If serotonin deficiency isn’t the cause of depression, then why do SSRIs work?

Acetaminophen (a.k.a paracetamol) relieves some types of headache. But this does not mean that these headaches are caused by acetaminophen deficiency. The brain doesn’t even produce acetaminophen.

The point of this analogy is to make clear that a medicine can work even if it is not acting on the cause of the symptom. In many cases a medicine can work even when the cause of the symptom is completely unknown.

This is the case with SSRIs — they alleviate some forms of depression, and also fail to work for many depressed people, but we still don’t know why. Lots of active research is going into this.

Quite a bit of research suggests that serotonin affects plasticity, so it seems as if the effectiveness of SSRIs arise through changes to neuronal circuits, rather than through changing the levels of serotonin as such. This would explain why the beneficial effects of SSRIs typically take weeks to show up, even though the levels of serotonin rise on the order of hours after taking a tablet. Changes to neuronal circuits involved in emotion and motivation may take quite a while to become effective.

Anyway, SSRIs remain controversial, and not just because they often fail to work. Even in people for whom it does work, the effects may not be long-lasting, and can often come with adverse side-effects. Much more research will be needed before we can say we understand what is going on with these medications, and with the disorders they are aimed at treating.

Further reading



This originally appeared on November 14, 2018 as an answer to the following question on Quora:

If it’s not clinically proven that the cause of depression is serotonin deficiency, then why do SSRI antidepressants work for many people?

4 thoughts on “If serotonin deficiency isn’t the cause of depression, then why do SSRIs work?

  1. Both St John’s Wort, an SSRI, which I tried once, and Prozac, with which I persisted for the three weeks of my initial prescription, made me feel utterly wretched, and disconnected from my own very existence. I cannot imagine how any degree of depression could have made me feel worse. Since then, I have avoided all mood-altering medication.

    I was slightly surprised not to see this sort of thing mentioned in your source’s list of side effects. Unless my reaction is highly unusual, I think it should be.

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