September 8, 2009

Unpublished Lamictal Studies Left Us Thinking It Was An Antidepressant

If you cheat on your wife, and later learn she had cheated on you, can you say you cheated because she cheated on you?

An great paper by Nassir Ghaemi, saying-- and this is a quote:

Some things we know, and know that we know. Other things we do not know, and know that we do not know. But perhaps the largest class involves those things we do not know, and do not realize that we do not know.

That kind of thinking exhausts me.


Thus I was surprised to discover the existence of several negative lamotrigine studies... Of the nine lamotrigine related bipolar disorder studies posted on the website, two were positive and published... Five other negative studies involving rapid cycling bipolar disorder, acute bipolar depression and acute mania have not been published and are only available on the GSK website.  Failure to adequately publish these negative studies led to the creation of a clinical impression that lamotrigine is an "antidepressant," a view innocently expressed to me as recently as last week by an academic colleague.

At this point I need to take a nap.  Ghaemi wrote one of the best books on statistics for psychiatrists; so I'm not defending the hiding of negative studies, but is this man seriously saying that the "hiding" of 2 negative bipolar depression studies is the reason an entire planet of psychiatrists thought Lamictal was an antidepressant when there never were any positive studies saying it was?

This is like Pfizer coming out and saying, "sorry we hid the negative data on Viagra and telepathy."  Ok, what?

In fact, there were already three negative studies about Lamictal as an antidepressant published:  the same three that said it wasn't an antimanic either, but only good for the "prophylaxis of mood states," which is like the rock that keeps tigers away. 

The fact that his academic colleague called it an antidepressant means, simply, that he's an idiot.  No, no, no, I'm not being disrespectful, I mean it completely seriously.  He's an academic.  He's supposed to know what the (only) three studies say, especially since he's teaching it to other people; and he's apparently prescribing this thing thinking that it is an antidepressant based on nothing at all.  Ok, maybe not nothing: based on the word of mouth from other people who didn't read the same three articles.

Does Ghaemi think that the unveiling of negative studies is going to change the behavior of a person who is making it up as he goes along anyway?  It doesn't stop astrologers, does it?


Don't look at me like that.  Five years ago if I stood in front of a bunch of psychiatrists and told them that there was no data for the use of Lamictal as an antidepressant or antimanic they would have condescendingly shaken their heads and told me that Charlie Nemeroff had just been there, and he said...

And if I challenged them to read the studies that I had brought with me to prove my point, they would have told me that of course these were only a select sample of studies, there were other studies showing that it was an antidepressant... and I'd say where? and they'd say well... and I'd say what? and someone would inevitably roll out the "if this is true, how come other [smarter than you] people  haven't said anything? And it would all degenerate into the DMZ of  "well, my clinical experience has been..." 

I have managed to publish quite a few papers; but when I tried to publish papers critical of the existing Guidelines--I had experiences quite similar to Ghaemi's:

The paper was immediately rejected by one of the editors in July 2006, without comment. I asked for specific feedback, and received a letter with numerous complaints, such as what follows: "There is a considerable literature on this specific topic, almost all of which you failed to cite". The editor goes on to note that some of these papers were co-written by the editor, which had "profound effects". He continued: "This failure on your part indicates a naivety [sic] or ignorance of the broader picture....You thus fail entirely to give the paper context...As a psychiatrist, you will appreciate the annoyance any JAMA editor might naturally feel when the manuscript he reads has an abstract written in the New England Journal of Medicine style..." He dismissed the abstract as "classic...pretty much useless," the methods as "wandering and discursive," the results as "incomplete ... trivial...If you had sent us a crisp paper that clearly stated a hypothesis, and a credible way of investigating it; if you'd given us the context, clear methods and adequate statistical analysis; if you had provided the relevant citations, and if your hypothesis and investigation had been on something that hadn't been already documented by others: then we might have been interested. Unhappily, you did not. I hope this will help you in the future. Best wishes."
Here's what you don't know about peer review: it's really peer pressure.


I have been too hard on psychiatrists who thought Lamictal was an antidepressant, or even a mood stabilizer.  They were-- pushed-- into thinking it.  If you only read the abstracts:

Conclusions  Both lamotrigine and lithium were superior to placebo for the prevention of relapse or recurrence of mood episodes in patients with bipolar I disorder who had recently experienced a manic or hypomanic episode. The results indicate that lamotrigine is an effective, well-tolerated maintenance treatment for bipolar disorder, particularly for prophylaxis of depression.
it's possible you might have misunderstood the paper and thought it was good for everything.  Hmm.  Maybe the peer reviewers missed that.


