CAM 219

Ketamine for the Treatment of Depression

Category:Medicine   Last Reviewed:April 2019
Department(s):Medical Affairs   Next Review:April 2020
Original Date:April 2019    

SPRAVATO™ is a non-competitive N-methyl D-aspartate (NMDA) receptor antagonist indicated, in conjunction with an oral antidepressant, for the treatment of treatment-resistant depression (TRD) in adults. (1)

Limitations of Use: SPRAVATO is not approved as an anesthetic agent. The safety and effectiveness of SPRAVATO as an anesthetic agent have not been established.

Ketamine (intranasal, intravenous, oral, or subcutaneous) for the treatment of depression is considered INVESTIGATIONAL because its clinical value for this indication has not been established.

Major depressive disorder (MDD) has one of the highest morbidities worldwide.  As reported in many clinical trials, standard anti-depressants are effective in only approximately 2/3 of patients.  Additionally, there is a substantial time-lag in response: 2 to 4 weeks for initial effect, and 6 to 12 weeks for maximal efficacy.  Treatment-resistant depression (TRD) is associated with substantial psychosocial dysfunction, morbidity, and mortality, due in part to suicide and under-treated medical co-morbidities.  Thus, there is a need for better and more rapid-acting anti-depressants to quickly alleviate the burden of depression for patients (Niciu et al., 2014; Fond et al., 2014).  Ketamine is a glutamate N-methyl-D-aspartate (NMDA) receptor antagonist; recent research has suggested that ketamine may be a novel, rapid-acting anti-depressant.

Schoevers and colleagues (2016) reviewed the literature about the dosing regimen, duration, effects and side effects of oral, intravenous, intranasal and subcutaneous routes of administration of ketamine for TRD and pain.  Searches in PubMed with the terms “oral ketamine,” “depression,” “chronic pain,” “neuropathic pain,” “intravenous ketamine,” “intranasal ketamine” and “subcutaneous ketamine” yielded 88 articles.  They reviewed all papers for information about dosing regimen, number of individuals who received ketamine, number of ketamine days per study, results and side effects, as well as study quality.  Overall, the methodological strength of studies investigating the anti-depressant effects of ketamine was considered low, regardless of the route of administration.  The doses for depression were in the lower range compared with studies that investigated analgesic use.  Studies on pain suggested that oral ketamine may be acceptable for TRD in terms of tolerability and side effects.  The authors concluded that oral ketamine, given for longer time periods in the described doses, appeared to be well-tolerated, but few studies had systematically examined the longer-term negative consequences.  These researchers stated that the short- and longer-term depression outcomes, as well as side effects, need to be studied with rigorous randomized controlled trials (RCTs).

Al Shirawi and co-workers (2017) evaluated the effectiveness, tolerability, and safety of oral ketamine as an anti-depressant treatment in adults with TRD.  These investigators reviewed retrospective data on 22 patients with TRD, who failed at least 3 adequate anti-depressant treatment trials and 1 adequate trial of repetitive transcranial magnetic stimulation (TMS); subsequently, they received open-label treatment with oral ketamine, commenced at a dose of 50 mg every 3 days, titrated up by 25 mg every 3 days, according to response and tolerability.  The primary outcome measure was the Beck Depression Inventory (BDI)-II, which was used to rate subjective mood improvement at baseline and then at each follow-up visit.  Data about adverse effects related to ketamine and a self-harm risk assessment were also obtained.  Over the course of treatment, 18% of the patients showed greater than 50% reduction in the BDI-II scores, 14% reported partial improvement in mood symptoms, while 45% had no response to ketamine and 23% showed a mild worsening in their depressive symptoms.  The most frequent adverse effects were acute dissociation, dizziness, blurred vision, numbness and sedation.  Neither serious adverse effects, nor any cases of abuse or dependence, were observed.  The authors concluded that although this case series found oral ketamine to be safe and well-tolerated, the findings also showed rather modest effectiveness of oral ketamine in TRD, with only approximately 30% reporting some benefit and approximately 70% reporting no change or worsening of mood.  They stated that further investigation of the effectiveness of oral ketamine is needed.

