A Cognitive-Neuropsychological Account of Treatment Action in Anxiety: Can We Augment Clinical Efficacy?

Patients with panic disorder show abnormalities in threat processing and regulation, both on a behavioral and neural level. Better understanding of the underlying mechanisms could help to develop new treatment strategies. In this study, we investigated brain region activation in 18 patients with untreated panic disorder (PD) and 17 healthy controls (HC) during the processing of emotional faces with fearful, happy and neutral expressions, using functional MRI. The intensity of the expressions was either prototypically high, medium or low. PD patients showed significantly increased activity in the dorso-medial prefrontal cortex (dmPFC) in response to faces in general and specifically for happy faces. While HC showed a decreased amygdala response to medium/low fearful versus high fearful faces, this effect was not present in PD: amygdala activation was stable across all fearful faces in this group. Psychophysiological interaction analyses indicated more negative connectivity between the amygdala and prefrontal areas in the PD group during the task. Amygdala activation in panic patients appears to be less sensitive to decreasing intensities of fearful facial expressions and salience monitoring areas were less active during fearful faces in general in this group. This suggests PD patients might avoid more extensive processing of fearful faces.

ObjectiveDrugs targeting the N-Methyl-D-aspartic acid (NMDA) system and the ability to learn new associations have been proposed as potential adjunct treatments to boost the success of exposure therapy for anxiety disorders. However, the effects of the NMDA partial agonist d-cycloserine on psychological treatment have been mixed. We investigated potential neurocognitive mechanisms underlying the clinical effects of d-cycloserine-augmented exposure, to inform the optimal combination of this and similar agents with psychological treatment.MethodsUnmedicated patients with panic disorder were randomised to single-dose d-cycloserine (250mg; N=17) or matching placebo (N=16) 2hrs before one session of exposure therapy. Neurocognitive markers were assessed one day after treatment, including reaction-time based threat bias for fearful faces and amygdala response to threat. Clinical symptom severity was measured using self-report and clinician-rated scales the day before and after treatment, and at 1- and 6-months follow-up. Analysis was by intention-to-treat.ResultsOne day after treatment, threat bias for fearful faces and amygdala threat response were attenuated in the drug compared to the placebo group. Lower amygdala magnitude predicted greater clinical improvement during follow-up across groups. D-cycloserine led to greater clinical recovery at 1-month follow-up (d-cycloserine 71% versus placebo 25%).DiscussionD-cycloserine-augmented single-session exposure therapy reduces amygdala threat response, and this effect predicts later clinical response. These findings highlight a neurocognitive mechanism by which d-cycloserine may exert its augmentative effects on psychological treatment and bring forward a marker that may help understand and facilitate future development of adjunct treatments with CBT for anxiety disorders. (D-cycloserine Augmented CBT for Panic Disorder; clinicaltrials.gov;NCT01680107)

Background and objectivesOne of the central assumptions of cognitive models of Panic Disorder (PD) is that automatic panic-related associations are a core feature of PD. However, empirical findings are mixed and inconsistent, rendering it difficult to evaluate the role of panic-related associations adequately, particularly in relation to the relevant theories. The present study aimed to further advance our understanding of automatic associations in PD, and therefore applied a paradigm novel in this context, namely an Extrinsic Affective Simon Task (EAST).MethodsParticipants involved treatment seeking, unmedicated panic patients (n = 45) and healthy controls (n = 38). The EAST was applied prior to treatment. It included the following stimuli as targets: panic-related bodily sensations and agoraphobia-related situations, and as attributes: pleasant versus unpleasant, fear-related words.ResultsContrary to our expectations, panic patients did not show stronger negative than positive automatic associations for either panic-related symptoms or agoraphobia-related situations, compared to healthy controls. Moreover, EAST effects did not correlate with panic-related self-report measures.LimitationsAlthough the present study involved patients who were actively seeking treatment, panic-related associations might not have been activated sufficiently. Hence, a brief activation procedure (e.g., hyperventilation) might have been needed to optimize the assessment condition.ConclusionsThe present findings do not support contemporary theories of panic-related associations. Therefore, follow-up work is needed to disentangle their functional and operational properties more thoroughly.