Heightened sensitivity to threat and reduced sensitivity to reward are potential mechanisms of dysfunction in anxiety and depressive disorders, respectively. However, few studies have simultaneously examined whether these mechanisms are unique or common to these disorders. In this study, sensitivity to predictable and unpredictable threat (measured by startle response during threat anticipation) and sensitivity to reward (measured by frontal electroencephalographic [EEG] asymmetry during reward anticipation) were assessed in 4 groups (N = 191): those with (1) panic disorder (PD) without a lifetime history of depression, (2) major depression (MDD) without a lifetime history of an anxiety disorder, (3) comorbid PD and MDD, and (4) controls. General distress/negative temperament (NT) was also assessed via self-report. Results indicated that PD (with or without comorbid MDD) was uniquely associated with heightened startle to predictable and unpredictable threat, and MDD (with or without comorbid PD) was uniquely associated with reduced frontal EEG asymmetry. Both psychophysiological measures of threat and reward sensitivity were stable on retest approximately 9 days later in a subsample of participants. Whereas the comorbid group did not respond differently on the tasks relative to the PD-only and MDD-only groups, they did report greater NT than these 2 groups (which did not differ from each other). Results suggest that heightened sensitivity to threat and reduced sensitivity to reward may be specific components of PD and MDD, respectively. In addition, relative to noncomorbid depression and PD, comorbid MDD and PD may be characterized by heightened NT, but not abnormal levels of these “specific” components.

Consistent with observations of HPA axis dysfunction in PTSD, several genes involved in glucocorticoid signaling are differentially expressed among those with current PTSD.

Abstract.We have previously reported the differential expression of 17 probe sets in survivors of the 9/11 attacks with current posttraumatic stress disorder (PTSD) compared to similarly exposed survivors with no lifetime PTSD. The current study presents an expanded analysis of these subjects, including genotype at FKBP5, a modulator of glucocorticoid receptor (GR) sensitivity. It includes data from additional subjects who developed PTSD following 9/11 but then recovered, distinguishing expression profiles associated with risk for developing PTSD, resilience, and symptom recovery. 40 Caucasians (20 with and 20 without PTSD, matched for exposure, age, and gender) were selected from a population-representative sample of persons exposed to the 9/11 attacks from which longitudinal data had been collected in four previous waves. Whole blood gene expression and cortisol levels were obtained and genome-wide gene expression was analyzed. 25 probe sets were differentially expressed in PTSD. Identified genes were generally involved in hypothalamic-pituitary-adrenal axis, signal transduction, or in brain and immune cell function. STAT5B, a direct inhibitor of GR, and nuclear factor I/A, both showed reduced expression in PTSD. Comparison of lifetime versus current PTSD identified overlapping genes with altered expression suggesting enduring markers, while some markers present only in current PTSD may reflect state measures. As a follow-up, direct comparisons of expression in current PTSD, lifetime-only PTSD, and control groups identified FKBP5 and MHC Class II as state markers, and also identified several trait markers. An analysis of indirect effects revealed that homozygosity for any of 4 PTSD risk-related polymorphisms at FKBP5 predicted FKBP5 expression, which mediated indirect effects of genotype on plasma cortisol and PTSD severity.

Two emotional/motivational constructs that have been posited to underlie anxiety and depressive disorders are heightened sensitivity to threat and reduced sensitivity to reward, respectively. It is unclear, though, whether these constructs are only epiphenomena or also connote risk for these disorders (and relatedly, whether they connote risk for separate disorders). Using family history of psychopathology as an indicator of risk, the present study examined whether biomarkers of sensitivity to threat (startle potentiation) and reward (frontal EEG asymmetry) were associated with similar or different familial liabilities. In addition, the present study examined whether these biomarkers were associated with risk independent of proband DSM-IV diagnosis. One hundred seventy-three individuals diagnosed with panic disorder (PD), early-onset major depressive disorder (MDD), both (comorbids), or controls completed two laboratory paradigms assessing sensitivity to predictable/unpredictable threat (measured via startle response) and reward (measured via frontal EEG asymmetry during a gambling task). Results indicated that across all participants: 1) startle potentiation to unpredictable threat was associated with family history of PD (but not MDD) and 2) frontal EEG asymmetry while anticipating reward was associated with family history of MDD (but not PD). Additionally, both measures continued to be associated with family history of psychopathology after controlling for proband DSM-IV diagnosis. Results suggest that the proposed biomarkers of sensitivity to unpredictable threat and reward exhibit discriminant validity and may add to the predictive validity of the DSM-IV defined constructs of PD and MDD, respectively.

