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Why would Bupropion take several weeks to kick in? (Depression)

vortex30

vortex30

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A friend of mine has been prescribed 150mg Wellbutrin/day as a second attempt to treat depression and anxiety (he was on Celexa for 6 months starting at 20mg, up to 30mg, he stopped taking it 1.75 years ago, Celexa just made him "lazy, cloudy minded and sleepy, with constant yawning"). When he got prescribed Wellbutrin I was fairly optimistic as I've heard some really good reports of Wellbutrin and the fact that it is a cathinone also seemed like a good indication that this could be an anti-depressant one will actually 'feel' in obvious ways. I've talked to a few people on this forum who said you can start to feel Wellbutrin after just 2-3 days of using it, making it unlike other anti-depressants that can take over a week, if not a month, to fully kick in.

He reported that he did feel the Wellbutrin a few times over the past week, the most when he switched from taking it in the evenings to mornings (300mg in 12 hours or so). He spoke with his doctor about it and she said that one week is far too soon to be feeling anything from Wellbutrin, that it could take up to 10 weeks, and that even the pharmaceutical company states 2 weeks or more.

To me, this doesn't seem to make sense. Peak plasma levels and metabolite ratios (which I understand, metabolites are very important with Wellbutrin) should be sorted out within a week (if not sooner) given it's half life, surely? Does Wellbutrin actually work on dopamine and norepinephrine transporters in the way that SSRIs work on serotonin transporters (making the 2-10 weeks claim legitimate)? If so, what exactly sets Wellbutrin apart from other cathinones/amphetamines and causes this delayed onset?

Basically, can anyone tell me why it would take 2-10 weeks for Wellbutrin to begin to work, and what mechanisms set it apart from a classic NDRI that I'm imagining it to be similar to?
 
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Yes I wondered the same thing a year ago when I was prescribed bupropion by my doctor and he told me I had to wait two weeks before I would feel a therapeutic effect. I think your question is a petitio principii, that is to say I think the reason it's odd that bupropion should take several weeks to exert an effect when peak plasma is reached within hours is because it does not take several weeks. Doctors simply say this because they want patients to give the substance time before dismissing it as ineffective. I have read the same thing written about methylphenidate, which certainly does not require weeks of use to feel an effect. One possibility is that drug naive individuals require a sensitization period to begin recognizing the drug's effects, in the same way the piracetam or marijuana often require several administrations before an effect is felt.
 
hamhurricane said:
Yes I wondered the same thing a year ago when I was prescribed bupropion by my doctor and he told me I had to wait two weeks before I would feel a therapeutic effect. I think your question is a petitio principii, that is to say I think the reason it's odd that bupropion should take several weeks to exert an effect when peak plasma is reached within hours is because it does not take several weeks. Doctors simply say this because they want patients to give the substance time before dismissing it as ineffective. I have read the same thing written about methylphenidate, which certainly does not require weeks of use to feel an effect. One possibility is that drug naive individuals require a sensitization period to begin recognizing the drug's effects, in the same way the piracetam or marijuana often require several administrations before an effect is felt.
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^ this.

You should also take in consideration the fact that many "professionals" don't know what they are talking about.;)
 
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nasir~ said:
You should also take in consideration the fact that many "professionals" don't know what the are talking about.;)
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Hehe! That's why I come here when it comes to things like this. I'd still like to hear from someone definitively though. Either yes, it could take 2-3+ weeks to fully feel the effects of Wellbutrin and here's why, or no, it could not take 2-3+ weeks to fully feel the effects and here's why.

For example, while we're on the subject...I've always been curious as to why many SSRIs do in fact require 2-3+ weeks to feel the effects. Perhaps someone explaining the mechanism/reason for this would help me in understanding the case with Wellbutrin, as I don't actually know why this is the case with most SSRIs, though I take it to be true with most accounts I hear confirming this timescale.
 
vortex30 said:
For example, while we're on the subject...I've always been curious as to why many SSRIs do in fact require 2-3+ weeks to feel the effects. Perhaps someone explaining the mechanism/reason for this would help me in understanding the case with Wellbutrin, as I don't actually know why this is the case with most SSRIs, though I take it to be true with most accounts I hear confirming this timescale.
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don't know that buproprion takes so long to work, but fluoxetine is very highly protein bound (94%)
 
One explanation for the therapeutic lag-time reported by SSRI users is that a couple of weeks are required before hippocampal volume is increased by the drug, given that bupropion is not associated with any changes in hippocampal volume such a therapeutic lag would not make sense, at least for that one possible antidepressant mechanism.
 
vortex30 said:
Hehe! That's why I come here when it comes to things like this. I'd still like to hear from someone definitively though. Either yes, it could take 2-3+ weeks to fully feel the effects of Wellbutrin and here's why, or no, it could not take 2-3+ weeks to fully feel the effects and here's why.

