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 Mar 7 2008, 02:40 PM
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Newbie
Group: Newbie
Posts: 21
Joined: 19-October 07
From: Ozarks
Member No.: 19,887
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You know - I just love researching this stuff in addition to it being personally applicable since I did take Wellbutrin for a short period of time. Some drugs - stimulants that act upon dopamine in particular have caused poor reactions in some people due to peculiarities in their brain chemistry or balance due to genetic or environmental causes thus causing depression, memory loss, etcetra, and even hair loss and such (google dopamine and follicle-stimulating hormone) Some stimulants can cause you to initially feel great after which you then feel like crap due to how your dopamine receptors regulate over the time you take the drug - Initially you feel great then your dopamine D2 receptors upregulate and then you feel like crap. Over time as you continue taking the drug though these receptors downregulate back to normal levels and you feel good again. Not as good as you felt when you started - but more normal. There is the possibility though I am loathe to admit it that if I continued taking the Wellbutrin longer than a month I may have felt 'normal' again (due to findings with other stimulants besides Wellbutrin) though I have not found the research to back this up with Wellbutrin yet. Still IMHO it is wisest to save the stimulants and dopaminergenics as a therapy of last resort and only with intense research and advice from a very knowledgeable doctor. Play with the SSRIs first. Dopaminergenics have too much potential to seriously screw one up. Admittedly other drugs have indirect actions on dopamine though. All the various systems in the brain are interconnected and changing one more than likely influences many others - even those that science may not have knowledge of. Better yet - try cognitive therapy first  Thusly for public consumption I submit my personal cache of research on the matter in addition to that which I have already submitted to the fourms. And it's nice to have a public cache of my research too. Please pm me for more detailed information on this.
This post has been edited by gentle sun: Mar 8 2008, 09:32 AM
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Mar 10 2008, 09:14 AM
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Junior Member
Group: Junior Member
Posts: 101
Joined: 2-March 08
Member No.: 23,242
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QUOTE (dreamwolf @ Mar 7 2008, 02:40 PM)  Some stimulants can cause you to initially feel great after which you then feel like crap due to how your dopamine receptors regulate over the time you take the drug - Initially you feel great then your dopamine D2 receptors upregulate and then you feel like crap. Over time as you continue taking the drug though these receptors downregulate back to normal levels and you feel good again. Not as good as you felt when you started - but more normal. There is the possibility though I am loathe to admit it that if I continued taking the Wellbutrin longer than a month I may have felt 'normal' again (due to findings with other stimulants besides Wellbutrin) though I have not found the research to back this up with Wellbutrin yet. Are you certain the brain upregulates receptors for DA? As far as I was aware, the number or receptors stays constant, but the receptors are activated much more often due to an increase in the chemical. Also, you have it mixed up. When the brain upregulates receptors of a neurotransmitter, the effect will be stronger. When it downregulates, it will be weaker. Thus if a brain were to upregulate DA receptors, that person would feel euphoric and may even hallucinate. The brain responds to most antidepressants (or any psychotropic drug for that matter) by downregulating receptors for the targeted neurotransmitter in order to try and bring the chemicals back to a preset equilibrium. Which means, the brain downregulates 5-HT receptors in the same manner it affects DA receptors. This explains why many SSRIs fail after a period of time as well. Of course, it takes the brain awhile to adjust. The brain should not become tolerant to DA much quicker than it becomes tolerant to an excess of 5-HT. I agree with most of your statements, but I still do not see why an SSRI should be used for primary treatment rather than an NDRI or SNRI. As for the difference in stimulants versus bupropion (Wellbutrin), most stimulants are very quick acting. They produce euphoric highs rather than a simple mood boost. This can be extremely problematic because it causes "crashes." Bupropion, while still a phenylethylamine, does not bind as strongly due to its unique t-butyl group, so its effects are much slower acting. For all we know, bupropion may have a novel effect on the brain. However, due to the similarity in side effects between bupropion and most amphetamines, most researchers tend to believe it functions the same way.
This post has been edited by Reborn: Mar 10 2008, 09:15 AM
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I may be crazy, but I'm not stupid! Why must people always equate the two?
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Apr 21 2008, 01:03 AM
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Newbie
Group: Newbie
Posts: 21
Joined: 19-October 07
From: Ozarks
Member No.: 19,887
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QUOTE (Reborn @ Mar 10 2008, 08:14 AM) Are you certain the brain upregulates receptors for DA? As far as I was aware, the number or receptors stays constant, but the receptors are activated much more often due to an increase in the chemical.
