Casey Sarapas

Gene Expression Patterns Associated with Posttraumatic Stress Disorder Following Exposure to the World Trade Center Attacks

BACKGROUND Although genetic risk factors for posttraumatic stress disorder (PTSD) in similarly traumatized cohorts can be confounded with risk for type of exposure, the primary risk for exposure to the 9/11 attack on New York City was proximity, allowing study of PTSD risk in a sample that is not confounded by exposure-related risk. METHODS Thirty-five Caucasians (15 with PTSD, stratified for exposure, age, and gender) were selected from a population-representative sample of persons exposed to the attack from which longitudinal data had been collected in four previous waves. Whole blood gene expression and cortisol levels were obtained. RESULTS Seventeen probe sets were differentially expressed in PTSD. Identified genes were generally involved in hypothalamic-pituitary-adrenal (HPA) axis, signal transduction, or brain and immune cell function. FKBP5, a modulator of glucocorticoid receptor (GR) sensitivity, showed reduced expression in PTSD, consistent with enhanced GR responsiveness. FKBP5 expression was predicted by cortisol when entered with PTSD severity in regression analysis. Quantitative polymerase chain reaction confirmed significant reductions in FKBP5. Also less expressed in PTSD were STAT5B, a direct inhibitor of GR, and major histocompatibility complex (MHC) Class II. CONCLUSIONS Consistent with observations of HPA axis dysfunction in PTSD, several genes involved in glucocorticoid signaling are differentially expressed among those with current PTSD.

Genetic markers for PTSD risk and resilience among survivors of the World Trade Center attacks

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.

Cortisol metabolic predictors of response to psychotherapy for symptoms of PTSD in survivors of the World Trade Center attacks on September 11, 2001

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 attacks 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-h mean integrated cortisol excretion was assessed by radioimmunoassay (RIA); urinary free cortisol and metabolites cortisone, 5alpha-tetrahydrocortisol (5alpha-THF), 5beta-tetrahydrocortisol, and tetrahydrocortisone were assessed by gas chromatography-mass spectrometry (GC-MS); and indices of enzyme activity for 5alpha- and 5beta-reductase and for the 11beta-hydroxysteroid dehydrogenases were derived from the metabolite and glucocorticoid measures. RESULTS 5alpha-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, 5alpha-reductase activity, as well as 5alpha-THF and total glucocorticoids, significantly differed between responders and non-responders. For urinary cortisol measured by RIA, there was a significant groupxtime 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 5alpha-reductase activity, including 5alpha-THF and total glucocorticoids, were significantly negatively correlated with avoidance symptom severity at pre-treatment. At follow-up, indices of 5alpha-reductase activity were significantly negatively correlated with severity of all three PTSD symptom clusters and with total PTSD severity scores. CONCLUSION Lower 5alpha-reductase activity is associated with avoidance severity and predicts non-responsiveness to psychological treatment for PTSD symptomatology. Relatively diminished 5alpha-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.

Biomarkers of Threat and Reward Sensitivity Demonstrate Unique Associations With Risk for Psychopathology

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 and 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: (a) startle potentiation to unpredictable threat was associated with family history of PD (but not MDD); and (b) 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.

Parsing trait and state effects of depression severity on neurocognition: Evidence from a 26-year longitudinal study.

Cognitive dysfunction in mood disorders falls along a continuum, such that more severe current depression is associated with greater cognitive impairment. It is not clear whether this association reflects transient state effects of current symptoms on cognitive performance, or persistent, trait-like differences in cognition that are related to overall disorder severity. We addressed this question in 42 unipolar and 47 bipolar participants drawn from a 26-year longitudinal study of psychopathology, using measures of attention/psychomotor processing speed, cognitive flexibility, verbal fluency, and verbal memory. We assessed (a) the extent to which current symptom severity and past average disorder severity predicted unique variance in cognitive performance; (b) whether cognitive performance covaried with within-individual changes in symptom severity; and (c) the stability of neurocognitive measures over six years. We also tested for differences among unipolar and bipolar groups and published norms. Past average depression severity predicted performance on attention/psychomotor processing speed in both groups, and in cognitive flexibility among unipolar participants, even after controlling for current symptom severity, which did not independently predict cognition. Within-participant state changes in depressive symptoms did not predict change in any cognitive domain. All domains were stable over the course of six years. Both groups showed generalized impairment relative to published norms, and bipolar participants performed more poorly than unipolar participants on attention/psychomotor processing speed. The results suggest a stable relationship between mood disorder severity and cognitive deficits.

