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Genecept Assay

Number 12.04.110

Effective Date December 9, 2013

Revision Date(s) N/A

Replaces 2.04.110

Policy

The Genecept™ panel assay is considered investigational for all indications.

Related Policies

12.04.38

Cytochrome p450 Genotyping

12.04.82

Genetic Testing for Inherited Thrombophilia

12.04.91

General Approach to Genetic Testing

Policy Guidelines

There is no specific CPT code for this testing panel.

There are specific codes for some of the component tests:

81225 CYP2C19 (cytochrome P450, family 2, subfamily C, polypeptide 19)(e.g., drug metabolism), gene analysis, common variants (e.g., *2, *3, *4, *8, *17)

81226 CYP2D6 (cytochrome P450, family 2, subfamily D, polypeptide 6)(e.g., drug metabolism), gene analysis, common variants (e.g., *2, *3, *4, *5, *6, *9, *10, *17, *19, *29, *35, *41, *1XN, *2XN, *4XN)

81291 MTHFR (5, 10-methylenetetrahydrofolate reductase) (e.g., hereditary hypercoagulability) gene analysis; common variants (e.g., 677T, 1298C)

And CPT code 81401 includes the following testing for CYP3A4:

CYP3A4 (cytochrome P450, family 3, subfamily A, polypeptide 4) (e.g., drug metabolism), common variants (e.g., *2, *3, *4, *5, *6)

Description

The Genecept™ Assay is a genetic panel that includes genes related to neurotransmitter function and pharmacokinetics of psychiatric drugs. It is 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 DSM-V classification. 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. 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.

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.

There are 10 genes that are included in the assay, as follows:

Serotonin Transporter (SLC6A4)

This gene is responsible for coding the protein that clears serotonin metabolites (5-HT) from the synaptic spaces in the central nervous system (CNS). This protein is the principal target for many of the serotonin reuptake inhibitors (SSRIs). By inhibiting the activity of the SLC6A4 protein, the concentration of 5-HT in the synaptic spaces is increased. A common polymorphism in this gene consists of insertion or deletion of 44 base pairs, leading to the terminology of the long (L) and short (S) variants of this gene. These polymorphisms have been studied in relation to a variety of psychiatric and non-psychiatric conditions, including anxiety, obsessive compulsive disorder, and response to SSRIs.

Serotonin Receptor (5HT2C)

This gene codes for a subtype of the serotonin receptor that is involved in the release of dopamine and norepinephrine. These receptors play a role in controlling mood, motor function, appetite, and endocrine secretion. Alterations in functional status have been associated with affective disorders such as anxiety and depression. Certain antidepressants, e.g., mirtazapine and nefazodone, are direct antagonists of this receptor. There is also interest in developing agonists of the 5HT2C receptor as treatment for obesity and schizophrenia, but no such medications are commercially available at present.

Dopamine Receptor (DRD2)

This gene codes for a subtype of the dopamine receptor, called the D2 subtype. The activity of this receptor is modulated by G-proteins, which inhibit adenyl cyclase. These receptors are involved in a variety of physiologic functions related to motor and endocrine processes. The D2 receptor is the target of certain antipsychotic drugs. Mutations in this gene have been associated with schizophrenia and myoclonic dystonia. Polymorphisms of the DRD2 gene have been associated with addictive behaviors, such as smoking and alcoholism.

Gated Calcium Channel (CACNA1C)

This gene is responsible for coding of a protein that controls activation of voltage-sensitive calcium channels. Receptors for this protein are found widely throughout the body, including skeletal muscle, cardiac muscle, and in neurons in the CNS. In the brain, different modes of calcium entry into neurons determine which signaling pathways are activated, thus modulating excitatory cellular mechanisms. Associations of polymorphisms of this gene have been most frequently studied in relation to cardiac disorders. Specific polymorphisms have been associated with Brugada syndrome and a subtype of long QT syndrome (Timothy syndrome).

Ankyrin 3 (ANK3)

Ankyrins are proteins that are components of the cell membrane and interconnect with the spectrin-based cell membrane skeleton. The ANK3 gene codes for the protein Ankyrin G, which has a role in regulating sodium channels in neurons. Alterations of this gene have been associated with cardiac arrhythmias such as Brugada syndrome. Polymorphisms of this gene have also been associated with bipolar disorder, cyclothymic depression, and schizophrenia.

Catechol-O-Methyltransferase (COMT)

This gene codes for the COMT enzyme that is responsible for the metabolism of the catecholamine neurotransmitters, dopamine, epinephrine and norepinephrine. COMT inhibitors, such as entacapone are currently used in the treatment of Parkinson’s disease. A polymorphism of the COMT gene, the Val158Met polymorphism, has been associated with alterations in emotional processing and executive function and has also been implicated in increasing susceptibility to schizophrenia.

