studies comprehensively evaluate which types of life stress are most strongly associated with depressive episode onsets, over and above other forms of stress, and comparisons between acute and chronic stress are particularly lacking. Past research implicates major (moderate to severe) stressful life events (SLEs), and to a lesser extent, interpersonal forms of stress; research conflicts on whether dependent or independent SLEs are more potent, but theory favors dependent SLEs. The present study used 5 years of annual diagnostic and life stress interviews of chronic stress and SLEs from 2 separate samples (Sample 1 N = 432; Sample 2 N = 146) transitioning into emerging adulthood; 1 sample also collected early adversity interviews. Multivariate analyses simultaneously examined multiple forms of life stress to test hypotheses that all major SLEs, then particularly interpersonal forms of stress, and then dependent SLEs would contribute unique variance to major depressive episode (MDE) onsets. Person-month survival analysis consistently implicated chronic interpersonal stress and major interpersonal SLEs as statistically unique predictors of risk for MDE onset. In addition, follow-up analyses demonstrated temporal precedence for chronic stress; tested differences by gender; showed that recent chronic stress mediates the relationship between adolescent adversity and later MDE onsets; and revealed interactions of several forms of stress with socioeconomic status (SES). Specifically, as SES declined, there was an increasing role for noninterpersonal chronic stress and noninterpersonal major SLEs, coupled with a decreasing role for interpersonal chronic stress. Implications for future etiological research were discussed.

Testing the CaR-FA-X Model: Investigating the Mechanisms Underlying Reduced Autobiographical Memory Specificity in Individuals With and Without a History of Depression

Reduced autobiographical memory specificity (AMS) is an important cognitive phenomenon in major depressive disorder (MDD), but knowledge about mechanisms is lacking. The CaR-FA-X model of Williams and colleagues (2007) proposed that 3 processes contributed to reduce AMS: capture and rumination (CaR), functional avoidance (FA), and impaired executive control (X). However, the entire CaR-FA-X model has not been tested. We addressed this gap in the literature by investigating contributions of the CaR-FA-X mechanisms to reduced AMS, alone or in interaction, in a subset of young adults (N = 439) from the Northwestern-UCLA Youth Emotion Project. Participants were classified as those with (n = 164) and without (n = 275) a history of MDD at AMS assessment. They completed measures of: AMS; rumination (the brooding factor; CaR); childhood, adolescent, and early adulthood adversity (FA); avoidant coping (FA); and verbal fluency (X). Using structural equation modeling, we found greatest support for associations between reduced AMS and the capture and rumination, and impaired executive control mechanisms. In those with and without a history of MDD, brooding and verbal fluency interacted to contribute to reduced AMS. For participants without a history of MDD, lower verbal fluency (indicating impaired executive control) was associated with reduced AMS among those high on brooding. For participants with a history of MDD, lower verbal fluency was associated with reduced AMS among those low on brooding. The first finding was consistent with the CaR-FA-X model but the latter was not. Implications for conceptualizations of reduced AMS and its mechanisms are discussed.

EXPERIENCING CORE SYMPTOMS OF ANXIETY AND UNIPOLAR MOOD DISORDERS IN LATE ADOLESCENCE PREDICTS DISORDER ONSET IN EARLY ADULTHOOD

Identification of youth at risk for anxiety and unipolar mood disorders (UMDs) can improve public health by targeting those who may warrant early or preventive intervention. This study examined whether endorsing core features of anxiety and UMDs predicted onset of later anxiety and UMDs across the next 7–9 years, and whether having subthreshold or subclinical manifestations of these disorders similarly predicted onset.