Can Ketamine Injections Help Treat Severe Depression?

What you need to know

• Ketamine injections given twice weekly for 4 weeks significantly improved depression symptoms compared to a placebo in people with treatment-resistant depression
• The treatment was most effective when the dose was gradually increased based on each person’s response
• Side effects like dissociation and increased blood pressure were common but resolved within 2 hours after each injection
• Benefits faded within 4 weeks of stopping treatment, suggesting ongoing treatment may be needed to maintain improvements

Background on ketamine for depression

Depression is one of the leading causes of disability worldwide. While there are many effective treatments available, about one-third of people with depression do not improve even after trying multiple standard therapies. This is known as treatment-resistant depression.

In recent years, researchers have been exploring new treatments for people with stubborn depression that doesn’t respond to typical antidepressants. One promising option is ketamine, which is commonly used as an anesthetic in medical settings. At lower doses, ketamine appears to have rapid antidepressant effects in some people.

Most studies of ketamine for depression have used intravenous infusions, where the drug is delivered directly into a vein. However, this requires specialized medical supervision and equipment. Researchers have been exploring other methods of delivering ketamine that may be more practical for widespread use.

About this study

This study, called the Ketamine for Adult Depression Study (KADS), was designed to test whether ketamine injections given just under the skin (subcutaneously) could effectively treat severe, treatment-resistant depression over 4 weeks.

The researchers recruited 174 adults with major depression that had not improved after at least two adequate trials of antidepressant medications. Many participants had very treatment-resistant depression - about 24% had not responded to electroconvulsive therapy (ECT).

Participants were randomly assigned to receive either ketamine or midazolam (a sedative medication used as an active placebo) injections twice per week for 4 weeks. The study was conducted at 7 medical centers in Australia and New Zealand.

How the treatment was given

The study was conducted in two phases:

1. Fixed-dose phase: 68 participants received a fixed dose of either ketamine (0.5 mg/kg) or midazolam (0.025 mg/kg) for all 8 treatments over 4 weeks.

2. Flexible-dose phase: 106 participants started at the same initial doses, but could have their dose increased at treatment 2, 4, and 6 if they had not improved by at least 50%. The maximum doses were 0.9 mg/kg for ketamine and 0.045 mg/kg for midazolam.

The flexible-dose approach allowed the researchers to individualize the treatment based on each person’s response and side effects.

Key findings on effectiveness

The main measure of effectiveness was the percentage of participants achieving remission from depression by the end of the 4 weeks. Remission was defined as scoring 10 or less on a standard depression rating scale.

In the fixed-dose group, there was no significant difference between ketamine and midazolam:

• 6.3% achieved remission with ketamine
• 8.8% achieved remission with midazolam

However, in the flexible-dose group, ketamine was clearly more effective:

• 19.6% achieved remission with ketamine
• 2.0% achieved remission with midazolam

This difference was statistically significant. The researchers calculated that you would need to treat about 6 people with ketamine to have one additional person achieve remission compared to the placebo treatment.

Ketamine also outperformed midazolam on other measures in the flexible-dose group, including:

• Percentage of participants with at least 50% improvement in depression symptoms (29% vs 4%)
• Average improvement in depression scores
• Clinician ratings of overall illness severity and improvement

Safety and side effects

The ketamine injections were generally well-tolerated, with no serious safety concerns identified. However, there were some common side effects, especially at higher doses:

• Dissociation (feeling detached from oneself or reality)
• Dizziness
• Numbness/tingling sensations
• Visual changes
• Confusion
• Anxiety

Most side effects peaked within the first hour after each injection and resolved within 2 hours. No participants required medical intervention for side effects.

There were two participants who experienced more severe psychiatric side effects (a major dissociative episode and auditory hallucinations) that were determined to be related to the ketamine. Four participants stopped the ketamine treatment early due to side effects like anxiety, headache, or skin rash.

The study did not find evidence of cognitive impairment or signs of drug abuse/dependence with the ketamine treatment over 4 weeks. However, longer-term effects beyond this timeframe were not assessed.

How long did the benefits last?

The researchers followed up with participants 4 weeks after the treatment period ended. By this point, most of the difference between the ketamine and placebo groups had faded:

• 8.0% were still in remission in the ketamine group
• 2.1% were in remission in the placebo group

This suggests that ongoing treatment may be needed to maintain the antidepressant effects for most people. The study was not designed to look at longer-term outcomes beyond 4 weeks after stopping treatment.

Conclusions

• Ketamine injections given under the skin twice weekly for 4 weeks can significantly improve depression symptoms in people with treatment-resistant depression
• A flexible dosing approach, gradually increasing the dose based on individual response, appears to be most effective
• The treatment was generally well-tolerated, with temporary side effects that resolved within hours
• Benefits tended to fade within a month of stopping treatment, suggesting ongoing therapy may be needed
• More research is needed on the long-term effects and optimal treatment approaches

This study provides strong evidence that ketamine could be a useful option for some people with severe depression that has not responded to standard treatments. The injection method tested may be more practical than IV infusions for widespread use. However, given the side effects and unclear long-term impacts, ketamine should be considered carefully and provided under close medical supervision.

If you are struggling with depression, talk to your doctor about whether ketamine or other novel treatments may be appropriate options to consider as part of your overall care plan. Never attempt to self-medicate with ketamine, as this can be dangerous without proper medical oversight.