Is Bereavement Part of Depression? And What the Hell is Depression, Anyway?

Willa Goodfellow’s latest Prozac Monologues piece raises the very important discussion about how bereavement fits (or not) into depression. Ronald Pies, one of the two principal figures behind the proposed DSM-5 “bereavement exclusion” to the depression diagnosis, has left a comment.

The discussion is framed in such a way that the nominal topic - bereavement - unlocks the key to the real issue, namely can any two people actually agree on what depression is all about? What about depression-like behavior?

Some background: The DSM-IV expressly rules out the depression diagnosis if the symptoms are attributable to bereavement for a period of two months or less. The DSM-5, due out in 2013, would drop this exclusion. This has created the mistaken notion that the DSM-5 is proposing to turn bereavement into a psychiatric illness. Allen Frances, who oversaw the DSM-IV, recently told the NY Times that “the revisions will medicalize normality.”

Let’s turn to what the DSM-5 is actually proposing. In the updated depression diagnosis, the symptom checklist would stay the same. In the fine print below, this gets the axe:

“The symptoms are not better accounted for by Bereavement ...”

Willa’s post sees this as the last piece in restoring the complete depression diagnosis. She points out that the DSMs I and II attempted to separate out depressions they saw as situational (exogenous) from those they saw as biological (endogenous). The DSM-III abolished this distinction, essentially viewing depression as a depression, but left in bereavement as an exception. The DSM-IV continued with this.

Willa asks us to view depression as something that happens when life throws too much at us, a point of view backed by some very impressive brain science. Some of us may be genetically resilient, but others (namely, us) prove highly vulnerable, owing to a hyperactive stress response. Says Willa:

What difference does it make whether the one damn thing too many is loss of a job or loss of a loved one?  It's still one damn thing too many.  And doctors need to take time to figure out what is going on with the person sitting in the office on her last nerve, not say, “There, there. You'll feel better in a couple months.”

As Dr Pies’ says in his comment:

[If] it looks like a duck, walks like a duck, and quacks like a duck, it's likely to be a duck, until proved otherwise. That is: if a patient shows up in the doctor's office meeting the full symptom and duration criteria for Major Depressive Disorder(MDD); but happens to have lost a loved one within the past two months, we should not withhold the diagnosis of MDD, simply because it occurs in the context of bereavement.

Are we clear on this? Good. Now let’s muddy it up. In an article on my website, Placing Depression in Context, I too observe the old clinical vs situational distinction, with reference to the DSMs I and II, and like Willa I view the distinction as naive and unscientific. But, nevertheless, I also see merit in bringing back some of the old reasoning. As I put it:

The endogenous-exogenous distinction does encourage us to examine where our depression might be coming from. If your marriage is falling apart, for instance, or your situation at work is going badly, it is obviously worth exploring this association. Sort of like investigating whether a person with a pulmonary disorder is working in an asbestos mine. For some crazy reason, the "modern" DSM-III of 1980 and its successors didn't think this was important.

I also looked at normal vs abnormal. In other words, are some of our depressions a normal reaction to an abnormal situation? Aren’t we supposed to feel depressed when we have lost a loved one? Moreover, if life is getting to be too much for us, our depressions may be telling us that we may need to make an immediate course correction. From my article:

This is straight out of evolutionary psychology. Depression has been called the end of denial. The rose-colored glasses come off. Reality takes over. Maybe instead of banging your head against the same wall - again and again and again - you need to cut loose destructive friends, bail out of a bad relationship, rethink that toxic work environment.

Listen to your depression. It may be an unwelcome guest in your brain, but it is definitely telling you something.

But my article also describes a situational depression I found myself in back in 2004, one that very easily could have led to a clinical depression. I simply did not have the luxury of leaving things to chance, not with my vulnerable brain. I immediately changed my routines and found a new project to work on.

In other words, I was feeling depressed. I needed to act right now.

This is precisely Willa’s point. Prior to reading her piece, I was on the side of not changing the bereavement exclusion. Now I’m teetering the other way. But this is because Willa’s piece challenged me to rethink depression, not bereavement. Depression is never what we think we think it is. Something to think about ....

Willa Goodfellow's Prozac Monologues: Still Going Strong

I’ve been telling people for years that my beat covers everything from God to neurons. A month or two ago, I incorporated “From God to Neurons” into the subtitle of Knowledge is Necessity. In mid-2009, I had the pleasure of discovering online the other person on the planet blogging from God to neurons, Willa Goodfellow (pictured here).

Willa was only a few months into her vastly wise and funny and totally unique Prozac Monologues. My hypomanic delight over my find was muted by my ever-faithful depressive realism. As I put it in a review at the time:

"Promising bloggers have an unfortunate tendency to burn out, so I urge all of you to drop a comment on her blog site offering encouragement. To Willa: It's very easy for bloggers to get discouraged, particularly when dealing with depression. But clearly we need you. Stick with it."

Willa stuck with it, and we established a great online friendship. Last summer, I had the pleasure of meeting her face-to-face at the NAMI national convention in Chicago. Think of below as a Willa sampler from the past several months. Enjoy, then check her out for real ...

Yes, we ARE getting sicker.  We live in times that make us sick.  We struggle to pay bills while our bosses speed up the assembly line.  Those of us who don't get laid off can't quit, because we can't afford health insurance.  Our support systems, extended family, neighborhoods, religious communities, social organizations - the buffers of stress - have been ripped away, replaced by reality TV and Facebook hysteria.

***

Keep skunks and bankers at a distance.

Live a good and honorable life.  Then when you get older and think back, you'll enjoy it a second time.

Timing has a lot to do with the outcome of a rain dance.

If you get to thinking you're a person of some influence, try ordering somebody else's dog around.

