HPA axis (depression and bipolar affective disorder)

Question 1

Glucocorticoids (e.g. cortisol) are hormones that are central in the stress response.

Answer 1

During acute stress, glucocorticoids induce changes such as mobilising energy reserves (e.g., to confront a threatening situation). Long-term changes include the regulation of immune responsiveness and activation of the sympathetic nervous system. Excessive secretion of cortisol leads to disruptions in cellular functioning and widespread physiologic dysfunction.

The HPA axis includes regulatory neural inputs (e.g., from the amygdala), a variety of releasing factors/hormones as well as a feedback loop which includes the hypothalamus, pituitary and adrenal glands. During stress, the hypothalamus secretes two hormones (from the paraventricular nucleus): corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP). CRH acts on the pituitary to secrete (from the anterior lobe of the pituitary) adrenocorticotropic hormone (ACTH), which in turn reaches the adrenal cortex through systemic circulation and causes it to secrete cortisol.

The functioning of the HPA axis is measured by levels of cortisol, CRH and ACTH release, and the dexamethasone (DEX) suppression test (DST) .

The dexamethasone suppression test measures the response of the adrenal glands to ACTH. Dexamethasone is given and levels of cortisol are measured. Cortisol levels should decrease in response to the administration of dexamethasone. In depressed patients cortisol levels often do not decrease as expected. Note however that abnormalities in the dexamethasone suppression test are not confined to mood disorders; they have also been reported in mania, chronic schizophrenia, and dementia.

In experimental animal studies, early adverse experiences produce longstanding changes in HPA axis regulation, indicating a possible neurobiological mechanism whereby childhood trauma could be translated into increased vulnerability to mood disorder. Previous studies have confirmed that adults who were abused as children have altered HPA responses to stress (Juruena, 2014).

The diminished responsivity to dexamethasone seen in studies led to the glucocorticoid-receptor hypothesis of depression. This hypothesis suggests that dysfunction of the HPA axis is linked to genetic or acquired defects of glucocorticoid receptors. This has coincided with findings from animal experimental studies that different classes of antidepressant medication increase expression of glucocorticoid receptors (Harrison, 2017). Interestingly, tricyclic antidepressants have been shown to effect changes in glucocorticoid receptors (Makin, 2004) whereas this is not the case for SSRIs such as citalopram or fluoxetine (suggesting a different mode of action).

Question 2

HPA axis dysfunction in depression

Answer 2

The hypothalamic-pituitary-adrenal (HPA) axis has been shown to be hyperactive in a significant number of patients with major depression.

There is hypersecretion of cortisol, corticotrophin-releasing factor (CRF), and ACTH, and associated adrenocortical enlargement. Levels of CRF have been shown to be elevated in the CSF.

The CRF hypersecretion normalises upon recovery of depression.

HPA abnormalities have been found in other psychiatric disorders including Alzheimer’s and PTSD.

About 50% of depressed inpatients do not show the normal suppression of cortisol secretion induced by administering 1 mg of the synthetic corticosteroid dexamethasone (Harrison, 2017).

In about 50% of patients whose depressive disorder is at least moderately severe, plasma cortisol secretion is increased throughout the 24-hour cycle. This increase in cortisol secretion is associated with enlargement of the adrenal gland (Harrison, 2017)

Question 3

HPA axis dysfunction in bipolar disorder (Daban, 2005)

Answer 3

Dysregulation of ACTH and cortisol response after CRH stimulation have been reported in bipolar patients. Changes in CRH secretion appear prior to manic or hypomanic symptoms are clinically evident.

Abnormal DST results are found more often during depressive episodes in the course of bipolar disorder than in unipolar disorder. Reduced pituitary volume secondary to LHPA stimulation, resulting in pituitary hypoactivity, has been observed in bipolar patients. The severity of the manic episode is highly correlated with the degree of neuroendocrine alteration.

Question 4

Summary points

Answer 4

HPA axis dysfunction is implicated in (but not specific to) mood disorders
Cortisol levels normally decrease in response to the administration of dexamethasone but this often does not occur in depressed patients
Early trauma can led to HPA axis dysfunction in adults (suggesting a predisposition to depression)
Glucocorticoid receptor dysfunction is thought to play a key role in some cases of depression
Some antidepressants (tricyclic) increase expression of effect glucocorticoid receptors but this is not the case for SSRIs
The hypothalamic-pituitary-adrenal (HPA) axis has been shown to be hyperactive in a significant number of patients with major depression