anachronistic inertia…

Posted on Saturday 28 December 2013

Earlier this year, I had what I called the you-really-are-an-old-man-now tests. Included were a stress test and an echocardiogram – all suprisingly normal. But in both instances, the technicians learning that I was a doctor and wanted to look proudly showed off their equipment and my results. My 1960s vintage Internist self was amazed. In my day, a stress test was walking on a treadmill with an EKG. They still do that, but there was also imaging showing the metabolism in my heart during stress that was better than a modern computer animated action flick. The echocardiogram was even more impressive. In the 1960s, it was grainy polaroids – stills. In 2013, it was amazingly clear movies of a heart in action with stop action replays. I had developed a little murmur recently, and the echo showed an inconsequential calcification on a valve that correlated with the murmur. And their ability to view things and move around was beyond my imagination. Mature technology is truly impressive!

As an aging computer type and technocrat, I read the neuroimaging studies in our journals when I run across them. My reaction is hardly similar to that described above. I’m impressed with the MRIs and CAT scans of the brain in a neurological setting – tumors, strokes, atrophy. It’s a diagnostic tool of extraordinary merit. But when I look at the PET scans and fMRIs being studied in psychiatric research, I always think about what a long way they have to go. And in most of the papers, I become a doubting Thomas. If I can’t see the results, I’m unconvinced. And in most of the papers, there are a few selected images with graphs and tables so far removed from the data that I tend to glaze over. I feel like I’m being asked to take the author’s word for the results – and that’s not okay in psychiatry these days, at least not for me.

A few days ago, I was writing about personalized medicine [$9,199,613.00 [and counting]…] and Dr. Trivedi’s study looking for a biomarker to predict responses to Zoloft® vs Wellbutrin®. I’ll admit that I can hardly keep a straight face when talking about it. There’s no evidence that there are populations with this differential response. To the contrary, Dr. Trivedi’s own CO-MED study suggests that there isn’t one since combining the two drug classes doesn’t improve responses. Psychiatry may need some biomarkers, but not for that! Which brings me to the announcement in various places that Helen Mayberg at Emory announces that she can show a difference in the brains of depressed patients who will respond to Lexapro® vs Cognitive Behavior Therapy [CBT] using PET Scans. My suspicions about "personalized medicine," about  Dr. Mayberg [one of Dr. Nemeroff’s Emory colleagues], and psychiatric neuroimaging reports in general created a cacophony of inner discord before I even looked at the paper. Here’s the abstract:
by McGrath CL, Kelley ME, Holtzheimer PE, Dunlop BW, Craighead WE, Franco AR, Craddock RC, and Mayberg HS.
JAMA Psychiatry. 2013 70[8]:821-829.

Currently, fewer than 40% of patients treated for major depressive disorder achieve remission with initial treatment. Identification of a biological marker that might improve these odds could have significant health and economic impact.
OBJECTIVE: To identify a candidate neuroimaging "treatment-specific biomarker" that predicts differential outcome to either medication or psychotherapy.
DESIGN: Brain glucose metabolism was measured with positron emission tomography prior to treatment randomization to either escitalopram oxalate or cognitive behavior therapy for 12 weeks. Patients who did not remit on completion of their phase 1 treatment were offered enrollment in phase 2 comprising an additional 12 weeks of treatment Men and women aged 18 to 60 years with currently untreated major depressive disorder.
INTERVENTION: Randomized assignment to 12 weeks of treatment with either escitalopram oxalate [10-20 mg/d] or 16 sessions of manual-based cognitive behavior therapy.
MAIN OUTCOME AND MEASURE: Remission, defined as a 17-item Hamilton depression rating scale score of 7 or less at both weeks 10 and 12, as assessed by raters blinded to treatment.
RESULTS: Positive and negative predictors of remission were identified with a 2-way analysis of variance treatment [escitalopram or cognitive behavior therapy] × outcome [remission or nonresponse] interaction. Of 65 protocol completers, 38 patients with clear outcomes and usable positron emission tomography scans were included in the primary analysis: 12 remitters to cognitive behavior therapy, 11 remitters to escitalopram, 9 nonresponders to cognitive behavior therapy, and 6 nonresponders to escitalopram. Six limbic and cortical regions were identified, with the right anterior insula showing the most robust discriminant properties across groups [effect size = 1.43]. Insula hypometabolism [relative to whole-brain mean] was associated with remission to cognitive behavior therapy and poor response to escitalopram, while insula hypermetabolism was associated with remission to escitalopram and poor response to cognitive behavior therapy.
CONCLUSIONS AND RELEVANCE: If verified with prospective testing, the insula metabolism-based treatment-specific biomarker defined in this study provides the first objective marker, to our knowledge, to guide initial treatment selection for depression.
This was another NIMH financed study that went on for five years at a bit over $2 M. The study compared metabolism in brain regions to the whole brain. The best case graph is above. It has the usual vagueness and dodgy stats, but I don’t want to talk about that part. I want to talk about this whole line of thinking.

