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Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 1 to 18 of 18. This is the beginning of the thread.
Posted by Cam W. on October 19, 2001, at 19:08:33
I believe it was Collette that had asked me to explain the mechanisms of action of Lamictal™ (lamotrigine). Although the mechanisms of action of Lamictal as an augmenting agent in bipolar disorder (esp. bipolar
depressiom), unipolar depression, and anxiety disorders are not fully understood, I will see if can talk my way through possible mechanisms, as I type.
Lamictal is related to antifolate compounds. It's positive benefits on mood were noted very early on, during clinical epilepsy trials in the early to mid-90s. As a matter of fact, in one clinical trial, conducted in 1993, 66% of those receiving Lamictal continued taking the drug after the trial was over, but only 18% of participants had improved seizure control.Lamictal is known to block sodium channels similar to valproate (Epival™/Depakote™ - divalproex & Tegretol™ carbamazepine). The reason that this is beneficial
relates to the way that an electrical signal travels down the length of an axon (the long part of the neuron). The inside of a nerve cell is slightly negatively charged, relative to the outside of a nerve cell. This electrical gradient is maintained by sodium ion pumps (pumping the positively charged sodium out of the cell) and chloride ion pumps (pumping negatively charged chloride ions into the cell) that are located within the nerve cell wall. Positively charged calcium ions and positively charged potassium ions are also involved in modifying the conduction of an electrical signal (called an action potential).During the firing of a nerve cell, the outside and inside of the cell temporarily reverses polarity (outside of the cell becomes negatively charged and inside of the cell positively charged). This change in polarity occurs because the electrical signal causes the the sodium ion channels and the chloride ion channels to open up. Because an osmotic gradient is set up by the ion pumps, the sodiums ions flow into the cell and the chloride ions flow out of the cell. The ion pumps almost immediately begin to pump their respective ions in (chloride) and out (sodium) of the cell. This flip-flop of polarity causes the movement (propagation) of the electrical signal (action potential) down the nerve cell toward the nerve terminus (where the action potential cause the release of the neurotransmitters into the synaptic gap and these neurotransmitters carry the electrical signal across the gap and stimulate post synaptic receptors and causes an action potential to propagate along the next neuron's axon).
By blocking sodium ion channels, by Lamictal, stops (or at least slows) the action potential from propagating down the axon as readily. This is because when the action potential causes the sodium and calcium ion channels to open, the chloride can flow freely, but the sodium channel is blocked by the Lamictal. Thus, a hypersensitive, or overactive nerve cell (perhaps caused by hypersecretion of cortisone from the adrenals, etc., that occurs in depression).
Lamictal also blocks calcium channels. As mentioned above calcium also modulates the propagation of an action potential. Also calcium plays a major role in the release of neurotransmitters, and is involved in other synaptic processs,in energy metabolism, in neuronal plasicity, heart function, etc. (Hence the advertising is correct: "Milk IS good for every body). Without going into the detail that I did above, blocking calcium ion channels, also slow down hyperactive nerve cells, or essentially helps to normalize the electrical flow within the nerves of the brain.
This normalization of an overexcited nervous system in depression (possibly partly die to the uncoupling of the HPA axis) by Lamictal is also helped to be accomplished by another of Lamictal's actions: the inhibition of glutamate release. Glutamate is the primary excitiatory neurotransmitter in the brain, and mainly causes it's excitatory action via stimulation of the NMDA receptor complex. Blocking glutamate release essntially slows excitatory neurotransmission and inihibitory transmitters (like GABA) are able to calm the nervous system more efficiently.
It has been also noted that Lamictal also weakly blocks the serotonin reuptake mechanism (like the SSRIs) and may have anti-kindling action (like valproate and carbamazepine).
I hope that this explains some of the actions of Lamictal. This drug basically slows overactive nerves, and allows antidepressants to help to recouple the body's stress defense, the HPA axis. Since Lamictal only calms neurons and doesn't "fix" the HPA axis, it would not make a good antidepressant by itself, but it does help antidepressants work better by calming down overactive neurons. This should also possibly explain why Lamictal augments other mood stabilizers in bipolar depression, as well.
