This qualitative review and meta-analysis (2017) summarizes major insights on the antidepressant efficacy of ketamine studies, with respect to differences across dosing, rate of administration, route of administration, duration of treatment, and frequency of sessions. It found that there is not enough supporting evidence to draw conclusions about best practices based on how these parameters interact with one another.

Abstract

“Background: Ketamine, administered in subanesthetic doses, is an effective off-label treatment for severe and even treatment-refractory depression; however, despite dozens of studies across nearly 2 decades of research, there is no definitive guidance on matters related to core practice issues.

Methods: This article presents a qualitative review and summary about what is known about ketamine dosing, rate of administration, route of administration, duration of treatment, and frequency of sessions.

Results: Ketamine is most commonly administered in the dose of 0.5 mg/kg, but some patients may respond to doses as low as 0.1 mg/kg, and others may require up to 0.75 mg/kg. The ketamine dose is conventionally administered across 40 minutes; however, safety and efficacy have been demonstrated in sessions ranging between 2 and 100 minutes in duration. Bolus administration is safe and effective when the drug is administered intramuscularly or subcutaneously. Whereas the intravenous route is the most commonly employed, safety and efficacy have been described with other routes of administration, as well; these include oral, sublingual, transmucosal, intranasal, intramuscular, and subcutaneous routes. Patients may receive a single session of treatment or a course of treatment during the acute phase, and treatment may rarely be continued for weeks to years to extend and maintain treatment gains in refractory cases. When so extended, the ideal frequency is perhaps best individualized wherein ketamine is dosed a little before the effect of the previous session is expected to wear off.

Conclusions: There is likely to be a complex interaction between ketamine dose, session duration, route of administration, frequency of administration, and related practice. Until definitive studies comparing different doses, rates of administration, routes of administration, and other considerations are conducted, firm recommendations are not possible. From the point of view of clinical practicability, subcutaneous, intranasal, and oral ketamine warrant further study. If domiciliary treatment is considered, the risk of abuse must be kept in mind.”

Author: Chittaranjan Andrade

Summary

Ketamine, administered in subanesthetic doses, is an effective off-label treatment for severe and treatment-refractory depression.

Introduction

The present article summarizes issues related to the use of ketamine for the treatment of depression, especially treatment-resistant depression, including dosing, rate of administration, route of administration, duration of treatment, and frequency of sessions.

What Dose?

Ketamine was administered intravenously in doses of 0.1 and 0.5 mg/kg for psychotomimetic and other effects. Lower doses have also been trialed, but 0.5 mg/kg remains the commonest dose.

In one uncontrolled, open-label study, 14 patients with treatment-resistant depression received ketamine augmentation of ongoing antidepressant pharmacotherapy. The response rate was only 7% after the first 3 infusions, but 42% after all 6 infusions.

Chilukuri et al11 randomized 27 severely depressed patients to receive ketamine in the dose of 0.5 mg/kg IV, 0.5 mg/kg IM, or 0.25 mg/kg IM. All 3 groups experienced similar benefits.

In a small double-blind, placebo-controlled, multiple crossover study, ketamine was incrementally dosed between 0.1 mg/kg and 0.5 mg/kg in TRD patients. Some patients responded at even 0.1 mg/kg, while others responded only at higher doses.

Singh et al12 randomized 30 patients with TRD to S-ketamine or placebo groups and found that ketamine reduced depression by 17 points.

At What Rate?

Ketamine has been administered in 2- to 5-minute IV infusions and even as an IM or SC bolus. Longer, 100-minute sessions have also been reported with a view to mitigating anesthesia risks.

Intranasal ketamine has been administered in sessions that are 20 – 40 minutes in duration to successfully “break” TRD. However, the case for prolonged ketamine infusion remains unestablished.

By What Route?

Ketamine has a low bioavailability when swallowed, but improves to about 24% – 30% with lozenge or liquid sublingual formulations. Its bioavailability is nearly complete when administered intranasally, SC, IM, and IV.

Oral ketamine can be used to treat anxiety and depression in patients receiving hospice care, and can be superior to diclofenac in patients with mild to moderate depression occurring in the context of chronic pain.

Ketamine was found to improve clinical outcomes in 20 of 26 patients with refractory depression when administered sublingually or intraorally.

Intranasal ketamine has been used to treat depression in 1 case and to maintain antidepressant response for years.

Subcutaneous ketamine was associated with a 100% remission rate in a double-blind, incrementally dosed crossover study of 6 TRD patients.

There have been case reports of the successful use of IM ketamine to treat depression, and a 3-arm, single-dose RCT found that ketamine dosed at 0.25 mg/kg IM resulted in a mean reduction of depression ratings by 57%, 2 hours after treatment.

Ketamine can be administered by oral, subcutaneous, intramuscular, or intranasal routes. The oral and subcutaneous routes are more convenient than IV administration and could open the doors wide for the use of ketamine in everyday clinical care.

For How Long and at What Frequency?

Many studies have found dramatic responses to a single treatment with IV ketamine, but not all patients respond. It is possible that some nonresponders may convert to responders if treated in serial sessions.

In a large RCT, patients receiving ketamine twice a week experienced better antidepressant effects than patients receiving placebo. In a smaller study, ketamine infusions given once a week produced similar though modest antidepressant results.

A course of 6 alternate-day IV ketamine infusions (0.5 mg/kg) was administered to a chronically depressed, antidepressant- and ECT-refractory male, and resulted in remission after the end of the ketamine course.

Ketamine infusions were given to 10 medication-free patients with TRD. Nine patients met response criteria and one patient remained in remission for > 3 months.

In another study, 6 ketamine infusions administered thrice a week to 14 on-medication patients with TRD, 11 of 12 patients achieved response, and 8 attained remission.

If ketamine has helped the patient, the next step depends on why ketamine was advised. If there is no continuation and maintenance therapy, some thought may need to be given to the intermediate- and even long-term continuation of ketamine.

In a study, 5 patients who had remitted after acute phase treatment received 4 once-weekly ketamine sessions. All 5 maintained improvement, but only 1 patient maintained remission status.

Ketamine benefits wear off after different durations in different patients, so the frequency at which ketamine needs to be administered should be determined by trial and error.

Summary

There are few RCTs that compare different doses, rates of administration, routes of administration, numbers of sessions, and intersession intervals, and no definitive recommendations can be made.

Notes on General Safety Issues

Ketamine is a drug that is associated with risks, but it is also useful in situations where cardiovascular and respiratory monitoring is unavailable. It can be administered as ambulatory and domiciliary treatment, but formal safety evaluations are required before firm conclusions can be drawn.

Future Directions

SC and intranasal ketamine demand further study because treatment by these routes is convenient. In fact, domiciliary treatment may someday become feasible with ketamine delivered by the intranasal route.

Ketamine may be useful for patients with TRD, but there is no well-accepted guidance for its use. Future research must also examine how best to use ketamine for continuation and maintenance treatment, after determining whether or not it is indeed safe and effective for this purpose.

Concluding Notes

Zhang et al53 found that media reports on ketamine treatment for depression were significantly more likely to support the use of ketamine than conventional antidepressants. However, more good quality RCT research is required before firm recommendations can be made.