Ghaemi has an optimistic bias: "had we known of these, we would have acted."  No, not in this generation's psychiatry.  If the overuse of Lamictal was due to hiding negative studies, does he think its rapid decline in the past two years has been due to the release of these studies?  Did we stop using Depakote because we all finally read the article from 2000?

They went generic.  That's all.  And it's not the absence of reps that made docs forget about these drugs; it's the absence of "studies" and reviews in all the journals telling us, over and over, to use them.

The problem of psychiatry isn't the hiding of negative studies-- even if they were available, it would make no difference, because we're not prescribing based on science, we're prescribing-- like Ghaemi's colleague-- on word of mouth.  Psychiatry is politics, and we basically toe the party line, no matter what common sense, logic, or even science tell us.

Americans learn their civics from the TV news; psychiatrists learn their psychiatry from their newspeople, too.  Those people are called thought leaders, and they have far more power to drive practice than any amount of data, hidden or not.


So, if not a mood stabilzer... (Below threshold)

September 9, 2009 1:58 AM | Posted by acute_mania: | Reply

So, if not a mood stabilzer or an antidepressant, what place if any does Lamictal have on psychiatry?

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Oh how I wish you were the ... (Below threshold)

September 9, 2009 3:15 AM | Posted by Meat Robot: | Reply

Oh how I wish you were the director of inpatient psychiatry at my facility.

@acute_mania: Lamictal very likely has no place at all in psychiatry, and the sooner we toss it aside, the better. Once you've seen a severe bullous erythema, you'll be more than happy to give this stuff the heave-ho. I've never once prescribed it.

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Do you ever consider gettin... (Below threshold)

September 9, 2009 4:46 AM | Posted by Anonymous: | Reply

Do you ever consider getting out of this field? Must be pretty angering to work with such impressionable morons. Kind of ironic considering psychiatrists themselves generally function as responsible parties for mental incompetents. It's almost as if pharma companies are punking you out, making a mockery of your practice, squaring things in a karmic way for the control you express over mental invalids. The doctor manipulates the schizophrenic, the bipolar, or the neurotic/lonely 20/30 something...the pharmaceutical companies manipulate the doctor in the same way. Kinda funny if you think about it like that.

Anyway. Eh, I guess every area of medicine is susceptible to a blitz advertising storm of wonder drugs that prove to be bullcrap when the patents expire. The difference is, I suppose, that with say diabetes there is more of a tendency to be cautious and wait and see. Only in psychiatry do the practitioners throw caution into the wind and jump on every single new drug bandwagon with full abandon. Why do you think that is? Lack of accountability for outcomes? It's easier to see the physician's responsibility in poorly managed diabetes; it's more difficult to see the physicians responsibility in poorly managed mood disorders because mood disorders are not as predictable and linear in course. Lack of understanding of the pathophys? There is more known about what leads to diabetes than there is mood disorders, which makes it a lot more difficult to sell drugs with specious or no real clinical benefits. Lack of efficacy in current therapies? Like cancer, when the future looks dismal why not jump on the newest thing.

Either way, it's pretty embarrassing. I'm embarrassed for everyone.

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Here's an interesting wuest... (Below threshold)

September 9, 2009 4:49 AM | Posted by Anonymous: | Reply

Here's an interesting wuestion: what to make of all the patients who report lamictal helped them. I know some people who say lamictal is their wonder drug. Placebo effect then? Or is it possible some mood disorders ("rapid cycling bipolar") may actually be epileptogenic?

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Alone's response: Of cou... (Below threshold)

September 9, 2009 9:32 AM | Posted by Alone: | Reply

Alone's response: Of course, Lamictal has helped lots of people. I'd even say I've seen it be an antimanic (maybe?) even though it's not supposed to be.

But the point is whether it should be first line. If you've tried six other meds and nothing works, by all means try valerian or rock salt or anything at all (under doctor's care, of course!)-- but should Lamitcal be at the top of every bipolar flowchart?

Clinical trials will never substitute for judgment and experience. But if the doc isn't even aware of the clinical trials, how good can his judgment really be?

Another way of saying it is this: in a new patient, should Lamictal be given before, say, Zoloft? Think about it....

