Some mental illness starts when the immune system turns its guns on the brain. Celeste McGovern investigates the emerging field of autoimmune psychiatry
For more than a century, psychiatry has sought answers to the dark mysteries of mental illness: What makes a child obsessively wash his hands? Why does depression sometimes become so deep and linger so long? Why does reality fracture into the distorted thinking and hallucinations of psychosis for some otherwise healthy young people?
The history of psychiatry is littered with horrors born of that search—from ice pick lobotomies, insulin comas and tranquilizer chairs through Freudian psychoanalysis and into repressed sexual desires and “bad mothering.” Today’s near-automatic drug prescriptions for anxiety, depression and even “toddler bipolar disorder” rest on a scientifically unsupported brain-chemicals theory that has been listing for years.
Several new frontiers are opening, however, and one of the most important, autoimmune psychiatry or autoimmune neurology, looks not only to the brain but to the immune system. Scientists are uncovering striking evidence that mental illness sometimes results from the body’s own defenses turning against the brain. The field is forcing mainstream psychiatry to rethink long-held assumptions about what causes mental illness and offering hope for lasting treatments.
“What excites me is that it’s breaking down the barriers between neurology and psychiatry, between diseases of the mind and diseases of the body,” says Alasdair Coles, professor of neuroimmunology at Cambridge University. He’s leading an ambitious clinical trial in the United Kingdom to test whether immune-based treatments can change outcomes for people diagnosed with psychosis (see below for more on the PPiP2 and SINAPPS trials).
Not long ago, neurologists believed the brain lived behind a fortress wall—“immunoprivileged,” completely sealed off from immune system attacks. Today that idea has evolved, and the blood-brain barrier is now seen as a sort of dynamic, living filter, a dense mesh of blood vessels that decides what may pass from blood to brain.
Certain immune cells, specifically T cells and to a lesser extent B cells, can slip quietly through to make their immune surveillance rounds like sentinels on patrol. Sometimes these cells go rogue, however. They spark inflammation, interfere with neurotransmission and wreak havoc on brain function, including thoughts and emotions.
For decades, these immune misfires have been recognized in autoimmune diseases like systemic lupus erythematosus. As many as two-thirds of lupus patients experience psychiatric symptoms—from depression and anxiety to frank psychosis—when antibodies and cytokines inflame the brain.
Other conditions, including multiple sclerosis and celiac disease, have higher rates of anxiety and depression than in the general population. They were once dismissed as the emotional fallout of chronic illness; we now know they can be direct consequences of immune system attacks on neural tissue. More evidence is accruing that shows the overlap between autoimmune diseases and psychiatric illness is not just coincidental.1
About 20 years ago, the mystery deepened and widened with an investigation of a series of puzzling cases. Neurologist Josep Dalmau and his colleagues at the University of Pennsylvania explored one case in which a 17-year-old girl—let’s call her Amelia—began a descent into madness in December 2005.
Previously healthy, she suddenly began having extreme mood swings between euphoria and despondency. Those close to her recognized she was also hallucinating.
At the emergency room of a children’s hospital, Amelia’s “disorganized thinking” and unresponsive “catatonia-like episodes” were noted, and she was sent to a psychiatric institute. But she was discharged shortly afterward because the staff felt she was “not cooperating” with therapy.
In the days that followed, Amelia was brought to two different emergency rooms and eventually admitted to another psychiatric unit. There nurses noted she was “emotionally detached, restless, wandering aimlessly, with episodes of yelling, and unable to carry a meaningful conversation.”
She fit the diagnosis of psychosis, but thankfully one sign kept her from being handed a prescription for antipsychotic drugs and put out the door again: Her body temperature was elevated, so she was sent off to a medical center to rule out a meningitis infection.
At admission, hospital staff noted the teenager’s episodes of unresponsiveness, or catatonia, although her brain scan was normal. A spinal tap revealed an elevated white blood cell count, so she was given antiviral and antibacterial drugs to fight infection, plus a sedative.
A few hours later, Amelia was found unresponsive—this time possibly due to multiple seizures—and transferred to an intensive care unit. Electroencephalogram (EEG) monitoring revealed no evidence of seizure activity, however. She was heavily sedated and intubated, yet multiple diagnostic tests failed to point to an underlying cause of illness.
Pondering Amelia’s puzzling symptoms, neurologists considered the girl’s unusual medical history. She’d had an ovarian tumor, called a teratoma, removed years earlier. The term teratoma is derived from the Greek word teratos, which means “monster” because these tumors—once considered benign—are made up of a glob of body tissues, including sometimes hair, skin, muscle and even brain cells.