For example, while we're on the subject...I've always been curious as to why many SSRIs do in fact require 2-3+ weeks to feel the effects. Perhaps someone explaining the mechanism/reason for this would help me in understanding the case with Wellbutrin, as I don't actually know why this is the case with most SSRIs, though I take it to be true with most accounts I hear confirming this timescale.
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For starts, there is no direct scientific proof behind the "low serotonin = depression" THEORY. I believe it takes so long because it's other changes that are occurring, because the direct effects of the SSRI do not take weeks to kick in. Remember other things like dopamine are also indirectly influenced.
 
hamhurricane said:
Yes I wondered the same thing a year ago when I was prescribed bupropion by my doctor and he told me I had to wait two weeks before I would feel a therapeutic effect. I think your question is a petitio principii, that is to say I think the reason it's odd that bupropion should take several weeks to exert an effect when peak plasma is reached within hours is because it does not take several weeks. Doctors simply say this because they want patients to give the substance time before dismissing it as ineffective. I have read the same thing written about methylphenidate, which certainly does not require weeks of use to feel an effect. One possibility is that drug naive individuals require a sensitization period to begin recognizing the drug's effects, in the same way the piracetam or marijuana often require several administrations before an effect is felt.
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I agree 100%, very well said.

Bupropion is also a nicotinic acetylcholine receptor antagonist.
 
hamhurricane said:
One explanation for the therapeutic lag-time reported by SSRI users is that a couple of weeks are required before hippocampal volume is increased by the drug
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this is interesting. Do you know if this is actually the case? I've always figured the reason for SSRIs' slow onset was straightforward and well understood, namely the sluggish kinetics of the popular early SSRIs, namely fluoxetine, paroxetine and sertraline. If I understand plasma proteins correctly, fluoxetine & co. are mostly not in circulation until the proteins are saturated. I mean, they're in circulation, but bound to albumin and friends.

excellent point about the petitio principii (had to go look that one up)
 
It takes several weeks to kick in because of the serotogenic effects:
Neuropharmacology. 2008 Dec;55(7):1191-8. Epub 2008 Jul 30.
Sustained administration of bupropion alters the neuronal activity of serotonin, norepinephrine but not dopamine neurons in the rat brain.
El Mansari M, Ghanbari R, Janssen S, Blier P.

University of Ottawa Institute of Mental Health Research, Room 7407, 1145 Carling Avenue, Ottawa, Ontario, Canada K1Z 7K4. [email protected]

Bupropion is widely used in the treatment of depression. There are, however, limited data on its long-term effects on monoaminergic neurons and therefore the mechanism of its delayed onset of action is at present not well understood. The present study was conducted to examine the effects of prolonged bupropion administration on the firing activity of dorsal raphe nucleus (DRN), locus coeruleus (LC), and ventral tegmental area (VTA) neurons. Spontaneously firing neurons were recorded extracellularly in rats anesthetized with chloral hydrate. Bupropion (30 mg/kg/day) was administered using subcutaneously implanted minipumps. In the DRN, the firing rate of serotonin (5-HT) neurons was significantly increased after 2, 7 and 14 days of administration. The suppressant effect of LSD was significantly diminished after the two-day regimen, indicating a desensitization of 5-HT1A autoreceptors. In the LC, the firing rate of norepinephrine (NE) neurons was significantly attenuated after a 2-day regimen, but recovered progressively over 14 days of administration. The suppressant effect of clonidine on NE neuronal firing was significantly attenuated in rats treated with bupropion for 14 days, indicating a desensitization of alpha2-adrenoceptors. In the VTA, neither 2 nor 14 days of bupropion administration altered the firing and burst activity of dopamine neurons. These results indicate that bupropion, unlike 5-HT reuptake inhibitors, promptly increased 5-HT neuronal activity, due to early desensitization of the 5-HT1A autoreceptor. The gradual recovery of neuronal firing of NE neurons, due to the desensitization of alpha2-adrenoceptors, in the presence of the sustained increase in 5-HT neuronal firing, may explain in part the delayed onset of action of bupropion in major depression.
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Besides that its a NE releasing agent wich insignificant effects on dopamine:
J Clin Psychopharmacol. 2003 Jun;23(3):233-9.
Neurochemical and psychotropic effects of bupropion in healthy male subjects.

Gobbi G, Slater S, Boucher N, Debonnel G, Blier P.

