#360 Ketamine for Depression
CLINICAL QUESTION
What are the benefits and harms of ketamine/esketamine for depression?
BOTTOM LINE
Ketamine/esketamine appears effective for moderate-severe depression (helping 10-20% more people respond over placebo at 1-4 weeks). However, biases are very common and large effects are likely exaggerated. Adverse events are common (example: 20% more nausea/vomiting). Considerable uncertainty remains (treating mid/long-term, misuse risk, and long-term harms) and treatment is costly.
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EVIDENCE
- 11 systematic reviews with meta-analyses (3-49 randomized controlled trials (RCTs), 703-3299 moderately-severely, mostly treatment-resistant, depressed patients) in last 3 years.1-11 Typically, ketamine single-dose intravenously 0.5mg/kg over 40 minutes or esketamine intranasally 28mg (1-3 puffs) twice weekly (less frequent when stable). Results statistically significant unless noted.
- Efficacy:
- Response rate (highest-quality review) versus placebo:1
- Ketamine (4-7 RCTs, 185-202 patients):
- Day 1: 27% versus 9%, number needed to treat (NNT)=6.
- Day 28: Not statistically different (week 1-2 becomes non-significant).
- Esketamine (5 RCTs, 1071-1117 patients):
- Day 1: 27% versus 15%, NNT=9.
- Day 28: 57% versus 42%, NNT=7.
- Others found similar.2-8,10
- Ketamine (4-7 RCTs, 185-202 patients):
- Changes in depression scale:
- Meta-analysis (3 RCTs, 703 patients):4 MADRS depression scale (scale 0-60, ≤6 normal), baseline ≥28:
- Mean improvement esketamine=18 versus placebo=14, difference=4 at 4 weeks. Minimal important difference12=3-6.
- Other found similar7 or statistics not clinically interpretable.1-3,5,6,9,11
- Meta-analysis (3 RCTs, 703 patients):4 MADRS depression scale (scale 0-60, ≤6 normal), baseline ≥28:
- Response rate (highest-quality review) versus placebo:1
- Versus active control:
- Electroconvulsive Therapy (ECT): One RCT favored ECT (186 more-severe patients),13 one favored ketamine (403 less-severe).14
- Anti-depressant augmentation with esketamine versus quetiapine (150-300mg):15 Remission (8 weeks), 27% versus 18%, NNT=11.
- Stopping: 297 esketamine responders (after 16 weeks) randomized to continue or placebo:16
- At 18 weeks, relapse 26% (continued esketamine) versus 50% (discontinued/placebo), NNT=5.
- Adverse Events:
- Esketamine: Dissociation (29% versus 4%); dizziness (32% versus 11%); nausea/vomiting (36% versus 15%); and more. Ketamine similar.1
- Serious events (examples: mortality, substance misuse) inadequately studied.17,18
- Ketamine research issues: Mostly small/short, single-dose RCTs;1,2,5-11 publication bias;2,5,6 benefit halved in higher-quality RCTs;5,6,11 unblinding common.19
- RCT: 40 depressed patients given ketamine or placebo under-anesthesia. No difference in depression efficacy.20
CONTEXT
- Mechanism of action remains uncertain.1,21-23
- Guidelines:23,24 Ketamine potential option for severe, treatment-resistant depression with awareness of risk mitigation, adequate delivery standards and uncertainty regarding medium/long-term management.
- Cost of intranasal esketamine:25 $15,000-45,000/year. Ketamine generally in-hospital or related outpatient IV clinic.
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good topic
very heigh risk of abuse
evidence not compelling
will probably not use it
will probably not use it
will not use it
its an option and may be cost /resource effective in our health care setting