Pharmacogenetic Testing: Does It Improve Therapy in Patients With MDD

metabolized via a given CYP450 enzyme subunit than patients who metabolize the drug as predicted. Laboratories often advise clinicians to proceed with caution when prescribing an antidepressant in a patient who is known to be an intermediate metabolizer. • Poor metabolizers process medications significantly more slowly, leaving the patient with higher plasma drug levels than patients who metabolize the medication as predicted. Thus, patients who are poor metabolizers are more susceptible to adverse effects or potential toxicity. Such patients are also at greater risk for adverse effects if practitioners increase dosages of a drug. Therefore, greater caution should be used during dosage changes in these patients, and closer followup should be considered. Clinicians may want to consider avoiding drugs metabolized via the given CYP450 enzyme subunit as first-line therapy and select a medication that uses an alternate enzymatic pathway instead.

Most of the laboratory testing companies create a report that categorizes antidepressants based on the prevalence of certain SNVs. For example, because sertraline is metabolized via the 2C19 subunit of CYP450, a patient with a SNV in CYP2C19 (poor metabolizer) would have sertraline listed as a drug that clinicians should use with caution at a lower starting dose.5

Current Research

To date, 7 studies have investigated the use of pharmacogenetic testing in a clinical setting: 2 open-label studies and 5 randomized controlled trials.8-15 All of the studies evaluated the effect of treatment based on pharmacogenetic testing results compared with treatment using the standard trial and error approach. The majority of the studies used different pharmacogenetic testing panels, with each laboratory testing company using proprietary methods to analyze and statistically weight SNVs in their panels.

When pharmacogenetic testing was used in these studies, most studies still relied on clinicians to make treatment decisions based on each antidepressant falling into a “use as directed” category or a “use with caution” category that recommended changing the starting dose or switching to an antidepressant metabolized through a different enzyme subunit.

Outcomes varied in these studies. Across all the studies, treatment groups that used pharmacogenetic testing to guide medication selection showed higher rates of remission,11,13 response14 (≥50% reduction in Hamilton Rating Scale for Depression-D17 scores), or both, particularly among patients with severe depression.8-12,15

In the GUIDED trial, treatment based on pharmacogenomic testing did not significantly improve mean symptoms but did significantly improve response and remission rates for patients with difficult-to-treat depression compared with the standard treatment approach.15 Patients who were taking drugs found to be incongruent with their genetic profile (incongruent) before baseline and switched to congruent medications experienced greater symptom improvement (33.5% vs 21.1%), response (28.5% vs 16.7%), and remission (21.5% vs 8.5%) compared with those remaining incongruent.15 Many of the studies, however, included a majority of White subjects, calling into question the external validity of these study results to other races and ethnicities.

A meta-analysis by Rosenblat et al showed that pooled results of 6 of the 7 studies resulted in risk ratios for remission and response that favored the use of pharmacogenetic testing over a standard approach, although the authors caution that there are limitations to combining data from studies using different methodologies.16 Despite the study limitations and the fact that many of the pharmacogenetic testing panels included SNVs unrelated to drug metabolism that lack clinically significant correlation to MDD, overall the pharmacogenetic testing groups fared better than the control groups.16

Clinical evidence supporting the use of pharmacogenetic testing to determine adverse effects of antidepressants is still lacking.16 No study to date has been able to predict or avoid adverse effects altogether by using the results of pharmacogenetic testing to select antidepressant therapy. However, although study participants still experienced adverse effects when clinicians used pharmacogenetic testing to guide prescribing practices, many patients had improved outcomes.16

Recommendations for Clinical Practice

When considering pharmacogenetic testing, clinicians should discuss the cost of testing with patients. The cost varies depending on the supplier, but out-of-pocket costs for patients can range from a few hundred dollars to a few thousand dollars. Some insurance companies may cover the testing or a portion of it, and some of the test manufacturers provide discounts for patients who struggle to pay.17,18

