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Biomarker Envy I: Cortical Thickness

May 13, 2011

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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How Lithium Works (Maybe)

February 17, 2011

“Half of what we have taught you is wrong.  Unfortunately, we don’t know which half.”

— attributed to a Harvard Medical School dean at commencement, sometime in the 20th century

The above, possibly apocryphal, statement is often invoked to illustrate how dynamic the field of medicine can be, and how what we thought we once knew beyond a shadow of a doubt, sometimes turns out to be dead wrong.  It’s also a celebration of scientific progress; as we revise our pathophysiological models, we can develop more targeted therapeutics.

In this regard, psychiatry is no different from any other field of medicine.  We don’t know (yet) what we don’t know, but once we do, our treatments will improve.  At the same time, we need to be careful how we use this new information, lest it give us a false sense that we “know” something we don’t.

I thought of this question when I encountered a headline earlier today at psychcentral.com“How Lithium Works Finally Explained.” Talk about a tantalizing headline!  First used clinically in the late 1800s (and later “rediscovered” in the 1940s), and still used extensively as a mood stabilizer in bipolar disorder and as adjunctive treatment for major depression, lithium is one of the most widely prescribed medications in all of medicine.  Many patients report a very good response to lithium, and its efficacy has not been surpassed by the multitude of other mood stabilizing agents introduced in the last 40 years.

But there’s just one problem.  Nobody really knows how lithium works.  It’s an ion (similar to sodium), so it doesn’t bind to a receptor or transporter, like most other psychiatric drugs.  It doesn’t seem to affect membrane potential (and therefore neuron excitability), and it doesn’t seem to target any particular region of the brain, much less those thought to be involved in mood disorders.  It may inhibit intracellular messengers (the phosphatidylinositol pathway) or it might inhibit cellular differentiation (via the Wnt signaling pathway).  Maybe it blocks sodium ion transport.  Maybe it interacts with nitric oxide.  No one knows.  And yet it works.

So it was with great interest that I read the original paper cited in the Psychcentral article.  It’s a “mega-analysis,” published in the February 15 issue of Biological Psychiatry, of 321 bipolar patients in 11 centers worldwide who underwent MRI scans and were compared to non-bipolar controls.  Half of the bipolar patients were taking lithium.  To summarize the results, patients taking lithium had larger hippocampal and amygdala volumes than those not taking lithium, and patients with a longer history of bipolar disorder had reduced cerebral volumes.

The data, then, seem to be consistent with the idea of lithium as having a “trophic” effect—i.e., as a promoter of neuronal growth, at least in some brain structures.  But that’s about all we can say.  Whether this has anything to do with intracellular signaling or the Wnt pathway, or with any known nerve growth factors, is beyond the scope of this study.

So despite the exciting headline claiming to identify the “mechanism of lithium,” this is simply an observation, much like the observation about how antipsychotics may decrease brain volumes, about which I wrote last week.  It suggests further research to understand lithium’s effect on these regions.  But it may not be clinically relevant.

Lithium is a widely used drug because it works.  Period.  These new data add to our knowledge about bipolar disorder, but to assume that they help us understand bipolar patients any better than we did before, is incorrect.  Moreover, it may lead us to draw false conclusions about our patients (i.e., “he’s not responding to lithium so his hippocampus must be atrophied”) or, worse, reject or disregard data that don’t fit with our hypothesis.  I’d much rather prescribe a drug because I have years of experience using it, and have heard hundreds of patients endorse its benefit, rather than adhere to an incorrect theory, even a theory with “face validity” like lithium promoting nerve cell growth and differentiation.  In fact it’s not too hard to find arguments against this theory:  for starters, consider lithium’s teratogenic effects during human embryonic development.

Anyone who wants an accurate explanation for how a psychiatric drug works is, unfortunately, out of luck.  The serotonin hypothesis is a perfect example:  SSRIs work in a lot of patients, and the serotonin hypothesis helps to guide treatment, but it might be absolutely incorrect.  How many alternate explanations have we ignored because we want to believe that our model must be right?

We can, and should, continue to use SSRIs to treat depression, and lithium to treat bipolar disorder.  But we should be aware that our explanations of their mechanisms are mere hypotheses—nothing more.  And, moreover, that these hypotheses may be contradicted or proven wrong.  Because we don’t know which half of our knowledge is the correct half.


