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Biomarker Envy I: Cortical Thickness

In the latest attempt to look for biological correlates or predictors of mental illness, a paper in this month’s Archives of General Psychiatry shows that children with major depressive disorder (MDD) have thinner cortical layers than “healthy” children, or children with obsessive-compulsive disorder (OCD).  Specifically, researchers performed brain MRI scans on 78 children with or without a diagnosis, and investigated seven specific areas of the cerebral cortex.  Results showed four areas which were thinner in children with MDD than in healthy children, two which were thicker, and one that did not vary.

These results add another small nugget of data to our (admittedly scant) understanding of mental illness—particularly in children, before the effects of years of continuous medication treatment.  They also represent the bias towards imaging studies in psychiatry, whose findings—even if statistically significant—are not always that reliable or meaningful.  (But I digress…)

An accompanying press release, however, was unrealistically enthusiastic.  It suggested that this study “offers an exciting new way to identify more objective markers of psychiatric illness in children.”  Indeed, the title of the paper itself (“Distinguishing between MDD and OCD in children by measuring regional cortical thickness”) might suggest a way to use this information in clinical practice right away.  But it’s best not to jump to these conclusions just yet.

For one, there was tremendous variability in the data, as shown in the figure at left (click for larger view).  While on average the children with MDD had a thinner right superior parietal gyrus (one of the cortical regions studied) than healthy children or children with OCD, no individual measurement was predictive of anything.

Second, the statement that we can “distinguish between depression and OCD” based on a brain scan reflects precisely the type of biological determinism and certainty (and hype?) that psychiatry has been striving for, but may never achieve (just look at the figure again).  Lay readers—and, unfortunately, many clinicians—might read the headline and believe that “if we just order an MRI for Junior, we’ll be able to get the true diagnosis.”  The positive predictive value of any test must be high enough to warrant its use in a larger population, and so far, the predictive value of most tests in psychiatry is poor.

Third, there is no a priori reason why there should be a difference between the brains (or anything else, for that matter) of patients with depression and patients with OCD, when you consider the overlap between these—and other—psychiatric conditions.  There are many shades of grey between “depression” and “OCD”:  some depressed children will certainly have OCD-like traits, and vice versa.  Treating the individual (and not necessarily the individual’s brain scan) is the best way to care for a person.

To be fair, the authors of the study, Erin Fallucca and David Rosenberg from Wayne State University in Detroit, do not state anywhere in their paper that this approach represents a “novel new diagnostic method” or make any other such sweeping claims about their findings.  In fact, they write that the differences they observed “merit further investigation” and highlight the need to look “beyond the frontal-limbic circuit.”  In other words, our current hypotheses about depression are not entirely supported by their findings (true), so we need to investigate further (also true).  And this, admittedly, is how science should proceed.

However, the history of psychiatry is dotted with tantalizing neurobiological theories or findings which find their way into clinical practice before they’ve been fully proven, or even shown any great clinical relevance.  Pertinent examples are the use of SPECT scans to diagnose ADHD, championed by Daniel Amen; quantitiative EEG to predict response to psychotropics; genotyping for metabolic enzymes; and the use of SSRIs to treat depression.  (Wait, did I say that???)

The quest to identify “biomarkers” of psychiatric illness may similarly lead us to believe we know more about a disease than we do.  A biomarker is a biological feature (an endocrine or inflammatory measure, a genotype, a biochemical response to a particular intervention) that distinguishes a person with a condition from one without.  They’re used throughout medicine for diagnosis, risk stratification and monitoring treatment response.   A true biomarker for mental illness would represent a significant leap ahead in personalized treatment.  Or would it?  What if a person’s clinical presentation differs from what the marker predicts?  “I’m sorry Mrs. Jones, but even though Katie compulsively washes her hands and counts to twelve hundreds of times a day, her right superior parietal gyrus is too thin for a diagnosis of OCD.”

Other fields of medicine don’t experience this dilemma.  If you have an elevated hsCRP and high LDL, even though you “feel fine,” you are still at elevated risk for cardiovascular disease and really ought to take preventive measures (exercise, diet, etc).  (However, see this recent editorial in the BMJ about “who should define disease.”)  But if your brain scan shows cortical thinning and you have no symptoms of depression, do you need to be treated?  Are you even at risk?

Some day (hopefully) these questions will be answered, as we gain a greater understanding of the biology of mental illness.  But until then, let’s keep research and clinical practice separate until we know what we’re doing.  Psychiatry doesn’t have to be like other fields of medicine.  Patients suffer and come to us for help; let’s open our eyes and ears before sending them off to the scanner or the lab.  In doing so, we might learn something important.

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13 Responses to Biomarker Envy I: Cortical Thickness

  1. Jackie says:

    Another aspect that makes psychiatric illness more challenging than a lot of other medical fields is that it’s not all about mood (depression, mania, etc.) and behavior but also about present and future cognition.

    So, if you have (from your example) cortical thinning but no depression, should you be treated to ward off cognitive problems in the future? This is obviously a rhetorical question! But it’s part of the puzzle.

