ModifiedUnitedHealthcarePolicy CS2O25DOO69W

Ketalar (ketamine) and Spravato (esketamine) medical benefit drug policy

UnitedHealthcare medical benefit drug policy governing coverage criteria, clinical documentation, REMS and dosing alignment for Spravato (esketamine) nasal spray and clinical indications/billing guidance for Ketalar (ketamine) injection. Applies to commercial medical benefit drug claims except for listed states with state-specific guidance.

Policy Summary

PayerUnitedHealthcare

PolicyKetalar (ketamine) and Spravato (esketamine) medical benefit drug policy

Policy CodePolicy CS2O25DOO69W

Change TypeCoverage criteria revised; REMS and dosing alignment updates

Effective DateJun 1, 2025

Next Review Date

Key ActionSubmit prior authorization with medical records documenting baseline depression assessment, evidence of at least two failed antidepressant trials (>=8 weeks each), REMS-certified provider/setting, and psychiatry involvement; initial auth limited to 12 months.

POLICY UPDATE CHANGES

Revised coverage criteria for Spravato: updated required clinical assessments list (added BDI; removed item counts for HAMD, MADRS, QIDS), removed requirement that Spravato be given with an oral antidepressant for TRD initial therapy, and changed treatment failure requirement to at least two antidepressant trials >=8 weeks each.

Application section: specified states where this medical benefit drug policy does not apply and provided state-specific guidance (e.g., Arizona, Colorado exceptions).

Updated supporting Clinical Evidence, FDA, and References sections to reflect current information; archived prior policy version CS2O24DOO69V.

Removed criterion requiring the patient is to receive Spravato therapy in conjunction with an oral antidepressant for Initial Therapy.

Replaced prior requirement of failure of at least three antidepressants with failure of at least two antidepressants or treatment regimens of at least 8 weeks each.

Clarified augmentation options wording to: 'antidepressant or treatment regimen of augmentation with antipsychotics, lithium, or thyroid hormone'.

Removed criterion that the patient has previously been treated with Spravato from Continuation Therapy.

Removed requirement that the patient be treated with Spravato in conjunction with an oral antidepressant for Continuation Therapy.

Policy now defers to product labeling for dosing.

Supporting information and references were updated; previous policy version CS2024DOO69V archived.

2Covered drug products (Spravato, Ketalar)

3Spravato coverage categories

3Not covered indications

2Required prior antidepressant trials

>=8wMin duration per antidepressant trial

Coverage Summary

Scope: This UnitedHealthcare medical benefit drug policy (Policy No. CS2O25DOO69W; effective 2025-06-01) governs coverage criteria, clinical documentation, REMS and dosing alignment for Spravato (esketamine) nasal spray and clinical indications/billing guidance for Ketalar (ketamine) injection. It applies to commercial medical benefit drug claims except in specified states listed with state-specific guidance (e.g., Arizona, Colorado, Florida, Louisiana, New Jersey, New York, Texas — see state application notes).

Overall coverage stance: mixed — some indications are covered (Spravato for TRD and MDD with acute suicidal ideation/behavior; Ketalar for approved anesthetic uses), while other indications are not covered or are investigational (chronic pain, psychiatric disorders for ketamine, anesthetic use for Spravato).

High-level covered vs not-covered indications: Covered drug products: 2 (Spravato, Ketalar). Spravato coverage categories: 3 (TRD initial, TRD continuation, MDD with acute suicidal ideation/behavior). Not covered indications: 3 (chronic pain, anesthetic agent for Spravato, migraine). Required prior antidepressant trials: 2 with minimum duration per trial of >= 8 weeks.

Ketalar (Ketamine) and Spravato (Esketamine) — Indications and Exclusions

This group surfaces anesthesia coverage for ketamine (Ketalar) and investigational exclusions for psychiatric and chronic pain uses, and also summarizes Spravato (esketamine) coverage and not medically necessary indications.

