Thursday, February 24, 2011

Gold Standard Clinical Trials - Opportunity Squandered

We left off with the proposition that for psychiatric purposes “randomized, double-blind, placebo-controlled” (RDPC) clinical trials - medicine’s gold standard - actually tell us nothing. One reason is that we know next to nothing about the phenomenon we’re supposed to be investigating (what the hell is depression, anyway?) which leads to a whole domino effect of faulty assumptions (such as testing “depression” with “antidepressants”).

The other reason has to do with the fact the only ones with the resources to run RDPCs - the drug companies - have marketing objectives in mind, which renders all their findings highly suspect from the outset. I could write a book about the manifold abuses (such as statistical manipulation, data-spinning, ghost-writing, payola to researchers and clinicians) associated with these enterprises. Other people have.

In the real world, if these studies actually told us something, our doctors would have something better to say to us than, “Let’s try Prozac (or Abilify, or whatever) and see how it works.” There would be no endless and frustrating rounds of pill roulette. And maybe there would be less mental illness kicking around.

Ironically, in their over-eager pursuit of “one-size-fits-all” treatments for depression and other common DSM illnesses, Pharma may have missed a golden opportunity to investigate specific things that truly go wrong with us - never mind the illness - where targeted meds treatment may indeed make a huge difference.

I came across my first taste of this at the very first American Psychiatric Association annual meeting I attended in 2002. The conference was stuck in an “antidepressants to treat depression” mindset, and so was I. Then I came across a poster of a very small pilot study (maybe ten patients) by Joseph Goldberg of the Mt Sinai School of Medicine involving treating bipolar depressed patients with Mirapex (pramipexole).

Mirapex, a “dopamine agonist,” is FDA-indicated for treating Parkinson’s. We know what dopamine can do for the brain - just ask any crackhead, tweaker, speed-freak, or anyone who craves a good buzz. But we also know that not enough dopamine equates with being a vegetable - just ask anyone overmedicated on an antipsychotic, which acts as a dopamine-blocker.

To vastly oversimplify, when dopamine is firing right, we have a feeling of being alive. We experience pleasure, our thinking is sharp, we are fully engaged, we look forward to our future. In short, we feel the very opposite to feeling “depressed.”

It’s easy to see where Dr Goldberg was coming from: If we could boot up the dopamine system in the brains of those who would appear to benefit from it, with a med that was safe and non-addictive, we might actually witness a number of patients suddenly coming to life. These type of patients were more likely to be found in the bipolar population, whose depressions tend to manifest as more “anergic” (lack of energy) than those with unipolar depression.

In another words, a depression is not just a depression. The unipolar-bipolar distinction is a very crude one (the DSM doesn’t even bother to make the distinction), but at least this is a move in the right direction.

Pharma already had clinical trials up and running for treating bipolar depression when I was at the 2002 APA, including GSK with Lamictal. Eli Lilly would be out in force the next year with its Prozac-Zyprexa combo Symbyax, and later AstraZeneca would produce two eye-popping results with Seroquel. But there was something different about Dr Goldberg’s approach. In a letter published three years earlier in the American Journal of Psychiatry, he and two colleagues observed:

The greater density of [dopamine] D3 receptors in the mesolimbic areas involved in mood regulation may relate to pramipexole's efficacy in psychomotor-retarded conditions (ie, negative symptoms, Parkinson's disease, depression).

Around the same time, the novel wakefulness agent Provigil (modafinil) came on the scene, FDA-indicated for treating narcolepsy. We didn’t exactly know how the stuff worked, but psychiatry viewed it essentially as “speed with brakes.” Not exactly an amphetamine, but with some effect at booting up dopamine (and possibly also hypocretin, which plays a major role in wakefulness). Could the med be recruited to treat certain types of depression?

Unfortunately, its manufacturer, Cephalon, figured it would be far more efficient to make its case directly to doctors rather than go through the trouble and expense of clinical trials. In 2008, Cephalon pled guilty to a criminal misdemeanor for illegally marketing Provigil and two other meds for off-label uses, and paid a $425 million fine.

