The report is a product of the VA/HSR Evidence Synthesis Program.

Evidence Brief: Pharmacogenomics-guided Antidepressant Treatment versus Usual Care for Major Depressive Disorder

Genetic variation has long been explored as a potential contributor to individual differences in antidepressant treatment outcome. Whether using genetic information can help predict how an individual might respond to a particular antidepressant – referred to as 'pharmacogenomics' – is of great interest for further advancing precision medicine efforts. The clinical rationale behind using pharmacogenomic data to inform antidepressant therapy is that a patient's unique genetic profile may help predict whether a patient will tolerate or respond to a drug, or help tailor the dose that will have the best effectiveness and tolerability.

In January 2015, the White House identified VA as a participating agency in the Precision Medicine Initiative, which takes into account individual differences in people's genes, environments, and lifestyles. To inform this initiative, VA's Office of Research and Development (ORD) is developing a clinical study that builds on the Million Veteran Program (MVP) by implementing Precision Medicine in Mental Health (PMH). The PMH committee focused on depression because of its high prevalence, a need for better treatment strategies, and a growing use of genetic testing for decision-making. To inform study development, ORD commissioned the Evidence-based Synthesis Program Coordinating Center (ESP CC) to conduct an evidence brief on the clinical utility of pharmacogenomics-guided treatment for major depressive disorder (MDD).

For this evidence brief, investigators with VA's Evidence-based Synthesis Program located in Portland, Oregon searched the literature through March 2016 and found 15 articles, including two randomized controlled trials, to examine the use of pharmacogenomic testing for antidepressant treatment for adults with depressive disorders. [An evidence brief differs from a full systematic review in that the scope is narrowly defined, and some traditional review methods may be streamlined in order to synthesize evidence within a shortened timeframe.] Specifically, investigators assessed the comparative effectiveness, harms, and cost-effectiveness of pharmacogenomic-guided antidepressant treatment versus usual care.

Summary of Findings
Effectiveness and Harms of Pharmacogenomics-guided Treatment vs Usual Care
Only three pharmacogenomics-guided treatment strategies have published studies that compare guided and usual care: 1) CNSDose, not yet commercially available; 2) ABCB1 genotyping; and 3) GeneSight.

• CNSDose (polygene panel of ABCB1, ABCC1, CYP2C19, CYP2D6, UGT1A1) has the most favorable preliminary findings. One additional patient had a remission by 12 weeks for every 3 genotyped, and the effect on intolerability was favorable compared to usual care.
• ABCB1 genotyping improved the chance of remission, with one additional remission at 5 weeks for every 3 to 20 patients genotyped. This difference could be due to the short duration of the study. Harms were not evaluated.
• For GeneSight (polygene panel of CYP2D6, CYPC19, CYP1A2, SLC6A4, HTR2A), the highest-quality study found its effects were not statistically significant and left unclear whether the chances were substantially better or worse than usual care for remission and response. Harms were not evaluated.

However, all studies involved non-Veterans. Also, most patients in these studies were females in their 40s who lacked comorbidities, such as PTSD, that are common among Veterans who have depression.

The validity of the findings are in some doubt because the studies were small, short-term, have not been replicated, and have numerous minor methodological limitations.

Effects of Following Pharmacogenomics-Recommended Medication Changes
In establishing the clinical utility of pharmacogenomics-guided treatment, a first step is to demonstrate an improvement in the key outcomes of remission, response, and tolerability for the guided group overall versus usual care. An essential second step is to demonstrate that the improvement on those key outcomes is due to a greater incidence in the guided group of actually implementing recommended medication changes to more genetically suitable regimens. At the time of this report, no pharmacogenomics-guided treatment strategy has met both of these criteria.

Improving Time to Antidepressant Effectiveness
No studies were found that evaluated the impact of pharmacogenomics-guided treatment on time to antidepressant effectiveness in patients with MDD or number of failed antidepressant trials.

Optimal Clinical Scenarios for Using Pharmacogenomics-guided Treatment
No studies were found that evaluated whether the impact of using pharmacogenomics-guided treatment on the effectiveness and harms of antidepressants differs according to the following key patient characteristics: demographics, psychiatric and medical comorbidities, depression symptomatology, depression severity and duration, history of antidepressant treatment resistance, concomitant medication, polypharmacy, medication side effects, non-adherence, or other health or lifestyle behaviors.

Cost-effectiveness
The cost-effectiveness of pharmacogenomics-guided care versus usual care in Veterans with major depressive disorder is not clear. This is primarily because there is too much uncertainty about the effectiveness of pharmacogenomics-guided care in Veteran-representative patients whose primary diagnosis is major depressive disorder.

Future Research
Findings from this review support the need for additional research in VA to better understand whether using pharmacogenomics-guided care can improve the effectiveness of antidepressant medications in Veterans with major depressive disorder. Therefore, a study that could augment the Million Veteran Program's capabilities, such as that proposed by ORD, has the potential to be very helpful toward their goals to:

• Better understand the lifestyle, genomics, and pharmacogenomics of depression in Veterans;
• Develop individualized approaches to treat depression in Veterans; and
• Develop and implement a responsible and efficient process of returning genetic data to providers and patients to determine how to use genetic findings in the clinical setting.

Moreover, as the duration of follow-up in available studies was only 5-12 weeks, the ORD study should seek to obtain longer-term follow-up of at least 6 months to one year. Longer-term follow-up would facilitate evaluation of maintenance of effects, relapse, and whether pharmacogenomics-guided care could reduce the number of failed antidepressant trials.

Next Steps
In response to the PMH initiative, there is ongoing coordination between VA national program offices to optimize the management of clinical services (Patient Care Services, Mental Health, Clinical Pathology), research, (ORD, MVP, MIRECC) and big data (e.g., GenISIS, VINCI) in regard to pharmacogenomics. Also, proposals for an RFA "HSR&D Implementation of VA Clinical Precision Medicine in Mental Health" (421KB, PDF) will be reviewed in August, with projects anticipated to start in FY2017. This RFA is intended to establish a service-directed program project that will support a multi-site clinical effectiveness trial in order to understand the impact of pharmacogenomics testing on depression treatment and outcomes among Veterans. An interdisciplinary research team is expected to conduct the trial to inform individualized approaches for depression treatment, as well as the implementation of an efficient process of returning genomic data to providers and patients in order to determine how genomic findings can be used in routine clinical practice.

Reference
Peterson K, Dieperink E, Ferguson L, Anderson J, Helfand M. Evidence Brief: The Comparative Effectiveness, Harms, and Cost-effectiveness of Pharmacogenomics-guided Antidepressant Treatment versus Usual Care for Major Depressive Disorder. VA ESP Project #09-199; 2016.

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This Management e-Brief is provided to inform you about recent HSR&D findings that may be of interest. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs. If you have any questions or comments about this Brief, please email CIDER. The Center for Information Dissemination and Education Resources (CIDER) is a VA HSR&D Resource Center charged with disseminating important HSR&D findings and information to policy makers, managers, clinicians, and researchers working to improve the health and care of Veterans.

This report is a product of VA/HSR&D's Quality Enhancement Research Initiative's (QUERI) Evidence-Based Synthesis Program (ESP), which was established to provide timely and accurate synthesis of targeted healthcare topics of particular importance to VA managers and policymakers – and to disseminate these reports throughout VA.

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