The Problem With Bipolar Meds

As you are aware, I am in the midst of a massive website overhaul. The last week has involved scrapping most of the articles in the Treatment section of mcmanweb and writing new ones (some of them based on recent blog posts here at Knowledge is Necessity). Thus far, I have 11 new articles, with more to follow, that I look forward to uploading two or three says from now. Following is a sneak peak at one of them, slightly chopped ...

The best data we have is from the NIMH-underwritten STEP-BD trials conducted over the mid-2000s. The study followed "real world" patients over two years, on a variety of meds. Of those who entered the study in a symptomatic state, 58 percent achieved recovery (nearly symptom-free for eight weeks). Of these, nearly half (48 percent) relapsed over two years, mostly into depression.

The math says it all: 1,469 symptomatic patients at study entry, a mere 422 (one in three) who managed to get well and stay well over two years. In classic understatement, the authors of STEP-BD concluded that:

The finding that nearly half of the study participants nonetheless suffered at least one recurrence during follow-up highlights the need for development of new interventions in bipolar disorder.

Cycling vs Episodic

The term, mood stabilizer, suggests that we are not merely treating episodes of an illness. Rather, we are looking to treat the cycle that drives these episodes. Accordingly, it is more helpful to think of bipolar (and recurrent depression) as a cycling illness rather than an episodic one.

Treating an episode for a patient who cycles is highly problematic - just ask any bipolar patient who has ever been prescribed an antidepressant to treat her depression. Too often, the patient flips into mania. Another result is the cycle may be speeded up, ironically resulting in more depression episodes.

An antimanic agent may not yield such a spectacular mirror effect, but the same principle is in play. As I heard it explained at an International Society of Bipolar Disorder conference I attended in 2006 (sorry, the name of the presenter escapes me), clinicians who treat a manic episode need to be aware of the next phase of the cycle, as well. In other words, being saddled with the sedating effects of an antimanic agent on top of a debilitating depression is the equivalent of pushing two rocks uphill.

So - in a perfect world, we would have a perfect mood stabilizer, one that brought the cycle under control and thus obviated the need for any other agents. Alas, our mood stabilizers (lithium, plus a range of antiepileptic agents pressed into service as bipolar meds) fall well short of even pretty good. This forces clinicians into an episode mindset, of devising pharmaceutical blockades to box in mania on one pole and coming up with entirely different blockades to keep depression at bay on the other.

In effect, our doctors are stepping on the bulges of an air mattress rather than regulating the flow beneath. Meanwhile, side effects pile up on top of side effects.

More to come ...

Rerun - Meds Compliance: The Problem Clinician

This from April ...

Yesterday, I raised the topic of physicians turning a deaf ear to our complaints about meds side effects. The obvious conclusion to draw is that patients will simply stop taking their meds. You don’t need a medical degree to understand that. In fact, it helps if you don’t have one.

Two and a half years ago, a psychiatrist who practices in Princeton, NJ (I used to live just outside Princeton) invited me to deliver a grand rounds to a psychiatric facility there. I was very hesitant. I’m a journalist, I explained. It’s not my place to tell others how to do their jobs.

But I had been doing my own research into meds compliance. Perhaps it would be okay, I suggested, if I were to report on my research from the perspective of a patient. The psychiatrist loved the idea, and we booked a date.

How controversial can meds compliance be, right? I mean, no one is against meds compliance. So I went back over my old research, then did some more, and started connecting the dots. Suddenly, I realized I was in big trouble. Psychiatrists came out looking worse than the patients. A lot worse.

There’s no way I can sugar-coat this, I confided to my friends. They’re going to run me out of town on a rail.

The first part of my talk - “The Problem Patient” - went over reasonably well. But I started sinking fast when I got into “Problem Meds.” Then “The Problem Clinician” went up on my PowerPoint.

Frozen silence. We’re not talking ordinary frozen silence, as in “stony cold” frozen silence. We’re talking zero degrees Kelvin silence, as in utter cessation of all molecular motion frozen silence.