Feifel and associates (2017) described the safety and efficacy of sub-anesthetic ketamine infusions in a TRD patient sample participating in a real-world TRD treatment program within a major university health system.  The effects of a sub-anesthetic dose (0.5 mg/kg) of ketamine infused intravenously over 40 minutes on TRD patients participating in a treatment program at the University of California, San Diego, was investigated by retrospectively analyzing the medical charts of 41 adult TRD patients with a diagnosis of MDD or bipolar disorder (BD).  Subjects were aged 48.6 years, 78% white, 36.6% women, and 82.9% had MDD.  Significant psychiatric co-morbidity existed in 73%.  Average pre-infusion BDI score was 32.6 ± 8.4 (S.D) and dropped to 16.8 ± 3.1 at 24-hour post-infusion (p < 0.001).  The 24-hour response (greater than or equal to 50% reduction from pre-infusion) and remission (BDI less than 13) rates were 53.7% and 41.5%, respectively; 3/4 of responders maintained responder status at 7 days.  Ketamine infusions were well-tolerated, with occasional nausea or anxiety and mild hemodynamic effects during the infusion.  The authors concluded that this was the first published study of sub-anesthetic ketamine infusions in a real-world TRD population.  They stated that the results suggested that this treatment was effective and well-tolerated in this population.  These researchers stated that the main drawbacks of this study were its retrospective nature, lack of control group, and use of self-reported depression ratings scales.

Kraus and colleagues (2017) reviewed available literature on efficacy, response rates and safety profile of ketamine for unipolar and bipolar depression -- 12 studies investigating unipolar depression, 7 on BD were included after searches in Medline, Scopus and Web of Science.  Randomized, placebo-controlled or open-label trials reported anti-depressant response rates after 24 hours on primary outcome measures at 61%.  The average reduction of Hamilton Depression Rating Scale (HAM-D) was 10.9 points, BDI 15.7 points and Montgomery-Asberg Depression Rating Scale (MADRS) 20.8 points.  Ketamine was always superior to placebo.  Most common side effects were dizziness, blurred vision, restlessness, nausea/vomiting and headache, which were all reversible.  Relapse rates ranged between 60% and 92%.  The authors concluded that ketamine constituted a novel, rapid and efficacious therapeutic option for patients suffering from TRD and exhibited rapid and significant anti-suicidal effects.  New administration routes might serve as alternative to intravenous regimes for potential usage in outpatient settings.  Moreover, they stated that long-term side effects are unknown and short duration of anti-depressant response shows a need to find ways to prolong ketamine's efficacy.

The authors stated that this study had several drawbacks.  First, all of patients in this series had highly resistant forms of depression, with failure of multiple treatment modalities (multiple anti-depressant medications, neuromodulation, and in most cases cognitive psychotherapy).  Second, adherence to the prescribed regimen could not be confirmed for at-home dosing regimens.  Third, because this report concerned a series of clinical cases rather than an RCT, standardized clinician ratings of mood symptom were not consistently obtained.  Fourth, a series of 22 patients was insufficiently large to assess the incidence of rare but serious adverse effects (medical or psychiatric) ensuing from the treatment.

In a pilot study, George and colleagues (2017) examined the safety and efficacy of subcutaneous ketamine for geriatric TRD.  Secondary aims were to examine if repeated treatments were safe and more effective in inducing or prolonging remission than a single treatment.  This was a controlled, double-blind, multiple-crossover study with a 6-month follow-up (RCT phase). Sixteen participants (greater than or equal to 60 years) with TRD who relapsed after remission or did not remit in the RCT were administered an open-label phase.  Up to 5 subcutaneous doses of ketamine (0.1, 0.2, 0.3, 0.4, and 0.5 mg/kg) were administered in separate sessions (greater than or equal to 1 week apart), with 1 active control (midazolam) randomly inserted (RCT phase); 12 ketamine treatments were given in the open-label phase.  Mood, hemodynamic, and psychotomimetic outcomes were assessed by blinded raters.  Remitters in each phase were followed up for 6 months; 7 of 14 RCT-phase completers remitted with ketamine treatment; 5 remitted at doses below 0.5 mg/kg.  Doses greater than or equal to 0.2 mg/kg were significantly more effective than midazolam.  Ketamine was well-tolerated.  Repeated treatments resulted in higher likelihood of remission or longer time to relapse.  The authors concluded that these findings provided preliminary evidence for the safety and efficacy of ketamine in treating elderly depressed.  Dose titration was recommended for optimizing anti-depressant and safety outcomes on an individual basis.  These preliminary findings need to be validated by well-designed studies.

