INFLAMMATION AND PSYCHOSIS

A report by Bloomfield et al. in the January 2016 issue of American Journal of Psychiatry showed further evidence that psychosis is associated with increased inflammatory activity in the brain.  What the researchers did was to use a marker, [11C]PBR28, which binds to activated white blood cells (microglia) in the brain.  None of the subjects had been treated with antipsychotic medications.  The researchers showed that in persons who are at high risk for the development of psychosis and in those in whom psychosis had emerged, there was a greater degree of binding of the marker indicating more activated microglia in the brain.  Moreover, they noted that degree of binding (degree of microglia activation) was correlated with the level of symptoms.

The Bloomfield et al. report fits in well with a larger literature pointing the finger at dysfunction in fast spiking GABA interneurons as the culprit in causing hallucinations and cognitive impairment. (This story is reviewed in chapter 6 in Neuroscience for Psychologists and Other Mental Health Professionals.) Inflammation negatively impacts fast spiking GABA interneurons.  Oxidative stress, a component of inflammation, also impairs the function of NMDA receptors which are the drive on the fast spiking GABA interneurons (Sorce, Schiavone, Tucci et al., 2010; Sullivan & O’Donnell, 2012).  Stressful life experiences can also increase oxidative stress and thus provides a mechanism for how trauma can increase the emergence of psychosis (Cabungcal, Steullet et al., 2013; Jing et al., 2013).  Many persons with psychosis relapse when they incur infections in other parts of the body which than can raise inflammatory factors in brain (see Brian Miller,  2016).

The Impact of Antipsychotic Drugs on Brain Inflammation: Bloomfield et al. (2016) cited two studies using microglia cells in a petri dish which showed that antipsychotics tamed activation of these cells (Bian et al., 2008; Kato et al., 2008).  They also cited a study by Zhu et al. (2014) in live rats which showed that when a molecule of the wall of a bacterium (lipopolysaccharide) is injected into the brain of a rat and subsequently the rat is given a 14 day administration of an antipsychotic the brain’s inflammatory response to the provocation is attenuated.  Bloomfield et al. did not cite the study by Cotel et al. The Cotel et al. study showed that antipsychotic treatment activates inflammation in the brain, the opposite of what the studies cited by Bloomfield et al. showed.  Arguably, the Cotel et al. study is more relevant to the question of how antipsychotic drugs influence inflammation in the brain.  Cotel et al. administered antipsychotics for 8 weeks, much longer than in the other studies.  Moreover, Cotel et al. did not use another activator of an inflammatory response (as was done in the other studies).  Cotel et al. only examined the impact of the antipsychotics in brains which were not exposed to another inflammatory provocation. The Cotel et al. study, which found that antipsychotics create brain inflammation, is important because it might offer an explanation/mechanism for how antipsychotics shrink cortex which was shown in the humans (see Ho et al., 2011) and in the primate studies (Dorph-Petersen et al., 2005). A study by Shao et al. (2013) further confirmed that blocking dopamine receptors, as antipsychotics do, will increase brain inflammation.

The Search for Alternatives to Antipsychotics:   There is a literature on using anti-inflammatories to treat psychosis.  In fact, in a study of children at high risk of converting to psychosis, omega-3s (which are anti-inflammatory) was the only treatment that prevented the emergence of frank psychosis with 27.5% becoming psychotic in the control group versus 4.9% in the omega-3 group at the 12 month follow-up (Amminger et al., 2010).  There is also a literature attesting to the beneficial effects of anti-inflammatories on psychosis.  The anti-inflammatories have included aspirin, minocycline, statins, N-acetylcysteine, and the COX-2 inhibitor, celecoxib (Keller et al., 2013; Sommer et al., 2014).  Sommer et al. concluded that aspirin, estrogen, and N-acetyl-cysteine showed the best effects.  Additionally, social support can also reduce systemic inflammation.  Hopefully, in the future, we’ll have drug trials of anti-inflammatories as the sole pharmacological treatment along with attention to an anti-inflammatory diet and Soteria Project support.  (There is little reason to believe that any chemical anti-inflammatory can eclipse the impact of an inflammatory diet.)  Perhaps the future will offer a better way.

