August 14, 2008

Seroquel For Bipolar Maintenance

A brief history of the past decade.

I. Background

A mood stabilizer is a drug that prevents mania and/or depression.  Depakote was the default mood stabilizer since 2000.  Hundreds of papers promoted its use, though all relied on a single double blind, placebo controlled trial as support for its efficacy.  Mentioned almost no where was that this trial did not show any superiority over placebo.  However, Depakote enjoyed tremendous sales in the years 2000-2008, showing 10-20% growth per year.   

II. But the bulk of the support, especially in journals, came from academics who believed in it, not Pharma? 

Since the academics have no relationship with Abbott and are motivated only by clinical efficacy, we can expect their promotion of Depakote to continue even after it goes generic.  Oh, wait, that happens in 2008.

III. The Sad, Quiet Story Of The Mainetance Trial That Wasn't

Here's a quick summary of the (only)  Depakote vs. placebo for maintenance study: manic patients were enrolled, put on Depakote + any other necessary meds until they were stabilized.  Then these patients were randomized to Depakote, lithium or placebo.

At the end of the study, all three groups had similar relapse rates.  Putting them on Depakote was not better than placebo for maintenance.  On this single, failed trial, an entire decade of psychiatry was premised.

However, there is one technical point that I have never, not once, in 8 years, seen written about, discussed, or even alluded to, and when you do bring it up people look at you blankly: the study patients were stabilized on meds, then randomized to drug or placebo.  So those that were randomized to placebo had their stabilizing meds stopped.  They were "taken off their meds."  So actually, being on Depakote was not simply no better than placebo, it was no better than abruptly going off your meds.  Take a long hard look at yourselves.

IV.  Two Drugs Are Better Than One

Depakote continued to be grow, continued to be a "mood stabilizer" when it was really simply an acute antimanic.  NB: it may be true that Depakote is a tremendous mood stabilizer; you can't condemn the drug on one study.  But, importantly, in the decade of "Evidence Based Medicine" why was it at the top of every treatment algorithm and guideline?  There's the rub.

But psychiatrists did not use it as a monotherapy mood stabilizer-- it was always "mood stabilizer" plus something else.   In fact, the major discussions in psychiatry 2001-2007 were whether/how additional medications would benefit when used with Depakote.  No one asked whether Depakote itself was a mood stabilzier-- that was assumed.  The question was whether adding antipsychotics to Depakote provided additional benefit.  The answer was always "yes" as long as the question had the caveat, "notwithstanding details or generalizability."

Consider the study of Depakote alone, or Depakote + Risperdal, for the treatment of acute mania.  Which is better?


The graph is clear: the combination is better than the single drug alone.  BTW, every atypical antipsychotic has a similar study with nearly identical results.

Two sleights of hand:
1.  This is a study of acute mania--3 weeks-- not maintenance.  The study does not say that Depakote + Risperdal will provide better maintenance control over a year.  Yet that is how the results were generalized-- psychiatrists left their patients on "whatever" broke their mania.  You can see how, over time, doses and number of meds keep going up.

2. See the y-axis?  It doesn't say "amount of improvement," it says "percent of patients."  It doesn't say that each person got more better, it says more people responded to two drugs than responded to one drug.  We assume the superiority was the result of the combination.  But how do you know it wasn't due entirely to the Risperdal?  If you give a room full of manics Depakote, 25% get better.    If you give a room full of manics Risperdal, 25% get better.  If you gave both to everyone, then 50% would get better, but it's pretty clear that the Depakote responders didn't need Risperdal, and the Risperdal responders didn't need Depakote.  Indeed, when you look at change of symptom severity, two meds was no better than more of one med.

This chart could simply be the result blasting patients with two drugs, hoping one works.  So this doesn't say "if a drug fails, add a second."  It says, "if a drug fails, switch to something else."

Which should have been so obvious as to never have necessitated a study.

V. So Then It's Agreed: Let's Change The Definitions So We Don't Get Caught

At some point, someone is going to notice that polypharmacy isn't working as promised; that it is not particularly safe; and that it certainly isn't worth the price.

And Depakote was going off patent.  What to do?

