Monday, February 23, 2009

Treatment-Emergent Mania Is A Myth

Let's say that you're at your buddy's house. You're watching a crappy prime-time network program (the episode where Jack Bauer goes down on Madam President). Suddenly, your friend stands up, goes to the fridge, and takes out a diet-coke in a black can (d-bags call it Coke Zero). Before opening the can, he methodically taps his index and middle fingers on top of the can.

When you hear the tapping, you casually turn your head toward your friend and ask, "Are you retarded?"

"No," says your soon to be former friend, "I'm knocking loose the bubbles from the bottom of the can so they float to the top, so it won't foam when opened."

If you haven't tried this technique, you have certainly seen someone do it, despite the fact that it doesn't work (1). It's simply just not true, yet people all over the world perform this little trick and proudly profess their discovery to others, who then spread this good news to even more people. After enough time, a myth is transformed into a fact.

Another myth that has been accepted as fact is antidepressant induced mania, which is the topic of study in this pointless investigation (2). The study is titled, "Correlates of Treatment-Emergent Mania Associated With Antidepressant Treatment in Bipolar Depression." The stated goal of the study is to examine "the correlates associated with treatment-emergent mania in patients receiving adjunctive antidepressant treatment for bipolar depression."

Hidden beneath these words is the assumption that antidepressant induced mania is a real phenomenon with legitimate scientific backing. Moreover, it means the authors (all 13 of them) cited research studies that support this assumption.

"While antidepressants may be effective in some individuals with bipolar disorder, they can precipitate a rapid mood switch from depression to mania (8, 14, 15), a phenomenon also known as treatment-emergent mania." (2). According to this sentence, studies 8, 14, 15 are studies that utilize the scientific method to provide nearly conclusive evidences that "treatment-emergent mania" is a real phenomenon.

Reference 8 is a letter to the editor (3). It's in reference to a study published in 2005, in which antidepressants were found not to induce mania. I'll repeat that, because it sounds mildly important. The study found that antidepressants did not induce mania, yet, this letter was referenced as evidence in support of antidepressant induced mania. Drater spelled backwards is what?

Reference 14 is titled, "A placebo-controlled evaluation of adjunctive modafinil in the treatment of bipolar depression" (4). First, modafinil is an arousal promoting agent (that's pharma speak for stimulant), not an antidepressant*. Secondly, the study found this, "there was no difference between groups in treatment-emergent hypomania or mania." They're 0 for 2.

Reference 15 is here (5). This study actually looked at the phenomenon of treatment emergent mania; however, it was a meta-analysis that found this, "In bipolar depressives, manic switch occurs substantially more often with TCAs (11.2%) than with SSRIs (3.7%) or placebo (4.2%)". The SSRI rate was lower than the placebo rate. Since this study (2) looked at the antidepressants sertraline, venlafaxine, and bupropion (SSRI, SNRI, & DNRI) and not TCAs**, that's strike three.

I vaguely recall myself complaining about not reading references before citing them (6, 7). What exactly to peer reviewers do anyway?

I had to re-read this study. When I found out that the authors cited 3 studies in support of their assertion that countered their assertion, I blacked out, only to wake-up 7 days later in Butte, Montana digging for copper in a pair of crotchless panties.

However, I should have stayed in Butte. When I picked-up where I left off, I read this, "more than 40% of patients enrolled in STEP-BD self-reported manic or hypomanic switch associated with antidepressant use." Self-reported? Parents self-reported that vaccines caused autism in their children. I'm suppose to accept patient self-reports as proof when patients cannot remember if they were hospitalized for a mood episode (8, I know the book has 1,200 pages; I'm too lazy to find the reference, but trust me it's in there, somewhere, I think..., don't quote me on that).

Here is where the researchers exhibit that special kind of stupid that I mentioned briefly in this post (9). The study found "that minimal manic symptoms at baseline coexisting with otherwise full syndromal bipolar depression are associated with antidepressant treatment-emergent mania or hypomania." Some could argue that the switch (as evidence by minimal manic symptoms) was already in progress, before the antidepressant was on board. Bipolar disorder is, after all, a highly recurrent disorder.

I could say more about this study, but my head hurts. I may have just popped an aneurysm. You can read more about this study and still learn nothing by going here (10).

