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Effective Date: 08/01/2020 Title: Outpatient Ketamine or Esketamine Therapy
Revision Date: 01/01/2021 Document: BI641:00
CPT Code(s): J3490, J3499, S0013
Public Statement

Effective Date:

a)    This policy will apply to all services performed on or after the above revision date which will become the new effective date.

b)    For all services referred to in this policy that were performed before the revision date, contact customer service for the rules that would apply.

Ketamine is an anesthetic agent that has been used in anesthesia, pain management, and psychiatry. It has been shown to reduce suicidal thoughts and can provide rapid relief from depression.  Intravenous infusion has the most rapid and dramatic effects. Response may not be as predictable or beneficial when given as an intranasal spray. In conjunction with therapy, it facilitates rapid healing of mood disorders due to its effects on the central nervous system (increased neuroplasticity, increased neurogenesis, and regulated glutamate).


Even though there has been extensive experience with the safe use of ketamine for surgical anesthesia, due to the potential for abuse/misuse, this has always been with direct medical supervision and monitoring.  A form of ketamine is now available by prescription (Spravato/esketamine).  However, this medication is a controlled substance that must be stored and dispensed under supervision in a medical office.


All forms of ketamine (including esketamine) administration for purposes other than surgical anesthesia require prior authorization.  The custom code used by QualChoice for this bundle of services is J3499.  In order to obtain the prior authorization, a QualChoice network provider is required to have a ketamine episode of payment contract amendment.  Please contact QualChoice if you have questions regarding your QualChoice provider contract.  

Medical Statement

Anesthesiologists have the greatest experience with physiologic monitoring of the effects of ketamine but are not as well prepared to handle behavioral changes or dissociative states that can be seen with ketamine use for behavioral disorders.  Psychiatrists, on the other hand, are not as experienced with physiologic monitoring of ketamine use but are the most qualified providers to handle behavioral changes or dissociative states that can be seen with ketamine use for behavioral disorders.  In light of this, the safest setting to administer and monitor IV or nasal ketamine, is a medical office that has a multidisciplinary team with  psychiatric supervision anesthesiology (or CRNA) available for consultation.

All forms of ketamine (including esketamine) administration and monitoring, for purposes other than surgical anesthesia, require prior authorization.  The custom code used by QualChoice for this bundle of services is J3499.

Ketamine or esketamine are welcome additions to the options available for treatment resistant depression.  While esketamine is the only FDA approved drug at this time, its approval would not have been possible without significant prior experience of the therapeutic effects of generic (racemic mixture) ketamine for this same indication.  In light of this, esketamine for treatment resistant depression is considered by QualChoice to be an established off-label use rather than experimental/investigational.  Furthermore, since nasally administered ketamine (or esketamine) has variable absorption (at best 45% compared with 100% when administered IV), IV ketamine is considered the preferred option during the induction phase.  If patients are sick enough to require ketamine/esketamine, they should be treated first with the most bioavailable form of the medicine to establish whether or not there is a therapeutic response (unless there is a contraindication to IV therapy).  After a therapeutic response has been established during the induction phase, it is reasonable to switch over to maintenance with a nasal spray.  If the compounded generic (racemic mixture) ketamine nasal spray is ineffective or not tolerated, then eskatamine nasal spray may be considered.

The experience with ketamine or esketamine is that many patients with prior treatment resistant depression can have a major shift in responsiveness to treatment.  In light of that, the need for ongoing (lifelong) treatment with ketamine or esketamine is not established.  Therefore, continued treatment with ketamine or esketamine needs to be re-evaluated through a new prior authorization process beyond 16 weeks.

