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Depression Tests: When “Basic” Research Becomes “Applied”

April 22, 2012

Anyone with an understanding of the scientific process can appreciate the difference between “basic” and “applied” research.  Basic research, often considered “pure” science, is the study of science for its own sake, motivated by curiosity and a desire to understand.  General questions and theories are tested, often without any obvious practical application.  On the other hand, “applied” research is usually done for a specific reason: to solve a real-world problem or to develop a new product: a better mousetrap, a faster computer, or a more effective way to diagnose illness.

In psychiatric research, the distinction between “basic” and “applied” research is often blurred.  Two recent articles (and the accompanying media attention they’ve received) provide very good examples of this phenomenon.  Both stories involve blood tests to diagnose depression.  Both are intriguing, novel studies.  Both may revolutionize our understanding of mental illness.  But responses to both have also been blown way out of proportion, seeking to “apply” what is clearly only at the “basic” stage.

The first study, by George Papakostas and his colleagues at Massachusetts General Hospital and Ridge Diagnostics, was published last December in the journal Molecular Psychiatry.  They developed a technique to measure nine proteins in the blood, plug those values into a fancy (although proprietary—i.e., unknown) algorithm, and calculate an “MDDScore” which, supposedly, diagnoses depression.  In their paper, they compared 70 depressed patients with 43 non-depressed people and showed that their assay identifies depression with a specificity of 81% and a sensitivity of 91%.

The other study, published two weeks ago in Translational Psychiatry by Eve Redei and her colleagues at Northwestern University, purports to diagnose depression in adolescents.  They didn’t measure proteins in patients’ blood, but rather levels of RNA.  (As a quick aside, RNA is the “messenger” molecule inside each cell that tells the cell which proteins to make.)  They studied a smaller number of patients—only 14 depressed teenagers, compared with 14 non-depressed controls—and identified 11 RNA molecules which were expressed differently between the two groups.  These were selected from a much larger number of RNA transcripts on the basis of an animal model of depression: specifically, a rat strain that was bred to show “depressive-like” behavior.

If we look at each of these studies as “basic” science, they offer some potentially tantalizing insights into what might be happening in the bodies of depressed people (or rats).  Even though some of us argue that no two “depressed” people are alike—and we should look instead at person-centered factors that might explain how they are unique—these studies nevertheless might have something to say about the common underlying biology of depression—if such a thing exists.  At the very least, further investigation might explain why proteins that have no logical connection with depression (such as apolipoprotein CIII or myeloperoxidase) or RNA transcripts (for genes like toll-like-receptor-1 or S-phase-cyclin-A-associated protein) might help us, someday, to develop more effective treatments than the often ineffective SSRIs that are the current standard of care.

Surprisingly, though, this is not how these articles have been greeted.  Take the Redei article, for instance.  Since its publication, there have been dozens of media mentions, with such headlines as “Depression Blood Test for Teens May Lead To Less Stigma” and “Depression Researchers May Have Developed First Blood Test For Teens.”  To the everyday reader, it seems as if we’ve gone straight from the bench to the bedside.  Granted, each story mentions that the test is not quite “ready for prime time,” but headlines draw readers’ attention.  Even the APA’s official Twitter feed mentioned it (“Blood test for early-onset #depression promising,” along with the tags “#childrenshealth” and “#fightstigma”), giving it a certain degree of legitimacy among doctors and patients alike.

(I should point out that one of Redei’s co-authors, Bill Gardner, emphasized—correctly—on his own blog that their study was NOT to be seen as a test for depression, and that it required refinement and replication before it could be used clinically.  He also acknowledged that their study population—adolescents—are often targets for unnecessary pharmacological intervention, demanding even further caution in interpreting their results.)

As for the Papakostas article, there was a similar flurry of articles about it when preliminary results were presented last year.  Like Redei’s research, it’s an interesting study that could change the way we diagnose depression.  However, unlike Redei’s study, it was funded by a private, self-proclaimed “neurodiagnostics” company.  (That company, Ridge Diagnostics, has not revealed the algorithm by which they calculate their “MDDScore,” essentially preventing any independent group from trying to replicate their findings.)

Incidentally, the Chairman of the Board of Ridge Diagnostics is David Hale, who also founded—and is Chairman of—Somaxon Pharmaceuticals, a company I wrote about last year when it tried to bring low-dose doxepin to the market as a sleep aid, and then used its patent muscle to issue cease-and-desist letters to people who suggested using the ultra-cheap generic version instead of Somaxon’s name-brand drug.

