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Biomarker Envy II: Ethanolamine Phosphate

May 27, 2011

In my inbox yesterday was a story describing a new biological test for a psychiatric disorder.  Hallelujah!  Is this the holy grail we’ve all been waiting for?

Specifically, scientists at Human Metabolome Technologies (HMT) and Japan’s Keio University presented data earlier this week at a scientific conference in Tokyo, showing that they could diagnose depression by measuring levels of a chemical—ethanolamine phosphate—in patients’ blood.

Let me repeat that once again, for emphasis:  Japanese scientists now have a blood test to diagnose depression!

Never mind all that messy “talk-to-the-patient” stuff.  And you can throw away your tired old DSM-IV, because this is the new world: biological diagnosis!!  The press release describing the research even suggests that the test “could improve early detection rates of depression if performed during regular medical checkups.”  That’s right:  next time you see your primary doc, he or she might order—along with your routine CBC and lipid panel—an ethanolamine phosphate test.  If it comes back positive, congratulations!  You’re depressed!

If you can detect the skepticism in my voice, good.  Because even if this “biomarker” for depression turns out to be 100% accurate (which it is not—see below), its use runs entirely against how we should be practicing person-centered (not to be confused with “personalized”) medicine.  As a doctor, I want to hear your experiences and feelings, and help you with those symptoms, not run a blood test and order a drug.

[Incidentally, the Asahi press release made me chuckle when it stated: “About 90 percent of doctors base their diagnosis of depression on experience and varying factors.”  What about the other 10%?  Magic?]

As it turns out, I think there’s a lot to suggest that this particular blood test may not yet be ready for prime time.  For one, the work has not yet been published (and deciphering scientific results from a press release is always a risky proposition).  Secondly, the test was not 100% accurate; it failed to identify depression in 18% of cases, and falsely labeled healthy people as “depressed” 5% of the time.  (That’s a sensitivity of 82% and a specificity of 95%, for those of you playing along at home.)

Further, what the heck is ethanolamine phosphate, and why would it be low in depressed people?  Is it a chemical secreted by the “happiness centers” of the brain?  Does it predict the onset or worsening of a depressive episode?  Is it somehow affected by antidepressant treatment?  As far as I can tell from a quick literature search, there has been no report—or even a suggestion—of ethanolamine (or any of its metabolites) being involved in the pathogenesis of mood disorders.  Then again, maybe I didn’t get the Japanese translation just right.

Anyway, where this “marker” came from is anybody’s guess.  It’s entirely possible (although I can’t be sure, because the Japanese group has not yet published their findings) that the researchers measured the blood levels of dozens of molecules and found the “best” results with this one.  We sometimes call this a “fishing expedition.”  Obviously, the finding has to be replicated, and if it was, in fact, just a lucky result, further research will bear that out.

But Dr Yoshiaki Ohashi, board director and chief security officer at HMT (“chief security officer”? does he wear a badge and sit at the front desk during the overnight shift, too?) maintains that the findings “will make it easier for an objective, biological diagnosis of depressive patients.”

Wow.  In 2011.  (And just in time for DSM-5.)

What if he’s right?  How would you feel if you went to a routine doctor’s visit next week, got an order for blood work, and a secretary called you a few days later to tell you that you have depression?  Even if you don’t feel depressed?

Were there other motives for developing such a test?  Probably.  One of the press releases quotes the Japanese Ministry of Health as saying that “only one quarter of the people who need treatment” actually get it.  So maybe this blood test is simply a way to offer treatment to more people expand the market for antidepressants—even to those who don’t want treatment.  And then, of course, HMT probably wants a piece of the pie.  HMT is already developing a commercial test to measure ethanolamine phosphate levels; obviously, widespread adoption of this test would translate into big bucks for HMT, indeed.

So while many other questions remain to be answered, I must say I’m not holding my breath. Biological screening tests for psychiatric disorders have no face validity (in other words, if a test is positive but a person shows no signs or symptoms, then what?) and a positive result may expose patients to “preventive” treatments that are costly and cause unwanted side effects.

In my opinion, the best way (if any) to use a biomarker is in a “confirmatory” or “rule-out” function.  Is that demoralized, ruminative, potentially suicidal patient in your office simply going through a rough period in her life?  Or is she clinically depressed?  Will she respond to medications, or is this something that will simply “pass”?  In cases like this, measuring ethanolamine phosphate (or another similar marker) might be helpful.

But I don’t think we’ll ever be able to screen for psychiatric illness the same way a primary care doc might screen for, say, breast cancer or diabetes.  To do so would redefine the entire concept of “mental” illness (perhaps making it “neurological” illness instead?).  It also takes the person out of the picture.  At the end of the day, it’s always the patient’s thoughts, words, and experiences that count.  Ignoring those—and focusing instead on a chemical in the bloodstream—would be an unfortunate path to tread.

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Obesity-Related Anxiety: A Me-Too Disease?