***

... This is why, if your antidepressant works for you, you are just plain lucky.  It happens to treat the problem in your particular brain.  Most of the time, it treats somebody else's problem.

***

While God was blessing Tim Tebow's hard work on Sunday afternoon, 720 children around the world died of hunger.  270 people committed suicide.  Two of them, by the way, were veterans of the United States Armed Forces.

That was before overtime.  Good thing overtime was short, huh?

So on Monday morning, nearly 1000 mothers were asking, If God could help Tim complete that pass, couldn't he have paid some attention to my child?  Billions still listen for their answer.

***

For the Israelites, the Babylonian Exile resulted in an explosion of creativity, poetry, philosophy, history, new forms of worship, the legal code, and the development of a religion that was larger than their prior notions of land=success=God's favor.  They came up with a religion that could handle exile, handle loss.  It could travel and face the future.

Their brains found new patterns. ...

***

I'm into changing my brain.  In that mass of electrical wiring, some potentially healthy pathways are blocked by the detritus of dead dendrites.  Other destructive pathways are carved into canyons of well-worn automatic responses.

Changing my brain will take time.  It is taking decades.  It will take at least another blogpost.

***

From the Damned-If-You-Do-And-Damned-If-You-Don't Department, the medications for schizophrenia and bipolar mostly reduce the positive symptoms (delusions in the case of schizophrenia, high energy in bipolar - the symptoms that scare your families and your care providers who write the prescriptions).  They tend to increase the negative symptoms (thereby relieving the anxieties of your families and your care providers who write the prescriptions), providing that synergistic effect that nails you to the sofa.

***

Evidently inspired by Fox News, Merry Christmas is no longer an expression of joy and good cheer, but a battle cry against the First Amendment and the great American experiment of freedom and tolerance of difference.

***

Inevitably, certain symptoms get more attention than others.  Psychiatrists are not concerned when patients sleep too much, do an astounding amount of work in three days or die twenty-five years before our natural lifespan due to complications of obesity, as long as we don't have hallucinations or delusions or try to end our misery by self-harm.

It's all about the descriptors, and how nervous they make people. ...

It's like, the DSM tells you what color the car is and how many cup holders it has.  Big Pharma has made a lot of money tinkering with the placement of the cup holders.  Meanwhile, what patients want to know and what scientists actually are working on nowadays is, what's under the hood?

***

Mahatma Gandhi was not the first freedom fighter.  But he is the great theoretician.  He gave us the map.

First they ignore you.
Then they laugh at you.
Then they fight you.
Then you win.

Four simple steps.  The good news -- we have already taken the first.  Got that one down pat.

Go to Prozac Monologues ...

Revisiting the Normal vs Crazy Thing

Last night, I had a nightmare that I danced like a white man. This was way worse than my recurring dream where I’m married to Sarah Palin. Naturally, it was a huge relief to wake up and - oh crap! - well, at least I’m bipolar.

Most of you know what I’m talking about. We have a different way of perceiving reality, which of course affects our behavior. Too often, the result is outsider status. No one wants that. On the other hand, I bet no one ever told you this: “You’ll really love So-and-So! He’s so normal!”

Funny thing about our doctors. They may inform us that they will have us back to normal in no time, but they never actually say, “We’ll have you normal again.”

“Normal” is a reference to the status quo, how things are going “out there.” This is the world we need to learn to function in. But we don’t necessarily have to be “normal” to function in “normal.” This is hardly a condition we would aspire to. I always sort of knew this, but the light bulb went off last year when I read Nassir Ghaemi’s 2011 “A First-Rate Madness.” Dr Ghaemi pointed out that normal merely represents a statistical average and hardly an ideal.

How about crazy, then? I love that 1997 Apple ad. “Here’s to the crazy ones,” it starts out. "The misfits. The rebels. The troublemakers. The round pegs in the square holes.”

We see short clips of Einstein, Edison, Amelia Earhart, and others. These are “the ones who see things differently. ... They change things. They push the human race forward. And while some may see them as the crazy ones, we see genius. Because the people who are crazy enough to think they can change the world, are the ones who do."

I keep coming back to crazy vs normal again and again. What prompted today’s piece is a comment from Liz in response to my recent repost on Darwin and evolutionary psychiatry:

I have been struggling for a long time to try and figure out how it is that bipolar disorder was somehow an evolutionary advantage. This comment of yours really hit home and brought tears to my eyes:

"I like to contend that it took a crazy person to run into a burning forest and enthusiastically bring a flaming souvenir back to the cave."

I know that as a bipolar person I am able to experience a different reality and range of emotions than people who have chemically "balanced" brains. It's helpful to hear an anecdote about how this difference in reality perception can actually make being bipolar useful rather than a burden.

Liz, I hear you. We are a minority surrounded by the chronically normal. It’s not easy living in a world where everyone dances like a white man. The only thing worse is actually dancing like a white man.

Further reading from mcmanweb

Normal - Highly Over-Rated
Creativity
Intuition
Psychic Perception
You See Four; I See 28

In Memoriam: Charles Sakai

I just learned that someone dear to me, Charles Sakai, passed away two or three weeks ago. Charles was a comrade-in-arms - mental health advocate, history buff, and Mahler fan. We’d been in each other’s lives for at least ten years, the last three or so as Facebook friends.

We met online sometime in the very early days of my writing about my illness, around 2000, and exchanged emails sporadically.

We met face-to-face in 2003 at a DBSA conference in Long Beach. Both of us had signed up for the talent show. I did a tap-dance number. That’s right, I really tap-danced. I can’t even begin to describe my inner wrestling match with my social anxiety as I got up on that stage. Charles, by contrast, was a natural. He sang karaoke in an unforgettable off-key voice, but the crazy thing was he seemed to be channeling the entire positive life force of the galaxy as he was doing it. It was an amazing performance. Needless to say, he drew the loudest applause of the evening.

