CurrentUnitedHealthcarePolicy CS2025D0069W

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

UnitedHealthcare medical benefit drug policy governing coverage criteria, required documentation, and exclusions for Spravato (esketamine) nasal spray and Ketalar (ketamine) injection for commercial lines (with state exceptions noted). This part covers indications, initial and continuation therapy criteria for Spravato, investigational determinations for ketamine, applicable billing codes, background, FDA REMS requirements, and revision history (effective 2025-06-01).

Policy Summary

PayerUnitedHealthcare

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

Policy CodePolicy CS2025D0069W

Change TypeCoverage criteria revised; assessments updated; dosing/co-administration requirements removed

Effective DateJun 1, 2025

Next Review Date

Key ActionSubmit medical records documenting baseline (and for continuation, recent within last month) scoring on at least one listed depression assessment and document failure of at least two antidepressant trials (>=8 weeks each); ensure provider/setting is REMS-certified and follow product labeling for dosing.

POLICY UPDATE CHANGES

Application: Added language to indicate this Medical Benefit Drug Policy does not apply to the state of Arizona; refer to the state's Medicaid clinical policy.

Coverage criteria for Spravato (esketamine) nasal spray: updated list of applicable clinical assessments and adjusted TRD trial requirements.

Continuation criteria: removed requirement that patient previously treated with Spravato and removed requirement to receive Spravato with an oral antidepressant.

Supporting information updated: Clinical Evidence, FDA, and References sections refreshed.

Added Beck Depression Inventory (BDI) to applicable clinical assessments for depression.

Removed requirement that Spravato be administered in conjunction with an oral antidepressant for initial and continuation therapy.

Reduced prior antidepressant trial requirement from at least three to at least two trials of adequate dose and duration (>= 8 weeks each).

Removed specific dosage requirements for Spravato (esketamine) from this policy.

Archived previous policy version CS2024D0069V and updated clinical evidence, FDA, and references sections.

2+Required failed antidepressant trials for TRD

<=12mInitial authorization duration

BDI/HAMD/MADRS/PHQ-9/QIDSAccepted depression assessments

RemovedOral antidepressant co-administration

Coverage Summary

This UnitedHealthcare Medical Benefit Drug Policy (Policy No. CS2025D0069W; effective 06/01/2025) governs coverage criteria, required documentation, and exclusions for Spravato (esketamine) nasal spray and Ketalar (ketamine) injection for commercial lines. It specifies initial and continuation therapy criteria for Spravato for treatment-resistant depression (TRD) and for major depressive disorder (MDD) with acute suicidal ideation or behavior, includes required documentation and REMS certification, and declares Ketalar (ketamine) injection investigational for psychiatric disorders and chronic pain indications. The policy notes state-specific application exceptions (this policy does not apply to Arizona and refers to the state's Medicaid clinical policy) and other state-specific guidance as listed.

Key thresholds

Adequate antidepressant trial duration>= 8 weeks per antidepressant trial

Number of failed antidepressant trials for TRD>= 2 different antidepressants or treatment regimens

Continuation documentation recencyRecent assessment within the last month

Initial authorization duration<= 12 months

Spravato (Esketamine) — Initial Therapy (TRD & MDD with Acute Suicidal Ideation)

Spravato (Esketamine) — MDD with Acute Suicidal Ideation or Behavior Initial Therapy

Authorization for MDD with acute suicidal ideation or behavior is proven and medically necessary when ALL of the following criteria are met. Note: policy revisions removed the prior requirement for co-administration with an oral antidepressant in some contexts; see policy history for details.

ALL of the following

Diagnosis of major depressive disorder according to the current DSM (i.e., DSM-5-TR), by a mental health professional
Patient is experiencing an acute suicidal ideation or behavior
Provider and/or the provider's healthcare setting is certified in the Spravato REMS program
Spravato dosing is in accordance with the U.S. Food and Drug Administration (FDA) approved labeling

Spravato (Esketamine) — Continuation Therapy

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

Authorization for continuation is proven and medically necessary when ALL of the following are met:

ALL of the following

Documentation of remission or a positive clinical response to Spravato therapy
ALL of the following
- ONE of
  - Beck Depression Inventory (BDI)
  - Hamilton Rating Scale for Depression (HAMD)

Unproven / Not Medically Necessary

Spravato — Not Medically Necessary

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

ANY of the following

Anesthetic agent
Chronic pain (including, but not limited to, nonmalignant pain, fibromyalgia, neuropathic pain, complex regional pain syndrome, reflex sympathetic dystrophy)
Migraine headaches

Ketamine injection — Investigational / Not Medically Necessary

Ketamine injection is investigational and therefore not proven or medically necessary for the following:

ANY of the following

Applicable Codes

HCPCS / J-codes and supplyHCPCS

J3490	Unclassified drugs
S0013	Esketamine, nasal spray, 1 mg

ICD-10 diagnosis codes referencedICD-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

Referenced policy versions / archivalmixed

CS2024D0069V

Archived previous policy version

Provider Actions / Prior Authorization

Prior Authorization

Initial authorization period

Initial authorization for Spravato is limited to no longer than 12 months.

Prior Authorization

Continuation authorization period

Authorization for continuation therapy will be for no longer than 12 months.