Methylenetetrahydrofolate reductase (MTHFR)

This is a widely studied gene that codes for the protein that converts folic acid to methylfolate. Methylfolate is a precursor for the synthesis of norepinephrine, dopamine, and serotonin. It is a key step in the metabolism of homocysteine to methionine, and deficiency of MTHFR can cause hyperhomocysteinemia and homocysteinuria. The MTHFR protein also plays a major role in epigenetics, through methylation of somatic genes. A number of polymorphisms have been identified that result in altered activity of the MTHFR enzyme. These polymorphisms have been associated with a wide variety of clinical disorders, including vascular disease, neural tube defects,

dementia, colon cancer, and leukemia.

Cytochrome P450 genes (CYP2D6, CYP2C19, CYP3A4)

These 3 genes code for hepatic enzymes that are members of the cytochrome p450 family, and are responsible for the metabolism of a wide variety of medications, including many psychotropic agents. For each of these genes, polymorphisms exist that impact the rate of activity, and therefore the rapidity of elimination of drugs and their metabolites. Based on the presence or absence of polymorphisms, patients can be classified as rapid metabolizers (RM), intermediate metabolizers (IM), and poor metabolizers (PM).

Regulatory Status

The Genecept Assay is a laboratory-developed test that is not subject to U.S. Food and Drug Administration (FDA) approval. Clinical laboratories may develop and validate tests in-house (“homebrew”) and market them as a laboratory service; such tests must meet the general regulatory standards of the Clinical Laboratory Improvement Act (CLIA).

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 benefit booklet or contact a customer service representative to determine whether there are any benefit limitations applicable to this service or supply.

Benefit Application

N/A

Rationale

This policy was created in November 2013 with literature review through September 30, 2013.

Analytic Validity

Information on analytic validity of the test is lacking. No published studies were identified that specifically evaluated the analytic validity of the test as performed commercially. There was no information identified in the published literature or from the manufacturer’s website concerning the genetic testing methods used for analysis. As a result, it is not possible to determine the analytic validity of the testing process.

Clinical Validity

Evidence on the clinical validity of testing consists primarily of genome-wide association studies that correlate genetic polymorphisms with clinical factors and case-control studies that examine the odds ratio for genetic variants in individuals with a clinical disorder compared to individuals without the disorder. There were no studies of clinical validity identified that evaluated defined groups of patients (e.g., patients with schizophrenia; patients with depression and non-response to serontonin reuptake inhibitors (SSRIs) 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 test as a diagnostic test for specific patient groups.

A comprehensive review of the genome-wide association studies (GWAS) and case control studies for all of these genes is beyond the scope of this policy. Some of the representative literature in this area is discussed below.

The SLC6A4 gene that codes for the serotonin transport protein has been studied in relation to a number of psychiatric conditions. Published literature has reported associations between variants in this gene and anxiety, bipolar disorder, and obsessive-compulsive disorder. (1, 2) However, these associations have not been reported consistently across studies. In a meta-analysis of 26 studies, Sen et al. reported that the overall association of SLC6A4 variants with anxiety approached, but did not quite reach, statistical significance (p=0.09). (3)

The CACNAIC gene has been studied most widely for its association with disorders of cardiac rhythm, such as long QT syndrome and Brugada syndrome. A lesser amount of research has reported associations of polymorphisms of this gene with schizophrenia and bipolar disorder. (4)

Kloiber et al. published results from t2 case-control studies evaluating the association of major depressive disorders with CACNAIC and ANK3. (5) The first population consisted of 720 patients with depression and 542 patients without psychiatric disease. The second population included 827 patients with recurrent depression and 860 patients without psychiatric disease. There were several single-nucleotide polymorphisms (SNPs) on both genes that showed a statistical association with depression on initial analysis, but none of these remained significant after controlling for multiple comparisons.

This evidence did not support a strong association between variants of these genes and depression. For the COMT gene, polymorphisms have been reported to be associated with cognitive function, emotional processing, and other cognitive tasks. (6, 7) However, associations with specific psychiatric conditions such as schizophrenia are less certain. (8)

For the DRD2 gene, a meta-analysis of case control studies that examined the presence of the cys311 polymorphism in patients with schizophrenia and patients without schizophrenia was published by Jonsson et al. (9) A total of 9,152 individuals were included, 3,707 individuals with schizophrenia and 5,363 control patients without schizophrenia. Combined analysis showed a significant association of this allele with schizophrenia (odds ratio [OR]: 1.43, 95% confidence interval [CI]: 1.16-1.78, p<0.001). Variants in the DRD2 gene have also shown associations with disorders other than schizophrenia.

