Background

This policy assesses whether genetic testing for the diagnosis and management of mental health conditions is clinically useful. To make a clinical management decision that improves the net health outcome; the balance of benefits and harms must be better when the test is used to manage the condition than when another test or no test is used. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

The primary goal of pharmacogenomics testing and personalized medicine is to achieve better clinical outcomes compared to managing the condition with the standard of care. Drug response varies greatly between individuals, and genetic factors are known to play a role. However, in most cases, the genetic variation only explains a modest portion of the variance in the individual response because clinical outcomes are also affected by a wide variety of factors including alternate pathways of metabolism and patient- and disease-related factors that may affect absorption, distribution, and elimination of the drug.

Therefore, assessment of clinical utility of a pharmacogenetic test cannot be made by a chain of evidence from clinical validity data alone. In such cases, evidence evaluation requires studies that directly demonstrate that the use of the pharmacogenomic test to make management decisions alters clinical outcomes; it is not sufficient to demonstrate that the test predicts a disorder or a phenotype. Direct evidence of clinical utility is provided by studies that compare health outcomes for patients managed with or without the test. Because these are intervention studies, the preferred evidence of from randomized controlled trials.

Study Selection Criteria

• We sought randomized controlled trials that reported the outcomes of pharmacogenetic testing to diagnose, assess the risk of developing, or to manage a mental health condition.
• We sought evidence on outcomes, with emphasis on efficacy outcomes, as the main purpose of genetic testing in mental health conditions is to achieve clinically meaningful improvement compared with standard of care.
• We also included studies that reported only on adverse events, although for medications where adverse events tend to be mild, efficacy outcomes are of greater importance.
• The specific patient indications, interventions, comparators and outcome measures of interest for each indication are described in the clinical context section.

Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments. The tests discussed in this section are available under the auspices of the Clinical Laboratory Improvement Amendments. Laboratories that offer laboratory-developed tests must be licensed by the Clinical Laboratory Improvement Amendments for high-complexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of this test.

Examples of commercially available panels include the following:

• Genecept™ Assay (Genomind);
• STA²R test (SureGene Test for Antipsychotic and Antidepressant Response; Clinical Reference Laboratory). Specific variants included in the panel were not easily identified from the manufacturer's website.
• GeneSight® Psychotropic panel (Assurex Health);
• Mental Health DNA Insight™ panel (Pathway Genomics);
• IDgenetix-branded tests (AltheaDx).

AltheaDx offers a number of IDgenetix-branded tests, which include several panels focusing on variants that affect medication pharmacokinetics for a variety of disorders, including psychiatric disorders.

Related Policies

• Cytochrome P450 Genotype-Guided Treatment Strategy (Policy #033 in the Medicine Section)
• Genetic Testing for Inherited Thrombophilias (Policy #056 in the Pathology Section)

NOTE: For Medicare Advantage, Medicaid and FIDE-SNP, please refer to the Coverage Sections below for coverage guidance.)

1. Genetic testing for diagnosis and management of mental health disorders is considered investigational in all situations, including but not limited to the following:
   1. To confirm a diagnosis of a mental health disorder in an individual with symptoms.
   2. To predict future risk of a mental health disorder in an asymptomatic individual.
   3. To inform the selection or dose of medications used to treat mental health disorders, including but not limited to the following medications:
      1. selective serotonin reuptake inhibitors
      2. selective norepinephrine reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors
      3. tricyclic antidepressants
      4. antipsychotic drugs.
2. Genetic testing panels for mental health disorders, including but not limited to the Genecept Assay, STA²R test, the GeneSight Psychotropic panel, the Proove Opioid Risk assay, and the Mental Health DNA Insight panel, are considered investigational for all indications.

• The beneficiary must display clinical features of an associated disease: and
• The result of the test will directly impact the treatment being delivered to the beneficiary; and
• A definitive diagnosis remains uncertain after history, physical examination, pedigree analysis, genetic counseling, and completion of conventional diagnostic studies.

FIDE-SNP Coverage:

For members enrolled in a Fully Integrated Dual Eligible Special Needs Plan (FIDE-SNP): (1) to the extent the service is covered under the Medicare portion of the member’s benefit package, the above Medicare Coverage statement applies; and (2) to the extent the service is not covered under the Medicare portion of the member’s benefit package, the above Medicaid Coverage statement applies.

Policy Guidelines: (Information to guide medical necessity determination based on the criteria contained within the policy statements above.)

Genetics Nomenclature Update
The Human Genome Variation Society nomenclature is used to report information on variants found in DNA and serves as an international standard in DNA diagnostics. It is being implemented for genetic testing medical policy updates starting in 2017 (see Table PG1). The Society’s nomenclature is recommended by the Human Variome Project, the HUman Genome Organization, and by the Human Genome Variation Society itself.

The American College of Medical Genetics and Genomics and the Association for Molecular Pathology standards and guidelines for interpretation of sequence variants represent expert opinion from both organizations, in addition to the College of American Pathologists. These recommendations primarily apply to genetic tests used in clinical laboratories, including genotyping, single genes, panels, exomes, and genomes. Table PG2 shows the recommended standard terminology“pathogenic,” “likely pathogenic,” “uncertain significance,” “likely benign,” and “benign”to describe variants identified that cause Mendelian disorders.

Table PG1. Nomenclature to Report on Variants Found in DNA

Previous	Updated	Definition
Mutation	Disease-associated variant	Disease-associated change in the DNA sequence
	Variant	Change in the DNA sequence
	Familial variant	Disease-associated variant identified in a proband for use in subsequent targeted genetic testing in first-degree relatives

Table PG2. ACMG-AMP Standards and Guidelines for Variant Classification

Variant Classification	Definition
Pathogenic	Disease-causing change in the DNA sequence
Likely pathogenic	Likely disease-causing change in the DNA sequence
Variant of uncertain significance	Change in DNA sequence with uncertain effects on disease
Likely benign	Likely benign change in the DNA sequence
Benign	Benign change in the DNA sequence

ACMG: American College of Medical Genetics and Genomics; AMP: Association for Molecular Pathology.

Genetic Counseling
Experts recommend formal genetic counseling for patients who are at risk for inherited disorders and who wish to undergo genetic testing. Interpreting the results of genetic tests and understanding risk factors can be difficult for some patients; genetic counseling helps individuals understand the impact of genetic testing, including the possible effects the test results could have on the individual or their family members. It should be noted that genetic counseling may alter the utilization of genetic testing substantially and may reduce inappropriate testing; further, genetic counseling should be performed by an individual with experience and expertise in genetic medicine and genetic testing methods.


[RATIONALE: This policy was created in 2014 and has been updated regularly with searches of the PubMed database. The most recent literature update was performed through April 24, 2020.

Testing For Diagnosis or Risk Of Mental Health Disorder
Clinical Context and Test Purpose

The purpose of testing for genes associated with increased risk of mental illness in patients who are currently asymptomatic is to identify those for whom an early intervention during a presymptomatic phase of the illness might facilitate improved outcomes.

The question addressed in this policy is: Does the use of testing for genes associated with increased risk of mental illness in patients who are currently asymptomatic improve the net health outcome?

The following PICO was used to select literature to inform this policy.

Patients

The relevant population of interest is asymptomatic individuals who would consider intervention if a genetic variant is detected.

