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Fifteen years ago, a cluster of women at a London neurological hospital presented with a perplexing array of symptoms. Ranging from stupor and rigidity to seizures and movement disorders, their conditions often began with what appeared to be classic episodes of psychosis, including agitation, hallucinations, and delusions. These early presentations led many to seek emergency care or admission to psychiatric facilities. Neuropsychiatrist Thomas Pollak, reviewing their initial case notes, recognized them as textbook examples of mental ill health. However, a groundbreaking discovery revealed these patients were suffering from autoimmune encephalitis, a condition where the immune system erroneously attacks the brain. The realization that an autoimmune disorder could manifest as psychosis "kind of blew my mind," Pollak admitted, shattering the conventional divide between psychiatric and neurological illnesses.

This pivotal moment marked the beginning of an emerging field of study, with Pollak at the forefront. His work, alongside that of other researchers, is increasingly demonstrating that autoimmune diseases play a more significant role in mental health conditions than previously understood. While a link between schizophrenia and autoimmune diseases has been observed for decades, with individuals diagnosed with schizophrenia showing a higher propensity for autoimmune conditions and vice versa, the scope of this overlap is now being dramatically expanded. Emerging research suggests that autoimmune processes may contribute to a wider spectrum of conditions, including post-traumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD), depression, and even dementia. This growing body of evidence points to a revolutionary possibility: that some cases currently diagnosed as mental health conditions could be effectively treated with immunomodulatory therapies, a therapeutic avenue often overlooked by clinicians. "The immune system is playing a role in behavior much more than we appreciate," stated Andrew Miller, a psychiatrist at Emory University School of Medicine in Georgia.

The Immune System’s Unseen Assault on the Brain

The human immune system, a sophisticated defense mechanism designed to neutralize pathogens like bacteria and viruses, can, under certain circumstances, malfunction. This misfiring, known as autoimmunity, leads the immune system to deploy its arsenal—antibodies, cytokines, and T-cells—against the body’s own tissues. "We know that every single organ system is affected by autoimmunity," explained Christopher Bartley, who heads the Translational Immunopsychiatry Unit at the U.S. National Institutes of Health. The brain, he noted, is not an exception.

The connection between the immune system and mental health is perhaps most starkly illustrated in psychotic disorders such as schizophrenia. Approximately twenty years ago, scientists first identified a form of autoimmune encephalitis known as anti-NMDAR encephalitis. In this condition, specific antibodies bind to receptors in the brain, triggering neuropsychiatric symptoms that can include delusions, hallucinations, memory loss, and peculiar behaviors.

Despite the symptomatic overlap, the treatment pathways for anti-NMDAR encephalitis and schizophrenia diverge significantly. Autoimmune encephalitis can often be successfully managed with medications that recalibrate the immune system. In contrast, individuals diagnosed with schizophrenia are typically prescribed antipsychotic drugs, which, for up to a third of patients, prove ineffective. This discrepancy highlights a critical diagnostic challenge: misidentifying an autoimmune condition as a primary psychiatric disorder can lead to prolonged and ineffective treatment.

Autoimmune Encephalitis: A Missed Diagnosis with Devastating Consequences

Autoimmune encephalitis is described by Belinda Lennox, a psychiatrist at the University of Oxford who specializes in psychotic illness, as "a wonderful diagnosis to be able to make, because you can literally get people better and transform their lives with relatively simple treatments." However, this diagnosis is frequently missed if individuals presenting with apparent mental health conditions are not screened for autoantibodies—immune system proteins that mistakenly target the body’s own cells—or other indicators of autoimmune dysfunction.

The women Thomas Pollak encountered were referred to the neurological hospital only after developing overt neurological symptoms like seizures and catatonia. Yet, as research indicates, some individuals with autoimmune encephalitis can exhibit symptoms that mimic schizophrenia for months or even years. This diagnostic delay can result in patients languishing in psychiatric facilities or receiving inappropriate treatments. A tragic case in the UK recently underscored these risks. A 12-year-old girl died by suicide, with an inquest jury finding that a failure by medical staff to conduct a lumbar puncture to test for autoimmune encephalitis possibly contributed to her death. This incident serves as a stark reminder of the potentially fatal consequences of diagnostic oversight.

