Turning psychiatry on its head
After more than two decades trapped in her mind, April Burrell woke up. Now new research suggests that a subset of patients with some psychiatric conditions may have autoimmune disease that attacks the brain. By
The young woman was catatonic, stuck at the nurses’ station – unmoving, unblinking and unknowing of where or who she was.
Her name was April Burrell. Before she became a patient, April had been an outgoing, straight-A student majoring in accounting at the University of Maryland Eastern Shore, in the US.
But after a traumatic event when she was 21, April suddenly developed psychosis and became lost in a constant state of visual and auditory hallucinations.
The former high school valedictorian could no longer communicate, bathe or take care of herself. April was diagnosed with a severe form of schizophrenia, an often devastating mental illness that affects approximately 1% of the global population and can drastically impair how patients behave and perceive reality.
‘‘She was the first person I ever saw as a patient,’’ said Sander Markx, director of precision psychiatry at Columbia University, who was still a medical student in 2000 when he first encountered April. ‘‘She is, to this day, the sickest patient I’ve ever seen.’’
It would be nearly two decades before their paths crossed again. But in 2018, another chance encounter led to several medical discoveries reminiscent of a scene from Awakenings, the famous book and movie inspired by the awakening of catatonic patients treated by the late neurologist and writer Oliver Sacks.
Markx and his colleagues discovered that although April’s illness was clinically indistinguishable from schizophrenia, she also had lupus, an underlying and treatable autoimmune condition that was attacking her brain.
After months of targeted treatments – and more than two decades trapped in her mind – April woke up. The awakening of April – and the successful treatment of other people with similar conditions – now stand to transform care for some of psychiatry’s sickest patients, many of whom are languishing in mental institutions.
‘‘These are the forgotten souls,’’ said Markx. ‘‘We’re not just improving the lives of these people, but we’re bringing them back from a place that I didn’t think they could come back from.’’
Losing April
In 1995, April’s family received a nightmarish phone call from one of her professors. April was incoherent and in hospital. Details were hazy, but it appeared that she had suffered a traumatic experience of some kind.
After April spent a few months at a short-term psychiatric hospital, schizophrenia was eventually diagnosed.
She was locked in her own world of psychosis, often appearing to draw with her fingers what appeared to be calculations. And she was unable to recognise, let alone engage with, her family. She did not want to be touched, hugged or kissed. Her family felt they had lost her.
When April was diagnosed with schizophrenia, Markx was still a promising medical student, an ocean away at the University of Amsterdam. His parents were both psychiatrists and he had grown up around psychiatry and its patients.
As a visiting Fulbright Scholar to the United States, he made the decision to head to Pilgrim Psychiatric Centre, a state hospital in Brentwood, New York, where many of the state’s most severe psychiatric patients live for months, years or even the rest of their lives.
It was during his early days at Pilgrim that he met April, an encounter that ‘‘changed everything’’, he said.
As a student, Markx was not in a position to help her. He moved on with his career, but always remembered the young woman frozen at the nurses’ station.
Bringing back April
Almost two decades after meeting April when he was a student, Markx and April’s paths unexpectedly crossed again.
In the years since they first met, April had undergone many courses of treatment – antipsychotics, mood stabilisers and electroconvulsive therapy – all to no avail.
Two decades on, Markx was able to get family consent for a full medical work-up. He convened a multidisciplinary team of more than 70 experts from Columbia and around the world – neuropsychiatrists, neurologists, neuroimmunologists, rheumatologists, medical ethicists – to figure out what was going on.
The first conclusive evidence was in April’s bloodwork: It showed that her immune system was producing copious amounts and types of antibodies that were attacking her body. Brain scans showed evidence these antibodies were damaging her brain’s temporal lobes, brain areas that are implicated in schizophrenia and psychosis.
The team hypothesised that these antibodies may have altered the receptors that bind glutamate, an important neurotransmitter, disrupting how neurons can send signals to one another.
Even though April had all the clinical signs of schizophrenia, the team believed that the underlying cause was lupus, a complex autoimmune disorder where the immune system turns on its own body, producing many antibodies that attack the skin, joints, kidneys or other organs.
But April’s symptoms weren’t typical, and there were no obvious external signs of the disease; the lupus appeared to only be affecting her brain.
The autoimmune disease, it seemed, was a specific biological cause – and potential treatment target – for the neuropsychiatric problems April faced. (Whether her earlier trauma had triggered the disease or was unrelated to her condition wasn’t clear.)
The medical team set to work counteracting April’s rampaging immune system and started her on an intensive immunotherapy treatment for neuropsychiatric lupus.
Every month for six months, April would receive short, but powerful ‘‘pulses’’ of intravenous steroids for five days, plus a single dose of cyclophosphamide, a heavyduty immunosuppressive drug typically used in chemotherapy and borrowed from the field of oncology.
She was also treated with rituximab, a drug initially developed for lymphoma. The regimen is gruelling, requiring a month-long break between each of the six rounds to allow the immune system to recover. But April started showing signs of improvement almost immediately.
