Fifteen years ago, a series of women at a London neurological hospital presented with a peculiar and shared illness. Their symptoms ranged from stiffness and stupor to seizures and movement difficulties. However, these manifest issues often began with what appeared to be classic psychotic episodes, complete with agitation, hallucinations, and delusions. In the grip of these symptoms, several sought help at emergency departments or psychiatric facilities.
Initially, their medical notes read to neuropsychiatrist Thomas Pollak as indicators of common mental health conditions. Yet, it was discovered these individuals actually had autoimmune encephalitis, a condition involving brain inflammation triggered by the immune system’s own attack. The realization that an autoimmune disorder could manifest as psychosis challenged the established separation between psychiatric and neurological illnesses, a revelation Pollak described as mind-blowing.
In the years that followed, Pollak, now affiliated with King’s College London, has been instrumental in shaping an emerging field of study. This area of research increasingly indicates that autoimmune diseases play a more significant role in mental illness than previously understood. While this connection is not entirely novel, with prior studies noting a predisposition to autoimmune conditions in individuals with schizophrenia and vice versa, the work of Pollak and his peers has substantially broadened the perceived overlap. It now suggests that the immune system might be implicated in a wide array of conditions, spanning post-traumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD), depression, and even dementia.
This evolving understanding opens a promising avenue: the potential to treat certain apparent mental health conditions with medications that modulate the immune system, an approach few clinicians routinely consider. “The immune system is playing a role in behaviour much more than we appreciate,” states psychiatrist Andrew Miller from Emory University School of Medicine in Georgia.
The Immune System’s Assault on the Brain
The human immune system is a complex, two-sided entity. The very mechanisms that neutralize external threats like bacteria and viruses can malfunction, directing the body’s own defense components—such as antibodies, cytokines, and T-cells—against its own tissues. This phenomenon is broadly termed autoimmunity. As Christopher Bartley, who leads the Translational Immunopsychiatry Unit at the US National Institutes of Health, notes, “We know that every single organ system is affected by autoimmunity.” The brain is no exception.
The intersection of the immune system and mental health is most evident in conditions like schizophrenia. Approximately two decades ago, scientists first identified a form of autoimmune encephalitis known as anti-NMDAR encephalitis. In this condition, specific antibodies bind to receptors within the brain, leading to neuropsychiatric symptoms that can include delusions, hallucinations, memory loss, and unusual behavior.
Despite the overlapping symptoms, the treatment strategies for these conditions differ significantly. Encephalitis can often be managed with medications that regulate the immune system. In contrast, individuals diagnosed with schizophrenia typically receive antipsychotic drugs, which prove ineffective for up to one-third of patients.
Autoimmune encephalitis is described as a “wonderful diagnosis to be able to make, because you can literally get people better and transform their lives with relatively simple treatments,” according to Belinda Lennox, a psychiatrist at the University of Oxford specializing in psychotic disorders. However, this diagnosis can be missed if individuals presenting with mental health symptoms are not screened for autoantibodies—malfunctioning immune cells that target the body—or other indicators of autoimmune dysfunction.
The women observed by Pollak were referred to the hospital only after developing neurological signs such as seizures and catatonia. Yet, some individuals with autoimmune encephalitis may exhibit symptoms that mimic mental health conditions for months or even years. This diagnostic delay has, in some instances, led to prolonged stays in psychiatric hospitals or inappropriate treatments. Tragically, a 12-year-old girl in the UK died by suicide after medical professionals reportedly failed to conduct a lumbar puncture to test for the illness, a factor an inquest jury later found “possibly contributed” to her death.
Established autoimmune diseases like multiple sclerosis and lupus are known to cause neurological symptoms. Researchers have long theorized a potential role for autoimmunity in schizophrenia. Since the discovery of anti-NMDAR encephalitis, interest in the interplay between immunology and psychology has markedly increased.