If you have anymore questions, don't hesitate to ask. I may not be able to answer them, but I will try. - Cam
Posted by Thrud on October 19, 2001, at 21:28:05
In reply to Proposed Mechanisms of Action of Lamotrigine, posted by Cam W. on October 19, 2001, at 19:08:33
> By blocking sodium ion channels, by Lamictal, stops (or at least slows) the action potential from propagating down the axon as readily. This is because when the action potential causes the sodium and calcium ion channels to open, the chloride can flow freely, but the sodium channel is blocked by the Lamictal. Thus, a hypersensitive, or overactive nerve cell (perhaps caused by hypersecretion of cortisone from the adrenals, etc., that occurs in depression).
>Without going into the detail that I did above, blocking calcium ion channels, also slow down hyperactive nerve cells, or essentially helps to normalize the electrical flow within the nerves of the brain.
>
> This normalization of an overexcited nervous system in depression (possibly partly die to the uncoupling of the HPA axis) by Lamictal is also helped to be accomplished by another of Lamictal's actions: the inhibition of glutamate release. Glutamate is the primary excitiatory neurotransmitter in the brain, and mainly causes it's excitatory action via stimulation of the NMDA receptor complex. Blocking glutamate release essntially slows excitatory neurotransmission and inihibitory transmitters (like GABA) are able to calm the nervous system more efficiently.Does it slow down nerve impulses related to intellect as well as emotion? Maybe that is why I feel "dumb" on 200 mg/day Lamictal? I am not the only poster complaining of the "cognitive dulling" effect of Lamictal, either.
Thrud
Posted by Hattree on October 19, 2001, at 21:56:11
In reply to Proposed Mechanisms of Action of Lamotrigine, posted by Cam W. on October 19, 2001, at 19:08:33
> It has been also noted that Lamictal also weakly blocks the serotonin reuptake mechanism (like the SSRIs) and may have anti-kindling action (like valproate and carbamazepine).
>
> I hope that this explains some of the actions of Lamictal. This drug basically slows overactive nerves, and allows antidepressants to help to recouple the body's stress defense, the HPA axis. Since Lamictal only calms neurons and doesn't "fix" the HPA axis, it would not make a good antidepressant by itself, but it does help antidepressants work better by calming down overactive neurons. This should also possibly explain why Lamictal augments other mood stabilizers in bipolar depression, as well.
>
I have good luck w/Lamictal and Zoloft, but would rather take Serzone because I experienced fewer side effects. Would this combo be likely to work?
Posted by Cam W. on October 20, 2001, at 4:01:16
In reply to Re: Proposed Mechanisms of Action of Lamotrigine » Cam W., posted by Hattree on October 19, 2001, at 21:56:11
Hattree - I have personally had no experience with Serzone™ (nefazodone) and Lamictal™ (lamotrigine), but this does not mean that they couldn't be used together, but the dosing of the Lamictal "might" possibly be tricky.
Serzone is a very potent inhibitor of the cytochrome-P450-3A4 (CYP-3A4) system, an enzyme system that is responsible for metabolizing many medications. Although Lamictal is not listed as being metabolized in the CYP-3A4 system, Lamictal's main metabolite is formed by glucuronidization in the liver, which (I believe, not absolutely sure) is one mechanism of metabolism used by the cytochrome system.
It may be prudent to watch carefully for an increase in Lamictal side effects if you switched from Zoloft™ (sertraline) to Serzone.
I am also a believer in "If it ain't broke, don't fix it". Unless the side effects from the Zoloft are intolerable, I would be reluctant to switch to Zoloft. If you switch, and Serzone doesn't hold your depression (or whatever syndrome you are using it for) at bay, "sometimes" upon retrial, an SSRI does not seem to work as well as it did originally. This is not always the case, but I say why risk it.
Talk to your doc about this and get his/her opinion on this, as well. I do hope that this has been of some help. - Cam
Posted by JohnX on October 20, 2001, at 11:48:09
In reply to Proposed Mechanisms of Action of Lamotrigine, posted by Cam W. on October 19, 2001, at 19:08:33
Cam,I'm tying to better understand how the electrolyte
meds differ from some of the antagonist meds.For example, In laymans how exactly would you explain that Lamictal tames NMDA receptors relative to (non)competive NMDA antagonists
like PCP,ketamine,dextromethorphan,memantine.