The MTHFR gene has been widely studied for non-psychiatric conditions such as hyperhomocysteinemia and thrombophilia. A review of evidence on the association between this gene and thrombophilia is included in MPRM policy 2.04.82 (Genetic Testing for Inherited Thrombophilia). In that policy, genetic testing of the MTHFR for inherited thrombophilia is considered investigational. For psychiatric disease, Wu et al. performed a meta-analysis of 26 GWAS evaluating the association of MTHFR variants with depression. (10) Overall, there were low-strength associations between numerous MTHFR SNPs and depression, with odds ratios ranging from 1.15 to 1.42. On subgroup analysis, the associations were stronger for Asian populations. In Caucasians, the associations were of marginal significance, and in elderly patients the associations were not statistically significant.

A large amount of research has been conducted on the cytochrome p450 genes, with variants associated with altered drug metabolism for a wide variety of medications. A review of specific associations between these variations and metabolism of some psychiatric medications is discussed in related MPRM policy 2.04.38 Cytochrome p450 Genotyping. For selection and/or dosing of all psychiatric medications included in that policy review, genetic testing for cytochrome p450 variants is considered investigational.

Clinical Utility

Direct evidence on clinical utility of the Genecept Assay is lacking. For the individual tests, results from GWAS and case control studies are insufficient to determine clinical utility. In order to determine clinical utility, evidence is needed that testing for variants in these genes leads to changes in clinical management that improve outcomes.

There are no specific recommended changes in management that are linked to specific test results. Management changes that might be made include selection of specific medications according to test results, discontinuation of medications, and changes in dosing of medications. However, these management changes are not well-defined and may vary according to the judgment of the treating clinician. Since management changes are ill-defined, it is not possible to determine whether management changes associated with the test lead to improvements in health outcomes.

Results of a survey of clinicians who have used the test are reported on the Genomind website. (11) A description of the methodology for this survey is not provided, therefore it is not possible to evaluate such factors as selection of the population or the survey response rate. Survey results were reported for 132 clinicians who used the test in the treatment of 545 patients. Clinicians reported that their treatment decisions were influenced by the test (definitely yes or probably yes) in 87% of cases. For patients in whom decisions were influenced, 76% of the treatment decisions involved a change in medication. Clinicians also reported that confidence in their treatment decisions were increased (definitely yes or probably yes) in 93% of the cases.

Evaluating the Clinical Utility of Genetic Panels

A framework for determining the clinical utility of genetic panels is provided in a separate Related Policy (General Approach to Evaluating the Utility of Genetic Panels). According to the classification of panels in that policy, the Genecept Assay is classified as a panel intended to assess risk for multiple conditions. The criteria to be used for evaluating panels in this category are as follows:

  • Clinical utility has been established for at least one component of the panel.
  • Test is performed in a CLIA-approved laboratory.
  • Analytic validity of the panel approaches that of direct sequencing
  • Panel offers substantial advantages (efficiency of work-up, cost) over sequential analysis of individual genes.
  • The impact of ancillary information is well-defined.

The Genecept Assay does not meet the majority of these criteria. Most importantly, clinical utility has not been established for any of the individual tests for their intended purpose in this assay. In addition, the analytic validity of the test is unknown. The testing methods are not well-described, so there is uncertainty as to whether the efficiency of testing is improved by use of this panel. Finally, the impact of ancillary information is not well-defined. It is not known how the results of various tests might be combined to determine overall risk, nor is it known how unexpected results may impact treatment decisions and health outcomes. It is also unknown as to how the results of genetic variants that indicate increased risk for non-psychiatric conditions, such as variants in the CACNA1C gene that may denote an increased risk of cardiac disorders, will impact patient management and outcomes.

Clinical Input Received through Physician Specialty Societies and Academic Medical Centers

None

Ongoing Clinical Trials

A search of ClinicalTrials.gov using the key word “Genecept” returned 4 results. Two of these were single-arm studies that will evaluate changes in treatment decisions and outcomes in patients who receive the Genecept Assay. The 2 remaining trials are randomized, controlled trials (RCTs), with similar design in slightly different patient populations, as summarized below.

  • PAGE trial (NCT01555021). The Pharmacogenomics for Antidepressant Guidance and Education trial is an RCT that is currently recruiting patients admitted to an inpatient psychiatric facility with treatment-resistant depression, as defined by a failure of at least one prior trial of antidepressant medication. Treatment guided by results of the Genecept Assay will be compared to usual care over a 6-month period. The primary outcome measure is the change in the Quick Inventory of Depressive Symptomatology-Self Report (QIDS-SR) at 6 months. Secondary outcomes include change in treatment decisions based on Genecept results, treatment adherence, and medication side effects. Planned enrollment is for 200 patients with an estimated completion date of December 2013.
  • PAGE-1_AG1 trial (NCT01426516). The Pharmacogenomics for Antidepressant Guidance and Education 1 trial is an RCT that is currently recruiting patients with treatment-resistant depression, as defined by a failure of at least one prior trial of antidepressant medication. Treatment guided by results of the Genecept Assay will be compared to usual care over a 6-month period. The primary outcome measure is the change in the Quick Inventory of Depressive Symptomatology-Self Report (QIDS-SR) at 6 months. Secondary outcomes include change in treatment decisions based on Genecept results, quality of life, cost and patient/provider satisfaction. Planned enrollment is for 100 patients with an estimated completion date of December 2014.

