A report by Bloomfield et al. in the January 2016 issue of American Journal of Psychiatry demonstrated that psychosis is associated with increased inflammatory activity in the brain. What the researchers did was to inject a marker, [11C]PBR28, which binds to activated white blood cells (microglia) in the brain and then can be seen on a brain scan. (None of the subjects had been treated with antipsychotic medications.) Bloomfield et al. 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, Bloomfield et al. noted that degree of binding (degree of microglia activation) was correlated with the level of symptoms.
Regardless of how readers of this website view the physiological basis for hearing voices, psychiatrists clearly do assume a physiological basis for hearing voices. A consensus is emerging in the psychiatric literature that the fast spiking GABA interneuron and the NMDA receptors on these fast spiking GABA interneurons form the basis for psychosis. Current issues of American Journal of Psychiatry and JAMA Psychiatry typically contain 4-6 articles per issue on either the NMDA receptors or the fast-spiking GABA interneurons. The Bloomfield et al. report fits in well with this 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.)
There is a strong connection between the NMDA receptors, fast-spiking GABA interneurons and inflammation. 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). Brain inflammation also fits well with the observation that 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).
Many posts on this website have cited studies linking stressful life events as a causal factor in the emergence of psychosis. What science requires is a mechanism connecting psychological stressors with functional changes that drive behavior. The whole field of psychoneuroimmunology has as its major premise that stress/trauma induce brain inflammation. Numerous studies have established a connection between psychological stress and inflammatory hormones in brain. Stressful life experiences can increase oxidative stress. Recent studies connect psychosis with inflammation in the brain. Thus, the studies provide a mechanism for how trauma can increase the emergence of psychosis (Cabungcal, Steullet et al., 2013; Jing et al., 2013).
With the emerging consensus, at least in psychiatric circles, that the fast-spiking GABA interneurons are key in creating psychosis and the acknowledged disabling effect of inflammation on the fast-spiking GABA interneurons, it is important to ask how current treatments impact inflammation.
The Impact of Antipsychotic Drugs on Brain Inflammation: A recent study by Cotel et al. showed that taken over the long-term, antipsychotics induce inflammation in the brain. The Cotel finding contradicts some of the studies cited by Bloomfield et al. 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). Bloomfield et al. 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 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 demonstrated that antipsychotics create brain inflammation.
The Cotel et al. study is important because it might offer an explanation/mechanism for how antipsychotics shrink cortex. Readers of this website probably remember the Ho et al. (2011) that showed that persons treated for several years with antipsychotics demonstrate a sizable reduction in cortex volumes. Studies in monkeys, none of whom were schizophrenic, confirmed that treatment with antipsychotics causes brain shrinkage (Dorph-Petersen et al., 2005). Inflammation, caused by long term use of antipsychotics, may be the proximal cause of brain shrinkage.
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.
Unfortunately, there are only a few studies in which anti-inflammatory interventions were used as the sole treatment for early psychosis. In line with Robert Whitaker’s response to Allen Frances yesterday, with everyone acknowledging the need for greater concern for those with psychosis, perhaps we all can join forces to demand more clinical trials of anti-inflammatories as the sole treatment for early psychosis. Anti-inflammatories such as aspirin and N-acetyl-cysteine have relatively benign side effects. 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. Even without additional studies, I think the review articles cited here legitimize a request to try an anti=inflammatory first. 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. Perhaps demanding that physicians become acquainted with their own literature might offer a way to proceed.
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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.
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Kato, T., Mizoguchi, Y., Monji, A. et al. (2008). Inhibitory effects of aripiprazole on interferon-γ-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.
Littrell, J. (2015). Neuroscience for Psychologists and Other Mental Health Professionals: Promoting Well-Being and Treating Mental Illness. New York: Springer.
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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.
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
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