Multigene testing is preferred over single-gene testing, given the complexities of MDD and drug metabolism genetics, and it is more cost-effective. In patients with severe depression, higher remission and response rates may make the cost of pharmacogenetic testing seem worthwhile.19 Higher remission rates may result in lower costs of care, greater productivity, and less burden on the patient.19

At this time, because of the limited clinical evidence available, the FDA warns against claims that genetic laboratory tests can predict patient response to specific drugs.20 In addition, the American Psychiatric Association has not incorporated pharmacogenetic testing into its clinical guidelines for treatment of MDD.2

Clinicians should also consider that pharmacogenetic testing has its limitations. It cannot account for food or drug interactions

PHARMACOGENETICS AND ANTIDEPRESSANT MANAGEMENT Cognitive behavioral therapy, interpersonal psychotherapy, and antidepressants are the mainstays of major depression treatment.

that also can affect how a patient metabolizes a drug. In addition, environmental factors play a significant role in the development of MDD, and these are unaccounted for if a clinician relies solely on pharmacogenetic testing to determine treatment.

Conclusion

Current research suggests that pharmacogenetic testing may improve response and remission rates among individuals with MDD, with several caveats. The cost of testing may not be worth it for patients with mild depression. Patients still may experience adverse effects despite using a drug selected using pharmacogenetic testing. The extent of the response across populations is unknown, particularly if a patient is an intermediate metabolizer.

More studies are needed with higher numbers of patients, which will allow analysis of large amounts of genetic data to increase the odds of uncovering additional SNVs. Health care practitioners still should rely on clinical judgment because even when using pharmacogenetic testing, they will need to interpret the patient’s genotype report to select an appropriate medication. In addition, providers who use pharmacogenetic testing to help inform antidepressant choice will need to manage patient expectations. Pharmacogenetic testing offers more information, but there are no guarantees that a patient will improve with the selected antidepressant. Providers should discuss options with patients and apply testing on a case-by-case basis. ■

Lauren Nolan, MMSc, PA-C, is a clinician at The Hope Clinic at Emory University, Atlanta, Georgia, and Tia M. Solh, MT(ASCP), MSPAS, PA-C, is associate program director, South College Physician Assistant Program, and a psychiatry physician assistant in Atlanta.