Ridge Diagnostics has apparently decided not to wait for replication of its findings, and instead is taking its MDDScore to the masses, complete with a Twitter feed, a Facebook Page, and a series of videos selling the MDDScore (priced at a low, low $745!), aimed directly at patients.  At this rate, it’s only a matter of time before the MDDScore is featured on the “Dr Oz Show” or “The Doctors.”  Take a look at this professionally produced video, for instance, posted last month on Youtube:


(Interesting—the host hardly even mentions the word “depression.”  A focus group must have told them that it detracted from his sales pitch.)

I think it’s great that scientists are investigating the basic biology of depression.  I also have no problem when private companies try to get in on the act.  However, when research that is obviously at the “basic” stage (and, yes, not ready for prime time) becomes the focus of a viral video marketing campaign or a major story on the Huffington Post, one must wonder why we’ve been so quick to cross the line from “basic” research into the “applied” uses of those preliminary findings.  Okay, okay, I know the answer is money.  But who has the authority—and the voice—to say, “not so fast” and preserve some integrity in the field of psychiatric research?  Where’s the money in that?

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Did The APA Miss A Defining Moment?

April 1, 2012

Sometimes an organization or individual facing a potential public-relations disaster can use the incident as a way to send a powerful message, as well as change the way that organization or individual is perceived.   I wonder whether the American Psychiatric Association (APA) may have missed its opportunity to do exactly that.

Several weeks ago, the CBS news program 60 Minutes ran a story with the provocative argument that antidepressants are no better than placebo.  Reporter Lesley Stahl highlighted the work of Irving Kirsch, a psychologist who has studied the placebo effect for decades.  He has concluded that most, and maybe all, of the benefit of antidepressants can be attributed to placebo.  Simply put, they work because patients (and their doctors) expect them to work.

Since then, the psychiatric establishment has offered several counterarguments.  All have placed psychiatry squarely on the defensive.  One psychiatrist (Michael Thase), interviewed on the CBS program, defended antidepressants, arguing that Kirsch “is confusing the results of studies with what goes on in practice.”  Alan Schatzberg, past APA president and former Stanford chairman, said at a conference last weekend (where he spoke about “new antidepressants”) that the APA executive committee was “outraged” at the story, glibly remarking, “In this nation, if you can attack a psychiatrist, you win a medal.”  The leadership of the APA has mounted an aggressive defense, too.  Incoming APA president and Columbia chairman Jeffrey Lieberman called Kirsch “mistaken and confused, … ideologically based, [and] … just plain wrong.”  Similarly, current APA president John Oldham called the story “irresponsible and dangerous [and] … at odds with common clinical experience.”

These are indeed strong words.  But it raises one very important question:  who or what exactly are these spokesmen defending?  Patients?  Psychiatrists?  Drugs?  It would seem to me that the leadership of a professional medical organization should be defending good patient care, or at the very least, greater opportunities for its members to provide good patient care.  The arguments put forth by APA leadership, however, seem to be defending none of the above.  Instead, they seem to be defending antidepressants.

For the purposes of this post, I won’t weigh in on the question of whether antidepressants work or not.  It’s a complicated issue with no easy answer (we’ll offer some insight in the May issue of the Carlat Psychiatry Report).  However, let’s just assume that the general public now has good reason to believe that current antidepressants are essentially worthless, thanks to the 60 Minutes story (not to mention—just a few weeks earlier—a report on NPR’s “Morning Edition,” as well as a two-part series by Marcia Angell in the New York Review of Books last summer).  Justifiably or not, our patients will be skeptical of psychopharmacology going forward.  If we psychiatrists are hell-bent on defending antidepressants, we’d better have even stronger reasons for doing so than simply “we know they work.”

But why are psychiatrists defending antidepressants in the first place?  If anyone should be defending antidepressants, it should be the drug companies, not psychiatrists.  Why didn’t 60 Minutes interview a Lilly medical expert to explain how they did the initial studies of Prozac, or a Pfizer scientist to explain why patients should be put on Pristiq?  (Now that would have been fun!!)  I would have loved to hear Michael Thase—or anyone from the psychiatric establishment—say to Lesley Stahl:

“You know, Dr. Kirsch might just be onto something.  His research is telling us that maybe antidepressants really don’t work as well as we once thought.  As a result, we psychiatrists want drug companies to do better studies on their drugs before approval, and stop marketing their drugs so aggressively to us—and to our patients—until they can show us better data.  In the meantime we want to get paid to provide therapy along with—or instead of—medications, and we hope that the APA puts more of an emphasis on non-biological treatments for depression in the future.”

