(Updated 3/2019)

In general “mood stabilizer” refers to medications which can treat depression and manic symptoms.  Some can treat depression but not mania, or vice versa.  But some can help you avoid the “big guns”, the antipsychotics. Others are antipsychotics.

The sections below have details about each medication.  Or you can walk you through how the main medications are used in the Treatment section of this website. I’ll focus here on mood stabilizers for use in Bipolar 2.

If you’re skeptical — good! — you can make sure this information matches other mood specialists’ opinion, comparing my lists to the recently updated bipolar treatment 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”, by the above definition: gabapentin/Neurontin; topiramate/Topomax; and tiagabine/Gabatril.

Table of all mood stabilizers

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**
lithium lamotrigine/
Lamictal
divalproex/
Depakote
risperidone/
Risperdal; paliperidone/
Invega
light therapy (except dawn simulators) E.M. Power Plus
quetiapine/
Seroquel
fish oil/
omega-3s
carbamazepine/
Tegretol;
ziprasidone/
Geodon
 n-acetyl
cysteine
zonisamide/
Zonegran
olanzapine/
Zyprexa
High-dose thyroid oxcarbazepine/
Trileptal
aripiprazole /
Abil……
transcranial magnetic stimulation (TMS) ketogenic diet?
lurasidone/
Latuda
Dopamine agonists:
pramipexole, ropinirole;
modafinil

 

*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

Mood stabilizers for Bipolar 2

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 2, one option really stands out, in my view: lamotrigine.  Think about it: in Bipolar 2, the main problem is repeated episodes of depression. That is precisely what lamotrigine is best at treating. Granted, some mood specialists don’t think as highly of lamotrigine because they think the research showing benefit is weak. If that’s a concern, see my lamotrigine page. If you’re wondering if I’m biased by money somehow (I believe I’m not), see Funding.

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
lamotrigine / Lamictal
  • Depression is the dominant symptom
  • Rapid cycling
  • Need all the antidepressant you can get
  • Afraid of weight gain
low-dose lithium
  • lamotrigine alone not sufficient
  • Need all the antidepressant you can get
  • Suicide risk is a concern
  • (not full dose lithium; that’s practically a different drug)
quetiapine / Seroquel
  • Depression and agitation are both severe
  • Severe sleep problems
  • Anxiety is a significant symptom also
  • No family history of diabetes
divalproex / Depakote
  • Need something strong and fast
  • Male (so not at risk of PCOS) and not afraid of weight gain
  • Rapid cycling
  • Significant manic or mixed state symptoms
carbamazepine / Tegretol
  • Rapid cycling
  • Severe sleep problems
  • Can’t take divalproex (e.g. female, or afraid of weight gain risk)
  • Depression is not the main problem: cycling or agitation is
olanzapine / Zyprexa
  • Emergency-level symptoms
  • Need help really fast
  • Can use on “as-needed” basis
  • (If you continue to use it regularly) Not afraid of weight gain
oxcarbazepine / Trileptal
  • Milder symptoms, can risk a using a probably-weaker agent
  • Significant manic symptoms
  • Alternative to divalproex as a starting place
  • Slightly lower long-term risk appealing
omega-3 fatty acids/fish oil
  • “Natural”; most common problem is “seal burps” (put the pills in the fridge)
  • Milder symptoms, can risk a weaker agent
  • You want to add a possible mood stabilizer without adding more medication
  • Depression is a major symptom
  • Willing to multiple pills, or swallow (flavored) fish oil
lurasidone
  • Most expensive of all, for a few years yet
  • Clearly helps in mixed states; yet not always, and occasionally induces manic symptoms
  • Not as weight-neutral as the manufacturer wants you to think
clozapine
  • Tried everything else
  • Severe symptoms
  • Ready for major weight gain, weekly blood tests
  • Ready for one of the most effective medications we have
atypical antipsychotics Low-dose boosters for specific problems (as add-ons to “real” mood stabilizers?)

  • quetiapine: for sleep and agitation; has weight gain risk
  • risperidone: for elderly, at very low doses; or BPI perhaps — tricky antidepressant effects in some
  • aripiprazole: strong antimanic. At low doses it’s more like an antidepressant; seems like it can induce subtle mixed states, and can be hard to stop
  • ziprasidone: no clear role; but hey, it causes less weight gain than olanzapine, and really helps an occasional patient
  • (lurasidone got it’s own category above as it’s pretty clearly different)

(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 and thyroid) are not likely ever to be “FDA approved”.

