February 13, 2008

What Does That Pharmaceutical Drug Actually Do? This Question Never Answered Before Drug Approval!

Though there were a lot of interesting stories in the news this week, the most interesting one seems to have been published without anyone in the media noticing it.

As reported in The Journal of Neuroscience,scientists seem to have finally discovered how Prozac really works.

For years the drug companies have been explaining that Prozac and other SSRI antidepressants work by raising serotonin levels in the brain, though this hypothesis was never well-supported by research, even though it was used very heavily in the marketing of these drugs.

Now, decades after this drug was prescribed to millions of people, researchers have learned that what Prozac really does is to stimulate the growth of new neurons in the hippocampus, the portion of the brain that, among other things, regulates how new information is stored in the brain and which, when it is damaged, produces dementia.

In some elegantly constructed rodent experiments the researchers showed that Prozac lessened the anxiety of mice given the drugs when compared to that of controls, and that it did so after the same time delay that humans experience before they respond to an SSRI drug.

Sure enough, when they looked at the brains of the mice who displayed the dramatic change in behavior, they saw that the change correlated with the growth of new neurons in their hippocampi.

Then the scientists irradiated the mouse brains in a way that prevented the growth of new neurons after taking the drug. Though their serotonin levels increased, these mice remained anxious, and on autopsy it was seen that indeed they hadn't grown those new neurons. Unless those new neurons grew in the hippocampus, the mice stayed "depressed".

What should make anyone not taking a drug that has modified how they store new information feel a lot of anxiety is the realization that it has taken almost 30 years after Prozac was approved by the FDA for anyone to investigate what it is really doing to the brain in a way that gives a valid answer. And what is even more worrisome is that the answer is one that should make any reasonable person ask, "Does anyone here have any clue what happens longterm when you continually stimulate the growth of new neurons in the part of the brain most closely associated with dementia?"

This brings home to me just how dangerous it is to take a drug year in and year out whose mechanism is not understood.

The general public has a touching but completely misguided trust that the drug approval process ensures their safety when they take a new drug. But what most people don't understand is that all the drug approval process ensures is that the new drug has some effect--however small--compared with a placebo and that it doesn't cause major organ failure or fast growing cancers during the period of up to two years that the typical drug approval trial lasts.

There's no requirement that the long term effects of the drug be monitored in any meaningful way. And there is certainly no requirement that research be done to illuminate exactly what the drug is doing to the body.

That is why it took about 12 years after the release of Avandia and Actos for scientists to get around to noticing that these drugs actually work by turning the stem cells that should turn into bone cells into baby fat cells instead, which over the long term causes serious ostoporosis leading to fractures.

This failure to investigate how drugs really work is why only now, decades after statins became the most heavily promoted drugs in history, evidence is accumulating that whatever impact these drugs have on heart disease--which turns out to be not much except in men under 56 with previous heart attacks--they appear work NOT by lowering LDL cholesterol, but by fighting inflammation.

This should make all of us think twice before taking any new drug, no matter how effective it is at doing what it is being sold (and tested) to do.

Before you add a new drug to your daily regimen, remind yourself that the explanation of how the drug achieves its effect printed in the drug's official Prescribing Information is probably nothing more than a guess. It might be decades until the actual effect that a powerful new drug has on the many interrelated systems of your body comes to light.

Scientists still don't fully understand how Metformin works, and it has been around for decades. What they are learning about the impact of TZD drugs, Avandia and Actos, on bone growth should make any thinking person give them a wide berth. The effect of inhibiting DPP-4, as Januvia and Galvus do, on anything but blood sugar levels has yet to be explored, though it is clear the enzyme in question is used all over the body, especially in the immune system. Even the long term impact of using insulin analogs which contain chains of amino acids that differ subtly from those of the insulin our body produces is a complete mystery.

As a scientist quoted in the article about the effect of Prozac on the brain says, "We still don't know, of all the effects Prozac has on young neurons, which ones are important." Another adds, "We need these leads to understand the cellular and circuit changes that occur with chronic drug administration to learn what the entire system is doing,"

Yes. We do. As we need to learn more about what every drug that millions of people are taking every day, year in and year out is doing.

Though you might want to take a drug that decreases your anxiety before you read the studies that answer those questions. . . .


Peter Atwood said...

Wow, definitely food for thought. As always, Jenny hits the nail squarely on the head.

Anonymous said...

And don't even get me started on off-label uses. I take Inderal as a migraine preventive. Nobody knows how it works to prevent migraine, as far as I can tell. On the other hand, at six migraines a month prior to Inderal, I was losing 20 percent of my life to migraine.

So I'm ambivalent. Do I submit to a disease that ruins 20% of my life upfront, or do I take a drug that may shorten my lifespan by 20% at the end? Or it may not. I don't think there's any clear answer to that question.

On the other hand, I would at least like to know that there IS a tradeoff. It makes it possible for me to make a more informed decision.

But what's even worse is the notion that the "how it works" statement on the label may be the product of someone's imagination!

Jenny said...


Your cost/benefit analysis is a good one. Intense pain is a good reason to risk long term consequences because it does ruin life now. So are severe conditions like cancer, heart failure, multiple sclerosis, Lupus etc. etc.

One huge problem is how many of these newer drugs are being prescribed for mild conditions. For every person with true depression--which is a severe incapacitating mental condition--there are hundreds who have been prescribed these drugs because they are feeling what is actually transitory sadness about things that should make a normal person sad, like a break up or difficult life situation, or even for PMS.

And even worse are the drugs with significant side effects like statins which are being given to to improve "risk factors", i.e. in the absence of any actual diagnosis.

I use the analog insulins because I have no doubt that prolonged exposure to blood sugars over 200 mg/dl is very dangerous. The alternative, a very low carb diet doesn't control my blood sugars well enough and leaves me exhausted and drained after a month.

I take very low dose estrogen knowing its risks, too, because without it I develop significant verbal memory problems that go away when I take it. I'm a writer and I would rather live a shorter life with a good verbal memory than a longer one without.

But even though Januvia gave me near normal blood sugars without insulin, I won't take it because I'm not willing to gamble on there being no more melanoma cells in my body. There is just enough data connecting melanoma with DPP-4 that I don't want to be a guinea pig in the experiment investigating that effect.

My main point here and elsewhere when I discuss drugs is not that people shouldn't take them, but that people should know that they are taking risks, many of them unknown when they take them, and should give some very serious thought to whether the benefits outweigh the possibility of nasty surprises up ahead.

Scott S said...

Very well said. To some extent, I think this is why the FDA's recent hearing and request for submissions regarding "Maximizing the Public Health Benefit of Adverse Event Collection Throughout A Product's Marketed Lifecycle" is so important. We cannot realistically get these things before approving new medicines, but we do have an obligation to continue collecting post-market surveillance. If you're interested in this, you may contact Lana Pauls, Center for Drug Evaluation and Research (HFD-006), Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857, 301-796-0518, FAX: 301-827-1069, e-mail: lana.pauls@fda.hhs.gov.

There are details disclosed in the Federal Register, but the deadline for public comments is February 28, 2008!