Wouldn’t that have been great?  For those of us (like me) who think the essence of depression is far more than faulty biology to be corrected with a pill, it would have been very refreshing to hear.  Moreover, it would help our field to reclaim some of the “territory” we’ve been abdicating to others (therapists, psychologists, social workers)—territory that may ultimately be shown to be more relevant for most patients than drugs.  (By the way, I don’t mean to drive a wedge between psychiatry and these other specialties, as I truly believe we can coexist and complement each other.  But as I wrote in my last post, psychiatry really needs to stand up for something, and this would have been a perfect opportunity to do exactly that.)

To his credit, Dr. Oldham wrote an editorial two weeks ago in Psychiatric News (the APA’s weekly newsletter) explaining that he was asked to contribute to the 60 Minutes piece, but CBS canceled his interview at the last minute.  He wrote a response but CBS refused to post it on its website (the official APA response can be found here).  Interestingly, he went on to acknowledge that “good care” (i.e., whatever works) is what our patients need, and also conceded that, at least for “milder forms of depression,” the “nonspecific [placebo] effect dwarfs the specific [drug] effect.”

I think the APA would have a pretty powerful argument if it emphasized this message (i.e., that the placebo effect might be much greater than we believe, and that we should study this more closely—maybe even harness it for the sake of our patients) over what sounds like a knee-jerk defense of drugs.  It’s a message that would demand better science, prioritize our patients’ well-being, and, perhaps even reduce treatment costs in the long run.  If, instead, we call “foul” on anyone who criticizes medications, not only do we send the message that we put our faith in only one form of therapy (out of many), but we also become de facto spokespersons for the pharmaceutical industry.  If the APA wants to change that perception among the general public, this would be a great place to start.


Antidepressants: The New Candy?

August 9, 2011

It should come as no surprise to anyone paying attention to health care (not to mention modern American society) that antidepressants are very heavily prescribed.  They are, in fact, the second most widely prescribed class of medicine in America, with 253 million prescriptions written in 2010 alone.  Whether this means we are suffering from an epidemic of depression is another thing.  In fact, a recent article questions whether we’re suffering from much of anything at all.

In the August issue of Health Affairs, Ramin Mojtabai and Mark Olfson present evidence that doctors are prescribing antidepressants at ever-higher rates.  Over a ten-year period (1996-2007), the percentage of all office visits to non-psychiatrists that included an antidepressant prescription rose from 4.1% to 8.8%.  The rates were even higher for primary care providers: from 6.2% to 11.5%.

But there’s more.  The investigators also found that in the majority of cases, antidepressants were given even in the absence of a psychiatric diagnosis.  In 1996, 59.5% of the antidepressant recipients lacked a psychiatric diagnosis.  In 2007, this number had increased to 72.7%.

In other words, nearly 3 out of 4 patients who visited a nonpsychiatrist and received a prescription for an antidepressant were not given a psychiatric diagnosis by that doctor.  Why might this be the case?  Well, as the authors point out, antidepressants are used off-label for a variety of conditions—fatigue, pain, headaches, PMS, irritability.  None of which have any good data supporting their use, mind you.

It’s possible that nonpsychiatrists might add an antidepressant to someone’s medication regimen because they “seem” depressed or anxious.  It is also true that primary care providers do manage mental illness sometimes, particularly in areas where psychiatrists are in short supply.  But remember, in the majority of cases the doctors did not even give a psychiatric diagnosis, which suggests that even if they did a “psychiatric evaluation,” the evaluation was likely quick and haphazard.

And then, of course, there were probably some cases in which the primary care docs just continued medications that were originally prescribed by a psychiatrist—in which case perhaps they simply didn’t report a diagnosis.

But is any of this okay?  Some, like a psychiatrist quoted in a Wall Street Journal article on this report, argue that antidepressants are safe.  They’re unlikely to be abused, often effective (if only as a placebo), and dirt cheap (well, at least the generic SSRIs and TCAs are).  But others have had very real problems discontinuing them, or have suffered particularly troublesome side effects.