April 15, 2011

Psychiatry seems to have a strange fascination with labels.  (I would say it has an obsession with labels, but then it would be labeled OCD.)  We’re so concerned with what we call something that we sometimes ignore the real phenomena staring us in the face every day.

Consider social anxiety disorder (SAD).  Some have argued that this is simply a technical, high-falutin’ label for general shyness, which even “normal” people experience in varying degrees.  There are indeed cases in which someone’s shyness can be horribly incapacitating—and these cases usually benefit from specialized treatment—but there also exists a broad gradient of social anxiety that we all experience.  If I spend too much time worrying about whether the shy patient in my office meets specific criteria for SAD, I might lose sight of why he came to my office in the first place.

So a news story this week caught my eye, with the headline “Obese People Can Suffer From Social Anxiety Due to Weight Alone.”  To a non-psychiatrist, this statement probably seems self-evident: people who are overweight or obese (just like people with any other aspect of their physical appearance that makes them appear “different from normal”) might be anxious or uncomfortable in social settings, simply because of their weight.

This discomfort doesn’t meet criteria for a DSM-IV diagnosis, though.  (At this point, you might ask, but who cares?  Good question—I’ll get to that below.)  The DSM-IV specifies that the symptoms of social anxiety must be unrelated to any medical condition (of which obesity could be considered one).  So if you’re overly self-conscious in social situations due to your weight, or due to an unsightly mole on your face, or due to a psoriasis flare-up, or because you’re a dwarf, sorry, you don’t “qualify” as SAD.

Apparently some researchers want to change this.  In a study to be published this month in the journal Depression and Anxiety, researchers at Brown University and Rhode Island Hospital investigated a large number of obese individuals and found that some of them have social anxiety due to their weight and nothing else, resulting in “greater impairment in social life and greater distress about their social anxiety” than those obese patients who had been diagnosed with (non-obesity-related) SAD earlier in life.  They argue that we should expand the diagnostic criteria in the upcoming DSM-5 to include these folks.  (Indeed, the subtitle of the article in question is “Implications for a Proposed Change in DSM-5.”)

An investigation of their methods, though, reveals that their key finding may have been a foregone conclusion from the start.  Here’s what they did: They interviewed 1,800 people who were being evaluated for weight loss surgery.  (A pre-op comprehensive psychiatric evaluation is often a requirement for bariatric surgery.)  616 people had no psychiatric history whatsoever, while 135 of them had been diagnosed with SAD at some point in their lives.  But then they found 40 additional people whom they labeled as having something they called “modified SAD,” or “clinically significant social anxiety … only related to weight concerns.”  The paper demonstrates that this “modified SAD” group had psychosocial characteristics (like work/social impairment, past/current social functioning, etc) which were strikingly similar to patients with SAD.

But wait a minute… they admit they “labeled” a subset of patients with something that resembled SAD.  So in other words, they pre-selected people with SAD-like symptoms, and then did the analysis to show that, sure enough, they looked like they have SAD!  It’s sort of like taking all the green M&Ms out of a bowl and then performing a series of chemical and physical tests to prove that they are green.  OK, maybe I shouldn’t have used a food analogy, but you get my point…

I don’t mean to be weigh too heavily (no pun intended) on study’s authors (for one thing, the lead author shared a draft of the article with me prior to publication).  I know why articles like this are written; I’m aware that the medical exclusion has made it impossible for us to diagnose SAD in many people who actually have debilitating anxiety due to some obvious cause, like obesity or stuttering.  And this is relevant because we have to give a DSM code in order to be paid for the services we provide.  As with much in life, it’s often all about the money.

But if that’s the only reason we’re squabbling over whether obesity-related anxiety deserves the DSM seal of approval, then I’m sorry, but it’s another example of psychiatrists and psychologists missing the point.  Whether we call something SAD—or depression, or panic disorder, or ADHD, or bipolar disorder, or whatever—means less to the patient than what he or she actually experiences.  Admittedly, we do have to give a “diagnosis” at some point, but we need to ensure our diagnoses don’t become so homogenized that we end up looking at all of our patients through the same lens.

The 40 obese Rhode Islanders who are socially distressed due to their weight probably don’t care whether they’re labeled “SAD,” “modified SAD,” or anythingelse, they just want help.  They want to feel better, and we owe it to them to get our heads out of our DSMs and back into the therapeutic setting where they belong.


What Psychiatrists Treat and Why

February 20, 2011

Do we treat diseases or symptoms in psychiatry?  While this question might sound philosophical in nature, it’s actually a very practical one in terms of treatment strategies we espouse, medications and other interventions we employ, and, of course, how we pay for mental health care.  It’s also a question that lies at the heart of what psychiatry is all about.

Anyone who has been to medical school or who has watched an episode of House knows that a disease has (a) an underlying pathology, often hidden to the naked eye but which is shared by all patients with that diagnosis, and (b) signs and symptoms, which are readily apparent upon exam but which may differ in subtle ways from patient to patient.  An expert physician performing a comprehensive examination can often make a diagnosis simply on the basis of signs and symptoms.  In some cases, more sophisticated tools (lab tests, scans, etc) are required to confirm the diagnosis.  In the end, once a diagnosis is obtained, treatment can commence.