Also, you have it mixed up. When the brain upregulates receptors of a neurotransmitter, the effect will be stronger. When it downregulates, it will be weaker. Thus if a brain were to upregulate DA receptors, that person would feel euphoric and may even hallucinate.
The brain responds to most antidepressants (or any psychotropic drug for that matter) by downregulating receptors for the targeted neurotransmitter in order to try and bring the chemicals back to a preset equilibrium. Which means, the brain downregulates 5-HT receptors in the same manner it affects DA receptors. This explains why many SSRIs fail after a period of time as well. Of course, it takes the brain awhile to adjust. The brain should not become tolerant to DA much quicker than it becomes tolerant to an excess of 5-HT. I agree with most of your statements, but I still do not see why an SSRI should be used for primary treatment rather than an NDRI or SNRI.
As for the difference in stimulants versus bupropion (Wellbutrin), most stimulants are very quick acting. They produce euphoric highs rather than a simple mood boost. This can be extremely problematic because it causes "crashes." Bupropion, while still a phenylethylamine, does not bind as strongly due to its unique t-butyl group, so its effects are much slower acting. For all we know, bupropion may have a novel effect on the brain. However, due to the similarity in side effects between bupropion and most amphetamines, most researchers tend to believe it functions the same way. Never are thing simplistic and clear-cut when it comes to the brain. Some receptor types/subtypes react differently than is the norm to agonists and antagonists. QUOTE 1: J Recept Res. 1993;13(1-4):341-54.
Regulation of dopamine receptors by bupropion: comparison with antidepressants and CNS stimulants.
Vassout A, Bruinink A, Krauss J, Waldmeier P, Bischoff S.
Research Department, CIBA-GEIGY Ltd., Basel, Switzerland.
Acute treatment of rats with the antidepressant bupropion increased [3H]spiperone binding to D2 receptors in vivo. This dose- and time-dependent effect was greatest in striatum and minimal in cerebellum and pituitary. A parallel behavioral stimulation occurred in the same rats. Among 21 antidepressants and CNS stimulants tested, only those that activate dopamine (DA) transmission had similar effects: nomifensine, amineptine, methylphenidate, D-amphetamine, amfonelic acid, cocaine, benztropine and GBR 12909. Decreasing DA transmission with reserpine plus alpha-methyl-p-tyrosine prevented the action of bupropion. Finally, bupropion was inactive in vitro and ex-vivo. Therefore, we propose that bupropion and other DA-enhancing agents modify the characteristics of [3H]spiperone binding through the intervention of a dynamic regulation of the D2 receptors by the neurotransmitter itself.
PMID: 8095555 [PubMed - indexed for MEDLINE] Higher amounts of dopamine-type receptors do not automatically equate to euphoria and hallucinations. The first clear dependency would be levels of dopamine or dopamine-agonist. Next would be he ratio of individual receptor subtypes, binding partners for each type/subtype, other neurotransmitters/hormones, genetics and so on....In particular the case of D2 requires a binding partner called Par-4 - without which dopamine binding at D2 receptors results in depression-like behaviours (in mice) instead of hyperactivity/euphoria. Also consider that drugs that have actions limited to serotonin receptors can induce hallucinations as well even though they _don't act_ directly upon dopamine. It is my view that SSRI's are safer - amphetamine and relatives are definitely to be avoided (google "Methamphetamine-induced Neurotoxicity: Structure Activity Relationships" and research/read), DRIs should be avoided as they increase oxidative stress (your brain potentially dies faster) as dopamine easily breaks down into radicals - and is broken down into radicals by MAO enzymes if not metabolized by other enzymes. SNRI's I might recant upon somewhat - but they may potentially be more anixogenic (cause anxiety). Anything that effects -choline directly (re: muscargenic/nicotinic) should be avoided as choline has been demonstrated to be too entwined with cognition and mood. Opinion - drugs acting directly upon dopamine are too close to cognitive functions for my taste. SSRIs would be my first line based upon my research and personal experience if I were a doctor and were to treat someone with medication *shrugs*. I also can add at this point that there is potential bad mojo for Wellbutrin since it affects choline levels as well - through it's actions upon dopamine (choline +) in combination with it's antagonist actions at nicotinic acytlcholine receptors (alpha(3)beta(2), alpha(4)beta(2), and alpha(7) ) (dopamine -, choline ??) At any rate the antagonism at alpha(7) alone could result in the sides of memory loss and such - though such effect should be dose-related and abate upon cessation of treatment. Why do I feel this thread has became more of a 'teaser' thread? :p