Interventions

The intervention of interest is testing for genes associated with increased risk of mental illness, either as a panel or single gene.

Comparators

At present, decisions about the management of mental illnesses are made when patients present with symptoms and are typically diagnosed based on clinical evaluation according to standard criteria (ie, Diagnostic and Statistical Manual of Mental Disorders).

Outcomes

The primary outcome of interest is change in disease outcomes, which would result directly from changes in management that could be instituted because of earlier disease detection. For many mental illnesses, there are standardized outcome measures (eg, Hamilton Rating Scale for Depression (for example, Hamilton Depression Rating Scale [HAMD] and Beck's Depression Inventory [BDI]).

Review of Evidence

We did not find any randomized controlled trial evaluating the use of genetic test results to inform decisions on mental health diagnoses or management of patients with risk for mental health conditions. Multiple cohort and case control studies examined the association between different genetic markers with different mental health disorders.^{1,2,3,4,5,6,7,8,} However, those observational studies did not examine the effect of genetic testing on disease outcome among patients with risk for mental health conditions.

Section Summary: Testing for Diagnosis or Risk of Mental Health Disorder

No studies were identified that used genetic testing results to inform decisions on mental health diagnoses or management of patients with risk for mental health conditions. There is no clear clinical strategy for how the associations of specific genes and mental health disorders would be used to diagnose a specific patient or to manage a patient at higher risk of a specific disorder.

Genetic Testing to Inform Medication Selection for Patients with Depression Inadequately Controlled with Medication

Evidence reviews assess whether a medical test is clinically useful. A useful test provides information to make a clinical management decision that improves the net health outcome. That is, the balance of benefits and harms is better when the test is used to manage the condition than when another test or no test is used to manage the condition. The first step in assessing a medical test is to formulate the clinical context and purpose of the test.

Clinical Context and Test Purpose

Major Depressive Disorder (MDD) is a mood disorder characterized by pervasive sadness, lack of interest and enjoyment in most activities, feelings of low self-worth, sleep disturbance, over-or under-eating, suicidal thoughts and suicide attempts. Duration of at least 2 weeks defines a major depressive episode (MDE).

Individuals who fail to achieve remission of MDD after 2 vigorous trials of treatment have a poor prognosis. The Sequenced Treatment Alternatives to Relieve Depression * (STAR*D) found that only about half of patients reached remission after 2 treatments.^9,

The purpose of pharmacogenetic testing in patients with depression inadequately controlled by medication is to inform antidepressant selection in order to improve symptoms (i.e., clinical response) and, preferably, to achieve remission of depression.

Patients

Adult patients who have a diagnosis of major depressive disorder who have had inadequate response to 2 or more trials of antidepressant therapy. MDD is defined by the presence of 5 or more of the symptoms below for a period of at least 2 weeks. At least 1 symptom must be: (1) lack of interest or enjoyment in most activities, almost every day; or (2) depressed mood almost every day for most of the day. And in addition at least 4 of the symptoms below must be present almost every day.

• Sleep disturbance, insomnia or excessive sleepiness
• Over-or under-eating with significant weight gain or loss
• Observable psychomotor agitation or retardation
• Fatigue or loss of energy
• Difficulty concentrating or making decisions
• Feelings of worthlessness or inappropriate guilt
• Thoughts of death or suicide, or suicide attempt.

Interventions

Three commercially available pharmacogenetic tests for antidepressant selection are reviewed here: GeneSight®, NeuroIDgenetix®, and Neuropharmagen®. Each test has its own proprietary algorithm for assessing genes associated with drug pharmacokinetics and pharmacodynamics. Each of these tests also has a proprietary format for reporting results and categorizing likely responsiveness or intolerance to available antidepressants.

All are laboratory developed tests and not subject to U.S. Food and Drug Administration (FDA) regulation. However, recently, the FDA has raised concerns about pharmacogenetic tests that claim to predict medication response where drug labeling does not describe a predictive relationship between genetic variation and drug response. The FDA has reportedly reached out to firms marketing such tests, including tests of antidepressant response, with concerns about claims of clinical benefit.^11,

Comparators

The comparator is antidepressant drug selection without pharmacogenetic testing. At present there is no definitive algorithm for selecting next line treatment after failure to respond to initial treatment.

Outcomes

Our source to identify preferred outcome measures is the FDA Draft Guidance (2018) on developing drugs for treatment of major depressive disorder.^12,

Trials of the tests included in this review reported the Hamilton Rating Scale for Depression. Clinical response is defined as a 50% or greater reduction from baseline. Remission is defined as a score of 7 or less.

Short-term pharmacological response is typically assessed at 6 to 8 weeks. Six month follow-up is typically required to assess reduction in recurrence.

Table 1: Measures of Depression in Adults^13,

Outcome Measure	Description	Scale	Clinically Meaningful Difference
Hamilton Rating Scale for Depression	Physician scored. Rates presence and intensity of symptoms. Symptom domains include depressive mood, guilt, insomnia, suicidality, work and activity. 17 item version is most common (HAM-D17).	0 to 7 normal (no depression); 8 to 13 mild depression; 14 to18 moderate depression; 19 to 22 severe depression; 23 or greater very severe depression	The goal of treatment is remission, typically defined as 7 or less. But 2 or less has been suggested as optimal. Response is 50% reduction from baseline.

GeneSight^® test
Review of Evidence
Systematic Reviews

A systematic review and meta-analysis (Brown et al 2019) of prospective, 2 arm studies to examine the clinical utility of using GeneSight® to inform treatment decisions for patients with MDD included 2 randomized controlled trials (Winner et al 2013 and Greden et al 2019) and 2 open label studies (Hall-Flavin et al 2012 and Hall-Flavin et al 2013).^{14,15,16,17,18,} Evidence from both the RCTs are discussed below.

Randomized Controlled Trials

Two randomized controlled trials compared response and remission with antidepressant therapy informed by gene test results to standard of care—antidepressant therapy selected without gene test results.

Greden et al (2019) presented results for the Genomics Used to Improve DEpression Decisions (GUIDED) trial in which patients with major depressive disorder (MDD) were randomized to receive treatment guided by results from a genotyping test (GeneSight®) or through standard physician assessment (Table 2).^16, GeneSight® evaluates 8 genes (59 variants) in relation to 38 psychotropic medications and the potential for gene-drug interactions. Based on results from the genotype test, the medications are categorized as either congruent ('use as directed' or 'use with caution') or incongruent ('use with increased caution and with more frequent monitoring') for a particular patient. The primary outcome was symptom improvement, measured by a change in HAMD. Secondary outcomes were a response (>50% decrease in HAMD, Quick Inventory of Depressive Symptomatology [QIDS], or Patient Health Questionnaire [PHQ]) and remission (score of <7 HAMD, <5 QIDS, and <5 PHQ). The study randomized 1799 patients, after post-randomization exclusions, 1541 patients remained in the intention to treat cohort, but the intention to treat results were not reported. The study reported only per protocol results showing per cent of patients achieving response and remission at 8 weeks. The per protocol cohort included 1398 patients, however, response and remission results were reported for 1167 of the per protocol cohort (Greden et al., (p. 63, Figure1). Of the per protocol group, 15% are missing from the standard of care arm, 11% from the Gene Sight informed group. Overall, approximately 35 per cent of randomized participants were missing from the reported results on response and remission. At 8 weeks follow-up, the primary outcome was not statistically different and the secondary outcomes were statistically different between the groups (Table 3). While the results significantly favored the Gene Sight informed group, the extent of unexplained missing data precludes conclusions on outcomes.

