The Third Ventricle Hypothesis of depression

C.A. Hendrie and A.R Pickles, University of Leeds, UK

The Third ventricle is shown in red

Third ventricle shown in red

The Third ventricle hypothesis  was first proposed by Colin Hendrie and Alasdair Pickles in 2010. It considers that the defensive behavioural cluster associated with depression is induced by cytokine release into the third ventricle and that this developed as a response to the social emergency of individuals of our ancestral stock needing to remain in social groups that had become hostile to their presence.

Proposed mechanism of action: The Third Ventricle Hypothesis (1, 2, 3, 4)  proposes the behavioural cluster associated with depression is produced by an acute release of inflammatory cytokines into the third ventricle. This causes damage to those structures and pathways that contact the ventricle and it is this damage that produces the defensive behavioural syndrome. Several lines of evidence are in keeping with predictions based upon the third ventricle hypothesis including (a) findings that show depression to be associated with a cytokine mediated inflammatory event somewhere in the system (5, 6, 7, 8) and (b) imaging studies revealing that the third ventricle is enlarged in depressives (9, 10), which indicates a damage-induced loss of volume in the structures surrounding it (See Hendrie & Pickles, 2010). The analogy proposed by Hendrie & Pickles (2010) is that of an explosion, where the damage produced by this cytokine release is detectable long after the event that caused it has dissipated.  

Ethological perspective: The behavioural cluster associated with depression includes hunched posture and avoidance of eye contact (which are primarily defensive), lack of appetites for food and sex (which reduce the need to compete for these resources) plus social withdrawal and sleep disturbance (which reduce the probability of engaging in potentially damaging social contact). This cluster together serves to reduce an individual’s attack provoking stimuli in a hostile social environment.

Evolutionary adaptation: Depression is not however a permanent state and is relieved, at least temporarily after a given period of time. Thus, individuals who managed to remain in their groups until after the social emergency had passed had at least some opportunity for further reproduction, no matter how slight and this provided the net gain in fertility (over those who did not remain in the group) necessary for this to become an evolutionary adaptation. Depression is primarily seen in adults and often experienced following the loss of a child; break-up of a relationship; loss of a partner/spouse; death of a parent and/or the loss of a job (and the social status that goes with it). Hence, the hypothesis holds that the key stimulus for triggering depression in individuals that have this adaptation is ‘damage to reproductive potential’. Damage to reproductive potential is most clearly seen where there has been a transition from high social status that also confers reproductive advantage to lower social status where this reproductive advantage is lost.  

Association with neuroanatomy: The third ventricle is implicated because the behaviours associated with depression can be related to structures that contact this ventricle. The hypothalamus lies at one end of the ventricle and this accounts for the effects on appetites for food and sex whilst the pineal lies at the other and has influence on circadian rhythms and sleep/wake cycles. Other behavioural symptoms of depression can be accounted for by effects of the amygdala and the hippocampus whose major pathways (stria terminalis and fornix) pass through the ventricle.

Progress: None, because of lack of funds. The development of the Third Ventricle hypothesis coincided with the period when most of the world’s big pharmaceutical companies were pulling out of psychiatric drug research and closing facilities. The consistent feedback we have had from these companies since then is that they are not interested in depression and hence have no interest in developing new theories. UK government funding for basic research into depression has also been withdrawn and there have been no grants for this for at least the last 5 years. Many university-based research facilities have also been closed in consequence and the expertise required to develop the new antidepressant drugs is being lost. New drugs are needed because we now know that the ones we currently have are no more effective than placebo (11).

Our conclusion is hence that the only way to move the Third Ventricle hypothesis forward is to seek funding that does not come from the pharmaceutical industry or government. We would therefore welcome contact from anyone who may be interested in sponsoring our research into the Third Ventricle hypothesis or who can help with ideas about how to raise the necessary funds.  An email address is given at the top of this page.


1. Hendrie, C. A., & Pickles, A. R. (2009). Depression as an evolutionary adaptation: Implications for the development of preclinical models. Medical hypotheses, 72(3), 342-347

2.Hendrie CA, Pickles AR (2010) “Depression as an Evolutionary Adaptation: Anatomical Organisation Around the Third Ventricle” Medical Hypotheses 74: 735-740

3. Hendrie CA, Pickles AR (2012) The failure of the antidepressant drug discovery process is systemic J Psychopharm 27(5) 407–416

4. Hendrie CA, Pickles AR (2010) Depression as an evolutionary adaptation: Implications for the development of new drug treatments. European Psychiatric Review 3:46

5. Hendrie CA, Pickles AR (2011) Depression: An evolutionary adaptation organised around the third ventricle In: Brinkworth M, Weinert F (eds) Darwinian Repercussions Darwinism in anInterdisciplinary Context Heidelberg, New York, London: Springer

6. Miller, A. H., Maletic, V., & Raison, C. L. (2009). Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression.Biological psychiatry, 65(9), 732-741.

7. Raison, C. L., Capuron, L., & Miller, A. H. (2006). Cytokines sing the blues: inflammation and the pathogenesis of depression. Trends in immunology, 27(1), 24-31

8. Rothwell, N. J. (2004). Cytokines‐killers in the brain?. The Journal of physiology, 514(1), 3-17

9. Baumann B, Bornschlegl C, Krell D, Bogerts B. Changes in CSF spaces differ in endogenous and neurotic depression A planimetric CT scan study. J Affect Dis 1997;45:179–88.

10. Cousins, D. A., Brian Moore, P., Watson, S., Harrison, L., Nicol Ferrier, I., Young, A. H., & Lloyd, A. J. (2010). Pituitary volume and third ventricle width in euthymic patients with bipolar disorder. Psychoneuroendocrinology, 35(7), 1074-1081

11. Khan, A., Faucett, J., Lichtenberg, P., Kirsch, I., & Brown, W. A. (2012). A systematic review of comparative efficacy of treatments and controls for depression. PloS one, 7(7), e41778.


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