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Is schizophrenia a rheumatological disease of the brain?

 

The role of inflammation in the pathogenesis of schizophrenia has gained wide attention and research on the association show an exponential growth in the last 15 years. Autoimmune diseases and severe infections are risk factors for later development of schizophrenia (Benros et al. 2011), elevated inflammatory markers in childhood or teenage are associated with a greater risk of schizophrenia in adulthood (Khandaker et al. 2014; Metcalf et al. 2017), individuals with schizophrenia have increased levels of pro-inflammatory cytokine compared to healthy controls (Miller et al., 2011; Szabo et al. 2022) and autoimmune diseases are overrepresented in schizophrenia (Eaton et al. 2006). However, treatments with anti-inflammatory agents are so far of doubtful clinical relevance (Jeppesen et al. 2020).



In 2014 a 22-year-old woman with a history of Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) came to our attention. PANDAS is thought to be a post infectious neuropsychiatric disorder akin to acute rheumatic fever and Sydenham's chorea. The patient had fallen ill at age 15 with headaches. When she was 17 years, she developed a brief period of anorexia nervosa and suddenly, later the same year, she felt numbness in the left side of her body, limb weakness, chest pain, headache, and nausea, and was admitted to the pediatric department when also severe gross motor tics emerged. Extensive assessments were made, including lumbar puncture, but without any pathological findings. She was later found to have a strep infection and when this was cured with antibiotics her symptoms abated.


A few years later the patient relapsed. When I saw her, she presented a total of 62 different symptoms, including rage attacks, obsessions, panic attacks, separation anxiety, regressive behaviours, painful spasms, muscle weakness, intermittent problems with walking, hallucinations, and tremors. For psychiatry she was such an atypical patient and therefore referred to the neurological department for an extensive examination. After two weeks of inpatient care, which included clinical examination and a second brain MRI examination, with and without contrast, as well as a sleep EEG, all interpreted to be within normal range, she was considered to have a ‘Conversion disorder’ (functional neurological symptom disorder) and was referred back to the psychiatric unit. However, some year later the patient developed pain in her eyes and loss of sight and was then diagnosed with neuromyelitis optica spectrum disorder. This is a rare autoimmune disorder that causes inflammation in nerves of the eye and the spinal cord. The patient was urgently treated with steroids, intravenous immunoglobulins and rituximab. Luckily all symptoms, not only the neuromyelitis optica spectrum disorder symptoms but also psychiatric symptoms remitted. She stayed well with rituximab infusions every 6 months. We published a report on her case in 2019 (Bejerot et al. 2019).


Rituximab was approved for use in the U.S. in 1997 to treat lymphoma. It is a monoclonal antibody directed against the B-cell antigen CD20. It depletes B cells by several mechanisms, including direct antibody-dependent cellular cytotoxicity, complement-mediated cell death, and signaling apoptosis. Today it is widely used for thousands of patients with rheumatoid arthritis, polyangiitis and multiple sclerosis (MS). Rituximab is also included in the treatment guidelines for anti-NMDA receptor encephalitis (Wandinger et al. 2011). It is generally well-tolerated but can in extremely rare cases (approximately 1/25 000) induce an activation of JC virus causing Progressive multifocal leukoencephalopathy (PML). However, when rituximab is administered as a monotherapy, without being combined with other immunosuppressive drugs, PML has to our knowledge never been reported. People treated with rituximab are nevertheless immunocompromised and elevated rates of long-term COVID-19 was recently reported among patients with multiple sclerosis.


To paraphrase Winston Churchill: This is not the end, not even the beginning of the end, but perhaps the end of the beginning, linking schizophrenia to immune dysfunction.

Based on our own case and reports of other patients with PANDAS who had remitted after immunomodulatory treatments, we decided to study the effect of rituximab as an adjunctive drug in treatment resistant patients with either obsessive compulsive disorder (OCD) or schizophrenia. PANDAS is believed to be an autoimmune reaction to a strep infection and there is multiple evidence indicating a role of inflammation and immunological mechanisms in schizophrenia providing the rationale to use a potent immunomodulatory drug in these disorders (Corsi-Zuelli and Deakin, 2021; Endres et al 2022).


