Antidepressants in Bipolar Disorder: The Controversies

Updated 11/2014

Bottom line: there are at least 9 alternatives with at least as much evidence as antidepressants for effectiveness in bipolar depression, that don’t make bipolar disorder worse, as is clearly a risk with antidepressants. So most of these questions are nearly moot, in my opinion. Just skip the antidepressants unless you’re backed into them by not getting better on less potentially risky stuff.  But that’s not widely agreed upon, even after 10 years of direct study. Here are the specific areas of controversy.

  1. Do antidepressants even work in bipolar depression? Yes, but it’s not very well, except perhaps in Bipolar II, depending on who you listen to. 
  2. Can antidepressants trigger manic symptoms? Yes, that’s completely agreed upon. But how often? That’s not agreed upon at all.
  3. Are antidepressants “mood de-stabilizers” ? This is a crucial question, at least as important as #2. Answer: uh, it’s complicated?
  4. If you’re on an antidepressant and doing well, should you stay on or taper off?  First, don’t do anything without talking with whoever prescribed it.  If you have more than 4 mood episodes per year — then maybe taper off? Careful here!

1. Do antidepressants even work in bipolar depression?

No. Yes. Maybe. Only in Bipolar II. Depends on how long you watch — and how you define “work”.

Let’s try that again. There are two big lines of research about this. In one, which led to a formal study that took years and was supposed to answer this question directly, antidepressants were no better than placebos for bipolar depression. Sachs

But in a whole series of studies in Bipolar II (no Bipolar I patients in these studies), antidepressants not only worked better than placebo, they worked better than lithium! (The Amsterdam studies; more on those herein).

Overall, nearly everyone would agree: it’s suprising how little evidence we have in support of using antidepressants for bipolar depression, especially given how often they’re used. When there’s very little evidence to consider, it’s easy for controversies to persist. Thus there are loud voices on both sides of this issue.

But in 2013 the International Society for Bipolar Disorders (ISBD) issued a very clear set of recommendations.Pachiarotti Simplified: don’t use antidepressants, except in patients who’ve:

  1. done well on them before
  2. get worse when they’re stopped
  3. have bipolar II (noting even this is controversial)

And finally, in 2014 editorial entitled “Never without a mood stabilizer”, a highly respected researcher asks strongly why:

  • 35% of bipolar patients get antidepressants without mood stabilizers
  • antidepressants aren’t stopped when patients are manic
  • antidepressants are given when patients are in mixed states Vieta   

More on this controversy…

2. Can antidepressants trigger manic symptoms?

Yes. Almost universal agreement. But, how often does this happen? Some say 4% of the timeGjisman, some say 44% of the timeTruman in some circumstances. Yet it doesn’t really make much difference, you see:   yes, there is significant risk, at least 1 per 25 users, maybe more like 1 per 3 or even 1 per 2 for some people.  But because there are at least 9 alternatives to using an antidepressant to treat bipolar depression, most patients with bipolarity do not have to decide whether to take the pro-mania/hypomania risk of an antidepressant. They can just use something else.

Here are some groups of people who are at greater risk for having hypomanic or manic symptoms if they use an antidepressant:

  • Bipolar I
  • Female
  • Frequent mood shifts (e.g. monthly or more often)
  • It happened before
  • It happened to someone in your family
  • Someone in your family has bipolar disorder
  • Your first depression was between the ages of 18 and 24
  • You’ve had a post-partum depression
  • You’ve been psychotic without street drugs

More on this controversy…

But remember: there are at least 9 alternatives.

 

3. Are antidepressants “mood de-stabilizers” ?

Quoting from an editorial in the American Journal of Psychiatry, March 2008, by Nassir Ghaemi, one of the principal investigators in the STEP-BD, a large bipolar research trial (emphases mine):

Mood destabilization with antidepressants should be distinguished from an acute manic “switch.” Antidepressant-induced mania, or switch, is a short-term phenomenon; one might define it as happening within 2 months of the beginning of antidepressant treatment. Mood destabilization is a long-term phenomenon, reflecting more mood episodes over time than would have occurred by natural history.

