ModifiedUnitedHealthcarePolicy 2025D0069O

Ketalar (Ketamine) and Spravato (Esketamine) — Coverage and Medical Necessity Criteria

Coverage and medical necessity criteria for Spravato (esketamine) nasal spray for TRD and MDD with acute suicidal ideation/behavior, and for Ketalar (ketamine) injection for anesthesia; defines investigational uses and prior authorization/REMS requirements affecting providers submitting requests for UnitedHealthcare members.

Policy Summary

PayerUnitedHealthcare

PolicyKetalar (Ketamine) and Spravato (Esketamine) — Coverage and Medical Necessity Criteria

Policy CodePolicy 2025D0069O

Change TypeRevised coverage criteria and assessment requirements

Effective Date05/01/2025

Next Review DateN/A

Key ActionSubmit prior authorization with documentation of diagnosis, baseline and recent depression assessment scores, and record of at least two failed antidepressant trials (medication, dates, durations) and REMS certification.

SourceLink

POLICY UPDATE CHANGES

Revised coverage criteria for Spravato (esketamine) nasal spray including updates to applicable clinical assessments and initial/continuation therapy requirements.

Replaced several prescriptive criteria (DSM-5-TR phrasing and specific rating scale item counts) with simplified language such as 'diagnosis of major depressive disorder' and removed item-count specifics for certain scales.

Changed required number/duration of failed antidepressant trials from three (8 weeks) to history of failure of at least two different antidepressants or regimens of at least 8 weeks each.

Added Benefit Considerations.

>=2antidepressant trials required for TRD definition

12 months

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Coverage and Medical Necessity Criteria

inv-01: Spravato for Treatment-Resistant Depression — Initial Therapy

Covered when ALL of the following are met

TRD Initial Therapy Criteria: Diagnosis of major depressive disorder (treatment-resistant); and patient has not experienced a clinically meaningful improvement after treatment with at least two different antidepressants; and history of failure of a trial of at least two different antidepressants or treatment regimens for a duration of at least 8 weeks each (document medication, date, and duration of trial); and provider and/or the provider's healthcare setting is certified in the Spravato REMS program; and prescribed by or in consultation with a psychiatrist; and Spravato dosing is in accordance with the United States Food and Drug Administration approved labeling; and initial authorization will be for no longer than 12 months.>=2 prior antidepressant trials

Includes acceptable antidepressant classes and augmentation strategies listed in policy

inv-02: Spravato — Continuation/Reauthorization

Covered when ALL of the following are met

Continuation Criteria: Documentation of remission or a positive clinical response to Spravato therapy; and submission of medical records documenting baseline and recent (within the last month) scoring on at least one accepted depression assessment (BDI, HAMD, MADRS, PHQ-9, or QIDS) demonstrating remission or clinical response; and provider and/or the provider's healthcare setting is certified in the Spravato REMS program; and prescribed by or in consultation with a psychiatrist; and Spravato dosing is in accordance with the United States FDA approved labeling; and reauthorization will be for no longer than 12 months.recent assessment within 1 month

Reauthorization limited to 12 months

inv-03: Spravato for MDD with Acute Suicidal Ideation or Behavior

Covered when ALL of the following are met

MDD with Acute Suicidality: Diagnosis of major depressive disorder; and patient is experiencing acute suicidal ideation or behavior; and patient is to receive Spravato therapy in conjunction with a newly initiated or optimized oral antidepressant (per ASPIRE trial standard of care); and provider and/or the provider's healthcare setting is certified in the Spravato REMS program; and Spravato dosing is in accordance with the United States FDA approved labeling; and initial authorization will be for no longer than 12 months.co-therapy with oral antidepressant

Prescribed by or in consultation with a psychiatrist implied

inv-04: Ketalar (Ketamine) Injection — Covered Uses

Covered when ALL of the following are met

Ketamine Injection Indications: Anesthesia for diagnostic and surgical procedures that do not require skeletal muscle relaxation; and the induction of anesthesia prior to administration of other anesthesia agents; and as supplemental anesthesia for low-potency agents, such as nitrous oxide.

