Correction: Augmenting extinction learning with D-cycloserine reduces return of fear: a randomized, placebo-controlled fMRI study.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Augmenting extinction learning with D-cycloserine reduces return of fear: a randomized, placebo-controlled fMRI study.

D-cycloserine (DCS), a partial NMDA-receptor agonist, seems to be a promising enhancer for exposure therapy in anxiety disorders. It has been tested successfully in animal models of fear extinction, where DCS enhanced extinction learning. Applied in clinical studies, results of DCS-augmented exposure therapy remain ambiguous, calling for a deeper understanding of the underlying mechanisms of DCS and its exact effect on extinction learning and return of fear (ROF) in humans. In the present study, we investigated the effect of DCS-augmented extinction learning on behavioral, psychophysiological, and neural indices of ROF during a 24-h delayed recall test. Thirty-seven participants entered a randomized, placebo-controlled, double-blind, 3-day fear conditioning and delayed extinction fMRI design. One hour before extinction training, participants received an oral dose of 50 mg of DCS or a placebo. Behavioral arousal ratings revealed a generalized ROF during extinction recall in the placebo but not DCS group. Furthermore, participants receiving DCS compared to placebo showed attenuated differential BOLD responses in left posterior hippocampus and amygdala from extinction learning to extinction recall, due to increased hippocampal recruitment in placebo and trendwise decreased amygdala responding in DCS subjects. Our finding that DCS reduces ROF in arousal ratings and neural structures subserving defensive reactions support a role for NMDA receptors in extinction memory consolidation and encourage further translational research.

Association of NPSR1 gene variation and neural activity in patients with panic disorder and agoraphobia and healthy controls.

INTRODUCTION: The neurobiological mechanisms behind panic disorder with agoraphobia (PD/AG) are not completely explored. The functional A/T single nucleotide polymorphism (SNP) rs324981 in the neuropeptide S receptor gene (NPSR1) has repeatedly been associated with panic disorder and might partly drive function respectively dysfunction of the neural "fear network". We aimed to investigate whether the NPSR1 T risk allele was associated with malfunctioning in a fronto-limbic network during the anticipation and perception of agoraphobia-specific stimuli. METHOD: 121 patients with PD/AG and 77 healthy controls (HC) underwent functional magnetic resonance imaging (fMRI) using the disorder specific "Westphal-Paradigm". It consists of neutral and agoraphobia-specific pictures, half of the pictures were cued to induce anticipatory anxiety. RESULTS: Risk allele carriers showed significantly higher amygdala activation during the perception of agoraphobia-specific stimuli than A/A homozygotes. A linear group x genotype interaction during the perception of agoraphobia-specific stimuli showed a strong trend towards significance. Patients with the one or two T alleles displayed the highest and HC with the A/A genotype the lowest activation in the inferior orbitofrontal cortex (iOFC). DISCUSSION: The study demonstrates an association of the NPSR1rs324981 genotype and the perception of agoraphobia-specific stimuli. These results support the assumption of a fronto-limbic dysfunction as an intermediate phenotype of PD/AG.

Patients' characteristics and their influence on course of fear during agoraphobic symptom provocation: may SS(N)RI treatment compensate unfavorable individual preconditions?

BACKGROUND: Patients' characteristics and antidepressants are discussed to be relevant in the context of phobic exposure. AIMS: To identify patients characteristics associated with a differential course of fear during disorder-specific symptom provocation as well as to elucidate the effect of selective serotonin-(noradrenalin-) reuptake inhibitors [SS(N)RI] on development of fear in the context of re-exposure to the phobic stimuli. METHODS: Twenty-eight clinically well-characterized patients with panic disorder and agoraphobia (PD/AG) were classified into subjects who show a reduction of fear ('Fear-') during a symptom provocation via a picture-based paradigm (T1) and those who did not ('Fear+'). Subsequently, SS(N)RI treatment was administered to all patients and subjects were re-exposed to the feared stimuli after 8 weeks of treatment (T2). Moreover, brain activity within the 'fear network' was measured via functional magnetic resonance imaging (fMRI) at T1 and T2. RESULTS: Fear - were significantly younger and demonstrated increased exposure-related fear as well as stronger activity in several fear-related brain areas than Fear+. We found significant improvements in all clinical parameters after pharmacological intervention for the whole sample (T1-T2; all measures p < .02). However, reduction of fear as well as activation in (para)limbic structures during symptom provocation were now attenuated in Fear - but increased in Fear+. CONCLUSIONS: Advanced age may predict a therapeutically unfavorable course of fear during agoraphobic symptom provocation. Since we found no negative impact of medication on fear development at all, there was some evidence that SS(N)RI treatment might improve the individual ability to get involved with the agoraphobic stimuli while conducting disorder-specific exposure.

Facing the fear--clinical and neural effects of cognitive behavioural and pharmacotherapy in panic disorder with agoraphobia.

INTRODUCTION: Cognitive behavioural therapy (CBT) and pharmacological treatment with selective serotonin or serotonin-noradrenalin reuptake inhibitors (SSRI/SSNRI) are regarded as efficacious treatments for panic disorder with agoraphobia (PD/AG). However, little is known about treatment-specific effects on symptoms and neurofunctional correlates. EXPERIMENTAL PROCEDURES: We used a comparative design with PD/AG patients receiving either two types of CBT (therapist-guided (n=29) or non-guided exposure (n=22)) or pharmacological treatment (SSRI/SSNRI; n=28) as well as a wait-list control group (WL; n=15) to investigate differential treatment effects in general aspects of fear and depression (Hamilton Anxiety Rating Scale HAM-A and Beck Depression Inventory BDI), disorder-specific symptoms (Mobility Inventory MI, Panic and Agoraphobia Scale subscale panic attacks PAS-panic, Anxiety Sensitivity Index ASI, rating of agoraphobic stimuli) and neurofunctional substrates during symptom provocation (Westphal-Paradigm) using functional magnetic resonance imaging (fMRI). Comparisons of neural activation patterns also included healthy controls (n=29). RESULTS: Both treatments led to a significantly greater reduction in panic attacks, depression and general anxiety than the WL group. The CBT groups, in particular, the therapist-guided arm, had a significantly greater decrease in avoidance, fear of phobic situations and anxiety symptoms and reduction in bilateral amygdala activation while the processing of agoraphobia-related pictures compared to the SSRI/SSNRI and WL groups. DISCUSSION: This study demonstrates that therapist-guided CBT leads to a more pronounced short-term impact on agoraphobic psychopathology and supports the assumption of the amygdala as a central structure in a complex fear processing system as well as the amygdala's involvement in the fear system's sensitivity to treatment.