Friday, January 8, 2010

Great Acts of Stupidity or How Science Shouldn't Work

Has anyone read the book Freakonomics? I have. And by "have," I mean that I read the first page of the table of contents (1). What I learned from that brief, yet informative passage is that "conventional wisdom is so often wrong."

Here's an example. "Lithium carbonate and valproate semisodium are both recommended as monotherapy for prevention of relapse in bipolar disorder, but are not individually fully effective in many patients. If combination therapy with both agents is better than monotherapy, many relapses and consequent disability could be avoided. We aimed to establish whether lithium plus valproate was better than monotherapy with either drug alone for relapse prevention in bipolar I disorder" (2).

For reasons of brevity, articles are worded so that certain assumptions are implied (implicit), while the main aim of the article can be stated explicitly.

What is the implicit assumption in this introduction?

It's this: Valproate (Depakote) and lithium are reasonably effective maintenance therapies. How do we know this? Because both drugs are recommended as monotherapy for the prevention of relapse in bipolar disorder.

Here is where it gets interesting (or pathetically sad). Lithium has over four decades of research supporting its efficacy. If we define a mood stabilizer as a drug that treats acute mania, acute depression, and prevents relapse into either mood episode, then lithium is the only drug on the market that meets those criteria (3). Valproate, on the other hand, has evidence to support its efficacy as an anti-manic agent. It meets only 1 out 3 criteria for a mood stabilizer.

"Then why is it recommended as a maintenance treatment?" Because of this study (4), which found that "divalproex...did not differ significantly from the placebo group in time to any mood episode."

If you are exceedingly sharp, you'll notice that it's a negative study. Yet valproate has managed to become a recommended monotherapy. To read more about this, check out this post (5).

This article, released online ahead of print, is known as the BALANCE study. (BALANCE is a backronym that stands for Bipolar Affective disorder Lithium/ANticonvulsant Evaluation). Here is the saddest fact of this study: Most of the mental effort that when into it was for creating the backronym. It goes down hill after that.

Here are the results: "For people with bipolar I disorder, for whom long-term therapy is clinically indicated, both combination therapy with lithium plus valproate and lithium monotherapy are more likely to prevent relapse than is valproate monotherapy. This benefit seems to be irrespective of baseline severity of illness and is maintained for up to 2 years. BALANCE could neither reliably confirm nor refute a benefit of combination therapy compared with lithium monotherapy."

It other words, lithium monotherapy or lithium with valproate adjunctive therapy is more effective at preventing relapse than valproate alone. The difference between lithium and the combination treatment was not statistically significant.

Here is where it gets really sad (6): "Welcome back lithium. After losing its luster because of concerns over potentially serious adverse effects, this drug is drawing increasing respect...This study, along with other recent research, goes a long way toward putting lithium back on top as the preferred treatment for bipolar disorder, said lead study author John R. Geddes, MD...We’ve got more evidence purporting the lithium efficacy, safety, and its antisuicidal effects than we’ve ever had before," Dr. Geddes told Medscape Psychiatry. "So don’t throw lithium away; it’s a highly effective treatment, and if people can tolerate it, then it’s worth trying."

"don't throw lithium away!?" Exactly, what study suggested that? Some of you might be thinking that atypicals have replaced lithium since they too are effective as anti-manic and maintenance treatments, but lithium's efficacy was compared to valproate, not an atypical.

In other words, lithium was more effective than a drug that is no more effective than placebo. Why is this a major finding? Why was this study done?

"Although the study could not confirm a benefit of the valproate-lithium combination therapy over lithium alone, its findings should challenge current clinical guidelines that recommend valproate monotherapy as a first-line option for long-term treatment of bipolar disorder."

There is one study, ONE! on maintenance treatment. It's NEGATIVE! That alone should have prevented valproate from becoming a first-line option.

Here is a special kind of stupid: "In an accompanying editorial (7), Rasmus W. Licht, MD, Mood Disorders Research Unit, Aarhus University Hospital, Risskov, Denmark, praised the BALANCE study, describing it as 'outstanding work' and 'an impressive example of international collaboration.'

He said that even without a placebo group*, the study 'confirms the long-term efficacy of lithium, not only for the prevention of mania but also for prevention of depression.'

On the basis of the study’s results, 'the BALANCE group rightly challenges the recommendation by present clinical guidelines that valproate monotherapy is a first-line option for long-term treatment."

Make sure you read the above carefully. I highlighted the parts that celebrate acts of stupidity. This "outstanding work" took an "international collaboration" to "confirm the long-term efficacy of lithium," which "rightly challenge" clinical guidelines.

