Latuda and Bipolar Depression

Have you seen them? The brand new, direct to consumer (DTC), ads touting the drug Latuda for bipolar depression? The drug company just received the indication for this purpose from the FDA a very short time ago, but the drug company, Sunovion Pharmaceuticals Inc., was ready to roll.

Latuda is a dopamine blocking drug, which makes it an antipsychotic medication and not an antidepressant.  We have known since the 1950’s that all antipsychotic medications have some effectiveness in bipolar disorder, although primarily for the prevention of the manic phase of the illness. We have known that they also may augment an antidepressant for those who only get a partial response to the antidepressant in both unipolar and bipolar depression. A colleague of mine routinely used the antipsychotic Navane to augment the old tricyclic antidepressants in the 1970's.

Only two other antipsychotic medications have official FDA indications for bipolar depression, probably because the other drug companies did not spend the money to get it.  If doctors know one member of a class works, they’ll know that the others probably will too, so why bother?  One of these two drugs that has the bipolar indication is actually a combination drug containing an antipsychotic medication (Olanzepine [Zyprexa]) AND the antidepressant Prozac. The other is Quetiapine [Seroquel].

The main problem with using an antipsychotic instead of an antidepressant in this condition – aside from the unequivocal fact that antidepressants are way more effective – is that antipsychotics have much more potential toxicity. Latuda is probably one of the safer ones in this regard, having a low incidence of the two biggest concerns, metabolic syndrome (weight gain, higher cholesterol, diabetes - horrible and very common problems with Zyprexa and Seroquel) and the long-term neurological side effect, tardive dyskinesia.  Interestingly, the FDA won’t let Sunovion make that claim despite the fact that it’s true!  Go figure.

Almost simultaneously with the start of Latuda's DTC ad campaign, two research studies of the drug’s use in bipolar depression were published in the February 2014 issue of the flagship psychiatry journal, the American Journal of Psychiatry (AJP). The studies showed that the drug was effective by itself for the disorder, and also effective as an adjunct treatment when combined with either of the two major anti-manic drugs, lithium and valproate.  Weirdly, the  “effect size” of the improvement in patients, a measure of how much better patients got, was less (0.34) with combination therapy than it was in the case of the drug by itself (0.51). Both of these effect sizes are moderate at best, btw.

That difference is particularly odd in the case of valproate, since there is zero evidence that it is effective for the depressed stage of bipolar disorder (lithium sometimes is, but not usually). Does valproate somehow make Latuda less effective than it would be otherwise?

There is a big issue here:  the question of whether antidepressants alone are the better choice for treatment of bipolar depression.

The last author of the first AJP Latuda  study is Gary Sachs, someone I have discussed previously in this blog [ 10/31/11].  He is the author of a major study that claimed to show that antidepressants were completely ineffective – worse than placebo – in the treatment of the depressed phase of bipolar disorder.  

He conveniently neglected to point out in the earlier paper that the sample of patients he used in this study had already proved to be resistant to antidepressant medication in the first place, and continued to dissemble about this omission when I had the opportunity to confront him about it. Some subjects of his had even failed a trial of a combined antidepressant and antipsychotic. The conclusion of the study as presented in the study was bogus as hell.

A defender of Dr. Sachs made this point: Dr Sachs and colleagues in the abstract did not say that they had proven that antidepressants were ineffective in bipolar depression. They reported their finding and immediately called for additional long-term well designed studies - what I have called plausible deniability.

The more recent Latuda article which Sachs co-authored did in fact state the following: “There is limited evidence of the use of standard antidepressants for the treatment of bipolar depression.”  I guess that isn’t exactly the same as saying they don’t work, is it?  Might as well be, though! It's not what you say, it's what people hear.

Furthermore, I learned from the article that Dr. Sachs is a paid consultant for Sunovion pharmaceuticals!  

The article’s reference for the statement about antidepressants not being effective was one study that was a meta-analysis of existing studies of antidepressants in bipolar depression (a study which combines the statistics from several other studies). In an editorial in the same AJP issue publishing the Latuda studies, one R.H. Belmaker restates the opinion that “the evidence that antidepressants can be useful seems less and less convincing.”  

His reference for this statement? It is an editorial he himself wrote in the same journal as the original bogus Sachs article appeared [New England Journal of Medicine 356 (17), 4/26/07 (NEJM)]!  I went and got a copy of it.  These folks seem to all run in the same circles, as well as in the same circular reasoning.

In that editorial, he mentions the same meta-analysis that was mentioned in the AJP Sachs article.  But he also mentions that there are two other meta-analytic studies, both totally ignored in the AJP Latuda articles, that showed that antidepressants could be “highly beneficial” in bipolar depression.

There is fairly subtle obfuscation of the evidence going on here, since the other two meta-analyses never seem to be mentioned in articles touting antipsychotics for bipolar depression any more.  I wonder why that is?

In Belmaker’s original NEJM editorial, he opines that maybe the condition is heterogeneous and that subjects in studies outside of the United States may be different than they are here. The two positive metastudies were by authors from outside the USA.

Aside from the fact that there is absolutely no clinical evidence for that whatsoever, Belmaker neglects to mention that at least one of the two meta-analyses showing that antidepressants were effective did not limit itself to studies done overseas, but included studies done in the States! (I could not get a hold of the second, but this is probably also true of that one as well).

Of course, the issue of antidepressants causing bipolar patients to switch into mania is also brought up again and again ad nauseum all over the place, even though everyone agrees – even the original Sachs article in NEJM - that the anti-manic drugs like lithium and divalproate prevent this.  Since true bipolar patients should be on one of those drugs to begin with, this is a superfluous issue.

I also have my doubts that all of the subjects in the Latuda studies were even diagnosed correctly, since one of the diagnostic tools used was the Bipolarity Index, which includes the items, “Episodes with characteristic symptoms of hypomania, but symptoms, duration or intensity are subthreshold for hypomania or cyclothymia” and “baseline hyperthymic personality when not manic or depressed. " 

For a discussion of the significance of that nonsense, see my posts about treatment resistant depression and bipolar disease mongering.

These folks are doing nothing but trying to sell expensive and potentially toxic drugs to both doctors and the public when more effective and safer alternatives already exist.