A pelvic MRI scan was ordered to see if any teratoma remained, and sure enough, it found a nearly 3-inch clump. Three days later, she had surgery to remove it and confirm its makeup.
Meanwhile, further examination of Amelia’s cerebrospinal fluid revealed autoantibodies—immune system players that had trained an attack on the teratoma and were now assaulting her brain tissue. Doctors began plasmapheresis, a process of filtering her blood of these rogue autoantibodies and infusing her with immunoglobulins, healthy antibodies from donors. Heavy doses of steroids tamped down her immune system’s attack on her brain.
Twelve days post-surgery, Amelia showed “striking improvement,” appropriately responding to questions and breathing on her own. Several months later, she was evaluated as “normal” on a neurological examination and was back at high school, achieving good grades.
Amelia was one of 12 women and girls described in a 2007 study as having a recognizable syndrome of autoimmune encephalitis. Most had come from psychiatric centers with confusion, restlessness, agitation, frequent paranoid or delusional thoughts, and quiet staring. Most developed seizures, and they frequently required mechanical ventilation.
All had teratomas and measurable autoimmune antibodies.
Nine of the 12 made astonishing recoveries after surgery to remove the teratoma and immune-modulating treatments. Seven returned to work or school. Two of the three who did not have the teratoma removed died of “neurological deterioration.”2
The lead author of the 2007 paper, Dr Dalmau, is a neurologist at the Hospital Clínic de Barcelona and adjunct professor of neurology at the University of Pennsylvania. He had published a landmark paper describing four similar cases two years earlier.
In their groundbreaking research, Dr Dalmau’s team had developed an intricate experiment, exposing thin slices of rat brain to the cerebrospinal fluid of these first four patients. After eight months of adjustments, they finally produced four striking images—resembling ammonite fossils—that clearly showed the antibody binding for the first time.
Not only were the women all suffering from the same illness but it was the same antibody attacking their brains. The binding was strongest in the hippocampus (a brain region responsible for information processing, memory and spatial awareness), but a key question remained: Which receptors were being targeted?
Through trial, error and educated guesses, Dalmau’s team kept going and solved the mystery: The culprit was NMDA-receptor–targeting antibodies.3
NMDA (n-methyl-D-aspartate) receptors are essential for learning, memory and behavior. Found throughout the brain, they enable neurons to respond to neurotransmitters, which either excite cells to fire or tamp their firing down. These basic interactions form the foundation of all thought and action.
In Dr Dalmau’s patients, the antibodies attacking components of the teratoma had also turned their stupendous immune artillery on the same type of receptors in the brain. The antibodies attached to the NMDA receptors and blocked their chemical signals, and the mental unraveling began.
The new condition was called anti-NMDA-receptor encephalitis (brain inflammation). Suddenly, psychosis—once treated purely as a disorder of the mind—was revealed, in some cases, to be a disease of the immune system. What’s more, it had a treatment with a 75 percent recovery outcome in people who would otherwise languish in a psychiatric bed, wander the streets or die.
Within a year of Dr Dalmau’s report, more than 100 patients were diagnosed with the condition.
Then, in 2009, a New York Post reporter, 24-year-old Susannah Cahalan, began feeling unwell. She became obsessed with the idea that her apartment was infested with bedbugs even though an exterminator could find no evidence of them. She began imagining her boyfriend was cheating on her, and then she collapsed in the newsroom.
Diagnoses ranged from mononucleosis to bipolar disorder and schizoaffective disorder (schizophrenia with a mood disorder). Her psychosis was dramatic at its height, including hallucinations of paintings coming alive and a delusion that she had the power to age people with her mind.
Her psychiatric symptoms were the main feature of her illness, but she also had a seizure in a hospital lobby. It was fortunate, in a way, because it saw her transferred to an epilepsy ward at New York University Langone Medical Center rather than a psychiatric ward—which made all the difference.
About a quarter of people with autoimmune encephalitis do not have known seizures. Even when patients are hospitalized and fitted with electrodes to record a seizure, it’s like fishing. The equipment may not always catch one.
Cahalan was hospitalized for a month before neurologist Dr Souhel Najjar did something no one else had: a “clock test.” He asked her to draw a clock with the numbers on it.
This test is ordinarily given to people with dementia or Alzheimer’s disease. Cahalan drew the circle easily, as even people with severe cognitive deficits can do. But the numbers on her clock were all squished to the right half of the circle.
