Schizophrenia is an idiopathic mental disorder with substantial morbidity, mortality and personal-societal costs. Understanding its genomic basis is one of the most significant pursuits in psychiatry today. A decade ago, there was perhaps one solid genomic finding for schizophrenia, but there are now 130+ loci that meet consensus criteria for significance and replication. Considerably larger group studies will be completed in the next year. These are projected to increase the numbers of loci into the high hundreds. This ever-increasing number of genomic loci, while encouraging, reflects a fundamental issue that plagues the field — the schizophrenia literature is based on large samples with considerable heterogeneity. Such high-throughput genomic sequencing of large cohorts is the standard approach to contemporary psychiatric genomics.
But Rita A. Shaughnessy, MD, PhD, associate professor of psychiatry, is collaborating with a team of investigators who have launched a study — supported by several grants from the National Institute of Mental Health — that takes a different approach. While subjects in the large cohort studies clearly have psychotic disorders, an alternative and time-honored strategy in genetics is to study the most severely ill subjects — in this case, individuals with longstanding, severe psychotic symptoms that are highly treatment-resistant.
The state psychiatric hospitals operated by the Pennsylvania Department of Human Services afford a unique opportunity to study this singular population of the "sickest of the sick" psychotic individuals. These individuals have been actively treated, are largely adherent to prescribed medications, and reside in a protected environment with adequate sustenance and minimal access to substances of abuse; yet many have remained severely psychotic for decades. This new project, "The Genomics of Treatment-Resistant Psychotic Symptoms," performs genomic assays on this unique population, on a case-by-case basis, to identify genomic changes that could lead to more effective therapeutics or to the discovery of important rare genetic mutations.
The core idea driving the project is that, infrequently or rarely, the initial presentation of schizophrenia is actually an undiagnosed genetic disorder. Therefore, the researchers wish to screen these atypical and severely affected individuals for rare variations that can cause a clinical presentation initially "confusable" with schizophrenia. The investigators hypothesize that a subset of subjects with highly treatment-resistant psychotic symptoms have rare genetic mutations of strong effect, such as a Mendelian disease. Effective treatments are available for some Mendelian diseases.
Rita A. Shaughnessy, MD, PhD
For the study, biospecimens are being processed and biobanked by the NIMH Human Genetics Initiative at the Rutgers University Cell and DNA Repository. To ensure the validity of the genomic data, the DNA assays are performed at the Stanley Center for Psychiatric Research at the Broad Institute of MIT and Harvard. Any actionable genomic information will be certified in a separate CLIA-certified* laboratory.
"This 'genome-first' approach has led to dramatically improved outcomes in general medicine," Shaughnessy says, "but the abundance of recent genetic findings in general medicine contrasts with the striking absence of discoveries that have been translated into the psychiatric clinic."
The study's co-principal investigators are Richard C. Josiassen, PhD, research professor of psychiatry at Drexel, who is also chief scientific officer of Translational Neuroscience, and Patrick Sullivan, MD, distinguished professor of genetics and professor of psychiatry at the University of North Carolina at Chapel Hill and distinguished professor of clinical neuroscience at the Karolinska Institutet in Stockholm.
Shaughnessy will play a leadership role in the committee that decides how to disclose information to the patient. She will be working with the chief medical officer for the commonwealth of Pennsylvania, as well as a diverse group of professionals from UNC, including a behavioral neurologist, a bioethicist and a genetics counselor. "If something interesting shows up and is verified, and the subject has indicated that he or she would like to be advised if something is found, then we will come up with a plan for the individual," Shaughnessy explains.
A subject may consent to a blood draw but want no further involvement. If a patient is too sick to consent, a person with power-of-attorney may give consent and ask to be informed of any finding, which — if something treatable is revealed — could lead to the patient's improvement.
By the end of September, the team had examined the DNA of three subjects — a kind of trial run for the larger study population. Of those three, one had a major genetic deletion, a finding that a CLIA-certified lab was re-evaluating.
"I am very excited to be working with the team in this unique effort," Shaughnessy says. "It has the potential to be phenomenally important, not only in the lives of individual subjects who may benefit but also in reducing the impact of serious mental illness on a significant fraction of the population we attempt to serve."
* CLIA (Clinical Laboratory Improvement Amendments) regulations establish quality standards for laboratory testing.