concept of allostatic load suggests that there is a fixed state in which enduring

environmental challenges are balanced by a hormonal response that is raised above

normal, basal levels. Patients with major depression, regardless of age, show higher

24-hour average cortisol levels when compared to normal subj ects (Linkowski et al.,

1985). Additionally, depressed patients reach the nadir of their daily cortisol cycle two to

three hours before control subj ects (Pfohl et al., 1985). This imbalance between

activation and recovery of the stress response is implicated in the inability to maintain

homeostasis, thus leading to neuroendocrine maladjustment and heightened risk for

depression (De Kloet, 2003).

 Stressful stimuli are categorized into two descriptive classes. Systemic stressors,

such as exposure to heat or cold, present immediate threats to somatic homeostasis while

processive stressors emphasize higher level cognitive processing (Herman and Cullinan,

1997). Common processive stressors include instability in the social hierarchy and loss

of environmental control. In accordance with the emotional nature of processive stress, it

is particularly implicated in a variety of psychiatric disorders including depression (for

review, see Anisman and Matheson, 2005).

 Inputs from the brainstem (if the stressor is systemic in nature) and cortical and

limbic structures (if the stressor is processive in nature) converge at the paraventricular

nucleus (PVN) of the hypothalamus where parvocellular neurons proj ect to the median

eminence. From there, corticotrophin-releasing hormone (CRH) and arginine

vasopressin (AVP) are released into the hypophyseal portal circulation, stimulating

adrenocorticotropic hormone (ACTH) release from the anterior pituitary corticotrope

cells into the general circulation. The release of ACTH then stimulates the synthesis and