In some cases, scientists can precisely map how autoimmune responses contribute to mental illness. In anti-NMDAR encephalitis, for instance, antibodies demonstrably target the brain. For others, while autoimmune reactions appear relevant, the exact mechanisms remain unclear.
Lennox’s research indicates that approximately 5 percent of individuals diagnosed with schizophrenia possess antibodies in their blood, even if they do not meet the stringent criteria for a formal autoimmune encephalitis diagnosis. She is currently overseeing a clinical trial investigating the effectiveness of immunomodulating treatments, specifically 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 concretely caused by antibodies leading to autoimmune encephalitis. “But if you ask what I consider to be the more curious and interesting and less-blinkered question”—namely, how many are experiencing some form of brain-related autoimmunity or inflammation—”then ‘the numbers start to get a little bit bigger,'” he remarks.
Bartley is also adopting a broader perspective on this issue. He suggests that focusing solely on the autoantibodies known to cause conditions like encephalitis might be too narrow. He posits the existence of other, currently unidentified autoantibodies that could contribute to psychosis and other psychiatric disorders. “Rather than testing for a dozen autoantibodies in schizophrenia that people have tested for 200 times,” Bartley proposes, “why don’t we widen the aperture and try to test for as many possible autoantibodies as we can?”
Antibody Factories
The human body is capable of producing an immense variety of antibodies, potentially trillions. While many are harmless, Bartley’s hypothesis centers on the idea that within this vast array, an undetermined number of autoantibodies may contribute to the symptoms of mental illness. His laboratory recently identified three novel autoantibodies potentially linked to these symptoms and is in the process of preparing a scientific publication on this discovery. In a paper published the previous year, neurologists at Charité-Universitätsmedizin Berlin described several other such antibodies.
Bartley’s lab is actively working to establish these connections. A significant indicator, he explains, would be if animals develop symptoms upon being exposed to cloned versions of these autoantibodies. An even stronger indication of potential human treatments arises if the removal of these autoantibodies leads to the disappearance of symptoms.
The notion that as-yet-undiscovered autoimmune factors might contribute to certain mental health conditions aligns with the experiences of Anthony Zoghbi at Baylor College of Medicine in Texas. In 2018, he was part of a research team involved in an unusual case. The subject was a woman who had been institutionalized in a New York state psychiatric hospital for approximately two decades, diagnosed with what was believed to be schizophrenia.
Her symptoms were so severe and resistant to conventional therapies that Zoghbi’s team eventually referred her to Columbia University in New York City for a comprehensive medical evaluation. A team of specialists ultimately identified biomarkers suggestive of the autoimmune disease lupus, despite her not exhibiting the condition’s characteristic symptoms.
Although the researchers could not pinpoint the exact condition the woman had, they treated her with immune-suppressing drugs, and the intervention proved successful. After years in a near-catatonic state, she began to recover within months of commencing the immune therapies.
This case profoundly impacted Zoghbi. The treatment was experimental, deviating from the medical establishment’s preference for large-scale drug testing and mechanistic understanding. Yet, it achieved for this patient what two decades of psychiatric treatment had not.
Such experiences suggest that known forms of autoimmune-related mental health conditions may represent only a fraction of the broader issue. “You can only diagnose what you have diagnostic tests for,” Zoghbi observes.
It is conceivable that a variety of autoimmune processes are either causing or exacerbating symptoms of mental illness. This potential involvement extends beyond the relatively well-researched area of psychosis to encompass broader psychiatric conditions such as obsessive-compulsive disorder and depression. For instance, a small study planned for 2025 found autoantibodies in the blood serum of eight out of twenty veterans who had both post-traumatic stress disorder and a history of traumatic brain injury.
Experts are not asserting that all, or even most, individuals diagnosed with mental health conditions actually suffer from an autoimmune disease. Pollak, for one, finds himself navigating a delicate balance as research progresses. He acknowledges the dual risks: failing to address autoimmune-related mental illness and, conversely, overdiagnosing it.