What’s totally weird is they should have been rolling in the aisles. My PowerPoint slide featured a photo of Hugh Laurie from the TV series “House” snapping on a latex glove. “House” is set in Princeton. Surely, my audience would at least chuckle in knowing appreciation.

Silence. Zero degrees Kelvin silence. 

Up went a slide of Heidi Klum. “Have you ever noticed how many drug reps look like Heidi Klum?” I asked. Or Russell Crowe?

To paraphrase George Bush, I “misunderestimated” my audience.

Let’s take a look at some of the hard cold facts from my PowerPoint:

• According to a 2002 study by Scott and Pope, 50% of  bipolar patients on mood stabilizers acknowledged some degree of medication nonadherence in the previous 2 years.
• According to a 2007 Swedish study, 25 percent stopped taking their lithium in 45 days. The median time to discontinuation of lithium was 181 days.
• In one of the NIMH-underwritten CATIE schizophrenia trials, no one completed the study.
• In a 2006 long-term Zyprexa trial, nearly 80 percent of the patients on the drug dropped out.
• A 2005 Medscape article reported that only 28% complied with their SSRIs at 6 months.

I asked the clinicians in the audience if these non-compliance rates were higher than they thought, and managed to coax out some reluctantly nodding responses.

Sending patients out the door with just a prescription is not treatment, I reminded them. (They positively hated hearing that.)

Obviously, I went on to say, a clear psychiatric disconnect exists. According to another study by Scott and Pope, clinicians felt their patients quit lithium owing to "missing highs." Patients who quit, on the other hand, cited other reasons.

At the 2006 national NAMI convention, Stephen Goldfinger MD of SUNY told his audience: “Patients will be adherent if the meds do their real job.”

I did my initial research into meds noncompliance about eight years ago when I came across a Kirsch meta-analysis (summarized in a recent piece) that revealed, amongst other things, that only 63 percent of the patients in antidepressant drug trials completed the four to six weeks these trials ran.

Curious, I began checking if these drop-out rates applied across the rest of medicine, such as cancer. So I picked a cancer med at random, Nolvadex (tamoxifen) and read that AstraZeneca had stopped a 1997 study due to 26 percent of patients quitting after one year.

Hmm, I thought. A 74 percent completion rate over one year, significantly higher than the antidepressant completion rate over a mere six weeks. Yet, this was totally unacceptable in the field of cancer. I remember reporting in a Newsletter at the time that a drug company would be touting the exact same completion rate for an antidepressant as a stunning success. Indeed, two weeks later, Lundbeck proved me right by publishing a one-year Lexapro trial that highlighted a mere 26 percent of patients dropping out of the study.

I didn’t bring this up this in my talk. What I did note was that the 26 percent Nolvadex drop-out rate almost exactly corresponded to the 21 percent Zyprexa completion rate.

Psychiatry and oncology clearly have different standards. So, are oncologists telling their patients something different? My guess is they are. I acknowledged to my audience I was speculating, but I managed to get them to sign off on this PowerPoint:

What oncologists may be telling their patients:

It's going to be hell, but there is an excellent chance your cancer will go away.

Then I showed them this PowerPoint:

What I know too many psychiatrists tell their patients:

What are you complaining about? These meds work. Something must be wrong with you. You're much better off than you were before. You need to stay on these drugs the rest of your life.

What I’m guessing the cancer patient may be thinking is this: One year of hell - if that's what it takes to get my old life back, I'm willing to put up with that.

What I know the psychiatric patient is thinking is this: This is the best you can do? You mean I'm going to have to spend the rest of my life - like this?

As Ross Baldessarini MD of Harvard told a 2006 American Psychiatric Association annual meeting: "We need to be a lot more sensitive to minor complaints."  Otherwise, "we will drive patients out of treatment."

