In a seemingly endless string of attempts to make the modern antidepressants more potent than they are, we went through algorithm·izing, sequencing, combining, and augmenting with little to no improvement in efficacy. That was followed by personalized medicine [fool me twice… etc], the notion that the response to antidepressants is genetically linked/determined. While I can’t figure out why that would be true, given that combining antidepressants doesn’t add anything, it is none-the-less written about and studied all over the place [iSPOT, EMBARC] and already becoming commercially available [take a look…]. My personal skepticism is a matter of public record. Comes now this report:
Genetic Predictors of Response to Serotonergic and Noradrenergic Antidepressants in Major Depressive Disorder: A Genome-Wide Analysis of Individual-Level Data and a Meta-Analysis
by Katherine E. Tansey, Michel Guipponi, Nader Perroud, Guido Bondolfi, Enrico Domenici, David Evans, Stephanie K. Hall, Joanna Hauser, Neven Henigsberg, Xiaolan Hu, Borut Jerman, Wolfgang Maier, Ole Mors, Michael O’Donovan, Tim J. Peters, Anna Placentino, Marcella Rietschel, Daniel Souery, Katherine J. Aitchison, Ian Craig, Anne Farmer, Jens R. Wendland, Alain Malafosse, Peter Holmans, Glyn Lewis, Cathryn M. Lewis, Tine Bryan Stensbøl, Shitij Kapur, Peter McGuffin, and Rudolf Uher
PLoS Med 9[10]:e1001326. doi:10.1371/journal.pmed.1001326.
[full text on-line]
Background: It has been suggested that outcomes of antidepressant treatment for major depressive disorder could be significantly improved if treatment choice is informed by genetic data. This study aims to test the hypothesis that common genetic variants can predict response to antidepressants in a clinically meaningful way.
Methods and Findings: The NEWMEDS consortium, an academia–industry partnership, assembled a database of over 2,000 European-ancestry individuals with major depressive disorder, prospectively measured treatment outcomes with serotonin reuptake inhibiting or noradrenaline reuptake inhibiting antidepressants and available genetic samples from five studies [three randomized controlled trials, one part-randomized controlled trial, and one treatment cohort study]. After quality control, a dataset of 1,790 individuals with high-quality genome-wide genotyping provided adequate power to test the hypotheses that antidepressant response or a clinically significant differential response to the two classes of antidepressants could be predicted from a single common genetic polymorphism. None of the more than half million genetic markers significantly predicted response to antidepressants overall, serotonin reuptake inhibitors, or noradrenaline reuptake inhibitors, or differential response to the two types of antidepressants [genome-wide significance p<5×10−8]. No biological pathways were significantly overrepresented in the results. No significant associations [genome-wide significance p<5×10−8] were detected in a meta-analysis of NEWMEDS and another large sample [STAR*D], with 2,897 individuals in total. Polygenic scoring found no convergence among multiple associations in NEWMEDS and STAR*D.
Conclusions: No single common genetic variant was associated with antidepressant response at a clinically relevant level in a European-ancestry cohort. Effects specific to particular antidepressant drugs could not be investigated in the current study.
Editor’s Note: The researchers selected 1,790 patients with severe depression who had participated in one of several research studies; 1,222 of the patients had been treated with an SRI, the remaining 568 with an NRI, and it was recorded how well the drugs worked for each patient. The researchers also had a detailed picture of the genetic make-up of each patient, with information for over half a million genetic variants. They then looked for an association between genetic variants and responses to drugs. They found not a single genetic variant that could predict clearly whether a person would respond to antidepressants in general, to one of the two main groups [SRIs and NRIs], or much better to one than the other. They also didn’t find any combination of variants in groups of genes that work together that could predict responses. Combining their data with those from another large study did not yield any robust predictors either. This study was large enough that it should have been possible to find common genetic variants that by themselves could predict a clinically meaningful response to SRIs and/or NRIs, had such variants existed. The fact that the study failed to find such variants suggests that such variants do not exist. It is still possible, however, that variants that are less common could predict response, or that combinations of variants could. To find those, if they do exist, even larger studies will need to be done.