Ketamine injection is FDA-approved as an anesthetic

inv-05: Esketamine (Spravato) coverage criteria

Covered when ALL of the following clinical trial–based criteria are met (evidence presented in document):

Population and diagnosis: Patient meets DSM-5 diagnostic criteria for major depressive disorder (recurrent MDD or single-episode MDD ≥ 2 years) without psychotic features, verified by structured interview (e.g., MINI), and has moderate to severe depressive symptoms as defined in phase 3 trials (e.g., elevated MADRS/IDS-C scores).

Based on phase 3 trial inclusion criteria.

Treatment resistance: Lack of clinically meaningful improvement (defined in phase 3 studies as ≤ 25%) in the current episode after treatment with at least 2 different antidepressant agents prescribed in adequate dosages for an adequate duration (defined for phase 3 studies as at least 6 weeks).

Per phase 3 study TRD definition.

Setting/administration requirements for Spravato: Spravato administration must occur in a certified REMS healthcare setting with patient REMS enrollment and monitoring (including observation per REMS, e.g., monitoring post-dose), and dispensing limited to certified pharmacies to certified healthcare settings.

inv-06: Ketamine evidence and coverage considerations

Ketamine (IV or other routes) — evidence summary and limited-use considerations:

Evidence summary: IV ketamine demonstrates rapid antidepressant effects in small randomized trials and meta-analyses with significant effects at 24 hours and sustained effects up to 7 days; repeated infusions may be more effective than single infusions, but long-term efficacy and safety data are limited.

Multiple systematic reviews and pooled analyses.

Use in bipolar depression: Limited evidence suggests a single IV ketamine dose may produce transient benefit in bipolar depression; overall data are limited and further placebo-controlled studies are needed.

Cochrane/systematic review conclusions.

inv-07: Revised coverage criteria highlights

Coverage rationale and criteria were revised for Spravato (esketamine) nasal spray for TRD and MDD as summarized below.

Assessment tools updated: Acceptable clinical assessments updated to include Beck Depression Inventory (BDI) and removed specific item-count requirements for HAMD, MADRS, and QIDS.

From Policy History

Diagnosis requirement simplified: Replaced 'diagnosis of major depressive disorder according to DSM-5-TR by a mental health professional' with a simplified 'diagnosis of major depressive disorder'.

From Policy History

Prior antidepressant trials for Initial Therapy: Replaced prior requirement of three antidepressant trials with history of failure of at least two different antidepressants or treatment regimens for a duration of at least 8 weeks each in some parts of the policy; documentation of medications, dates, and durations required.>=2 prior antidepressant trials

From Policy History

Spravato (esketamine) nasal spray and ketamine formulations are explicitly identified in this policy as unproven and not medically necessary for certain uses. Specifically, Spravato is not medically necessary when used as an anesthetic agent, and both Spravato and ketamine are not medically necessary for treatment of chronic pain (including fibromyalgia, neuropathic pain, CRPS) and migraine headaches. Ketamine injection is also considered not medically necessary for psychiatric disorders (including but not limited to depression, bipolar disorder, and PTSD).

Per FDA labeling, Spravato is not approved as an anesthetic agent and its safety and effectiveness for anesthetic use have not been established. Spravato is indicated for treatment-resistant depression and depressive symptoms in adults with MDD with acute suicidal ideation or behavior (in conjunction with an oral antidepressant), and is available only through the Spravato REMS program.

The FDA has issued a public warning about potential risks associated with compounded ketamine products, including oral formulations, for the treatment of psychiatric disorders. The policy references this FDA safety communication as a rationale for caution and exclusion of compounded ketamine products for psychiatric indications.

Ketamine injection (e.g., Ketalar) is FDA‑approved as an anesthetic agent for induction and supplementation of anesthesia, but its use for psychiatric disorders and for chronic pain (including fibromyalgia, neuropathic pain, CRPS) is considered investigational and not medically necessary. The policy therefore covers ketamine injection for FDA‑approved anesthetic indications only and designates non‑anesthetic psychiatric and chronic pain uses as investigational/not covered.

Hayes technology assessments rate ketamine for treatment‑resistant unipolar depression as rating C (potential but unproven benefit), reflecting preliminary positive but methodologically limited evidence. For posttraumatic stress disorder and treatment‑resistant bipolar depression Hayes assigned rating D2 (insufficient evidence). These assessments support the policy stance that ketamine’s benefit for many psychiatric indications remains unproven.