A small RCT by Winner et al (2013) evaluated the effect of providing the GeneSight® test on the management of psychotropic medications used for major depressive disorder in a single outpatient psychiatric practice (see Table 2).^15, Fifty-one subjects were enrolled and randomized to treatment as usual or treatment guided by GeneSight® testing. All subjects underwent GeneSight® testing, though results were not given to the physicians in the treatment as a usual group until after study completion. At 10-week follow-up, treating physicians dose-adjusted subjects' medication regimens with the same likelihood in the GeneSight® group (53%) and the treatment as usual group (58%; p=0.66). However, patients in the GeneSight® group who were initially on a medication classified as "use with caution and with more frequent monitoring" were more likely than those with the same classification in the unguided group to have a medication change or dose adjustment (100% vs 50% respectively; p=0.02). Depression outcomes, measured by the HAMD-17 score, did not differ significantly between groups at the 10-week follow-up (see Table 3). This trial's small size may have limited the ability to detect a significant effect, as the authors estimated that 92 patients per arm would be required; but the Gene Sight directed arm and the standard care arm included 26 and 25 patients, respectively.

Table 2: Summary Characteristics of RCTs Assessing GeneSight® Test

Study	Country	Sites	Dates	Participants	Intervention
					Active	Comparator
Greden et al (2019)16,16	U.S.	60	2014-2017	Patients with MDD based on QIDS assessment; inadequately controlled with medication	Treatment guided by GeneSight® (n=681)* *Per protocol 1398 of 1799 randomized	SOC (n=717)* *Per protocol cohort is 1398 of 1799 randomized
Winner et al (2013)15,	U.S.	1	NR	Patients with major depressive disorder, HAM D-17>14 (moderate)	Treatment guided by GeneSight® (n=26)	SOC (n=25)

Table 3: Summary of Results of RCTs Assessing GeneSight®

Study	N	Outcomes
		Response ≥50% decrease in HAM-D17		Remission: HAM-D17≤7
Greden et al (2019)16,		8 weeks	P		P
GeneSight®	560	26.0%		15.3%
Standard Care	607	19.9%	0.01	10.1%	0.007
Winner et al (2013)15,		10 weeks
GeneSight®	26	36%		20%
Standard Care	25	20.8%		8.3%
		OR 2.14 95% CI: 0.59-7.79		OR 2.75 95% CI: 0.48-15.8

Table 4: Study Relevance Limitations: GeneSight®

Study	Population	Intervention	Comparator	Outcomes	Duration of follow-up
Greden et al (2019)16,	1Patients with mild depression excluded from per protocol analysis				124-week follow-up was treatment arm only
Winner et al (2013)15,	2MDD diagnostic criteria. Prior medication response not described				1Follow-up limited to 10 weeks

^a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use.
^b Intervention key: 1. Classification thresholds not defined; 2. Version used unclear; 3. Not intervention of interest.
^c Comparator key: 1. Classification thresholds not defined; 2. Not compared to credible reference standard; 3. Not compared to other tests in use for same purpose.
^d Outcomes key: 1. Study does not directly assess a key health outcome; 2. Evidence chain or decision model not explicated; 3. Key clinical validity outcomes not reported (sensitivity, specificity and predictive values); 4. Reclassification of diagnostic or risk categories not reported; 5. Adverse events of the test not described (excluding minor discomforts and inconvenience of venipuncture or noninvasive tests).
^e Follow-Up key: 1. Follow-up duration not sufficient with respect to natural history of disease (true-positives, true-negatives, false-positives, false-negatives cannot be determined).

Study	Allocations	Blinding	Selective Reporting	Data Completeness	Power	Statistical
Greden et al (2019)16,	4Of 1799 patients randomized, 258 (14%) were excluded from the intent to treat cohort			1,28 week response and remission results reported only for per protocol cohort No explanation for mission per protocol patients (15% of SOC group; 11% of test group)	1No description of power and sample size calculations
Winner et al (2013)15,				1No N’s provided in results, so unknown if any patients did not complete study		4 Underpowered. 92N per arm required to detect remission or response

^a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias.
^b Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician.
^c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.
^d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent-to-treat analysis (per protocol for non inferiority trials).
^e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference.
^f Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4. Comparative treatment effects not calculated.

Evidence for the use of GeneSight® test to inform antidepressant selection for patients who have failed 2 or more courses of antidepressant therapy includes 2 RCTs. None of the trials provided adequate evidence. Greden et al 2019 reported potential supportive evidence on a relevant population. Both studies have major limitations in design and conduct and in consistency and precision. The evidence is insufficient to permit conclusions on the health outcome – effects of managing antidepressant therapy with the GeneSight® test.

NeuroIDgenetix^® test
Review of Evidence
Randomized Controlled Trials

Two randomized controlled trials reported results of antidepressant therapy selection, informed by NeuroIDgenetix® test results compared to standard of care —antidepressant therapy selected without gene test results.

Bradley et al (2018) conducted a double-blinded RCT in which 685 patients with depression and/or anxiety disorders were randomized to treatment guided by either NeuroIDgenetix® or standard of care (Table 6).^19, Outcomes included HAMD and the Hamilton Rating Scale for Anxiety (HAMA) and adverse drug events. Trained and blinded clinicians conducted interviews using the HAMD and HAMA. Approximately 15% of randomized patients were lost to follow up over the 12 week period. Response results were only reported for 261 moderate and severe group of patients and remission results were reported for 93 severe group of patients. Response rates (p<0.001; OR: 4.72 [1.93-11.52]) and remission rates (p<0.02; OR: 3.54 [1.27-9.88]) were significantly higher in the NeuroIDgenetix®-guided group as compared to the control group at 12 weeks. The frequency of adverse drug events did not differ statistically between groups. Study does not report clearly if the analysis was based on intention to treat population. Reporting is incomplete, and suggestive of selective reporting.

Olson et al (2017) conducted an RCT in which patients with neuropsychiatric disorders were randomized to treatment guided by NeuroIDgenetix® or standard of care (see Table 6).^20, A majority of the patients, 56% in the intervention group and 64% in the control group had a primary diagnosis of depression. Subgroup analyses by neuropsychiatric disorder were not conducted. Outcomes included Neuropsychiatric Questionnaire, Symbol Digit Coding test, and adverse drug events. The Neuropsychiatric Questionnaire is a computerized survey addressing symptoms of neuropsychoses, and the SCD assesses attention and processing speed, which is sensitive to medication effects. The study did not report on response or remission of depression. There were no significant differences in Neuropsychiatric Questionnaire or Symbol Digit Coding scores between groups (see Table 7). However, the patients receiving standard of care reported significantly more adverse events (53%) than patients receiving NeuroIDgenetix®-guided care (28%). The comparison of adverse drug events did not report the number of patients included in the analysis. ClinicalTrials.gov lists neurocognitive measures as co-primary outcomes, but these are not reported, suggestive of selective reporting.

