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?


14 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.

  2. As far as I know, SSRIs don`t work at all for more than 1/3 of patients.
    Even the theory of increased plasticity cannot explain this phenomena.
    In line with critics, therapists often highlight that you have to “believe in” the effect of SSRIs.
    …which means if there is no effect, it is the responsibility / negative attitude of the patient.

      • In fact, nero-science and the know how of the brain is very limited. If you look at the history of SSRIs, you will discover that there is no evidence of anti depressant effects or root-cause relations between depression and serotonin levels.
        SSRIs also work with a placebo effect.

      • Well I am a neuroscientist and I can assure you that that is not quite right. There are people who do experience an anti-depressant effect over-and-above placebo. All drugs that are approved for use have to exceed the placebo effect. That is distinct from the observation that serotonin levels are not causal when it comes to depression. Paracetamol can still help with pain relief even though pain is not caused by lack of paracetamol.

      • right but according to my research it was an incident that an anti depressant effect was discovered …and it shall be still unclear if serotonin increase is effective.

      • I disagree. If you experience the bundle of very negative side effects, you want to know how it works and if there are long term undesirable damages.
        Besides it is important to understand anti- depressants better if they are not of help for a huge group of patients. Of course, you have to investigate the reason for failure to be able to exclude options on your search for something new.
        Another challenge might be the fact that the cause for depression is not clear.
        The theory of a chemical imbalance is not proven 100% but used as a frequent marketing slogan.

  3. If they wouldn’t overprescribe SSRIs to get complaining patients out of their faces quicker, we’d see them work better.
    In my country, SSRIs are prescribed for Premenstrual Dysphoric Disorder – before PMDD is even proven to exist in the patient. So if they took a guess at why they felt bad, took Prozac (the one most billed for success with PMDD) and felt better, it’s recorded to “cure” PMDD.

    Trying to get through the wave of artificial cures for this extremely basic problem (that involves the maladaptive interaction of cycle-based oestrogen and progesterone with brain chemicals) has been a three year long nightmare thanks to unhelpful detours like SSRIs (and the Mirena Coil, but that’s another rant entirely.)

    I’ve known several people IRL who have struggled with poverty, anxiety, terrible jobs and living conditions, who tried SSRIs. Didn’t help them, either. Almost like the main reason most people are depressed is because of their environment, not their brain.

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