The Future is Bright -- For Whom?

The Future is Bright for Psychopharmocology Breakthroughs --

Okay, I'll bite.

I subscribe to an online journal Psychiatric Times.  Or at least, I have access to the articles for which there is no charge.  I don't get paid for this, you know.  Anyway, I get emails that link to the articles of the week.

So that was the subject line on the email dated 4/21/11, The Future is Bright for Psychopharmocology Breakthroughs.

This I'd like to know about.

Inside the email was a link to Novel Treatment Avenues for Bipolar Depression: Going Beyond Lithium, by Roger S. McIntyre and Danielle S. Cha.

This I'd really like to know about.

The article was not what I had been led to believe.  But I learned a lot, will share some of that with you, and explore the miscommunication at the end. 

First Paragraph: Disclosures

Dr. McIntyre disclosed financial ties of various sorts with (listed alphabetically): AstraZeneca, Biovail, Bristol-Myers Squibb, CME Outfitters, Eli Lilly, France Foundation, GlaxoSmithKline, I3 CME, Janssen-Ortho, Lundbeck, OptumHealth, Organon, Pfizer, Physicians Postgraduate Press, Schering-Plough, Shire, Solvay/Wyeth, and Wyeth.  The usual -- advisory boards, speakers bureau, faculty of pharm-sponsored continuing education and research grants.

Ms. Cha disclosed no conflicts of interest.  She is the research assistant.  Which means her job depends on the person with the conflicts of interest.  By the way, given the extent of Dr. McIntyre's extracurricular activities and the nature of the article (reporting on other people's research) I presume that Ms. Cha did the heavy-lifting here.  Props to her for her concise writing style.

I concluded that the interests of the pharmaceutical companies would be well represented in this article.  Which made the rest of the article all the more intriguing.

Second Paragraph: We're Not Doing So Good

McIntyre says that bipolar disorders are highly prevalent, misdiagnosed and underrecognized.  It takes 10-15 years to be correctly diagnosed.  People with bipolar lose 15-25 years of lifespan, largely because of associated cardiometabolic disorders. 

Okay, now I am really, really interested.  One of McIntyre's gravy trains, Eli Lilly settled a class action suit for Zyprexa and cardiometabolic disorders.  The author is shaking my preconceptions of what he might have to say.

Third Paragraph: Outcomes Of Treatments Are Disappointing

Results from efficacy as well as effectiveness studies indicate that the majority of individuals with bipolar disorder who receive guideline-concordant measurement-based care fail to achieve symptomatic, syndromal, or functional recovery.

Translation:  He is not writing about people who don't take their meds because they miss their highs.  He is writing about people who do take their meds, who are getting the right treatment and are being evaluated objectively.  Most of them don't get better, whether you look at the DSM's shopping list of symptoms, or their experience of cycling, or how they get along in the world, i.e., not well.

Now check that first paragraph again.  It's not me telling you that most of us who take our meds don't get better.  It's the guy who works for the guys who sell the meds.

Interlude: Weigh Your Costs And Benefits

So, what if you are one of these people who are not getting better?  And your meds carry a high risk of diabetes, pancreatitis, high cholesterol, heart disease, obesity, kidney damage...  And in fact, you are on the road to some serious and permanent health problems.

And -- this part is important -- you are not getting better.

Are you still taking your meds?  What, are you nuts?

I just had to get that out of my system.  Returning now to Novel Treatment Avenues for Bipolar Depression...

Why Are Most Not Getting Better?

The thing is, they don't know why we are sick.  They don't know why we are sick.

Except for lithium, every other medication for bipolar was first developed for something else and then used off-label for us.  A major limitation to genuinely novel drug discovery in bipolar disorder is the absence of a consensually agreed-on neuropathology as well as the unavailability of a sufficient animal model with appropriate face, construct, and pathological and pharmacological validity.

Translation:  They don't know why we are sick.  Plus, other animals don't get bipolar.  So they have to invent something that looks like bipolar to give to animals to conduct their experiments.  Or experiment on us.

Still Looking For The Cause Of Bipolar

Didn't they have this figured out, the chemical imbalance thing?  They are still hanging on to that general idea.  But which chemical?

And that is the rest of the article.

Maybe it's monoamines that are out of whack.  Monoamines are neurotransmitters, including dopamine, noradrenaline and adrenaline.  Too much of these could make you rush around pursuing pleasure or doing other things you don't want your mother or your boss to know about.  Not enough could collapse you under the covers sucking your thumb.  Sounds like classic bipolar to me.  This hypothesis is the starting point for current therapies.  It's just that it doesn't work for most of us.

Maybe it's glutamate.  Glutamate is the transmitter that says Go for just about anything that happens inside your brain.  Go is good.  Stuck on Go, not so much.  Stop is good on occasion.  Just depends.  Messing with glutamate with a variety of chemicals has decreased depressive symptoms in some small short-term studies.

Maybe it's cytokines, proteins that signal parts of the immune system.  There are pro-inflammatory and anti-inflammatory cytokines.  The problem in bipolar seems to be the pro-inflammatory ones.