1.    IV ketamine (generic racemic mixture) or compounded ketamine nasal spray (generic racemic mixture of 34.6 mg ketamine hydrochloride in 0.2 mL of a clear aqueous solution with a pH of 5.0 – 7.0—delivering an equivalent of two sprays with 15 mg each of ketamine) is considered medically necessary for up to 16 weeks when the following criteria are met:

a.    Adult patients > 18yo

b.    Diagnosis of Treatment Resistant Depression (TRD):

                                          i.    With a Dx of major depressive disorder (MDD),

                                        ii.    Has failed to respond to at least two adequate treatment trials (90 days each) of two different classes of antidepressant medications,

                                       iii.    Currently prescribed a new antidepressant

c.    Pre-procedure evaluation and referral by a physician, nurse practitioner or mental health clinician. Documentation of suicide assessment and use of validated depression rating scales are encouraged (such as PHQ9, BDI, MADRAS)

d.    Standard pre-procedure pre-anesthetic evaluation should be done to determine no contraindications to Ketamine, such as active psychotic or manic symptoms, known hypersensitivity to the medication, uncontrolled hypertension, or past or current history of Ketamine abuse

e.    Informed Consent, including informing patient of possible side effects such as high or low BP, fast or slow HR, abnormal heart rhythms, nausea, vomiting, double vision, dissociation, or sedation. Patient should be notified that the use of IV Ketamine is off-label and not FDA indicated as distinguished by the use of intranasal Spravato which is FDA indicated for Treatment Resistant Depression

f.     Facility: the room or facility where Ketamine administration is performed must have the personnel and equipment available to manage emergency situations or have rapid access to the specialized resuscitation team.

g.    The facility should have written protocols for IV or Nasal Ketamine administration

h.    The facility participates in the Spravato REMS program.

i.      The dispensing pharmacy is Spravato REMS certified.

j.      The compounded ketamine nasal spray is never dispensed directly to a patient for home use.

k.    Patient Monitor: A qualified medical provider (e.g., attending or resident physician, Nurse Practitioner-NP, CRNA, or Physician Assistant-PA), or registered nurse (RN), or a paramedic who observes, assesses, and documents the patient’s response during ketamine administration. The Patient Monitor must have current credentials in basic life support (BLS) and be competent in the administration of medications. Similar to the conscious sedation guidelines, RNs acting as Patient Monitor must have completed Staff-Nurse core competencies including medication administration and rhythm recognition competency.

l.      For an IV infusion of Ketamine, the patient should have IV access maintained throughout the procedure (including the monitoring period after the IV Ketamine infusion has been completed) as well as close monitoring of mental status and vital signs (noninvasive BP at a minimum of every 15 minutes, continuous pulse oximetry, continuous EKG, and end-tidal CO2 when appropriate)

m.  The provider administering and supervising the administration of ketamine must remain readily available for the entire duration of procedure. The authorized psychiatrist or his team will be present and/or available for questions and documentation purposes.

n.    Recovery and post-ketamine administrative care: the patient monitor should observe the patient for at least 1 hour after completion of ketamine administration. Cardiovascular function, airway patency, and oxygen saturation should be stable at pre-procedure level. Prior to discharge the patient should be easily aroused and return to baseline ambulation status.

o.    Ketamine therapy is most effective when it is provided in the context of a treatment plan which combines with regular psychotherapy with other psychopharmacologic medications if needed.

p.    Post procedure rating scales should be done as appropriate to document changes in depressive symptoms and function

q.    Induction phase treatments (to determine response) may be up to twice weekly for 4 weeks.

r.     Maintenance phase treatments (up to 12 weeks beyond the initial 4 weeks of induction if there is a favorable response during the induction phase) may be up to weekly or every other week (minimum needed to maintain response).

s.    Any continuation beyond 16 weeks requires re-evaluation and a new prior authorization.

2.    Spravato/esketamine (unlike the generic racemic mixture of ketamine) is comprised of only the S (+) enantiomer of ketamine.  Spravato/esketamine is considered medically necessary when the following criteria are met:

a.    All criteria for IV ketamine or compounded ketamine nasal spray (generic racemic mixture) have been met, AND

b.    Member has had a favorable induction phase response to IV ketamine (generic racemic mixture) but an unfavorable maintenance phase response to compounded ketamine nasal spray (generic racemic mixture), OR

c.    Member has not had a favorable induction phase response to compounded ketamine nasal spray (generic racemic mixture), AND

d.    Spravato is stored, administered and monitored by a medical office meeting the criteria above for safe administration of IV ketamine or compounded ketamine nasal spray.


