Medical Policy

Policy Num:      11.003.049
Policy Name:    Genetic Testing for Diagnosis and Management of Mental Health Conditions
Policy ID:          [11.003.049]  [Ac / B / M- / P-]  [2.04.110]

Last Review:       August 20, 2024
Next Review:      August 20, 2025
 

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02.001.033 - Transcranial Magnetic Stimulation as a Treatment of Depression and Other Psychiatric/Neurologic Disorders
11.003.008 - Cytochrome P450 Genotype-Guided Treatment Strategy
07.001.030 - Vagus Nerve Stimulation
07.001.031 - Deep Brain Stimulation
08.001.045 - Cranial Electrotherapy Stimulation and Auricular Electrostimulation

Genetic Testing for Diagnosis and Management of Mental Health Conditions

Summary

Description

Individual genes have been shown to be associated with the risk of psychiatric disorders and specific aspects of psychiatric drug treatment such as drug metabolism, treatment response, and risk of adverse events. Commercially available testing panels include several of these genes and are intended to aid in the diagnosis and management of mental health disorders.

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 individuals at 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 that the technology results in an improvement in the net health outcome.

For adult individuals with major depressive disorder (MDD) who receive GeneSight testing guided drug treatment, the evidence includes 4 randomized controlled trials (RCTs). Relevant outcomes are symptoms, change in disease status, morbid events, functional outcomes, health status measures, quality of life, and treatment-related morbidity. The RCTs compared response (≥50% decrease in Hamilton Depression Rating Scale-17 [HAM-D17] or Patient Health Questionnaire-9 [PHQ-9]), remission (HAM-D17 ≤7 or PHQ-9 ≤5), and symptom improvement (mean % change in HAM-D17 or PHQ-9) with antidepressant therapy informed by GeneSight test results to antidepressant therapy selected without GeneSight test results (ie, standard of care [SOC]). The PRecision Medicine In MEntal Health Care (PRIME Care) trial did not find a statistically significant difference between GeneSight guided treatment and SOC in the primary outcome of remission at 24 weeks follow-up, but significant differences in the secondary outcome of symptom score improvement and treatment response were observed, favoring the GeneSight group. However, this trial had a high loss to follow-up (21%) and had inadequate participant recruitment based on a priori sample size estimation and power analysis. The GUIDED trial reported statistically significant improvements in response and remission in the GeneSight arm compared to SOC at 8 weeks among individuals with MDD. However, depending on the population (intention to treat [ITT] or per protocol), up to one-third of GUIDED randomized participants were missing from the reported results; the extent of missing data following randomization precludes conclusions on outcomes at 8 weeks. The GAPP-MDD trial, also comparing GeneSight guided treatment with SOC, found no statistically significant differences between groups in response, remission or symptom improvement at 8 weeks follow-up, although like the GUIDED trial, a high proportion (up to 69%) of randomized participants were excluded from outcome analysis and the study was not adequately powered to detect between-group differences. In the third trial, a small, single-center pilot study by Winner et al (2013), depression outcomes did not differ significantly between GeneSight-guided care and SOC groups at the 10-week follow-up, though the study was underpowered to detect significant differences in outcomes between study arms. All of these trials have major limitations in design and conduct and in consistency and precision, thus none provided adequate evidence. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For adult individuals with MDD who receive NeuroIDgenetix testing guided drug treatment, the evidence includes 2 RCTs. 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 (p=.01) and significant improvement in remission (HAM-D17 ≤7) in the NeuroIDgenetix arm (35% of 40) compared to SOC (13% of 53) at 12 weeks (p=.02). There was evidence of reporting bias and ,it was unclear if the analysis was based on ITT population; there was also 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 studies have major limitations in design and conduct and in consistency and precision. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For adult individuals with MDD who receive Neuropharmagen testing guided drug treatment, the evidence includes 2 RCTs. 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 (HAM-D17 ≤7) with antidepressant therapy informed by Neuropharmagen test results to antidepressant therapy selected without Neuropharmagen test results (ie, SOC). The single-blinded RCT by Han et al (2018) reported statistically significant improvement in response (72% of 52 vs. 44% of 48; p=.01) but no statistically significant improvement in remission (46% of 52 vs. 26% of 48; p=.07) in the Neuropharmagen arm compared to SOC at 8 weeks among patients with MDD. The study reported an early dropout of 25% in guided-care and 38% in the standard care arm and used the last observation carried forward (LOCF) approach in the ITT analysis of effectiveness. Use of LOCF assumes data are missing completely at random, 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 non-statistically significant improvement in response (45% of 141 vs. 40% of 139; p=.39) and remission (34% of 141 vs. 33% of 139; p=.87) in the Neuropharmagen arm compared to SOC at 12 weeks among individuals with MDD. Response and remission data were missing for 9% of individuals in the guided care group and 14% in the SOC 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 that the technology results in an improvement in the net health outcome.

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 individuals with anxiety disorders and reported statistically significant improvement in response (≥50% decrease in Hamilton Rating Scale for Anxiety [HAM-A] ) in the NeuroIDgenetix arm (63% of 82) compared to SOC (50% of 95) at 12 weeks among a moderate and severe group of patients (p=.04). There was evidence of reporting bias and, it was unclear if the analysis was based on the ITT population. Furthermore, among the randomized moderate and severe anxiety patients with only anxiety, 25% in the experimental arm and 17% in the SOC arm were lost to follow-up over the 12-week period. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Additional Information

Not applicable

Objective

The objective of this evidence review is to assess whether the use of genetic tests for diagnosis or management improves the net health outcome of individuals with mental health disorders. Assessment of the clinical utility of a pharmacogenomic test requires direct evidence from intervention studies that compare health outcomes of patients managed with and without the test.

