Clinical Policy Title: Pharmacogenomic testing for psychoses

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1 Clinical Policy Title: Pharmacogenomic testing for psychoses Clinical Policy Number: Effective Date: July 1, 2018 Initial Review Date: May 1, 2018 Most Recent Review Date: June 1, 2018 Next Review Date: June 2019 Related policies: Policy contains: Genetic testing. Polymorphism. Pharmacogenomic testing. Psychosis. Schizophrenia. CP# Pharmacogenomic tests for psychiatric medications ABOUT THIS POLICY: AmeriHealth Caritas has developed clinical policies to assist with making coverage determinations. AmeriHealth Caritas clinical policies are based on guidelines from established industry sources, such as the Centers for Medicare & Medicaid Services (CMS), state regulatory agencies, the American Medical Association (AMA), medical specialty professional societies, and peer-reviewed professional literature. These clinical policies along with other sources, such as plan benefits and state and federal laws and regulatory requirements, including any state- or plan-specific definition of medically necessary, and the specific facts of the particular situation are considered by AmeriHealth Caritas when making coverage determinations. In the event of conflict between this clinical policy and plan benefits and/or state or federal laws and/or regulatory requirements, the plan benefits and/or state and federal laws and/or regulatory requirements shall control. AmeriHealth Caritas clinical policies are for informational purposes only and not intended as medical advice or to direct treatment. Physicians and other health care providers are solely responsible for the treatment decisions for their patients. AmeriHealth Caritas clinical policies are reflective of evidence-based medicine at the time of review. As medical science evolves, AmeriHealth Caritas will update its clinical policies as necessary. AmeriHealth Caritas clinical policies are not guarantees of payment. Coverage policy AmeriHealth Caritas considers the use of genetics tests for medications to treat psychosis to be investigational or experimental and, therefore, not medically necessary, including, but not limited to, the use of the tests GeneSight Psychotropic, Psychia Gene, You Script psychotropic, Mental Health DNA Insight, STA2R Sure Gene, GeneSightRx, or PHARMAchip for assay genotyping of genes CYP1A2, CYP2C9, CYP2C19, CYP2D6, HTR2A, and SCL6A4 to help guide administration of antipsychotics. Note: The Food and Drug Administration includes CYP2D6 metabolizer status for dosing, administration, and determining drug response in the labels for several psychiatric medications, and thus, medical necessity for this test would be determined on a case by case basis. Limitations: None. Alternative covered services: 1

2 Office visits to diagnose psychoses, manage medication. Background Psychoses include a series of mental health disorders in which the affected person loses some contact with reality. Thoughts and perceptions are affected, and the person may have difficulty in discerning what is and is not real. Delusions and hallucinations are common markers of the condition. Psychosis may be caused by other mental illnesses, sleep deprivation, general medical conditions, prescription medications, or substance abuse (National Institute of Mental Health, 2018). The multiple forms of psychosis often include schizophrenia, schizoaffective disorder, schizophreniform disorder, dementia, bipolar disorder, delusional disorder, substance-induced psychosis, postpartum psychosis, delirium, and psychosis due to a general medical condition (Centre for Addiction and Mental Health, 2012). Incidence of first-diagnosed psychotic disorders from were studied, using 2,774 adults ages 18 to 64. Nations included Brazil, England, France, Italy, the Netherlands, and Spain. Incidence in 100,000 person-years was 21.4, and varied between 6.0 in Santiago, Spain, and 46.1 in Paris, France. Rates were elevated for racial and ethnic minorities, males ages 18 24, and areas with a lower percent of owner-occupied homes, seen as a measure of low socioeconomic status (Jongsma, 2018). A study of 8,028 residents of Finland ages 30 and older calculated a 3.06 percent lifetime prevalence of all psychoses, a number that rises to 3.48 percent when register diagnoses of non-respondents were added. The percent lifetime prevalence by type of psychosis included: 0.87 percent for schizophrenia percent for schizoaffective disorder percent for schizophreniform disorder percent for delusional disorder percent for bipolar I disorder percent for major depressive disorder with psychotic features percent for substance-induced psychotic disorders percent for psychotic disorders due to a general medical condition percent for other psychoses (Perala, 2007). Psychoses are diagnosed by a clinician or team of clinicians observing a person s behavior and other symptoms. No lab test or biological marker can clearly identify psychosis (Insel, 2016). Treatments vary by the type of psychosis, but always include a combination of antipsychotic medicines, psychological therapies, and social support, ideally administered by a team of clinical experts (National Health Service, 2016). 2