We were also participants in a talent show together the next time DBSA came to California in 2006. Again, he brought down the house. The last time we saw each other was the last DBSA conference I attended, in Orlando in 2007. I was one of the break-out speakers, and for my talk I unpacked my didgeridoo.

The purpose of the didgeridoo in my talk was to illustrate the benefits of settling into the kind of stop-and-smell-the-roses state that is vital to managing stress and maintaining wellness. I had only just taken up the didgeridoo three or four months earlier, and about all I could do with it was drone a single monotonous tone. But I thought this would be good enough to lead my audience through a guided meditation.

I think I succeeded, instead, in mystifying just about everyone in the room. My audience was quiet when I stopped, the response I anticipated with a meditative exercise. Suddenly, there was Charles, bursting into loud applause, carrying on as if he had just heard Louie Armstrong reincarnated belting out West End Blues. Charlie came up to me right after his talk, enthusiastically snapping photos of me with my didge and posing for photos with me.

Gotta love this guy.

I last saw him as the conference was breaking up. We would, of course, see each other at the next conference.

I finally figured out how to use Facebook sometime in 2008. Charles was there, constantly encouraging me, giving me a reason to keep going through all my constant down periods when I would have gladly pulled the plug on writing about mental health in exchange for spending the rest of my life rolling pizza dough. I would post a link to my latest blog piece, he would reply with a “like” or a comment.

Okay, not when my posts revealed my politically liberal tendencies. But I was delighted to discover we both resonated to a lot of the same off-beat stuff, such as military history and Mahler.

I can’t remember precisely when I shared on Facebook a YouTube video of a snippet of a Mahler symphony, but there was Charles, enthusiastically responding. Holy cow! both of us seemed to be saying at once. You’re a Mahler fan, too?

To the uninitiated, Mahler is a cult. Mahler fans worldwide share a special bond. Not any old special bond. A special special bond.

Charles, of course, would keep asking if I would be attending this DBSA conference or that DBSA conference. I would keep informing him, no, not this year, maybe next year. We would also talk about my visiting Colorado Springs. Charles was very involved with DBSA there, which has a very active chapter with lots of great people I have bonded with over the years.

I kept thinking that one of these days I would get to Colorado Springs. Alas ...

But we still had Facebook. I recall enthusiastically informing him late last year that I had purchased a ticket to see Dudamel conduct the LA Phil in Mahler’s Sixth Symphony. He responded with equal enthusiasm.

Then, soon after, his “likes” and “comments” stopped. I didn’t think too much of it at first. People go into hibernation. Maybe my liberal politics was getting too much for him. The Presidential primary season was in full swing, and I was making no secret of the fact that I considered Republicanism a diagnosable illness. Surely, he would be back.

Two weeks ago, I attended my Mahler concert. It was the most profound musical experience of my life. As soon as I got in the door, I was posting on Facebook. Not just one post. A status post, two YouTube snippets, a link to a just uploaded rerun of an old Mahler blog. Charles will love this, I thought.

No “like.” No comments.

A week went by. Two. I was going through one of my rolling pizza dough moments. Where was Charles? This morning I went to the wall of his Facebook page. Someone had posted:

For everyone that was unaware of what happened to Charles, he got sick, so they took him to the ER and then he was put in ICU in Denver. One week later he died. He had a very advanced form of cancer. By the time he found out, it was too late ...

Now I know. Charles, you were there at the Mahler with me. You had to be. I was thinking of you the whole time. It was one hell of a concert, wasn’t it?

Can Integrative Psychiatry Save Psychiatry?

Integrative psychiatry involves incorporating complementary and alternative medicine (CAM) into clinical practice. I first came across the term in mid-2003 at a two-day conference, “Non-Pharmaceutical Approaches to Mental Disorders” staged in Pasadena by the nonprofit organization, Safe Harbor.

Two weeks earlier, I had attended the six-day American Psychiatric Association annual meeting in San Francisco. The main event there was Pharma-driven psychiatry, but the brain science on display signaled a new paradigm in the making. Only one session (to my knowledge) involved vitamins and supplements. This wasn’t going to change.

So, here we are, nearly nine years later. Psychiatry is facing a major identity crisis and Safe Harbor keeps soldiering on. Safe Harbor was founded by businessman Dan Stradford, who lost the dad he knew to mental illness. Medical treatment failed to return his father, at least the father he knew. There had to be a better way,

Several months after the conference - I ran into Dan at a NAMI national convention in Cincinnati. I was outside, taking a break, enjoying the sun. I greeted Dan walking past, and he sat down beside me. It looked like he needed a break, as well. One of the loneliest feelings in the world is being outside of your time zone when exhaustion overtakes you. I think Dan was having one of those moments.

In vulnerability lies strength.

Safe Harbor just released the 108-page “The Flying Publisher Guide to Complementary and Alternative Treatments in Psychiatry,” available as a free download. Dan is one of the four authors. The document gives a good run-down on lifestyle, nutrition, mindfulness, and other things we need to consider incorporating into our recovery. Of particular interest is a chapter co-authored by Hyla Cass (pictured here) entitled, “The Integrative Psychiatrist.”

Dr Cass is another person I met at the Safe Harbor conference. A former assistant professor at UCLA, she now runs her own private practice, appears regularly in the media, and markets her own line of supplements. Yes, this raises the same kind of concerns as MDs financially linked to Pharma, but let’s focus on what she says:

“During my residency at Cedars-Sinai/UCLA Medical Center,” she writes, “I eventually found that the standard ‘couch and Prozac’ combination of psychoanalytic and pharmacological treatments had their limitations.” This would lead her down the path of nutrition and lifestyle. Depressive or anxious or other symptoms, she found, could be related to such things as low blood sugar. viral and fungal infections, hormonal imbalances, allergies, toxins, and specific nutrient deficiencies.