There is a significant danger, Pollak warns, in attributing all symptoms to the immune system and prescribing expensive treatments with extensive side effects without thorough analysis. “I have had patients sell assets to try to get treatment in another country [when] I have been absolutely convinced from the start that that treatment would not work,” he recounts.
Likely, only a small segment of individuals experiencing mental illness symptoms fall into this category. “But the stakes are so high for that very small fraction that we have to get to the answer,” Zoghbi emphasizes.
A New Treatment Paradigm
The quest for effective treatments for mental health conditions can be a frustrating endeavor. “What we have in psychiatry is basically chemotherapy for the brain,” comments Miller. These broad-reaching treatments can be effective across a range of conditions but often lack precision and can carry severe side effects.
In many instances, the precise mechanisms by which psychiatric drugs exert their effects remain unclear; clinicians primarily rely on their empirical efficacy. Consequently, a significant portion of Pollak’s current research is dedicated to better understanding the actions of antipsychotic drugs, particularly their influence on the immune system.
In collaboration with researchers such as Katharina Schmack, who studies psychosis at the Francis Crick Institute in the UK, Pollak has initiated a project to investigate this relationship. Schmack’s team induces immune responses in mice that target their brains, simulating what they hypothesize occurs in some individuals with psychosis. Using these animal models allows researchers to analyze how antipsychotic drugs affect the mice’s immune systems and behavior.
If their findings suggest that antipsychotics function by altering the immune system, this would further bolster the connection between the immune system and mental illness and support the consideration of a wider range of immune-targeting treatments. “The good thing about immune drugs is [that] we already have a whole array of drugs available,” says Schmack. For example, methotrexate, an immunosuppressant already used for autoimmune conditions like rheumatoid arthritis and psoriasis, is currently being evaluated as a potential treatment for schizophrenia.
Certain immunomodulating drugs are already employed in the treatment of autoimmune encephalitis, notably in countries like Germany, where a national research network facilitates more routine screening for these conditions. These therapies include plasmapheresis—a process that filters antibodies from the blood, which are then discarded and replaced with new fluid—along with medications such as corticosteroids, IVIG, and rituximab.
Other nations may soon follow Germany’s lead in expanding screening initiatives. In the United States, researchers at Columbia University have launched an ambitious project to screen all individuals 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. Those with positive initial blood tests will be recommended for further evaluation, such as a lumbar puncture. Psychiatrist Steven Kushner at Columbia University explains that these individuals could then receive “treatments that are fundamentally different than the standard treatments that are given for people with severe mental illness.”
Kushner acknowledges that it is premature to determine the proportion of individuals who will test positive for any of these conditions. However, he states, “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 percentage, Kushner suggests, would also indicate the value of replicating similar screening processes in other healthcare systems. Even identifying and treating a few cases promptly could enable those individuals to “avoid many years currently lost to mental health disability.” He concludes, “To identify the treatable entities as early as possible in their trajectory is a major responsibility for the field.”
The objective is not to supplant mental healthcare with immune treatments, Pollak clarifies, but rather to develop an integrated approach. Identifying and appropriately treating individuals with an autoimmune condition could revolutionize their care and fundamentally alter our understanding of mental illness. Such advancements should not be underestimated. Nevertheless, many patients will continue to benefit from psychotherapy and other established pillars of traditional psychiatric medicine, Pollak notes, emphasizing that there is no reason to abandon these conventional therapies.
Ultimately, it is increasingly clear that autoimmune and mental health conditions are more interconnected than previously realized. Ensuring that individuals presenting with apparent mental health issues also have access to neurological screenings will inevitably transform treatments, potentially leading to cures for some seemingly intractable illnesses. While this outcome may not apply to the majority, the profound implications of this research cannot be dismissed. “A smart future medicine,” Pollak posits, “is going to combine all of these different aspects at the same time.”