What is the efficacy of ketamine in treating major depressive disorder (MDD)?

From the Guidelines

Ketamine is a recommended treatment option for patients with major depressive disorder (MDD) who have not responded to at least two previous adequate trials of antidepressant medications. According to the 2022 U.S. Department of Veterans Affairs and U.S. Department of Defense clinical practice guideline 1, ketamine infusion and intranasal esketamine have been shown to improve depressive symptoms in patients with MDD. The guideline suggests that ketamine or esketamine can be used as a treatment option in patients who have not responded to several adequate pharmacologic trials.

Key Findings

• A meta-analysis of 20 RCTs found that ketamine used as monotherapy or in conjunction with an antidepressant in patients with treatment-resistant depression (TRD) resulted in significant improvement in depressive symptoms after 24 hours, with improvements persisting at 3- and 4-day follow-up visits 1.
• Significant improvements compared with controls were observed for up to 7 days in the TRD group when ketamine was added to ongoing antidepressant treatment 1.
• A meta-analysis of 5 RCTs examining esketamine as augmentation therapy found that twice-weekly dosing of esketamine as augmentation to ongoing oral antidepressant use improved depressive symptoms and remission rates in patients with MDD at up to 28 days of follow-up 1.

Treatment Administration

• Ketamine is typically administered as an IV infusion at doses of 0.5-1.0 mg/kg over 40 minutes, with treatments usually given 2-3 times per week for 2-3 weeks initially, followed by maintenance sessions as needed.
• Some clinics also offer intranasal esketamine (Spravato), which is FDA-approved specifically for treatment-resistant depression.

Potential Side Effects

• Potential side effects of ketamine include dissociation, dizziness, nausea, and increased blood pressure during infusions.
• Treatment requires medical supervision and isn't typically covered by insurance, with costs ranging from $400-800 per infusion.

Important Considerations

• Patients should be aware that while many experience significant improvement, effects are often temporary, requiring ongoing treatments to maintain benefits.
• The effectiveness of esketamine in preventing suicide or reducing suicidal ideation or behavior has not been established 1.

From the Research

Ketamine Treatment for Depression

• Ketamine has emerged as a novel therapy for treatment-resistant depression (TRD), demonstrating rapid and robust antidepressant effects within hours of administration 2.
• A combination of transcranial magnetic stimulation (TMS) and ketamine has been shown to be an effective long-term therapy for TRD patients, with a mean reduction in clinical global impression (CGI) severity of 4.46 ± 0.54 at a 99% confidence interval 3.
• Ketamine is a racemic mixture composed of equal amounts of (S)-ketamine and (R)-ketamine, and an (S)-ketamine nasal spray has been approved for use in TRD in conjunction with an oral antidepressant in the United States and Europe 2.

Benefits and Concerns

• The use of ketamine for depression has several benefits, including rapid onset of action and effectiveness in treatment-resistant patients 4.
• However, concerns remain regarding the potential for abuse, short- and long-term side effects, and the need for further research to identify biomarkers for predicting response and treatment targets 2, 4.
• Chronic, recreational use of ketamine has been reported to substantially impair cognitive function in most domains, but the therapeutic use of ketamine for depression has not been shown to induce cognitive impairment in several human and animal studies 4.

Combination Therapies

• The combination of ketamine and electroconvulsive therapy (ECT) has been shown to be effective in treatment-resistant depression, with no significant difference in treatment rates between patients receiving concurrent treatment and those receiving ECT alone 5.
• The use of ketamine in combination with other therapies, such as TMS, may allow for higher intensities of treatment to be tolerated by patients 3.

Safety and Efficacy

• Low-dose ketamine infusions have been shown to be a safe and effective alternative to standard depression treatment, with a thorough literature review supporting its use in treatment-resistant depression 6.
• Educational initiatives, such as videos and social media campaigns, can help disseminate information about the safety and efficacy of ketamine treatment for depression 6.