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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
Select a hyperlink below to be directed to that section.
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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57. 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. Sep
2014; 53(9):801-811. PMID 25154506
58. Serretti A, Calati R, Massat I, et al. Cytochrome P450
CYP1A2, CYP2C9, CYP2C19 and CYP2D6 genes are not associated
with
response and remission in a sample of depressive patients. Int
Clin Psychopharmacol. Sep 2009; 24(5):250-256. PMID 19593158
59. Sim SC, Nordin L, Andersson TM, et al. Association between
CYP2C19 polymorphism and depressive symptoms. Am J Med
Genet B Neuropsychiatr Genet. Sep 2010; 153B (6):1160-1166. PMID
20468063
60. Bertilsson L. Metabolism of antidepressant and neuroleptic
drugs by cytochrome p450s: clinical and interethnic aspects.
Clin
Pharmacol Ther. Nov 2007; 82(5):606-609. PMID 17898711
61. 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. Nov 2010; 71(11):1482-1487.
PMID
20441720
62. Waade RB, Hermann M, Moe HL, et al. Impact of age on serum
concentrations of venlafaxine and escitalopram in different
CYP2D6 and CYP2C19 genotype subgroups. Eur J Clin Pharmacol. Aug
2014; 70(8):933-940. PMID 24858822
63. Skinner MH, Kuan HY, Pan A, et al. Duloxetine is both an
inhibitor and a substrate of cytochrome P4502D6 in healthy
volunteers. Clin Pharmacol Ther. Mar 2003; 73(3):170-177. PMID
12621382
64. de Leon J. The crucial role of the therapeutic window in
understanding the clinical relevance of the poor versus the
ultrarapid
metabolizer phenotypes in subjects taking drugs metabolized by
CYP2D6 or CYP2C19. J Clin Psychopharmacol. Jun
2007;27(3):241-245. PMID 17502769
65. Trzepacz PT, Williams DW, Feldman PD, et al. CYP2D6
metabolizer status and atomoxetine dosing in children and
adolescents
with ADHD. Eur Neuropsychopharmacol. Feb 2008; 18(2):79-86. PMID
17698328
66. Michelson D, Read HA, Ruff DD, et al. CYP2D6 and clinical
response to atomoxetine in children and adolescents with ADHD.
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17242628
67. Wernicke JF, Kratochvil CJ. Safety profile of atomoxetine in
the treatment of children and adolescents with ADHD. J Clin
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68.
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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.
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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
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44(3):265-272. PMID 21854846
75. Maier W, Zobel A. Contribution of allelic variations to the
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76. Crescenti A, Mas S, Gasso P, et al. Cyp2d6*3, *4, *5 and *6
polymorphisms and antipsychotic induced extrapyramidal side-
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78. Panagiotidis G, Arthur HW, Lindh JD, et al. Depot
haloperidol treatment in outpatients with schizophrenia on
monotherapy:
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PMID 17667795
79. Murray M, Petrovic N. Cytochromes P450: decision-making
tools for personalized therapeutics. Curr Opin Mol Ther. Dec
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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-
130. PMID 17278909
82. Vandel P, Talon JM, Haffen E, et al. Pharmacogenetics and
drug therapy in psychiatry--the role of the CYP2D6
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83. Dorado P, Berecz R, Penas-Lledo EM, et al. Clinical
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84. Fleeman N, McLeod C, Bagust A, et al. The clinical
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86. Jovanovic N, Bozina N, Lovric M, et al. The role of CYP2D6
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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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walang gastos. Tumawag sa 800-722-1471 (TTY: 800-842-5357). (Thai):
Premera Blue Cross 800-722-1471 (TTY: 800-842-5357) (Ukrainian): .
Premera Blue Cross. , . , , . . 800-722-1471 (TTY: 800-842-5357).
Ting Vit (Vietnamese): Thng bo ny cung cp thng tin quan trng. Thng
bo ny c thng tin quan trng v n xin tham gia hoc hp ng bo him ca qu
v qua chng trnh Premera Blue Cross. Xin xem ngy quan trng trong
thng bo ny. Qu v c th phi thc hin theo thng bo ng trong thi hn duy
tr bo him sc khe hoc c tr gip thm v chi ph. Qu v c quyn c bit thng
tin ny v c tr gip bng ngn ng ca mnh min ph. Xin gi s 800-722-1471
(TTY: 800-842-5357).