So maybe psychiatrists need to be working off a bad news/good news script. First the bad news:

Your meds are only part of the equation. You are unique. It may take time to find the right meds and doses that work right for you. Until we dial in your meds just right, you may have to put up with significant side effects. You may also not feel like yourself. You may feel you want to quit altogether.

Now the good news:

We are going to work together on your recovery. As your knowledge and skills improve, I will be in a better position to help you. You will also be in a better position to help yourself. Trust me, there is light at the end of this tunnel.

I wrapped up my talk a few minutes later. The audience, composed entirely of clinicians, showed their appreciation by stampeding for the exits the second my lips stopped moving.

Rerun: Treating Marilyn

My most recent blog piece touched on a section of a grand rounds I delivered on meds compliance two years ago at a psychiatric facility in Princeton. That section, "The Problem Clinician," received a decidedly frosty reception from my audience of clinicians. This section, from "The Problem Patient," went over a lot better.

This piece first appeared on my blog in Feb, 2009.

The following is based on the first part of a talk I gave to clinicians on meds compliance as part of a grand rounds at a psychiatric facility in Princeton:

'Marilyn walks into your office," I began. "She reveals her moods have been all over the place. Everything points to bipolar. Okay. How do you treat her?"

Believe it or not, no one raised their hands. I was the one who had to suggest that a mood stabilizer might be a good idea, then I had to make sure we had a consensus. Then I went to the catch, namely how does the most important person in the equation - the patient - feel? After all, even the best med in the world is useless if patients won't take it.

Maybe we need to ask Marilyn a few more questions, I suggested. Consider:

Marilyn is literally larger than life. Over the top is her baseline. It's a legitimate part of her personality. How long do you think she is going to stay on her mood stabilizer if she thinks her personality is getting medicated out of her?

Hypomania is the first thing to come to mind when thinking of Marilyn, but the operative word from the DSM regarding this type of behavior is "uncharacteristic."

"For someone else to act like Marilyn," I said, "that may be hypomanic. For Marilyn to act like Marilyn - that's normal."

In support, I cited Ronald Fieve MD of Columbia University, who coined the term, "the hypomanic advantage."

"Keep in mind," I said, "a lot of us view the world through the eyes of artists and poets and visionaries and mystics. Not to mention through the eyes of highly successful professionals and entrepreneurs. We don't want to be like you."

How can I describe the look of surprise from my audience? Like I had let rip a roof-rattler and they were too polite to laugh - I think that best sums it up. I should have thrown away my prepared talk at that stage. Seriously, I should have said. We don't want to be like you. Why should that surprise you?

Instead I plowed ahead:

"We don't want to fly too close to the sun," I continued. "But don't clip our wings. Obviously Marilyn needs to be reeled in a bit. But how do we proceed? What do we have to go on?"

Believe it or not, there are zero published studies for treating hypomania. Zip, zilch, nada. The only solid evidence base involves the acute phase of full-blown mania, when we're bouncing off walls, 911 cases.

"So," I asked, "are you thinking of giving someone with hypomania an industrial strength dose?"

What else is going on with Marilyn? Personality issues? Quirky behavior? Does the bipolar itself affect her capacity to think rationally?

"You're the rational ones," I said. "We know where you are coming from. But do you know where your patients are coming from?"

I clicked to two slides: Fear/feeling threatened, problems accepting authority, cognitive distortions ...

The list went on and on. "Looking like a lot of your patients?" I asked.

"Here's the point I'm making," I continued. "Not only are you treating the illness. You are treating any behaviors and attitudes that come in the way of treatment. And you're not going to find that out unless you talk to the patient - and listen."

I wasn't through: "Just sending a patient out the door with a prescription - in my opinion - is not treatment."

Back to Marilyn. She's Marilyn. She has enormous gifts and doesn't want her wings clipped. She has various personality issues. And her illness is affecting her judgment.

"We have the advantage of knowing the tragic outcome," I concluded. "Knowing what you know, are you happy just writing her a prescription and sending her out the door?"

