Psychiatric Pharmacogenomics: Research Directions

More and more research is being conducted in the US and abroad on the role of psychiatric pharmacogenomics in identifying new gene variants and in predicting treatment response to specific medications.

David Mrazek, MD, (see accompanying report) is conducting a pharmacogenomics study using escitalopram. It involves 529 patients and is designed to identify “new gene variants that might improve the algorithm for predicting medication response.”

Three genome-wide pharmacogenomic studies of response to antidepressants have brought promising findings of pharmacogenomic associations in previously unsuspected yet functionally plausible genes.

In the Genome-Based Therapeutic Drugs for Depression (GENDEP) study that involved 811 adult patients with unipolar depression, researchers identified genes likely to be involved in the response to escitalopram or nortriptyline.⁷

“The most novel and promising findings include a neurogenesis-related gene UST [uronyl-2-sulfotransferase] that influences response to nortriptyline and the inflammation and serotonin function-related gene IL11 [interleukin-11] that appears to influence response to escitalopram,” said lead investigator Professor Peter McGuffin, PhD, from the Institute of Psychiatry at King’s College London. “None of these findings has an effect size and confirmed replicability across populations that would make it a clinically suitable predictor.”

There are 2 other large published pharmacogenomics studies of antidepressants. One is the Munich Antidepressant Response Signature (MARS) project, a naturalistic pharmacogenomics study of inpatients with major depression or bipolar depression treated with various medication regimens. The other is the STAR*D study, a pragmatic treatment study of 4041 outpatients with unipolar depression, all initially treated with citalopram; many individuals (1149 to 1963) were included in pharmacogenomics studies.⁸

McGuffin added that his team is part of a consortium that is conducting a meta-analysis of the GENDEP, MARS, and STAR*D studies.

“This meta-analysis includes more than 2000 subjects and is expected to be published in early 2012,” he said in an exclusive interview.

Also scheduled for next year is publication of the results of the largest pharmacogenomics study conducted to date, according to McGuffin. It is called Novel Methods leading to New Medications in Depression and Schizophrenia (NEWMEDS).⁹

“A European Union–funded transparent collaboration between universities and the pharmaceutical industry, [the study] allowed us to assemble a sample of 2000 subjects with a diagnosis of major depressive disorder, available genetic samples, and prospectively recorded response to antidepressants,” he said.

According to McGuffin, the depression section of the study finally gives “us a big enough, powerful enough sample to address how genetics influences antidepressant response.”

For more on psychiatric pharmacogenomics, click here.