Fifteen years ago, a perplexing cluster of women admitted to a London neurological hospital presented with a bewildering array of symptoms. Some were lethargic and unresponsive, while others experienced debilitating seizures or profound movement disorders. The common thread, however, was an initial presentation that mimicked textbook episodes of severe mental illness, complete with extreme agitation, vivid hallucinations, and pervasive delusions. Their early medical records, reviewed by neuropsychiatrist Thomas Pollak, painted a picture of acute psychiatric distress, leading some to seek emergency care in psychiatric facilities.
Pollak, then a clinician faced with these complex cases, initially viewed them through the lens of psychiatric disorders. However, a groundbreaking realization emerged: these women were suffering from autoimmune encephalitis, a condition where the body’s own immune system mistakenly attacks the brain. The discovery that an autoimmune disorder could manifest with such classic psychiatric symptoms fundamentally challenged the long-held dichotomy between mental and neurological illnesses. "It kind of blew my mind," Pollak recounted, reflecting on the paradigm shift this observation represented.
In the intervening years, Pollak, now a leading figure at King’s College London, has been instrumental in forging a new field of study. This burgeoning area of research is increasingly demonstrating that autoimmune diseases play a far more significant role in mental health conditions than previously acknowledged. While the connection between autoimmunity and mental illness is not entirely novel – studies have long indicated a higher prevalence of autoimmune diseases in individuals with schizophrenia and vice versa – the work of Pollak and his contemporaries has dramatically expanded the perceived scope of this overlap. Their research now suggests that the immune system may be implicated in a wide spectrum of conditions, including post-traumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD), depression, and even dementia.
This evolving understanding opens a compelling avenue for treatment: the possibility that some cases of apparent mental health conditions could be effectively managed with therapies that target the immune system, a therapeutic approach largely overlooked by conventional psychiatric practice. "The immune system is playing a role in behaviour much more than we appreciate," stated Andrew Miller, a psychiatrist at Emory University School of Medicine in Georgia, highlighting the underestimation of the immune system’s influence on the mind.
The Immune System’s Assault on the Brain
The human immune system, a sophisticated defense mechanism, is a double-edged sword. While it expertly neutralizes external threats like bacteria and viruses, it can also malfunction, turning its potent arsenal—including antibodies, cytokines, and T-cells—against the body’s own tissues. This phenomenon is broadly termed autoimmunity. "We know that every single organ system is affected by autoimmunity," explained Christopher Bartley, who leads the Translational Immunopsychiatry Unit at the U.S. National Institutes of Health. "The brain is no exception."
The intricate relationship between the immune system and mental health is perhaps most vividly illustrated in psychotic conditions such as schizophrenia. Approximately two decades ago, scientists first described a form of autoimmune encephalitis known as anti-NMDAR encephalitis. In this condition, specific antibodies bind to crucial receptors in the brain, triggering a cascade of neuropsychiatric symptoms that can include delusions, hallucinations, memory deficits, and profoundly unusual behavior.
Despite the striking symptomatic overlap, the treatment paradigms for anti-NMDAR encephalitis and schizophrenia diverge significantly. Autoimmune encephalitis is often treatable with medications designed to modulate and calm the immune system, offering a direct path to recovery for many patients. In contrast, individuals diagnosed with schizophrenia typically receive antipsychotic drugs, a treatment regimen that proves ineffective for a substantial portion of patients, estimated to be up to one-third. This discrepancy underscores the critical importance of accurate diagnosis and the potential for misdiagnosis to delay or prevent effective treatment.
The case of Christy Morrill, who lost decades of memories to autoimmune encephalitis, serves as a poignant example of the devastating impact of this condition and the potential for recovery with the right intervention. Morrill, pictured holding a viewfinder with a slide film of himself as a college student, represents the many individuals whose lives have been profoundly altered by autoimmune brain disorders.
Belinda Lennox, a psychiatrist at the University of Oxford specializing in psychotic illness, described autoimmune encephalitis as "just a wonderful diagnosis to be able to make, because you can literally get people better and transform their lives with relatively simple treatments." However, she cautioned that this diagnosis can be easily missed if patients presenting with symptoms suggestive of mental health conditions are not adequately screened for autoantibodies – rogue immune cells that target the body – or other indicators of autoimmune dysfunction.
