An illuminating trial of an anti-inflammatory agent for depression

As discussed in chapter 7 of my book, major depressive disorder displays many features that indicate immune involvement. Depressed patients exhibit immune dysregulation, and many of their symptoms resemble those of “sickness behavior”, which is cytokine-driven. Moreover, major depression can by induced in psychologically normal people by injection of certain cytokines. Thus, it is reasonable to ask whether treatment with a known anti-inflammatory agent would alter depressive symptoms. Asdresearchinitiative alerted to me to a small, proof-of-concept stage 4 clinical trial (double-blind, placebo-controlled, randomized) just completed at Emory Medical School that was run by Andy Miller and Charles Raison. This involved periodic  intravenous injection of infliximab (Remicade), an antibody that blocks the action of the pro-inflammatory cytokine TNFa. This agent is FDA approved for use in Crohns disease and rheumatoid arthritis, which are conditions with extensive inflammation. Importantly, Miller and colleagues are not only monitoring depressive symptoms and improvement in quality of life, but they are also assaying a blood marker of inflammation, C-Reactive Protein (CRP). (this last test is what is missing in several of the autism treatment trials I’ve discussed here). The patients in this study were resistant to other depression medications.

Aha! A new paper providing the results of this trial has just appeared 2 days ago! Patients who responded to this treatment were those who exhibited elevated CRP at the beginning of the trial. Baseline TNF levels were also higher in the responders than in the non-responders. These results reinforce the point I’ve been making in autism and schizophrenia trials that if one pre-selects patients for a an anti-inflammatory trial that start with elevated inflammatory markers, one is more likely to see a result of the intervention. If the patient pool is diluted with people who aren’t going to respond to the anti-inflammatory agent because they don’t have elevated levels of inflammation to start with, then they will dilute out the results, and investigators will end up with a failed trial and conclude that inflammation is not involved. This Emory trial also indicates that there is diversity among the major depressive disorder population with regard to immune status – which, of course, is also true in autism and schizophrenia. This must be taken into account in planning clinical trials.

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4 Responses to An illuminating trial of an anti-inflammatory agent for depression

  1. passionlessdrone says:

    Hi Paul Patterson –
    Thinking on this study and the whole NYT thing, I was poking around some references and found another RDBPC study targeting the immune system in autism with an add on therapy:
    Double-blind placebo-controlled trial of pentoxifylline added to risperidone: effects on aberrant behavior in children with autism
    The agent in question has a large body of studies indicating immunomodulatory, anti-inflammatory effects.
    The NAC study that came out this year, also placebo controlled and double blinded showed significant effects; i.e.,
    A randomized controlled pilot trial of oral N-acetylcysteine in children with autism
    It turns out, in conditions characterized by increased oxidative stress and inflammation, NAC has been shown to downregulate inflammation.
    Nice.
    – pD

  2. Melanie Ciccone says:

    hello paul, i live around the corner here in adjacent south pasadena. i am a science enthusiast who would very much like to put myself to use in this greater dialogue – immune dysregulation, inflammation, epigenetic engineering…. -Being someone who has struggled with chronic inflammation for the lion’s share of my 50 years on the planet, as do my children, surprise, it is hard not to do back flips when i read articles taking up a dance with these subjects.
    For better or worse, the NY Times is one of m greatest consistent sources.

    i learned about your work from the recent NY Times article by Moises Velasquez-Manoff… be still my beating naive and hopeful heart, i was thrilled to read his article and learn about your work, and that of others on all sides of the trenches of scientific exploration, revelation and discovery. Evidence of the creative process unfolding on the topic of immune dysregulation. Regardless of the parade of critics I was made hopeful, inspired, and more informed by his reaching perceptive thoughts.( if there is no room in the science community for creativity, we are all doomed.) i am so grateful. to have a dialogue; for it to be brought front and center, flaws and all so we can *see* more clearly and work, hopefully, more cooperatively. we are better off, history and evolutions tells us so, with more than our just our own vision applied to living and learning.

    like so many other * inflamed* fellow humans i have dragged myself from doctor to doctor with all kinds of curious ticks, trying to get better, posing the same questions. I have found SOME relief in diet modification, lifestyle changes, probiotic, ezymatic, and vitamin therapies, but never overcoming my issues. its always a battle. is this as good as it gets?
    the greatest lesson has been learn to live with IT.
    IT takes its toll and aging is its own wrench. my central question remains: did my mother’s systemic breast cancer affect me; do you think my problems stem in some way to her illness; is there anything that I can do about it to help myself and my children? I have never met a doctor who could even acknowledge the question. About a decade ago, I got my first diagnosis of Inflammation from an Santa Barbara Endocrinologist who applies integrative medicine into her practice. I have made it a personal priority to self-educate about the “I” word, as it relates to my immune, GI, and nervous systems, issues – assuming they are in some way correlated – and I suppose this is one of the reasons I am writing you.

    There are so many questions provoked/inspired by this article (and I wish I didn’t have to be good at math to become a scientist to engage in the greater dialogue, alas, I am relegated to what Robert Provine calls “sidewalk science” … if my mom had cancer, she must have had a whole lot of circulating inflammatory molecules, she also had allergies, and suffered bladder infections. ergo a possible answer to my lifelong question.) so, to the point of your work, if you can induce an inflammatory response -without infective agenting- in your pregnant mice at the Cal Tech Lab. AND, the “Swiss scientists” in the Velasquez-Manoff article can create a lineage of mice inflamed pregnant mice without the collateral damage of inflammation due to genetically reinforced anti-inflammatory molecules/techniques. Than, (apologies for the “if this, than that” reductionism) can we not offer the proverbial oxygen mask to the mother first
    so the baby can have a healthy mama too, you know kill two birds with one stone? Do we really all have to suffer so? Can biotechnology offer relief in genetic modification only at the developmental stages, limiting – albeit huge – only to the next generation? Cant we not naturally select in real time for the walking wounded?

    thanks for your work and time. I look forward to reading your book, assuming my mind can makes its way through such a subject.

    best, melanie ciccone

    • phpatterson says:

      Thx for your note Melanie. For sure, elements of inflammatory diseases can be inherited genetically. It would also not be surprising if your mother’s cancer influenced your fetal development (if the cancer was present then). Your view of the NYT article parallels some of my comments as well. Regarding hope for the future, the final chapter in my book is titled, “Reasons for optimism”. Cheers, PHP

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