I fully admit that my skepticism was not just scientific, but based on the track record of the researchers who jumped at the concept – Nemeroff, Schatzberg, Rush, Trivedi, etc, people who have been too involved with pharmaceutical companies, too speculative in their biologizing, and published too many articles along the way. People involved with the$e enterpri$e$:
My scientific skepticism starts with the fact that there’s no real evidence that sequencing, combining, or augmenting in garden variety MDD adds any efficacy. I can’t divine any reason that natural selection would create such a genetic system. And finally, I know of no evidence that suggests genetic control except for the variable response of depressed people to these drugs – and there are a gajillion other more likely reasons for that [variable conditions lumped as MDD, lousy drugs, personality disorders, life histories, etc]. But that aside, this article appears to me to be a state-of-the-art-slam-dunk refutation of the hypothesis. They had a huge subject cohort, well documented outcomes, and tested the genome every way but sideways. I doubt that there’s ever been a drug class in history that people have tried so hard or spent so much trying to turn up the efficacy. In the end, the SSRIs and SRNIs are WYSIWYG [what you see is what you get].
While it should dampen the enthusiasm of those involved in the other ongoing studies, I doubt that it will. Both iSPOT and EMBARC seem to be aiming to add other parameters into the mix with the genetic studies in hopes of finding some kind of combo biosignatures to direct drug choice. But my skepticism remains very high. And we have much more important matters to think about in psychiatry and in patient care than further wild goo$e cha$e$…
hat tip to Rob Purssey 
New targets.
The same people, the same kind of language:
http://www.sciencemag.org/content/338/6103/67.full
Charney (the coming of Ketamine and synaptogenesis), Thase, …etc.
How many junior scientists do you think have trained with and/or worked within the Kingdoms of Charney, Nemeroff, et al.
Perhaps one day you will chart the path of more of these individuals. Try to retrace the evolution for example of Dr. Charney. He will have great impact on how clinicians conceptualize depression and how they practice. An interesting point in Keller’s deposition surrounding Study 329 is that he denied being an expert clinician in psychopharmacology for children as he had almost no direct clinical experience relevant to this. He described himself as an expert on clinical trials or some such.
The AACAP’s national conference is this week. There will likely be some media releases/coverage. Hope you keep a studied eye out for them.
It doesn’t appear that anyone from AACAP (or currently active in Academic Child Mental Health) reads your blog. But perhaps someone from healthcare media does? You’ve posted so much important information on AACAP and on academic psychiatry, perhaps you could put together a summary post on those topics to orient a new reader to your blog.
A summary that could look something like this:
http://1boringoldman.com/index.php/2012/10/20/a-symptom/
http://hcrenewal.blogspot.com/2012/08/continuing-dissection-of-infamous-study.html?m=1
http://1boringoldman.com/index.php/2012/09/17/psychotropic-talking-points/
http://1boringoldman.com/index.php/2012/09/17/talking-points-2/
http://1boringoldman.com/index.php/2012/09/13/something-terribly-wrong-here/
http://1boringoldman.com/index.php/2012/09/14/a-firm-line-in-the-sand/
http://1boringoldman.com/index.php/2012/10/17/no-fault-retraction/
http://1boringoldman.com/index.php/2012/10/07/the-letter-and-spirit-of-the-law-a-time-for-a-new-precedent/
But it would be SO much better in the form of a real post. It would be great for a journalist to link the story of their annual meeting to the questions raised by your posts above. Perhaps it’s more than just Ms. Bass that reads your blog. How many months has Dr. Drell of the AACAP been “vetting” these issues? Wasn’t that his response to you? After Dr. Martin simply dismissed the question.
Psychiatry just knows there’s a pony somewhere in that heap of dung it calls research!