When documentation or prior treatment requirements specified in the revised coverage criteria are not met, there is an implied risk that the request will be denied. Providers should note that the policy now requires documentation of prior antidepressant trials and accepted assessment scores as described in the coverage criteria; failure to provide these records may render therapy not medically necessary under the policy.

Relevant Billing and Diagnosis Codes

Applicable HCPCS/Procedure CodesHCPCS

J3490	Unclassified drugs.
S0013	Esketamine, nasal spray, 1 mg

Applicable ICD-10 CodesICD-10

F33.0	Major depressive disorder, recurrent, mild.
F33.1	Major depressive disorder, recurrent, moderate.
F33.2	Major depressive disorder, recurrent severe without psychotic features.
F33.3	Major depressive disorder, recurrent, severe with psychotic symptoms.
F33.40	Major depressive disorder, recurrent, in remission, unspecified.
F33.41	Major depressive disorder, recurrent, in partial remission.
F33.42	Major depressive disorder, recurrent, in full remission.
F33.8	Other recurrent depressive disorders.
F33.9	Major depressive disorder, recurrent, unspecified

Antidepressant trial duration

Policy requirementAntidepressant trial duration: at least 8 weeks each for prior treatment documentation required by the policy.

Phase 3 studies definitionPhase 3 trial definition used in studies: adequate duration defined as at least 6 weeks per antidepressant trial.

Documentation neededProviders must document medication name, date, and duration for each antidepressant trial (each ≥8 weeks per policy).

Adequate prior antidepressant trials

Minimum number of agentsAt least 2 different antidepressant agents required (per phase 3 study definition and policy step requirement).

Minimum duration per agent (study)

Documentation, Prior Authorization, and REMS Requirements

Prior Authorization

Prior Authorization Required

Prior authorization is required for Spravato (esketamine) and for Ketalar (ketamine) when used for indications covered by this policy. Requests must include supporting clinical documentation as described below. Dispensing or administration of Spravato outside of the REMS-certified setting or without documented patient enrollment in the Spravato REMS may result in denial of coverage.

Prior authorization required for Spravato and Ketalar when used for covered psychiatric indications.
Requests lacking REMS documentation or REMS-certified setting will be at risk for denial.

Denial Risk

Unproven Indications — Denial Risk

Providers must document that the requested use is for a medically accepted indication per this policy. Use of Spravato or ketamine for unproven or investigational indications is not covered and will be denied.

Initial Spravato Therapy Requirements

inv-38: Spravato Initial — Initial Spravato therapy coverage requirements

Covered when ALL of the following are met

Initial Spravato therapy coverage requirements: Diagnosis of major depressive disorder (treatment-resistant); patient has not experienced a clinically meaningful improvement after treatment with at least two different antidepressants; history of failure of at least two different antidepressant trials or regimens for at least 8 weeks each (document medication, date, duration); provider/setting REMS certified; prescribed by or in consultation with a psychiatrist; dosing per FDA labeling; initial authorization will be for no longer than 12 months.>=2 prior antidepressant trials

Initial authorization ≤ 12 months

inv-39: Spravato monotherapy — Monotherapy indication basis

Covered when ALL of the following are met

Monotherapy indication basis: Randomized double-blind placebo-controlled study in 378 TRD adults showed statistically significant improvement in MADRS at day 28 for Spravato 56 mg and 84 mg versus placebo when used as monotherapy, supporting the monotherapy indication.

Continuation / Reauthorization Requirements

inv-41: Spravato Continuation — Continuation therapy requires evidence of response/remission and REMS certification

Covered when ALL of the following are met

Continuation Spravato: Documentation of remission or positive clinical response with submission of baseline and recent (within last month) depression scale scores; provider/setting REMS certified; dosing per FDA labeling; reauthorization will be for no longer than 12 months.

Continuation therapy requires evidence of response/remission and REMS certification

inv-42: Esketamine continuation/relapse prevention — Evidence from SUSTAIN-1 randomized withdrawal

Covered when ALL of the following are met

Relapse prevention (SUSTAIN-1 evidence): Continuation of esketamine plus oral antidepressant reduced time to relapse compared with switch to placebo (oral antidepressant ongoing) in stable remitters/responders in SUSTAIN-1, supporting continuation to prevent relapse.

