## Neurobiological Basis of Panic Disorder **Key Point:** Panic disorder involves dysregulation of multiple neurotransmitter systems, with the serotonergic and noradrenergic systems being the primary targets of pharmacotherapy. ### Serotonergic System - Decreased serotonin (5-HT) activity in the prefrontal cortex and amygdala - Leads to impaired emotional regulation and fear processing - SSRIs are first-line pharmacotherapy, targeting this dysfunction ### Noradrenergic System - Hyperactivity of the locus coeruleus (LC) in the brainstem - Excessive norepinephrine release contributes to autonomic hyperarousal - SNRIs and tricyclic antidepressants address this abnormality ### GABAergic System - Decreased inhibitory GABA function in the amygdala and prefrontal cortex - Loss of normal inhibitory control over fear responses - Benzodiazepines enhance GABA-A receptor function (short-term management) **High-Yield:** The "fear circuit" involves the amygdala (threat detection), prefrontal cortex (threat appraisal), and anterior insula (interoceptive awareness). Dysregulation of this circuit with serotonergic and noradrenergic imbalance is the cornerstone of panic pathophysiology. **Clinical Pearl:** SSRIs and SNRIs take 2–4 weeks to show efficacy because they require downstream neuroadaptation and increased GABA tone, not just acute neurotransmitter elevation. [cite:Harrison 21e Ch 397]
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