Documentation Required

Assessment score documentation

Clinical Evidence

Clinical evidence for intranasal esketamine includes four Phase‑3 international randomized controlled trials (ASPIRE/TRANSFORM/SUSTAIN and others) with mixed primary endpoint results (some trials demonstrated statistical superiority while others did not). A pooled meta-analysis of four RCTs (total n = 708) showed greater response and remission versus placebo, an earlier onset of effect (as early as 2 hours and peaking at 24 hours), and a significantly higher rate of discontinuation for intolerability. Evidence for ketamine (intravenous or other formulations) is limited and of variable quality; systematic reviews and meta-analyses indicate short-lived, rapid antidepressant effects in some studies, but ketamine is not FDA‑approved for psychiatric disorders and the overall evidence is inconsistent.

4international trials; mixed primary endpoint results

4trials; 708 patients; earlier onset (2h–24h); higher discontinuation due to intolerability

variablequality, inconsistent; not FDA-approved for psychiatric disorders

Background

Background: Major depressive disorder (MDD) is a common, serious, and potentially life‑threatening condition; approximately 30–40% of patients with MDD fail to respond to first‑line treatments, and patients who have failed at least two antidepressant trials generally comprise the treatment‑resistant depression (TRD) population. Spravato (esketamine) is the S‑enantiomer of racemic ketamine and acts as a non‑competitive NMDA receptor antagonist; ketamine is an NMDA antagonist and a rapid‑acting general anesthetic. Known safety concerns for ketamine products and esketamine include risk of abuse and misuse, psychiatric adverse events (including dissociation), increases in blood pressure, respiratory depression, and lower urinary tract/bladder symptoms. Because of risks for sedation, dissociation, and abuse, Spravato is available only through the Spravato REMS program: healthcare settings and pharmacies must be certified, Spravato must be dispensed/administered only in certified healthcare settings, administered under direct observation, and patients must be monitored by a healthcare provider for at least 2 hours after administration.

Definitions

Treatment-Resistant Depression (TRD)History of failure of adequate trials of antidepressant treatment defined as failure of at least two different antidepressants or treatment regimens of >=8 weeks each.

Spravato REMS programRestricted program requiring provider/setting certification; Spravato only dispensed in certified healthcare settings, administered under direct observation, and patients monitored for at least 2 hours after administration.

Revision History

2025-06-01policy_effectiveLatest

Policy effective date set to June 1, 2025; revised Spravato (esketamine) coverage criteria (BDI added; item counts removed for HAMD, MADRS, QIDS; prior antidepressant trial requirement reduced from ≥3 to ≥2 trials of ≥8 weeks each; removed requirement for initial co-administration with an oral antidepressant; removed requirement for prior Spravato exposure for continuation; dosing requirements removed and now to follow product labeling or applicable UnitedHealthcare Community Plan Medical Benefit Drug Policy).

2025-06-01application_updateLatest

Application section updated to indicate the policy does not apply to specified states (e.g., Arizona — refer to state's Medicaid clinical policy) and lists other state-specific guidance.

Policy Summary

PayerUnitedHealthcare

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

Policy CodePolicy CS2025D0069W

Change TypeCoverage criteria revised; assessments updated; dosing/co-administration requirements removed

Effective DateJun 1, 2025

Next Review Date

On This Page

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

(Formerly required) Patient was to receive Spravato therapy in conjunction with a newly initiated or optimized oral antidepressant — requirement removed in recent revisions

Montgomery-Asberg Depression Rating Scale (MADRS)

9-item Patient Health Questionnaire (PHQ-9)

Quick Inventory of Depressive Symptomatology (QIDS)

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

Prescribed by or in consultation with a psychiatrist

Spravato dosing is in accordance with the U.S. Food and Drug Administration (FDA) approved labeling

Authorization will be for no longer than 12 months<= 12 months

Policy changes: prior requirements that the patient previously was treated with Spravato and that Spravato be given with an oral antidepressant have been removed; dosing specifics were removed from this policy and are referenced to product labeling or the applicable UnitedHealthcare Community Plan Medical Benefit Drug Policy

Psychiatric disorders (including, but not limited to, depression, bipolar disorder, and post-traumatic stress disorder)
Chronic pain (including, but not limited to, nonmalignant pain, fibromyalgia, neuropathic pain, complex regional pain syndrome, and reflex sympathetic dystrophy)
Migraine headaches

Submit medical records documenting baseline (and for continuation, recent within last month) scoring on at least one listed depression assessment (BDI, HAMD, MADRS, PHQ-9, or QIDS). Document which validated scale was used and include results.

Documentation Required

Antidepressant trial history

Document history of failure of at least two different antidepressants or treatment regimens, including medication name, date, and duration of each trial (>=8 weeks each). An antidepressant or treatment regimen may include SSRIs, SNRIs, bupropion, TCAs, mirtazapine, MAOIs, serotonin modulators, or augmentation with antipsychotics, lithium, or thyroid hormone.

Documentation Required

REMS certification requirement

Provider and/or healthcare setting must be certified in the Spravato REMS program and administer/dispense Spravato only in certified healthcare settings with patient enrollment in REMS.

Documentation Required

Prescriber specialty

Spravato must be prescribed by or in consultation with a psychiatrist.

Documentation Required

Use updated depression rating scales

Beck Depression Inventory (BDI) added; item-count specifics removed for HAMD/MADRS/QIDS — document which validated scale was used and results.

Billing Rule

Refer to dosing guidance elsewhere

Specific dosage requirements for Spravato were removed from this policy; providers must follow the applicable UnitedHealthcare Community Plan Medical Benefit Drug Policy dosing guidance or product labeling.

archivalLatest

Archived previous policy version CS2024D0069V.