MEDICAL POLICY 12.04.515

Genetic Testing for Mental Health Conditions

BCBSA Ref. Policy: 2.04.110

Effective Date: Aug. 1, 2017

Last Revised: Jan. 30, 2018

Replaces: 2.04.110

RELATED MEDICAL POLICIES:

12.04.131 Pharmacogenetic Testing for Pain Management

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POLICY CRITERIA | CODING | RELATED INFORMATION

EVIDENCE REVIEW | REFERENCES | HISTORY

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Introduction

Genetic testing is done to see if there are changes in chromosomes, genes, or the proteins made

by genes. There are many reasons to do a genetic test, such as to confirm or rule out a genetic

condition, to determine the chance of developing or passing on a genetic disorder, or to see if a

person has an increased risk of having health problems. When it comes to mental health,

genetic tests generally try to determine if a person is at risk for a condition such as

schizophrenia. Other mental health genetic tests try to find out a persons response to a certain

drug or which dose to use for medications that might treat a mental health condition.. To date,

the medical studies on genetic testing for mental health or for managing drug dosing do not

show that information from the test will change treatment or lead to better outcomes.

Note: The Introduction section is for your general knowledge and is not to be taken as policy coverage criteria. The

rest of the policy uses specific words and concepts familiar to medical professionals. It is intended for

providers. A provider can be a person, such as a doctor, nurse, psychologist, or dentist. A provider also can

be a place where medical care is given, like a hospital, clinic, or lab. This policy informs them about when a

service may be covered.

Policy Coverage Criteria

https://www.premera.com/medicalpolicies/12.04.131.pdf

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Testing Investigational Genetic testing for mental

health conditions

Genetic testing for variants associated with mental health

disorders is considered investigational in all situations,

including but not limited to the following:

To confirm a diagnosis of a mental health disorder in an

affected individual.

To predict future risk of a mental health disorder in an

asymptomatic individual.

To choose a medication or decide on its dose in order to treat

mental health disorders in an affected individual.

Genetic panels for

selecting medications or

doses of medication

Genetic testing panels, including but not limited to the

following tests, are considered investigational for selecting

medications or doses of medications for the treatment of

psychiatric or mental health symptoms or disorders:

Ally Diagnostics Genetic Testing Panel

Alpha Genomics Psychiatry/ADHD Panel

Frontier PGx Pharmacogenomic Testing

Genecept Assay

GeneSight Psychotropic Panel

Genetic Technological Innovations Pharmacogenetic Testing

Luminex xTAG CYP2C19 assay

Luminex xTAG CYP2D6 assay

Mental Health Insight DNA

Millennium Pharmacogenetic Testing

Molecular Testing Labs Psychotropic Medication Panel

PersonaGene

PGXL Multi-Drug Panel

PharmaRisk Basic

PharmaRisk Psychiatric Panel

Physicians Choice Laboratory Services (PCLS) Pharmacogenetic

Testing

Primex Expanded Pharmacogenomics Panel

Progenity Informed PGx Pharmacogenetic Testing

Proove Drug Metabolism Panel

Proove Opioid Risk assay

STA2R SureGene

YouScript Panel

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Coding

Code Description

CPT 0015U Drug metabolism (adverse drug reactions), DNA, 22 drug metabolism and transporter

genes, real-time PCR, blood or buccal swab, genotype and metabolizer status for

therapeutic decision support (code terminated 1/1/18)

81225 CYP2C19 (cytochrome P450, family 2, subfamily C, polypeptide 19)(eg, drug

metabolism), gene analysis, common variants (eg, *2, *3, *4, *8, *17)

81226 CYP2D6 (cytochrome P450, family 2, subfamily D, polypeptide 6)(eg, drug metabolism),

gene analysis, common variants (eg, *2, *3, *4, *5, *6, *9, *10, *17, *19, *29, *35, *41,

*1XN, *2XN, *4XN)

81291 MTHFR (5, 10-methylenetetrahydrofolate reductase) (eg, hereditary hypercoagulability)

gene analysis; common variants (eg, 677T, 1298C)

81328 SLCO1B1 (solute carrier organic anion transporter family, member 1B1) (eg, adverse

drug reaction), gene analysis, common variant(s) (eg, *5) (new code effective 1/1/18)

81355 VKORC1 (vitamin K epoxide reductase complex, subunit 1) (eg, warfarin metabolism),

gene analysis, common variant(s) (eg, -1639G>A, c.173+1000C>T)

81401 CYP3A4 (cytochrome P450, family 3, subfamily A, polypeptide 4) (eg, drug

metabolism), common variants (eg, *2, *3, *4, *5, *6)

81479 Unlisted molecular pathology procedure

Note: CPT codes, descriptions and materials are copyrighted by the American Medical Association (AMA). HCPCS

codes, descriptions and materials are copyrighted by Centers for Medicare Services (CMS).