You need pro-inflammatory cytokines on occasion, to protect damaged tissue.  However, an excess is associated with behavioral symptoms.  They also can wreck havoc with the cardio system, which may explain that average of 15-25 years life-span we lose to bipolar.  Meds that inhibit pro-inflammatory cytokines seem to decrease depressive symptoms.  Come to think of it, an anti-inflammatory diet does the same.  Ditto omega-3, the backbone of the anti-inflammatory diet.

Maybe it's insulinAnother system, the metabolic one, converting matter into energy and building cells.  You thought insulin was just about metabolizing blood sugar?  So did I.  Nope, not just.  Insulin [also] inhibits the firing of neurons in the hippocampus and hypothalamus, inhibits the reuptake of noradrenaline in rat brains, modulates catecholamine turnover in the hypothalamus, stimulates phosphorinositide turnover in the hippocampus and regulates the noradrenaline and dopamine transporter messenger RNA concentration in neurons.

Translation: Insulin has profound effects in the brain, particularly in memory processes.  We need it to do its job.  We need it to do its job well.  It is one more thing that doesn't do its job well for people with bipolar disorder.

Or maybe it's not enough antioxidants.  You mostly hear about antioxidants in relation to cancer and aging.  They rein in those nasty free radicals.  (What button-down type came up with free radicals to name the things that destroy cells?)

Those of us with bipolar need to protect every blessed little brain cell we have.  So antioxidants are our friends.  The clinical trials of one of them, N-acetylcysteine showed a benefit by reducing depressive symptoms.  Of course, you could eat more fruits, vegetables and whole grains.  But that's not psychopharmacology.  Healthy eating habits don't brighten the future of psychopharmacology.

Random Stuff

McIntyre concludes with a reminder that the pharmacological treatment of bipolar depression is part of a multicomponent chronic disease management approach.  He includes exercise, weight loss, diet, ECT and psychotherapy among those components.

McIntyre never said the future is bright.  That was the magazine's subject line.  He said simply there are a jillion clinical trials currently and yet to be conducted in this continuing effort to find the fix for the majority of us who have not yet found it. 

Swatting Mosquitoes

Did you notice that each of these novel approaches is a variation on one theme, disregulation?  There is nothing missing from the bodies and brains of those of us who have bipolar disorder.  There is no foreign invader.  It's all good.  It's just not in the right proportion, or not responding properly at the right time.

Monoamines, glutamate, cytokines, insulin and antioxidants are all part of dynamic systems, with feedback mechanisms designed to maintain a balance.  If you tinker with one part of the system, the rest adjusts around it to reassert the previous balance. 

There is no chemical imbalance to fix.  It's the balancing itself that needs to be fixed!

Back in 1990, Goodwin and Jamison published their landmark textbook, Manic-Depressive Illness, now revised and reissued in 2007.  Two decades ago they said that instability is the fundamental dysfunction in bipolar.

This is global dysfunction.  The whole ecosystem needs to be treated.  These novel approaches that address one neurotransmitter, one protein, one whatever in one system at a time are like trying to prevent malaria one mosquito at a time.

What did Psychiatric Times mean by its subject line The Future is Bright for Psychopharmocology Breakthroughs?  Near as I can figure, the future is bright for people who make a living running clinical trials.  There are indeed lots of mosquitoes in this swamp.

For those of us who will be the subjects of these experiments, not so bright.  More like the same old nightmare.

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  1. Excellent blog post. I took myself out of the psychiatric system of "treatment" for Bipolar 2 Disorder, in April of 2006, after just 22 months (during which time I became substantially worse.) Instead I became determined to apply a holistic approach and treat myself as the guinea pig, rather than allowing Big Pharma to use me as their very profitable guinea pig. I am much better now, and have developed a treatment protocol that is somewhat complicated (which I continue to tweak) that keeps me fairly well balanced. I am not cured. But the highs are now milder, and the lows are also milder (although more frequent), and I have developed strategies to handle both when they occur. I feel like I dodged a bullet by getting out of the psychiatric system when I did. I am now past 50 years old, and my physical health is still excellent, which wasn't the case during the short 22 months I spent on psychotropic medications. Thanks for maintaining this interesting and thoughtful blog.

  2. Maybe they're looking at the wrong place. Maybe it's not biochemical in origin at all. Maybe it's about time they start looking outside their neat little box.

  3. What we call "mental" illness has manifestations throughout the whole system, energy fields, thought processes, circadian rhythms, genetics. And yes, biochemical processes. I have a stack of books to work through, but will post something about the INTRAcellular level sometime this year.

    Remember who "they" are. As my therapist said, If you go into a screwdriver store, you can expect they will try to sell you a screwdriver.

    That said, the evidence is clear that there are biochemical things going on in mental illness. SOMEbody ought to be studying that aspect of the beast.

    Point of origin? The evidence is accumulating that dysfunction has to develop in several of these different systems and their interactions with each other before the person succumbs. Solutions? Because we are a system, you can start anywhere. But no one part of the system can carry the whole weight.

    I am excited about Ellen Frank's work, because she begins the process of developing a unified theory and a unified treatment. Not complete, but a good start.

    The nature of research is that the boxes get smaller and smaller and smaller. What we really need here are some generalists, some big picture people who will open up the boxes and give us a new paradigm.


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