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Practice Signal
Ketamine & Esketamine for Treatment-Resistant Depression
Psychiatry7 sources · Updated Oct 12, 2026
This review helps pharmacists distinguish approved, evidence-supported ketamine routes from investigational oral formulations and apply consistent monitoring and counseling across both unipolar and bipolar treatment-resistant depression.
Bottom Line
Intranasal esketamine is now supported by controlled data as monotherapy for treatment-resistant depression (TRD), while oral ketamine and esketamine formulations remain investigational and should not displace guideline-supported routes.
0.63
Cohen d, esketamine 84 mg monotherapy
6.5 to 7.1
NNT for response, esketamine
3.8% vs 96.0%
dissociation, KET01 vs esketamine
42.9% vs 70.6%
relapse, R-107 180 mg vs placebo
State of Play
Intranasal esketamine remains the only US Food and Drug Administration (FDA) approved formulation for treatment-resistant depression (TRD), with intravenous (IV) racemic ketamine used off-label and supported by strong rapid-onset efficacy data. Oral racemic ketamine and oral esketamine are either compounded off-label or investigational, with efficacy evidence that is preliminary, inconsistent, or negative. Across formulations, the short-term safety signature is well characterized: frequent but transient, dose-dependent dissociation, dizziness, nausea, and blood pressure elevation without excess serious adverse events.
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Not medical advice. PharmD Signal provides educational synthesis of published pharmacy and medical literature for practicing pharmacists. It is not a treatment recommendation for any individual patient; clinical decisions remain the responsibility of the treating clinician exercising independent professional judgment.