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.