(To be sure, sometimes a diagnosis is not apparent, and a provisional or “rule-out” diagnosis is given.  The doctor may initiate treatment on an empiric basis but will refine the diagnosis on the basis of future observations, responses to treatment, and/or disease course.)

In psychiatry, which is recognized as a branch of medicine and (should) subscribe to the same principles of diagnosis and treatment, the expectations are the same.  There are a number of diseases (or disorders) listed in the DSM-IV, each theoretically with its own underlying pathology and natural history, and each recognizable by a set of signs and symptoms.  A careful psychiatric evaluation and mental status exam will reveal the true diagnosis and suggest a treatment plan to the clinician.

It sounds simple, but it doesn’t always work out this way.  Psychiatrists may disagree about a given diagnosis, or make diagnoses based on “soft” signs.  Moreover, there are very few biological or biochemical tests to “rule in” a psychiatric diagnosis.  As a result, treatment plans for psychiatric patients often include multiple approaches that don’t make sense;  for example, using an antidepressant to treat bipolar disorder, or using antipsychotics to treat anxiety or insomnia symptoms in major depression.

The psychiatrist Nassir Ghaemi at Tufts has written about this before (click here for a very accessible version of his argument and here [registration required] for a more recent dialogue in which he argues his point further).  Ghaemi argues in favor of what he calls “Hippocratic psychopharmacology.” Specifically, we should understand and respect the normal course of a disease before initiating treatment.  He also emphasizes that we not treat symptoms, but rather the disease (this is also known as Osler’s Rule, in honor of Sir William Osler, the “founder of modern medicine”).  For example, Ghaemi makes a fairly compelling argument that bipolar disorder should be treated with a mood stabilizer alone, and not with an antidepressant, or an antipsychotic, or a sedative, because those drugs treat symptoms which should resolve as a person goes through the natural course of the disease.  In other words, we miss the diagnostic forest by focusing on the symptomatic trees.

The problem is, this is a compelling argument only if there is such a diagnosis as “bipolar disorder.”  Or, to be more specific, a clear, unitary entity with a distinct pathophysiological basis that gives rise to the symptoms that we see as mania and depression, and which all “bipolar” patients share.  And I don’t believe this assumption has been borne out.

My personal bias is that bipolar disorder does exist.  So do major depression, schizophrenia, panic disorder, anorexia nervosa, ADHD, and (almost) all the other diagnoses listed in the DSM-IV.  And a deeper understanding of the pathophysiology of each might help us to develop targeted treatments that will be far more effective than what have now.  But we’re not there yet.  In the case of bipolar disorder, lithium is a very effective drug, but it doesn’t work in everyone with “bipolar.”  Why not?  Perhaps “bipolar disorder” is actually several different disorders.  Not just formes frustes of the same condition but separate entities altogether, with entirely different pathophysiologies which might appear roughly the same on the outside (sort of like obesity or alcoholism).  Of course, there are also many diagnosed with “bipolar” who might really have no pathology at all– so it is no surprise that they don’t respond to a mood stabilizer (I won’t elaborate on this possibility here, maybe some other time).

The committee in charge of writing the DSM-5 is almost certainly facing this conundrum.  One of the “holy grails” of 21st century psychiatry (which I wrote about here) is to identify biochemical or genetic markers that predict or diagnose psychiatric disease, and it was hoped that the next version of the DSM would include these markers amongst its diagnostic criteria.   Unfortunately, this isn’t happening, at least not with DSM-5.  In fact, what we’re likely to get is a reshuffling and expansion of diagnostic criteria.  Which just makes matters worse:  how can we follow Osler’s advice to treat the disease and not the symptom when the definition of disease will change with the publication of a new handbook?

As a practicing psychiatrist, I’d love to be able to make a sound and accurate diagnosis and to use this diagnosis to inform my treatment, practicing in the true Hippocratic tradition and following Osler’s Rule, which has benefited my colleagues in other fields of medicine.  I also recognize that this approach would respect Dr Ghaemi’s attempt at bringing some order and sensibility to psychiatric practice.  Unfortunately, this is hard to do because (a) we still don’t know the underlying cause(s) of psychiatric disorders, and (b) restricting myself to pathophysiology and diagnosis means ignoring the psychosocial and environmental factors that are (in many ways) even more important to patients than what “disease” they have.

It has frequently been said that medicine is an art, not a science, and psychiatry is probably the best example of this truism.  Let’s not stop searching for the biological basis of mental illness, but also be aware that it may not be easy to find.  Until then, whether we treat “diagnoses” or “symptoms” is a matter of style.  Yes, the insurance company wants a diagnosis in order to provide reimbursement, but the patient wants management of his or her symptoms in order to live a more satisfying life.


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