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Early-onset MDD* blood biomarker pilot study.
April 18, 2012 2:14 PM   Subscribe

A pilot study testing for statistically significant blood biomarkers found in early-onset MDD: "Discovery of blood transcriptomic markers for depression in animal models and pilot validation in subjects with early-onset major depression" [PDF], published by the online, open source journal Translational Psychiatry**, April 2012, Volume 2.

Study excerpt:
Chronic stress gene transcripts and chronic stress in youths. Youths with depression had more exposure to maltreatment than did those who did not have any disorder (MeanMDD = 41.1±5.9 (s.d.) vs MeanND = 30.2±5.9 (s.d.), effect size = 1.74). CTQ*** Total score was correlated with 4 of the 26 gene transcripts at the level of a medium effect size or greater: CMAS, PSME1, PTP4A3 and IRF3. These markers were all derived from the chronic stress model (K. Pajer, et al., p. 7).

Despite over 30 years' research, there are currently no known "valid, reliable, selective and feasible biomarkers for MDD" (K. Pajer, et al., p. 1). The researchers monitored blood transcript, rather than serum protein, levels for the study. This study uniquely focuses on young people who experience early-onset MDD. Early-onset MDD is statistically correlated to higher incidence of future episodes of MDD later in life.

In total, 53 young people between the ages of 15-19 were included in the study. Tested blood biomarkers focused on those gene transcripts with known functions in processes mediating neuronal damage, as well as those involved in immunoregulation and neurodegeneration. The first biomarker panel, consisting of 11 transcripts, differentiated young people with MDD versus those without any psychiatric diagnosis (ND), with genes belonging broadly to the categories associated with transcription, neurodevelopment, and neurodegeneration.

Additional resources:
1) Robert Sapolsky's lecture on clinical depression, also described as a major stress response [YT link].
2) LA Times article on K. Pajer, et al. study, with quote by lead researcher, Eva Redei, PhD.


_________________________________________

* Major Depressive Disorder.
** Translational Psychiatry "explores the more translational area between the research in neuroscience and conceptually novel treatments."
*** Childhood Trauma Questionnaire; see p. 3 in attached PDF article.
posted by simulacra (22 comments total) 3 users marked this as a favorite

 
I was diagnosed with MDD at 18 - I had my first major Episode at 14 and absolutely, if there had been a blood test to show that my mood problems were beyond "being a teenager blows, AMIRITE?" my high school years would have played out very differently.

Not having a history of abuse/emotional trauma, there was nothing to point my doctors to a depression diagnosis until I spiraled so far down that I had to seek emergency treatment. It really would have been completely 100% life-changing to have gotten an anti-depressant 4 years earlier.

While I'm happy with my life now, it would have been completely different to have actual *coping skills* in high school beyond "I can't deal with anything so I think I'm just never going to eat again." When I think about the decisions I was making my senior year that affected how things have turned out now... man, it would have been awesome to be even marginally saner at that point.
posted by sonika at 3:22 PM on April 18, 2012 [2 favorites]


I hope the people doing these studies understand Multiple Comparisons and Tukey's HSD etc. When you have so much data, false positives are inevitable.
posted by gyp casino at 3:40 PM on April 18, 2012


Biomarkers for mental illness are something of a fascination of mine for a variety of reasons for which I won't bother to drag out the soapbox. But let's run a couple of thought experiments on the idea of having a blood test to see whether someone has major depressive disorder (MDD).

(1) A patient comes into the primary care doctor and says that they don't seem to have any zest for life, haven't been able to sleep, and upon probing confesses of thinking a lot about death and self-harm. Now, the doctor has a few choices, some of which are (a) refer to a psychiatrist, (b) look up (or remember, but let's be serious here) the criteria for MDD and ask a few questions to see whether the patient meets them, or (c) order a blood panel to determine whether the person has MDD. Option (b) is far cheaper and faster than (c), and the results of (c) would have to either be vetted by option (b) or (a) anyway, as the next thought experiment shows.

