Major depressive disorder and bistability in an HPA-CNS toggle switch

Major depressive disorder (MDD) is the most common psychiatric disorder. It has a complex and heterogeneous etiology. Most treatments take weeks to show effects and work well only for a fraction of the patients. Thus, new concepts are needed to understand MDD and its dynamics. One of the strong correlates of MDD is increased activity and dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis which produces the stress hormone cortisol. Existing mathematical models of the HPA axis describe its operation on the scale of hours, and thus are unable to explore the dynamic on the scale of weeks that characterizes many aspects of MDD. Here, we propose a mathematical model of MDD on the scale of weeks, a timescale provided by the growth of the HPA hormone glands under control of HPA hormones. We add to this the mutual inhibition of the HPA axis and the hippocampus and other regions of the central nervous system (CNS) that forms a toggle switch. The model shows bistability between euthymic and depressed states, with a slow timescale of weeks in its dynamics. It explains why prolonged but not acute stress can trigger a self-sustaining depressive episode that persists even after the stress is removed. The model explains the weeks timescale for drugs to take effect, as well as the dysregulation of the HPA axis in MDD, based on gland mass changes. This understanding of MDD dynamics may help to guide strategies for treatment.Author summary: Major depressive disorder (MDD) is a prevalent psychiatric condition whose mechanisms are not fully understood. Existing treatments often take weeks to be effective and only benefit a portion of patients, necessitating a fresh perspective on understanding MDD. Research has shown a strong association between MDD and the dysregulation of the human stress hormone pathway. However, previous mathematical models of the stress hormone pathway have only explored its dynamics over a few hours or days, not capturing the weeks-long timescale relevant to MDD. To address this, we present a new mathematical model that incorporates the growth of the stress hormone glands, and their mutually inhibitory interactions with the brain. This model reveals how the brain and the stress axis toggle between normal and depressed states, with slow dynamics over weeks. It also explains why prolonged stress—but not brief stress—can trigger a sustained depressive episode. The model further sheds light on why antidepressant drugs take weeks to take effect. By comprehending the dynamics of depression, this model may provide valuable insights for guiding treatment strategies in the future.