Biomarkers Overview

This LCD supplements but does not replace, modify or supersede existing Medicare applicable National Coverage Determinations (NCDs) or payment policy rules and regulations for biomarker overview services. Federal statute and subsequent Medicare regulations regarding provision and payment for medical services are lengthy. They are not repeated in this LCD. Neither Medicare payment policy rules nor this LCD replace, modify or supersede applicable state statutes regarding medical practice or other health practice professions acts, definitions and/or scopes of practice. All providers who report services for Medicare payment must fully understand and follow all existing laws, regulations and rules for Medicare payment for biomarker overview services and must properly submit only valid claims for them. Please review and understand them and apply the medical necessity provisions in the policy within the context of the manual rules. Relevant CMS manual instructions and policies regarding services may be found in the following Internet-Only Manuals (IOMs) published on the CMS Web site.

IOM Citations:

• CMS IOM Publication 100-02, Medicare Benefit Policy Manual, Chapter 15, Sections 80.1, 80.1.1, 80.1.2, 80.1.3, Laboratory services must meet applicable requirements of CLIA, and Section 280, Preventive and Screening Services
• CMS IOM Publication 100-08, Medicare Program Integrity Manual
• Chapter 3, Sections 3.4.1.3 Diagnosis Code Requirements and 3.6.2.3 Limitation of Liability Determinations
• Chapter 13, Section 13.5.4 Reasonable and Necessary Provision in an LCD

Social Security Act (Title XVIII) Standard References:

• Title XVIII of the Social Security Act, Section 1862(a)(1)(A) states that no Medicare payment shall be made for items or services which are not reasonable and necessary for the diagnosis or treatment of illness or injury.
• Title XVIII of the Social Security Act, Section 1862(a)(7). This section excludes routine physical examinations.

Code of Federal Regulations (CFR) References:

• CFR, Title 42 Section 410.32: Diagnostic x-ray tests, diagnostic laboratory tests, and other diagnostic tests: Conditions
• CFR, Title 42 Section 411.15: Particular services excluded from coverage

 Compliance with the provisions in this policy may be monitored and addressed through post payment data analysis and subsequent medical review audits.

History/Background and/or General Information

The emergence of personalized laboratory medicine has been characterized by a multitude of testing options which may more precisely pinpoint management needs of individual patients. As a result, the growing compendium of biomarkers requires a more careful evaluation by both clinicians and laboratorians as to what testing configurations can more optimally realize the promises of personalized medicine. There are a plethora of burgeoning tools, including both gene-based (genomic) and protein-based (proteomic) assay formats, in tandem with more conventional (longstanding) flow cytometric, cytogenetic, etc. biomarkers. Classified somewhat differently, there are highly diverse approaches ranging from single mutation biomarkers to multiple biomarker platforms, the latter of which often depend upon sophisticated biomathematical interpretative algorithms. This policy will provide guidance on the broad range of (recently coded) biomarkers, and how such a wide array of testing platforms can be best accommodated by this local Medicare Administrative Contractor.

Medicare coverage for screening of those individuals with a family history of certain disease is covered only for a limited number of services as listed in the Section 280 – Preventative and Screening Services of the IOM 100-02, Medicare Benefit Policy Manual, Chapter 15.

Tests performed without relationship to treatment or diagnosis of a patient with no findings or history for a specific illness, symptom, complaint or injury unless set exclusion are so noted in Title 42 CFR, Section 411.15(a)(1).

Local Medicare coverage of such biomarkers must be predicated upon three fundamental principles:

First, there must be an underlying performance of acceptable, high-quality analytical validity for all such laboratory testing. As a result, the laboratory shall have available upon request:

• Analytical and clinical validation reports for Clinical Laboratory Improvement Amendments (CLIA), including the test description, intended use, and indications for testing.
• If applicable, all formal, written minutes and correspondences (including any Q & A and supporting documentation) with the New York State Department of Health (NYSDOH) or the US Food and Drug Administration (FDA).
• Most recent inspection results (including recommendations) or scheduled inspection(s) from CLIA, College of American Pathologists (CAP), or NYSDOH, as applicable.

Second, there must be an appreciation of evidence-in-transition where new biomarkers should be brought on-line in harmonization with their proven clinical validity/utility (CVU). Although analytical validity is an equally important metric, it remains more outside of a payer's purview to conduct such detailed evaluations. Therefore, in the absence of a standard CVU referee process (e.g., although FDA labeling of biomarkers can be a helpful adjunct, it may not always be relevant), the key imperative is for medical necessity to be reflected by the clear articulation of a particular biomarker niche.

Third, there must be a recognized decision impact of such biomarkers by the clinical community. In other words, there must be acceptance/uptake of specific testing into patient management. It should be taken into account that to reach the medical necessity threshold, such acceptance should be based on the strongest evidence available, ideally from along the spectrum of high-quality masked, randomized controlled clinical trials, and much less preferably from lower levels of evidence, which are predicated upon expert opinion only without primary study data.

Per above, it is relevant to categorize biomarkers into functional clusters which, in turn, can enable longitudinal coverage guidance that is most relevant to the Medicare program mission:

The commercial availability does not ensure that a molecular diagnostic test is indicated for clinical application. Molecular diagnostic testing is a rapidly evolving science in which the significance of detecting specific mutations has yet to be clarified in many circumstances. Analytical and clinical validity as well as clinical utility are the responsibility of the provider, and all testing must meet standards of care.

Covered Indications

1.GERMLINE (HEREDITARY) MUTATIONS

Medicare considers genetic testing medically necessary to establish a molecular diagnosis of an inheritable disease when all of the following criteria are met:

• The beneficiary must display clinical features of an associated disease, but noting that coverage of molecular testing for carrier status or family studies is considered screening and is statutorily excluded from coverage; and
• The result of the test will directly impact the treatment being delivered to the beneficiary; and
• A definitive diagnosis remains uncertain after history, physical examination, pedigree analysis, genetic counseling, and completion of conventional diagnostic studies.

Note: The following two germline hereditary mutation tests will be considered medically reasonable and necessary when performed for evaluation of venous thromboembolism. Refer to ICD-10 Code Group 3 in the related Local Coverage Article: Billing and Coding: Biomarkers Overview A56541.