Related Information

Genes Relevant to Mental Health Disorders

Mental disorders encompass a wide range of conditions: the DSM-5 includes more than 300

different disorders. However, currently available genetic testing for mental health disorders is

primarily related to several clinical situations:

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1. Risk stratifying patients for one of several mental health conditions, including schizophrenia

and related psychotic disorders, bipolar and related disorders, depressive disorders,

obsessive-compulsive and related disorders, and substance-related and addictive disorders.

2. Predicting patients response to, dose requirement for, or adverse effects from one of several

medications (or classes of medications) used to treat mental health conditions, including:

typical and atypical antipsychotic agents, serotonin and serotonin/norepinephrine reuptake

inhibitors (SSRIs), and medications used to treat addiction, such as disulfiram.

Panels of genetic tests have been developed and have been proposed for use in the

management of mental health disorders.

Commercially Available Genetic Tests

Several test labs market either panels of tests or individual tests designed as being relevant for

mental health disorders. The following list includes many examples, but not necessarily all, of the

available tests.

The Genecept Assay (Genomind, LLC, Chalfont, PA) is a genetic panel test that includes a

range of genetic mutations and/or polymorphisms that have been associated with psychiatric

disorders and/or response to psychotropic medication. The test consists of a group of individual

genes, and the results are reported separately for each gene. There is no summary score or

aggregate results derived from this test. The intent of the test is as a decision aid for treatment

interventions, particularly in the choice and dosing of medications. However, guidance on

specific actions that should be taken following specific results of the test is vague. Interpretation

of the results and any management changes as a result of the test are left to the judgment of

the treating clinician.

The STA2R (SureGene Test for Antipsychotic and Antidepressant Response, SureGene, LLC,

Louisville, KY) is another genetic panel that provides information about medication response,

adverse event likelihood, and drug metabolism. According to the manufacturers website, the

test is recommended for initial medication selection, for patients who have poor efficacy,

tolerability, or satisfaction with existing medications, and in cases of severe treatment failure.1

Specific mutations included in the panel were not easily identified from the manufacturers

website.

GeneSight Psychotropic (Assurex Health, Mason, OH) is a genetic panel that provides

information about genes that may affect a patients response to antidepressant and

antipsychotic pharmacotherapy. According to the manufacturers website, following testing the

treating provider receives a report with the most common medications for the patients

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diagnosed condition categorized by cautionary level, along with a report of the patients genetic

variants.2 Details are not provided about the algorithm used by the manufacturer to generate

risk levels.

The Proove Opioid Risk Panel (Proove Biosciences, Irvine, CA) is a panel to evaluate genes

involved in the development of substance abuse or dependence and in response to medical

therapy for substance abuse or dependence.

Pathway Genomics (San Diego, CA) offers the Mental Health DNA Insight panel, which is a

single nucleotide polymorphism-based array test which evaluates a number of genes associated

with the metabolism and efficacy of psychiatric medications.

AltheaDx (San Diego, CA) offers a number of IDgenetix-branded tests, which include several

panels focusing on polymorphisms that affect medication pharmacokinetics for a variety of

disorders, including psychiatric disorders. Specific mutations included in the panel were not

easily identified from the manufacturers website.

The Ally Diagnostics Genetic Testing Panel (Ally Clinical Diagnostics, Farmers Branch, Texas) is

a panel to evaluate genes that may affect a patients response to medications for the treatment

of psychiatric or mental health symptoms or disorders. The panel includes three CYP450 tests,

vitamin K epoxide reductase, and a non-specific molecular pathology procedure.

Molecular Testing Labs Psychotropic Medication Panel (Molecular Testing Labs, Vancouver,

WA) offers a genetic testing panel which their website describes as identifying five different

categories of patients by the way they metabolize specific drugs. The only specific gene

mentioned is CYP2D6.

The PharmaRisk Basic Panel Is described by OptimumMeds as a test that analyzes the genes

that metabolize many commonly prescribed medications used in all clinical practices including:

internal medicine, cardiology, geriatrics, psychiatry and chronic pain management. The test

analyzes 55 genetic markers across 4 genes CYP2C19, CYP2C9, CYP2D6 and VKORC1.

The PharmaRisk Psychiatric Panel Includes CYP2D6, OPRM1, CYP2C9, COMT, DRD2, CYP2B6,

CYP2C19, CYP1A2, UGT2B15.

