Below you will find a list of the medications currently referred to as “mood stabilizers,” or at least regularly named as treatment options for bipolar disorder. (Here are some thoughts on what ought to be called a “mood stabilizer“).
Pregnancy reminder/warning: with the probable exception of fish oil and low-dose thyroid, none of these options is known for certain to be safe during pregnancy. The strategy for women wanting to become pregnant is very complicated and requires a knowledgeable psychiatrist. Therefore: any woman taking any of the medications below should have a very reliable plan for avoiding pregnancy (you know how that works, I’m sure you do . . . Oh, I suppose I could add the old adage: “if in doubt, ask your doctor”).
You can click links in the first table below for details about each one (or you can walk you through how the main medications are used, and how we choose between them, in the Treatment section of this website). If you’d like to see them listed by how you might choose, based on your needs, see the second table. If you’d like a comparison of all of them, try the third table.
To make sure this information matches current other mood specialists’ opinion, compare my lists to the recently updated expert consensus guidelines.
Before we begin, let’s just take a couple of medications off the table, because randomized trials showed them no better than a placebo in the treatment of bipolar disorder (they have other uses, and benefits, but they aren’t “mood stabilizers”): gabapentin/Neurontin; topiramate/Topomax; and tiagabine/Gabatril.
Table of the main options
Use the links in the table to get more information on each medication. Each column shows what makes the medication in that group distinctive. These are generalizations, and my opinions — but overall I think these are fair classifications.
|Treats manic symptoms and depression||Treats depression without worsening cycling||Treats manic symptoms, and cycling||Too much antidepressant effect||Can make bipolar worse*||Case reports only**|
|Light therapy (except dawn simulators)||E.M. Power Plus|
|High-dose thyroid||verapamil?||aripiprazole (trade name is too smarmy)/
|transcranial magnetic stimulation (TMS)||ketogenic diet?|
*along with all the traditional “antidepressants” like fluoxetine/Prozac, sertraline/Zoloft, etc., etc.
**here’s an essay on why randomized trials are so important in evaluating treatments, from panic disorder research
Gets pretty confusing, doesn’t it? It used to be simpler, just lithium and divalproex, maybe carbamazepine if those didn’t work. Now we have all these choices.
However, for Bipolar II, one option really stands out, in my view: lamotrigine/Lamictal. Until 2008, I could not state this strongly because I was using the manufacturer’s money to support my talks about bipolar disorder (see Funding). I had to hold back lest I seem biased by their money. But now lamotrigine is generic, and their marketing efforts are over. Since I will not be taking any money from GlaxoSmithKline (haven’t since 2008), I can finally speak with my full enthusiasm about lamotrigine.
Think about it: in Bipolar II, the main problem is repeated episodes of depression. That is precisely what lamotrigine is best at treating. Secondly, lamotrigine does not cause weight gain. Nearly all of the other options can cause very significant weight gain. The weight issue alone propels lamotrigine to the very top of the list, as long as no anti-manic component is crucial (because it does not protect against manic symptoms, except indirectly, by preventing cycling. The anti-cycling effect can be enough, fortunately, for many people). Third, lamotrigine causes no side effects at all in the vast majority of people who take it (there are always a few who will get something, headache or hair loss perhaps). Fourth, to our knowledge at present, there are no major long-term risks of staying on lamotrigine for years. It has been used for nearly 15 years as an anti-seizure medication, so we have a pretty solid basis for concluding that long-term use is relatively safe. Only a few other mood stabilizer options have this many years of observation, and each of them has recognized long-term problems. taken together, all of these factors make lamotrigine the obvious best choice amongst mood stabilizers — as long as you do not need an anti-manic component.
Yet some people will not respond to lamotrigine, and about one in 20-30 people will actually get worse on it. (Worse? yes, in my experience, and that of numerous other psychiatrists who have used a lot of lamotrigine; the worsening is an increase in anxiety, irritability, or sleep problems, as though a lamotrigine was acting too much like an antidepressant). So, many people will have to consider or move on to other mood stabilizer options. How to choose among these?
How might you choose?
The table below presents another way to view this choice, followed by a more detailed discussion of each option. Please understand that these are only suggestions based on the literature and experience with patients, not “guidelines” for choosing.
|Medication||Why you might choose it|
|omega-3 fatty acids/fish oil||
|atypical antipsychotics||Low-dose boosters for specific problems (as add-ons to “real” mood stabilizers?)