In a “Consensus statement on the use of ketamine in the treatment of mood disorders” from the American Psychiatric Association (APA), Sanacora and associates (2017) noted that several studies provided evidence of ketamine hydrochloride's ability to produce rapid and robust anti-depressant effects in patients with mood and anxiety disorders that were previously resistant to treatment.  Despite the relatively small sample sizes, lack of longer-term data on efficacy, and limited data on safety provided by these studies, they have led to increased use of ketamine as an off-label treatment for mood and other psychiatric disorders.  This review and consensus statement provided a general overview of the data on the use of ketamine for the treatment of mood disorders and highlighted the limitations of the existing evidence.  While ketamine may be beneficial to some patients with mood disorders, it is important to consider the limitations of the available data and the potential risk associated with the drug when considering the therapeutic option.  The authors concluded that the suggestions provided were intended to facilitate clinical decision-making and encourage an evidence-based approach to using ketamine in the treatment of psychiatric disorders, considering the limited information that is currently available.  This article provided information on potentially important issues related to the off-label therapeutic approach that should be considered to help ensure patient safety.

Short and co-workers (2018) provided the first systematic review of the safety of ketamine in the treatment of depression after single and repeated doses.  These investigators searched Medline, PubMed, PsycINFO, and Cochrane Databases and identified 288 articles, 60 of which met the inclusion criteria.  After acute dosing, psychiatric, psychotomimetic, cardiovascular, neurological, and other side effects were more frequently reported after ketamine treatment than after placebo in patients with depression.  These findings suggested a selective reporting bias with limited assessment of long-term use and safety and after repeated dosing, despite these being reported in other patient groups exposed to ketamine (e.g., those with chronic pain) and in recreational users.  The authors recommended large-scale clinical trials that include multiple doses of ketamine and long-term follow-up to assess the safety of long-term regular use.

Wilkinson and associates (2018) conducted a systematic review and individual participant data meta-analysis examining the effects of a single dose of ketamine on suicidal ideation.  Individual participant data were obtained from 10 of 11 identified comparison intervention studies that used either saline or midazolam as a control treatment.  The analysis included only participants who had suicidal ideation at baseline (n = 167).  A 1-stage, individual participant data, meta-analytic procedure was employed using a mixed-effects, multi-level, general linear model.  The primary outcome measures were the suicide items from clinician-administered (the MADRS or the HAM-D) and self-reported scales (the Quick Inventory of Depressive Symptomatology-Self Report [QIDS-SR] or the BDI), obtained for up to 1 week after ketamine administration.  Ketamine rapidly (within 1 day) reduced suicidal ideation significantly on both the clinician-administered and self-reported outcome measures.  Effect sizes were moderate to large (Cohen's d = 0.48 to 0.85) at all time points after dosing.  A sensitivity analysis demonstrated that, compared with control treatments, ketamine had significant benefits on the individual suicide items of the MADRS, the HAM-D, and the QIDS-SR, but not the BDI.  Ketamine's effect on suicidal ideation remained significant after adjusting for concurrent changes in severity of depressive symptoms.  The authors concluded that ketamine rapidly reduced suicidal thoughts, within 1 day and for up to 1 week in depressed patients with suicidal ideation.  Ketamine's effects on suicidal ideation were partially independent of its effects on mood, although subsequent trials in trans-diagnostic samples are needed to confirm that ketamine exerts a specific effect on suicidal ideation.  They stated that additional research on ketamine's long-term safety and its efficacy in reducing suicide risk is needed before clinical implementation.

