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

CAR:
[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 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].

Conclusion
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.

References

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