(2) As a matter of course, Dr. Cautious orders an MDD panel for every new patient. One day, a patient comes in who screens positive on the biomarker panel, but has never been depressed a day in his life, feels fine, is perfectly healthy, and has no psychosocial problems. What does Dr. Cautious do? She can either preemptively treat the patient for MDD, running the risk of side-effects, cost, and mental-health stigma associated with psychiatric care, or she can ignore the test. What would you do?

Here's what I would do: ignore the test, and stop giving it entirely. What would the expensive blood test tell me that talking with the patient for half an hour couldn't?

Despite all the similarities, mental illnesses are very much unlike physical illness in a key respect. Take for example an elevated antigen as a biomarker for prostate cancer. There are 'surface' symptoms of prostate cancer such as nocturia or dysuria, and there are 'deep' symptoms of prostate cancern such as a tumor found in surgery on the prostate gland. The foregoing sentence contains a mistake, however: the tumor on the prostate is no mere symptom of prostate cancer; rather, it is a criterion (in the philosophical sense, not as an everyday synonym for 'symptom') of having prostate cancer. Loosely speaking, having prostate cancer means having a tumor. The reason that the elevated antigen can be a biomarker for prostate cancer is because of nomological links between symptoms (e.g. nocturia) and the elevated antigen on the one hand, and between the elevated antigen and the disease criterion on the other hand. The biomarker serves, essentially, as an indicate of pathogenic process; in most of medicine, that kind of pathogenic process has some kind of criterion (again, in the philosophical sense) that can be pointed to and verified to be pathogenic independently of the symptoms. An abscessed appendix can be seen to be diseased independently of abdominal pain.

Now consider psychiatric disorders. The idea that there could be a criterion for depression independent of e.g. low mood or anhedonia is not merely an optimistic assumption. I think it is an incoherent picture. Consider prostate cancer again for a moment. I'm not a doctor, but it makes sense to me -- it seems to be conceptually possible -- that one could have a (benign) tumor of the prostate and experience no symptoms. In such a case, one could meet the criterion for having a disease, yet not be disordered (in the sense of having symptoms). And a doctor could say, and it would make sense, "You have prostate cancer, even though you're perfectly healthy." Switch back to depression. I think it is incoherent for psychiatrist to say, "You have depression, even though you're perfectly happy and functioning normally in your job and relationships." If someone said that to me and said that I needed to take antidepressants just in case, I would find another doctor. It is just nonsense to imagine that a test could make me believe that I had Major Depressive Disorder in the biological sense if there was no evidence of depression in the psychological sense. The psychological features -- the symptoms -- of depression just are what it is, what it means, to be depressed.

To be sure, the test could help someone (e.g. a teenager) in the strange situation of having to prove that they are really depressed if for example their parents refused to believe the teen's self-reports or didn't believe in psychiatry or something like that. So while I wouldn't write off biomarker research as irrelevant, neuroscience is only ever as good as our psychology.

The point goes a little deeper, I think. In lung cancer, for example, there is an important sense in which you can "abstract away from" the fact that a given individual with lung cancer smoked for thirty years. The etiology and the pathogenic process 'come apart'. But I'm incredibly skeptical that in most cases this could be done for the majority of mental illnesses (i.e., don't try to pin me down on Alzheimers or schizophrenia). For a programmatic example, consider prescribing Ritalin and Lexapro to a hyperactive, aggressive child and then shipping him back to his abusive, alcoholic, impoverished father; now imagine yourself patting yourself on the back for addressing "the real issue". The two do not come apart.