Spravato (Esketamine) — Indications: Spravato (esketamine) is FDA-indicated for treatment-resistant depression (TRD) in adults and for depressive symptoms in adults with major depressive disorder (MDD) with acute suicidal ideation or behavior; it is available only through the Spravato REMS program (restricted dispensing and administration requirements).

Refer to product labeling and REMS for administration and monitoring requirements.

Ketalar (Ketamine) Injection — Indications: Ketalar (ketamine) injection is indicated and may be covered for: anesthesia for diagnostic and surgical procedures that do not require skeletal muscle relaxation; induction of anesthesia prior to administration of other anesthetic agents; and supplemental anesthesia for low-potency agents (e.g., nitrous oxide).

Ketamine is FDA-approved as an anesthetic agent; Spravato is not an anesthetic.

Ketamine Injection — Not Medically Necessary / Investigational: Ketamine injection is investigational and not medically necessary for chronic pain (including nonmalignant pain, fibromyalgia, neuropathic pain, complex regional pain syndrome, reflex sympathetic dystrophy), psychiatric disorders (including but not limited to depression, bipolar disorder, post-traumatic stress disorder), and migraine headaches.

Evidence for ketamine in psychiatric disorders and chronic pain is limited and not sufficient for coverage.

Spravato — Not Medically Necessary: Spravato (esketamine) is unproven and not medically necessary for chronic pain (including nonmalignant pain, fibromyalgia, neuropathic pain, complex regional pain syndrome, reflex sympathetic dystrophy), as an anesthetic agent, and for migraine headaches.

Spravato is not approved as an anesthetic agent and safety/effectiveness for that use have not been established.

Initial Therapy Criteria — Spravato (Esketamine) for TRD and MDD with Acute Suicidal Ideation

Spravato (Esketamine) — Treatment-Resistant Depression (TRD) Initial Therapy

Spravato is proven and medically necessary for TRD when ALL of the following are met:

TRD Initial Therapy

Baseline assessment (ONE of)
- Beck Depression Inventory (BDI)
- Montgomery-Asberg Depression Rating Scale (MADRS)
- Hamilton Rating Scale for Depression (HAMD)
- 9-item Patient Health Questionnaire (PHQ-9)

Continuation Therapy Criteria — Spravato (Esketamine)

Unproven / Not Medically Necessary Indications

Spravato — Not Medically Necessary

Spravato is unproven and not medically necessary for the following indications:

Not Medically Necessary Indications: Spravato (esketamine) is not medically necessary for: chronic pain (including but not limited to nonmalignant pain, fibromyalgia, neuropathic pain, complex regional pain syndrome, reflex sympathetic dystrophy), as an anesthetic agent, and for migraine headaches.

Ketamine Injection — Not Medically Necessary / Investigational

Ketamine injection is investigational and not medically necessary for psychiatric and many chronic pain indications per policy.

Ketamine Injection — Investigational / Not Medically Necessary: Ketamine injection is investigational and not medically necessary for: chronic pain (including but not limited to nonmalignant pain, fibromyalgia, neuropathic pain, complex regional pain syndrome, reflex sympathetic dystrophy); psychiatric disorders (including but not limited to depression, bipolar disorder, post-traumatic stress disorder); and migraine headaches.

Policy cites limited, low-quality evidence and FDA warnings regarding compounded ketamine for psychiatric disorders.

Applicable Codes

HCPCS / Misc procedure codes referencedHCPCS

J3490	Unclassified drugs
S0013	Esketamine, nasal spray, mg

ICD-10 Diagnosis codes referenced (Major Depressive Disorder recurrent / related)ICD-10

F33.0
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

Inclusion of procedure and diagnosis codes in this policy is for reference only and does not guarantee reimbursement; see provider actions for billing guidance and applicable federal, state, or contractual coverage requirements.