We carried out two pilot studies in parallel between 2019 and 2022. The results were recently published in Journal of Psychiatric Research (Bejerot et al., 2023). Ten individuals with treatment resistant OCD (mean age 26) and 9 individuals with treatment resistant schizophrenia (mean age 27) with a mean duration of illness exceeding 12 years, received an add on treatment with a single infusion of 1000 mg rituximab on the Rheumatology department at Örebro university hospital, Sweden. The participants were severely ill with mean Y-BOCS and PANSS scores of 27.5±7 and 99±32 respectively, and with poor overall functioning. None of the schizophrenia patients were employed but four of the OCD patients had employment or were students. Only one patient out of 19 lived with a partner. Of the schizophrenia patients, six had previously tested clozapine, and all were presently treated with antipsychotics; four with long-acting injectables. Seven of the OCD patients were on serotonin reuptake inhibitors, two augmented with antipsychotics while three were presently unmedicated due to lack of effect from anti-obsessive drugs. The illicit drug screen was negative for all patients.


Patients remained on their maintenance psychiatric treatment for OCD or schizophrenia respectively until 5 months and treatment had to be stable for 1 month prior to baseline. Primary outcome was measured with the PANSS scale for the schizophrenia group and Y-BOCS for the OCD group. In addition, The Clinical Global Impression–Improvement (CGI-I) and the Personal and Social Performance Scale (PSP) were assessed in all patients.


People treated with rituximab are nevertheless immunocompromised and elevated rates of long-term COVID-19 was recently reported among patients with multiple sclerosis. Image by Unsplash.
People treated with rituximab are nevertheless immunocompromised and elevated rates of long-term COVID-19 was recently reported among patients with multiple sclerosis. Image by Unsplash.

In schizophrenia marked improvements were seen in all PANSS subscales after 3 months, when 7 of 9 patients had decreased more than 40% on PANSS. Thereafter there was a gradual return to the pre-treatment state. In contrast only 2 out of 10 patients in the OCD group improved on Y-BOCS. Interestingly, 3 schizo-obsessive patients, i.e., patients who fulfil diagnostic criteria for schizophrenia and OCD simultaneously and were included in the schizophrenia group, were markedly improved both on PANSS and Y-BOCS. However, OCD patients with a history of Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS, an umbrella term that includes PANDAS) did not improve. Psychosocial functioning improved in the schizophrenia group by 62% after 5 months while only a 16% improvement was found in the OCD group.


One patient with schizophrenia deteriorated, she had refused to continue with antipsychotics (injectable) after inclusion, thus gradually losing the antipsychotic effect which presumably caused the deterioration. Obviously, rituximab cannot replace antipsychotics, but it seems to enhance the antipsychotic effects of D2 blockers, reduce negative symptoms and curiously also lessen D2 blocker related side-effects according to the self-rated UKU Side Effect Rating Scale. The most common side-effect among the participants was a running nose, a well- known side effect from rituximab. Symptoms such as anxiety and depression, also acknowledged side-effects from rituximab, wererarely reported, on the contrary both the depression and anxiety item in PANSS showed improvement. However, one of the schizophrenia patients developed abdominal pain. After examination by several surgeons, the patient was deemed as having so-called functional symptoms. One OCD patient deteriorated compared to her status at inclusion at the one year follow up, presumably due to long-term COVID-19. One of the responding schizophrenia patients who previously had severe and recurrent psychotic relapses was allowed to continue the rituximab treatment due her remarkable improvement. Since 2019, she has stayed well, and claims that rituximab gave her her life back.


In March 2023 we started a multicenter double-blinded controlled trial with rituximab on patients, ages 18 to 55, with schizophrenia or schizoaffective disorder. Hopefully we will be able to replicate the successful results from the pilot study, but regardless of the outcome the study is important. The study will tell if schizophrenia is associated with an inflammation of the brain and if this is the case, it may open new venues for treatments. To paraphrase Winston Churchill: This is not the end, not even the beginning of the end, but perhaps the end of the beginning, linking schizophrenia to immune dysfunction.