Codes Used In This BI:



99211 - 99215

Eval & Mgmt Office Visit, established patient


Prolonged service(s) in the outpt setting requiring direct patient contact beyond the time of the usual service; first hr (code revised eff 01-01-2021)


Prolonged service(s) in the outpt setting requiring direct pt contact beyond the time of the usual svc; each add`l 30 min (code revised eff 01-01-2021)


Prolonged patient service without direct patient contact first hour


Prolonged patient service without direct patient contact each 30 minutes beyond first hour


Prolonged clinical staff svc (the svc beyond the highest time in the range of total time of the svc) during an eval/mgt svc in the ofc or outpt setting, direct pt contact with physician supervision; first hr (code revised eff 01-01-2021)


Prolonged clinical staff svc during an eval/mgt svc in the ofc or outpt setting, direct pt contact with physician supervision; each add;l 30 min (code revised eff 01-01-2021)


Insertion of needle or catheter into a vein


Tracing of electrical activity of the heart using 1-3 leads


Multiple measurements of oxygen saturation in blood using ear or finger device


Brief emotional or behavioral assessment


Hydration infusion into a vein 31 minutes to 1 hour


Infusion into a vein for therapy, prevention, or diagnosis up to 1 hour


Infusion into a vein for therapy, prevention, or diagnosis


Injection of drug or substance into a vein for therapy, diagnosis, or prevention


Injection of different drug or substance into a vein for therapy, diagnosis, or prevention


Blood Pressure Measured


Vital Signs Recorded


Injection, hydralazine HCl, up to 20mg


Injection, prochlorperazine, up to 10 mg


Injection, dexamethasone sodium phosphate, 1 mg


Injection, ketorolac tromethamine, per 15 mg


Injection, midazolam hydrochloride, per 1 mg


Injection, ondansetron hydrochloride, per 1 mg


Injection, promethazine HCl, up to 50 mg


Injection, propofol, 10 mg


Injection, magnesium sulfate, per 500 mg


Unclassified drugs


QualChoice custom code for bundle of services involving ketamine/esketamine administration and monitoring


Infusion, normal saline solution, 1,000 cc


Infusion, normal saline solution, sterile (500 mL = 1 unit)


Infusion, normal saline solution, 250 cc


Esketamine, nasal spray, 1 mg


Patients meeting the following criteria should be excluded:

a. Active psychotic symptoms, manic symptoms, or a history of a primary psychotic disorder

b.  ASA PS 5 or 6, or uncontrolled hypertension

c. Known hypersensitivity to ketamine or its components

d. History of ketamine abuse or dependence


Ketamine is a safe, fast-acting anesthetic that was first synthetized at Parke Davis in 1963 as an alternative to phencyclidine (PCP). Unlike PCP, ketamine was found to provide anesthesia without negatively affecting the cardiopulmonary system, and had a reduced recovery period, with decreased potential for adverse side-effects. During the Vietnam War, and subsequent trauma situations, it has been administered by non-medical personnel on the battlefield for safe and rapid pain relief.


However, the focus of development of antidepressants by pharmaceutical companies turned to tricyclics, selective serotonin reuptake inhibitors, and other monoamine promotion strategies.  Since ketamine has been generic, the first randomized controlled trial of ketamine for depression was not published until 2000. It showed 50% of patients with 50% decrease in depression symptoms within 3 days of treatment in a single dose trial.1


Since 2000, numerous studies have been performed on ketamine to better understand its mechanism(s) of action and efficacy. 2, 3 These studies have shown that ketamine works as a N-Methyl-D-Aspartate Receptor (NMDA-R) antagonist, increasing the glutamate available to the brain and leading to excitation of synapses. Moreover, ketamine causes ɑ-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor potentiation, which promotes neuroplasticity and synaptogenesis. And lastly, ketamine reduces inflammation by interacting with inflammatory cells recruitment, cytokines production, and inflammatory mediators regulation.


Today, ketamine is the only drug shown to rapidly reduce suicidal thoughts. Further studies have shown potential benefits for the treatment of PTSD, OCD, Anxiety, Bipolar Depression, Fibromyalgia, CRPS, Peripheral Neuropathy and other pain disorders.


