Saturday, May 26, 2007

Depakote & Ammonia


This is a brief post about the underrecognized side effect of elevated serum ammonia (NH3) levels causing altered mental status, confusion, and delirium in people taking valproic acid or valproate (Depakene is US brand name... also applies to divalproex sodium, or Depakote).

A case of Depakote-induced hyperammonemic encephalopathy was presented at last week's Annual APA meeting. Here's another case (actually, this one is mostly valproic acid toxicity) on Erik Mattison's blog. This problem is often not recognized because ammonia levels are not standard blood tests to do (this test is also a bit of a pain, in that the blood has to be kept on ice immediately after drawing it).

In his presentation on May 21st, Dr. Rasimas discussed the case of a 36-year-old with treatment-resistant schizoaffective disorder and quiescent hepatitis C who returned to the emergency department in a state of lethargy and confusion less than 3 weeks after being hospitalised for lithium toxicity. Personnel in the ER started the man on sodium divalproex, which is chemically related to valproic acid, at a dosage of 1000 mg in the interim to treat hypomania. A nightly dosage ultimately resulted in a serum level of 114 mcg/mL...

When the patient was admitted to the hospital, his AST and ALT were normal at levels of 17 U/L and 44 U/L, respectively, while ammonia was elevated at 66 mcg N/dL. Serum lithium was 1.2 mmol/L.


Dr. Rasimas said he was asked to consult on the case, at which time he determined that the patient's dose of sodium divalproex should be immediately discontinued, suspecting a case of hepatotoxicity. The patient's other psychotropic medications, including lithium, were then resumed. Lactulose and supportive care were given. Ammonia peaked at 111 mcg N/dl within 36 hours of presentation while AST and ALT never exceeded 38 U/L and 81 U/L, respectively.


The symptoms of delirium resolved slowly during the 96 hours following the discontinuation of divalproex sodium.

Typical symptoms for this type of metabolic encephalopathy include confusion, agitation, disorientation, insomnia, hallucinations, picking at bedclothes or in the air, twitching, and asterixis (also called "liver flap", where your hands twitch when holding your arms outstretched as if you were stopping traffic). If an EEG is performed, this usually demonstrates a diffuse encephalopathy.

I've seen several cases of this, and it is gratifying to recognize it, stop the Depakote, add lactulose (helps to reduce the ammonia), and see improvement. I've seen it with even lower ammonia levels (40's) when GI docs say that they doubt that is the problem. But when it improves, it is hard to think that it is anything else.

11 comments:

dinah said...

I am so pleased that you found your own picture.

Midwife with a Knife said...

Thanks for such a nice teaching point. I think there's a huge tendency (I know I have one) to discount hepatotoxicity with normal LFTs. :)

NeoNurseChic said...

This is interesting... When I had the first anticholinergic toxicity psychosis episode, it had gone on for about 3 or 4 days (not nearly as severe as the 2nd episode, which happened in the ER over a span of 8 hours). My family noted how wacky I was being, as did the nurses, but the doctors weren't picking up on it. I'm not sure what the nurses told the docs - I never requested copies of my chart from that stay. But basically, I was hallucinating - I would go out into the hallway and say that there was a baby crying - I'd be so sure this was the case - and the nurses would tell me that we don't have babies on that unit. They knew me really well - I was a patient there several times before and I also did my first nursing rotation on that unit - so they knew this wasn't like me. One night during this episode, my IV meds finished in my PICC line, and I took down the bags and had the line hanging open - the nurses said, "You can't be a nurse - you have to be a patient..." (Had I been with it, I never would have done this!!) My computer saved the IM conversations I had at the time - but I didn't even remmeber having them until I happened to see the logs several months later - entire conversations I had with my ex-boyfriend (boyfriend at the time) are very sad to read - I was obviously delirious, and I wasn't really making any sense - and he was cursing me out and yelling at me for being drugged up and acting like I was doing this on purpose. When my family and friends visited, they knew something wasn't right. And there were more instances, too - but this is some of what I vaguely remember and/or was told - my mom finally called the nurse's station from home one night and told them that they really needed to do something because she was worried about the way I was behaving. I'd been through a lot of hospitalizations on the same meds, and this had never happened before. My brother was even trying to reassure my mom, saying, "You know this isn't like her. She'll be fine - she'll be back to her normal self."

