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SIRS 2016—Tracing Trajectories in Longitudinal Studies

12 Apr 2016

April 13, 2016. On Monday, April 4, at the Schizophrenia International Research Society meeting in Florence, Italy, plenary speaker Raquel Gur of the University of Pennsylvania in Philadelphia argued that getting a better idea of the earliest stages of risk for mental illness is essential for precision medicine. Gur outlined four mandates for the field to understand the run-up toward mental illness: to bridge pediatric and adult psychiatry; to dissect complex phenotypes based on neuroscience; to study large samples obtained through collaboration; and to integrate findings with genomics. "We have no choice if we want to advance care of our patients," she said.

Gur gave the audience an overview of her prized Philadelphia Neurodevelopment Cohort, a longitudinal, population-based study of 10,000 children designed to detect the earliest glimmers of mental illness. Of nearly 5,000 subjects, a striking 20 percent reported subthreshold symptoms such as hallucinations, delusions, and disorganized thoughts. This "psychosis spectrum" state—considered earlier than a typical prodromal stage—shares some of the same cognitive and brain features seen in schizophrenia, albeit to a lesser degree (e.g., Satterthwaite et al., 2016). New data also showed a striking effect of environment, particularly for females: in poor or uneducated homes, males and females had the highest risk for developing schizophrenia, whereas this risk dropped for females in average homes and even further for females in wealthy, or educated homes. "The role of environment should not be neglected," Gur said.

Opportunities to intervene

A separate symposium collected four talks on longitudinal studies of children at high risk for developing a severe mental illness due to having a parent with schizophrenia, major depressive disorder, or bipolar disorder. Michel Maziade of Universite Laval in Quebec City, Canada, explored the accumulation of established risk factors in these offspring, including cognition, clinical and social function, trauma, attenuated symptoms of psychosis, and drug use. Though each risk factor on its own is not terribly predictive, an accumulation of them may be. Maziade noted that 40 percent of the population had three or more of these factors, and those who developed a mental illness carried more of these risk factors 10 years prior to their diagnosis compared to those who did not develop a disorder. He suggested that the accumulation of these indicators over time could provide a basis for staging the beginnings of mental illness, akin to the progression to heart disease.

Rudolf Uher of Dalhousie University followed with a similar message based on the FORBOW (Families Overcoming Risk and Building Opportunities for Well-being) cohort consisting of children of people with severe mental illness and healthy controls. The study follows family history, genetics, and several "antecedents" (emotional lability, anxiety, psychotic symptoms, and basic symptoms in which people experience unusual thoughts or perceptions). Of 274 children enrolled so far who had no diagnosis at intake, 10 have developed schizophrenia, major depressive disorder, or bipolar disorder. Of these, nine had at least one antecedent at baseline, and risk for severe mental illness steadily increased with each additional antecedent present at baseline.

Focusing on developmental trajectories leading to mood disorders, Martin Preisig of University Hospital of Lausanne in Switzerland presented data detailing the development of bipolar disorder and depression in children with a parent with one of these disorders. With assessments every three years of nearly 400 children, the study has found that children of a parent who had had an early onset of bipolar disorder (before age 21) were at greatest risk for developing bipolar disorder, with an eightfold higher chance than controls (Preisig et al., 2016). In contrast, children whose parents developed bipolar disorder after 21 years of age, or whose parents had major depressive disorder, had much lower risk for developing either mood disorder, suggesting a more "sporadic" etiology. Bipolar disorder in children of a parent with an early onset was further distinguished by the run-up to diagnosis: These children had more conduct disorder and issues with alcohol than children of parents with the other types of mood disorders.

Sifting through clues to see what kinds of symptoms precede the development of a mood disorder, Manon Hillegers of University Medical Center Utrecht in the Netherlands described results from the Dutch bipolar offspring study, consisting of 86 families and 140 children. Twelve years after entering the study, 54 percent have developed some kind of mood disorder (Mesman et al., 2013). Hillegers presented new data showing that for children who had mild depression at baseline, an elated mood, decreased need for sleep, increased goal-directed behavior, and racing thoughts presaged development of bipolar disorder. For those with no mood disorder at baseline, a subthreshold depressed mood, compulsions, self-consciousness, and recurrent thoughts of death were associated with the development of major depressive disorder.

Though the rates of pathology in these high-risk groups are striking, the environment might help mitigate the risk, suggested discussant Patrick McGorry of Orygen Youth Health and University of Melbourne in Australia. McGorry noted that children of parents with severe mental illness often live in chaotic and disturbed environments. "If we address the deprivation, it may allow their own resilience to take over," he said.—Michele Solis.