Antidepressants, particularly tricyclic antidepressants (TCAs) like amitriptyline, modulate neurotransmitter systems by inhibiting serotonin and norepinephrine reuptake, which can reduce neurogenic inflammation and alter pain perception in cluster headache pathophysiology. While not a first-line treatment, these medications may help manage pain, reduce headache frequency, and provide prophylactic benefits through their central nervous system effects on pain modulation and neuronal sensitization.