The increasingly indiscriminate use of antidepressants might also open the door to the (ab)use of other, more costly drugs with potentially more devastating side effects.  I continue to be amazed, for example, by the number of primary care docs who prescribe Seroquel (an antipsychotic) for insomnia, when multiple other pharmacologic and nonpharmacologic options are ignored.  In my experience, in the vast majority of these cases, the (well-known) risks of increased appetite and blood sugar were never discussed with the patient.  And then there are other antipsychotics like Abilify and Seroquel XR, which are increasingly being used in primary care as drugs to “augment” antidepressants and will probably be prescribed as freely as the antidepressants themselves.  (Case in point: a senior medical student was shocked when I told her a few days ago that Abilify is an antipsychotic.  “I always thought it was an antidepressant,” she remarked, “after seeing all those TV commercials.”)

For better or for worse, the increased use of antidepressants in primary care may prove to be yet another blow to the foundation of biological psychiatry.  Doctors prescribe—and continue to prescribe—these drugs because they “work.”  It’s probably more accurate, however, to say that doctors and patients think they work.  And this may have nothing to do with biology.  As the saying goes, it’s the thought that counts.

Anyway, if this is true—and you consider the fact that these drugs are prescribed on the basis of a rudimentary workup (remember, no diagnosis was given 72.7% of the time)—then the use of an antidepressant probably has no more justification than the addition of a multivitamin, the admonition to eat less red meat, or the suggestion to “get more fresh air.”

The bottom line: If we’re going to give out antidepressants like candy, then let’s treat them as such.  Too much candy can be a bad thing—something that primary care doctors can certainly understand.  So if our patients ask for candy, then we need to find a substitute—something equally soothing and comforting—or provide them instead with a healthy diet of interventions to address the real issues, rather than masking those problems with a treat to satisfy their sweet tooth and bring them back for more.


Maybe Stuart Smalley Was Right All Along

July 31, 2011

To many people, the self-help movement—with its positive self-talk, daily feel-good affirmations, and emphasis on vague concepts like “gratitude” and “acceptance”—seems like cheesy psychobabble.  Take, for instance, Al Franken’s fictional early-1990s SNL character Stuart Smalley: a perennially cheerful, cardigan-clad “member of several 12-step groups but not a licensed therapist,” whose annoyingly positive attitude mocked the idea that personal suffering could be overcome with absurdly simple affirmative self-talk.

Stuart Smalley was clearly a caricature of the 12-step movement (in fact, many of his “catchphrases” came directly from 12-step principles), but there’s little doubt that the strategies he espoused have worked for many patients in their efforts to overcome alcoholism, drug addiction, and other types of mental illness.

Twenty years later, we now realize Stuart may have been onto something.

A review by Kristin Layous and her colleagues, published in this month’s Journal of Alternative and Complementary Medicine, shows evidence that daily affirmations and other “positive activity interventions” (PAIs) may have a place in the treatment of depression.  They summarize recent studies examining such interventions, including two randomized controlled studies in patients with mild clinical depression, which show that PAIs do, in fact, have a significant (and rapid) effect on reducing depressive symptoms.

What exactly is a PAI?  The authors offer some examples:  “writing letters of gratitude, counting one’s blessings, practicing optimism, performing acts of kindness, meditation on positive feelings toward others, and using one’s signature strengths.”  They argue that when a depressed person engages in any of these activities, he or she not only overcomes depressed feelings (if only transiently) but can also can use this to “move past the point of simply ‘not feeling depressed’ to the point of flourishing.”

Layous and her colleagues even summarize results of clinical trials of self-administered PAIs.  They report that PAIs had effect sizes of 0.31 for depressive symptoms in a community sample, and 0.24 and 0.23 in two studies specifically with depressed patients.  By comparison, psychotherapy has an average effect size of approximately 0.32, and psychotropic medications (although there is some controversy) have roughly the same effect.

[BTW, an “effect size” is a standardized measure of the magnitude of an observed effect.  An effect size of 0.00 means the intervention has no impact at all; an effect size of 1.00 means the intervention causes an average change (measured across the whole group) equivalent to one standard deviation of the baseline measurement in that group.  An effect size of 0.5 means the average change is half the standard deviation, and so forth.  In general, an effect size of 0.10 is considered to be “small,” 0.30 is “medium,” and 0.50 is a “large” effect.  For more information, see this excellent summary.]

