Why do antidepressants have a delayed onset of action?

Question

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.

Answer 1

The currently held belief for the delayed onset of action of most antidepressants is because it takes that amount of time (1 - 2 weeks) for the antidepressant drug to cause the down-regulation of a previously up-regulated receptor. This is believed to involved new protein synthesis of receptors moeities, and modification of other receptor proteins.

Answer 2

The delayed (full) onset of action of antidepressants such as SSRI's (selective serotonin reuptake inhibitors) can be due to a variety of factors, but I will limit the scope in terms of talking about reaching a drug's steady state levels (assuming not missing any doses of the drug). This is not to say a drug will not initially start having some effects in the beginning, but to reach full effect is usually warranted when a drug reaches steady state. Steady state levels are where the amount of drug intake is relatively consistent with the amount of drug excreted. As drugs are metabolized through multiple enzymes in the body, sometimes a drug may be metabolized to a form of active metabolite. The amount of time it takes typically for a drug to reach steady state is 3.3 to 5 half-lives of a drug. An example of this would be the SSRI drug sertaline. Sertraline's half-life elimination is 26 hours, but it also has an active metabolite, N-desmethylsertraline, which has a half-life of 62-104 hours. Thus, if you apply the rules, it can take up to 3-4 weeks to see full effect or response. Some clinicians and general practice guidelines from the American Psychiatric Association recommend 4-8 weeks to see whether or not a drug is truly working or not (Gelenberg 2010. Accessed on 8/23/19. Available at https://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/mdd.pdf).

Another theory in combination with the steady state explanation is that the antidepressants may have a difficult time either binding to specific receptors due to interference or are targeting hard to reach areas such at DNA (Erb SJ et al. 2016. Accessed on 8/23/19. Available at http://www.jbc.org/content/291/38/19725; Baudry A et al. 2010. Accessed on 8/23/19. Available at https://www.ncbi.nlm.nih.gov/pubmed/20847275).

This does not replace medical advice. This information is for educational/informational purposes only. Please consult with your doctor regarding disease and medication specifics.