Depakote

[ara96]

Hi,
I have a patient with Bipolar Dx who is doing beautifully on Depakote. However, he is concerned about his weight gain (has been taking it for a few months). He is taking 1,000 mg of the Delayed Release. I would like to taper it off and start him on Lamictal or Topamax. I was wondering generally, how do you guys taper Depakote to discontinue?

I hate taking the medication away as he is doing so well. 🙁

Thanks

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[thoffen]

Topiramate is not evidence based for treatment of bipolar disorder. Lamotrigine has high quality evidence only for prevention of depressive relapse. Additionally, valproate will decrease metabolism of lamotrigine so you would need to half the dose during a painfully long titration.

 

[slappy]

Are you still in residency? If so, I'd check with your supervisor first to make sure he/she is comfortable with this plan.

Lamotrigene sounds like a good idea since weight is a concern. But, issue 1 is that it's not very effective in preventing mania. It is good for the depression phase though. The second issue is with the cross-taper since VPA's inhibitory effects on LTG clearance is quite variable, and can last anywhere from a few days to several weeks (six, iirc) even after it is completely discontinued. This necessitates a very careful and slow uptitration of LTG while you're downtitrating the VPA.

Because of issues 1 and 2, there is a good chance of a relapse -- so you'll likely need to see her much more often in the coming weeks. Finally, there aren't any accepted guidelines as far as I know for this cross taper, but remember that at a dose of 250+ mg qd, VPA doubles the AUC of LTG, and at a dose of 125 mg qd, it increases it by a third.

 

[birchswing]

Lamotrigine actually has very specific instructions for cross-tapering from Depakote in the PI.

 

[slappy]

Lamotrigine actually has very specific instructions for cross-tapering from Depakote in the PI.

I don't remember seeing it. Would you mind posting it in case you have the primary source? I know they kind of mention it for seizures, but doses for bipolar disorder are different and don't translate exactly.

 

[hamstergang]

Lamotrigine actually has very specific instructions for cross-tapering from Depakote in the PI.

You sure you're talking about cross tapering or just concurrent use? Those aren't the same thing.

 

[birchswing]

I don't remember seeing it. Would you mind posting it in case you have the primary source? I know they kind of mention it for seizures, but doses for bipolar disorder are different and don't translate exactly.

You sure you're talking about cross tapering or just concurrent use? Those aren't the same thing.

My reasons for looking involved epilepsy so I didn't see the distinction at the time.

But in Table 4 on this page they show a cross-taper from Depakote to Lamictal:
Lamictal - FDA prescribing information, side effects and uses

But as you said that's epilepsy.

Table 6 with regard to bipolar is what confused me at first. I thought it was saying you should discontinue Depakote to go on Lamictal. But it's showing how the dose of Lamictal should be increased *if* Depakote is discontinued and they were already prescribed in tandem previously.

Sorry if I sprouted misinformation. I had read it for a different purpose and just vaguely remembered the tables.

 

[HarryMTieboutMD]

1) Has the pt tried diet modification/exercise? (always my go to and for antipsychotic- different but same concept- induced weight gain there's evidece)

2) Just a nuance as to what was said above. Lamictal has the most evidence for prophylaxis against bipolar depression, but it definitely can be useful for prophylaxis (though not treatment) against mania as well

3) That said, for reasons other people mentioned the cross taper from VPA to lamictal can get kind of messy, so I just don't do it. I've had a few patients that were on VPA plus an atypical (usually invega sustenna) and I tapered off the depakote, waited a little, then uptitrated lamictal.

4) Owning to point #2- what has the course of the illness been like in terms of valence of the episodes? Lithium is the best prophylactic medication against all episodes , but you do have weight gain potential. I have had a fair amount of patients do nicely on abilify monotherapy as well, though according to the literature it's not useful for depression prophylaxis... and again... weight gain. I have one patient who is actually pretty stable (horrible, rapid cycling, severe psychotic mania) who is stable on trileptal (it's the only thing he wants to take- i didn't start it though), but the evidence for that is limited.

5) Please don't acknowledge posting about psychopharmacology management from a patient who posts...

 

[birchswing]

1) Has the pt tried diet modification/exercise? (always my go to and for antipsychotic- different but same concept- induced weight gain there's evidece)

Point 5) withstanding, I know the SIMPLE program you're referring to (assuming that's the one), but the evidence is better for both metformin alone and even more so for metformin plus lifestyle change over lifestyle change in the face of weight gain and metabolic dysfunction with atypical antipsychotic use. Can metformin undo weight gain induced by antipsychotics?

 

[lyla]

Convince him to stay on the depakote if he is doing "beautifully" on it.

 

[ara96]

Thanks for the responses, I am a resident and I do know about the interaction between VPA/Lamictal, but did not know the waiting period. I think we will need to swtich to Latuda or Abilify soon.

One question, I read that VPA is very protein bound, what does this mean exactly? Does it mean that a lot of it will cross blood brain barrier, resulting in toxicity? Forgive me, for my pharmacokinetics knowledge has atrophied.

 

[Amygdarya]

One question, I read that VPA is very protein bound, what does this mean exactly? Does it mean that a lot of it will cross blood brain barrier, resulting in toxicity? Forgive me, for my pharmacokinetics knowledge has atrophied.

About 90% of valproate is protein bound. This means that in people with low blood protein/albumin levels (e.g., liver and kidney disease) there is much more free/non-protein bound valproate, which may be toxic. That's why sometimes it makes sense to check not only valproate levels (the standard test) but *free* valproate.

 

[ara96]

About 90% of valproate is protein bound. This means that in people with low blood protein/albumin levels (e.g., liver and kidney disease) there is much more free/non-protein bound valproate, which may be toxic. That's why sometimes it makes sense to check not only valproate levels (the standard test) but *free* valproate.

Thank you, for the refresher. I don't even know if we can order the Free VPA test at our hospital.

 

[slappy]

About 90% of valproate is protein bound. This means that in people with low blood protein/albumin levels (e.g., liver and kidney disease) there is much more free/non-protein bound valproate, which may be toxic. That's why sometimes it makes sense to check not only valproate levels (the standard test) but *free* valproate.

Um, yes, but not quite. Increased free levels also mean increased volume of distribution and increased rate of elimination. So while the active, free fraction does increase in hypoalbuminemia, it rarely gets toxic. That said, I always get both free and total valproate levels for monitoring. A much more important implication of valproate's high protein binding is that a very large proportion of valproate in the body is sitting dormant on protein molecules, and they could be displaced into the plasma if the patient starts taking a medication that the proteins have an even higher affinity for, thereby increasing the levels of the toxic free valproate.

 

[Amygdarya]

A much more important implication of valproate's high protein binding is that a very large proportion of valproate in the body is sitting dormant on protein molecules, and they could be displaced into the plasma if the patient starts taking a medication that the proteins have an even higher affinity for, thereby increasing the levels of the toxic free valproate.

Thank you for the clarification, this is good to know.

 

[hamstergang]

a medication that the proteins have an even higher affinity for

Any common examples come to mind?

 

[slappy]

VPA has such high affinity for albumin it is unlikely to be displaced by other drugs; rather it can displace other drugs that are protein bound (like warfarin, phenytoin etc)

Actually, several drugs have higher affinity and have been known to displace valproate. Common ones are aspirin and NSAIDs like ibuprofen and naproxen.