The women whom Pollak encountered were referred to the hospital only after exhibiting overt neurological signs like seizures and catatonia. Yet, research indicates that some individuals with autoimmune encephalitis can present with symptoms that are mistaken for schizophrenia for months, or even years. This diagnostic delay has led to individuals languishing in psychiatric care or receiving inappropriate treatments. A tragic instance in the UK, where a 12-year-old girl died by suicide after medical staff failed to diagnose a brain disorder, highlighted the critical need for thorough investigation. An inquest jury later found that this failure possibly contributed to her death, emphasizing the high stakes involved in identifying autoimmune causes of psychiatric symptoms.
While autoimmune diseases such as multiple sclerosis and lupus are well-established causes of neurological symptoms, the hypothesis that autoimmunity might contribute to schizophrenia has been a subject of scientific inquiry for decades. The advent of understanding anti-NMDAR encephalitis has significantly intensified interest in the intersection of immunology and psychology.
In some instances, the precise mechanisms by which autoimmune reactions precipitate mental illness are becoming clearer. For example, in anti-NMDAR encephalitis, antibodies directly target and damage brain tissue. For other patients, autoimmune responses are implicated, but the exact pathways remain elusive.
Lennox’s research suggests that approximately 5 percent of individuals diagnosed with schizophrenia exhibit autoantibodies in their blood, even if they do not meet the stringent criteria for a full diagnosis of autoimmune encephalitis. She is currently overseeing a clinical trial investigating the efficacy of immunomodulating treatments, such as intravenous immunoglobulin (IVIG) and the monoclonal antibody rituximab, for patients experiencing acute psychosis.
Pollak estimates that no more than 1 percent of individuals with acute psychosis have symptoms directly and unequivocally caused by antibodies leading to autoimmune encephalitis. However, he posits a broader, more intriguing question: "If you ask what I consider to be the more curious and interesting and less-blinkered question" – how many are experiencing some form of brain-related autoimmunity or inflammation – "then the numbers start to get a little bit bigger."
Bartley approaches the issue from a wider perspective, arguing that focusing solely on known autoantibodies responsible for conditions like encephalitis is too narrow. He hypothesizes that a multitude of other, as-yet-undiscovered autoantibodies may contribute to psychosis and other psychiatric disorders. "Rather than testing for a dozen autoantibodies in schizophrenia that people have tested for 200 times," he suggests, "why don’t we widen the aperture and try to test for as many possible autoantibodies as we can?"
The Vast Repertoire of Autoantibodies
The human body is capable of producing an astonishing number of antibodies, potentially quintillions. While many are benign, Bartley’s hypothesis centers on the idea that within this vast pool, an untold number of autoantibodies could be contributing to mental illness symptoms. His laboratory has recently identified three novel autoantibodies that may play such a role, with a research paper detailing these findings currently in preparation. Similarly, neurologists at the Charité-Universitätsmedizin Berlin hospital published a paper last year describing several other potentially relevant autoantibodies.
Bartley’s lab is actively working to solidify the causal link. Evidence of this connection would emerge if animals develop symptoms upon introduction of cloned versions of these autoantibodies. Even stronger evidence would arise if the removal of these autoantibodies leads to symptom resolution, pointing towards potential therapeutic targets for humans.
The notion that unknown autoimmune factors might contribute to mental health conditions resonates with the 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 state psychiatric hospital for approximately two decades, diagnosed with schizophrenia. Her symptoms were so severe and treatment-resistant that Zoghbi’s team referred her for a comprehensive medical evaluation. Specialists eventually identified biomarkers suggestive of lupus, an autoimmune disease, although she did not exhibit the condition’s typical hallmark symptoms.
Despite the diagnostic uncertainty, the researchers administered immune-suppressing drugs, which proved remarkably effective. After years spent in a near-catatonic state, the woman began to recover within months of commencing immune therapy. This case profoundly impacted Zoghbi, highlighting how an experimental approach, deviating from the conventional preference for large-scale drug testing and mechanistic understanding, yielded results that decades of psychiatric treatment had failed to achieve.
Such experiences suggest that the known autoimmune-related mental health conditions might represent only the tip of a much larger iceberg. "You can only diagnose what you have diagnostic tests for," Zoghbi observed, emphasizing the limitations imposed by current diagnostic capabilities.