Table 6: Summary Characteristics of RCTs Assessing NeuroIDgenetix^®

Study	Country	Sites	Dates	Participants	Intervention
					Active	Comparator
Bradley et al (2019)19,	U.S.	20 Psychiatry and primary care settings	2016	Patients with depression and/or anxiety disorders using either HAM D-17 or HAM A score≥18 (moderate and severe) were included in efficacy analysis. Either new to medication or inadequately controlled with medication	Treatment guided by NeuroIDgenetix® (n=352)	SOC (n=333)
Olson et al (2017)20,	U.S.	6	2015	Patients with ADHD, anxiety, depression, or psychosis; currently receiving antidepressants	Treatment guided by NeuroIDgenetix® (n=178)	SOC (n=25)

Table 7: Summary of Results of RCTs Assessing NeuroIDgenetix®

Study	N	Outcome
		Response ≥50% decrease in HAM-D17		Remission: HAM-D17≤7
Bradley et al (2019)19,		12 weeks	P	12 weeks	P
NeuroIDgenetix®	140 (moderate/severe)	64%		NR
Standard Care	121 (moderate/severe)	46%	0.01	NR
NeuroIDgenetix®	40 (severe)			35%
Standard Care	53 (severe)			13%	0.02
		≤1 Adverse Drug Event		≥2 Adverse Drug Events
Olson et al (2017)20,		10 weeks
NeuroIDgenetix®	NR	28%		5%
Standard Care	NR	53%	0.001	24%	0.001

Table 8: Study Relevance Limitations: NeuroIDgenetix®

Study	Population	Intervention	Comparator	Outcomes	Duration of follow-up
Bradley et al (2019)19,
Olson et al (2017)20,	2 No description of criteria used to determine mental health condition diagnosis. 4 Majority of patients with depression (57%); remaining with ADHD, anxiety, or psychosis			1 Adverse drug events. Did not report response or remission

^a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use.
^b Intervention key: 1. Classification thresholds not defined; 2. Version used unclear; 3. Not intervention of interest.
^c Comparator key: 1. Classification thresholds not defined; 2. Not compared to credible reference standard; 3. Not compared to other tests in use for same purpose.
^d Outcomes key: 1. Study does not directly assess a key health outcome; 2. Evidence chain or decision model not explicated; 3. Key clinical validity outcomes not reported (sensitivity, specificity and predictive values); 4. Reclassification of diagnostic or risk categories not reported; 5. Adverse events of the test not described (excluding minor discomforts and inconvenience of venipuncture or noninvasive tests).
^e Follow-Up key: 1. Follow-up duration not sufficient with respect to natural history of disease (true-positives, true-negatives, false-positives, false-negatives cannot be determined).

Study	Allocations	Blinding	Selective Reporting	Data Completeness	Power	Statistical
Bradley et al (2019)19,			2 In the clinicaltrials.gov listing, reduction of adverse drug events was listed as the primary outcome, but was not reported as primary outcome Remission not reported for moderate/sever, only severe	1 Approximately 15% of randomized patients were lost to follow-up over the 12 week trial. Analysis does not appear to be intent to treat.	1No description of power and sample size calculations
Olson et al (2017)20,	1 Randomization procedure not described		2 In the clinicaltrials.gov listing, change in Neuropsychiatric Questionnaire and Symbol Digit Coding at 4 months were listed as coprimary outcomes. Four month results not reported	1 In the 3-month analyses, it appears that more than 30% of randomized patients were not included. 6 Unclear if analysis was intention-to-treat	1 No description of power and sample size calculations	1 Comparative statistics not reported for clinical or neurocognitive outcomes

^a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias.
^b Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician.
^c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.
^d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent-to-treat analysis (per protocol for non inferiority trials).
^e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference.
^f Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4. Comparative treatment effects not calculated.

Evidence for the use of NeuroIDgenetix® test to inform antidepressant selection includes 2 RCTs, one reporting reponse and remission as outcomes and another reporting adverse events as outcome. None of the trials provided adequate or supportive evidence in terms of relevance, design and conduct or consistency and precision. Both studies have major limitations in design and conduct and in consistency and precision. The evidence is insufficient to permit conclusions on the health outcome – effects of managing antidepressant therapy with the NeuroIDgenetix® test

Neuropharmagen® Test
Review of Evidence
Systematic Review and Meta-analysis

Vilches et al (2019) conducted a meta-analysis with the aim to assess the clinical utility of Neuropharmagen® in the treatment management of depressive patients.^21, The study included 2 RCTs and a multicenter retrospective observational study.^22,23,24, Evidence from both the RCTs are discussed below.

Randomized Controlled Trials

Han et al (2018) conducted a randomized single-blind clinical trial among patients with MDD to evaluate the effectiveness of Neuropharmagen® test guided antidepressant treatment (N=52) compared to receiving antidepressants through standard physician assessment (N=48) (Table 10).^22, Neuropharmagen® analyzes 30 genes associated with drug metabolism and 59 medications used to treat MDD. Primary endpoint was change in HAMD-17 score from baseline to 8 weeks follow-up. Response rate (at least 50% reduction in HAMD-17 score from baseline), remission rate (HAMD-17 score ≤7 at the end of treatment) as well as the change of total score of Frequency, Intensity, and Burden of Side Effects Ratings (FIBSER) from baseline to end of treatment were also investigated. (Table 4). The intention-to-treat (ITT) population consisted of all patients who had at least 1 post-treatment assessment for effectiveness during the study. The effectiveness evaluation was based on the analyses with ITT on last observation carried forward. The mean change of HAMD-17 score was significantly different between 2 groups favoring guided arm by −4.1 point of difference (p=0.010) at the end of treatment. The response rate (71.7 % vs. 43.6%, p=0.014) were also significantly higher in the guided arm than in standard care arm at the end of treatment, while the remission rate was numerically higher in the guided arm than in standard care arm without statistical difference (45.5% vs. 25.6%, p=0.071). The study reported early dropout of 25% in guided-care and 38% in in standard care arm. The reason for early dropout associated with adverse events was higher in standard care arm (n=9, 50.0%) than in guided care arm (n=4, 30.8%). The effectiveness evaluation was based on the analyses with ITT on last observation carried forward (LOCF). Use of LOCF assumes data are missing completely at random (MCAR).^25, The distribution of reasons for termination among early dropouts indicates that the assumption of MCAR is unlikely to hold in this analysis. Study did not report registration in any clinical trial database.

Perez et al (2017) conducted a single-blind RCT (AB-GEN trial) of patients diagnosed with major depressive disorder randomized to genotype-guided treatment (Neuropharmagen®) or treatment as usual (see Table 10).^23, The pharmacogenetics report from Neuropharmagen® provided information on 50 drugs, highlighting gene-drug interactions and drug recommendations from the U.S. Food and Drug Administration and Clinical Pharmacogenetics Implementation Consortium. The primary outcome was Patient Global Impression of Improvement (PGI-I), which was collected by telephone interviewers blinded to treatment allocation group. A response was defined as a PGI-I of 2 or less. Percent responders differed nominally between groups (p=0.05) at the end of the 12-week study (see Table 11). Changes in 17-item HAMD (HAMD-17) scores were significant at 5 weeks (p=0.04) but not at 12 weeks (p=0.08). Response and remission rates were calculated post-hoc based on the HDRS-17 (single-blinded). There was no significant difference in response (45.4% vs 40.3%, p=0.39) or remission (34.0% vs 33.1%, p=0.87) between guided care and standard care arms at 12 weeks. However, response and remission data were missing for 9% patients in the guided care group and 14% of the standard care group.