Policy Statements

Genetic testing for diagnosis and management of mental health disorders is considered investigational in all situations, including but not limited to the following:

• To confirm a diagnosis of a mental health disorder in an individual with symptoms.

• To predict future risk of a mental health disorder in an asymptomatic individual.

• To inform the selection or dose of medications used to treat mental health disorders, including but not limited to the following medications:

  • selective serotonin reuptake inhibitors

  • selective norepinephrine reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors

  • tricyclic antidepressants

  • antipsychotic drugs.

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.

Policy Guidelines

Coding

Please see the Codes table for details.

Benefit Application

Benefits are determined by the group contract, member benefit booklet, and/or individual subscriber certificate in effect at the time services were rendered.  Benefit products or negotiated coverages may have all or some of the services discussed in this medical policy excluded from their coverage.

BlueCard/National Account Issues

Some Plans may have contract or benefit exclusions for genetic testing.

Background

This evidence review 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 individuals receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

The primary goal of pharmacogenomic 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 is from randomized controlled trials.

Regulatory Status

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).

Also, many labs offer genetic testing for individual genes, including MTFHR (GeneSight Rx and other laboratories), cytochrome P450 variants, and SULT4A1.

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.

Rationale

This evidence review was created in November 2013 and has been updated regularly with searches of the PubMed database. The most recent literature update was performed through May 27, 2024.

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. The test must be technically reliable, clinically valid, and clinically useful for that purpose. Evidence reviews assess the evidence on whether a test is clinically valid and clinically useful. Technical reliability is outside the scope of these reviews, and credible information on technical reliability is available from other sources.

Promotion of greater diversity and inclusion in clinical research of historically marginalized groups (e.g., People of Color [African-American, Asian, Black, Latino and Native American]; LGBTQIA (Lesbian, Gay, Bisexual, Transgender, Queer, Intersex, Asexual); Women; and People with Disabilities [Physical and Invisible]) allows policy populations to be more reflective of and findings more applicable to our diverse members. While we also strive to use inclusive language related to these groups in our policies, use of gender-specific nouns (e.g., women, men, sisters, etc.) will continue when reflective of language used in publications describing study populations.

Population Reference No. 1 

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 individuals 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 following PICO was used to select literature to inform this review.

Populations

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

Interventions

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

Comparators

The following practices are currently being used to make decisions about management of mental illness: diagnosis and risk assessment without genetic testing.

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 general outcomes of interest are change in disease state, morbid events, functional outcomes, health status measures, quality of life and treatment-related morbidity.

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. Standardized outcome measures are available for many mental illnesses. Commonly used measures for the evaluation of depression in clinical trials are described in the next section.

Study Selection Criteria

Assessment of clinical utility of a genomic test cannot be made by a chain of evidence from clinical validity data alone. 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, randomized controlled trials (RCTs) are needed.

• We sought RCTs 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 to achieve clinically meaningful improvement compared with standard of care (SOC).

• 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.

Review of Evidence

We did not find any RCT evaluating the use of genetic test results to inform decisions on mental health diagnoses or management of patients at 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 at 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 at 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.

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 individuals at 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 that the technology results in an improvement in the net health outcome.

Population Reference No. 2 

Genetic Testing to Inform Medication Selection for Patients with Depression

Clinical Context and Test Purpose

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

Populations

The relevant population of interest is adult individuals who have a diagnosis of major depressive disorder (MDD).

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. 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.

The symptoms are not attributable to another medical condition, or behavioral disorder or substance abuse.^9,The goal of treatment is remission of depression. While response to treatment is defined as 50% or greater reduction of symptoms; the patient who has responded, but is not in remission, may still bear a considerable burden of depression. Moreover, the risk of recurrence is greater than when remission is achieved. The main categories of treatment for MDD are psychotherapy, pharmacotherapy, and brain stimulation therapies. These may be used in combination. First-generation antidepressants are tricyclic antidepressants and monoamine oxidase inhibitors. Classes of second-generation antidepressants are: selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors and atypical agents.

Individuals who fail to achieve remission of MDD after 2 vigorous trials of antidepressant medications 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.^10, Individuals may stop treatment due to side effects of antidepressants, which can include drowsiness; insomnia/agitation; orthostatic hypotension; QTc prolongation; gastrointestinal toxicity; weight gain; and sexual dysfunction.

Interventions

The interventions being considered are commercially available pharmacogenetic tests to inform medication selection.

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 following practices are currently being used to make decisions about antidepressant drug selection: antidepressant selection without pharmacogenetic testing.

At present, there is no definitive algorithm for selecting next line treatment after failure to respond to initial treatment.

Outcomes

The general outcomes of interest are symptoms, change in disease state, morbid events, functional outcomes, health status measures, quality of life, and treatment-related morbidity.

There are standardized outcome measures for depression (eg, Hamilton Rating Scale for Depression [HAM-D], Montgomery-Asberg Depression Rating Scale [MADRS], Patient Health Questionnaire 9 item [PHQ-9], and Beck's Depression Inventory [BDI]). Scoring for the HAM-D, MADRS, and PHQ-9 are shown in Table 1.