Postscript: This first part of my talk - "The Problem Patient" - went fairly well, perhaps because the audience could spin my message in a way that assigned all blame to the patient. There was no way they could do that with the next two sections, "Problem Meds" and "The Problem Clinician," and I got a very different reaction.

More later ...

Meds Compliance: The Problem Clinician

Yesterday, I raised the topic of physicians turning a deaf ear to our complaints about meds side effects. The obvious conclusion to draw is that patients will simply stop taking their meds. You don’t need a medical degree to understand that. In fact, it helps if you don’t have one.

Two and a half years ago, a psychiatrist who practices in Princeton, NJ (I used to live just outside Princeton) invited me to deliver a grand rounds to a psychiatric facility there. I was very hesitant. I’m a journalist, I explained. It’s not my place to tell others how to do their jobs.

But I had been doing my own research into meds compliance. Perhaps it would be okay, I suggested, if I were to report on my research from the perspective of a patient. The psychiatrist loved the idea, and we booked a date.

How controversial can meds compliance be, right? I mean, no one is against meds compliance. So I went back over my old research, then did some more, and started connecting the dots. Suddenly, I realized I was in big trouble. Psychiatrists came out looking worse than the patients. A lot worse.

There’s no way I can sugar-coat this, I confided to my friends. They’re going to run me out of town on a rail.

The first part of my talk - “The Problem Patient” - went over reasonably well. But I started sinking fast when I got into “Problem Meds.” Then “The Problem Clinician” went up on my PowerPoint.

Frozen silence. We’re not talking ordinary frozen silence, as in “stony cold” frozen silence. We’re talking zero degrees Kelvin silence, as in utter cessation of all molecular motion frozen silence.

What’s totally weird is they should have been rolling in the aisles. My PowerPoint slide featured a photo of Hugh Laurie from the TV series “House” snapping on a latex glove. “House” is set in Princeton. Surely, my audience would at least chuckle in knowing appreciation.

Silence. Zero degrees Kelvin silence. 

Up went a slide of Heidi Klum. “Have you ever noticed how many drug reps look like Heidi Klum?” I asked. Or Russell Crowe?

To paraphrase George Bush, I “misunderestimated” my audience.

Let’s take a look at some of the hard cold facts from my PowerPoint:

• According to a 2002 study by Scott and Pope, 50% of  bipolar patients on mood stabilizers acknowledged some degree of medication nonadherence in the previous 2 years.
• According to a 2007 Swedish study, 25 percent stopped taking their lithium in 45 days. The median time to discontinuation of lithium was 181 days.
• In one of the NIMH-underwritten CATIE schizophrenia trials, no one completed the study.
• In a 2006 long-term Zyprexa trial, nearly 80 percent of the patients on the drug dropped out.
• A 2005 Medscape article reported that only 28% complied with their SSRIs at 6 months.

I asked the clinicians in the audience if these non-compliance rates were higher than they thought, and managed to coax out some reluctantly nodding responses.

Sending patients out the door with just a prescription is not treatment, I reminded them. (They positively hated hearing that.)

Obviously, I went on to say, a clear psychiatric disconnect exists. According to another study by Scott and Pope, clinicians felt their patients quit lithium owing to "missing highs." Patients who quit, on the other hand, cited other reasons.

At the 2006 national NAMI convention, Stephen Goldfinger MD of SUNY told his audience: “Patients will be adherent if the meds do their real job.”

I did my initial research into meds noncompliance about eight years ago when I came across a Kirsch meta-analysis (summarized in a recent piece) that revealed, amongst other things, that only 63 percent of the patients in antidepressant drug trials completed the four to six weeks these trials ran.

Curious, I began checking if these drop-out rates applied across the rest of medicine, such as cancer. So I picked a cancer med at random, Nolvadex (tamoxifen) and read that AstraZeneca had stopped a 1997 study due to 26 percent of patients quitting after one year.