• Factor II (F2 gene)
• Factor V (F5 gene)

* While not required for payment, NCCN Guidelines recommend referral to a cancer genetics professional with expertise and experience in cancer genetics prior to genetic testing and after genetic testing. Examples of cancer genetics professionals with expertise and experience in cancer genetics include: an American Board of Medical Genetics or American Board of Genetic Counseling certified or board eligible Clinical Geneticist, Medical Geneticist or Genetic Counselor not employed by a commercial genetic testing laboratory (excludes individuals employed by or contracted with a laboratory that is part of an Integrated Health System which routinely delivers health care services beyond just the laboratory test itself as these individuals are also considered independent); medical oncologist, obstetrician-gynecologist or other physician trained in medical cancer genetics, a genetic nurse credentialed as either a Genetic Clinical Nurse or an Advanced Practice Nurse in Genetics by either the Genetic Nursing Credentialing Commission (GNCC) or the American Nurses Credentialing Center (ANCC) who is not employed by a commercial genetic testing laboratory (excludes individuals employed by or contracted with a laboratory that is part of an Integrated Health System which routinely delivers health care services beyond just the laboratory test itself as these individuals are also considered independent).

2. PHARMACOGENOMICS

The cytochrome P450 (CYP450) gene superfamily is composed of many isoenzymes that are involved in the metabolism of many medications. Although this superfamily has more than 50 enzymes, six of them metabolize 90% of clinically used drugs. Each cytochrome P450 gene is named with CYP indicating it is part of the cytochrome P450 family. CYP2C19 metabolizes at least 10% of all commonly prescribed drugs, whereas CYP2D6 enzymes metabolize approximately 20-25%, and CYP2C9 metabolizes approximately 10%.

Human CYP genes are highly polymorphic. As a result, polymorphisms are classified into four groups based on the level of CYP enzyme activity and include poor (abolished activity), intermediate (reduced activity), extensive (normal activity) and ultra-rapid metabolizers (enhanced activity). Genetic variability or polymorphism in these enzymes may influence a patient’s response to commonly prescribed drug classes. The most pharmacologically and clinically relevant CYP polymorphisms are found in CYP2D6, CYP2C9, and CYP2C19. The genotypic rates vary by ethnicity.

A. CYP2C19 Genotyping

Background on CYP2C19 Testing

Genetic alterations or polymorphisms are common in these isoenzymes, with more than 30 polymorphisms identified in CYP2C19. These polymorphisms can lead to differences in individual drug response secondary to variation in metabolism.

The frequency of the various CYP2C19 metabolizer phenotypes has been estimated as follows:

• 2-15% - poor metabolizers
• 18-45% - intermediate metabolizers
• 35-50% - extensive metabolizers
• 5-30% - ultra-rapid metabolizers

Pharmacogenetic testing has been proposed to predict individual response to a variety of CYP2C19-metabolized drugs including clopidogrel, proton pump inhibitors, and tricyclic antidepressants, among others. In certain scenarios, an individual patient may benefit from genetic testing in determining dosage and likely response to specific medications.

Clopidogrel bisulfate (Plavix) is a widely prescribed medication to/for:

• Prevent blood clots in patients with acute coronary syndrome (ACS),
• Other cardiovascular (CV) disease-related events,
• Undergoing percutaneous coronary intervention.

Clopidogrel response varies significantly due to genetic and acquired factors including obesity, smoking and non-compliance. Patients with poor response to clopidogrel may experience recurrent CV event or thrombotic events while taking clopidogrel. They are at greater risk for major adverse CV events such as heart attack, stroke and death. These individuals are typically poor to intermediate metabolizers of clopidogrel due to the presence of the associated CYP2C19 polymorphisms. These individuals should be given an alternate treatment strategy (Plavix PI). As such, the clinical utility of CYP2C19 genotyping has been supported with net benefits on improving health outcomes for individuals with ACS who are undergoing percutaneous coronary interventions (PCI). There is insufficient evidence of clinical utility of CYP2C19 genotyping for individuals considering clopidogrel therapy for other indications.

With regards to CYP2C19 testing for antidepressant treatment, recent evidence has suggested genetic testing prior to initiating certain tricyclic antidepressants, namely amitriptyline, due to the effects of the genotype on drug efficacy and safety. Use of this information to determine dosing has been proposed to improve clinical outcomes and reduce the failure rate of initial treatment. However, the Clinical Pharmaco-genetics Implementation Consortium did not have enough evidence to make a strong recommendation for dose modification based on genotype, and a moderate recommendation was given based on data outside of randomized trials. Additionally, even with genotype information, a suggestion is given to start patients on low dose, gradually increasing to avoid adverse side effects. Consequently, genotyping is not needed with this approach.

Proton pump inhibitors are used to treat several gastric acid-related conditions including duodenal ulcer, gastric ulcer and gastroesophageal reflux disease. Proton pump inhibitors can also be used to treat Helicobactor pylori. Several proton pump inhibitors are metabolized by CYP2C19. However, there is insufficient data to warrant CYP2C19 genotyping to determine health outcomes or adverse drug reactions in treatment with proton pump inhibitors.

With regards to Serotonin reuptake inhibitors, there is insufficient evidence to support CYP2C19 genotyping to determine medical management for the treatment of obsessive compulsive disorder at this time.

This policy limits CYP2C19 genetic testing to patients with ACS undergoing PCI who are initiating or reinitiating Clopidogrel (Plavix) therapy.

Genetic testing for the CYP2C19 gene is considered investigational at this time for all other indications including, but not limited to the following medications:

• Amitriptyline
• Clopidogrel for indications other than above
• Proton pump inhibitors
• Selective serotonin reuptake inhibitors
• Warfarin

B.CYP2D6 Genotyping

Background on CYP2D6 Testing

Genetic alterations or polymorphisms are common in these isoenzymes, with more than 100 polymorphisms identified in CYP2D6. These polymorphisms can lead to differences in individual drug response secondary to variation in metabolism.

Genetic variation, as well as drug-drug interactions, can influence the classification of CYP2D6 metabolism into one of the above phenotypes. In addition, chronic dosing of a CYP2D6 drug can inhibit its own metabolism over time as the concentration of the drug approaches a steady state.

