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 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

Trait and State Effects of Depression Severity on Neurocognition: Evidence from a Longitudinal Study

Unipolar and bipolar depression are associated with neurocognitive impairment. However, both the specific pattern of deficits and whether unipolar and bipolar individuals differ on neurocognition remain unclear. Furthermore, neurocognition is related to current depression severity, but it is unknown whether this association stems from between-individual trait differences in disorder severity or from within-individual state variation in symptom severity. We addressed these questions in 43 unipolar and 51 bipolar participants drawn from a 25-year longitudinal study of severe mental illness. We assessed (1) differences among unipolar and bipolar individuals and the general population in attention/processing speed, verbal fluency, cognitive flexibility, and verbal memory; (2) the extent to which current symptom severity, overall trait disorder severity, and within-participant changes in symptom severity predicted neurocognition; and (3) the stability of neurocognitive measures over six years. Both groups showed generalized impairment relative to population norms. Bipolar participants performed more poorly than unipolar participants on measures of attention/processing speed; this may be attributable to differences in medication. Trait disorder severity predicted performance on attention/processing speed, cognitive flexibility, and long-term verbal memory. In contrast, within-participant state changes in depressive symptoms predicted change in only one non-specific cognitive measure. Most measures were stable over six years. Findings are consistent with previous evidence of generalized cognitive impairment in severe mood disorders. Associations of attention/processing speed, cognitive flexibility, and long-term memory with trait depression severity suggest these measures may be dimensional risk markers for severity of depressive illness

Patterns and Mediators of Emotion Regulatory Disturbance in Panic Disorder

Emotion dysregulation is an oft-cited and potentially valuable explanation for panic disorder and other anxiety disorders. However, theoretical accounts conflict regarding whether panic disorder is associated with deficient or excessive emotion regulation, and these contradictory predictions have not been resolved by extant, primarily self-report-based studies. The present study (1) attempted to clarify the functioning of emotion regulation in panic disorder and (2) examined a putative mechanism for emotion regulatory dysfunction, effortful control. In a sample of 38 individuals with panic disorder and 37 controls, we gauged participants’ ability to voluntarily regulate emotional responding to unpredictable threat of shock using physiological indices of negative emotion (startle eye-blink reflex and corrugator activity). We also assessed performance on 3 behavioral measures of effortful control; the degree to which these measures were disrupted in a threatening context; and whether effortful control abilities were associated with emotion regulatory ability. Individuals with panic disorder with agoraphobia (PD/A) demonstrated an enhanced ability to voluntarily suppress both startle and corrugator responding to threat relative to controls and panic disorder without agoraphobia (PD/NA). Individuals with PD/NA showed poorer attentional control compared to controls and PD/A. All 3 measures of effortful control were positively correlated with startle suppression ability, and path analyses revealed indirect effects of PD/NA on emotion regulatory ability via attentional control. The results implicate excessive suppression of negative emotion in the maintenance of PD/A and add to a growing literature linking non-emotional effortful cognitive abilities to emotion regulation and psychopathology

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

Frontal brain asymmetry in depression with comorbid anxiety: A neuropsychological investigation.

The approach-withdrawal model posits that depression and anxiety are associated with a relative right asymmetry in frontal brain activity. Most studies have tested this model using measures of cortical brain activity such as electroencephalography. However, neuropsychological tasks that differentially employ left vs. right frontal cortical regions can also be used to test hypotheses from the model. In two independent samples (Study 1 and 2), the present study investigated the performance of currently depressed individuals with or without a comorbid anxiety disorder and healthy controls on neuropsychological tasks tapping primarily left (verbal fluency) or right (design fluency) frontal brain regions. Across both samples, results indicated that comorbid participants performed more poorly than depressed only and control participants on design fluency, while all groups showed equivalent performance on verbal fluency. Moreover, comorbid participants showed “asymmetrical” performance on these two tasks (i.e., poorer design [right frontal] relative to verbal [left frontal] fluency), while depressed only and control participants showed approximately symmetrical profiles of performance. Results from these two samples suggest an abnormal frontal asymmetry in neurocognitive performance driven primarily by right frontal dysfunction among anxious-depressed individuals and highlight the importance of considering comorbid anxiety when examining frontal brain functioning in depression