VA RESEARCH: PRECISION MEDICINE IN MENTAL HEALTH

VA’s PRIME Care study aims to take the guesswork out of prescribing antidepressants.

By Craig Collins

It’s not clear when the term “precision medicine” was coined, but medical researchers began to use it much more after April 2003, when the international Human Genome Project gave us the ability to read nature’s complete genetic blueprint for a human being. Understanding every human gene, from both a physical and functional standpoint, created the possibility of individualized treatments: Genomic sequencing could yield molecular targets for drugs or other interventions.

Many Americans associate precision medicine with cancer treatment, which is understandable. A major focus of the federal Precision Medicine Initiative, launched in 2015, was to expand cancer genomics to develop prevention and treatment methods. Relying heavily on the VA’s Million Veteran Program, the largest genomic database linked to a health care system, investigators across the country have learned, using genomic sequencing, how to evaluate a patient’s cancer risk; prevent some types of cancer; diagnose certain cancers early and with greater specificity; choose the best treatment option; and evaluate how a treatment is working. For many cancers, drugs have been developed based on a specific genotype – the set of genes, either within tumor cells or the patient’s own inherited genes or “germline,” known to be cancer-associated. The study of the role of the genome in drug response is known as pharmacogenetics.

Test tubes used in genetic testing, part of VA’s Million Veteran Program.

David Oslin, MD, chief of behavioral health and director of the Mental Illness Research, Education, and Clinical Center at the Corporal Michael J. Crescenz (Philadelphia) Veterans Affairs Medical Center and a professor of psychiatry at the University of Pennsylvania’s Perelman School of Medicine, was among the first researchers to recognize the potential of pharmacogenetics in treating mental health disorders. In June 2003 – just weeks after the Human Genome Project had wrapped up its work – Oslin was lead author on a paper exploring whether the genotypes of alcohol-dependent subjects might predict their responsiveness to treatment with naltrexone, a drug commonly used to manage alcohol or opioid dependence.

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Naltrexone was first synthesized more than 50 years ago and has proven to be an effective drug – but not for everyone. Oslin’s 2003 study investigated how effective it would be, and for whom, based on genotype. Many mental health disorders, including substance use disorders; depression; anxiety; post-traumatic stress (PTSD); and others, are by definition heterogeneous: risk factors, causes, symptoms, severity, and recurrence vary from patient to patient. This is a circumstance that doesn’t neatly fit with our most basic understanding of “precision medicine” – but Oslin views precision medicine a little differently than, say, an oncologist.

In mental health, Oslin said, “genes can predict the metabolism of medicine – and metabolism is important for two reasons.” First, he explained, some medicines can have harmful side effects. Second, some medicines – an obvious example is the blood-thinner warfarin – have what Oslin calls a “narrow therapeutic index.” If the warfarin dose is just right, it can prevent blood clotting. Too little, and a patient could suffer an embolism or stroke; too much, and they could bleed to death from a cut or injury.

“Some medications have incredibly narrow therapeutic ranges,” Oslin said. “And pharmacogenetics can help us understand that variability from patient to patient, and help us dose better.”

THE PRIME CARE STUDY

Many antidepressant drugs have notoriously narrow therapeutic ranges. Two of the drugs most widely used to treat depression, tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs), are associated with a variety of side effects; among all medications, TCAs have been named as a leading cause of toxic exposure.

Traditionally, selecting and dosing an antidepressant drug is a painstaking trial-and-error process. It takes a while for a drug to take effect, and in the case of SSRIs, it also takes a long time to transition to another drug; patients can suffer from “discontinuation syndrome,” or physical withdrawal symptoms, unless their dosage is tapered off over a period of several weeks. It’s not unusual for a patient and clinician to struggle for more than a year to find the right medication at the right dose.

The PRIME Care study seeks to use genomic information of patients to match the best drugs to treat the particular patient’s mental illness.

Depression is a disorder that disproportionately affects active-duty service members and veterans. A 2008 VA study estimated that about a third of veteran patients who visited primary care facilities displayed at least one symptom of depression; about 20 percent had serious symptoms suggesting the need for further evaluation. For Oslin and other VA clinicians, avoiding this often painful trial-and-error period is a priority.

“We have twenty-some antidepressants out there today,” Oslin said. “For two or three of those, a patient might have a genetic variant that causes them to be metabolized very differently – and therefore makes the dosing of those more complex. The easiest thing for me to do as a clinician is just to pick one that’s just as good, but not influenced by the patient’s genetics. I would have more confidence to know how to prescribe and how to adjust that other treatment.”

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Pharmacogenetic (PGx) investigations have so far suggested about a dozen of what Oslin calls “actionable genotypes”: specific gene variations that may affect how a patient metabolizes certain antidepressants. Knowing how well a certain patient is likely to metabolize a medication in the liver, or process it in the brain, can allow a clinician to tailor medications and dosages. The standard dosage of the SSRI sertraline (Zoloft), for example, is 100 milligrams. Some patients may need half that dose; some may need twice as much based on their genetics.

A few years ago, with funding from the VA’s Office of Research and Development, Oslin and his team launched a study known as the PRIME (Precision Medicine in Mental Health) Care initiative, aimed at improving outcomes for veterans who haven’t responded well to previous treatments for depression. The team recruited 1,944 veterans to participate at 22 sites in 18 states, and has so far compared these subjects’ genomes to a panel of 12 potential gene-drug interactions. Subjects’ genomic information is gathered by means of a simple cheek swab, and analyzed with an algorithm designed by a private company.

President Barack Obama announced the launch of the Precision Medicine Initiative in 2015 – a bold new research effort to revolutionize health care and change the way we treat disease.

In March 2021, the team reported in the Journal of Affective Disorders that this PGx panel had the potential to improve outcomes for about 20 percent of the study’s subjects: Around 1 in 5 subjects, Oslin said, had a genotype that would influence how the patient metabolized the antidepressant they were currently on, or the medication that was about to be prescribed by their clinician.

In other words, PGx testing has the potential to benefit 1 out of every 5 patients who are prescribed antidepressants that have the potential for clinically significant gene-drug interactions. “So about 1 in 5 times,” said Oslin, “drug X for that patient would not have been the greatest choice for them from a genetics perspective. I would have either been giving them too much of a dose or too little, because I didn’t know they actually metabolized that drug poorly.” Given the number of effective antidepressants, it’s likely that there’s a “drug Y” available for these patients that’s just as effective, and won’t be influenced by genetics.

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The point of the PRIME Care study, ultimately, is to see whether clinicians, armed with this PGx panel, will achieve better outcomes. PRIME Care is a randomized trial: Half the subjects are treated with the benefit of insights offered by the PGx panel; half are treated in the traditional way, informed by a clinician’s best judgment. Results will be available in the fall of 2021.

“We’re looking at two outcomes,” said Oslin. “One: Were we able to reduce that 20 percent of the time, when they were going to choose a medicine that was genetically influenced, to 5 or 1 percent or even zero? Did they avoid using medicines that would be more complicated for this patient? And second: If they did, did patients and providers actually get better results, in terms of their treatment for depression? That’s ultimately the goal. We want healthier veterans, and we’re looking for better care, plain and simple.”