Antidepressants may cause long-term mood destabilization without a short-term manic switch, and vice versa. Although some agents may have low rates of acute manic switch, especially when used with mood stabilizers, the data from STEP-BD suggest that even the new generation of antidepressants can produce long-term mood destabilization.

In that editorial, Dr. Ghaemi also emphasizes an approach I’ve been espousing for years: if a mood stabilizer is tried with an antidepressant also in use at the same time, and the mood stabilizer “doesn’t work”, that was an unfair trial of the mood stabilizer. It will need to be tried again later with no antidepressant in the picture.

If you’re skeptical about these conclusions I’ll show you some data I think supports them, but it’s pretty technical stuff.  Before I invite you there, does anyone think antidepressants have a stabilizing effect? Well, in Bipolar II,  Dr. Gordon Parker thinks so.Parker So do Drs. Amsterdam and Shults, whose 2013 study is similar but much bigger (however, read the Comments you’ll see linked at the bottom of their abstract; very telling, I think.)

I think they’re right, that antidepressants can have a stabilizing effect — for a while.  Consider two cases.

When people ask me “how long does it take for an antidepressant to cause manic or hypomanic symptoms?”, I answer with the experience of two patients. First, one guy told me “20 minutes after my first dose of Paxil I felt like I was shot out of a cannon.” So that’s the fastest it can happen, I figure.

The second I wrote up as a case report, it was so telling. Phelps One of my patients went 7 years on sertraline/Zoloft, doing really well, much better than on other antidepressants she’d tried. She’d “joined the human race”, she said, after years of depression. Then she developed anxiety. So her primary care provider increased her antidepressant (because antidepressants are used to treat anxiety; not an unreasonable move).

Ka-boom, she had horrible anxiety, agitation (like wanting to crawl out of her skin), suicidal ideation, terrible insomnia, and restlessness). This did not subside until she tapered off sertraline, despite desperate attempts with a bunch of medications including antipsychotics, anti-anxiety medications, and mood stabilizers. But the clincher was when she tried, about a year later, going back on sertraline, trying to get that “normal” feeling back.  One quarter of the dose she did so well on for 7 years produced the same agitated state within three days.

So, I think antidepressants can work quite well, for a while. Somewhere between 20 minutes and 7 years… But then they can cause mixed states and suicidal ideation, at least in some people. How many people? that’s a complete unknown. I don’t get to see the folks who are doing great years later, so I can’t judge by all the patients I see whose antidepressants seem like part of the problem. My colleague Dr. Manipod and I published a case series of 12 people who looked “unipolar”, i.e. not bipolar, but who got much better when their antidepressant was stopped.Phelps/Manipod 

Other colleagues have reported similar findings, e.g. 15 more cases.Sharma One has gone so far as to publish a couple of papers describing what he calls “tardive dysphoria” .  Short explanation of the term: he’s describing what happened to my patient above who did so well on sertraline for 7 years. El-Mallakh 

Want to see more data on this question? Dr. Ghaemi refers to two randomized trials.  More….

 

     (3b: Kindling and Long-term Worsening)

Could antidepressants cause kindling”? The phrase “kindling” is borrowed from neurology, where it has been used to describe forms of epilepsy, which appear to worsen with time. In this model, it is as though each episode of illness makes later episodes both more likely and more severe. It is clear that some patients’ bipolar disorder worsens as they get older, with more frequent and more severe episodes. Could this kind of pattern be triggered by antidepressants, at least in some susceptible patients?

Here is good visual example of the phenomenon we’re talking about here. The graph shows the mood episodes of a man whose bipolar disorder seemed to clearly worsen with time (his age is shown at the bottom of the timeline; red
means hospitalized, up is manic and down is depressed, of course):

contro8

Note the pattern: after each episode, the next episodes tend to come sooner and become more severe. This is the “kindling” pattern, though this man’s experience alone of course does not prove that the illness itself can do this. There could have been some other factors, such as alcohol or other drugs, etc.