The no-brainer approach to this is a generous order of lab tests. Dr Cass cites one instance of a 55-year-old woman arriving at her practice being treated for numerous physical complaints by her internist and depression and anxiety and insomnia by her psychiatrist. A lab test revealed a magnesium deficiency.

Dr Cass’ exams include a standard range of screenings that measure for anemia, thyroid, cholesterol, and so on. In addition, depending on the patient’s symptoms and information she has gathered, she will order additional labs that measure for nutritional deficiencies, toxic minerals, and allergies.

Every patient fills out an inventory checking for stress, depression, anxiety, and sleep, plus a far more involved questionnaire that screens for symptoms that suggest issues with lifestyle, brain chemistry, thyroid function, adrenal function, blood sugar, digestive imbalances, toxin overload, headaches, arthritis, and osteoporosis, plus men-only and women-only problems.

In addition, Dr Cass screens for personal and family histories. According to Dr Cass:

From the patient information, physical assessment, and labs, a picture begins to emerge. While the client could be primarily suffering from stress, where lifestyle changes or counseling would be in order, more often I find physical issues - commonly a number of them - impacting behavior, emotions, and cognitive function.

When these issues can be pinned down (such as hormonal imbalances) the solutions may present themselves. Various specific nutritional remedies tend to be her first choice, her credo being: “Apply a continuum of treatments, always beginning with the safest, most natural, and most benign.” Medications as needed are also part of her toolbox. Hence the “integrative” in integrative psychiatry.

In essence, what do we make of a depressed individual with a vitamin B deficiency? Is it depression? Or is the vitamin B deficiency the real issue? These are the very same type of questions brain scientists are asking, namely what is really going on? Sensitivity to certain substances? A glitch in the wiring? How about what is going on in the person’s life right now? How about family? On and on.

Our new understanding is screaming for new diagnostics. The kind of lab screens and surveys that Dr Cass employs, but also the type of gene scans and qEEGs that are coming on the scene. And - always, always, always - sitting down and listening to the patient. High tech with human touch. Integrative psychiatry - we are long overdue.

Charles Darwin and Evolutionary Psychiatry

In honor of Darwin's 2003rd birthday, from mcmanweb ...

Here's an interesting fact: Peacock tails drove Darwin crazy. The sight of one "makes me sick," he wrote. These feathered accessories played havoc with his work-in-progress theory of natural selection. Surely, any bird stupid enough to flaunt their colors in the wild wouldn't live long enough to mate.

Darwin's solution seems obvious enough today, but back in the nineteenth century it was a scientific breakthrough, a work of genius. The showy tails, he figured out, were chick magnets. The flashier, the better. The well-endowed cock, so to speak, won the right to make a deposit. The bird's genes would live on, even if its owners' days were numbered.

Evolutionary biologists refer to this as a trade-off. A high fever, for instance, may aid in the destruction of deadly pathogens, and without the inconvenience of coughing we would all likely die from pneumonia. Take away our ability to experience pain and we would never know our appendix has burst. The sickle cell gene, in turn, is protection against malaria.

A Darwinian Explanation for Mental Illness

Fine. But how does Darwin apply to mental illness? According to evolutionary biologist Randolph Nesse MD of the University of Michigan:

Psychiatrists still act as if all anxiety, sadness, and jealousy is abnormal and they don't yet look for the selective advantages of genes that predispose to schizophrenia and bipolar disorder.

I heard Dr Nesse at the 2005 American Psychiatric Association annual meeting talk about the selective advantage in anxiety. Obviously, sufficiently anxious cave men and women were able to steer clear of saber toothed tigers long enough to find an opportunity to pass on their genes to the next generation.

Dr Nesse asks us to imagine a distant ancestor of ours at an ancient watering hole. The poor guy hears a sound behind him. A lion? A monkey? Even if it’s just a mouse, panicking first and thinking later is not such a half-bad idea.

Anxiety traits are no mere artifacts of an earlier age. Anxiety is crucial to marshaling our wits. We could never survive one day in traffic without it, let alone the full range of personal interactions.

Dr Nesse compared the brain's limbic system to a smoke detector that is programmed to deliver 1000 false alarms for every genuine alert. The false alarms are the price of survival. Better to be too anxious.

Now imagine modern man in the supermarket having a panic attack while reaching for a bottle of water. The seriously anxious, it turns out, have hyper-sensitive smoke detectors. The false alarms and the hyper-sensitive in our midst tend to blind us to the fact that a certain degree of anxiety is good, that we would fail to exist as a species without it.

An application of evolutionary biology is Darwinian medicine. For instance, a medical doctor might want to think twice before prescribing something to lower a patient’s temperature. In patients with panic attacks, Dr Nesse has had success once he helps them realize that their response is not necessarily abnormal. Once that happens, often the power of the panic attack dissipates.

The Darwinian Bipolar Advantage

Our behaviors and emotions, according to evolutionary psychiatry, are adaptations the mind has made to recurring situations. In making a Darwinian case for bipolar, it’s easy to imagine highly energetic and productive and creative types having a selective advantage over their more mundane kinfolk. Think of mania lite. Passing on the risk of more serious manifestations was an acceptable trade-off.

I like to contend that it took a crazy person to run into a burning forest and enthusiastically bring a flaming souvenir back to the cave, raving on about the glories of barbeque. I’m sure this individual's reward was summary eviction by an enraged spouse. Ah, the price we have to pay. It’s never been easy being bipolar.

In my version of the story, the two made up and lived long enough to pass on their traits to the next generation, but only after one of them arrived at the concept of putting the meat on a spit rather than holding it bare-handed over the open flame.

Or bipolar could be a lot more elemental. The illness could be an adaptation to changes in the seasons. Think seasonal affective disorder. Think of a very long cycle. (Goodwin and Jamison refer to this in the second edition to “Manic-Depressive Illness.”)

