Why would bupropion take a number of weeks to start working

[CrimpJiggler]

Doctors tell their patients that bupropion takes 2 weeks before its antidepressant effects can be felt. Theres no pharmacological reason for this at all, I think whats going on here is they're giving a time window to enable the placebo effect to start working. I believe this is why they say SSRIs take a number of weeks too. If you keep thinking it is going to start working eventually, then you are incrementally increasing the odds of having a positive placebo response. I notice with bupropion loads of people say that Wellbutrin worked well for them but the generic stuff doesn't work. I've seen the same thing with all kinds of meds, like the manufacturer changing the colour of a pill and it stops working for people. If inert ingredients had effects this extreme, then eating your dinner or taking non psychoactive pharmaceuticals like aspirin would likely interact greatly with the psychoactive effects of the drug. I think these are all examples of the placebo effect. The problem with double blind studies is the subjects know they only have 50% chance of getting the drug so that will lower the amount of people feeling placebo response. With something like bupropion, you feel immediate effects so the subjects have a massive hint that they're part of the 50% that got the drug. In this way double blind studies for CNS active drugs are flawed. In reality the effect is probably way more prevalent. They can't measure the belief of the subjects. God knows how much of the effects of pharmaceuticals are actually due to placebo responses.

 

[sekio]

It may not neccesarily be placebo, more like time to let your body reach a new equilibrium.

 

[endotropic]

I think you make a good point about exaggerated placebo effects in the active arm due to participants recognizing a side effect of the drug. A control group given an active but ineffective drug would make a better comparison, but what pharmaceutical company would go that route unless the FDA requires them to?

About your main point, have you looked back at any of the clinical efficacy trials for bupropion? I wouldn't be surprised if a good proportion of responders felt effects almost immediately.

 

[serotonin2A]

I think you make a good point about exaggerated placebo effects in the active arm due to participants recognizing a side effect of the drug. A control group given an active but ineffective drug would make a better comparison, but what pharmaceutical company would go that route unless the FDA requires them to?

About your main point, have you looked back at any of the clinical efficacy trials for bupropion? I wouldn't be surprised if a good proportion of responders felt effects almost immediately.

Antidepressants generally take a few weeks to reach maximum efficacy. I think that is the same with all classes. The reason this delay seems to occur is that it is not the direct pharmacological effects of the drug that cause the antidepressant effect but rather compensatory changes in gene expression. Gene expression changes occur over a much longer time scale then typical pharmacological effects. With SSRIs esspecially it is very easy to understand why they wouldn't work immediately -- SERT blockade doesn't do anything acutely because of feedback due to serotonin autoreceptors, which then gradually become desensitized, allowing serotonin levels to rise.

The delayed action actually suggests the response isn't placebo effect because the placebo effect should occur immediately. It is true that patients are often told the effect occurs gradually but that isn't always the case. I've never heard of a patient, not informed of the delayed action, who felt an immediate effect. That certainly makes the placebo effect a little less likely.

Most antidepressant drug trials that are conducted these days require an active control group based on an established drug, and the test drug is required to show a superior response. That is because effectiveness isn't the only criterea for drug approval. Rather, the FDA wants new drugs to be superior to existing drugs. I don't think the fact that buproprion produces an interoceptove stimulus is as detrimental for trials as the OP is assuming because pretty much all antidepressants produce some effect initially that the subjects would be aware of.

There are two common reasons why branded drugs and generic drugs produce different effects. FDA regulations allow the amount of a drug in a single dose unit to vary over a range of plus/minus 15%. So if the brand name is 15% high and the generic is 15% low (which might not be uncommon because generic drugs have low profit margins) then there would be a 30% difference in dosing. That would be noticeable by some patients. Second, things like crystal polymorphisms (which influence solubility) can cause marked differences in bioequivalence.

 

[endotropic]

Placebo responses accumulate over time in clinical trials, you can't determine whether a response is placebo or not based on how long it took the effect to happen. Another way to put it is that depressed people recover spontaneously over time, so over a longer time period placebos look more effective.

The fact that all antidepressants produce a response the subject is aware of is exactly the problem that could lead to false positive for both the test drug and the active EFFECTIVE control, which is why an active ineffective control would be much better. Inactive placebo is still the gold standard negative control for drug trials, and it shouldn't be.

