What is the specific neurochemical way that Lamictal exerts it's antidepressant effects?
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Q:  What is the specific neurochemical way that Lamictal exerts it's antidepressant effects? (I read in one article that it may be a 5ht1a agonist)

I ask because I had hoped to be able to add an SSRI to my lamictal and to that end I have been trying Lexapro. However, each time I go up in dose on the Lexapro, even by a small increment, I become overstimulated and have realized that I can relieve this by coming down on my Lamictal dose. There seems to be some kind of inverse and mutually exclusive relationship between the Lamictal and the Lexapro. What could be happening? 

Could Buspar be a better choice for increasing my serotonin and if so, can it be used long-term?

If a serotonin receptor is downregulated, does that mean that it becomes more activated rather than less or that it begins to receive serotonin for a longer period of time than it normally would?

Does Lexapro inhibit reuptake of serotonin only at a specific receptor and if so, which one?

Should an anti-psychotic, 5ht2a antagonist be considered as an option in my situation.

Dear Alex -- 
Let's see if I can explain how your question strikes me. Not your fault, by the way; I hear psychiatrists talk like this too, and it always bugs me, so I don't mean to take it out on you; its just that the explanatory model implies that we know more than we may actually know; and since we do indeed actually know a lot more than we've generally been given credit for by people who think we're still following the teachings of Sigmund Freud, I hate to jeopardize that by overstating our knowledge. 

It's as though you're asking if you need to reposition the fuel injectors in an aircraft engine when the real question is whether you should be flying a biplane or jet or a helicopter.  To my knowledge no one has yet established precisely (or even very roughly) how lamotrigine exerts its apparent antidepressant-like effects. I've seen more speculation about glutamate than about serotonin in this respect. But the bigger question you're trying to address, it seems to me, is how to accomplish whatever it is you're trying to accomplish by adding Lexapro to Lamictal (remaining depression? some sort of obsessive-compulsive type symptom?)

Meanwhile, however, you're recognizing something very interesting here: sounds like the same "overstimulation" that can be brought on by increasing Lexapro can be diminished by lowering Lamictal. Rather than inverse and mutually exclusive, might this suggest that the two of them are doing something very similar, so that you can solve the problem caused by one, by lowering the other? Although the manufacturer of lamotrigine (and even most of the researchers who've done the tests showing its antidepressant effects) say this doesn't happen, I'm convinced that this medication can act too much like an antidepressant in some people (as you probably know, antidepressants in bipolar disorder can push people toward manic-side symptoms. Another psychiatrist who uses it a lot estimates this happens about one in every 20 or 30 patients, which was just my estimate before talking with him. Since this effect can occur with no antidepressant around, perhaps it might happen even more often in people who are also taking antidepressants. That might be what you're seeing. 

So I'd be more concerned about figuring that part out, and how to address it (find more mood stabilizer effect from some source? lower the antidepressant effects somehow? thereby avoid having to add the antipsychotic?) than figuring out which neurotransmitter might be responsible. You're right, it would be great if we knew enough about what we were doing to approach a puzzle like this in just the way you suggest: do we have too much serotonin effect at this receptor? too little at that receptor? Can we get a GABA effect in just the right brain region to damp this down without sedation? But overall, I'm afraid we're still back at the level of trying one standard solution, and if it doesn't work, going on to the next standard solution. Someday we might be able to tailor a regimen even before we start, based on your genes and your transmitter levels and your liver enzymes, and such; but for now, we're flying by the seat of our pants, not by the instrument reading about minute-to-minute fuel consumption.  Darn. Good luck figuring out your airplane. 

Dr. Phelps

Published January, 2007

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