Medical policy: Genetic Testing for Diagnosis and Management of Mental Health Conditions

Policy number: MP 2.264

Effective date: 4/1/2026

Policy

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. There is insufficient evidence to support a general conclusion concerning the health outcomes or benefits associated with this procedure.

Cross-references

• MP 2.234 Cytochrome P450 Genotype Guided Treatment Strategy
• MP 2.253 Genetic Testing for Inherited Thrombophilia
• MP 2.233 General Approach to Evaluating the Utility of Genetic Panels

Product variations

This policy is only applicable to certain programs and products administered by Capital Blue Cross and subject to benefit variations. Please see additional information below.

FEP PPO - Refer to FEP Medical Policy Manual.

Description/background

Individual genes have been shown to be associated with the risk of psychiatric disorders or 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.

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 evaluating requires that directly demonstrate that the use of the test changes 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 (CLIA). Laboratories that offer laboratory-developed tests must be licensed under the auspices of 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 these tests.

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 MTHFR (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

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 largest trial, GUIDED, compared GeneSight‑guided treatment to standard of care (SOC). The primary difference 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 secondary outcomes were observed favoring the GeneSight group. However, the trial had a high loss to follow‑up (21%) and inadequate participant recruitment based on a priori sample size estimation and power analysis.

The GENE-SIGHT arm compared to SOC at 8 weeks among individuals with MDD. However, one‑third of the 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 compared GeneSight guided treatment with SOC, found no statistically significant differences between groups in response or remission on symptom improvement at 8 weeks.

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.

The studies reported statistically significant improvement in response but no statistically significant improvement in remission. One trial reported an early dropout of 25% in the guided arm and 38% in the standard care arm and used the last observation carried forward (LOCF) approach in the ITT analysis of effectiveness. Loss of outcomes data are missing completely at random, which is unlikely to hold in this analysis. Also, the single‑blinded RCT by Perez et al. (2017) reported no statistically significant improvement in response or remission at 12 weeks. None of these trials provided adequate evidence.

For individuals with a mental illness other than depression who are undergoing drug treatment and 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.

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.

A single‑center RCT (2018) conducted a double‑blind RCT among individuals with anxiety disorders and reported statistically significant improvement in response in the NeuroIDgenetix arm compared with SOC at 12 weeks among a moderate and severe anxiety group of patients. 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.

Definitions

N/A

Disclaimer

Capital Blue Cross’ medical policies are used to determine coverage for specific medical technologies, procedures, equipment, and services. These medical policies do not constitute medical advice and are subject to change as permitted by law or applicable clinical evidence from independent treatment guidelines. Treating providers are solely responsible for medical advice and treatment of members. These policies are not a guarantee of coverage or payment. Payment of claims is subject to a determination regarding the member’s benefit program and eligibility on the date of service, and a determination that the services are medically necessary and appropriate. Final processing of a claim is based upon the terms of contract that applies to the member’s benefit program, including benefit limitations and exclusions. If a provider or a member has a question concerning this medical policy, please contact Capital Blue Cross’ Provider Services or Member Services.

Coding information

Note: This list of codes may not be all-inclusive, and codes are subject to change at any time. The identification of a code in this section does not denote coverage as coverage is determined by the terms of member benefit information. In addition, not all covered services are eligible for separate reimbursement.

Genetic testing for mutations associated with mental health disorders are investigational; therefore, not covered

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