Genetic variation in the endocannabinoid system and response to Cognitive Behavior Therapy for child anxiety disorders

Abstract

Extinction learning is an important mechanism in the successful psychological treatment of anxiety. Individual differences in response and relapse following Cognitive Behavior Therapy may in part be explained by variability in the ease with which fears are extinguished or the vulnerability of these fears to re‐emerge. Given the role of the endocannabinoid system in fear extinction, this study investigates whether genetic variation in the endocannabinoid system explains individual differences in response to CBT. Children (N = 1,309) with a primary anxiety disorder diagnosis were recruited. We investigated the relationship between variation in the CNR1, CNR2, and FAAH genes and change in primary anxiety disorder severity between pre‐ and post‐treatment and during the follow‐up period in the full sample and a subset with fear‐based anxiety disorder diagnoses. Change in symptom severity during active treatment was nominally associated (P < 0.05) with two SNPs. During the follow‐up period, five SNPs were nominally associated with a poorer treatment response (rs806365 [CNR1]; rs2501431 [CNR2]; rs2070956 [CNR2]; rs7769940 [CNR1]; rs2209172 [FAAH]) and one with a more favorable response (rs6928813 [CNR1]). Within the fear‐based subset, the effect of rs806365 survived multiple testing corrections (P < 0.0016). We found very limited evidence for an association between variants in endocannabinoid system genes and treatment response once multiple testing corrections were applied. Larger, more homogenous cohorts are needed to allow the identification of variants of small but statistically significant effect and to estimate effect sizes for these variants with greater precision in order to determine their potential clinical utility. © 2016 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals, Inc.

The endocannabinoid system in mental disorders: Evidence from human brain studies

“…Moreover, a favorable and a poorer response during the active treatment period were associated with minor allele of rs12133557 and rs6454676, respectively. Regarding the CNR2 gene, unlike to previous findings in depression [81], the rs2501431 genotype was not associated with anxiety symptoms or treatment response [99].…”

“…This makes the endocannabinoid signaling quite sensitive for developmental fluctuations due to environmental causes, which may increase the risk of anxiety and other stress-related disorders. Interestingly, a recent study show the impact of the variation in the CNR1, CNR2, and FAAH genes in a sample of children with a primary anxiety disorder diagnosis [99]. These authors nicely reported an association between two SNPs (rs12133557 and rs6454676) in the CNR1 gene and the change in symptom severity in both the entire sample and a subset of patients with fear based diagnoses [99].…”

“…Interestingly, a recent study show the impact of the variation in the CNR1, CNR2, and FAAH genes in a sample of children with a primary anxiety disorder diagnosis [99]. These authors nicely reported an association between two SNPs (rs12133557 and rs6454676) in the CNR1 gene and the change in symptom severity in both the entire sample and a subset of patients with fear based diagnoses [99]. Moreover, a favorable and a poorer response during the active treatment period were associated with minor allele of rs12133557 and rs6454676, respectively.…”

Anxiety genetics: Dispatches from the frontier

“…Recently, Kathryn Lester, Thalia Eley and colleagues have pursued a genetic approach to predicting response to psychosocial therapies (dubbed “therapygenetics”) analogous to traditional pharmacogenetic research. In this issue, they report a genetic analysis of CBT for childhood anxiety disorders in the largest such analysis to date (comprising more than 1,300 children) [Lester et al, ]. The analyses focused on genes in the endocannabinoid system which has been shown to mediate fear extinction, a key mechanism in CBT for pathologic anxiety.…”

Anxiety genetics: Dispatches from the frontier

“…Recently, Kathryn Lester, Thalia Eley and colleagues have pursued a genetic approach to predicting response to psychosocial therapies (dubbed "therapygenetics") analogous to traditional pharmacogenetic research. In this issue, they report a genetic analysis of CBT for childhood anxiety disorders in the largest such analysis to date (comprising more than 1,300 children) [Lester et al, 2016]. The analyses focused on genes in the endocannabinoid system which has been shown to mediate fear extinction, a key mechanism in CBT for pathologic anxiety.…”