It is plausible that a diverse range of autoimmune processes contribute to mental illness symptoms, not only within the relatively well-studied domain of psychosis but also across a broader spectrum of psychiatric disorders, including OCD and depression. A small study conducted in 2025 provided further intriguing data: researchers detected autoantibodies in the blood serum of eight out of twenty veterans who had both PTSD and a history of traumatic brain injury.
Leading experts are careful to clarify that they are not asserting that all or even most individuals diagnosed with mental health conditions are suffering from an underlying autoimmune disease. Pollak, for instance, navigates a delicate balance as research evolves. He has cautioned against both the risks of overlooking autoimmune-related mental illness and the dangers of overdiagnosing it.
Pollak warns of a significant peril in attributing all symptoms to the immune system and indiscriminately administering treatments – many of which are costly and carry substantial side effects – without meticulous analysis. He shared instances where patients have liquidated assets to seek treatment abroad, convinced of its efficacy, when he was certain it would be ineffective.
While only a small fraction of individuals experiencing mental health symptoms likely fall into this treatable autoimmune category, "the stakes are so high for that very small fraction that we have to get to the answer," Zoghbi emphasized.
A Paradigm Shift in Treatment Approaches
The pursuit of effective treatments for mental health conditions can be a frustrating endeavor. Andrew Miller likens current psychiatric interventions to "chemotherapy for the brain," acknowledging that while these blunt instruments can be broadly effective, they often lack precision and can result in severe side effects. The precise mechanisms by which many psychiatric drugs exert their effects remain unclear; clinicians often rely on their observed efficacy rather than a complete understanding of their biological pathways.
Pollak’s current research is focused on gaining a deeper understanding of how antipsychotic drugs function, particularly their impact on the immune system. In collaboration with researchers like Katharina Schmack, who investigates psychosis at the Francis Crick Institute in the UK, Pollak has initiated a project to explore this connection. Schmack’s team uses mouse models to simulate immune system activation against the brain, aiming to mimic aspects of what may occur in some individuals experiencing psychosis. These models allow researchers to analyze how antipsychotic medications influence the immune system and behavior of the mice.
If their findings suggest that antipsychotics operate by modulating the immune system, it would further bolster the link between immunity and mental illness, and lend credence to the idea of treating a broader population with direct immune-targeting therapies. "The good thing about immune drugs is [that] we already have a whole array of drugs available," Schmack noted. For example, methotrexate, an immunosuppressant commonly used for autoimmune 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 more widespread screening for these conditions. Treatments include plasmapheresis, a process that filters harmful antibodies from the blood, and medications such as corticosteroids, IVIG, and rituximab.
The visual of a hematologist with bags of plasma underscores the advanced medical procedures available for autoimmune conditions. Plasmapheresis, a blood-filtering treatment, can be a crucial intervention in addressing these complex autoimmune disorders.
Other nations are likely to 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. Patients with positive initial blood tests will be recommended for further diagnostic evaluations, 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," stated Steven Kushner, a psychiatrist at Columbia University.
While it is premature to predict the exact proportion of individuals who will test positive for these conditions, 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 positive rate would also support the replication of similar screening processes in other healthcare systems, according to Kushner. Even identifying and treating a small number of cases promptly could help individuals "avoid many years currently lost to mental health disability," he explained. "To identify the treatable entities as early as possible in their trajectory is a major responsibility for the field."
The solution, according to Pollak, is not to replace mental healthcare with immune treatments, but rather to integrate these approaches. Identifying and effectively treating individuals with autoimmune conditions could revolutionize their care and fundamentally alter our understanding of mental illness. However, he stressed that many patients will continue to benefit from psychotherapy and other established pillars of psychiatric medicine, emphasizing that these therapies should not be discarded.
Ultimately, the growing evidence indicates that autoimmune and mental health conditions are far more intertwined than previously understood. Enabling individuals presenting with psychiatric symptoms to access neurological screenings has the potential to transform treatments, leading to cures for seemingly intractable illnesses. While this may not apply to the majority, the profound impact on those who do benefit is undeniable. "A smart future medicine," Pollak concluded, "is going to combine all of these different aspects at the same time."
If you or someone you know is struggling, please reach out for help. In the UK, Samaritans can be contacted at 116 123 or visited at samaritans.org. In the US, the Suicide & Crisis Lifeline is available at 988. A comprehensive list of suicide helplines for various countries can be found at bit.ly/SuicideHelplines.
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