For Najjar, it was proof that Cahalan’s disorder was neurological rather than psychiatric, and he finally ordered her cerebrospinal fluid sent to Dr Dalmau’s lab for testing. A positive result made Cahalan the world’s 217th patient diagnosed with anti-NMDA-receptor encephalitis.
A relatively simple combination of steroids and immune therapies (immunoglobulin treatment and plasmapheresis) led to her full recovery after several months and then the publication of her New York Times best-selling memoir Brain on Fire (Free Press, 2012). Her story, and the work of Drs Dalmau and Najjar, exploded in the media across the globe and led to countless medical school lectures as well as a Netflix movie in 2018. As a result, more people have heard of autoimmune encephalitis.
What haunts Cahalan, though, is how narrowly she escaped indefinite shuffling through the psychiatric system because of her mental health symptoms while her immune system burned her brain. In her book, she asked, “If it took so long for one of the best hospitals in the world to get to this step, how many other people were going untreated, diagnosed with a mental illness or condemned to a life in a nursing home or a psychiatric ward?” Or to death.
That was nearly 15 years ago, and thanks to her and other patients’ testimonies and the dedication of scientists like Dr Dalmau, research in the field has taken off (a PubMed search for “autoimmune encephalitis” three years ago yielded 2,000 results; today it gives more than 12,000). More people are being screened for autoimmune antibodies when they present with neurological symptoms of autoimmune encephalitis. Tens of thousands have been treated now.
In a case reported by the Washington Post, a woman who had been catatonic for 20 years and housed in a psychiatric institution “woke up” and made an astonishing recovery after her underlying autoimmune condition was treated. April Burrell was only 21 when she began to experience hallucinations and confusion in 1995. She was diagnosed with schizophrenia and, in a bizarre twist of fate, was seen by psychiatrist Sander Markx, who was only a medical student at the time.
“She would just stare and just stand there,” recalls Markx, now a professor and director of precision psychiatry at Columbia University. “She wouldn’t shower, she wouldn’t go outside, she wouldn’t smile, she wouldn’t laugh. And the nursing staff had to physically maneuver her.”
Nearly two decades later, one of Markx’s students told him about a woman he had seen at the hospital. It turned out it was April, and Markx couldn’t believe she was still at the same hospital in the same dreadful state.
He contacted her family and asked experts to reanalyze April’s condition; they ran blood tests for immune markers. Sure enough, April, who had been locked inside her mind for close to two decades, was suffering from psychosis induced by her lupus. Her immune system was attacking her brain.
After she received immunotherapy, the results were astonishing. The hallucinations faded. Her awareness returned. She recognized her family again and finally went home.
April’s recovery has become a touchstone in the rise of autoimmune psychiatry. It raises a haunting question, though: How many others are there, long written off as incurable, warehoused in some institution or pacing the streets?
Twenty years after Dalmau’s groundbreaking study, today most patients with first episodes of psychosis are still never screened for immune markers unless they happen into one of the large research centers. Most mainstream psychiatrists still haven’t heard of autoimmune psychosis, or they dismiss the immune system involvement as a rarity.
Psychiatric guidelines still treat psychosis as a primarily psychiatric disorder unless there are neurological or systemic red flags, such as seizures, movement disorders, or a history of tumor, infection or autoimmune disorders. Yet, as the growing research shows, these red flags are frequently absent.
Notably, Cahalan didn’t have a teratoma. Only about one-third to one-half of adult women with anti-NMDA-receptor encephalitis do, and most men and children do not. Removing a teratoma, when present, greatly improves outcome odds and reduces relapse risk. But in many cases, including Cahalan’s, the trigger remains uncertain.
Infection triggers. Autoimmune encephalitis, like many mental illnesses, is known to follow infection. The most famous predecessor is herpes simplex encephalitis, but a range of viral and bacterial infections can lead to it.
Other immune-mediated brain conditions, such as PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections) result from an immune system gone awry. PANDAS is a sudden onset (literally overnight, in some cases) of obsessive-compulsive disorder symptoms or other behavioral changes in children after a Group A streptococcal infection such as strep throat or scarlet fever.
During strep infection, the immune system produces antibodies to fight the bacteria, but some of them mistakenly attack brain tissue due to molecular mimicry—a similarity between the bacteria and the brain cells. In PANDAS, cells in the basal ganglia, a region involved in movement, emotion and habit formation, come under fire.