(As a methodological point, they did not correct for multiple comparisons, "as the goal of a pilot study is to detect as many potentially clinically significant relationships as possible", but were instead looking at effect sizes. People do this all the time in psychology and psychiatry, ignoring that most people who read it will gloss over "pilot study blah blah blah" and just look to see that there's a significant effect and then go on as if it were true. Sure, with very little resources it's hard to conduct a tightly controlled study with a sufficiently large sample size, but this practice just plays into everyone's cognitive biases.)
posted by mister-o at 5:28 PM on April 18, 2012 [8 favorites]


An interesting response mister-o however: (1) it is entirely possible for a person to suffer long-term depression and yet be functioning socially, and they can report that they "feel fine" because they have no higher state in recent memory to compare to (in summary, try the antidepressants before you reflexively "change doctor" because the doctor tells you something you are not ready to hear); (2) disbelief or framing depressive behaviour as a "discipline problem" is incredibly, hilariously, horribly common among employers, teachers, parents and other authority figures.

Your criticisms put the cart before the horse. The doctor will rarely need to blood-test someone who attends the clinic. The better use of this is to blood-test a cohort, eg students or employees, and call in the ones who show results, for clinic attendance.
posted by aeschenkarnos at 5:54 PM on April 18, 2012 [2 favorites]


To be sure, the test could help someone (e.g. a teenager) in the strange situation of having to prove that they are really depressed if for example their parents refused to believe the teen's self-reports or didn't believe in psychiatry or something like that. So while I wouldn't write off biomarker research as irrelevant, neuroscience is only ever as good as our psychology.

The point with teenagers is that doctors don't want to treat for MDD in a fourteen year old because it's rare, the treatment itself (anti-depressants) is controversial in that age group, and the symptoms themselves are often simple exaggerations of, well, being a teenager. Since mental illness is largely based on self-reporting, teenagers will often report feeling shitty. How do you differentiate normal teenage "I hate myself" from MDD "No seriously, I HATE myself"?

It's tough and the issue isn't that parents don't want to treat their kids, is that doctors themselves are torn on whether to even diagnose MDD in a teenager in the first place - especially since diagnostic criteria for MDD includes having had *two* depressive episodes (the episodes themselves having to meet certain criteria to count as an actual Major Depressive Episode and not just "Well, life is shitty right now").

My own doctors wouldn't diagnose me with MDD at 14 and I wish they had. If a biomarker can help distinguish teenagers who have MDD and need anti-depressants from teens who are having different problems, I think it's an avenue worth exploring. The point isn't to give random teenagers blood tests and treat them for depression - the point is to give *depressed* teens the blood test to help diagnose the ones with MDD.

And it should also be noted that MDD and what we think of when we think of "depression"... if you met me when I'm not having an episode, you would never know that I have MDD. Even unmedicated. Unmedicated, I'm fine... until I'm not. I do not have the kind of lingering dysthmia or anhedonia associate with classic depression. 90% of the time, I'm functional. And then...

... I can't eat. I can't leave the house. It's not that I don't want to. It's not that doing so is difficult. It's impossible. The IDEA of leaving the house will have me screaming in the fetal position on my kitchen floor. I lash out at anyone and everyone around me. I sleep 18hrs a day and feel exhausted all the time. Sometimes, I cut myself. The only times I *do* manage to leave the house are to pull stunning and completely incomprehensible disappearing acts. It's so, so far beyond what "ordinary" depression looks like.

The worst part of MDD is that once you have enough episodes to get diagnosed, you're pretty much guaranteed to keep having them. I take anti-depressants and will keep doing so for the rest of my life just as a pre-emptive strike. If I go off my meds, I'd likely be fine for a very long time... until I very, very suddenly won't be. I'm quite lucky that I didn't experience postpartum depression with my son, but there's a giant red "WARNING!" in my medical file that I'm especially at risk for some serious disturbances in that arena.

Depression sucks and people who have it deserve to be treated. MDD sucks EVEN MORE and if it can be caught early in teens, to say that it would save lives is no understatement. Giving anti-depressants to teens is very tricky as it can *cause* suicidal ideation, but leaving MDD untreated is far, far riskier.
posted by sonika at 6:09 PM on April 18, 2012


For a programmatic example, consider prescribing Ritalin and Lexapro to a hyperactive, aggressive child and then shipping him back to his abusive, alcoholic, impoverished father; now imagine yourself patting yourself on the back for addressing "the real issue". The two do not come apart.