This post has been edited by dreamwolf: Apr 21 2008, 01:28 AM
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Apr 21 2008, 01:01 PM
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Newbie
Group: Newbie
Posts: 8
Joined: 21-April 08
Member No.: 24,615
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Dreamwolf, The Vassout abstract from 1993 you've quoted is hard to interpret without knowing whether the increased D2 receptor expression is pre- or postsynaptic. Postsynaptic D2 receptors have roles in movement, reward, cognition, etc. Presynaptic D2 receptors are autoreceptors, found on dopamine neurons themselves, that regulate dopamine release. When a neuron releases dopamine, some of that dopamine will bind to the autoreceptors, which inhibit the dopamine neuron. This prevents the release from being excessive. Autoreceptors are a general feature of the nervous system. 5-HT1A and 5-HT1B are autoreceptors for serotonin. Alpha-2a receptors are the autoreceptors for norepinephrine, etc. It would make sense that increasing dopamine release might cause autoreceptors to upregulate, as a compensatory mechanism. It might even have something to do with why I feel much less stimulated after being on Wellbutrin for two weeks than I did when I first took it. You would probably think this abstract is interesting: QUOTE Mol Pharmacol. 2007 May;71(5):1222-32. Epub 2007 Jan 31.Click here to read
D2 receptors regulate dopamine transporter function via an extracellular signal-regulated kinases 1 and 2-dependent and phosphoinositide 3 kinase-independent mechanism.
Bolan EA, Kivell B, Jaligam V, Oz M, Jayanthi LD, Han Y, Sen N, Urizar E, Gomes I, Devi LA, Ramamoorthy S, Javitch JA, Zapata A, Shippenberg TS.
Integrative Neuroscience Section, National Institute on Drug Abuse Intramural Research Program/National Institutes of Health/Department of Health and Human Services, Baltimore, MD 21224, USA.
The dopamine transporter (DAT) terminates dopamine (DA) neurotransmission by reuptake of DA into presynaptic neurons. Regulation of DA uptake by D(2) dopamine receptors (D(2)R) has been reported. The high affinity of DA and other DAT substrates for the D(2)R, however, has complicated investigation of the intracellular mechanisms mediating this effect. The present studies used the fluorescent DAT substrate, 4-[4-(diethylamino)-styryl]-N-methylpyridinium iodide (ASP(+)) with live cell imaging techniques to identify the role of two D(2)R-linked signaling pathways, extracellular signal-regulated kinases 1 and 2 (ERK1/2), and phosphoinositide 3 kinase (PI3K) in mediating D(2)R regulation of DAT. Addition of the D(2)/D(3) receptor agonist quinpirole (0.1-10 muM) to human embryonic kidney cells coexpressing human DAT and D(2) receptor (short splice variant, D(2S)R) induced a rapid, concentration-dependent and pertussis toxin-sensitive increase in ASP(+) accumulation. The D(2)/D(3) agonist (S)-(+)-(4aR, 10bR)-3,4,4a, 10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano-[4,3-b]-1,4-oxazin-9-ol hydrochloride (PD128907) also increased ASP(+) accumulation. D(2S)R activation increased phosphorylation of ERK1/2 and Akt, a major target of PI3K. The mitogen-activated protein kinase kinase inhibitor 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one (PD98059) prevented the quinpirole-evoked increase in ASP(+) accumulation, whereas inhibition of PI3K was without effect. Fluorescence flow cytometry and biotinylation studies revealed a rapid increase in DAT cell-surface expression in response to D(2)R stimulation. These experiments demonstrate that D(2S)R stimulation increases DAT cell surface expression and therefore enhances substrate clearance. Furthermore, they show that the increase in DAT function is ERK1/2-dependent but PI3K-independent. Our data also suggest the possibility of a direct physical interaction between DAT and D(2)R. Together, these results suggest a novel mechanism by which D(2S)R autoreceptors may regulate DAT in the central nervous system. In English, stimulating D2 receptors causes more dopamine transporters to be expressed. This makes perfect sense, since Wellbutrin works in part by blocking the dopamine transporter. In my very brief experience, I haven't felt "dumber" on Wellbutrin. I was sort of concerned about the nicotinic acetylcholine receptor antagonism, too :-).