Table 10: Summary Characteristics of RCTs Assessing Neuropharmagen®

Study	Country	Sites	Dates	Participants	Intervention
					Active	Comparator
Han et al (2018)22,	Korea	2	NR	Patients with MDD using DSM-5 criteria; currently receiving antidepressant therapy at least 6 weeks with an inadequate response (CGI-I >3)	Treatment guided by Neuropharmagen® (n=52)	SOC (n=48)
Perez et al (2017)23,	Spain	18	2014-2015	Patients with MDD using DSM-IV-TR criteria; either new to medication or inadequately controlled with medication	Treatment guided by Neuropharmagen® (n=155)	SOC (n=161)

Table 11: Summary of Results of RCTs Assessing Neuropharmagen®

Study	N	Outcomes
		Response ≥50% decrease in HAM-D17		Remission: HAM-D17≤7
Han et al (2018)22,		8 weeks	P		P
Neuropharmagen®	52	71.7%		45.5%
Standard Care	48	43.6%	0.01	25.6%	0.07
Perez et al (2017)23,		12 weeks		12 weeks
Neuropharmagen®	141	45.4%		34.0%
Standard Care	139	40.3%	0.39	33.1%	0.87
		OR = 1.23 (95%CI: 0.77 – 1.98)		OR = 1.04 (95%CI: 0.64 – 1.71)

Table 12: Study Relevance Limitations: Neuropharmagen®

Study	Population	Intervention	Comparator	Outcomes	Duration of follow-up
Han et al (2018)22,
Perez et al (2017)23,

^a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use.
^b Intervention key: 1. Classification thresholds not defined; 2. Version used unclear; 3. Not intervention of interest.
^c Comparator key: 1. Classification thresholds not defined; 2. Not compared to credible reference standard; 3. Not compared to other tests in use for same purpose.
^d Outcomes key: 1. Study does not directly assess a key health outcome; 2. Evidence chain or decision model not explicated; 3. Key clinical validity outcomes not reported (sensitivity, specificity and predictive values); 4. Reclassification of diagnostic or risk categories not reported; 5. Adverse events of the test not described (excluding minor discomforts and inconvenience of venipuncture or noninvasive tests).
^e Follow-Up key: 1. Follow-up duration not sufficient with respect to natural history of disease (true-positives, true-negatives, false-positives, false-negatives cannot be determined).

Study	Allocations	Blinding	Selective Reporting	Data Completeness	Power	Statistical
Han et al (2018)22,		3Subjects were blinded, but unknown if outcome assessors were blinded	1 Not registered	1 High loss to follow-up or missing data 2 Inadequate handling of missing data. LOCF may not be the most appropriate approach
Perez et al (2017)23,		3 Subjects were blinded, outcome (HDRS-17) assessed by treating physicians		Response and remission data were missing for 9% patients in the guided care group and 14% of the standard care group.

^a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias.
^b Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician.
^c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.
^d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent-to-treat analysis (per protocol for non inferiority trials).
^e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference.
^f Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4. Comparative treatment effects not calculated.

Evidence for the use of Neuropharmagen® test to inform antidepressant selection for patients who have failed 2 or more courses of antidepressant therapy includes 2 RCTs. Han et al (2018) provided adequate evidence for ‘Response’ on a relevant population. Both studies have major limitations in design and conduct and inconsistency and precision. The evidence is insufficient to permit conclusions on the health outcome – effects of managing antidepressant therapy with the Neuropharmagen® test.

Genetic Testing to Inform Medication Selection for Patients with a Mental Illness other than Depression Inadequately Controlled with Medication
Clinical Context and Test Purpose

The purpose of pharmacogenetic testing in patients diagnosed with a mental illness other than depression is to inform management decisions such as starting a particular drug, determining or adjusting a dose, or changing drugs when therapy fails.

The question addressed in this policy is: Does psychopharmacologic management aided by genetic testing improve the net health outcome compared with management guided by clinical symptoms alone in patients with a mental illness other than depression inadequately controlled with medication?

The following PICO was used to select literature to inform this policy.

Patients

The relevant population of interest is individuals with a mental illness other than depression inadequately managed with psychopharmacologic drugs.

Interventions

Interventions of interest include testing for genes (single or as part of a panel) associated with medication pharmacokinetics and/or pharmacodynamics.

Comparators

Currently, decisions about medication management for patients with mental illnesses are based on clinical response, potentially informed by studies such as the Sequenced Treatment Alternatives to Relieve Depression study, which evaluated specific medication sequences.

Outcomes

The primary outcome of interest is change in disease outcomes resulting from a more appropriate selection of specific drugs or doses for the patient's condition. Also, avoidance of adverse events is an important outcome.

Review of Evidence
Systematic Review

Hartwell et al (2020) conducted a systematic review and meta-analysis of the moderating effect of rs1799971, a single nucleotide polymorphism (SNP) that encodes a non-synonymous substitution (Asn40Asp) in the mu-opioid receptor gene, OPRM1 on response to naltrexone treatment of alcohol use disorder. The meta-analysis included 7 RCTs (659 subjects randomly assigned to receive naltrexone and 597 received placebo).^26, Of the 5 alcohol consumption outcomes considered, there was a nominally significant moderating effect of the Asn40Asp SNP only on drinks per day (d = −0.18, 95% CI=−0.32 to −0.03, P = 0.02). However, the effect was not significant when multiple comparisons were taken into account. There was no statistically significant heterogeneity (I² = 33.8%, P = 0.18).

Randomized Controlled Trials

Bradley et al (2018) conducted a double-blinded RCT in which 685 patients with depression and/or anxiety disorders were randomized to treatment guided by either NeuroIDgenetix® or standard of care (Table 14).^19, Among the participants, 115 in the experimental arm and 120 in the standard of care arm had only anxiety. Outcomes included percent reduction in Hamilton Rating Scale for Anxiety (HAM-A) and response (50% reduction in HAM-A) rate. Trained and blinded clinicians conducted interviews using the HAMA. Response results were only reported for 224 moderate and severe anxiety (Anxiety Only HAM-A≥18) group of patients (109 in the experimental arm and 115 in the standard of care arm). Among the randomized moderate and severe anxiety patients with only anxiety, 25% in the experimental arm and 17% in the standard care arm were lost to follow up over the 12 week period. Response rate was significantly higher in the NeuroIDgenetix®-guided group as compared to the control group at 12 weeks (63% vs 50%, p=0.04). Study does not report clearly if the analysis was based on intention to treat population. Reporting is incomplete, and suggestive of selective reporting.

