Friday, June 22, 2012

Anti-inflammatories and Schizophrenia

Short little post on a paper from a few weeks ago from the Journal of Clinical Psychiatry:  Nonsteroidal Anti-Inflammatory Drugs in Schizophrenia: Ready for Practice or a Good Start?  A Meta-Analysis.

Nothing spectacular here, just some interesting arguments and correlations to add to the literature that major mental illness has an inflammatory pathology, and that searching for anti-inflammatory solutions (and I consider an anti-inflammatory (nutrient-rich, low toxin) diet, proper sleep, proper coping, appropriate exercise and stress reduction as some of these non-prescription solutions to be examined further) is a reasonable course of action, and not woo-ville.

My usual radio haunts have been disappointing recently for brand new music.  But The Heavy came out with a new single this week, and I'm liking it:  What Makes A Good Man.  It sounds really good in the car, but I hope you're not driving right now.

All right, some suspicious correlations suggesting the immune system and inflammation may be involved:

1) People with schizophrenia and their close family members have higher risk of autoimmune disorders.
2) Men who have used steroids and NSAIDS (such as naproxen or ibuprofen) have a decreased prevalence of schizophrenia.
3) PET scans of folks with schizophrenia show increased numbers of active microglia in the brains (microglia are immune cells in the central nervous system, activated to fight infection or in autoimmune conditions or inflammation).
4) With brute force hacks of genomes of folks with schizophrenia, one of the gene areas that keeps popping up are markers in the major histocompatibility complex (MHC) region on chromosome 6.  MHC genes code for the markers we put up on our cells to label them as ME so our own immune army doesn't take us out.
5) There are abnormal levels of inflammatory cytokines, immune markers, and autoimmune antibodies in the serum and spinal fluid of folks with schizophrenia.

So something in the immune system is amiss.  Maybe gut-punching inflammation could help the symptoms.  Enter the NSAIDS (non-steroidal anti-inflammatory drugs).  They work by inhibiting the conversion of our old frenemy arachidonic acid (AA, made from the omega 6 linoleic acid, but also available as is from various animal foods) into the class of molecules called prostaglandins.  Prostaglandins help mediate pain, inflammation, and thermal regulation, which is why you might pop an Advil when you have a fever or a muscle ache (or both).

Now, NSAIDS are known to trash the gut and the kidneys if you aren't careful, and various versions may kill you dead with a heart attack (Vioxx) in the long term, and pregnant women and those with ulcers and ulcerative colitis and some others should avoid them…but as I am not currently afflicted with any of the previous conditions I would still take it in lieu of acetaminophen, personally, when I am not toughing it out. Like last Monday, when my children gave me a little virus that toasted me all the way up to 103.3. Personally I'm cool with 102s but the 103s start to make me worry about brain fry-age, particularly in adults.

(An oldie but a goodie:  Neil Finn: She Will Have Her Way   Definitely worth the ad…)

More specifically:  AA + the enzymes COX1 and COX2 make prostaglandins, which mediate pieces of the inflammatory response.  NSAIDS like ibuprofen, naproxen, diclofenac and acetylsalicylic acid (otherwise known as aspirin) will block COX1 and COX2, reducing the ability of the body to make prostaglandins.

So will doing that not only help a fever or an aching muscle, but also the symptoms of schizophrenia?  What does the literature say?

All the randomized controlled trials of antipsychotic medication augmentation with an NSAID were analyzed in this meta-analysis.  (No one official is just using Advil for psychosis.)  In the literature there were 5 (small) RCTs, for a total of 264 patients.  The trials all used celecoxib (a selective COX2 inhibitor) or aspirin, and lasted from 5 weeks to 3 months.  4 of the 5 studies all had similar results, modestly but significantly helpful in both "positive" symptoms such as hearing voices and "negative" symptoms such as social withdrawal.  One study showed the NSAIDs not to be helpful, compared to placebo.   Apparently two other unpublished studies also showed celecoxib to be unhelpful, so we have to be cautious about these findings.

More specifically, with a few of the celecoxib studies, the NSAID didn't appear to be particularly active in the central nervous system, as expression of COX2 wasn't altered in the hippocampus and there were no changes in the cytokine profiles in immune cells called mononuclear cells.  In the aspirin study, however, they were able to detect a treatment effect with differences in cytokine profiles due to the drug.  Since COX1 prostaglandins cause platelet aggregation, inhibiting COX1 leads to the supposed cardioprotective effects (but also the increased risk of ulcers) of the nonselective NSAIDS.  It's a bit irritating that all these studies were done with the selective COX2 inhibitor, celecoxib, but since it was the one on patent, I'm guessing that's why the money was spent there.  It would be interesting to see larger studies done with ibuprofen or aspirin, frankly.

Well!  More wait and see.

13 comments:

  1. "Personally I'm cool with 102s but the 103s start to make me worry about brain fry-age, particularly in adults."

    Start getting worried about 106 or so...

    "Are fevers Paleo?"
    http://yelling-stop.blogspot.com/2012/04/are-fevers-paleo.html

    (Includes link to randomized, prospective study on fever treatment and outcomes.)