HAM-D and MADRS are physician scored scales that rate the presence and intensity of attributes of depression. The HAM-D, introduced by Max Hamilton in 1960, is the progenitor of depression measurement scales. Attributes rated include depressive mood, guilt feelings, insomnia, suicidal ideas or attempts, work, and activity. However, shortcomings of HAM-D are incomplete overlap with the Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV criteria for MDD and weak item-level inter-rarer reliability.^12, Nonetheless, HAM-D has moderate to high correlation with other depression scales. Various versions have been developed, intended to make the instrument easier to use. The 17-item HAM-D (HAM-D17) is the most commonly used instrument in trials of depression drugs.^13, The MADRS is the next most commonly used instrument in trials of depression drugs. Attributes scored include sadness, pessimism, inability to feel, and suicidal thoughts. As with HAM-D, MADRS has incomplete overlap with DSM criteria for MDD. MADRS is reported to correlate to other depression scales, including the HAM-D17. MADRS is generally reported to be more sensitive to treatment related change and to have better inter-rater reliability than HAM-D17; perhaps because of its more uniform structure.

The PHQ-9 is a self-administered scale used to assess depression based on the 9 criteria for depression outlined in the DSM-IV. It rates symptoms on a scale from "0" (not at all) to "3" (nearly every day) over a 2-week period.^14,The criteria include: little interest in doing things, feeling down or depressed, difficulty with sleep, low energy levels, poor appetite or overeating, poor self-perception, difficulty concentrating, high or low speed of functioning, and thoughts of suicidality or self-harm. Cut-offs at scores of 5, 10, 15, and 20 represent mild, moderate, moderately severe, and severe depression. The PHQ-9 has been extensively validated for accuracy in over 30 clinical studies.^15,

Table 1. Measures of Depression in Adults

Secondary endpoints are:

• Clinical Global Impression (CGI)
• Sheehan Disability Scale (SDS)

The CGI and SDS may supplement depression rating scales, by assessing the severity of illness and functional impairment, respectively. However, the measurement properties of these instruments are not well characterized.

The CGI “asks that the clinician rate the patient relative to their experience with other patients with the same diagnosis, with or without collateral information.” There are 3 components: Severity of Illness (CGI-S), Improvement (CGI-I), and the efficacy index, each rated on a scale of 1 to 7. Severity of Illness ranges from 1 “not ill at all” to 7 “among the most extremely ill.” A comparative meta-analysis of change in CGI in antidepressant trials found that, among double-blind trials, the CGI-S was more conservative than HAM-D and MADRS in showing change in severity of depression.^16, There is little evidence available on the validity and reliability of these measures.^13,

The SDS was developed as a simple tool to address the “desynchrony between psychiatric symptoms and disability”: that some “very symptomatic patients who still functioned reasonably well socially and at work, while other patients with less severe and less frequent symptoms were quite disabled.”^17, The SDS is a self-reported 3-item instrument used to assess the impact of symptoms on the individual’s work, family, and social life. Each item is scored on an 11-point scale with 0 indicating no impairment and 10 extreme impairment, with a score greater than 5 suggesting functional impairment. A study of 1001 primary care patients showed that almost half of patients with elevated SDS score had a psychiatric disorder diagnosis.^18, No minimally important clinical difference has been set for assessing change in SDS score.^13,

Typically, short term response for established classes of antidepressants is assessed in studies of 6 to 8 weeks duration, based on mechanism of pharmacologic response. As rapid-acting anti-depressants become available, a week or even less could be sufficient.

Maintenance, the ability of a treatment to reduce recurrence of MDD, is equally important. At least 6 months of follow-up is typically required to assess the ability of an agent to reduce recurrence.

Study Selection Criteria

Assessment of clinical utility of a genomic test cannot be made by a chain of evidence from clinical validity data alone. 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, RCTs are needed.

• We sought RCTs 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 to achieve clinically meaningful improvement compared with SOC.

• 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.

Review of Evidence

GeneSight^® test

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 individual.

Systematic Reviews and Meta-Analyses

Brown et al (2022) conducted a comprehensive meta-analysis that synthesized the findings of prospective RCTs and open-label trials investigating the efficacy of pharmacogenomic guided testing in achieving remission of depressive symptoms.^19, The meta-analysis revealed a favorable rate of remission among individuals who received therapy guided by pharmacogenomics compared to those receiving SOC treatment for depression. The analysis included a total of 13 trials, consisting of 10 RCTs and 3 open-label studies published through July 2022. Six of these included studies utilized the GeneSight test for guiding pharmacogenomic therapy. The analysis encompassed a sample of 4,767 individuals across these 13 trials, with individual study sample sizes ranging from 44 to 1,944 participants. With the exception of 2 trials, all studies exclusively enrolled individuals diagnosed with MDD. The majority of trials (69%) measured their primary endpoint at 8 weeks after baseline, although the range extended to 24 weeks. Remission was primarily assessed using the HAM-D17, while alternative rating scales were used in 2 trials. Notably, all studies included pharmacogenomic assessments of the cytochrome P450 (CYP)-C19 and CYP2D6 genes, although other genes tested varied across studies.

The pooled risk ratio (RR) for remission, comparing pharmacogenomic guided therapy (n=2395) to unguided therapy (n=2372), was 1.41 (95% confidence interval [CI], 1.15 to 1.74), favoring guided therapy. The authors observed moderate to substantial heterogeneity between the studies (I²=62%). Stratifying the analysis to only include RCTs (n=10) yielded a similar effect size for remission rates (RR, 1.45; 95% CI, 1.13 to 1.88), which remained statistically significant. However, when limiting the analysis to the open-label trials (n=3), the effect size was no longer statistically significant (RR, 1.26; 95% CI, 0.84 to 1.88). The authors also found that the number of prior antidepressant therapies and severity of depression symptoms had moderating effects on the RR for pharmacogenomic guided therapy, suggesting that as the severity and number of treatments increased, the RR for guided therapy also increased. No moderating effects were observed for age, sex, ancestry, or weeks to the primary endpoint. A subgroup analysis omitted the 6 GeneSight studies and found that the pooled RR for remission remained significant across the remaining trials (RR, 1.46; 95% CI, 1.02 to 2.09; p=.04).