The PGXL Multi-Drug Panel Includes CYP2D6, CYP2C9, CYP2C190, CYP1A2, CYP3A4, CYP3A5,

SLC6A4, OPRM1, VKORC1, SLCO1B1, SULT24A1, Factor II, Factor V, MTHFR and COM.

The Alpha Genomix Psychiatry/ADHD Panel Includes CYP1A2, CYP2C9, CYP2C19, CYP2D6,

CYP3A, ADRA2A, and COMT.

Genetic Technological Innovations (DBA Vantari Genetics) offers genetic testing for drug

metabolism, preconception and pregnancy, inherited conditions and inherited cancer. Their

pharmacogenetic panel for drug metabolism includes CYP2C19, CYP2D6, MTHFR and CYP3A4.

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The PersonaGene panel Uses next generation sequencing to test for metabolism of common

drugs for pain management, cardiology, psychiatry and urology. Although this large panel

encompassing four specialties, all of the mutations tested are within the CYP450 family.

Luminex Offers a genotyping assay which can aid clinicians in determining therapeutic strategy

for drugs metabolized by cytochrome P450.

There are three Progenity Informed PGx genetic testing panels ADHD (4 mutations),

Depression (7 mutations) and Psychotropic (7 mutations) - and each panel tests a variety of

CYP450 genes, MTHFR, etc. In addition to the available panel tests, several labs offer genetic

testing for individual genes, including MTFHR, CYP450 genes, and SULT4A1.

Evidence Review

Description

Several commercially available testing panels include genes related to neurotransmitter function

and pharmacokinetics of psychiatric drugs. They are intended to be an aid in clinical decision

making regarding interventions for psychiatric conditions.

Background

Psychiatric disorders cover a wide range of clinical phenotypes and are generally classified by

symptomatology in systems such as the classification outlined in the American Psychiatric

Associations Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). In

addition to counseling and other forms of behavioral treatment, treatment commonly involves

one or more psychotropic medications that are aimed at alleviating symptoms of the disorder.

Although there are a wide variety of effective medications, treatment of psychiatric disease is

characterized by relatively high rates of inadequate response. This often necessitates numerous

trials of individual agents and combinations of medications in order to achieve optimal

response.

Knowledge of the physiologic and genetic underpinnings of psychiatric disorders is advancing

rapidly and may substantially alter the way in which these disorders are classified and treated.

Genetic testing could potentially be used in several ways including stratifying patients risks of

developing a particular disorder, aiding diagnosis, targeting medication therapy, and optimally

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dosing medication. Better understanding of these factors may lead to an improved ability to

target medications to the specific underlying abnormalities, with potential improvement in the

efficiency and efficacy of treatment.

Summary of Evidence

Panels of multiple genetic tests have been developed to aid in the diagnosis and treatment of

mental health disorders. Genes included in the panels have shown some association with

psychiatric disorders or with the pharmacokinetics of psychotropic medications.

Evidence on the clinical validity of genetic testing for mental health disorders consists primarily

of genome-wide association studies (GWAS) that correlate specific genetic polymorphisms with

clinical factors, and case-control studies that examine the odds ratio for genetic variants in

individuals with a clinical disorder compared with individuals without the disorder. In general,

cross-sectional and case-control studies cannot be used to generate diagnostic characteristics

such as sensitivity and specificity or clinically relevant risk prediction.

Studies suggest that there may be a number of genetic variants associated with increased risk of

mental health disorders and/or response to specific treatment, although estimates of the

magnitude of the increased risk and findings of significance are variable across studies. For the

individual tests, results from GWAS and case control studies are insufficient to determine clinical

utility. To determine clinical utility, evidence is needed that testing for variants in these genes

leads to changes in clinical management that improve outcomes.

No clinically valid studies were identified that evaluated defined groups of patients (eg, patients

with schizophrenia) and reported the sensitivity and specificity of the panel results for those

patients. Therefore it is not possible to estimate the clinical sensitivity and specificity of the tests

as a diagnostic tool for specific patient groups.

Practice Guidelines and Position Statements

None identified.

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Regulatory Status

The Genecept Assay, STA2R test, the GeneSight Psychotropic panel and the GeneSight MTFHR

tests are laboratory-developed tests that are not subject to U.S. Food and Drug Administration

(FDA) approval. Clinical laboratories may develop and validate tests in-house (home-brew) and

market them as a laboratory service; such tests must meet the general regulatory standards of

the Clinical Laboratory Improvement Act (CLIA). Other examples of these tests are YouScript

(Genelex), Proove Drug Metabolism (PROOVEBio), Mental Health Insight DNA (Pathway

Genomics), Millennium Pharmacogenetic Testing (Millennium Health), Primex Expanded

Pharmacogenomics Panel (PrimexLab) and DNA Test Assay Pain Management Panel (Ally Clinical

Diagnostics).