What you do is write a completely unimpressive, pointless article (Effectiveness of Adjunct Antidepressant Treatment for Bipolar Depression) based on a multimillion dollar government finded study that tells us nothing we didn't already know for decades, in the most prestigious medical journal (NEJM) available, and in it sneakily and gigantically change the definitions of words to prepare for the next wave of  psychopharmacology, granting plausible deniability.

Mood stabilizers were initially limited to lithium, valproate, the combination of lithium and valproate, or carbamazepine. In 2004, the protocol was amended to define mood stabilizers operationally as any FDA-approved antimanic agent.

Now, in two sentences, all the junk articles that used to apply only to Depakote can now be reused to apply to antipsychotics.  "We've known since 2001 that mood stabilizers, for example Depakote or Seroquel or Abilify, are maintenance agents..."

VI.  But How Can Antipsychotics Be Mood Stabilizers If They Are For Psychosis?

At first glance, the question seems reasonable, but for the fact that the none of the capitalized words above have any meaning at all, except those with three or less letters.

Seroquel for maintenance bipolar.  Why not, a priori?  Why would it be any worse than Depakote, a drug which didn't work anyway?

The problem, however, is that by pushing Depakote as a maintenance agent for so long, everything is reflexively considered second line, an add-on.

So because of the artifice, the semiotics, "bipolar requires mood stabilizers; Depakote is a mood stabilizer; bipolar needs Depakote" you can't do a Seroquel monotherapy study. It has to be done as an adjunct to Depakote or lithium.   Therein lies the problem with the interpretation of the results.

The results are, indeed, impressive: people on both Seroquel and Depakote had fewer, and later, relapses than those on Depakote alone.  This holds true whether you are looking at relapses into depression, mania, or all mood episodes.

126 time mood episodes.JPG

So, for example, by 52 weeks, about 25% of Seroquel + mood stabilizer patients had relapsed, while 62% of mood stabilizer alone patients had relapsed. That's an NNT of roughly 2.5, i.e. you need to put 2.5 people on Seroquel to reliably know one person benefited.  Lipitor's NNT for reducing heart attacks is 25.

Although you're not supposed to compare results from different studies, I feel completely comfortable saying that the Depakote curve here is about the same as it was the in other maintenance study, i.e. no better than placebo.  (Stop using Depakote.)

VII.  But Is It Measuring Prophylaxis Or Relapse?

Look back at the Depakote study for a hint.

Patients were all stabilized on Depakote/Li with Seroquel over 36 weeks, and then randomized to either continuing Depakote/Li + Seroquel,  or to being taken off Seroquel and being left on Depakote/Li.  Those left on Seroquel did well; those who had the Seroquel removed did not.

So on the one hand, you could say "the combination prevented relapse," or, you could say, "abruptly stopping your Seroquel results in a relapse." Do you see the difference? 

With the Depakote study, stopping your Depakote had no adverse effect.  For whatever reason, stopping your Seroquel apparently does result in prompt relapse.

You are being tricked (not on purpose) by the presence of the Depakote, thinking that this is providing you some degree of mood stabilization, and the Seroquel is adding to it.  Wrong.  The Depakote is providing you nothing.  The Seroquel is the mood stabilizer.  And "stopping your meds" is, after all, not a good idea.

VIII.  What Dose?

There is one other important result of this study.  The patients were not simply on Seroquel; they were on Seroquel at fluctuating doses, per the judgment of the doctor, 400mg to 800mg.  That is key.  Seroquel didn't prevent relapse; rather, raising the dose whenever they needed it, and possibly lowering it when they didn't, is what kept them stable.  Maybe if they were on a fixed dose of Seroquel the whole time, no opportunity to raise the dose, people would have relapsed more frequently.  But this way, at the first sign of trouble, you pre-empt it by increasing the dose.

In other words, Seroquel didn't prevent relapse; prompt intervention by the doctor as things developed (using Seroquel) prevented the relapse.  This doesn't diminish the utility of Seroquel, but it also doesn't mean you can put everyone on 600mg and say, "see you in a year."