3 For decades, clinicians have recognized that patients may respond differently to the same dose of a given drug. As more of the human genetic makeup is understood, the goal of personalized medicine comes closer to realization, and some relatively new tests can assist physicians in selecting therapies. The concept of an inherited predisposition in mental health raises the potential for genomics to lead to improved selection of pharmacotherapy, and several genomic tests are now available. Cytochrome P450 enzymes, located primarily in the liver, account for most drug metabolism in the body. Genotyping for cytochrome P450 enzymes is the subject of recent research to identify which patients are more likely to respond to a drug for diseases, including mental health disorders like psychosis. Genotyping panels currently being used for mental health disorders like psychosis include: GeneSight Psychotropic. Psychia Gene. You Script psychotropic. Mental Health DNA Insight. STA2R Sure Gene. Gene Sight Rx. PharmaChip. Research has identified genes that may guide drug administration by evaluating a person s likelihood of responding to an antipsychotic or other mental health drug. These genes include CYP450, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5, HTR2A, and SCL6A4. An October 2015 article stated that over 600,000 genetic tests to help guide mental health treatment had been administered in the prior three years. The article also states that few professional articles have addressed efficacy of treatment based on these tests. Many of these studies are funded by test manufacturers, or researchers they compensate, casting doubt on their objectivity (Daley, 2015). Some of these tests are covered by third-party insurance. For example, GeneSight Psychotropic is covered by Medicare and Medicaid, only if ordered by psychiatrists for patients diagnosed with major depressive disorder with persistent symptoms after at least one neuropsychiatric drug (Centers for Medicare & Medicaid Services [CMS] Local Coverage Determination [LCD], 2015). While some genes can predict elevated risk of mental health disorders, no genetic marker has yet been shown to (prospectively) effectively identify which persons with a specific psychiatric disorder will respond well to treatment (Dubovsky, 2016). Thus, no known professional guidelines governing use of pharmacogenomic testing for psychoses exist as of April Searches AmeriHealth Caritas searched PubMed and the databases of: 3

4 UK National Health Services Centre for Reviews and Dissemination. Agency for Healthcare Research and Quality s National Guideline Clearinghouse and other evidence-based practice centers. CMS. We conducted searches on March 26, Search terms were: genetic test, psychosis, schizophrenia, bipolar, GeneSight, Psychia Gene, You Script, Mental Health DNA Insight, and PharmaChip. We included: Systematic reviews, which pool results from multiple studies to achieve larger sample sizes and greater precision of effect estimation than in smaller primary studies. Systematic reviews use predetermined transparent methods to minimize bias, effectively treating the review as a scientific endeavor, and are thus rated highest in evidence-grading hierarchies. Guidelines based on systematic reviews. Economic analyses, such as cost-effectiveness, and benefit or utility studies (but not simple cost studies), reporting both costs and outcomes sometimes referred to as efficiency studies which also rank near the top of evidence hierarchies. Findings Three European genome-wide pharmacogenetics studies of genetic variation and selection of the most effective therapy have been conducted. These include the Genome-Based Therapeutic Drugs for Depression project, the Munich Antidepressant Response Signature project, and the Sequenced Treatment Alternatives to Relieve Depression study (GENDEP Investigators, 2013). A systematic literature review assessed responses of eight genes (CYP2D6, CYP2C19, CYP2C9, CYP1A2, CYP3A4, HTR2C, HTR2A, and SLC6A4) to 26 commonly used antipsychotic and antidepressant medications. Of 294 publications, 57 percent showed significant associations, with the strongest being pharmacokinetic profiles of CYP2C19 and CYP2D6 (93 percent and 90 percent), suggesting that genetic testing could lead to the matching of medications to particular patients (Altar, 2013). A literature review of clozapine, which is commonly used for treatment-refractory schizophrenia, assessed any linkage between genetic polymorphism and response to the drug, but found mostly negative results, aside from the ABCB1 gene (Krivoy, 2016). One of the earliest systematic reviews of the effects of genetic testing for psychosis involved CYP2D6 polymorphism of risperidone for schizophrenia or bipolar disorder. The review included 13 trials, 10 of which were not randomized or controlled. Most studies were of short duration, reported non-significant trends, and elevated adverse effects were observed in poor metabolizers. Authors recommended that 4