To evaluate the risk of bias in the included studies, the authors employed the Cochrane Risk of Bias Tools, specifically Cochrane Risk of Bias version 2 for RCTs and Risk Of Bias In Non-randomized Studies of Interventions for open-label controlled studies. The majority of trials (n=10) were sponsored by industry, and 77% of them had published protocols prior to the commencement of the study. Among the 10 included RCTs, low risk of bias was observed for attrition and selection, while high risk of bias was identified for performance. Blinding procedures varied across the studies, with participants being blinded in all RCTs, but treating physicians and, in 2 cases, outcome assessors were not blinded. One RCT was found to have a high risk of reporting bias due to selectively reporting outcomes for a subset of patients. Regarding the 3 open-label studies, low risk of bias was observed for pre-intervention selection, at-intervention information, and post-intervention confounding. However, the authors reported that post-intervention information and industry biases were high in 2 trials. Additionally, 1 trial exhibited a moderate risk of reporting bias, and 2 studies demonstrated post-intervention selection bias. Assessment of publication bias using funnel plot asymmetry and Egger's regression indicated no indication of publication bias. Although the authors found an increased likelihood of remission among individuals with depression who received pharmacogenomic guided therapy, the heterogeneity in study methodology, such as the variations in the genetic variants tested, poses challenges in making recommendations for a specific testing strategy.

Randomized Controlled Trials

Four RCTs compared response and remission with antidepressant therapy informed by GeneSight test results to antidepressant therapy selected without gene test results (ie, SOC)(Table 2).^20,21,22,23,Due to limitations in these trials, discussed below, no conclusions can be drawn from these trials about the differential effect of treatment guided by GeneSight versus SOC.

The PRecision Medicine In MEntal Health Care (PRIME Care) RCT compared 24-week outcomes in adults with MDD who received either GeneSight-guided therapy or SOC.^20, The study included 1,944 participants from 22 Veteran’s Affairs medical centers who were randomly assigned to either pharmacogenomic-guided treatment (n=966) or SOC (n=978). Assessments were conducted at baseline and every 4 weeks until 24-weeks follow-up.

The authors reported a small and nonpersistent effect on the co-primary outcome of symptom remission. A significant difference in symptom remission rates on the PHQ-9 was reported favoring the GeneSight group at weeks 8 and 12, but no meaningful differences were detected at weeks 4, 18, or 24. The overall pooled effect over time for remission, however, remained favorable for the GeneSight group by a small margin (odds ratio [OR], 1.28; 95% CI, 1.05 to 1.5; p=.02) (Table 3). The other co-primary outcome, treatment initiation after pharmacogenomics testing, showed that more GeneSight-guided participants were likely to be prescribed an antidepressant in the first 30 days after testing (OR, 0.74; 95% CI, 0.6 to 0.92; p=.005). The pharmacogenomic-guided patients were less also likely to be classified as having no antidepressant and gene interaction compared to moderate or substantial interaction compared to SOC (OR, 2.08; 95% CI, 1.52 to 2.84; p=.005). The selection of genetic markers for antidepressant response has faced challenges due to the presence of confounding factors among the studied populations and large heterogeneity between studies, and we are unable to determine the clinical significance of the proprietary GeneSight algorithm used for predicted drug-gene interactions.^24, The secondary outcomes of response rate (OR, 1.25; 95% CI, 1.07 to 1.46; p=.005) and symptom improvement (risk difference [RD], 0.56; 95% CI, 0.17 to 0.95; p=.005) on the PHQ-9 also demonstrated an overall pooled effect over time (Table 3).

Study relevance and design/conduct limitations are summarized in Tables 4 and 5. The PRIME trial exhibits a notable methodological limitation by lacking an intention-to-treat analysis. A power calculation was performed, indicating that each treatment arm necessitated 1000 participants to detect a 5% disparity in the remission rate, accounting for an estimated 20% loss to follow-up and possessing 80% statistical power. The trial fell short of achieving the desired recruitment level, and by the conclusion of the 24-week follow-up period, approximately 22% (n=196) of the GeneSight group and 20% (n=172) of the SOC group were lost to follow-up, exacerbating the recruitment issue. In the PRIME trial, solely the outcome assessors were subject to blinding, while both the participants and their treating clinicians were informed of the treatment allocation. Consequently, the potential placebo effect within this trial remains uncertain.

Two similarly-designed RCTs (GUIDED^21, and GAPP-MDD^22,) compared 8-week outcomes in individuals who received treatment for MDD guided by GeneSight testing or SOC. In both GUIDED (N=1,799) and GAPP-MDD (N=437), the primary outcome was symptom improvement, measured by a change in HAM-D. Secondary outcomes were response and remission. Neither trial found a significant difference between GeneSight guided treatment and SOC in symptom improvement (Table 3). The GUIDED trial found treatment guided by GeneSight associated with a statistically significant benefit for response and remission compared with treatment as usual, while there were no significant differences between GeneSight and TAU groups in the GAPP-MDD trial for response or remission (Table 3).

