How come certain drugs (i.e. antidepressants) take days/weeks before they work?

[red22]

A doctor once told me that it was something to do with the "genetic transcription", but that's all I was able to get from him at the time. Real curious about this.

 

[tweex]

http://www.oxfordmhf.org.uk/blog/2012/03/why-do-antidepressants-take-so-long-to-work/

Some don't, notably Tianeptine.

 

[ebola?]

Their mechanism (insofar as it actually functions; SSRIs aren't too reliably effective) is somehow downstream, and the anti-depressant effect depends on neural adaptation to the effects of the drug, not the effects themselves.

ebola

 

[Zalo]

From my understanding one of the possible reasons for why it takes awhile is due to 5-HT1A autoreceptor desensitization. Autoreceptors are found on the pre-synaptic membrane of a neuron and it modulates the release of serotonin. The neurotransmitter that the neuron releases also inhibits it so that it doesn't release too much. With SSRIs you can feel the effects of the drug when you first take it, which would imply an immediate increase in serotonin in the synapse. This would most likely lead to serotonin binding to the autoreceptors more often than it normally would. To counterbalance this the autoreceptors will desensitize, or downregulate, which would lead to less inhibition of serotonin release. This would lead to an increase in activation of post-synaptic 5-HT1A receptors, due to increased levels of serotonin, leading to the therapeutic benefits of SSRIs. The downregulation of autoreceptors take awhile, which is why it takes SSRIs a few weeks before they start to truly work. The build up of serotonin from the SSRI alone simply isn't enough for the anti-depressive effects.

Here's the link for 5-HT1A receptors if you want to read more on it, or if I didn't explain it well enough.
http://en.wikipedia.org/wiki/5-HT1A_receptor

There's also another theory or hypothesis on how SSRIs work. The monoamine hypothesis talks about how neurological disorders, such as depression, are due to an imbalance in neurochemicals. Another idea, for depression that is, is that the hippocampus of depressed/anxious individuals are atrophied. The HPA-axis (hypothalamus-pituitary-adrenal axis) regulates cortisol production, the stress hormone. The HPA-axis is controlled by the hippocampus through a negative feedback loop. Too much cortisol triggers the hippocampus to tell the HPA-axis to stop producing cortisol. The silly thing about our brains is that too much cortisol will actually cause the cells in the hippocampus to die, too little also causes cells to die as well. If the hippocampus is damaged its no longer as efficient at shutting down the production of cortisol, which would cause an increase in cortisol production killing more hippocampal cells. This loop continues and your hippocampus continues to atrophy. Your hippocampal cells do regenerate, but the damage exceeds the gains. The thing with cortisol is that it helps us wake up/sleep normally, and depressed individuals usually have problems with sleep. They have irregular cortisol spikes throughout the night causing them to wake up at random times and preventing sleep. This may also explain the difficulties depressed/anxious individuals have with dealing with stress because their brains are no longer capable of dealing with it. Now back to how SSRIs may work. I'm not quite sure about the mechanism behind this but the idea is that the SSRIs help with the growth of neurons in the hippocampus so that there's a surplus of cell growth instead of cell death. The regeneration of the hippocampus is possibly why there's a delay before the therapeutic effects of SSRIs are noticed.

 

[pasha]

I was under the impression that this was simply due to the fact that SSRI's, much like benzodiazepines, are lipophilic drugs in which consistent dosing leads to higher and optimal blood concentrations causing increased efficiency.

 

[ebola?]

Nope: most induce maximally increased concentrations of intersynaptic 5ht in a matter of hours.

 

[pasha]

You're right. There is yet no evidence to show that blood concentrations are correlated with clinical response.

Although many attempts were made, to date no convincing evidence exists of a relationship between plasma concentrations of any of the SSRIs and clinical efficacy.

http://www.ncbi.nlm.nih.gov/pubmed/8384945

Following administration of single doses, fluvoxamine shows a biphasic elimination with a mean terminal elimination half-life of about 15 to 20 hours. Steady-state plasma fluvoxamine concentrations are achieved 5 to 10 days after initiation of therapy and are 30 to 50% higher than those predicted from single-dose data. Preliminary data also suggest that plasma drug concentrations may increase non-linearly with increasing daily dosage. The relationship between plasma fluvoxamine concentration and clinical response has not been clearly defined.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC181142/#i1523-5998-002-06-0205-b15

I've only been under that impression because many times I've read things like this:

The serum concentrations of citalopram were highly correlated with inhibition of serotonin uptake. Less of the metabolite was found, it being detected only in the higher dose groups. Steady state levels of citalopram, attained after 1 week, were linearly related to dose. The relationship between improvement (percentage reduction in total score on the Montgomery-Åsberg Depression Rating Scale) and serum level of citalopram indicated a lower limit of effect in endogenous depression at about 100 nM, corresponding to an average dose of 15 mg.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC181142/#i1523-5998-002-06-0205-b15

 

[endotropic]

I was under the impression that this was simply due to the fact that SSRI's, much like benzodiazepines, are lipophilic drugs in which consistent dosing leads to higher and optimal blood concentrations causing increased efficiency.

When Fluoxetine was the only SSRI around, this was in fact the leading hypothesis. Fluoxetine and it's active metabolite have crazy long half lives, and they inhibit their own metabolism, meaning that their levels increase in the blood during the first few weeks of treatment. That led people to think that the slow increase in drug level was causing the slow onset of therapeutic action. Years later we know that's not the case.

