What evidence is available for oral ketamine in treatment-resistant major depressive disorder?

Introduction
Major depressive disorder (MDD) is one of the most common mental disorders in the United States; an estimated 8.4% of adults experience a major depressive episode each year, and approximately half of these patients receive treatment with medication.1,2 Guideline-recommended treatment options for the initial management of MDD include psychotherapy or pharmacologic treatment with a selective serotonin reuptake inhibitor [SSRI],  a serotonin/norepinephrine reuptake inhibitor [SNRI], bupropion, mirtazapine, trazodone, vilazodone, or vortioxetine.3,4 Options for patients who fail to respond to initial antidepressant therapy include combining medication treatment with psychotherapy, changing to an alternative antidepressant, or augmenting antidepressant therapy with an antipsychotic medication.4

Currently available antidepressants may take weeks to improve symptoms and are not effective for every patient.5 Although many medications have been approved for use in MDD, approximately 30% of patients with medication-treated MDD will have treatment-resistant depression (TRD), which is typically defined as depression that fails to respond to 2 or more trials of medication treatment.2 As a result, there is an ongoing need for additional MDD treatment options, particularly those that work via novel mechanisms of action.

Ketamine is an antagonist of the N-methyl D-aspartate (NMDA) receptor; it is currently Food and Drug Administration (FDA)-approved for parenteral use in general anesthesia, but it has also been studied as a potential treatment option for patients with MDD.5-7 Ketamine is thought to treat depression by blocking NMDA receptors on gamma-aminobutyric acid (GABA) inhibitory interneurons in the prefrontal cortex, leading to an increase in glutamatergic release and activation of post-synaptic alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptors (AMPARs).5 Ketamine may be administered via many different routes, but the most commonly studied route for the treatment of TRD is the intravenous route.4,6 Studies with intravenous ketamine have concluded that ketamine infusions are effective for the rapid treatment of TRD, and the Veterans Affairs/Department of Defense (VA/DoD) guideline for management of MDD recommends intravenous ketamine as an option for treatment augmentation in patients who have not responded to several adequate pharmacologic trials.4 However, there are a number of disadvantages associated with ketamine infusions, including cost, painful phlebitis, and difficulty of administration in an outpatient setting.6,8  An intranasal formulation of the S-enantiomer of ketamine, esketamine, was recently approved for use in patients with TRD; however, this formulation may also be associated with significant costs.4,6 Oral administration of ketamine would be a cheaper, more convenient alternative to these routes of administration. This article will review the clinical evidence for oral formulations of ketamine in MDD.

Efficacy literature for oral ketamine in MDD
Three small randomized controlled trials (RCTs) have examined the safety and efficacy of oral ketamine in the treatment of depression (Table 1).8-10 These studies varied in terms of the patient population enrolled and the dosage of ketamine used; only one trial (Domany et al) specifically sought to enroll patients with TRD. The length of follow-up also varied between the trials, with the longest trials lasting only 6 weeks. Overall, these studies concluded that ketamine may be a safe and effective option in patients with depression. However, these trials generally did not include patients with psychotic symptoms or patients with comorbidities such as alcohol or substance abuse, cardiovascular disease, and thyroid disease. Common limitations within these trials are limited follow-up time and small sample sizes.

In addition to the RCTs, a 28-day, single-arm, open-label study published in 2013 examined the efficacy of oral ketamine 0.5 mg/kg per day in 14 patients with symptoms of depression.11 The primary outcome measure of the trial was improvement in Hospital Anxiety and Depression Scale (HADS) scores. Of the 8 subjects that completed the study, all had a 30% or greater improvement in their HADS depression and anxiety subscale scores from baseline to day 28. However, the 6 patients who withdrew from the study prematurely did not experience any improvement in their HADS depression subscale scores. This trial was limited by its small sample size and open label design. It was also unclear whether these patients had received any previous treatment for depression.