The GUIDED trial randomized 1,799 individuals. After post-randomization exclusions, according to the text, 1,541 individuals remained, in what was labeled the intention to treat (ITT) cohort, but the ITT results reported in Figure 2 included only 1,299 participants. The publication text also describes a per protocol cohort that included 1,398 participants, yet only 1,167 of these participants are accounted for in the study results reported in Figure 1 of the text. The participant flow chart included in the Supplement describes missing data as occurring because of loss to follow-up, or study withdrawal due to inclusion/exclusion violations, HAM-D or Quick Inventory of Depressive Symptomatology (QIDS) scores, out of window visits, withdrawal of consent, or other reasons. Depending on the population (ITT or per protocol), up to one third of GUIDED randomized participants were missing from the reported results. The GAPP-MDD trial had similar limitations. The trial initially randomized 437 individuals, and the publication supplement indicates an ITT population of 363 individuals and a per protocol population of 202 individuals at 8 weeks. Reasons given for post-randomization exclusions were similar to those in the GUIDED trial: loss to follow-up, or study withdrawal due to inclusion/exclusion violations, QIDS score, withdrawal of consent or "other." The GAPP-MDD publication reported symptom improvement for 203 individuals in the ITT population and for 134 individuals in the per protocol population; data from 308 ITT and 196 per protocol individuals were reported for response and remission. Depending on the population (ITT or per protocol) and the outcome analyzed, data from 30% to 69% of randomized individuals were missing. In both trials, the post-randomization exclusions and analysis methods do not conform with definitions of ITT and there were no sensitivity analyses for the missing data provided.^25,26, In addition to these limitations, enrollment in the GAPP-MDD trial was stopped early due to a determination that it would not be possible to enroll enough participants to adequately power the trial. Although initially designed to enroll 570 participants, GAPP-MDD investigators revised that calculation based on results from the GUIDED trial, subsequently determining that a sample size of 4,000 would be required to achieve 90% power. Based on the recalculation, the GAPP-MDD results would have been powered at less than 25% probability to detect a difference between treatment groups even if the full, planned enrollment of 570 had been achieved.

A pilot RCT by Winner et al (2013) evaluated the effect of providing the GeneSight test on the management of psychotropic medications used for MDD in a single outpatient psychiatric practice (see Table 2).^23, Fifty-one patients were enrolled and randomized to treatment as usual or treatment guided by GeneSight testing. All patients 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 patients' medication regimens with the same likelihood in the GeneSight group (53%) and the treatment as usual group (58%; p=.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=.02). Depression outcomes, measured by the HAM-D17 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. The GeneSight directed arm and the SOC arm included 26 and 25 patients, respectively, in this pilot study for a larger trial.

Table 2. Summary Characteristics of RCTs Assessing GeneSight Test

HAM-D17: Hamilton Depression Rating Scale 17 item; MDD: major depressive disorder; NR: not reported; PRIME Care: PRecision Medicine In MEntal Health Care; QIDS: Quick Inventory of Depressive Symptomatology; QIDS-C16: 16-item Quick Inventory of Depressive Symptomatology (clinician rated); QIDS-SR16: 16-item Quick Inventory of Depressive Symptomatology (self rated); RCT: randomized controlled trial; SOC: standard of care.

Table 3. Summary of Results of RCTs Assessing GeneSight

CI: Confidence interval; HAM-D17: Hamilton Depression Rating Scale 17 item; ITT: intention to treat; MD: mean difference; OR: odds ratio; PHQ-9: Physcian Health Questionnaire 9 item; PP: per protocol; PRIME Care: PRecision Medicine In MEntal Health Care; SE: standard error; SOC: standard of care.

Table 4. Study Relevance Limitations: GeneSight

MDD: major depressive disorder; PRIME Care: PRecision Medicine In MEntal Health Care.The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.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 predictivevalues); 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).

Table 5. Study Design and Conduct Limitations: GeneSight

ITT: intention to treat; PRIME Care: PRecision Medicine In MEntal Health Care; SOC: standard of careThe study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.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.

Section Summary: GeneSight test

Evidence for the use of GeneSight test to inform antidepressant selection includes 4 RCTs. None of the trials provided adequate evidence, and all have major limitations in design and conduct, and in consistency and precision.

Summary of Evidence

For adult individuals with major depressive disorder (MDD) who receive GeneSight testing guided drug treatment, the evidence includes 4 randomized controlled trials (RCTs). Relevant outcomes are symptoms, change in disease status, morbid events, functional outcomes, health status measures, quality of life, and treatment-related morbidity. The RCTs compared response (≥50% decrease in Hamilton Depression Rating Scale-17 [HAM-D17] or Patient Health Questionnaire-9 [PHQ-9]), remission (HAM-D17 ≤7 or PHQ-9 ≤5), and symptom improvement (mean % change in HAM-D17 or PHQ-9) with antidepressant therapy informed by GeneSight test results to antidepressant therapy selected without GeneSight test results (ie, standard of care [SOC]). The PRecision Medicine In MEntal Health Care (PRIME Care) trial did not find a statistically significant difference between GeneSight guided treatment and SOC in the primary outcome of remission at 24 weeks follow-up, but significant differences in the secondary outcome of symptom score improvement and treatment response were observed, favoring the GeneSight group. However, this trial had a high loss to follow-up (21%) and had inadequate participant recruitment based on a priori sample size estimation and power analysis. The GUIDED trial reported statistically significant improvements in response and remission in the GeneSight arm compared to SOC at 8 weeks among individuals with MDD. However, depending on the population (intention to treat [ITT] or per protocol), up to one-third of GUIDED randomized participants were missing from the reported results; the extent of missing data following randomization precludes conclusions on outcomes at 8 weeks. The GAPP-MDD trial, also comparing GeneSight guided treatment with SOC, found no statistically significant differences between groups in response, remission or symptom improvement at 8 weeks follow-up, although like the GUIDED trial, a high proportion (up to 69%) of randomized participants were excluded from outcome analysis and the study was not adequately powered to detect between-group differences. In the third trial, a small, single-center pilot study by Winner et al (2013), depression outcomes did not differ significantly between GeneSight-guided care and SOC groups at the 10-week follow-up, though the study was underpowered to detect significant differences in outcomes between study arms. All of these trials have major limitations in design and conduct and in consistency and precision, thus none provided adequate evidence. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Population Reference No. 3 