Table 14: Summary Characteristics of RCTs Assessing NeuroIDgenetix®

Study	Country	Sites	Dates	Participants	Intervention
					Active	Comparator
Bradley et al (2019)19,	U.S.	20 Psychiatry and primary care settings	2016	Patients with depression and/or anxiety disorders using either HAM D-17 or HAM A score≥18 (moderate and severe) were included in efficacy analysis. Either new to medication or inadequately controlled with medication	Treatment guided by NeuroIDgenetix® (n=352)	SOC (n=333)

Table 15: Summary of Results of RCTs Assessing NeuroIDgenetix®

Study	N	Outcomes
		Response ≥50% decrease in HAM-A 17		Remission: HAM- A17≤7
Bradley et al (2019)19,		12 weeks	P	12 weeks	P
NeuroIDgenetix®	82 (moderate/severe)	63%		NR
Standard Care	95 (moderate/severe)	50%	0.04	NR

Table 16: Study Relevance Limitations: NeuroIDgenetix®

Study	Population	Intervention	Comparator	Outcomes	Duration of follow-up
Bradley et al (2019)19,

^a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use.
^b Intervention key: 1. Classification thresholds not defined; 2. Version used unclear; 3. Not intervention of interest.
^c Comparator key: 1. Classification thresholds not defined; 2. Not compared to credible reference standard; 3. Not compared to other tests in use for same purpose.
^d Outcomes key: 1. Study does not directly assess a key health outcome; 2. Evidence chain or decision model not explicated; 3. Key clinical validity outcomes not reported (sensitivity, specificity and predictive values); 4. Reclassification of diagnostic or risk categories not reported; 5. Adverse events of the test not described (excluding minor discomforts and inconvenience of venipuncture or noninvasive tests).
^e Follow-Up key: 1. Follow-up duration not sufficient with respect to natural history of disease (true-positives, true-negatives, false-positives, false-negatives cannot be determined).

Study	Allocations	Blinding	Selective Reporting	Data Completeness	Power	Statistical
Bradley et al (2019)19,			2 In the clinicaltrials.gov listing, reduction of adverse drug events was listed as the primary outcome, but was not reported as primary outcome Also, Anxiety remission was listed as a secondary outcome but was not reported.	1 Approximately 25% of randomized patients were lost to follow-up or were not included in the outcome analysis at 12 week. Analysis does not appear to be intent to treat.	1 No description of power and sample size calculations

^a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias.
^b Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician.
^c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.
^d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent-to-treat analysis (per protocol for non inferiority trials).
^e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference.
^f Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4. Comparative treatment effects not calculated.

Naumova el al (2019) conducted a randomized pharmacodynamic investigation to evaluate the effect of DRD4 exon 3 polymorphism on child behaviors in response to treatment of ADHD with methylphenidate.^28, In this 2-week prospective within-subject, placebo-controlled, crossover trial there was significant interaction between DRD4 genotype and treatment when the child's behavior was evaluated by the parents (P = 0.035, effect size of 0.014), driven by a better treatment response in children homozygous for long 7-repeat allele.

Section Summary: Genetic Testing to Inform Medication Selection for Patients with a Mental Illness other than Depression Inadequately Controlled with Medication

Evidence for the use of pharmacogenetic testing in patients with mental health conditions other than depression includes a meta-analysis on alcohol use disorder and an RCT on anxiety disorder. The metaanalysis found no significant effect of Asn40Asp on the response to naltrexone treatment of heavy drinking or AUD. The single available trial did not provide adequate or supportive evidence effect of pharmacogenetic testing on managing moderate to severe anxiety. The study had major limitations in design and conduct and precision. The evidence is insufficient to permit conclusions on the health outcome – effects of managing mental health conditions other than depression using pharmacogenetic testing.

No other studies performed a direct intervention study. Jukic et al (2019) conducted a retrospective cohort study using patient data from a routine therapeutic drug monitoring database and showed that CYP2D6 genetic variability had significant effect on risperidone and aripiprazole exposure and treatment and lower doses should be administered to CYP2D6 poor metabolisers to avoid overdosing and dose-dependent side-effects.^29,

Summary of Evidence

For individuals who are evaluated for diagnosis or risk of a mental illness who receive genetic testing for risk of that disorder, the evidence includes various observational studies (cohort, case-control, genome-wide association study). Relevant outcomes are changes in disease status, morbid events, functional outcomes, health status measures, quality of life, and treatment-related morbidity. Most studies evaluated the association between genotype and mental health disorders or gene-drug interactions among patients with risk for mental health conditions. No studies were identified that evaluated whether testing for variants changed clinical management or affected health outcomes. The evidence is insufficient to determine the effects of the technology on health outcomes.

For adult patients with major depressive disorder who have had inadequate response to antidepressant therapy who receive GeneSight® testing guided drug treatment, the evidence includes 2 randomized controlled trials (RCT). Relevant outcomes are symptoms, changes in disease status, morbid events, functional outcomes, health status measures, quality of life, and treatment-related morbidity. The 2 RCTs compared response (≥50% decrease in HAM-D17) and remission (HAMD-17≤7) with antidepressant therapy informed by GeneSight® test results to standard of care (SOC)—antidepressant therapy selected without GeneSight® test results. The Genomics Used to Improve DEpression Decisions (GUIDED) trial by Greden et al (2019) reported statistically significant improvement in response (26% of 560 vs 20% of 607, p=0.01) and remission (15% of 560 vs 10% of 607, p=0.007) in the GeneSight® arm compared to SOC at 8 weeks among patients with MDD using per protocol analysis. Per protocol cohort excluded 401 (22%) of 1799 randomized patients, and additional 231 patients from the per protocol cohort did not complete the study through the blinded week 8 endpoint. The extent of missing data following randomization (35%) precludes conclusions on outcomes at 8 weeks. In the small single center study by Winner et al (2013), depression outcomes did not differ significantly between guided care and SOC groups at the 10-week follow-up and the study was underpowered to detect significant differences in outcomes between study arms. None of these trials provided adequate evidence. Both studies have major limitations in design and conduct and in consistency and precision. The evidence is insufficient to determine the effects of the technology on health outcomes.

For adult patients with major depressive disorder who have had inadequate response to antidepressant therapy who receive NeuroIDgenetix® testing guided drug treatment, the evidence includes 2 randomized controlled trials (RCT). Relevant outcomes are symptoms, changes in disease status, morbid events, functional outcomes, health status measures, quality of life, and treatment-related morbidity. Bradley et al (2018) conducted a double-blind RCT among patients with MDD and reported statistically significant improvement in response (≥50% decrease in HAM-D17) in the NeuroIDgenetix® arm (64% of 140) compared to SOC (46% of 121) at 12 weeks among moderate and severe group of patients (p=0.01) and significant improvement in remission (HAMD-17≤7) in the NeuroIDgenetix® arm (35% of 40) compared to SOC (13% of 53) at 12 weeks among severe group of patients only (p=0.02). There was evidence suggesting selective reporting, as remission was reported for only those with severe depression and contrary to the listing in clinicaltrials.gov adverse drug events was not reported as the primary outcome. It was unclear if the analysis was based on intention-to-treat population and there was high loss to follow-up (15%). In the RCT conducted by Olson et al (2017), among patients with neuropsychiatric disorders those receiving SOC reported significantly more adverse events (53%) than those receiving NeuroIDgenetix® guided care (28%), however, the study did not report the number of patients included in this analysis. The study did not describe the randomization procedure and in ClinicalTrials.gov neurocognitive measures were listed as co-primary outcomes, which were not reported, suggesting possible selective reporting. None of these trials provided adequate evidence. The Olson et al (2017) study had major relevance limitations and both the studies have major limitations in design and conduct and in consistency and precision. The evidence is insufficient to determine the effects of the technology on health outcomes.

