Re-reading the interview with Roland Kuhn (discoverer of the first tricyclic antidepressant Imipramine, and thereby discoverer of the concept of antidepressant) in David Healy's The Psychopharmacologists II; I noticed Kuhn's emphasis on the diurnal (daily) cycle of mood in melancholia (also known as endogenous depression), which he regarded as having core diagnostic significance.
Patients with endogenous depression tend to wake very early in the morning, feeling terrible and improve somewhat through the day.
This is the opposite of the much commoner 'neurotic' depression, where patients feel worse as the day goes on and have difficulty getting off to sleep.
Kuhn regards the distinctive diurnal rhythm of melancholia as evidence that it is an illness, something which comes-upon the patient rather than a consequence of their personality or being caused by the stresses of life.
This is a good argument, and I realized that I did not have any theory as to the cause of the diurnal rhythm.
In general, I have focused on two contributory causes to melacholia:
1. The Malaise theory - that immune activation of cytokines causes feelings of illness, fatigue and the 'vital' or physical signs such as aches, pains, heaviness. This would be a positive cause of misery.
The causes of malaise are the causes of immune activation: infection, autoimmunity, inflammation due to tissue damage, cancer etc.
2. Demotivation due to central dopamine deficiency, - this would be a cause of negative phenomena such as anhedonia (inability to feel pleasure) and probably psychomotor retardation (subjective slowing of thought, and observable slowing of response and speech; and reduced movement - resembling Parkinsonism, catatonia and the side effects of antipsychotics/ neuroleptics - which are all dopamine deficiency states).
Malaise or dopamine-deficiency-demotivation independently could cause mild to moderate depression, but when these two are powerful, sustained and coincident - perhaps this leads to the (thankfully) very rare phenomenon of severe melancholia.
Of these supposed factors in melancholia, it is cytokines (comprising some dozens of related and interacting immune chemicals - interleukins, tumor necrosis factors etc) which are the most most obvious candidate cause for the diurnal rhythm.
Some cytokines (like the interferons) can cause acute depression within minutes if injected; and (from a quick survey of the literature) it seems that some cytokines exhibit diurnal rhythms in blood levels - some seem to peak in the early morning when depressed mood is at its worst.
(Alternatively, some kind of 'analgesic' cytokine - or perhaps cortisol - which protects against low mood may have a trough at the time when mood is worst.)
So it seems possible that a daily cycle in cytokines might lead to daily changes in malaise (feelings of fatigue, aches and pains, and feeling ill) which might drive the cyclical pattern of mood in endogenous depression.
So, I am suggesting that the daily cycle of cytokine blood levels drives the daily cycle in depressed mood in melancholia.
This hypothesis is straightforward to test in principle, by recording diurnal changes in mood and behaviour and charting them against frequent sampling of cytokines (and perhaps other immune chemicals including cortisol).
The hypothesis would be that the profile of mood change (severity of depression) would superimpose on the profile of cytokine change - probably with some time lag between the chemical change and the effect on mood.
But this would be extremely difficult to test in practice.
Melancholia is rare, with an incidence of probably only tens of cases per million population per year; and most of these would be too severe to conduct research on (especially research requiring multiple and frequent blood samples) and it is dubious whether such patients could give informed consent to research anyway.
(The problem is stopping such patients committing suicide (or becoming dehydrated) while waiting for them to recover; and the effective treatments with tricyclic drugs, and the possibility of electroconvulsive therapy every few days, might well be expected to interfere with cytokines.)
Still, the idea of cytokine rhythms causing diurnal mood patterns seems worth floating as a potential way of comprehending this core feature of melancholia, and an idea which may at some point become testable indirectly in a few patients - even if not testable in large trials, or by an obvious and direct experiment using current technology.