That is, perhaps, why Depakote failed: it relied on a steady dose, titrated to an imaginarily important blood level that it seems never to have occurred to anyone to ask why we target.

IX.  The King Is Dead, Long Live The King

Just as Depakote was an overhyped drug that will thankfully die with its patent, it is more than likely that Seroquel for maintenance bipolar disorder represents some sort of top in the antipsychotic market.  It will enjoy massive, and steady, use for several years, but I doubt if there is much growth left in it.  Astra Zeneca thinks it has penetrated a market; but it has really opened the doors for all antipsychotics in the same market.  You can prescribe Seroquel; don't invest in it.

Simultaneoulsy, just as I was a vocal advocate for the use of antipsychotics over the massive overuse of Depakote-- and I thus contributed to the rise of Seroquel (and others), my new target may be the overuse of antipsychotics.

The target is not Pharma or reps, but academic physicians who are politicians posing as  scienticians.  Completely absent is the pursuit of science or truth-- e.g, "we didn't expect this result, I guess we were wrong"-- but diversions and sleight of hand.  The point is not the results; the point is the discussion.  The message doesn't matter, the medium is the message.   They have an allegiance to a given concept, and they defend it, promote it.  No different than a PAC.  And when their King dies, they celebrate as if they never believed in him at all. 

But at least the rise of Seroquel will benefit humanity in two important ways.  First, it brings evidentiary support to the not common enough practice of fluctuating the doses as needed, up and down, rather than relying on a set dose. 

Second, it means the demise of polypharmacy (until they invent a new class of drugs), the drastic reduction of the number of medications patients will be prescribed, especially when coupled with the slow demise of SSRIs.



I found your medal-tossing ... (Below threshold)

August 15, 2008 9:50 AM | Posted by Paul: | Reply

I found your medal-tossing post interesting. I haven't been following the Olympics at all, so that was the first I'd heard of it.

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Nice analysis. With these a... (Below threshold)

August 15, 2008 1:28 PM | Posted by MedsVsTherapy: | Reply

Nice analysis. With these articles, Dig deep for rewards! A decent alternative to litium would be nice, for the shakey-hands, the narrow gap from efficacy to toxicity, and the photosensitivity.

However, Seroquel is shaping up as a big sales leader for diabetes drugs, just as Zyprexa has been (just like giving away the pretzels at the bar).

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I'd like to hear more about... (Below threshold)

August 15, 2008 3:59 PM | Posted by ME: | Reply

I'd like to hear more about your opnion of SSRIs.

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I like the way you ask the ... (Below threshold)

August 16, 2008 12:44 PM | Posted by CzechShrink: | Reply

I like the way you ask the questions we do not ask. I partly escape from the medication dillemata to psychotherapy wich might be just as "usless" as Depakine/Depakote (I love to think about the linguistic-economic part of the pharm business, any comments of yours on this? heard about a study that found letters X and R are the most persuasive...I kind of understend the trend to swich to softer names recently...gentle Mollome instead of agressive Argofan for depressed in need of love and care in this rough assertive world...), but lets you use more than a small part of your brain in the experience of meeting a person...

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What about lamictal as a mo... (Below threshold)

August 16, 2008 2:12 PM | Posted by Anonymous: | Reply

What about lamictal as a mood stabilizer? The GSK studies used to support it are crap. If that's brought up then people say, "well it has good clinical efficacy." What are your thoughts? What about the study design of stabilizing everyone on the drug and then randomizing to taking it off, like you talk about here. Why is that accepted as a good study?

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interesting "coin"-scientic... (Below threshold)

August 16, 2008 8:41 PM | Posted by Diane Abus: | Reply

interesting "coin"-scienticians,-implying interesting permatations
and connotations.a semiological goldmine.


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I wonder what would happen ... (Below threshold)

August 18, 2008 11:48 AM | Posted by SusanC: | Reply

I wonder what would happen if the health insurance companies hired their own experts in pharmaceuticals. In other areas, insurance industry bodies like the Loss Prevention Council hire their own experts (because they don't trust claims made by technology vendors).