Readers on this website may object to any notion that biology influences human behavior. At risk of offending this audience, I present the findings in these studies because they demonstrate the folly of antipsychotics even for those who believe in physiological explanations for hearing voices.  Since doctors probably won’t ever give up their prescription pads, perhaps they can be coaxed into gentler drugs to prescribe.  I think that for those who are involuntarily committed to the psychiatric hospital, telling the doctor to prescribe “this” instead of “that” and backing up the demand with a study published in a legitimate journal might hold some weight.  If asking for a legitimate alternative does not influence the doctor, it might influence a judge.  In fact, most states have informed consent laws which mandate that physicians discuss all the options available for treating a given condition so that the patient can choose which option they prefer.

Amminger, G. P., Schafer, M. R., Papageorgiou, K. et al. (2010). Long-chain omega-3 fatty acids for indicated prevention of psychotic disorders:  a randomized, placebo-control trial. Archives of General Psychiatry, 67, 146-154.

Bian, Q., Kato, T., Monji, A. et al. (2008). The effect of atypical antipsychotics, perospirone, ziprasidone, and quetiapine on microglia activation induced by interferon-gamma. Progress in Neuropsychophamacology and Biological Psychiatry, 32, 42-48.

Bloomfield, P. S., Selvaraj, S., Veronese, M., Rizzo, G., Bertoldo, A., Owen, D. R., Bloomfield, M.A.P., Bonoldi, I., Kalk, N., Turkheimer, F., McGuire, P., de Paola, V., & Howes, O. D. (2016).  Microglia activity in people at ultra high risk of psychosis and in schizophrenia:  An [11C]PBR28 PET brain imaging study. American Journal of Psychiatry, 173 (1), 44-52.

Cabungcal, J-H., Steullet, P., Morishita, H., Kraftsik, R., Cuenod, M., Hensch, T. K., & Do, K. Q. (2013).  Perineuronal nets protect fast-spiking interneurons against oxidative stress. Proceedings of the National Academy of Sciences, 110(22), 9130-9135.

Chaudhry, I. B. Hallak, J., Husain, N. (2012).  Minocycline benefits negative symptoms in early schizophrenia: a randomized double-blind placebo controlled clinical trial in patients on standard treatment. Journal of Psychopharmacology, 26, 1185-1193.

Cotel, M-C., Lenartowicz, E. M., Natesan, S., Modo, M. M., Cooper, J. D., Willaims, S. C. R., Kapur, S., & Vernon, A. C.  (2015).  Microglia activation in the rat brain following chronic antipsychotic treatment at clinically relevant doses. European Neuropsychopharmacology, http://dx.doi.org/10.1016/j.euroneuro.2015.08.004

Dorph-Petersen, K. A., Pierri, J. N., Perel, J. M., Sun, Z., Sampson, A. R., & Lewis, D. A. (2005).  The influence of chronic exposure to anti-psychotic medications on brain size before and after tissue fixation:  A comparison of haloperiodol and olanzapine in macaque monkeys. Neuropsychopharmacology, 30 (9), 1649-1661.

Ho, B. C., Andreasen, N. C., Ziebell, S., Pierson, R., & Magnotta, V. (2011).  Long-term antipsychotic treatment and brain volumes:  a longitudinal study of first-episode schizophrenia. Archives of General Psychiatry, 68(2), 128-137.

Jiang, Z., Rompala, G. R., Zhang, S., Cowell, R. M., & Nakazawa, K. (2013).  Social isolation exacerbates schizophrenia-like phenotypes via oxidative stress in cortical interneurons. Biological Psychiatry, 73 (10), 1024-1034.

Kato, T., Mizoguchi, Y., Monji, A. et al. (2008).  Inhibitory effects of aripiprazole on interferonγ-induced microglia activation via intracellular Ca2+ regulation in vitro. Journal of Neurochemistry, 106, 815-825.

Keller, W. R., Kum, L. M., Wehring, H. J., Koola, M. M., Buchanan, R. W., & Kelly, D. L. (2013).  A review of anti-inflammatory agents for symptoms of schizophrenia. Journal of Psychopharmacology, 27 (4), 337-342.

Kirkpatrick, N., & Miller, B. J. (2013).  Inflammation and schizophrenia. Schizophrenia Bulletin, 39 (6), 1174-1179.

Miller, B. J. (2016, January 7).  Adjunctive monoclonal antibody immunotherapy in schizophrenia. Psychiatric Times

Miller, B. J., Graham, K. L., Bodenheimer, C. M., Culpepper, N. H., Waller, J. L., & Buckley, P. F. (2013).  A prevalence study of urinary tract infections in acute relapse of schizophrenia. Journal of Clinical Psychiatry, 74(3), 271-277.

