Trazodone: from the mental pain to the "dys-stress" hypothesis of depression

Trazodone was developed according to the mental pain hypothesis, which was postulated from studying patients and which proposes that depression is associated with a decreased pain threshold. Trazodone is devoid of the typical aminergic properties of tricyclics and monoamine oxidase inhibitors. Its preeminent effects are increased pain threshold and alpha-adrenergic blockade. The "dys-stress" hypothesis maintains the concept of the decreased pain threshold in depression, but attributes it to a pathology of the stress response. Whereas physiologically this response produces various effects, including analgesia and alertness that improve the mental and physical performance, in some individuals it is impaired. Abnormalities of the stress response are proposed to be a predisposing or pathogenetic factor for depression and other conditions. According to the "dys-stress" hypothesis, the alpha-adrenergic blockade produced by trazodone and its congeners would also be implicated in its antidepressant activity, as well as its side effects and preferential uses in depressive states associated with adrenergic hyperactivity.