References

1. World Health Organization. Depression. WHO website. https://www.who. int/news-room/fact-sheets/detail/depression. January 30, 2020. Accessed August 26, 2020. 2. Gelenberg AJ, Freeman MP, Markowitz JC, et al. Practice Guideline for the Treatment of Patients With Major Depressive Disorder. 3rd ed. American Psychiatric Association; 2010. 3. Border R, Johnson EC, Evans LM, et al. No support for historical candidate gene or candidate gene-by-interaction hypotheses for major depression across multiple large samples. Am J Psychiatry. 2019;176(5):376-387. 4. Guengerich FP. Cytochrome P450 and chemical toxicology. Chem Res Toxicol. 2008;21(1):70-83. 5. Hicks JK, Bishop JR, Sangkuhl K, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2D6 and CYP2C19 genotypes and dosing of selective serotonin reuptake inhibitors. Clin Pharmacol Ther. 2015;98(2):127-134. 6. National Library of Medicine. Genetics Home Reference. What are genome-side association studies? NIH website. https://ghr.nlm.nih.gov/primer/ genomicresearch/gwastudies. Accessed August 26, 2020. 7. Food and Drug Association. Direct-to-consumer tests. FDA website. https:// www.fda.gov/medical-devices/vitro-diagnostics/direct-consumer-tests#list. Accessed August 26, 2020. 8. Gaedigk A, Simon SD, Pearce RE, Bradford LD, Kennedy MJ, Leeder JS. The CYP2D6 activity score: translating genotype information into a qualitative measure of phenotype. Clin Pharmacol Ther. 2008;83(2):234-242. 9. Bradley P, Shiekh M, Mehra V, et al. Improved efficacy with targeted pharmacogenetics-guided treatment of patients with depression and anxiety: a randomized clinical trial demonstrating clinical utility. J Psychiatr Res. 2018;96:100-107. 10. Hall-Flavin DK, Winner JG, Allen JD, et al. Utility of integrated pharmaco- genomic testing to support the treatment of major depressive disorder in a psychiatric outpatient setting. Pharmacogenet Genomics. 2013;23(10):535-548. 11. Singh AB. Improved antidepressant remission in major depression via a pharmacokinetic pathway polygene pharmacogenetic report. Clin Psychopharmacol Neurosci. 2015;13(2):150-156. 12. Perez V, Salvert A, Espadaler J, et al. Efficacy of prospective pharmacogenetic testing in the treatment of major depressive disorder: results of a randomized, double-blind clinical trial. BMC Psychiatry. 2017;17(1):250. 13. Winner JG, Carhart JM, Altar CA, Allen JD, Dechairo BM. A prospective, randomized, double-blind study assessing the clinical impact of integrated pharmacogenomic testing for major depressive disorder. Discov Med. 2013;16(89):219-227. 14. Hall-Flavin DK, Winner JG, Allen JD, et al. Using a pharmacogenomic algorithm to guide the treatment of depression. Transl Psychiatry. 2012;2(10):e172. 15. Greden JF, Parikh SV, Rothschild AJ, et al. Impact of pharmacogenomics on clinical outcomes in major depressive disorder in the GUIDED trial: a large, patient- and rater-blinded, randomized, controlled study. J Psychiatr Res. 2019;111:59-67. 16. Rosenblat JD, Lee Y, McIntyre RS. The effect of pharmacogenomic testing on response and remission rates in the acute treatment of major depressive disorder: a meta-analysis. J Affect Disord. 2018;241:484-491. 17. Bousman, CA, Hopwood M. Commercial pharmacogenetic-based decision-support tools in psychiatry. Lancet Psychiatry. 2016;3(6):585-590. 18. Bousman CA, Forbes M, Jayaram M, et al. Antidepressant prescribing in the precision medicine era: a prescriber’s primer on pharmacogenetic tools. BMC Psychiatry. 2017;17(1):60. 19. Groessl EJ, Tally SR, Hillery N, Maciel A, Garces JA. Cost-effectiveness of a pharmacogenetic test to guide treatment for major depressive disorder. J Manag Care Spec Pharm. 2018;24(8):726-734. 20. Food and Drug Administration. Recommendations for genetic test manufacturers and developers. FDA website. https://www.fda.gov/medical-devices/ safety-communications/fda-warns-against-use-many-genetic-tests-unapprovedclaims-predict-patient-response-specific#actions. Accessed August 20, 2020.

The Art of Managing Long-Acting Reversible Contraception for Teens

Hormonal and nonhormonal intrauterine devices and hormonal implants have been proven safe and effective for adolescent patients.

LARC provides protection from pregnancy for 3 to 10 years.

Adolescent pregnancy rates have been declining steadily since their peak in 1957, largely due to increased access to and use of effective forms of birth control.1,2 Long-acting reversible contraception (LARC) methods, such as hormonal and nonhormonal intrauterine devices (IUDs) and hormonal implants, have been proven safe and effective forms of birth control for adolescent patients and should be included among the full range of contraceptive options they are offered.3,4

LARC provides protection from pregnancy for 3 to 10 years depending on the method, offers noncontraceptive benefits, and may be preferred for adolescents with chronic conditions or with relative cautions or contraindications to estrogencontaining birth control options.5,6

Despite the wide acceptance of LARC methods, a number of barriers can impact their use: medical eligibility, adverse effects, access to methods, and the reluctance of some adolescents and families to consider these methods due to historical coercive uses of birth control among poor women and women of color.5-7 Effective counseling about contraception must take into account individual, sociocultural, and ethical-legal complexities, addressing the developmental needs and personal context of each adolescent patient.