Its my understanding that the NMDA antagonists
act more by competing for the receptors that open/close the channels rather than modifying the action potential. Is this correct? And if so what would be the impact?Thanks,
John> I believe it was Collette that had asked me to explain the mechanisms of action of Lamictal™ (lamotrigine). Although the mechanisms of action of Lamictal as an augmenting agent in bipolar disorder (esp. bipolar
> depressiom), unipolar depression, and anxiety disorders are not fully understood, I will see if can talk my way through possible mechanisms, as I type.
>
> Lamictal is related to antifolate compounds. It's positive benefits on mood were noted very early on, during clinical epilepsy trials in the early to mid-90s. As a matter of fact, in one clinical trial, conducted in 1993, 66% of those receiving Lamictal continued taking the drug after the trial was over, but only 18% of participants had improved seizure control.
>
> Lamictal is known to block sodium channels similar to valproate (Epival™/Depakote™ - divalproex & Tegretol™ carbamazepine). The reason that this is beneficial
> relates to the way that an electrical signal travels down the length of an axon (the long part of the neuron). The inside of a nerve cell is slightly negatively charged, relative to the outside of a nerve cell. This electrical gradient is maintained by sodium ion pumps (pumping the positively charged sodium out of the cell) and chloride ion pumps (pumping negatively charged chloride ions into the cell) that are located within the nerve cell wall. Positively charged calcium ions and positively charged potassium ions are also involved in modifying the conduction of an electrical signal (called an action potential).
>
> During the firing of a nerve cell, the outside and inside of the cell temporarily reverses polarity (outside of the cell becomes negatively charged and inside of the cell positively charged). This change in polarity occurs because the electrical signal causes the the sodium ion channels and the chloride ion channels to open up. Because an osmotic gradient is set up by the ion pumps, the sodiums ions flow into the cell and the chloride ions flow out of the cell. The ion pumps almost immediately begin to pump their respective ions in (chloride) and out (sodium) of the cell. This flip-flop of polarity causes the movement (propagation) of the electrical signal (action potential) down the nerve cell toward the nerve terminus (where the action potential cause the release of the neurotransmitters into the synaptic gap and these neurotransmitters carry the electrical signal across the gap and stimulate post synaptic receptors and causes an action potential to propagate along the next neuron's axon).
>
> By blocking sodium ion channels, by Lamictal, stops (or at least slows) the action potential from propagating down the axon as readily. This is because when the action potential causes the sodium and calcium ion channels to open, the chloride can flow freely, but the sodium channel is blocked by the Lamictal. Thus, a hypersensitive, or overactive nerve cell (perhaps caused by hypersecretion of cortisone from the adrenals, etc., that occurs in depression).
>
> Lamictal also blocks calcium channels. As mentioned above calcium also modulates the propagation of an action potential. Also calcium plays a major role in the release of neurotransmitters, and is involved in other synaptic processs,in energy metabolism, in neuronal plasicity, heart function, etc. (Hence the advertising is correct: "Milk IS good for every body). Without going into the detail that I did above, blocking calcium ion channels, also slow down hyperactive nerve cells, or essentially helps to normalize the electrical flow within the nerves of the brain.
>
> This normalization of an overexcited nervous system in depression (possibly partly die to the uncoupling of the HPA axis) by Lamictal is also helped to be accomplished by another of Lamictal's actions: the inhibition of glutamate release. Glutamate is the primary excitiatory neurotransmitter in the brain, and mainly causes it's excitatory action via stimulation of the NMDA receptor complex. Blocking glutamate release essntially slows excitatory neurotransmission and inihibitory transmitters (like GABA) are able to calm the nervous system more efficiently.
>
> It has been also noted that Lamictal also weakly blocks the serotonin reuptake mechanism (like the SSRIs) and may have anti-kindling action (like valproate and carbamazepine).
>
> I hope that this explains some of the actions of Lamictal. This drug basically slows overactive nerves, and allows antidepressants to help to recouple the body's stress defense, the HPA axis. Since Lamictal only calms neurons and doesn't "fix" the HPA axis, it would not make a good antidepressant by itself, but it does help antidepressants work better by calming down overactive neurons. This should also possibly explain why Lamictal augments other mood stabilizers in bipolar depression, as well.
>
> If you have anymore questions, don't hesitate to ask. I may not be able to answer them, but I will try. - Cam
Posted by Jane D on October 20, 2001, at 11:57:36
In reply to Re: Proposed Mechanisms of Action of Lamotrigine » ADgirl, posted by Cam W. on October 20, 2001, at 4:04:45
> Sal - Yes, cognitive dulling can be caused by Lamictal.
