Noxious mystery substance released into the third ventricle is the cause of depression!

The Ventricles of the Brain (Ross & Wilson)

You can always count on the journal Medical Hypotheses (published by Elsevier) for a good laugh. The Editor-in-Chief (Bruce G. Charlton) accepts all sorts of completely speculative crackpot articles. Who can forget the classic, Is there an association between the use of heeled footwear and schizophrenia? [see The Journal of Truly, Truly Outrageous Medical Hypotheses.] Or the crowd favorite, Ejaculation as a potential treatment of nasal congestion in mature males? [see More Truly, Truly Outrageous Medical Hypotheses.]

The latest masterwork (Hendrie & Pickles, 2009) contends that major depression is an evolutionary adaptation triggered by damage to one's reproductive potential, which in turn causes the release of a yet-to-be-discovered nasty substance into the third ventricle:

...depression is an evolutionary adaptation that emerged where displaced dominants needed to make a transition to lower social status and that is now triggered, in those individuals that have this adaptation, by damage to reproductive potential from any source. The behavioural cluster associated with depression includes adoption of a hunched posture, avoidance of eye contact, loss of appetite for food and sex and sleep disruption. This behavioural cluster serves to reduce an individuals’ attack provoking stimuli and so facilitates this social change. When viewed in this context, it becomes clear that many of the brain areas that mediate these behaviours (e.g. the pineal, hypothalamus and amygdala, whose main output, the stria terminalis passes through) all lie in close physical proximity to the third ventricle. In consequence, it is proposed that depression has its origins within this ventricle. Disruption of circadian rhythms, appetite for sex and food and fear/defence responses would all ensue if structures that border the third ventricle, or whose main connections pass through it, were damaged. Therefore, it is hypothesised that the behavioural expression of this adaptation is mediated by a single or pulsatile release of a yet to be identified noxious factor into the ventricular space.

Where did these ideas come from?? Like most everyone else, Hendrie and Pickles (2009) are not satisfied with the current crop of antidepressants or with the monoamine hypothesis of depression (Hirschfeld, 2000), which is incomplete at best. Then they take a giant leap and make up one of those evo psych just-so stories:

...damage to reproductive potential is now the key stimulus that triggers depression in those modern humans that have this adaptation, rather than loss of status per se.This analysis accounts for why it is life events such as the death of a spouse or a child that are major causes of depression.

How about the death of a sister or a grandmother or an uncle? Or a beloved pet? Do these tragic events damage the reproductive potential of those who are prone to depression in such circumstances?

And why is the third ventricle so important?

...many of the brain areas mediating the behavioural cluster associated with depression are in close physical proximity to the third ventricle. For example, the pineal is involved with the regulation of sleep/wake cycles, the hypothalamus regulates appetite for food and sex and the amygdala, whose main output, the stria terminalis passes through the third ventricle has an influence on social affiliation as well as fear and defensive behaviours. Hence, it is proposed that this may well be the site where the behavioural expressions of depression are initiated.

Fig. 3 (Hendrie & Pickles, 2009). Functions of structures closely associated with the third ventricle. The table shows those structures that directly border the third ventricle and those that are connected to it via structures that pass through. The function of the behavioural cluster associated with depression is to reduce the emission of attack provoking stimuli. This is achieved through increased defensiveness, decreased motivation to engage in consummatory behaviours and sleep disturbance, so that there are activity peaks at times when other individuals are inactive. The damage produced by the release of a noxious substance into the CSF [cerebrospinal fluid] is not under precise control...

Uh huh. And how are we supposed to identify this unknown toxin released into the CSF in order to develop new treatments? They come up with two ideas:

The first is to try and identify the proposed substance that is causing the damage with a view to blocking its action or preventing its’ release. This would however be technically difficult as it relies on obtaining samples of CSF from the third ventricle at a precise time, to catch the pulse or pulses. As this would probably not be possible in humans, animal models will be of importance...

The second approach is to develop treatments that target the damage and so reverse its effects. Given that for purely statistical reasons, it is mostly glial cells that are affected, as may also be reflected in alterations to peripheral measures, growth factors such as BDNF and GDNF could be of benefit. ... Nonetheless, treatment using this approach will always be vulnerable to a second or subsequent release of the causative agent and hence the identification of that remains the real prize.

Any takers? What a wonderful project for a graduate student!

References

Hendrie, C., & Pickles, A. (2009). Depression as an evolutionary adaptation: Anatomical organisation around the third ventricle. Medical Hypotheses DOI: 10.1016/j.mehy.2009.10.026

Hirschfeld RM. (2000). History and evolution of the monoamine hypothesis of depression. J Clin Psychiatry 61 Suppl 6:4-6.