Supports continuation/relapse prevention per SUSTAIN-1.

Required Prior Treatment Trials

Requirement	Provider action / documentation
Document history of prior antidepressant trials
List each medication or treatment regimen with start and stop dates and duration (document medication, date, and duration of trial)

Evidence requirement	Policy interpretation / required documentation
Clinical trials defined TRD as lack of clinically meaningful improvement (≤25%) after treatment with ≥2 different antidepressant agents at adequate dose and duration (phase 3 definition: ≥6 weeks)
Policy requires history of failure of at least two different antidepressants or treatment regimens, with each trial documented and of at least 8 weeks duration (document medication, date, and duration)

Indication / scenario	Prior trial requirement
Treatment‑Resistant Depression (policy initial therapy)
History of failure of at least two different antidepressants or treatment regimens, each for at least 8 weeks (document medication, date, duration)

Administration Setting and REMS Certification

Note

Administer only in REMS‑certified office or infusion center

The administering provider or healthcare setting must be certified in the Spravato REMS program, which implies administration in controlled settings such as an office or infusion center with monitoring.

Confirm office or infusion center REMS certification prior to scheduling treatment.
Document the REMS-certified location on the prior authorization and in treatment records.

Billing Rule

No home administration — use certified infusion center or office

Spravato must be administered and monitored in REMS‑certified healthcare settings; it cannot be dispensed for home administration.

Schedule administration in a certified setting with capability for direct observation and post‑dose monitoring.

Key Terms and Definitions

Treatment-Resistant Depression (TRD)

TRD operational definitionTreatment‑Resistant Depression (TRD): patients who have failed at least two trials of antidepressant treatment in the current episode (documented inadequate response).

Clinical implicationsPatients with TRD often have more severe morbidity, higher hospitalization and suicide risk, and may require switching agents, augmentation, psychotherapy, or procedural referral (ECT/TMS).

Policy useCoverage and step therapy criteria reference failure of ≥2 adequate antidepressant trials as qualifying TRD population for esketamine consideration.

Esketamine (Spravato)

Drug identityEsketamine (Spravato) is the S‑enantiomer of racemic ketamine and a non‑competitive NMDA receptor antagonist.

Indications

Clinical and Evidence Background

Major depressive disorder (MDD) is common and can be treatment‑resistant; approximately 30–40% of patients fail to respond to first‑line treatments. Treatment‑resistant depression (TRD) is generally defined in this policy and the cited phase 3 trials as failure to achieve a clinically meaningful response after treatment with at least two adequate antidepressant trials in the current episode.

Policy Summary

PayerUnitedHealthcare

PolicyKetalar (Ketamine) and Spravato (Esketamine) — Coverage and Medical Necessity Criteria

Policy CodePolicy 2025D0069O

Change TypeRevised coverage criteria and assessment requirements

Effective Date05/01/2025

Next Review DateN/A

SourceLink

On This Page

Documentation Required

Documentation for Prior Therapy

Submit clinical documentation of prior antidepressant treatment trials to demonstrate treatment resistance. Documentation must include medication name, dose, dates, duration of trial, and reason for discontinuation when applicable.

Document at least two different antidepressant trials (or regimens) of at least 8 weeks each, including classes or augmentation strategies where applicable (e.g., SSRI, SNRI, bupropion, mirtazapine, tricyclics, MAOI, augmentation with antipsychotics, lithium, or thyroid hormone).
If prior records are from another provider or facility, include chart notes or pharmacy records confirming dates and durations.
Failure to provide adequate prior therapy documentation may result in denial.

Documentation Required

REMS Certification and FDA Dosing Requirements

Providers and healthcare settings administering or dispensing Spravato must be certified in the Spravato REMS program. Spravato must be dosed and administered in accordance with the FDA-approved labeling. Records must document patient enrollment in the REMS program and REMS-related actions.

Healthcare setting and provider REMS certification is required prior to dispensing or administration.
Spravato must only be dispensed to and administered in REMS-certified healthcare settings; pharmacies must only dispense to certified healthcare settings.
Dosing and administration must follow the current FDA-approved labeling; do not substitute non‑labeled dosing.
REM S documentation should include: patient enrollment confirmation, observation and monitoring records (including the required post‑dose observation period), and REMS program actions taken.

