Science Watch

Where does mental illness begin? New research suggests the seeds of psychological problems are planted well before birth.

Schizophrenia, for example, is often thought of as a genetic disorder. But environmental factors can also boost risk – sometimes considerably. Alan Brown, MD, MPH, a professor of psychiatry and epidemiology at Columbia University and the New York State Psychiatric Institute, has found that a variety of early-life events significantly increase schizophrenia risk (Progress in Neurobiology, 2011). The risk is three times greater in people whose mothers had the flu during pregnancy, for example, while maternal iron deficiency during pregnancy increases the offspring's risk of the disease fourfold.

"These aren't small effects," Brown says.

Schizophrenia isn't the only mental illness linked to prenatal events. Using data from a Dutch birth cohort, Brown found that people whose mothers were undernourished while pregnant had a significantly increased risk of major affective disorders, such as mania and depression, severe enough to require hospitalization (American Journal of Psychiatry, 2000).

Other researchers have shown that adverse events during pregnancy, including infections, toxin exposure and maternal stress, can boost the fetus's future risk of problems such as depression, anxiety, autism, mood disorders and attention-deficit hyperactivity disorder. Events in early childhood are also linked to persistent mental health problems. Childhood maltreatment, for example, increases the odds of developing depression or post-traumatic stress disorder in adulthood.

Now, researchers are finally beginning to understand the biological processes that underlie these links—findings that could point to new directions in treatment for mental illness and behavior disorders, and may even suggest routes to prevention. Something as simple as good prenatal care—from flu shots to proper nutrition—may help to prevent the biological chain reactions that underlie many psychological problems.

Stress is suspect

Scientists studying the developmental roots of mental illness have zeroed in on a likely suspect: the body's stress response. When the body reacts to stressors, two systems kick into gear. The endocrine system produces stress hormones such as cortisol. And the sympathetic nervous system churns out other stress-related hormones such as epinephrine and norepinephrine—the factors responsible for the heart-pounding, sweaty-palms sensation known as the fight-or-flight response.

Yet stress physiology encompasses much more than just stress hormones, says Thaddeus Pace, PhD, an assistant professor of psychiatry and behavioral sciences at Emory University School of Medicine. Stress also impacts immune function. "A stressful event can have profound effects on the amount of activity that's going on in the inflammatory immune system," he says.

Inflammation is a key part of the stress response. It has also been linked to a variety of bodily ills, from diabetes and heart disease to depression and Alzheimer's disease. "I see inflammation as one of the chief evils in mammalian biology," Pace says.

Of course, the immune system serves a critical function—and not just for fighting disease. "The immune system is really important for how the brain develops normally," says Staci Bilbo, PhD, an assistant professor of psychology and neuroscience at Duke University. Cells called microglia are the resident immune cells in the brain. They're the central nervous system's first-line defense against infections and other invaders. And, Bilbo says, "they do a lot of important things for building a brain."

For starters, microglia are involved in synaptic pruning and programmed cell death. They also express cytokines, the signaling molecules that serve as messengers between cells and are a key component of the body's inflammatory response. Cytokines are important for the development of basic brain structures from blood vessels to axons. They are also involved in regulating cognition and mood, Bilbo says.

She explored the brain's immune cells by infecting infant rats with the bacterium E. coli four days after birth, a developmental period comparable to the third trimester of pregnancy in humans. The young rats recovered fully from the infection, and as adults they performed as well as control rats on tests of memory and cognition. But their early infections had left their mark.

The rats' microglia had been "primed," Bilbo says; in essence, the cells had been put on high alert for future infections. When the rats experienced a second infection—what she calls a "second hit"—around the time they were learning a new task, they showed profound memory impairments for that task. The primed rats, she discovered, were dramatically over-expressing cytokines in response to the second hit (Journal of Neuroscience, 2011). "Their immune system is changed long-term as a result of the neonatal infection," she says. "And because the immune system impacts brain function, they are altered behaviorally."

That same pattern appears in many neurodegenerative diseases in humans, she says. "A peripheral infection will suddenly make mental functions decline sharply, and you can measure concentrations of cytokines in the cerebrospinal fluid that were previously undetectable."

Inflammation running wild

Other animal studies have further filled in some details. Paul Patterson, PhD, a neurobiologist at the California Institute of Technology and author of the book "Infectious Behavior: Brain-Immune Connections in Autism, Schizophrenia, and Depression" (2011), explores the origins of mental illness in mice. He's infected pregnant mice with influenza virus and also stimulated their immune systems in the absence of a pathogen. "When you activate the mother's immune system, you turn on a variety of cytokines to fight the infection," he says.

Patterson found that the offspring of the infected mothers exhibited a whole list of abnormal behaviors. Among them were the three "cardinal behavioral symptoms of autism," he says: impaired communication, reduced social interaction and repetitive, stereotyped behaviors (Trends in Molecular Medicine, 2011). What's more, the mice showed heightened anxiety and were more sensitive to hallucinogenic drugs—a sensitivity also seen in humans with schizophrenia.

These changes can be traced to the presence of a cytokine called interleukin-6 (IL-6). When produced in excess by a pregnant mouse, the molecule activates subsets of neurons in the fetus's brain. IL-6 also activates cells in the placenta, altering endocrine function and changing growth hormones. "That's bound to have an effect on [fetal] development," he says.

Cytokines including IL-6 can also interfere with the synthesis of serotonin in the brain, Pace adds. An excess of cytokines leads to a cascade of molecular events that interrupts the synthesis pathway, preventing serotonin from being produced. And serotonin, of course, is a necessary ingredient for healthy mood.

This finding may be particularly relevant for depressed patients taking selective serotonin reuptake inhibitors (SSRIs). A study by Charles Nemeroff, MD, PhD, of the University of Miami, and colleagues suggests that depressed people who experienced an adverse event in early life may be less likely to respond to SSRIs than depressed patients who did not endure an early-life stressor (Proceedings of the National Academy of Sciences, 2003). That makes sense if an overactive immune response is working against serotonin in the brain, Pace says. "If inflammation really is driving that problem, then something like Zoloft isn't going to be as effective while inflammation is running wild."

For that reason, Pace says, "it's important to get a sense of whether or not somebody has had an early-life traumatic experience." Such a patient may be more likely to respond to psychotherapy than to antidepressants alone, for instance.

Pace and other researchers are now exploring alternative therapies for reducing inflammation and treating depression. He has found evidence that compassion meditation decreases the stress hormone cortisol as well as inflammation, at least in healthy subjects (Psychoneuroendocrinology, 2009). Testing the technique in depressed patients is the next step.

Scientists are also investigating the use of anti-inflammatory drugs to treat depression, either alone or in conjunction with traditional antidepressants. Others have begun to test anti-inflammatories for treating autism and schizophrenia. The research is still in early stages, but initial results are promising, Patterson says.

He predicts that it won't be long before anti-inflammatory medications are prescribed to treat mood and behavioral disorders. "Watch out for those studies coming along," he says. "If you modify the immune status, you should be able to modify behavior."

Kirsten Weir is a writer in Minneapolis.