Mṻller, N., Riedel, M., Scheppach, C. et al. (2002).  Beneficial antipsychotic effects of celecoxib add-on therapy compared to risperidone alone in schizophrenia. American Journal of Psychiatry, 159, 1029-1034.

Shao, W., Zhang, S.Z., Tang, M., Zhang, X. H., Zhou, Z., Yin, Y.Q., Zhou, Q. B., Hang, Y. Y., Liu, Y. J., Wawrousek, E., Chen, T., Li. S. B., Xu, M., Zhou, J. N., Hu, G., & Zhou, J. W. (2013).  Suppression  of neuroinflammation by astrocytic dopamine D2 receptors via alphaB-crystallin.  Nature, 494, (7435), 90-94.

Sorce, S., Schiavone, S., Tucci, P., Colaianna, M., Jaquet, V., Cuomo, V., Dubois-Dauphin, M., Trabace, L., & Krause, K-H. (2010). The NADPH oxidase NOX2 controls glutamate release: a novel mechanism involved in psychosis like ketamine responses. Journal of Neuroscience, 30(34), 11317-11325.

Sommer, I. E., van Westrhenen, R., Begemann, M. J., de Witte, L. D., Leucht, S., & Kahn, R. S. (2014).  Efficacy of anti-inflammatory agents to improve symptoms in patients with schizophrenia: an update. Schizophrenia Bulletin, 40 (1), 181-191.

Sommer, I. E., de Witte, L., Begemann, M., & Kahn, R. S. (2012). Nonsteroidal anti-inflammatory drugs in schizophrenia:  ready for practice or a good start? Journal of Clinical Psychiatry, 73(4), 414-419.

Sorce, S., Schiavone, S., Tucci, P., (2010). The NADPH oxidase NOX2 controls glutamate release:  a novel mechanism involved in psychosis-like ketamine response. Journal of Neuroscience, 30, 11317-11325.

Sullivan, E. M., & O’Donnell, P. (2012). Inhibitory interneurons, oxidative stress, and schizophrenia. Schizophrenia Bulletin, 38 (3), 373-376.

Zhou, F., Zheng, Y., Ding, Y.Q. et al. (2014). Minocycline and risperidone prevent microglia activation and rescue behavioral deficits induced by neonatal intrahippocampal injection of lipopolysaccharide in rats. PLoS One, 2014, 9:e93966

 

2 thoughts on “INFLAMMATION AND PSYCHOSIS

  1. Dr. Littrell,

    First off, I want to say you have been a hero of mine for some time because of your excellent postings on MIA. As an LCSW with an interest in neuroscience, I have found the tendency among critics of the current medical model to more often than not be guilty of “throwing the brain out with the bathwater.” I really appreciate your approach, which I believe is “holistic” in the true meaning of that word.

    I recently retired from CooperRiis, where I was last in the position of Clinical Director, which is attempting to put forth a more enlightened model. During my time there I started a “neuroenhancement program”, which eventually attracted Dr. Carl Anderson (from Marty Teicher’s lab at Harvard) to come down and join me in my efforts. Ultimately we were frustrated by the inability to to really move the model forward and we recently left CooperRiis.

    On the topic of inflammation, I am so appreciative of your efforts to get this information better known. I preach good nutrition, targeted supplementation and exercise to everyone I work with. Our particular focus was, and continues to be, using neurofeedback and other technologies and techniques to help leverage “positive” neuroplastic change. Some of our results were pretty astounding at CR with this combined approach, and I presented them at a few national conferences.

    Specifically, I am wondering if you are aware of some of the research being done in the area of infra-red stimulation? I thought you might find the following interesting:

    https://www.researchgate.net/publication/297611258_Review_of_transcranial_photobiomodulation_for_major_depressive_disorder_Targeting_brain_metabolism_inflammation_oxidative_stress_and_neurogenesis

    Anyway, I really wanted to just connect with you in some way to express my appreciation for the excellent public service you have been providing with your scholarship.

    Best,
    Stephen Barnard

    Like

    • thanks so much for the information. I will check this out.

      I just returned from the American Association of Immunologists annual convention. There was a lot of attention on the microbiota and its influence on the immune system. There are data that the microbiota even influences the response to cancer treatments. This is truly an exciting time.

      Like

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