For adult patients with major depressive disorder who have had inadequate response to antidepressant therapy who receive Neuropharmagen® testing guided drug treatment, the evidence includes 2 randomized controlled trials (RCT). Relevant outcomes are symptoms, changes in disease status, morbid events, functional outcomes, health status measures, quality of life, and treatment-related morbidity. The 2 RCTs compared response (≥50% decrease in HAM-D17) and remission (HAMD-17≤7) with antidepressant therapy informed by Neuropharmagen ® test results to standard of care (SOC)—antidepressant therapy selected without Neuropharmagen ® test results. The single-blinded RCT by Han et al (2018) reported statistically significant improvement in response (72% of 52 vs 44% of 48, p=0.01) and not statistically significant improvement in remission (46% of 52 vs 26% of 48, p=0.07) in the Neuropharmagen® arm compared to SOC at 8 weeks among patients with MDD. The study reported early dropout of 25% in guided-care and 38% in the standard care arm and used last observation carried forward (LOCF) approach in intention to treat analysis of effectiveness. Use of LOCF assumes data are missing completely at random (MCAR), which is unlikely to hold in this analysis. Also, the study did not report registration in any clinical trial database. The single-blinded RCT by Perez et al (2017) reported statistically not significant improvement in response (45% of 141 vs 40% of 139, p=0.39) and remission (34% of 141 vs 33% of 139, p=0.87) in the Neuropharmagen® arm compared to SOC at 12 weeks among patients with MDD. Response and remission data were missing for 9% patients in the guided care group and 14% of the standard care group. None of these trials provided adequate evidence. Both studies have major limitations in design and conduct and in consistency and precision. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals with a mental illness other than depression who are undergoing drug treatment who receive genetic testing for genes associated with medication pharmacokinetics and pharmacodynamics, the evidence includes a systematic review and meta-analysis and RCTs evaluating associations between specific genes and outcomes of drug treatment. Relevant outcomes are symptoms, changes in disease status, morbid events, functional outcomes, health status measures, quality of life, and treatment-related morbidity. The systematic review and meta-analysis by Hartwell et al (2020) included 7 RCTs and reported no significant moderating effect of rs1799971, a single nucleotide polymorphism (SNP) that encodes a non-synonymous substitution (Asn40Asp) in the mu-opioid receptor gene, OPRM1 on response to naltrexone treatment of alcohol use disorder. Bradley et al (2018) conducted a double-blind RCT among patients with anxiety disorders and reported statistically significant improvement in response (≥50% decrease in HAM-A17) in the NeuroIDgenetix® arm (63% of 82) compared to SOC (50% of 95) at 12 weeks among moderate and severe group of patients (p=0.04). There was evidence suggesting selective reporting, as anxiety remission was not reported and contrary to the listing in clinicaltrials.gov adverse drug events was not reported as the primary outcome. It was unclear if the analysis was based on intention-to-treat population and among the randomized moderate and severe anxiety patients with only anxiety, 25% in the experimental arm and 17% in the standard care arm were lost to follow up over the 12 week period. The evidence is insufficient to determine the effects of the technology on health outcomes.

SUPPLEMENTAL INFORMATION
Practice Guidelines and Position Statements
Clinical Pharmacogenetics Implementation Consortium

In 2009, the Clinical Pharmacogenetics Implementation Consortium (CPIC) was established to develop practice guidelines on the use of genetic laboratory results to inform prescribing decisions.^30, The panel consists of experts from the U. S., Europe, and Asia.

In 2015, the CPIC conducted a systematic literature review on the influence of CYP2D6 and CYP2C19 genotyping on selective serotonin reuptake inhibitor (SSRI) therapy.^31, The CPIC provided dosing recommendations for SSRIs based on phenotypes that classified patients as ultrarapid metabolizers, extensive metabolizers, intermediate metabolizers, and poor metabolizers. However, CPIC noted that patients on an effective and stable dose of SSRIs would not benefit from dose modifications based on CYP2D6 and CYP2C19 genotype results. Additionally, CPIC asserted that genetic testing is only one factor among several clinical factors that should be considered when determining a therapeutic approach.

In 2016, the CPIC conducted a systematic literature review of the influence of CYP2D6 and CYP2C19 genotype on the dosing of tricyclic antidepressants.^32, Dosing recommendations for tricyclic antidepressants were provided, based on patient classifications of ultrarapid metabolizers, extensive metabolizers, intermediate metabolizers, and poor metabolizers (Table 7 and 8).

Table 18. Dosing Recommendations for Antidepressants Based on CYP2D6 and CYP2C19 Phenotype^32,

Recommendations for Tricyclic Antidepressants
Phenotype	Implications	Recommendation	Class of recommendation for amitriptyline and nortripyline	Class of recommendation for other TCAsa
CYP2D6 ultrarapid metabolizer	Increased metabolism to less active compound results in lower plasma concentrations of active drug and decreased probability of drug effectiveness.	Avoid TCA due to potential lack of efficacy. If TCA warranted, consider higher dose with monitoring to guide dose adjustments.	strong	optional
CYP2D6 rapid metabolizer	Normal metabolism of TCAs	Initiate TCA with recommended steady-state dose.	strong	strong
CYP2D6 intermediate metabolizer	Reduced metabolism to less active compound results in higher plasma concentrations of active drug and increased probability of side effects.	Consider 25% reduced starting dose with monitoring to guide dose adjustments.	moderate	optional
CYP2D6 poor metabolizer	Greatly reduced metabolism to less active compound results in higher plasma concentrations of active drug and increased probability of side effects.	Avoid TCA due to potential side effects. If TCA is warranted, consider 50% reduced starting dose with monitoring to guide dose adjustments.	strong	optional
Recommendations for Tertiary Amines Amytriptyline, Clomipramine, Doxepin, Imipramine, and Trimipramine
Phenotype	Implications	Recommendation	Class of recommendation for amitriptyline	Class of recommendation for other tertiary amine TCAs
CYP2C19 ultrarapid and rapid metabolizer	Increased metabolism of tertiary amines to secondary amines may affect efficacy and side effects	Avoid tertiary amines due to potential sub-optimal response. Consider secondary amines. If tertiary amines warranted, use monitoring to guide dose adjustments.	optional	optional
CYP2C19 normal metabolizer	Normal metabolism of tertiary amines	Initiate tertiary amine with recommended steady-state dose.	strong	strong
CYP2C19 intermediate metabolizer	Reduced metabolism of tertiary amines	Initiate tertiary amine with recommended steady-state dose.	strong	optional
CYP2C19 poor metabolizer	Greatly reduced metabolism of tertiary amines to secondary amines may affect efficacy and side effects	Avoid tertiary amines due to potential sub-optimal response. Consider secondary amines. If tertiary amines warranted, consider 50% reduced starting dose with monitoring to guide dose adjustments.	moderate	optional

^a There is less clinical and pharmacokinetic evidence to support genotype-guided dose adjustments for TCAs other than amitriptyline or nortriptyline, though it may be reasonable to apply the same recommendations.
TCA: tricyclic antidepressants.

