Optimizing treatments for anxiety by age and genetics

Abstract

This paper highlights recent human neuroimaging and cross-species developmental and genetic studies that examine how fear regulation varies by age and the individual, especially during the period of adolescence, when there is a peak in the prevalence of anxiety disorders. The findings have significant implications for understanding who may be at risk for anxiety disorders and for whom, and when, an exposure-based therapy may be most effective. We provide proof of concept for targeting treatment to the individual as a function of age and genetics, inferred from mouse and human studies, and suggest optimization of treatment for nonresponders.

Keywords: anxiety; development; genetics.

Figure 1

Emergence and peak in mental disorders during adolescence. One in five adolescents have a mental illness that will persist into adulthood (adapted from Ref. , with permission).

Figure 2

Developmental course of brain maturation during adolescence. Behavioral attributes are paralleled by hormonal and neurobiological changes that target specific brain regions and cell populations (adapted from Ref. , with permission).

Figure 3

Developmental and individual differences in emotional reactivity to cues of threat. (A) Adolescents show greater amygdala reactivity to threat cues (fearful faces) compared to children and adults. (B) Cortical and subcortical regions associated with reaction time for fear targets. The region of the left amygdala showed a positive correlation with reaction time (top panel), and the region of vPFC showed a negative correlation with reaction time (bottom panel). (Adapted from Ref. , with permission.)

Figure 4

Emotion regulation involves negative coupling of ventromedial frontoamygdala circuitry. (Adapted from Refs. and , with permission.)

Figure 5

Diminished fear extinction and anxiety symptoms following cognitive behavioral therapy (CBT) during adolescence. (A) Diminished extinction learning and retention of extinction memory is shown in adolescent mice compared to preadolescents and adults, as measured by freezing (taken from Ref. , with permission). (B) Similarly diminished fear-extinction learning was observed in human adolescents, as indexed by changes in skin conductance responses (SCRs) from early to late extinction (taken from Ref. , with permission). (C) Adolescents showed a trend toward diminished treatment effect size for anxiety symptoms after CBT compared to preadolescents or adults (taken from Ref. , with permission).

Figure 6

BDNF Val66Met polymorphism diminishes fear-extinction learning and efficacy of exposure therapy for PTSD. (A) Diminished extinction in adult knock-in mice with the BDNF Val66Met SNP as indexed by changes in freezing across extinction (taken from Ref. , with permission). (B) Similar effects were shown in human Met allele carriers, as measured by changes in skin conductance response (SCR) during extinction (taken from Ref. , with permission). (C) Met carriers showed less improvement after 8 weeks of CBT compared to non-Met carriers, as indexed by pre- and post-treatment scores on the Clinician-Administered PTSD Scale (adapted from Ref. , with permission).