Q:  Treatment-resistant Bipolar Disorder

My husband has bipolar 1, and has been on zyprexa, wellbutrin, and prozac for the last three years, and this combo has worked well until now. Zyprexa is not controlling the manic phase at all. He has been taken off antidepressants, and is still continuing 20 mg of zyprexa, but its not working any longer. We had a lot of faith in zyprexa, as it always worked and fast at 20 mg ( 3 or 4 days). He is manic now and has been for 4 weeks. He has not experienced an episode like this in 4 years. The dose was raised to 25 mg for 3 days nothing, then 30 mg.for one day, then he freaked and refused to take that high of a dose again, as he claimed it made him ill. Trileptal was suggested at 600 mg a day, but due to his manic state grew angry at me and refused to take it! Four years ago he was taking Depakote for mania (and had been for about 6 yrs) and it failed to help also. I might add that every time he had a mania while on Depakote it required more of the drug to stop the mana. Is this drug tolerance? When he is first started on a drug for mania it works well for a while, a few years or more then it gets where it takes more to get a  mania under arrest. He has always been told by doctors to take a low maintinancedose when he's not having trouble. Is there such a thing as treatment resistant bipolar? What are the chances that is what is happening this time?

Dear Ms. S' -- 
Sorry to hear this story.  Unfortunately, an apparent worsening of the illness is common, with more frequent and more severe episodes over time, as shown in a graph of the experience of one young man (fortunately they're not all like this, but your husband's is sounding quite analogous): 

Is this "drug tolerance"?  It seems at this point to be better understood as an evolution of the illness.  Compare the "drug tolerance" of Valium-like medications ("benzodiazepines"), which is well known:  in that case, when the medication is tapered off, the underlying condition is no worse than it was before, and when the medication is added again after several weeks, it works as well as it did the first time.   This does not appear to be the case with bipolar disorder when it is worsening -- though often that's hard to say for sure because we usually add medications, rather than taper them off and wait and try them again!

Instead it looks like the worsening course is just part of the illness for some people.  One of my greatest fears is that antidepressants can actually cause this worsening, but that has not been fully established or agreed upon by other mood experts (though it is the view of the ones I most respect for seeming to know everything there is to know about the treatment angle especially, like Nassir Ghaemi and Gary Sachs).  Your husband's doctor cannot be faulted for using antidepressants, because this is routine in bipolar disorder treatment (less so in the hands of the experts I just mentioned, who have about 20% of their patients on antidepressants; versus 40% in patients of other presumed mood experts, versus 60% for the general psychiatry community  -- as reported by Dr. Ghaemi at a recent bipolar meeting).  

Is there such a thing as treatment-resistant bipolar disorder?  Oh yes, surely many of the readers of this website would regard themselves as members of such a group.  Unfortunately, there are a whole bunch of folks under that umbrella.  That's why the Harvard clinic has so many of its patients on (an average of) 4 medications at a time, or more.  That is, the usual plan in the face of "treatment resistance" is to increase the dose of, or the number of, mood stabilizers.  However, there is also general agreement that one of the first steps in the face of "treatment resistance", especially if there is rapid cycling, is to gradually withdraw any antidepressant medications.  

So, there's a lot to do in your husband's case.  Hopefully things will turn soon to allow he and his doctor to resume their efforts toward getting the cycling to stop.  I hope you are safe in the interim and that this comes soon. 

Dr. Phelp



Published September, 2003