Cam,
Do you have any feel for how frequent this is, how severe, whether or not it is dose related and whether it subsides with time?
Dully yours,
Jane
Posted by Cindylou on October 21, 2001, at 14:25:26
In reply to Re: Proposed Mechanisms of Action of Lamotrigine » ADgirl, posted by Cam W. on October 20, 2001, at 4:04:45
Hi Cam,
Another Lamictal question -- this may be pretty basic, but I'm wondering about the dreaded "rash" everyone talks about. I am currently taking 25 mg and working my way up to 100 mg -- and I'm nervous about developing the rash.Do you know about what % of people on Lamictal develop a rash? Is anyone more predisposed to developing the rash than others (I am very med-sensitive--get strong side effects at low doses from most meds, so I'm wondering if I might be at risk for the rash.) So far, I haven't noticed many side effects from the Lamictal which is pretty amazing.
Thanks in advance for your help,
cindy
Posted by Cam W. on October 22, 2001, at 23:12:37
In reply to Re: Proposed Mechanisms of Action of Lamotrigine » Cam W., posted by JohnX on October 20, 2001, at 11:48:09
John - The difference between pre- and post-synaptic receptor agonists and antagonists (like NMDA antagonists) and sodium ion (Na+) (like lamotrigine) and calcium ion (Ca2+) (like nifedipine) blockers is that the former acts between 2 neurons and the latter is on an axon of one neuron.
When talking about NMDA (D2, 5-HT2, alpha-1, etc) antagonists we usually mean that we are either blocking the signal on the post-synaptic membrane. These drugs block post-synaptic receptors and do not allow the natural neurotransmitter to stimulate the receptor and thus the signal carried by the neurotransmitter is blocked (for NMDA receptors the neurotransmitter is glutamate; for D2 it is dopamine; for 5-HT2 it is serotonin).
Agonists on the other hand act like the neurotransmitter and cause a signal to go through (causing the neuron to fire) without the presence of a neurotransmitter, when the receptor for the agonist is on the post-synaptic membrane.
When on the pre-synaptic membrane (eg. 5-HT1A on the somatodentritic surface - neuron cell body; or 5-HT1B on the axon terminal) agonist are usually stimulating autoreceptors, which act as a negative feedback mechanism. When stimulated (by agonists or neurotransmitters) autoreceptors shut off the flow of neurotransmitter from the pre-synaptic nerve terminal, slowing the electrical impulse from on neuron to another. When blocked by an antagonist the flow of transmitter is increased from the pre-synaptic terminal, increasing the eletrical flow from on neuron to another.
Then there are different agonists and antagonists. Noncompetitive antagonists block the receptor outright and are usually irreversible. Competitive antagonists compete with the neurotransmitter and can be displaced if the neurotransmitter level is high enough.
This is a very basic outline of agonists and antagonists, and I hope that you are able to wrap your brain around some of the logic. It actually took me a few years to figure it all out (and I still occasionally get thrown when combinations are working at the same time).
