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This new avenue of research suggests the need for immunopsychiatry to treat the immune system and the brain in tandem, says McMaster University’s Boris Sakic.Peter Power/The Globe and Mail

Kelly O'Donnell watched in alarm as her happy, healthy seven-year-old daughter suddenly developed signs of neurological and mental illness.

It started with tearfulness and a tic that came out of nowhere on a Wednesday evening in September, 2012 – the girl kept looking over her shoulder every few seconds, but couldn't explain why. Then came the constant blinking, characteristic of Tourette syndrome, and the uncontrollable urge to repeat rituals, typical of obsessive-compulsive disorder – touching her shoulders, hips and knees, and furiously erasing and redoing her schoolwork until she wore holes in the paper. By Friday morning, the erratic behaviour had become so acute, the Ottawa mother took her to the emergency room.

As dramatically as the symptoms emerged, however, all signs of the girl's apparent mental illness vanished two days later. The remedy? Antibiotics.

Suspecting O'Donnell's daughter was suffering a little-known condition brought on by a streptococcal infection, a doctor at the emergency department offered a throat swab to test for strep. To O'Donnell's surprise and relief, the test came back positive, and her daughter was prescribed penicillin. Within 24 hours, she was well enough to return to school.

Her illness – believed to be Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections, or PANDAS – highlights a game-changing idea in the research of psychiatric disorders. Namely that a malfunctioning immune system can cause mental illness.

For years, studies have shown that patients with a wide range of mental illnesses tend to have signs of inflammation, the body's natural response against infection and injury. But lately, scientists have been zeroing in on an explanation. They're accumulating evidence to suggest that infection, autoimmune diseases and environmental factors such as stress or diet can trigger the immune system to go awry, causing it to damage the brain instead of attacking foreign pathogens. The result: an array of psychiatric conditions, including schizophrenia, autism spectrum disorder, Alzheimer's disease, depression and anorexia nervosa.

This hypothesis does not suggest immune responses are at the root of all psychiatric cases. Rather, it points to the idea that common mental illnesses have multiple causes, a haywire immune system being just one. The immune hypothesis is nevertheless a paradigm shift that not only offers a tangible, biological basis for subsets of many previously inexplicable psychiatric conditions, it raises the possibility of successfully diagnosing, treating and perhaps even preventing them by homing in on the immune system and managing inflammation. Although the research is still in its early days, there's a growing sense of excitement over the prospect that certain individuals may regain mental health with antibiotics, intravenous immunoglobulin (IVIG) treatments (infusions of antibodies) and possibly dietary changes, instead of traditional psychiatric drugs and brain stimulation treatments.

"I think we're on the cusp of something that's really huge and truly revolutionary in the way in which we ... both diagnose people, as well as to make them better," says Mady Hornig, associate professor of epidemiology at the Columbia University Medical Center, whose research focuses on the role of microbes and immune factors in neuropsychiatric illness.

Scientists are now recognizing that a host of external stimuli can disrupt the normal crosstalk between the brain and the immune system. Those stimuli can include stress, changes in the microbiome (the universe of microbes that live in our bodies), and certain viruses and bacteria.

It's believed this disruption can affect the brain, and thereby behaviour. In PANDAS, it is suggested that streptococcal bacteria may mimic brain proteins, prompting the body to produce antibodies that mistakenly target the brain.

So why doesn't everyone infected with strep throat come down with the same neurological and psychiatric symptoms that O'Donnell's daughter experienced? The answer may lie in genetics. Hornig explains that some individuals may be more genetically susceptible to producing a faulty immune response.

What is so remarkable and so exciting to researchers is that if certain neuropsychiatric disorders are triggered by external stimuli, it means they can be controlled, Hornig says. However, she adds, since genetics likely play a role, susceptible individuals could be vulnerable to falling ill again whenever they encounter such triggers.