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Anonymous 4:46: I think you... (Below threshold)

September 9, 2009 10:08 AM | Posted by Tom: | Reply

Anonymous 4:46: I think you misunderstood the point. I don't think Alone is talking about Big Pharma; He/She seems to be talking about the action of social networks on psychiatry. The sort of thing described in this post happen in many non-medical fields, and it comes back to what Gladwell (uhhg) talks about in Tipping Point. There are lots and lots of regular people who have an average number of social connections, and then there are a handful of people who have a huge number of social connections. If, in psychiatry, those people who have a huge number of social connections are operating under a false assumption, it appears that the entire community picks up those false assumptions. In this case, the people with a huge number of social connections are the ones who decide what gets published. They, very literally, control the knowledge of the community. It's not a problem with psychiatry or big pharma, as much as it's a problem with academia.

Or at least, that's the meaning I took. Perhaps I misunderstood.

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You know the paradox of the... (Below threshold)

September 9, 2009 11:46 AM | Posted by D.N.: | Reply

You know the paradox of the heap? When you pile together a bunch of anecdotes and...

I was "rapid cycling" (four times a year) between mild yucky depression and a yucky mixed state and Lamictal sent me into rapid cycling (four times a month!) between fun-fun-fun hypomania and a mild dysthymia that felt like depression in contrast.

The takeaway? It was more of a mood amplifier than a mood stabilizer. It did shift the median to the right though.

After a wild goose chase with other anticonvulsants, we eventually settled with Lamictal + an antipsychotic (Seroquel for the more manic seasons, Geodon for the more depressive ones. Now these seasons last for 12 our 18 months). But from what I remember you aren't really sympathetic to antipsychotic therapy for "bipolar depression".

I could try flower remedies, but I feel good right now.

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Alone,What's your ... (Below threshold)

September 9, 2009 11:56 AM | Posted by bitpunk: | Reply


What's your take on the "epileptology" of bipolar disorder? There's been a lot of pop culture fluff along the lines of "is bipolar disorder really temporal lobe epilepsy?" and a couple of hungarian papers, but it seems to me that many bipolar patients have been evaluated for TLE after complaining about certain dissociative symptoms. Do you personally think that there's a connection beyond mere symptom overlap?

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Another one for Alone. With... (Below threshold)

September 9, 2009 1:50 PM | Posted by acute_mania: | Reply

Another one for Alone. With all this talk of Kindling theory of bipolar and the use of anticonvulsants to treat bipolar, even topamax and neurontin, tegretol seems to have fallen by the wayside. Tegretol was the first anticonvulsant successfully used to treat mood disorders. Is there reasonable evidence supporting its use?

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For an opposing viewpoint (... (Below threshold)

September 9, 2009 2:09 PM | Posted by bitpunk: | Reply

For an opposing viewpoint (not that I've reached a conclusion), see:
Discovery and development of lamotrigine for bipolar disorder: A
story of serendipity, clinical observations, risk taking, and persistence
Journal of Affective Disorders 108 (2008) 1 – 9

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Over the years, I have had ... (Below threshold)

September 9, 2009 2:43 PM | Posted by David Johnson: | Reply

Over the years, I have had several major depressive episodes, resulting in hospitalization, primarily for severe self-harming and/or suicidal behaviors and ideation. I've pretty much had the full spectrum of drug therapy- so much so, I really lost any faith that there might be a drug or two that would be of benefit to me. The antipsychotics didn't work, the SSRI's set me off or were ineffective. Finally, I had a GP and then a psychiatrist recommend lamotrigine. The GP had talked to the head psychiatrist at a regional hospital who reported having beneficial outcomes using lamotrigine with patients who had both high anxiety levels and major depression. The psychiatrist from a local clinic, a year or so later, diagnosed me as Bipolar I, ultradian cycle. Whatever. I currently take lamotrigine and have been working with a cognitive-behavioral therapist. Anxiety is still a serious problem, but I don't have as marked a level of sudden mood swings. Because it is the only drug I've taken that doesn't seem to have significant side-effects and because I seem to have a dampening, rather than absence of symptoms, I've often wondered if it really helps me. I've tried twice to taper off it and have seen my anxiety levels, depression, mood swings and self-harming behaviors/ideation return. So I keep taking it. I don't see a placebo effect for these two reasons- 1. I had given up any expectation a medication would be helpful and 2. Truly feeling like lamotrigine wasn't "doing anything," I tapered off it and had a resumption of some of my symptoms.