 

[ThePharmacist4925]

Studies are complicated by the scientific concept of regression towards the mean. This theory would state that if all patients in a study are depressed, at the end of the study a decent quantity of the patients would have moved towards mean (feeling neutral or even better) regardless of the medication administered. Even more so the placebo group has the benefit of minimal medication side effects due to the lack of administration of medication. Therefore the placebo group will not only have people that regress towards the mean, but also people that think the medication is helping them (therefore presenting with less depression symptoms, or even presenting with symptoms of positivity). The medication group will also regress towards the mean and feel the benefit of the medication, but also get direct symptoms from using the actual medication. Not to mention the real medication group will also experience the placebo effect on top of the actual effect of the medication. So my question is are the actual side effects of the medication so great that they diminish the placebo effect or prevent regression towards the mean? But also I wonder will the medication work so well that they not only encourage the placebo affect or encourage regression towards the mean and/or actually make the patient feel better. It's a very complicated question when challenging the efficacy of a medication or its mechanism of action. In my experience bupropion started working within a few days, but that's me and I'm just one test subject. Remember also that it may take two weeks to achieve a stable blood level and that is what they mean when they say it takes a few days to work. It's also important to remember that if the drug companies or studies are cautious in what they say about a medication then what they said is less likely to come back and haunt them because they were too aggressive in their presentation of the medication. Unrealistic presentation of medication is a class action law suit waiting to happen, so two weeks is a safe amount of time to suggest that bupropion will take to work. I'm not always right and it is all very complicated, but perhaps thinking about some things I've said should allow you to clarify the conclusion you reach regarding the efficacy and time to reach efficacious stable plasma levels of bupropion. Good Day.

 

[serotonin2A]

Placebo responses accumulate over time in clinical trials, you can't determine whether a response is placebo or not based on how long it took the effect to happen. Another way to put it is that depressed people recover spontaneously over time, so over a longer time period placebos look more effective. The fact that all antidepressants produce a response the subject is aware of is exactly the problem that could lead to false positive for both the test drug and the active EFFECTIVE control, which is why an active ineffective control would be much better. Inactive placebo is still the gold standard negative control for drug trials, and it shouldn't be.

Often they would run a placebo control arm in the same study, or will make that comparison separately. But why would it be a drawback if the control is active? In that case you are much less likely to have a false positive response, because the response of the novel antidepressant has to exceed that of the active control to a significant degree. It is a much higher bar to climb. In those studies it isn't sufficient to show that the novel antidepressant is as effective as an existing drug, it has to be better.

 

[endotropic]

^the problem comes from having an inactive negative control arm, not from the presence of an active control arm. Participants can recognize the interoceptive cues provided by the side effects of an active drug and conclude that they didn't receive placebo. The fact that the participant knows they received active drug confounds the blinding and can artificially inflate the effects of ANY active drug vs. inactive placebo.

 

[PsychedelicWizard]

Think of serotonin as water and your brain as the bathtub. It slowly fills with water, it doesn`t fill instantly. You can enter with only a two-inch water height, but it won`t be satisfactory for bathing, likewise, you will feel better, but won`t feel properly good until there`s enough water in the tub to bathe, or in your case, serotonin in your brain.

And you can`t just dump it all in at once, either, because these drugs don`t just release serotonin, they hinder the reuptake, which to use the bath tub analogy, your tub has no drain plug, the SSRI is the drain plug. All tubs slowly fill with water, some do it moderately slow, others too slow, likewise the drug increases the water amount and stops it from going down the drain, and building the drain plug takes time, dumping serotonin is quick, but you just lose it when the drug wears off without the synapses being reinforced constantly like a dam that wells, eventually, you can stop taking the pill like you can stop reinforcing a dam....

 

[serotonin2A]

^the problem comes from having an inactive negative control arm, not from the presence of an active control arm. Participants can recognize the interoceptive cues provided by the side effects of an active drug and conclude that they didn't receive placebo. The fact that the participant knows they received active drug confounds the blinding and can artificially inflate the effects of ANY active drug vs. inactive placebo.

I'm a little bit confused by your response. You said "the major problem comes from having an inactive control arm" but then you go on to discuss the problems caused by giving subjects an active control. Which is the problem, the inactive control or the active control?