Pharmacogenetic testing has been proposed to predict individual response to a variety of CYP2D6-metabolized drugs including tamoxifen, antidepressants, opioid analgesics, and tetrabenazine for chorea, among others. In certain scenarios, an individual patient may benefit from this genetic testing in determining dosage and likely response to specific medications.

Tamoxifen

Available evidence fails to support direct evidence of clinical utility for testing of CYP2D6 in treatment with tamoxifen. Tamoxifen metabolism and the causes for resistance are complex rather than the result of a single polymorphism.

Antidepressants

In regards to CYP2D6 testing for antidepressant treatment, there was insufficient evidence in the past to support testing to determine treatment. More recently, evidence has supported the use of genetic testing prior to initiating certain tricyclic antidepressants due to the effects of genotype on drug efficacy and safety. Use of this information to determine dosing can improve clinical outcomes and reduce the failure rate of initial treatment. However, there is insufficient evidence for CYP2D6 genotyping for individuals considering antipsychotic medications or other antidepressants with CYP2D6 as a metabolizing enzyme.

Codeine

In addition, the role of CYP2D6 genotyping has been evaluated for use in opioid analgesic drug therapy, specifically codeine analgesia. The efficacy and toxicity, including severe or life-threatening toxicity after normal doses of codeine has been linked to an individual’s CYP2D6 genotype. However, genotyping would indicate avoidance of codeine due to risk of adverse events in only 1-2% of the populations, and there is considerable variation in the degree of severity of adverse events, with most not classified as serious. Furthermore, codeine is widely used without genotyping. At this time, there is insufficient evidence to support clinical utility of genotyping for management of codeine therapy.

Tetrabenazine

The dosing of tetrabenazine is based, in part, on CYP2D6 genotyping. However, a recent study suggests that the necessity to genotype may need to be reconsidered. The manufacturer package insert indicates that poor metabolizers of CYP2D6 should not exceed a maximum dose of 50 mg/day.

Drugs for Alzheimer’s Disease

• • Galantamine is an antidementia drug used in the treatment of Alzheimer’s disease. Studies have been performed that reveal the CYP2D6 genotype significantly influences galantamine concentrations in blood. Still other studies have revealed that urinary assays for CYP2D6 phenotype are technically feasible. At this time, the association between phenotype and drug responsiveness remains unknown. It has been suggested that confirmation studies in larger populations are necessary to establish evidence regarding individuals most likely to benefit from galatamine, including information on treatment efficacy and tolerability.
    
    
  • Donepezil (Aricept) is a drug used to treat Alzheimer’s disease. Some studies have reported an influence of the CYP2D6 on the response to treatment with this drug. Other studies suggest that therapy based on CYP2D6 genotype is unlikely to be beneficial for treating Alzheimer’s disease patients in routine clinical practice. Additional studies are needed to determine the efficacy and utility of CYP2D6 genotyping in those patients who are treated with donepezil.

Covered Indications for CYP2D6

Genetic testing of the CYP2D6 gene is considered medically necessary to guide medical treatment or dosing for individuals for whom initial therapy is planned with:

• Amitriptyline or nortriptyline for treatment of depressive disorders
• Tetrabenazine doses greater than 50 mg/day, or re-initiation of therapy with doses greater than 50 mg/day

Indications considered not reasonable and necessary for CYP2D6

There is insufficient evidence to demonstrate that genetic testing for the CYP2D6 gene improves clinical outcomes for the following medications. Consequently, genetic testing for the CYP2D6 gene is considered investigational for the following:

• Antidepressants other than those listed above
• Antipsychotics
• Codeine
• Donepezil
• Galantamine
• Tamoxifen

3. SOMATIC MUTATIONS, ONCOLOGY:

• Please Refer to LCD L35396, Biomarkers for Oncology.

CYP2C9 Genotyping

• This policy does not address coverage with evidence development (CED) under section 1862(a)(1)(E). For CED coverage information related to CYP2C9 and VKORC1 for warfarin responsiveness please refer to the NCD for Pharmacogenomic Testing for Warfarin Response (90.1).

This LCD imposes frequency limitations. For frequency limitations please refer to the Utilization Guidelines section below.

Notice: Services performed for any given diagnosis must meet all of the indications and limitations stated in this policy, the general requirements for medical necessity as stated in CMS payment policy manuals, any and all existing CMS national coverage determinations, and all Medicare payment rules.

The redetermination process may be utilized for consideration of services performed outside of the reasonable and necessary requirements in this LCD.

N/A

N/A

Refer to the Local Coverage Article: Billing and Coding: Biomarkers Overview, A56541, for all coding information.

Documentation Requirements

1. All documentation must be maintained in the patient’s medical record and made available to the contractor upon request.
2. Every page of the record must be legible and include appropriate patient identification information (e.g., complete name, dates of service[s]). The documentation must include the legible signature of the physician or non-physician practitioner responsible for and providing the care to the patient.
3. The medical record documentation must support the medical necessity of the services as stated in this policy.

Utilization Guidelines

In accordance with CMS Ruling 95-1 (V), utilization of these services should be consistent with locally acceptable standards of practice, whereby more than once per lifetime testing is not deemed medically necessary, except under special clinical scenarios which will be handled through the redetermination process. The medical record must support the medical necessity of the increased frequency.

Autoimmune (rheumatoid arthritis), is limited to two services per rolling year per beneficiary.

Contractor is not responsible for the continued viability of websites listed.