The reason I weigh in on the subject is to suggest there definitely is a place for anecdotal evidence when taking a look at medication. Like you suggest, it may not be at the top of the flow chart, but I think it should be on the flow chart.

Finally, I really appreciate your continuing to bring up the connection between the number of studies done and the amount of advertising, with whether or not a drug has gone generic. It helps to put the subject in perspective and I simply have not read anyone else who depicts the connection so clearly.

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Alone-You would love... (Below threshold)

September 9, 2009 3:26 PM | Posted by V: | Reply

You would love "Epistemology and the Psychology of Human Judgment" by Michael Bishop and J.D. Trout. I don't remember much about psychiatry, but there was a lot about clinicians in general.

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But this is entirely dif... (Below threshold)

September 9, 2009 4:29 PM | Posted, in reply to bitpunk's comment, by Alone: | Reply

But this is entirely different than a classist approach to pharmacology, let alone diagnosis. "A seizure drug worked here, let's try a different seizure drug of a completely different pharmacology since all seizure drugs are alike..."

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It's quite clear that you h... (Below threshold)

September 9, 2009 6:58 PM | Posted, in reply to David Johnson's comment, by Anonymous: | Reply

It's quite clear that you have Borderline Personality Disorder. Bipolar I pays the bills, though.

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Thanks for the diagnosis-I ... (Below threshold)

September 10, 2009 12:02 AM | Posted, in reply to Anonymous's comment, by David Johnson: | Reply

Thanks for the diagnosis-I just wish my psych and therapist could get the info. If you could take a few minutes, could you let me know how Bipolar I can pay my bills? I'm evidently doing something wrong because I feel the need to work in order to pay my bills.

It'd be appreciated.

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Sorry...Pays the hospital's... (Below threshold)

September 10, 2009 12:17 AM | Posted, in reply to David Johnson's comment, by Anonymous: | Reply

Sorry...Pays the hospital's bills. Bipolar is gold. Borderline, not so much. Did the hospital psychiatrist give a diagnosis in order to get reimbursed? Yes, s/he did.

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@Anonymous: quit being suc... (Below threshold)

September 10, 2009 3:55 AM | Posted by Meat Robot: | Reply

@Anonymous: quit being such a wanker. How on earth can you come to diagnostic certainty about D. Johnson merely from reading one comment after a blog post which discloses only a very brief history? If you're a shrink, you suck, and I hope your local college is on to you. If you're a resident, I'd fail your ass if you offered that kind of faux certainty in a clinical setting.

@Everyone else: great discussion. Psychiatry both needs more and is more open to (in relation to other medical specialties) frequent soul-searching and purging.

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I love the flatly snarky re... (Below threshold)

September 10, 2009 10:51 AM | Posted by Anonymous: | Reply

I love the flatly snarky response you got from JAMA! It's good to see medicine is a field of dispassionate inquiry.

At least I'm not alone in my frequent feeling that my professional peers base their expertise on similar hearsay and circular argument. The older I've gotten, the more I realize how superficial and populist most experts are. No one looks under the covers.

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Thank you for this educated... (Below threshold)

September 10, 2009 11:32 AM | Posted by Kellen: | Reply

Thank you for this educated and enlightened viewpoint on the politics of prescribing. Can the same thing be said for the diagnosis du jour? It seems the current ones are Bipolar Disorder and ADHD.

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Anyone that even thinks in ... (Below threshold)

September 10, 2009 4:11 PM | Posted, in reply to Meat Robot's comment, by Anonymous: | Reply

Anyone that even thinks in terms of "diagnostic certainty" is truly lost, wanker.

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Haha! Brilliant. You disa... (Below threshold)

September 10, 2009 9:59 PM | Posted by Meat Robot: | Reply

Haha! Brilliant. You disavow your very crime, displace it onto me, and your best reply is the good old grade 7 "I know you are, but what am I?"


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Your word "merely" suggests... (Below threshold)

September 10, 2009 11:06 PM | Posted, in reply to Meat Robot's comment, by Anonymous: | Reply

Your word "merely" suggests that it is possible to obtain "diagnostic certainty" from any amount of history taking or specialized training. That must be why it's necessary to explain further.

