#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