Therefore many of the older medications above are used “off label” in bipolar disorder. 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 usual standards of evidence.

Four main mood stabilizers

Here are four mood stabilizers that help avoid turning to the antipsychotics and their heavier side effects and risks.  Three of the following have antidepressant effects; and one more — divalproex — has special issues for women and men.

lamotrigine

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
2 25 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).

moodst1

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.

Two different lithiums

“Lithium” is a scary word for many people.  That’s understandable: it’s associated with significant risks; and it’s been used for severe mental illness for decades, so people think that if they’re being offered lithium, someone is telling them they are really ill. But much of this is inaccurate.

Low-dose lithium

This is like a different drug, compared to full-dose lithium. The lower dose means far less risk for kidneys, almost taking that issue off the table. Low-dose lithium can still mess with your thyroid; and it can still cause weight gain (though far less than the antipsychotics I’m generally trying to avoid). But handled properly it should not cause any side effects at all. And it can help a lot, even at blood levels below the lab “therapeutic” range.

People with Bipolar 1 need anti-manic clout: to treat a manic phase, or to prevent the next one. But people with Bipolar 2 don’t need that. They need an antidepressant. If it also helps damp down cycling, that would be great. Lamotrigine has these properties. But sometimes it doesn’t work, or work well enough. Then you can augment with low-dose lithium. It can also be used to augment an antidepressant in plain (not bipolar) depression.

In my hands, low-dose lithium means: start low, with 150 mg nightly. Increase weekly until you’re clearly better: then keep that dose. Or until you hit a side effect: then go back down one step. Or until you’re taking 600 mg per night: then a week later, get a blood level.

Slow release (SR) or immediate release (IR)?

It doesn’t seem to make much difference: if you get nausea, that can be relieved by switching to the SR. On the SR, many people get loose stool or diarrhea, which can be relieved by switching to the IR. I just start with IR and watch for the nausea as a sign to try SR.

Lab testing

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:

  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). The dulling thing usually means you’ll have to stop lithium. About 1 person in 10 gets this. It doesn’t get better with time. Drat!

Make sure your provider is following your thyroid test (TSH) as well: before you start, and routinely for the first few months until that’s clearly not going anywhere. Then you’ll need a TSH once a year.

Non-steroidal anti-inflammatories” (e.g. ibuprofen/Motrin, naproxen/Naprosyn, many others) and most blood pressure medications can raise your blood level. If you add one of those, get your level checked again until it’s clearly not going up. But that’s all stuff your doc’ or NP should explain and manage.

Full-dose lithium

For full anti-manic benefits in Bipolar 1, full doses of lithium are often needed. This means going to the middle or the top of the therapeutic range. That means you have to be careful about getting too much lithium: lab testing may be needed more often to monitor that risk.

You can see: too many people associate “lithium” with the full-dose approach. They don’t know that lithium can be used other ways, in much lower doses.

quetiapine

Okay, you’re right: quetiapine is an antipsychotic. But not exactly: it doesn’t really have antipsychotic effects until the high end of its dose range, like 400 mg and up. Whereas 100 or 150 or 200-300 mg can have very strong antidepressant effects. So low-dose quetiapine is, like lithium, sort of a different medication.

The big problem with quetiapine, like its antipsychotic cousins, is profound weight gain. You need to have a plan to handle this: identify it, and thwart it, or activate your plan to get off quetiapine and on to something else. You can gain 10’s of pounds, pretty fast.

Some evidence suggests the very low doses of quetiapine, like 50-150, may not cause as much weight gain. Okay, great. But these low doses still have the other main problem associated with quetiapine: it makes people sleep. For many, that’s not a problem, it’s an advantage. There is usually some daytime sedation when you first start, and every time you turn the dose up, but that should fade away rapidly. Most people have “morning slowness” (a shower and a cup of coffee and by then they’re starting to perk up to normal), and that tends to continue.

Quetiapine wouldn’t even be on my list here except for the very strong antidepressant effects it can offer. Sometimes that makes the weight gain risk worth taking, especially if insomnia is also a huge problem.

valproate/divalproex

Lastly, here’s a medication that used to be one of our main options. But then we saw weight gain nearly as bad as with the antipsychotics. And then we learned about PCOS…

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, called polycystic ovarian syndrome (PCOS). For more on this risk, read 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.

For men, however, especially when a rapid anti-manic effect is needed, divalproex is still an option.  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.