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Apr 26 2008, 04:24 AM
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Newbie
Group: Newbie
Posts: 5
Joined: 22-April 08
Member No.: 24,653
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QUOTE (dreamwolf @ Mar 8 2008, 05:40 AM) You know - I just love researching this stuff in addition to it being personally applicable since I did take Wellbutrin for a short period of time. Some drugs - stimulants that act upon dopamine in particular have caused poor reactions in some people due to peculiarities in their brain chemistry or balance due to genetic or environmental causes thus causing depression, memory loss, etcetra, and even hair loss and such (google dopamine and follicle-stimulating hormone) Some stimulants can cause you to initially feel great after which you then feel like crap due to how your dopamine receptors regulate over the time you take the drug - Initially you feel great then your dopamine D2 receptors upregulate and then you feel like crap. Over time as you continue taking the drug though these receptors downregulate back to normal levels and you feel good again. Not as good as you felt when you started - but more normal. There is the possibility though I am loathe to admit it that if I continued taking the Wellbutrin longer than a month I may have felt 'normal' again (due to findings with other stimulants besides Wellbutrin) though I have not found the research to back this up with Wellbutrin yet. Still IMHO it is wisest to save the stimulants and dopaminergenics as a therapy of last resort and only with intense research and advice from a very knowledgeable doctor. Play with the SSRIs first. Dopaminergenics have too much potential to seriously screw one up. Admittedly other drugs have indirect actions on dopamine though. All the various systems in the brain are interconnected and changing one more than likely influences many others - even those that science may not have knowledge of. Better yet - try cognitive therapy first Thusly for public consumption I submit my personal cache of research on the matter in addition to that which I have already submitted to the fourms. And it's nice to have a public cache of my research too. Please pm me for more detailed information on this. This is really interesting. I find it all fascinating too... what I am wondering though, is why the anti-depressant effect works for some people in spite of the potentially depressing mechanism you're talking about - could it be there is another, separate regulation happening that's responsible for the anti-depressant effect? Dopamine is also cited as a major neurotransmitter responsible for anhedonia, low motivation and low libido. Could it be the reason that the SSRI/Wellbutrin combo works better than either drug alone is because the SSRI balances the increased depression, while the Wellbutrin resolves motivation and anhedonia issues? Of course this is all completely speculative and is no indication that it will work for anyone - but then, selecting medication is a fairly random process much of the time anyway. As I posted recently, I'm in the middle of the "feel like crap" phase and wondering just HOW much of mood raise I can expect. The responses to my post said that, for the respondents at least, they felt better after 4 weeks than they did before they started taking it. So there will be a few of us who will be able to provide you with some empirical data over the coming months! Sure, it won't be an n=400 double-blind placebo-controlled trial, but then it won't be influenced by a drug company either so you'll know the results aren't being manipulated.  But thank you very much for posting that - you have further convinced me that, if I can put up with the horrible month ahead of me, it's worth sticking with it. I have about eight failed trials of nearly every class over the past five years, the dopaminergics are the last of the major ones, so in my case it's worth a try.
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Apr 26 2008, 05:58 AM
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Newbie
Group: Newbie
Posts: 26
Joined: 21-February 08
From: North of Detroit
Member No.: 22,965
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QUOTE (psi81 @ Apr 26 2008, 05:24 AM) But thank you very much for posting that - you have further convinced me that, if I can put up with the horrible month ahead of me, it's worth sticking with it. I have about eight failed trials of nearly every class over the past five years, the dopaminergics are the last of the major ones, so in my case it's worth a try. I feel exactly the same way. I was on Wellbutrin years ago, and it really worked wonders for 5-6 years. For a few reasons, I got off of it, most notably was switched to generic and that's where I believe it stopped working so well. I've been back on brand name for exactly one week, and am now fighting out the "feel like crap" period. The first 4 days were awesome, felt just like it did before, and I was elated. I'm not worried as much as I thought I would be since I've found this message board, and read how many others also experienced a "honeymoon" period prior to the drug eventually leveling off and working. So, time to stick it out for a "horrible month". I hope it works for you as well as myself.
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May 18 2008, 09:27 PM
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Newbie
Group: Newbie
Posts: 38
Joined: 1-May 08
From: Missouri
Member No.: 24,907
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Wow, are you people for real? Are you doctors or scientists? LOL! I didn't understand one bit of this thread! I prefer to stick to the I felt better, I felt worse, it took time...ah, much easier for my little drugged up brain to understand! Ha! But it's a good thread anyway. I suppose you smart people need to post too.
Totally just kidding. :) You have all impressed me.
Feeling really dumb right now, but will blame it on the drugs...
--------------------
Kaygirl
"Perhaps your crisis is an opportunity to receive a deeper faith in God and a greater compassion for others, or to witness to those who do not yet believe in Christ." Author Unknown
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May 22 2008, 02:31 AM
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Newbie
Group: Newbie
Posts: 6
Joined: 19-May 08
Member No.: 25,353
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Just wanted to say...I just started Wellbutrin 3 days ago..my doc put me on a very low dose to start and will up it if needed in a few weeks. So I'm on 100mg sr once in the am..