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    1. Yes, I'm more likely to not treat pain or a fever than not, but if it interferes with my precious sleep, I will take a small amount. I did try a 24 hour fast (because I certainly didn't feel like eating), and once I ate, my fever went up a whole degree. I wonder if ketosis is outdone by being unable to mount as much of a fever, or if it was just coincidence. After looking at some studies, I'm not sure fasting is the greatest idea, but hey, it seemed only natural...

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  2. Naproxyn has the lowest rate of cardiovascular morbidity and GI irritation. It would also be a good one to include in studies.

    I wonder about the efficacy of anti-inflammatory lifestyle as preventative vs corrective. Have any studies looked at epidemiology?

    Why don't inpatient psych units have default anti-inflammatory foods both as open stock and on patient menus? Do IP psychiatry medical directors have influence over menus and therapeutic diets?

    -aek

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    1. No inpatient med director I ever knew had control over the menus, other than sometimes special occasions like Thanksgiving or something.

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  3. I also heard that long-term NSAIDs may be associated with lower risk of Alzheimer's in some people under some conditions -- again possibly due to the anti-inflammatory effect. However, that does not necessarily mean that it is a good idea to use NSAIDs for that reason.

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  4. I'm seen some interesting stuff on the role of the maternal immune response to infection in the pre-natal environment as it relates to the prevalence of schizophrenia in the offspring. If I recall correctly (I may well not!) there's some studies in humans that suggest a CORRELATION between maternal flu during pregnancy and schizophrenia. Then there's some animal studies that seem to suggest that dams that produce a certain profile of cytokines in response to viral infection during pregnancy give birth to pups more prone to showing whatever the animal model of schizophrenia is (in comparison to dams that had a more appropriate response to the virus who have unaffected pups). I can't help but wonder if it's another arm of the hygiene hypothesis...

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  5. What about cytokine profiles looking at specific diets? I have been following cytokines now for over a decade and have not come across much in terms of diets and cytokine profiles.

    The correlation of flu-like symptoms (FLS) and cytokines is interesting. FLS occurs with a number of immunotherapetic drugs and there are various studies looking at prophylaxis to treat this response (NSAIDs, paracetamol, prednisone, etc). It also occurs with drug therapy and it is a standard question I ask anyone who reports any type of malaise side effect with medications. I have also observed that symptoms of depression and mania can improve with concurrent viral illness.

    I am with you if you are skeptical about what is known about the upstream action of cytokines affecting by COX-1 and COX-2 downstream. As an example IL-1 is a central orchestrator of immune modulation. IL-1 knockout mice show a general decrease in inflammatory response but more specifically decreased brain inflammation in response to anoxia. We need better metrics.

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  6. 2) Men who have used steroids and NSAIDS (such as naproxen or ibuprofen) have a decreased prevalence of schizophrenia.

    Doesn't schizophrenia tend to go with a lower sensitivity to pain in any case?
    And what about the lower cancer rate in schizophrenic chain-smokers, and the promotion of NSAIDs as cancer preventives?
    http://www.sciencedaily.com/releases/2007/12/071208092440.htm
    Medications that promote metabolic syndrome etc have probably undone some of the anti-cancer protection associated with schizophrenia, which was historically very strong. And wherever the syndrome is over-diagnosed out of the desire to medicate away the inconvenient and unlucky, this will also be distorting the correlation.

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  7. Excellent review article in Focus (Spring 2012, vol X, No.2: "Is relapse in schizophrenia an immune-mediated effect?". The authors have an excellent diagram (Potential mechanisms for an immune system-mediated relapse in schizophrenia) that can be downloaded as a PowerPoint if you are a subscriber that looks at what is known about the immune response and incorporates some symbols about correlations with the literature on inflammatory markers. Great sort of diagram to modify and to use in presentations on this subject.

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  8. Nature Reviews article today on how inflammatory mechanisms associated with depression can affect arterial endothelial cell repair/apoptosis in heart disease.

    They have a rough schematic on their FB site: http://www.facebook.com/#!/pages/Nature-Reviews/328116510545096

    but article is not publically available.

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  9. Hey Emily, I was wondering what your thoughts are on the prostaglandin deficiency theory of schizophrenia, as put forth by David Horrobin. Another commentator pointed out that NSAID's reduce pain and seem to reduce the risk of cancer. Less pain and cancer are traits often seen in schizophrenics. NSAID's increase intestinal permeability and may induce food intolerances (e.g. to gluten). Schizophrenics seem to have greater intestinal permeability and rates of gluten intolerance. This and a number of other observations seem consistent with the idea that some sort of prostaglandin deficiency may be at play in schizophrenia.

    I'm not currently sure how to interpret this post with respect to this, but I would love to hear your opinion of this theory.

    Morgan

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  10. Hi. i just came across your website, which is very interesting. What about anti-inflammatory methods that don't rely on NSAIDs (given that they destroy your stomach lining). Any thoughts, by anyone?

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  11. Taking at least 2 ibuprofen a week reduces Parkinson's disease risk by 38%:

    http://www.hsph.harvard.edu/news/press-releases/parkinsons-disease-ibuprofen/

    Parkinson's, schizophrenia and Crohn's disease(s) are genetically related:

    http://www.ncbi.nlm.nih.gov/pubmed/24057672

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