Back to Basics

As Stefanie introduced last week, Talal is one of our more elusive subjects, and sources about his mental illness are slim. This makes it hard for us to determine if his abdication was truly the result of psychiatric illness, or just a plot by political adversaries. All of the Jordanian sources I read indicate that Talal abdicated due to “health issues”, but it seems like his struggles with mental illness have long been an open secret. In an obituary in The New York Times, Talal was described as becoming “increasingly subject to attacks of schizophrenia in which he indulged in morbid suspicions of his family and officials and sometimes violently attacked them.” This account is supported by the book When Illness Strikes the Leader: The Dilemma of the Captive King, which claims Talal “showed signs of weakness and emotional instability” as a child, later leading to “withdrawal and fits of violence”.

If you’re a day one ULTC follower, you’ll remember that this is not the first subject we’ve covered who suffered from schizophrenia. In our very first series exactly two years ago (and accompanying podcast), we talked about Charles VI of France. So it’s fitting that on our second birthday, we are circling back to the same disease. If you want to take a deeper look at the diagnosis, biology, and treatment of schizophrenia, I highly recommend going back and reading that post or listening to that episode. But just so we’re all on the same page, here’s a quick refresher. 

The hallmark symptoms of schizophrenia are delusions, hallucination, and paranoia. These are examples of “positive symptoms”, which also include disordered speech and thought. There are also “negative symptoms” like social withdrawal and depressed mood. The obituary and book I referenced earlier described Talal as experiencing both positive and negative symptoms – paranoia and social withdrawal. As we talked about in the Charles VI post, there is some association between positive symptoms and violence, but patients with schizophrenia are not inherently more violent, so keep that in mind if trying to generalize Talal’s symptoms to the larger patient population.

Alpining for Change

Despite the caginess and paucity of details surrounding Talal’s mental health, the one detail that every source seems to note and agree on is that he was being treated in Switzerland at the time when his father was killed, subsequently making him king. I did a little digging to see if there was any significance to Talal going to Switzerland, and was surprised to learn that the country was actually a trailblazer in the treatment of schizophrenia.

While it isn’t known which facility Talal visited for treatment, we’ll focus on the most famous in Switzerland: Burgholzli Hospital (where psychoanalyst Carl Jung came to notoriety!). The facility was founded in Zurich in 1870 by Wilheim Griesenger, a groundbreaking psychiatrist who “strongly believed in the biological causation of mental illness” (Kallivayalli). In 1898, a doctor named Eugene Bleuler took over as Burgholzli’s director. In 1908, Bleuer was giving a talk in Berlin when he introduced the term “schizophrenia” to replace the diagnosis of “dementia-praecox” that the illness had previously been known as. Bleuler’s conceptualization of schizophrenia was revolutionary. According to Britannica, he believed “dementia praecox was not a single disease, was not invariably incurable, and did not always progress to full dementia…He described a group of diseases, the schizophrenias, the basic symptoms of which were a disordered train of mental associations and splitting or fragmentation of the personality.” 

Bleuler’s new description of schizophrenia changed the way clinicians thought about the disease by distinguishing it from dementia. But that did not immediately solve the issues surrounding patient care. Talal became king in 1951, the same year that the first schizophrenia drug, chlorpromazine, was synthesized. Chlorpromazine was the first of a group of drugs known as neuroleptics used to treat psychiatric disorders, which eventually shifted the focus of schizophrenia treatment from institutionalization in asylums to pharmacological management of symptoms. 

However, the first case study of successful treatment with chlorpromazine was not published until 1952 by a group in France, so Talal was likely receiving more “traditional” treatments in Switzerland or the other countries he visited for treatment throughout his youth. Early treatments for schizophrenia were heartbreakingly brutal. If you were lucky, you got sedated with a lot of barbiturates. If your symptoms couldn’t be managed that way, you might face electroconvulsive shock therapy, insulin-induced coma, or a lobotomy. Burgholzli may have been on the cutting edge of mental health treatment, but whether Talal was seen there or another hospital in Switzerland, his experience as a schizophrenic patient in the early 1950s was likely a difficult one.

The Inflame Game

Given that I work in a neuroimmunology lab, you’ve probably noticed that I focus a lot on interactions between the immune system and the brain. In our original post on schizophrenia, we focused on one mechanism that might give rise to the altered brain connectivity in the disease: abnormal synaptic pruning. As a brief summary, the developing brain uses an immune system pathway called complement to tag connections between neurons for disposal. In the second wave of so-called pruning in adolescence, it is believed that there is excessive elimination of synapses in patients with schizophrenia. When I was deciding how to take us deeper in this blog, I was excited to see some recent research that strengthens the connections between immunity and schizophrenia.