As I understand it, some DSM-IV conditions are already not convered by some U.S. health insurance policies, so the insurers are already taking clinical decisions on what to cover. It's not that big a step to say "We won't cover maintenance with Depakote, because our experts say it's no better than placebo".

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(I hit "post" by surprise. ... (Below threshold)

August 22, 2008 9:46 AM | Posted by Dayvan Cowboy: | Reply

(I hit "post" by surprise. Don't you moderate comments anymore?)

Anyway, to give a spoiler on the subject of the link, Hickham's dictum is stated as "Patients can have as many diseases as they damn well please".

Ask me if I could care less about whether I was never bipolar in first place, whether bipolar/ADD is a common combination or whether the ADD diagnosis is valid. I'm managing a productive life.

(I actually do care about that stuff on an intellectual curiosity level, basically because I'm intellectually curious about everything. I also love your blog.)

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I believe there are so many... (Below threshold)

October 22, 2008 11:21 PM | Posted by Antidepressants : | Reply

I believe there are so many depressed people in our society because they aren’t happy with themselves. There are so many outside pressures——including the ones we let in through the media etc., that we are bombarded with how we should act, feel , work, play and so on. Come on people—-forget the status quo!!!

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Depression is a commonplace... (Below threshold)

October 22, 2008 11:21 PM | Posted by Antidepressants : | Reply

Depression is a commonplace event in modern times, taking on many different forms, including physical, sexual, emotional, and verbal abuse, occurring in many different contexts.

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My name is Paul Harris and ... (Below threshold)

December 10, 2008 1:34 AM | Posted by Seroquel Side Effects: | Reply

My name is Paul Harris and i would like to show you my personal experience with Seroquel.

I am 47 years old. Have been on Seroquel for 2 weeks now. I would NOT recommend this drug to anyone except those who only want to sleep all the time. Very poor!

I have experienced some of these side effects-
This drug knocks you out. Slept 17 hours with 200 mg dose the first time. Even 100 mg. makes me tired, dizzy, clouded mind, slurred speach and etc. all day.

I hope this information will be useful to others,
Paul Harris

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Super article, thanks. Sums... (Below threshold)

January 15, 2009 1:31 PM | Posted by abysmal musings: | Reply

Super article, thanks. Sums up most of my suspicions re: Depakote - i.e. when you need to come down it works, but the stats don't bear out putting up with the side-effects for maintenance. And agree with the earlier poster - quetiapine is a horrible cosh.

p.s. I noticed recently that Depakote is an anagram of Take Dope. Hmmm.

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I realize this post is rath... (Below threshold)

June 28, 2009 11:03 AM | Posted by Katie: | Reply

I realize this post is rather old, but I would love to hear more about what you think the front-line treatment for bipolar *should* be. In particular,one of the things I have been told is that Lithium/anticonvulsants should always be used for the maintenance of Bipolar Disorder- and antipsychotics should only be used PRN- because Lithium/anticonvulsants have neuroprotective properties and promote neural growth in a way that antipsychotics do not. I gather the idea is then that even if Lithium/anticonvulsants do not prevent future episodes, they do slow down the degenerative progress of the disease, making future episodes less severe and, I dunno, preventing neurodegeneration. I have heard this line a couple of times. Is this too bad science? As a patient desperately struggling to get and stay well, without destroying any internal organs, I would love to hear your thoughts.

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I too was once on Seroquel.... (Below threshold)

November 21, 2009 4:10 AM | Posted by Sarah: | Reply

I too was once on Seroquel. I can't imagine why anyone would use this from my experience. I slept 16+ hours a day and dropped a good 30 pounds. Sounds nice in theory, but as a college freshman it started me on a gradual downward spiral. Now I'm out of there and am left wondering how it would have all gone down if I had actually been awake my first two months. Not to mention some of the wicked drug interactions I experienced.

Also, my dose was 50mg, then 100mg. I didn't even get up to these huge doses they give to most other people I've encountered.

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Thanks for sharing. Browse ... (Below threshold)

December 8, 2009 7:16 AM | Posted by Arthur: | Reply

Thanks for sharing. Browse and Buy all Anti-depressants drugs at our discount pharmacy.

