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Epigenome Variants Define Regulatory Pathways in Neuropsychiatric Drug Response and Adverse Events

Gerry Higgins PhD, MDAdjunct Research Professor, Computational Medicine and Bioinformatics, University of Michigan Medical School;Vice President, Pharmacogenomic Science, Assurex Health, Inc.

PSYCHIATRIC PHARMACOGENOMICS:Clinical Translation & Novel Variant Discovery

Conflict of interest statement:

Dr. Gerald A. Higgins is an employee of AssureRx Health, Inc. (Mason, OH) and holds options in the company. He serves as an Adjunct Research Professor at the University of Michigan Medical School. He states that he has no financial interest in the response to this presentation.

CLINICAL TRANSLATION

The Impact of Psychiatric DiseaseMore than 350 million people are affected by depression;

It is the number 1 cause of disability, U.S. and worldwide;

Almost 2/3 of those who commit suicide have depression;

34% of female patients diagnosed with bipolar disorder attempt suicide, 19% of male bipolar patients attempt suicide;

Majority of perpetrators of mass shootings in the U.S. since 1970 displayed psychiatric symptoms including paranoia, delusions, and depression, and 74% were on psychiatric medications; but

In the new 2016 NIH budget, $5.6 B is earmarked for cancer research, only $404 M for depression research and $259 M for research on schizophrenia.

Challenges in Psychiatric Pharmacogenomics No usable objective diagnostic measures in clinical practice, must rely on surrogate phenotypes and rating scales;

Comorbid psychiatric conditions and comorbid non-psychiatric conditions confound differential diagnosis;

Most psychiatric medications were developed in the 1950s, including lithium, chlorpromazine and imipramine;

There has been virtually no CNS drug development since 2000, with the exception of ketamine-like antidepressants;

79 M Americans were prescribed psychiatric medications in 2014 - 25% of the U.S. population;

Psychiatric medications exhibit unacceptably high levels of adverse events 90,000 annual visits to the ER in the U.S. 50% of all prescription drug-related hospitalizations.

David Mrazek, Psychiatric Pharmacogenomics & Assurex Health, Inc.

CYP2C19CYP2D6

Use with CautionCYP1A2SLC6A45HTR2AGenotypePhenotypeInterpretive Drug SortingMedication Binning

Effect of Composite Phenotype on Each Drug

Use as DirectedUse with Caution and More Frequent MonitoringMetabolizer StatusMetabolizer StatusMetabolizer StatusTransporter ActivityReceptor Activity

CYP2C9Metabolizer Status

One reason why pharmacogenomic testing is adopted in psychiatry, but not in cardiology (e.g., warfarin, clopidogrel)

Cardiologists:17% in solo practice in U.S.

Psychiatrists:85% in solo practice in U.S.

Another reason why pharmacogenomic testing is being adopted in psychiatry?

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