The Darwinian Depression Advantage

But what about depression? Surely, there can be no selective advantage here. Think again. For one, depression may amount to a failure of denial. Depression is when the rose-colored glasses come off, when reality sets in. It opens the way to acceptance, to setting new goals and moving on with our lives.

Also, sometimes it’s helpful to be too depressed to press our luck. If mania is all about daring, depression is about caution. The daring have an advantage in life's ultimate prize, the opportunity to mate. So do the cautious.

Depression also provides an opportunity for regrouping and recouping, not to mention a time of introspection and reflection. Think of depression as an enforced time-out. In its own perverse way, depression may set the stage for needed psychic healing.

As with anxiety and mania, we are talking more benign manifestations. The more virulent versions of depression, it seems, are part of the price we have to pay.

Schizophrenia?

Schizophrenia is far too horrific an illness to see any obvious selective advantage. Yet, the culprit genes have been transmitted from generation to generation, even in Einstein's family. What gives?

First, it is not helpful to look upon schizophrenia as a simple disease. About a hundred suspect genes have been fingered. One of these genes - COMT - has a variation that enhances thought processing in one context but disrupts it in another. Another gene - DISC 1 - helps integrate neurons into the mature brain.

In this context, schizophrenia can be seen as the breakdown in the processes responsible for building and maintaining a complex brain.

Schizophrenia may also be seen as part of a spectrum. At the schizophrenia extreme, the brain is far too active for its own good, characterized by runway thoughts such as psychotic delusions. A lighter version may well be schizotypal personality disorder, characterized by various oddball behaviors and "magical thinking." Tone this down a bit more and we may be talking about eccentrics who think outside the box.

Nancy Andreasen MD, PhD of the University of Iowa describes Einstein as having having schizotypal traits, as well as a son with schizophrenia. Her original enquiry into creativity involved looking for a schizophrenia connection (also citing Newton and James Watson) but very quickly changed to bipolar.

There may be another aspect to "schizophrenia lite." The book, "A Beautiful Mind," chronicles the life of Nobel Laureate John Nash. His breakthrough accomplishments occurred as a young adult, before his outbreak of schizophrenia. But as the book makes clear, there is no way we can describe an apparently healthy John Nash as "normal." Even in a profession notorious for its eccentrics, Nash was very much an outsider.

We tend to think of mental illness as a complete break with reality or rationality, but these breaks don't just happen overnight. Subtle symptoms may manifest many years earlier, what the experts describe as "prodromal" states. Could Nash's "beautiful mind" be attributed to such a state? Who knows?

Working With What We're Stuck With

"Human biology," says Dr Nesse, "is designed for stone age conditions." Or, as Leda Cosmides and John Tooby of the University of California at Santa Barbara put it, "our modern skulls house a stone age mind."

In other words, we are the beneficiaries of a group of genes that did not anticipate the demands of modern living. Were we mere machines with replaceable parts, we could simply send our brains back to the manufacturer for a retooling. Instead, we are forced to work with what we're stuck with.

Dr Nesse cites the example of the eye. Those who champion intelligent design point to the wonders of the eye in support of their theory that creation is way too complicated to be left for chance.

But look closely at the eye, Dr Nesse advises. We have wires running between the lens and where the image is processed. No camera manufacturer would be dumb enough to do that. Plus the eye has a blind spot where the retina meets the optic nerve.

The eye of the octopus, Dr Nesse points out, has a far better "design." Through pure chance, he says, we and practically all the rest of the animal kingdom got stuck with the inferior version.

Scientists are in virtual unanimous agreement on evolution's main points, but evolutionary psychiatry is a speculative enterprise, not capable of definitive proofs. Indeed, a legitimate argument can be made that we are retrofitting psychiatry to conform to evolutionary precepts.

Then again, a much stronger case can be made that our behavior makes no sense without taking evolution into account. Instead of viewing all mental illness as solely destructive, we are forced to consider its advantages. And in looking at the advantages, we find potential in our own worth.

Call it the twenty-first century Darwinian challenge. Our ability to feel on levels deeper and higher than the rest of the population, crippling as it may be, has also given wings to our thoughts, ones that motivated our distant ancestors to climb out of their cozy rock condos in the first place and now seem destined to have us reach for the stars.

Rerun: My Visit to the Local Creationist Museum (Seriously, I'm Not Making This Up)

In honor of Charles Darwin's birthday tomorrow, this piece from Dec 2010 ...

Believe it or not, this museum is only 10 or 12 miles from my home, outside San Diego.

This journey through time will be a very short one, as the entire universe, earth included, according to creationist belief, is only 6,000 years old.

This works way better than carbon-14 dating.

I missed whether it was a standard day or a metric day.

In support of a worldwide catastrophe, creationism cites the same geological evidence as science, though with some rather significant differences in interpretation.

Noah's sons went their separate ways, assisted by land bridges spanning the oceans, thanks to a Flood-induced ice age. The animals from the Ark dispersed along these same land bridges, perhaps not whales and other sea creatures.

And I thought Neanderthals survived in the form of Tea Party followers.

I wish I had our high school class valedictorian, Karl Van Bibber, to explain this to me.

If I can follow the logic, mutations (which are all bad) get filtered out of the gene pool, keeping creation constant. There is, however, the mother-in-law exception.

That's right, evolution is just a religion, which makes creationism the true science. Why aren't our kids being taught this in school?

The "bad fruits" of evolution. No good can come from allowing people to think for themselves. That's why we need knowledgeable people in authority to do our thinking for us.

Evolution apparently played a part in the Final Solution. Actually, murderous bigots were killing Jews en masse long before Darwin. The Catholic Church even made saints out of some of these medieval pre-Hitlers. (Sorry, I was trying really hard to keep this objective.)