5 testing for an association between risperidone and outcomes for treating schizophrenia or bipolar disorder not be used routinely (Cartwright, 2013). A systematic review of studies on the ability of biological markers to predict response to psychosis treatment noted that only a few such trials have been published, with mostly preliminary results. Three trials with conflicting results were cited, and authors concluded that no such markers have become part of daily clinical practice (Fond, 2015). Another literature review found fewer than 200 studies of biomarkers ability to predict illness course and treatment response for schizophrenia, and only one of these were considered clinically applicable (Prata, 2014). A systematic review of four studies compared outcomes of GeneSight-guided care and usual care in several mental health disorders, but the large majority were patients with depression. Patients with guided treatments had significantly greater proportions with 1) remission of depressive symptoms, 2) response to treatment, and 3) patient satisfaction. There were no observed differences between groups in complete remission of depression. Psychosis data were not reported (Health Quality Ontario, 2015). Research has begun to pinpoint presence of genetic variants as evidence of the likelihood of positive responses for certain anti-psychotic medications, even though confirming that individuals with these variants will respond to certain treatment is incomplete. Examples of these variants include: A study of 419 cases with bipolar disorder and 1,034 controls identified no nucleotide polymorphism association that was genome-wide significant, but follow up did identify variant rs in the muskelin gene to be linked with bipolar disorder (Nassan, 2017). A review of 21 studies (n = 64,472 Asian cases and controls) suggested variant rs might be associated with schizophrenia (Falola, 2017), the opposite finding of a previous meta-analysis of 12 case-control studies (n = 21,324) of Chinese persons (Li, 2013). A review of 12 case control studies (n = 25,898) showed presence of the mir-137 polymorphism variant rs significantly (p <.001) increases schizophrenia risk (Ou, 2016). A study of 995 Han Chinese verified response for schizophrenia treatments for several genes such as CYP2D6, CYP2C19, COMT, ABCB1, DRD3, and HTR2C, and several candidate new genes and combination variants were identified (Xu, 2016). A summary of the progress and problems in pharmacogenomics-based treatment for psychosis was presented in a 2016 article. The review focused on treatment-resistant schizophrenia and clozapine, the only evidence-based treatment for the disorder; only 60 percent 70 percent respond to the drug, and it is only prescribed in 5.5 percent of cases, according to a study of 326,119 Medicaid patients (Stroup, 2014). In 2000, landmark genetic research found a 77 percent success rate in predicting response to clozapine (Arranz, 2000); however, the study could not be replicated and the test was withdrawn from the market (Schumacher, 2000). The authors state that to identify a single polymorphism with the ability to predict if clozapine will be effective for a patient, future research must integrate clinical risk factors, increase sample sizes, improve homogeneity of patient samples, and to account for effects of concurrent medications (Lally, 2016). 5