Table 19. Dosing Recommendations for Amitriptyline Based on Both CYP2D6 and CYP2C19 Phenotypes^a,b

Phenotype	CYP2D6 ultrarapid metabolizer	CYP2D6 normal metabolizer	CYP2D6 intermediate metabolizer	CYP2D6 poor metabolizer
CYP2C19 ultrarapid or rapid metabolizer	Avoid amitryptyline, (optional)	Consider alternative drug. (optional)	Consider alternative drug. (optional)	Avoid amitryptyline. (optional)
CYP2C19 normal metabolizer	Avoid amitryptyline. If amitryptyline is warranted, consider higher target dose, (strong)	Initiate therapy with recommended starting dose. (strong)	Consider 25% reduction of recommended starting dose. (moderate)	Avoid amitryptyline. If amitryptyline is warranted, consider 50% reduction of recommended starting dose. (strong)
CYP2C19 intermediate metabolizer	Avoid amitryptyline. (optional)	Initiate therapy with recommended starting dose. (strong)	Consider 25% reduction of recommended starting dose.(optional)	Avoid amitryptyline. If amitryptyline is warranted, consider 50% reduction of recommended starting dose. (optional)
CYP2C19 poor metabolizer	Avoid amitryptyline. (optional)	Avoid amitryptyline. If amitryptyline is warranted, consider 50% reduction of recommended starting dose. (moderate)	Avoid amitryptyline. (optional)	Avoid amitryptyline. (optional)

^a classification of recommendation appears in parenthesis after every recommendation
^b Recommendations from studies focused on amitryptyline; however, since tricyclic antidepressants have comparable pharmacokinetic properties, these guidelines may apply to other tertiary amines.

In 2007, the EGAPP Working Group commissioned the Agency for Healthcare Research and Quality to conduct a systematic review on CYP450 testing in patients receiving SSRIs.^33, Based on results from the review, EGAPP "found insufficient evidence to support a recommendation for or against use of CYP450 testing in adults beginning SSRI treatment for non-psychotic depression. In the absence of supporting evidence, and with consideration of other contextual issues, EGAPP discourages use of CYP450 testing for patients beginning SSRI treatment until further clinical trials are complete."

International Society of Psychiatric Genetics

In 2018, the International Society of Psychiatric Genetics published a review and recommendations from its Residency Education Committee regarding genetic issues relevant to psychiatric training programs.^34, The Committee only recommends genetic testing as part of a diagnostic workup for patients with autism spectrum disorders or intellectual disability. In regards to pharmacogenetic testing, the Committee states that the "efficacy of these pharmacogenomic profiles requires further investigation in controlled studies."

U.S. Preventive Services Task Force Recommendations

Not applicable.

Ongoing and Unpublished Clinical Trials

Some currently ongoing and unpublished trials that might influence this policy are listed in Table 20.

Table 20. Summary of Key Trials

NCT Number	Title	Enrollment	Completion Date
Ongoing
NCT04207385	Accurate Clinical Study of Medication in Patients With Depression Via Pharmacogenomics (PGx) and Therapeutic Drug Monitoring (TDM) of Venlafaxine	160	November 20, 2021
NCT03952494	Individualizing Antidepressant Treatment Using Pharmacogenomics and EHR-driven Clinical Decision Support	500	April 30, 2021
NCT03907124	Clinical Utility of Pharmacogenomics of Psychotropic Medications	60	February 1, 2021
NCT03749629	Comparative Effectiveness of Pharmacogenomics for Treatment of Depression	400	February 28, 2022
NCT03674138	Pharmacogenomic-Guided Antidepressant Drug Prescribing in Cancer Patients	300	December 10, 2021
NCT03591224a	Pharmacogenomic Testing to Optimize Antidepressant Drug Therapy	200	April 17, 2019
NCT03537547a	Combinatorial Pharmacogenomics Testing in Treatment-Naïve Major Depressive Disorder	120	May 31, 2021
NCT03302364	A Research in Pharmacogenomics and Accurate Medication of Risperidone	800	June 1, 2020
NCT03228953	Pharmacogenomic Testing in Major Depressive Disorder	206	May 15, 2021
NCT02573168a	Pharmacogenomic Decision Support With GeneSight Psychotropic to Guide the Treatment of Schizophrenia/Schizoaffective Disorder	531	September 1, 2020
NCT03270891
Unpublished
NCT02497027	Pharmacogenetic Testing in an Outpatient Population of Patients With Depression	83	April 1, 2017
NCT02474680	Evaluation of Pharmacogenetic Testing In a Mental Health Population and Economic Outcomes	84	January 1, 2017
NCT02479464	Clinical Impact of the Antidepressant Pharmacogenomic Algorithm in an Outpatient Therapy-based Clinical Setting	60	August 1, 2014
NCT02466477a	Pharmacogenomic Decision Support With GeneSight Psychotropic to Guide the Treatment of Major Depressive Disorder	570	September 1, 2019
NCT02443584	Pharmacogenetic Testing on an Outpatient Population With a Depression Diagnosis	84	April 1, 2017
NCT01610063	Evaluation of an Antidepressant Pharmacogenomic Algorithm in an Outpatient Clinical Setting	227	May 1, 2013
NCT01261364	Pharmacogenetic-Directed Treatment for Major Depression	50	September 1, 2011
NCT02855580	Integrating Pharmacogenomic Testing Into a Child Psychiatry Clinic	71	July 6, 2017

NCT: national clinical trial.
^a Denotes industry-sponsored or cosponsored trial.]
________________________________________________________________________________________

Horizon BCBSNJ Medical Policy Development Process:

This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.

___________________________________________________________________________________________________________________________

Index:
Genetic Testing for Diagnosis and Management of Mental Health Conditions
Genetic Testing for Mental Health Conditions
Genecept Assay
STA2R Genetic Panel
SureGene Test for Antipsychotic and Antidepressant Response (STA2R) Genetic Panel
GeneSight Psychotropic Genetic Panel
Proove Opioid Risk Panel
Mental Health DNA Insight Panel
IDgenetix-Branded Tests

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2. Ghafouri-Fard S, Taheri M, Omrani MD, et al. Application of Single-Nucleotide Polymorphisms in the Diagnosis of Autism Spectrum Disorders: A Preliminary Study with Artificial Neural Networks. J Mol Neurosci. Aug 2019; 68(4): 515-521. PMID 30937628

3. Ran L, Ai M, Wang W, et al. Rare variants in SLC6A4 cause susceptibility to major depressive disorder with suicidal ideation in Han Chinese adolescents and young adults. Gene. Feb 05 2020; 726: 144147. PMID 31629822

4. Wan L, Zhang G, Liu M, et al. Sex-specific effects of methylenetetrahydrofolate reductase polymorphisms on schizophrenia with methylation changes. Compr Psychiatry. Oct 2019; 94: 152121. PMID 31476590

5. Zhu D, Yin J, Liang C, et al. CACNA1C (rs1006737) may be a susceptibility gene for schizophrenia: An updated meta-analysis. Brain Behav. Jun 2019; 9(6): e01292. PMID 31033230

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Codes:
(The list of codes is not intended to be all-inclusive and is included below for informational purposes only. Inclusion or exclusion of a procedure, diagnosis, drug or device code(s) does not constitute or imply authorization, certification, approval, offer of coverage or guarantee of payment.)

CPT*

There is no specific CPT code for testing panel. There are specific codes for some of the component tests:
81225
81226
81230
81231
81291
81479
0032U
0033U
0070U
0071U
0072U
0073U
0074U
0075U
0076U