Meanwhile, various small studies were proving a clear disincentive for Cephalon to gamble on a major trial. The studies tended to focus on Provigil as an augmenting agent to treat depression, but with no attempt made to single out those patients most likely to respond to an energizing agent. In other words, the failures from treating those who didn’t belong in any of these studies (even if they were “depressed”) masked the successes of those who did (but who were they?).

The Aug 2007 American Journal of Psychiatry published an RDPC study that actually provided a clue. The study followed the approach of Dr Goldberg’s 2002 pilot study that tested Mirapex on a depressed bipolar population, but with Provigil as the dopamine med of choice. The study was funded by the Stanley Medical Research Institute. Cephalon’s involvement was peripheral. The company provided the meds and some supplementary funding.

Eighty-five depressed patients already on bipolar meds (including some on antidepressants) were enrolled in the trial (way less than the 250-500 patients typical of industry-sponsored trials). After six weeks, 44 percent responded (ie depression scores reduced by at least half) vs 23 percent in the placebo group. Nothing to write home about, but clearly a finding that that actually tells us something and demonstrates the potential of RDPCs.

Imagine what we would be able to learn if we were to slice and dice depressed populations in far more sophisticated ways, and run full-scale trials on these various subgroups with both established and novel agents.

Alas, virtually no progress has been made since I stumbled upon Dr Goldberg and his poster way back in 2002.


Porcelaine said...

Unfortunately meds suit the pharma companies better that the benefits trickle down till the patient is last.

John McManamy said...

Right on the money, Porcelaine. When's the last time a Pharm rep has taken YOU out to lunch or plied you with free stuff? They don't want to know us. We're nobodies to them. If they actually even pretended to take an interest in us, the might be motivated to come out with meds that don't suck. I'm still waiting.

Carolyn Anderson said...

I have always felt that dopamine was the culprit in Bipolar Disorder. However I feel sure that we can now move away from the "drugs" and their horrendous side effects to alternative methods. I would like you to take a look at A friend of mine has been able to come off Zoloft by taking these amino acids. Please let me know what you think.

John McManamy said...

Hey, Carolyn. Dopamine is one of the usual suspects in mania, and a dopamine-depression strategy would have to take that into consideration.

I'm all for any alternatives to meds. On mcmanweb I have four articles on supplements, beginning here:

The catch with supplements is the same as meds - we think of them as natural "antidepressants" to treat "depression." Thus, those wanting to go on natural alternatives are subjected to the same kind of chemistry experiment as meds. B6? B12? Chromium? Tryptophan? A supplement cocktail? Who knows?

We know these things work - but on whom (or is it who)?

We don't have any guidance - no studies for our illness equating to what lutein does to prevent macular degeneration.

I heard Julia Ross, author of The Mood Cure, talk on amino acids back in 2002 or 2003. It makes good sense, and under the guidance of a smart clinician such as Ms Ross the chemistry experiment becomes more controlled.

On my website, I advise exercising the same skepticism to supplements as meds. They all talk a very similar game. My guess is the skeptics do much better on alternative treatments than the believers. They won't just gulp down any pill handed to them. They'll do the research, ask the tough questions, figure out was is really wrong with them (such as lack of energy) and start with the type of supplement with a reputation for helping with this particular condition.

Also, as a general rule, it's a good idea to take supplements anyway just for normal "brain maintenance."

I'll check out the site you recommended.

I'm all in favor of getting off meds - or at least much lower doses - so please keep commenting, let's get people talking, and let's learn more.

John McManamy said...

Hey, Carolyn. I'm rushing out the door and may not be able to get back to you until Sunday. But a quick look at the neuroassist site: One of the supplements they work with to treat depression is levodopa. Another is tyrosine.

Bingo! L-dopa is the precursor to dopamine and tyrosine is the precursor to the precursor.

So, low energy depression - something that works on the dopamine system makes sense. Whether we're talking meds or natural, the reasoning is the same.

But no one is studying this!

It also follows if you have an agitated depression to go with something that calms you down, such as a GABA supplement or kava or a med that works on the GABA system. Whatever works for you.

Alas - again - no one is studying this.

Again, the point I keep coming back to - the burden of being smart is on us. We can't count on others to be smart for us.