6 Another concern raised by genetic testing to guide individual treatment of mental health disorders such as psychoses is the presence of the manufacturers of tests in the literature, and the resulting marketing based on results of these studies. Eric Lander, Ph.D., a leader of the Human Genome Project, states that despite great promise in genetic-based treatment, unsupported claims made by these companies that genetic tests can predict which persons will respond well to medication are not harmless and may be quite dangerous in the New England Journal of Medicine (Lander, 2015). Policy updates: None. Summary of clinical evidence: Citation Falola (2017) Assessment of the link between polymorphism involving variant rs from the ZNF804A gene and risk of schizophrenia Nassan (2017) Assessing if the MKLN1 (mulkelin) gene is associated with early onset bipolar disorder Ou (2016) Investigation of a particular variant s ability to identify persons with schizophrenia who can be effectively treated Xu (2016) Content, Methods, Recommendations Key points: Meta-analysis of a total of 21 studies including 28,842 cases and 35,630 controls, from China, Indonesia, Japan, Kazakhstan, and Singapore. Assessment made of the link between variant rs from the ZNF804A gene and risk of schizophrenia. Test for heterogeneity (p = 0.002) indicated no publication bias. Results suggest that genetic variant rs might be associated with the development of schizophrenia in Asians. Key points: Meta-analysis of a sample of 419 cases and 1,034 controls and a replication sample of 181 cases and 777 controls, plus a replication of 181 cases and 777 controls, assessing any link with early onset bipolar disorder. No single nucleotide polymorphism associations were genome-wide significant. Of the top 15 polymorphisms in the discovery analysis, rs in the muskelin (MKLN1) gene was nominally significant in the replication analysis, and was among the top associations in the meta-analysis (OR = 1.9). In the third sample, this SNP was associated with bipolar disorder (p = 0.036, OR = 1.6). Key points: Meta-analysis of 12 studies, comparing 11,583 cases 14,315 controls. Evaluation of association with schizophrenia of polymorphism rs in the gene mir-137 (known to regulate many genes implicated in schizophrenia risk). A significant association was observed using allelic and homogeneous codominant models (p < 0.001), but not the heterogeneous codominant model (p = 0.11). Key points: 6

7 Citation Genomic variants that respond to four drugs for schizophrenia Lally (2016) Content, Methods, Recommendations Study of 995 subjects assessing which genes and variants are linked with effective response to schizophrenia drugs (risperidone, clozapine, quetiapine, chlorpromazine). 77 polymorphisms of 25 genes were investigated. Significant associations with treatment response for several genes, such as CYP2D6, CYP2C19, COMT, ABCB1, DRD3, and HTR2C were verified in our study. Study identified several new candidate genes (TNIK, RELN, NOTCH4, and SLC6A2) and combinations (haplotype rs rs rs6269-rs4818 in COMT) linked with treatment response to the four drugs. Key points: Progress in treatment for schizophrenia based on pharmacogenomics testing Clozapine is the only evidence-based medication for schizophrenia. Clozapine only gets a 60 percent 70 percent response rate. Clozapine is only prescribed in 5.5 percent of schizophrenia cases. In 2000, landmark genetic research found a 77 percent success rate in predicting response to clozapine; inability to replicate the study resulted in the test being withdrawn from the market. Identifying a single polymorphism with the ability to predict if clozapine will be effective for a patient will require research that integrates clinical risk factors, increases sample sizes, improves homogeneity of patient samples, and accounts for effects of concurrent medications. References Professional society guidelines/other: Center for Addiction and Mental Health (CAMH). Toronto: CAMH, psychosis/first_episode_psychosis_information_guide/pages/fep_types.aspx. Accessed March 22, Daley B. Genetic tests for psychiatric drugs spur hope, doubts. New England Center for Investigative Reporting, October 3, Accessed March 23, Insel TR. Is there a better way to diagnosis psychosis? New York: Scientific American, March 1, Accessed March 22, National Health Service. NHS Choices: Psychosis. London: NHS, last updated December 23, Accessed March 22, National Institute of Mental Health (NIMH). What is Psychosis? Bethesda, MD: NIMH, Accessed March 22,