I missed this part of your comment, but I'd like to address it.

I have MDD. I had my first episode at 14. I do not, nor have I ever had, an abusive home. I did not suffer emotional trauma. Sure, my family was weird and slightly unhinged at times - but there was absolutely no cause whatsoever for my depression except for the fact that my brain chemistry was very, very wrong.

You do not need to have some kind of underlying trauma to be depressed. You can have MDD and have been raised by Mother Theresa and a bunch of singing monkeys. Think of giving antidepressants to someone with MDD less in terms of giving Ritalin to a hyper kid and more in terms of a diabetic having insulin shock.

(Note: I am talking specifically about MDD and not PTSD or depression *caused* by abuse/trauma.)
posted by sonika at 6:16 PM on April 18, 2012


I hope the people doing these studies understand Multiple Comparisons and Tukey's HSD etc. When you have so much data, false positives are inevitable.

From the paper:
We did not control for multiple comparisons, as the goal of a pilot study is to detect as many potentially clinically signi´Čücant relationships as possible.
They looked for "significant" (p < 0.01) results in a set of >28,000 genes. One would expect that 280 of those genes would have appeared by chance at p < 0.01. Of course, they did this in three different tissues (which means even more multiple tests), finding 238, 396, and 141 genes respectively, all easily explainable by chance. Then they do some tortured intersection analysis to exclude things that are obviously wrong and end up with a set of 11 "candidate" endogenous depression genes. They did this same kind of multiple testing again to find 125 "candidate" chronic stress genes, and then picked 15 at random.

They did not report using any control genes when testing these candidate genes in humans.

That means these results are basically worthless. This paper should not have been published.
posted by grouse at 7:17 PM on April 18, 2012 [7 favorites]


Wow, I can't believe they didn't control for multiple hypothesis testing. What a terrible paper.
posted by pombe at 7:49 PM on April 18, 2012


The psychological features -- the symptoms -- of depression just are what it is, what it means, to be depressed.

It sounds to me like you're making the assumption that the symptoms of depression are the lesion, and that mental illness cannot ever be reduced to a physiological state:

So while I wouldn't write off biomarker research as irrelevant, neuroscience is only ever as good as our psychology.

I tend to think that our psychiatry is only ever as good as our neuroscience. Which is to say, it may not be great now, but this seems like a good direction in which to be making inquiries. We're just not there yet.
posted by pullayup at 8:33 PM on April 18, 2012


posted by sonika

Are you aware of what effects of going off antidepressants [SSRIs] precipitously can cause? It really made my depressions so much worse. NPR link My regular physician was the one who started me on it at age 22. I REALLY now wish that I had never been on it because it is impossible for me to get off it [even with gradual dosage decreases] without me going insane with all types of severe depressive symptoms just like you seem to be describing. I wish that she had at least warned me that it is extra difficult to get off this addictive [physically] drug. Discontinuation syndrome
posted by RuvaBlue at 9:24 PM on April 18, 2012


I'm missing the connection between what Sonika said and the issues of going off SSRIs precipitously. Giving insulin to someone who doesn't need it is bad, but that doesn't make it less important to the diabetics out there.
posted by Kid Charlemagne at 11:14 PM on April 18, 2012


Grouse, was just about to post something similar. At first I was all, "oh I'm sure they used FDR or something" and then I read the Methods section and stared for a while and then I went home and shot myself.
posted by en forme de poire at 11:18 PM on April 18, 2012 [1 favorite]


The following has been linked before on Metafilter -- it makes a humorous finding of brain activity in a dead fish when ignoring the multiple comparisons problem: http://prefrontal.org/files/posters/Bennett-Salmon-2009.jpg
posted by JimDe at 4:17 AM on April 19, 2012


Are you aware of what effects of going off antidepressants [SSRIs] precipitously can cause?