Provider Actions & Authorization Requirements

Prior Authorization

Initial authorization and documentation for Spravato (TRD)

Prior authorization requires submission of medical records documenting baseline scoring on an approved depression assessment (BDI, MADRS, HAMD, PHQ-9, or QIDS), documentation of at least two failed antidepressant trials or treatment regimens of adequate dose and duration (>= 8 weeks each), provider and/or treatment setting certified in the Spravato REMS program, prescribed by or in consultation with a psychiatrist, and initial authorization limited to no longer than 12 months.

Baseline assessment on BDI, MADRS, HAMD, PHQ-9, or QIDS
At least 2 failed antidepressant trials or regimens (>= 8 weeks each) with documentation of medication, date, and duration
REMS-certified provider and/or healthcare setting
Prescribed by or in consultation with a psychiatrist
Initial authorization ≤ 12 months

Clinical Evidence Summary

Mixed results across 4 RCTsPhase 3 trials: two of four short-term RCTs met primary endpoints; SUSTAIN-1 showed benefit on time to relapse

Greater response/remission vs placebo; higher discontinuationMeta-analysis: adjunctive intranasal esketamine showed greater response and remission vs placebo but higher discontinuation due to intolerability

Phase 3 randomized controlled trials of intranasal esketamine yielded mixed results: across four Phase 3 RCTs two studies demonstrated statistical superiority on primary endpoints while two did not. The randomized withdrawal trial SUSTAIN-1 showed a benefit favoring continued esketamine on time to relapse.

A pooled meta-analysis of adjunctive intranasal esketamine RCTs (4 trials, n=708) found greater study-defined response and remission versus placebo at multiple time points (effects seen as early as 2 hours and persisting to 28 days) but also a significantly higher rate of discontinuation due to intolerability.

Clinical Evidence and reference sections were updated in the current policy revision (see Summary of Changes) to reflect these trial results and supporting publications.

Background & Definitions

Major depressive disorder (MDD) is a common, often chronic and disabling illness affecting over 16 million people in the United States and over 300 million worldwide, with substantial morbidity, functional impairment, hospitalization risk, suicide risk, and increased mortality. Approximately 30–40% of patients with MDD fail to respond to first-line treatments and patients who have failed at least two adequate antidepressant trials generally comprise the treatment-resistant depression (TRD) population.

Spravato (esketamine) is FDA-indicated for treatment-resistant depression (TRD) in adults and for depressive symptoms in adults with MDD with acute suicidal ideation or behavior; Spravato is available only through the Spravato REMS program, which requires certified healthcare settings and pharmacies, patient enrollment, direct observation at dosing, and monitoring for at least 2 hours post-dose.

Ketamine (Ketalar) is FDA-indicated as an anesthetic agent (induction and supplemental anesthesia for procedures not requiring skeletal muscle relaxation). Use of ketamine for psychiatric disorders or pain is considered investigational per this policy and is not FDA-approved for psychiatric indications.

Revision History

2025-06-01material_revisedLatest

Revised coverage criteria for Spravato: updated required clinical assessments list (added Beck Depression Inventory; removed specific item counts for HAMD, MADRS, QIDS); removed requirement that Spravato be given with an oral antidepressant for TRD initial therapy; changed treatment failure requirement to at least two antidepressant trials >=8 weeks each; clarified augmentation options wording to antipsychotics, lithium, or thyroid hormone; initial authorization length clarified as up to 12 months; dosing to follow FDA labeling.

2025-06-01material_addedLatest

Application section: specified states where this medical benefit drug policy does not apply and provided state-specific guidance (examples: Arizona — refer to state's Medicaid clinical policy; Colorado — for Ketalar (ketamine) MDD refer to Colorado plan criteria).