I'm not making up the fact that using an active reference drug as a control (sometimes with a placebo control group, sometimes not) is now the gold standard for depression and schizophrenia studies. The goal of the studies is to prove not only that the new drug is active, but more importantly that it is significantly more efficacious then an existing drug. If the subjects recognize they have taken the reference drug, and show a large response, then that makes any significant result with the new drug all the more impressive. The use of an active reference drug minimizes the confounding influence of drug interoceptive cues because both the test drug and the active drug would be subject to this phenomenon.

For example, with the new antidepressant vortioxetone, here are a sampling of these type of trials:

http://www.ncbi.nlm.nih.gov/pubmed/25650503
http://www.ncbi.nlm.nih.gov/pubmed/25575488
http://www.ncbi.nlm.nih.gov/pubmed/24257717
http://www.ncbi.nlm.nih.gov/pubmed/22572889

Let's put this another way. If you were depressed, would you rather take something like bupropion or fluoxetine (which you know have been shown to be superior to placebo), or would you prefer an antidepressant that was shown in trials to be significantly more effective than bupropion or fluoxetine? I think most people would make the latter choice.

 

[PsychedelicWizard]

I'm a little bit confused by your response. You said "the major problem comes from having an inactive control arm" but then you go on to discuss the problems caused by giving subjects an active control. Which is the problem, the inactive control or the active control?

I'm not making up the fact that using an active reference drug as a control (sometimes with a placebo control group, sometimes not) is now the gold standard for depression and schizophrenia studies. The goal of the studies is to prove not only that the new drug is active, but more importantly that it is significantly more efficacious then an existing drug. If the subjects recognize they have taken the reference drug, and show a large response, then that makes any significant result with the new drug all the more impressive. The use of an active reference drug minimizes the confounding influence of drug interoceptive cues because both the test drug and the active drug would be subject to this phenomenon.

For example, with the new antidepressant vortioxetone, here are a sampling of these type of trials:

http://www.ncbi.nlm.nih.gov/pubmed/25650503
http://www.ncbi.nlm.nih.gov/pubmed/25575488
http://www.ncbi.nlm.nih.gov/pubmed/24257717
http://www.ncbi.nlm.nih.gov/pubmed/22572889

Let's put this another way. If you were depressed, would you rather take something like bupropion or fluoxetine (which you know have been shown to be superior to placebo), or would you prefer an antidepressant that was shown in trials to be significantly more effective than bupropion or fluoxetine? I think most people would make the latter choice.

I think I can easily summarize how the placebo effect works in regard to neurochemistry.

You can actually produce any chemical just by thoughts, actions, and perceiving your environment, without any drugs at all. I mean do something you associate with fun and your brain releases dopamine, watch a sad movie and your eyes water up and serotonin is transmitted, get your car hit by another at a four-way intersection, then you will have a lot of adrenaline and cortisol in your blood suddenly. The point is that the placebo is really cognitive behavior therapy, tricking the person into teaching their brain to release the correct chemicals.

But placebo really is not too neccessary, not with new state-of-the-art neuroscientific exercises, like those brain games they have on computer software now.

The point is that it takes a concious effort to make your brain produce chemicals, swallowing a pill or snorting a line doesn`t take much effort at all, and you get the same result. But somebody who has disciplined their mental energy enough, can have basically a drug trip without drugs, they get high on life as they say, in reality, they have just learned how to think the same chemical process to occur that a drug user would use a drug to have happen.

EDIT:

Also for depression, the placebo will never work as good as the real thing.

While you can trick your brain to release serotonin the same way an anti-depressant does, this serotonin simply does not get transmitted because a depressed person has damaged receptors which do not receive the serotonin fully, so when it does get generated by a placebo and is sent out through synapses, it eventually hits a river so to speak and the bridge that allows crossing is destroyed, so what does it do, it simply goes back the direction it came from like a ghost from pacman and then once it returns from where it was synthesized, it literally just fizzles out of existence.

So a placebo can release the serotonin, but it cannot repair the damaged connectors that allow it to move to where it needs to be.

