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FDA-Approved — or not
The FDA has approved few of these medications for the treatment of bipolar disorder. Why not? Here’s a short version of a complicated answer.
A medication cannot be advertised for a specific purpose (like treating bipolar disorder) until it is FDA-approved for that purpose. To get FDA approved, strict research guidelines must be met, including the “gold standard” randomized controlled trial as described above on this page.

These trials cost millions of dollars. So if the manufacturer is not in a position to earn millions of dollars from promoting use of their product, there is a strong reason not to bother to get FDA approval — it costs them money they’ll not see coming back in return.
Therefore the FDA-approved drugs are those where the manufacturer stands to benefit by supporting the expensive research. These tend to be the newer drugs — because the patent may have run out, or will soon, on many of the older medications. So these older drugs (e.g. carbamazepine; Trileptal; verapamil; and certainly thyroid) are not likely ever to be “FDA approved”.

Therefore all the medications above except lithium, Depakote, Zyprexa and Lamictal are used “off label” in bipolar disorder (7/2004). This does not mean they don’t work, or carry more risk than other options. Those medications which have been around a long time may actually be even better understood in terms of their risks, such as carbamazepine. However, FDA approval does tell you that the medication has been studied directly for the purpose described and meets rigorous standards of evidence. (well, fairly rigorous, anyway. Watch out, here comes a Phelps’ Soapbox, you can probably safely leave now…)

Lately companies have been using a research approach called “enriched design” which massively biases the results in favor of their medication. The FDA approved their drugs based on such research. Unfortunately, one of the medications that I find especially effective was studied in this way, lamotrigine. It would be very nice to see this particular medication studied under truly “randomized” conditions, as I think it would still come out looking great. But to do the research this way means the company runs the risk of spending millions of dollars for results that don’t look so hot, as occurred in the biggest long-term study of Depakote, scaring a lot of companies into using this looks-scientific-but-takes-fewer-risks design. To their credit, the makers of quetiapine did not do this in their recent longer-term research. Interestingly, the same brilliant guy, Joseph Calabrese, directed both studies. It would be really interesting to know how these design choices were made. Ah well, they certainly aren’t listening to me go on and on; so let’s move on …
Specific guidelines for lamotrigine and lithium (and valproate)
Despite the exciting new research coming out on new treatments for bipolar disorder, these three medications are hard to beat if “years and years of experience using them” matters in your case.

Lamotrigine:
Just don’t be in a hurry. The primary risk of this medication is a bad rash, Stevens Johnson Syndrome. It can be bad enough to put you in the hospital, in the intensive care unit. It is like having a severe burn. The risk of this reaction is generally given as about one in 3000, although some experts use in number as low as one in 10,000. On the other hand, if you have had allergic reactions to other medications in the past, the risk might be higher, e.g. one in a thousand. This risk is dramatically increased if you go faster than the usual manufacturer recommendations. I often go a bit more slowly just to lower that risk as much as possible (although going more slowly than the standard recommendations probably lowers the risk very, very little).
We used to use the manufacturer’s starter kit, but a 25 mg pill is already generic (January 2008). So here are my slightly-more-conservative-than-the-manufacturer’s-recommendations starting doses:
Week Dose (mg) Pill Size (example) 1 12.5 one half of a 25 mg 2 25 25 mg 3 37.5 1 1/2 25 mg 4 50 two 25 mg 5 75 three 25 mg 6 100 four 25 mg 7 150 six 25 mg 8 200 one 200 mg pill daily

(Your doctor will need to prescribe 126 25 mg pills for this slow increase, then a 200 mg pill once daily. However, you must not miss more than three doses of this medication in a row, where you have to start the increase all over again from the beginning. If after four days or more of missed doses, you just jump in again at the full dose you were supposed to be taking, you have a risk of getting the Stevens Johnson Syndrome rash much like when you started. So make sure that you do not run out.)
People think that this slow “titration” means having to wait for a long time for the benefits of this medication.

However, we already know that 50 mg is more effective than a placebo (from a randomized trial years ago). Indeed, I was pretty sure I had seen people respond even in the first week, and this was shown in a recent study.Since the result is so stunning, and so few psychiatrists know about it, allow me to show you please.
A competitor’s manufacturer sponsored a study comparing lamotrigine with “olanzapine/fluoxetine combination” (a combination of Zyprexa and Prozac they call Symbyax). It was already known that this is a very good medication, particularly a good antidepressant and bipolar disorder (except for the massive weight gain that can result, which is why I don’t use it at all). The manufacturer surely thought that Symbyax would trounce lamotrigine, at least in the first several weeks while the dose of lamotrigine was being slowly increased. But as you can see in the graph below, Symbyax had a slight edge throughout the study, but lamotrigine did not lag behind: it showed benefits in the very first week (decreasing scores are good, reflecting less depression; lamotrigine is the dark rectangle, Symbyax the gray circle).

Back to the rash story: unfortunately, a mild allergic reaction, appearing as a mild skin rash, is common. About one person in 10 gets it. This rash poses no major risk — unlike the severe Stevens Johnson Syndrome version. So, as you can imagine, the issue of “rash” comes up frequently this medication. Your doctor will have to determine, if you get a rash, whether you might be getting the bad one, Stevens Johnson Syndrome. The simplest way to manage this problem is simply to tell everyone to stop the medication entirely if they get a rash. No further doses, that’s it, you’re done. That is what the manufacturer recommends.
Instead, as many other mood experts have described, I tell my patients: “if you get a rash of any kind, or a fever, call me and describe what is going on, and do not take any further doses until you hear back from me”. Your doctor may also feel comfortable trying to tell the difference between the bad rash and the benign rash, or she/he might refer you to a dermatologist. In any case, you have to be extremely careful about all this.