NeuroIDgenetix test

Randomized Controlled Trials

Two RCTs reported results of antidepressant therapy selection, informed by NeuroIDgenetix test results compared to antidepressant therapy selected without Neuropharmagen test results (ie, SOC).

Bradley et al (2018) conducted a double-blinded RCT in which 685 individuals with depression and/or anxiety disorders were randomized to treatment guided by either NeuroIDgenetix or SOC (Table 6).^27, Outcomes included HAM-D, the Hamilton Rating Scale for Anxiety (HAM-A), and adverse drug events. Trained and blinded clinicians conducted interviews using the HAM-D and HAM-A. Approximately 15% of randomized patients were lost to follow up over the 12-week period. Response results were only reported for 261 individuals in the moderate and severe group and remission results were reported for 93 individuals in the severe group. Response rates (p<.001; OR: 4.72; 95% CI, 1.93 to 11.52) and remission rates (p<.02; OR: 3.54; 95% CI, 1.27 to 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 ITT population. Reporting is incomplete and suggestive of selective reporting.

Olson et al (2017) conducted an RCT in which individuals with neuropsychiatric disorders were randomized to treatment guided by NeuroIDgenetix or SOC (see Table 6).^28, A majority of the individuals, 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 Symbol Digit Coding test 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 individuals receiving SOC 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 individuals 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

ADHD: attention deficit hyperactivity disorder; HAM-A: Hamilton Anxiety Rating Scale; HAM-D17: Hamilton Depression Rating Scale 17 item; RCT: randomized controlled trial; SOC: standard of care.

Table 7. Summary of Results of RCTs Assessing NeuroIDgenetix

 HAM-D17: Hamilton Depression Rating Scale 17 item; NR; not reported; RCT: randomized controlled trial; SOC: standard of care.

Table 8. Study Relevance Limitations: NeuroIDgenetix

ADHD: attention deficit hyperactivity disorder.The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.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).

Table 9. Study Design and Conduct Limitations: NeuroIDgenetix

ITT: intention to treat.The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.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.

Section Summary: NeuroIDgenetix test

Evidence for the use of NeuroIDgenetix test to inform antidepressant selection includes 2 RCTs, 1 reporting response and remission as outcomes and another reporting adverse events as the 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.

Summary of Evidence

For adult individuals with MDD who receive NeuroIDgenetix testing guided drug treatment, the evidence includes 2 RCTs. 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 (p=.01) and significant improvement in remission (HAM-D17 ≤7) in the NeuroIDgenetix arm (35% of 40) compared to SOC (13% of 53) at 12 weeks (p=.02). There was evidence of reporting bias and ,it was unclear if the analysis was based on ITT population; there was also 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 studies have major limitations in design and conduct and in consistency and precision. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Population Reference No. 4 

Neuropharmagen Test

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 management of individuals with depression.^29, The study included 2 RCTs and a multicenter, retrospective, observational study.^30,31,32, Evidence from both RCTs are discussed below.

Randomized Controlled Trials

Han et al (2018) conducted a randomized, single-blind clinical trial among individuals 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).^30, Neuropharmagen analyzes 30 genes associated with drug metabolism and 59 medications used to treat MDD. The primary endpoint was change in HAM-D17 score from baseline to 8 weeks follow-up. Response rate (at least 50% reduction in HAM-D17 score from baseline), remission rate (HAM-D17 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. The ITT population consisted of all individuals who had at least 1 post-treatment assessment for effectiveness during the study. The effectiveness evaluation was based on ITT analysis with last observation carried forward (LOCF). The mean change of HAM-D17 score was significantly different between the 2 groups favoring the guided arm by a −4.1 point of difference (p=.010) at the end of treatment. The response rate (71.7 % vs. 43.6%; p=.014) was also significantly higher in the guided arm than in the SOC arm at the end of treatment, while the remission rate was numerically higher in the guided arm than in the SOC arm without statistical difference (45.5% vs. 25.6%; p=.071). The study reported an early dropout of 25% in the guided-care and 38% in the SOC arms. The reason for early dropout associated with adverse events was higher in the SOC arm (n=9, 50.0%) than in the guided care arm (n=4, 30.8%). The effectiveness evaluation was based on ITT analyses with LOCF. Use of LOCF assumes data are missing completely at random (MCAR).^33, The distribution of reasons for termination among early dropouts indicates that the assumption of MCAR is unlikely to hold in this analysis. The study did not report registration in any clinical trial database.

Perez et al (2017) conducted a single-blind RCT (AB-GEN trial) of individuals diagnosed with MDD randomized to genotype-guided treatment (Neuropharmagen) or treatment as usual (see Table 10).^31, The pharmacogenetics report from Neuropharmagen provided information on 50 drugs, highlighting gene-drug interactions and drug recommendations from the FDA 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=.05) at the end of the 12-week study (see Table 11). Changes in HAM-D17 scores were significant at 5 weeks (p=.04) but not at 12 weeks (p=.08). Response and remission rates were calculated post-hoc based on the HAM-D17 (single-blinded). There was no significant difference in response (45.4% vs. 40.3%; p=.39) or remission (34.0% vs. 33.1%; p=.87) between guided care and SOC arms at 12 weeks. However, response and remission data were missing for 9% of patients in the guided care group and 14% in the SOC group.

