Establishing the Neurobiologic Basis of Treatment in Children and Adolescents With Generalized Anxiety Disorder

Abstract

Generalized anxiety disorder (GAD) is associated with significant morbidity in children and adolescents, yet only recently have the neuropharmacology and neurophysiology of this condition been studied in youth. Accumulating data suggest structural and functional abnormalities within the brain's fear networks in youth with GAD. Additionally, seven studies examined the efficacy of medications that modulate this system and, in some cases, the direct effects of these medications on structures within these networks (e.g. amygdala, ventrolateral prefrontal cortex [VLPFC]). In this review, we summarize the extant functional, functional connectivity, and structural neuroimaging data in children and adolescents with GAD. In addition, data concerning selective serotonin reuptake inhibitors (SSRIs), selective serotonin norepinephrine reuptake inhibitors (SSNRIs), atypical anxiolytics, benzodiazepines, and psychotherapy are reviewed in the context of the neurophysiology of pediatric GAD. The existing data suggest abnormal activity within the amygdala, VLPFC, and anterior cingulate cortex, as well as the possibility of impaired connectivity among these brain regions. In addition to numerous cognitive behavioral therapy (CBT) trials, five randomized, controlled psychopharmacologic trials primarily in youth with GAD suggest that SSRIs and SSNRIs are effective for this condition. These findings also raise the possibility that functional activity within the amygdala and VLPFC may be altered following successful treatment.

A Pilot Study of Anterior Cingulate Cortex Neurochemistry in Adolescents with Generalized Anxiety Disorder

“…Currently, first-line psychopharmacological treatments in pediatric patients with GAD are restricted to SSRIs [44] yet many adolescents do not respond to ‘first-line' psychopharmacological or psychotherapeutic interventions [9,45]. Recently however, a potent and selective mGlu receptor 2/3 agonist (LY354740) which acts presynaptically has been shown to decrease anxiety in a double-blind, placebo-controlled trial of adults with GAD [46].…”

“…In adolescents with anxiety disorders, dysfunction in the neural network responsible for emotional processing has frequently been observed [9]. Specifically, the anterior limbic network (ALN), a collection of subcortical and cortical structures which modulate complex emotional and fear processing capacities, is dysregulated in pediatric patients with GAD [10,11,12,13,14].…”

“…Specifically, the anterior limbic network (ALN), a collection of subcortical and cortical structures which modulate complex emotional and fear processing capacities, is dysregulated in pediatric patients with GAD [10,11,12,13,14]. Within the ALN, the anterior cingulate cortex (ACC) is implicated in the integration of cognitive and emotional processing [15,16,17,18,19], which are both thought to be disrupted in pediatric patients with GAD [9], and in fMRI studies of pediatric patients with GAD, the ACC is hyperactivated [12]. …”

Neural Function Before and After Mindfulness-Based Cognitive Therapy in Anxious Adolescents at Risk for Developing Bipolar Disorder

“…These circuits, which modulate emotional and social behavior and, ultimately, maintain emotional homeostasis (Strakowski et al 2011), include the amygdala, medial prefrontal cortex (Brodmann area [BA] 10/ 11), rostral insula, subgenual/rostral anterior cingulate cortex (ACC) (BA 25, BA 24/32), ventrolateral prefrontal cortex (VLPFC) (BA 10/47), and dorsolateral prefrontal cortex, structures that are frequently implicated in pediatric anxiety disorders (Blackford and Pine 2012;Strawn et al 2012cStrawn et al , 2013Strawn et al , 2014b.…”

Is There any Association Between Nesfatin-1 and Generalized Anxiety Disorder?

“…There is strong evidence for a neurobiological contribution to GAD. Some neurotransmitters have been indicated as possible contributors in the pathogenesis of GAD, including g a m m a -a m i n o b u t y r i c a c i d ( G A B A ) / benzodiazepine complexes 2,3 , serotonin and norepinephrine [4][5][6][7] and cholecystokinin 8 . Nesfatin-1 was discovered in 2006 by Oh-I et al 9 as an 82 amino acid polypeptide derived from the calcium and DNA-binding protein.…”