Other Contractor Policies

First Coast Service Options (FCSO) LCD, L35366, CYP2C19, CYP2D6, CYP2C9, and VKORC1 Genetic Testing

Palmetto GBA

Contractor Medical Directors

1. Aetna Clinical Policy Bulletin: Genetic Testing (Number: 0140)
2. Altar CA, Hornberger J, Shewade A, et al. Clinical validity of cytochrome P450 metabolism and serotonin gene variants in psychiatric pharmacotherapy. Int Rev Psychiatry, 2013; 25(5): 509-533.
3. Apud JA, Mattay V, Chen J, et al. Tolcapone improves cognition and cortical information processing in normal human subjects. Neuropsychopharmacology, 2007; 32(5): 1011-1020.
4. Apud JA, Weinberger DR, Treatment of cognitive deficits associated with schizophrenia: potential role of catechol-O-methyltransferase inhibitors. CNS Drugs, 2007; 21(7): 535-557.
5. Baeken C, De Raedt R, Van Hove C, et al. HF-rTMS treatment in medication-resistant melancholic depression: results from 18FDG-PET brain imaging. CNS Spectr, 2009; 14(8): 439-448.
6. Barnett JH, Jones PB, Robbins TW, et al. Effects of the catechol-O-methyltransferase Val158Met polymorphism on executive function: a meta-analysis of the Wisconsin Card Sort Test in schizophrenia and healthy controls. Mol Psychiatry, 2007; 12(5): 502-509.
7. Bhat S, Dao DT, Terrillion C E, et al. CACNA1C (Cav1.2) in the pathophysiology of psychiatric disease. Prog Neurobiol, 2012; 99(1): 1-14.
8. Brennan MD, Pharmacogenetics of second-generation antipsychotics. Pharmacogenomics, 2014; 15(6): 869-884.
9. Brewer LD, Thibault O, Staton J, et al. Increased vulnerability of hippocampal neurons with age in culture: temporal association with increases in NMDA receptor current, NR2A subunit expression and recruitment of L-type calcium channels. Brain Res, 2007; 1151: 20-31.
10. Capasso I, Esposito E, Maurea N, et al. Combination of inositol and alpha lipoic acid in metabolic syndrome-affected women: a randomized placebo-controlled trial. Trials, 2013; 14: 273.
11. Chang M, Tybring G, Dahl ML, et al. Impact of Cytochrome P450 2C19 Polymorphisms on Citalopram/Escitalopram Exposure: A Systematic Review and Meta-Analysis. Clin Pharmacokinet. 2014; 53(9):801–811.
12. Chen J, Lipska BK, Halim N, et al. Functional analysis of genetic variation in catechol-O-methyltransferase (COMT): effects on mRNA, protein, and enzyme activity in postmortem human brain. Am J Hum Genet, 2004; 75(5): 807-821.
13. Choi CI, Bae JW, Lee YJ, et al. Effects of CYP2C19 genetic polymorphisms on atomoxetine pharmacokinetics. J Clin Psychopharmacol, 2014; 34(1): 139-142.
14. Cools R, Role of dopamine in the motivational and cognitive control of behavior. Neuroscientist, 2008; 14(4): 381-395.
15. Cools R, D'Esposito M, Inverted-U-shaped dopamine actions on human working memory and cognitive control. Biol Psychiatry, 2011; 69(12): e113-125.
16. Crews KR, Gaedigk A, Dunnenberger HM, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for Codeine Therapy in the Context of Cytochrome P450 2D6(CYP2D6) Genotype. Clinical Pharmacol & Ther. 2012; 91(2): 321-326.
17. de Leon J, Armstrong SC, Cozza KL, The dosing of atypical antipsychotics. Psychosomatics, 2005; 46(3), 262-273.
18. de Leon J, Susce MT, Pan R, et al. The CYP2D6 poor metabolizer phenotype may be associated with risperidone adverse drug reactions and discontinuation. J Clin Psychiatry, 2005; 66(1): 15-27.
19. El-Mallakh RS, Roberts RJ, El-Mallakh PL, et al. Pharmacogenomics in Psychiatric Practice. Clin Lab Med. 2016; 36:507-523. Doi: 10.1016/j.cll.2016.05.001
20. Erk S, Meyer-Lindenberg A, Linden DE, et al. Replication of brain function effects of a genome-wide supported psychiatric risk variant in the CACNA1C gene and new multi-locus effects. Neuroimage, 2014; 94: 147-154.
21. Ferreira MA, O'Donovan MC, Meng YA, et al. Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder. Nat Genet, 2008; 40(9): 1056-1058.
22. Fourcaudot E, Gambino F, Casassus G, et al. L-type voltage-dependent Ca(2+) channels mediate expression of presynaptic LTP in amygdala. Nat Neurosci, 2009; 12(9): 1093-1095.
23. Frank M J, Fossella JA, Neurogenetics and pharmacology of learning, motivation, and cognition. Neuropsychopharmacology, 2011; 36(1): 133-152.
24. Gaedigk A, Gotschall RR, Forbes NS, et al. Optimization of cytochrome P4502D6 (CYP2D6) phenotype assignment using a genotyping algorithm based on allele frequency data. Pharmacogenetics, 1999; 9(6): 669-682.
25. Gargus JJ, Ion channel functional candidate genes in multigenic neuropsychiatric disease. Biol Psychiatry, 2006; 60(2): 177-185.
26. George MS, Taylor JJ, Short EB, The expanding evidence base for rTMS treatment of depression. Curr Opin Psychiatry, 2013; 26(1): 13-18.
27. Gerli S, Papaleo E, Ferrari A, et al. Randomized, double blind placebo-controlled trial: effects of myo-inositol on ovarian function and metabolic factors in women with PCOS. Eur Rev Med Pharmacol Sci, 2007; 11(5): 347-354.
28. Gilbody S, Lewis S, Lightfoot T, Methylenetetrahydrofolate reductase (MTHFR) genetic polymorphisms and psychiatric disorders: a HuGE review. Am J Epidemiol, 2007; 165(1): 1-13.
29. Ginsberg LD, Oubre AY, Daoud YA, L-methylfolate Plus SSRI or SNRI from Treatment Initiation Compared to SSRI or SNRI Monotherapy in a Major Depressive Episode. Innov Clin Neurosci, 2011; 8(1): 19-28.
30. Giordano D, Corrado F, Santamaria A, et al. Effects of myo-inositol supplementation in postmenopausal women with metabolic syndrome: a perspective, randomized, placebo-controlled study. Menopause, 2011; 18(1): 102-104.
