Emotion regulation difficulty in panic disorder patients and their first-degree relatives: An endophenotype study

Introduction and Objective: The endophenotype approach is a powerful strategy for elucidating the complex genetic architecture of psychiatric disorders by targeting measurable and heritable intermediate phenotypes between genotype and clinical phenotype. Emotion Regulation Difficulty (ERD) is considered a transdiagnostic construct that plays a central role in the psychopathology of Panic Disorder (PD). The primary aim of this study was to investigate whether ERD is a potential endophenotype for PD by conducting a comparative analysis among PD patients, their unaffected first-degree relatives (FDR), and healthy controls (HC). The study tested whether ERD exhibits a gradient pattern (PD > FDR > HC), which would reflect a familial vulnerability. Method: The study included 40 patients diagnosed with PD according to DSM-5 criteria, 40 of their unaffected FDRs, and 40 HCs. Participants' emotion regulation difficulties were assessed using the Difficulties in Emotion Regulation Scale (DERS), panic-agoraphobia severity with the Panic and Agoraphobia Scale (PAS), depressive and anxiety symptoms with the Hamilton Depression (HAM-D) and Anxiety (HAM-A) Rating Scales, and functional impairment with the Sheehan Disability Scale (SDS). Statistical methods such as ANOVA, ANCOVA, and the Jonckheere-Terpstra test were used for data analysis. Results: DERS total scores exhibited a statistically highly significant gradient pattern among the groups (PD > FDR > HC; p < .001, ηp2 = .41). This fundamental gradient difference remained significant even after controlling for confounding variables such as age, gender, education, and current depression/anxiety levels. A similar gradient was detected in the 'Impulse' and 'Strategies' subscales. The 'Clarity' subscale showed a 'PD ≈ FDR > HC' pattern, while the 'Awareness' subscale revealed a unique 'FDR < HC < PD' ranking. In the PD group, a significant positive correlation was found between DERS total scores and PAS scores (r = .412, p < .01). Within the PD group, the presence of a family history of PD or comorbid agoraphobia did not significantly alter ERD levels. Conclusion: The study findings strongly support that ERD is not merely an epiphenomenon of PD but a promising endophenotype candidate, as it is associated with the illness, shows familial transmission, is relatively independent of the current clinical state, and is a measurable trait. Specifically, difficulties in impulse control, limited access to effective strategies, and a lack of emotional clarity emerge as core components of the hereditary vulnerability to PD. These findings suggest that ERD could be a crucial biomarker for the early identification of individuals at risk for PD and for the development of preventive interventions targeting emotion regulation skills. Keywords: Panic Disorder, Emotion Regulation Difficulty, Endophenotype, First-Degree Relatives, Family Study.