Where to start?
Here’s a more wordy, more referenced version of the table you just read. (Do you really need this?)
Since the BALANCE study by a wonderful collaboration of investigators led by two great British researchersGeddes (you can tell I think these guys are great to have set this up and run it), this question is a little easier. Lithium and valproate/divalproex had been running neck-and-neck for years for “where to start?” In this study, the combination was best but if you were to start with one alone, lithium was well ahead of valproate/divalproex.
Lithium has a clear track record of reducing the risk of suicide, which can be as high as 10% in bipolar disorder. But valproate may have a slight edge in treating “mixed state” symptoms and rapid cycling.Bowden You should start by educating yourself about the benefits and risks of each (use links from first table above). Ending up on low doses of each is very common.
Lithium is even effective as an “add-on” medication in unipolar and “treatment resistant” depression, so can be a good approach when a bipolar component is not crystal clear. Lamotrigine has been stunningly effective, in my experience, for patients whose mood problems look like “highly recurrent unipolar” or “recurrent depression with just a hint of or rare hypomanic phases” — that is, where depression is by far the more predominant problem.
On the other hand, if sleep problems and anxiety are prominent, valproate/divalproex/Depakote may be a better starting place: it almost always helps at least a little with insomnia, even at the low doses discussed here (unless you are on an antidepressant). We have a great deal of experience with it, and we know what problems to anticipate; and we know from years of experience that it works, especially when irritability and lability (changeable, brittle moods) are present, or when anxiety is prominent. But it now seems clear that divalproex can cause a hormone problem called polycystic ovarian syndrome in women of reproductive age (here are those PCOS data), so I generally use it only in men and post-menopausal women.
Oxcarbazepine/Trileptal caught everyone’s attention when it became available in the United States (after nearly 10 years in Europe). Because carbamazepine can be so tricky to use because of side effects (risks as well as nuisance symptoms), oxcarbazepine looked really good at first. It has less risk than carbamazepine and fewer side effects initially (more later, though). Oxcarbazepine is somewhat similar to carbamazepine in terms of those who it helps, though there is concern that it just doesn’t have as much “punch”, i.e. that is is not as fully effective. Every time I revise this I have fewer patients on Trileptal alone. I think it might be zero, or very close, now.
(Some of you might be old enough to remember a Bud Light commercial in which football guys debate: “tastes great!” vs. “less filling!” Well, oxcarbazepine has been called “Carbamazepine Light”: “less side effects!” vs. “less effective“! You can tell I’m not a big fan. But the child/adolescent psychiatrists use it a lot: no blood tests)
Finally, olanzapine /Zyprexa has been shown to be a very effective mood stabilizer.Tohen But it causes dramatic weight gain in a very large number of people who take it, and it can cause diabetes in some cases even without extreme weight gain. Gianfrancesco,Caro, Hedenmalm However, for short term almost immediate control of severe symptoms, this is an outstanding medication: people can feel benefit within an hour, and other than weight gain, there appear to be very few short-term risks with this medication. Long-term is a different story.
So, the bottom line here is: learn about your options and work closely with your doctor making the choice among them (here’s that essay on how to talk to your doctor again).
Which one is the best?
For one more way to look at all these options, here are the same medications listed by their specific advantages. Some of these advantages might be more important to one person than another. There really is no “best one”. Over time, you might end up taking several of them, one at a time or together.
