The HPA Axis: A Target for Antidepressants?

Stress serves an important role in our lives. It propels us to jump out of the way of speeding cars, finish papers by their deadlines, and push ourselves to excel in sports. However, when stress becomes a chronic occurrence, it can wreak havoc on both our psychological and physical selves. Due in large part to the over-activation of the hypothalamic-pituitary-adrenal (HPA) axis, long-term stress can lead to, among other things, mood disorders, chronic fatigue syndrome, and diminished immunity. However, new treatments and screening methods are being developed to both assess the functionality of the HPA axis as well as target it for treatment. For those suffering from mental illness, this could mean a broader range of options not currently used in psychiatry.

The HPA Axis – What is it?

The HPA axis is a system in the body designed to handle acute stress situations. As part of the sympathetic nervous system, it regulates the body’s response to stress via the release of glucocorticoids, epinephrine, and norepinephrine into the periphery (Olson, Marc, Grude, McManus & Kellermann, 2011). Through input from the cortex and feedback through the blood, the hypothalamus synthesizes and releases corticotropin-releasing hormone (CRH) into the circulation; CRH stimulates the anterior pituitary gland to secrete adrenocorticotropic hormone (ACTH). ACTH continues on to stimulate the release of glucocorticoids (cortisol, norepinephrine, and epinephrine) from the adrenal cortex (Higgins and George, 2007).


The result of these hormones is enhanced attention, accelerated cardiac output and respiration, increased catabolism, and redirection of blood flow to provide the best perfusion to the brain, heart, and muscles – commonly known as the “fight or flight” response (Olsen et al., 2011). Under healthy circumstances, this system will shut itself off via a negative feedback loop once the stressor has dissipated. If left unchecked, chronic stress causes the system to essentially become desensitized; the brain is unable to turn down the HPA axis, which exposes the brain to excess glucocorticoids (Higgins and George, 2007)

According to Olsen et al. (2011), different types of stress, physiological and emotional, activate the HPA axis through separate, but convergent, pathways with both circuits resulting in glucocorticoid release. Physiological stress is detected by somatic, visceral, or circumventricular pathways; this sensory information is communicated through the vagus nerve to the NTS, causing stimulation of the hypothalamus (specifically, the paraventricular nucleus of the hypothalamus, or PVN). An emotional response to stress, however, can occur without a primary sensory stimulus. When activated, limbic regions of the brain, such as the amygdala and hippocampus, highly involved in emotional processing, can also stimulate the hypothalamus (Olsen et al., 2011).

Impact of chronic stress

As mentioned previously, excessive and prolonged activation of the body’s stress system can disturb normal physiological and behavioral functions (Lo Sauro, Ravaldi, Cabras, Faravelli & Ricca, 2008). According to Stangor (2012) the experience of prolonged stress has a direct negative influence on physical health because at the same time that stress increases activity in the sympathetic division of the ANS, it also suppresses activity in the parasympathetic division of the ANS. When stress is long-term, the HPA axis remains active and the adrenals continue to produce cortisol. This increased cortisol production exhausts the stress mechanism, leading to fatigue and depression.

Along with weakening the immune system, decreasing energy, and contributing to heart disease, dysfunctions in the HPA axis have been reported in several psychiatric conditions, including mood disorders, anxiety disorders, obsessive-compulsive disorder, post-traumatic stress disorder, alcohol dependence, and schizophrenia (Lo Sauro et al., 2008).  Recent studies have identified the following unusual symptoms in patients: high concentrations of CRF in the central nervous system (CNS), abnormal results to corticoid response tests, hyperactive CRF neuron activity, and abnormal CRF receptor expression patterns (Keller, McCluskey, Morgan, O’Connor, 2006). Continual activation of the HPA axis leads to an excess of cortisol in the body. The subsequent desensitization of cortisol receptors leads to increased activity of the pro-inflammatory immune mediators and disturbances in neurotransmitter transmission (Lundbeck Institute, n.d).            



Treatment Developments

Due to recent research linking HPA axis dysregulation and psychiatric illnesses, studies have been underway to find medications aimed at targeting components of the HPA axis, with CRH and glucocorticoid receptor antagonists (to lower cortisol) at the forefront.

Many of the current antidepressants may already exert therapeutic effects partly through regulation of the HPA axis. Such a hypothesis was first considered when exposing rats to imipramine, a tricyclic antidepressant (TCA), resulted in decreased immobility, indicating a reduction of CRH influence was linked to a reversal of anxiety and depression through classical treatments (Keller et al., 2006). These studies were further expanded when it was discovered that rats who had undergone imipramine treatment for two weeks showed signs of increased glucocorticoid receptor reactivity (Keller et al., 2006). Anti-anxiety treatments have shown similar results: benzodiazepines have been shown to result in a reduction of CRH concentration in the locus coeruleus, amygdala and the pyriform cortex, all of which are associated with stress behavior (Keller et al., 2006).

Along with medications already used to treat mental illness, drugs commonly used for other purposes have been looked into as potential regulators of the HPA axis. According to Howland (2013), mifepristone, as a potent antagonist of glucocorticoid receptors, is currently being investigated as a potential therapeutic agent for psychotic depression, posttraumatic stress disorder, and alcohol and cocaine dependence, as well as for mitigating the weight gain associated with the use of antipsychotic drugs and for improving cognitive dysfunction in schizophrenia and bipolar disorder. An analysis of mifepristone plasma concentrations from participants in three studies demonstrated a statistically significant correlation between plasma concentration and psychotic symptom improvement (Howland, 2013). In two studies, the response rate of patients with mifepristone concentrations greater than 1,660 ng/mL was significantly greater than the response rate in placebo-treated patients. Based on this analysis, another psychotic depression study is being conducted (Howland, 2013).

According to Scott and Dinan (2002), there is an accumulating body of evidence to support a significant role for vasopressin (AVP) in the treatment of depression. Conducting a review of available evidence between 1980 and 2001, they concluded that baseline plasma AVP is likely elevated in those with major depressive disorder. Although not entirely consistent, the bulk of the literature would, however, support either a normal or enhanced ACTH response to vasopressin and its analogues in depressed subjects, leading to an excess of cortisol in the system (Scott and Dinan, 2002). Thus, vasopressin antagonists have the potential to treat depression and other mental illnesses.

Although further research needs to be done, addressing the dysfunction of the HPA axis in psychiatric illnesses seems to be of vital importance, both for the person’s psychological as well as physical well-being. Although medications are often the first-line treatment for severe mental illnesses, there is also room for exploration of other stress-reduction techniques such as meditation, yoga, and deep-breathing. In addition to medicines, these techniques may also aid in regulating the HPA axis and thus, may be an important additive treatment method.


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Howland, R. (2013). Mifepristone as a Therapeutic Agent in Psychiatry. Journal of Psychosocial Nursing and Mental Health Services, 11-14.

Keller, P., Mccluskey, A., Morgan, J., & O’connor, S. (2006). The Role of the HPA Axis in Psychiatric Disorders and CRF Antagonists as Potential Treatments. Archiv Der Pharmazie,346-355.

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