The cortisol hypothesis fails to establish a causal relationship. Supporting empirical evidence only demonstrates a correlation between elevated cortisol levels and depression. There is an ambiguity concerning whether high cortisol levels cause depression or if depression increases cortisol levels. Additionally, the increased incidence of MDD in females is associated with greater cortisol response variability rather than higher baseline levels of cortisol.
The association between cortisol and MDD in humans is complex. It appears dependent on the stage of illness, severity, and type of challenge employed. Cortisol dysregulation, specifically in response to stress, is associated with severe and acute presentations of MDD. However, chronic and less severe subtypes of MDD do not exhibit this association. Personality and social factors may be major drivers of these subtypes instead of cortisol levels. This fact weakens the cortisol hypothesis.