    • stevebMD says:

      Jackie,

      I figured I’d re-post the link you provided in a comment yesterday, since it makes more sense here:

      http://blogs.wsj.com/health/2011/05/11/public-education-and-gene-testing-to-improve-medication-adherence/?mod=WSJBlog

      Gene testing (or using “pharmacogenomics”) to predict treatment response or avoid side effects is yet another example of “personalized medicine” that is simply not ready for prime time. I’m not saying the research shouldn’t be done, or that it may not provide anything valuable for the future of psychiatry, but in its present state, telling my patient to pay hundreds of dollars for genomic testing is like putting the cart in front of the horse.

      At the risk of sounding too cynical, it’s yet another example of something that sounds good in theory, and might have a bit of evidence to back it up, but is at risk of becoming established as “fact” before well-controlled studies have been performed. (And don’t forget, the biotech companies offering the tests are more than happy to accept our patients’ money for the testing, data be damned.)

      My fear as a young psychiatrist is that, if we get too carried away, our field will be doing a lot of back-pedaling in the future. I’d rather not be the one doing it.

      • Jackie says:

        Dr. Steve,

        From the way I am reading things, the test doesn’t do much more than tell what kind of metabolizer of a certain drug a person is, or how a drug-drug interaction is affecting levels of each drug. And I think you can do that from a simple blood test, if it’s an issue.

        You know I’m no doctor, but I am very interested in the
        pharmacodynamics and pharmacokinetics of drugs. Reading the basics has helped me understand things a little bit better.

        I wish there were simple genetic tests, but there aren’t and I agree with you that caution is needed. It is an exciting field and I enjoy reading your blog so much. Thanks for doing this.

  2. duanesherry says:

    Canadian psychiatrists look at taking things in a different direction –

    http://www.mcgill.ca/newsroom/news/item/?item_id=174348

    Actually, this seem much safer.

    Duane Sherry, M.S.
    discoveranrecover.wordpress.com

  3. duanesherry says:

    A more accurate segue might have been –

    Majority of Canadian physicians believe placebos can have therapeutic effects, many use them… Psychiatrists more likely to place value in their influence.

    At-ease.

    Duane

    • duanesherry says:

      Actually, they’re doing more than “looking” into the benefits of placebo… A third of the psychiatrists in Canada (by survey) use placebo in their practice!

      Why?

      Could it be that to capitalizing on the “placebo effect” without the fallout of psychiatric drugs is what motivates their decisions to use placebo?

      Placebo effect is strong.
      Placebo effect works, and it works well.

      Drug makers need only beat placebo by a few points… Even AFTER they toss out half the data, it’s hard for them to do! –

      http://www.ahrp.org/cms/index.php?searchword=placebo&option=com_search&Itemid=5

      If a placebo pill is colored, marked (to look like a real drug), it’s tough for ANY psychiatric drug to beat a placebo. The amazing part is what happens when a side-effect, such as a dry mouth is put into the equation with placebo…

      That’s when the real “magic” of medicine happens.
      That’s when term “more harm than good” begins to really resonate with psychiatric drugs!
      Read ‘Anatomy of an Epidemic’ by Robert Whitaker

      Psychiatry.
      Is it science?
      Is it “magic?”

      … Interesting that the survey from McGill (cited above) was commented on by not only a psychiatrist, but one who was a former MAGICIAN!

      If so many people weren’t being injured by these drugs, it would be hilarious! Unfortunately, people are being injured… gravely injured –

      http://breggin.com/index.php?option=com_docman&Itemid=37

      And yet, psychiatry continues on its path… and those of us who choose to stand-up, and speak-out are called ‘scientologists’, or worse.

      It reminds me of some of the lines from one of my favorite movies…

      “Pay no attention to the man behind the curtain…. The great ans powerful OZ has spoken”

      The Problem with Drug Related Studies, Timothy Scott, Ph.D. –

      http://www.ihealthtube.com/aspx/viewvideo.aspx?v=337dc5fa25677983

      Duane Sherry, M.S.
      discoverandrecover.wordpress.com

  4. duanesherry says:

    Steve,

    If the hoopla over the 2nd generation, atypical antipsychotics (neuroleptics) was not a lesson for psychiatry…

    There are lots of ways to treat “mental illness”…
    These are some options for miltary service members and veterans –

    http://discoverandrecover.wordpress.com/2011/03/12/recovery-resources-military-service-members-and-veterans

    Duane Sherry

  5. Tom says:

    Isn’t the “personalized medicine” approach in psychiatry being led by a well known gang of . . . well, let’s see how to phrase this … how about “Nemeroffian” psychiatrists? You know the creepy crew– Schatzberg, Keller, Charlie “Bling Bling”, Thase, and others of this infamous ilk? It sure gives me the creeps! Hold onto to your wallets, folks!!!

  6. duanesherry says:

    Hold onto your kids, too.

    Duane

  7. Mickey says:

    That graph is truly remarkable! Makes one wonder what “p” really stands for…

  8. coping anxiety, coping panic, coping phobias, coping fear…

    […]Biomarker Envy I: Cortical Thickness « Thought Broadcast[…]…

  9. Margot says:

    Hey! This post couldn’t be written any better! Reading through this post reminds
    me of my good old room mate! He always kept chatting about this.

    I will forward this write-up to him. Pretty sure he will
    have a good read. Many thanks for sharing!

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