Warning — the following table is subjective in some places, based on my personal experience: see the notes below. For simplicity, only significant benefits are listed (negatives are even more subjective and are not ranked, just left as blanks). Sorry about all the notes. Somebody was going to ask or raise a fuss otherwise. Here’s the key:
|Li+, lithium.||VPA, valproate/divalproex (Depakote)||CBZ, carbamazepine (Tegretol)|
|LTG, lamotrigine (Lamictal)||OLZ, olanzapine (Zyprexa)||OXC, oxcarbazepine (Trileptal)|
|O-3, omega-3 fatty acids (fish oil)||QTP, quetiapine (Seroquel)||ARIP, aripiprazole (“Abilify” — too cute)|
And the table:
|Many years of experience using medication||++||++||++||++||+||+||+|
|Antidepressant effects||++||+||(+)||(+)||+||+||++||not in bipolar depression||lurasidone|
|Few short-term side effects1||++||+||+||+|
|Few long-term risks2||++||+||+||+++||?|
|Weight “neutral”, not gain||+||+||+||+||ziprasidone|
|Low cost||++||++||++||++||++||+||++||co-pay often very high||not lurasidone!|
|Maintenance benefit shown||+||+||+||+||++||+|
|Safety in pregnancy3||?||?||?|
|Breastfeeding okay (others)||4||4||++|
Further comments on this last table:
1. This is based on my experience using these medications. It is nearly impossible to compare these medications directly in an objective way. Low dose lithium would merit a ” + ” on this scale; high dose lithium is probably the worst on this list for short-term side effects, setting the standard by which to judge the rest. Clozapine would be similar to high-dose lithium. Lamotrigine gets one ” + ” because apart from the significant risk of a severe skin rash, it has very few other common side effects.
2. Similarly, long term risk is a subjective matter, though perhaps less so than the common immediate side effects. Lamotrigine gets a ” + +” because its main risk, the rash, was listed as an immediate side effect problem; beyond 8 weeks the rash risk falls to very low levels.
3. Some might consider Zyprexa and perhaps other new-generation antipsychotics as safe in pregnancy. The Harvard Women’s Mental Health clinic does not. It’s easier to say which are clearly not safe: lithium, divalproex, and carbamazepine. Oh, that’s interesting, notice that’s all the old ones? Maybe it just takes that long to really find out what’s safe?
4. Valproate and carbamazepine have been listed by the American Academy of Pediatrics as safe for breastfeeding but a more recent review by Chaudron and Jefferson Chaudron calls this into question because the number of infants studied was so small, and there were some problems observed in a few children among those small groups. This leaves no mood stabilizer clearly safe for use while breastfeeding — except for maybe lamotrigine.MGH Fish oil in the doses used in research studies has not been studied. There is reason to think it might be safe — possibly even beneficialInnis — in both pregnancy and breastfeeding, at least at doses approximating human historical fish consumption.
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 . . .
Have a look at the three main mood stabilizers — well, in my practice, anyway.
A few more details to add to my favorable diatribe above:
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 1000, although some experts use a number as low as one in 3,000. On the other hand, if you have had allergic reactions to other medications in the past, the risk might be higher, e.g. maybe even like double — two in a thousand. See what I mean? it’s a small risk; you can double it and it’s still small. But it’s bad. And the risk is dramatically increased if you go faster than the usual manufacturer recommendations. So don’t be in a hurry.
Here are my slightly-more-conservative-than-the-manufacturer’s-recommended starting doses:
|Week||Dose (mg)||Pill Size (example)|
|1||12.5||one half of a 25 mg|
|3||37.5||1 1/2 25 mg|
|4||50||two 25 mg|
|5||75||three 25 mg|
|6||100||half a 200 mg|
|7||150||half a 200 plus 2 25’s|
|8||200||one 200 mg pill daily|
Your doctor will need to prescribe about 100 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.Brown 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.
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 300 mg alone.
Over the last 10 years I’ve waffled back and forth as to whether it’s better to start with immediate release lithium (IR) or the slow-release (SR), now that the SR is generic. But it doesn’t seem to make much difference where I start: some people have nausea, which is relieved by switching to the SR. Some people have diarrhea, which is often relieved by switching to the IR. Go figure. It’s about 50/50.
Understanding when to have a lithium level can be complicated. 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:
- loose stool, progressing to diarrhea (worse with slow-release forms; try switching to regular)
- 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/Naprosyn, many others) and many blood pressure medications all can raise the risk of getting too high a blood level.
(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 divalproex 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 ( called divalproex), 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.
Divalproex can be “loaded” with a large dose in the first day, to get it working faster (technically 20 mg per kilogram of body weight, but in practice it’s about 1500 mg in the first 24 hrs; some rare inpatient doc’s might give that as a single dose for a “loading strategy”. Going slower, to find the lowest dose that actually helps, 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 this appetite effect.
Fortunately, the appetite increase shows when this problem is going to occur. I have seen very 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).
Divalproex 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 divalproex and hair loss.
Remember, after considering lithium and lamotrigine and divalproex, there are also other mood stabilizer options, from aripiprazole to ziprasidone, so to speak.