Polygenic Scores Help Predict Trajectory of Schizophrenia

Dwight Dickinson, PhD

The 2020 American Psychiatric Association (APA) Annual Meeting was cancelled this year, with plans made to convert the world-leading psychiatry conference into a two-part virtual session and educational platform for attendees.

In lieu of regular on-site coverage, HCPLive® will be running a series of interviews, insights, and reporting on topics that frequently headline the APA meeting—featuring familiar experts.

The polygenic scores (PGS) of schizophrenia patients could forecast an individual’s cognitive development.

A team, led by Dwight Dickinson, PhD, National Institute of Mental Health, examined whether different cognitive development histories in schizophrenia could reflect variation across dimensions of genetic influence.

The investigators derived and characterized cognitive development trajectory subgroups within a schizophrenia sample through cluster analysis using estimated of premorbid and current IQ and profiled the subgroups across polygenic scores for schizophrenia, cognition, educational attainment, and ADHD using standard methods.

The team collected demographic, clinical, and genetic data for 540 schizophrenia patients, 237 unaffected siblings, and 844 control subjects at the National Institute of Mental Health.

The associations were tested using general linear models and logistic regression.

Through cluster analyses, the investigators identified 3 cognitive trajectory subgroups in the schizophrenia group—preadolescent cognitive impairment (19%), adolescent disruption of cognitive development (44%), and cognitively stable adolescent development (37%).

Together, the 4 polygenic scores predicted 7.9% of the variance in subgroup membership. Subgroup characteristics converged with genetic patterns and cognitively stable participants had the best adult clinical outcomes and differed from control subjects only in schizophrenia polygenic scores.

Individuals with adolescent disruption of cognitive development showed the most severe symptoms following their diagnosis and were cognitively impaired. This subgroup also had the highest schizophrenia polygenic scores and had disadvantageous cognitive polygenic scores relative to both the control subjects and cognitively stable individuals.

On the other hand, individuals showing preadolescent impairment in cognitive and academic performance and poor adult outcome exhibited a generalized polygenic score disadvantage relative to control subjects and were the only subgroup to differ significantly in education and ADHD polygenic scores.

“Subgroups derived from patterns of premorbid and current IQ showed different premorbid and clinical characteristics, which converged with broad genetic profiles,” the authors said. “Simultaneous analysis of multiple PGSs may contribute to useful clinical stratification in schizophrenia.”

One drug that has proven to be successful in treating schizophrenia patients is clozapine.

However, rechallenging a schizophrenia patient following a clozapine-induced major adverse event can be difficult.

While effective in reducing schizophrenia symptoms, clozapine treatment is known to increase the risk of serious adverse events including agranulocytosis and severe neutropenia, myocarditis and cardiomyopathy, gastrointestinal hypomotility leading to bowel infarction, pancreatitis, and renal insufficiency.

Peter Manu, MD, a professor of Internal Medicine at the Donald and Barbara Zucker School of Medicine at Hofstra University/Northwell Health, explained in an interview with HCPLive® that faulty data on the risk of adverse events induced by clozapine may be causing patients to discontinue use following the complication.

Manu said most of the adverse events occur in the first few weeks of treatment. But the major side effects only occur in a small proportion of patients.

“It has adverse effects, we know that,” Manu said. “The idea is we challenged the patient after an adverse event. We rarely deal with more than 1 really life-threatening complication.”

Ultimately, Manu deemed the widely used treatment as safe, saying the incidence of suicide in patients who discontinue treatment is higher than the fatality rate of the adverse events caused by the treatment.

The study, “Distinct Polygenic Score Profiles in Schizophrenia Subgroups With Different Trajectories of Cognitive Development,” was published online in The American Journal of Psychiatry.