Well, I guess the nurses finally alerted the docs, and they looked into all of it. The next day, they came and spoke with my mom and I. They said I'd had the anticholinergic toxicity reaction - which they said had only happened in like 20 patients at their center, ever....and hardly ever happens in young people, which was why nobody had picked up on it. The meds they said they had to stop were the depacon and cogentin.

Now I'm kinda curious what my labs looked like at the time - I don't really remember as I had so many labs, and I don't know if I specifically took note of ones they drew at the time - or even if they drew them. The 2nd anticholinergic reaction happened a couple weeks after being discharged from the hospital, and I was no longer on those meds - and the ER attributed it to the mexiletine, but my neurologist thought it was from a "confusional" migraine - my personal feeling now is that it could have been a TIA (given all of the WMLs I have, it is entirely possible that I've had TIAs already - also because I've had 2 blood clots in my arm, and the AVN in the knees, plus having weak positive antiphospholipid antibodies/lupus anticoagulant), a basilar migraine, anticholinergic toxicity, a drug-drug interaction, or something else. I don't know - but I was chewing on my pulseox, completely delirious, calling my brother a green dog, telling my best friend to kiss me, and flailing my arms around so that my mom held my hand to keep me from hitting things and biting the pulseox. I was totally nuts.

Since then, the only 2 times it's happened again (on a much much smaller scale) were the last 2 times I had infusion - in December and March (or was it April? a couple months ago, whenever it was!) Both of those times, I received depacon and cogentin, along with other things... The 1st time, I cleaned my entire apartment (it was an absolute disaster), cleaned out the fridge, had an IV in my arm and all, and then the 2nd day - drove from my apartment to my parents' house....drove home terribly but had somehow convinced my dad that I was okay to drive. (When I have this mildly, the ONLY way you can tell that something is off about me is by listening to me speak - I use strange language and combine things that don't really go together - make these odd associations...because otherwise, I seem totally fine - very alert, active, chatty...)

When I got to their house and got out my car, my dad (who had been following me home in his car) started yelling at me for passing him on the highway, driving erratically, and getting off at the wrong exit to go home to our house, but still getting home... My response to him was, "Dad! I couldn't SEE!" (as if this was a perfectly valid excuse for driving erratically...and he shouldn't have been yelling at me...lol) He said, "Oh $h...! I knew you were talking crazy!" And then I just said, "Don't tell mom...just please don't tell mom." haha...

When it happened this last time, I was a lot more mild. Cleaned some again - but mainly the only thing I did was fill out my employee annual review self eval, which I later had to ask my boss if I could have back since I couldn't remember what I wrote. My boss was very nice about that. And, thankfully, I hadn't written anything nutty - didn't have to change a thing!

These were just the psych symptoms in these instances - there were also assorted physical symptoms such as tachycardia, EKG changes, blood pressure changes, visual symptoms, and other things....

So now I'm wondering - does depacon actually have the potential to cause anticholinergic toxicity? Or might it have been some other depacon-related mental status change. I've taken depakote for months several years ago, and I've also received depacon IV countless times - and until December 2004, I have NEVER had anything like this happen - but since then, it's happened every single time I've received that med (along with other things though - which is why it's hard to single out the one cause). I have suffered from elevated LFTs after receiving IV depacon on at least one occasion, but as far as I know, they weren't elevated the first time I had the psychosis.

Freaky... Anyway - sorry to ramble, yet again! But thanks for posting this - good info!

Take care,
Carrie :)

JC Jones MA RN said...

Anecdotal comment on your Gender Identity Podcast - re the issue of the effects of surgical gender reassignment on children: A gay male friend in his 40's decided to pursue gender reassignment surgery. When his decision was explained to children of his friends, they became very angry. At ages 7-9, they were old enough to reduce it to the most fundamental basics - he was getting his penis cut off & becoming a woman. This made them very angry and they rejected him. They had loved and accepted him as a gay man. They had loved and accepted his partner. They could not wrap their heads around Gender Reassignment Surgery or Andy becoming Adrianna (names changed, obviously). Eventually, Andy changed his mind and stayed Andy. But the kids never did change their minds about Andy.

