Abstract
Epigenetic signatures such as methylation of the monoamine oxidase A (MAOA) gene have been found to be altered in panic disorder (PD). Hypothesizing temporal plasticity of epigenetic processes as a mechanism of successful fear extinction, the present psychotherapy-epigenetic study for we believe the first time investigated MAOA methylation changes during the course of exposure-based cognitive behavioral therapy (CBT) in PD. MAOA methylation was compared between N=28 female Caucasian PD patients (discovery sample) and N=28 age- and sex-matched healthy controls via direct sequencing of sodium bisulfite-treated DNA extracted from blood cells. MAOA methylation was furthermore analyzed at baseline (T0) and after a 6-week CBT (T1) in the discovery sample parallelized by a waiting time in healthy controls, as well as in an independent sample of female PD patients (N=20). Patients exhibited lower MAOA methylation than healthy controls (P<0.001), and baseline PD severity correlated negatively with MAOA methylation (P=0.01). In the discovery sample, MAOA methylation increased up to the level of healthy controls along with CBT response (number of panic attacks; T0–T1: +3.37±2.17%), while non-responders further decreased in methylation (−2.00±1.28% P=0.001). In the replication sample, increases in MAOA methylation correlated with agoraphobic symptom reduction after CBT (P=0.02–0.03). The present results support previous evidence for MAOA hypomethylation as a PD risk marker and suggest reversibility of MAOA hypomethylation as a potential epigenetic correlate of response to CBT. The emerging notion of epigenetic signatures as a mechanism of action of psychotherapeutic interventions may promote epigenetic patterns as biomarkers of lasting extinction effects.
Highlights
Panic disorder (PD) is an anxiety disorder characterized by sudden, unexpected attacks of intense fear and anticipatory anxiety— often comorbid with agoraphobia—and a life-time prevalence of 1-3%.1 The pathomechanism of PD is genetically complex with an estimated heritability of 48%.2 Both cognitive behavioral therapy (CBT) and pharmacotherapy are highly effective for a large proportion of patients with anxiety disorders
Mixed linear models for repeated measures revealed that monoamine oxidase A (MAOA) methylation differed significantly between PD patients and controls (P o 0.001), with decreased average methylation in PD patients compared with healthy controls (P o 0.001)
PD severity was inversely correlated with MAOA methylation at baseline
Summary
Panic disorder (PD) is an anxiety disorder characterized by sudden, unexpected attacks of intense fear and anticipatory anxiety— often comorbid with agoraphobia—and a life-time prevalence of 1-3%.1 The pathomechanism of PD is genetically complex with an estimated heritability of 48%.2 Both cognitive behavioral therapy (CBT) and pharmacotherapy are highly effective for a large proportion of patients with anxiety disorders. Patients with a primary diagnosis of PD with agoraphobia received a 12-session written manualized treatment protocol focusing on in situ exposure to target avoidance behavior that was implemented over 6 weeks and was highly comparable to the protocol used in the first clinical trial of the MAC study[15] with some modifications. The protocol of the two different CBT variants, to which patients could be randomized, consisted of psychoeducation and an individualized behavioral analysis of the patient’s symptoms and coping behavior, providing the treatment successfully applied previously to study DNA methylation profiles in mental disorders.[10,17,18,19,21,22] To account for run variability, all samples were tested in duplicate, yielding a mean individual methylation score for each CpG, as well as an individual s.d. for each duplicate.
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