Table 10. Summary Characteristics of RCTs Assessing Neuropharmagen

CGI-I: Clinical Global Impression-Improvement; DSM: Diagnostic and Statistical Manual of Mental Disorders; MDD: major depressive disorder; NR: not reported; RCT: randomzied controlled trial; SOC: standard of care; TR: text revision.

Table 11. Summary of Results of RCTs Assessing Neuropharmagen

CI: confidence interval; HAM-D17: Hamilton Depression Rating Scale 17 item; OR: odds ratio; RCT: randomized controlled trial; SOC: standard of care.

Table 12. Study Relevance Limitations: Neuropharmagen

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment. 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. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4.Not the intervention of interest.c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively.d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. No CONSORT reporting of harms; 4. Not establish and validated measurements; 5. Clinical significant difference not prespecified; 6. Clinical significant difference not supported.e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms.

Table 13. Study Design and Conduct Limitations: Neuropharmagen

HAM-D17: Hamilton Depression Rating Scale 17 item; LOCF: last observation carried forward; SOC: standard of care.The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.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.

Section Summary: Neuropharmagen Test

Evidence for the use of Neuropharmagen test to inform antidepressant selection for patients with MDD 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.

Summary of Evidence

For adult individuals with MDD who receive Neuropharmagen testing guided drug treatment, the evidence includes 2 RCTs. 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 (HAM-D17 ≤7) with antidepressant therapy informed by Neuropharmagen test results to antidepressant therapy selected without Neuropharmagen test results (ie, SOC). The single-blinded RCT by Han et al (2018) reported statistically significant improvement in response (72% of 52 vs. 44% of 48; p=.01) but no statistically significant improvement in remission (46% of 52 vs. 26% of 48; p=.07) in the Neuropharmagen arm compared to SOC at 8 weeks among patients with MDD. The study reported an early dropout of 25% in guided-care and 38% in the standard care arm and used the last observation carried forward (LOCF) approach in the ITT analysis of effectiveness. Use of LOCF assumes data are missing completely at random, 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 non-statistically significant improvement in response (45% of 141 vs. 40% of 139; p=.39) and remission (34% of 141 vs. 33% of 139; p=.87) in the Neuropharmagen arm compared to SOC at 12 weeks among individuals with MDD. Response and remission data were missing for 9% of individuals in the guided care group and 14% in the SOC 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 that the technology results in an improvement in the net health outcome.

Population Reference No. 5 

Genetic Testing to Inform Medication Selection for Patients with a Mental Illness other than Depression

Clinical Context and Test Purpose

The purpose of pharmacogenetic testing in individuals 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 following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with a mental illness other than depression.

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 STAR*D 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.

Study Selection Criteria

Assessment of clinical utility of a genomic test cannot be made by a chain of evidence from clinical validity data alone. 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, RCTs are needed..

• We sought RCTs 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 to achieve clinically meaningful improvement compared with SOC.

• 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.

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 patients randomly assigned to receive naltrexone and 597 received placebo).^34, 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=.02). However, the effect was not significant when multiple comparisons were taken into account. There was no statistically significant heterogeneity (I²=33.8%, p=.18).

Randomized Controlled Trials

Bradley et al (2018) conducted a double-blind RCT in which 685 individuals with depression and/or anxiety disorders were randomized to treatment guided by either NeuroIDgenetix or SOC (Table 14).^27, Among the participants, 115 in the experimental arm and 120 in the SOC arm had only anxiety. Outcomes included percent reduction in HAM-A and response (50% reduction in HAM-A) rate. Trained and blinded clinicians conducted interviews using the HAM-A. 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 SOC arm). Among the randomized moderate and severe anxiety patients with only anxiety, 25% in the experimental arm and 17% in the SOC 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=.04). The study does not report clearly if the analysis was based on the ITT population. Reporting is incomplete and suggestive of selective reporting.

Table 14. Summary Characteristics of RCTs Assessing NeuroIDgenetix

HAM-A: Hamilton Anxiety Rating Scale; HAM-D17: Hamilton Depression Rating Scale 17 item; RCT: randomzied contolled trial; SOC: standard of care.

Table 15. Summary of Results of RCTs Assessing NeuroIDgenetix

HAM-A: Hamilton Anxiety Rating Scale; NR: not reported; RCT: randomzied contolled trial; SOC: standard of care.

Table 16. Study Relevance Limitations: NeuroIDgenetix

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.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).

Table 17. Study Design and Conduct Limitations: NeuroIDgenetix

ITT: intention to treat.The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.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.

Kampangkaew et al (2019) conducted a study among cocaine and opioid codependent individuals randomized into disulfiram (n=32) and placebo (n=35) groups for 12 weeks of treatment and evaluated the role of SLC6A3 (DAT1) 40 bp 3′‐untranslated region variable number tandem repeat variant in moderating disulfiram efficacy for cocaine dependence.^35, Study reported better treatment outcomes with disulfiram pharmacotherapy of cocaine dependence among individuals with genetically higher dopamine transporter (DAT) levels compared to those with lower DAT levels.

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 attention deficit hyperactivity disorder (ADHD) with methylphenidate.^36, 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=.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 individuals with mental health conditions other than depression includes a meta-analysis on alcohol use disorder and an RCT on anxiety disorder. The meta-analysis found no significant effect of Asn40Asp on the response to naltrexone treatment of heavy drinking or alcohol use. 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.

