In a 27‑year‑old patient with panic attacks presenting with tachycardia and dyspnea, which neurotransmitter system is most commonly overactive in panic disorder: dopamine, serotonin, γ‑aminobutyric acid (GABA), or norepinephrine?

Noradrenergic System Overactivity in Panic Disorder

The noradrenergic (norepinephrine) system is the neurotransmitter system most commonly overactive in panic disorder, particularly in relation to the racing heart (tachycardia) and shortness of breath (dyspnea) symptoms this patient experiences. 1, 2

Neurobiological Basis

The noradrenergic system, originating primarily from the locus ceruleus, plays a central role in panic disorder pathophysiology:

• Norepinephrine levels are consistently elevated in cerebrospinal fluid and urine of patients with PTSD and panic disorder, with CSF norepinephrine concentration correlating directly with symptom severity 1

• The locus ceruleus (the major norepinephrine-containing nucleus) drives the autonomic symptoms characteristic of panic attacks, including tachycardia, dyspnea, and the sensation of impending doom 3

• Suppression of locus ceruleus activity produces calming effects, while agents that increase noradrenergic activity (such as yohimbine, an alpha-2 antagonist) can provoke panic attacks in susceptible individuals 3

• Medications that reduce CNS adrenergic activity (such as prazosin, an alpha-1 antagonist) effectively treat panic-related symptoms, providing further evidence of noradrenergic overactivity 1

Why Not the Other Systems?

While panic disorder involves multiple neurotransmitter abnormalities, the other options are less directly responsible for the specific symptoms described:

• Serotonin dysfunction exists but plays a modulatory role rather than directly causing the acute autonomic symptoms; SSRIs are effective treatments but work by regulating the raphe nucleus and modulating anxiety over time, not by addressing the immediate tachycardia and dyspnea 3, 4

• GABA deficiency contributes to anxiety susceptibility and benzodiazepines (which enhance GABA activity) are effective treatments, but GABA dysfunction represents reduced inhibitory tone rather than the active overactivity driving sympathetic symptoms 4, 5

• Dopamine has minimal direct involvement in panic disorder pathophysiology compared to norepinephrine, serotonin, and GABA systems 2, 5

Clinical Correlation

This patient's presentation is classic for panic disorder with prominent noradrenergic-mediated autonomic symptoms:

• Tachycardia and dyspnea are direct manifestations of excessive sympathetic nervous system activation driven by noradrenergic overactivity 1

• The sensation of impending death ("feeling she's having a heart attack or about to die") reflects the suffocation and air hunger sensations associated with CO2-induced panic attacks, which are mediated through noradrenergic pathways 1

• Post-attack exhaustion is consistent with the physiologic aftermath of sustained noradrenergic surge 6

Therapeutic Implications

Understanding noradrenergic overactivity guides treatment selection:

• Alpha-1 antagonists like prazosin (1-10+ mg at bedtime) directly reduce noradrenergic activity and are Level A recommended for panic-related symptoms 1

• High-potency benzodiazepines (such as alprazolam or lorazepam 3 mg/day average) provide rapid relief by enhancing GABA inhibition of the overactive noradrenergic system 7, 6

• SSRIs and SNRIs work through serotonergic modulation of noradrenergic tone but require 4-8 weeks for full effect 8, 2