How Will Precision Medicine Advance Psychopharmacology?

Certain areas of medicine—notably oncology—have successfully leveraged objective biomarkers to fuel the advent of precision medicine, helping clinicians tailor targeted treatments to a patient’s genetic, cellular, or molecular profile.

To date, implementation of precision medicine in psychiatry (or precision psychiatry) has not yielded significant real-world clinical impacts. But some of the latest research reveals important clues about its potential to advance pharmacotherapy development and prescribing practices in the future.

Targeting Treatment Decisions

Precision medicine is an approach to research and patient care that incorporates individual differences in biology, lifestyle, environment, and social determinants of health with the goal of more effectively identifying what underlies an individual’s illness.

“Many psychiatric conditions are very heterogenous, and the notion that depression, for instance, represents ‘one’ thing, I think we would all agree, is not accurate,” said Jordan W. Smoller, M.D., Sc.D., Trustees Endowed Chair in Psychiatric Neuroscience at Massachusetts General Hospital, in an interview with Psychiatric News. “There are probably many forms of the disorders that we see in psychiatry, and by understanding and leveraging individual differences, we can [care for patients] better.”

Among the numerous goals of precision medicine is to identify biomarkers linked to disease vulnerability, such as the BRCA gene variants for breast cancer or the ApoE4 gene for Alzheimer’s disease. A second aim involves tailoring prevention strategies or treatments for each patient to offer the intervention with the greatest likelihood of favorable response and minimal side effects. Numerous biomarkers may be involved in such tailoring and include findings from brain imaging, inflammatory markers, and more.

“In cancer, precision medicine is pretty advanced compared with psychiatry because they have good biomarkers to differentiate subtypes of the same cancer and match patients to the right chemotherapy. This is what we want for psychiatry,” Andreas Menke, M.D., senior consultant psychiatrist in the Department of Psychiatry, Psychosomatics, and Psychotherapy at University Hospital Wuerzburg in Germany, told Psychiatric News. “We want to find biomarkers that tell us, ‘OK, this patient needs Antidepressant A, and that patient needs Antidepressant B, or this patient does not respond at all to antidepressants and needs ECT [electroconvulsive therapy] or psychotherapy.’”

So far, such breakthroughs have remained elusive. Large-scale research initiatives, like the National Institute of Mental Health’s Research Domain Criteria (RDoC) project and the PsycheMERGE Consortium within the National Institutes of Health’s Electronic Medical Records and Genomics Network, are seeking to identify neurobiological underpinnings and objective markers that portend psychiatric illness. But psychiatrists have grappled with translating results from studies into meaningful targets for treatment matching.

Smoller and colleagues from the PsycheMERGE Consortium found that among more than 100,000 patients, those in the top 10% of polygenic risk scores for schizophrenia were about 2.3 times likely to have schizophrenia compared with everyone else. The study was published in October in the American Journal of Psychiatry.

“That is more than a doubling of risk,” he said. Still, more research is needed before researchers know how such information will translate to the clinic. “[W]hether we can use that diagnostically or prognostically yet is still unclear,” he said.

One innovation that could impact prognosis and treatment selection is pharmacogenetics—or the ways in which genes affect medication efficacy and safety in an individual. In theory, knowing whether a patient is a poor, intermediate, rapid, or ultra-rapid metabolizer of a given enzyme in the cytochrome P450 system may inform selection and dosing of tricyclic antidepressants and selective serotonin reuptake inhibitors (SSRIs).

But theory and actuality often differ, as reflected in the findings of the Genomics Used to Improve DEpression Decisions (GUIDED) Trial. In this trial, researchers compared depressive symptoms in patients who were prescribed antidepressants based on their pharmacogenomic tests with those who received treatment as usual. While patients who received pharmacogenomics-guided care had an increased chance of achieving treatment response and remission by week 8 of the study, there were no significant differences between the groups in the primary outcome of study—percent change in Hamilton Depression Rating Scale score—at week 8.

A recent meta-analysis of five randomized, controlled trials, including the GUIDED Trial, also found improved remission with pharmacogenetic-based antidepressant prescribing. There were numerous methodological limitations identified that possibly undercut this finding, such as recruitment bias and lack of generalizability across genders and ethnicities.

Several dozen commercial entities currently offer pharmacogenetic testing for depression in the United States, but Charles B. Nemeroff, M.D., Ph.D., a professor and chair of the Department of Psychiatry at the University of Texas at Austin Dell Medical School, cautioned that evidence, such as that from the GUIDED Trial, suggests this approach is not currently clinically useful.

“Part of the problem is that the commercially available tests do not include several candidate genes that have been reported to influence antidepressant response,” Nemeroff explained to Psychiatric News. “Moreover, the companies do not provide ‘proprietary’ information on their algorithms, so the field cannot really assess their methods. I think that eventually this field will help predict antidepressant treatment response, but it’s not ready for prime time.”

Revolutionizing Drug Discovery

Along with treatment decision-making, precision medicine may influence the drug development pipeline. In oncology, for example, the discovery of human epidermal growth factor receptor-2 (HER-2) mutations in people with breast cancer led directly to the creation of the medication trastuzumab (Herceptin). This medication, often given in combination with chemotherapy, is now a first-line treatment for patients with metastatic breast cancer whose tumors overexpress HER-2.

The discovery of innovative psychiatric medications over the last 50 years has been stymied in part by the field’s inability to identify medications that exert their therapeutic effect in ways different from existing psychotropic medications (ketamine and esketamine are notable exceptions). Smoller told Psychiatric News that precision psychiatry may offer a pathway to changing that.

“Genomic studies that implicate specific genes or pathways offer the potential to identify novel biological mechanisms that were previously unsuspected,” he said. Smoller pointed to the discovery from genome-wide studies that the complement pathway, known to be involved in immune response, may play a role in schizophrenia. “From that research, we then showed that [this pathway] may accelerate the pruning of synapses by marking synapses for destruction by microglia.” Consequently, Smoller said, this has led to a new understanding of the biology of schizophrenia and offers new opportunities for therapy targets.

Such discoveries point to a need for pharmaceutical companies to change their approach to drug development so that investigatory treatments are better matched to individuals’ unique biology.

“Previous drug development aimed at what we used to call ‘carpet bombing’, where we tried to identify one drug for all people who suffer from a given disease. We now know that this is silly,” Nemeroff said.

As medicine continues moving away from “one-size-fits-all” strategies, research on individual immune responses, such as the expression of certain tumor-specific antigens in oncology, has proliferated. Immunotherapy in psychiatry is still nascent and only speculative, Menke told Psychiatric News, but it may play a role in depression and stress-related mental disorders, especially given the known effects of trauma on the immune system and its functioning across the lifespan.

Beyond the future discovery of novel medications and immune-based approaches, precision psychiatry also may benefit clinical trial design and recruitment strategies. Biologically based stratification could help researchers better understand why a particular group of participants did or did not respond to an investigatory medication or better predict which participants might be placebo responders. Not only might this help detect an effect that otherwise could have gotten lost amongst a mixed group of responders and nonresponders, it could make clinical trials shorter, less costly, and more efficient, potentially increasing the speed at which regulatory approval is acquired.

“Psychiatry needs to and is beginning to move in the direction of taking advantage of the latest advances in genomics, large-scale data analyses, and integrating information from multiple streams to identify the key profiles or individual differences that matter,” Smoller said. “We are at the very early stages of doing this, but the potential is large. And for a field that, in some ways, has not had transformative advances in treatment and in which identifying individuals at high risk for illness or predicting outcomes that matter has largely been beyond our capacity, it’s exciting to be moving in this direction.” ■