Hmm, I thought. A 74 percent completion rate over one year, significantly higher than the antidepressant completion rate over a mere six weeks. Yet, this was totally unacceptable in the field of cancer. I remember reporting in a Newsletter at the time that a drug company would be touting the exact same completion rate for an antidepressant as a stunning success. Indeed, two weeks later, Lundbeck proved me right by publishing a one-year Lexapro trial that highlighted a mere 26 percent of patients dropping out of the study.

I didn’t bring this up this in my talk. What I did note was that the 26 percent Nolvadex drop-out rate almost exactly corresponded to the 21 percent Zyprexa completion rate.

Psychiatry and oncology clearly have different standards. So, are oncologists telling their patients something different? My guess is they are. I acknowledged to my audience I was speculating, but I managed to get them to sign off on this PowerPoint:

What oncologists may be telling their patients:

It's going to be hell, but there is an excellent chance your cancer will go away.

Then I showed them this PowerPoint:

What I know too many psychiatrists tell their patients:

What are you complaining about? These meds work. Something must be wrong with you. You're much better off than you were before. You need to stay on these drugs the rest of your life.

What I’m guessing the cancer patient may be thinking is this: One year of hell - if that's what it takes to get my old life back, I'm willing to put up with that.

What I know the psychiatric patient is thinking is this: This is the best you can do? You mean I'm going to have to spend the rest of my life - like this?

As Ross Baldessarini MD of Harvard told a 2006 American Psychiatric Association annual meeting: "We need to be a lot more sensitive to minor complaints."  Otherwise, "we will drive patients out of treatment."

So maybe psychiatrists need to be working off a bad news/good news script. First the bad news:

Your meds are only part of the equation. You are unique. It may take time to find the right meds and doses that work right for you. Until we dial in your meds just right, you may have to put up with significant side effects. You may also not feel like yourself. You may feel you want to quit altogether.

Now the good news:

We are going to work together on your recovery. As your knowledge and skills improve, I will be in a better position to help you. You will also be in a better position to help yourself. Trust me, there is light at the end of this tunnel.

I wrapped up my talk a few minutes later. The audience, composed entirely of clinicians, showed their appreciation by stampeding for the exits the second my lips stopped moving.

A Smart Drug Company? Holy Crap!

This week's Business Week cover story features Novartis, apparently the one drug company not as dumb as Detroit. The good news is that smart management there may provide a new model for badly needed new drug development. The bad news is that none of these drugs are likely to be psychiatric meds.

Novartis is the one drug company headed by a medical doctor, Don Vasella (pictured here). The others are dominated by lawyers and accountants and marketers who fail to appreciate science and who have forgotten who their true customers are. According to Business Week:

"Most big drugmakers shower their research and development funds on diseases such as cancer or depression, where huge potential markets beckon despite a deficit of scientific understanding. In recent years this approach has led to high rates of failure when drugs are tested in clinical trials."

In contrast, seven years ago, Novartis embarked on a policy of pushing drugs through testing and development only if they were backed by proven science. It didn't matter that the particular diseases the drugs treated were rare. In the words of Dr Vasella: "If you are guided purely by financial estimates and not the science, you end up wasting time and money."

Novartis' Gleevec was initially approved for a rare blood cancer that strikes just a few thousand people a year, but has since proved effective against six other diseases. Last year, the drug pulled in $3.7 billion in sales.

The idea is that although there are 24,000 genes in the human genome, there are only a few dozen pathways that are shared by virtually all diseases. The trick is to track down all the links in a pathway, then locate the key signals that switch genes on and off.

In the development phase at Novartis is a drug to treat a rare inflammatory disorder called Muckle-Wells syndrome, involving a single gene variation that may be implicated in other illnesses. Thus, the rare diseases may shed light on a host of other illnesses and hold the key to future drug discovery.