In 2017, the American Psychiatric Association published a consensus statement for use of ketamine for the Treatment of Mood Disorders, and the American Academy of Pain Medicine and the American Society of Anesthesiologists published a Consensus Guideline of use of IV Ketamine Infusions for Chronic Pain in 2018.


In March of 2019 the FDA approved the use of esketamine (S-enantiomere of ketamine) nasal spray Spravato for treatment-resistant depression administered in certified clinics. While Spravato esketamine is conveniently packaged for safe administration and FDA regulations prevents its misuse through in-clinic post-procedure monitoring, nasal administration reduces its bioavailability to 45%.4


1.    Sanacora G, Frye MA, McDonald W et al. A Consensus Statement on the Use of Ketamine in the Treatment of Mood Disorders JAMA Psychiatry. 2017;74(4):399-405.

2.     Bratsos S, Saleh SN. Clinical Efficacy of Ketamine for Treatment-resistant Depression. Cureus. 2019 Jul 22; 11(7):e5189.  

3.    Cohen SP, Bhatia A, Buvanendran A, et al. Consensus Guidelines on the Use of Intravenous Ketamine Infusions for Chronic Pain From the American Society of Regional Anesthesia and Pain Medicine, the American Academy of Pain Medicine, and the American Society of Anesthesiologists Reg Anesth Pain Med 2018;43: 521–546

4.    FDA approval of Spravato march5, 2019:  

5.    Dore J, Turnipseed B, Dwyer S, et al.  Ketamine Assisted Psychotherapy (KAP): Patient Demographics, Clinical Data and Outcomes in Three Large Practices Administering Ketamine with Psychotherapy. J Psychoactive Drugs. 2019 Apr-Jun;51(2):189-198.  

6.    Newport DJ, Carpenter LL, McDonald WM, et al. Reviews and Overviews: Ketamine and Other NMDA Antagonists: Early Clinical Trials and Possible Mechanisms in Depression D. Am Journal of Psychiatry. 2015; 172:950-966.

7.    Diamond PR, Farmery AD, Atkinson S, et al. Ketamine infusions for treatment resistant depression: a series of 28 patients treated weekly or twice weekly in an ECT clinic. J Psychopharmacol. 2014 Jun; 28(6):536-44.  

8.    Lapidus KAB, Levitch CF, Perez AM, et al. A Randomized Controlled Trial of Intranasal Ketamine in Major Depressive Disorder Biol Psychiatry. 2014 December 15; 76(12): 970–976.

9.    Murrough JW, Perez AM, Pillemer S, et al. Rapid and longer-term antidepressant effects of repeated ketamine infusions in treatment-resistant major depression. Biol Psychiatry. 2013 Aug 15; 74(4):250-6.  

10. Covvey JR, Crawford AN and Lowe DK.  Intravenous ketamine for treatment-resistant major depressive disorder. Ann Pharmacother. 2012 Jan; 46(1):117-23.  

11. Agbooda F, Atlas SJ, Touchette DR, et al. The Effectiveness and Value of Esketamine for the Management of Treatment-Resistant Depression. J Manag Care Spec Pharm. 2020; 26(1):16-20.

12. Dadiomov D. Dissociating the Clinical Role and Economic Value of Intranasal Esketamine. J Manag Care Spec Pharm. 2020; 26(1):20-22.



1)    Effective: 08/01/2020

2)    Effective 01/01/2021: New code S0013.

3)    Effective 01/01/2021: Updated the code descriptions on 99354, 99355, 99415 & 99416.

Application to Products
This policy applies to all health plans administered by QualChoice, both those insured by QualChoice and those that are self-funded by the sponsoring employer, unless there is indication in this policy otherwise or a stated exclusion in your medical plan booklet. Consult the individual plan sponsor Summary Plan Description (SPD) for self-insured plans or the specific Evidence of Coverage (EOC) for those plans insured by QualChoice. In the event of a discrepancy between this policy and a self-insured customer’s SPD or the specific QualChoice EOC, the SPD or EOC, as applicable, will prevail. State and federal mandates will be followed as they apply.
Changes: QualChoice reserves the right to alter, amend, change or supplement benefit interpretations as needed.
This policy has recently been updated. Please use the index above or enter policy title in search bar for the latest version.