So if PAIs work about as well as medications or psychotherapy, then why don’t we use them more often in our depressed patients?   Well, there are a number of reasons.  First of all, until recently, no one has taken such an approach very seriously.  Despite its enormous common-sense appeal, “positive psychology” has only been a field of legitimate scientific study for the last ten years or so (one of its major proponents, Sonja Lyubomirsky, is a co-author on this review) and therefore has not received the sort of scientific scrutiny demanded by “evidence-based” medicine.

A related explanation may be that people just don’t think that “positive thinking” can cure what they feel must be a disease.  As Albert Einstein once said, “You cannot solve a problem from the same consciousness that created it.”  The implication is that one must seek outside help—a drug, a therapist, some expert—to treat one’s illness.  But the reality is that for most cases of depression, “positive thinking” is outside help.  It’s something that—almost by definition—depressed people don’t do.  If they were to try it, they may reap great benefits, while simultaneously changing neural pathways responsible for the depression in the first place.

Which brings me to the final two reasons why “positive thinking” isn’t part of our treatment repertoire.  For one thing, there’s little financial incentive (to people like me) to do it.  If my patients can overcome their depression by “counting their blessings” for 30 minutes each day, or acting kindly towards strangers ten times a week, then they’ll be less likely to pay me for psychotherapy or for a refill of their antidepressant prescription.  Thus, psychiatrists and psychologists have a vested interest in patients believing that their expert skills and knowledge (of esoteric neural pathways) are vital for a full recovery, when, in fact, they may not be.

Finally, the “positive thinking” concept may itself become too “medicalized,” which may ruin an otherwise very good idea.  The Layous article, for example, tries to give a neuroanatomical explanation for why PAIs are effective.  They write that PAIs “might be linked to downregulation of the hyperactivated amygdala response” or might cause “activation in the left frontal region” and lower activity in the right frontal region.  Okay, these explanations might be true, but the real question is: does it matter?  Is it necessary to identify a mechanism for everything, even interventions that are (a) non-invasive, (b) cheap, (c) easy, (d) safe, and (e) effective?   In our great desire to identify neural mechanisms or “pathways” of PAIs, we might end up finding nothing;  it would be a shame if this result (or, more accurately, the lack thereof) leads us to the conclusion that it’s all “pseudoscience,” hocus-pocus, psychobabble stuff, and not worthy of our time or resources.

At any rate, it’s great to see that alternative methods of treating depression are receiving some attention.  I just hope that their “alternative-ness” doesn’t earn immediate rejection by the medical community.  On the contrary, we need to identify those for whom such approaches are beneficial; engaging in “positive activities” to treat depression is an obvious idea whose time has come.


Another Day, Another Seroquel XR Indication?

June 1, 2011

Just when you thought the antipsychotic drug Seroquel had fully penetrated doctors’ offices and patients’ medicine chests (not to mention law offices and children’s tummies) all across America, a new clinical trial is recruiting subjects for yet another indication for this ubiquitous drug.

Technically, the trial is of Seroquel XR, not Seroquel.  (Because, you know, the two are COMPLETELY different drugs, as described in this YouTube video.)  But you get the idea.  Anything to keep the money flowing for Astra-Zeneca, especially after Seroquel goes generic in 2012.

Thanks to a tip from Stephany at Soulful Sepulcher, you can read all the details of this study here.  It’s called the “Quietude Study,” a trial of Seroquel XR for the treatment of agitated depression.  Specifically, they want to compare Seroquel XR (at doses up to 150 or 300 mg/day) with Lexapro (up to 20 mg/day), and the investigators predict that Seroquel XR will be more effective in the management of depression “with prominent agitation.”

Two things caught my eye right away:  First, the name of the study (“Quietude”) is obviously a play on words, since the generic name for Seroquel is quetiapine.  How cute.  I also noticed that the study is being conducted by Roger McIntyre, MD, whom I saw just yesterday on the medical website QuantiaMD giving a blatantly obvious “infomercial” for Geodon (for Quantia members, here’s the link), a competitor’s drug.  [And for more info on QuantiaMD, see Daniel Carlat’s recent post about this site.])

But let’s get more substantive, shall we?  A look at the details of this new “Quietude” study is revealing.  For one thing, the opening statement of the study’s “Purpose” is:  “Most individuals with major depressive disorder manifest clinically significant agitation.”  Really?  I’ve certainly seen cases of agitated depression, but are “most” depressed patients agitated?  Not in my experience.  Maybe when they say “agitation” they’re including patients with akathisia, an occasional side effect of some antidepressant medication.  I understand research proposals always have to start with a statement about how widespread the problem is, but this one seems a bit of a stretch.