Neurobiological Psychiatry Unit, Department of Psychiatry, McGill University, Montréal, Quebec, Canada.
Abstract

Bupropion is a weak inhibitor of noradrenaline (NE) and dopamine (DA) reuptake and has no direct action on serotonin (5-HT) neuronal elements. In the rat brain, bupropion suppresses NE neuron firing activity via the activation of alpha(2)-adrenoceptors and increases that of 5-HT neurons through an indirect action on NE neurons. Twenty-five healthy young male volunteers, with no previous history of psychiatric disorders, were randomized to one of four 7-day regimens: placebo, bupropion (150 mg) once daily, bupropion (150 mg) twice a day, and methylphenidate SR (20 mg daily). To assess the activity of the NE reuptake process, the blood pressure response to intravenous tyramine was determined. A decrease in the systolic pressure response to tyramine was considered evidence of NE reuptake inhibition. Effects on 5-HT reuptake were assessed by measuring whole blood 5-HT concentration, with a decrease serving as an index of 5-HT reuptake blockade. The Profile of Mood States (POMS) scale was used to assess behavioral and psychological changes. Neither bupropion nor methylphenidate altered the tyramine pressor response, in contrast to previous data that demonstrated decreases were obtained with NE reuptake inhibitors. Neither drug modified 5-HT concentrations. However, POMS scores revealed that bupropion at a dosage of 150 mg/day increased composedness, agreeability, and energy, whereas 300 mg/day improved only attention. In contrast, methylphenidate improved only energy. These data provide no evidence that bupropion acts as an inhibitor of NE or 5-HT reuptake in healthy humans. Presumably it enhances synaptic availability of NE by increasing release. Yet, because its behavioral profile is different from that of methylphenidate, it may not share all the biochemical properties of psychostimulants.

PMID: 12826985
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Psychopharmacology (Berl). 2001 Apr;155(1):52-7.
Modification of norepinephrine and serotonin, but not dopamine, neuron firing by sustained bupropion treatment.

Dong J, Blier P.

Department of Psychiatry and Neuroscience, McKnight Brain Institute, University of Florida, P.O. Box 100256, Gainesville, FL 32610, USA.
Abstract

RATIONALE: Bupropion is widely used in the treatment of depression and as an anti-craving medication for the cessation of tobacco smoking. Because it is a very weak inhibitor of norepinephrine (NE) and dopamine (DA) reuptake, its mechanisms of action remain to be elucidated.

METHODS: Bupropion was administered subcutaneously via osmotic minipumps over 2 days to determine its effects on the spontaneous firing activity of NE, serotonin (5-HT), and DA neurons in the brain of anaesthetised male Sprague-Dawley rats. This treatment was used in order to obtain levels of the parent compound and its putatively active metabolites that would more adequately reflect the clinical condition than utilizing acute injections.

RESULTS: When given by minipump for 2 days, bupropion produced a dose-dependent attenuation of the mean spontaneous firing NE neurons (7.5 mg/kg per day: 15%; 15 mg/kg per day: 61%; 30 mg/kg per day: 80%) which was reversed by the alpha 2-adrenoceptor antagonist idazoxan. At the highest regimen, the mean firing rate of 5-HT neurons was 100% higher than in control rats, but unaffected in NE-lesioned rats. In contrast, DA neurons in the ventral tegmental area displayed a normal firing rate during the latter bupropion treatment.

CONCLUSIONS: Sustained bupropion administration decreased the firing rate of NE neurons due to an increased activation of their inhibitory somatodendritic alpha 2-adrenoceptors. This effect of the bupropion treatment would be attributable mainly to an enhancement of NE release and not to reuptake inhibition. This contention is based essentially on the observation that NE reuptake blockers leave unaltered the firing rate of 5-HT neurons, whereas bupropion enhanced it via a NE-dependent mechanism. The present study did not put into evidence any DA activity of bupropion at the level of the cell body of mesolimbic/cortical DA neurons at a regimen exerting profound alterations of the firing activity of NE and 5-HT neurons.

PMID: 11374336
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vortex30 said:
Hehe! That's why I come here when it comes to things like this. I'd still like to hear from someone definitively though. Either yes, it could take 2-3+ weeks to fully feel the effects of Wellbutrin and here's why, or no, it could not take 2-3+ weeks to fully feel the effects and here's why.

For example, while we're on the subject...I've always been curious as to why many SSRIs do in fact require 2-3+ weeks to feel the effects. Perhaps someone explaining the mechanism/reason for this would help me in understanding the case with Wellbutrin, as I don't actually know why this is the case with most SSRIs, though I take it to be true with most accounts I hear confirming this timescale.
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In melancholic depression it takes several weeks because of 5-HT2A, 5-HT2C, 5-HT1B, and 5-HT1A autoreceptor downregulation, in atypical depression a response is seen faster because of 5HT2A agonism.
 
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melange said:
that's funny

me and a lot of other people can feel effects from it after a few hours of taking it

Bupropion is a dopamine and norepinephrine reuptake inhibitor

it's effects on 5ht are negligible
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Yes, its likely you will notice effects acutely, i did too, however the effects get better over time for many ppl, its also highly dependent on your own brain chemistry, as an example ssri's will work much faster for atypical depression compared to melancholic depression.

It hasnt got any direct effects on serotonine, so your right in that way, however it indirectly causes 5HT1A downregulation, increasing serotogenic transmission over time.

Its not a NE reuptake inhibitor, its a NE releasing agent (check the refs above) its effects on dopamine are neglible, it only occupy's around 12 - 20% of the transporter.
 
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