31. Gonzalez S, Xu C, Ramirez M, et al. Suggestive evidence for association between L-type voltage-gated calcium channel (CACNA1C) gene haplotypes and bipolar disorder in Latinos: a family-based association study. Bipolar Disord, 2013; 15(2): 206-214.
32. Hadley D, Anderson BS, Borckardt JJ, et al. Safety, tolerability, and effectiveness of high doses of adjunctive daily left prefrontal repetitive transcranial magnetic stimulation for treatment-resistant depression in a clinical setting. J ECT, 2011; 27(1): 18-25.
33. Haertter S, Recent examples on the clinical relevance of the CYP2D6 polymorphism and endogenous functionality of CYP2D6. Drug Metabol Drug Interact, 2013; 28(4): 209-216.
34. Halford JC, Harrold JA, 5-HT(2C) receptor agonists and the control of appetite. Handb Exp Pharmacol, 2012; (209): 349-356.
35. Hall-Flavin DK, Winner JG, Allen JD, et al. Using a pharmacogenomic algorithm to guide the treatment of depression. Transl Psychiatry. 2012; 2(e172): Doi: 10.1038/tp.2012.99
36. Hall-Flavin DK, Winner JG, Allen JD, et al. Utility of integrated pharmacogenomic testing to support the treatment of major depressive disorder in a psychiatric outpatient setting. Pharmacogenetics and Genomics. 2013; 23: 535-548. DOI: 10.1097/FPC.0b013e3283649b9a
37. Hamidovic A, Dlugos A, Palmer AA, et al. Catechol-O-methyltransferase val158met genotype modulates sustained attention in both the drug-free state and in response to amphetamine. Psychiatr Genet, 2010; 20(3): 85-92.
38. 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. doi:10.1002/cpt.147.
39. Hicks JK, Swen JJ, Thorn CF, et al. Clinical Pharmacogenetics Implementation Consortium Guideline for CYP2D6 and CYP2C19 Genotypes and Dosing of Tricyclic Antidepressants. Clin Pharmacol Ther. 2013; 93(5): 402-408. doi: 10.1038/clpt.2013.2.
40. Holmes DR, Dehmer GJ, Kaul S, et al. ACCF/AHA Clopidogrel Clinical Alert: Approaches to the FDA "Boxed Warning": Title and subTitle BreakA Report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents and the American Heart Association Endorsed by the Society for Cardiovascular Angiography and Interventions and the Society of Thoracic Surgeons. J Am Coll Cardiol. 2010; 56(4): 321-341.
41. Hori H, Yamamoto N, Fujii T, et al. Effects of the CACNA1C risk allele on neurocognition in patients with schizophrenia and healthy individuals. Sci Rep, 2012; 2: 634.
42. Hulot JS, Collet JP, Silvain J, et al. Cardiovascular risk in clopidogrel-treated patients according to cytochrome P450 2C19*2 loss-of-function allele or proton pump inhibitor coadministration: a systematic meta-analysis. J Am Coll Cardiol, 2010; 56(2): 134-143.
43. Ivorra JL, Rivero O, Costas J, et al. Replication of previous genome-wide association studies of psychiatric diseases in a large schizophrenia case-control sample from Spain. Schizophr Res, 2014; 159(1): 107-113.
44. Jibson MD, Second-generation antipsychotic medications: Pharmacology, administration, and comparative side effects. UpToDate, 2013.
45. Kato M, Serretti A, Review and meta-analysis of antidepressant pharmacogenetic findings in major depressive disorder. Mol Psychiatry, 2010; 15(5): 473-500.
46. Keers R, Uher R, Huezo-Diaz P, et al. Interaction between serotonin transporter gene variants and life events predicts response to antidepressants in the GENDEP project. The Pharmacogenomics Journal. 2011; 11:138-145.
47. Kraguljac NV, Montori VM, Pavuluri M, et al. Efficacy of omega-3 fatty acids in mood disorders - a systematic review and metaanalysis. Psychopharmacol Bull, 2009; 42(3): 39-54.
48. Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4. Nat Genet, 2011; 43(10): 977-983.
49. Le Meur Y, Djebli N, Szelag JC, et al. CYP3A5*3 influences sirolimus oral clearance in de novo and stable renal transplant recipients. Clin Pharmacol Ther, 2006; 80(1): 51-60.
50. Lemaillet G, Walker B, Lambert S, Identification of a conserved ankyrin-binding motif in the family of sodium channel alpha subunits. J Biol Chem, 2003; 278(30): 27333-27339.
51. Lencer R, Bishop JR, Harris MS, et al. Association of variants in DRD2 and GRM3 with motor and cognitive function in first-episode psychosis. Eur Arch Psychiatry Clin Neurosci, 2014; 264(4): 345-355.
52. Lencz T, Robinson D G, Napolitano B, et al. DRD2 promoter region variation predicts antipsychotic-induced weight gain in first episode schizophrenia. Pharmacogenet Genomics, 2010; 20(9): 569-572.
53. Leussis MP, Berry-Scott EM, Saito M, et al. The ANK3 bipolar disorder gene regulates psychiatric-related behaviors that are modulated by lithium and stress. Biol Psychiatry, 2013; 73(7): 683-690.
54. Leussis MP, Madison JM, Petryshen TL, (2012). Ankyrin 3: genetic association with bipolar disorder and relevance to disease pathophysiology. Biol Mood Anxiety Disord, 2012; 2(1): 18.
55. Li J and Bluth MH. Pharmacogenomics of drug metabolizing enzymes and transporters: implications for cancer therapy. Pharmgenomics Pers Med. 2011; 4: 11-33. doi: 10.2147/PGPM.S18861
56. Lin PY, Huang SY, Su KP, A meta-analytic review of polyunsaturated fatty acid compositions in patients with depression. Biol Psychiatry, 2010; 68(2): 140-147.
57. Linke J, Witt SH, King AV, et al. Genome-wide supported risk variant for bipolar disorder alters anatomical connectivity in the human brain. Neuroimage, 2012; 59(4): 3288-3296.