A systematic review on oral ketamine use for MDD (regardless of previous treatment history) evaluated data from 10 studies, including 3 RCTs, 2 open-label studies, 3 retrospective studies, and 2 case series.12 In a meta-analysis of the 3 RCTs, ketamine was found to have a significant antidepressant effect, although responder rates and remission rates were marginal compared to placebo. In general, the antidepressant effects of oral ketamine became evident during the second week of treatment. Authors of the review concluded that the evidence for use of oral ketamine in patients with MDD suggests marginal efficacy without an increased risk for adverse effects. Limitations to this systematic review and meta-analysis include the small number of studies, variability among studies in terms of dosing, and lack of data on long-term maintenance therapy with ketamine.

Table 1. Clinical trials of oral ketamine in patients with MDD.8-10
Study design and duration
Subjects
Interventions
Results
Conclusion
Domany 20199
 
DB, PC, RCT
 
Treatment for 21 days; follow-up for 28 days
N=41 outpatients aged 18 to 75 years with MDD (as determined by the MINI), MADRS score ≥19, and inadequate response to ≥2 antidepressants
 
Mean age: 38.7 years in the ketamine group and 37.9 years in the placebo group
 
Mean MADRS scores at baseline: 33.4 in the ketamine group vs. 29.99 in the placebo group
Ketamine 1 mg/kg PO 3 times weekly for 21 days (n=22)
 
Placebo 3 times weekly for 21 days (n=19)
 
Patients continued to receive their usual treatment regimen in addition to study treatment for the duration of the trial
 
Primary: At day 21, the mean reduction in the MADRS score was -12.75 in the ketamine-treated group vs. -2.49 in the placebo group (p<0.001).
 
Secondary:
At day 21, 31.8% of patients in the ketamine group were classified as responders compared to 5.6% of patients in the placebo group (p<0.05); response was defined as a 50% or greater reduction in MADRS score from baseline
 
At day 21, 27.3% of patients in the ketamine group achieved remission (MADRS score ≤10 points) compared to 0% of patients in the placebo group (p<0.05)
 
Safety:
Systolic blood pressure elevations of more than 20 mmHg were observed in 40% of ketamine-treated patients and 18.2% of placebo-treated patients following the first study drug administration; the peak of this transient elevation occurred 40 min post-drug administration and it resolved spontaneously within 1 hour
 
The most common side effects observed in the ketamine group (vs. placebo) included euphoria (18.2% vs. 0.0%), drowsiness (9.1% vs. 5.6%), and dizziness (18.2% vs. 5.6%).
Repeated oral doses of ketamine may be safe and effective for patients with TRD in a community setting.
 
Limitations of this study included the short duration of follow-up, the difficulty in masking ketamine, and lack of blood levels drawn throughout the follow-up period.
Arabzadeh 20188
 
DB, PC, RCT
 
Treatment and follow-up over 6 weeks
 
N=81 patients aged 18 to 60 years with a diagnosis of moderate to severe MDD (HDRS score ≥20)
 
Mean age: 34.31 years in the ketamine group and 33.72 years in the placebo group
 
Mean HDRS scores at baseline: 24.17 in the ketamine group and 24.62 in the placebo group
Ketamine 25 mg PO twice daily (n=41)
 
Placebo (n=40)
 
Patients in both groups also received sertraline 150 mg per day
Primary: Ketamine-treated patients had lower HDRS scores at week 2 than patients who received placebo (mean between-group difference, ‑3.41; 95% CI, -5.07 to ‑1.75; p<0.001)
 
Secondary:
Ketamine-treated patients had lower HDRS scores at week 4 than patients who received placebo (mean between-group difference, ‑2.61; 95% CI, -4.11 to ‑1.11; p=0.001)
 
Ketamine-treated patients had lower HDRS scores at week 6 than patients who received placebo (mean between-group difference, ‑1.91; 95% CI, -3.34 to ‑0.48; p=0.009)
 
Early improvement (defined as a ≥20% reduction in HDRS score during the first 2 weeks) was observed in 85.4% of ketamine-treated patients and 42.5% of patients receiving placebo (p<0.001)
 
Rates of treatment response (defined as a ≥50% reduction in HDRS score from baseline) were 85.4% in the ketamine group and 57.5% in the placebo group (OR, 4.31; 95% CI, 1.48 to 12.55; p=0.005)
 
Rates of remission (defined as a HDRS score ≤7) were similar between the two groups
 
Safety:
Adverse effects were not significantly different between groups; most were mild, with the most common adverse events in the ketamine group being tremor (9.7% vs. 7.5%), dizziness (7.3% vs. 5%), blurred vision (7.3% vs. 2.5%), restlessness (7.3% vs. 5%), and nausea (7.3% vs. 5%)
 
No dissociative symptoms were reported
Adding oral ketamine to sertraline improved HDRS scores compared to sertraline alone.
 