The inclusion and exclusion criteria are also included in the study design.  One of the inclusion criteria, along with the typical symptomatic measures (i.e., HAM-D >20 and CGI-S >4), is “significant agitation.”  That’s it.  By whose measure?  Patient report?  Clinician’s evaluation?  I’d really like to know more about how the “agitated” folks are going to be selected.

Some interesting exclusion criteria are (a) “known lack of antidepressant response to escitalopram [Lexapro]” and (b) “known lack of antidepressant response to quetiapine [Seroquel].”  So they’re enriching their population for individuals who have not already tried Lexapro or Seroquel and failed to respond to the antidepressant effect. Perhaps this isn’t a huge problem, but Seroquel XR is not the greatest antidepressant (see below), and this exclusion criterion will probably weed out the patients who gained weight on Seroquel or “felt like a zombie”—two common complaints with this medication which often lead to its discontinuation.

But what disturbs me the most about this trial is the fact that it seems entirely unnecessary.  The fact of the matter is that Seroquel XR is–for better or for worse—already used for many cases of “agitated depression.”  And it’s not even entirely off-label, because Seroquel XR is approved for bipolar depression and for the adjunctive treatment of MDD (whether it actually works as an antidepressant is another story).  As mentioned above, quetiapine is a sedating drug in many patients, so of course a psychiatrist is going to think about it for “agitated depression.”  (Unless he/she wants to take the time to determine the causes of the patient’s agitation, which, unfortunately, often does not happen.)

But there’s more.  When Seroquel XR was first introduced, with much fanfare, for the treatment of depression, I remember being somewhat skeptical and asking my local AstraZeneca sales force whether it had any “antidepressant effect” other than its well-known sedative and appetite-enhancing effects (because, after all, those are two of the symptoms of depression typically measured in clinical trials).  I was reassured that, no, no, Seroquel XR is more than that; it acts on all depressive symptoms, probably through its metabolite norquetiapine.

In fact, a year ago I emailed a local “key opinion leader” who spoke extensively for AstraZeneca and was told the following (emphasis added; BTW, if it’s too technical for you, don’t worry, go ahead and skip):

I think the concept is that quetapine at low doses (25-50-100 mg) is almost entirely anti-histaminergic and anti-muscarinic. However at the 150-300 mg doses there is significant norepinephrine transporter inhibition from the metabolite norquetapine as well as 5HT 1A agonism and 5HT2A AND 5HT2-C antagonism which all increase dopamine. Thus at the higher doses of 150-300 mg there is significant antidepressant activity but also increases in frontal, limbic and striatal dopamine which can be stimulatory (as well as having anti-depressant effects). At the 600-800 mg doses there is significant D-2 antagonism which is where the antipsychotic effect (D-2 antagonism) kicks in. Thus as the doses escalate patients go from pure sedation to antidepressant to antipsychotic effects.  At least this is the theory based on the dose related relative strength and affinities for its respective receptors.

The premise of the “Quietude” study seems to be telling us something different—even though it’s what we already knew if we only paid attention to what our patients tell us (and not necessarily to AstraZeneca): namely, that the primary advantage of intermediate-dose Seroquel XR does seem to be its sedative effect.  And this might indeed make it effective for the treatment of the “psychological and physical restlessness” associated with depression.

Anyway, because the trial is only being run in Canadian sites, I won’t have to worry about whether to refer my patients to it.  But it’s also a trial whose results I won’t exactly be anxiously awaiting.


Biomarker Envy III: Medial Prefrontal Cortex

May 28, 2011

Well, what do you know…. No sooner did I publish my last post about the “depression biomarker” discovered by a group of Japanese scientists, than yet another article appeared, describing a completely different biomarker.  This time, however, instead of simply diagnosing depression, the goal was to identify who’s at risk of relapse.  And the results are rather tantalizing… Could this be the real deal?

The paper, to be published in the journal Biological Psychiatry, by Norman Farb, Adam Anderson, and colleagues at the University of Toronto, had a simple research design.  They recruited 16 patients with a history of depression, but who were currently in remission (i.e., symptom-free for at least five months), as well as 16 control subjects.  They performed functional MRI (fMRI) imaging on all 32 participants while exposing them to an emotional stressor: specifically, they showed the subjects “sad” or “neutral” film clips while they were in the MRI scanner.