Why is that you might ask... because thought is electricity, so when you think happy thoughts, your brain can release an electrical impulse allowing some serotonin to be released, but electricity is energy, the brain is matter, and the electricity itself that makes up thought can NEVER alone repair the physical brain synapses and cells which are made of matter, that is where drugs come in, the drug is matter that interacts with the matter of the brain.

So a drug trip is half energy-based, in which it is all placebo, but the matter base of it is undeniably real and can not currently be received any other way.

Now I believe that perhaps everything is energy or energy and matter can become one or the other, if that is true, one day thought alone might be able to literally repair and part of the body just using mental energy, until then, all your thoughts and feelings can do is make electricity which can cause a chemical reaction, but thought itself cannot effect damaged grey matter.

 

[endotropic]

I'm a little bit confused by your response. You said "the major problem comes from having an inactive control arm" but then you go on to discuss the problems caused by giving subjects an active control. Which is the problem, the inactive control or the active control?

The inactive control.

I'm not making up the fact that using an active reference drug as a control (sometimes with a placebo control group, sometimes not) is now the gold standard for depression and schizophrenia studies..

Yes we're on the same page here, and with the rest you wrote. I was responding to OP's point about false positives in placebo controlled trials due to subjects recognizing which arm of the trial they're in. A placebo controlled drug trial with an active drug control arm generally has three groups:

Inactive placebo <-negative control
Active effective drug <-positive control
Test drug

I'm suggesting a better design would look like:

Active but ineffective drug <-negative control
Active effective drug <- positive control
Test drug

The rationale being that if you experience side effects regardless of what arm of the trial you're in you can't use the presence of side effects to deduce whether or not you've been given an effective drug.

 

[serotonin2A]

Yes we're on the same page here, and with the rest you wrote. I was responding to OP's point about false positives in placebo controlled trials due to subjects recognizing which arm of the trial they're in. .

OK that makes more sense. I thought you were responding to my post.

 

[PsychedelicWizard]

Another way of looking at this is that while the organic matter fuses quite quickly, the energy has a much harder time accepting a new form of energy. So what happens is the serotonin molecules stick to the brain and the energy creates an electric storm and this feels good or can make you feel sick, and some of it may now merge, but most of this energy is discarded when the drug wears off. But like a lover that keeps courting at the door, eventually the door opens, and the energy of the soul and the serotonin energy found in the molecule, finally embrace and make love, and are forever joined together.

At that point the neuro-receptors are repaired, basically the heart is mended, the soul has been shown love by connecting with a pure love soul, the loving plants and flowers which anti-depressants are derived from, not to mention the heat energy that superheats the plants, which has been here since before matter existed. Anyway, once the serotonin matter has repaired the brain, it basically now can store the physical matter, as well as energy.

However, the serotonin physical matter is different than serotonin energy. This is why people don't all need anti-depressant drugs, many people's souls have received enough love that they do not need their brain to have as much serotonin matter, as their soul has much more serotonin soul energy. However, energy can split from energy, and if a person is hurt with fear instead of love, it can cause the serotonin energy to split from their soul, in essence, when you have your heart broken, your soul is literally being ripped apart, the parts of love are taken, and that which remains turns dark, corrupted by fear. However, no matter how corrupted energy of the soul might become, love can restore any soul.

So basically if you have a matter deficiency in your brain, the drug builds a dam and keeps it full, and when the matter sits there, the soul starts absorbing its energy as well.

We are after all, both physical and spiritual beings, hence why some like science, the physical matter, others, art/religion/spirituality/philosophy, the spiritual energy.

Men are like energy, women are like matter. When the man inpregnants the woiman, he is like passing his energy into her matter, and when energy and matter meet, they change each other until they are like both, but different from the way they started, and because they can't agree on everything, that is why you get "random mutations", where the new being formed, the baby, is like the dad, mom, but also unique, and that uniqueness is because the baby's actual soul energy comes from the ethereal realm of heaven, which then enters the baby like a vessel, and that is when the baby achieves consciousness, when true life is made, before that, it is just a pile of matter and base energy, not soul energy.