When the COVID-19 vaccine first came on the scene, public health officials did their best to prioritize groups known to be at risk for severe disease: the elderly, immunocompromised, those with heart problems, low socioeconomic status groups, etc. But epidemiological research continued to search for more populations that might be predisposed to more severe disease. Multiple studies had shown that there was an increased rate of COVID-19 infections in people with mental illnesses. Some of this association is thought to be related to socioeconomic status and access to health care, which are affected by severe mental illness. In 2021, a group of doctors from New York published a paper going one step further to ask if specific psychiatric diagnoses were associated with worse outcomes after COVID-19 infection. 

The researchers looked at over 7,000 patients with severe COVID-19 symptoms, up to 45 days after they tested positive. Their study cohort included 75 patients with a previous diagnosis of schizophrenia, 564 with mood disorders, and 360 with anxiety disorders. Factors like race, age, sex, and health conditions that could have affected patient outcomes were considered and controlled for in all of their analysis. Shockingly, they found that patients with schizophrenia were almost three times as likely to die or end up in hospice care from COVID-19 as controls, while patients with mood or anxiety disorders showed no increased risk. 

Of course, every study is limited, and a single report of an increased risk from a three-month span in one region of the United States cannot necessarily be generalized to the entire world. But the interesting thing is, this is not an isolated report. A paper from the United Kingdom saw the same pattern of increased mortality in schizophrenia patients, but to a greater degree: patients were nearly five times as likely to die. And a meta-analysis of papers from seven different countries found people with severe psychiatric disease were twice as likely to die from COVID-19 as controls, and this pattern was driven mostly by patients with schizophrenia and bipolar disorder. 

Not only is this leading to calls for people with psychiatric disease to be prioritized for future boosters, it is also leading scientists to wonder how schizophrenia is contributing to COVID-19 severity. The authors of the New York paper I mentioned have a couple of theories. One is that genetic risk factors associated with schizophrenia may influence immune system functioning. They also point out that previous research has shown that patients with schizophrenia have altered immune cell compositions, which might contribute to severe disease. The paper the authors were referencing looked at blood samples from patients with schizophrenia and saw that compared to healthy controls, they had more B cells (the antibody-producing cells of the immune cells), fewer immunosuppressive T cells, and a higher proportion of T cells that kill other cells. T cells and B cells are the workhorses of the immune system, and increased inflammatory subsets of these cells could contribute to poor outcomes after COVID infection.

And while there’s an abundance of evidence that schizophrenia could be affecting COVID-19 progression, there’s also anecdotal evidence that COVID can cause psychiatric symptoms similar to those seen in schizophrenia. Several case studies have been published describing people with no history of mental illness experiencing hallucinations, delusions, and paranoia after testing positive for COVID-19. While these symptoms are fleeting and rare, they point to an effect of coronavirus on the brain. The mechanism by which COVID-induced psychosis occurs isn’t known, but a recent paper from Yale proposes one possible (and sensational) hypothesis. The study analyzed the cerebrospinal fluid (CSF), the liquid that bathes the brain and spinal cord, of six patients with COVID-19 who also experienced neurological symptoms. They found that there were antibodies in the CSF of sick patients that reacted both against the coronavirus and brain tissue, suggesting that COVID could provoke an autoimmune response against the nervous system. It’s a provocative and preliminary finding, but it’s not an entirely new concept. This is a theory of molecular mimicry, where infection can elicit an immune response to something in the body that looks similar to the pathogen, and is one of the hypotheses for the development of multiple sclerosis. The brain was long thought to be “immune-privileged” or protected from immune cells that could cause inflammation and harm, but as science advances, that seems less and less true.

Talal Order

I took a long detour there, and you’re probably wondering what any of this has to do with Talal. Talal was diagnosed with schizophrenia in an era before pharmaceutical treatments were available, less than 50 years after the disease got its name. Even when medicines like chlorpromazine hit the market, doctors and scientists still did not know how these drugs were helping patients or what caused schizophrenia in the first place. And 50 years after Talal’s death, we are still grappling with the same questions. 