A five word sentence or a five hour interview are equally valid ways for determining dx, so that's how he was diagnosed by me with "merely" a brief internet history. Surely the original psychiatrist, who was obviously "wrong", did more than that. If only the original psychiatrist had been a wanker, he could have saved Mr. Johnson a whole series of harmful med trials and started him with a cognitive-based therapy immediately. There would have been no pretense that meds would be helpful or that Bipolar I existed. So, that's how how you do it--rules of thumb. Numerous failed med trials, "ultraridian cycling" (by definition you cannot "rapid cycle" four times per month), several bogus suicide attempts (are we to believe that he can type a blog response, but not figure out how to kill himself?), Lamictal was helpful, and Cognitive therapy is helpful.

But, again, this isn't profitable for the hospital, so you have the um...faux...diagnosis.

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@Anonymous - ok, now you're... (Below threshold)

September 12, 2009 2:31 PM | Posted by Meat Robot: | Reply

@Anonymous - ok, now you're finally saying something useful here.

It is funny (peculiar, not ha ha) that you're very quick to slap on labels and yet continue to accuse me of being the guy looking for certainty. Your microscopic parsing of my language doesn't hide your behaviour, sir.

Now, going one further, if you actually believe there is no such thing as Bipolar I disorder, then you may be safely dispensed with as a crank of the highest order, either that or you were willfuly deaf and blind when you rotated on a psychiatric inpatient unit.

You don't strike me as willful but rather engaged, so crank it is.

Let me say finally that your grasp of pharmacoeconomics is just as bad. If you think it's profitable for hospitals to treat psychiatric patients, then you've missed the continent-wide reduction in both acute psychiatric beds and chronic care beds which has been underway for, oh, 50 years. Read much?

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Anon 6:58 - To be fair DJ p... (Below threshold)

September 12, 2009 11:21 PM | Posted, in reply to Anonymous's comment, by Anonymous: | Reply

Anon 6:58 - To be fair DJ put a "whatever" after his diagnosis. I find the whole concept of ultradian cycling to be ridiculous. I do believe sometimes it is actually real. I don't necessarily believe it is "borderline personality" (which probably doesn't even exist). However, I think it is just common sense that if you are "ultradian cycling" you are clearly not manic depressive, you have a disorder which may be perhaps as yet unnamed... but it isn't manic depression. The hallmark, cardinal sign of mania is lack of sleep with great mental and physical energy. If you are "cycling" every other day, or thoughout the day, by definition you cannot manifest the cardinal sign of mania.

Why do lazy ass psychiatrists call every patient who presents with labile mood / energy bipolar? You can't create a disease based in a symptom that is as generalized as that. Diabetes model makes sense - hyperglycemia is a very specific symptom. Mood/energy lability/cycling is generalized. Lots and lots of things can cause that.

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Re: meat robot... I'm prett... (Below threshold)

September 12, 2009 11:38 PM | Posted by Anonymous: | Reply

Re: meat robot... I'm pretty sure anon 11:06 believes bipolar I/manic depression itself is a real disorder... the word "existed" was in reference to the individual david johnson (where, in this person, it did not exist). This is indicated by the implication that medication trials would be warranted if DJ had BP1 after all.

I don't think it is fair to say lamictal helped as a placebo and that he absolutely had borderline personality. I don't think 11:06 is a real psychiatrist or health practitioner or else he would never say such a thing. Borderline is not the only other explanation for such symptoms in spite of what armchair epsychiatrists would say.

It is possible DJ may/might have an epileptic disorder, which would explain why lamictal helps, and also explain the nature of his symptoms (the psychotic-type symptoms and rapid onset/termination of them within a day... I am assuming these are present if he was diagnosed with "bipolar I ultradian cycling").

This isn't well known but mood disturbance like depression, psychotic symptoms and even manic symptoms (grandiosity and high energy/well being) do occur as a result of seizures or inter-ictally. Classic seizures (that affect movement and/or awareness) are comorbid in individuals who have bogus diagnoses of "bipolar ultradian cycling" and even "borderline personality". This can't be incidental.
If we admit that a lot of these "bipolar like" disorders is actually seizure activity, it cuts into the profits of psychiatry.
Psychiatry has worked very hard to make mental illness fashionable (with myths that being bipolar is actually a benefit, an advantage, it makes you creative and brilliant and such)... it isn't about to admit that most "bipolar disorders" are bullcrap.

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