Here is more detail about handling this rash issue.
In general, the target dose for most people is 200 mg. This probably provides more insurance against relapse than lower doses, even if depression is completely gone at a lower dose. I do have a few patients who are maintained at lower doses. If depression comes back at 200 mg, it is possible to move the dose up (I use 50 mg steps per week) to a maximum of 400 mg. At 300 mg and below, most patients have no side effects at all. But at the higher doses, many people get side effects. However, these side effects can be quite subtle and sometimes it takes a while to figure out that they are really happening, and that they are coming from the medication. These effects include: difficulty finding simple words you know very well (this has been called “word searching”), trouble remembering people’s names whom you know quite well; mild dizziness, or mild balance problems. I instruct my patients to turn their dose back down if they run into one of these problems.

Lithium
(updated 10/08)
If you are not familiar with lithium, I recommend you have a look at my patient education handout first.
With any of these medications, the goal is 100% symptom control, with 0% side effects. Some people can reach that goal with lithium. There is a lot of variation in side effects with lithium: some people can handle blood levels above 1.2 mmol/L without any side effects at all (e.g. doses of 2100 mg), where others will have severe side effects with 300mg alone.

I sometimes start with 300mg slow-release lithium, available in the U.S. as a generic now. It can be cut in half and thus increased by 150mg steps if needed; and it is generally much better tolerated than elemental lithium (usually given as lithium carbonate; a liquid lithium citrate is also available). If it works, you can try switching to immediate-release lithium capsules, to reduce costs, as the slow-release generic is still a bit more expensive than plain old lithium. But starting with the cheaper immediate-release capsules runs the risk of “giving lithium a bad name” if you have a bad reaction that could have been avoided with a slow-release pill. It really makes quite a difference!

Understanding when to have a lithium level can be complicated (see more on lithium for how I do this). Generally, if the level on 600mg is less than 0.7 mmol/L, severe side effects are unlikely with a 300mg step up. Minor side effects such as dry mouth and urinating a lot, including having to get up at night to urinate, are common. These side effects generally increase with each dose increase, but most people can handle moderate levels of these effects.
There are three side effects that commonly limit lithium dosing before dangerous side effects show up:1.loose stool, progressing to diarrhea (worse with slow-release forms; try switching to regular)
2.tremor
3.mental dulling
None of these is likely to decrease with time: most people have to reduce the dose (try twice a day dosing first).

Lithium should not be used if you have kidney problems, unless very carefully regulated by someone who knows what to watch for. The levels may rise unpredictably to a dangerous range. “Non-steroidal anti-inflammatories” (e.g. ibuprofen/Motrin, Naproxen, many others; and even the new “Cox-II” versions) and many blood pressure medications all can raise the risk of getting too high a blood level.

Valproate (U.S.A.: “Depakote”)
If you are not familiar with Depakote, I recommend you have a look at my patient education handout first.
(If you are a woman between the ages of 12 and 50, unfortunately you should probably take this medication off your list of options, for two reasons. First, there may be a risk for women due to a possible shift in reproductive hormone regulation. For a discussion of the latest data on this risk, read about Depakote and PCOS. Secondly, this medication can cause abnormalities in developing children, so very effective precautions against becoming pregnant must be used for women who could become pregnant while taking it.)

Remember, the goal is 100% symptom control, with 0% side effects. In general, with slow-release valproate (Depakote), there are very few side effect problems. About 1 person in every 10 will have some nausea when starting, reduced if the medication is taken with meals. About 1 in 30 (in my experience) will have severe nausea. Even these folks can get used to the medication if the smallest size (125mg “sprinkles”) are used and increased by one pill per week or so. Other than nausea, however, other side effects are very uncommon — except weight gain, discussed in detail below.

The basics-of-Depakote handout shows my current start-up strategies, including using the new “ER” (extended release) formula. Since we can start a person on his/her entire dose in 24 hours, when we’re in a hurry, we know it’s safe to start really fast. Going slower may help prevent the most frequent problem with this medication: an appetite increase that leads to increased weight. Weight gain obviously carries health risks.

Many male patients can take 1500 or even 2000mg of valproate and not gain weight. Fewer women can, though, and many patients seem to hit a “weight gain threshold” somewhere around 1000mg. This threshold seems clearly to be higher when the new ER version is used; it looks like more patients can reach solid doses like 1500 mg with the new form. In my experience, more than 50% of women will gain weight at 1250mg or above (1500 or above with the ER version). Is this an appetite increase, as patients almost all experience when gaining weight? Or is there some metabolic shift, such as “metabolic syndrome“? The basis for this problem is still unknown. Some psychiatrists have tried using low doses of topiramate, another anti-seizure medication that tends to decrease appetite but has its own side effect problems, as an “antidote” to Depakote’s appetite effects.

Fortunately, the appetite increase shows when this problem is going to occur. I have seen few patients gain weight who did not experience the appetite increase. When people lower their dose, they can tell when their appetite returns to normal, and they do not seem to gain weight. So, I tell patients that if they get an abnormal appetite, they should lower their dose until their appetite returns to normal. The “threshold” seems to lie between 1000 mg and 1500 mg per day for most patients (if using the “ER” version). I don’t think I’ve seen a patient who experienced weight gain at 500 mg per day (there probably is one somewhere).
Depakote at 500mg/day is not generally enough for symptom control, but when combined with low-dose lithium, it can be a very effective medication. And, not all patients will experience the weight gain problem. Hair loss is also common when people hit the weight gain range, but the dose decreases required for appetite control generally take people out of the “hair loss range” as well. For a bit more on this issue, read

Depakote and hair loss.
Remember, after considering lithium and Depakote (and, as of 2008, lamotrigine, now generic), there are also other mood stabilizer options, from aripiprazole to Zyprexa, so to speak.