A month after her symptoms disappeared, O'Donnell's daughter experienced a relapse of Tourette and OCD-like behaviour, and again tested positive for strep. Though she fully recovered a second time, O'Donnell notes that her child has since shown other signs of potential immune-related sensitivities. For example, she experienced a bout of anxiety after an unidentified viral infection. Meanwhile, recent dietary changes aimed at reducing inflammation, specifically eliminating gluten, seemed to alleviate her anxiety.

"Anything that your immune system sees as an invader, whether it's gluten or a bee sting or whatever, or a virus or a bacteria, you now have to be careful and watching for almost a mental health symptom," O'Donnell says.

Much about PANDAS remains unknown. Still, O'Donnell believes that had her child not been diagnosed early, she would likely have been put on anti-anxiety medications and diagnosed with OCD, anxiety and possibly autism or attention deficit hyperactivity disorder. Based on the experience of other PANDAS cases she has encountered, she believes her daughter's mental and social faculties could have deteriorated if her out-of-control immune system was left unchecked.

The suspicion that infections and other external stimuli contribute to mental illness goes back centuries. But it's only in the past two decades that scientists have really begun to understand the molecular mechanisms at work between the immune system and the brain. Notably, the discovery in 2007 of a type of brain inflammation, called anti-NMDA receptor encephalitis, provided direct evidence of an association between the immune system and psychiatric symptoms, says Michael Benros, a senior researcher at the Copenhagen University Hospital and Aarhus University in Denmark.

With anti-NMDA receptor encephalitis, scientists were able to identify specific antibodies that attack the brain. The discovery opened a new line of investigation into whether the same kind of mechanism could explain a number of other psychiatric illnesses.

Anti-NMDA receptor encephalitis was brought into public awareness with the 2012 bestselling memoir Brain on Fire: My Month of Madness, by New York reporter Susannah Cahalan. Cahalan was diagnosed with autoimmune encephalitis in 2009 after suddenly experiencing paranoia, hallucinations and seizures. At the time, hers was only the 217th known case of the disorder in the world. Since the publication of her book, however, Cahalan has encountered hundreds of others who have been given the same diagnosis. She is optimistic that awareness of the biological underpinnings of the disease can help lift the social stigma around mental illness.

"It probably brings us closer to hammering in the idea that mental illness is a disease," she says. "It's a disease we don't fully understand."

Each new finding, however, is tempered with caution.

Using nationwide data from Denmark, Benros found a strong link between infection and autoimmune diseases and mood disorders. People who had visited the hospital for an infection at any time had a 62-per-cent higher risk of later being diagnosed with depression or bipolar disorder. Those who were hospitalized for autoimmune diseases had a 45-per-cent risk of subsequent depression or bipolar disorder.

As significant as his findings may be, Benros is cautious about overstating the association between inflammation and mental illness. While there's growing evidence to provide "proof of concept" of the immune hypothesis, he notes that more research must be done to show causality. "If it's true, it's probably a minor group" of psychiatric cases that are caused by an immune response, he says.

Boris Sakic, associate professor of psychiatry and behavioural neurosciences at McMaster University, suggests immune-related mental illnesses could be more prevalent than we may think. Consider, for example, that 70 per cent of people who suffer from the autoimmune illness lupus develop neurological and psychiatric symptoms, he says. Within Canada and the U.S., millions of individuals suffer from lupus. If 70 per cent of those lupus patients develop depression, anxiety, psychosis and dementia, "then this number is quite significant," he says.

Sakic notes that patients with multiple sclerosis, an autoimmune disease with well-recognized effects on the nervous system, also tend to suffer from psychiatric symptoms, such as excessive crying and inappropriate laughing.

While it may not always be clear whether inflammation is a cause or consequence of a psychiatric condition, Sakic says this new avenue of research underscores the notion that there are many factors that can lead to the same brain dysfunction. Mental health, he says, is like a window. "We can break the window in many ways."

This suggests the need for immunopsychiatry, a new approach that recognizes the immune system and the brain are inexorably linked and should be treated in tandem, he adds.

"I am one of the believers who thinks that the body is one big entity that shouldn't be split into different disciplines," Sakic says. "The problem is it's way more complex than we like to think."