For several decades, most psychiatrists have propagated the idea that 'depression' (Major Depressive Disorder, Endogenous Depression, Melancholia) is a brain disease.
For example it is often said that depression is caused by some kind of chemical abnormality involving serotonin (5-HT) or its receptors, or involving norepinephrine or dopamine or something.
But if depression really is a brain disease, then it would have to be a disease of the brain substance, and this pathological process would necessarily need to be detectable using normal medical science.
There are only a limited number of pathologies recognized by medical science, and 'neurotransmitter abnormalities' is not one of them. Abnormalities of messenger chemicals are a consequence, not a cause.
When I was a medical student we were taught a diagnostic scheme called the 'surgical sieve' since it was often used in creating a list of possible ('differential') diagnoses for someone with an unknown problem that might be admitted for surgical assessment. Another name is the pathologic(al) classification.
What happens is that each of the potential pathological causes is considered in tune. There are many versions and many use acronyms to make them memorable - for use in actual clinical practice.
Here is the 'surgical sieve' described in Wikipedia
1. There are two basic categories of disease - congenital (inborn - for example genetic) versus acquired.
Among acquired pathologies there are:
2. Neoplastic (eg cancer)
3. Metabolic (chemical)
4. Infective (germs)
5. Traumatic (accidents)
7. Vascular (caused by blood vessels)
9. Degenerative (due to age)
10.Idiopathic (caused by medical treatment - side effects)
Classic melancholia or endogenous depression is rare - probably less than 1 percent of the population would have an episode during their lifetime and it is devastating; usually it requires hospitalization or equivalent, and lasts for several months at least - but not more than a year or two (unless the person commits suicide, or dies of dehydration or starvation). It is perhaps the most intense suffering which a human can experience, survive and recover-from.
So, in melancholia which of the above might be a causal brain disease?
The point is that the pathological cause of melancholia needs to be relatively long lasting (months, a year) but also fully reversible.
What pathological processes fit that pattern?
The short answer is that none of them have been detected in the brain as a cause, not even metabolism (which is not a primary cause anyway - or when it metabolism is regarded as a primary cause it is usually congenital and usually long lasting and not spontaneously reversible, self-curing).
Whatever is the primary cause must be of a type that leads to a disease which lasts some months but potentially completely goes away - so the cause is *not* going to be neoplasia, for instance.
On this basis the clinical pattern of classic depression best fits with either infective or autoimmune disease.
For example an untreated infection will get worse for a while, then will eventually be defeated by the body - in pre-antibiotic days it might take months to recover from some infections.
Autoimmune disease exacerbations (e.g. rheumatoid arthritis) are not well understood, but the diseases may also wax and wane over a timescale of months.
However, it seems unlikely that there is a primary infective cause in the brain, because this is an encephalitis, and that produces different symptoms from melancholia (especially delirium).
However, depression might well be caused by infective causes elsewhere in the body since immune chemicals travel in the blood; and indeed it is well known that many infections can produce depressive symptoms (as a consequence of immune activation).
Perhaps some people with melancholia also suffer an autoimmune disease - could this primarily be a disease of the brain itself? It seems implausible, since autoimmune changes would produce inflammatory changes that would probably produce encephalitis type symptoms of delirium.
So as with infection it seems likely that melancholia may be a consequence of autoimmune disease elsewhere in the body, but not the brain itself.
In conclusion - it is not plausible that depression (classic melancholia) is a primary brain disease since the pattern of disease does not plausibly fit any of the possible causes; and it is more likely to be a consequence of pathological processes (one or more pathological processes such as infective or autoimmune disease) elsewhere in the body.
On these grounds, I would not be surprised if some episodes of serious endogenous depression/ melancholia turned out often (not always) to have an infective cause - or rather, a variety of infective causes.
This may even apply to autoimmunity, since autoimmunity can be caused by an infection.
So a fruitful investigative strategy might be 'search for infection'; and then treat it, if possible.
Or maybe even try treating presumed infection blind, by trying-out several different antimicrobial agents that cover a range of presumed infective causes?