The ongoing study is generously supported by Torsten Söderbergs stiftelse, The Swedish Brain Foundation and The Swedish Research Council. □


References by request

  • Bejerot S, Hesselmark E, Mobarrez F, Wallén H, Hietala MA, Nybom R, Wetterberg L.., 2019. Neuromyelitis optica spectrum disorder with increased aquaporin-4 microparticles prior to autoantibodies in cerebrospinal fluid: a case report. J Med Case Rep. 2019 13(1):27. doi: 10.1186/s13256-018-1929-z.

  • Bejerot S, Sigra Stein S, Welin E, Eklund D, Hylén U, Humble MB., 2023 Rituximab as an adjunctive treatment for schizophrenia spectrum disorder or obsessive-compulsive disorder: Two open-label pilot studies on treatment-resistant patients. J Psychiatr Res 158:319-329. doi: 10.1016/j.jpsychires.2022.12.003.

  • Benros M.E., Nielsen P.R., Nordentoft M., Eaton W.W., Dalton S.O., Mortensen P.B., 2011. Autoimmune diseases and severe infections as risk factors for schizophrenia: a 30-year population-based register study. Am. J. Psychiatry 168:1303–1310.

  • Corsi-Zuelli, F., Deakin, B., 2021. Impaired regulatory T cell control of astroglial overdrive and microglial pruning in schizophrenia. Neurosci. Biobehav. Rev. 125, 637-653. doi: 10.1016/j.neubiorev.2021.03.004.

  • Eaton W.W., Byrne M., Ewald H., Mors O., Chen C.Y., Agerbo E., Mortensen P.B., 2006, Association of schizophrenia and autoimmune diseases: linkage of Danish national registers. Am. J. Psychiatry 163:521–528.

  • Endres, D., Pollak, T. A., Bechter, K., Denzel, D., Pitsch, et al, 2022. Immunological causes of obsessive-compulsive disorder: is it time for the concept of an "autoimmune OCD" subtype? Transl. Psychiatry 12 (1), 5. https://doi.org/10.1038/s41398-021-01700-4.

  • Jeppesen R, Christensen RHB, Pedersen EMJ, Nordentoft M, Hjorthøj C et al, 2020. Efficacy and safety of anti-inflammatory agents in treatment of psychotic disorders - A comprehensive systematic review and meta-analysis. Brain Behav Immun. 90:364-380. doi: 10.1016/j.bbi.2020.08.028.

  • Khandaker G.M., Pearson R.M., Zammit S., Lewis G., Jones P.B, 2014. Association of serum interleukin 6 and C-reactive protein in childhood with depression and psychosis in young adult life: a population-based longitudinal study. JAMA Psychiatry. 71:1121–1128.

  • Miller BJ, Buckley P, Seabolt W, Mellor A, Kirkpatrick B, 2011. Meta-Analysis of Cytokine Alterations in Schizophrenia: Clinical Status and Antipsychotic Effects. Biol Psychiatry 70(7):663–71.

  • Metcalf SA, Jones PB, Nordstrom T, Timonen M, Mäki P, et al, 2017 Serum C-reactive protein in adolescence and risk of schizophrenia in adulthood: A prospective birth cohort study. Brain Behav Immun. 59:253-259. doi: 10.1016/j.bbi.2016.09.008.

  • Szabo A, O'Connell KS, Ueland T, Sheikh MA, Agartz I, et al, 2022. Increased circulating IL-18 levels in severe mental disorders indicate systemic inflammasome activation. Brain Behav Immun. 99:299-306. doi: 10.1016/j.bbi.2021.10.017.

  • Wandinger, K.P., Saschenbrecker, S., Stoecker, W., Dalmau, J., 2011. Anti-NMDA-receptor encephalitis: a severe, multistage, treatable disorder presenting with psychosis. J. Neuroimmunol. 231, 86-91.


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