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Personally, I like Seroquel... (Below threshold)

July 16, 2010 9:46 PM | Posted by koshka: | Reply

Personally, I like Seroquel. I have been on it for nearly six years, and it has served me well. My doctor and I have an agreement where I can take fluxuating doses of 300-600 as needed.

Sure, I sleep, ahem, well. But it has been a life-saving drug, literally, more than once.

No other medicaton has worked as well for me in the 10 years I've been on them. Doctors have tried to switch me off of Seroquel slowly, but I end up hospitalized every time.

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Personally, I like Seroquel... (Below threshold)

July 16, 2010 9:46 PM | Posted by koshka: | Reply

Personally, I like Seroquel. I have been on it for nearly six years, and it has served me well. My doctor and I have an agreement where I can take fluxuating doses of 300-600 as needed.

Sure, I sleep, ahem, well. But it has been a life-saving drug, literally, more than once.

No other medicaton has worked as well for me in the 10 years I've been on them. Doctors have tried to switch me off of Seroquel slowly, but I end up hospitalized every time.

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My boyfriend is on seroquel... (Below threshold)

July 17, 2010 3:30 PM | Posted by kathy: | Reply

My boyfriend is on seroquel and depakote. He just went ballistic on me and started screaming "Clean your room" for 2 hours when I was trying to study for a final exam. He held me down while screaming, and now I have big bruises on my arms. Back in the psych ward, he is trying to blame me by saying I have a bad temper. I put up with his mania for 2 weeks--demons, name calling, smacks to the face. I wish they could help him. I wish the drugs would work. I love the guy and he is in hell.

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my partner had four lapses ... (Below threshold)

October 21, 2011 7:32 PM | Posted by Tom: | Reply

my partner had four lapses in three years, it happen everytime they start reducing the dose of Seroquel while she is also on lithium. she is on 1000mg lithum and last laps happen when went down to 400mg Seroquel. The previous laps happened when they went down to 150mg Serquel. Also the relaps seems to happen a lot more frequent, not sure what to do, it is very difficult to control. Not sure how the idea of fluctuating the does will work as last couple of times the seroquel were increased to 600mg straight away when we noticed the early signs but she still gone through the whole relaps and taking weeks to recover, When would you change the dose and how frequent to prevent relaps????? Love someone to send me the answer or if they have any idea on how to prevent relaps, my email [email protected] Thanks

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Kathy: My mother has bipola... (Below threshold)

September 15, 2012 11:21 AM | Posted, in reply to kathy's comment, by Anonymous: | Reply

Kathy: My mother has bipolar & it was kicked off (began) when her sister-in-law was killed in a car accident & left her brother w/ four small children and her mother died suddenly at the age of 62 and she became pregnant (didn't want to be) for the third time at the age of 30 yrs. Anyway, I was 9 yrs when this happened; my life was hell from that day until I left home at the age of 18 yrs. My mother didn't believe in 'depression', so there was no reason to take medicine for it. I am now 52 & mom is 72; she has been through many manic & depressive events over these past 43 yrs. She last crashed in October of 2010 after a major dental operation (6 implants) & is still in depression 2 yrs later. Her GP put her on 25 mg of Celexa which has done nothing. By her stubbornness in not seeing a psychiatrist, she has pushed away her children & now her 4 grandchildren (which are all my kids). It is so sad & maddening! I feel for her because I have depressive disorder, but I resent her for not taking the care that is available. If your boyfriend does not get the help he needs, you need to separate yourself from him! If he is genuinely willing to get help, then walk beside him. Do not allow him to abuse you though! My mother abused me & I had no choice but to take it; you have a choice. Protect your own sanity!

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Seroquel is just very stron... (Below threshold)

January 12, 2013 10:25 AM | Posted by John Smith: | Reply

Seroquel is just very strong medication which lots of side-effects and should be avoided at all costs. There are often simply better and safer alternatives to the seroquel. People who use seroquel often become ill (heart attacks), especially if dosage is reduced or discontinued but it can take months or years. Moreover, these medications just mask the symptoms and cause dependency without fixing anything and you are now dependent on drug that don't work very well.

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