My hope in sharing the research about the connections between COVID and schizophrenia is that you can appreciate that the neurobiology of mental illness is still an incomplete story. Researchers are actively trying to unravel the complex genetic and environmental factors that trigger schizophrenia and understand how the disease changes the brain. From Bleuler to the teams behind recent pandemic studies, doctors are adding to the narrative. Each discovery inches us closer to a complete understanding of the disease that afflicted Talal. And as with the best of things, the answers might come when and where we least expect them.

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References

Ban, T. (2007). Fifty years of chlorpromazine: a historical perspective. Neuropsychiatric Disease and Treatment, 3(4), 495–500. 

Dembosky, A. (2022, March 25). Covid and schizophrenia: Why this deadly mix can deepen understanding of the brain. NPR. Retrieved April 5, 2022, from https://www.npr.org/sections/health-shots/2022/03/25/1088058422/covid-and-schizophrenia 

Encyclopædia Britannica, inc. (n.d.). Eugen Bleuler. Encyclopædia Britannica. Retrieved April 5, 2022, from https://www.britannica.com/biography/Eugen-Bleuler 

Fond, G., Nemani, K., Etchecopar-Etchart, D., Loundou, A., Goff, D. C., Lee, S. W., Lancon, C., Auquier, P., Baumstarck, K., Llorca, P.-M., Yon, D. K., & Boyer, L. (2021). Association between mental health disorders and mortality among patients with COVID-19 in 7 countries. JAMA Psychiatry, 78(11), 1208. https://doi.org/10.1001/jamapsychiatry.2021.2274 

Hassan, L., Peek, N., Lovell, K., Carvalho, A. F., Solmi, M., Stubbs, B., & Firth, J. (2021). Disparities in covid-19 infection, hospitalisation and death in people with schizophrenia, bipolar disorder, and major depressive disorder: A cohort study of the UK Biobank. Molecular Psychiatry. https://doi.org/10.1038/s41380-021-01344-2 

Kallivayalil, R. A. (2016). The Burgholzli Hospital: Its history and legacy. Indian Journal of Psychiatry, 58(2), 226. https://doi.org/10.4103/0019-5545.183772 

Kluger, J. (2022, March 4). Covid-19 may be linked to spontaneous psychosis. Time. Retrieved April 6, 2022, from https://time.com/6153809/covid-19-psychosis-symptoms/ 

Nemani, K., Li, C., Olfson, M., Blessing, E. M., Razavian, N., Chen, J., Petkova, E., & Goff, D. C. (2021). Association of psychiatric disorders with mortality among patients with COVID-19. JAMA Psychiatry, 78(4), 380. https://doi.org/10.1001/jamapsychiatry.2020.4442 

The New York Times. (n.d.). Ex-King Talal of Jordan Dies; Abdicated in ’52 in Favor of Son. The New York Times. Retrieved April 3, 2022, from https://timesmachine.nytimes.com/timesmachine/1972/07/09/91335273.html?pageNumber=51 

Post, J. M. (1995). The Mad King. In When illness strikes the leader: The dilemma of the captive king (pp. 36–38). essay, Yale Univ Press. 

Song, E., Bartley, C. M., Chow, R. D., Ngo, T. T., Jiang, R., Zamecnik, C. R., Dandekar, R., Loudermilk, R. P., Dai, Y., Liu, F., Sunshine, S., Liu, J., Wu, W., Hawes, I. A., Alvarenga, B. D., Huynh, T., McAlpine, L., Rahman, N.-T., Geng, B., … Farhadian, S. F. (2021). Divergent and self-reactive immune responses in the CNS of COVID-19 patients with neurological symptoms. Cell Reports Medicine, 2(5), 100288. https://doi.org/10.1016/j.xcrm.2021.100288 

Steiner, J., Jacobs, R., Panteli, B., Brauner, M., Schiltz, K., Bahn, S., Herberth, M., Westphal, S., Gos, T., Walter, M., Bernstein, H.-G., Myint, A. M., & Bogerts, B. (2010). Acute schizophrenia is accompanied by reduced T cell and increased B cell immunity. European Archives of Psychiatry and Clinical Neuroscience, 260(7), 509–518. https://doi.org/10.1007/s00406-010-0098-x 

Tueth, M. J. (1995). Schizophrenia: Emil Kraepelin, Adolph Meyer, and beyond. The Journal of Emergency Medicine, 13(6), 805–809. https://doi.org/10.1016/0736-4679(95)02022-5