Lithium has been the most empirically supported bipolar drug to date. It's the only drug that meets all three defining criteria for a mood stabilizer. Valproate has proven efficacy as an anti-manic only. This study, along with the accompanying editorial, and subsequent press releases should not exist. This is just plain fucking stupid!

A few years ago, articles, based on data that has been around for 20 years, stated that that antidepressants were not as effective as initially stated.

Last year, research showed that vaccines didn't cause autism (even though no research showed that they did).

Now, research is showing us that lithium is effective (never disputed) when compared to a drug that was never shown to be effective.

This is science, telling us what we should already know!

* Just as a side note. The press releases for this study (8) are pushing the combination treatment as the preferred method of treatment. Here is my problem with that: I don't interpret these results as supporting polypharmacy as superior. Although there was a trend for the combination treatment over lithium alone, the difference was not statistically significant. Second, since valproate never had proven efficacy, I view it as an "active placebo," which could also explain the the better performance of the combination treatment. Sadly, the damage is done.

The BALANCE investigators and collaborators (2009). Lithium plus valproate combination therapy versus monotherapy for relapse prevention in bipolar I disorder (BALANCE): a randomised open-label trial The Lancent : doi:10.1016/S0140-6736(09)61828-6


Neuroskeptic said...

As I understand it there are big national differences here - in the UK lithium is the first choice treatment for bipolar and is also regarded by most specialists (that I've spoken to) as the first choice for antidepressant-resistant depression (i.e. ahead of atypicals). Which is far from the case in the US, afaik.

But this goes way back, lithium didn't get FDA approved until 1970 even though it was discovered to be antimanic in 1949 and was quickly adopted in Europe.

NeuroPsych said...

I believe that you're right. I have read that lithium is still quite popular in Europe in general, whereas it has fallen out of fashion here in the states.

I've also heard (not confirmed though)that pediatric bipolar is primarily a American phenomenon, while in European children are diagnosed with behavioral disorders such as ADHD in place of bipolar disorder.

I wonder if European practices, in general, have been changing to become more similar to US practices or if practice has remained static? Any comments?

Bernard Carroll said...

Valproate (Depakote) didn’t appear out of nowhere for bipolar disorder. It was put into clinical trials for mania by Abbott in pursuit of the bipolar market based on the prior work of Robert Post and James Ballenger with carbamazepine (Tegretol). Both drugs are anticonvulsants, and their use in bipolar disorder was an outcome of the kindling theory that Post proposed. Now, any pharmaceutical company that finds a new anticonvulsant goes straight for the bipolar indications.

Despite my friendship with both Post and Ballenger, I always thought the kindling theory was strained, and it remains speculative to this day. But it was used by Abbott as a scientific underpinning for Depakote in bipolar disorder. Once they had their foot in the door with an indication for acute mania, then they could go after longer term use, as Parousia describes so well in this post. Meanwhile, Ciba Geigy was unwilling to invest in trials of Tegretol, so its use in bipolar disorder has always been off label and unpromoted. A large part of Abbott’s campaign for Depakote involved subtle and not so subtle badmouthing of lithium, which had no corporate defender. An army of clinical investigators just followed the money, and in the US a generation of patients was deprived of the benefit of lithium.

Disclosure: I trained in Melbourne, Australia, where the discoverer of lithium, John Cade, was one of my teachers.

Neuroskeptic said...

That's what I've heard re: childhood bipolar, although this is all anecdotal, but I suspect if you looked at the author affiliations on childhood bipolar papers you'd find they were disproportionately American. Maybe I'll do that some day...

Although for what it's worth, "p(a)ediatric bipolar" returns just 6 hits in the British Journal of Psychiatry, all of which are in the references rather than in the articles themselves!

Whereas the American Journal of Psychiatry has 36 hits, most of which are in the titles. Also, the BJP recently published a (Canadian!) paper looking at the offspring of bipolar patients finding that if they developed bipolar they did so at adolescence not before: Early course of bipolar disorder in high-risk offspring: prospective study

Neuroskeptic said...

As we suspected, pediatric bipolar is almost entirely an American phenomenon, I just did a post examining the publications about it, and with very few exceptions they're from US authors, and from the last 10 years.

Jen said...

I love your blog. You are dispelling many myths, and as a consumer, I appreciate that! My husband has schizoaffective disorder and I was intrigued by Fanapt (which looks more and more like an "i want a piece of the pie, too" drug. He's on lithium for the mood component of his schizophrenia. He was on everything under the sun, including Depakote, until we found a brilliant psychiatrist who asked us "has anyone ever tried Lithium? It really is the gold standard...". Keep writing!