Here's where the drug industry's blockbuster/me-too mentality has left us, according to Business Week:

Experts say drug companies have exhausted the easy targets. With patents on many older blockbusters starting to expire, the industry is poised to lose an estimated $140 billion in sales to generic competition over the next five years. Those revenue sources must be replaced.

Despite multibillion-dollar research budgets, none of the top companies has a wealth of promising compounds in its development pipeline. The industry also faces regulators more vigilant than ever about safety, and health insurers starting to balk at covering costly drugs that bring only modest benefits.

Dr Vasella shook things up when he moved Novartis' main global research operation from Basel, Switzerland to Cambridge, MA, and got a Harvard cardiologist to run it, with a brief to turn things upside down. Under the new order, scientists stared calling the shots rather than executives in sales and marketing.

The men and women in suits fought back hard, but ultimately more than a thousand sales and marketing execs were purged and medically trained scientists brought on board.

Here's the catch: Our current scientific understanding of mental illness would not meet Novartis' rigorous standards for green-lighting new drug development. According to its 2008 Annual Report: "Diseases affecting the brain and central nervous system pose exceptional hurdles in drug discovery."

All our current psychiatric meds are the result of serendipitous discovery, based on old technologies. They get some of the people somewhat better some of the time, and we have no idea why. The drug industry made vast sums of money essentially putting old pills in new bottles. That era is just about over.

The new era would involve finding the precise illness pathways that cause specific mental illness symptoms and figuring out which gene variations are involved. Forget about a treatment for all of depression. Rather, it might be more productive to uncover the underlying mechanisms to, say, lack of motivation. Maybe only a small percentage of depressions involve lack of motivation. But maybe such a drug would get a lot of these people a lot better a lot of the time.

Maybe, also, this motivation drug would help with other diseases and conditions that involve lack of motivation, such as various neurological ills. Maybe also various fatigue ills, and maybe even the flat affect symptoms of schizophrenia.

And maybe the best way of testing the drug would be to first try it on some really rare disease that only two people in the world know anything about, and then branch out.

Would your typical drug company be interested? No way.

Might Novartis be interested? You bet, assuming the science is sound. A ray of hope ...

Related Blog Pieces

It's Official: Pharma is Dead to Us

Pharma and Biotech: No Practical Solution Yet

New Poll Results: Meds in Our Treatment - How Does "Smart" Factor In?

"How well have your meds worked for you?" I asked you in a poll I ran here through the month of May. Of the 168 who responded, only 14 percent of you answered, "very well." In other words, only a small percentage of you thought your meds worked like gang-busters. The overwhelming rest of you had reservations.

Thirty-six percent of you - about one-third - responded, "conditionally well." In other words, your meds may not be perfect but they were meeting your expectations. When you add in the "very well" group, fully half you reported satisfactory results with your meds.

So, can we put a positive spin on the results? Hold that thought.

One in five of you (19 percent) told me that your meds were "rather problematic." In other words, you're not happy with your meds, but you are experiencing some benefit.

Nearly one in five (17 percent) responded that your meds were "very problematic" and 11 percent told me your meds were "a complete disaster." Added together, nearly one-third of you have given an unambiguous thumbs down to your meds.

So, how do we interpret the results? Keep in mind this is hardly a scientific survey. Let's go negative, first:

The fact that more than eight in ten of you reported that your meds are not working "very well" - for whatever reasons - speaks volumes. Add to that the fact that the "complete disaster" group is running in a virtual dead heat with the "very well" group and we are talking very low levels of customer satisfaction.

In other words, if meds were automobiles, car makers like General Motors would be in bankruptcy. Wait, let me rephrase that. Uh, never mind ...

Now let's go positive. This means first seeing possibilities in the "rather problematic" grouping. Suppose, for instance, half of you in this group were to graduate to "conditionally well." Then 60 percent of you - nearly two thirds - would at least be reasonably satisfied with your meds. Suppose we could get similar conversion rates from the "very problematic" and "complete disaster" groups. Then three-quarters of you would be happy customers.

How is that possible?

