Mechanisms of depression: role of the HPA axis

Hyperactivity of the hypothalamic–pituitary–adrenal (HPA) axis is a core neurobiological feature of major depression. The responsible mechanisms are unclear. Hyperactivity is arguably a causal factor of depression, and not an epiphenomenon. It can be that the antidepressants used in clinical practice are efficacious through their effect on the HPA axis. Several drugs directly targeting the HPA axis are in development, but currently none of these has shown satisfactory efficacy and tolerability in large-scale trials.