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Trainee-Led Study Seeks to Better Understand All-Cause Mortality in Schizophrenia Patients

February 11, 2020

A new study led by a Yale Department of Psychiatry trainee sought to better understand why people with schizophrenia have dramatically increased all-cause mortality, and whether living with severe mental illness accelerates the aging process.

Albert Higgins-Chen, MD, PhD, a third-year resident, worked with Morgan Levine, PhD, Assistant Professor of Pathology at Yale School of Medicine to thoroughly characterize aging in 567 schizophrenia patients and 594 non-psychiatric controls using “epigenetic clocks” - biomarkers based on DNA methylation that measure biological age. They analyzed 14 unique epigenetic clocks that each examine distinct aspects of aging.

The analysis, published in Biological Psychiatry, revealed striking differences in aging between controls and schizophrenia patients, who often live 15 to 20 fewer years than those without severe mental illness.

According to multiple epigenetic clocks that measure age-related mortality risk, schizophrenia patients are up to 5 years older, corresponding to a 74 percent increased risk of death at all ages. Most of this increased risk appears related to smoking, highlighting the importance of smoking cessation as part of schizophrenia treatment.

However, six serum proteins previously identified as dysregulated in schizophrenia also accelerate aging independent of smoking, suggesting the underlying biology of mental illness may directly increase mortality risk. This raised the possibility of novel treatments that simultaneously improve physical and mental health.

Unexpectedly, two “mitotic clocks” that measure the number of cell divisions in a tissue and correlate with cancer risk were consistently reduced in schizophrenia. “We were initially very confused because these same subjects had very high rates of smoking,” Higgins-Chen said. “Though smoking did increase cancer risk in our data, an independent phenomenon seemed to protect the individuals with schizophrenia.”

A literature search quickly turned up a controversial topic in schizophrenia epidemiology: observations of reduced cancer risk in schizophrenia, even before the onset of psychosis and possibly in first-degree relatives of patients, Higgins-Chen said.

“Many people have been skeptical of this observation, because a possible explanation is that people with schizophrenia simply die of other causes before they develop cancer,” he said. But the epigenetic clocks suggest a biological basis may in fact exist for reduced cancer risk.

Finally, schizophrenia patients who take clozapine, the most effective antipsychotic medication, had a biological age up to 7 years younger than either controls or people taking other antipsychotics. Previous studies showed clozapine is associated with a 50% reduction in all-cause and cardiovascular mortality in humans, and clozapine can affect aging in animals. Thus, clozapine may improve survival by influencing the aging process. However, the authors note there are many alternative explanations for the clozapine effect, and further studies are needed.

The researchers say the epigenetic aging biomarkers could be integrated into epidemiological studies to understand how aging is impacted by specific psychiatric symptoms, genetics, developmental stressors, lifestyle factors, stigma, and socioeconomic factors. The biomarkers  could also help scientists identify which schizophrenia patients are at higher or lower risk of death or cancer, enabling personalized, tailored treatment to protect the long-term health of an aging psychiatric population.

Submitted by Christopher Gardner on February 10, 2020