Damned if you do. . .

Do you know how many medications are FDA-certified to treatbipolar depression? Come on–give it a a try. Do I hear 15? 10? The SSRI’s (selective serotonin re-uptake inhibitors) can boast 6 on the market: Celexa, Lexapro, Prozac, Luvox, Paxil, and Zoloft.

If we add the SNRI’s (serotonin and norepinephrine re-uptake inhibitors, just in case there’s someone not “in the know”) — Pristiq, Effexor, Cymbalta, Savella–we’re up to 10. Toss in the atypicals– Aplenzin, Wellbutrin , Wellbutrin SR (isn’t re-marketing wonderful?) and. . (don’t get too excited. . . Wellbutrin XL. There’s Remeron, Trazodone–and don’t forget Zyban. We finish with the “oldies but goodies”–remember the tricyclics  (Elavil, Pamelor , Amitriptyline, Imipramine [with many variants]) and the MAOI’s (monoamine oxidase inhibitors, which I never remember)–Marplan, Nardil, Selegiline with its 3 variants, and Parnate)? So if people ask how much anti-depression medication we’ve got? Answer: oodles and oodles.

Well. Sure hope that walk down antidepressant memory lane has been a serotonin kick for you – because not one of the meds we mentioned – with one small exception – is approved for treatment of bipolar depression. (If you take Prozac, mix it up with the antipsychotic Zyprexa, call it Symbyax, and re-market it under a new patent, you do have a player.)

In fact, if you’re a psychiatrist, and you want an FDA-approved treatment for your depressed bipolar patient you have – count them – two, that’s right, two – treatments available–and in fact, in some cases, you might have only one.


It’s not cause to lose hope. I just wrote another piece on eight potential treatments, some of them already in use, despite the FDA. But what we have now available to us is:

  • Symbyax, that mixture we spoke about, approved in 2003, and, rather inconveniently, approved only for bipolar I (the one with more severe mood swings, ranging from depression to mania), and
  • Seroquel, an antipsychotic also approved for bipolar mania, and the only drug approved for treatment of acute depression in both  bipolar I and bipolar II (supposedly the milder form, with episodes of depression that alternate with ‘hypomania,’ a milder form of mania) disorders.

Which is all well and good if they:

  • are effective, and
  • are tolerable.

But anyone who’s been around the bipolar disorder world for a while knows that side effects come with the territory. Seems like all the drugs involved can cause the standard battery of complaints: headache, nausea, diarrhea, dizziness, fatigue, thirst–that’s just for starters.

In fact, when I checked out Seroquel on Drugs.com, I was horrified to find there were enough side effects for the website to put them in little chapters (gastrointestinal, cardiovascular, metabolic, ocular, hematologic, etc.). I didn’t think it was a good sign.

As we’ll see, based on some newly popular medical abbreviations, researchers knew about these effects long before the drugs made their public appearances – and so did doctors. You could choose to be angry at them – but when you think of the symptoms that they’re fighting against, you might come to understand their choices.

Okay, so here comes the meat of the story: It revolves around two big abbreviations in medical-land:   NNH and NNT.

I’m totally, totally serious when I tell you that  NNH stands for Number Needed to Harm. I admit that it doesn’t sound good on the surface.

Perhaps I should have started with NNT, a friendly Number Needed to Treat. But here we are.

NNH indicates how many subjects need to be exposed to a certain factor–in our case a trial medication–to cause harm in one patient.

It sounds a bit obscure, I acknowledge, but, never fear, your government is here to help you. The U.S. Department of Health and Human Services runs an Agency for Healthcare Research and Quality, which clarifies this alphabet soup for us via an example:

In this example, Alzheimer’s patients were put on atypical antipsychotic medication, which carries some–although quite low–risk for death. Researchers found that for every 100 patients taking the drugs, there was one additional death when compared to 100 people with Alzheimer’s disease using placebo. Hence the Number Needed to Harm=100.

Simple enough. And, in more simple talk:

Large numbers–good (that means adverse events are rare).

Small numbers–bad (adverse events are too common).