I have never been on anything else before....but have had no energy for YEARS!! The last few days (not counting today) were incredible...I was practically high but in a productive non grumpy get my crap done kind of way. Is that what "regular" people feel like all the time. I can't fathom that. It was gone today. Today I carb loaded all day...very tired....and way crabby. I want to feel like I did yesterday and the day before. Was this what everyone elses wellbutrin honeymoon was like...and what is it like after the crappy month is over??
Thanks,
Red
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May 22 2008, 12:42 PM
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Newbie
Group: Newbie
Posts: 8
Joined: 21-April 08
Member No.: 24,615
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This is the start of my 7th week on 150 mg XL/day, also my first antidepressant. I got that same burst of energy at first and then had a couple days of feeling exhausted all the time. Maybe you're doing a lot more during the day than you normally would and then not getting good sleep because you're not adjusted to the Wellbutrin, yet. Possibly made worse by not eating enough... At this point I feel more "balanced" and less lazy. Mornings aren't so painful. It's nothing intense and dramatic like the first couple days, but it's made a noticeable difference in terms of concentrating and getting things done and being social and not spending so much time wanting to crawl into a hole and die. So far I'm impressed with it and I don't know if I want to go up to the "normal" 300 mg/day or not. Anyway, that's been my experience. To answer kaygirl's question, yes, I'm in school trying to be a scientist. Haha. Don't feel dumb, anyone can memorize a lot of obscure facts if they have enough time. QUOTE (Red Zinfindel @ May 22 2008, 02:31 AM) Just wanted to say...I just started Wellbutrin 3 days ago..my doc put me on a very low dose to start and will up it if needed in a few weeks. So I'm on 100mg sr once in the am..
I have never been on anything else before....but have had no energy for YEARS!! The last few days (not counting today) were incredible...I was practically high but in a productive non grumpy get my crap done kind of way. Is that what "regular" people feel like all the time. I can't fathom that. It was gone today. Today I carb loaded all day...very tired....and way crabby. I want to feel like I did yesterday and the day before. Was this what everyone elses wellbutrin honeymoon was like...and what is it like after the crappy month is over??
Thanks,
Red
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May 23 2008, 03:26 PM
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Newbie
Group: Newbie
Posts: 6
Joined: 19-May 08
Member No.: 25,353
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Well its good to know that at least my reaction is normal. How long did it take to strike that balance. Yesterday I was wasted like all day...then suddenly in the evening had a burst of energy and cleaned my whole house. I even had a little trouble stopping but once I forced myself to sit...my energy leveled off and I wound down. I love it though. But clearly its not balanced....If I had that all day then felt exhausted in the evening that would be fine. I'm rambling....
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May 23 2008, 10:44 PM
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Newbie
Group: Newbie
Posts: 12
Joined: 8-May 08
Member No.: 25,085
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QUOTE (Minot @ May 23 2008, 02:26 PM) Well its good to know that at least my reaction is normal. How long did it take to strike that balance. Yesterday I was wasted like all day...then suddenly in the evening had a burst of energy and cleaned my whole house. I even had a little trouble stopping but once I forced myself to sit...my energy leveled off and I wound down. I love it though. But clearly its not balanced....If I had that all day then felt exhausted in the evening that would be fine. I'm rambling.... I'm still in that phase even after almost 7 weeks...sometimes I ramble and my thoughts race. Other days, I'm just so exhausted I can hardly get out of a chair. Today was a down day in the morning, but by 3pm, I was reorganizing closets and the pantry. It's weird because weeks 2-4. I was down all the time. All I can say is this: I was on WB once before and it definitely leveled out after about 8 weeks. Give yourself plenty of time 'cuz WB is funny like that. I have been frustrated this time because I want to feel NOW what I did at like 3 months the last time. But I remember how good I felt several years ago and I'm willing to wait it out...I urge you to do the same. If you're feeling like you are now, it's going to all balance out for you eventually!
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Potentially Why Some People Experience Poor Reactions To Wellbutrin And Potental Reasoning For The Wellbutrin Honeymoon., And more! A veritable treasure trove of information! |
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Depression Forums - A Depression & Mental Health Community Support Group > DEPRESSION & ANXIETY MEDICATIONS - LOOKING FOR ANSWERS > WellbutrinŽ - (also marketed as ZybanŽ & Bupropion)
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