Generalized anxiety disorder

Clinical picture (children and adolescents)

• In children, worry often centers on school performance, family members' health, punctuality, natural disasters and "doing it wrong"; perfectionism, frequent reassurance seeking and bodily complaints such as stomach aches and headaches are common. In children, a single physical symptom is enough for the diagnosis. A
• Prevalence: any anxiety disorder affects about 6.5% of children and adolescents worldwide, making it the most common group of mental disorders (Polanczyk et al., 2015). A
• Co-occurring conditions: other anxiety disorders (separation anxiety, social anxiety), depression, ADHD. Childhood anxiety is a risk factor for later depression. A
• Temperament: behavioral inhibition (wariness of the new) in early childhood is a known precursor of anxiety disorders. B

Circuits and networks

• Amygdala: threat perception; in children and adolescents with GAD, the right amygdala responds more strongly to angry faces shown too briefly to be noticed, in proportion to anxiety severity (Monk et al., 2008). B
• Prefrontal regulation: in healthy youth, the ventrolateral prefrontal cortex counterbalances the amygdala during threat; in GAD this counter-regulation is weak (Monk et al., 2008). B
• Bed Nucleus of the Stria Terminalis (bed nucleus of the stria terminalis): the amygdala runs the fear response to concrete threat, while the BNST runs sustained anxiety in the face of uncertain and unpredictable threat (Davis et al., 2010). The "something bad will happen" feeling of GAD fits this second circuit. B
• Insula: awareness of bodily sensations and intolerance of uncertainty; in anxious people, its activity increases while anticipating uncertain threat (Grupe and Nitschke, 2013). B
• Anterior Cingulate Cortex and Medial & Frontopolar Prefrontal Cortex: appraisal of threat and recall of extinction. B
• Hippocampus: telling contexts apart; failing to distinguish safe from dangerous settings spreads anxiety. B
• Hypothalamus & Pituitary and Locus Coeruleus: the stress response (HPA axis) and arousal. A
• Structural findings: in ENIGMA-Anxiety's GAD study (ages 5–90), differences in brain structure were small; GAD most likely rests on function and connectivity more than on structure (Harrewijn et al., 2021). A
• Networks: increased activity in the Salience network (salience and threat) network, worry-related repetitive thinking within the Default mode network (DMN). C

Neurotransmitter systems

• Serotonin (serotonin): the efficacy of SSRIs and SNRIs is the key evidence. A
• Noradrenaline (noradrenaline): arousal and vigilance; the locus coeruleus. The second target of SNRIs. B
• GABA: the target of benzodiazepines; long-term use is not recommended in children and adolescents because of the risk of dependence and misuse. A
• CRF and cortisol: the stress axis; part of the chemistry of the FEAR system in the book. B
• Heritability: about 30% in twin studies; the environmental contribution is large (Hettema et al., 2001). A

Developmental course

• Anxiety disorders are among the earliest-onset mental disorders; GAD usually becomes evident in late childhood and adolescence. A
• The amygdala matures early while prefrontal regulation keeps maturing through adolescence; this maturational gap is linked to the rise in emotional reactivity during adolescence. B
• Untreated childhood anxiety often continues into adulthood and raises the risk of depression and substance use. B

Treatment and the systems it targets

• In children and adolescents (ages 7–17, 488 patients; GAD, separation anxiety and social anxiety), clear improvement at 12 weeks: CBT + sertraline 80.7%, CBT alone 59.7%, sertraline alone 54.9%, placebo about 24% (CAMS; Walkup et al., 2008). A
• First line: cognitive behavioral therapy (CBT) with exposure; parent involvement and breaking the cycle of parental reassurance and support for avoidance. A
• Medication: SSRIs (sertraline, fluoxetine, fluvoxamine) are effective; the FDA-approved medication for GAD in children and adolescents is duloxetine (ages 7–17, an SNRI). The suicidal-thinking warning and close monitoring apply to antidepressants. A

Link to the book (The Green Walnut on the Couch)

• In the book (translated from the Turkish original):
  • FEAR system, clinical: "phobias, generalized anxiety, PTSD, behavioral inhibition".
  • BNST, clinical: "Generalized anxiety, chronic stress".
  • BNST, note: "Generalized anxiety and the “feeling that something bad will happen” (the description of PANIC in Chapter 3) may be better explained by a BNST-dominant pattern."
  • Amygdala, clinical: "Anxiety, behavioral inhibition, PTSD, callous-unemotional traits".
  • Hippocampus, clinical: "PTSD, generalized anxiety, childhood amnesia".
  • PANIC/GRIEF system, clinical: "separation anxiety, panic, depression, complicated grief".

In the atlas

Regions

Core structures in bold.

Networks

Neurotransmitter pathways

Panksepp systems

References

1. Davis M, Walker DL, Miles L, Grillon C (2010). Phasic vs sustained fear in rats and humans: role of the extended amygdala in fear vs anxiety. Neuropsychopharmacology, 35(1), 105–135. Search PubMed
2. Grupe DW, Nitschke JB (2013). Uncertainty and anticipation in anxiety: an integrated neurobiological and psychological perspective. Nature Reviews Neuroscience, 14(7), 488–501. Search PubMed
3. Harrewijn A et al. (2021). Cortical and subcortical brain structure in generalized anxiety disorder: findings from 28 research sites in the ENIGMA-Anxiety Working Group. Translational Psychiatry, 11, 502. Search PubMed
4. Hettema JM, Neale MC, Kendler KS (2001). A review and meta-analysis of the genetic epidemiology of anxiety disorders. American Journal of Psychiatry, 158(10), 1568–1578. Search PubMed
5. Monk CS et al. (2008). Amygdala and ventrolateral prefrontal cortex activation to masked angry faces in children and adolescents with generalized anxiety disorder. Archives of General Psychiatry, 65(5), 568–576. Search PubMed
6. Polanczyk GV et al. (2015). Annual research review: a meta-analysis of the worldwide prevalence of mental disorders in children and adolescents. Journal of Child Psychology and Psychiatry, 56(3), 345–365. Search PubMed
7. Walkup JT et al. (2008). Cognitive behavioral therapy, sertraline, or a combination in childhood anxiety. New England Journal of Medicine, 359(26), 2753–2766. Search PubMed