Afterward, they followed all 16 depressed patients for a total of 18 months.  Ten of these patients relapsed during this period.  When the group went back to look for fMRI features that distinguished the relapsers from the non-relapsers, they found that the relapsers, while viewing the “sad” film clips, had greater activity in the medial prefrontal cortex (mPFC).  The non-relapsers, on the other hand, showed greater activation in the visual cortex when viewing the same emotional trigger.

Even though the number of patients was very small (16 total), the predictive power of the tests was actually quite high (see the figure at right – click for a larger version).  It’s certainly conceivable that a test like this one might be used in the future to determine who needs more aggressive treatment—even if our checklists show that a depressed patient is in remission.  As an added bonus, it has better face validity than simply measuring a chemical in the bloodstream: in other words, it makes sense that a depressed person’s brain responds differently to sad stimuli, and that we might use this to predict outcomes.

As with most neuroimaging research, the study itself was fairly straightforward.  Making some sense out of the results, however, is another story.  (Especially if you like salmon.)

The researchers had predicted, based on previous studies, that patients who are prone to relapse might show greater activity in the ventromedial prefrontal cortex (VMPFC) and lower activity in the dorsolateral PFC (DLPFC).  But that’s not what they found.  Instead, relapsers had greater activity in the mPFC (which is slightly different from the VMPFC).  Moreover, non-relapsers had greater activity in the visual cortex (specifically the calcarine sulcus).

What might this mean?  The authors hypothesize that mPFC activity may lead to greater “ruminative thought” (i.e., worrying, brooding).  In fact, they did show that mPFC activation was correlated with scores on the RSQ-R, a psychological test of ruminative thought patterns.  Regarding the increased visual cortex activity, the authors suggest that this may be protective against further depressive episodes.  They surmise that it may be a “compensatory response” which might reflect “an attitude of acceptance or observation, rather than interpretation and analysis.”

In other words, to grossly oversimplify:  if you’re in recovery from depression, it’s not a good idea to ruminate, worry, and brood over your losses, or to internalize someone else’s sadness (even if it’s just a 45-second clip from the movie “Terms of Endearment”—which, by the way, was the “sad stimulus” in this experiment).  Instead, to prevent another depressive episode, you should strengthen your visual skills and use your visual cortex to observe and accept (i.e., just watch the darn movie!).

This all seems plausible, and the explanation certainly “fits” with the data.  But different conclusions can also be drawn.  Maybe those “recovered” patients who had less mPFC activity were simply “numb” to any emotional stimuli.  (All patients were taking antidepressants at the time of the fMRI study, which some patients report as having a “numbing” effect on emotions.)  Moreover, it has been said that depression can sometimes be beneficial; maybe the elevated mPFC activity in relapsers was an ongoing attempt to process the “sad” inputs in a more productive way?  As for the protective effect of visual cortex activity, maybe it isn’t about “acceptance” or “non-judgment” at all, but something else entirely?  Maybe those patients just enjoyed watching Shirley Maclaine and Jack Nicholson.

Nevertheless, the more psychologically minded among us might gladly embrace their explanations.  After all, it just seems “right” to say:  “Rumination is bad, acceptance and mindfulness (NB:  the authors did not use this term) is good.”  However, their “mediation analysis” showed that rumination scores did not predict relapse, and acceptance scores did not predict prolonged remission.  In other words, even though these psychological measures were correlated with the MRI findings, the psychological test results didn’t predict outcome.  Only the MRI findings did.

This leads to an interesting take-home message.  The results seem to support a psychological approach to maintaining remission—i.e., teaching acceptance and mindfulness, and avoiding ruminative tendencies—but this is only part of the solution.  Activity in the mPFC and the visual cortex might underlie pro-depressive and anti-depressive tendencies, respectively, in depressed patients, via mechanisms that are entirely unknown (and, dare I say it, entirely biologic?).

[An interesting footnote:  the risk of relapse was not correlated with medications.  Out of the ten who relapsed, three were still taking antidepressants.  Of the other seven, four were engaged in mindfulness-based cognitive therapy (MBCT), while the others were taking a placebo.]

Anyway, this paper describes an interesting finding with potential real-world application.  Although it’s a small study, it’s loaded with testable follow-up hypotheses.  I sincerely hope they continue to fire up the scanner, find some patients, and test them.  Who knows—we might just find something worth using.


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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