That is also what separates our species from others on this planet, however things like domestic pets do have lesser evolved souls, as you get further down the chain, things like insects or viruses are just matter beings with base energy, not soul energy, and things like plants, trees, rocks, are also all alive as energy, but they are too base energy. Soul energy can change base energy to anything it desires, but only in the spirit world, in the world of matter, we have laws of nature, in heaven we can do as we will and have only love and pleasure, as the final form of energy is the God energy, the only energy which can create matter. We are the highest as we can perceive the spirit world, which is why we have a thing called abstract thought, dreams, or ideas, we draw from the unseen realm and bring it to the world of matter in the grand act of creation, which is the purpose of all of our lives, to shape the matter of our reality in the image of our own unique energy, which was designed in the likeness of the originator of all energy and matter, God.

To put it in other terms, a man who is attracted to a woman but not a man, could still have sex with a man's body if he was visualizing a woman's body, as his visualization is the energy of his soul interacting with the energy of the soul being of the spirit world he has connected with through spirit. The two bodies are just matter interacting, but sex is more about energy than matter, which is why you can have bad sex or amazing sex, depending if your soul is there or somewhere else.

 

[Downloader08]

"To put it in other terms, a man who is attracted to a woman but not a man, could still have sex with a man's body if he was visualizing a woman's body, as his visualization is the energy of his soul interacting with the energy of the soul being of the spirit world he has connected with through spirit. The two bodies are just matter interacting, but sex is more about energy than matter, which is why you can have bad sex or amazing sex, depending if your soul is there or somewhere else."
Errr...

So THAT'S why bupropion has a two week period until 'full effect'

 

[endotropic]

So THAT'S why bupropion has a two week period until 'full effect'

Well steering this back on topic, if you believe in the neurogenesis model of antidepressant action, even after 5-HT autoreceptors desensitize following a few weeks of SSRI treatment, markers for neuro- and synaptogenesis still continue to accumulate for a few weeks. I wouldn't be surprised if the neurogenic processes were similarly slow with bupropion, even though the autoreceptor desensitization process doesn't have to occur first.

Combined with a gradual accumulation of the drug and its active metabolites in the blood I think those processes could explain why some people wouldn't experience positive effects immediately.

 

[Dresden]

Because (1) Wellbutrin, like the SSRIs, doesn't work for depression and (2) most doctors don't care enough or know enough to see that bupropion is a cathinone, not an SSRI. Contrary to popular belief, Wellbutrin will NOT get you high, but if you take enough, it WILL give you seizures.

 

[serotonin2A]

Because...bupropion is a cathinone, not an SSRI.

You seem to be suggesting that cathinone is a pharmacological class but that isn't the case. It is a structural class (phenethylamines with an alpha-alkyl group and a beta-ketone). There is no reason that a drug couldn't be a cathinone and a SSRI.

 

[Nagelfar]

… But somebody who has disciplined their mental energy enough, can have basically a drug trip without drugs, they get high on life as they say, in reality, they have just learned how to think the same chemical process to occur that a drug user would use a drug to have happen. …

I once read a heroin addict who got into a Buddhist system of meditation could thereafter claim to get "the same high now" as heroin from "simply meditating". That's quite a fantastical claim, but if true, good on them. I wish I could become that adept at focusing my mental wherewithal and sheer willpower / fortitude to generate & elicit the same G-coupled protein μ-receptor agonism that exogenous super-agonists like esters of morphine take to produce. That's quite an overhaul of your neurological system from psychological starting points. If such is feasible, I would try, though I tend to think that is an exceptional (if not exaggerated) case. (Though my pessimism in this regard could be much of what is holding me back from success, that, and not actually trying on any regular basis)

 

[Dresden]

The cathinones are a class of stimulant drugs similar to the amphetamines but with (usually) shorter effects than amphetamines have. Feel free to point out to me a cathinone SSRI. Wellbutrin (bupropion) acts as the worst possible cathinone stimulant I've yet to try but is a cathinone stimulant, not an SSRI, none the less. The whole "low 5-HT levels cause depression and are cured by SSRIs" argument has, thankfully, now been discredited. Not only do low levels of serotonin not cause depression, but the SSRIs don't help cure it (in fact, they have been shown to work slightly less well than a placebo sugar pill) and can cause suicidal ideation sometimes leading up to actual suicide, flat affect / not caring about anything, and can make orgasm damn near impossible. If you take SSRIs and think they help your depression, just remember: The placebo effect is all in your head.