AbstractThis chapter reviews and discusses the evidence supporting the role of 5‐HT in the mechanism of action of antidepressants in panic disorder (PD). The data were interpreted as compelling evidence in favour of a specific pharmacological effect on symptoms of panic and phobic avoidance. Results from our group provide strong circumstantial evidence as to the role of 5‐HT in these effects. In the light of the available data we have advanced the hypothesis that this effect of antidepressants might be mediated through stimulation of the postsynaptic, probably inhibitory, elements of the 5‐HT receptor in the septohippocampal area of the brain. Finally, the proposed mechanism of action does not preclude the involvement of other neuronal systems in certain dimensions of the psychopathology