I hope that this is what you were looking for. - Cam
Posted by Cam W. on October 22, 2001, at 23:15:45
In reply to Cognitive dulling » Cam W., posted by Jane D on October 20, 2001, at 11:57:36
Jane - Most people do not experience cognitive dulling beyond the titration phase, but I have seen a few people who never seem to shake this side effect. They complain of not being able to remember names as readily, even after 2 or 3 months of Lamictal use. If I had to make an informal guess, I'd say that about 1 in 10 seem to have problems with name finding after the titration phase (but this is a very unscientific guess). - Cam
Posted by Cam W. on October 22, 2001, at 23:21:40
In reply to Re: Proposed Mechanisms of Action of Lamotrigine » Cam W., posted by Cindylou on October 21, 2001, at 14:25:26
Cindy - The dreaded rash (Steven-Johnson syndrome) is very rare in adults and affects mainly young children. I believe that the incidence of this is 1 in 1000 in adults (1 in 100 if including children), but the incidence of an ordinary, sunburn-like rash is about 1 in 10. The minor and major rashes are usually seen when the dose of Lamictal is raised too fast. Most docs will stop Lamictal at the first sign of any rash (with good reason). Upon rechallenge, at a lower dose, and slower titration, most people do not develop a rash when tried on Lamictal the second time around. I haven't noticed if anyone is more predisposed to the rash than other people, but I may be missing a link. - Cam
Posted by Cindylou on October 23, 2001, at 7:05:46
In reply to Lamotrigine Rash » Cindylou, posted by Cam W. on October 22, 2001, at 23:21:40
Hi Cam,
Thanks for the info. The other night, my back was itching like crazy, and I looked in the mirror and it did look like I had patches of sunburn on my back. That went away in a couple of hours, though. Now I just have about 10 or 15 little "bug bites" scattered around ... I'm wondering if this is something to bother my pdoc about. (I bother her enough as it is.) It doesn't seem alarming to me, but I just thought I'd see what you thought.Thanks,
cindy> Cindy - The dreaded rash (Steven-Johnson syndrome) is very rare in adults and affects mainly young children. I believe that the incidence of this is 1 in 1000 in adults (1 in 100 if including children), but the incidence of an ordinary, sunburn-like rash is about 1 in 10. The minor and major rashes are usually seen when the dose of Lamictal is raised too fast. Most docs will stop Lamictal at the first sign of any rash (with good reason). Upon rechallenge, at a lower dose, and slower titration, most people do not develop a rash when tried on Lamictal the second time around. I haven't noticed if anyone is more predisposed to the rash than other people, but I may be missing a link. - Cam
Posted by Cam W. on October 23, 2001, at 8:25:22
In reply to Re: Lamotrigine Rash » Cam W., posted by Cindylou on October 23, 2001, at 7:05:46
Cindy - Definitely tell your doc about these. Steven-Johnson syndrome looks like a very severe sunburn, that doesn't go away. The "bug bites" may, and I say only "may" be a very mild allergic reaction. Let your doc know and he/she will probably want a look at them before determining whether to discontinue you from the Lamictal or not. - Cam
Posted by Jane D on October 24, 2001, at 0:08:02
In reply to Re: Cognitive dulling » Jane D , posted by Cam W. on October 22, 2001, at 23:15:45
Uh... uh... uh.. don't tell me .. that's it! Cam, right?
Shit!
Thanks for answering.
Jane
> Jane - Most people do not experience cognitive dulling beyond the titration phase, but I have seen a few people who never seem to shake this side effect. They complain of not being able to remember names as readily, even after 2 or 3 months of Lamictal use. If I had to make an informal guess, I'd say that about 1 in 10 seem to have problems with name finding after the titration phase (but this is a very unscientific guess). - Cam
Posted by Cam W. on October 24, 2001, at 0:36:04
In reply to Re: Cognitive dulling » Cam W., posted by Jane D on October 24, 2001, at 0:08:02
Jane - I hear ya; but I don't have the Lamictal to blame it on ;^) - Cam
Posted by Jane D on October 24, 2001, at 0:46:40
In reply to Re: Cognitive dulling » Jane D, posted by Cam W. on October 24, 2001, at 0:36:04
> Jane - I hear ya; but I don't have the Lamictal to blame it on ;^) - Cam
Cam,
I wonder about that possibility too. Ah well... ; >)
Jane
Posted by susan C on October 24, 2001, at 14:04:35
In reply to Re: Cognitive dulling » Cam W., posted by Jane D on October 24, 2001, at 0:46:40
how old are you all?
mouse with a mouth
susan C> > Jane - I hear ya; but I don't have the Lamictal to blame it on ;^) - Cam
>
> Cam,
> I wonder about that possibility too. Ah well... ; >)
> Jane
Posted by Jane D on October 24, 2001, at 15:58:06
In reply to Re: Cognitive dulling Cam and » Jane D, posted by susan C on October 24, 2001, at 14:04:35
> how old are you all?
>
> mouse with a mouth
> susan CHush! (How come there's never a good cat around when you need it?)
;^)
Jane
Posted by Cam W. on October 24, 2001, at 20:16:59
In reply to Re: Cognitive dulling Cam and » Jane D, posted by susan C on October 24, 2001, at 14:04:35
Susan - Not old enough to retire and not young enough to get away with things like I use to. I was actually joking about most of my cognitive troubles. I find that you have to exercise your brain as well the muscles of your body, if you want to keep sharp (mentally speaking). Every now and then depression can give my cognitive abilities a real "whack", at times. - Cam
This is the end of the thread.
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