I am and I never advocated that any one do it, so I'm not sure what this is addressing.
posted by sonika at 5:08 AM on April 19, 2012


It sounds to me like you're making the assumption that the symptoms of depression are the lesion, and that mental illness cannot ever be reduced to a physiological state

No, the question is: what would it mean to have biomarkers for depression but not be depressed? This is orthogonal to whether or not people who are depressed have biomarkers of that depression. The point is that depression is psychological in nature whether we find biomarkers or not, and it doesn't make sense to speak of it as present in biology when we don't see it present in psychology.
posted by OmieWise at 7:09 AM on April 19, 2012


(Ignoring the statistical validity of this particular study) I'm thinking that such a biomarker test could also be incredibly useful for diagnosing other conditions.

Many people with autoimmune or thyroid disorders (among many other things) spend months or frequently years being told that their symptoms are those of depression and being denied further studies or treatments for the actual underlying condition. A biomarker test that would state "It is unlikely that this person is depressed because they lack all of these biomarkers for depression" might greatly reduce the time to diagnosis for other chronic illness by forcing doctors to take patients reporting of their symptoms more seriously.
posted by hydropsyche at 7:30 AM on April 19, 2012


A point I didn't see here is that doctors might not order the blood test simply because insurance won't pay for it and the patient can't or the doctors don't think the patient can.
posted by tilde at 8:54 AM on April 19, 2012


A point I didn't see here is that doctors might not order the blood test simply because insurance won't pay for it

Do you know that insurance won't pay for this?

I have depression and epilepsy. I'm in doctors' offices all the time and have had to have shit tons of testing done. In my experience, insurance is more willing to pay for a test to rule out having to pay for expensive shit later on than they are to pay for prescriptions, ER visits, or specialists. I've had to do some finagling to get MRIs covered as they're $2k a pop, but I've absolutely never had blood work come under the category of "things to bug my insurance provider about."

(I've also had to go through the horrors of treatment without insurance and the resultant credit card bills and yeah... it's pretty heinous to the wallet.)

Also, quite a lot of good doctors find ways around insurance SNAFUs. There's no reason to preemptively say that a test is useless or won't be performed because insurance sucks. Especially since each company has their own unique way of sucking and the test isn't even on the market yet and I'm fairly certain that you don't know how much it costs. Bloodwork can be pricey, but hardly ranks on the scale of diagnostic testing when you're looking at neuropysch issues.
posted by sonika at 9:10 AM on April 19, 2012


Also: diagnosing MDD properly early on can save insurance companies a spazillion dollars (give or take) on inpatient psych admissions for depressive episodes gone awry and can also rule out patients who *don't* need aggressive anti-depressant regimes and thus save a bundle on prescription costs. Not to say that insurance companies work on logic, but, y'know. There is some.
posted by sonika at 9:15 AM on April 19, 2012


I was considering writing a technical comment on this paper for the journal. Their editorial office told me they do not accept such comments.
posted by grouse at 2:21 PM on April 19, 2012


These markers were all derived from the chronic stress model (K. Pajer, et al., p. 7).

I've always thought that chronic stress was a likely etiology for major depression. Short-term stress is a motivator for action. Long-term stress is a poison, especially to the CNS.

Not sure if this finding supports that theory.
posted by Mental Wimp at 6:08 PM on April 20, 2012


Sorry for being late coming back to this, sonika.

I did say might. :) And I probably don't take my health seriously enough, I know; when I've spoken to my specialists on something, I have occasionally gotten a response of, "Yes, there are some studies starting to show this test can show some degree of change as compared to what insurance usually pays for, but since insurance doesn't pay for it, I don't generally use it."

Yes, I need to push that doctor harder if things aren't working and I don't see results that this test could tell us more about. Or more likely, find another doctor. At least at this point I know how far that doc is willing to go, and know what I need to ask the next doc if/when I change. I changed (and got fired a lot) during my pregnancies, so I'm used to the routine.
posted by tilde at 6:19 AM on May 18, 2012


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