What is the etiology of depression (Major Depressive Disorder)?

High cortisol hormone levels cause depression

Question: What is the etiology of depression (Major Depressive Disorder)?
Position1 of 3›: Depression has a biological etiology
Argument1 of 3›: High cortisol hormone levels cause depression

The cortisol hypothesis states that depression results from the cessation of neuron birth in the hippocampus and other neural networks related to serotonin, dopamine, and norepinephrine. Cortisol appears to be the reason for this lack of neurogenesis.

The argument

The cortisol hypothesis of depression argues that depression is the result of the cessation of neuron birth in the hippocampus as well as in other neural networks related to serotonin, dopamine, and norepinephrine. Cortisol appears to be the reason for this lack of neurogenesis. Cortisol is a hormone produced by the adrenal glands and secreted by the body in response to stress. It is involved in the fight or flight response. MDD patients display a symptom called HPA-Axis hyperactivity. Over secretion of cortisol leads to reduced serotonin, dopamine, and noradrenaline in the brain. As a result, MDD patients have smaller hippocampi. Empirical evidence also revealed that cortisol dysfunction is proportionate to MDD severity. The study of Maberg et al. (2000) supports this hypothesis. Researchers concluded that neurogenesis supports the effect of antidepressants in a rat model for depression. The meta-analysis of Videbech and Ravnkilde (2004) also found up to a 10% reduction of the hippocampus in the brains of depressed patients. The shrinking of the hippocampus was significantly correlated to the number of depressive episodes. Overall, the cortisol hypothesis explains depression in terms of neuroplasticity and hormonal imbalance.

Premises

[P1]Excess cortisol from HPA-axis hyperactivity suppresses neurogenesis in the hippocampus and reduces serotonin, dopamine, and noradrenaline levels. [P2] MDD patients exhibit cortisol dysfunction and hippocampal shrinkage proportionate to the severity and number of depressive episodes. [P3] Empirical studies show that restoring neurogenesis underlies antidepressant efficacy, linking the hormonal–neural mechanism to depression itself. [C] Therefore, depression has a biological etiology rooted in cortisol-driven hormonal and neuroplastic dysfunction.

Counter-arguments

The cortisol hypothesis fails to establish a causal relationship. Supporting empirical evidence only demonstrates a correlation between elevated cortisol levels and depression. There is an ambiguity concerning whether high cortisol levels cause depression or if depression increases cortisol levels. Additionally, the increased incidence of MDD in females is associated with greater cortisol response variability rather than higher baseline levels of cortisol. The association between cortisol and MDD in humans is complex. It appears dependent on the stage of illness, severity, and type of challenge employed. Cortisol dysregulation, specifically in response to stress, is associated with severe and acute presentations of MDD. However, chronic and less severe subtypes of MDD do not exhibit this association. Personality and social factors may be major drivers of these subtypes instead of cortisol levels. This fact weakens the cortisol hypothesis.

Rejecting the premises

[Rejecting P1] The mechanism is described in one direction only. Depression itself disrupts sleep, appetite, activity and stress exposure, all of which move cortisol, so the ordering the premise needs — hormone first, illness second — is assumed rather than demonstrated. [Rejecting P2] The association is neither universal nor uniform. Hippocampal volume differences are group averages with wide overlap between depressed and non-depressed people, and cortisol dysregulation tracks acute, severe presentations while chronic and milder subtypes frequently show no such pattern. [Rejecting P3] That neurogenesis accompanies antidepressant response does not establish that its absence caused the illness. A treatment can work through a pathway that is not the origin of the disorder, and the rodent work involved measures behaviour under stress rather than the human condition being explained.