Tests include three CYP450 tests, vitamin K epoxide reductase, and a non-specific molecular

pathology procedure.

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66. Michelson D, Read HA, Ruff DD, et al. CYP2D6 and clinical response to atomoxetine in children and adolescents with ADHD. J

Am Acad Child Adolesc Psychiatry. Feb 2007; 46(2):242-251. PMID 17242628

67. Wernicke JF, Kratochvil CJ. Safety profile of atomoxetine in the treatment of children and adolescents with ADHD. J Clin

Psychiatry. 2002; 63 Suppl 12:50-55. PMID 12562062

68. http://www.ehs.lilly.com/msds/msds_atomoxetine_hydrochloride_tablets_and_capsules.pdf Accessed July 2017.

69. Ramoz N, Boni C, Downing AM, et al. A haplotype of the norepinephrine transporter (Net) gene Slc6a2 is associated with clinical

response to atomoxetine in attention-deficit hyperactivity disorder (ADHD). Neuropsychopharmacology. Aug 2009; 34(9):2135-

2142. PMID 19387424

70. ter Laak MA, Temmink AH, Koeken A, et al. Recognition of impaired atomoxetine metabolism because of low CYP2D6 activity.

Pediatr Neurol. Sep 2010; 43(3):159-162. PMID 20691935

http://www.ehs.lilly.com/msds/msds_atomoxetine_hydrochloride_tablets_and_capsules.pdf

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71. Macaluso M, Preskorn SH. CYP 2D6 PM status and antidepressant response to nortriptyline and venlafaxine: is it more than just

drug metabolism? J Clin Psychopharmacol. Apr 2011; 31(2):143-145. PMID 21346604

72. de Vos A, van der Weide J, Loovers HM. Association between CYP2C19*17 and metabolism of amitriptyline, citalopram and

clomipramine in Dutch hospitalized patients. Pharmacogenomics J. Oct 2011; 11(5):359-367. PMID 20531370

73. Hodgson K, Tansey K, Dernovsek MZ et al. Genetic differences in cytochrome P450 enzymes and antidepressant treatment

response. J Psychopharmacol. Feb 2014;28(2):133-141. PMID 24257813

74. Jornil J, Jensen KG, Larsen F, et al. Risk assessment of accidental nortriptyline poisoning: the importance of cytochrome P450 for

nortriptyline elimination investigated using a population-based pharmacokinetic simulator. Eur J Pharm Sci. Oct 9 2011;

44(3):265-272. PMID 21854846

75. Maier W, Zobel A. Contribution of allelic variations to the phenotype of response to antidepressants and antipsychotics. Eur

Arch Psychiatry Clin Neurosci. Mar 2008; 258 Suppl 1:12-20. PMID 18344045

76. Crescenti A, Mas S, Gasso P, et al. Cyp2d6*3, *4, *5 and *6 polymorphisms and antipsychotic induced extrapyramidal side-

effects in patients receiving antipsychotic therapy. Clin Exp Pharmacol Physiol. Jul 2008; 35(7):807-811. PMID 18346175

77. Smoller JW. Incorporating pharmacogenetics into clinical practice: reality of a new tool in psychiatry. Practical issues related to

medication selection. CNS Spectr. Mar 2006; 11(3 Suppl 3):5-7. PMID 17760223

78. Panagiotidis G, Arthur HW, Lindh JD, et al. Depot haloperidol treatment in outpatients with schizophrenia on monotherapy:

impact of CYP2D6 polymorphism on pharmacokinetics and treatment outcome. Ther Drug Monit. Aug 2007; 29(4):417-422.

PMID 17667795

79. Murray M, Petrovic N. Cytochromes P450: decision-making tools for personalized therapeutics. Curr Opin Mol Ther. Dec 2006;

8(6):480-486. PMID 17243482

80. Murray M. Role of CYP pharmacogenetics and drug-drug interactions in the efficacy and safety of atypical and other

antipsychotic agents. J Pharm Pharmacol. Jul 2006; 58(7):871-885. PMID 16805946

81. Bondy B, Spellmann I. Pharmacogenetics of antipsychotics: useful for the clinician? Curr Opin Psychiatry. Mar 2007; 20(2):126-

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82. Vandel P, Talon JM, Haffen E, et al. Pharmacogenetics and drug therapy in psychiatry--the role of the CYP2D6 polymorphism.