That all sounded quite good -it was when we got to the formula that all failed me (you divide 1 by some number known as the absolute risk increase, and then multiply by 100 when this risk increase  is expressed as a percentage. I really tried, but in the end, we’ll have to be moving on. . .).

NNT is much less negative, and it’s clearly a very happening concept, as it has its own website dedicated to it, http://www.thennt.com, [which poor NNH is sorely lacking]. It’s an estimate of the number of patients you need to treat with a given treatment for one of them to have the desired result–a result they wouldn’t have achieved on placebo.

Ideally you’d have an NNT of 1–meaning all the patients in the groups improve, but that’s not how reality works.  In essence, the higher the NNT, the less effective the treatment is–because it means that more people need to receive the treatment to get a benefit. [I tried, I really tried, to get you the formula, but the best I can do is tell you this that NNT = 100/ARR, where ARR is the ‘absolute risk reduction’, and I thought it best to throw in the towel at that.]

So, basically, what everybody involved in treatment wants, it goes without saying, is that the drug has a lower NNT than NNH.

So let us us return to our  vast array of choices for treating bipolar depression: Symbyax and Seroquel.

As with any meds, we really need to determine two components, when faced with taking–or giving–them: Efficacy (enter NNT) and Tolerability (NNH).

Let me stop to note that much of this was taken from the article, “Important distinctions between bipolar I and bipolar II depression,” by Terence A. Ketter, MD.  Because it’s a subscription, I can’t link you to it. All I can tell you is that it’s put out by the Continuing Medical Education (CME) Institute, sponsored by the National Institutes of Health, and, in this case, the pre-article blurb promises its professional readers:

“”New! Learn how to apply study results to calculate the risk/benefit ratio of agents and determine the best treatment plan for your patients with bipolar depression.”

It all sounds very exciting.  Meanwhile, I owe a huge debt of gratitude to Dr. Ketter, who did all the math for me in this situation.


[And before we go into the poor side effect profiles of the approved meds, we really do need to take a step back for a moment.  Anybody who has experienced a severe depression, or anyone who has treated someone who has experienced such, especially in cases where functioning is affected, knows that the need to treat the pain and suffering immediately takes precedence over side effect issues. These become relevant again as the immediacy of the horror subsides.]

But back to the doctor, who took a look at quetiapine (Seroquel), and found that the NNT in order to get a response and the NNH (in the case of sedation) were both 6–while the NNH for weight gain was 19. Which, if I’ve got this right, means you’re just as likely to be sedated by Seroquel as you are to feel better–and more likely to gain weight than to respond.

Very heartening.

Dr. Ketter then turned  to the Symbyax option, and shared the following information:

  • it has an NNT of 4 for response,
  • it has an NNH of 6 for weight gain, and
  • an NNH of 12 for sedation.

Fortunately, I got further help interpreting this situation here from Sherry Boschert in her very matter-of-fact article, “Balance efficacy, safety in bipolar depression.

She clarified that, when compared with placebo, one in six patients treated with Symbyax will be harmed by having an increase in body weight of 7% or more.  Back to Seroquel: treating five with it will ‘harm’ one by causing sedation.   Concludes Dr. Ketter about Seroquel, “[t]his means that quetiapine, although effective, is as likely to cause harm as benefit.”  And he’s equally upbeat about Symbyax: “Thus, the likelihood of weight gain with the olanzapine plus fluoxetine combination is comparable to that of response, as the NNH and NNT for these outcomes are 6 and 4, respectively. This means that the olanzapine plus fluoxetine combination, although effective, is comparably likely to cause harm and benefit.”

And, really, I’m about at the end of the post.  Did you think I had a solution to the problem?

There are times when all your choices seem like wrong ones–but I do know that bipolar depression is intolerable, and sometimes you’re just stuck with a lousy lot–even with one that has ‘chapters’ of side effects (did I fail to mention genitourinary?).

It was Eleanor Roosevelt who told us to go our own ways, because, she said, “You’ll be damned if you do, and damned if you don’t.”

My intuition tells me wasn’t aware she was describing treatments for bipolar depression. . .



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