“That’s OK, I Didn’t Need That Brain Anyway”

February 10, 2011

Long-term treatment with antipsychotic medication apparently causes a decrease in brain volume, according to a new report by Nancy Andreasen’s group at the University of Iowa in this month’s Archives of General Psychiatry. In the study, over 200 schizophrenic patients, treated with antipsychotics, underwent MRI scans of their brains at various intervals over a 5-14 year period. The results showed that the “intensity” of antipsychotic treatment (i.e., doses and lengths of treatment) correlated with the reduction in brain tissue.

Instead of just looking at an overall “snapshot” of the brain, researchers calculated the volumes of several brain regions (from the whole-brain MRI scans) and found, on average, subtle decreases in both gray matter and white matter volumes, as well as enlargement of the ventricles (the “spaces” in the normal brain). The changes were more pronounced with longer time periods of treatment and, in particular, when higher doses of antipsychotics were used for extended periods of time.

As expected, this finding has generated a great deal of interest— if not concern– and more than a touch of “I-told-you-so” from certain camps (see “Antipsychotics Shrink the Brain” by Robert Whitaker). Indeed, at first blush, it is quite shocking to think that the first-line treatment for such a devastating brain disease might cause damage to the very organ we are trying to treat.

But is it really “damage”? All joking aside, I think the title of this post needs to be taken seriously. Does the observed loss in brain tissue loss mean that a person is incapacitated in any way? That he can no longer think, feel, see, taste, or make plans for the future? Moreover, despite the headlines, the tissue loss was not incredibly dramatic. In other words, we’re not talking about a healthy, robust brain turning into a moth-eaten mass of Swiss cheese. In fact, by my read of the data, the largest individual change in frontal gray matter volume was from about 330 cm3 to 290 cm3 over a 10-year period (yes, that’s >10%, but who knows what else was happening in that patient?). Other changes were much smaller, and many patients actually showed increases in brain volumes.

There were slight correlations with disease severity (more symptomatic disease was associated with a greater decrease in brain volume), and different classes of antipsychotics affected some regions of the brain differently than others. Interestingly, there seemed to be no independent effect of substance abuse on brain volume changes, despite the oft-heard warning that drugs and alcohol “kill brain cells.”

So what does this all mean? Obviously, some will say that this provides evidence that antipsychotics are toxic to brain cells. But there’s no clear evidence that neurons are actually dying; in some studies in monkeys taking antipsychotic medication, the number of neurons remains constant, but they increase in density because support cells (called glia) decrease in number– resulting in the macroscopic appearance of a “smaller brain.”

Moreover, it is quite possible that the disease process itself already leads to a decrease in brain volume (actually, we know this already) and effective treatment helps to further “prune” dysfunctional areas of the brain. In fact, an editorial accompanying the article claims that “strategic reductions in brain volume” might actually be therapeutic, and reminds us that gray matter volume decreases significantly during human adolescence, a process thought to underlie the organization and refinement of brain cells, and elimination of redundancy. (No wonder you have to tell your teenage son six times to clean his room.)

The best way to tackle this question, of course, is to take two groups of schizophrenics, treat one “as usual” with antipsychotics and the other with no medication at all, and perform brain scans at regular intervals. For ethical reasons, we can’t do this (it’s unethical not to treat a psychotic patient with an antipsychotic– although some would argue differently). Another way is to take advantage of the fact that many non-schizophrenic patients are now taking antipsychotics for OTHER diagnoses– bipolar disorder, depression, anxiety, insomnia, PTSD (just to name a few)– and we could compare those on antipsychotics to those on other drugs. If we see brain tissue loss across a wide spectrum of diagnoses, it suggests that this effect may be a direct result of antipsychotic treatment, even though the mechanism remains unknown.

Regardless of what’s actually happening in the brains of treated schizophrenics– and whether it’s “good” or “bad,” or whether it resembles the brain loss observed in birds living near Chernobyl— two things must be kept in mind. First, the patient’s well-being is of utmost importance; it would be inappropriate to withhold antipsychotic treatment from a patient who is clearly tormented and disabled from his paranoia, his delusional preoccupations, and his absolute lack of insight, particularly when we know that such medications do, in most cases, result in dramatic improvement. At the same time, we must also consider the other side of the coin, namely that if antipsychotics might cause an unexplained loss in brain tissue—or any other anatomic defect elsewhere, for that matter—we must seriously consider our rationale for these drugs. In particular, brain development in children is an ongoing process, not complete until late adolescence or early adulthood.

Hopefully this finding will stimulate research to determine how antipsychotics affect brain cells over time. Perhaps then we can find ways to preserve brain structure – or, at least, essential brain structure—while still treating the symptoms of mental illness. In other words, avoiding harm, while still doing good.


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