The effect of pre- vs. post-reward attainment on EEG asymmetry in melancholic depression

Clinical investigators have long theorized about the role of reward processing and positive affect in depression. One theory posits that compared to nonmelancholic depressives, melancholic depressives experience less consummatory (i.e., post-reward), but comparably low anticipatory (prior to reward), positive affect. We tested whether frontal EEG asymmetry, a putative marker of the anticipatory reward system, is present only before an individual receives a reward or also after receiving a reward (i.e., during consummatory reward processing). We also examined whether melancholic depression, a condition characterized by a deficit in consummatory reward processing, is associated with abnormal EEG asymmetries in alpha band power. Effects in other frequency bands (delta, theta, or beta) were also explored. EEG was recorded in 34 controls, 48 nonmelancholic depressives, and 17 melancholic depressives during a slot machine task designed to elicit anticipatory and consummatory reward processing. Results indicated that, for alpha, the frontal EEG asymmetry of greater relative left activity was specific to anticipatory reward processing. During the consummatory phase, individuals with melancholic depression exhibited different posterior EEG asymmetries than individuals with nonmelancholic depression (and controls at a trend level). This second finding was largely due to melancholics exhibiting relatively lower right posterior activity and nonmelancholics exhibiting relatively lower left activity. These results suggest that a posterior asymmetry may be a marker for melancholic depression and aberrant consummatory reward processing.

Aversive responding to safety signals in panic disorder: The moderating role of intolerance of uncertainty

An inability to inhibit aversive responding during conditions that signal safety may be a core dysfunction associated with anxiety disorders. However, there has been inconsistent evidence as to whether individuals with panic disorder (PD) exhibit aversive responding during safety signals. It is therefore possible that only certain subgroups of PD patients, particularly those with high levels of intolerance of uncertainty (IU), evidence this type of abnormal responding. The aim of the current study was to examine whether IU moderates the association between PD and startle potentiation during (a) safety and (b) threat periods during a threat-of-shock task. Participants included 172 adults, 74 of which had current diagnoses of PD. Results indicated that at high levels of IU, PD was associated with greater startle potentiation during safety. At low levels of IU, PD was not associated with startle potentiation during safety. IU did not moderate the effect of PD on threat responding. These results suggest that PD patients with high levels of IU fail to inhibit aversive responding during safety, possibly due to a tendency to interpret distal threat as distressing.

The Different Facets of Anhedonia and Their Associations with Different Psychopathologies

Over the last several decades, there has been increasing interest in the role that anhedonia plays in various psychopathologies, ranging from mood disorders, to eating disorders, to psychotic disorders. The term ‘anhedonia’ (which simply means, without pleasure) has been used to describe a wide range of constructs, affective experiences, and events. Given the breadth of the term, it is likely that different aspects of anhedonia may be related to different psychopathologies in various ways. This review discusses how the literature has parsed anhedonia and how the various components and facets of anhedonia may relate to various psychopathological constructs. In addition, this review takes concepts and theories from the broad affective science literature and identifies additional components of anhedonia that may be critical to the field’s understanding of the construct. Given the importance that anhedonia plays in a multitude of psychopathological constructs, a careful analysis of the various components and facets of anhedonia may provide a conceptual framework for research in this area.

How many blinks are necessary for a reliable startle response? A test using the NPU-threat task

Emotion-modulated startle is a frequently used method in affective science. Although there is a growing literature on the reliability of this measure, it is presently unclear how many startle responses are necessary to obtain a reliable signal. The present study therefore evaluated the reliability of startle responding as a function of number of startle responses (NoS) during a widely used threat-of-shock paradigm, the NPU-threat task, in a clinical (N=205) and non-clinical (N=92) sample. In the clinical sample, internal consistency was also examined independently for healthy controls vs. those with panic disorder and/or major depression and retest reliability was assessed as a function of NoS. Although results varied somewhat by diagnosis and for retest reliability, the overall pattern of results suggested that six startle responses per condition were necessary to obtain acceptable reliability in clinical and non-clinical samples during this threat-of-shock paradigm in the present study.

Anticipatory Reward Deficits in Melancholia

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 1 source of heterogeneity, melancholic symptoms, and its association with reward processing. In individuals with MDD (N = 141) and MDD-free controls (N = 113), electroencephalogram (EEG) alpha asymmetry was measured during a behavioral reward task that probed reward anticipation. Melancholic depression was measured both categorically (Diagnostic and Statistical Manual of Mental Disorders [DSM] diagnosis) and dimensionally (Hamilton Endogenomorphy Scale [HES]). 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. (PsycINFO Database Record