A browse through the museum's book store. No, I didn't Photoshop the book title.

Shedding Light on Brain Research: A Scientist Responds to Whitaker

Last week, I wrote a piece highly critical of a post Robert Whitaker published on his blog, Mad in America. His post attacked a very recent Scripps Institute study, which became the basis of his own editorializing on the research agenda of the NIMH, namely that “decades of such brain research has not produced any notable therapeutic payoff.”

My post noted that Whitaker had a point concerning one issue (namely, the need to control for the effects of psychiatric meds in genes-brain research), but that he had left out some critical information about the study and that his editorializing was way off-base.

You can check out Whitaker's post: Rethinking Brain Research in Psychiatry.

And my post: Robert Whitaker: Dangerous in America

Several days ago, I emailed Elizabeth Thomas PhD (pictured here), lead author of the study in question. I did not ask her to take sides. I simply directed her to both blogs (if she were morbidly curious about our food fight) and asked for points of clarification. Following is her response in full, published here with her permission ...

Hi, John

Thanks for your email. Yes, I was morbidly curious about your blogging battle with Mr. Whitaker and I did want to respond. Sorry this is long-winded…..

First to defend our work a bit. Like most researchers working with post-mortem brain tissue, we are aware that a confounding factor in post-mortem research on schizophrenia is the unknown effect of antipsychotic drugs, which are known to alter gene expression. (I have actually published two reviews on the topic of antipsychotic drugs and regulation of gene expression [1, 2]). It is an issue that cannot be avoided, as most if not all collected brains deemed “psychiatric” are due to information from a psychiatrist’s report and, hence that patient would be receiving some type of medication.

Just FYI, to address this in our research, we do typically do two things: 1) treat rodents with the drug in question, to look for effect on gene expression in the brain; and 2) perform correlation analysis between expression values in each human subject and the recorded drug dose of each subject. In our recent paper, we did provide drug information in Suppl. Table 1 for a portion of the subjects we studied; unfortunately, drug information was not available for the Harvard subjects.

Nonetheless, Mr. Whitaker is correct in that we should have discussed the potential effects of antipsychotic drug exposure in that paper, as we have in previous studies using post-mortem brains from some of these same subjects ([4, 5]). As it turns out, previous studies have looked at the effects of antipsychotic drugs on histone acetylation in rodent brain [5, 6], as Mr. Whitaker suggested should be done.

It was found that haloperidol, one of the most commonly used drugs, did not alter global histone acetylation in the brain, but could elevate a phospho-acetyl mark on histone H3 at a particular residue [5]. Another study found that clozapine and sulpiride could elicit small increases in acetylation of histone H3 [6]. Hence, the findings in our paper showing lower histone acetylation in patients, who in fact were treated with haloperidol or other D2 receptor antagonists, are unlikely due to drug treatment (if you want to use the rodent argument). I regret that we did not mention these studies in the current paper.

The finding that histone acetylation is lower at certain gene promoters is consistent with a lowered gene expression profiles for these given genes that have been observed in subjects with schizophrenia. On a whole, dozens of papers have shown that brains from patients with schizophrenia show substantial deficits in gene expression; this was the impetus for our studies investigating whether epigenetic mechanisms of gene regulation could be responsible and or contributing to this phenomenon. 

Certainly, we cannot rule out that antipsychotic drugs could have an effect on gene expression in these subjects, but drug exposure is unlikely to explain the wide range of gene expression deficits detected. In any case, I do think Mr. Whitaker is correct about the importance of studies that would address the question of how psychotropic drugs may be affecting the developing brain, as many of these drugs are now given to younger patients.

Despite Mr. Whitaker’s claim that my response to our work was “the usual concluding pronouncement from such studies”, the reality is, in my opinion, that our findings provide a starting point to consider the only real new drug development for psychiatric disorders the field has seen in 50 years. Because we have shown that histone acetylation is lower in young subjects with schizophrenia, and that the acetylaton marks we studied are known to govern gene regulation, the use of compounds that could elevate histone acetylation (i.e. histone deacetylase [HDAC] inhibitors) could be useful to of restoring abnormal histone acetylation patterns and accompanying gene expression deficits in schizophrenia, leading to improved clinical outcome.

The possibility that these compounds could improve symptoms is supported by a recent study by Engmann et al., 2011 [7], who showed that the HDAC inhibitor, MS-275 could rescue cognitive deficits in a mouse model of schizophrenia. And further, that the mechanism for beneficial effects were via restoration of histone H3K18 acetylation deficits in the mouse brain. Other ongoing studies are testing other HDAC inhibitors in different rodent models of psychiatric disorders as well. (If my recent NIH application is funded, we will be testing novel HDAC inhibitors in a prenatal immune activation model of psychiatric disease).

As for your question about testing whether psychotropic drugs alter epigenetic pathways: There are two studies, as I mentioned above, that have been published, although the drawbacks of these studies were that only short-term treatments were used and epigenetic changes at specific genomic loci were not tested (only global levels measured by Western blotting).

A more important issue, in my opinion, is whether epigenetic drugs, such as HDAC inhibitors will truly represent a novel therapeutic avenue for psychiatric disorders. I would argue YES. New and improved HDAC inhibitors are currently being developed for various CNS disorders and my prediction is that they will also prove to be beneficial in treating patients with psychiatric disorders.

While it is expected that such compounds will have some “to be determined” side effects, they are unlikely to cause the same detrimental side effects of Parkinsonian symptoms and metabolic syndrome associated with the currently used antipsychotic medications. There is one recent clinical trial that has been completed showing improvement with valproate (an HDAC inhibitor) in schizophrenia, and several other trials are underway. (For more information see the clinical trial gov website). (Although it must be noted that the currently FDA approved HDAC inhibitors, such as valproate, are broadly acting compounds, unlike the ones in development, which would be more specific, hence less likely to cause unwanted side effects).