This causes inflammation leading to abrupt changes in behavior, motor control (such as tics), mood swings or fits of rage, trouble sleeping, regressive behavior (like bedwetting, clinginess or baby talk in older children) and a decline in school performance.
PANS (pediatric acute-onset neuropsychiatric syndrome) is a broader category that includes PANDAS but also applies when the trigger isn’t necessarily strep. It may be caused by influenza, Lyme disease and Epstein-Barr virus.
Narcolepsy is a disorder that causes sleep paralysis and intense hallucinations when falling asleep, daytime sleepiness and cataplexy (sudden muscle weakness triggered by emotion). It’s another striking example of the immune system turning against the brain in a way that parallels autoimmune encephalitis.
All evidence now points to an autoimmune basis of most cases of narcolepsy type 1, the kind with cataplexy. In this type, the body’s own immune cells destroy a tiny cluster of neurons in the hypothalamus that produce hypocretin, a protein that regulates sleep-wake cycles.
Most research suggests the destruction occurs through molecular mimicry, the same process underlying autoimmune encephalitis. In a case of mistaken identity, immune cells primed to fight off a virus turn their assault on similar-looking proteins in the brain.
Vaccine triggers. The 2009 H1N1 flu pandemic provided a vivid example of how vaccination, rather than infection, could cause autoimmune narcolepsy. Clusters of new narcolepsy cases emerged in the UK and Europe after immunization with the Pandemrix flu vaccine.
More than 1,500 people, including children as young as two years old, were struck with the lifelong, devastating sleep disorder. Studies later showed that, just as in autoimmune encephalitis, the immune system’s defense against vaccination wound up storming the blood-brain barrier and attacking critical neural circuits. It left behind a lifetime of prescription drugs to stay awake or sleep at the right time along with night terrors and cataplectic collapses.
The Pandemrix narcolepsy episode was a turning point in neuroimmunology. It showed that vaccination can trigger autoimmune attacks on very specialized brain tissue and confirmed that the blood-brain barrier is far from concrete. It also showed that psychiatric diseases may often have immune fingerprints.4
What’s largely unknown to the public, and even to most psychiatrists, is there are hundreds of thousands of reports to health agencies about adverse psychiatric symptoms following vaccination. The World Health Organization’s VigiBase—a global database—lists more than a quarter million (252,031) psychiatric adverse events.
They range from anxiety and depression to new psychoses, suicides and suicidal ideation following Covid vaccines alone. Dozens of case reports describe previously healthy patients who developed anti-NMDR-receptor encephalitis and other psychiatric conditions following the shots.5
Chronic stress. Ongoing stress can lead to immune system dysregulation, potentially triggering autoimmune responses. One recent report highlights a case in which stress from exams and a urological surgery apparently triggered anti-NMDA-receptor psychosis in a 20-year-old woman with no history of psychiatric illness.6
Whatever the causes of autoimmune mental illness, the research arena has exploded. Scientists have moved on from NMDA receptor autoantibodies to identify several others, each with their own collection of symptoms in the brain.
Some researchers are asking a bigger question: Could subtler versions of this process underlie a portion of the psychiatric disorders that affect millions worldwide?
Teams at Columbia University, Oxford and Yale, among others, are exploring whether certain forms of schizophrenia, depression or obsessive-compulsive disorder actually stem from hidden autoimmune activity. Blood tests for immune markers, brain scans showing signs of inflammation and case reports of patients improving with immunotherapy all point to an immune-psychiatric link that was once unthinkable.
For patients and families, the implications are profound. If even a fraction of mental illness has an autoimmune basis, it opens the door to entirely new treatments—ones that don’t just manage symptoms but strike at the root cause.
“Here we have a really good example of an immunological mechanism, an antibody, potentially causing something as mysterious as psychosis and potentially being treated like something as humdrum as what you might get in your regular hospital for a disease like psoriasis or arthritis,” says Cambridge’s Dr Coles.
This new frontier could also pull mental illness out of psychiatry’s long, stigma-shadowed past. Journalist Cahalan, whose own brain inflammation was once mistaken for psychosis, reflected on this divide after her recovery. “When I was thought to be suffering from a psychiatric disorder,” she told a psychiatry magazine, “my care was less sympathetic than it was later, when doctors discovered it was my immune system attacking my brain.”
She asked a haunting question: Why is this? “At the height of my disease, nothing distinguished me from a person with schizoaffective disorder or schizophrenia,” she said. “The only difference came later—when I was cured.” Her experience exposes a deep bias in how we treat mental illness: Compassion and urgency often come only when the cause can be seen under a microscope.