While autoimmune diseases like multiple sclerosis and lupus are well-established causes of neurological symptoms, the hypothesis that autoimmunity might play a role in schizophrenia has been present for some time. The discovery of anti-NMDAR encephalitis has significantly intensified research interest in the intersection of immunology and psychology. In some instances, the mechanism by which autoimmune reactions precipitate mental ill health is clear, as with anti-NMDAR encephalitis where antibodies directly attack brain receptors. For other patients, autoimmune reactions are implicated, but the precise biological pathways remain elusive.

Belinda Lennox’s research indicates that approximately 5% of individuals diagnosed with schizophrenia possess detectable antibodies in their blood, even if they do not meet the stringent diagnostic criteria for autoimmune encephalitis. She is currently overseeing a clinical trial investigating the efficacy of immunomodulatory treatments, including intravenous immunoglobulin (IVIG) and the monoclonal antibody rituximab, for patients experiencing acute psychosis.

Thomas Pollak estimates that direct antibody-mediated autoimmune encephalitis accounts for no more than 1% of acute psychosis cases. However, he poses a broader question: "how many are experiencing some kind of brain-related autoimmunity or inflammation?" He suggests that when this wider lens is applied, "the numbers start to get a little bit bigger."

Christopher Bartley is adopting an even more expansive perspective. He argues that focusing solely on known autoantibodies responsible for conditions like encephalitis might be too narrow. Bartley hypothesizes that a vast array of currently unidentified autoantibodies could be contributing to psychosis and other psychiatric disorders. "Rather than testing for a dozen autoantibodies in schizophrenia that people have tested for 200 times," he proposes, "why don’t we widen the aperture and try to test for as many possible autoantibodies as we can?"

Unlocking the Potential of Unknown Autoantibodies

The human body possesses an extraordinary capacity to generate an estimated quintillion different types of antibodies. While most are benign, Bartley’s hypothesis posits that within this immense repertoire, an untold number of autoantibodies may contribute to the manifestation of mental illness symptoms. His laboratory has recently identified three novel autoantibodies that show potential links to these conditions, with a research paper detailing these findings reportedly in preparation. Furthermore, neurologists at the Charité-Universitätsmedizin Berlin hospital described several other potentially implicated autoantibodies in a paper published last year.

Bartley’s lab is actively pursuing evidence to solidify these connections. The development of symptoms in animals upon introduction of cloned versions of these autoantibodies would serve as a significant indicator. Even more compelling would be the disappearance of symptoms upon removal of these antibodies, providing strong evidence for their role and suggesting potential therapeutic targets for humans.

The concept that as-yet-undiscovered autoimmune factors might influence mental health conditions aligns with the clinical experience of Anthony Zoghbi at the Baylor College of Medicine in Texas. In 2018, Zoghbi was part of a research team that investigated an extraordinary case: a woman who had been institutionalized in a New York psychiatric hospital for approximately two decades, diagnosed with schizophrenia. Her symptoms were so severe and treatment-resistant that her case was referred for a comprehensive medical evaluation. Specialists eventually identified biomarkers suggestive of lupus, although she did not exhibit the condition’s typical symptoms.

Despite the diagnostic uncertainty, the researchers administered immunomodulatory drugs to the patient. The intervention proved remarkably effective. After nearly twenty years in a near-catatonic state, she began to recover within months of commencing immune therapy. This case profoundly impacted Zoghbi, as the treatment was experimental, deviating from the standard medical approach of large-scale drug testing and mechanistic understanding. Yet, it achieved what two decades of psychiatric treatment had not.

Such experiences suggest that the currently recognized autoimmune-related mental health conditions may represent only a fraction of the actual prevalence. "You can only diagnose what you have diagnostic tests for," Zoghbi commented. It is increasingly plausible that diverse autoimmune processes contribute to mental illness symptoms across a broad spectrum of psychiatric conditions, extending beyond psychosis to include OCD and depression. A small study conducted in 2025, for instance, detected autoantibodies in the blood serum of eight out of twenty veterans who had both PTSD and a history of traumatic brain injury.