Documentation Required

REMS Documentation — What to Submit

Maintain and submit REMS-related documentation with prior authorization requests and for audit. This includes proof of REMS certification for the setting, patient REMS enrollment, and monitoring/observation records for each administration.

Proof of facility and/or provider certification in the Spravato REMS program.
Confirmation that the patient is enrolled in the Spravato REMS prior to dosing.
Documentation of direct observation during administration and monitoring records demonstrating at least the required post‑dose observation period (per REMS/FDA guidance).
Pharmacy records showing certified-dispensation to REMS-certified healthcare settings, when applicable.

Documentation Required

Required Clinical Documentation

Required clinical documentation must accompany prior authorization requests. Provide diagnostic confirmation, baseline and follow-up assessment scores, and evidence of treatment response (for continuation requests).

Diagnosis: Major depressive disorder (MDD) or treatment‑resistant depression (TRD) as specified in this policy.
Baseline assessment: Submit baseline score from at least one accepted depression assessment (BDI, HAMD, MADRS, PHQ‑9, QIDS).
For continuation: Submit recent assessment (within the last month) showing remission or clinically meaningful improvement (e.g., score reduction from baseline) on one of the accepted scales.
Prescriber: Must be prescribed by or in consultation with a psychiatrist when required by criteria in this policy.

Step Therapy

Definition of Treatment‑Resistant Depression (TRD) and Step Requirement

Treatment-resistant depression (TRD) is defined for coverage as inadequate clinically meaningful improvement after appropriate antidepressant therapy. For the purposes of this policy, TRD requires failure of at least two different antidepressant agents or treatment regimens in the current depressive episode.

Phase 3 clinical study definitions: lack of clinically meaningful improvement (≤25% improvement in some studies) after ≥2 adequate antidepressant trials.
This policy operationalizes TRD as failure of at least two different antidepressants or regimens, each of at least 8 weeks' duration (document medications, dates, doses, and durations).
Providers should document the specific antidepressants or augmentation regimens tried, doses, duration, and reason for discontinuation.

inv-40: Initial Therapy — Initial therapy criteria were simplified

Covered when ALL of the following are met

Initial Therapy: Diagnosis of major depressive disorder; and failure to experience clinically meaningful improvement after treatment with at least two different antidepressants (policy language simplified from earlier versions); and provider/setting REMS certified; and Spravato dosing per FDA labeling; and initial authorization ≤ 12 months.>=2 prior antidepressant trials

Initial therapy criteria were simplified in policy revision.

inv-43: Continuation Therapy — Continuation therapy criteria were revised

Covered when ALL of the following are met

Continuation therapy changes: Removed requirement that the patient previously be treated with Spravato and removed requirement to receive Spravato with an oral antidepressant; removed specific dosage requirements and refer to FDA labeling for dosing; reauthorization limited to 12 months.

From Policy History

TRD — Phase 3 study definition

Phase 3 TRD definitionIn phase 3 studies, TRD was defined as lack of clinically meaningful improvement (≤25%) in the current depressive episode after treatment with at least 2 different antidepressant agents prescribed at adequate dosages for an adequate duration.

Adequate duration in studiesAdequate duration for those trials in the phase 3 studies was defined as at least 6 weeks per agent.

MeasurementClinical improvement assessment used standardized scales (e.g., MADRS) with centralized blinded raters to determine response in trials.

Spravato REMS

REMS requirementSpravato is available only through a restricted REMS program requiring healthcare settings and pharmacies to be certified; patients must be enrolled in the REMS.

Dispensing/administration settingSpravato must be dispensed and administered only in certified healthcare settings with monitoring per REMS (includes observation post-dose).

Certification and recordsProviders/settings must be certified in the Spravato REMS and records should document enrollment, observed administration, and monitoring (e.g., at least 2 hours post-dose).

TRD implied definition

Implied TRD definition in policyMajor depressive disorder not responding to adequate trials of antidepressants; policy references failure of at least two trials in the current episode as qualifying TRD.

Required documentationPolicy requires documentation of prior antidepressant trials (medication, date, duration) to support TRD designation and coverage decisions.

Policy threshold alignmentThe policy aligns the TRD concept with phase 3 trial definitions (≥2 failed agents) while specifying longer durations for policy documentation (≥8 weeks each where specified).