ORGANUM
Since the time of Krapelin, a psychiatric pioneer who made us rethink mental as clinical rather than symptomatic, researchers have examined the brains and bodies of deceased patients suffering with depression in the clues for the underlying pathology of depression. This search for this underlying pathology is complicated by the fact that there is a general consensus major depressive disorder is not a single disease, but rather a collection of disorders that overlap with each other. Despite this, we are yet to find conclusive evidence allowing us to confidently group depression into separate disorders.
With the ever-growing fields of imaging, genotyping and computation, the 'biotypes' of depression are closer than they have been in history
There are some solid pathological findings in depression that have been reasonably replicated by different investigators. Some pathological findings have been known for a long time, while some are recent discoveries.
On average, patients have an overactive HPA axis. Compared with controls, depressed patients have increased cortisol levels over 24 hours. There is documentation elevated HPA activity in depression via excretion of urinary-free cortisol (UFC), 24-hour (or shorter) IV collections of plasma cortisol levels, salivary cortisol levels, and tests of the inhibition of the feedback loop. Evidence of increased HPA activity is seen in 20% to 40% of depressed outpatients and 40% to 60% of depressed inpatients.
Hypercortisolemia is due to increased corticotropin-releasing hormone (CRH) from the hypothalamus, along with decreased feedback inhibition. We can test for a disturbance of feedback inhibition using the dexamethasone suppression test (DST). Depressed patients show an initial decrease but then 'escape' from the suppression and return to abnormally high levels of cortisol. Although DST is replicable, it is not sensitive enough (many patients with depression will have normal cortisol/normal DST) or specific (Cushing's syndrome or simple environmental tests can cause an abnormal DST).
Postmortem studies have shown increased neurons in the hypothalamus, likely driving the process of increased HPA activity. This neuronal increase is likely in response to chronic stress.
Ahmed's conjuncture : We can think of HPA axis dysfunction as an underlying pathology/'cause', but in reality, we must question whether the constant low mood state of depression will cause overactivation of the HPA axis, leading to increased neuronal growth. As mentioned below, we can tie HPA dysfunction to a central disturbance linked with depressive disorders.
Elevated HPA activity is a hallmark of the mammalian stress response and one of the most unambiguous links between depression and the biology of chronic stress. Hypercortisolemia in depression suggests one or more of the following central disturbances:
Decreased inhibitory serotonin tone
Increased drive from norepinephrine, acetylcholine (ACh), or CRH
Decreased feedback inhibition from the hippocampus
Some studies in depressed humans indicate that a history of early trauma is associated with increased HPA activity accompanied by structural changes (atrophy or decreased volume) in the cerebral cortex.