The meds are constant in this equation. The two variables are you and your psychiatrist. First imagine a smart patient working with a smart psychiatrist. Now picture a naive patient placing his or her trust in a lazy psychiatrist. Are we likely to see dramatically different outcomes? I rest my case.

Okay, one example: You come to your psychiatrist depressed. He diagnoses you with clinical depression. The antidepressant doesn't work. In fact, it makes you feel worse. The psychiatrist tries you on another antidepressant, then another. You are starting to feel like you are crawling out of your skin.

Then your psychiatrist gets a bright idea - or rather a thought implanted in him by a drug rep the day before. Based on his conversation with someone way too dumb to get into med school in the first place but attractive enough to take up a career in modeling (whether male or female), he now decides that the answer to your problem is an atypical antipsychotic to kickstart the antidepressant.

A smart psychiatrist will know exactly the right situation to make this call, but in your case would probably never have to make it. Instead, after not getting a good result with your second antidepressant, she - the smart psychiatrist, that is - would probably revisit the diagnosis. It could turn out - on further enquiry - that you have bipolar or something in the bipolar spectrum. So she takes you off the antidepressant and puts you on a mood stabilizer.

If the mood stabilizer works, your "complete disaster" scenario has been turned around. Maybe not all the way. In all likelihood, in fact, you still have a long way to go. But now, at least, you are in a position to learn more, to move up to from being a naive patient to a smart one.

What a difference "smart" makes in the equation.

Pharma and Biotech: No Practical Solution Yet

I concluded my last blog piece on this downbeat note:

So, where are the new meds going to come from? Don't bank on Pharma. They got out of drug development - assuming they were ever in it - at least a decade ago. Hopefully, new players looking to make profits based on innovation will fill the vacuum.

In the meantime, it's as if Pharma doesn't exist. Those meds you are taking right now? Probably generic from generic suppliers. Get used to them - these will be your only choices for quite some time.

An article by NY Times business journalist Lawrence Fisher appearing in the quarterly publication, The Milken Institute Review, provides the lowdown:

In theory, "biotech" is where the innovation is supposed to be coming from. As opposed to Pharma, which is rooted in ancient chemistry, biotech is all about sexy proteins and genes and stuff. These are your go-go companies founded by brainy people using smart-money venture capital. Think Genentech, Amgen, Gilead.

One catch: Take these three companies out of the mix "and the cumulative return on investment over the life of the sector was negative even before the financial markets' collapse."

In hindsight, it's easy to see why. It takes ten years to bring a new drug to market, but the way the game is set up investors need to see returns in five years. We're talking on average a billion-dollar stake in a high-risk crap shoot where nine out of ten compounds in development fail.

Not surprisingly, innovation-rich and cash-strapped biotech turned to innovation-poor and cash-rich Pharma. Unfortunately, the marriage didn't quite work out as planned. As Lawrence Fisher explains:

"Pharma ideally seeks companies with products on the market close to receiving approval. But most biotechs are risk years away from that goal, and those that are closest often come with substantial infrastructure and big employee bases that the majors neither need nor want."

Then, there's the matter of niche vs one-size-fits-all drugs. It's a question I have been asking virtually the entire ten years I have been writing on mental health, and I have yet to receive a satisfactory answer.

We know, for instance, that antidepressants work really well for about one-third of those who take them. But what about the other two-thirds? We need more flavors aimed at different palates. But Pharma is not set up for that. Plain vanilla spells blockbuster, their license to print money.

Biotech is all about the sophisticated niche meds we badly need. But who wants to roll the dice on a high-risk, low return product? Thus, when biotech meets Pharma worlds collide.

The two somehow need to figure out how to work together, most likely with government partnership. Foundation money and NIH grants are keeping the biotechs on a Ramen noodle diet for the time being, but this isn't going to last forever. Meanwhile, Pharma has run out of products, together with its license to print money.

And here we are, stuck with meds based on technologies that were considered new when Eisenhower was President.