As part of a standard cognitive test, she was asked to draw a clock – a common way to assess cognitive impairment.
Within the first two rounds of treatment, she was able to draw half a clock – as if one half of her brain was coming back online, Markx said. After the third round of treatment a month later, the clock looked almost perfect.
Despite this improvement, her psychosis remained and as a result, some members of the team wanted to transfer April back to Pilgrim Psychiatric Centre.
On the day Markx was scheduled to fly home to the Netherlands, he entered the hospital one last time to check on his patient, who he typically found sitting in the dining room in her catatonic state.
But when Markx walked in, he saw another woman sitting in the room. ‘‘It didn’t look like the person I had known for 20 years and had seen so impaired,’’ Markx said. ‘‘And then I look a little closer, and I’m like, ‘Holy s.... It’s her.’’’
It was as if April had awakened after more than 20 years.
Finding more patients
Markx talks about how, as a teenager, he saw the movie adaptation of Oliver Sacks’ Awakenings, featuring Robin
Williams and Robert DeNiro, and how it had haunted him.
‘‘The notion that people are gone in these mental institutes and that they come back still, that has always stuck with me,’’ he said.
Before his death in 2015, Sacks had spoken to Markx about the discoveries involving patients like April. Sacks, a professor at Columbia University, had a personal interest in the work. He had a brother with schizophrenia.
‘‘Your work gives me hope about the outcomes we can achieve with our patients that I never before would have dreamed possible, as these are true cases of ‘Awakenings’ where people get to go back home to their families to live out their lives,’’ he said, according to contemporaneous notes kept by Markx.
After April’s unexpected recovery, the medical team put out an alert to the hospital system to identify any patients with antibody markers for autoimmune disease. A few months later Anca Askanase, a Columbia rheumatologist who had been on April’s treatment team, approached Markx. ‘‘I think we found our girl,’’ she said.
Bringing back Devine
When Devine Cruz was 9, she began to hear voices. At first, the voices fought with one another. But as she grew older, the voices would talk about her. One night, the voices urged her to kill herself.
For more than a decade, the young woman moved in and out of hospitals for treatment.
Her symptoms included visual and auditory hallucinations, as well as delusions that prevented her from living a normal life.
Devine was eventually diagnosed with schizoaffective disorder, which can result in symptoms of both schizophrenia and bipolar disorder. She also was diagnosed with intellectual disability.
She was on a laundry list of drugs that came with a litany of side effects but didn’t resolve all her symptoms. She also had lupus, although doctors had never made a connection between the disease and her mental health.
When Markx and his team found Devine, she was 20 and held the adamant delusion that she was pregnant despite multiple negative pregnancy tests.
Last August, the medical team prescribed monthly immunosuppressive infusions of corticosteroids and chemotherapy drugs, a regime similar to what April had been given a few years prior. By October, there were already dramatic signs of improvement.
After several treatments, Devine began developing awareness that the voices in her head were different from real voices, a sign that she was reconnecting with reality. She finished her sixth and final round of infusions in January.
Her recovery is remarkable for several reasons, her doctors said. The voices and visions have stopped. And she no longer meets the diagnostic criteria for either schizoaffective disorder or intellectual disability, Markx said.
In a recent neuropsychiatric evaluation, Devine not only drew a perfect clock, but also asked how the physician was doing.
But more importantly, Devine now recognises that her previous delusions weren’t real.
Such awareness is profound because many severely sick mental health patients never reach that understanding, said Sophia Chaudry, a precision psychiatry fellow at Columbia University Medical Centre, who was closely involved in Devine’s care.
Today, Devine lives with her mother and is leading a more active and engaged life. She helps her mother cook, goes to the grocery store and navigates public transportation to keep her appointments.
She is even babysitting her siblings’ young children – listening to music, taking them to the park or watching Frozen 2 – responsibilities her family never would have entrusted her with before her recovery.
She is grateful for her treatment and the team that made it possible. ‘‘Without their help, I wouldn’t be here. I feel more excited,’’ she said. ‘‘Like a new chapter is beginning.’’
Expanding the search
While it is likely that only a subset of people diagnosed with schizophrenia and psychotic disorders have an underlying autoimmune condition, Markx and other doctors believe there are likely many more patients whose psychiatric conditions are caused or exacerbated by autoimmune issues.
The cases of April and Devine also helped inspire the development of the SNF Centre for Precision Psychiatry and Mental Health at Columbia University.
The goal of the centre is to develop new treatments based on specific genetic and autoimmune causes of psychiatric illness, said Joseph Gogos, co-director of the SNF Centre.
Markx said he has begun care and treatment on about 40 patients since the SNF Centre opened..
For ‘‘the most disabled, the sickest of the sick, even if we can help just a small fraction of them, by doing these detailed analyses, that’s worth something’’, said Thomas Smith, chief medical officer for the New York State Office of Mental Health. ‘‘You’re helping save someone’s life, get them out of the hospital, have them live in the community, go home.’’
Discussions are under way to extend the search to the 20,000 outpatients in the New York state system as well.