References:
1. Thomas, E.A. Molecular Profiling of Antipsychotic Drug Function: Convergent Mechanisms in the Pathology and Treatment of Psychiatric Disorders. Molecular Neurobiology 34:109-28 (2006).
2. Thomas, E.A. Transcriptomics of antipsychotic drug function: What have we learned from rodent studies? Current Psychopharmacology, In Press.
3. Narayan, S., Tang, B., Steven Head, S.R., Gilmartin, T.J., Sutcliffe, J.G., Dean, B. and Thomas, E.A. Molecular Profiles of Schizophrenia in the CNS at Different Stages of Illness. Brain Research 1239:235-248 (2008).
4. Narayan, S., Head, S.R., Gilmartin, T.J., Dean, B. and Thomas, E.A. Evidence for Disruption of Sphingolipid Metabolism in Schizophrenia. Journal of Neuroscience Research 87:278-288 (2009).
5. Li J, Guo Y, Schroeder FA, Youngs RM, Schmidt TW, Ferris C, Konradi C, Akbarian S. Dopamine D2-like antagonists induce chromatin remodeling in striatal neurons through cyclic AMP-protein kinase A and NMDA receptor signaling. J Neurochem. 2004 Sep;90(5):1117-31.
6. Dong E, Nelson M, Grayson DR, Costa E, and Guidotti A. Clozapine and sulpiride but not haloperidol or olanzapine activate brain DNA demethylation. Proc Natl Acad Sci U S A 2008; 105: 13614-9.
7. Engmann O, Hortobágyi T, Pidsley R, Troakes C, Bernstein HG, Kreutz MR, Mill J, Nikolic M, Giese KP. Schizophrenia is associated with dysregulation of a Cdk5 activator that regulates synaptic protein expression and cognition. Brain. 2011 Aug;134(Pt 8):2408-21

Finally, thank you for supporting NIH funding for basic and medical research in your blog – we are definitely in dire need and without continued funding, we will not be able to address these critical questions that could help patients with psychiatric disorders.

Best wishes,

Elizabeth A. Thomas, Ph.D.
Associate Professor

Department of Molecular Biology

The Scripps Research Institute

3030 Science Park Rd, SP2030

La Jolla, CA  92037

The Cortical Factor: What Is Going On In Our Brains With Gay Marriage and All That?

Picking up from where we left off:

According to Robert Sapolsky of Stanford, the amygdala and the frontal cortex essentially regulate each other. The projections from the frontal cortex are inhibitory, as are the projections from the amygdala. In Sapolsky's words: “The frontal cortex is trying to get the amygdala to restrain itself. The amygdala is trying to get the frontal cortex to stop sermonizing at it.”

The two parts of the brain essentially work in opposition, and when the amygdala succeeds in silencing the frontal cortex, “that’s the world in which you are making astonishingly bad decisions. ... That’s the world of the amygdala getting very inaccurate rapid-fire information.” Out comes behavior that is seriously unregulated.

Eventually, in certain situations, the amygdala will habituate and learn not to be afraid, but only if the frontal cortex is healthy enough to convey the lesson.

Enter the anterior cingulate (ACC), part of the cingular cortex snaking beneath the outer cortices. This is a region of the brain implicated in empathy. Typically, in hypothetical exercises involving agonizing moral choices (such as do you strangle a crying baby to save the lives of a group of people hiding out from the Nazis?), those who make the cold-blooded utilitarian decision are shown to have the least activation in the ACC.

But life is more complicated than simple thought vs emotion, especially when the brain goes metaphorical on us. We are called upon to make judgments concerning abstract moral concepts. The problem is our brains did not evolve for doing symbols and metaphors. We are stuck with the old circuitry.

Thus, a test subject handed a warm drink in an elevator by a stranger will rate that individual as warm. Cold for a cold cup. This really happens. The brain mixes metaphor with reality.

Wait, it gets even more weird. Registering moral disgust? The insular cortex activates. This is the part of the brain that processes foul stimuli such as rotting fish. Contemplate the etymology of the word, disgust. Further contemplate that every language on earth employs similar terms for the same phenomenon. Says Dr Sapolsky: “When humans came up with something as fancy as moral transgression, where are you going to stick the sense of outrage you feel? I know - let’s hijack the part of the brain that tells you you’re eating rotten food.”

Dr Sapolsky cites a number of studies, one of which includes people wanting to wash their hands a la Pontius Pilate after recounting some moral failing in their lives.

As you will recall from the previous piece, Dr Sapolsky mentioned that by age 5 there is already a correlation between socio-economic status and the thickness of the frontal cortex and its resting metabolic rate. No question about it - this stinks. Dr Sapolsky agrees. As he observed: “That is one of those factoids that should have people rioting at the barricades.”

But Presidential candidate Mitt Romney would disagree. As he recently declared: “I'm not concerned about the very poor.” (And no, this is not out of context.)

This is a guy who obviously has no problem digesting unpleasant factoids and who is not losing any sleep over it, but that’s mixing yet another metaphor. Could it be that Mitt is one of those low-activating anterior cingulate types?

Dr Sapolsky does not mention Republicans, but that shouldn’t stop us from making our own connections. Says Sapolsky, citing Nobel Laureate Eli Wiesel: “The opposite of love is not hate. The opposite of love is indifference.”

Dr Sapolsky points out that love and hate are physiologically very similar. From a strictly biological perspective (such as brain activation, heart rate, and so on) it is very difficult to tell the two apart. Indifference is the real evil, which is another good reason to register our disgust.