In a retrospective, case-series study, Archer and colleagues (2018) reported on the clinical use of ongoing maintenance ketamine infusions in a group of patients with TRD, beyond an acute course of 6 to 8 ketamine infusions.  This trial included 11 patients with TRD who received maintenance ketamine infusions, defined as treatments beyond an initial series of up to 8 infusions.  Charts were reviewed to collect data on response to treatment and side effects.  All 11 patients in this case series were noted to have a reduction in their BDI-II score after an acute course of treatment and a lower median BDI-II during their maintenance treatments than their baseline BDI-II.  At the study end-point, 4 patients were continuing maintenance ketamine and 1 patient had transitioned to maintenance intranasal ketamine; 4 patients discontinued ketamine due to loss of effect and 1 due to side effects, and the reason for discontinuation was not noted for the remaining 2 patients.  No major adverse events (AEs) were noted in these patients receiving maintenance treatments, and it was well-tolerated overall.  The authors concluded that maintenance ketamine treatments may be an effective way of maintaining therapeutic response in some ketamine responders.  Moreover, they stated that future research is needed to determine optimal length of treatment in those who respond to ketamine and to track ARs over a longer time.

An UpToDate review on “Unipolar depression in adults: Treatment of resistant depression” (Thase and Connolly, 2018a) does not mention ketamine as a therapeutic option.

Furthermore, an UpToDate review on “Unipolar depression in adults: Management of highly resistant (refractory) depression” (Thase and Connolly, 2018b) lists ketamine as an investigational procedure.


  1. Niciu MJ, Luckenbaugh DA, Ionescu DF, et al. Ketamine's antidepressant efficacy is extended for at least four weeks in subjects with a family history of an alcohol use disorder. Int J Neuropsychopharmacol. 2014;18(1).
  2. Fond G, Loundou A, Rabu C, et al. Ketamine administration in depressive disorders: A systematic review and meta-analysis. Psychopharmacology (Berl). 2014;231(18):3663-3676.
  3. Schoevers RA, Chaves TV, Balukova SM, et al. Oral ketamine for the treatment of pain and treatment-resistant depression. Br J Psychiatry. 2016;208(2):108-113.
  4. Al Shirawi MI, Kennedy SH, Ho KT, et al. Oral ketamine in treatment-resistant depression: A clinical effectiveness case series. J Clin Psychopharmacol. 2017;37(4):464-467.
  5. Feifel D, Malcolm B, Boggie D, Lee K. Low-dose ketamine for treatment resistant depression in an academic clinical practice setting. J Affect Disord. 2017;221:283-288.
  6. Kraus C, Rabl U, Vanicek T, et al. Administration of ketamine for unipolar and bipolar depression. Int J Psychiatry Clin Pract. 2017;21(1):2-12.
  7. George D, Galvez V, Martin D, et al. Pilot Randomized Controlled Trial of Titrated Subcutaneous Ketamine in Older Patients with Treatment-Resistant Depression. Am J Geriatr Psychiatry. 2017;25(11):1199-1209.
  8. Sanacora G, Frye MA, McDonald W, et al; American Psychiatric Association (APA) Council of Research Task Force on Novel Biomarkers and Treatments. A consensus statement on the use of ketamine in the treatment of mood disorders. JAMA Psychiatry. 2017;74(4):399-405.
  9. Short B, Fong J, Galvez V, et al. Side-effects associated with ketamine use in depression: A systematic review. Lancet Psychiatry. 2018;5(1):65-78.
  10. Wilkinson ST, Ballard ED, Bloch MH, et al. The effect of a single dose of intravenous ketamine on suicidal ideation: A systematic review and individual participant data meta-analysis. Am J Psychiatry. 2018;175(2):150-158.
  11. Archer S, Chrenek C, Swainson J. Maintenance ketamine therapy for treatment-resistant depression. J Clin Psychopharmacol. 2018;38(4):380-384.
  12. Thase M, Connolly KR. Unipolar depression in adults: Treatment of resistant depression. UpToDate Inc., Waltham, MA. Last reviewed June 2018a.
  13. Thase M, Connolly KR. Unipolar depression in adults: Management of highly resistant (refractory) depression. UpToDate Inc., Waltham, MA. Last reviewed June 2018b.

Coding Section 

Code Number Description
CPT 96365 - 96368  Intravenous infusion administration
  96372 Therapeutic, prophylactic, or diagnostic injection (specify substance or drug); subcutaneous or intramuscular
HCPCS   No Specific Code
ICD-10 CM  F32.0 - F33.9 Major depressive disorders

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each Policy. They may not be all-inclusive. 

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross and Blue Shield Association technology assessment program (TEC) and other non-affiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

"Current Procedural Terminology © American Medical Association.  All Rights Reserved" 

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