Seeds of Psychosis: Rejecting Parenting Myths, Revealing Underlying Genetic Origins

The search for the seeds of psychosis goes back to the very start of psychiatry. In the late 19th century, Emil Kraepelin, one of the first adherents of the idea that mental disorders have biological causes, described psychosis as a form of early-onset dementia. But he struggled to find associated brain abnormalities. In a recent Foundation-hosted webinar, Dolores Malaspina, M.D., M.S., MSPH, of the NYU Langone Medical Center makes the case that studies focused not on the brain itself but rather on genetics may soon provide an opportunity to discover treatments for psychosis that are personalized – geared to the needs of specific patients.

Dr. Malaspina’s own work has revealed that the age of a patient’s father is a significant factor in psychosis risk—research that, she believes, “no one would have taken a chance on” if not for early support from the Brain and Behavior Research Foundation. Subsequent genetic discoveries showed that the disease was strongly associated with rare and novel variants of genes, which most often arise in the male parent and occur more frequently with increasing age.

In addition to receiving Young Investigator grants in 1995 and 1993, Dr. Malaspina is a 2007 Distinguished Investigator and 2001 Independent Investigator Grantee. By recounting the oftentimes reprehensible interpretations of schizophrenia throughout history, she highlights just how much progress scientists have made in just the past few decades.

“Bad Parenting” Myth

Today, ample evidence shows that genetic factors contribute significantly to the risks for psychiatric illnesses, including schizophrenia, bipolar disorder, and depression. People with psychotic disorders have fewer children, by and large, so one question in the field was to understand how these conditions persist in the population. This fact fueled the concoction of non-genetic explanations, Dr. Malaspina says, and including the idea that schizophrenia was a social disorder.” From the 1940s to the 1970s, particularly in the United States, the prevailing notion was that parental behaviors caused schizophrenia in a child, an idea as scientifically baseless as it is heartless.

Fortunately, the emergence of CAT scan imaging technology in the 1970s helped dispel this harmful myth. Studies of the brains of schizophrenia patients revealed abnormalities suggesting a loss of brain tissue. Later, studies showed cognitive abnormalities, even in schizophrenia patients judged to have relatively normal mental capacity. This concrete evidence confirmed the earlier view that “schizophrenia was in fact a brain disorder,” according to Dr. Malaspina.

The “Aging Father” Effect

Recent advances in genetics have given rise to a new explanation for how illnesses such as schizophrenia can have a genetic component, despite the fact that few of these patients pass their genes on to children. One striking phenomenon that has come to light is that a father’s sperm – produced throughout the lifespan -- is the source of “the vast majority of all new mutations in humans,” perhaps as much as 90 percent, according to Dr. Malaspina. Older fathers are more likely to pass potentially harmful mutations on to their kids, because the risk of mutations magnifies as a man ages. (Eggs, in contrast, are produced all at once at the dawn of a female’s life, and hence are not a source of “new” mutation due to aging.)

This is what inspired Dr. Malaspina and colleagues to look into whether the age of a patient’s father was linked to schizophrenia risk in a population in Jerusalem. In a landmark study in 2001, they found the age of a patient’s father explained about one-quarter of schizophrenia cases, and more than a dozen studies have since turned up similar results.

Brain gene mutations

After discovering a father’s age is a substantial factor in a child’s psychosis risk, Dr. Malaspina set out to find the specific mutations that were disrupting “brain genes”—those whose function is critical to normal brain development. They found that mutations in genes for brain growth factors, as well as for tumor-suppressor proteins, and even one that encodes a molecule that transports zinc within cells, were among the genes that had a strong effect on the clinical presentation of schizophrenia. Patient symptoms and severity vary according to which category or categories of mutated genes they possessed.

Discoveries like these are important steps in finding more personalized and effective treatments for psychosis, with strategies guided by genetic differences. For this, Dr. Malaspina says, “I am hopeful.”