Nope: most induce maximally increased concentrations of intersynaptic 5ht in a matter of hours.

Actually this isn't entirely true, for the reason that Zalo posted above. 5-HT1A autoreceptors initially limit synaptic 5-HT. The first few doses of SSRI hardly increase 5-HT over baseline, maybe only 10-30%. Over the first few weeks of treatment the autoreceptors will desensitize. Synaptic 5-HT levels increase dramatically once that process is completed.

 

[ebola?]

I stand corrected. The diversity of effects at varied 5ht receptor subtypes is so intriguing.

ebola

 

[pasha]

When Fluoxetine was the only SSRI around, this was in fact the leading hypothesis. Fluoxetine and it's active metabolite have crazy long half lives, and they inhibit their own metabolism, meaning that their levels increase in the blood during the first few weeks of treatment. That led people to think that the slow increase in drug level was causing the slow onset of therapeutic action. Years later we know that's not the case.

Thanks for clarifying.

 

[The God]

What about an NDRI such as bupropion? I felt the effects about 1-2 hours after my first dose.

 

[red22]

Great responses. Thanks a lot, guys. Glad I made this thread.

 

[Manchurian]

NDRIs such as bupropion while generally considered antidepressants are essentially stimulant drugs with pharmacological activity similar to that of the classical stimulants such as cocaine, ritalin and the amphetamines. They just don't cross the blood brain barrier and take effect as rapidly which translates into reduced abuse potential and therefore classification as antidepressants.

But I digress, I don't know if there is research indicating why buproprion takes effect more quickly but I would hypothesize that it's antidepressant effects are more directly related to enhancing norepinephrine and dopamine activity in the synapses themselves, leading to a more immediate effect, similarly to how amphetamines, when used as ADHD medications take effect when they reach effective blood plasma concentrations.

All that being said buproprion does increase in effectiveness with consistent use over the course of 2-8 weeks much like the SSRIs. I'm not sure if that is due to a leveling out of blood plasma concentrations of the drug, or a receptor downregulation situation similar to what is seen in the SSRIs. Possibly both.

An interesting addendum to this is that the older tricyclic (and tetracyclic) antidepressants also work on Serotonin, as well as a number of other neurotransmitters (Norepinephrine, dopamine, histamine, etc.) but have been reported to take effect more rapidly than SSRIs by some sources.

 

[MrSpeedyG]

I believe as mentioned it is the neural adaptation that occurs with SSRI's that causes the effect, not so much that it takes time to build in the blood.

 

[The God]

NDRIs such as bupropion while generally considered antidepressants are essentially stimulant drugs with pharmacological activity similar to that of the classical stimulants such as cocaine, ritalin and the amphetamines. They just don't cross the blood brain barrier and take effect as rapidly which translates into reduced abuse potential and therefore classification as antidepressants.

But I digress, I don't know if there is research indicating why buproprion takes effect more quickly but I would hypothesize that it's antidepressant effects are more directly related to enhancing norepinephrine and dopamine activity in the synapses themselves, leading to a more immediate effect, similarly to how amphetamines, when used as ADHD medications take effect when they reach effective blood plasma concentrations.

All that being said buproprion does increase in effectiveness with consistent use over the course of 2-8 weeks much like the SSRIs. I'm not sure if that is due to a leveling out of blood plasma concentrations of the drug, or a receptor downregulation situation similar to what is seen in the SSRIs. Possibly both.

An interesting addendum to this is that the older tricyclic (and tetracyclic) antidepressants also work on Serotonin, as well as a number of other neurotransmitters (Norepinephrine, dopamine, histamine, etc.) but have been reported to take effect more rapidly than SSRIs by some sources.

Informative and in line with my assumtions.

Thanks.

 

[red22]

Do MAOIs take time to work or do they work immediately?

 

[JWills20]

I remember reading something similar to this:

Their mechanism (insofar as it actually functions; SSRIs aren't too reliably effective) is somehow downstream, and the anti-depressant effect depends on neural adaptation to the effects of the drug, not the effects themselves.

Increased synaptic serotonin has downstream effects on Brain-derived Neurotrophic Factor, causing neuroplasticity and neural adaptation. This also goes some way to explain the delayed effect (if any) they seem to exhibit.

 

[MichelJacques]

I remember reading something similar to this:

Increased synaptic serotonin has downstream effects on Brain-derived Neurotrophic Factor, causing neuroplasticity and neural adaptation. This also goes some way to explain the delayed effect (if any) they seem to exhibit.

This is related to sigma receptor agonism, is it not?

 

[WSH]

Do MAOIs take time to work or do they work immediately?

Moclobemide takes about as long as SSRIs:

link

Onset of therapeutic actions usually not immediate, but often delayed 2-4 weeks

I guess the mechanism is the same for both SSRIs and MAOIs:
They increase serotonin, but they have to desensitize presynaptic 5-ht1a autoreceptors first (which takes about 2 weeks) before they can activate postsynaptic 5-ht1a heteroreceptors.

 

[endotropic]

Moclobemide takes about as long as SSRIs:

link



I guess the mechanism is the same for both SSRIs and MAOIs:
They increase serotonin, but they have to desensitize presynaptic 5-ht1a autoreceptors first (which takes about 2 weeks) before they can activate postsynaptic 5-ht1a heteroreceptors.

5-HT1A heteroreceptor activation can then stimulate neuro/synaptogenesis, another slow process. I think when you consider both processes as complementary actions, rather than competing hypotheses, the whole phenomenon makes a lot more sense.