Limitations of this trial include the short duration of follow-up and small sample size. Number of previous MDD treatments not reported.
 
Jafarinia 201610
 
DB, RCT
 
Treatment and follow-up over 6 weeks
 
N=40 patients aged 20 to 55 years with mild to moderate depression (HDRS score <19) and a diagnosis of chronic and persistent mild-to-moderate headache requiring an analgesic
 
Mean age: 40.7 years in the ketamine group and 38.95 years in the diclofenac group
 
Mean HDRS score at baseline: 15 in the ketamine group and 14.95 in the diclofenac group
Ketamine 50 mg PO 3 times daily for 6 weeks (n=20)
 
Diclofenac 50 mg 3 times daily for 6 weeks (n=20)
 
Primary: At week 6, HDRS scores in the ketamine group were lower than HDRS scores in the diclofenac group (mean between-group difference, 2.85; 95% CI, 0.54 to 5.16; p=0.017)
 
Secondary:
At week 6, rates of treatment response (defined as a ≥50% reduction in HDRS score from baseline) were higher among ketamine-treated patients (60% vs. 15%; OR, 8.50; p=0.008)
 
Rates of remission (defined as HDRS ≤7) at 6 weeks were greater among patients treated with ketamine (45% vs. 10%; p=0.031)
 
Safety:
Adverse effects were not significantly different between groups; events reported in the ketamine and diclofenac groups respectively included blurred vision (5% vs. 5%), tremor (5% vs. 5%), restlessness (0% vs. 5%), nervousness (0% vs. 5%), abdominal pain (5% vs. 5%), and loss of appetite (5% vs. 0%)
Oral ketamine given at 50 mg 3 times a day appears to be a safe and effective option for improving depressive symptoms in patients with chronic pain with mild-to-moderate depression.
 
Limitations of this trial included the small sample size and limited duration of follow-up. Number of previous MDD treatments not reported.
Abbreviations: CI=confidence interval; DB=double blind; HDRS=Hamilton Depression Rating Scale; MADRS=Montgomery-Asberg Depression Rating Scale; MDD=major depressive disorder; MINI=Mini International Neuropsychiatric Interview; OR=odds ratio; PC=placebo-controlled; PO=oral; RCT=randomized controlled trial; TRD=treatment resistant depression.

Discussion
Although the literature reviewed is positive towards the use of oral ketamine in depression, there are significant questions that remain with regard to its efficacy and safety in MDD. A major limitation of the available RCTs is their length; the longest trial was only 6 weeks long, so the efficacy and safety of oral ketamine in the long term remains unclear.8-10 Other limitations include small sample sizes and the lack of consistency across trials with respect to ketamine doses or concomitant therapies used. Further studies should look at different doses of ketamine to determine the most effective dosing regimen and include a longer follow-up period (both during and after treatment) in order to obtain an accurate safety profile.

Use of oral ketamine may be hindered by several relevant practical considerations. There is no commercially available oral ketamine formulation at this time; therefore, an oral solution would need to be compounded from the injectable formulation.13 Ketamine is also a schedule III controlled substance, which may limit availability/accessibility; the potential for misuse and abuse should be considered if prescribing for outpatient use.7,14

Ongoing studies will further investigate the safety and efficacy of oral ketamine for depression.15 A prospective naturalistic cohort study examining oral, intranasal, and intravenous ketamine for TRD is expected to be complete by the end of 2022 (NCT04226963). Additionally, a phase 2 RCT is planned to compare the antidepressant effects of oral ketamine and oral psilocybin in patients with TRD (NCT05383313).