Policy Summary

PayerUnitedHealthcare

PolicyKetalar (ketamine) and Spravato (esketamine) medical benefit drug policy

Policy CodePolicy CS2O25DOO69W

Change TypeCoverage criteria revised; REMS and dosing alignment updates

Effective DateJun 1, 2025

Next Review Date

On This Page

Quick Inventory of Depressive Symptomatology (QIDS)

Diagnosis of major depressive disorder (treatment-resistant) according to the current DSM (e.g., DSM-5-TR) by a mental health professional

Prior antidepressant trials: 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)>= 2 trials, >= 8 weeks each

Allowed classes and augmentation approaches include SSRIs, SNRIs, bupropion, mirtazapine, serotonin modulators, MAOIs, and augmentation with antipsychotics, lithium, or thyroid hormone.

REMS certification: Provider and/or the provider's healthcare setting is certified in the Spravato REMS program

REMS requires enrollment, administration under direct observation, and monitoring for at least 2 hours post-dose.

Psychiatrist involvement: Prescribed by or in consultation with a psychiatrist

Authorization length: Initial authorization will be for no longer than 12 months<= 12 months

Dosing: Spravato dosing is in accordance with the U.S. FDA approved labeling

Policy defers to product labeling for dosing.

Documentation Required

Continuation authorization documentation

For continuation authorization, submit medical records showing baseline and recent (within the last month) assessment scores on an approved depression scale (BDI, HAMD, MADRS, PHQ-9, or QIDS) demonstrating remission or a positive clinical response (e.g., score reduction from baseline). Provider and/or the provider's healthcare setting must be certified in the Spravato REMS program, prescribed by or in consultation with a psychiatrist, and authorization will be for no longer than 12 months.

Baseline and recent (within 1 month) assessment scores (BDI, HAMD, MADRS, PHQ-9, or QIDS)
Documentation of remission or clinical response to Spravato
REMS-certified provider/setting
Prescribed by or in consultation with a psychiatrist
Authorization ≤ 12 months

Documentation Required

Spravato REMS program requirements

Comply with Spravato REMS program requirements: enroll the patient in the Spravato REMS program; Spravato is dispensed only to and administered in REMS-certified healthcare settings; administration must occur under direct observation with monitoring of the patient for at least 2 hours after each dose; and pharmacies must be REMS-certified and may only dispense Spravato to certified healthcare settings.

Patient enrollment in the Spravato REMS program
Dispensed only to REMS-certified healthcare settings and certified pharmacies
Administer under direct observation with at least 2 hours of post-dose monitoring

Billing Rule

Coding references

Report applicable procedure codes for esketamine as appropriate (examples referenced in this policy include HCPCS S0013 for esketamine, nasal spray, mg, and J3490 for unclassified drugs). Inclusion of codes in the policy is for reference only and does not guarantee reimbursement or claim payment.

HCPCS S0013 — Esketamine, nasal spray, mg
J3490 — Unclassified drugs
Listing of codes does not imply coverage or guarantee payment

Documentation Required

Document prior antidepressant trials

Document the history of failure of at least two different antidepressants or treatment regimens of adequate dose and duration (at least 8 weeks each). Documentation should include the medication(s), dates, and duration of each trial and may include augmentation treatments such as antipsychotics, lithium, or thyroid hormone.

At least 2 different antidepressant trials or regimens documented
Each trial >= 8 weeks with medication name, start/stop dates, and duration
Include any augmentation treatments (antipsychotics, lithium, or thyroid hormone)

Documentation Required

Follow current dosing guidance

Follow current product labeling for Spravato dosing. The policy removed specific dosage requirements and defers to the U.S. FDA–approved labeling or other applicable dosing guidance for appropriate dosing schedules.

Refer to Spravato (esketamine) FDA-approved labeling for dosing
Policy does not specify fixed dose requirements

2025-06-01non_material_revisedLatest

Administrative/documentation updates to Clinical Evidence, FDA, and References sections; archived prior policy version CS2024DOO69V.

2025-06-01material_removedLatest

Removed specific dosage requirements for Spravato from the policy and removed requirement that prior Spravato exposure or concurrent oral antidepressant use be present for Continuation Therapy; policy now defers to product labeling for dosing.