But hold on. We may be disgusted at people who are indifferent to injustice (who obviously lack the capacity to register a mental gustatory response), but then we have a whole class of liberal-haters who define themselves as being disgusted with the disgusted. Recall this from yet another Presidential candidate, Newt Gingrich, in reference to Occupy Wall Street: “Go get a job, right after you take a bath.”

Ah, another stinking Republican (using a bath metaphor at that) who makes liberals want to throw up. Confused? So, apparently, is everyone. Dr Sapolsky cites the work of John Haidt of the University of Virginia in support of the proposition that affective response drives moral decision-making rather than the other way around.

Say, for instance, a brother and a post-reproductive sister want to have a sexual relationship? Is it okay for them to have one in private? How about burning a flag and stomping on it? Or cutting up your dead pet and eating it?

I don’t know about you, but I definitely registered a high-level gut reaction to that last proposition. Fine, but can I come up with a rational answer in response to the question: “What’s wrong with that?”

This is essentially the same question Dr Haidt asked his test subjects. They, too, had trouble framing rational responses. Basically, on an emotional level, something doesn’t “feel right.” The frontal cortex is spinning its wheels, the gut makes the call. Eventually, the thinking parts of the brain lock in, but too often in a rationalizing display of post hoc rubber-stamping.

As Sapolsky explains: “We are dealing with a very ancient brain, one that is not very good yet at separating the limbic world from the cortical one.”

Maybe that’s why we need a judiciary to protect ourselves from our own inept decision-making. Yesterday, a federal appeals court struck down California’s infamous Proposition 8, a voter referendum passed in 2008 that would have banned gay marriages in the state.

Is there anything wrong with disgust? Of course not. Of all things, disgust is morally neutral. Whether we’re dealing with moral issues or food, this is basically a rotten fish reaction we are talking about. We need our rotten fish reactions. They drove the civil rights movement, which is why we need to be suspicious of low-activation anterior cingulate guys who lack the kind of empathy that makes us capable of moral outrage in the first place.

The problem is we often fail to couple thinking to our disgust. “What is wrong with that?” It’s a question we need to be asking - over and over and over.

***

This concludes my three-part series on The Cortical Factor, based on Lecture 18 from Robert Sapolsky’s 25-part video series. See Part I, Part II. Stay tuned for more of Sapolsky, probably in another week or two ...

The Cortical Factor: Developing the Optimum Brain

Take the teen-age brain - please!

First, a quick review: In our previous post, Robert Sapolsky of Stanford (pictured here) explained how the frontal cortex is about doing the harder thing, if it is the right thing to do. Essentially, the more developed cortical areas modulate our more primitive limbic impulses, including learned (and virtually automatic) behaviors that are no longer stored in the frontal cortex.

This tends to involve the frontal cortex, boosted by dopamine, amping up weaker neural circuits and inhibiting stronger ones. Those with cortical damage or dementia experience major system failures. Their brains default to the stronger circuits, even if these represent the wrong thing to do in the particular situation. They fail to stay on task. They give into temptation. They fail to delay gratification in pursuit of the long-term reward.

REM sleep offers a spectacular example of the frontal cortex going off-line. We dream all kinds of crazy stuff. We do things in our dreams we would never contemplate doing awake, that is assuming we are adults. But there is a strange phenomenon called teen-agers.

The frontal cortex is the last part of the brain to fully develop - to fully form all the myelin on its axons, to get its full complement of synapses. The front part of the brain fully goes online for the first time at around age 25. Younger than that and we’re dealing with limbic systems with feet.

Interestingly enough, says Dr Sapolsky, because the frontal cortex is the last part of the brain to develop it is the part of the brain least constrained by genes and most sculpted by environment and experience.

So - take an adult and take a teen-ager. Assign each one a task and give a greater reward than anticipated. Dopamine levels go up, driving frontal metabolism, but a lot higher in the teen-ager. Then change things around. Do not give out the reward. Dopamine levels go down, only much lower in the teen-ager. Says Sapolsky:

The gyrations are much more extreme. The dopamine-driven metabolic changes in the frontal cortex are more dramatically large for reward, are more dramatically having the floor fall out from under it for lack of reward, for disappointment. It is a system that is essentially less regulated.

Major bummer: The frontal cortex loses neurons as it ages, which explains your grandmother telling you that your new hairdo looks rotten.

Can elevated resting metabolism in the frontal cortex be too much of a good thing? Dr Sapolsky gives the example of repressive personalities, individuals who are highly regimented, highly disciplined, not depressed or anxious, who do not express emotions very readily and are very bad at reading emotions in other people. “This is the roommate who always has all the work done three weeks before the due date.”

But low resting metabolism in the frontal cortex is not such a good thing, either. Think sociopath. Give a sociopath a routine brain task and they have to activate more of the frontal cortex than other people do.

Meanwhile, see how long a marshmallow on the table lasts with a four-year-old kid in the vicinity. Can the kid rein in his impulse with the promise there will be more marshmallows in 20 minutes if he leaves that one alone? In other words, how many frontal synapses do you have? Funny you should ask. The kids who held out the longest scored much higher on their SATs and other success measures years later.

Depressing fact: Already by age five there is a relationship between your socio-economic status and the thickness of your frontal cortex and its resting metabolic rate. What is that all about? This is the part of the brain that has one of the highest rates of receptors for glucocorticoids. Glucocorticoids are released in response to stress, and when too many of them are on the rampage neurons atrophy. Get born into the wrong family, be raised with the stress of poverty and already by age five the size and activity of the brain has taken a major hit.

Says Sapolsky: “That is one of those factoids that should have people rioting at the barricades.”

Instead, we have the phenomenon of Presidential candidate Mitt Romney, who recently declared: “I'm not concerned about the very poor.”

Have no fear, there is a neurobiological explanation for that. There is also an explanation for your moral outrage. More to come ...

Highly recommended: Dr Sapolsky's 25-part video lecture series, Human Behavioral Biology.