It is crucial to note that experts are not suggesting that all or even most individuals diagnosed with mental health conditions have an underlying autoimmune disease. Pollak, for example, navigates a delicate balance as research expands. He has cautioned against both under-diagnosing and over-diagnosing autoimmune-related mental illness. "There is a real danger," Pollak stated, "in blaming everything on the immune system and throwing treatments—many with high price tags and long lists of side effects—at people without careful analysis." He recounted instances of patients selling assets to seek experimental treatments abroad, despite his strong conviction that those treatments would be ineffective.

While only a small percentage of individuals experiencing mental health symptoms may fall into this autoimmune category, "the stakes are so high for that very small fraction that we have to get to the answer," emphasized Zoghbi.

A New Treatment Paradigm on the Horizon

The pursuit of effective treatments for mental health conditions can be a frustrating endeavor. Andrew Miller described current psychiatric interventions as "basically chemotherapy for the brain," acknowledging that while these blunt instruments can be broadly effective, they often lack precision and carry significant side effects. The precise mechanisms by which many psychiatric medications work remain unclear; clinicians often rely on empirical evidence of their efficacy. In response, a significant portion of Pollak’s current research is dedicated to understanding how antipsychotic drugs function at a biological level, particularly their impact on the immune system.

In collaboration with researchers like Katharina Schmack, who studies psychosis at the Francis Crick Institute in the UK, Pollak has initiated a project to investigate this link. Schmack’s team utilizes animal models to simulate immune system activation in the brain, aiming to approximate the processes believed to occur in some individuals with psychosis. Studying these models allows researchers to analyze the effects of antipsychotic drugs on the immune system and behavior of mice.

Should their research indicate that antipsychotics exert their effects by modulating the immune system, it would further bolster the hypothesis of a link between the immune system and mental illness, and underscore the potential for treating a broader patient population with immunomodulatory therapies. "The good thing about immune drugs is [that] we already have a whole array of drugs available," said Schmack. For example, methotrexate, an immunosuppressant already used for conditions like rheumatoid arthritis and psoriasis, is currently under investigation as a potential treatment for schizophrenia.

Certain immunomodulating drugs are already employed in the management of autoimmune encephalitis, particularly in countries like Germany, where a national research network facilitates widespread screening for these conditions. Treatment protocols can include plasmapheresis—a procedure that filters the blood to remove plasma containing harmful antibodies—alongside medications such as corticosteroids, IVIG, and rituximab.

Other nations may soon follow Germany’s lead in expanding autoimmune screening. In the United States, researchers at Columbia University have launched an ambitious initiative to screen every individual institutionalized in New York state’s psychiatric hospitals—a system housing approximately 3,000 people—for biomarkers associated with 12 autoimmune, metabolic, or genetic underpinnings of mental health conditions. Individuals with positive initial blood tests will be recommended for further diagnostic procedures, such as lumbar punctures. This approach could lead to "treatments that are fundamentally different than the standard treatments that are given for people with severe mental illness," explained Steven Kushner, a psychiatrist at Columbia University.

While the proportion of individuals who will test positive for these conditions remains to be determined, Kushner asserted, "to me, it doesn’t matter how small that percentage is. If [the number] is non-zero, this is worthwhile to do." A non-zero finding, he added, would justify replicating similar screening processes in other healthcare systems. Early identification and treatment of even a small number of individuals could prevent "many years currently lost to mental health disability." He concluded, "To identify the treatable entities as early as possible in their trajectory is a major responsibility for the field."

The objective, as Pollak emphasizes, is not to supplant mental healthcare with immune treatments but to foster an integrated approach. Identifying and effectively treating individuals with autoimmune conditions could revolutionize their care and fundamentally alter our understanding of mental illness. However, he stressed that psychotherapy and other established psychiatric interventions remain vital for many patients and should not be discarded.

The growing evidence clearly indicates that autoimmune and mental health conditions are far more intertwined than previously recognized. Expanding neurological screenings for individuals presenting with mental health symptoms has the potential to transform treatments, leading to cures for some seemingly intractable illnesses. While this may not apply to the majority, the profound impact on those affected cannot be overlooked. "A smart future medicine," Pollak posited, "is going to combine all of these different aspects at the same time."

For those seeking support, UK Samaritans are available at 116123 (samaritans.org). In the US, the Suicide & Crisis Lifeline can be reached at 988 (988lifeline.org). A comprehensive list of suicide helplines in other countries can be found at bit.ly/SuicideHelplines.