Why do antidepressants take so long to reach efficacy? I've read of theories about it perhaps being due to the strength of negative feedback via serotonergic and adrenergic autoreceptors during the first few weeks of treatment. What I'm looking for in an answer is the following:

  • The current theories regarding why currently-in-practise antidepressant regimens have a delayed onset of action.
  • The evidence for these theories.
  • How these theories fit in with the monoamine hypothesis or whether it is inconsistent with the monoamine hypothesis and how.
  • Possible solutions to this problem of delayed responses to antidepressant therapy.

All of this is strictly theoretical, there are no actual people involved here, this is simply a scientific inquiry.


1 Answer 1


Short answer
The mechanism of action of serotonin-specific reuptake inhibitors, a commonly-prescribed class of antidepressants, is a downregulation of 5HT1A receptors through negative feedback. This downregulation of receptors takes time.

Serotonin-specific reuptake inhibitors (SSRIs) are a class of antidepressants commonly prescribed to treat depression. Their therapeuric effects may need weeks of treatment (Celada, 2004), which can be explained by their action on 5HT1A receptors in the dendritic region of the serotoninergic neurons in the raphe nucleus. By blocking serotonin (5HT) reuptake, negative feedback mechanisms cause the 5HT1A receptors to downregulate. This downregulation of the presynaptic modulatory 5HT1A receptors changes the firing pattern of the serotonergic neuron into a more fluttering mode, so that it releases more 5HT (Duman, 2007). More 5HT makes you feel better. That is how it fits into the monoaminergic hypothesis. To have the 5HT1A receptors respond this way takes time, as it is an adaptive response that downregulates of 5HT1A receptors, i.e., less receptors are present on the cell's membrane.

This is only an expanation of delayed action of SSRIs, a specific subclass of antidepressants. For example, there are newer classes of antidepressants that seem to work faster (5HT4 action) (Duman, 2007).

- Celada et al., J Psychiatry Neurosci (2004); 29(4): 252–65
- Duman, Neuron (2007); 55(5): 712-25

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    $\begingroup$ All regulatory administration (any reg. admin, FDA, TGA, EMA, MHRA, etc.)-approved antidepressants have a delayed onset of action, although mirtazapine may act slightly faster. So it isn't just the SSRIs. Even antidepressants with no appreciable serotonergic effects (e.g., bupropion) have a delayed onset of action. $\endgroup$
    – Josh Pinto
    Commented Oct 30, 2014 at 13:39
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    $\begingroup$ Intetesting! I wasn't aware of that. I have made some changes in my answer, as it applies to SSRIs only. Thanks! $\endgroup$
    – AliceD
    Commented Oct 30, 2014 at 13:48
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    $\begingroup$ Did I start a trend?!? @AliceD $\endgroup$
    – One Face
    Commented Mar 9, 2015 at 11:32
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    $\begingroup$ +1 thanks bunches Alice! Interesting that there are delayed and non delayed classes. I was not aware of this. Very cool $\endgroup$ Commented Jul 31, 2015 at 0:23
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    $\begingroup$ @AliceD I have realized how much effort some contributors put in and appreciate it. I also know the feeling of writing an answer and having no one say anything and no acceptance! I'm sure u understand that feeling. I have gotten in the habit of thanking more as a result, where appropriate. :D $\endgroup$ Commented Jul 31, 2015 at 12:41

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