Curr Pharm Des. 2007; 13(2):241-250. PMID 17269931

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antipsychotic drugs. Curr Drug Targets. Dec 2006; 7(12):1671-1680. PMID 17168842

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85. Fleeman N, Dundar Y, Dickson R, et al. Cytochrome P450 testing for prescribing antipsychotics in adults with schizophrenia:

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History

Date Comments 12/09/13 New Policy. New policy developed with literature review through September 30, 2013.

The Genecept assay is investigational for all indications.

05/23/14 Update Related Policies. Add 12.04.509 and removed 12.04.82 as it was deleted.

08/11/14 Annual Review. Policy updated with literature review through April 14, 2014. Policy

expanded to include other genetic testing panels for mental health disorders; title of

policy changed to Genetic Testing Panels for Mental Health Conditions. Rationale

extensively revised. References 1, 2, 7-11, 19-26, 28-8 added. Policy statement

changed to indicate that individual genetic tests (as mutations or genetic variations)

and genetic testing panels for mental health disorders are investigational.

09/10/14 Minor update. New test added to Policy Statement for genetic testing panels: Primex

Expanded Pharmacogenomics Panel.

12/17/14 Minor update. New tests added to investigational Policy Statement for genetic testing

panels: Ally Diagnostics Genetic Testing Panel and Molecular Testing Labs

Psychotropic Medication Panel. Section reformatted for ease of reading.

01/20/15 Minor update. New tests added to investigational Policy Statement for genetic testing

http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm124889.htmhttp://genomind.com/

Page | 14 of 15

Date Comments panels: PharmaRisk Basic and PharmaRisk Psychiatric Panel.

02/27/15 Minor update. New test added to investigational Policy Statement for genetic testing

panels: Physicians Choice Laboratory Services (PCLS) Pharmacogenetic Testing. Related

policies updated with new policy 12.04.131.

03/24/15 Minor update. New test added to investigational Policy statement for genetic testing

panels: Frontier Toxicology PGx Pharmacogenomic Testing.

04/24/15 Minor update: Alpha Genomix Psychiatry/ADHD Panel and PGXL Multi-Drug Panel

added to investigational Policy statement for genetic testing panels.

07/14/15 Annual Review. Policy number changed from 12.04.110 to 12.04.515 due to the

addition of several local plan tests to the Policy Statement, Description and Reference

section. In this revision, PersonaGene, Progenity PGx Informed and two Luminex panel

tests added. Policy updated with literature review through April 21, 2015. Numerous

references added. Policy statements changed to clarify which categories of genetic

testing the policy addresses; intent of policy statements unchanged.

10/19/15 Update Related Policies. Remove 12.04.509 as it was archived.

05/01/16 Annual Review, approved April 12, 2016. Added rationale and references for CYP450

for use in review of mental health conditions/medications. References 51-93 added.

No change in policy statements.

10/07/16 Coding update. Reference codes removed from Description section; these were

informational only. CPT codes 81355 and 81479 added to the Coding section.

02/14/17 Policy moved into new format; no change to policy statements. References missing in

error adding to Reference section.

08/01/17 Annual Review. Policy approved on July 25, 2017. No changes to policy statement.

10/01/17 Coding update. Added new CPT code 0015U (effective 8/1/17).

01/23/18 Coding update. Added new CPT code 81328 (new code effective 1/1/18).

01/30/18 Coding update, added note that CPT code 0015U was terminated 1/1/18.

Disclaimer: This medical policy is a guide in evaluating the medical necessity of a particular service or treatment. The

Company adopts policies after careful review of published peer-reviewed scientific literature, national guidelines and

local standards of practice. Since medical technology is constantly changing, the Company reserves the right to review

and update policies as appropriate. Member contracts differ in their benefits. Always consult the member benefit

booklet or contact a member service representative to determine coverage for a specific medical service or supply.

CPT codes, descriptions and materials are copyrighted by the American Medical Association (AMA). 2018 Premera

All Rights Reserved.

Scope: Medical policies are systematically developed guidelines that serve as a resource for Company staff when

determining coverage for specific medical procedures, drugs or devices. Coverage for medical services is subject to

the limits and conditions of the member benefit plan. Members and their providers should consult the member

Page | 15 of 15

benefit booklet or contact a customer service representative to determine whether there are any benefit limitations

applicable to this service or supply. This medical policy does not apply to Medicare Advantage.

037338 (07-2016)

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effectively with us, such as: Qualified sign language interpreters Written information in other formats (large print, audio, accessible

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