There is wide agreement that the category MDD [Major Depressive Disorder] is not an entity, not a disease, and is used clinically to code almost any depressed person. There is presumptive evidence that there is a genetic/biological basis for some depressions, by no means the majority, certainly not the category of MDD. The search for biomarkers among the depressions themselves is at a standstill,  Added to that, there is no compelling evidence that the antidepressants have specificity for anything clearly etiologic in depression. Since time long past, we know that CBT+Antidepressant is a bit more effective that either CBT or Antidepressant alone, and all three beat nothing. We know that simultaneous antidepressants aren’t better than a single drug. So why are we doing studies like this one? What are we looking for?

I don’t know the answer to that question. The notion of doing a PET Scan to decide between Lexapro® vs Cognitive Behavior Therapy seems absurd to me. If I had to guess what we’re looking for, I’d say "grant money," or "tenure," or maybe something to study with the expensive scanners. There’s this study, a huge study by Evian Gordon’s Brain Resources, and Trivedi’s big study all costing big bucks for no obvious yield even if they find something that matters [big skepticism]. In the Psychiatric News article, Dr. Mayberg says:
“An obvious next step is to see whether we can improve remission rates if we assign treatment based on the brain type,” Mayberg told Psychiatric News. “The subjects with high insula activity would get the drug, and the subjects with low insula activity would get CBT. We have a competitive grant renewal application currently under review at the National Institute of Mental Health…?This would be a prospective testing of the utility of the insula biomarker.”
Spare us. The technology isn’t mature; the questions are trivial; the results are dodgy; and nobody is really very interested. I call it anachronistic inertia…
    Bernard Carroll
    December 28, 2013 | 3:21 PM

    This report from Dr. Helen Mayberg’s group got some air when it first appeared on-line back in the summer. Here is a link to the discussion on the very solid Neurocritic blog. The main reservation I expressed concerned cherry picking of the data (40 of 82 randomized cases were excluded from analysis – apparently to suit a narrative). You can read the details on the link. As to Dr. Mickey’s larger point, yes this study wouldn’t carry the ball far down the field anyway.

    December 28, 2013 | 4:38 PM

    The comments, as well as the main post, are also worth a read from that link. Dobbs seems to have a more positive take on the study, but don’t know that he really adequately addressed your concerns.

    Bernard Carroll
    December 28, 2013 | 7:18 PM

    Thanks for seeing that. David Dobbs is a journalist, not an active scientist, and I for one am not surprised that he didn’t see the problems with the Mayberg report. A parallel would be Dr. Mickey’s description of Jeffrey Lieberman blowing away Steve Croft on 60 Minutes with hand waving.

    December 28, 2013 | 9:43 PM

    I have seen some psychoanalytically-informed imaging research trying to see whether you can observe self-reflective functioning and to see whether it is a biomarker for schizophrenia. That’s not ready for prime-time, but I think it’s interesting and might help with the development of *psychosocial* interventions which could reduce disability in individuals with schizophrenia.

    Coming up with good treatments for the negative symptoms and poor social functioning in schizophrenia is not a trivial question at all. I’m not sure how much brain imaging can help, but I don’t want to dismiss the researchers just yet.