58. Lobello KW, Preskorn SH, Guico-Pabia CJ, et al. Cytochrome P450 2D6 phenotype predicts antidepressant efficacy of venlafaxine: a secondary analysis of 4 studies in major depressive disorder. J Clin Psychiatry, 2010; 71(11): 1482-1487.
59. Loffler S, Gasca F, Richter L, et al. The effect of repetitive transcranial magnetic stimulation on monoamine outflow in the nucleus accumbens shell in freely moving rats. Neuropharmacology, 2012; 63(5): 898-904.
60. Lynch T and Price A. The Effect of Cytochrome P450 Metabolism on Drug Response, Interactions, and Adverse Effect. American Family Physician. 2007. www.aafp.org/afp
61. Mannheimer B, von Bahr C, Pettersson H, et al. Impact of multiple inhibitors or substrates of cytochrome P450 2D6 on plasma risperidone levels in patients on polypharmacy. Ther Drug Monit, 2008; 30(5): 565-569.
62. McCoy TH, Castro VM, Cagan A, et al. Prevalence and implications of cytochrome P450 substrates in Massachusetts hospital discharges. Pharmacogenomics Journal. 2016; 1–4.
63. Miller DD, Ellingrod VL, Holman TL, et al. Clozapine-induced weight gain associated with the 5HT2C receptor -759C/T polymorphism. Am J Med Genet B Neuropsychiatr Genet, 2005; 133B(1): 97-100.
64. Morgan AJ, Jorm AF, Self-help interventions for depressive disorders and depressive symptoms: a systematic review. Ann Gen Psychiatry, 2008; 7: 13.
65. Mrazek DA. Psychiatric pharmacogenomic testing in clinical practice. Dialogues in Clinical Neuroscience. 2010; 12:69-76.
66. Mrazek DA, Biernacka JM, O'Kane DJ, et al. CYP2C19 variation and citalopram response. Pharmacogenet Genomics, 2011; 21(1): 1-9.
67. Mulder H, Franke B, van der-Beek AA, et al. The association between HTR2C gene polymorphisms and the metabolic syndrome in patients with schizophrenia. J Clin Psychopharmacol, 2007; 27(4): 338-343.
68. Müller DJ, Kekin I, Kao AC, et al. Towards the implementation of CYP2D6 and CYP2C19 genotypes in clinical practice: Update and report from a pharmacogenetic service clinic. International Review of Psychiatry. 2013; 25(5): 554–571.
69. Nahas RaS O. Complementary and alternative medicine for the treatment of major depressive disorder. Canadian Family Physician, 2011; 57(6): 659-663.
70. Nasrallah HA, Atypical antipsychotic-induced metabolic side effects: insights from receptor-binding profiles. Mol Psychiatry, 2008; 13(1): 27-35.
71. Nichols AI, Focht K, Jiang Q, et al. Pharmacokinetics of venlafaxine extended release 75 mg and desvenlafaxine 50 mg in healthy CYP2D6 extensive and poor metabolizers: a randomized, open-label, two-period, parallel-group, crossover study. Clin Drug Investig, 2011; 31(3): 155-167.
72. Nurnberger JI, Jr Koller DL, Jung J, et al. Identification of pathways for bipolar disorder: a meta-analysis. JAMA Psychiatry, 2014; 71(6): 657-664.
73. Paillere Martinot ML, Martinot JL, Ringuenet D, et al. (2011). Baseline brain metabolism in resistant depression and response to transcranial magnetic stimulation. Neuropsychopharmacology, 2011; 36(13): 2710-2719.
74. Papakostas GI, Evidence for S-adenosyl-L-methionine (SAM-e) for the treatment of major depressive disorder. J Clin Psychiatry, 2009; 70 Suppl 5: 18-22.
75. Papakostas GI, Cassiello CF, Iovieno N, Folates and S-adenosylmethionine for major depressive disorder. Can J Psychiatry, 2012; 57(7): 406-413.
76. Papakostas GI, Shelton RC, Zajecka JM, et al. Effect of adjunctive L-methylfolate 15 mg among inadequate responders to SSRIs in depressed patients who were stratified by biomarker levels and genotype: results from a randomized clinical trial. J Clin Psychiatry, 2014; 75(8): 855-863.
77. Papakostas GI, Shelton RC, Zajecka JM, et al. L-methylfolate as adjunctive therapy for SSRI-resistant major depression: results of two randomized, double-blind, parallel-sequential trials. Am J Psychiatry, 2012; 169(12): 1267-1274.
78. Paulus FM, Bedenbender J, Krach S, et al. Association of rs1006737 in CACNA1C with alterations in prefrontal activation and fronto-hippocampal connectivity. Hum Brain Mapp, 2014; 35(4): 1190-1200.
79. Peters EJ, Slager SL, Jenkins GD, et al. Resequencing of serotonin-related genes and association of tagging SNPs to citalopram response. Pharmacogenet Genomics. 2009; 19(1): 1-10. Doi: doi:10.1097/FPC.0b013e3283163ecd.
80. Porcelli S, Fabbri C, Serretti A, Meta-analysis of serotonin transporter gene promoter polymorphism (5-HTTLPR) association with antidepressant efficacy. Eur Neuropsychopharmacol, 2012; 22(4): 239-258.
81. Pratt VM, Zehnbauer B, Wilson JA, et al. Characterization of 107 genomic DNA reference materials for CYP2D6, CYP2C19, CYP2C9, VKORC1, and UGT1A1: a GeT-RM and Association for Molecular Pathology collaborative project. J Mol Diagn, 2010; 12(6): 835-846.
82. Reynolds GP, Pharmacogenetic Aspects of Antipsychotic Drug-induced Weight Gain - A Critical Review. Clin Psychopharmacol Neurosci, 2012; 10(2): 71-77.
83. Reynolds G P, Hill MJ, Kirk SL, The 5-HT2C receptor and antipsychoticinduced weight gain - mechanisms and genetics. J Psychopharmacol, 2006; 20(4 Suppl): 15-18.
84. Robinson DM, Vitamins, Monoamines, and Depression. Primary Psychiatry, 2009; 16(2):, 19-21.
85. Roy JN, Lajoie J, Zijenah L S, et al. CYP3A5 genetic polymorphisms in different ethnic populations. Drug Metab Dispos, 2005; 33(7): 884-887.