8 Peer-reviewed references: Altar CA, Hornberger J, Shewade A, Cruz V, Garrison J, Mrazek D. Clinical validity of cytochrome P450 metabolism and serotonin gene variants in psychiatric pharmacotherapy. Int Rev Psychiatry. 2013;25(5): Arranz MJ, Munro J, Birkett J, et al. Pharmacogenetic prediction of clozapine response. Lancet. 2000;355(9215): Cartwright AL, Wilby KJ, Corrigan S, Ensom MH. Pharmacogenetics of risperidone: a systematic review of the clinical effects of CYP2D5 polymorphisms. Ann Pharmacother. 2013;47(3): Dubofsky SL. The limitations of genetic testing in psychiatry. Psychother Psychosom. 2016;85(3): Falola O, Osamor VC, Adebiyi M, Adebiyi E. Analyzing a single nucleotide polymorphism in schizophrenia: a meta-analysis approach. Neuropsychiatr Dis Treat. 2017;13: Fond G, d Albis MA, Jamain S, et al. The promise of biological markers for treatment response in firstepisode psychosis: a systematic review. Schizophr Bull. 2015;41(3): GENDEP Investigators; MARS Investigators; STAR*D Investigators. Common genetic variation and antidepressant efficacy in major depressive disorder: a meta-analysis of three genome-wide pharmacogenetics studies. Am J Psychiatry. 2013;170(2): Health Quality Ontario. Pharmacogenomic testing for psychotropic medication selection: A systematic review of the Assurex GeneSight psychotropic test. Ont Health Technol Assess Ser. 2017;17(4):1 39. Jongsma HE, Gayer-Anderson C, Lasalvia A, et al. European Network of National Schizophrenia Networks Studying Gene-Environment Interactions Work Package 2 (EU-GEI WP2 Group). Treated incidence of psychotic disorders in the multinational EU-GEI study. JAMA Psychiatry. 2018;75(1): Krivoy A, Gaughran F, Weizman A, Breen G, MacCabe JH. Gene polymorphisms potentially related to the pharmacokinetics of clozapine: a systematic review. Int Clin Psychopharmacol. 2016;31(4): Lally J, Gaughran F, Timms P, Curran SR. Treatment-resistant schizophrenia: current insights on the pharmacogenomics of antipsychotics. Pharmgenomics Pers Med. 2016;9: Lander ES. Cutting the Gordian helix regulating genomic testing in the era of precision medicine. N Engl J Med. 2015;372(13): Li M, Zhang H, Luo XJ, et al. Meta-analysis indicates that the European GWAS-identified risk SNP rs within ZNF804A is not associated with schizophrenia in Han Chinese population. PLoS One. 2013;8(6):e Doi: /journal.pone

9 Nassan M, Li Q, Croarkin PE, et al. A genome wide association study suggests the association of muskelin with early onset bipolar disorder: Implications for a GABAergic epileptogenic neurogenesis model. J Affect Disord. 2017;208: Ou ML, Liu G, Xiao D, et al. Association between mir-137 polymorphism and risk of schizophrenia: a meta-analysis. Genet Mol Res. 2016;15(3):Doi: /gmr Perala J, Suvisaari J, Saami SI, et al. Lifetime prevalence of psychotic and bipolar I disorders in a general population. Arch Gen Psychiatry. 2007;64(1): Prata D, Mechelli A, Kapur S. Clinically meaningful biomarkers for psychosis: a systematic and quantitative review. Neurosci Biobehav Rev. 2014;45: Schumacher J, Schulze TG, Wienker TF, Rietschel M, Nothen MM. Pharmacogenetics of the clozapine response. Lancet. 2000;356(9228): Stroup TS, Gerhard T, Crystal S, Huang C, Olfson M. Geographic and clinical variations in clozapine use in the United States. Psychatr Serv. 2014;65(2): Xu Q, Wu X, Li M, et al. Association studies of genomic variants with treatment response to risperidone, clozapine, quetiapine and chlorpromazine in the Chinese Han population. Pharmacogenomics J. 2016;16(4): CMS National Coverage Determinations (NCDs): No NCDs identified as of the writing of this policy. LCDs: L36325 MolDX. GeneSight Assay for Refractory Depression. Effective date October 1, Solutions%2c+LLC+(Noridian+Healthcare+Solutions%2c+LLC+(02402%2c+A+and+B+MAC%2c+J+- +F))&LCntrctr=358*1&DocType=Active&bc=AAAAAAIBAAAA&. Accessed March 23, Commonly submitted codes Below are the most commonly submitted codes for the service(s)/item(s) subject to this policy. This is not an exhaustive list of codes. Providers are expected to consult the appropriate coding manuals and bill accordingly. CPT Code Description Comments Unlisted Molecular Pathology Procedure 9

10 CPT Code Description Comments Cytogenomic constitutional (genome-wide) microarray analysis; interrogation of genomic regions for copy number and single nucleotide polymorphism (SNP) variants for chromosomal abnormalities Clozapine Psychiatric Collaborative Care Behavioral Health Integration Care ICD-10 Code Description Comments F32.1-F32.9 Major depressive disorder, single episode F33.1-F33.9 Major depressive disorder, recurrent F20.0-F20.9 Schizophrenia HCPCS Level II Code S0136 Description Clozapine, 25 mg Comments 10