Conclusion
Current guidelines for MDD do not make specific recommendations regarding the use of oral ketamine. There are a few studies available that compare oral ketamine to placebo as an add-on treatment for MDD, but these studies have several significant limitations, and only 1 study specifically sought to enroll patients with TRD. Additional studies with larger sample sizes and longer follow-up times are needed before the place in therapy for oral ketamine can be fully determined.

References

  1. Major depression. National Institute of Mental Health. Updated January 2022. Accessed July 24, 2022. https://www.nimh.nih.gov/health/statistics/major-depression
  2. Zhdanava M, Pilon D, Ghelerter I, et al. The prevalence and national burden of treatment-resistant depression and major depressive disorder in the United States. J Clin Psychiatry. 2021;82(2):20m13699. doi:10.4088/JCP.20m13699
  3. APA clinical practice guideline for the treatment of depression across three age cohorts. American Psychological Association. Published February 2019. Accessed September 21, 2022. https://www.apa.org/depression-guideline/guideline.pdf
  4. VA/DoD clinical practice guideline for the management of major depressive disorder. U.S. Department of Veterans Affairs. Published February 2022. Accessed September 21, 2022. https://www.healthquality.va.gov/guidelines/MH/mdd/VADoDMDDCPGFinal508.pdf
  5. Xu S, Yao X, Li B, et al. Uncovering the underlying mechanisms of ketamine as a novel antidepressant. Front Pharmacol. 2022;12:740996. doi:10.3389/fphar.2021.740996
  6. Andrade C. Oral ketamine for depression, 1: pharmacologic considerations and clinical evidence. J Clin Psychiatry. 2019;80(2):19f12820. doi:10.4088/JCP.19f12820
  7. Ketalar. Package Insert. Par Pharmaceutical; 2022.
  8. Arabzadeh S, Hakkikazazi E, Shahmansouri N, et al. Does oral administration of ketamine accelerate response to treatment in major depressive disorder? Results of a double-blind controlled trial. J Affect Disord. 2018;235:236-241. doi:10.1016/j.jad.2018.02.056
  9. Domany Y, Bleich-Cohen M, Tarrasch R, et al. Repeated oral ketamine for out-patient treatment of resistant depression: randomised, double-blind, placebo-controlled, proof-of-concept study. Br J Psychiatry. 2019;214(1):20-26. doi:10.1192/bjp.2018.196
  10. Jafarinia M, Afarideh M, Tafakhori A, et al. Efficacy and safety of oral ketamine versus diclofenac to alleviate mild to moderate depression in chronic pain patients: a double-blind, randomized, controlled trial. J Affect Disord. 2016;204:1-8. doi:10.1016/j.jad.2016.05.076
  11. Irwin SA, Iglewicz A, Nelesen RA, et al. Daily oral ketamine for the treatment of depression and anxiety in patients receiving hospice care: a 28-day open-label proof-of-concept trial. J Palliat Med. 2013;16(8):958-965. doi:10.1089/jpm.2012.0617
  12. Nuñez NA, Joseph B, Pahwa M, et al. An update on the efficacy and tolerability of oral ketamine for major depression: a systematic review and meta-analysis. Psychopharmacol Bull. 2020;50(4):137-163.
  13. Clinical Pharmacology. Elsevier; 2022. Accessed September 21, 2022. https://www.clinicalkey.com/pharmacology
  14. Schoevers RA, Chaves TV, Balukova SM, aan het Rot M, Kortekaas R. Oral ketamine for the treatment of pain and treatment-resistant depression. Br J Psychiatry. 2016;208(2):108-113. doi:10.1192/bjp.bp.115.165498
  15. Clinicaltrials.gov. U.S. National Library of Medicine. Accessed July 24, 2022. https://clinicaltrials.gov/

Prepared by:
Cayley Krkljes
PharmD Candidate Class of 2023
University of Illinois at Chicago College of Pharmacy

Edited by:
Laura Koppen, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

October 2022

The information presented is current as of July 24, 2022. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.