However, suppose some forms of bipolar disorder really do “kindle” themselves. If that is so, then any worsening has the potential to be a “permanent” worsening. What if the patient above had been treated with psychotherapy at age 18, during that first depression? Compare what might have happened if he had been given an antidepressant, triggering a manic episode: might his graph have changed from the course we saw just above (a real patient’s experience):

course (1)

to this (a hypothetical example):

contro1

The difference, as you can see, is that this hypothetical patient lost 5 years of symptom free life. And he arrives at a nearly continuous course of illness by age 35, instead of age 40.

This “kindling” concern is very rarely raised in the bipolar literature, at least as regards the risks of antidepressants. Wouldn’t you think that if antidepressants could really cause or accelerate the course of bipolar disorders, that we should be freaked out about using them? and really careful to indentify anyone who might have that happen to them?  But no, it’s not a big deal in the literature.

So I invited people to tell their story, if it had happened to them. The good news is that over years, I received only a handful. Here’s one that seems to me a perfect example. But remember, he’s only one case and there were plenty of people who read that invitation.

Mr. B (direct quote from an email, used by permission):

Before my first use of an antidepressant, I had never suffered mania. I had been diagnosed with depression and anxiety, but not bipolar disorder. I was prescribed Lexapro for anxiety (I had never used psychiatric medication before) and used it for five or six days, taking a small dose (half tablet each day). It induced mania so I was hospitalized for a week or so.

 

Since then, I have steadily had irrational grandiose thoughts. In hindsight, I can see that I had some irrational grandiose thoughts before my Lexapro use, but since my Lexapro use they are far stronger. As far as permanence goes, so far I have not noticed any improvement at all coming simply from time passing (although therapy and other active approaches have been helpful). I had a second manic episode less than a year later (I was not on any medication at the time).

So there’s one case. There is also one published example of a patient given steroids for colitis, with a similar course.Pies Here’s another widely regarded expert expressing the same concern — in a different contex, but same resulting worry, from a 2008 New York Times article

Kiki Chang, director of the pediatric bipolar-disorders program at Stanford, has embraced the kindling theory. “We are interested in looking at medication not just to treat and prevent future episodes, but also to get in early and — this is the controversial part — to prevent the manic episode,” he told me. “Once you’ve had a manic episode, you’ve already crossed the threshold, you’ve jumped off the bridge: it’s done. The chances that you’re going to have another episode are extremely high.”

More…

 

4. If you’re on an antidepressant and doing well, should you stay on or taper off?

Three studies address this issue directly — and they have different conclusions! Make sure you know about the second one, the results of which are a more reliable guidepost by standard criteria for judgement (randomized trials trump naturalistic studies).

  1. Altshuler et al , Am J Psych 2003 – naturalistic
  2. Ghaemi, STEP-BD – randomized
  3. Altshuler et al, J Clin Psych 2009 – randomized? no, even though it looks like it

Bottom line: the randomized trial says “if you have had rapid cycling (more than 4 mood episodes in a year), you should try tapering off.” For patients with more rare episodes, they actually did slightly better staying on (but not much, and it’s another long-term medication to carry, so I figure even those folks ought to try tapering off at least once, really really slowly).

For more, we’re digging into those studies, if you’re up to it: more….

 Conclusions

1. There are a lot of alternatives to antidepressants for the treatment of bipolar depression, most of which have at least as much evidence for their effectiveness in bipolar depression as antidepressants do. Use those alternatives first, all that are workable (some may not be) — especially if you’ve already had several antidepressants and you’re not better. Here’s a page with nine such alternatives.

2. Do not use antidepressants if rapid cycling or severe insomnia/agitation/irritability is already present.

3. Almost every patient with bipolar disorder who is taking an antidepressant deserves a trial off of that antidepressant to see if things are more stable (or at least, no worse). When trying this, taper off the antidepressant very slowly: four months, 25% per month, is a good rate (agreed upon in 31 ways by two psychiatrists!).