Depression: the role of HPA abnormalities

It has been well-established for nearly 40 years that depression is associated with dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis. This manifests itself in two ways; activation of the HPA axis and blunting of the normal diurnal cortisol profiles. Cortisol is a counterregulatory hormone and with prolonged exposure it will induce visceral/central adiposity, insulin resistance, dyslipidemia, and hypertension, all of which are metabolic precursors to type 2 diabetes. Therefore, it may provide an additional explanatory link between depression and type 2 diabetes.

Assessment of the HPA Axis [1]

Conventional measures used to assess HPA axis activity include 24-hour urine free cortisol (UFC) levels, measurement of 8 am morning cortisol levels following administration of dexamethasone at 11 pm the evening before sampling (dexamethasone suppression test), measurement of adrenal gland size or volume, and performing the dexamethasone-corticotrophin releasing hormone (CRH) test. The dexamethsone-CRH test is performed by administering low dose dexamethasone for 2 days (or sometimes just the night before) and then measuring cortisol at 8 am following an attempt to stimulate cortisol secretion with CRH infusion. The failure to suppress cortisol with the dexamethasone suppression test or the dexamethasone-CRH test suggests damage to the HPA axis negative feedback loop and an inability of the HPA axis to terminate the stress response appropriately, resulting in excessive cortisol exposure.

Serum and salivary cortisol levels follow a distinct diurnal pattern. Under normal circumstances, cortisol reaches a peak in the morning 30-45 minutes after awakening. The rise in cortisol in the morning from awakening to 30-45 minutes post-awakening is termed the cortisol awakening response (CAR)[2]. Cortisol levels then gradually decline throughout the day, reaching a nadir between 11 pm and midnight. The use of salivary cortisol sample collection in field settings has allowed measurement of the cortisol awakening response as well as assessment of the diurnal cortisol curve from multiple sample collections from awakening to bedtime under ambient conditions[3].

HPA Axis Activation in Depression

Prior literature shows excessive cortisol exposure in individuals with depression, including elevated cortisol and adrenocorticotrophin hormone (ACTH), elevated 24-hour UFC levels, adrenal gland enlargement, and failure to suppress cortisol in response to the dexamethasone suppression test[4][1]. While one study failed to show an association of the response to the dexamethasone-CRH test with depression[5], another study found that cortisol levels were decreased in patients treated for major depressive episode following dexamethasone-CRH testing compared to baseline, suggesting the presence of HPA hyperactivity prior to treatment that responsive to intervention[6].

Altered HPA Axis Diurnal Profile in Depression


[2].These data classically been obtained by measuring salivary or serum cortisol levels immediately upon awakening and also 30-45 minutes after awakening and observing the difference between the two times or assessing the area under the curve. A few recent studies have demonstrated a low/blunted CAR in depressed states, indicating HPA axis dysfunction[7][8]. While a lower/blunted CAR might appear to contradict hyperactivity of the HPA axis suggested using the other measures summarized above, there is a growing literature suggesting that reduced variation and responsivity of the HPA axis to physiologic and experimental stimuli may be a consequence of chronic hyperactivity of the axis[9]. Thus one can measure elevated urine cortisol and a blunted CAR in the same depressed person.

Diurnal cortisol from awakening to bedtime:

Recent studies have examined cortisol diurnal variation in relation to depression using multiple salivary cortisol samples collected throughout the day. Two studies have shown a flatter diurnal cortisol profile in individuals with depression[10][11]. In addition, among individuals with coronary heart disease, the cortisol slope was flatter in a greater proportion of depressed patients than non-depressed patients, and this association was not seen in patients without coronary heart disease[12]. In contrast, one study did not find any significant differences in salivary cortisol diurnal variation among depressed compared to non-depressed subjects[13].

Cortisol reactivity to acute mental stress:

Two recent studies have shown that depressed individuals have a blunted cortisol response to acute mental stressors[14][15], which was even seen in individuals in remission from depression[15]. Similar to CAR, a blunted cortisol response to acute stressors may be suggestive of overactive HPA axis[9].

Impact of HPA Axis Dysfunction on the Pathophysiology of Depression and Diabetes

Mechanisms Through Which HPA Axis Dysfunction May Lead to Depression Both animal and human studies show that early adversity and chronic stress results in hyperactivity and long-term dysregulation of the HPA axis. This can result in several abnormalities that enhance the vulnerability to depression, including epigenetic modification of the glucocorticoid receptor[16] and cortisol-mediated abnormalities in neurogenesis, neuroplasticity, and/or neurotoxicity[16][17], particularly in the hippocampus, which is implicated in the pathogenesis of depression[17].

Mechanisms Through Which HPA Axis Dysfunction and Subclinical Hypercortisolism Lead to Insulin Resistance, Obesity, and Type 2 Diabetes (See Figures 1 & 2 - Proposed mechanisms through which hypothalamic-pituitary-adrenal axis dysfunction may lead to type 2 diabetes in the setting of depression[18])

Figure 1
Figure 1
Figure 2
Figure 2

Subclinical hypercortisolism can lead to accumulation of visceral fat by promoting differentiation and proliferation of adipocytes, redistributing fat from peripheral to central depots, and increasing the size and number of adipocytes[19]. These effects are likely mediated through glucocorticoid receptors that are more abundant on visceral than subcutaneous adipose tissue[19]. Cortisol also activates lipolysis and release of free fatty acids, which can induce insulin resistance[19]. Thus, because cortisol leads to visceral adiposity and insulin resistance, metabolic precursors to type 2 diabetes, subclinical hypercortisolism may provide an additional biological explanatory link between depression and type 2 diabetes[1]. Additionally, activation of the HPA axis leads to enhanced activity of the sympathetic nervous system, which ultimately leads to release of catecholamines and stimulation of the cytokine pathway[1]. Both catecholamines and cytokines are hormones that also induce insulin resistance[1].


The presence of HPA axis dysfunction in the setting of depressive disorders is well-established and manifests as multiple abnormalities, including hyperactivity, resulting in subclinical hypercortisolism, a blunted overall diurnal cortisol profile, and a blunted response to acute stress. Most studies examining these associations have been cross-sectional, so it remains unclear whether the HPA axis abnormalities preceded the onset of depression or whether depression precipitated the HPA axis dysfunction. However, data from human studies have shown that dysfunction of the HPA axis increases the risk for depression in healthy individuals[20]. Regardless of which abnormality occurs first (depression or HPA axis dysfunction), the HPA axis abnormalities associated with depression in individuals without diabetes provide a plausible biological mechanism through which depression leads to diabetes risk. Finally, HPA axis dysfunction has been cross-sectionally associated with diabetes, independent of depression[1][21], raising the possibility that HPA axis abnormalities represent a shared pathogenic mechanism leading to both disorders.


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