The science is still young, but if immune-based therapies can make even a small dent in something as intransigent as schizophrenia, the effects are sure to ripple out to other mental illnesses. Not every case of psychosis or depression may turn out to be immune-driven, but the possibility has the power not just to offer healing but to shift psychiatry’s view of mental illness.
Doctors can see not just a broken brain but a whole body in need of help. For the millions who have long been written off, it’s a reason for hope.
In recent years, two new frameworks—metabolic psychiatry and autoimmune psychiatry—have begun to examine the biological roots of mental illness from converging directions.
Metabolic psychiatry views mental disorders as conditions of cellular energy failure in which neurons struggle to generate or use fuel efficiently. It uses therapies including a high-fat ketogenic diet (to switch the brain’s fuel source from glucose to ketones) and other mitochondria-targeted strategies to restore energy balance.
Autoimmune psychiatry, by contrast, sees many mental illnesses as friendly fire from the immune system, in which inflammation or rogue antibodies turn the body’s defenses against the brain. It uses immune therapies to quash the assault.
Yet these two stories dovetail. The immune response is one of the body’s most energy-intensive processes, and chronic inflammation can cripple mitochondria, drain metabolic reserves and disrupt neurotransmission.
Meanwhile, metabolic breakdown—through insulin resistance, oxidative stress or nutrient imbalance—can inflame the immune system, breach the blood-brain barrier and expose the brain to further attack. Together, these fields suggest mental illness can arise from a vicious loop between immune activation and metabolic collapse in the brain.
The keto diet doesn’t just change how the brain burns fuel—it also reshapes the community of gut microbes, which can calm the immune system and influence the brain. By cutting carbs, keto starves sugar-loving bacteria and favors species like Akkermansia and Parabacteroides that strengthen the gut barrier and reduce inflammation.
The resulting mix of fats, ketones and microbial byproducts signals the immune system to stand down, dampening inflammatory pathways that can drive both autoimmune and psychiatric illness. In this way, keto’s power may reach beyond metabolism—reshaping the dialogue between the gut, immune system and mind.
Ryan Baldridge Jr. was a bright toddler who could whiz through his flashcards until suddenly, at 18 months old, he lost the ability to speak. Doctors told his parents their son’s autism was permanent, according to the New York Post.
Years later, a blood test revealed something different: folate receptor alpha (FRα) autoantibodies, rogue immune proteins that block essential folate from reaching the brain. The diagnosis, cerebral folate deficiency, has quietly emerged as a biological subtype of autism in which the problem isn’t the brain itself but immune system interference with receptors that allow folate (vitamin B9) to do its vital jobs in the brain.
As far back as 2012, research was pointing to FRα antibodies in as many as 75 percent of autistic children compared to just 10–15 percent of children without the disorder. Scientists began recommending leucovorin, a prescription folinic acid (an active form of folate) that bypasses the blocked pathway and restores folate metabolism in the brain.
Ryan began speaking again within weeks of taking leucovorin, and his parents described it as “getting him back.”
This fall, the Trump administration announced FDA approval of leucovorin for autism associated with autoimmune cerebral folate deficiency—an unprecedented move that has stirred hope for those with a previously untreatable disorder that has been growing year on year and now affects 3.5 percent of American children.
Oxford University is among the institutions diving into autoimmune encephalitis research.
“We have described antibodies against the NMDA receptor, and other neuronal targets, in 10 percent of people with a first episode of psychosis. We have described how people with psychosis and these antibodies get better when treated with immune treatment,” says Belinda Lennox, head of the Department of Psychiatry at Oxford University (psych.ox.ac.uk).
Her lab published the SINAPPS1 pilot study in 2019. The team, led by Alasdair Coles, recruited 10 patients with first-episode psychosis and high autoantibody levels to receive immunotherapy in the form of immunoglobulins, plasmapheresis and/or steroids.
“All patients with NMDAR antibodies showed a dramatic improvement, if not complete resolution of psychotic symptoms following treatment,” the paper reports, and there were no adverse events.1 The team is now aiming to determine causality via the SINAPPS2 trial, which is recruiting adult patients (16–70 years old) with psychosis and high levels of autoantibodies.
A larger study, also at Oxford, is inviting all people with a first episode of psychosis or a relapse of psychosis in remission to come to one of 40 centers across England and Scotland and undergo blood testing for the autoantibodies. The PPiP2 study is ongoing until 2027.
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