86. Ruberto G, Vassos E, Lewis C M, et al. The cognitive impact of the ANK3 risk variant for bipolar disorder: initial evidence of selectivity to signal detection during sustained attention. PLoS One, 2011; 6(1): e16671.
87. Rudberg I, Mohebi B, Hermann M, et al. Impact of the ultrarapid CYP2C19*17 allele on serum concentration of escitalopram in psychiatric patients. Clin Pharmacol Ther, 2008; 83(2): 322-327.
88. Samer CF, Lorenzini KI, Rollason V, et al. Applications of CYP450 testing in the clinical setting. Mol Diagn Ther, 2013; 17(3): 165-184.
89. Sarris J, Mischoulon D, Schweitzer I, Omega-3 for bipolar disorder: meta-analyses of use in mania and bipolar depression. J Clin Psychiatry, 2012; 73(1): 81-86.
90. Sauer JM, RB, Witcher JW, Clinical Pharmacokinetics of Atomoxetine. Clin Pharmacokinet, 2005; 44(6): 571-590.
91. Schenk PW, van Vliet M, Mathot RA, et al. The CYP2C19*17 genotype is associated with lower imipramine plasma concentrations in a large group of depressed patients. Pharmacogenomics J, 2010; 10(3): 219-225.
92. Schloss P, Williams DC, The serotonin transporter: a primary target for antidepressant drugs. J Psychopharmacol, 1998; 12(2): 115-121.
93. Schulze TG, Detera-Wadleigh SD, Akula N, et al. Two variants in Ankyrin 3 (ANK3) are independent genetic risk factors for bipolar disorder. Mol Psychiatry, 2009; 14(5): 487-491.
94. Serretti A, Kato M, De Ronchi D, et al. Meta-analysis of serotonin transporter gene promoter polymorphism (5-HTTLPR) association with selective serotonin reuptake inhibitor efficacy in depressed patients. Mol Psychiatry, 2007; 12(3): 247-257.
95. Shams TA, Muller DJ, Antipsychotic induced weight gain: genetics, epigenetics, and biomarkers reviewed. Curr Psychiatry Rep, 2014; 16(10): 473.
96. Sheldrick AJ, Krug A, Markov V, et al. Effect of COMT val158met genotype on cognition and personality. Eur Psychiatry, 2008; 23(6): 385-389.
97. Shiroma PR, Drews MS, Geske JR, et al. SLC6A4 polymorphisms and age of onset in late-life depression on treatment outcomes with citalopram: a Sequenced Treatment Alternatives to Relieve Depression (STAR*D) report. Am J Geriatr Psychiatry, 2014; 22(11): 1140-1148.
98. Sibbing D, Koch W, Gebhard D, et al. Cytochrome 2C19*17 allelic variant, platelet aggregation, bleeding events, and stent thrombosis in clopidogrel-treated patients with coronary stent placement. Circulation, 2010; 121(4): 512-518.
99. Sim SC, Kacevska M, Ingelman-Sundberg M, Pharmacogenomics of drug-metabolizing enzymes: a recent update on clinical implications and endogenous effects. Pharmacogenomics J, 2013; 13(1): 1-11.
100. Sirot EJ, Harenberg S, Vandel P, et al. Multicenter Study on the Clinical Effectiveness, Pharmacokinetics, and Pharmacogenetics of Mirtazapine in Depression. Journal of Clinical Psychopharmacology. 2012; 32(5): 622-629.
101. Sistonen J, Sajantila A, Lao O, et al. CYP2D6 worldwide genetic variation shows high frequency of altered activity variants and no continental structure. Pharmacogenet Genomics, 2007; 17(2): 93-101.
102. Slotema CW, Blom JD, Hoek HW, et al. Should we expand the toolbox of psychiatric treatment methods to include Repetitive Transcranial Magnetic Stimulation (rTMS)? A meta-analysis of the efficacy of rTMS in psychiatric disorders. J Clin Psychiatry, 2010; 71(7): 873-884.
103. Smits KM, Smits LJ, Schouten JS, et al. Does pretreatment testing for serotonin transporter polymorphisms lead to earlier effects of drug treatment in patients with major depression? A decision-analytic model. Clin Ther, 2007; 29(4):, 691-702.
104. Soeiro-de-Souza MG, Bio DS, Dias VV, et al. The CACNA1C risk allele selectively impacts on executive function in bipolar type I disorder. Acta Psychiatr Scand, 2013; 128(5): 362-369.
105. Spina E, de Leon J, Clinical applications of CYP genotyping in psychiatry. J Neural Transm, 2015; 122(1): 5-28.
106. Staeker J, Leucht S, Laika B, et al. Polymorphisms in serotonergic pathways influence the outcome of antidepressant therapy in psychiatric inpatients. Genet Test Mol Biomarkers, 2014; 18(1), 20-31.
107. Stahl SM, L-methylfolate: a vitamin for your monoamines. J Clin Psychiatry, 2008; 69(9): 1352-1353.
108. Strange PG, Antipsychotic drugs: importance of dopamine receptors for mechanisms of therapeutic actions and side effects. Pharmacol Rev, 2011; 53(1): 119-133.
109. Su KP, Wang SM, Pae CU, Omega-3 polyunsaturated fatty acids for major depressive disorder. Expert Opin Investig Drugs, 2013; 22(12): 1519-1534.
110. Swen JJ, Nijenhuis M, de Boer A, et al. Pharmacogenetics: from bench to bytean update of guidelines. Clin Pharmacol Ther, 2011; 89(5): 662-673.
111. Szczepankiewicz A, Evidence for single nucleotide polymorphisms and their association with bipolar disorder. Neuropsychiatr Dis Treat, 2013; 9: 1573-1582.
112. Tsao D, Diatchenko L, Dokholyan NV, Structural mechanism of S-adenosyl methionine binding to catechol O-methyltransferase. PLoS One, 2011; 6(8): e24287.
113. van der Weide J, van Baalen-Benedek EH, Kootstra-Ros JE, Metabolic ratios of psychotropics as indication of cytochrome P450 2D6/2C19 genotype. Ther Drug Monit, 2005; 27(4): 478-483.
114. Wada K, Hu L, Mores N, et al. Serotonin (5-HT) receptor GEN-RS032-v1-022015 5 subtypes mediate specific modes of 5-HT-induced signaling and regulation of neurosecretion in gonadotropin-releasing hormone neurons. Mol Endocrinol, 2006; 20(1): 125-135.
