Why does it take several days for antidepressant medication to work – when its effect ofÂ increasing brain serotonin is almost immediate? Â Current thinking is that neurogenesis, the birth of new neurons, Â is responsible.
Prolonged, major depression is associated with atrophy (or wasting away) ofÂ the hippocampus, probably due to high levels of stress hormones in the brain, which prevent neurogenesis. The jury is out as to whether this atrophy causes depression, or whether it’s the other way round.
The neurogenesis theory really got going in around 2000 when researchers noticed that SSRI antidepressant medication (which increases serotonin levels) seemed to promote neurogenesis in the hippocampus:
Neurogenesis (the birth of new neurons) continues postnatally and into adulthood in the brains of many animal species, including humans. This is particularly prominent in the dentate gyrus of the hippocampal formation. One of the factors that potently suppresses adult neurogenesis is stress, probably due to increased glucocorticoid release.
Complementing this, we have recently found that increasing brain levels of serotonin enhance the basal rate of dentate gyrus neurogenesis. These and other data have led us to propose the following theory regarding clinical depression. Stress-induced decreases in dentate gyrus neurogenesis are an important causal factor in precipitating episodes of depression.
Reciprocally, therapeutic interventions for depression that increase serotonergic neurotransmission act at least in part by augmenting dentate gyrus neurogenesis and thereby promoting recovery from depression. Thus, we hypothesize that the waning and waxing of neurogenesis in the hippocampal formation are important causal factors, respectively, in the precipitation of, and recovery from, episodes of clinical depression.Â (Jacobs et al, 2000)
Now the thinking is that SSRI antidepressants don’t necessarily work by boosting brain signals whichÂ rely on lots of serotonin floating about, but that the extra serotonin helps our hippocampus grow. That in turn makes us feel better.
This would explain why the effect of SSRIs is delayed: the brain gets busy growing new neurons once you start taking them, and it takes a while before this makes a difference to how you feel. Â Interestingly, this growth occurs even when there is no apparent antidepressant effect (Campbell and MacQueen, 2004).
The neurogenesis theory needs more work though. A summary of current thinking published this month (Miller and Hen, Feb 2015) says:
- Diverse animal models of depression and anxiety have impaired neurogenesis
- Neurogenesis is consistently boosted by antidepressants in animal models when animals are stressed
- StoppingÂ neurogenesis in animal models impairs cognitive functions relevant to depression, but only a minority of studies find that stopping neurogenesisÂ causes depression or anxiety
- Recent human neuroimaging and postmortem studies are consistent with the neurogenic theory, but they are indirect
- A novel drug developed based on the neurogenic theory is promising in animal models
So researchersÂ are still trying to understand how neurogenesis is linked to depressive symptoms, and they are looking for a drug that boosts neuron birth better than existing antidepressants.
Implications of the neurogenesis theory
If we accept neurogenesis is a Good Thing that will make us feel better, then taking SSRI antidepressants for that effect alone (even if they have no impact on mood etc) may be sensible.
And/or we could look to boost neurogenesis naturally, through aerobic exercise (like running or dancing) and environmentalÂ enrichment (stimulation of the brain through physical and social environment).
Further reading and references
R Sapolsky (2001) Depression, antidepressants, and the shrinking hippocampus
B Jacobs et al (2000)Â Adult brain neurogenesis and psychiatry: A novel theory of depression
Campbell and MacQueen (2004)Â The role of the hippocampus in the pathophysiology of major depressionÂ
Miller and Hen (2015)Â The current state of the neurogenic theory of depression and anxiety
H van Pragg et al (1999) Running enhances neurogenesis, learning, and long-term potentiation in mice