LARC METHODS

Both the American Academy of Pediatrics and the American College of Obstetricians and

Continues on page 20

Gynecologists recommend LARC methods as first-line options for adolescent patients.4,8 These recommendations are based on the proven safety record of LARC in young and nulliparous patients as well as its increased efficacy and greater continuation and satisfaction rates among adolescents compared with short-acting methods.3,9

Several LARC methods are available in the United States, including 1 progestin-containing subdermal implant (etonogestrel [ENG]), 4 progestin-containing (levonorgestrel [LNG]) IUDs, and 1 nonhormonal copper IUD (Table 1).10-15

Rosenstock et al evaluated 7472 participants enrolled in the Contraceptive CHOICE Project, a prospective cohort study of women offered no-cost contraception.16 The study’s primary objective was to compare 12-month continuation rates among women of various ages. Among adolescents aged 14 to 19 years, method satisfaction rates 1 year after initiation were 54%, 56%, and 65.7% for the ENG implant, copper IUD, and LNG IUD, respectively, versus 33.1% for oral contraceptive pills.16 However, uptake and use of LARC is relatively lower than uptake and use of shorter-acting methods among adolescents.3,9

For many teens, the decision to start a LARC method may be made over several appointments and conversations with providers, possibly after trials of other methods. Clinicians need to be open to this process and assure that scheduling practices can accommodate their patients’ needs. It is important to respect the adolescent’s choice as well as the process and time it may take to make that choice.

Although a LARC method is not going to be the best fit for every adolescent, all patients should be informed about LARC options during comprehensive birth control counseling. This counseling should be patient-centered and not directive or coercive; the focus should be on the patient’s priorities and goals (Table 2).5

Contraindications Outside of confirmed or suspected pregnancy and unexplained genital bleeding, there are few absolute contraindications to LARC for the majority of adolescents. In the case of LNG IUDs and the ENG implant, sensitivity to progestin is a contraindication, as is a history of breast cancer, hepatic tumors, or active liver disease.10-14

Contraindications for both LNG and copper IUDs include distortion of the uterine cavity, pelvic tuberculosis, systemic lupus erythematosus with positive or unknown antiphospholipid

TABLE 1. LARC Medications, Dosage, Duration, Mechanisms of Action, and Adverse Effects

Etonogestrel (ENG) Subdermal Implant10 Levonorgestrel (LNG) IUD11-14 Copper (CuT380A) IUD15

Dose 68 mg (Nexplanon™)

Duration of efficacy FDA approved for 3 y; research suggests 4-5 y

Effects on ovulation, fertilization, and implantation May inhibit ovulation (first year); changes in cervical mucus and tubal motility inhibit sperm migration and fertilization

Onset of effectiveness

Adverse effects Back-up method for 7 days

• Irregular spotting/bleeding; may decrease by 6 months • Insertion site briefly sore, bruised • Menstrual cramps, mood changes, weight gain, headaches, acne (less common) • Skin changes to the upper arm (rare) • 52 mg (Liletta™, Mirena™) • 19.5 mg (Kyleena™) • 13.5 mg (Skyla™)

FDA approved for 3-5 y, depending on product

Inhibition of ovulation not a major mechanism of action; thickens cervical mucus; sterile inflammatory action of foreign body in uterus causes release of glycodelin-A, inhibits fertilization; endometrial sloughing and glandular activity prevents implantation

Back-up method for 7 days

• Spotting, irregular bleeding, usually markedly decreased by 6 months • Lighter to no periods • Post-insertion cramping; usually subsides by 6 months • Bloating, nausea, headaches, breast pain, acne (less common) Paragard™

FDA approved for 10 y

Does not inhibit ovulation; sterile inflammatory action of foreign body in the uterus causes cytotoxic reaction to both sperm and ovum impairing fertilization; cytotoxic reaction impairs implantation

May be used as emergency contraception; back-up method not needed

• Heavier, longer periods, no change in timing of menstrual cycle • Post-insertion cramping for several months, stronger cramps during periods • Anemia (less common) • Allergic urticaria (rare)

LARC, long-acting reversible contraception; IUD, intrauterine device; y, years

antibodies, cervical or endometrial cancer, and a history of complicated solid organ transplant with failure or rejection.17 Severe thrombocytopenia, Wilson disease, and an allergy to copper are additional contraindications for the copper IUD.17