115. Wade RL, Kindermann SL, Hou Q, et al. Comparative assessment of adherence measures and resource use in SSRI/SNRI-treated patients with depression using second-generation antipsychotics or L-methylfolate as adjunctive therapy. J Manag Care Pharm, 2014; 20(1): 76-85.
116. Watanabe J, Suzuki Y, Fukui N, et al. Dose-dependent effect of the CYP2D6 genotype on the steady-state fluvoxamine concentration. Ther Drug Monit, 2008; 30(6): 705-708.
117. Whyte EM, Romkes M, Mulsant BH, et al. CYP2D6 genotype and venlafaxine-XR concentrations in depressed elderly. Int J Geriatr Psychiatry, 2006; 21(6): 542-549.
118. Williams AL, Girard C, Jui D, et al. S-adenosylmethionine (SAMe) as treatment for depression: a systematic review. Clin Invest Med, 2005; 28(3): 132-139.
119. Winner J, Allen JD, Altar CA, et al. Psychiatric pharmacogenomics predicts health resource utilization of outpatients with anxiety and depression. Translational Psychiatry. 2013; 3(e242): doi:10.1038/tp.2013.2
120. Winner JG, Carhart JM, Altar CA, et al. A Prospective, Randomized, Double-Blind Study Assessing the Clinical Impact of Integrated Pharmacogenomic Testing for Major Depressive Disorder. Discovery Medicine. 2013; 16(89): 219-227.
121. Wolf C, Mohr H, Schneider-Axmann T, et al. CACNA1C genotype explains interindividual differences in amygdala volume among patients with schizophrenia. Eur Arch Psychiatry Clin Neurosci, 2014; 264(2): 93-102.
122. Wu AH, Drug metabolizing enzyme activities versus genetic variances for drug of clinical pharmacogenomic relevance. Clin Proteomics, 2011; 8(1): 12.
123. Wu YL, Ding XX, Sun YH, et al. Association between MTHFR C677T polymorphism and depression: An updated meta-analysis of 26 studies. Prog Neuropsychopharmacol Biol Psychiatry, 2013; 46: 78-85.
124. Xie P, Kranzler HR, Farrer L, et al. Serotonin transporter 5-HTTLPR genotype moderates the effects of childhood adversity on posttraumatic stress disorder risk: a replication study. Am J Med Genet B Neuropsychiatr Genet, 2012; 159B(6): 644-652.
125. Yang L, Wang Z, Wang B, et al. Amyloid precursor protein regulates Cav1.2 L-type calcium channel levels and function to influence GABAergic short-term plasticity. J Neurosci, 2009; 29(50): 15660-15668.
126. Yang X, Zhang B, Molony C, et al. Systematic genetic and genomic analysis of cytochrome P450 enzyme activities in human liver. Genome Res, 2010; 20(8): 1020-1036.
127. Yin OQ, Wing YK, Cheung Y, et al. Phenotype-genotype relationship and clinical effects of citalopram in Chinese patients. J Clin Psychopharmacol, 2006; 26(4): 367-372.
128. Yuan A, Yi Z, Wang Q, et al. ANK3 as a risk gene for schizophrenia: new data in Han Chinese and meta analysis. Am J Med Genet B Neuropsychiatr Genet, 2012; 159B(8): 997-1005.
129. Zhang JP, Lencz T, Malhotra AK, D2 receptor genetic variation and clinical response to antipsychotic drug treatment: a meta-analysis. Am J Psychiatry, 2010; 167(7):, 763-772.
130. Zhou D, Lambert S, Malen PL, et al. AnkyrinG is required for clustering of voltage-gated Na channels at axon initial segments and for normal action potential firing. J Cell Biol, 1998; 143(5): 1295-1304.
131. Zhou SF, Polymorphism of human cytochrome P450 2D6 and its clinical significance: Part I. Clin Pharmacokinet, 2009a; 48(11): 689-723.
132. Zhou SF, Polymorphism of human cytochrome P450 2D6 and its clinical significance: part II. Clin Pharmacokinet, 2009b; 48(12): 761-804.
133. http:// www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafety InformationforPatientsandProviders/ucm107834.htm
134. http:// www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/HIVandAIDSActivities/ucm121646.htm
135. http://www.egappreviews.org/docs/EGAPPWG-CYP450Rec.pdf
136. http://www.nanosphere.us/news/ nanosphere-receives-fda-clearance-market-test-detection- cyp2c19-mutations-affecting-drug
137. http://ghr.nlm.nih.gov/condition/canavan-disease
138. http://ghr.nlm.nih.gov/condition/maple-syrup-urine-disease
139. http://ghr.nlm.nih.gov/condition/glycogen-storage-disease-type-i
140. http://ghr.nlm.nih.gov/condition/gaucher-disease
141. http://www.ncbi.nlm.nih.gov/books/NBK1269/
142. http://ghr.nlm.nih.gov/gene/GJB2
143. http://www.ncbi.nlm.nih.gov/books/NBK1536/
144. http://www.ncbi.nlm.nih.gov/books/NBK1272/
145. http://ghr.nlm.nih.gov/condition/tay-sachs-disease
146. http://www.ncbi.nlm.nih.gov/books/NBK1218/
147. http://ghr.nlm.nih.gov/condition/hemochromatosis
148. http://www.ncbi.nlm.nih.gov/books/NBK1440/
149. http://ghr.nlm.nih.gov/gene/HFE
150. http://ghr.nlm.nih.gov/gene/HBA1
151. http://www.ncbi.nlm.nih.gov/books/NBK1435/
152. http://ghr.nlm.nih.gov/gene/HBA2
153. http://ghr.nlm.nih.gov/condition/familial-dysautonomia
154. http://www.ncbi.nlm.nih.gov/books/NBK1180/
155. http://ghr.nlm.nih.gov/gene/KCNH2
156. http://www.ncbi.nlm.nih.gov/books/NBK1129/ + Input from Palmetto GBA.
157. http://ghr.nlm.nih.gov/condition/mucolipidosis-type-iv
158. http://www.ncbi.nlm.nih.gov/books/NBK1214/
159. http://ghr.nlm.nih.gov/gene/MTHFR
160. http://www.lynchscreening.net/developmen/supporting-guidelines/nccn-practice-guidelines/
161. http://ghr.nlm.nih.gov/condition/cowden-syndrome
162. http://www.ncbi.nlm.nih.gov/books/NBK1488/
163. http://www.cancer.gov/cancertopics/factsheet/Risk/BRCA

There were extensive in-person consultations with both CAC representatives and nationally-recognized experts in order to assist with the above medical necessity language and procedure-to-diagnosis code pairings.