    Bernard Carroll
    December 28, 2013 | 10:00 PM

    Sure… but the study discussed here concerned depression, not schizophrenia. Real time interactive cognitive shaping strategies are conceivable for both depression and schizophrenia but in this study they took only snapshots pre- and post-treatment.

    Bernard Carroll
    December 28, 2013 | 10:05 PM

    Actually, they ran only 1 scan, pre-treatment.

    December 28, 2013 | 10:21 PM

    I agree that this particular study was weak. But it seemed to me that a broader point about the limits of using scanning usefully (in psychiatry as opposed to neurology) was being made. I wanted to clarify the point.

    December 29, 2013 | 12:23 AM

    East Coaster

    Thanks for your comments.

    Perhaps I overstated my case about neuroimaging in psychiatric disorders. My frustration is that most studies are presented like this one with a ton of data manipulation and very little that can be checked or sometimes even followed. In the specific, this study discarded a lot of data before the primary analysis and then used ANOVA to analyze it. The basis of an ANOVA is to compare all of the variance to the variance in various subgroups and their interactions. How can that work if the data has been trimmed prior to analysis?. And then there’s this, “A positive correlation was shown for the CBT group (r = 0.55; df = 31; P = .001). In contrast, the escitalopram-treated patients showed an opposite but less significant correlation (r = ?0.31; df = 28;P = .09)..” This was an important test because it was on untruncated data. So what does “less significant correlation… (… P = 0.09)” mean? Significant doesn’t come in “less significant.” P=0.09 is simply “not significant” – and that’s a game changer. Those are the kinds of things that seem to pepper these studies. I recognize they’re hard to do and analyze, but as a reader in a climate where data dabbling is rampant, I think we need more clarity than neuroimaging papers usually give us.

    Nancy Wilson
    December 29, 2013 | 12:41 AM

    Trivedi always seems to run out of money before he completes a study. Francis Collins ought to look into this. I have given up on Thomas Insel.

    December 29, 2013 | 1:27 PM

    It’s true, fields like cardiology are doing amazing things with various imaging technologies, real cutting-edge medicine (including the cutting). Relatively, psychiatry is still investigating phrenology.

    December 29, 2013 | 2:46 PM

    Alto, what points are you trying to make with that? I could see points I could agree with and points I might not. Perhaps you could expand?

    Brett Deacon
    December 29, 2013 | 3:04 PM

    So, is the idea behind this study that possibly, in the future, every patient who seeks treatment for depression should receive a PET scan? Does anyone think this is actually feasible? If I may borrow a line from a blog I’ve just posted, “Under the leadership of biological psychiatrist Thomas Insel, the NIMH is committed to a future in which all patients with mental disorders undergo expensive biological testing administered by psychiatrists in medical settings to facilitate the use of personalized biological treatments provided by psychiatrists.”

    December 29, 2013 | 4:25 PM

    As someone with MS, I must say that seeing my neurologist zoom in and out, moving around in the images of my brain is kicky. MS is not considered an hereditary disease, though some genetic variations increase the risks. The chances that an identical twin would be affected when their sibling has MS is only 30%.

    Surely, even without taking into account how many “mental illnesses” were the result of environmental issues, “mental illnesses” are likely to be no more hereditary than MS which has been studied since 1868.

    What strikes me about conversations with neurologists is their forthrightness and open recognition of limits. We can see that most of the legions are in white matter in my corpus callosum. They showed me a view that helped me to see the characteristic Dawson Fingers. They let me know that they cannot tell what lesion is responsible for what malfunction.

    I just got my fourth MRI, and for the first time, after three years, they can tell that the Copaxone is working. They saw one additional small lesion, that they think they might have missed on other scans because of the angles. Who knows? The important thing was that the brain is better.

    Neurologists, are specialists. Still, too many people with MS are sent to a psychiatrist before their condition deteriorates to the degree that an MRI is finally, obviously, necessary. It makes no sense to me that psychiatrists— who are medical doctors, would use imaging in an effort to support the hypothesis that is so richly rewarded by the market— instead of trying to eliminate medical illnesses with psychiatric symptoms, before trying to pin down “mental illness” in the brains of people they have christened as “mentally ill”.

    What cruel irony that these KOLs are medical doctors.

    January 1, 2014 | 1:41 PM

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