Summary

The Genecept Assay is a panel of 10 genes, each of which has shown some association with psychiatric disorders or with the pharmacokinetics of psychotropic medications. The analytic validity of the assay cannot be determined due to a lack of information on the testing methods. The available evidence on clinical validity consists of genome-wide association studies and case-control studies that indicate a correlation between variants of these genes and clinical factors. This evidence shows low-strength associations with a variety of psychiatric and non-psychiatric conditions. Often the evidence for an association is not consistently reported across all studies, and in many cases, there are correlations of the same genetic variants with other non-psychiatric disorders. There are also a range of associations reported for response to certain medications and alterations in pharmacokinetics. Evidence on clinical utility is lacking. Management changes that occur as a result of this assay are ill-defined, with uncertain impact on clinical outcomes. In addition, it is not well understood how unexpected results or unknown variants are handled, and whether these type of results have an impact on diagnostic work-up, treatment decisions, and health outcomes. Due to these deficiencies in the evidence base, the Genecept assay is considered investigational for all indications.

Practice Guidelines and Position Statements

None

Medicare National Coverage

None

References

  1. Hariri AR, Mattay VS, Tessitore A et al. Serotonin transporter genetic variation and the response of the human amygdala. Science 2002; 297(5580):400-3.
  2. Lasky-Su JA, Faraone SV, Glatt SJ et al. Meta-analysis of the association between two polymorphisms in the serotonin transporter gene and affective disorders. Am J Med Genet B Neuropsychiatr Genet 2005; 133B(1):110-5.
  3. Sen S, Burmeister M, Ghosh D. Meta-analysis of the association between a serotonin transporter promoter polymorphism (5-HTTLPR) and anxiety-related personality traits. Am J Med Genet B Neuropsychiatr Genet 2004; 127B(1):85-9.
  4. Craddock N, Sklar P. Genetics of bipolar disorder. Lancet 2013; 381(9878):1654-62.
  5. Kloiber S, Czamara D, Karbalai N et al. ANK3 and CACNA1C--missing genetic link for bipolar disorder and major depressive disorder in two German case-control samples. J Psychiatr Res 2012; 46(8):973-9.
  6. Bruder GE, Keilp JG, Xu H et al. Catechol-O-methyltransferase (COMT) genotypes and working memory: associations with differing cognitive operations. Biol Psychiatry 2005; 58(11):901-7.
  7. Lelli-Chiesa G, Kempton MJ, Jogia J et al. The impact of the Val158Met catechol-O-methyltransferase genotype on neural correlates of sad facial affect processing in patients with bipolar disorder and their relatives. Psychol Med 2011; 41(4):779-88.
  8. Zammit S, Spurlock G, Williams H et al. Genotype effects of CHRNA7, CNR1 and COMT in schizophrenia: interactions with tobacco and cannabis use. Br J Psychiatry 2007; 191:402-7.
  9. Jonsson EG, Sillen A, Vares M et al. Dopamine D2 receptor gene Ser311Cys variant and schizophrenia: association study and meta-analysis. Am J Med Genet B Neuropsychiatr Genet 2003; 119B(1):28-34.
  10. 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.
  11. Genomind (Chalfont, PA) website. Available online at: http://www.genomind.com/products/assay. Last accessed November 18 2013.

Coding

Codes

Number

Description

CPT

81225

CYP2C19 (cytochrome P450, family 2, subfamily C, polypeptide 19)(e.g., drug metabolism), gene analysis, common variants (e.g., *2, *3, *4, *8, *17)

 

81226

CYP2D6 (cytochrome P450, family 2, subfamily D, polypeptide 6)(e.g., drug metabolism), gene analysis, common variants (e.g., *2, *3, *4, *5, *6, *9, *10, *17, *19, *29, *35, *41, *1XN, *2XN, *4XN)

 

81291

MTHFR (5, 10-methylenetetrahydrofolate reductase) (e.g., hereditary hypercoagulability) gene analysis; common variants (e.g., 677T, 1298C)

 

81401

CYP3A4 (cytochrome P450, family 3, subfamily A, polypeptide 4) (e.g., drug metabolism), common variants (e.g., *2, *3, *4, *5, *6)

Appendix

N/A

History

Date

Reason

12/09/13

New Policy. New policy developed with literature review through September 30, 2013. The Genecept™ assay is investigational for all indications.


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