You can read more about antidepressant induced mania here (11).

* Technically, "antidepressant" is a meaningless term. The FDA regulates what drug companies can advertise their drugs as treating. There are many classes of drugs (e.g., TCA, SSRI, NASSA), all of which have different mechanisms of action and are all equal in efficacy (roughly). A drug can have antidepressant properties and not be labeled as an antidepressant. Just because one subclass of antidepressant might increase switch rates does not mean all antidepressants increase switch rates. Modafinil works by stimulating the tuberomammillary nucleus of the hypothalamus, thus increasing arousal (in case you cared to know).

** Although the proposed mechanism of action for TCAs is through serotonin-norepinephrine re-uptake (SNRI), they are dirty drugs. They also block histamine receptors, muscarine receptors, and alpha adrenergic receptors. Those additional properties might explain the differences between TCA and SSRI in that one study.

M. A. Frye, G. Helleman, S. L. McElroy, L. L. Altshuler, D. O. Black, P. E. Keck, W. A. Nolen, R. Kupka, G. S. Leverich, H. Grunze, J. Mintz, R. M. Post, T. Suppes (2009). Correlates of Treatment-Emergent Mania Associated With Antidepressant Treatment in Bipolar Depression American Journal of Psychiatry, 166 (2), 164-172 DOI: 10.1176/appi.ajp.2008.08030322


Anonymous said...

This contradicts my personal experience. I realize that you don't put much stock in self-reports, with some good reason. I certainly don't totally trust my own mind. But I confess that my experience with both lexapro and celexa has been that they both often induce manic-like states: racing thoughts, poor judgment, risky behavior, etc. And this, of course, occurred without having been told that anti-depressants might cause these things.

I don't mean to suggest that you're wrong. You're clearly right in your criticism of the article; the citations were poor, precisely because there isn't sufficient evidence to assert the truth of the phenomenon. But I do think you are too quick to dismiss the self-reports of paitents on this matter. And the analogy between these self-reports and those of parents of autism is not a good one. One cannot self-report that a vaccine caused autism. One can, however, self-report the symptoms of autism, or mania.

NeuroPsych said...

I appreciate your comments. There are a few points I want to address.

First, I should stop drinking scotch before I write these posts.

Second, it was not my intention to dismiss self-reports per se as it was my intention to dismiss the assertion of causation. I frequently hear patients state that an antidepressant made them manic, and trying to convice them otherwise is usually fruitless. When two events occur in close proximitity of each other (although I don't count 10-12 as close), we naturally connect them in our minds.

Just because a patient has racing thoughts does not necessarily mean it was caused by the drug (conversely, it does not necessarily mean the person is becoming manic either). Look at the percentages of side effects attributed to placebo in clinical trials. Clearly the drug cannot cause those side effects, yet people will attribute them to the pill.

As a general rule, certain antidepressants (SRI, NRI, DRI) are stimulating (think cocain, which is a potent SRI, DRI, & DRI). Common side effects in non-bipolars (I don't buy the bipolar spectrum concept) are irritability, agitation, and insomnia. That's why they are commonly co-prescirbed with sedatives (a practice also done during the clinical trials) These are common stimulant effects.

In this study (Incidence and predictors of activation syndrome induced by antidepressants.Harada T, Sakamoto K, Ishigooka J. 2008). 4.3% of nonbipolar developed an activation syndrome. That's similar to the bipolar switch rate in one of the cited studies in my post (interestingly, the only variable the did predict onset of the syndrome was personality disorder).

How does one distinguish side effect from actual manic switch?

The Shrink said...

Generally, we see antidepressants as stimulating or sedating but we don't think of antidepressants as specifically mood elating. Although things like procyclidine have street value, there ain't folk on street corners pushing antidepressants as a recreational drug elating mood, in my corner.

Which fits with what we see. We treat a lot of patients with antidepressants, we don't see lots of folk develop elated mood.

So if it's postulated that antideprssants don't elate mood (in euthymic or depressed folk) but can exacerbate manic moods, that seems a curious claim to make, to me.