In the setting of current pelvic inflammatory disease (PID), purulent cervicitis, or known gonorrheal or chlamydial infection, IUD insertion should be deferred until after successful treatment.18 Unknown gonorrhea or chlamydia status is not a reason to delay insertion, but adolescents should be screened at the time of insertion and treated appropriately if one of these infections is detected (a positive result does not require removal of the IUD).19

Drug Interactions Both ENG and LNG are progestins, synthetic steroid hormones that activate the progesterone receptor. Progestins are metabolized via the cytochrome P450 (CYP) 3A4 pathway.10-14 Other medications, including many anti-inflammatory and anti-seizure medications, are CYP3A4 enzyme-inducing and can increase the metabolism of progestins; there have been documented contraceptive failures in patients taking CYP3A4 enzyme-inducing anti-seizure medications while using the ENG implant and other low-dose progestins. However, LNG’s primary action in IUDs is local and contributes to only part of the IUD’s efficacy, making it an available option for patients on these anti-seizure medications.19

The copper IUD has no drug interactions,15 which can be especially beneficial for individuals taking multiple medications.

Noncontraceptive Benefits In addition to being effective, reversible contraception, LARC methods offer several potential noncontraceptive benefits, which may be the reason some adolescents are interested in a particular method.

One noncontraceptive use for LNG IUDs is treatment of heavy uterine bleeding and/or dysmenorrhea.20 This can be relevant for individuals with anemia and/or bleeding disorders (eg, von Willebrand disease), for whom hormonal therapy often is required as part of a regimen to limit heavy menstrual bleeding.4,5 The LNG IUD is also the most effective method of achieving amenorrhea in individuals who have difficulty managing menstrual flow or for whom menstrual flow is distressing (eg, adolescents with developmental delays and transgender or nonbinary youth).20,21 The hormonal implant also can be beneficial for this indication but

TABLE 2. Tips for Counseling Adolescent Patients About Contraception5

• Ask about long-term reproductive plans: if, when, and under what conditions a patient would like to have children. • Ask what is most important in a method; do not assume that efficacy is the only or the most important characteristic. • Encourage adolescents to think about birth control not only in the context of any current relationships but also in relation to how it can support their life, educational, and career goals. • Be inclusive: talk to all adolescents with a uterus about contraceptive options, including those who may identify as male, transgender, or nonbinary, and those who may have an interest in either contraceptive or noncontraceptive benefits of long-acting reversible contraception (LARC). • Be aware of the potential impact of racism and class prejudice on a patient’s beliefs and experiences as well as your own implicit biases.5

• Practice within a reproductive justice framework: respect the patient’s autonomy over their body and choices.5

• Go over expected adverse effects as well as pros and cons of each method, encouraging the patient to ask questions. • Listen to each patient’s concerns, dispel myths, and provide accurate information to help them make their decision. • Always start the conversation about contraception with a teen alone to elicit their confidentiality needs and preferences and to discern whether or not they are being coerced by others. Use this time to screen for sexual abuse or exploitation. • For teens who wish to involve a parent or caregiver in their contraceptive decisions, include that person in the discussion, in the office or by phone. • Make sure you are familiar with the minor consent and confidentiality laws in your statea and how your practice bills for confidential services.

For adolescents who cannot involve family members, make sure there is a system set up to protect their confidentiality. • For many teens, the decision to start a LARC method may be made over several appointments and may involve trials of other methods; be open to this and assure that scheduling practices can accommodate these needs. • When a patient decides on a LARC method, include a written consent form that outlines the details of insertion, removal, and potential adverse effects, and give the patient a copy to keep.

a Guttmacher Institute. An overview of minors’ consent law. Guttmacher Institute. State policies in brief Web site. https://www.guttmacher.org/state-policy/explore/overview-minors-consent-law.

Published 2020. Updated May 1, 2020. Accessed August 3, 2020. b Reproductive Health Access Project. www.reproductiveaccess.org. Accessed August 14, 2020.