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 a significant effect on risperidone and aripiprazole exposure and treatment and lower doses should be administered to CYP2D6 poor metabolizers to avoid overdosing and dose-dependent side-effects.^37,

Summary of Evidence

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 individuals with anxiety disorders and reported statistically significant improvement in response (≥50% decrease in Hamilton Rating Scale for Anxiety [HAM-A] ) in the NeuroIDgenetix arm (63% of 82) compared to SOC (50% of 95) at 12 weeks among a moderate and severe group of patients (p=.04). There was evidence of reporting bias and, it was unclear if the analysis was based on the ITT population. Furthermore, among the randomized moderate and severe anxiety patients with only anxiety, 25% in the experimental arm and 17% in the SOC arm were lost to follow-up over the 12-week period. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Supplemental Information

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Practice Guidelines and Position Statements

Guidelines or position statements will be considered for inclusion in ‘Supplemental Information’ if they were issued by, or jointly by, a US professional society, an international society with US representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

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.^38, The panel consists of experts from the U. S., Europe, and Asia.

In 2023, the CPIC conducted a systematic literature review on the influence of CYP2D6, CYP2C19, CYP2B6, SLC6A4, and HTR2A genotyping on selective serotonin reuptake inhibitor (SSRI) therapy.^39, The CPIC concluded that SLC6A4 and HTR2A are not yet supported for clinical use in antidepressant prescribing. Dosing recommendations for SSRIs based on CYP2D6, CYP2C19, and CYP2B6 phenotypes that classified patients as ultrarapid metabolizers, rapid metabolizers, intermediate metabolizers, poor metabolizers, or indeterminant metabolizers are presented in Tables 18 and 19. However, the CPIC noted that individuals on an effective and stable dose of SSRIs would not benefit from dose modifications based on 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.

Table 18. Dosing Recommendations for Antidepressants Based on CYP2D6, CYP2C19, and CYP2B6 Phenotype^39,

CYP: cytochrome P450

Table 19. Dosing Recommendations for Sertraline Based on CYP2C19 and CYP2B6 phenotypes

CYP: cytochrome P450.

International Society of Psychiatric Genetics

In 2019, The International Society of Psychiatric Genetics (ISPG) issued recommendations on the use of pharmacogenetic testing in the management of psychiatric disorders, and in 2020 published the evidence review used to inform the recommendations.^40,41, The recommendations state: "we recommend HLA [human leukocyte antigen]-A and HLA-B testing prior to use of carbamazepine and oxcarbazepine, in alignment with regulatory agencies and expert groups. Evidence to support widespread use of other pharmacogenetic tests at this time is still inconclusive, but when pharmacogenetic testing results are already available, providers are encouraged to integrate this information into their medication selection and dosing decisions. Genetic information for CYP2C19 and CYP2D6 would likely be most beneficial for individuals who have experienced an inadequate response or adverse reaction to a previous antidepressant or antipsychotic trial."

The ISPG also included the following considerations regarding pharmacogenetic testing:

• Common genetic variants alone are not sufficient to cause psychiatric disorders such as depression, bipolar disorder, substance dependence, or schizophrenia. Genotypes from large numbers of common variants can be combined to produce an overall genetic risk score which can identify individuals at higher or lower risk, but at present it is not clear that this has clinical value.

• There is growing evidence that rare, pathogenic variants with large effects on brain function play a causative role in a significant minority of individuals with psychiatric disorders and may be a major cause of illness in some families. Identification of known pathogenic variants may help diagnose rare conditions that have important medical and psychiatric implications for individual patients and may inform family counseling. Identification of de novo mutations and copy number variants (CNVs) may also have a place in the management of serious psychiatric disorders. CNV testing may also prove useful for persons requesting counseling on familial risk. While the Committee did not reach consensus on widespread use of CNV testing in adult-onset disorders, most agreed that such tests may have value in cases that present atypically or in the context of intellectual disability, autism spectrum disorder, learning disorders, or certain medical syndromes.

• Professional counseling can play an important role in the decision to undergo genetic testing and in the interpretation of genetic test results. We recommend that diagnostic or genome-wide genetic testing should include counseling by a professional with expertise in both mental health and the interpretation of genetic tests. Consultation with a medical geneticist is recommended, if available, when a recognized genetic disorder is identified or when findings have reproductive or other broad health implications.

• Whenever genome-wide testing is performed, the possibility of incidental (secondary) findings must be communicated in a clear and open manner. Procedures for dealing with such findings should be made explicit and should be agreed with the patient or study participant in advance. The autonomy of competent individuals regarding preferences for notification of incidental findings should be respected.

• Genetic test results, like all medical records, are private data and must be safeguarded against unauthorized disclosure with advanced encryption and computer security systems.

• We advocate the development and dissemination of education programs and curricula to enhance knowledge of genetic medicine among trainees and mental health professionals, increase public awareness of genetics and genetic testing, and reduce stigma.

• Expanded research efforts are needed to identify relevant genes and clarify the proper role of genetic testing and its clinical utility in psychiatric care.

• Pharmacogenetic testing should be viewed as a decision-support tool to assist in thoughtful implementation of good clinical care.

U.S. Preventive Services Task Force Recommendations

Not applicable.

Medicare National Coverage

There is no national coverage determination. In the absence of a national coverage determination, coverage decisions are left to the discretion of local Medicare carriers.

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: national clinical trial.a Denotes industry-sponsored or cosponsored trial.

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Policy History