But isn't it all old hat? I thought that a very good review 5 years ago nailed this question for us :
HJ Gijsman et al. Antidepressants for bipolar depression: a systematic review of randomized, controlled trials. American Journal of Psychiatry 2004 161: 1537-1547

This is excellently summarised at Bandolier.

Neuroskeptic said...

Joanna Moncrieff implied (here) that the treatment-emergent mania idea was pushed as part of the early attempts to establish imipramine as an antidepressant agent. Presumably because if something can induce mania it makes a certain intuitive sense that it would also treat depression.

But on the other hand that paper you linked to found that TCAs *do* precipitate mania more often than placebo...

Anonymous said...


What about this study and this study

The Switcher said...

Wow. It must be nice to live in theory. It must be nice to smuggly dismiss mania as if it were agitation. It must be nice to be you.

It took less than 24 hours to go from serious depression *with NO energy/agitation* to manic. Psychosis included. That was Effexor. Prozac, lovely drug, lovely mixed state. Same again with Geodon, and that time was while on Lithium and Depakote. The switches were not just my conclusion, but that of my psychiatrist, therapist, and family who watched.

I'm fine with anyone saying that it might not be the norm or common or whatever you want. But, please, get real. Saying no one w/bipolar is extremely sensitive to antidepressants makes you sound just as ignorant as the authors of the article you trashed.

NeuroPsych said...

I didn't "dismiss mania" as if it were agitation. I reported on a study, in non-bipolar patients, which showed that antidepressant use was associated with agitation.

Secondly, I didn't say "no one w/bipolar is extremely sensitive to antidepressants." I said that the research doesn't support the notion of tx emergent mania as fact. The specific study I critiqued didn't even come close to proving that. It was a poorly done analysis.

keely blue said...

I realize this discussion is a bit dated, and I apologize for my any blatant ignorance here, but I'm in a relevant situation and would greatly appreciate your thoughts. I have been on and off SSRIs and SNRIs for 16 years- all seemed to greatly elevate mood and several to the point of reckless mania (120 mg of Cymbalta = gradiosity, auditory hallucinations, hasty divorce, max'd credit cards, walk out of job, buy 2 motorcycles, opiate abuse, promiscuity...)I have never experienced mania off an antidepressant. Currently unmedicated, I have extreme anxiety with panic and moderate depression. Doc says mood stabilizers. I say wtf I'm not bipolar.

NeuroPsych said...

In my post, I discuss treatment emergent mania in bipolar disorder as the myth, that does not mean antidepressants are not capable of causing a manic syndrome in individuals (regardless of diagnosis).

Professionally, I have only had one patient where that was the case (it appears to be a very rare side-effect). However, this view is controversial. The mainstream argues that if a depressed person becomes manic shortly after starting an antidepressant, then the latent bipolar disorder was "revealed." I believe this to be a means of not accepting responsibility for prescribe potentially dangerous drugs to patients (my personal bias). In this study (Incidence and predictors of activation syndrome induced by antidepressants.Harada T, Sakamoto K, Ishigooka J. 2008). 4.3% of nonbipolar developed an activation syndrome. That's similar to the bipolar switch rate in one of the cited studies in my post.If antidepressants can cause an activation syndrome, then mania can be considered a very extreme (and rare) form of this syndrome.

Keep in the mind that our brains are learning machines, and once the brain has learned a behavior, it cannot unlearn it. This is why an individual who has a post-traumatic seizure (from a mild TBI)is vulnerable to having subsequent seizures (kindling theory). I believe this to be the case with mania. If a drug induced a manic episode, then you're vulnerable for that to happen again when the conditions are right (i.e., being on an antidepressant).

Another explanation is that you do have bipolar disorder. If you have been on antidepressants on and off for 16 years, it is possible that your manic episodes occurred coincidentally while you were on an antidepressant (I really don't know you history so I am just speculating here).

I think another reason the tx emergent mania myth has perpetuated is that bipolar disorder often presents with depression, not mania, therefore, when someone is on an antidepressant and eventually becomes manic, this can lead to confusion.

Personally, I don't care what the research says about drugs, patients with moderate-severe conditions should never be treated with medications alone. Psychotherapy (CBT for anxiety works the best) should also accompany tx. The research is pretty clear; the combination of two txs are superior compared to any one treatment alone.