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Background A proportion of subjects with symptoms of posttraumatic stress disorder (PTSD) are unresponsive to specialized psychotherapy, but a biological basis for this has not been described. To observe whether differences in cortisol or its metabolites predict or correlate with response to therapy for PTSD symptoms, cortisol and its metabolites were measured from urine samples at pre-treatment, at the conclusion of psychotherapy, and at 3-month follow-up. Methods 28 survivors of the World Trade Center attack on September 11, 2001 seeking psychological treatment for PTSD symptoms received four sessions of either exposure therapy or supportive counseling, followed by up to 10 sessions of prolonged exposure in a specialized PTSD treatment program at a private hospital serving the New York City metropolitan area. 24-hr mean integrated cortisol excretion was assessed by radioimmunoassay (RIA); urinary free cortisol and metabolites cortisone, 5α–tetrahydrocortisol (5α-THF), 5β–tetrahydrocortisol, and tetrahydrocortisone were assessed by gas chromatography-mass spectrometry (GCMS); and indices of enzyme activities for 5α–and 5β–reductase and for the 11β–hydroxysteroid dehydrogenases were derived from the metabolite and glucocorticoid measures. Results 5α-reductase activity was significantly lower at pre-treatment among non-responders, whereas there were no significant pre-treatment differences between responders and non-responders in any other hormone or metabolite level. In repeated-measures analyses across the three time points, 5α-reductase activity, as well as 5α-THF and total glucocorticoids, significantly differed between responders and non-responders. For urinary cortisol measured by RIA, there was a significant group × time interaction indicating that, although not different at pre-treatment, urinary cortisol levels declined over time in the non-responder group, such that by follow-up, lowered cortisol significantly distinguished non-responders from responders. Indices of 5α-reductase activity, including 5α-THF and total glucocorticoids, were significantly negatively correlated with avoidance symptom severity at pre-treatment. At follow-up, indices of 5α-reductase activity were significantly negatively correlated with severity of all three PTSD symptom clusters and with total PTSD severity scores. Conclusion Lower 5α–reductase activity is associated with avoidance severity and predicts non-responsiveness to psychological treatment for PTSD symptomatology. Relatively diminished 5α–reductase activity may mark a state of primary vulnerability, perhaps via attenuated peripheral catabolism of cortisol resulting in the suppression of hypothalamic-pituitary-adrenal axis responsiveness. Lower cortisol levels appear later in the progression to chronic, treatment-resistant PTSD.

Individuals with anxiety disorders have previously demonstrated abnormal habituation to aversiveness over time. As anxiety sensitivity (AS), or an individuals’ propensity to fear anxiety-related sensations, has been shown to be a risk factor for anxiety disorders (particularly panic disorder), the present study examined whether AS was also associated with abnormal habituation. This association was examined in two independent samples of undergraduates (total N=178). Habituation was operationalized as the reduction in startle response to multiple startle probes presented over 2.5 minutes and three definitions of this reduction were employed. Results indicated that individuals with higher levels of AS evidenced deficits in startle habituation, but the strength of this relationship was somewhat dependent on the definition of startle habituation, with the most robust definition being an analysis of participants’ individual slopes across all nine blinks. The present findings suggest that startle habituation is key mechanism underlying AS, and may help elucidate the role this risk factor plays in the pathogenesis of anxiety disorders.

Dysfunctional reward processing has long been considered an important feature of major depressive disorder (MDD). However, depression is a heterogeneous construct and the nature of this heterogeneity may contribute to some of the inconsistent empirical findings on reward dysfunction in MDD. The current study examined one source of heterogeneity, melancholic symptoms, and its association with reward processing. In individuals with MDD (N=141) and MDD-free controls (N=113), EEG alpha asymmetry was measured during a behavioral reward task that probed reward anticipation. Melancholic depression was measured both categorically (DSM diagnosis) and dimensionally (Hamilton Endogenomorphy Scale). Results showed that a dimensional (and not categorical) definition of melancholia predicted reward processing, with higher melancholic symptoms predicting reduced reward anticipation. Importantly, the effects of melancholic symptoms on reduced reward anticipation remained above and beyond overall depression severity. These results suggest that dysfunctional reward processing may only be associated with melancholic symptoms, not depression in general.