Anonymous said...

Long term depakote use is directly linked to dangerous levels of ammonia. Neurologists and psychiatrists should regularly test for ammonia when patient takes more than 500 mg depakote daily. Autistic non verbal boy's self injurious behavior skyrocketed while suffering from undetected hyperammonia due to depakote use. Nobody bothered to check for ammonia....

Anonymous said...

Abbott Pharmaceuticals sent out a warning letter to neurologists, telling them long term depakote leads to elevated ammonia levels in patients. I wonder how many doctors read the letter? Or even bothered to test their patients taking depakote for high ammonia? Probably none.

Anonymous said...

Thank you for this information. My father has been on Depakote for almost 20 years. He started having a number of these symptoms and almost died last week from heightened Ammonia levels. Luckily the ER doc knew enough to check his Ammonia levels and they figured out the problem in time. The doc took him off of Depakote completely and he is now pretty much back to his old self. Whew! The info here was helpful to me in knowing that the docs were giving him the right treatment. Thank you again. :)

Anonymous said...

My mom was admitted about 2 weeks ago for this too. They thought she had a stroke at first. They took her off Depakote, gave her some meds to get rid of the amonia and almost immediately she got better.

They put her back on Depakote and her amonia levels went right back up.

Anonymous said...

Case of severely autistic adult male suffering from hyperammonia due to depakote: Was brought into ER by paramedics after family had to call because "he was exhibiting unusually severe self-injurious behaviors that could not be controlled by usual methods to control behavior." Geodon. Ativan, Benadryl failed to resolve behavioral emergency. Not until morphine given did patient calm. That allowed labs to be done, which subsequently led to discovery of hyperammonia. This is patients second time on depakote. Depakote was stopped in 2009, due to same hyperammonia problem: {hyperammonia causing extreme self-injury and erratic mood swings, patient tried to jump in pool, was crying and laughing}. Returned to baseline "autistic like behavior" upon discontinuance of depakote, but then had breakthrough seizures. Was placed on Keppra and Lamictal with no further hyperammonia issues. Keppra and Lamictal at therapeutic levels resolved tonic clonic seizure activity but didn't resolve nocturnal myoclonus. Depakote later re-introduced at lower levels (500 mg bid, divided doses). Within a few months, patient resumed erratic severe outbursts of hyper-irregular self injurious behaviors, laughing and crying fits (Decemember, 2010). Labs again, as aforementioned, showed hyperammonia. REsearch shows CASES OF LIFE-THREATENING PANCREATITIS HAVE BEEN REPORTED IN BOTH CHILDREN AND ADULTS RECEIVING VALPROATE. SOME OF THE CASES HAVE BEEN DESCRIBED AS HEMORRHAGIC WITH A RAPID PROGRESSION FROM INITIAL SYMPTOMS TO DEATH. CASES HAVE BEEN REPORTED SHORTLY AFTER INITIAL USE AS WELL AS AFTER SEVERAL YEARS OF USE.Hyperammonemia and hyperammonemic encephalopathy; measure ammonia level if unexplained lethargy and vomiting or changes in mental status, and also with concomitant topiramate use; consider discontinuation of valproate therapy. Very complex case, given patient is non-verbal, severely autistic. Case illuminates the need of all involved to be especially cautious in prescribing medications that exacerbate self-injurious behaviors and seizure activity. Also illuminates need of comprehensive behavioral and medical management and treatment without delay.

Anonymous said...

autism and depakote: Hyperammonemia and hyperammonemic encephalopathy; measure ammonia level if unexplained lethargy and vomiting or changes in mental status, and also with concomitant topiramate use; consider discontinuation of valproate therapy

Anonymous said...

Abbott pharmaceuticals should be sued for creating valporic acid. How in the world can anyone create a drug that knowingly causes BRAIN damage! when you are supposed to be marketing it for epilepsy?> what idiots.